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WO2022240897A1 - Pharmaceutical composition comprising delafloxacin for administration into the lung - Google Patents

Pharmaceutical composition comprising delafloxacin for administration into the lung Download PDF

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Publication number
WO2022240897A1
WO2022240897A1 PCT/US2022/028618 US2022028618W WO2022240897A1 WO 2022240897 A1 WO2022240897 A1 WO 2022240897A1 US 2022028618 W US2022028618 W US 2022028618W WO 2022240897 A1 WO2022240897 A1 WO 2022240897A1
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WO
WIPO (PCT)
Prior art keywords
delafloxacin
composition
certain embodiments
aerosol
microns
Prior art date
Application number
PCT/US2022/028618
Other languages
French (fr)
Inventor
Emil Samara
Tomasz Glinka
Original Assignee
Sepelo Therapeutics, Llc
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Filing date
Publication date
Application filed by Sepelo Therapeutics, Llc filed Critical Sepelo Therapeutics, Llc
Publication of WO2022240897A1 publication Critical patent/WO2022240897A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • delafloxacin A relatively new member of the fluoroquinolone family, delafloxacin, has recently been approved and shows effectiveness against Gram-negative bacteria, and also has activity against some Gram-positive bacteria. Though it has been approved for limited use in the United States and Europe, inhalable forms are not currently available. Because respiratory diseases are 10 common and cause suffering, premature death, and economic consequences, and because inhalation therapy for such diseases has many advantages over systemic administration, it is desirable to provide compositions and methods directed to inhalable forms of delafloxacin, and treatments using inhalation therapy of delafloxacin and its derivatives, including salts, esters, prodrugs and conjugates.
  • compositions and methods related to inhalation therapy with delafloxacin e.g., for treatment of respiratory infections.
  • compositions suitable for inhalation of delafloxacin including liquid compositions, liposomal compositions, and dry 30 powder compositions are provided.
  • methods of treatment of respiratory infections include liquid compositions, liposomal compositions, and dry 30 powder compositions.
  • kits, dosage form, systems, and other compositions and methods associated with providing delafloxacin for inhalation are provided.
  • Similar compositions and methods may be used for other fluoroquinolones sharing physicochemical properties with delafloxacin, e.g., alcohol functionality and no basic amine, such as levonadifloxacin, and it is understood that the following description, while in terms of delafloxacin, applies to levonadifloxacin, as well.
  • Delafloxacin also known as ABT-492, RX-3341, and WQ-3034 while it was under development, is a fluoroquinolone antibiotic with a structure shown in Figure 1. Details on the structure, preparation, and action of delafloxacin may be found in US Patent Nos. RE46,617; 7,728,143; 8,252,813; 8,273,892; 10,329,276; and 8,648,093. Delafloxacin is more active than other quinolones against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • delafloxacin in contrast to most approved fluoroquinolones, which are zwitterionic, delafloxacin, devoid of easily protonable amine, has an anionic character, which results in a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH. It is potentially more effective than cationic inhalatory antibacterials such as levofloxacin or tobramycin. This property is believed to confer to delafloxacin an advantage for the eradication of S. aureus acidic environments, including intracellular infections and biofilms.
  • delafloxacin is also active against Gram negative bacteria, e.g., delafloxacin has similar or slightly better activity against P. aeruginosa compared to ciprofloxacin and levofloxacin.
  • delafloxacin includes all forms of delafloxacin suitable for formulation into a composition suitable for delivery by inhalation, including salts, esters, prodrugs, conjugates, and other pharmaceutically acceptable forms, as known in the art. Particular forms are specified or clear from context.
  • delafloxacin is present with a counterion that is an amine counterion, such as meglumine, arginine, ornithine, lysine, trientine, or an aminoglycoside such as tobramycin or amikacin; it will be appreciated that when the counterion is an aminoglycoside antibiotic, this component can also have antibacterial activity in the composition.
  • an amine counterion such as meglumine, arginine, ornithine, lysine, trientine
  • an aminoglycoside such as tobramycin or amikacin
  • compositions provided herein are useful in treating conditions in a subject suffering from the condition, for which inhalation therapy with delafloxacin is effective.
  • pulmonary infections may be treated by administration of delafloxacin, generally at high concentrations directly to the site of infection without incurring large systemic concentrations of delafloxacin. Accordingly, some embodiments disclosed herein are methods
  • Such infections are common in certain disorders, such as cystic fibrosis and chronic obstructive pulmonary disease, chronic bronchitis, and some asthmas.
  • a “subject,” as that term is used herein, includes animals that can suffer from a pulmonary condition, e.g., infection; in particular, the subject can be a mammal, wherein that term is used in its ordinary biological sense, and includes, without limitation, humans, cattle, horses, dogs, and cats.
  • the subject is a human.
  • the subject is a human with cystic fibrosis.
  • the subject is a human with pneumonia, a chronic obstructive pulmonary disease, or sinusitis, or a human being mechanically ventilated.
  • compositions provided herein can be used to treat pulmonary infections, in certain embodiments, a pulmonary infection associated with on or more disorders.
  • disorders can include cystic fibrosis, pneumonia, and chronic obstructive pulmonary disease, including chronic bronchitis, and some asthmas.
  • methods and compositions provided herein can be especially appropriate for the treatment of pulmonary infections and disorders that include microbial strains that can be difficult to treat using parenterally administered antimicrobial, e.g., either because of the need for high parenteral dose levels, leading to undesirable side effects, or because of lack of any clinically effective antimicrobial agents.
  • parenterally administered antimicrobial e.g., either because of the need for high parenteral dose levels, leading to undesirable side effects, or because of lack of any clinically effective antimicrobial agents.
  • inhaled administration of delafloxacin directly to the site of infection can reduce systemic exposure and can maximize the amount of delafloxacin to the site of microbial infection.
  • Such methods can be appropriate for treating infections involving microbes that are susceptible to delafloxacin, e.g., as a way of reducing the frequency of selection of resistant microbes.
  • the aerosol delafloxacin in an appropriate formulation is administered in an amount sufficient to overcome the emergent resistance in bacteria or increase killing efficiency such that resistance does not have the opportunity to develop.
  • compositions comprising delafloxacin, or a salt, ester, prodrug, or conjugate thereof, or other pharmaceutically acceptable form thereof, in a form suitable for inhalation therapy, which includes any suitable method for delivering the composition to the middle and lower airways and the lungs.
  • the composition is suitable for
  • delafloxacin is produced as a pharmaceutical composition suitable for aerosol formation, acceptable taste, storage stability, and patient safety and tolerability.
  • Delafloxacin compositions as described herein are administered as an aerosol, e.g., to a site of infection in the respiratory tract.
  • aerosol delivery is used to treat an infection in the lungs.
  • An “aerosol,” as that term is used herein, includes a suspension of particles, which may comprise liquid, solid, liposomes, or a combination thereof, dispersed in air or gas.
  • Dry powder formulations generally require less time for drug administration, while liquid formulations generally have longer administration times.
  • a particular formulation of fluoroquinolone antimicrobial agent disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for maximum drug deposition at a site of infection and maximal tolerability.
  • Factors that can be optimized include solution or solid particle formulation, rate of delivery, and particle size and distribution produced by the aerosolizing device.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., powders, liquids, suspensions, complexations, liposomes, particulates, or the like.
  • the composition is a solid composition suitable for dry powder aerosol formation and inhalation.
  • the composition is a liquid composition suitable for liquid aerosol formation and inhalation, e.g., a suspension or solution.
  • the composition is a liposomal composition.
  • a complex of delafloxacin with a suitable divalent or trivalent cation e.g., magnesium
  • a suitable divalent or trivalent cation e.g., magnesium
  • additional agents e.g., agents to provide ease of handling, such as bulking agents, as known in the art.
  • Delafloxacin can be administered either alone, as a pre-formed complex with di- or trivalent metal ion, or in combination with a suitable pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like) and/or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • a suitable pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose,
  • composition can lack a conventional pharmaceutical carrier, excipient or the like.
  • Certain embodiments include a formulation lacking lactose.
  • Certain embodiments comprise lactose at a concentration less than about 10%, 5%, 1%, or 0.1%.
  • the pharmaceutical formulation will contain about 0.005% to 95%, such as about 0.5% to 50%, for example 5 to 40% by weight of delafloxacin or a salt, ester, or prodrug thereof.
  • the pharmaceutical formulation comprises delafloxacin and a divalent or trivalent metal ion, such as magnesium.
  • a pharmaceutical formulation includes a prodrug or conjugate of delafloxacin.
  • a conjugate of delafloxacin includes a composition in which delafloxacin is linked, e.g., covalently linked, to another compound;
  • a prodrug is a modified form of delafloxacin that requires further treatment, e.g., cleavage at one or more points, to release active drug, e.g., active delafloxacin.
  • Some conjugates are also prodrugs.
  • Exemplary conjugates and prodrugs include phosphate derivatives, where a phosphate can be linked to a suitable group on the delafloxacin, e.g., at a carboxyl, an amine, or a hydroxyl; such phosphates are readily cleaved by a variety of phosphatases that are ubiquitous in bodily tissues.
  • a phosphate linked to the active carboxyl such a conjugate is a prodrug in that the phosphate must be released for the delafloxacin to exhibit maximum activity.
  • Other suitable conjugates and prodrugs are described in PCT Publication No. W 02022031761.
  • prodrugs or conjugates can be useful in increasing residence time of delafloxacin in, e.g., lung spaces to which it delivered, e.g., decrease absorption into systemic circulation.
  • some conjugates/prodrues such as phosphate conjugates/prodrugs, which are highly charged, are less likely to cross cell membranes.
  • release of active delafloxacin from a prodrug can allow for more prolonged maintenance of effective levels in the desired area of activity, e.g., lung spaces to which it is delivered.
  • Liquid compositions suitable for administration by inhalation can be prepared by dissolving, dispersing, etc. delafloxacin and optional pharmaceutical adjuvants in a liquid carrier, such as water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like, to form a solution or suspension.
  • a liquid carrier such as water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like.
  • Solutions to be aerosolized can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to aerosol production and inhalation.
  • the percentage of delafloxacin contained in such aerosol compositions can be, e.g., 0.01% to 90% in solution, or higher if the composition is a solid, which will be subsequently diluted to the above percentages.
  • the composition comprises 1.0%-50.0% of delafloxacin in solution.
  • a liquid formulation e.g., aqueous formulation, suitable for administration by inhalation can have a delafloxacin concentration of at least 5, 10, 12, 15, 17, 20, 22, 25, 30, 40,
  • the formulation has a delafloxacin concentration of 10-200 mg/ml, or 10-100 mg/ml, or 20-50 mg/ml, or 20-40 mg/ml, or 50-200 mg/ml, or 75-150 mg/ml, or 80-125 mg/ml, or 80-120 mg/ml, or 90-125 mg/ml, or 90-120 mg/ml, or 90-110 mg/ml preferably 10-200 mg/ml, more preferably 20-50 mg/ml , even more 50-200 mg/ml, still more preferably 75-150 mg/ml, yet more preferably 80-120 mg/ml.
  • delafloxacin is present at a concentration of 20-1000, 50-800, 50-750, 50-700, 50-675, 50-650, 50-600, 50-500, 50-400, 50-300, 50-200, 50-100, 75-800, 75-750, 75-700, 75-675, 75-650, 75- 600, 75-500, 75-400, 75-300, 75-200, 75-100, 100-800, 100-750, 100-700, 100-675, 100-650,
  • a liquid formulation, e.g., aqueous formulation, suitable for administration by inhalation can have any suitable osmolarity, such as 200-1250, 300-500, 325-450, 350-425, or 350-400 mOsmol/kg.
  • the osmolality of the formulation is greater than about 300, 325, 350, 375, 400, 425, 450, 475, or 500 mOsmol/kg.
  • solution osmolality is 100-600 mOsmol/kg.
  • the solution osmolality is 200-1250 mOsmol/kg; in more preferred embodiments 250-1050 mOsmol/kg; in stil more preferred embodiments 350-750 mOsmol/kg.
  • the osmolality of aqueous solutions of delafloxacin is adjusted by any suitable method, e.g., by providing excipients. Many patients have increased sensitivity to various chemical agents and have high incidence of bronchospastic, asthmatic or other coughing incidents. Their airways are particularly sensitive to hypotonic or hypertonic and acidic or alkaline conditions and to the presence of any permanent ion, such as chloride.
  • any imbalance in these conditions or a presence of chloride above certain value leads to bronchospastic or inflammatory events and/or cough which greatly impair treatment with inhalable formulations. Both these conditions prevent efficient delivery of aerosolized drugs into the endobronchial space.
  • a certain amount of chloride or another anion is needed for successful and efficacious delivery of aerosolized delafloxacin.
  • the chloride concentration is 30-300 mM, more preferably 50-150 mM.
  • Bromide or iodide anions may, in some cases, be substituted for chloride; in some cases, bicarbonate ion may be substituted for chloride.
  • permeant ion concentration is 25-400 mM, or 30-300 mM; or 40-200 mM; or 50-150 mM.
  • delafloxacin pharmaceutical compositions suitable for administration by inhalation are formulated to have good taste, pH of 5.5-7, osmolarity of 200-1250 mOsmol/kg, and permeant ion concentration of 30-300 mM.
  • the solution or diluent used for preparation of an aerosol formulation has a pH high enough that it does not cause bronchospasm and low enough that it has tolerability in body tissues unable to buffer alkaline aerosols and also does not cause bronchospasm, e.g., a pH of at least 4, 4.2, 4.5, 4.7, 5, 5.2, 5.5, 5.7, 6, 6.2, 6.5, 6.7, 7.0, 7.2, 7.5, or 7.7, and/or not more than 4.2, 4.5, 4.7, 5, 5.2, 5.5, 5.7, 6, 6.2, 6.5, 6.7, 7, 7.2, 7.5, 7.7, or 8.
  • Exemplary suitable pH ranges include 4.5-7.5, or 5.5-7.5, preferably 5.0-7.5, more preferably 5.0-7.0, even more preferably 5.5-7.0.
  • Other possible pH ranges include, for example 4.5-8.5,
  • a pharmaceutical composition may include a buffer or a pH adjusting agent, such as a salt prepared from an organic acid or base.
  • buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine, hydrochloride, or phosphate buffers.
  • a pharmaceutical composition suitable for administration by inhalation can include a divalent or trivalent cation, or a combination thereof.
  • the divalent or trivalent cation can be one or more of, magnesium, calcium, zinc, copper, aluminum, and/or iron, or a combination thereof.
  • the composition e.g., a solution, comprises magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride.
  • the divalent or trivalent cation (or combination) concentration is from about 25- 400, or 50-400, or 100-300, preferably 100-250, more preferably 125-250, still more preferably 150-250, yet more preferably 175-225, or even more preferably 190-200 mM.
  • the magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride has a concentration of 5-25%, 10-20%, or 15-20%.
  • the ratio of delafloxacin to divalent or trivalent cation (or combination) is 1 : 1 to 2: 1 or 1 : 1 to 1 :2.
  • the ion is magnesium, for example, magnesium supplied by magnesium chloride.
  • aqueous formulations containing soluble or nanoparticulate delafloxacin particles are provided.
  • delafloxacin may be present at a concentration of about 1 mg/mL up to about 700 mg/mL.
  • Such formulations provide effective delivery to appropriate areas of the lung, with the more concentrated aerosol formulations having the additional advantage of enabling large quantities of drug substance to be delivered to the lung in a very short period of time.
  • a formulation is
  • aqueous pharmaceutical solution of delafloxacin formulated to have good taste, pH of 5.5-7, osmolarity of 200-1250 mOsmol/kg, permeant ion concentration of 30-300 mM.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 5-500, 10-200, 20-500, 50-450, or 100-400 mg delafloxacin, such as at least or about 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin, in some cases in a volume of preferably 0.5-10, more preferably 0.5-5, still more preferably 1-10, even more preferably 1-5 ml.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
  • an aqueous pharmaceutical solution comprising 5-80, 10-70, 20-60, 20-50, 20-40, 30-100, 40-100, preferably 50-120, more preferably 60-120, even more preferably 80-120, still more preferably 90-110, e.g. 100 mg/ml, of delafloxacin and preferably 160-240, more preferably 175-225, even more preferably 190-210, e.g. 200 mM, of a cation.
  • the cation is magnesium, calcium, zinc, copper, aluminum, or iron, or a combination thereof.
  • the cation is magnesium, such as magnesium supplied by magnesium chloride or magnesium sulfate.
  • the osmolarity is 200-700, preferably 300-500, more preferably 350-400 mOsmol/kg.
  • the solution comprises a dose of delafloxacin of 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290,
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 5-200, 10-100, 10-60, 20-500, 50-450, or 100-400 mg delafloxacin, such as at least or about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330,
  • aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
  • an aqueous pharmaceutical solution comprising 20-40, e.g., 30 mg/ml, or 40-60, e.g., 50 mg/ml, or 60-80, e.g., 70 mg/ml, or 80-100, e.g., 90 mg/ml, or 90-110, e.g., 100 mg/ml of delafloxacin and 190-210, e.g., 200 mM of a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate.
  • the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg.
  • the solution comprises a dose of delafloxacin of 10, 20, 30,
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 20-500, 50-450, or 100- 400 mg delafloxacin, such as at least or about 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin, for example in 0.5-10, 0.5-5, 1-10, or 1-5 ml.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
  • a pharmaceutical composition comprising an aqueous solution of delafloxacin and a divalent or trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung.
  • the cation is a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate.
  • the concentration of chloride is 25-400, 100-250, or 125-250 mM.
  • the divalent or trivalent cation, or combination thereof is selected from one or more of calcium, aluminum, zinc, and iron, or a combination thereof.
  • the concentration of delafloxacin is at least 5, 10, 25, 35, 40, 50, 60, 70, 80, 90, or 100 mg/ml. In certain embodiments, the concentration of delafloxacin is 5-80, 10-70, 20-60, 20-50, 20-40, 80- 120, 5-200, 10-100, 10-60, 50-800, 75-700, 100-650, or 150-500 mM. In certain embodiments, the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg. In certain embodiments, the solution has a pH of 4.5-8, 4.5-7.5, 4.5-6, 5-6.5, or 5.5-6.5.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 20-500, 50-450, or 100-400 mg delafloxacin, such as at least or about 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin, for example in 0.5-10, 0.5-5, 1-10, or 1-5 ml.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer.
  • the cation is a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate.
  • the concentration of chloride is 25-400, 100-250, or 125-250 mM.
  • the divalent or trivalent cation is selected from one or more of calcium, aluminum, zinc, and iron, or a combination thereof.
  • the concentration of delafloxacin is at least 1, 5, 7, 10, 12, 15, 20, 25, 3035, 40, 50, 60, 70, 80, 90, or 100 mg/ml.
  • the concentration of delafloxacin is 10-600, 50-800, 75-700, 100-650, or
  • the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg.
  • the solution has a pH of 4.5-8, 4.5- 7.5, 4.5-6, 5-6.5, or 5.5-6.5. In certain embodiments the solution comprises greater than 20, 30, 40, or 50 mg/ml delafloxacin and magnesium chloride, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to 2.5 microns.
  • the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to 2 microns.
  • the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to 1.8 microns.
  • the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg
  • an aerosol dose of a delafloxacin and magnesium solution comprised of a concentration of delafloxacin greater than 20, 30, 40, or 50 mg/ml and a taste-masking concentration of magnesium wherein the aerosol is comprised of a mist having a mean particle size of between 2 and 5 microns or a particle size geometric standard deviation of less than or equal to 2 microns.
  • the magnesium concentration is 100-250 mM.
  • the pH of the aerosol is 4.5-8, 4.5-7.5, 4.5-6, 5-6.5, 5.5-7.5 or 5.5-6.5.
  • a quantity of the mist contains at least 0.1, 0.5, 0.7, 1, 1.5, 2, 5, 7, 10, 20, 50, 70, or 100 mg of delafloxacin.
  • the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg.
  • the permeant ion concentration is 100-500, 100-450, 200-500, 200-450, 300-500, 300-450, or 350-450 mM.
  • a pharmaceutical aerosol for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises or consists essentially of aqueous droplets
  • the aerosol comprises at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, antivirals, lung surfactant, steroids, mucolytics, heparin, and anti inflammatory drugs.
  • the aerosol comprises at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, antivirals, lung surfactant, steroids, mucolytics, and heparin.
  • the aerosol is being emitted from an aerosol generator at a rate of at least about 0.1 ml dispersed liquid phase per minute.
  • the liquid phase has a viscosity in the range from about 0.8 to about 3 mPa s, wherein a volume of not more than about 10 ml, or 1-5 ml, of the composition comprises an effective dose of the active compound.
  • the aerosol has a surface tension in the range from about 25 to 80 mN/m.
  • the liquid phase comprises at least one excipient capable of affecting the local bioavailability, the release, and/or the local residence time of the active compound at the site of aerosol deposition, such as one or more complexing agents, polymers, or amphiphilic compounds.
  • the liquid phase comprises at least one excipient capable of enhancing the AUC shape of the active compound.
  • the liquid phase comprises at least one taste-modifying excipient selected from the group consisting of flavors, sweeteners, complexing agents and taste masking agents, such as one or more of cyclodextrin, sugar, sugar alcohol, saccharin, aspartame, and arginine.
  • the one or more excipients can improve local tolerability and/or reduce local adverse events.
  • the liquid phase comprises at least one excipient selected from the group of divalent or trivalent metal ions
  • compositions for the preparation of an aerosol comprising an active compound comprising delafloxacin, and an excipient comprising a polymeric compound, wherein the polymeric compound is selected from the group consisting of derivatized cellulose, dextran, polymeric sugar, polyethylene glycols, pectin and cyclodextrins.
  • kits for the preparation and delivery of a delafloxacin aerosol for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises or consists essentially of aqueous droplets comprising delafloxacin, and, in some cases, at least one
  • kits comprising a nebulizer and an aqueous liquid composition, said composition comprising an effective dose of delafloxacin within a volume of not more than about 10 ml.
  • the dispersed liquid phase has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 2 pm.
  • the composition comprises an effective dose of delafloxacin within a volume from about 1 to about 5 ml.
  • the nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, jet collision nebulizers, electrohydrodynamic nebulizers, capillary force nebulizers, perforated membrane nebulizers and perforated vibrating membrane nebulizers.
  • nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, and perforated vibrating membrane nebulizers.
  • the nebulizer is adapted to be capable of aerosolizing the liquid composition at a rate of at least about 0.1 ml/min.
  • the nebulizer is adapted to be capable of aerosolizing a volume of the liquid composition comprising an effective dose of delafloxacin within not more than about 20 minutes. In certain embodiments the nebulizer is adapted to be capable of emitting at least about 50 wt.-% of the aqueous liquid composition as aerosol. In certain embodiments at least about 40 wt.-% of the loaded dose is comprised of droplets having a diameter of not more than about 5 um.
  • a method of preparing and delivering an aerosol to a person in need of nasal, sinonasal or pulmonary antibiotic treatment or prophylaxis comprising the steps of providing a liquid pharmaceutical composition comprising an effective dose of delafloxacin, and, in some cases, at least one excipient comprising a multivalent metal ion, in a volume of not more than about 10 ml; providing a nebulizer capable of aerosolizing said liquid pharmaceutical composition at a total output rate of at least 0.1 ml/min, the nebulizer further being adapted to emit an aerosol comprising a dispersed phase having a mass median diameter from about 1 to about 5 pm and a geometrical standard deviation less than or equal to about 3.0 pm; and operating the nebulizer to aerosolize the liquid composition.
  • the volume is from about 1 to about 5 ml.
  • the dispersed phase has a mass median diameter from 2 to about 5 pm.
  • the dispersed phase has a distribution exhibiting a geometrical standard deviation less than or equal to about 2.5 pm.
  • administration is conducted to last not more than about 20 minutes, or less than about 5 minutes.
  • kits comprising a sterile single use container comprising an aqueous solution of delafloxacin, in some cases also a divalent or
  • the solution is suitable for inhalation into a lung; and a nebulizer adapted to receive solution from the container and to aerosolize the solution for delivery to the lung through oral inhalation.
  • the nebulizer operates by ultrasonic atomization.
  • the nebulizer operates by hydraulic atomization.
  • the nebulizer operates by a vibrating mesh.
  • the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2 microns to about 5.
  • the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
  • the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • a system comprising: a reservoir comprising an aqueous solution of delafloxacin and, in some cases, a divalent or trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung; and a nebulizer configured to aerosolize the solution for delivery to the lung through oral inhalation.
  • the nebulizer operates by ultrasonic atomization.
  • the nebulizer operates by hydraulic atomization.
  • the nebulizer operates by a vibrating mesh.
  • the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
  • the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • a pharmaceutical composition consisting essentially of an aqueous solution of greater than 20, 30, 40, or 50 mg/ml delafloxacin and a divalent or trivalent cation, or a combination thereof, wherein the solution has a pH from about
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer.
  • a pharmaceutical aerosol for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase: consists essentially of aqueous droplets comprising an active compound comprising delafloxacin, and at least one excipient comprising a multivalent metal ion; has a mass median diameter from about 1 to about 5 pm; and has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 um.
  • an aqueous pharmaceutical solution comprising about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml of delafloxacin and about 200 mM of magnesium chloride.
  • the solution can have a pH from 5-7.
  • the solution can have an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg.
  • the solution can comprise a dose of delafloxacin of 300 mg, or 280 mg, or 260 mg, or 240 mg, or 200 mg, or 180 mg, or 160 mg, or 140 mg, or 120 mg, or 100 mg, or 90 mg, or 80 mg, or 70 mg, or 60 mg, or 50 mg, or 40 mg, or 30 mg.
  • a pharmaceutical composition suitable for administration by inhalation can comprise a delafloxacin concentration of 20-100, or 20-80, or 20-60, or 40-100, or 75-150 mg/ml, a magnesium chloride concentration of 150-250 mM, a pH of 5-7; an osmolality of 300-500 mOsmol/kg.
  • the composition lacks lactose.
  • a pharmaceutical composition comprising delafloxacin may comprise 7-700 mg, 14-300 mg, or 28-280 mg delafloxacin per l-5ml of dilute saline (e.g., between 1/10 to 1/1 normal saline).
  • concentration of a delafloxacin solution may be greater than about 15 mg/ml, 25 mg/ml, greater than about 35 mg/ml, greater than about 40 mg/ml, or greater than 50 mg/ml.
  • a pharmaceutical composition suitable for administration by inhalation comprises a delafloxacin concentration of about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration of about 200 mM, a pH about 6.2, an osmolality about 383 mOsmol/kg, and, optionally, lacks lactose.
  • a pharmaceutical composition suitable for administration by inhalation consists essentially of a delafloxacin concentration of about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration about of 200 mM, a pH of about 6.2 an osmolality of about 383 mOsmol/kg, and optionally, lacks lactose.
  • a pharmaceutical composition suitable for administration by inhalation consists of a delafloxacin concentration of about 20, 30, 40, 50, 60,
  • a pharmaceutical composition suitable for administration by inhalation can include delafloxacin in combination with an additional active agent.
  • additional active agents can include one or more antibiotics, as described above.
  • additional active agents can include bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof.
  • bronchodilators include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutlaine, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, theophylline, roflumilast, cilomilast.
  • anticholinergics include pratropium, and tiotropium.
  • glucocorticoids examples include prednisone, fluticasone, budesonide, mometasone, ciclesonide, and beclomethasone.
  • eicosanoids examples include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, and seratrodast.
  • More additional active agents can include pulmozyme, hypertonic saline, agents that restore chloride channel function in CF, inhaled beta-agonists, inhaled antimuscarinic agents, inhaled corticosteroids, and inhaled phosphodiesterase inhibitors.
  • the aerosol antibiotic therapy administered as a treatment or prophylaxis may be used in combination or alternating therapeutic sequence with an additional active agent.
  • the additional active agent may be administered as a treatment, alone, co-formulated, or administered with the aerosol antibiotic therapy.
  • the additional active agent can be mannitol.
  • a pharmaceutical composition suitable for administration by inhalation for example for use in cystic fibrosis, can include delafloxacin in combination with mannitol.
  • compositions may further include flavoring agents, taste-masking agents, inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and “TWEEN 80"), sorbitan esters, saccharin, cyclodextrins, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (e.g., cholesterol), and chelating agents (e.g., EDTA, zinc and other such suitable cations).
  • inorganic salts e.g., sodium chloride
  • antimicrobial agents e.g., benzalkonium chloride
  • sweeteners e.g., pepperminophene, pepperminophen, pepperminophen, pepperminoph
  • a pharmaceutical composition is formulated to improve and/or mask taste. Any suitable manner of improving and/or masking taste may be used.
  • Classes of taste-masking agents for delafloxacin formulation include the addition of flavorings, sweeteners, and other various coating strategies.
  • Exemplary substances include sugars such as sucrose, dextrose, and lactose, carboxylic acids, salts such as magnesium and calcium (non specific or chelation-based fluoroquinolone taste masking), menthol, amino acids or amino acid derivatives such as arginine, lysine, and monosodium glutamate, and synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, etc. and combinations thereof.
  • cinnamon oils may include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc.
  • Additional sweeteners include sucrose, dextrose, aspartame (NutrasweetTM.), acesulfame-K, sucralose and saccharin, organic acids (by non-limiting example citric acid and aspartic acid).
  • Such flavors may be present at any suitable concentration, for example, 0.05-4%.
  • Another approach to improve or mask the taste of unpleasant inhaled drugs is to decrease the drugs solubility, e.g.
  • cyclodextrins may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, randomly methylated beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, maltosyl-alpha- cyclodextrin, glucosyl-1 -alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and sulfobutylether-beta-cyclodextr
  • non-dissolved forms of delafloxacin are to administer the drug alone or in simple, non-solubilty affecting formulation as a crystalline micronized, dry powder, spray-dried, and nanosuspension formulation.
  • an alternative method is to include taste -modifying agents. These include a taste-masking substance that is mixed with, coated onto or otherwise combined with the delafloxacin active medicament.
  • this addition may also serve to improve the taste of another chosen drug product addition, e.g. a mucolytic agent.
  • Such substances include acid phospholipids, lysophospholipid,
  • a method of making a taste-masked delafloxacin pharmaceutical composition comprising forming a solution of delafloxacin and a divalent or trivalent cation, or a combination thereof, having a pH from about 5.5 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the solution comprises greater than 50 mg/ml delafloxacin.
  • the divalent or trivalent cation is in magnesium chloride.
  • the pharmaceutical composition is provided in unit dosage form suitable for single administration of a precise dose.
  • the unit dosage form can also be assembled and packaged together to provide a patient with a prolonged supply, e.g., a weekly or monthly supply and can also incorporate other compounds such as saline, taste masking agents, pharmaceutical excipients, and/or other active ingredients or carriers.
  • solid drug nanoparticles are provided for use in generating dry aerosols or for generating nanoparticles in liquid suspension. Any suitable method may be used to produce the solid composition.
  • powder is made by spray-drying aqueous dispersions of a nanoparticulate drug and a surface modifier to form a dry powder which consists of aggregated drug nanoparticles.
  • the aggregates can have a size of 1-2 microns, which is suitable for deep lung delivery.
  • the aggregate particle size can be increased to target alternative delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of drug in the spray-dried dispersion or by increasing the droplet size generated by the spray dryer.
  • an aqueous dispersion of drug and surface modifier can contain a dissolved diluent such as lactose, mannitol, maltitol, erythritol, and/or allulose, which, when spray dried, forms respirable diluent particles, each of which contains at least one embedded drug nanoparticle and surface modifier.
  • a dissolved diluent such as lactose, mannitol, maltitol, erythritol, and/or allulose, which, when spray dried, forms respirable diluent particles, each of which contains at least one embedded drug nanoparticle and surface modifier.
  • the diluent particles with embedded drug can have a particle size of, e.g., 1-2 microns, suitable for deep lung delivery.
  • the diluent particle size can be increased to target alternate delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of dissolved diluent in the aqueous dispersion prior to spray drying, or by increasing the droplet size generated by the spray dryer.
  • Spray-dried powders can be used in DPIs or pMDIs, either alone or combined with freeze-dried nanoparticulate powder.
  • spray-dried powders containing drug can be used in DPIs or pMDIs, either alone or combined with freeze-dried nanoparticulate powder.
  • spray-dried powders containing drug can be used in DPIs or pMDIs, either alone or combined with freeze-dried nanoparticulate powder.
  • spray-dried powders containing drug can be used in DPIs or pMDIs, either alone or combined with freeze-dried nanoparticulate powder.
  • nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions having respirable droplet sizes, where each droplet contains at least one drug nanoparticle.
  • Concentrated nanoparticulate dispersions may also be used in these aspects of the invention.
  • Nanoparticulate drug dispersions can also be freeze-dried to obtain powders suitable for nasal or pulmonary delivery.
  • Such powders may contain aggregated nanoparticulate drug particles having a surface modifier.
  • Such aggregates may have sizes within a respirable range, e.g., 2-5 microns MMAD.
  • Freeze dried powders of the appropriate particle size can also be obtained by freeze drying aqueous dispersions of drug and surface modifier, which additionally contain a dissolved diluent such as lactose or mannitol.
  • the freeze dried powders consist of respirable particles of diluent, each of which contains at least one embedded drug nanoparticle.
  • Freeze-dried powders can be used in DPIs or pMDIs, either alone or combined with spray-dried nanoparticulate powder.
  • freeze -dried powders containing drug nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions that have respirable droplet sizes, where each droplet contains at least one drug nanoparticle.
  • Certain embodiments are directed to a process and composition for propellant-based systems comprising nanoparticulate drug particles and a surface modifier.
  • Such formulations may be prepared by wet milling the coarse drug substance and surface modifier in liquid propellant, either at ambient pressure or under high pressure conditions.
  • dry powders containing drug nanoparticles may be prepared by spray-drying or freeze-drying aqueous dispersions of drug nanoparticles and the resultant powders dispersed into suitable propellants for use in conventional pMDIs.
  • Such nanoparticulate pMDI formulations can be used for either nasal or pulmonary delivery. For pulmonary administration, such formulations afford increased delivery to the deep lung regions because of the small (e.g., 1-2 microns MMAD) particle sizes available from these methods.
  • Concentrated aerosol formulations can also be employed in pMDIs.
  • Another embodiment is directed to dry powders which contain nanoparticulate compositions for pulmonary or nasal delivery.
  • the powders may consist of respirable aggregates of nanoparticulate drug particles, or of respirable particles of a diluent which contains at least one embedded drug nanoparticle.
  • Powders containing nanoparticulate drug particles can be prepared from aqueous dispersions of nanoparticles by removing the water via spray-drying or lyophilization (freeze drying).
  • the dry powder aerosols which contain nanoparticulate drugs can be made smaller than comparable micronized drug substance and, therefore, are appropriate for efficient delivery to the deep lung. Moreover, aggregates of nanoparticulate drugs are spherical in geometry and have good flow properties, thereby aiding in dose metering and deposition of the administered composition in the lung or nasal cavities.
  • Dry nanoparticulate compositions can be used in both dry powder inhaler devices (DPIs) and pressurized metered does inhalers (pMDIs).
  • DPIs dry powder inhaler devices
  • pMDIs pressurized metered does inhalers
  • dry includes a composition having less than about 5% water.
  • compositions are provided containing nanoparticles which have an effective average particle size of less than 1000 nm, or less than 400 nm, or less than 300 nm, or less than 250 nm, or less than 200 nm, as measured by, for example, light-scattering methods.
  • an effective average particle size of less than 1000 nm it is meant that at least 50% of the drug particles have a weight average particle size of less than 1000 nm when measured by, e.g., light scattering techniques.
  • At least 70% of the drug particles have an average particle size of less than 1000 nm, or at least 90% of the drug particles have an average particle size of less than 1000 nm, or at least 95% of the particles have a weight average particle size of less than 1000 nm.
  • the nanoparticulate agent may be present at a concentration of about 5.0 mg/mL up to about 700 mg/mL.
  • the nanoparticulate agent may be present at a concentration of about 5.0 mg/g up to about 1000 mg/g, depending on the desired drug dosage.
  • Concentrated nanoparticulate aerosols defined as containing a nanoparticulate drug at a concentration of 5.0-700 mg/mL for aqueous aerosol formulations, and 5.0-1000 mg/g for dry powder aerosol formulations, are specifically provided.
  • Such formulations provide effective delivery to appropriate areas of the lung or nasal cavities in short administration times, i.e., less than about 3-15 seconds per dose as compared to administration times of up to 4 to 20 minutes as found in conventional pulmonary nebulizer therapies. Further characteristic suitable for dry powder formulations may be found in
  • Nanoparticulate drug compositions for aerosol administration can be made by, for example, (1) nebulizing a dispersion of a nanoparticulate drug, obtained by either grinding or precipitation; (2) aerosolizing a dry powder of aggregates of nanoparticulate drug and surface modifier (the aerosolized composition may additionally contain a diluent); or (3) aerosolizing a suspension of nanoparticulate drug or drug aggregates in a non-aqueous propellant.
  • the aggregates of nanoparticulate drug and surface modifier which may additionally contain a diluent, can be made in a non-pressurized or a pressurized non-aqueous system. Concentrated aerosol formulations may also be made via such methods.
  • Milling of aqueous drug to obtain nanoparticulate drug may be performed by dispersing drug particles in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug to the desired effective average particle size.
  • the particles can be reduced in size in the presence of one or more surface modifiers.
  • the particles can be contacted with one or more surface modifiers after attrition.
  • Other compounds, such as a diluent, can be added to the drug/surface modifier composition during the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • Another method of forming nanoparticle dispersion is by microprecipitation.
  • This is a method of preparing stable dispersions of drugs in the presence of one or more surface modifiers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
  • Such a method comprises, for example, (1) dissolving the drug in a suitable solvent with mixing; (2) adding the formulation from step (1) with mixing to a solution comprising at least one surface modifier to form a clear solution; and (3) precipitating the formulation from step (2) with mixing using an appropriate nonsolvent.
  • the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
  • the resultant nanoparticulate drug dispersion can be utilized in liquid nebulizers or processed to form a dry powder for use in a DPI or pMDI.
  • a non-aqueous liquid having a vapor pressure of about 1 atm or less at room temperature and in which the drug substance is essentially insoluble may be used as a wet milling medium to make a nanoparticulate drug composition.
  • a slurry of drug and surface modifier may be milled in the non- aqueous medium to generate nanoparticulate drug particles.
  • suitable non-aqueous media include ethanol, trichloromonofluoromethane, (CFC-11), and dichlorotetrafluoroethane
  • CFC-114 An advantage of using CFC-11 is that it can be handled at only marginally cool room temperatures, whereas CFC-114 requires more controlled conditions to avoid evaporation.
  • the liquid medium may be removed and recovered under vacuum or heating, resulting in a dry nanoparticulate composition.
  • the dry composition may then be filled into a suitable container and charged with a final propellant.
  • exemplary final product propellants which ideally do not contain chlorinated hydrocarbons, include HFA-134a (tetrafluoroethane) and HFA-227 (heptafluoropropane). While non-chlorinated propellants may be preferred for environmental reasons, chlorinated propellants may also be used in this aspect of the invention.
  • a non-aqueous liquid medium having a vapor pressure significantly greater than 1 atm at room temperature may be used in the milling process to make nanoparticulate drug compositions.
  • the milling medium is a suitable halogenated hydrocarbon propellant
  • the resultant dispersion may be filled directly into a suitable pMDI container.
  • the milling medium can be removed and recovered under vacuum or heating to yield a dry nanoparticulate composition. This composition can then be filled into an appropriate container and charged with a suitable propellant for use in a pMDI.
  • Spray drying is a process used to obtain a powder containing nanoparticulate drug particles following particle size reduction of the drug in a liquid medium.
  • spray drying may be used when the liquid medium has a vapor pressure of less than about 1 atm at room temperature.
  • a spray-dryer is a device which allows for liquid evaporation and drug powder collection. A liquid sample, either a solution or suspension, is fed into a spray nozzle.
  • the nozzle generates droplets of the sample within a range of about 20 to about 100 pm in diameter which are then transported by a carrier gas into a drying chamber.
  • the carrier gas temperature is typically from 80-200 °C.
  • the droplets are subjected to rapid liquid evaporation, leaving behind dry particles which are collected in a special reservoir beneath a cyclone apparatus.
  • the collected product will consist of spherical aggregates of the nanoparticulate drug particles. If the liquid sample consists of an aqueous dispersion of nanoparticles in which an inert diluent material was dissolved (such as lactose or mannitol), the collected product will consist of diluent (e.g., lactose or mannitol) particles which contain embedded nanoparticulate drug particles.
  • an inert diluent material such as lactose or mannitol
  • the collected product will consist of diluent (e.g., lactose or mannitol) particles which contain embedded nanoparticulate drug particles.
  • the final size of the collected product can be controlled and depends on the concentration of nanoparticulate drug and/or diluent in the liquid sample, as well as the droplet size produced by the spray-dryer nozzle. Collected products may be used in conventional DPIs
  • an inert carrier to the spray-dried material to improve the metering properties of the final product. This may especially be the case when the spray dried powder is very small (less than about 5 pm) or when the intended dose is extremely small, whereby dose metering becomes difficult.
  • carrier particles also known as bulking agents
  • Such carriers typically consist of sugars such as lactose, mannitol, or trehalose.
  • Other inert materials including polysaccharides and cellulosics, may also be useful as carriers.
  • Spray-dried powders containing nanoparticulate drug particles may be used in conventional DPIs, disperse in propellants for use in pMDIs, or reconstituted in a liquid medium for use with nebulizers.
  • sublimation is preferred over evaporation to obtain a dry powder nanoparticulate drug composition. This is because sublimation avoids the high process temperatures associated with spray-drying.
  • sublimation also known as freeze-drying or lyophilization, can increase the shelf stability of drug compounds, particularly for biological products. Freeze-dried particles can also be reconstituted and used in nebulizers. Aggregates of freeze-dried nanoparticulate drug particles can be blended with either dry powder intermediates or used alone in DPIs and pMDIs for either nasal or pulmonary delivery.
  • Sublimation involves freezing the product and subjecting the sample to strong vacuum conditions. This allows for the formed ice to be transformed directly from a solid state to a vapor state. Such a process is highly efficient and, therefore, provides greater yields than spray drying.
  • the resultant freeze-dried product contains drug and modifier(s).
  • the drug is typically present in an aggregated state and can be used for inhalation alone (either pulmonary or nasal), in conjunction with diluent materials (lactose, mannitol, etc.), in DPIs or pMDIs, or reconstituted for use in a nebulizer.
  • delafloxacin is formulated into liposome particles, which can then be aerosolized for inhaled delivery.
  • Suitable lipids can be any of a variety of lipids including both neutral lipids and charged lipids.
  • Carrier systems having desirable properties can be
  • compositions provided herein can be in the form of liposomes or lipid particles, preferably lipid particles.
  • lipid particle includes a lipid bilayer carrier which "coats" a substance and has little or no aqueous interior.
  • the outer layer of the particle will typically comprise mixtures of lipids oriented in a tail-to-tail fashion (as in liposomes) with the hydrophobic tails of the interior layer.
  • the polar head groups present on the lipids of the outer layer will form the external surface of the particle.
  • Liposomal bioactive agents can be designed to have a sustained therapeutic effect or lower toxicity allowing less frequent administration and an enhanced therapeutic index.
  • Liposomes are composed of bilayers that entrap the desired pharmaceutical. These can be configured as multilamellar vesicles of concentric bilayers with the pharmaceutical trapped within either the lipid of the different layers or the aqueous space between the layers.
  • lipids used in the compositions may be synthetic, semi synthetic or naturally-occurring lipids, including phospholipids, tocopherols, steroids, fatty acids, glycoproteins such as albumin, negatively-charged lipids and cationic lipids.
  • Phospholipids include egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine (EPE), and egg phosphatidic acid (EPA); the soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the hydrogenated egg and soya counterparts (e.g., HEPC, HSPC), other phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol positions containing chains of 12 to 26 carbon atoms and different head groups in the 1 position of glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as the corresponding phosphatidic acids.
  • EPC egg phosphatidylcholine
  • EPG
  • compositions of the formulations can include dipalmitoyl phosphatidylcholine (DPPC), a major constituent of naturally-occurring lung surfactant as well as dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG).
  • DPPC dipalmitoyl phosphatidylcholine
  • DOPC dioleoylphosphatidylcholine
  • DOPG dioleoylphosphatidylglycerol
  • DMPC dimyristoylphosphatidycholine
  • DMPG dimyristoylphosphatidylglycerol
  • DPPC dipalmitoylphosphatidcholine
  • DPPG dipalmitoylphosphatidylglycerol
  • DSPC distearoylphosphatidylcholine
  • DSPG distearoylphosphatidylglycerol
  • DOPE dioleylphosphatidylethanolamine
  • PSPC palmitoylstearoylphosphatidylcholine
  • PSPG palmitoylstearoylphosphatidylglycerol
  • MOPE mono- oleoyl-phosphatidylethanolamine
  • PEG-modified lipids are incorporated into compositions as an aggregation-preventing agent.
  • the use of a PEG-ceramide has the additional advantages of stabilizing membrane bilayers and lengthening circulation lifetimes.
  • PEG- ceramides can be prepared with different lipid tail lengths to control the lifetime of the PEG- ceramide in the lipid bilayer. In this manner, "programmable" release can be accomplished which results in the control of lipid carrier fusion. For example, PEG-ceramides having C2o-acyl groups attached to the ceramide moiety will diffuse out of a lipid bilayer carrier with a half-life of 22 hours.
  • PEG-ceramides having CM- and Cs-acyl groups will diffuse out of the same carrier with half-lives of 10 minutes and less than 1 minute, respectively.
  • selection of lipid tail length provides a composition in which the bilayer becomes destabilized (and thus fusogenic) at a known rate.
  • PEG-lipids or lipid-polyoxyethylene conjugates are useful in the present compositions.
  • suitable PEG-modified lipids include PEG- modified phosphatidylethanolamine and phosphatidic acid, PEG-modified diacylglycerols and dialkylglycerols, PEG-modified dialkylamines and PEG-modified l,2-diacyloxypropan-3- amines.
  • PEG-ceramide conjugates e.g., PEG-Cer-Cs, PEG-Cer-Ci4 or PEG-Cer-C2o
  • PEG-ceramide conjugates e.g., PEG-Cer-Cs, PEG-Cer-Ci4 or PEG-Cer-C2o
  • Liposomal compositions can be 50-400 nm in diameter.
  • the size of the compositions can be larger or smaller depending upon the volume which is encapsulated. Thus, for larger volumes, the size distribution will typically be 80-300 nm.
  • Dry powder formulations generally require less time for drug administration, yet longer and more expensive development efforts.
  • liquid formulations have historically suffered from longer administration times, yet have the advantage of shorter and less expensive development efforts.
  • a particular formulation of delafloxacin disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for acceptable drug deposition at a site of infection and acceptable tolerability.
  • Factors that can be optimized include solution or solid particle formulation, rate of delivery, and particle size and distribution produced by the aerosolizing device.
  • Pulmonary drug delivery may be accomplished by inhalation of an aerosol through the mouth and throat. Particles having a mass median aerodynamic diameter (MMAD)
  • VMD volumetric mean diameter
  • MMD mass median diameter
  • MMAD MMAD
  • VMD, MMD and MMAD may be the same if environmental conditions are maintained, e.g. standard humidity. However, if humidity is not maintained, MMD and MMAD determinations will be smaller than VMD due to dehydration during impactor measurements. For the purposes of this description, VMD, MMD and MMAD measurements are considered to be under standard conditions such that descriptions of VMD, MMD and MMAD will be comparable. Similarly, dry powder particle size determinations in MMD, and MMAD are also considered comparable.
  • the particle size of the aerosol is optimized to maximize delafloxacin deposition at the site of infection and to maximize tolerability.
  • Aerosol particle size may be expressed in terms of the mass median aerodynamic diameter (MMAD). Large particles (e.g., MMAD>5 um) may deposit in the upper airway because they are too large to navigate the curvature of the upper airway. Small particles (e.g., MMAD ⁇ 2 um) may be poorly deposited in the lower airways and thus become exhaled, providing additional opportunity for upper airway deposition.
  • MMAD mass median aerodynamic diameter
  • intolerability may occur from upper airway deposition from both inhalation impaction of large particles and settling of small particles during repeated inhalation and expiration.
  • generation of a defined particle size with limited geometric standard deviation (GSD) may optimize deposition and tolerability. Narrow GSD limits the number of particles outside the desired MMAD size range.
  • an aerosol containing delafloxacin having a MMAD from about 2 microns to about 5 microns with a GSD of less than or equal to about 2.5 microns. In another embodiment, an aerosol having an MMAD from about 2.8 microns to about 4.3 microns with a GSD less than or equal to 2 microns is provided. In another embodiment, an aerosol having an MMAD from about 2.5 microns to about 4.5 microns with a GSD less than or equal to 1.8 microns is provided.
  • Delafloxacin intended for respiratory delivery can be administered as aqueous formulations, as suspensions or solutions in halogenated hydrocarbon propellants, or as dry powders.
  • Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization.
  • Propellant- based systems may use suitable pressurized metered-dose inhalers (pMDIs).
  • Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively.
  • DPIs dry powder inhaler devices
  • a nebulizer is selected on the basis of allowing the formation of an aerosol of delafloxacin having an MMAD predominantly between about 2 to about 5 microns.
  • the delivered amount of delafloxacin provides a therapeutic effect for respiratory infections.
  • nebulizers jet and ultrasonic, have been shown to be able to produce and deliver aerosol particles having sizes between 2 and 4 um. These particle sizes have been shown as being optimal for treatment of pulmonary bacterial infection cause by gram negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Enterobacter species, Klebsiella pneumoniae, K.
  • a jet nebulizer utilizes air pressure breakage of an aqueous solution into aerosol droplets.
  • An ultrasonic nebulizer utilizes shearing of the aqueous solution by a piezoelectric crystal.
  • the jet nebulizers are only about 10% efficient under clinical conditions, while the ultrasonic nebulizer is only about 5% efficient.
  • the amount of pharmaceutical deposited and absorbed in the lungs is thus a fraction of the 10% in spite of the large amounts of the drug placed in the nebulizer.
  • a vibrating mesh nebulizer is used to deliver an aerosol of delafloxacin.
  • a vibrating mesh nebulizer consists of a liquid storage container in fluid contact with a diaphragm and inhalation and exhalation valves.
  • about 1 to about 5 ml of the delafloxacin composition is placed in the storage container and the aerosol generator is engaged producing atomized aerosol of particle sizes selectively between about 1 and about 5 um.
  • delafloxacin is placed in a liquid nebulization inhaler and prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, preferably from about 14 to about 350 mg in about 1 to about 5 ml, and most preferably from about 28 to about 280 mg in about 1 to about 5 ml with MMAD particles sizes between about 2 to about 5 um being produced.
  • nebulized delafloxacin may be administered in the described respirable delivered dose in less than about 20 min, preferably less than about 10 min, more preferably less than about 7 min, more preferably less than about 5 min, more preferably less than about 3 min, and in some cases most preferable if less than about 2 min.
  • nebulized delafloxacin may achieve improved tolerability and/or exhibit an AUC shape -enhancing characteristic when administered over longer periods of time.
  • the described respirable delivered dose in more than about 2 min, preferably more than about 3 min, more preferably more than about 5 min, more preferably more than about 7 min, more preferably more than about 10 min, and in some cases most preferable from about 10 to about 20 min.
  • nebulizers for aqueous and other non-pressurized liquid systems, a variety of nebulizers (including small volume nebulizers) are available to aerosolize the formulations.
  • Compressor- driven nebulizers incorporate jet technology and use compressed air to generate the liquid aerosol.
  • Such devices are commercially available from, for example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc.
  • Ultrasonic nebulizers rely on mechanical energy in the form of vibration of a piezoelectric crystal to generate respirable liquid droplets and are commercially available from, for example, Omron Healthcare, Inc. and DeVilbiss Health Care, Inc. Vibrating mesh nebulizers rely upon either piezoelectric or mechanical pulses to respirable liquid droplets generate.
  • Other examples of nebulizers suitable for use with delafloxacin compositions described herein are described in U.S. Pat. Nos.
  • nebulizers that can be used with the delafloxacin compositions described herein include Respirgard IITM, AeronebTM, AeronebTM Pro, and AeronebTM. Go produced by Aerogen; AERxTM and AERx EssenceTM produced by Aradigm;
  • the drug solution is formed prior to use of the nebulizer by a patient.
  • the drug is stored in the nebulizer in solid form.
  • the solution is mixed upon activation of the nebulizer, such as described in U.S. Pat. No. 6,427,682 and PCT Publication No. WO 03/035030, both of which are hereby incorporated by reference in their entirety.
  • the solid drug optionally combined with excipients to form a solid composition, is stored in a separate compartment from a liquid solvent.
  • the liquid solvent is capable of dissolving the solid composition to form a liquid composition, which can be aerosolized and inhaled. Such capability is, among other factors, a function of the selected amount and, potentially, the composition of the liquid.
  • the sterile aqueous liquid may be able to dissolve the solid composition within a short period of time, possibly under gentle shaking.
  • the final liquid is ready to use after no longer than about 30 seconds.
  • the solid composition is dissolved within about 20 seconds, and advantageously, within about 10 seconds.
  • the terms "dissolve(d)", “dissolving”, and “dissolution” include the disintegration of the solid composition and the release, i.e.
  • the dissolution, of the active compound As a result of dissolving the solid composition with the liquid solvent a liquid composition is formed in which the active compound is contained in the dissolved state.
  • the active compound is in the dissolved state when at least about 90 wt.-% are dissolved, and more preferably when at least about 95 wt.-% are dissolved.
  • nebulizer design With regard to basic separated-compartment nebulizer design, it primarily depends on the specific application whether it is more useful to accommodate the aqueous liquid and the solid composition within separate chambers of the same container or primary package, or whether they should be provided in separate containers. If separate containers are used, these are provided as a set within the same secondary package. The use of separate containers is especially preferred for nebulizers containing two or more doses of the active compound. There is no limit to the total number of containers provided in a multi-dose kit.
  • the solid composition is provided as unit doses within multiple containers or within multiple chambers of a container, whereas the liquid solvent is provided within one chamber or container.
  • a favorable design provides the liquid in a metered-dose dispenser, which may consist of a glass or plastic bottle closed with a dispensing device, such as a mechanical pump for metering the
  • one actuation of the pumping mechanism may dispense the exact amount of liquid for dissolving one dose unit of the solid composition.
  • both the solid composition and the liquid solvent are provided as matched unit doses within multiple containers or within multiple chambers of a container.
  • two-chambered containers can be used to hold one unit of the solid composition in one of the chambers and one unit of liquid in the other.
  • one unit is defined by the amount of drug present in the solid composition, which is one unit dose.
  • Such two-chambered containers may, however, also be used advantageously for nebulizers containing only one single drug dose.
  • a blister pack having two blisters is used, the blisters representing the chambers for containing the solid composition and the liquid solvent in matched quantities for preparing a dose unit of the final liquid composition.
  • a blister pack represents a thermoformed or pressure-formed primary packaging unit, most likely comprising a polymeric packaging material that optionally includes a metal foil, such as aluminum.
  • the blister pack may be shaped to allow easy dispensing of the contents. For instance, one side of the pack may be tapered or have a tapered portion or region through which the content is dispensable into another vessel upon opening the blister pack at the tapered end.
  • the tapered end may represent a tip.
  • the two chambers of the blister pack are connected by a channel, the channel being adapted to direct fluid from the blister containing the liquid solvent to the blister containing the solid composition.
  • the channel is closed with a seal.
  • a seal is any structure that prevents the liquid solvent from contacting the solid composition.
  • the seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition.
  • the dissolution process may be improved by shaking the blister pack.
  • the final liquid composition for inhalation is obtained, the liquid being present in one or both of the chambers of the pack connected by the channel, depending on how the pack is held.
  • one of the chambers communicates with a second channel, the channel extending from the chamber to a distal position of the tapered portion.
  • this second channel does not communicate with the outside of the pack but is closed in an air tight fashion.
  • the distal end of the second channel is closed by a breakable or removable cap or closure, which may e.g. be a twist-off cap, a break-off cap, or a cut-off cap.
  • a vial or container having two compartments is used, the compartment representing the chambers for containing the solid composition and the liquid solvent in matched quantities for preparing a dose unit of the final liquid composition.
  • the liquid composition and a second liquid solvent may be contained in matched quantities for preparing a dose unit of the final liquid composition (by non-limiting example in cases where two soluble excipients or the delafloxacin and excipient are unstable for storage, yet desired in the same mixture for administration.
  • the two compartments are physically separated but in fluid communication so that when the vial or container are connected by a channel or breakable barrier, the channel or breakable barrier being adapted to direct fluid between the two compartments to enable mixing prior to administration.
  • the channel is closed with a seal or the breakable barrier intact.
  • a seal is any structure that prevents mixing of contents in the two compartments.
  • the seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition or in the case of two liquids permit mixing.
  • the dissolution or mixing process may be improved by shaking the container.
  • the final liquid composition for inhalation is obtained, the liquid being present in one or both of the chambers of the pack connected by the channel or breakable barrier, depending on how the pack is held.
  • the solid composition itself can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria.
  • the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
  • Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like.
  • the solid composition is a highly porous lyophilized form.
  • Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.
  • the solid composition may also be formed as a multiple unit dosage form as defined above.
  • multiple units are powders, granules, microparticles, pellets, beads, lyophilized powders, and the like.
  • composition is a lyophilized powder.
  • a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution.
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles.
  • the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
  • the solid composition resembles a coating layer that is coated on multiple units made of insoluble material.
  • insoluble units include beads made of glass, polymers, metals, and mineral salts.
  • the desired effect is primarily rapid disintegration of the coating layer and quick drug dissolution, which is achieved by providing the solid composition in a physical form that has a particularly high surface-to-volume ratio.
  • the coating composition will, in addition to the drug and the water-soluble low molecular weight excipient, comprise one or more excipients, such as those mentioned above for coating soluble particles, or any other excipient known to be useful in pharmaceutical coating compositions.
  • one excipient may be selected for its drug carrier and diluent capability, while another excipient may be selected to adjust the pH. If the final liquid composition needs to be buffered, two excipients that together form a buffer system may be selected.
  • the liquid to be used in a separated-compartment nebulizer is an aqueous liquid, which is herein defined as a liquid whose major component is water.
  • the liquid does not necessarily consist of water only; however, in one embodiment it is purified water.
  • the liquid contains other components or substances, preferably other liquid components, but possibly also dissolved solids.
  • Liquid components other than water which may be useful include propylene glycol, glycerol, and polyethylene glycol.
  • composition but is incompatible with the solid composition or with a component thereof, such as the active ingredient.
  • the liquid solvent is sterile.
  • An aqueous liquid would be subject to the risk of considerable microbiological contamination and growth if no measures are taken to ensure sterility.
  • an effective amount of an acceptable antimicrobial agent or preservative can be incorporated or the liquid can be sterilized prior to providing it and to seal it with an air-tight seal.
  • the liquid is a sterilized liquid free of preservatives and provided in an appropriate air-tight container.
  • the liquid may be supplied in a multiple-dose container, such as a metered-dose dispenser, and may require a preservative to prevent microbial contamination after the first use.
  • MDI Meter Dose Inhaler
  • a propellant driven inhaler releases a metered dose of medicine upon each actuation.
  • the medicine is formulated as a suspension or solution of a drug substance in a suitable propellant such as a halogenated hydrocarbon.
  • pMDIs are described in, for example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224 (Butterworths, London, England, 1984).
  • the particle size of the drug substance in an MDI may be optimally chosen.
  • the particles of active ingredient have diameters of less than about 50 microns. In some embodiments, the particles have diameters of less than about 10 microns. In some embodiments, the particles have diameters of from about 1 micron to about 5 microns. In some embodiments, the particles have diameters of less than about 1 micron. In one advantageous embodiment, the particles have diameters of from about 2 microns to about 5 microns.
  • the propellants for use with the MDIs may be any propellants known in the art.
  • propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofhioromethane, and dichlorotetrafluoroethane; hydrofluoroalkanes (HFAs); and carbon dioxide.
  • CFCs chlorofluorocarbons
  • HFAs hydrofluoroalkanes
  • Examples of medicinal aerosol preparations containing HFAs are presented in U.S. Pat. Nos. 6,585,958; 2,868,691 and 3,014,844, all of which are hereby incorporated by reference in their entirety.
  • a co-solvent is mixed with the propellant to facilitate dissolution or suspension of the drug substance.
  • the propellant and active ingredient are contained in separate containers, such as described in U.S. Pat. No. 4,534,345, which is hereby incorporated by reference in its entirety.
  • the MDI used herein is activated by a patient pushing a lever, button, or other actuator.
  • the release of the aerosol is breath activated such that, after initially arming the unit, the active compound aerosol is released once the patient begins to inhale, such as described in U.S. Pat. Nos.
  • MDIs known in the art and suitable for use herein include U.S. Pat. Nos. 6,435,177; 6,585,958; 5,642,730; 6,223,746; 4,955,371; 5,404,871; 5,364,838; and 6,523,536, all of which are hereby incorporated by reference in their entirety.
  • DPI Dry Powder Inhaler
  • particle size of the delafloxacin aerosol formulation may be optimized. If the particle size is larger than about 5 um MMAD then the particles are deposited in upper airways.
  • delafloxacin compositions are prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, preferably from about 14 to about 350 mg in about 1 to about 5 ml, and most preferably from about 28 to about 280 mg in about 1 to about 5 ml with MMAD particles sizes between about 2 to about 5 um being produced.
  • a dry powder inhaler is used to dispense the delafloxacin.
  • DPIs contain the drug substance in fine dry particle form.
  • inhalation by a patient causes the dry particles to form an aerosol cloud that is drawn into the patient's lungs.
  • the fine dry drug particles may be produced by any technique known in the art. Some well-known techniques include use of a jet mill or other comminution equipment, precipitation from saturated or super saturated solutions, spray drying, in situ micronization (Hovione), or supercritical fluid methods.
  • Typical powder formulations include production of spherical pellets or adhesive mixtures.
  • the drug particles are atached to larger carrier particles, such as lactose monohydrate of size about 50 to about 100 microns in diameter.
  • the larger carrier particles increase the aerodynamic forces on the carrier/drug agglomerates to improve aerosol formation. Turbulence and/or mechanical devices break the agglomerates into their constituent parts. The smaller drug particles are then drawn into the lungs while the larger carrier particles deposit in the mouth or throat.
  • DPIs There are three common types of DPIs, all of which may be used with the delafloxacin compositions described herein.
  • a single-dose DPI a capsule containing one dose of dry drug substance/excipients is loaded into the inhaler. Upon activation, the capsule is breached, allowing the dry powder to be dispersed and inhaled using a dry powder inhaler. To dispense additional doses, the old capsule must be removed, and an additional capsule loaded. Examples of single-dose DPIs are described in U.S. Pat. Nos. 3,807,400; 3,906,950; 3,991,761; and 4,013,075, all of which are hereby incorporated by reference in their entirety.
  • a package containing multiple single dose compartments is provided.
  • the package may comprise a blister pack, where each blister compartment contains one dose.
  • Each dose can be dispensed upon breach of a blister compartment.
  • Any of several arrangements of compartments in the package can be used. For example, rotary or strip arrangements are common.
  • Examples of multiple unit does DPIs are described in EPO Patent Application Publication Nos. 0211595A2, 0455463A1, and 0467172A1, all of which are hereby incorporated by reference in their entirety.
  • a single reservoir of dry powder are described in EPO Patent Application Publication Nos. 0211595A2, 0455463A1, and 0467172A1, all of which are hereby incorporated by reference in their entirety.
  • auxiliary energy in addition to or other than a patient's inhalation may be provided to facilitate operation of a DPI.
  • pressurized air may be provided to aid in powder de-agglomeration, such as described in U.S. Pat. Nos. 3,906,950; 5,113,855; 5,388,572; 6,029,662 and PCT Publication Nos. WO 93/12831, WO 90/07351, and WO 99/62495, all of which are hereby incorporated by reference in their entirety.
  • Electrically driven impellers may also be provided, such as described in U.S. Pat. Nos. 3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT Publication No.
  • WO 98/03217 all of which are hereby incorporated by reference in their entirety.
  • Another mechanism is an electrically poared tapping piston, such as described in PCT Publication No. WO 90/13327, which is hereby incorporated by reference in its entirety.
  • Other DPIs use a vibrator, such as described in U.S. Pat. Nos. 5,694,920 and 6,026,809, both of which are hereby incorporated by reference in their entirety.
  • a scraper system may be employed, such as described in PCT Publication No. WO 93/24165, which is hereby incorporated by reference in its entirety.
  • a spacer or chamber may be used with any of the inhalers described herein to increase the amount of drug substance that gets absorbed by the patient, such as is described in U.S. Pat. Nos. 4,470,412; 4,790,305; 4,926,852; 5,012,803; 5,040,527; 5,024,467; 5,816,240; 5,027,806; and 6,026,807, all of which are hereby incorporated by reference in their entirety.
  • a spacer may delay the time from aerosol production to the time when the aerosol enters a patient's mouth. Such a delay may improve synchronization between the patient's inhalation and the aerosol production.
  • a mask may also be incorporated for infants or other patients that have difficulty using the traditional mouthpiece, such as is described in U.S. Pat. Nos. 4,809,692; 4,832,015; 5,012,804; 5,427,089; 5,645,049; and 5,988,160, all of which are hereby incorporated by reference in their entirety.
  • Dry powder inhalers which involve deaggregation and aerosolization of dry powders, normally rely upon a burst of inspired air that is drawn through the unit to deliver a drug dosage.
  • DPIs Dry powder inhalers
  • Certain methods provided herein relate to the use of aerosolized delafloxacin for the treatment or prophylaxis of lung conditions, in particular, bacterial infections of the lung and upper respiratory tract.
  • Methods include treating a pulmonary infection by administering to a subject in need thereof a therapeutically effective amount of an aerosol comprising delafloxacin.
  • the aerosol comprising delafloxacin comprises an aerosol of a liquid solution or suspension of delafloxacin, such as an aqueous solution or suspension.
  • the aerosol comprising delafloxacin comprises solid particles comprising delafloxacin.
  • the aerosol comprising delafloxacin comprises liposomes comprising delafloxacin.
  • Administration can be performed by any suitable method, such as the use of an inhaler, such as a dry powder inhaler or liquid nebulizer, as described elsewhere herein.
  • an inhaler such as a dry powder inhaler or liquid nebulizer, as described elsewhere herein.
  • the aerosolized delafloxacin is administered using a ventilator.
  • a "therapeutically effective amount” or “pharmaceutically effective amount” includes those amounts of a delafloxacin composition that produce a desired therapeutic effect.
  • the delafloxacin is administered in a pre-determined dose, and thus a therapeutically effective amount would be an amount of the dose administered.
  • This amount and the amount of the delafloxacin can be routinely determined by one of skill in the art, and can vary, depending on several factors, such as the particular microbial strain involved. This amount can further depend upon the patient's height, weight, sex, age, medical history, and the like.
  • a therapeutically effective amount is that amount which would be effective to prevent a microbial infection.
  • Certain methods provided herein relate to administering aerosolized delafloxacin to a subject so that a desired level of delafloxacin is achieved, for example a desired level in one or more pulmonary structures to be treated, or a desired level in one or more samples that are related to pulmonary structures to be treated, such as for example, bronchial alveolar lavage or sputum.
  • Certain methods provided herein relate to administering aerosolized delafloxacin to a subject so that a desired degree of reduction in pulmonary infection is achieved. Any suitable
  • the manner of measuring a level of pulmonary infection may be used, for example, measuring a reduction in the density of the organism in a sample, such as for example, bronchial alveolar lavage or sputum.
  • the density of the organism in a sample e.g. a sputum sample or a bronchial alveolar lavage sample, is reduced by at least 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%.
  • the density of the organism in a sample is reduced by at least 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9, 99.95, 99.99, or 100%.
  • the density of an organism in a sample is reduced by at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 logio CFU/g sputum or lavage fluid, or more.
  • Methods and compositions described herein can be used to treat pulmonary infections disorders, in particular pulmonary bacterial infections.
  • the infection is associated with another disorder.
  • the other disorder is cystic fibrosis.
  • the disorder is chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the other disorder is asthma.
  • the disorder is sinusitis.
  • the disorder is rhinosinusitis.
  • a subject suffering from a bacterial infection is on a ventilator.
  • the bacterial infection is tuberculosis, e.g., drug-resistant tuberculosis.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin can be any suitable dose.
  • the amount of delafloxacin that can be administered can include at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, about 30 mg, 35 mg, about 40 mg, 45 mg, about 50 mg, 55 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-80, 1-70, 2-60, 5-50, 10-30, or 20 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-90, 1-80, 2-70, 5-60, 20-40, or 30 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-110, 1-100, 1-90, 2-80, 5-70, 40-60, or 50 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 10-140, 20-130, 40-120, 50-110, 60-100, 70-90, or 80 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-160, 50-150, 60-140, 70-130, 80-120, 90-110, or lOOmg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-200, 60-180, 70-170, 80-160, 90-150, 100-140, 110-130, or 120mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 80-220, 90-210, 100-200, 110-190, 120-180, 130-170, 140-160, or 150 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 90-210, 100-220, 110-210, 120-200, 130-190, 140-180, 150-170, or 160 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-140, 110-130, 120-220, 130-210, 140-200, 150-190, 160-180, or 170 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-250, 120-240, 130-230, 140-220, 150-210, 160-200, 170-190, or 180 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-260, 130-250, 140-240, 150-230, 160-220, 170-210, 180-200, or 190 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-300, 120-270, 150-250, 160-240, 170-230, 180-220, 190-210, or 200 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-390, 100-320, 120-300, 150-270, 170-250, 180-240, 190-230, 200-220, or 210 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-390, 100-340, 130-310, 160-280, 180-260, 190-250, 200-240, 210-230, 220 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-350, 140-320, 170-290, 190-270, 200-260, 210-250, 220-240, or 230 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-430, 100-380, 130-350, 160-320, 180-300, 200-280, 210-270, 220-260, 230-250, or 240 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-400, 130-370, 160-340, 180-320, 200-300, 210-290, 220-280, 230-270, 240-260, or 250 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-420, 120-400, 150-370, 170-350, 200-320, 220-300, 230-290, 240-280, 250-270, or 260 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-440, 150-390, 180-360, 210-330, 230-310, 240-300, 250-290, 260-280, or 270 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-450, 140-420, 170-390, 200-360, 220-340, 240-320, 250-310, 260-300, 270-290, or 280 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-460, 150-430, 180-400, 210-370, 230-350, 250-330, 260-320, 270-310, 280-300, or 290 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 70-430, 100-400, 120-380, 140-360, 160-340, 170-330, 180-320, 190-310, 190-310, 195-305, or 300 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-520, 170-450, 200-420, 230-390, 250-370, 270-350, 280-340, 290-330, 300-320, 310 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 190-450, 220-420, 250-390, 270-370, 290-350, 300-340, 310-330, or 320 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-460, 240-420, 270-390, 290-370, 300-360, 310-350, 320-340, or 330 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-490, 240-450, 270-410, 290-390, 310-370, 320-360, 330-350, or 340 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-500, 240-460, 270-430, 300-400, 320-380, 330-370, 340-360, or 350 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-520, 230-490, 260-460, 290-430, 310-410, 330-390, 340-380, 350-370, or 360 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-490, 290-450, 310-430, 330-410, 340-400, 350-390, 360-380, or 370 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 230-530, 270-490, 300-460, 320-440, 340-420, 350-410, 360-400, 370-390, or 380 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-530, 300-480, 330-450, 350-430, 360-420, 370-410, 380-400, or 390 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 260-540, 300-500, 330-470, 350-450, 370-430, 380-420, 390-410, or 400 mg.
  • the subject is an adult and the dosage per administration is 50-500, 100-450, 200-400, 250-350, 280-320, 290-310, or 300 mg; or 100-600, 200-500, 300- 400, 320-380, 340-360, or 350 mg; or 100-700, 200-600, 300-500, 350-450, 380-420, 390-410, or 400 mg; or 50-600, 100-500, 200-400, 230-270, 240-260, or 250 mg; or 50-400, 100-300, 150-250, 180-220, 190-210, or 200 mg.
  • the subject is a pediatric patient and, as appropriate, the dosage may be reduced, e.g., to less than 90, 80, 70, 60, 50, 40, 30, or 20% of the adult dose.
  • a respirable drug dose of at least 20, 100, 125, or 150mg of delafloxacin is administered to the lung.
  • a loaded dose of at least 100, 200, 250, 300, 350, or 400 mg of delafloxacin is aerosolized.
  • a method of treating a subject such as a mammal, e.g., a human subject, suffering from a bacterial infection by administering a therapeutically effective amount of an aerosolized delafloxacin composition, such as one of the compositions described herein, e.g., a liquid formulation such as an aqueous formulation, a dry powder formulation, or a liposomal formulation.
  • an aerosolized delafloxacin composition such as one of the compositions described herein, e.g., a liquid formulation such as an aqueous formulation, a dry powder formulation, or a liposomal formulation.
  • the subject is a human with pneumonia, a chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis,
  • the subject is a human with pneumonia. In certain embodiments the subject is a human with COPD. In certain embodiments the subject is a human with chronic bronchitis. In certain embodiments the subject is a human with bronchiectasis. In certain embodiments the subject is a human with asthma. In certain embodiments the subject is a human with sinusitis. In certain embodiments the subject is a human with rhinosinusitis. In certain embodiments the subject is a human with cystic fibrosis. In certain embodiments the subject is a human that is mechanically ventilated. In certain embodiments the subject is a human with tuberculosis, e.g., multi-drug resistant tuberculosis.
  • tuberculosis e.g., multi-drug resistant tuberculosis.
  • the infection can be any pulmonary infection suitable for treatment with aerosolized delafloxacin.
  • the infection comprises one or more bacteria that can include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas sp., e.g., Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrohacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis.
  • Shigella dysenteriae Shigella flexneri, Shigella sonnei, Enterohacter cloacae, Enterohacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus paraha
  • Pasteurella multocida Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia sp., e.g., Burkholderia cepacia, Francisella tularensis, Kingella, Moraxella, or a combination of two or more of the above.
  • the pulmonary infection can include a gram-negative anaerobic bacteria.
  • the pulmonary infection can include one or more of Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus .
  • the pulmonary infection can include a gram-positive bacteria.
  • the pulmonary infection can include one or more of Corynebacterium
  • the pulmonary infection can include a gram-positive anaerobic bacteria.
  • the pulmonary infection can include one or more of Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum.
  • the pulmonary infection can include an acid-fast bacteria.
  • the pulmonary infection can include one or more of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium leprae.
  • the pulmonary infection can include an atypical bacteria.
  • the pulmonary infection can include one or more of Chlamydia pneumoniae and Mycoplasma pneumoniae.
  • the pulmonary infection can comprise a non-fermenting gram-negative bacteria (NFGNB).
  • NFGNB non-fermenting gram-negative bacteria
  • Examples of NFGNB can include Burkholeria spp., Stenotrophomonas spp., Acinetobacter spp; Pseudomonas spp., and Achromobacter spp .
  • the bacterial infection is an antibiotic-resistant bacterial infection.
  • the bacterial infection comprises Pseudomonas bacteria, such as is Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, or a combination of two or more thereof.
  • the infection is a Pseudomonas aeruginosa infection.
  • the bacterial infection is a methicillin resistant Staphylococcus aureus (MRSA) infection.
  • MRSA methicillin resistant Staphylococcus aureus
  • the infection is a Streptococcus pneumonia (Sp) infection.
  • the infection comprises one or more Mycobacterium, such as one or more of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, or Mycobacterium leprae , for ex ple Mycobacterium avium or Mycobacterium intracellulare .
  • the bacterial infection comprises Haemophilus influenzae .
  • the bacterial infection comprises Haemophilus parainfluenza.
  • the bacterial infection comprises Moraxella catarrhalis .
  • composition can be in in any pharmaceutically acceptable dosage form.
  • the composition is an aqueous composition.
  • the composition is an aqueous composition.
  • composition is a dry powder formulation.
  • the composition is a liposomal composition.
  • the composition comprises a combination of formulations, e.g., aqueous solution and liposomal suspension; such a formulation can allow for both immediate effects, e.g., from the aqueous solution, and longer-term effects, e.g., from liposomes. Distribution of the different formulations may also be different, increasing effectiveness. Delafloxacin in the aerosolized delafloxacin composition may be in any suitable form, as described herein.
  • the delafloxacin is administered with a divalent or trivalent cation, or combination thereof, such as magnesium, calcium, zinc, copper, aluminum, or iron, or a combination thereof; in certain embodiments, the delafloxacin is administered with a divalent cation, such as magnesium or calcium; in certain embodiments, the delafloxacin is administered with a divalent cation, such as magnesium, for example, magnesium chloride.
  • concentrations of the divalent or trivalent cation, or combination thereof, e.g., magnesium, such as magnesium chloride may be any suitable concentration, such as 50-400 mM, e.g., where the delafloxacin concentration is 5-80, 10-70, 20- 60, 20-50, 20-40, 30-100, 40-100, 50-120, 60-120, or 50-200 mg/ml, or 100-300 mM, e.g., where the delafloxacin concentration is 75-150 mg/ml, or 150-250 mM, e.g., where the delafloxacin concentration is 5-80, 10-70, 20-60, 20-50, 20-40, 30-100, 40-100, 50-120, 60-120, or 90-125 mg/ml.
  • the delafloxacin composition is an aqueous composition.
  • the osmolarity of the composition may be any suitable osmolarity, as described herein, for example 200-1250, 250-1050, 300-500, 350-750, or 350-425 mOsmol/kg.
  • a permeant ion concentration may be any suitable concentration as described herein, for example 30-300 mM, such as 50-200 mM.
  • one or more permeant ions in the composition are selected from the group consisting of chloride and bromide.
  • the delafloxacin composition comprises a taste-masking agent, which can be any taste-masking agent as described herein, such as a sugar, a divalent or trivalent cation or combination thereof that complexes with the delafloxacin, optimized osmolality, and/or an optimized permeant ion concentration.
  • pH can be any suitable pH, e.g., 5-8, 5-7.5, 5-7, 5-6.5, 5- 6, 5.5-8, 5.5-7.5, 5.5-7, 5.5-6.5, 6-8, 6-7.5, 6-7, 6-6.5, 6.5-8, 6.5-7.5, or 6.5-7.
  • the pH is 5-8.
  • the pH is 5-6.5.
  • the pH is 5.5-6.5.
  • the delafloxacin composition is an aqueous composition with a divalent cation, e.g., magnesium, at a concentration of 50-400 mM, a pH of 5-8, and an osmolarity of 200-1250 mOsmol/kg.
  • a divalent cation e.g., magnesium
  • the delafloxacin composition is an aqueous composition comprising delafloxacin at a concentration between 5-80, 10-70, 20-60, 20-50, 20-40, 30-100, 40-100, 50-120, 60-120, or 50-200 mg/ml, such as 20-100 mg/ml, or 20-80 mg/ml, or 30-100 mg/ml, or 30-80 mg/ml, or 80-150 mg/ml, in some cases 90-110 mg/ml, a magnesium chloride concentration of 100-400 mM, such as 125-300 mM, in some cases 175 mM to about 225 mM, and a pH of 5-8, in some cases 5-7.5, such as 5-7; an osmolarity of 200-1250 mOsmol/kg, in some cases 250-1050 mOsmol/kg, for example 250-550 mOsmol/kg, in particular 300-500 mOsmol/kg, and, optionally, lack
  • the delafloxacin composition is an aqueous composition with a delafloxacin concentration of 20-50 mg/ml or 90-110 mg/ml, a magnesium chloride concentration of 175-225 mM, a pH of 5-7; an osmolarity of 300- mOsmol/kg. In certain embodiments the delafloxacin composition lacks lactose.
  • the delafloxacin composition is a dry powder composition, such as a dry powder composition as described herein, e.g. a dry powder composition with or without a blending agent such as lactose.
  • the delafloxacin composition is a liposomal composition, such as a liposomal composition described herein.
  • the delafloxacin is administered in any suitable manner, depending on the nature of the delafloxacin composition, e.g., by liquid nebulizer, dry powder inhaler, ventilator, or any other suitable method as described herein. Further description of specific inhalers
  • the duration of a therapy can include at least about 1 day/month, at least about 2 days/month, at least about 3 days/month, at least about 4 days/month, at least about 5 days/month, at least about 6 days/month, at least about 7 days/month, at least about 8 days/month, at least about 9 days/month, at least about 10 days/month, at least about 11 days/month, at least about 12 days/month, at least about 13 days/month, at least about 14 days/month, at least about 15 days/month, at least about 16 days/month, at least about 17 days/month, at least about 18 days/month, at least about 19 days/month, at least about 20 days/month, at least about 21 days/month, at least about 22 days/month, at least about 23 days/month, at least about 24 days/month, at least about 25 days/month, at least about 26 days/month, at least about 27 days/month, at least about 28 days
  • An aerosolized delafloxacin composition can be administered with a frequency of about 1, 2, 3, 4, or more times daily, 1, 2, 3, 4, 5, 6, 7 or more times weekly, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times monthly. In certain embodiments, the compositions are administered twice daily.
  • the aerosol delafloxacin can be administered once daily, twice daily, three times daily, or four times daily. In certain embodiments, the aerosol delafloxacin is administered once daily. In certain embodiments, the aerosol delafloxacin is administered twice daily. In certain embodiments, the aerosolized delafloxacin is delivered more than twice daily. In certain embodiments, the aerosol delafloxacin can be administered for a period of at least 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 days. In certain embodiments, the aerosol delafloxacin can be administered for about 14 days. In particular embodiments the aerosol delafloxacin is administered daily for 14 days.
  • delafloxacin treatment is cycled, for example delafloxacin is delivered in a time period as above, then treatment is stopped for a suitable amount of time, e.g., at least 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 days, then treatment is resumed, e.g., for a period as described herein.
  • delafloxacin is delivered in a 28 day on/28 day off cycle.
  • the daily dosage of delafloxacin can depend on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration, and the judgment of the prescribing physician; for example, a likely dose range for aerosol administration of delafloxacin would be about 20 to 800 mg per day.
  • a daily aerosol dose of delafloxacin can be from about 0.1 to 10 mg/kg of body weight, for example about 0.20 to 8.0 mg/kg of body weight, such as 0.4 to 6.0 mg/kg of body weight.
  • the dosage range would be 7.0 to 840.0 mg per day, such as 14.0 to 470.0 mg per day, such as 28.0 to 350 mg per day.
  • the dosage of delafloxacin per administration can be any suitable dosage, such as a dosage described herein.
  • the amount of delafloxacin that can be administered can include at least about 5 mg, 10 mg, 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-80, 1-70, 2-60, 5-50, 10-30, or 20 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-90, 1-80, 2-70, 5-60, 20-40, or 30 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-110, 1-100, 1-90, 2-80, 5-70, 40-60, or 50 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 10-140, 20-130, 40-120, 50-110, 60-100, 70-90, or 80 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-160, 50-150, 60-140, 70-130, 80-120, 90-110, or lOOmg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-200, 60-180, 70-170, 80-160, 90-150, 100-140, 110-130, or 120mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 80-220, 90-210, 100-200, 110-190, 120-180, 130-170, 140-160, or 150 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 90-210, 100-220, 110-210, 120-200, 130-190, 140-180, 150-170, or 160 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-140, 110-130, 120-220, 130-210, 140-200, 150-190, 160-180, or 170 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-250, 120-240, 130-230, 140-220, 150-210, 160-200, 170-190, or 180 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-260, 130-250, 140-240, 150-230, 160-220, 170-210, 180-200, or 190 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-300, 120-270, 150-250, 160-240, 170-230, 180-220, 190-210, or 200 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-390, 100-320, 120-300, 150-270, 170-250, 180-240, 190-230, 200-220, or 210 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-390, 100-340, 130-310, 160-280, 180-260, 190-250, 200-240, 210-230, 220 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-350, 140-320, 170-290, 190-270, 200-260, 210-250, 220-240, or 230 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-430, 100-380, 130-350, 160-320, 180-300, 200-280, 210-270, 220-260, 230-250, or 240 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-400, 130-370, 160-340, 180-320, 200-300, 210-290, 220-280, 230-270, 240-260, or 250 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-420, 120-400, 150-370, 170-350, 200-320, 220-300, 230-290, 240-280, 250-270, or 260 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-440, 150-390, 180-360, 210-330, 230-310, 240-300, 250-290, 260-280, or 270 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-450, 140-420, 170-390, 200-360, 220-340, 240-320, 250-310, 260-300, 270-290, or 280 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-460, 150-430, 180-400, 210-370, 230-350, 250-330, 260-320, 270-310, 280-300, or 290 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 70-430, 100-400, 120-380, 140-360, 160-340, 170-330, 180-320, 190-310, 190-310, 195-305, or 300 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-520, 170-450, 200-420, 230-390, 250-370, 270-350, 280-340, 290-330, 300-320, 310 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 190-450, 220-420, 250-390, 270-370, 290-350, 300-340, 310-330, or 320 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-460, 240-420, 270-390, 290-370, 300-360, 310-350, 320-340, or 330 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-490, 240-450, 270-410, 290-390, 310-370, 320-360, 330-350, or 340 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-500, 240-460, 270-430, 300-400, 320-380, 330-370, 340-360, or 350 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-520, 230-490, 260-460, 290-430, 310-410, 330-390, 340-380, 350-370, or 360 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-490, 290-450, 310-430, 330-410, 340-400, 350-390, 360-380, or 370 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 230-530, 270-490, 300-460, 320-440, 340-420, 350-410, 360-400, 370-390, or 380 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-530, 300-480, 330-450, 350-430, 360-420, 370-410, 380-400, or 390 mg.
  • the dosage of delafloxacin per administration of the aerosolized delafloxacin is 260-540, 300-500, 330-470, 350-450, 370-430, 380-420, 390-410, or 400 mg.
  • the subject is an adult and the dosage per administration is 50-500, 100-450, 200-400, 250-350, 280-320, 290-310, or 300 mg; or 100-600, 200-500, 300- 400, 320-380, 340-360, or 350 mg; or 100-700, 200-600, 300-500, 350-450, 380-420, 390-410, or 400 mg; or 50-600, 100-500, 200-400, 230-270, 240-260, or 250 mg; or 50-400, 100-300, 150-250, 180-220, 190-210, or 200 mg.
  • the subject is a pediatric patient and, as appropriate, the dosage may be reduced, e.g., to less than 90, 80, 70, 60, 50, 40, 30, or 20% of the adult dose.
  • a respirable drug dose of at least 5, 10, 20, 100, 125, or 150mg of delafloxacin is administered to the lung.
  • a loaded dose of at least 20, 40, 60, 80, 100, 200, 250, 300, 350, or 400 mg of delafloxacin is aerosolized.
  • the aerosol can be administered to the lungs in less than 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, orl minute.
  • administration of the aerosolized delafloxacin achieves a maximum lung sputum concentration (C max ) of at least 1200, 1700, 2000, 3000, or 4000 mg/L, for example at least 1200 mg/L and a lung sputum area under the curve (AUC) of at least 1500, 1700, 2000, 3000, or 4000 h mg/L, for example at least 1500 h mg/L.
  • C max maximum lung sputum concentration
  • AUC lung sputum area under the curve
  • the delafloxacin composition comprises a divalent or trivalent cation, or a combination thereof, e.g., magnesium, calcium, zinc, copper, aluminum, or iron, or a combination thereof, such as magnesium, in some cases in the form of magnesium chloride, e.g., at a concentration of 50- 400 mM.
  • the delafloxacin concentration in the delafloxacin composition can be 10-100, or 10-200, or 20-100, or 20-80, or 50-200 mg/mL.
  • the delafloxacin composition consists essentially of delafloxacin and the divalent or trivalent cation or combination thereof.
  • the delafloxacin composition comprises no lactose. In certain embodiments, the delafloxacin composition comprises a divalent or trivalent cation, or combination thereof, such as a divalent cation, e.g., magnesium, at a concentration of 50-400, 100-300, or 150-250 mM. In certain embodiments, the delafloxacin composition comprises delafloxacin at a concentration of 10-100, 10-200, 20-100, or 20-80, 50- 200, 75-150, or 90-125 mg/mL. In certain embodiments, the osmolarity of the delafloxacin composition is 200-800, 300-600, or 350-425 mOsmol/kg.
  • the pH of the delafloxacin composition is 5-8, 5-7, 5-6.5, or 5.5-6.5.
  • the delafloxacin composition comprises a delafloxacin concentration of 20-80 mg/ml, or 20-40 mg/ml, or 90-110 mg/ml, a magnesium chloride concentration of 175-225 mM, a pH of 5-7; an osmolarity of 300-500 mOsmol/kg, and, optionally, lacks lactose.
  • the method comprises administering delafloxacin to the subject, e.g., human, to achieve a concentration in a lung of the subject of at least 5, 10, 20, 25, 27, 32, 35, 40, 45, 50, 70, 100, 200, 500, 800, 1000, 1200, or 1500 pg/ml of delafloxacin, wherein the delafloxacin is administered as an aerosol.
  • the aerosol comprises a divalent or trivalent cation or combination thereof.
  • the aerosol comprises greater than 50 mg/ml delafloxacin and, in certain embodiments, a divalent or trivalent cation, or combination thereof, e.g., magnesium, such as magnesium supplied by magnesium chloride, has a pH of 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, or 5.5-6.5, and an osmolality of 100-1200, 200-1000, 300-900, or 350-750 mOsmol/kg.
  • a divalent or trivalent cation, or combination thereof e.g., magnesium, such as magnesium supplied by magnesium chloride, has a pH of 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, or 5.5-6.5, and an osmolality of 100-1200, 200-1000, 300-900, or 350-750 mOsmol/kg.
  • the method comprises administering delafloxacin to a subject, e.g., human suffering from a bacterial infection caused by at least one type of bacteria, wherein
  • the bacteria is exposed to at least 0.01, 0.05, 0.07, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.2, 1.5, 1.7, 2, 2.5, 3, 4, 5, 7, or 10 mg/L of the delafloxacin, wherein the delafloxacin is administered as an aerosol.
  • the aerosol comprises a divalent or trivalent cation or combination thereof.
  • the aerosol comprises greater than 50 mg/ml delafloxacin and, in certain embodiments, a divalent or trivalent cation, or combination thereof, e.g., magnesium, such as magnesium supplied by magnesium chloride, has a pH of 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, or 5.5-6.5, and an osmolality of 100- 1200, 200-1000, 300-900, or 350-750 mOsmol/kg.
  • no other antibiotics are administered by inhalation; in certain embodiments, no other antibiotics are administered.
  • at least 5, 10, 20, 50, 70, 100, 120, 150, 170, 200, 220, 250, 270, or 300 mg of delafloxacin is administered.
  • aerosolized delafloxacin is repeatedly administered to a subject, e.g., human, where repeated administration does not result in an incidence of arthralgia.
  • administering is repeated at least once daily for 14 days, at least once daily for 28 days, and at least once daily for 35 days.
  • administering is repeated at least twice daily for at least 14 days, at least twice daily for at least 28 days, and at least twice daily for at least 35 days.
  • the delafloxacin compositions is in a unit dosage form, such as vial containing a liquid, solid to be suspended, dry powder, lyophilizate, or other composition.
  • the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • the particles of the aerosol containing delafloxacin have a mass median aerodynamic diameter of 2-5 with a geometric standard deviation less than or equal to about 2.5 microns.
  • the particles of the aerosol containing delafloxacin have a mass median aerodynamic diameter of 2.5-4.5 microns with a geometric standard deviation less than or equal to 1.8 microns.
  • the particles of the aerosol containing delafloxacin have a mass median aerodynamic diameter of 2.8-4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
  • the method also includes producing the aerosol with a vibrating mesh nebulizer.
  • the vibrating mesh nebulizer is a PARI E- FLOWTM nebulizer.
  • the amount of delafloxacin administered to the lung is at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 100 mg, at least about 125 mg, and at least about 150 mg.
  • At least about 20, 40, 60, 80, or 100 mg the aerosol is administered to the lung in less than about 60, 50, 40, 30, 20, 10, 5, 3 or 2 minutes, preferably less than 40 min, more preferably less than 30 min, even more preferably less than 20 min, still more preferably less than 10 min.
  • the treatment includes administering an additional active agent, for example one or more antibiotics, bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, CFTR modulators, agents to restore airway surface liquid, anti inflammatory agents, or combinations thereof.
  • an additional active agent for example one or more antibiotics, bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, CFTR modulators, agents to restore airway surface liquid, anti inflammatory agents, or combinations thereof.
  • the coadministration can comprise inhalation of the agent.
  • the agent may be administered as part of the aerosolized delafloxacin, separately, or a combination thereof.
  • the antibiotic can include tobramycin, aztreonam, ciprofloxacin, azithromycin, tetracycline, quinupristin, linezolid, vancomycin, and chloramphenicol, colisitin or combinations thereof.
  • the bronchodilator can include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutlaine, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, theophylline, roflumilast, cilomilast, or combinations thereof.
  • the anticholinergic can be ipratropium, tiotropium, and combinations thereof.
  • the glucocorticoid can include prednisone, fluticasone, budesonide, mometasone, ciclesonide, beclomethasone, or combinations thereof.
  • the eicosanoid inhibitor can include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, seratrodast, or combinations thereof.
  • the CFTR modulator includes VX-770, atluren, VX-809, or combinations thereof.
  • the agent to restore airway surface liquid includes denufosol, mannitol, GS-9411, SPI-8811, or combinations thereof.
  • the anti-inflammatory agent includes ibuprofen, sildenafd, simavastatin, or combinations thereof.
  • co-administering comprises inhaling the additional active agent.
  • the additional active ingredient comprises mannitol.
  • the aerosol delafloxacin therapy may be administered as a treatment or prophylaxis in combination or alternating therapeutic sequence with other aerosol,
  • antibiotics Any suitable antibiotic may be used, e.g., tobramycin and/or other aminoglycoside, aztreonam, carumonam and/or tigemonam and/or other beta or mono-bactam, ciprofloxacin and/or other fluoroquinolones, azithromycin and/or other macrolides or ketolides, tetracycline and/or other tetracyclines, quinupristin and/or other streptogramins, linezolid and/or other oxazolidinones, vancomycin and/or other glycopeptides, rifampicin, and/or chloramphenicol and/or other phenicols, and/or colisitin and/or other polymyxins.
  • any suitable antibiotic may be used, e.g., tobramycin and/or other aminoglycoside, aztreonam, carumonam and/or tigemonam and/or other beta or mono-bactam,
  • the antibiotic can include quinolones, tetracyclines, glycopeptides, aminoglycosides, beta-lactams, rifamycins, macrolides/ketolides, oxazolidinones, coumermycins, chloramphenicol, streptogramins, trimethoprim, sulfamethoxazole, or polymyxins.
  • any of the foregoing antibiotics can be administered by any acceptable method or route, for example, by aerosol, orally or parenterally.
  • Beta-lactam antibiotics suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, imipenem, meropenem, biapenem, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephaacetrile, cephalexin, cephaloglycin, cephaloridine, cephalothin, cephapirin, cephradine, cefmetazole, cefox
  • Macrolides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, azithromycin, clarithromycin, erythromycin, oleandomycin, rokitamycin, rosaramicin, roxithromycin, and troleandomycin.
  • Ketolides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, telithromycin and cethromycin.
  • Quinolones suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, amifloxacin, cinoxacin, ciprofloxacin, enoxacin, fleroxacin, flumequine, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, levofloxacin, oxolinic acid, pefloxacin, rosoxacin, temafloxacin, tosufloxacin, sparfloxacin, clinafloxacin, moxifloxacin; gemifloxacin; garenofloxacin; PD131628, PD138312, PD140248, Q-35, AM-1155, NM394, T- 3761, rufloxacin, OPC-17116, DU-6859a (see, e.g., Sato, K.
  • Tetracyclines, glycylcyclines, and oxazolidinones suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, chlortetracycline, demeclocycline, doxycycline, lymecycline, methacycline, minocycline, oxytetracycline, tetracycline, tigecycline, linezolide, and eperozolid.
  • Aminoglycosides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to amikacin, arbekacin, butirosin, dibekacin, fortimicins, gentamicin, kanamycin, neomycin, netilmicin, ribostamycin, sisomicin, spectinomycin, streptomycin, and tobramycin.
  • Lincosamides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, clindamycin and lincomycin.
  • Streptogramins suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to quinupristin.
  • Glycopeptides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to vancomycin.
  • Polymyxins suitable for administration in conjunction with inhaled delafloxacin include but are not limited to colisitin.
  • Additional antibiotics suitable for administration in conjunction with inhaled delafloxacin include fosfomycin, penicillins, cephalosporins, carbapenems, penems, and carbacephems.
  • treating a subject e.g., human, suffering from a pulmonary bacterial infection with aerosolized delafloxacin can result in a clinically measurable response, such as a reduction in pulmonary infection, an improvement in a pulmonary function characteristic, such as an improvement in forced expiratory volume (FEV), FEV i (forced expiratory volume in 1 second), and FEF 25-75 (forced expiratory flow 25-75%), reducing the need for other inhaled or systemic antibiotics, decreasing frequency, severity, duration, and/or likelihood of exacerbations.
  • FEV forced expiratory volume
  • FEV i forced expiratory volume in 1 second
  • FEF 25-75 forced expiratory flow 25-75%
  • a reduction in a pulmonary infection can be measured using any suitable method.
  • a reduction in the density of the organism can be measured.
  • treatment can achieve a reduction in the density of an organism by at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%.
  • treatment can achieve a reduction in the density of an organism by at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 100%.
  • the density of an organism can be measured in a sample taken from a subject, for example, bronchial alveolar lavage, sputum, or serum.
  • the density of an organism can be reduced by at least about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.8, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5 logio CFU/g sputum, or more.
  • Certain embodiments of the methods and compositions described herein can include achieving an improvement in a pulmonary function parameter.
  • a pulmonary function parameter can include FEV (forced expiratory volume), FEV i (forced expiratory volume in 1 second), and/or FEF 25-75 (forced expiratory flow 25-75%).
  • FEV force expiratory volume
  • FEV i force expiratory volume in 1 second
  • FEF 25-75 force expiratory flow 25-75%
  • the FEViof a subject can be increased using the methods and compositions described herein, by at least about 1%, 2%,
  • the FEViof a subject can be increased using the methods and compositions described herein, by at least about 0.01 L, 0.02 L,
  • the FEF 25-75 of a subject can be increased using the methods and compositions described herein, by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%,
  • the FEF 25-75 of a subject can be increased using the methods and compositions described herein, by at least about 0.01 L, 0.02 L, 0.03 L, 0.04 L, and 0.05 L, and by at least about 0.1 L, 0.2 L, 0.3 L, 0.4 L, 0.5 L, 0.6 L, 0.7 L, 0.8 L, 0.9 L, 1.0 L, or more.
  • Certain embodiments of the methods and compositions described herein can include reducing the need for a subject to need other inhaled or systemic antibiotics, such as anti- pseudomonal antimicrobials. Such a reduction can be measured by any suitable method, for example, by the increase in time to need other inhaled or systemic antibiotics. A reduction in such a need can be measured by a variety of statistical means. For example, hazard ratios may be used in a survival analysis. In some embodiments, the hazard ratio is less than about 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, and less.
  • Some embodiments of the methods and compositions described herein can include decreasing the frequency of exacerbations, the severity of exacerbations, the duration of exacerbations, and/or the likelihood that an exacerbation will occur.
  • An exacerbation can be defined by any of several methods and criteria provided by such methods.
  • a patient can concurrently meet at least 4 symptoms/signs of the Fuchs definition of an exacerbation (Fuchs H J, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994; 331:637-642).
  • the symptoms/signs defined by the Fuchs criteria include: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue or lethargy; temperature above 38 °C.; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10% or more from a previously recorded value; and radiographic changes indicative of pulmonary infection.
  • a patient with an improved exacerbation profile can have at least 1, at least 2, at least 3, and at least 4 of the following signs/symptoms, where changes can be relative to a patient's typical experience, for example daily experience, and weekly experience.
  • Change in sputum e.g., for sputum production: patients have no change, a little less or much less amounts of sputum when coughing up, or for change in sputum appearance: for sputum thickness, patients have a little thinner or much thinner sputum; for sputum color, patients have a
  • Malaise, fatigue or lethargy e.g., patients have a little more energy or much more energy, and/or patients perform daily activities, e.g., climbing stairs, a little easier, or much easier.
  • Temperature e.g., patients have normal healthy temperature e.g., about 37 °C., or patients have no recent history of fever.
  • Anorexia or weight loss e.g., patients have no change in weight, or a little weight gain, and/or patients have a little increase in appetite (8)
  • Sinus pain or tenderness e.g., patient has no sinus pain or tenderness, or less sinus pain or tenderness.
  • Change in sinus discharge e.g., patients have better sinus discharge (a decrease in thickness and/or better color).
  • Change in physical examination of the chest e.g., patients have improved signs on examination of the chest and may report for example, a little decrease chest congestion, or a large decrease in chest congestion.
  • Pulmonary function by 10% or more from a previously recorded value e.g., patients have improved pulmonary function in pulmonary function tests.
  • Radiographic changes indicative of pulmonary infection e.g. patients show improved radiographic changes indicating reduced pulmonary infection.
  • exercise tolerance and/or absenteeism from scheduled events can be measured as signs/symptoms of exacerbations.
  • the treatment results in one, two, three, four, five, or six of an increase in a CFQ-R respiratory domain greater than 1; a reduction in the density of bacteria by at least 40%; an increase in FEVi of at least 2%; an increase in FEF 25-75 of at least 5%; a hazard ratio less than 1.0; a dose-normalized serum Cm ax of delafloxacin greater than 2 pg/L/mg; and/or a dose-normalized serum AUC of delafloxacin of at least 20 (ng h/L)/mg.
  • Some embodiments of any of the above methods include administering delafloxacin in combination with a divalent or trivalent cation, or combination thereof, in a dosage amount, administration schedule, and/or method of administration sufficient to achieve the above recited outcomes.
  • Delafloxacin compositions such as those described herein may be particularly effective against bacteria in biofilms; without being bound by theory, it is thought that this is because,
  • a method of treating a human subject with cystic fibrosis who is suffering from a bacterial infection by administering a therapeutically effective amount of an aerosolized delafloxacin composition, such as one of the compositions described herein, e.g., a liquid formulation such as an aqueous formulation, a dry powder formulation, or a liposomal formulation.
  • an aerosolized delafloxacin composition such as one of the compositions described herein, e.g., a liquid formulation such as an aqueous formulation, a dry powder formulation, or a liposomal formulation.
  • Bacteria to be treated, delafloxacin compositions, frequency of dosing, dosage amounts, duration of aerosol administration, concentrations or effects to be achieved, particle size of the aerosols, additional treatment modalities, indications of effective treatment, and the like may be any suitable embodiment, as described above, “Treatment of pulmonary bacterial infections.”
  • the bacterial infection can be any bacterial infection susceptible to treatment with delafloxacin.
  • the bacterial infection is an antibiotic-resistant bacterial infection.
  • the bacterial infection comprises Pseudomonas bacteria, such as is Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, or a combination of two or more thereof.
  • the infection is a Pseudomonas aeruginosa infection.
  • the bacterial infection is a methicillin resistant Staphylococcus aureus (MRSA) infection.
  • the infection is a Streptocossus pneumonia (Sp) infection.
  • the infection comprises one or more Mycobacterium, such as one or more of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, or Mycobacterium leprae, for example Mycobacterium avium or Mycobacterium intracellulare .
  • the bacterial infection comprises Haemophilus influenzae .
  • the bacterial infection comprises Haemophilus parainfluenza.
  • the bacterial infection comprises Moraxella catarrhalis. Other bacteria that can be treated include those described in Treatment of pulmonary bacterial infections”.
  • the aerosol delafloxacin can be administered daily, or twice daily. In certain embodiments, the aerosol delafloxacin can be administered for a period of at least 1 day, 3 days, 5 days, 10 days, 15 days, 20 days, or 30 days. In certain embodiments, the aerosol delafloxacin can be administered for about 14 days. In particular embodiments the
  • aerosol delafloxacin is administered daily for 14 days.
  • the aerosol delafloxacin is delivered for a period of 28 days on, 28 days off.
  • the subject is an adult.
  • the subject is a pediatric patient.
  • the subject has an age less than about 18 years, less than about 17 years, less than about 16 years, less than about 15 years, less than about 14 years, less than about 13 years, less than about 12 years, less than about 11 years, less than about 10 years, less than about 9 years, less than about 8 years, less than about 7 years, less than about 6 years, less than about 5 years, less than about 4 years, less than about 3 years, less than about 2 years, and less than about 1 year.
  • Dosage will generally depend on the age and/or weight of the subject.
  • the subject is an adult and the dosage pre administration is 10-100, 10-200, 20- 100, 20-80, 50-500, 100-450, 200-400, 250-350, 280-320, 290-310, or 300 mg; or 100-600, 200- 500, 300-400, 320-380, 340-360, or 350 mg; or 100-700, 200-600, 300-500, 350-450, 380-420, 390-410, or 400 mg; or 50-600, 100-500, 200-400, 230-270, 240-260, or 250 mg; or 50-400, 100-300, 150-250, 180-220, 190-210, or 200 mg.
  • suitable dosages are as described in “Treatment of pulmonary bacterial infections”
  • the subject is a pediatric patient and the dosage is reduced appropriately, e.g., to less than 90, 80, 70, 60, 50, 40, 30, or 20% of the adult dose.
  • a method for treating a pulmonary infection in a human having cystic fibrosis, wherein the pulmonary infection comprises one or more Mycobacterium comprising administering via inhalation 50-1000, 75-800, 100-500, 100-400, 200-500, 200-400, 250-350, or 300 mg of delafloxacin twice daily for 28 days to the human having cystic fibrosis to treat the Mycobacterium pulmonary infection.
  • the delafloxacin can in an aerosol of a solution comprising delafloxacin at a concentration from about 10, 20, 30, 40, 50, 60, 70, 80, or 90 mg/ml to about 20, 30, 40, 50, 60, 70, 80, 90, 100 orl 10 mg/ml, a magnesium cation at a concentration from about 175 mM to about 225 mM, wherein the solution has a pH from about 5 to about 7, and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg.
  • the delafloxacin composition lacks lactose.
  • a method for treating a chronic pulmonary infection due to Pseudomonas e.g., Pseudomonas aeruginosa in a subject, e.g., human, with cystic fibrosis in need thereof, the method comprising administering to the lungs of the subject with cystic fibrosis an aerosol of a solution comprising 10-500, 20-400, 20-100, 30-300, 30-100, 40-200, 50-200, 70-200, 50-150, 90-110, or 100 mg/ml of delafloxacin to treat the chronic pulmonary infection due to Pseudomonas, e.g., Pseudomonas aeruginosa.
  • the composition further comprises a trivalent or divalent cation, or a combination thereof, e.g., a divalent cation, such as magnesium, for example magnesium at a concentration of
  • the solution has a pH from about 5 to about 7. In certain embodiments the solution has an osmolality of 100-600, 150-550, 200-500, 250-450, 225-425, 250-450, 300-500, 300-450, or 350-400 mOsmol/kg.
  • the goal of this study is to prepare delafloxacin of various chelate salt forms to obtain, e.g., taste-masking properties, AUC shape-enhancing properties through changes in solubility, dissolution and/or bioavailability.
  • These benefits may enhance the pharmacodynamic properties of delafloxacin following pulmonary administration using nanoparticle suspension, dry powder inhalation or simple liquid formulations.
  • These formulations may be optimized to create AUC shape -enhancing formulations of delafloxacin from altered solubility, or slow- release or low bioavailability chelates.
  • a mixture of delafloxacin and a salt of a given cation is solubilized in deionized water and titrated with sodium hydroxide.
  • the titration curve is compared against one obtained for delafloxacin alone to assess formation of delafloxacin-metal complex as described in Physical Pharmacy (4th Edition) by Alfred Martin (pp 261-263).
  • Salts of various metal cations e.g. Ca2+, Mg2+, etc
  • Different molar ratios of cations and delafloxacin are also evaluated.
  • Delafloxacin solutions are titrated against aqueous solutions of selected metal salts. Titrations are carried out at a constant pH. Formation of complexes is monitored by different methods including titrimetry, spectrofluorometry, solubility, etc. as applicable. The end point of the complexation reaction depended on the method adopted.
  • Delafloxacin-metal cation complexes are characterized for stoichiometry, formation constants and dissociation kinetics using appropriate methodology.
  • Titrimetry is performed according to known methods and titrations performed in the presence of metal cations resulted in a positive shift of the titration curves as compared to the one obtained with delafloxacin alone suggesting that additional NaOH (titrant) is required to obtain a specific pH of the solution in the presence of metal cation.
  • the magnitude of the shift in titration curve at any point represents moles of proton released due to complexation and hence moles of complexed delafloxacin.
  • plateau regions are extrapolated to obtain total amount of NaOH required to neutralize the change in pH due to complexation. These values also represent the amounts of delafloxacin in the complexed form (assuming that complexation of delafloxacin results in an equimolar release of protons).
  • the binding constants as well as the stoichiometry of complexation for the delafloxacin complexes with the metal cations are determined as follows:
  • Eq.2 can be modified to obtain, [Ab ound /
  • Solubility This method allows for a relatively simple way of determining the stoichiometry of complexation.
  • the approach involves evaluation of solubility of the drug (delafloxacin) in the presence of increasing concentrations of complexation agent (a given metal cation).
  • the total solubility of the drug (complexed+uncomplexed) is expected to increase linearly owing to complexation and to reach a plateau corresponding to the saturation solubility of both the drug and the complex. Determination of the stoichiometry from such a solubility curve is explained in detail elsewhere (Physical Pharmacy: 4.sup.th Edition by Alfred Martin; pp 265).
  • Protocols are as appropriate for delafloxacin, for example, excess quantities of delafloxacin (amounts are recorded) are agitated, in the presence of increasing concentrations of MgCh, with 25 mM MES buffer (pH 5.99) using a vortex mixer. The samples are then filtered and the filtrate is diluted appropriately and analyzed spectrophotometrically to determine delafloxacin concentrations. The solubility of delafloxacin increases with increasing MgCh concentrations.
  • aerosolized delafloxacin is administered daily with an average dose of 6.92 mg/kg/day to the males and 10.04 mg/kg/day for the females over 4 days using a nose-only aerosol delivery device. Total exposures are 10-30 mg/kg and 30-50 mg/kg for males and females, respectively over the study period. Each dose is delivered over 2 hours daily. The dose for this study is chosen based on the maximum solubility of delafloxacin that could be administered in the device over 2 hours. No clinical signs of toxicity are observed, and all animals survive during the 4 day treatment period.
  • Necropsy of animals after administration of the last dose does not show any findings.
  • animals are randomized to 3 dose levels of aerosolized delafloxacin or saline. Additional recovery groups using the vehicle control and the highest dose are also treated and observed for a 14 day recovery period following the last dose.
  • Average aerosolized delafloxacin doses are 0.5-3, 2-5, and 5-9 mg/kg/day for male rats, and 0.5-3, 3-7, and 9-13 mg/kg/day in female rats.
  • the total exposures over the 28-day treatment period range between 20 and 300 mg/kg for males and 40 and 400 mg/kg for females. Each dose is delivered over 2 hours daily. No dose related clinical signs of toxicity are observed, and all animals survive during the 28 day treatment period.
  • Aerosol administration of fluoroquinolones such as delafloxacin produces high concentrations in the epithelial lining fluid (ELF) of rats and humans. However, this dose has been observed to rapidly decline following administration.
  • EEF epithelial lining fluid
  • PAM 1020 is the parent wild-type strain
  • PAM 1032 contains nalB mutation which results in increased delafloxacin resistance due to overexpression of the MexAB-OprM efflux pump which can extrude delafloxacin out of cells.
  • Other strains include PAM 1032
  • 64 are diluted 1 : 1000 into 100 ml of fresh MHB and grown to O ⁇ boo about.0.3 to reach CFU/ml aboutlO 8 .
  • 10 ml of this culture was moved to 50 ml flasks, each containing 10 ml of pre-warmed MHB broth with appropriate concentrations of delafloxacin (2x as compared to the exposure concentrations). All strains are treated for 10 min., 20 min., 40 min., 80 min. and 160 minutes.
  • concentrations of delafloxacin are used for the exposure of PAM 1020 and PAM1032: 1—20 (e.g.,16,) 20-40 (e.g., 32), 40-75 (e.g.,64), 100-150 (e.g.,128( and 220-320 (e.g., 256). All strains are treated at each concentration for 10 min., 20 min., 40 min., 80 min. and 160 minutes. At appropriate times, 1 ml of each exposure culture is centrifuged for 2 minutes, the pellet is washed twice with 1 ml of drug-free MHB, and re-suspended in 1 ml of MHB.
  • the viable cell numbers are enumerated by plating serially diluted samples (in duplicates) on MHB plates by the drop (10 ul) plating method. Killing is reported as the log reduction calculated relative to cell count at the time of initiation of antibiotic exposure. Relative antibiotic concentrations (relative to MIC of the corresponding strains) are used. For every strain at each concentration , maximum killing (e.g., 5.5 log decrease in viable cell counts) can be achieved at one or more time points and one or more concentrations. These results inducate that logarithmic cells of P. aeruginosa are efficiently killed after short duration exposures to high concentrations of delafloxacin.
  • delafloxacin 400-600 (e.g., 512) ug/ml, 50-200 (e.g.,128) ug/ml, 20-40 (e.g., 32) ug/ml, 4-13, (e.g., 8) ug/ml, 1-3 (e.g., 2) ug/ml, and 0.1-1 (e.g., 0.5) ug/ml) are added.
  • 10 ul of each treatment culture is diluted 100-fold in MHB to minimize the carryover of delafloxacin. Viable cell numbers are enumerated by plating serially diluted samples on MHB plates by the drop (10 ul) plating method.
  • the limit of detection is 10 4 CFU/ml. Killing is reported as the percentage of the starting inoculum survived after the delafloxacin treatment. The results indicate that while sputum slightly affected the degree of killing by delafloxacin, rapid and extensive (up to five orders of magnitude) killing by delafloxacin in sputum was still observed after short duration of treatment at high concentrations of antibiotic.
  • tubes are vigorously vortexed (A) or sonicated and vortexed (B) to detach cells.
  • 1 ml of each exposure culture is centrifuged for 2 minutes, the pellet is washed twice with 1 ml of drug-free MHB, and re-suspended in 1 ml of MHB.
  • the viable cell numbers are enumerated by plating serially diluted samples on MHB plates by the drop (10 ul) plating method. Maximum killing (.about.2 logs) is obtained after 10 min with the lowest concentration of delafloxacin tested. No additional killing is observed at the higher delafloxacin concentration.
  • the in vitro pharmacodynamic model consists of a central (analogous "serum" compartment) and peripheral ("extravascular") compartment.
  • the peripheral compartments consist of artificial capillary units arranged in series with the central compartment. Each capillary unit has a bundle of small semi-permeable fibers with a molecular size retention of ca.
  • Samples (0.3 ml) are collected from peripheral compartments at various intervals for determination of drug and bacterial concentrations. Samples are collected from the peripheral compartments and assayed for drug concentrations by HPLC. Test strains are Pseudomonas aeruginosa PAM 1032 and PAM 1582. Strains are grown aerobically overnight in Mueller-Hinton Broth (MHB) at 35° C. and subcultured to fresh MHB and reincubated at 35°
  • the inoculum is further diluted 1: 1000 to a final concentration of approx. TOxlO 6 CFU/ml.
  • 2.3 ml is injected into each peripheral chamber of the hollow-fiber bioreacters.
  • the half-life of delafloxacin was adjusted to be 10 minutes to be equivalent to that observed following aerosol delivery of delafloxacin to the pulmonary compartment of man.
  • the targeted Cmax was 1000 and 600 ug/ml over two experiments. As targeted, the model exhibits a delafloxacin half-life of 10 minutes and a Cmax of 1000 ug/ml in one experiment.
  • Experiment 6 is modified to achieve the same half-life as the first experiment, but with a targeted Cmax of 600 ug/ml.
  • the bactericidal effects of these two regimens correlated with the Cmax.
  • the maximum bactericidal effect is observed as a 5 log reduction in bacterial counts within 10 minutes with PAM 1032 and a 4 log reduction in bacterial counts within 20 minutes with PAM 1582 and no re-growth observed over the remaining 2 hours of the experiment.
  • the Cmax of 600 ug/ml used in the second experiment maintains the 5 -log reduction in
  • Delafloxacin can produce up to a 99.9999% bacterial reduction with a Cmax of both 600 and 1000 ug/ml against a strain with an MIC of 1 ug/ml. ug/ml).
  • a Phase lb single-blind, placebo-control, dose-escalating multicenter study is carried out to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of aerosolized delafloxacin administered to stable CF patients. All patients have had P. aeruginosa cultured from sputum within the previous 24 months and at the screening visit. Study drug is administered twice daily for up to 14 days at three doses by aerosol using a PARI eflow device. Respirable delivered doses (RDD) are approximately 40 mg, 80 mg, and 120 mg per treatment, corresponding to loaded doses of 78 mg, 175 mg, and 260 mg, respectively. Thus, the estimated total daily RDDs are 80 mg, 160 mg, and 240 mg. Study drugs are administered at 30 mg/ml (for 40 mg dose) or 50 mg/ml (for 80 mg and 120 mg doses).
  • RDD Respirable delivered doses
  • a Phase 1 multicenter, open-label study is carried out to evaluate the safety, tolerability and pharmacokinetics of weight-adjusted doses of delafloxacin formulated with MgCh administered once daily for 14 days to stable pediatric CF patients.
  • Patients are divided into 2 groups based on their age: 6-11 years of age and 12-16 years of age.
  • the daily dose administered of delafloxacin formulated with MgCh is divided as follows: patients that weighed 14-21 kg receive a 120 mg dose, patients that weighed 22-30 kg receive a 180 mg dose, and patients that weighed more than 30 kg receive a 240 mg dose.
  • a total of 27 patients are enrolled
  • embodiment 1 provided herein is a pharmaceutical composition comprising delafloxacin or a salt, ester, prodrug, or conjugate thereof, wherein the composition is suitable for inhalation into a lung.
  • embodiment 2 provided herein is the composition of embodiment 1 wherein the delafloxacin or salt, ester, prodrug, or conjugate thereof is in aqueous solution.
  • embodiment 3 provided herein is the composition of embodiment 1 or 2 further comprising a divalent or trivalent cation.
  • embodiment 4 provided herein is the composition of embodiment 3 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof.
  • composition of embodiment 4 further comprising a counterion wherein the counterion comprises chloride.
  • the divalent or trivalent cation is magnesium.
  • embodiment 7 provided herein is the composition of embodiment 6 wherein the magnesium is in the form of magnesium chloride.
  • embodiment 8 provided herein is the composition of embodiment 5 or embodiment 7 comprising a chloride concentration from about 25 mM to about 400 mM.
  • embodiment 9 provided herein is the composition of embodiment 7, wherein the magnesium chloride has a concentration from about 100 mM to about 250 mM.
  • the magnesium chloride has a concentration from about 125 mM to about 250 mM.
  • composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 10 mg/ml.
  • composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 25 mg/ml.
  • embodiment 13 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 35 mg/ml.
  • composition of embodiment 1 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 50 mg/ml.
  • embodiment 16 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of
  • composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof from about 100 mM to about 625 mM.
  • composition of any one of embodiments 2 through 17 wherein the solution has an osmolality from about 200 mOsmol/kg to about 1250 mOsmol/kg.
  • any one of embodiments 2 through 17 wherein the solution has an osmolality from about 250 mOsmol/kg to about 1050 mOsmol/kg.
  • the composition of any one of embodiments 2 through 17 wherein the solution has an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the composition of any one of embodiments 2 through 20 wherein the solution has a pH from about 4.5 to about 7.5.
  • the composition of any one of embodiments 2 through 20 wherein the solution has a pH from about 5 to about 6.5.
  • embodiment 24 provided herein is the composition of embodiment 1 wherein the delafloxacin or salt, ester, prodrug, or conjugate thereof is in solid form.
  • embodiment 25 provided herein is the composition of embodiment 24 further comprising a divalent or trivalent cation.
  • embodiment 26 provided herein is the composition of embodiment 25 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof.
  • embodiment 27 provided herein is the composition of embodiment 24 or 25 comprising a counterion, wherein the counterion comprises chloride.
  • embodiment 28 provided herein is the composition of any one of embodiments 24 through 27 wherein the divalent or trivalent cation is magnesium.
  • embodiment 29 provided herein is the composition of embodiment 28 wherein the magnesium is in the form of magnesium chloride
  • embodiment 30 provided herein is a sterile, single use container, comprising the composition of any previous embodiment.
  • embodiment 31 provided herein is the container of embodiment 30 comprising from about 20 mg to about 400 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof.
  • embodiment 32 provided herein is the container of embodiment 30 comprising from about 28 mg to about 280 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof.
  • embodiment 33 provided herein is the container of embodiment 30 wherein the composition comprising delafloxacin or a salt, ester, prodrug, or conjugate thereof, and the single use container comprises from about 1 ml to about 5 ml of the composition.
  • embodiment 34 provided herein is the composition of any one of embodiments 30 through 33 comprising at least 100 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof.
  • composition of any one of embodiments 30 through 33 comprising at least 400 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof
  • embodiment 36 provided herein is a method of treating a bacterial lung infection in a subject, comprising administering delafloxacin or a salt, ester, prodrug, or conjugate thereof in a form suitable for inhalation, to a lung of the subject.
  • embodiment 37 provided herein is the method of embodiment 36 wherein the delafloxacin or a salt, ester, prodrug, or conjugate thereof is delivered as an aerosol of a solution comprising delafloxacin.
  • embodiment 38 provided herein is the method of embodiment 36 wherein the delafloxacin or a salt, ester, prodrug, or conjugate thereof is delivered as an aerosol of a solid comprising delafloxacin
  • embodiment 39 provided herein is the method of embodiment 37 or 38 wherein the solution or solid further comprises a divalent or trivalent cation.
  • embodiment 40 provided herein is the method of embodiment 39 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof.
  • embodiment 41 provided herein is the method of embodiment 39 or 40 wherein the solution or solid further comprises a counterion wherein the counterion comprises chloride.
  • embodiment 42 provided herein is the method of embodiment 40 or 41 wherein the divalent or trivalent cation is magnesium.
  • embodiment 43 provided herein is the method of any one of embodiments 36 through 42 delivered as solution wherein the solution comprises delafloxacin or a salt, ester, prodrug, or conjugate thereof at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • any one of embodiments 36 through 42 wherein the lung infection is caused by one or more of the following bacteria: Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrohacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterohacter cloacae, Enterohacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Pro
  • any one of embodiments 36 through 42 wherein the lung infection is caused by one or more of the following bacteria: Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Haemophilus influenzae, Burkholderia cepacia, and Moraxella.
  • the lung infection is caused by a Burkholderia bacteria.
  • embodiment 47 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is associated with a bacterial pneumonia.
  • embodiment 48 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by a gram-negative anaerobic bacteria.
  • any one of embodiments 36 through 42 wherein the lung infection is caused by one or more of the bacteria selected from the group consisting of Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.
  • the lung infection is caused by a gram-positive bacteria.
  • the lung infection is caused by one or more of the bacteria selected from the group consisting of Corynebacterium diphtherias,
  • Streptococcus pneumoniae Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus milleri; Streptococcus (Group G); Streptococcus (Group C/F); Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp.
  • any one of embodiments 36 through 42 wherein the lung infection is caused by a gram-positive anaerobic bacteria.
  • the lung infection is caused by one or more bacteria selected from the group consisting of Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum.
  • the lung infection is caused by an acid-fast bacteria.
  • embodiment 55 is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by a Mycobacterium bacteria.
  • embodiment 56 provided herein is the method of embodiment 54 wherein the lung infection is caused by one or more bacteria selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare , and
  • any one of embodiments 36 through 42 wherein the lung infection is caused by an atypical bacteria.
  • the lung infection is caused by one or more bacteria selected from the group consisting of Chlamydia pneumoniae and Mycoplasma pneumoniae.
  • the lung infection is caused by an atypical bacteria.
  • the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.
  • any one of embodiments 36 through 59 wherein the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
  • the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
  • the method of any one of embodiments 36 through 59 comprising producing the aerosol with a vibrating mesh nebulizer.
  • embodiment 64 provided herein is the method of embodiment 63 wherein the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.
  • embodiment 65 provided herein is the method of embodiment 63 wherein the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
  • embodiment 66 provided herein is the method of embodiment 63 wherein the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
  • embodiment 67 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 20 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
  • embodiment 68 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 100 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
  • embodiment 69 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 125 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
  • embodiment 70 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 150 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
  • embodiment 71 provided herein is the method of any one of embodiments 36 through 70 wherein
  • the aerosol is administered to the lung in less than about 45 minutes.
  • embodiment 72 provided herein is the method of any one of embodiments 36 through 70 wherein the aerosol is administered to the lung in less than about 30 minutes.
  • embodiment 73 provided herein is the method of any one of embodiments 36 through 70 wherein the aerosol is administered to the lung in less than about 10 minutes.
  • embodiment 74 provided herein is the method of any one of embodiments 36 through 70 wherein the aerosol is administered to the lung in less than about 5 minutes.
  • embodiment 75 provided herein is the method of any one of embodiments 36 through 74 further comprising the step of alternating the administration of said aerosol with administration of a second inhaled antimicrobial.
  • embodiment 76 provided herein is the method of embodiment 75 wherein the second inhaled antimicrobial is an aminoglycoside.
  • embodiment 77 provided herein is the method of embodiment 76 wherein the aminoglycoside is tobramycin.
  • embodiment 78 provided herein is the method of embodiment 75 wherein the second inhaled antimicrobial is a polymyxin.
  • embodiment 79 provided herein is the method of embodiment 78 wherein the polymyxin is colistin.
  • embodiment 80 provided herein is the method of embodiment 75 wherein the second inhaled antimicrobial is a monobactam.
  • embodiment 81 provided herein is the method of embodiment 80 wherein the monobactam is aztreonam.
  • embodiment 82 provided herein is the method of any one of embodiments 36 through 81 comprising administering the aerosol once daily.
  • embodiment 83 provided herein is the method of any one of embodiments 36 through 81 comprising administering the aerosol twice daily.
  • embodiment 84 provided herein is the method of any one of embodiments 36 through 83 wherein the bacterial infection is tuberculosis.
  • embodiment 85 provided herein is the method of any one of embodiments 36 through 83 wherein the subject suffers from cystic fibrosis (CF) and the bacterial infection is a bacterial infection associated with CF.
  • embodiment 86 provided herein is the method of embodiment 85 wherein the infection comprises a Pseudomonas aeruginosa infection.
  • embodiment 87 provided herein is the method of any one of embodiments 84 through 86 further comprising administering an adjunct therapy in conjunction with the delafloxacin or a salt, ester, prodrug, or conjugate thereof.
  • an aerosol dose of a delafloxacin and magnesium solution comprising (i) a concentration of delafloxacin greater than 50 mg/ml and (ii) a taste-masking concentration of a divalent or trivalent cation, wherein the aerosol comprises of a mist having a mean particle size of between 2 and 5 microns or a particle size geometric standard deviation of less than or equal to 2 microns.
  • the aerosol dose of embodiment 91 wherein the divalent or trivalent cation comprises magnesium ion.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

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Abstract

Provided herein are methods and compositions related to the preparation and use of inhaled delafloxacin. Included are pharmaceutical compositions, such as liquid formulations, dry powder formulations, and liposomal formulations, and methods, such as methods of treating pulmonary bacterial infections.

Description

PHARMACEUTICAL COMPOSITION COMPRISING DELAFLOXACIN FOR
ADMINISTRATION INTO THE LUNG
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No. 63/186,699, filed May 10, 2021, which application is incorporated herein by reference.
5 BACKGROUND
[0002] A relatively new member of the fluoroquinolone family, delafloxacin, has recently been approved and shows effectiveness against Gram-negative bacteria, and also has activity against some Gram-positive bacteria. Though it has been approved for limited use in the United States and Europe, inhalable forms are not currently available. Because respiratory diseases are 10 common and cause suffering, premature death, and economic consequences, and because inhalation therapy for such diseases has many advantages over systemic administration, it is desirable to provide compositions and methods directed to inhalable forms of delafloxacin, and treatments using inhalation therapy of delafloxacin and its derivatives, including salts, esters, prodrugs and conjugates.
15 INCORPORATION BY REFERENCE
[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
20 [0004] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
25 [0005] Figure 1 shows delafloxacin structure
DETAILED DESCRIPTION
[0006] Provided herein are compositions and methods related to inhalation therapy with delafloxacin, e.g., for treatment of respiratory infections. In particular, compositions suitable for inhalation of delafloxacin, including liquid compositions, liposomal compositions, and dry 30 powder compositions are provided. In addition, methods of treatment of respiratory infections
1 by inhalation therapy with delafloxacin are provided. Also provided are kits, dosage form, systems, and other compositions and methods associated with providing delafloxacin for inhalation. Similar compositions and methods may be used for other fluoroquinolones sharing physicochemical properties with delafloxacin, e.g., alcohol functionality and no basic amine, such as levonadifloxacin, and it is understood that the following description, while in terms of delafloxacin, applies to levonadifloxacin, as well.
Delafloxacin
[0007] Delafloxacin, also known as ABT-492, RX-3341, and WQ-3034 while it was under development, is a fluoroquinolone antibiotic with a structure shown in Figure 1. Details on the structure, preparation, and action of delafloxacin may be found in US Patent Nos. RE46,617; 7,728,143; 8,252,813; 8,273,892; 10,329,276; and 8,648,093. Delafloxacin is more active than other quinolones against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In addition, in contrast to most approved fluoroquinolones, which are zwitterionic, delafloxacin, devoid of easily protonable amine, has an anionic character, which results in a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH. It is potentially more effective than cationic inhalatory antibacterials such as levofloxacin or tobramycin. This property is believed to confer to delafloxacin an advantage for the eradication of S. aureus acidic environments, including intracellular infections and biofilms. In addition, delafloxacin is also active against Gram negative bacteria, e.g., delafloxacin has similar or slightly better activity against P. aeruginosa compared to ciprofloxacin and levofloxacin.
[0008] Unless indicated otherwise, or clear from context, as used herein, the term “delafloxacin” includes all forms of delafloxacin suitable for formulation into a composition suitable for delivery by inhalation, including salts, esters, prodrugs, conjugates, and other pharmaceutically acceptable forms, as known in the art. Particular forms are specified or clear from context. In certain embodiments, delafloxacin is present with a counterion that is an amine counterion, such as meglumine, arginine, ornithine, lysine, trientine, or an aminoglycoside such as tobramycin or amikacin; it will be appreciated that when the counterion is an aminoglycoside antibiotic, this component can also have antibacterial activity in the composition.
Conditions
[0009] The methods and compositions provided herein are useful in treating conditions in a subject suffering from the condition, for which inhalation therapy with delafloxacin is effective. For example, pulmonary infections may be treated by administration of delafloxacin, generally at high concentrations directly to the site of infection without incurring large systemic concentrations of delafloxacin. Accordingly, some embodiments disclosed herein are methods
2 for delivering delafloxacin drug compositions to treat pulmonary bacterial infections. Such infections are common in certain disorders, such as cystic fibrosis and chronic obstructive pulmonary disease, chronic bronchitis, and some asthmas.
[0010] A “subject,” as that term is used herein, includes animals that can suffer from a pulmonary condition, e.g., infection; in particular, the subject can be a mammal, wherein that term is used in its ordinary biological sense, and includes, without limitation, humans, cattle, horses, dogs, and cats. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human with cystic fibrosis. In certain embodiments, the subject is a human with pneumonia, a chronic obstructive pulmonary disease, or sinusitis, or a human being mechanically ventilated.
[0011] Thus, methods and compositions provided herein can be used to treat pulmonary infections, in certain embodiments, a pulmonary infection associated with on or more disorders. Examples of such disorders can include cystic fibrosis, pneumonia, and chronic obstructive pulmonary disease, including chronic bronchitis, and some asthmas.
[0012] Because direct administration to lungs and upper airways via inhalation can lead to a high local concentration of delafloxacin without a high systemic concentration, methods and compositions provided herein can be especially appropriate for the treatment of pulmonary infections and disorders that include microbial strains that can be difficult to treat using parenterally administered antimicrobial, e.g., either because of the need for high parenteral dose levels, leading to undesirable side effects, or because of lack of any clinically effective antimicrobial agents. For example, inhaled administration of delafloxacin directly to the site of infection can reduce systemic exposure and can maximize the amount of delafloxacin to the site of microbial infection. Such methods can be appropriate for treating infections involving microbes that are susceptible to delafloxacin, e.g., as a way of reducing the frequency of selection of resistant microbes.
[0013] In some embodiments, the aerosol delafloxacin in an appropriate formulation is administered in an amount sufficient to overcome the emergent resistance in bacteria or increase killing efficiency such that resistance does not have the opportunity to develop.
Pharmaceutical compositions
[0014] Provided herein are pharmaceutical compositions comprising delafloxacin, or a salt, ester, prodrug, or conjugate thereof, or other pharmaceutically acceptable form thereof, in a form suitable for inhalation therapy, which includes any suitable method for delivering the composition to the middle and lower airways and the lungs. Thus, the composition is suitable for
3 administration by an inhaler, by a ventilation apparatus, or by any other suitable means for introducing the composition into the airways and lungs of a subject. In certain embodiments, delafloxacin is produced as a pharmaceutical composition suitable for aerosol formation, acceptable taste, storage stability, and patient safety and tolerability.
[0015] Delafloxacin compositions as described herein are administered as an aerosol, e.g., to a site of infection in the respiratory tract. In certain embodiments, aerosol delivery is used to treat an infection in the lungs. An “aerosol,” as that term is used herein, includes a suspension of particles, which may comprise liquid, solid, liposomes, or a combination thereof, dispersed in air or gas.
[0016] Several device technologies exist to deliver either dry powder or liquid aerosolized products. Dry powder formulations generally require less time for drug administration, while liquid formulations generally have longer administration times.
[0017] Accordingly, in one embodiment, a particular formulation of fluoroquinolone antimicrobial agent disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for maximum drug deposition at a site of infection and maximal tolerability. Factors that can be optimized include solution or solid particle formulation, rate of delivery, and particle size and distribution produced by the aerosolizing device.
[0018] Any form of delafloxacin that is suitable for administration by inhalation may be used. Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., powders, liquids, suspensions, complexations, liposomes, particulates, or the like. In certain embodiments, the composition is a solid composition suitable for dry powder aerosol formation and inhalation. In certain embodiments, the composition is a liquid composition suitable for liquid aerosol formation and inhalation, e.g., a suspension or solution. In certain embodiments, the composition is a liposomal composition. In certain embodiments, a complex of delafloxacin with a suitable divalent or trivalent cation, e.g., magnesium, can be used as is in a dry formulation, or in combination with additional agents, e.g., agents to provide ease of handling, such as bulking agents, as known in the art.
[0019] Delafloxacin can be administered either alone, as a pre-formed complex with di- or trivalent metal ion, or in combination with a suitable pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like) and/or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). In certain embodiments, the
4 formulation can lack a conventional pharmaceutical carrier, excipient or the like. Certain embodiments include a formulation lacking lactose. Certain embodiments comprise lactose at a concentration less than about 10%, 5%, 1%, or 0.1%. Generally, depending on the intended mode of administration, the pharmaceutical formulation will contain about 0.005% to 95%, such as about 0.5% to 50%, for example 5 to 40% by weight of delafloxacin or a salt, ester, or prodrug thereof. In certain embodiments, the pharmaceutical formulation comprises delafloxacin and a divalent or trivalent metal ion, such as magnesium.
[0020] In certain embodiemnts, a pharmaceutical formulation includes a prodrug or conjugate of delafloxacin. It will be appreciated that a conjugate of delafloxacin includes a composition in which delafloxacin is linked, e.g., covalently linked, to another compound; a prodrug is a modified form of delafloxacin that requires further treatment, e.g., cleavage at one or more points, to release active drug, e.g., active delafloxacin. Some conjugates are also prodrugs. Exemplary conjugates and prodrugs include phosphate derivatives, where a phosphate can be linked to a suitable group on the delafloxacin, e.g., at a carboxyl, an amine, or a hydroxyl; such phosphates are readily cleaved by a variety of phosphatases that are ubiquitous in bodily tissues. In the case of a phosphate linked to the active carboxyl, such a conjugate is a prodrug in that the phosphate must be released for the delafloxacin to exhibit maximum activity. Other suitable conjugates and prodrugs are described in PCT Publication No. W 02022031761. The use of such prodrugs or conjugates can be useful in increasing residence time of delafloxacin in, e.g., lung spaces to which it delivered, e.g., decrease absorption into systemic circulation. For example, some conjugates/prodrues, such as phosphate conjugates/prodrugs, which are highly charged, are less likely to cross cell membranes. Alternatively or additionally, release of active delafloxacin from a prodrug can allow for more prolonged maintenance of effective levels in the desired area of activity, e.g., lung spaces to which it is delivered.
Liquid formulations
[0021] Liquid compositions suitable for administration by inhalation can be prepared by dissolving, dispersing, etc. delafloxacin and optional pharmaceutical adjuvants in a liquid carrier, such as water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like, to form a solution or suspension. Solutions to be aerosolized can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to aerosol production and inhalation. The percentage of delafloxacin contained in such aerosol compositions can be, e.g., 0.01% to 90% in solution, or higher if the composition is a solid, which will be subsequently diluted to the above percentages. In certain embodiments, the composition comprises 1.0%-50.0% of delafloxacin in solution.
5 [0022] A liquid formulation, e.g., aqueous formulation, suitable for administration by inhalation can have a delafloxacin concentration of at least 5, 10, 12, 15, 17, 20, 22, 25, 30, 40,
50, 60, 70, 80, 90, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250,
300, 400, 500, or 600 mg/ml, and/or not more than 10, 12, 15, 17, 20, 22, 25, 30, 40, 50, 60, 70, 80, 90, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 400, 500, 600 or 700 mg/ml. In certain embodiments, the formulation has a delafloxacin concentration of 10-200 mg/ml, or 10-100 mg/ml, or 20-50 mg/ml, or 20-40 mg/ml, or 50-200 mg/ml, or 75-150 mg/ml, or 80-125 mg/ml, or 80-120 mg/ml, or 90-125 mg/ml, or 90-120 mg/ml, or 90-110 mg/ml preferably 10-200 mg/ml, more preferably 20-50 mg/ml , even more 50-200 mg/ml, still more preferably 75-150 mg/ml, yet more preferably 80-120 mg/ml. In certain embodiments, delafloxacin is present at a concentration of 20-1000, 50-800, 50-750, 50-700, 50-675, 50-650, 50-600, 50-500, 50-400, 50-300, 50-200, 50-100, 75-800, 75-750, 75-700, 75-675, 75-650, 75- 600, 75-500, 75-400, 75-300, 75-200, 75-100, 100-800, 100-750, 100-700, 100-675, 100-650,
100-600, 100-500, 100-400, 100-300, or 100-200 mM, preferably 100-625 mM, more preferably 100-500 mM, even more preferably 100-300 mM.
[0023] A liquid formulation, e.g., aqueous formulation, suitable for administration by inhalation can have any suitable osmolarity, such as 200-1250, 300-500, 325-450, 350-425, or 350-400 mOsmol/kg. In certain embodiments, the osmolality of the formulation is greater than about 300, 325, 350, 375, 400, 425, 450, 475, or 500 mOsmol/kg. In certain embodiments solution osmolality is 100-600 mOsmol/kg. In preferred embodiments, the solution osmolality is 200-1250 mOsmol/kg; in more preferred embodiments 250-1050 mOsmol/kg; in stil more preferred embodiments 350-750 mOsmol/kg. The osmolality of aqueous solutions of delafloxacin is adjusted by any suitable method, e.g., by providing excipients. Many patients have increased sensitivity to various chemical agents and have high incidence of bronchospastic, asthmatic or other coughing incidents. Their airways are particularly sensitive to hypotonic or hypertonic and acidic or alkaline conditions and to the presence of any permanent ion, such as chloride. Any imbalance in these conditions or a presence of chloride above certain value leads to bronchospastic or inflammatory events and/or cough which greatly impair treatment with inhalable formulations. Both these conditions prevent efficient delivery of aerosolized drugs into the endobronchial space. In some cases, a certain amount of chloride or another anion is needed for successful and efficacious delivery of aerosolized delafloxacin. In preferred embodiments, the chloride concentration is 30-300 mM, more preferably 50-150 mM. Bromide or iodide anions may, in some cases, be substituted for chloride; in some cases, bicarbonate ion may be substituted for chloride.
6 [0024] In certain embodiments, permeant ion concentration is 25-400 mM, or 30-300 mM; or 40-200 mM; or 50-150 mM. In certain embodiments, delafloxacin pharmaceutical compositions suitable for administration by inhalation are formulated to have good taste, pH of 5.5-7, osmolarity of 200-1250 mOsmol/kg, and permeant ion concentration of 30-300 mM.
[0025] In certain embodiments, the solution or diluent used for preparation of an aerosol formulation has a pH high enough that it does not cause bronchospasm and low enough that it has tolerability in body tissues unable to buffer alkaline aerosols and also does not cause bronchospasm, e.g., a pH of at least 4, 4.2, 4.5, 4.7, 5, 5.2, 5.5, 5.7, 6, 6.2, 6.5, 6.7, 7.0, 7.2, 7.5, or 7.7, and/or not more than 4.2, 4.5, 4.7, 5, 5.2, 5.5, 5.7, 6, 6.2, 6.5, 6.7, 7, 7.2, 7.5, 7.7, or 8. Exemplary suitable pH ranges include 4.5-7.5, or 5.5-7.5, preferably 5.0-7.5, more preferably 5.0-7.0, even more preferably 5.5-7.0. Other possible pH ranges include, for example 4.5-8.5,
5.0-8.0, 5.0-6.5, 5.5-6.5, or 6.0 to about 6.5. In order to regulate pH, a pharmaceutical composition may include a buffer or a pH adjusting agent, such as a salt prepared from an organic acid or base. Exemplary buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine, hydrochloride, or phosphate buffers.
[0026] In certain embodiments, a pharmaceutical composition suitable for administration by inhalation can include a divalent or trivalent cation, or a combination thereof. The divalent or trivalent cation can be one or more of, magnesium, calcium, zinc, copper, aluminum, and/or iron, or a combination thereof. In certain embodiments, the composition, e.g., a solution, comprises magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride. In certain embodiments, the divalent or trivalent cation (or combination) concentration is from about 25- 400, or 50-400, or 100-300, preferably 100-250, more preferably 125-250, still more preferably 150-250, yet more preferably 175-225, or even more preferably 190-200 mM. In certain embodiments, the magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride has a concentration of 5-25%, 10-20%, or 15-20%. In certain embodiments, the ratio of delafloxacin to divalent or trivalent cation (or combination) is 1 : 1 to 2: 1 or 1 : 1 to 1 :2. In certain embodiments, the ion is magnesium, for example, magnesium supplied by magnesium chloride.
[0027] In certain embodiments, aqueous formulations containing soluble or nanoparticulate delafloxacin particles are provided. For aqueous aerosol formulations, delafloxacin may be present at a concentration of about 1 mg/mL up to about 700 mg/mL. Such formulations provide effective delivery to appropriate areas of the lung, with the more concentrated aerosol formulations having the additional advantage of enabling large quantities of drug substance to be delivered to the lung in a very short period of time. In certain embodiments, a formulation is
7 optimized to provide a well tolerated formulation, e.g., a formulation with acceptable safety profile and acceptable taste. In certain embodiments, provided is an aqueous pharmaceutical solution of delafloxacin formulated to have good taste, pH of 5.5-7, osmolarity of 200-1250 mOsmol/kg, permeant ion concentration of 30-300 mM. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 5-500, 10-200, 20-500, 50-450, or 100-400 mg delafloxacin, such as at least or about 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin, in some cases in a volume of preferably 0.5-10, more preferably 0.5-5, still more preferably 1-10, even more preferably 1-5 ml. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
[0028] In certain embodiments, provided is an aqueous pharmaceutical solution comprising 5-80, 10-70, 20-60, 20-50, 20-40, 30-100, 40-100, preferably 50-120, more preferably 60-120, even more preferably 80-120, still more preferably 90-110, e.g. 100 mg/ml, of delafloxacin and preferably 160-240, more preferably 175-225, even more preferably 190-210, e.g. 200 mM, of a cation. In certain embodiments, the cation is magnesium, calcium, zinc, copper, aluminum, or iron, or a combination thereof. In preferred embodiments, the cation is magnesium, such as magnesium supplied by magnesium chloride or magnesium sulfate. In certain embodiments, the osmolarity is 200-700, preferably 300-500, more preferably 350-400 mOsmol/kg. In certain embodiments the solution comprises a dose of delafloxacin of 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290,
300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 5-200, 10-100, 10-60, 20-500, 50-450, or 100-400 mg delafloxacin, such as at least or about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330,
340, 350, 360, 370, 380, 390, or 400 mg delafloxacin, for example in 0.5-10, 0.5-5, 1-10, or 1-5 ml. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
[0029] In certain embodiments, provided is an aqueous pharmaceutical solution comprising 20-40, e.g., 30 mg/ml, or 40-60, e.g., 50 mg/ml, or 60-80, e.g., 70 mg/ml, or 80-100, e.g., 90 mg/ml, or 90-110, e.g., 100 mg/ml of delafloxacin and 190-210, e.g., 200 mM of a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate. In certain embodiments, the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg. In certain embodiments the solution comprises a dose of delafloxacin of 10, 20, 30,
8 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 20-500, 50-450, or 100- 400 mg delafloxacin, such as at least or about 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin, for example in 0.5-10, 0.5-5, 1-10, or 1-5 ml. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
[0030] In certain embodiments, provided is a pharmaceutical composition, comprising an aqueous solution of delafloxacin and a divalent or trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung. In certain embodiments, the cation is a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate. In certain embodiments, the concentration of chloride is 25-400, 100-250, or 125-250 mM. In certain embodiments the divalent or trivalent cation, or combination thereof, is selected from one or more of calcium, aluminum, zinc, and iron, or a combination thereof. In certain embodiments, the concentration of delafloxacin is at least 5, 10, 25, 35, 40, 50, 60, 70, 80, 90, or 100 mg/ml. In certain embodiments, the concentration of delafloxacin is 5-80, 10-70, 20-60, 20-50, 20-40, 80- 120, 5-200, 10-100, 10-60, 50-800, 75-700, 100-650, or 150-500 mM. In certain embodiments, the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg. In certain embodiments, the solution has a pH of 4.5-8, 4.5-7.5, 4.5-6, 5-6.5, or 5.5-6.5. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 20-500, 50-450, or 100-400 mg delafloxacin, such as at least or about 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg delafloxacin, for example in 0.5-10, 0.5-5, 1-10, or 1-5 ml. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer.
[0031] In certain embodiments, provided is an aerosol of a solution comprising delafloxacin and a divalent or trivalent cation, or a combination thereof. In certain embodiments, the cation is a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate. In certain embodiments, the concentration of chloride is 25-400, 100-250, or 125-250 mM. In certain embodiments the divalent or trivalent cation is selected from one or more of calcium, aluminum, zinc, and iron, or a combination thereof. In certain embodiments, the concentration of delafloxacin is at least 1, 5, 7, 10, 12, 15, 20, 25, 3035, 40, 50, 60, 70, 80, 90, or 100 mg/ml.
In certain embodiments, the concentration of delafloxacin is 10-600, 50-800, 75-700, 100-650, or
9 150-500 mM. In certain embodiments, the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg. In certain embodiments, the solution has a pH of 4.5-8, 4.5- 7.5, 4.5-6, 5-6.5, or 5.5-6.5. In certain embodiments the solution comprises greater than 20, 30, 40, or 50 mg/ml delafloxacin and magnesium chloride, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. In certain embodiments the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to 2.5 microns. In certain of these embodiments the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. In certain embodiments the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to 2 microns. In certain of these embodiments the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. In certain embodiments the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to 1.8 microns. In certain of these embodiments the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg
[0032] In certain embodiments provided herein is an aerosol dose of a delafloxacin and magnesium solution comprised of a concentration of delafloxacin greater than 20, 30, 40, or 50 mg/ml and a taste-masking concentration of magnesium wherein the aerosol is comprised of a mist having a mean particle size of between 2 and 5 microns or a particle size geometric standard deviation of less than or equal to 2 microns. In certain embodiments, the magnesium concentration is 100-250 mM. In certain embodiments the pH of the aerosol is 4.5-8, 4.5-7.5, 4.5-6, 5-6.5, 5.5-7.5 or 5.5-6.5. In certain embodiments a quantity of the mist contains at least 0.1, 0.5, 0.7, 1, 1.5, 2, 5, 7, 10, 20, 50, 70, or 100 mg of delafloxacin. In certain embodiments, the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg. In certain embodiments, the permeant ion concentration is 100-500, 100-450, 200-500, 200-450, 300-500, 300-450, or 350-450 mM.
[0033] In certain embodiments provided herein is a pharmaceutical aerosol for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises or consists essentially of aqueous droplets
10 comprising delafloxacin, and at least one excipient, for example comprising a multivalent metal ion; has a mass median diameter from about 1 to about 5 pm; and has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 pm. In certain embodiments the dispersed liquid phase has a mass median diameter from 2 to about 5 pm. In certain embodiments the dispersed liquid phase has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 2 pm. In certain embodiments the aerosol comprises at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, antivirals, lung surfactant, steroids, mucolytics, heparin, and anti inflammatory drugs. In certain embodiments the aerosol comprises at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, antivirals, lung surfactant, steroids, mucolytics, and heparin. In certain embodiments the aerosol is being emitted from an aerosol generator at a rate of at least about 0.1 ml dispersed liquid phase per minute. In certain embodiments the liquid phase has a viscosity in the range from about 0.8 to about 3 mPa s, wherein a volume of not more than about 10 ml, or 1-5 ml, of the composition comprises an effective dose of the active compound. In certain embodiments the aerosol has a surface tension in the range from about 25 to 80 mN/m. In certain embodiments the liquid phase comprises at least one excipient capable of affecting the local bioavailability, the release, and/or the local residence time of the active compound at the site of aerosol deposition, such as one or more complexing agents, polymers, or amphiphilic compounds. In certain embodiments, the liquid phase comprises at least one excipient capable of enhancing the AUC shape of the active compound. In certain embodiments the liquid phase comprises at least one taste-modifying excipient selected from the group consisting of flavors, sweeteners, complexing agents and taste masking agents, such as one or more of cyclodextrin, sugar, sugar alcohol, saccharin, aspartame, and arginine. Additionally or alternatively, the one or more excipients can improve local tolerability and/or reduce local adverse events. In certain embodiments the liquid phase comprises at least one excipient selected from the group of divalent or trivalent metal ions
[0034] In certain embodiments provided herein is a pharmaceutical composition for the preparation of an aerosol comprising an active compound comprising delafloxacin, and an excipient comprising a polymeric compound, wherein the polymeric compound is selected from the group consisting of derivatized cellulose, dextran, polymeric sugar, polyethylene glycols, pectin and cyclodextrins.
[0035] In certain embodiments provided herein is a kit for the preparation and delivery of a delafloxacin aerosol for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises or consists essentially of aqueous droplets comprising delafloxacin, and, in some cases, at least one
11 excipient comprising a multivalent metal ion; has a mass median diameter from of 1-5, or 2-5 pm; and has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 pm, wherein the kit comprises a nebulizer and an aqueous liquid composition, said composition comprising an effective dose of delafloxacin within a volume of not more than about 10 ml. In certain embodiments the dispersed liquid phase has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 2 pm. In certain embodiments the composition comprises an effective dose of delafloxacin within a volume from about 1 to about 5 ml. In certain embodiments the nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, jet collision nebulizers, electrohydrodynamic nebulizers, capillary force nebulizers, perforated membrane nebulizers and perforated vibrating membrane nebulizers. In certain embodiments nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, and perforated vibrating membrane nebulizers. In certain embodiments the nebulizer is adapted to be capable of aerosolizing the liquid composition at a rate of at least about 0.1 ml/min. In certain embodiments the nebulizer is adapted to be capable of aerosolizing a volume of the liquid composition comprising an effective dose of delafloxacin within not more than about 20 minutes. In certain embodiments the nebulizer is adapted to be capable of emitting at least about 50 wt.-% of the aqueous liquid composition as aerosol. In certain embodiments at least about 40 wt.-% of the loaded dose is comprised of droplets having a diameter of not more than about 5 um.
[0036] In certain embodiments provided herein is a method of preparing and delivering an aerosol to a person in need of nasal, sinonasal or pulmonary antibiotic treatment or prophylaxis, said method comprising the steps of providing a liquid pharmaceutical composition comprising an effective dose of delafloxacin, and, in some cases, at least one excipient comprising a multivalent metal ion, in a volume of not more than about 10 ml; providing a nebulizer capable of aerosolizing said liquid pharmaceutical composition at a total output rate of at least 0.1 ml/min, the nebulizer further being adapted to emit an aerosol comprising a dispersed phase having a mass median diameter from about 1 to about 5 pm and a geometrical standard deviation less than or equal to about 3.0 pm; and operating the nebulizer to aerosolize the liquid composition. In certain embodiments the volume is from about 1 to about 5 ml. In certain embodiments the dispersed phase has a mass median diameter from 2 to about 5 pm. In certain embodiments the dispersed phase has a distribution exhibiting a geometrical standard deviation less than or equal to about 2.5 pm. In certain embodiments administration is conducted to last not more than about 20 minutes, or less than about 5 minutes.
[0037] In certain embodiments provided herein is a kit comprising a sterile single use container comprising an aqueous solution of delafloxacin, in some cases also a divalent or
12 trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung; and a nebulizer adapted to receive solution from the container and to aerosolize the solution for delivery to the lung through oral inhalation. In certain embodiments the nebulizer operates by ultrasonic atomization. In certain embodiments the nebulizer operates by hydraulic atomization. In certain embodiments the nebulizer operates by a vibrating mesh. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2 microns to about 5. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns. In certain embodiments the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
[0038] In certain embodiments provided herein is a system comprising: a reservoir comprising an aqueous solution of delafloxacin and, in some cases, a divalent or trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung; and a nebulizer configured to aerosolize the solution for delivery to the lung through oral inhalation. In certain embodiments the nebulizer operates by ultrasonic atomization. In certain embodiments the nebulizer operates by hydraulic atomization. In certain embodiments the nebulizer operates by a vibrating mesh. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns. In certain embodiments the solution comprises delafloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
[0039] In certain embodiments, provided is a pharmaceutical composition, consisting essentially of an aqueous solution of greater than 20, 30, 40, or 50 mg/ml delafloxacin and a divalent or trivalent cation, or a combination thereof, wherein the solution has a pH from about
13 5.5 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. In certain embodiments an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer.
[0040] In certain embodiments, provided is pharmaceutical aerosol for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase: consists essentially of aqueous droplets comprising an active compound comprising delafloxacin, and at least one excipient comprising a multivalent metal ion; has a mass median diameter from about 1 to about 5 pm; and has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 um.
[0041] In certain embodiments, provided is an aqueous pharmaceutical solution comprising about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml of delafloxacin and about 200 mM of magnesium chloride. The solution can have a pH from 5-7. The solution can have an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg. The solution can comprise a dose of delafloxacin of 300 mg, or 280 mg, or 260 mg, or 240 mg, or 200 mg, or 180 mg, or 160 mg, or 140 mg, or 120 mg, or 100 mg, or 90 mg, or 80 mg, or 70 mg, or 60 mg, or 50 mg, or 40 mg, or 30 mg.
[0042] In certain embodiments, a pharmaceutical composition suitable for administration by inhalation can comprise a delafloxacin concentration of 20-100, or 20-80, or 20-60, or 40-100, or 75-150 mg/ml, a magnesium chloride concentration of 150-250 mM, a pH of 5-7; an osmolality of 300-500 mOsmol/kg. In certain embodiments, the composition lacks lactose.
[0043] In certain embodiments, a pharmaceutical composition comprising delafloxacin may comprise 7-700 mg, 14-300 mg, or 28-280 mg delafloxacin per l-5ml of dilute saline (e.g., between 1/10 to 1/1 normal saline). Thus, the concentration of a delafloxacin solution may be greater than about 15 mg/ml, 25 mg/ml, greater than about 35 mg/ml, greater than about 40 mg/ml, or greater than 50 mg/ml.
[0044] In certain embodiments, a pharmaceutical composition suitable for administration by inhalation comprises a delafloxacin concentration of about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration of about 200 mM, a pH about 6.2, an osmolality about 383 mOsmol/kg, and, optionally, lacks lactose. In some embodiments, a pharmaceutical composition suitable for administration by inhalation consists essentially of a delafloxacin concentration of about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration about of 200 mM, a pH of about 6.2 an osmolality of about 383 mOsmol/kg, and optionally, lacks lactose. In some embodiments, a pharmaceutical composition suitable for administration by inhalation consists of a delafloxacin concentration of about 20, 30, 40, 50, 60,
14 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration of about 200 mM, a pH of about 6.2 an osmolality of about 383 mOsmol/kg, and, optionally, lacks lactose.
[0045] In certain embodiments, a pharmaceutical composition suitable for administration by inhalation can include delafloxacin in combination with an additional active agent. Such additional active agents can include one or more antibiotics, as described above. Other additional active agents can include bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof. Examples of bronchodilators include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutlaine, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, theophylline, roflumilast, cilomilast. Examples of anticholinergics include pratropium, and tiotropium. Examples of glucocorticoids include prednisone, fluticasone, budesonide, mometasone, ciclesonide, and beclomethasone. Examples of eicosanoids include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, and seratrodast. More additional active agents can include pulmozyme, hypertonic saline, agents that restore chloride channel function in CF, inhaled beta-agonists, inhaled antimuscarinic agents, inhaled corticosteroids, and inhaled phosphodiesterase inhibitors. In certain embodiments, the aerosol antibiotic therapy administered as a treatment or prophylaxis may be used in combination or alternating therapeutic sequence with an additional active agent. In certain embodiments, the additional active agent may be administered as a treatment, alone, co-formulated, or administered with the aerosol antibiotic therapy. In certain embodiments, e.g. treatment of CF, the additional active agent can be mannitol.
[0046] In certain embodiments, a pharmaceutical composition suitable for administration by inhalation, for example for use in cystic fibrosis, can include delafloxacin in combination with mannitol.
Taste Masking, Flavor, Other
[0047] Compositions may further include flavoring agents, taste-masking agents, inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), sorbitan esters, saccharin, cyclodextrins, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (e.g., cholesterol), and chelating agents (e.g., EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and/or additives suitable for use in the compositions according to the invention are listed in "Remington: The Science & Practice of Pharmacy", 19.sup.th ed.,
15 Williams & Williams, (1995), and in the "Physician's Desk Reference", 52.sup.nd ed., Medical Economics, Montvale, N.J. (1998).
[0048] In certain embodiments, a pharmaceutical composition is formulated to improve and/or mask taste. Any suitable manner of improving and/or masking taste may be used.
Classes of taste-masking agents for delafloxacin formulation include the addition of flavorings, sweeteners, and other various coating strategies. Exemplary substances include sugars such as sucrose, dextrose, and lactose, carboxylic acids, salts such as magnesium and calcium (non specific or chelation-based fluoroquinolone taste masking), menthol, amino acids or amino acid derivatives such as arginine, lysine, and monosodium glutamate, and synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, etc. and combinations thereof. These may include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. Additional sweeteners include sucrose, dextrose, aspartame (Nutrasweet™.), acesulfame-K, sucralose and saccharin, organic acids (by non-limiting example citric acid and aspartic acid). Such flavors may be present at any suitable concentration, for example, 0.05-4%. Another approach to improve or mask the taste of unpleasant inhaled drugs is to decrease the drugs solubility, e.g. drugs must dissolve to interact with taste receptors. Hence, to deliver solid forms of the drug may avoid the taste response and acquire the desired improved taste effect. Taste-masking may be accomplished by creation of lipophilic vesicles. Additional coating or capping agents include dextrates (by non-limiting example cyclodextrins may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, randomly methylated beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, maltosyl-alpha- cyclodextrin, glucosyl-1 -alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and sulfobutylether-beta-cyclodextrin), modified celluloses such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose, polyalkylene glycols, polyalkylene oxides, sugars and sugar alcohols, waxes, shellacs, acrylics and mixtures thereof. Other methods to deliver non-dissolved forms of delafloxacin are to administer the drug alone or in simple, non-solubilty affecting formulation as a crystalline micronized, dry powder, spray-dried, and nanosuspension formulation. However, an alternative method is to include taste -modifying agents. These include a taste-masking substance that is mixed with, coated onto or otherwise combined with the delafloxacin active medicament. However, this addition may also serve to improve the taste of another chosen drug product addition, e.g. a mucolytic agent. Such substances include acid phospholipids, lysophospholipid,
16 tocopherol polyethylene glycol succinate, and embonic acid (pamoate). Many of these agents can be used alone or in combination with delafloxacin for aerosol administration.
[0049] In certain embodiments provided herein is a method of making a taste-masked delafloxacin pharmaceutical composition, comprising forming a solution of delafloxacin and a divalent or trivalent cation, or a combination thereof, having a pH from about 5.5 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. In certain embodiments the solution comprises greater than 50 mg/ml delafloxacin. In certain embodiments the divalent or trivalent cation is in magnesium chloride.
[0050] In certain embodiments, the pharmaceutical composition is provided in unit dosage form suitable for single administration of a precise dose. The unit dosage form can also be assembled and packaged together to provide a patient with a prolonged supply, e.g., a weekly or monthly supply and can also incorporate other compounds such as saline, taste masking agents, pharmaceutical excipients, and/or other active ingredients or carriers.
Solid particle compositions
[0051] In certain embodiments, solid drug nanoparticles are provided for use in generating dry aerosols or for generating nanoparticles in liquid suspension. Any suitable method may be used to produce the solid composition. In certain embodiments, powder is made by spray-drying aqueous dispersions of a nanoparticulate drug and a surface modifier to form a dry powder which consists of aggregated drug nanoparticles. In certain embodiments, the aggregates can have a size of 1-2 microns, which is suitable for deep lung delivery. The aggregate particle size can be increased to target alternative delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of drug in the spray-dried dispersion or by increasing the droplet size generated by the spray dryer.
[0052] In certain embodiments, an aqueous dispersion of drug and surface modifier can contain a dissolved diluent such as lactose, mannitol, maltitol, erythritol, and/or allulose, which, when spray dried, forms respirable diluent particles, each of which contains at least one embedded drug nanoparticle and surface modifier. The diluent particles with embedded drug can have a particle size of, e.g., 1-2 microns, suitable for deep lung delivery. In addition, the diluent particle size can be increased to target alternate delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of dissolved diluent in the aqueous dispersion prior to spray drying, or by increasing the droplet size generated by the spray dryer.
[0053] Spray-dried powders can be used in DPIs or pMDIs, either alone or combined with freeze-dried nanoparticulate powder. In addition, spray-dried powders containing drug
17 nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions having respirable droplet sizes, where each droplet contains at least one drug nanoparticle. Concentrated nanoparticulate dispersions may also be used in these aspects of the invention.
[0054] Nanoparticulate drug dispersions can also be freeze-dried to obtain powders suitable for nasal or pulmonary delivery. Such powders may contain aggregated nanoparticulate drug particles having a surface modifier. Such aggregates may have sizes within a respirable range, e.g., 2-5 microns MMAD.
[0055] Freeze dried powders of the appropriate particle size can also be obtained by freeze drying aqueous dispersions of drug and surface modifier, which additionally contain a dissolved diluent such as lactose or mannitol. In these instances the freeze dried powders consist of respirable particles of diluent, each of which contains at least one embedded drug nanoparticle.
[0056] Freeze-dried powders can be used in DPIs or pMDIs, either alone or combined with spray-dried nanoparticulate powder. In addition, freeze -dried powders containing drug nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions that have respirable droplet sizes, where each droplet contains at least one drug nanoparticle.
[0057] Certain embodiments are directed to a process and composition for propellant-based systems comprising nanoparticulate drug particles and a surface modifier. Such formulations may be prepared by wet milling the coarse drug substance and surface modifier in liquid propellant, either at ambient pressure or under high pressure conditions. Alternatively, dry powders containing drug nanoparticles may be prepared by spray-drying or freeze-drying aqueous dispersions of drug nanoparticles and the resultant powders dispersed into suitable propellants for use in conventional pMDIs. Such nanoparticulate pMDI formulations can be used for either nasal or pulmonary delivery. For pulmonary administration, such formulations afford increased delivery to the deep lung regions because of the small (e.g., 1-2 microns MMAD) particle sizes available from these methods. Concentrated aerosol formulations can also be employed in pMDIs.
[0058] Another embodiment is directed to dry powders which contain nanoparticulate compositions for pulmonary or nasal delivery. The powders may consist of respirable aggregates of nanoparticulate drug particles, or of respirable particles of a diluent which contains at least one embedded drug nanoparticle. Powders containing nanoparticulate drug particles can be prepared from aqueous dispersions of nanoparticles by removing the water via spray-drying or lyophilization (freeze drying).
18 [0059] Conventional micronized drug particles used in dry powder aerosol delivery having particle diameters of 2-5 microns MMAD are often difficult to meter and disperse in small quantities because of the electrostatic cohesive forces inherent in such powders. These difficulties can lead to loss of drug substance to the delivery device as well as incomplete powder dispersion and sub-optimal delivery to the lung. Since the average particle sizes of conventionally prepared dry powders are usually in the range of from about 2 to about 5 microns MMAD, the fraction of material which actually reaches the alveolar region may be quite small.
[0060] The dry powder aerosols which contain nanoparticulate drugs can be made smaller than comparable micronized drug substance and, therefore, are appropriate for efficient delivery to the deep lung. Moreover, aggregates of nanoparticulate drugs are spherical in geometry and have good flow properties, thereby aiding in dose metering and deposition of the administered composition in the lung or nasal cavities.
[0061] Dry nanoparticulate compositions can be used in both dry powder inhaler devices (DPIs) and pressurized metered does inhalers (pMDIs). As used herein, "dry" includes a composition having less than about 5% water.
[0062] In one embodiment, compositions are provided containing nanoparticles which have an effective average particle size of less than 1000 nm, or less than 400 nm, or less than 300 nm, or less than 250 nm, or less than 200 nm, as measured by, for example, light-scattering methods. By "an effective average particle size of less than 1000 nm" it is meant that at least 50% of the drug particles have a weight average particle size of less than 1000 nm when measured by, e.g., light scattering techniques. In certain embodiments at least 70% of the drug particles have an average particle size of less than 1000 nm, or at least 90% of the drug particles have an average particle size of less than 1000 nm, or at least 95% of the particles have a weight average particle size of less than 1000 nm.
[0063] For aqueous aerosol formulations, the nanoparticulate agent may be present at a concentration of about 5.0 mg/mL up to about 700 mg/mL. For dry powder aerosol formulations, the nanoparticulate agent may be present at a concentration of about 5.0 mg/g up to about 1000 mg/g, depending on the desired drug dosage. Concentrated nanoparticulate aerosols, defined as containing a nanoparticulate drug at a concentration of 5.0-700 mg/mL for aqueous aerosol formulations, and 5.0-1000 mg/g for dry powder aerosol formulations, are specifically provided. Such formulations provide effective delivery to appropriate areas of the lung or nasal cavities in short administration times, i.e., less than about 3-15 seconds per dose as compared to administration times of up to 4 to 20 minutes as found in conventional pulmonary nebulizer therapies. Further characteristic suitable for dry powder formulations may be found in
19 Muralidharan et al., Inhalable nanoparticulate powders for respiratory delivery, Nanomedicine: Nanotechnology, Biology, and Medicine 11(2015) 1189-1199.
[0064] Nanoparticulate drug compositions for aerosol administration can be made by, for example, (1) nebulizing a dispersion of a nanoparticulate drug, obtained by either grinding or precipitation; (2) aerosolizing a dry powder of aggregates of nanoparticulate drug and surface modifier (the aerosolized composition may additionally contain a diluent); or (3) aerosolizing a suspension of nanoparticulate drug or drug aggregates in a non-aqueous propellant. The aggregates of nanoparticulate drug and surface modifier, which may additionally contain a diluent, can be made in a non-pressurized or a pressurized non-aqueous system. Concentrated aerosol formulations may also be made via such methods.
[0065] Milling of aqueous drug to obtain nanoparticulate drug may be performed by dispersing drug particles in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug to the desired effective average particle size. The particles can be reduced in size in the presence of one or more surface modifiers. Alternatively, the particles can be contacted with one or more surface modifiers after attrition. Other compounds, such as a diluent, can be added to the drug/surface modifier composition during the size reduction process. Dispersions can be manufactured continuously or in a batch mode.
[0066] Another method of forming nanoparticle dispersion is by microprecipitation. This is a method of preparing stable dispersions of drugs in the presence of one or more surface modifiers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities. Such a method comprises, for example, (1) dissolving the drug in a suitable solvent with mixing; (2) adding the formulation from step (1) with mixing to a solution comprising at least one surface modifier to form a clear solution; and (3) precipitating the formulation from step (2) with mixing using an appropriate nonsolvent. The method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means. The resultant nanoparticulate drug dispersion can be utilized in liquid nebulizers or processed to form a dry powder for use in a DPI or pMDI.
[0067] In a non-aqueous, non-pressurized milling system, a non-aqueous liquid having a vapor pressure of about 1 atm or less at room temperature and in which the drug substance is essentially insoluble may be used as a wet milling medium to make a nanoparticulate drug composition. In such a process, a slurry of drug and surface modifier may be milled in the non- aqueous medium to generate nanoparticulate drug particles. Examples of suitable non-aqueous media include ethanol, trichloromonofluoromethane, (CFC-11), and dichlorotetrafluoroethane
20 (CFC-114). An advantage of using CFC-11 is that it can be handled at only marginally cool room temperatures, whereas CFC-114 requires more controlled conditions to avoid evaporation. Upon completion of milling the liquid medium may be removed and recovered under vacuum or heating, resulting in a dry nanoparticulate composition. The dry composition may then be filled into a suitable container and charged with a final propellant. Exemplary final product propellants, which ideally do not contain chlorinated hydrocarbons, include HFA-134a (tetrafluoroethane) and HFA-227 (heptafluoropropane). While non-chlorinated propellants may be preferred for environmental reasons, chlorinated propellants may also be used in this aspect of the invention.
[0068] In a non-aqueous, pressurized milling system, a non-aqueous liquid medium having a vapor pressure significantly greater than 1 atm at room temperature may be used in the milling process to make nanoparticulate drug compositions. If the milling medium is a suitable halogenated hydrocarbon propellant, the resultant dispersion may be filled directly into a suitable pMDI container. Alternately, the milling medium can be removed and recovered under vacuum or heating to yield a dry nanoparticulate composition. This composition can then be filled into an appropriate container and charged with a suitable propellant for use in a pMDI.
[0069] Spray drying is a process used to obtain a powder containing nanoparticulate drug particles following particle size reduction of the drug in a liquid medium. In general, spray drying may be used when the liquid medium has a vapor pressure of less than about 1 atm at room temperature. A spray-dryer is a device which allows for liquid evaporation and drug powder collection. A liquid sample, either a solution or suspension, is fed into a spray nozzle.
The nozzle generates droplets of the sample within a range of about 20 to about 100 pm in diameter which are then transported by a carrier gas into a drying chamber. The carrier gas temperature is typically from 80-200 °C. The droplets are subjected to rapid liquid evaporation, leaving behind dry particles which are collected in a special reservoir beneath a cyclone apparatus.
[0070] If the liquid sample consists of an aqueous dispersion of nanoparticles and surface modifier, the collected product will consist of spherical aggregates of the nanoparticulate drug particles. If the liquid sample consists of an aqueous dispersion of nanoparticles in which an inert diluent material was dissolved (such as lactose or mannitol), the collected product will consist of diluent (e.g., lactose or mannitol) particles which contain embedded nanoparticulate drug particles. The final size of the collected product can be controlled and depends on the concentration of nanoparticulate drug and/or diluent in the liquid sample, as well as the droplet size produced by the spray-dryer nozzle. Collected products may be used in conventional DPIs
21 for pulmonary or nasal delivery, dispersed in propellants for use in pMDIs, or the particles may be reconstituted in water for use in nebulizers.
[0071] In some instances it may be desirable to add an inert carrier to the spray-dried material to improve the metering properties of the final product. This may especially be the case when the spray dried powder is very small (less than about 5 pm) or when the intended dose is extremely small, whereby dose metering becomes difficult. In general, such carrier particles (also known as bulking agents) are too large to be delivered to the lung and simply impact the mouth and throat and are swallowed. Such carriers typically consist of sugars such as lactose, mannitol, or trehalose. Other inert materials, including polysaccharides and cellulosics, may also be useful as carriers.
[0072] Spray-dried powders containing nanoparticulate drug particles may be used in conventional DPIs, disperse in propellants for use in pMDIs, or reconstituted in a liquid medium for use with nebulizers.
[0073] For compounds that are denatured or destabilized by heat, such as compounds having a low melting point (i.e., 70-150 °C.), or for example, biologies, sublimation is preferred over evaporation to obtain a dry powder nanoparticulate drug composition. This is because sublimation avoids the high process temperatures associated with spray-drying. In addition, sublimation, also known as freeze-drying or lyophilization, can increase the shelf stability of drug compounds, particularly for biological products. Freeze-dried particles can also be reconstituted and used in nebulizers. Aggregates of freeze-dried nanoparticulate drug particles can be blended with either dry powder intermediates or used alone in DPIs and pMDIs for either nasal or pulmonary delivery.
[0074] Sublimation involves freezing the product and subjecting the sample to strong vacuum conditions. This allows for the formed ice to be transformed directly from a solid state to a vapor state. Such a process is highly efficient and, therefore, provides greater yields than spray drying. The resultant freeze-dried product contains drug and modifier(s). The drug is typically present in an aggregated state and can be used for inhalation alone (either pulmonary or nasal), in conjunction with diluent materials (lactose, mannitol, etc.), in DPIs or pMDIs, or reconstituted for use in a nebulizer.
Liposomal compositions
[0075] In certain embodiments, delafloxacin is formulated into liposome particles, which can then be aerosolized for inhaled delivery. Suitable lipids can be any of a variety of lipids including both neutral lipids and charged lipids. Carrier systems having desirable properties can be
22 prepared using appropriate combinations of lipids, targeting groups and circulation enhancers. Additionally, the compositions provided herein can be in the form of liposomes or lipid particles, preferably lipid particles. As used herein, the term "lipid particle" includes a lipid bilayer carrier which "coats" a substance and has little or no aqueous interior. The outer layer of the particle will typically comprise mixtures of lipids oriented in a tail-to-tail fashion (as in liposomes) with the hydrophobic tails of the interior layer. The polar head groups present on the lipids of the outer layer will form the external surface of the particle.
[0076] Liposomal bioactive agents can be designed to have a sustained therapeutic effect or lower toxicity allowing less frequent administration and an enhanced therapeutic index. Liposomes are composed of bilayers that entrap the desired pharmaceutical. These can be configured as multilamellar vesicles of concentric bilayers with the pharmaceutical trapped within either the lipid of the different layers or the aqueous space between the layers.
[0077] By non-limiting example, lipids used in the compositions may be synthetic, semi synthetic or naturally-occurring lipids, including phospholipids, tocopherols, steroids, fatty acids, glycoproteins such as albumin, negatively-charged lipids and cationic lipids. Phospholipids include egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine (EPE), and egg phosphatidic acid (EPA); the soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the hydrogenated egg and soya counterparts (e.g., HEPC, HSPC), other phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol positions containing chains of 12 to 26 carbon atoms and different head groups in the 1 position of glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as the corresponding phosphatidic acids. The chains on these fatty acids can be saturated or unsaturated, and the phospholipid can be made up of fatty acids of different chain lengths and different degrees of unsaturation. In particular, the compositions of the formulations can include dipalmitoyl phosphatidylcholine (DPPC), a major constituent of naturally-occurring lung surfactant as well as dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG). Other examples include dimyristoylphosphatidycholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) dipalmitoylphosphatidcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) distearoylphosphatidylcholine (DSPC) and distearoylphosphatidylglycerol (DSPG), dioleylphosphatidylethanolamine (DOPE) and mixed phospholipids like palmitoylstearoylphosphatidylcholine (PSPC) and palmitoylstearoylphosphatidylglycerol (PSPG), and single acylated phospholipids like mono- oleoyl-phosphatidylethanolamine (MOPE).
23 [0078] In certain embodiments, PEG-modified lipids are incorporated into compositions as an aggregation-preventing agent. The use of a PEG-ceramide has the additional advantages of stabilizing membrane bilayers and lengthening circulation lifetimes. Additionally, PEG- ceramides can be prepared with different lipid tail lengths to control the lifetime of the PEG- ceramide in the lipid bilayer. In this manner, "programmable" release can be accomplished which results in the control of lipid carrier fusion. For example, PEG-ceramides having C2o-acyl groups attached to the ceramide moiety will diffuse out of a lipid bilayer carrier with a half-life of 22 hours. PEG-ceramides having CM- and Cs-acyl groups will diffuse out of the same carrier with half-lives of 10 minutes and less than 1 minute, respectively. As a result, selection of lipid tail length provides a composition in which the bilayer becomes destabilized (and thus fusogenic) at a known rate. Though less preferred, other PEG-lipids or lipid-polyoxyethylene conjugates are useful in the present compositions. Examples of suitable PEG-modified lipids include PEG- modified phosphatidylethanolamine and phosphatidic acid, PEG-modified diacylglycerols and dialkylglycerols, PEG-modified dialkylamines and PEG-modified l,2-diacyloxypropan-3- amines. Particularly preferred are PEG-ceramide conjugates (e.g., PEG-Cer-Cs, PEG-Cer-Ci4 or PEG-Cer-C2o) which are described in U.S. Pat. No. 5,820,873.
[0079] Liposomal compositions can be 50-400 nm in diameter. One with skill in the art will understand that the size of the compositions can be larger or smaller depending upon the volume which is encapsulated. Thus, for larger volumes, the size distribution will typically be 80-300 nm.
Delivery systems
[0080] Several device technologies exist to deliver either dry powder or liquid aerosolized products. Dry powder formulations generally require less time for drug administration, yet longer and more expensive development efforts. Conversely, liquid formulations have historically suffered from longer administration times, yet have the advantage of shorter and less expensive development efforts.
[0081] Accordingly, in one embodiment, a particular formulation of delafloxacin disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for acceptable drug deposition at a site of infection and acceptable tolerability. Factors that can be optimized include solution or solid particle formulation, rate of delivery, and particle size and distribution produced by the aerosolizing device.
[0082] For pulmonary administration, the upper airways are avoided in favor of the middle and lower airways. Pulmonary drug delivery may be accomplished by inhalation of an aerosol through the mouth and throat. Particles having a mass median aerodynamic diameter (MMAD)
24 of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed. Particles having diameters of about 2 to about 5 microns are small enough to reach the upper- to mid-pulmonary region (conducting airways), but are too large to reach the alveoli. Smaller particles, i.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region. Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles may be exhaled. Measures of particle size can be referred to as volumetric mean diameter (VMD), mass median diameter (MMD), or MMAD. These measurements may be made by impaction (MMD and MMAD) or by laser (VMD). For liquid particles, VMD, MMD and MMAD may be the same if environmental conditions are maintained, e.g. standard humidity. However, if humidity is not maintained, MMD and MMAD determinations will be smaller than VMD due to dehydration during impactor measurements. For the purposes of this description, VMD, MMD and MMAD measurements are considered to be under standard conditions such that descriptions of VMD, MMD and MMAD will be comparable. Similarly, dry powder particle size determinations in MMD, and MMAD are also considered comparable.
[0083] In certain embodiments, the particle size of the aerosol is optimized to maximize delafloxacin deposition at the site of infection and to maximize tolerability. Aerosol particle size may be expressed in terms of the mass median aerodynamic diameter (MMAD). Large particles (e.g., MMAD>5 um) may deposit in the upper airway because they are too large to navigate the curvature of the upper airway. Small particles (e.g., MMAD<2 um) may be poorly deposited in the lower airways and thus become exhaled, providing additional opportunity for upper airway deposition. Hence, intolerability (e.g., cough and bronchospasm) may occur from upper airway deposition from both inhalation impaction of large particles and settling of small particles during repeated inhalation and expiration. Thus, in one embodiment, an optimum particle size is used (e.g., MMAD=2-5 um) in order to maximize deposition at a mid-lung site of infection and to minimize intolerability associated with upper airway deposition. Moreover, generation of a defined particle size with limited geometric standard deviation (GSD) may optimize deposition and tolerability. Narrow GSD limits the number of particles outside the desired MMAD size range. In one embodiment, an aerosol containing delafloxacin is provided having a MMAD from about 2 microns to about 5 microns with a GSD of less than or equal to about 2.5 microns. In another embodiment, an aerosol having an MMAD from about 2.8 microns to about 4.3 microns with a GSD less than or equal to 2 microns is provided. In another embodiment, an aerosol having an MMAD from about 2.5 microns to about 4.5 microns with a GSD less than or equal to 1.8 microns is provided.
25 [0084] Delafloxacin intended for respiratory delivery (for either systemic or local distribution) can be administered as aqueous formulations, as suspensions or solutions in halogenated hydrocarbon propellants, or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization. Propellant- based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
Liquid Nebulizer
[0085] In certain embodiments, a nebulizer is selected on the basis of allowing the formation of an aerosol of delafloxacin having an MMAD predominantly between about 2 to about 5 microns. In one embodiment, the delivered amount of delafloxacin provides a therapeutic effect for respiratory infections.
[0086] Previously, two types of nebulizers, jet and ultrasonic, have been shown to be able to produce and deliver aerosol particles having sizes between 2 and 4 um. These particle sizes have been shown as being optimal for treatment of pulmonary bacterial infection cause by gram negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Enterobacter species, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, Haemophilus influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, and multidrug resistant Pseudomonas aeruginosa. However, unless a specially formulated solution is used, these nebulizers typically need larger volumes to administer sufficient amount of drug to obtain a therapeutic effect. A jet nebulizer utilizes air pressure breakage of an aqueous solution into aerosol droplets. An ultrasonic nebulizer utilizes shearing of the aqueous solution by a piezoelectric crystal. Typically, however, the jet nebulizers are only about 10% efficient under clinical conditions, while the ultrasonic nebulizer is only about 5% efficient. The amount of pharmaceutical deposited and absorbed in the lungs is thus a fraction of the 10% in spite of the large amounts of the drug placed in the nebulizer.
[0087] Accordingly, in one embodiment, a vibrating mesh nebulizer is used to deliver an aerosol of delafloxacin. A vibrating mesh nebulizer consists of a liquid storage container in fluid contact with a diaphragm and inhalation and exhalation valves. In one embodiment, about 1 to about 5 ml of the delafloxacin composition is placed in the storage container and the aerosol generator is engaged producing atomized aerosol of particle sizes selectively between about 1 and about 5 um.
26 [0088] By non-limiting example, delafloxacin is placed in a liquid nebulization inhaler and prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, preferably from about 14 to about 350 mg in about 1 to about 5 ml, and most preferably from about 28 to about 280 mg in about 1 to about 5 ml with MMAD particles sizes between about 2 to about 5 um being produced.
[0089] By non-limiting example, nebulized delafloxacin may be administered in the described respirable delivered dose in less than about 20 min, preferably less than about 10 min, more preferably less than about 7 min, more preferably less than about 5 min, more preferably less than about 3 min, and in some cases most preferable if less than about 2 min.
[0090] By non-limiting example, in other circumstances, nebulized delafloxacin may achieve improved tolerability and/or exhibit an AUC shape -enhancing characteristic when administered over longer periods of time. Under these conditions, the described respirable delivered dose in more than about 2 min, preferably more than about 3 min, more preferably more than about 5 min, more preferably more than about 7 min, more preferably more than about 10 min, and in some cases most preferable from about 10 to about 20 min.
[0091] For aqueous and other non-pressurized liquid systems, a variety of nebulizers (including small volume nebulizers) are available to aerosolize the formulations. Compressor- driven nebulizers incorporate jet technology and use compressed air to generate the liquid aerosol. Such devices are commercially available from, for example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc. Ultrasonic nebulizers rely on mechanical energy in the form of vibration of a piezoelectric crystal to generate respirable liquid droplets and are commercially available from, for example, Omron Healthcare, Inc. and DeVilbiss Health Care, Inc. Vibrating mesh nebulizers rely upon either piezoelectric or mechanical pulses to respirable liquid droplets generate. Other examples of nebulizers suitable for use with delafloxacin compositions described herein are described in U.S. Pat. Nos. 4,268,460; 4,253,468; 4,046,146; 3,826,255; 4,649,911; 4,510,929; 4,624,251; 5,164,740; 5,586,550; 5,758,637; 6,644,304; 6,338,443; 5,906,202; 5,934,272; 5,960,792; 5,971,951; 6,070,575; 6,192,876; 6,230,706; 6,349,719; 6,367,470; 6,543,442; 6,584,971; 6,601,581; 4,263,907; 5,709,202; 5,823,179; 6,192,876; 6,644,304; 5,549,102; 6,083,922; 6,161,536; 6,264,922; 6,557,549; and 6,612,303 all of which are hereby incorporated by reference in their entirety. Commercial examples of nebulizers that can be used with the delafloxacin compositions described herein include Respirgard II™, Aeroneb™, Aeroneb™ Pro, and Aeroneb™. Go produced by Aerogen; AERx™ and AERx Essence™ produced by Aradigm;
27 Porta-Neb™, Freeway Freedom™, Sidestream, Ventstream and I-neb produced by Respironics, Inc.; and PARI LC-Plus™, PARI LC-Star™, and e-Flow.sup.7m produced by PARI, GmbH. By further non-limiting example, U.S. Pat. No. 6,196,219, is hereby incorporated by reference in its entirety.
[0092] In some embodiments, the drug solution is formed prior to use of the nebulizer by a patient. In other embodiments, the drug is stored in the nebulizer in solid form. In this case, the solution is mixed upon activation of the nebulizer, such as described in U.S. Pat. No. 6,427,682 and PCT Publication No. WO 03/035030, both of which are hereby incorporated by reference in their entirety. In these nebulizers, the solid drug, optionally combined with excipients to form a solid composition, is stored in a separate compartment from a liquid solvent.
[0093] The liquid solvent is capable of dissolving the solid composition to form a liquid composition, which can be aerosolized and inhaled. Such capability is, among other factors, a function of the selected amount and, potentially, the composition of the liquid. To allow easy handling and reproducible dosing, the sterile aqueous liquid may be able to dissolve the solid composition within a short period of time, possibly under gentle shaking. In some embodiments, the final liquid is ready to use after no longer than about 30 seconds. In some cases, the solid composition is dissolved within about 20 seconds, and advantageously, within about 10 seconds. As used herein, the terms "dissolve(d)", "dissolving", and "dissolution" include the disintegration of the solid composition and the release, i.e. the dissolution, of the active compound. As a result of dissolving the solid composition with the liquid solvent a liquid composition is formed in which the active compound is contained in the dissolved state. As used herein, the active compound is in the dissolved state when at least about 90 wt.-% are dissolved, and more preferably when at least about 95 wt.-% are dissolved.
[0094] With regard to basic separated-compartment nebulizer design, it primarily depends on the specific application whether it is more useful to accommodate the aqueous liquid and the solid composition within separate chambers of the same container or primary package, or whether they should be provided in separate containers. If separate containers are used, these are provided as a set within the same secondary package. The use of separate containers is especially preferred for nebulizers containing two or more doses of the active compound. There is no limit to the total number of containers provided in a multi-dose kit. In one embodiment, the solid composition is provided as unit doses within multiple containers or within multiple chambers of a container, whereas the liquid solvent is provided within one chamber or container. In this case, a favorable design provides the liquid in a metered-dose dispenser, which may consist of a glass or plastic bottle closed with a dispensing device, such as a mechanical pump for metering the
28 liquid. For instance, one actuation of the pumping mechanism may dispense the exact amount of liquid for dissolving one dose unit of the solid composition.
[0095] In another embodiment for multiple-dose separated-compartment nebulizers, both the solid composition and the liquid solvent are provided as matched unit doses within multiple containers or within multiple chambers of a container. For instance, two-chambered containers can be used to hold one unit of the solid composition in one of the chambers and one unit of liquid in the other. As used herein, one unit is defined by the amount of drug present in the solid composition, which is one unit dose. Such two-chambered containers may, however, also be used advantageously for nebulizers containing only one single drug dose.
[0096] In one embodiment of a separated-compartment nebulizer, a blister pack having two blisters is used, the blisters representing the chambers for containing the solid composition and the liquid solvent in matched quantities for preparing a dose unit of the final liquid composition. As used herein, a blister pack represents a thermoformed or pressure-formed primary packaging unit, most likely comprising a polymeric packaging material that optionally includes a metal foil, such as aluminum. The blister pack may be shaped to allow easy dispensing of the contents. For instance, one side of the pack may be tapered or have a tapered portion or region through which the content is dispensable into another vessel upon opening the blister pack at the tapered end.
The tapered end may represent a tip.
[0097] In certain embodiments, the two chambers of the blister pack are connected by a channel, the channel being adapted to direct fluid from the blister containing the liquid solvent to the blister containing the solid composition. During storage, the channel is closed with a seal. In this sense, a seal is any structure that prevents the liquid solvent from contacting the solid composition. The seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition. The dissolution process may be improved by shaking the blister pack. Thus, the final liquid composition for inhalation is obtained, the liquid being present in one or both of the chambers of the pack connected by the channel, depending on how the pack is held.
[0098] According to another embodiment, one of the chambers, preferably the one that is closer to the tapered portion of the blister pack, communicates with a second channel, the channel extending from the chamber to a distal position of the tapered portion. During storage, this second channel does not communicate with the outside of the pack but is closed in an air tight fashion. Optionally, the distal end of the second channel is closed by a breakable or removable cap or closure, which may e.g. be a twist-off cap, a break-off cap, or a cut-off cap.
29 [0099] In one embodiment, a vial or container having two compartments is used, the compartment representing the chambers for containing the solid composition and the liquid solvent in matched quantities for preparing a dose unit of the final liquid composition. The liquid composition and a second liquid solvent may be contained in matched quantities for preparing a dose unit of the final liquid composition (by non-limiting example in cases where two soluble excipients or the delafloxacin and excipient are unstable for storage, yet desired in the same mixture for administration.
[0100] In some embodiments, the two compartments are physically separated but in fluid communication so that when the vial or container are connected by a channel or breakable barrier, the channel or breakable barrier being adapted to direct fluid between the two compartments to enable mixing prior to administration. During storage, the channel is closed with a seal or the breakable barrier intact. In this sense, a seal is any structure that prevents mixing of contents in the two compartments. The seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition or in the case of two liquids permit mixing. The dissolution or mixing process may be improved by shaking the container. Thus, the final liquid composition for inhalation is obtained, the liquid being present in one or both of the chambers of the pack connected by the channel or breakable barrier, depending on how the pack is held.
[0101] The solid composition itself can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
[0102] Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In a preferred embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.
[0103] On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, beads, lyophilized powders, and the like. In one embodiment, the solid
30 composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution.
[0104] Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
[0105] In another embodiment, the solid composition resembles a coating layer that is coated on multiple units made of insoluble material. Examples of insoluble units include beads made of glass, polymers, metals, and mineral salts. Again, the desired effect is primarily rapid disintegration of the coating layer and quick drug dissolution, which is achieved by providing the solid composition in a physical form that has a particularly high surface-to-volume ratio. Typically, the coating composition will, in addition to the drug and the water-soluble low molecular weight excipient, comprise one or more excipients, such as those mentioned above for coating soluble particles, or any other excipient known to be useful in pharmaceutical coating compositions.
[0106] To achieve the desired effects, it may be useful to incorporate more than one water- soluble low molecular weight excipient into the solid composition. For instance, one excipient may be selected for its drug carrier and diluent capability, while another excipient may be selected to adjust the pH. If the final liquid composition needs to be buffered, two excipients that together form a buffer system may be selected.
[0107] In one embodiment, the liquid to be used in a separated-compartment nebulizer is an aqueous liquid, which is herein defined as a liquid whose major component is water. The liquid does not necessarily consist of water only; however, in one embodiment it is purified water. In another embodiment, the liquid contains other components or substances, preferably other liquid components, but possibly also dissolved solids. Liquid components other than water which may be useful include propylene glycol, glycerol, and polyethylene glycol. One of the reasons to incorporate a solid compound as a solute is that such a compound is desirable in the final liquid
31 composition, but is incompatible with the solid composition or with a component thereof, such as the active ingredient.
[0108] Another desirable characteristic for the liquid solvent is that it is sterile. An aqueous liquid would be subject to the risk of considerable microbiological contamination and growth if no measures are taken to ensure sterility. In order to provide a substantially sterile liquid, an effective amount of an acceptable antimicrobial agent or preservative can be incorporated or the liquid can be sterilized prior to providing it and to seal it with an air-tight seal. In one embodiment, the liquid is a sterilized liquid free of preservatives and provided in an appropriate air-tight container. However, according to another embodiment in which the nebulizer contains multiple doses of the active compound, the liquid may be supplied in a multiple-dose container, such as a metered-dose dispenser, and may require a preservative to prevent microbial contamination after the first use.
Meter Dose Inhaler (MDI)
[0109] A propellant driven inhaler (pMDI) releases a metered dose of medicine upon each actuation. The medicine is formulated as a suspension or solution of a drug substance in a suitable propellant such as a halogenated hydrocarbon. pMDIs are described in, for example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224 (Butterworths, London, England, 1984).
[0110] In some embodiments, the particle size of the drug substance in an MDI may be optimally chosen. In some embodiments, the particles of active ingredient have diameters of less than about 50 microns. In some embodiments, the particles have diameters of less than about 10 microns. In some embodiments, the particles have diameters of from about 1 micron to about 5 microns. In some embodiments, the particles have diameters of less than about 1 micron. In one advantageous embodiment, the particles have diameters of from about 2 microns to about 5 microns.
[0111] The propellants for use with the MDIs may be any propellants known in the art. Examples of propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofhioromethane, and dichlorotetrafluoroethane; hydrofluoroalkanes (HFAs); and carbon dioxide. It may be advantageous to use HFAs instead of CFCs due to the environmental concerns associated with the use of CFCs. Examples of medicinal aerosol preparations containing HFAs are presented in U.S. Pat. Nos. 6,585,958; 2,868,691 and 3,014,844, all of which are hereby incorporated by reference in their entirety. In some embodiments, a co-solvent is mixed with the propellant to facilitate dissolution or suspension of the drug substance.
32 [0112] In some embodiments, the propellant and active ingredient are contained in separate containers, such as described in U.S. Pat. No. 4,534,345, which is hereby incorporated by reference in its entirety.
[0113] In some embodiments, the MDI used herein is activated by a patient pushing a lever, button, or other actuator. In other embodiments, the release of the aerosol is breath activated such that, after initially arming the unit, the active compound aerosol is released once the patient begins to inhale, such as described in U.S. Pat. Nos. 6,672,304; 5,404,871; 5,347,998; 5,284,133; 5,217,004; 5,119,806; 5,060,643; 4,664,107; 4,648,393; 3,789,843; 3,732,864; 3,636,949; 3,598,294; 3,565,070; 3,456,646; 3,456,645; and 3,456,644, each of which is hereby incorporated by reference in its entirety. Such a system enables more of the active compound to get into the lungs of the patient. Another mechanism to help a patient get adequate dosage with the active ingredient may include a valve mechanism that allows a patient to use more than one breath to inhale the drug, such as described in U.S. Pat. Nos. 4,470,412 and 5,385,140, both of which are hereby incorporated by reference in their entirety.
[0114] Additional examples of MDIs known in the art and suitable for use herein include U.S. Pat. Nos. 6,435,177; 6,585,958; 5,642,730; 6,223,746; 4,955,371; 5,404,871; 5,364,838; and 6,523,536, all of which are hereby incorporated by reference in their entirety.
Dry Powder Inhaler (DPI)
[0115] There are two major designs of dry powder inhalers. One design is the metering device in which a reservoir for the drug is placed within the device and the patient adds a dose of the drug into the inhalation chamber. The second is a factory -metered device in which each individual dose has been manufactured in a separate container. Both systems depend upon the formulation of drug into small particles of mass median diameters from about 1 to about 5 um, and usually involve co-formulation with larger excipient particles (typically 100 um diameter lactose particles). Drug powder is placed into the inhalation chamber (either by device metering or by breakage of a factory -metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs.
[0116] As with liquid nebulization and MDIs, particle size of the delafloxacin aerosol formulation may be optimized. If the particle size is larger than about 5 um MMAD then the particles are deposited in upper airways.
33 [0117] By non-limiting example, in dry powder inhalers, delafloxacin compositions are prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, preferably from about 14 to about 350 mg in about 1 to about 5 ml, and most preferably from about 28 to about 280 mg in about 1 to about 5 ml with MMAD particles sizes between about 2 to about 5 um being produced.
[0118] In some embodiments, a dry powder inhaler (DPI) is used to dispense the delafloxacin. DPIs contain the drug substance in fine dry particle form. Typically, inhalation by a patient causes the dry particles to form an aerosol cloud that is drawn into the patient's lungs. The fine dry drug particles may be produced by any technique known in the art. Some well-known techniques include use of a jet mill or other comminution equipment, precipitation from saturated or super saturated solutions, spray drying, in situ micronization (Hovione), or supercritical fluid methods. Typical powder formulations include production of spherical pellets or adhesive mixtures. In adhesive mixtures, the drug particles are atached to larger carrier particles, such as lactose monohydrate of size about 50 to about 100 microns in diameter. The larger carrier particles increase the aerodynamic forces on the carrier/drug agglomerates to improve aerosol formation. Turbulence and/or mechanical devices break the agglomerates into their constituent parts. The smaller drug particles are then drawn into the lungs while the larger carrier particles deposit in the mouth or throat. Some examples of adhesive mixtures are described in U.S. Pat.
No. 5,478,578 and PCT Publication Nos. WO 95/11666, WO 87/05213, WO 96/23485, and WO 97/03649, all of which are incorporated by reference in their entirety. Additional excipients may also be included with the drug substance.
[0119] There are three common types of DPIs, all of which may be used with the delafloxacin compositions described herein. In a single-dose DPI, a capsule containing one dose of dry drug substance/excipients is loaded into the inhaler. Upon activation, the capsule is breached, allowing the dry powder to be dispersed and inhaled using a dry powder inhaler. To dispense additional doses, the old capsule must be removed, and an additional capsule loaded. Examples of single-dose DPIs are described in U.S. Pat. Nos. 3,807,400; 3,906,950; 3,991,761; and 4,013,075, all of which are hereby incorporated by reference in their entirety. In a multiple unit dose DPI, a package containing multiple single dose compartments is provided. For example, the package may comprise a blister pack, where each blister compartment contains one dose. Each dose can be dispensed upon breach of a blister compartment. Any of several arrangements of compartments in the package can be used. For example, rotary or strip arrangements are common. Examples of multiple unit does DPIs are described in EPO Patent Application Publication Nos. 0211595A2, 0455463A1, and 0467172A1, all of which are hereby incorporated by reference in their entirety. In a multi-dose DPI, a single reservoir of dry powder
34 is used. Mechanisms are provided that measure out single dose amounts from the reservoir to be aerosolized and inhaled, such as described in U.S. Pat. Nos. 5,829,434; 5,437,270; 2,587,215; 5,113,855; 5,840,279; 4,688,218; 4,667,668; 5,033,463; and 4,805,811 and PCT Publication No. WO 92/09322, all of which are hereby incorporated by reference in their entirety.
[0120] In some embodiments, auxiliary energy in addition to or other than a patient's inhalation may be provided to facilitate operation of a DPI. For example, pressurized air may be provided to aid in powder de-agglomeration, such as described in U.S. Pat. Nos. 3,906,950; 5,113,855; 5,388,572; 6,029,662 and PCT Publication Nos. WO 93/12831, WO 90/07351, and WO 99/62495, all of which are hereby incorporated by reference in their entirety. Electrically driven impellers may also be provided, such as described in U.S. Pat. Nos. 3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT Publication No. WO 98/03217, all of which are hereby incorporated by reference in their entirety. Another mechanism is an electrically poared tapping piston, such as described in PCT Publication No. WO 90/13327, which is hereby incorporated by reference in its entirety. Other DPIs use a vibrator, such as described in U.S. Pat. Nos. 5,694,920 and 6,026,809, both of which are hereby incorporated by reference in their entirety. Finally, a scraper system may be employed, such as described in PCT Publication No. WO 93/24165, which is hereby incorporated by reference in its entirety.
[0121] Additional examples of DPIs for use herein are described in U.S. Pat. Nos. 4,811,731;
5,113,855; 5,840,279; 3,507,277; 3,669,113; 3,635,219; 3,991,761; 4,353,365; 4,889,144,
4,907,538; 5,829,434; 6,681,768; 6,561,186; 5,918,594; 6,003,512; 5,775,320; 5,740,794; and
6,626,173, all of which are hereby incorporated by reference in their entirety.
[0122] In certain embodiments, a spacer or chamber may be used with any of the inhalers described herein to increase the amount of drug substance that gets absorbed by the patient, such as is described in U.S. Pat. Nos. 4,470,412; 4,790,305; 4,926,852; 5,012,803; 5,040,527; 5,024,467; 5,816,240; 5,027,806; and 6,026,807, all of which are hereby incorporated by reference in their entirety. For example, a spacer may delay the time from aerosol production to the time when the aerosol enters a patient's mouth. Such a delay may improve synchronization between the patient's inhalation and the aerosol production. A mask may also be incorporated for infants or other patients that have difficulty using the traditional mouthpiece, such as is described in U.S. Pat. Nos. 4,809,692; 4,832,015; 5,012,804; 5,427,089; 5,645,049; and 5,988,160, all of which are hereby incorporated by reference in their entirety.
[0123] Dry powder inhalers (DPIs), which involve deaggregation and aerosolization of dry powders, normally rely upon a burst of inspired air that is drawn through the unit to deliver a drug dosage. Such devices are described in, for example, U.S. Pat. No. 4,807,814, which is
35 directed to a pneumatic powder ejector having a suction stage and an injection stage; SU 628930 (Abstract), describing a hand-held powder disperser having an axial air flow tube; Fox et al., Powder and Bulk Engineering, pages 33-36 (March 1988), describing a venturi eductor having an axial air inlet tube upstream of a venturi restriction; EP 347779, describing a hand-held powder disperser having a collapsible expansion chamber, and U.S. Pat. No. 5,785,049, directed to dry powder delivery devices for drugs.
Methods
[0124] Certain methods provided herein relate to the use of aerosolized delafloxacin for the treatment or prophylaxis of lung conditions, in particular, bacterial infections of the lung and upper respiratory tract. Methods include treating a pulmonary infection by administering to a subject in need thereof a therapeutically effective amount of an aerosol comprising delafloxacin. In certain embodiments, the aerosol comprising delafloxacin comprises an aerosol of a liquid solution or suspension of delafloxacin, such as an aqueous solution or suspension. In certain embodiments, the aerosol comprising delafloxacin comprises solid particles comprising delafloxacin. In certain embodiments, the aerosol comprising delafloxacin comprises liposomes comprising delafloxacin. Administration can be performed by any suitable method, such as the use of an inhaler, such as a dry powder inhaler or liquid nebulizer, as described elsewhere herein. In certain embodiments, the aerosolized delafloxacin is administered using a ventilator.
[0125] As used herein, a "therapeutically effective amount" or "pharmaceutically effective amount" includes those amounts of a delafloxacin composition that produce a desired therapeutic effect. In particular embodiments, the delafloxacin is administered in a pre-determined dose, and thus a therapeutically effective amount would be an amount of the dose administered. This amount and the amount of the delafloxacin can be routinely determined by one of skill in the art, and can vary, depending on several factors, such as the particular microbial strain involved. This amount can further depend upon the patient's height, weight, sex, age, medical history, and the like. For prophylactic treatments, a therapeutically effective amount is that amount which would be effective to prevent a microbial infection.
[0126] Certain methods provided herein relate to administering aerosolized delafloxacin to a subject so that a desired level of delafloxacin is achieved, for example a desired level in one or more pulmonary structures to be treated, or a desired level in one or more samples that are related to pulmonary structures to be treated, such as for example, bronchial alveolar lavage or sputum.
[0127] Certain methods provided herein relate to administering aerosolized delafloxacin to a subject so that a desired degree of reduction in pulmonary infection is achieved. Any suitable
36 manner of measuring a level of pulmonary infection may be used, for example, measuring a reduction in the density of the organism in a sample, such as for example, bronchial alveolar lavage or sputum. In certain embodiments, the density of the organism in a sample, e.g. a sputum sample or a bronchial alveolar lavage sample, is reduced by at least 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%. In certain embodiments, the density of the organism in a sample, e.g., a sputum sample or bronchial alveolar lavage sample, is reduced by at least 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9, 99.95, 99.99, or 100%. In certain embodiments the density of an organism in a sample, e.g., a sputum or bronchial lavage sample, is reduced by at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 logio CFU/g sputum or lavage fluid, or more.
[0128] Methods and compositions described herein can be used to treat pulmonary infections disorders, in particular pulmonary bacterial infections. In certain embodiments, the infection is associated with another disorder. In certain embodiments, the other disorder is cystic fibrosis. In certain embodiments, the disorder is chronic obstructive pulmonary disease (COPD). In certain embodiments the other disorder is asthma. In certain embodiments, the disorder is sinusitis. In certain embodiments, the disorder is rhinosinusitis. In certain embodiments, a subject suffering from a bacterial infection is on a ventilator. In certain embodiments, the bacterial infection is tuberculosis, e.g., drug-resistant tuberculosis.
[0129] The dosage of delafloxacin per administration of the aerosolized delafloxacin can be any suitable dose.
[0130] The amount of delafloxacin that can be administered (as a respirable dose, nebulizer loaded dose, and/or deposited dose) can include at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, about 30 mg, 35 mg, about 40 mg, 45 mg, about 50 mg, 55 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700
37 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or 800 mg and/or not more than about 10 mg, 15 mg, 20 mg, 25 mg, about 30 mg, 35 mg, about 40 mg, 45 mg, about 50 mg, 55 mg, about 60 mg„ about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, or about 900 mg.
[0131] For an adult, the following dosages per administration may be used:
[0132] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-80, 1-70, 2-60, 5-50, 10-30, or 20 mg.
[0133] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-90, 1-80, 2-70, 5-60, 20-40, or 30 mg.
[0134] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-110, 1-100, 1-90, 2-80, 5-70, 40-60, or 50 mg.
[0135] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 10-140, 20-130, 40-120, 50-110, 60-100, 70-90, or 80 mg.
[0136] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-160, 50-150, 60-140, 70-130, 80-120, 90-110, or lOOmg.
[0137] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-200, 60-180, 70-170, 80-160, 90-150, 100-140, 110-130, or 120mg.
[0138] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 80-220, 90-210, 100-200, 110-190, 120-180, 130-170, 140-160, or 150 mg.
38 [0139] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 90-210, 100-220, 110-210, 120-200, 130-190, 140-180, 150-170, or 160 mg.
[0140] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-140, 110-130, 120-220, 130-210, 140-200, 150-190, 160-180, or 170 mg.
[0141] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-250, 120-240, 130-230, 140-220, 150-210, 160-200, 170-190, or 180 mg.
[0142] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-260, 130-250, 140-240, 150-230, 160-220, 170-210, 180-200, or 190 mg.
[0143] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-300, 120-270, 150-250, 160-240, 170-230, 180-220, 190-210, or 200 mg.
[0144] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-390, 100-320, 120-300, 150-270, 170-250, 180-240, 190-230, 200-220, or 210 mg.
[0145] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-390, 100-340, 130-310, 160-280, 180-260, 190-250, 200-240, 210-230, 220 mg.
[0146] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-350, 140-320, 170-290, 190-270, 200-260, 210-250, 220-240, or 230 mg.
[0147] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-430, 100-380, 130-350, 160-320, 180-300, 200-280, 210-270, 220-260, 230-250, or 240 mg.
[0148] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-400, 130-370, 160-340, 180-320, 200-300, 210-290, 220-280, 230-270, 240-260, or 250 mg.
39 [0149] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-420, 120-400, 150-370, 170-350, 200-320, 220-300, 230-290, 240-280, 250-270, or 260 mg.
[0150] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-440, 150-390, 180-360, 210-330, 230-310, 240-300, 250-290, 260-280, or 270 mg.
[0151] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-450, 140-420, 170-390, 200-360, 220-340, 240-320, 250-310, 260-300, 270-290, or 280 mg.
[0152] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-460, 150-430, 180-400, 210-370, 230-350, 250-330, 260-320, 270-310, 280-300, or 290 mg.
[0153] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 70-430, 100-400, 120-380, 140-360, 160-340, 170-330, 180-320, 190-310, 190-310, 195-305, or 300 mg.
[0154] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-520, 170-450, 200-420, 230-390, 250-370, 270-350, 280-340, 290-330, 300-320, 310 mg.
[0155] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 190-450, 220-420, 250-390, 270-370, 290-350, 300-340, 310-330, or 320 mg.
[0156] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-460, 240-420, 270-390, 290-370, 300-360, 310-350, 320-340, or 330 mg.
[0157] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-490, 240-450, 270-410, 290-390, 310-370, 320-360, 330-350, or 340 mg.
[0158] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-500, 240-460, 270-430, 300-400, 320-380, 330-370, 340-360, or 350 mg.
40 [0159] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-520, 230-490, 260-460, 290-430, 310-410, 330-390, 340-380, 350-370, or 360 mg.
[0160] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-490, 290-450, 310-430, 330-410, 340-400, 350-390, 360-380, or 370 mg.
[0161] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 230-530, 270-490, 300-460, 320-440, 340-420, 350-410, 360-400, 370-390, or 380 mg.
[0162] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-530, 300-480, 330-450, 350-430, 360-420, 370-410, 380-400, or 390 mg.
[0163] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 260-540, 300-500, 330-470, 350-450, 370-430, 380-420, 390-410, or 400 mg.
[0164] In certain embodiments, the subject is an adult and the dosage per administration is 50-500, 100-450, 200-400, 250-350, 280-320, 290-310, or 300 mg; or 100-600, 200-500, 300- 400, 320-380, 340-360, or 350 mg; or 100-700, 200-600, 300-500, 350-450, 380-420, 390-410, or 400 mg; or 50-600, 100-500, 200-400, 230-270, 240-260, or 250 mg; or 50-400, 100-300, 150-250, 180-220, 190-210, or 200 mg.
[0165] In certain embodiments, the subject is a pediatric patient and, as appropriate, the dosage may be reduced, e.g., to less than 90, 80, 70, 60, 50, 40, 30, or 20% of the adult dose.
[0166] In certain embodiments, a respirable drug dose (RDD) of at least 20, 100, 125, or 150mg of delafloxacin is administered to the lung. In certain embodiments, a loaded dose of at least 100, 200, 250, 300, 350, or 400 mg of delafloxacin is aerosolized.
Treatment of pulmonary bacterial infection
[0167] In certain embodiments, provided herein is a method of treating a subject, such as a mammal, e.g., a human subject, suffering from a bacterial infection by administering a therapeutically effective amount of an aerosolized delafloxacin composition, such as one of the compositions described herein, e.g., a liquid formulation such as an aqueous formulation, a dry powder formulation, or a liposomal formulation. In certain embodiments the subject is a human with pneumonia, a chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis,
41 asthma, sinusitis, rhinosinusitis, or cystic fibrosis, or a human being mechanically ventilated. In certain embodiments the subject is a human with pneumonia. In certain embodiments the subject is a human with COPD. In certain embodiments the subject is a human with chronic bronchitis. In certain embodiments the subject is a human with bronchiectasis. In certain embodiments the subject is a human with asthma. In certain embodiments the subject is a human with sinusitis. In certain embodiments the subject is a human with rhinosinusitis. In certain embodiments the subject is a human with cystic fibrosis. In certain embodiments the subject is a human that is mechanically ventilated. In certain embodiments the subject is a human with tuberculosis, e.g., multi-drug resistant tuberculosis.
[0168] The infection can be any pulmonary infection suitable for treatment with aerosolized delafloxacin. In certain embodiments the infection comprises one or more bacteria that can include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas sp., e.g., Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrohacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis. Shigella dysenteriae. Shigella flexneri, Shigella sonnei, Enterohacter cloacae, Enterohacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi. Pasteurella multocida, Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia sp., e.g., Burkholderia cepacia, Francisella tularensis, Kingella, Moraxella, or a combination of two or more of the above.
[0169] In certain embodiments, the pulmonary infection can include a gram-negative anaerobic bacteria. In certain embodiments, the pulmonary infection can include one or more of Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus .
[0170] In certain embodiments, the pulmonary infection can include a gram-positive bacteria. In certain embodiments, the pulmonary infection can include one or more of Corynebacterium
42 diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus milleri; Streptococcus (Group G); Streptococcus (Group C/F); Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius. Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus .
[0171] In some embodiments, the pulmonary infection can include a gram-positive anaerobic bacteria. In some embodiments, the pulmonary infection can include one or more of Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum.
[0172] In certain embodiments, the pulmonary infection can include an acid-fast bacteria. In certain embodiments, the pulmonary infection can include one or more of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium leprae.
[0173] In certain embodiments, the pulmonary infection can include an atypical bacteria. In certain embodiments, the pulmonary infection can include one or more of Chlamydia pneumoniae and Mycoplasma pneumoniae.
[0174] In certain embodiments, the pulmonary infection can comprise a non-fermenting gram-negative bacteria (NFGNB). Examples of NFGNB can include Burkholeria spp., Stenotrophomonas spp., Acinetobacter spp; Pseudomonas spp., and Achromobacter spp .
[0175] In certain embodiments, the bacterial infection is an antibiotic-resistant bacterial infection. In certain embodiments, the bacterial infection comprises Pseudomonas bacteria, such as is Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, or a combination of two or more thereof. In certain embodiments, the infection is a Pseudomonas aeruginosa infection. In certain embodiments, the bacterial infection is a methicillin resistant Staphylococcus aureus (MRSA) infection. In certain embodiments, the infection is a Streptococcus pneumonia (Sp) infection. In certain embodiments, the infection comprises one or more Mycobacterium, such as one or more of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, or Mycobacterium leprae , for ex ple Mycobacterium avium or Mycobacterium intracellulare . In certain embodiments, the bacterial infection comprises Haemophilus influenzae . In certain embodiments the bacterial infection comprises Haemophilus parainfluenza. In certain embodiments the bacterial infection comprises Moraxella catarrhalis .
[0176] The composition can be in in any pharmaceutically acceptable dosage form. In certain embodiments, the composition is an aqueous composition. In certain embodiments, the
43 composition is a dry powder formulation. In certain embodiments, the composition is a liposomal composition. In certain embodiments, the composition comprises a combination of formulations, e.g., aqueous solution and liposomal suspension; such a formulation can allow for both immediate effects, e.g., from the aqueous solution, and longer-term effects, e.g., from liposomes. Distribution of the different formulations may also be different, increasing effectiveness. Delafloxacin in the aerosolized delafloxacin composition may be in any suitable form, as described herein.
[0177] In certain embodiments, the delafloxacin is administered with a divalent or trivalent cation, or combination thereof, such as magnesium, calcium, zinc, copper, aluminum, or iron, or a combination thereof; in certain embodiments, the delafloxacin is administered with a divalent cation, such as magnesium or calcium; in certain embodiments, the delafloxacin is administered with a divalent cation, such as magnesium, for example, magnesium chloride. In liquid formulations, e.g., aqueous formulations, concentrations of the divalent or trivalent cation, or combination thereof, e.g., magnesium, such as magnesium chloride, may be any suitable concentration, such as 50-400 mM, e.g., where the delafloxacin concentration is 5-80, 10-70, 20- 60, 20-50, 20-40, 30-100, 40-100, 50-120, 60-120, or 50-200 mg/ml, or 100-300 mM, e.g., where the delafloxacin concentration is 75-150 mg/ml, or 150-250 mM, e.g., where the delafloxacin concentration is 5-80, 10-70, 20-60, 20-50, 20-40, 30-100, 40-100, 50-120, 60-120, or 90-125 mg/ml.
[0178] In certain embodiments, the delafloxacin composition is an aqueous composition. In these embodiments, the osmolarity of the composition may be any suitable osmolarity, as described herein, for example 200-1250, 250-1050, 300-500, 350-750, or 350-425 mOsmol/kg.
A permeant ion concentration may be any suitable concentration as described herein, for example 30-300 mM, such as 50-200 mM. In one such embodiment, one or more permeant ions in the composition are selected from the group consisting of chloride and bromide. In certain embodiments, the delafloxacin composition comprises a taste-masking agent, which can be any taste-masking agent as described herein, such as a sugar, a divalent or trivalent cation or combination thereof that complexes with the delafloxacin, optimized osmolality, and/or an optimized permeant ion concentration. pH can be any suitable pH, e.g., 5-8, 5-7.5, 5-7, 5-6.5, 5- 6, 5.5-8, 5.5-7.5, 5.5-7, 5.5-6.5, 6-8, 6-7.5, 6-7, 6-6.5, 6.5-8, 6.5-7.5, or 6.5-7. In certain embodiments the pH is 5-8. In certain embodiments the pH is 5-6.5. In certain embodiments the pH is 5.5-6.5.
44 [0179] In certain embodiments the delafloxacin composition is an aqueous composition with a divalent cation, e.g., magnesium, at a concentration of 50-400 mM, a pH of 5-8, and an osmolarity of 200-1250 mOsmol/kg.
[0180] In certain embodiments, the delafloxacin composition is an aqueous composition comprising delafloxacin at a concentration between 5-80, 10-70, 20-60, 20-50, 20-40, 30-100, 40-100, 50-120, 60-120, or 50-200 mg/ml, such as 20-100 mg/ml, or 20-80 mg/ml, or 30-100 mg/ml, or 30-80 mg/ml, or 80-150 mg/ml, in some cases 90-110 mg/ml, a magnesium chloride concentration of 100-400 mM, such as 125-300 mM, in some cases 175 mM to about 225 mM, and a pH of 5-8, in some cases 5-7.5, such as 5-7; an osmolarity of 200-1250 mOsmol/kg, in some cases 250-1050 mOsmol/kg, for example 250-550 mOsmol/kg, in particular 300-500 mOsmol/kg, and, optionally, lacks lactose. In certain embodiments the delafloxacin composition is an aqueous composition with a delafloxacin concentration of 20-50 mg/ml or 90-110 mg/ml, a magnesium chloride concentration of 175-225 mM, a pH of 5-7; an osmolarity of 300- mOsmol/kg. In certain embodiments the delafloxacin composition lacks lactose.
[0181] In certain embodiments, the delafloxacin composition is a dry powder composition, such as a dry powder composition as described herein, e.g. a dry powder composition with or without a blending agent such as lactose.
[0182] In certain embodiments, the delafloxacin composition is a liposomal composition, such as a liposomal composition described herein.
[0183] The delafloxacin is administered in any suitable manner, depending on the nature of the delafloxacin composition, e.g., by liquid nebulizer, dry powder inhaler, ventilator, or any other suitable method as described herein. Further description of specific inhalers
[0184] In certain embodiments the duration of a therapy, e.g., an aerosolized delafloxacin therapy can include at least about 1 day/month, at least about 2 days/month, at least about 3 days/month, at least about 4 days/month, at least about 5 days/month, at least about 6 days/month, at least about 7 days/month, at least about 8 days/month, at least about 9 days/month, at least about 10 days/month, at least about 11 days/month, at least about 12 days/month, at least about 13 days/month, at least about 14 days/month, at least about 15 days/month, at least about 16 days/month, at least about 17 days/month, at least about 18 days/month, at least about 19 days/month, at least about 20 days/month, at least about 21 days/month, at least about 22 days/month, at least about 23 days/month, at least about 24 days/month, at least about 25 days/month, at least about 26 days/month, at least about 27 days/month, at least about 28 days/month, at least about 29 days/month, at least about 30 days/month, and at least about 31 days/month.
45 [0185] An aerosolized delafloxacin composition can be administered with a frequency of about 1, 2, 3, 4, or more times daily, 1, 2, 3, 4, 5, 6, 7 or more times weekly, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times monthly. In certain embodiments, the compositions are administered twice daily.
[0186] In certain embodiments, the aerosol delafloxacin can be administered once daily, twice daily, three times daily, or four times daily. In certain embodiments, the aerosol delafloxacin is administered once daily. In certain embodiments, the aerosol delafloxacin is administered twice daily. In certain embodiments, the aerosolized delafloxacin is delivered more than twice daily. In certain embodiments, the aerosol delafloxacin can be administered for a period of at least 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 days. In certain embodiments, the aerosol delafloxacin can be administered for about 14 days. In particular embodiments the aerosol delafloxacin is administered daily for 14 days. In certain embodiments, delafloxacin treatment is cycled, for example delafloxacin is delivered in a time period as above, then treatment is stopped for a suitable amount of time, e.g., at least 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 days, then treatment is resumed, e.g., for a period as described herein. In certain embodiments, e.g., treatment of CF, delafloxacin is delivered in a 28 day on/28 day off cycle.
[0187] The daily dosage of delafloxacin can depend on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration, and the judgment of the prescribing physician; for example, a likely dose range for aerosol administration of delafloxacin would be about 20 to 800 mg per day. A daily aerosol dose of delafloxacin can be from about 0.1 to 10 mg/kg of body weight, for example about 0.20 to 8.0 mg/kg of body weight, such as 0.4 to 6.0 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be 7.0 to 840.0 mg per day, such as 14.0 to 470.0 mg per day, such as 28.0 to 350 mg per day.
[0188] The dosage of delafloxacin per administration can be any suitable dosage, such as a dosage described herein.
[0189] The amount of delafloxacin that can be administered (as a respirable dose, nebulizer loaded dose, and/or deposited dose) can include at least about 5 mg, 10 mg, 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about
46 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or 800 mg and/or not more than about 10 mg, 20 mg, 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, or about 900 mg.
[0190] For an adult, the following dosages per administration may be used.
[0191] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-80, 1-70, 2-60, 5-50, 10-30, or 20 mg.
[0192] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-100, 1-90, 1-80, 2-70, 5-60, 20-40, or 30 mg.
[0193] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 1-110, 1-100, 1-90, 2-80, 5-70, 40-60, or 50 mg.
[0194] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 10-140, 20-130, 40-120, 50-110, 60-100, 70-90, or 80 mg.
[0195] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-160, 50-150, 60-140, 70-130, 80-120, 90-110, or lOOmg.
47 [0196] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-200, 60-180, 70-170, 80-160, 90-150, 100-140, 110-130, or 120mg.
[0197] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 80-220, 90-210, 100-200, 110-190, 120-180, 130-170, 140-160, or 150 mg.
[0198] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 90-210, 100-220, 110-210, 120-200, 130-190, 140-180, 150-170, or 160 mg. [0199] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-140, 110-130, 120-220, 130-210, 140-200, 150-190, 160-180, or 170 mg.
[0200] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-250, 120-240, 130-230, 140-220, 150-210, 160-200, 170-190, or 180 mg.
[0201] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-260, 130-250, 140-240, 150-230, 160-220, 170-210, 180-200, or 190 mg.
[0202] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-300, 120-270, 150-250, 160-240, 170-230, 180-220, 190-210, or 200 mg.
[0203] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 40-390, 100-320, 120-300, 150-270, 170-250, 180-240, 190-230, 200-220, or 210 mg. [0204] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-390, 100-340, 130-310, 160-280, 180-260, 190-250, 200-240, 210-230, 220 mg.
[0205] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-400, 100-350, 140-320, 170-290, 190-270, 200-260, 210-250, 220-240, or 230 mg.
48 [0206] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 50-430, 100-380, 130-350, 160-320, 180-300, 200-280, 210-270, 220-260, 230-250, or 240 mg.
[0207] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-400, 130-370, 160-340, 180-320, 200-300, 210-290, 220-280, 230-270, 240-260, or 250 mg.
[0208] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-420, 120-400, 150-370, 170-350, 200-320, 220-300, 230-290, 240-280, 250-270, or 260 mg.
[0209] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-440, 150-390, 180-360, 210-330, 230-310, 240-300, 250-290, 260-280, or 270 mg.
[0210] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 110-450, 140-420, 170-390, 200-360, 220-340, 240-320, 250-310, 260-300, 270-290, or 280 mg.
[0211] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 120-460, 150-430, 180-400, 210-370, 230-350, 250-330, 260-320, 270-310, 280-300, or 290 mg.
[0212] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 70-430, 100-400, 120-380, 140-360, 160-340, 170-330, 180-320, 190-310, 190-310, 195-305, or 300 mg.
[0213] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 100-520, 170-450, 200-420, 230-390, 250-370, 270-350, 280-340, 290-330, 300-320, 310 mg.
[0214] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 190-450, 220-420, 250-390, 270-370, 290-350, 300-340, 310-330, or 320 mg.
[0215] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-460, 240-420, 270-390, 290-370, 300-360, 310-350, 320-340, or 330 mg.
49 [0216] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-490, 240-450, 270-410, 290-390, 310-370, 320-360, 330-350, or 340 mg.
[0217] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-500, 240-460, 270-430, 300-400, 320-380, 330-370, 340-360, or 350 mg.
[0218] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 200-520, 230-490, 260-460, 290-430, 310-410, 330-390, 340-380, 350-370, or 360 mg.
[0219] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-490, 290-450, 310-430, 330-410, 340-400, 350-390, 360-380, or 370 mg.
[0220] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 230-530, 270-490, 300-460, 320-440, 340-420, 350-410, 360-400, 370-390, or 380 mg.
[0221] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 250-530, 300-480, 330-450, 350-430, 360-420, 370-410, 380-400, or 390 mg.
[0222] In certain embodiments, the dosage of delafloxacin per administration of the aerosolized delafloxacin is 260-540, 300-500, 330-470, 350-450, 370-430, 380-420, 390-410, or 400 mg.
[0223] In certain embodiments, the subject is an adult and the dosage per administration is 50-500, 100-450, 200-400, 250-350, 280-320, 290-310, or 300 mg; or 100-600, 200-500, 300- 400, 320-380, 340-360, or 350 mg; or 100-700, 200-600, 300-500, 350-450, 380-420, 390-410, or 400 mg; or 50-600, 100-500, 200-400, 230-270, 240-260, or 250 mg; or 50-400, 100-300, 150-250, 180-220, 190-210, or 200 mg.
[0224] In certain embodiments, the subject is a pediatric patient and, as appropriate, the dosage may be reduced, e.g., to less than 90, 80, 70, 60, 50, 40, 30, or 20% of the adult dose.
[0225] In certain embodiments, a respirable drug dose (RDD) of at least 5, 10, 20, 100, 125, or 150mg of delafloxacin is administered to the lung. In certain embodiments, a loaded dose of at least 20, 40, 60, 80, 100, 200, 250, 300, 350, or 400 mg of delafloxacin is aerosolized.
50 [0226] The aerosol can be administered to the lungs in less than 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, orl minute.
[0227] In certain embodiments, administration of the aerosolized delafloxacin achieves a maximum lung sputum concentration (Cmax) of at least 1200, 1700, 2000, 3000, or 4000 mg/L, for example at least 1200 mg/L and a lung sputum area under the curve (AUC) of at least 1500, 1700, 2000, 3000, or 4000 h mg/L, for example at least 1500 h mg/L. In certain of these embodiments, the delafloxacin composition comprises a divalent or trivalent cation, or a combination thereof, e.g., magnesium, calcium, zinc, copper, aluminum, or iron, or a combination thereof, such as magnesium, in some cases in the form of magnesium chloride, e.g., at a concentration of 50- 400 mM. The delafloxacin concentration in the delafloxacin composition can be 10-100, or 10-200, or 20-100, or 20-80, or 50-200 mg/mL. In certain embodiments, the delafloxacin composition consists essentially of delafloxacin and the divalent or trivalent cation or combination thereof. In certain embodiments, the delafloxacin composition comprises no lactose. In certain embodiments, the delafloxacin composition comprises a divalent or trivalent cation, or combination thereof, such as a divalent cation, e.g., magnesium, at a concentration of 50-400, 100-300, or 150-250 mM. In certain embodiments, the delafloxacin composition comprises delafloxacin at a concentration of 10-100, 10-200, 20-100, or 20-80, 50- 200, 75-150, or 90-125 mg/mL. In certain embodiments, the osmolarity of the delafloxacin composition is 200-800, 300-600, or 350-425 mOsmol/kg. In certain embodiments, the pH of the delafloxacin composition is 5-8, 5-7, 5-6.5, or 5.5-6.5. In certain embodiments the delafloxacin composition comprises a delafloxacin concentration of 20-80 mg/ml, or 20-40 mg/ml, or 90-110 mg/ml, a magnesium chloride concentration of 175-225 mM, a pH of 5-7; an osmolarity of 300-500 mOsmol/kg, and, optionally, lacks lactose.
[0228] In certain embodiments the method comprises administering delafloxacin to the subject, e.g., human, to achieve a concentration in a lung of the subject of at least 5, 10, 20, 25, 27, 32, 35, 40, 45, 50, 70, 100, 200, 500, 800, 1000, 1200, or 1500 pg/ml of delafloxacin, wherein the delafloxacin is administered as an aerosol. In certain embodiments the aerosol comprises a divalent or trivalent cation or combination thereof. In certain embodiments, the aerosol comprises greater than 50 mg/ml delafloxacin and, in certain embodiments, a divalent or trivalent cation, or combination thereof, e.g., magnesium, such as magnesium supplied by magnesium chloride, has a pH of 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, or 5.5-6.5, and an osmolality of 100-1200, 200-1000, 300-900, or 350-750 mOsmol/kg.
[0229] In certain embodiments the method comprises administering delafloxacin to a subject, e.g., human suffering from a bacterial infection caused by at least one type of bacteria, wherein
51 the bacteria is exposed to at least 0.01, 0.05, 0.07, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.2, 1.5, 1.7, 2, 2.5, 3, 4, 5, 7, or 10 mg/L of the delafloxacin, wherein the delafloxacin is administered as an aerosol. In certain embodiments the aerosol comprises a divalent or trivalent cation or combination thereof. In certain embodiments, the aerosol comprises greater than 50 mg/ml delafloxacin and, in certain embodiments, a divalent or trivalent cation, or combination thereof, e.g., magnesium, such as magnesium supplied by magnesium chloride, has a pH of 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, or 5.5-6.5, and an osmolality of 100- 1200, 200-1000, 300-900, or 350-750 mOsmol/kg. In certain embodiments, no other antibiotics are administered by inhalation; in certain embodiments, no other antibiotics are administered. In certain embodiments, at least 5, 10, 20, 50, 70, 100, 120, 150, 170, 200, 220, 250, 270, or 300 mg of delafloxacin is administered.
[0230] In certain embodiments aerosolized delafloxacin is repeatedly administered to a subject, e.g., human, where repeated administration does not result in an incidence of arthralgia. In certain embodiments, administering is repeated at least once daily for 14 days, at least once daily for 28 days, and at least once daily for 35 days. In certain embodiments, administering is repeated at least twice daily for at least 14 days, at least twice daily for at least 28 days, and at least twice daily for at least 35 days.
[0231] In certain embodiments, the delafloxacin compositions is in a unit dosage form, such as vial containing a liquid, solid to be suspended, dry powder, lyophilizate, or other composition. In these embodiments, the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
[0232] In certain embodiments, the particles of the aerosol containing delafloxacin have a mass median aerodynamic diameter of 2-5 with a geometric standard deviation less than or equal to about 2.5 microns.
[0233] In certain embodiments, the particles of the aerosol containing delafloxacin have a mass median aerodynamic diameter of 2.5-4.5 microns with a geometric standard deviation less than or equal to 1.8 microns.
[0234] In certain embodiments, the particles of the aerosol containing delafloxacin have a mass median aerodynamic diameter of 2.8-4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
52 [0235] In certain embodiments, the method also includes producing the aerosol with a vibrating mesh nebulizer. In some such embodiments, the vibrating mesh nebulizer is a PARI E- FLOW™ nebulizer.
[0236] In certain embodiments, the amount of delafloxacin administered to the lung is at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 100 mg, at least about 125 mg, and at least about 150 mg.
[0237] In certain embodiments, at least about 20, 40, 60, 80, or 100 mg the aerosol is administered to the lung in less than about 60, 50, 40, 30, 20, 10, 5, 3 or 2 minutes, preferably less than 40 min, more preferably less than 30 min, even more preferably less than 20 min, still more preferably less than 10 min.
[0238] In certain embodiments the treatment includes administering an additional active agent, for example one or more antibiotics, bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, CFTR modulators, agents to restore airway surface liquid, anti inflammatory agents, or combinations thereof. The coadministration can comprise inhalation of the agent. The agent may be administered as part of the aerosolized delafloxacin, separately, or a combination thereof. In certain embodiments, the antibiotic can include tobramycin, aztreonam, ciprofloxacin, azithromycin, tetracycline, quinupristin, linezolid, vancomycin, and chloramphenicol, colisitin or combinations thereof. In some embodiments, the bronchodilator can include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutlaine, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, theophylline, roflumilast, cilomilast, or combinations thereof. In certain embodiments, the anticholinergic can be ipratropium, tiotropium, and combinations thereof. In certain embodiments, the glucocorticoid can include prednisone, fluticasone, budesonide, mometasone, ciclesonide, beclomethasone, or combinations thereof. In certain embodiments, the eicosanoid inhibitor can include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, seratrodast, or combinations thereof. In certain embodiments the CFTR modulator includes VX-770, atluren, VX-809, or combinations thereof. In certain embodiments, the agent to restore airway surface liquid includes denufosol, mannitol, GS-9411, SPI-8811, or combinations thereof. In certain embodiments, the anti-inflammatory agent includes ibuprofen, sildenafd, simavastatin, or combinations thereof. In certain embodiments, co-administering comprises inhaling the additional active agent. In certain embodiments, e.g., the treatment of CF, the additional active ingredient comprises mannitol.
[0239] In certain embodiments, the aerosol delafloxacin therapy may be administered as a treatment or prophylaxis in combination or alternating therapeutic sequence with other aerosol,
53 oral or parenteral antibiotics. Any suitable antibiotic may be used, e.g., tobramycin and/or other aminoglycoside, aztreonam, carumonam and/or tigemonam and/or other beta or mono-bactam, ciprofloxacin and/or other fluoroquinolones, azithromycin and/or other macrolides or ketolides, tetracycline and/or other tetracyclines, quinupristin and/or other streptogramins, linezolid and/or other oxazolidinones, vancomycin and/or other glycopeptides, rifampicin, and/or chloramphenicol and/or other phenicols, and/or colisitin and/or other polymyxins. In certain embodiments, the antibiotic can include quinolones, tetracyclines, glycopeptides, aminoglycosides, beta-lactams, rifamycins, macrolides/ketolides, oxazolidinones, coumermycins, chloramphenicol, streptogramins, trimethoprim, sulfamethoxazole, or polymyxins. In some embodiments, any of the foregoing antibiotics can be administered by any acceptable method or route, for example, by aerosol, orally or parenterally.
Beta-Lactam Antibiotics
[0240] Beta-lactam antibiotics suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, imipenem, meropenem, biapenem, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephaacetrile, cephalexin, cephaloglycin, cephaloridine, cephalothin, cephapirin, cephradine, cefmetazole, cefoxitin, cefotetan, azthreonam, carumonam, flomoxef, moxalactam, amidinocillin, amoxicillin, ampicillin, azlocillin, carbenicillin, benzylpenicillin, carfecillin, cloxacillin, dicloxacillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin G, piperacillin, sulbenicillin, temocillin, ticarcillin, cefditoren, SC004, KY-020, cefdinir, ceftibuten, FK-312, S-1090, CP-0467, BK-218, FK-037, DQ-2556, FK-518, cefozopran, ME1228, KP-736, CP-6232, Ro 09-1227, OPC-20000, and LY206763.
Macrolides
[0241] Macrolides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, azithromycin, clarithromycin, erythromycin, oleandomycin, rokitamycin, rosaramicin, roxithromycin, and troleandomycin.
Ketolides
[0242] Ketolides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, telithromycin and cethromycin.
Quinolones
54 [0243] Quinolones suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, amifloxacin, cinoxacin, ciprofloxacin, enoxacin, fleroxacin, flumequine, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, levofloxacin, oxolinic acid, pefloxacin, rosoxacin, temafloxacin, tosufloxacin, sparfloxacin, clinafloxacin, moxifloxacin; gemifloxacin; garenofloxacin; PD131628, PD138312, PD140248, Q-35, AM-1155, NM394, T- 3761, rufloxacin, OPC-17116, DU-6859a (see, e.g., Sato, K. et al., 1992, Antimicrob Agents Chemother. 37:1491-98), and DV-7751a (see, e.g., Tanaka, M. et al., 1992, Antimicrob. Agents Chemother. 37:2212-18).
Tetracyclines, Glycylcyclines and Oxazolidinones
[0244] Tetracyclines, glycylcyclines, and oxazolidinones suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, chlortetracycline, demeclocycline, doxycycline, lymecycline, methacycline, minocycline, oxytetracycline, tetracycline, tigecycline, linezolide, and eperozolid.
Aminoglycosides
[0245] Aminoglycosides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to amikacin, arbekacin, butirosin, dibekacin, fortimicins, gentamicin, kanamycin, neomycin, netilmicin, ribostamycin, sisomicin, spectinomycin, streptomycin, and tobramycin.
Lincosamides
[0246] Lincosamides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to, clindamycin and lincomycin.
Streptogramins
[0247] Streptogramins suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to quinupristin.
Glycopeptides
[0248] Glycopeptides suitable for administration in conjunction with inhaled delafloxacin include, but are not limited to vancomycin.
Polymyxins
[0249] Polymyxins suitable for administration in conjunction with inhaled delafloxacin include but are not limited to colisitin.
55 [0250] Additional antibiotics suitable for administration in conjunction with inhaled delafloxacin include fosfomycin, penicillins, cephalosporins, carbapenems, penems, and carbacephems.
[0251] In certain embodiments, treating a subject, e.g., human, suffering from a pulmonary bacterial infection with aerosolized delafloxacin can result in a clinically measurable response, such as a reduction in pulmonary infection, an improvement in a pulmonary function characteristic, such as an improvement in forced expiratory volume (FEV), FEV i (forced expiratory volume in 1 second), and FEF 25-75 (forced expiratory flow 25-75%), reducing the need for other inhaled or systemic antibiotics, decreasing frequency, severity, duration, and/or likelihood of exacerbations.
[0252] A reduction in a pulmonary infection can be measured using any suitable method. For example, in a pulmonary infection comprising one or more organisms, a reduction in the density of the organism can be measured. In some embodiments, treatment can achieve a reduction in the density of an organism by at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%. In some embodiments, treatment can achieve a reduction in the density of an organism by at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 100%.
[0253] The density of an organism can be measured in a sample taken from a subject, for example, bronchial alveolar lavage, sputum, or serum. In certain embodiments the density of an organism can be reduced by at least about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.8, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5 logio CFU/g sputum, or more.
[0254] Certain embodiments of the methods and compositions described herein can include achieving an improvement in a pulmonary function parameter. Examples of such parameters can include FEV (forced expiratory volume), FEV i (forced expiratory volume in 1 second), and/or FEF 25-75 (forced expiratory flow 25-75%). In certain embodiments, the FEViof a subject can be increased using the methods and compositions described herein, by at least about 1%, 2%,
3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, and more. In certain embodiments, the FEViof a subject can be increased using the methods and compositions described herein, by at least about 0.01 L, 0.02 L,
56 0.03 L, 0.04 L, and 0.05 L, and by at least about 0.1 L, 0.2 L, 0.3 L, 0.4 L, 0.5 L, 0.6 L, 0.7 L, 0.8 L, 0.9 L, 1.0 L, and more.
[0255] In certain embodiments, the FEF 25-75 of a subject can be increased using the methods and compositions described herein, by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%,
8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, and 25%. In certain embodiments, the FEF 25-75 of a subject can be increased using the methods and compositions described herein, by at least about 0.01 L, 0.02 L, 0.03 L, 0.04 L, and 0.05 L, and by at least about 0.1 L, 0.2 L, 0.3 L, 0.4 L, 0.5 L, 0.6 L, 0.7 L, 0.8 L, 0.9 L, 1.0 L, or more.
[0256] Certain embodiments of the methods and compositions described herein can include reducing the need for a subject to need other inhaled or systemic antibiotics, such as anti- pseudomonal antimicrobials. Such a reduction can be measured by any suitable method, for example, by the increase in time to need other inhaled or systemic antibiotics. A reduction in such a need can be measured by a variety of statistical means. For example, hazard ratios may be used in a survival analysis. In some embodiments, the hazard ratio is less than about 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, and less.
[0257] Some embodiments of the methods and compositions described herein can include decreasing the frequency of exacerbations, the severity of exacerbations, the duration of exacerbations, and/or the likelihood that an exacerbation will occur. An exacerbation can be defined by any of several methods and criteria provided by such methods. In certain embodiments, a patient can concurrently meet at least 4 symptoms/signs of the Fuchs definition of an exacerbation (Fuchs H J, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994; 331:637-642). The symptoms/signs defined by the Fuchs criteria include: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue or lethargy; temperature above 38 °C.; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10% or more from a previously recorded value; and radiographic changes indicative of pulmonary infection.
[0258] In certain embodiments, a patient with an improved exacerbation profile can have at least 1, at least 2, at least 3, and at least 4 of the following signs/symptoms, where changes can be relative to a patient's typical experience, for example daily experience, and weekly experience. (1) Change in sputum, e.g., for sputum production: patients have no change, a little less or much less amounts of sputum when coughing up, or for change in sputum appearance: for sputum thickness, patients have a little thinner or much thinner sputum; for sputum color, patients have a
57 better color of sputum (better increases from brown-^green-^yellow-^clear). (2) Hemoptysis, e.g., patients have a little decrease or a large decrease in the amount of blood coughed up. (3) Cough, e.g., for intensity of cough, patients have a little lighter, or much lighter coughs; for frequency of cough, patients cough a little less often or much less often. (4) Dyspnea, e.g., for dyspnea with exertion, patients breathe a little easier or much easier when performing daily activities. (5) Malaise, fatigue or lethargy, e.g., patients have a little more energy or much more energy, and/or patients perform daily activities, e.g., climbing stairs, a little easier, or much easier. (6) Temperature, e.g., patients have normal healthy temperature e.g., about 37 °C., or patients have no recent history of fever. (7) Anorexia or weight loss, e.g., patients have no change in weight, or a little weight gain, and/or patients have a little increase in appetite (8)
Sinus pain or tenderness, e.g., patient has no sinus pain or tenderness, or less sinus pain or tenderness. (9) Change in sinus discharge, e.g., patients have better sinus discharge (a decrease in thickness and/or better color). (10) Change in physical examination of the chest, e.g., patients have improved signs on examination of the chest and may report for example, a little decrease chest congestion, or a large decrease in chest congestion. (11) Pulmonary function by 10% or more from a previously recorded value, e.g., patients have improved pulmonary function in pulmonary function tests. (12) Radiographic changes indicative of pulmonary infection, e.g. patients show improved radiographic changes indicating reduced pulmonary infection.
[0259] In certain embodiments, exercise tolerance and/or absenteeism from scheduled events, e.g., school or work can be measured as signs/symptoms of exacerbations.
[0260] Summaries of such characteristics are known in the art; see, e.g., Table 1 of U.S. Patent No. 10,792,289.
[0261] In certain embodiments, the treatment results in one, two, three, four, five, or six of an increase in a CFQ-R respiratory domain greater than 1; a reduction in the density of bacteria by at least 40%; an increase in FEVi of at least 2%; an increase in FEF 25-75 of at least 5%; a hazard ratio less than 1.0; a dose-normalized serum Cmaxof delafloxacin greater than 2 pg/L/mg; and/or a dose-normalized serum AUC of delafloxacin of at least 20 (ng h/L)/mg.
[0262] Some embodiments of any of the above methods include administering delafloxacin in combination with a divalent or trivalent cation, or combination thereof, in a dosage amount, administration schedule, and/or method of administration sufficient to achieve the above recited outcomes.
[0263] In some cases some or all of bacteria causing an infection can be distributed in a biofilm. Delafloxacin compositions such as those described herein may be particularly effective against bacteria in biofilms; without being bound by theory, it is thought that this is because,
58 unlike most other fluoroquinolones, it lacks an easily protonable functionality responsible for reduced activity these antibiotics in the biofilm environment. See, e.g., Tulkens, et al., Profile of a novel anionic fluorquinolone — delafloxacin, Clin Inf Dis 68:S213-S222, http://doi.org/10.1093/cid/ciyl079.
Treatment of pulmonary infection in a human with cystic fibrosis
[0264] In certain embodiments, provided herein is a method of treating a human subject with cystic fibrosis who is suffering from a bacterial infection by administering a therapeutically effective amount of an aerosolized delafloxacin composition, such as one of the compositions described herein, e.g., a liquid formulation such as an aqueous formulation, a dry powder formulation, or a liposomal formulation. Bacteria to be treated, delafloxacin compositions, frequency of dosing, dosage amounts, duration of aerosol administration, concentrations or effects to be achieved, particle size of the aerosols, additional treatment modalities, indications of effective treatment, and the like, may be any suitable embodiment, as described above, “Treatment of pulmonary bacterial infections.”
[0265] In certain embodiments, the bacterial infection can be any bacterial infection susceptible to treatment with delafloxacin. In certain embodiments, the bacterial infection is an antibiotic-resistant bacterial infection. In certain embodiments, the bacterial infection comprises Pseudomonas bacteria, such as is Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, or a combination of two or more thereof. In certain embodiments, the infection is a Pseudomonas aeruginosa infection. In certain embodiments, the bacterial infection is a methicillin resistant Staphylococcus aureus (MRSA) infection. In certain embodiments, the infection is a Streptocossus pneumonia (Sp) infection. In certain embodiments, the infection comprises one or more Mycobacterium, such as one or more of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, or Mycobacterium leprae, for example Mycobacterium avium or Mycobacterium intracellulare . In In certain embodiments, the bacterial infection comprises Haemophilus influenzae . In certain embodiments the bacterial infection comprises Haemophilus parainfluenza. In certain embodiments the bacterial infection comprises Moraxella catarrhalis. Other bacteria that can be treated include those described in Treatment of pulmonary bacterial infections”.
[0266] In certain embodiments, the aerosol delafloxacin can be administered daily, or twice daily. In certain embodiments, the aerosol delafloxacin can be administered for a period of at least 1 day, 3 days, 5 days, 10 days, 15 days, 20 days, or 30 days. In certain embodiments, the aerosol delafloxacin can be administered for about 14 days. In particular embodiments the
59 aerosol delafloxacin is administered daily for 14 days. In certain embodiments, the aerosol delafloxacin is delivered for a period of 28 days on, 28 days off. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a pediatric patient. In certain embodiments, the subject has an age less than about 18 years, less than about 17 years, less than about 16 years, less than about 15 years, less than about 14 years, less than about 13 years, less than about 12 years, less than about 11 years, less than about 10 years, less than about 9 years, less than about 8 years, less than about 7 years, less than about 6 years, less than about 5 years, less than about 4 years, less than about 3 years, less than about 2 years, and less than about 1 year. Dosage will generally depend on the age and/or weight of the subject. In certain embodiments, the subject is an adult and the dosage pre administration is 10-100, 10-200, 20- 100, 20-80, 50-500, 100-450, 200-400, 250-350, 280-320, 290-310, or 300 mg; or 100-600, 200- 500, 300-400, 320-380, 340-360, or 350 mg; or 100-700, 200-600, 300-500, 350-450, 380-420, 390-410, or 400 mg; or 50-600, 100-500, 200-400, 230-270, 240-260, or 250 mg; or 50-400, 100-300, 150-250, 180-220, 190-210, or 200 mg. Other suitable dosages are as described in “Treatment of pulmonary bacterial infections” In certain embodiments, the subject is a pediatric patient and the dosage is reduced appropriately, e.g., to less than 90, 80, 70, 60, 50, 40, 30, or 20% of the adult dose.
[0267] In certain embodiments, provided is a method for treating a pulmonary infection in a human having cystic fibrosis, wherein the pulmonary infection comprises one or more Mycobacterium, comprising administering via inhalation 50-1000, 75-800, 100-500, 100-400, 200-500, 200-400, 250-350, or 300 mg of delafloxacin twice daily for 28 days to the human having cystic fibrosis to treat the Mycobacterium pulmonary infection. The delafloxacin can in an aerosol of a solution comprising delafloxacin at a concentration from about 10, 20, 30, 40, 50, 60, 70, 80, or 90 mg/ml to about 20, 30, 40, 50, 60, 70, 80, 90, 100 orl 10 mg/ml, a magnesium cation at a concentration from about 175 mM to about 225 mM, wherein the solution has a pH from about 5 to about 7, and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg. In certain embodiments the delafloxacin composition lacks lactose.
[0268] In certain embodiments, provided is a method for treating a chronic pulmonary infection due to Pseudomonas, e.g., Pseudomonas aeruginosa in a subject, e.g., human, with cystic fibrosis in need thereof, the method comprising administering to the lungs of the subject with cystic fibrosis an aerosol of a solution comprising 10-500, 20-400, 20-100, 30-300, 30-100, 40-200, 50-200, 70-200, 50-150, 90-110, or 100 mg/ml of delafloxacin to treat the chronic pulmonary infection due to Pseudomonas, e.g., Pseudomonas aeruginosa. In certain embodiments the composition further comprises a trivalent or divalent cation, or a combination thereof, e.g., a divalent cation, such as magnesium, for example magnesium at a concentration of
60 50-300, 100-250, 120-220, 180-220, 190-210, or 200 mM of magnesium chloride. In certain embodiments the solution has a pH from about 5 to about 7. In certain embodiments the solution has an osmolality of 100-600, 150-550, 200-500, 250-450, 225-425, 250-450, 300-500, 300-450, or 350-400 mOsmol/kg.
EXAMPLES
Example 1
Delafloxacin Metal Ion Complexes
[0269] The goal of this study is to prepare delafloxacin of various chelate salt forms to obtain, e.g., taste-masking properties, AUC shape-enhancing properties through changes in solubility, dissolution and/or bioavailability. These benefits may enhance the pharmacodynamic properties of delafloxacin following pulmonary administration using nanoparticle suspension, dry powder inhalation or simple liquid formulations. These formulations may be optimized to create AUC shape -enhancing formulations of delafloxacin from altered solubility, or slow- release or low bioavailability chelates.
Preparation of Delafloxacin-Metal Ion Complexes
Preliminary Studies
[0270] A mixture of delafloxacin and a salt of a given cation is solubilized in deionized water and titrated with sodium hydroxide. The titration curve is compared against one obtained for delafloxacin alone to assess formation of delafloxacin-metal complex as described in Physical Pharmacy (4th Edition) by Alfred Martin (pp 261-263). Salts of various metal cations (e.g. Ca2+, Mg2+, etc) are then evaluated to identify suitable candidate(s) for subsequent evaluations. Different molar ratios of cations and delafloxacin are also evaluated.
Preparation of Complexes
[0271] Delafloxacin solutions are titrated against aqueous solutions of selected metal salts. Titrations are carried out at a constant pH. Formation of complexes is monitored by different methods including titrimetry, spectrofluorometry, solubility, etc. as applicable. The end point of the complexation reaction depended on the method adopted.
Characterization of Delafloxacin Complexes
[0272] Delafloxacin-metal cation complexes are characterized for stoichiometry, formation constants and dissociation kinetics using appropriate methodology.
Assessment of Complexation
61 Titrimetry
[0273] This approach is based on the assumption that the carboxylic acid moiety of delafloxacin is involved in complex formation with a given metal cation and that complexation results in the release of a proton from delafloxacin. The concentration of released protons would thus be proportional to the extent of complexation (depending on the binding constant) and the stoichiometry of the complex (Physical Pharmacy: 4.sup.th Edition by Alfred Martin; pp-261- 263). Titrimetry is performed according to known methods and titrations performed in the presence of metal cations resulted in a positive shift of the titration curves as compared to the one obtained with delafloxacin alone suggesting that additional NaOH (titrant) is required to obtain a specific pH of the solution in the presence of metal cation. The magnitude of the shift in titration curve at any point represents moles of proton released due to complexation and hence moles of complexed delafloxacin.
Dual Titration
[0274] In this approach delafloxacin solution is titrated with a solution of a given metal cation to observe a drop in pH presumably due to release of protons through complexation. This is followed by addition of NaOH to revert back to the initial pH of the delafloxacin solution (prior to addition of solution of cation). This enables determination of the fraction of delafloxacin in the complexed form at a given pH. Experimental methodology, as appropriate for delafloxacin and metal ions, such as is known in the art, is used. The cumulative amounts of metal cation added are plotted against cumulative amounts of NaOH required to neutralize the change in pH. The plateau regions are extrapolated to obtain total amount of NaOH required to neutralize the change in pH due to complexation. These values also represent the amounts of delafloxacin in the complexed form (assuming that complexation of delafloxacin results in an equimolar release of protons). The binding constants as well as the stoichiometry of complexation for the delafloxacin complexes with the metal cations are determined as follows:
M +nAfc=>MA„ Kb
[0275] Where M, A and MA.sub.n represent the metal cation, delafloxacin and the complex, respectively. Kb is the equilibrium binding constant. The above reaction assumes that 'h' moles of delafloxacin react with one mole of metal to yield one mole of complex. Kb=[MAn]/{[M][A]n} (units M n) Eq. 1 [MAn] is the concentration of complex formed [M] and [A] are the concentrations of the unbound metal and unbound delafloxacin, respectively. Rearranging Eq. 1, [MAn]/[A] "=Kb* | M | Eq. 2 [A]=[A]Totai-[A]bound=[A] Totai-[NaOH]Used [M]=[M]Totai- [M]bound=[M]Total_[NaOH]used/n [MAn]= [A]bound /n=[NaOH]Used /n
62 [0276] Eq.2 can be modified to obtain, [Abound /| A |"=n Kb *[M] Eq. 3 It is inferred from Eq.3 that a plot of [M] versus [A]bound/[A]n would result in a straight line with a slope of n Kb when, n=l, for a 1:1 complex n=2, for a 2: 1 complex n=3, for a 3:1 complex etc.
[0277] Plots for Ca, Mg, Fe, and Zn are obtained and binding constants are calculated.
[0278] Solubility This method allows for a relatively simple way of determining the stoichiometry of complexation. The approach involves evaluation of solubility of the drug (delafloxacin) in the presence of increasing concentrations of complexation agent (a given metal cation). The total solubility of the drug (complexed+uncomplexed) is expected to increase linearly owing to complexation and to reach a plateau corresponding to the saturation solubility of both the drug and the complex. Determination of the stoichiometry from such a solubility curve is explained in detail elsewhere (Physical Pharmacy: 4.sup.th Edition by Alfred Martin; pp 265). Protocols are as appropriate for delafloxacin, for example, excess quantities of delafloxacin (amounts are recorded) are agitated, in the presence of increasing concentrations of MgCh, with 25 mM MES buffer (pH 5.99) using a vortex mixer. The samples are then filtered and the filtrate is diluted appropriately and analyzed spectrophotometrically to determine delafloxacin concentrations. The solubility of delafloxacin increases with increasing MgCh concentrations.
[0279] Spectrofluorometry This approach is adopted to evaluate delafloxacin complexation based on existing literature evidence that the complexation process is associated with a change in the fluoroquinolone fluorescence properties. By monitoring the change in fluorescence emission of delafloxacin in the presence of different concentrations of a given metal cation it is possible to determine the binding constant of complexation as well as the stoichiometry. Experimental methodology is as appropriate for delafloxacin. The influence of increasing concentrations of various cations on delafloxacin fluorescence emission are determined.
Samples of Delafloxacin Complexes
[0280] A number of samples of delafloxacin complexes are evaluated in vivo for efficacy and pharmacokinetics respectively.
Example 2
Inhalation Toxicology in Rats
[0281] In a 4 day non-GLP ascending dose study of aerosolized delafloxacin in male and female Sprague-Dawley rats, a 10-40, e.g., 25 mg/ml, solution of delafloxacin is administered for one hour on day one and a 30-70, e.g., 50 mg/ml, solution of delafloxacin is administered for two
63 hours per day on days 2 thru 4. No clinical signs of toxicity are observed during the treatment period. Necropsy 24 hours after administration of the last dose does not show any findings.
[0282] In a GLP study of aerosolized delafloxacin in male and female Sprague-Dawley rats, aerosolized delafloxacin is administered daily with an average dose of 6.92 mg/kg/day to the males and 10.04 mg/kg/day for the females over 4 days using a nose-only aerosol delivery device. Total exposures are 10-30 mg/kg and 30-50 mg/kg for males and females, respectively over the study period. Each dose is delivered over 2 hours daily. The dose for this study is chosen based on the maximum solubility of delafloxacin that could be administered in the device over 2 hours. No clinical signs of toxicity are observed, and all animals survive during the 4 day treatment period. Necropsy of animals after administration of the last dose does not show any findings. In a 28-day GLP study in Sprague-Dawley rats, animals are randomized to 3 dose levels of aerosolized delafloxacin or saline. Additional recovery groups using the vehicle control and the highest dose are also treated and observed for a 14 day recovery period following the last dose. Average aerosolized delafloxacin doses are 0.5-3, 2-5, and 5-9 mg/kg/day for male rats, and 0.5-3, 3-7, and 9-13 mg/kg/day in female rats. The total exposures over the 28-day treatment period range between 20 and 300 mg/kg for males and 40 and 400 mg/kg for females. Each dose is delivered over 2 hours daily. No dose related clinical signs of toxicity are observed, and all animals survive during the 28 day treatment period.
Example 3
High Local Concentration with Short Duration Aerosol Fluoroquinolone Exposure
[0283] Aerosol administration of fluoroquinolones such as delafloxacin produces high concentrations in the epithelial lining fluid (ELF) of rats and humans. However, this dose has been observed to rapidly decline following administration.
[0284] In order to determine if short duration, high concentrations of delafloxacin could be effective in treatment of P. aeruginosa (PA), studies are conducted to measure their bactericidal activity on various strains of this organism which are grown at different conditions. Those are chosen based on what is known about conditions and growth of PA in a cystic fibrosis (CF) lung. Four isogenic strains of P. aeruginosa are used for these experiments). PAM 1020 is the parent wild-type strain, PAM 1032 contains nalB mutation which results in increased delafloxacin resistance due to overexpression of the MexAB-OprM efflux pump which can extrude delafloxacin out of cells. Other strains include PAM 1032
[0285] Activity of Delafloxacin Against Exponentially Grown Cells is tested as follows: Strains are grown aerobically overnight in Mueller-Hinton Broth (MHB) at 35° C. Next, cultures
64 are diluted 1 : 1000 into 100 ml of fresh MHB and grown to Oϋboo about.0.3 to reach CFU/ml aboutlO8. 10 ml of this culture was moved to 50 ml flasks, each containing 10 ml of pre-warmed MHB broth with appropriate concentrations of delafloxacin (2x as compared to the exposure concentrations). All strains are treated for 10 min., 20 min., 40 min., 80 min. and 160 minutes. The following concentrations of delafloxacin (ug/ml) are used for the exposure of PAM 1020 and PAM1032: 1—20 (e.g.,16,) 20-40 (e.g., 32), 40-75 (e.g.,64), 100-150 (e.g.,128( and 220-320 (e.g., 256). All strains are treated at each concentration for 10 min., 20 min., 40 min., 80 min. and 160 minutes. At appropriate times, 1 ml of each exposure culture is centrifuged for 2 minutes, the pellet is washed twice with 1 ml of drug-free MHB, and re-suspended in 1 ml of MHB. The viable cell numbers are enumerated by plating serially diluted samples (in duplicates) on MHB plates by the drop (10 ul) plating method. Killing is reported as the log reduction calculated relative to cell count at the time of initiation of antibiotic exposure. Relative antibiotic concentrations (relative to MIC of the corresponding strains) are used. For every strain at each concentration , maximum killing (e.g., 5.5 log decrease in viable cell counts) can be achieved at one or more time points and one or more concentrations. These results inducate that logarithmic cells of P. aeruginosa are efficiently killed after short duration exposures to high concentrations of delafloxacin.
Activity of Delafloxacin Against Stationary Phase Cells
[0286] Strains are grown aerobically overnight in Mueller-Hinton Broth (MHB) at 35. degree. C. (350 ml total). The spent medium is obtained after centrifugation of overnight cultures and filtering the supernatant. Cultures are diluted to OD=0.3 into spent medium. The same medium is also used to prepare antibiotic concentrations (the same as in Experiment 1). Antibiotic concentrations, time of exposure as determination of viable cell counts are the same as in the previous experiement. Maximum killing was achieved for each strain at appropriate concentration and duration.
[0287] The re-growth of PAM 1020 and PAM 1032 after either 10 minutes or 160 minutes of treatment with various concentrations of delafloxacin can be compared. After the corresponding treatments, cells are washed twice with antibiotic-free medium. 150 ul of cells is placed into 96- well plate and the growth is continuously monitored at Ar ,o using, e.g., SpectraMax (Molecular Devices). The results demonstrate that the re-growth of both strains is observed at approximately the same time whether cells are treated with high concentrations of delafloxacin for 10 minutes or 160 minutes. These results further support the efficiency of short duration treatment with high concentrations of delafloxacin.
65 Activity of Delafloxacin Against PAM1032 in CF Sputum
[0288] Cells of strain PAM 1032 (MIC=1 ug/ml) are grown to OD=l (late-exponential/early stationary phase of growth) in MHB and next concentrated 10-fold in 10-fold concentrated MHB. 10 ul of cells are then added to 90 ul of sputum or water in 96-well round bottom plates, restoring MHB to its original concentration. Quantitation plates are pre-warmed for 5 minutes at 37° C. and different concentrations of delafloxacin (400-600 (e.g., 512) ug/ml, 50-200 (e.g.,128) ug/ml, 20-40 (e.g., 32) ug/ml, 4-13, (e.g., 8) ug/ml, 1-3 (e.g., 2) ug/ml, and 0.1-1 (e.g., 0.5) ug/ml) are added. At appropriate times, 10 ul of each treatment culture is diluted 100-fold in MHB to minimize the carryover of delafloxacin. Viable cell numbers are enumerated by plating serially diluted samples on MHB plates by the drop (10 ul) plating method. The limit of detection is 104 CFU/ml. Killing is reported as the percentage of the starting inoculum survived after the delafloxacin treatment. The results indicate that while sputum slightly affected the degree of killing by delafloxacin, rapid and extensive (up to five orders of magnitude) killing by delafloxacin in sputum was still observed after short duration of treatment at high concentrations of antibiotic.
Activity of Delafloxacin Against Colony Biofilms of PAM1032
[0289] Colony biofilms are grown on polycarbonate membrane filters resting on MHB plates. Overnight culture of PAM1032 is diluted to OD=0.3, and then diluted 1: 100 in fresh MHB. 5 ul of this culture is spotted on the membrane filter. Bacteria are incubated at 37° C. for 48 hours (mature biofilms). After growth filters are placed into tubes containing 3 ml saline or saline and delafloxacin at 75-175 (e.g.,128) ug/ml and 700-1300 (e.g., 1024) ug/ml. Each tube is treated for 10 minutes and 80 minutes. At about 5 min. before incubation time elapsed, tubes are vigorously vortexed (A) or sonicated and vortexed (B) to detach cells. 1 ml of each exposure culture is centrifuged for 2 minutes, the pellet is washed twice with 1 ml of drug-free MHB, and re-suspended in 1 ml of MHB. The viable cell numbers are enumerated by plating serially diluted samples on MHB plates by the drop (10 ul) plating method. Maximum killing (.about.2 logs) is obtained after 10 min with the lowest concentration of delafloxacin tested. No additional killing is observed at the higher delafloxacin concentration. These data indicate that colony biofdms are more resistant to killing as compared to logarithmic or stationary phase cells. However, the maximum observed bactericidal activity against biofilms (99% under these conditions) is achieved after 10 minutes of delafloxacin exposure.
[0290] Simulated Short-Term, Rapid Aerosol Administration, Delivering High Concentration Drug Exposure in In Vitro Pharmacodynamic Model
66 [0291] In vitro pharmacodynamic models of infection allow for exposure of a growing bacterial inoculum to changing concentrations of drug as would occur in vivo. The strength of this approach is that the serum concentration vs. time profde of a drug in man can be simulated in the laboratory in vitro to determine the optimal exposure profile (i.e., dose and dosing interval) for a drug and target pathogen. The in vitro pharmacodynamic model consists of a central (analogous "serum" compartment) and peripheral ("extravascular") compartment. The peripheral compartments consist of artificial capillary units arranged in series with the central compartment. Each capillary unit has a bundle of small semi-permeable fibers with a molecular size retention of ca. 10,000 MW to allow passage of nutrients but not bacteria. The entire system is set up in a dry heat incubator adjusted to 37° C. Both the central and peripheral compartments are filled with Mueller-Hinton broth. Each peripheral compartment (capillary unit and tubing) contained ca. 23 ml of growth medium. Bacteria are introduced into the peripheral chamber of the model and allowed to grow for 2 hours prior to the first "dose" of drug. Drug doses are administered into the central compartment and pumped to peripheral chambers by a peristaltic pump. Concentrations in the model declined according to first order elimination (half-life) by dilution of the central compartment with drug free medium introduced by an additional peristaltic pump adjusted to the desired clearance. Samples (0.3 ml) are collected from peripheral compartments at various intervals for determination of drug and bacterial concentrations. Samples are collected from the peripheral compartments and assayed for drug concentrations by HPLC. Test strains are Pseudomonas aeruginosa PAM 1032 and PAM 1582. Strains are grown aerobically overnight in Mueller-Hinton Broth (MHB) at 35° C. and subcultured to fresh MHB and reincubated at 35°
C. for 2 hours. After 2 hours, the inoculum is further diluted 1: 1000 to a final concentration of approx. TOxlO6 CFU/ml. Of the resulting dilution, 2.3 ml is injected into each peripheral chamber of the hollow-fiber bioreacters. The half-life of delafloxacin was adjusted to be 10 minutes to be equivalent to that observed following aerosol delivery of delafloxacin to the pulmonary compartment of man. The targeted Cmax was 1000 and 600 ug/ml over two experiments. As targeted, the model exhibits a delafloxacin half-life of 10 minutes and a Cmax of 1000 ug/ml in one experiment. By comparison, Experiment 6 is modified to achieve the same half-life as the first experiment, but with a targeted Cmax of 600 ug/ml. The bactericidal effects of these two regimens correlated with the Cmax. In the first experiment with a Cmax of 1000 ug/ml, the maximum bactericidal effect is observed as a 5 log reduction in bacterial counts within 10 minutes with PAM 1032 and a 4 log reduction in bacterial counts within 20 minutes with PAM 1582 and no re-growth observed over the remaining 2 hours of the experiment. In contrast, while the Cmax of 600 ug/ml used in the second experiment maintains the 5 -log reduction in
67 bacterial counts for PAM1032, albeit taking 30 min instead of 10 min observed in the first experiment, only a 3-log reduction in bacterial counts is observed for PAM1582 after 45 min.
[0292] Delafloxacin can produce up to a 99.9999% bacterial reduction with a Cmax of both 600 and 1000 ug/ml against a strain with an MIC of 1 ug/ml. ug/ml).
Example 4
Tolerability of Aerosol Delafloxacin in a Healthy Human Subject
[0293] In a single subject, healthy volunteer the feasibility of delivering delafloxacin as an aerosol is established using either an Aerogen Clinical vibrating mesh device creating a 3.4 micron volumetric mean diameter (VMD) particle, or ~2 micron MMAD (hereinafter "Aerogen Small"), or using a PARI eFlow nebulizer producing a ~4.7 micron VMD particle (hereinafter "PARI Large"). Delafloxacin is tested at a concentration of 3-5 (e.g., 4.25) mg/mL or 12-25 (.e.g, 18.75) mg/mL at doses of 10 mg, 35 mg and 55 mg, in isotonic solution. In the first test, 6 mL of the 3-5 (e.g., 4.25) mg/mL solution is inhaled using the Aerogen Small nebulizer. The estimated RDD based on separate in vitro device characterization studies using breath simulation is estimated to be 10 mg. Delivery time is 22 minutes. No discemable adverse effects are observed in the throat, airway or lungs, during or after administration, including cough sensation or cough, and there is only a slight chemical taste during and after administration. No adverse effects or taste are observed over a 30 minute monitoring period following drug administration. At this low concentration and dose, and slow rate of administration, delafloxacin is well tolerated.
[0294] In a second test, 4 ml of the 12-25 (e.g., 18.75) mg/mL solution is inhaled using the Aerogen Small nebulizer. The estimated RDD based on separate in vitro device characterization studies using a breath simulator is 35 mg. Delivery time for administration of the drug is 14 minutes. Despite the increased dose, the acute tolerability is very comparable to the first test both during and after administration.
[0295] In a third test, 4 ml of the 12-25 (e.g., 18.75) mg/mL solution is inhaled using the PARI Large device. The estimated RDD based on separate in vitro device characterization studies is .about.55 mg (using the <5 microns FPD definition). Delivery time for administration of the drug is about 5 minutes. Despite the significantly increased particle size and delivery rate for drug compared to test 2, no adverse effects in the throat, airway or lungs, other than the acute effects of taste noted above, are experienced, including cough sensation or coughing, throughout the dosing period and for a 30 minute observation period following delivery of the dose. Urinary recovery of the drug, which is an accurate measure of exposure, confirms that the projected respirable dose of approximately 55 mg was successfully delivered.
68 [0296] These results demonstrate the feasibility of aerosol delivery of delafloxacin in a human subject at the intermediate concentrations tested, and suggest that higher concentrations and doses, properly formulated for tolerability and taste are achievable.
Example 5
Phase IB Clinical Study with Delafloxacin
[0297] A Phase lb single-blind, placebo-control, dose-escalating multicenter study is carried out to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of aerosolized delafloxacin administered to stable CF patients. All patients have had P. aeruginosa cultured from sputum within the previous 24 months and at the screening visit. Study drug is administered twice daily for up to 14 days at three doses by aerosol using a PARI eflow device. Respirable delivered doses (RDD) are approximately 40 mg, 80 mg, and 120 mg per treatment, corresponding to loaded doses of 78 mg, 175 mg, and 260 mg, respectively. Thus, the estimated total daily RDDs are 80 mg, 160 mg, and 240 mg. Study drugs are administered at 30 mg/ml (for 40 mg dose) or 50 mg/ml (for 80 mg and 120 mg doses).
[0298] All patients us at least 1 concomitant medication during the study. Concomitant medications are those medications taken after the first dose of Study Drug regardless of medication start date. The greatest relative improvement in FEVi after 7 and 14 days of dosing is observed in the 120 mg RDD (260 mg loaded) delafloxacin cohort,. Improvement persists over the 2 weeks to the follow-up visit. Colony-forming units of P. aeruginosa at Day 1 are compared with colony-forming units at Day 7 and 14. Declines in sputum P. aeruginosa are observed over all days of dosing. No study drug-related serious adverse events are reported. Most adverse events are mild or moderate in severity and self-limiting. The majority of adverse events are mild, with taste complaints, cough and headache as the most commonly observed adverse events. No patients receiving delafloxacin solution for inhalation meet drug intolerability criteria.
Example 6
Phase I Clinical Study in Pediatric CF Patients
[0299] A Phase 1 multicenter, open-label study is carried out to evaluate the safety, tolerability and pharmacokinetics of weight-adjusted doses of delafloxacin formulated with MgCh administered once daily for 14 days to stable pediatric CF patients. Patients are divided into 2 groups based on their age: 6-11 years of age and 12-16 years of age. The daily dose administered of delafloxacin formulated with MgCh is divided as follows: patients that weighed 14-21 kg receive a 120 mg dose, patients that weighed 22-30 kg receive a 180 mg dose, and patients that weighed more than 30 kg receive a 240 mg dose. A total of 27 patients are enrolled
69 and all patients complete the study. There are 14 patients in the 6-11 years of age group and 13 patients in the 12-16 years of age group. Seven patients (all in the 6-11 age group) receive 180 mg QD delafloxacin formulated with MgCk and the remaining 20 patients received 240 mg QD delafloxacin formulated with MgCk..
EMBODIMENTS
[0300] In embodiment 1 provided herein is a pharmaceutical composition comprising delafloxacin or a salt, ester, prodrug, or conjugate thereof, wherein the composition is suitable for inhalation into a lung. In embodiment 2 provided herein is the composition of embodiment 1 wherein the delafloxacin or salt, ester, prodrug, or conjugate thereof is in aqueous solution. In embodiment 3 provided herein is the composition of embodiment 1 or 2 further comprising a divalent or trivalent cation. In embodiment 4 provided herein is the composition of embodiment 3 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof. In embodiment 5 provided herein is the composition of embodiment 4 further comprising a counterion wherein the counterion comprises chloride. In embodiment 6 provided herein is the composition of embodiment 4 wherein the divalent or trivalent cation is magnesium. In embodiment 7 provided herein is the composition of embodiment 6 wherein the magnesium is in the form of magnesium chloride. In embodiment 8 provided herein is the composition of embodiment 5 or embodiment 7 comprising a chloride concentration from about 25 mM to about 400 mM. In embodiment 9 provided herein is the composition of embodiment 7, wherein the magnesium chloride has a concentration from about 100 mM to about 250 mM. In embodiment 10 provided herein is the composition of embodiment 7, wherein the magnesium chloride has a concentration from about 125 mM to about 250 mM. In embodiment 11 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 10 mg/ml. In embodiment 12 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 25 mg/ml. In embodiment 13 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 35 mg/ml. In embodiment 14 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 40 mg/ml. In embodiment 15 provided herein is the composition of embodiment 1, wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 50 mg/ml. In embodiment 16 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of
70 delafloxacin or a salt, ester, prodrug, or conjugate thereof of greater than 100 mg/ml. In embodiment 17 provided herein is the composition of any one of embodiments 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof from about 100 mM to about 625 mM. In embodiment 18 provided herein is the composition of any one of embodiments 2 through 17 wherein the solution has an osmolality from about 200 mOsmol/kg to about 1250 mOsmol/kg. In embodiment 19 provided herein is the composition of any one of embodiments 2 through 17 wherein the solution has an osmolality from about 250 mOsmol/kg to about 1050 mOsmol/kg. In embodiment 20 provided herein is the composition of any one of embodiments 2 through 17 wherein the solution has an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. In embodiment 21 provided herein is the composition of any one of embodiments 2 through 20 wherein the solution has a pH from about 4.5 to about 7.5. In embodiment 22 provided herein is the composition of any one of embodiments 2 through 20 wherein the solution has a pH from about 5 to about 6.5. In embodiment 23 provided herein is the composition of any one of embodiments 2 through 20 wherein the solution has a pH from about 5.5 to about 6.5. In embodiment 24 provided herein is the composition of embodiment 1 wherein the delafloxacin or salt, ester, prodrug, or conjugate thereof is in solid form. In embodiment 25 provided herein is the composition of embodiment 24 further comprising a divalent or trivalent cation. In embodiment 26 provided herein is the composition of embodiment 25 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof. In embodiment 27 provided herein is the composition of embodiment 24 or 25 comprising a counterion, wherein the counterion comprises chloride. In embodiment 28 provided herein is the composition of any one of embodiments 24 through 27 wherein the divalent or trivalent cation is magnesium. In embodiment 29 provided herein is the composition of embodiment 28 wherein the magnesium is in the form of magnesium chloride
[0301] In embodiment 30 provided herein is a sterile, single use container, comprising the composition of any previous embodiment. In embodiment 31 provided herein is the container of embodiment 30 comprising from about 20 mg to about 400 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof. In embodiment 32 provided herein is the container of embodiment 30 comprising from about 28 mg to about 280 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof. In embodiment 33 provided herein is the container of embodiment 30 wherein the composition comprising delafloxacin or a salt, ester, prodrug, or conjugate thereof, and the single use container comprises from about 1 ml to about 5 ml of the composition. In embodiment 34 provided herein is the composition of any one of embodiments 30 through 33 comprising at least 100 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof. In embodiment 35
71 provided herein is the composition of any one of embodiments 30 through 33 comprising at least 400 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof
[0302] In embodiment 36 provided herein is a method of treating a bacterial lung infection in a subject, comprising administering delafloxacin or a salt, ester, prodrug, or conjugate thereof in a form suitable for inhalation, to a lung of the subject. In embodiment 37 provided herein is the method of embodiment 36 wherein the delafloxacin or a salt, ester, prodrug, or conjugate thereof is delivered as an aerosol of a solution comprising delafloxacin. In embodiment 38 provided herein is the method of embodiment 36 wherein the delafloxacin or a salt, ester, prodrug, or conjugate thereof is delivered as an aerosol of a solid comprising delafloxacin In embodiment 39 provided herein is the method of embodiment 37 or 38 wherein the solution or solid further comprises a divalent or trivalent cation. In embodiment 40 provided herein is the method of embodiment 39 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof. In embodiment 41 provided herein is the method of embodiment 39 or 40 wherein the solution or solid further comprises a counterion wherein the counterion comprises chloride. In embodiment 42 provided herein is the method of embodiment 40 or 41 wherein the divalent or trivalent cation is magnesium. In embodiment 43 provided herein is the method of any one of embodiments 36 through 42 delivered as solution wherein the solution comprises delafloxacin or a salt, ester, prodrug, or conjugate thereof at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. In embodiment 44 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by one or more of the following bacteria: Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrohacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterohacter cloacae, Enterohacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus,
72 Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia cepacia, Francisella tularensis, Kingella, and Moraxella. In embodiment 45 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by one or more of the following bacteria: Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Haemophilus influenzae, Burkholderia cepacia, and Moraxella. In embodiment 46 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by a Burkholderia bacteria. In embodiment 47 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is associated with a bacterial pneumonia. In embodiment 48 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by a gram-negative anaerobic bacteria. In embodiment 49 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by one or more of the bacteria selected from the group consisting of Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus. In embodiment 50 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by a gram-positive bacteria. In embodiment 51 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by one or more of the bacteria selected from the group consisting of Corynebacterium diphtherias,
Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus milleri; Streptococcus (Group G); Streptococcus (Group C/F); Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus . In embodiment 52 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by a gram-positive anaerobic bacteria. In embodiment 53 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by one or more bacteria selected from the group consisting of Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum. In embodiment 54 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by an acid-fast bacteria. In embodiment 55 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by a Mycobacterium bacteria. In embodiment 56 provided herein is the method of embodiment 54 wherein the lung infection is caused by one or more bacteria selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare , and
73 Mycobacterium leprae. In embodiment 57 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by an atypical bacteria. In embodiment 58 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by one or more bacteria selected from the group consisting of Chlamydia pneumoniae and Mycoplasma pneumoniae. In embodiment 59 provided herein is the method of any one of embodiments 36 through 42 wherein the lung infection is caused by an atypical bacteria. In embodiment 60 provided herein is the method of any one of embodiments 36 through 59 wherein the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.
In embodiment 61 provided herein is the method of any one of embodiments 36 through 59 wherein the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns. In embodiment 62 provided herein is the method of any one of embodiments 36 through 59 wherein the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In embodiment 63 provided herein is the method of any one of embodiments 36 through 59 comprising producing the aerosol with a vibrating mesh nebulizer. In embodiment 64 provided herein is the method of embodiment 63 wherein the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns. In embodiment 65 provided herein is the method of embodiment 63 wherein the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In embodiment 66 provided herein is the method of embodiment 63 wherein the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns. In embodiment 67 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 20 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung. In embodiment 68 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 100 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung. In embodiment 69 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 125 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung. In embodiment 70 provided herein is the method of any one of embodiments 36 through 66 wherein at least about 150 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung. In embodiment 71 provided herein is the method of any one of embodiments 36 through 70 wherein
74 the aerosol is administered to the lung in less than about 45 minutes. In embodiment 72 provided herein is the method of any one of embodiments 36 through 70 wherein the aerosol is administered to the lung in less than about 30 minutes. In embodiment 73 provided herein is the method of any one of embodiments 36 through 70 wherein the aerosol is administered to the lung in less than about 10 minutes. In embodiment 74 provided herein is the method of any one of embodiments 36 through 70 wherein the aerosol is administered to the lung in less than about 5 minutes. In embodiment 75 provided herein is the method of any one of embodiments 36 through 74 further comprising the step of alternating the administration of said aerosol with administration of a second inhaled antimicrobial. In embodiment 76 provided herein is the method of embodiment 75 wherein the second inhaled antimicrobial is an aminoglycoside. In embodiment 77 provided herein is the method of embodiment 76 wherein the aminoglycoside is tobramycin. In embodiment 78 provided herein is the method of embodiment 75 wherein the second inhaled antimicrobial is a polymyxin. In embodiment 79 provided herein is the method of embodiment 78 wherein the polymyxin is colistin. In embodiment 80 provided herein is the method of embodiment 75 wherein the second inhaled antimicrobial is a monobactam. In embodiment 81 provided herein is the method of embodiment 80 wherein the monobactam is aztreonam. In embodiment 82 provided herein is the method of any one of embodiments 36 through 81 comprising administering the aerosol once daily. In embodiment 83 provided herein is the method of any one of embodiments 36 through 81 comprising administering the aerosol twice daily. In embodiment 84 provided herein is the method of any one of embodiments 36 through 83 wherein the bacterial infection is tuberculosis. In embodiment 85 provided herein is the method of any one of embodiments 36 through 83 wherein the subject suffers from cystic fibrosis (CF) and the bacterial infection is a bacterial infection associated with CF. In embodiment 86 provided herein is the method of embodiment 85 wherein the infection comprises a Pseudomonas aeruginosa infection. In embodiment 87 provided herein is the method of any one of embodiments 84 through 86 further comprising administering an adjunct therapy in conjunction with the delafloxacin or a salt, ester, prodrug, or conjugate thereof.
[0303] In embodiment 88 provided herein is an aerosol dose of a delafloxacin and magnesium solution comprising (i) a concentration of delafloxacin greater than 50 mg/ml and (ii) a taste-masking concentration of a divalent or trivalent cation, wherein the aerosol comprises of a mist having a mean particle size of between 2 and 5 microns or a particle size geometric standard deviation of less than or equal to 2 microns. In embodiment 89 provided herein is the aerosol dose of embodiment 91 wherein the divalent or trivalent cation comprises magnesium ion.
75 EQUIVALENTS
[0304] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
[0305] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
[0306] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.
[0307] The terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. Where the plural form is used for compounds, salts, or the like, this is taken to mean also a single compound, salt, or the like.
[0308] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.
76 [0309] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. [0310] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.
[0311] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.
[0312] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.
[0313] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
77

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising delafloxacin or a salt, ester, prodrug, or conjugate thereof, wherein the composition is suitable for inhalation into a lung.
2. The composition of claim 1 wherein the delafloxacin or salt, ester, prodrug, or conjugate thereof is in aqueous solution.
3. The composition of claim 1 or 2 further comprising a divalent or trivalent cation.
4. The composition of claim 3 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof.
5. The composition of claim 4 further comprising a counterion wherein the counterion comprises chloride.
6. The composition of claim 4 wherein the divalent or trivalent cation is magnesium.
7. The composition of claim 6 wherein the magnesium is in the form of magnesium chloride.
8. The composition of claim 5 or claim 7 comprising a chloride concentration from about 25 mM to about 400 mM.
9. The composition of claim 7, wherein the magnesium chloride has a concentration from about 100 mM to about 250 mM.
10. The composition of claim 7, wherein the magnesium chloride has a concentration from about 125 mM to about 250 mM.
11. The composition of any one of claims 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 10 mg/ml.
12. The composition of any one of claims 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 25 mg/ml.
13. The composition of any one of claims 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 35 mg/ml.
78
14. The composition of any one of claims 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 40 mg/ml.
15. The composition of claim 1, wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof greater than 50 mg/ml.
16. The composition of any one of claims 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof of greater than 100 mg/ml.
17. The composition of any one of claims 2 through 7 wherein the solution has a concentration of delafloxacin or a salt, ester, prodrug, or conjugate thereof from about 100 mM to about 625 mM.
18. The composition of any one of claims 2 through 17 wherein the solution has an osmolality from about 200 mOsmol/kg to about 1250 mOsmol/kg.
19. The composition of any one of claims 2 through 17 wherein the solution has an osmolality from about 250 mOsmol/kg to about 1050 mOsmol/kg.
20. The composition of any one of claims 2 through 17 wherein the solution has an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
21. The composition of any one of claims 2 through 20 wherein the solution has a pH from about 4.5 to about 7.5.
22. The composition of any one of claims 2 through 20 wherein the solution has a pH from about 5 to about 6.5.
23. The composition of any one of claims 2 through 20 wherein the solution has a pH from about 5.5 to about 6.5.
24. The composition of claim 1 wherein the delafloxacin or salt, ester, prodrug, or conjugate thereof is in solid form.
25. The composition of claim 24 further comprising a divalent or trivalent cation.
26. The composition of claim 25 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof.
79
27. The composition of claim 24 or 25 comprising a counterion, wherein the counterion comprises chloride.
28. The composition of any one of claims 24 through 27 wherein the divalent or trivalent cation is magnesium.
29. The composition of claim 28 wherein the magnesium is in the form of magnesium chloride.
30. A sterile, single use container, comprising the composition of any previous claim.
31. The container of claim 30 comprising from about 20 mg to about 400 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof.
32. The container of claim 30 comprising from about 28 mg to about 280 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof.
33. The container of claim 30 wherein the composition comprising delafloxacin or a salt, ester, prodrug, or conjugate thereof, and the single use container comprises from about 1 ml to about 5 ml of the composition.
34. The container of any one of claims 30 through 33 comprising at least 100 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof.
35. The container of any one of claims 30 through 33 comprising at least 400 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof.
36. A method of treating a bacterial lung infection in a subject, comprising administering delafloxacin or a salt, ester, prodrug, or conjugate thereof in a form suitable for inhalation, to a lung of the subject.
37. The method of claim 36 wherein the delafloxacin or a salt, ester, prodrug, or conjugate thereof is delivered as an aerosol of a solution comprising delafloxacin.
38. The method of claim 36 wherein the delafloxacin or a salt, ester, prodrug, or conjugate thereof is delivered as an aerosol of a solid comprising delafloxacin
39. The method of claim 37 or 38 wherein the solution or solid further comprises a divalent or trivalent cation.
40. The method of claim 39 wherein the divalent or trivalent cation is calcium, aluminum, zinc, iron, magnesium and/or copper, or a combination thereof.
80
41. The method of claim 39 or 40 wherein the solution or solid further comprises a counterion wherein the counterion comprises chloride.
42. The method of claim 40 or 41 wherein the divalent or trivalent cation is magnesium.
43. The method of any one of claims 36 through 42 delivered as solution wherein the solution comprises delafloxacin or a salt, ester, prodrug, or conjugate thereof at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
44. The method of any one of claims 36 through 42 wherein the lung infection is caused by one or more of the following bacteria: Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrohacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterohacter cloacae, Enterohacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia cepacia, Francisella tularensis, Kingella, and Moraxella.
45. The method of any one of claims 36 through 42 wherein the lung infection is caused by one or more of the following bacteria: Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Haemophilus influenzae, Burkholderia cepacia, and Moraxella.
46. The method of any one of claims 36 through 42 wherein the lung infection is caused by a Burkholderia bacteria.
47. The method of any one of claims 36 through 42 wherein the lung infection is associated with a bacterial pneumonia.
81
48. The method of any one of claims 36 through 42 wherein the lung infection is caused by a gram-negative anaerobic bacteria.
49. The method of any one of claims 36 through 42 wherein the lung infection is caused by one or more of the bacteria selected from the group consisting of Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.
50. The method of any one of claims 36 through 42 wherein the lung infection is caused by a gram-positive bacteria.
51. The method of any one of claims 36 through 42 wherein the lung infection is caused by one or more of the bacteria selected from the group consisting of Corynebacterium diphtherias, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus milleri; Streptococcus (Group G); Streptococcus (Group C/F); Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus .
52. The method of any one of claims 36 through 42 wherein the lung infection is caused by a gram-positive anaerobic bacteria.
53. The method of any one of claims 36 through 42 wherein the lung infection is caused by one or more bacteria selected from the group consisting of Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum.
54. The method of any one of claims 36 through 42 wherein the lung infection is caused by an acid-fast bacteria.
55. The method of any one of claims 36 through 42 wherein the lung infection is caused by a Mycobacterium bacteria.
56. The method of claim 55 wherein the lung infection is caused by one or more bacteria selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare , and Mycobacterium leprae.
57. The method of any one of claims 36 through 42 wherein the lung infection is caused by an atypical bacteria.
82
58. The method of any one of claims 36 through 42 wherein the lung infection is caused by one or more bacteria selected from the group consisting of Chlamydia pneumoniae and Mycoplasma pneumoniae.
59. The method of any one of claims 36 through 42 wherein the lung infection is caused by an atypical bacteria.
60. The method of any one of claims 36 through 59 wherein the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.
61. The method of any one of claims 36 through 59 wherein the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
62. The method of any one of claims 36 through 59 wherein the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
63. The method of any one of claims 36 through 59 comprising producing the aerosol with a vibrating mesh nebulizer.
64. The method of claim 63 wherein the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.
65. The method of claim 63 wherein the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
66. The method of claim 63 wherein the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
67. The method of any one of claims 36 through 66 wherein at least about 20 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
68. The method of any one of claims 36 through 66 wherein at least about 100 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
83
69. The method of any one of claims 36 through 66 wherein at least about 125 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
70. The method of any one of claims 36 through 66 wherein at least about 150 mg of delafloxacin or a salt, ester, prodrug, or conjugate thereof is administered to the lung.
71. The method of any one of claims 36 through 70 wherein the aerosol is administered to the lung in less than about 45 minutes.
72. The method of any one of claims 36 through 70 wherein the aerosol is administered to the lung in less than about 30 minutes.
73. The method of any one of claims 36 through 70 wherein the aerosol is administered to the lung in less than about 10 minutes.
74. The method of any one of claims 36 through 70 wherein the aerosol is administered to the lung in less than about 5 minutes.
75. The method of any one of claims 36 through 74 further comprising the step of alternating the administration of said aerosol with administration of a second inhaled antimicrobial.
76. The method of claim 75 wherein the second inhaled antimicrobial is an aminoglycoside.
77. The method of claim 76 wherein the aminoglycoside is tobramycin.
78. The method of claim 75 wherein the second inhaled antimicrobial is a polymyxin.
79. The method of claim 78 wherein the polymyxin is colistin.
80. The method of claim 75 wherein the second inhaled antimicrobial is a monobactam.
81. The method of claim 80 wherein the monobactam is aztreonam.
82. The method of any one of claims 36 through 81 comprising administering the aerosol once daily.
83. The method of any one of claims 36 through 81 comprising administering the aerosol twice daily. 84. The method of any one of claims 36 through 83 wherein the bacterial infection is tuberculosis.
84
85. The method of any one of claims 36 through 83 wherein the subject suffers from cystic fibrosis (CF) and the bacterial infection is a bacterial infection associated with CF.
86. The method of claim 85 wherein the infection comprises a Pseudomonas aeruginosa infection.
87. The method of any one of claims 84 through 86 further comprising administering an adjunct therapy in conjunction with the delafloxacin or a salt, ester, prodrug, or conjugate thereof.
88 An aerosol dose of a delafloxacin and magnesium solution comprising
(i) a concentration of delafloxacin greater than 50 mg/ml and
(ii) a taste-masking concentration of a divalent or trivalent cation, wherein the aerosol comprises of a mist having a mean particle size of between 2 and 5 microns or a particle size geometric standard deviation of less than or equal to 2 microns.
89. The aerosol dose of claim 0 wherein the divalent or trivalent cation comprises magnesium ion.
85
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