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WO1991016882A1 - Composition de medicament/lipides en poudre sechee par pulverisation directe - Google Patents

Composition de medicament/lipides en poudre sechee par pulverisation directe Download PDF

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Publication number
WO1991016882A1
WO1991016882A1 PCT/US1991/003092 US9103092W WO9116882A1 WO 1991016882 A1 WO1991016882 A1 WO 1991016882A1 US 9103092 W US9103092 W US 9103092W WO 9116882 A1 WO9116882 A1 WO 9116882A1
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WO
WIPO (PCT)
Prior art keywords
drug
powder
lipid
sulfate
spray
Prior art date
Application number
PCT/US1991/003092
Other languages
English (en)
Inventor
Manzer Durrani
Wendy Fitch
Katherine Fok
Ramachandran Radhakrishnan
Paul S. Uster
Original Assignee
Liposome Technology, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Liposome Technology, Inc. filed Critical Liposome Technology, Inc.
Priority to JP91510167A priority Critical patent/JPH05507090A/ja
Publication of WO1991016882A1 publication Critical patent/WO1991016882A1/fr

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Classifications

    • 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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A61K9/1277—Preparation processes; Proliposomes

Definitions

  • the present invention relates to drug delivery by inhalation, and, in particular, to a method of preparing direct spray-dried drug/lipid powders containing a me- tered drug dose for use via inhalation.
  • Inhalation provides an effective means for delivering a variety of drugs, including nasal decongestants, drugs useful in the treatment of asthma and other bronchial and pulmonary conditions.
  • One advantage of inhalation in treating nasal, bronchial, and pulmonary conditions is the ability to deliver the drug directly to the site of drug action.
  • a related advantage is the rapid onset of the therapeutic effect, compared with other routes of administration such as intramuscular and oral routes.
  • inhalation may be preferred for a variety of reasons over intravenous or intramuscular injection.
  • Other drugs such as nitroglycerin, whose primary drug action is systemic, can also be delivered efficiently by inhalation.
  • the drug is dissolved in a suitable solvent which can be aerosolized to form a small-particle mist.
  • the drug solution may be aerosolized by pneumatic or ultrasonic nebulizer or, more conveniently, by means of a self-contained nebulizer containing a pressurized, fluorocarbon propellant.
  • Inhalation of the aerosol mist i.e., drawing the mist from the mouth or nose into the respiratory tract, acts to deposit the drug-containing aerosol particles on various sites of the respiratory tract, including the upper nasopharyngeal region, the tracheobronchial region, and the pulmonary region. In the latter region, the drug has the opportunity for rapid absorption into the bloodstream for systemic action.
  • inhalation systems in which a drug is administered in particulate form, either as a dry powder or as a micronized suspension in a suitable carrier solvent system.
  • the drug is a water-soluble compound which is suspended in micronized form in a fluorocarbon-type propellant solvent.
  • propellant solvent is lost through flash evaporation and replaced by moisture in the respiratory tract, leading to the deposition of hydrated micronized particles.
  • Both types of inhalation systems mentioned above are based on delivery of the drug in a free form to sites in the respiratory tract.
  • the drug is rapidly utilized and, in the case of pulmonary deposition, taken up systemically at the site of deposition. Because of this rapid drug uptake and utilization, the drug effect may be relatively short-lived, requiring frequent dosing.
  • a related problem is the limited amount of drug that can be administered safely at each dosing, particularly where the drug has unwanted systemic side effects. This problem is illustrated by a number of ⁇ 2 -adrenergic agonist type bronchodilators which also produce marked tachycardia. Even at relatively low doses of these drugs, the stimulatory effect of the drug on the heart and other side effects, such as dizziness and insomnia, are a nuisance to the patient. Additionally, micronized particles may irritate the respiratory tract.
  • PCT WO/87/07502 describes a sprayable composition consisiting of a propellent solvent in which at least one membrane lipid is partially dissolved or dispersed and a biologically active compound which is insoluble in the solvent. All of these approaches are characterized by a multiphase solvent system in the atomizer wherein one phase contains dissolved lipid components. None of the prior art references teach bulk direct spray-drying of a drug/lipid solution to generate a drug/lipid powder effective to form liposomes with a high drug encapsulation efficiency upon rehydration of the dried powder particles.
  • the concentration and size of the liposomes formed by the prior art methods, and the percentage of drug entrapment in the liposomes will vary from one dose delivery to another, depending upon temperature and humidity conditions, the extent of solvent mixing, and the total and relative amounts of solvent components present in the system. Thus each of these systems would be difficult to adapt for metered dose delivery, in which a reproducible amount of liposome-encapsulated drug is needed.
  • the present direct spray-dried drug/lipid powder provides a convenient and efficient way to accurately deliver metered-drug doses.
  • the present invention is directed to a process for direct spray-drying a drug/lipid powder composition.
  • This process involves preparing an aqueous solution, having no phosphate buffer salts, containing a water- soluble drug, and preparing a lipid-containing ethanol solution. These two solutions are then mixed in a weight to weight (w/w) ratio in the range of about 1:1 ethanol:water to 5:1 ethanol:water, to form a solution mixture.
  • the mixture is formulated to have between about 3% to 4% weight to volume (w/v) total solids. This mixture is then spray dried and the resulting dried particle powder collected.
  • the above process can be used to generate drug/lipid powder compositions containing a variety of water-soluble drugs including: albuteral sulfate, ephidrine sulfate, ephidrine bitartrate, isoetharine hydrochloride, isoetharine mesylate, isoproteranol hydrochloride, isoproteranol sulfate, metaproteranol sulfate, terbutaline sulfate, procaterol, and bitolterol mesylate, atropine methyl nitrate, cromolyn sodium, propranalol, fluoroisolide, ibuprofin, gentamycin, tobermycin, pentamidine, penicillin, theophylline, bleomycin, etoposide, captopril, n- acetyl cysteine, verapamil, calcitonin, atriopeptin, ⁇ -1 antitryp
  • the lipid containing ethanol solution must contain at least one membrane-forming lipid.
  • Exempliary lipids for use in the powders of the present invention include the following lipids, their analogues and derivatives: phosphatidyl choline, phosphatidylglycerol, phosphatidic acid, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, sphingomyeline, and cholesterol. Representative analogues and derivatives of these lipids are presented in Table 1.
  • a preferred embodiment of the invention uses a lipid-containing ethanol solution containing phosphotidylcholine, phosphatidylglycerol, and .alpha.-tocopherol in a w/w ratio of about 167:15:0.1.
  • the process can also utilize other organic solvents, such as "Freons" which do solubilize lipids, and further include non-membrane forming lipids, such as cholesterol.
  • the drug/lipid powder composition of the present invention can be packaged into packets containing a selected dose of the drug.
  • the present invention also includes a number of methods for administering a water-soluble drug to the respiratory tract at a selected dose which involve producing an airborne suspension of the above described drug/lipid powder composition.
  • the drug/lipid composition powder particles are suspended in a fluorocarbon propellant which does not solubilize the particles.
  • the suspension is stored under pressure in a cannister and a selected amount of the suspension can be released from the cannister in an aerosolized form which is inhaled by the user.
  • the drug/lipid powder particles are provided in moisture-free packets, each containing a metered dose of the drug in the powder, and the particles are expelled from the packet in an air-borne form by either a propellant or an airstream produced by user inhalation.
  • Figure 1 is a side cutaway view of a delivery system to be used with the direct spray-dried drug/lipid composition of the present invention.
  • the composition powder is contained in a capsule-like packet, and the packet is supported in the air passageway of a delivery device, for entrainment of the powder in a stream of air drawn through the passageway.
  • Figure 2 displays the data for encapsulation of albuterol sulfate versus volume of rehydration using the direct spray-dried powders.
  • Figure 3 shows the data for a linear regression of the log (percent encapsulation) versus volume of water used in rehydration of the direct spray-dried powders.
  • Figure 4 shows a comparison of spray-dried liposome encapsulated albuterol sulfate and ProventilTM effects on airways resistance response to histamine in guinea pigs after metered dose aerosol administration.
  • This section discusses methods of preparing the direct spray-dried drug/lipid composition of the present invention.
  • This composition has a number of properties which make it valuable for use with inhalation therapies including: (a) the ability to form fine particle sizes on spray drying; (b) stability on storage in dehydrated or propellant suspension form; (c) high liposomal drug entrapment efficiency upon rehydration of the composition; and, (d) selected pharmacokinetic behavior when delivered to the respiratory tract.
  • the prior art spray-drying methods all require preformation of the liposome-encapsulated drug suspension, dilution, and then spray-drying of the liposome suspension (see, for example, U. S. Patent No. 4,895,719).
  • the present invention has the important advantage that preformation of the liposome-drug suspension is not required.
  • the only requirement for lipid components to be used in the method of the present invention is that the lipids are able to form membranes in aqueous solutions.
  • Lipids typically used in the present invention are egg phosphatidylcholine (EPC) and egg phosphatidylglycerol (EPG).
  • membrane-forming lipids can be used in the present invention either singly or in combination; a sampling of such lipids is presented in Table 1.
  • other lipid components such as cholesterol can be used to formulate the drug/lipid composition.
  • cholesterol has a fluidizing effect in rehydrated liposomes of the present invention which containing predominantly saturated phospholipid components.
  • the specific lipid composition of liposomes can affect the rate of drug release in the respiratory tract (reported in co-owned U. S. Patent No. 4,895,719).
  • the direct spray-dried drug/lipid composition of the present invention may also be formulated to include various types of drug-protective or lipid-protective agents, such as the antioxidant .alpha.-tocopherol, which is typically included at a mole ratio of between about 0.1- 2.0 mole percent of total lipids.
  • drug-protective or lipid-protective agents such as the antioxidant .alpha.-tocopherol, which is typically included at a mole ratio of between about 0.1- 2.0 mole percent of total lipids.
  • a typical formulation for the present invention is partially hydrogenated EPC: Cholesterol: EPG: ⁇ -tocopher- ol in the mole ratio of 55:40:5:0.1 (Example 1). Cholesterol can be omitted from the formulations of the present invention (Example 3). Further, single lipids, such as EPC, have been effectively used as the sole lipid component of the drug/lipid composition of the present invention.
  • the lipid components of the composition are combined in a solvent which completely solubilizes them and which solvent is able to form a clear solution when mixed with an aqueous solution.
  • a particularly useful solvent in this regard is ethanol. Ethanol is used as the primary solvent in all the Examples; in several of the examples (Examples 1 and 2) a small quantity of "Freon 11" (CCl 3 F) was used to facilitate the solubilization of the lipid components.
  • a clear solution is desirable it is most important that (i) the lipid components be solubilized, (i) the liquid be free-flowing when it is used as a feed solution in the spray-drying process, and (iii) there is no solid precipitate in the feed line.
  • drug is intended to include any pharmacologically active agent which has a site of action in the respiratory tract or is therapeutically active when it is taken up systemicaUy from the respiratory tract.
  • drugs may include antibiotics, peptide hormones, enzymes, enzyme inhibitors, anti-tumor agents, bronchodilators, allergens, and antihistamines.
  • the most important class of drugs for use with the present invention are predominantly water-soluble drugs which tend to partition into the aqueous phase of a water/oil two-phase system. More particularly, this class of drugs tend to partition preferentially in the aqueous interior phase of liposomes, rather than in the lipophilic bilayer hase.
  • Drugs in this class include relatively small, liposome-permeable drugs such as albuteral (salbutamol) sulfate, ephidrine sulfate, ephidrine bitartrate, isoetharine hydrochloride, isoetharine mesylate, isop4roteranol hydrochloride, isoproteranol sulfate, metaproteranol sulfate, terbutaline sulfate, procaterol, and bitolterol mesylate, atropine methyl nitrate, cromolyn sodium, propranalol, fluoroisolide, ibuprofin, gentamycin, bobermycin, pentamidine, penicillin, theophylline, bleomycin, etoposide, captopril, n-acetyl cysteine, and verapamil; and relatively large, liposome-impermeable drugs, such as peptide
  • the drug of choice is dissolved in an aqueous solution at a specified concentration.
  • concentration of the drug is established relative to the amount of lipid solids present in the composition.
  • ratio of albuterol sulfate to total lipid was approximately 1:2.6 (w/w).
  • the drug-containing aqueous solution is then mixed with the lipid-containing solution, resulting in the feed solution. It is important that the feed solution be free-flowing. For this reason it is important that the aqueous solution be free of phosphate salts; the presence of phosphate buffer salts typically results in a cloudy precipitate after mixing the aqueous solution with the lipid-containing solvent. If the pH of the feed solution is a problem, then a different buffer salt might be used in the formulation of the aqueous solution. If some haziness of the solution occurs, the temperature of the feed solution can be slightly elevated to prevent crystallization. Also, the ratio of lipid-containing solvent to aqueous solution can be adjusted to optimize clarity.
  • the presence of crystals in the feed solution creates problems with line clogging and effective atomization of the feed solution. Further, if the feed solution is not free-flowing the dried product may not be homogeneous if one or more components selectively precipitates before the solution reaches the atomizer.
  • Feed solutions have been successfully spray dried at concentrations ranging from 3-4% total solids in suspension in the final feed solution. Drying at a concentration of 3.5% solids consistantly yielded a good powder product. Stickiness of the powder is also affected by the ambient humidity. To minimize the influence of ambient humidity either compressed air or nitrogen gas were used as the source of heated inlet gas. The powder quality of samples can sometimes be improved by overnight vacuum drying. After additional drying, the powders become more free flowing and easier to work with for further measurements, such as percent encapsulation.
  • a number of commercially available spray-drying devices can be used to spray-dry the feed solution.
  • the spray-driers involve atomization of the feed solution into a large chamber and entrainment of the atomized solution in a moving stream of hot gas, such as heated compressed air or nitrogen gas.
  • the feed solution is usually maintained at a constant temperature.
  • the temperature of spray-drying must be sufficient to volatilize the liquid in the microscopic droplets.
  • the remaining particles then either fall to the bottom of the chamber and are collected there, or are carried by the hot gas and collected by, for example, forcing the hot gas flow to form a cyclone causing even small particles to fall from the gas flow.
  • the heated gas which has been somewhat cooled at this point, is either released to the atmosphere or recycled through condensers.
  • Example 1.2 discloses the characteristics of Buchi spray-dried powders using two water: ethanol: "Freon 11" solvent systems having the ratios of 25:70:5 and 14.3:80:5.7 (v/v/v).
  • the percent encapsulation ranged from 69-80% and the moisture content of the powders were low, from about 1-3%.
  • the data presented in Table 2 also show that the powders obtained by the method were generally flowable either directly after spray-drying or after a secondary drying performed under vacuum.
  • the sticki ness of the powder has also been reduced by keeping the ambiant humidity low or collecting the powder with immediate storage over DrieriteTM. Also the use of nitrogen as the source of inlet gas has repeatedly yielded flowable powders.
  • the percent drug encapsulation achieved by the present invention is routinely about 70% or greater (Tables 2 and 3). Typically the percent encapsulation is measured by adding water to the powder in a 2:1 weight ratio. Drug encapsulations for the direct spray-dried powders of the present invention were also determined in varying volumes of water, ranging from 100 ul (standard condition) to 2000 ul per 50 mg of bulk powder. Results obtained are shown in Table 4 and semi-log plots of the data are shown in Figure 2. The data demonstrate an inverse proportion between volume of rehydration and apparent percent encapsulation.
  • Example 2 presents data which compare the encapsulation efficiency of spray-dried preformed liposomes to the direct spray-dried drug/lipid composition of the present invention. The data show that ommision of the phosphate buffer salts from spray-dried preformed liposomes results in powders having essentially equivalent encapsulation efficiencies as the direct spray-dried drug/lipid powder (Table 5).
  • the direct spray-dried drug/lipid composition of the present invention can be formulated, as mentioned above, using a variety of lipids.
  • the only requirement for the primary lipid of the composition is that it be a membrane-forming lipid.
  • Example 3 describes a phosphatidylcholine/phosphatidylglycerol lipid formulation of the drug/lipid composition. This formulation has proven effective in repeated large scale runs to generate the direct spray-dried powder. Only ethanol was used as the lipid-dissolving solvent in Example 3; there was no addition of "Freon".
  • this drug/lipid composition dries well and has approximately the same residual moisture as the formulations containing cholesterol.
  • the percent encapsulation of albuterol sulfate was approximately 70%.
  • the mass median diameter of the dried particles as determined by static laser ensemble light scattering, had a bimodal distribution with peaks at about 1 and at 7-10 microns with a distribution over the range of about 0.1 to 20 microns.
  • the optimal size for respirable particles is less than about 5 microns.
  • the majority of the particles of the direct spray-dried drug/lipid powder fall well within this range.
  • the bimodal distribution of the dried particles is replaced by a normal distribution of liposomes having a single-peak at approximately 1.5 microns. Accordingly, the composition of the present invention is well suited for use in inhalation therapies and respiratory tract administation of sysytemic drugs.
  • This section describes three self-contained delivery devices designed for producing an airborne suspension of the direct-dried drug/lipid powder of the present invention.
  • self-contained means that the powder aerosol is produced in a self-contained device that is propelled by a pressure differential created either by release of a pressurized fluorochlorocarbon propellant or by a stream of air drawn through or created in the device by the user.
  • An important feature of delivery devices using pressureized fluorochlorocarbon propellant is that the powder is insoluble in the propellant, ie. the powder particles remain intact.
  • This system uses a conventional pressurized propellant spray device for delivering a metered amount of the direct-dried drug/lipid composition powder which is suspended in the propellant. Since the system requires long-term suspension of the powder in a suitable propellant, the powder and propellant components of the suspension must be selected for stability on storage. To this end, experiments performed in support of the present invention indicate that the lipids used to genrate the powder are preferably partially or totally hydrogenated lipids.
  • the direct spray-dried drug/lipid powder is added to the selected propellant to a final concentration of about 10-25 weight percent of powder to total propellant. Further, the final concentration of drug/lipid powder in the propellant is adjusted to yield a selected metered dose of the drug in a given aerosol suspension volume.
  • the powder is formulated to contain 0.05 mg drug per mg direct-dried powder, and the selected dose of drug to be administered is 1 mg, the suspension is formulated to contain 20 mg of powder per aerosol dose.
  • the suspension is packaged in a conventional selfcontained propellant device, such as described in coowned U.S. Patent No. 4,895,719.
  • the device generally includes a replaceable propellant cartridge which holds the propellant suspension under a suitable aerosolizing pressure.
  • the cartridge is equipped with a metering valve which is designed to release a selected volume of the suspension, under pressure, when the valve is activated by being pushed inwardly.
  • the cartridge is supported in a conventional atomizer which functions to aerosolize the suspension released from the cartridge, on valve actuation, and direct the aerosol in a stream toward the user's mouth, which may engage the mouthpiece of the atomizer. Aerosol delivery devices of this type are well known.
  • the aerosol particles which are initially formed are propellant droplets containing the powder in suspended form. As these droplets are propelled through the air, the propellant rapidly evaporates, leaving an airborne suspension of the powder particles containing a selected dose of drug. When the powder particles come in contact with moisture, e.g. on mucosal tissue, liposomes encapsulating the drug are spontaneously formed.
  • direct-dried drug/lipid powder containing a metered-dose quantity of drug is prepackaged in dehydrated form in a delivery packet.
  • the packet is used with a propellant spray device, to eject the powder contents of the packet in an airborne suspension of liposome particles; such a system is described in coowned U.S. Patent No. 4,895,719.
  • the packet contains a quantity of direct-dried drug/lipid powder containing a metered dose of a selected drug.
  • the packet when supplied to the user, is sealed at its opposite ends to keep moisture out, and the powder is loosely held in the tubing.
  • the seal is preferably a conventionally formed thin polymer barrier which is easily rupturable at each tubing end to create an unobstructed passageway through the tubing.
  • the system also includes a propellant spray device which contains a charge of pressurized propellant, such as a "Freon,” and which is equipped with a valve for releasing a stream of aerosolized propellant.
  • a propellant spray device which contains a charge of pressurized propellant, such as a "Freon,” and which is equipped with a valve for releasing a stream of aerosolized propellant.
  • a valve for releasing a stream of aerosolized propellant.
  • the downstream end of the valve terminates in a nozzle which is adapted to receive an end of the packet to attach the packet operably to the device.
  • a packet is attached to the nozzle, preferably by inserting a sealed end of the packet tubing over the nozzle, to break the seal.
  • the seal at the free end of the tubing is also punctured, for example, in the case of a friable seal, by pinching the tube end of the tubing.
  • the valve in the spray device is actuated briefly. It can be appreciated that the powder in the packet becomes entrained in the stream of aerosolized propellant passing through the tubing. The propellant in turn rapidly evaporates, yielding an airborne suspension of the powder. Administration of the powder occurs, as above, by the user drawing in breath at the same time the powder suspension is delivered.
  • the device is supplied as a spray device with a plurality of powder packets, one for each dosing.
  • a third type of delivery system uses an airstream produced by user inhalation to entrain the drug/lipid powder particles and draw them into the user's respiratory tract.
  • One exemplary system based on a known type of aerosolizing device, is shown at 42 in Figure 1.
  • the drug/lipid powder in this system is provided in moisturefree packets, such as packet 44, each containing a metered dose of the drug in the powder.
  • a delivery device 46 in the system includes a curved pipe 48 which defines an inlet passageway 50 terminating at a reduced diameter nozzle 52 which is dimensioned to receive and hold packet 44, as shown.
  • the other end of the pipe confines a convection region 54 where the powder drawn out of the packet is distributed throughout the cross-section of the downstream end of the pipe, while being drawn into the user's respiratory tract by inhalation.
  • Air convection in the downstream pipe region is created by a paddle 56 which is freely rotatable on a shaft 58 supported within region 54.
  • the pipe is provided with a mouthpiece 60 at its downstream end.
  • a packet is placed on the nozzle, preferably in a manner which ruptures the seal at the "inner" end of the packet, as above, and the other end of the packet is unsealed.
  • the user now places his lips about the mouthpiece and inhales forcefully, to draw air rapidly into and through the pipe.
  • the air drawn through the pipe becomes concentrated at the nozzle, creating a high-velocity airstream which carries the powder out of the packet and into the convection region.
  • the airstream and entrained powder impinge on the paddle, causing it to rotate and set up a convection within region 54.
  • the powder is thus distributed more evenly, and over a broader cross-section, just prior to being drawn into the user's respiratory tract by the inhalation.
  • the powder spontaneously rehydrates to form liposomes encapsulating the drug.
  • the system here is supplied to the user in the form of a single aerosol pipe with a plurality of single-dose packets.
  • the present invention is useful in treating a variety of bronchoconstriction conditions, such as bronchial asthma, emphysema, bronchitis, and bronchiectasis. These conditions are responsive to ⁇ 2 -agonists, which are also useful in treating peripheral vascular disease and shock, and may be used to delay delivery in cases of premature labor.
  • bronchoconstriction conditions such as bronchial asthma, emphysema, bronchitis, and bronchiectasis.
  • Another important advantage is that the drug, when administered in therapeutic dose via liposomes, shows more effective bronchodilation, at times greater than about 1 hour after drug administration, than a comparable amount of drug given in free form. This means that effective relief from asthma or other bronchoconstriction condition is provided with each administration, fewer administrations are needed, and the patient is subject to less drastic swings in the ⁇ 2 -agonist levels in the body.
  • the rate of drug release from the site of administration in the lungs can be modulated, according to the lipid composition of the liposomes.
  • liposomes act to protect the drug from oxidation and protect the respiratory tract from potentially irritating drugs, particularly those which, because of solubility properties, must be administered in micronized form.
  • Example 4 describes the procedures used to compare the bronchodilator and cardiovascular effects of a suspension of spray-dried liposomal albuteral sulfate versus a commercially available microcrystalline suspension of free base albuterol (ProventilTM).
  • Figure 4 graphically illustrates the data (Table 8) showing that the spray-dried liposomal albuteral sulfate provides longer term effects of albuterol sulfate, up to at least 2 hours, as compared to microcrystalline administration of free base albuterol sulfate (less than 1 hour). Further, the data in Table 9 show that there was no sig nificant difference in the cardio/pulmonary effects of albuterol independent of method of administration.
  • ⁇ -1-protease inhibitor is delivered to the pulmonary interstitium in liposome-encapsulated form to stem the development of pulmonary emphysema.
  • the liposomes act to protect the protease inhibitor's tertiary structure from oxidation, and facilitate its transport across the pulmonary cell membranes.
  • the present invention provides a convenient, selfcontained system for administering a direct spray-dried drug/lipid composition to the respiratory tract in a metered dose form.
  • Some of the drug eg., Table 7, the approximately 30% non-encapsulated drug
  • Another advantage of the system is that a relatively constant and predictable drug dose can be administered with each dosing, since the amount of lipid and entrapped drug remains substantially constant from one administration to another.
  • the system is also convenient to use, since only a small, self-contained device -- no larger than the aerosoling devices described in Section II -- is needed.
  • drugs whose primary mode of action requires uptake into the bloodstream can also be delivered by inhalation.
  • the inhalation route allows the drug to be delivered rapidly to the bloodstream, is much more conve nient to the patient than intramuscular or intravenous injection, and is suitable for drugs which cannot be delivered orally because of drug stability of the like.
  • drug delivery by inhalation has been limited by a number of factors, including (a) lack of control of total drug dose, (b) inability to achieve long-term or controlled-released drug delivery, (c) the requirement for expensive and cumbersome inhalation equipment for drugs which cannot be suspended in free form in a propellant solvent or are otherwise unstable in free form, (d) the extremely unpleasant taste of some drugs, and (e) drug irritation to the respiratory tract.
  • the present invention overcomes or minimizes many of the problems which have limited systemic drug delivery by inhalation heretofore.
  • the problem of regulating drug dose is the most difficult problem to resolve.
  • Using the present drug/lipid composition there will be some variability, from dose to dose, in the amount of aerosolized material which actually reaches the respiratory tract at a level which allows systemic uptake.
  • some aspects of the direct dried drug/lipid composition are designed to facilitate more consistent total uptake.
  • the lipids themselves function as a bulking agent, i.e., solid particle carrier or filler, and given that the drug can be entrapped in the powder particles at high concentration, much less total particulate material may need to be administered. Accordingly, less drug would be list in "non-target" areas of the mouth and throat.
  • delivering a drug in particulate form from a propellant aerosol favors good drug uptake, and the present system allows many drugs to be administered in this form.
  • the direct-dried drug/lipid composition provides controlled-release systemic uptake, and the rate of uptake of a water-soluble drug can be controlled to some extent by the lipid composition of the liposomes.
  • the system of the invention allows water-soluble drugs to be delivered from a convenient, relatively inexpensive self-contained delivery device.
  • the drug in lipid-entrapped powder form may be more stable and less irritating to the respiratory tract when administered. Further, the taste of the drug may be substantially masked in lipid-entrapped powder form.
  • nitroglycerin a coronary vasodilator used to relieve the symptoms of angina pectoris.
  • the drug formulation typically will contain about 30% free drug, which can be rapidly absorbed by the pulmonary bloodflow and transported directly to the heart, its primary site of action, to provide immediate relief from the chest pain associated with angina.
  • the remaining 70% or more of the liposome-encapsulated drug which is liposome encapsulated upon rehydration is released slowly, at a rate controlled by liposome composition, to afford prolonged coronary vasodilation, and thus relief from chest pain for an extended period.
  • Oxytocin a peptide hormone that induces and augments the strength of uterine muscle contractions during labor, can be formulated and delivered in a manner similar to that described for nitroglycerin. It is currently delivered by intravenous infusion, a process that requires placement and maintenance of a venous cannula, a sometimes difficult procedure that limits the patient movement and posture. Aerosols of direct spray-dried lipid-oxytocin powders would provide immediate and sustained delivery to the systemic circulation, similar to that provided by IV infusion, without restricting patient motion. A wide range of other systemic-acting drugs, such as those named above in Section I, could also be administered advantageously by the system of the invention. While preferred embodiments, uses, and methods of practicing the present invention have been described in detail, it will be appreciated that various other uses, formulations, and methods of practice as indicated herein are within the contemplation of the present invention.
  • This example describes the basic formulation of and general procedures for the production of the drug/lipid composition.
  • the spray drying runs described in this example were conducted using the following lipid composition: PHEPC IV-40: Cholesterol: EPG: ⁇ -tocopherol / 55:40:5:0.1 (mole ratio).
  • the ratio of albuterol sulfate to total lipid was approximately 1:2.6 (w/w).
  • the solvent composition for direct drying in this example was the single-phase solvent system water/ethanol/Freon 11 (v/v/v ratios are given in the footnote to Table 2).
  • the solutions were spray-dried at a final concentration of 3.5% total solids in solution.
  • the drug was dissolved in water, the cholesterol in Freon and the remaining remaining lipids in ethanol.
  • the lipid solutions were combined, followed by addition of the aqueous drug solution. This final solution was clear and used as the feed solution for spray-drying.
  • the feed solution was stable and did not form precipitates for at least 24 hours at room temperature.
  • Compressed air was used for atomization of the feed solution and for the heated inlet air in order to standardize conditions.
  • the air used for spray drying should be at a consistent humidity to reproducibly generate free flowing powders on days with different ambient weather conditions.
  • Small scale spray drying of the drug/lipid composition was accomplished in the Buchi 190 mini spray drier (Buchi Laboratoriumstechnik AG, CH-9230 Flawil, Switzerland), using a gas flow setting of 700 Nl/h (nominal liters/hr), 1-2 ml/min sample input of the feed solution and inlet/outlet temperatures of 58-72°C/34-42°C.
  • the powders generated by spray-drying were formulat- ed to yield total lipid 680 mg/g and albuterol sulfate 275 mg/g.
  • the nominal composition of the powders were as follows (values given as milligram compound per gram total powder): albuterol sulfate 274 mg/g; phosphatidylcholine 500 mg/g; phosphatidylglycerol 45.4 mg/g; cholesterol 181 mg/g; and, .alpha.- tocopherol 0.5 mg/g.
  • the percent encapsulation of the spray-dried bulk powders was routinely measured as follows.
  • the powder was rehydrated using twice its weight in water (typically 50 mg of bulk powder in 100 ul of deonized water) and allowed to sit for several hours.
  • the suspension was mixed intermittently on a vortex mixer for approximately two hours before being left to rehydrate overnight.
  • This suspension was then diluted in isotonic buffer and the liposomes pelleted by centrifugation. The supernatant was removed.
  • the water content of the powders was determined by
  • Powders were also assessed for visual appearance, including description of color and whether or not they were flowable.
  • the drug/lipid composition gave drug encapsulation efficiencies in the range of 69% to 80% and moisture contents of less than 2.7% or less. Further, the powders were white and generally flowable. If the direct-dried powders were sticky they were further dried by overnight vacuum drying. After this additional drying the powders became more free flowing and easier to work with for other measurements, such as percent encapsulation. 1.3 Comparison of the Spray-Dried Products Generated by the Buchi and Niro Spray Driers
  • the spray drying run conducted using the Niro spray dryer produced a fine powder which was collected into a jar and placed over DrieriteTM immediately after collection. Scanning electromicroscopic analysis indicated that the powder particles were 2-3 um in diameter. Encapsulation of albuterol sulfate after rehydration was 70%.
  • Drug encapsulations were determined following rehydration in varying volumes of water, ranging from 100 ul (standard condition) to 2000 ul per 50 mg of bulk powder. Results obtained are shown in Table 4 and semilog plots of the data are shown in Figure 2.
  • the data demonstrate a dramatic inverse proportion between volume of rehydration and apparent percent encapsulation.
  • the powder shows a significant drop in encapsulation as the volume of rehydration is increased.
  • This example compares the drug/lipid compositions of the present invention to prior art methods for generating spray-dried liposome compositions.
  • the lipid composition, drug content, and solvent formulations were essentially as described in Example 1.
  • Unencapsulated drug was removed from all liposome preparations by ultracentrifugation with an iso-osmotic phosphate buffer.
  • the resulting liposome pastes (LP-phosphate) were then stored at 2-8°C in butyl rubber stoppered glass serum bottles under nitrogen.
  • the liposome pastes LP-phosphate and LP-water from 2.1 were diluted in, respectively, isotonic phosphate buffer or water. Individually, the resulting liposome suspensions were combined with the ethanol/freon solvent system to yeild a final concentration of 3.5% solids. These feed solutions were then dried using the Niro spray-drier as described in Example 1.1.
  • the drug/lipid composition was produced as described in Example 1.
  • the spray-dried liposomes (LP-phosphate and LP-water) and drug/lipid (D/L-comp) compositions were all rehydrated as described in Example 1.2 and the percent encapsulation achieved with each composition is given in Table 5.
  • This example describes a lipid/drug formulation that does not contain cholesterol and is effective in forming liposome-encapsulated drug compositions upon rehydration.
  • the spray-drying procedure was as described in Example 1 for use of the Niro Spray-drier with the exception that nitrogen was used as the inlet air source in place of compressed air .
  • the drug/lipid feed solution contained the components listed in Table 6.
  • the nominal analyte concentrations in the feed solution were as follows: albuterol sulfate, 12.3 mg/g feed and total phosphorous 904.5 ⁇ g/g feed.
  • Table 7 summarizes the data collected to characterize the spray-dried drug/lipid compositions.
  • the concentration of albuterol sulfate was determined using HPLC analysis under conditions which solubilized the liposomes and freed the albuterol sulfate.
  • the peak corresponding to the freed albuterol sulfate was quantitated by comparison to known concentrations of commercially available albuterol sulfate.
  • the identity of the albuterol sulfate was determined by comigration of the freed albuterol sulfate with commercially available albuterol sulfate.
  • Total phosphate was determined by the Bartlett assay (Bartlett, 1959). The identities of the phospholipids and .alpha.-tocopherol were determined by thin-layer chromatography and comparison to commercially available standards. The residual moisture content of the powders was determined by the method of Fisher. The residual ethanol concentration was determined by gas chromatography. The microbial limits were determined by plating serial dilutions of the rehydrated drug/lipid compositions onto solid agar rich media (eg., LB, Maniatis et al.) and counting the colony forming units (CFU).
  • solid agar rich media eg., LB, Maniatis et al.
  • the mass median diameter of the powder particles of the direct-dried drug/lipid powder and of lipsomes resulting from the rehydration of the powder were determined using static laser ensemble light scattering (Malveen Mastersizer II, Malveen Instruments, Southborough, MA).
  • the mass median diameter of the dried particles was 5 microns, however, the distribution of particle sizes was bimodal with peaks at approximately 1 micron and 7-10 microns. Upon rehydration a normal distribution having single peak appears at approximately 1.5 microns.
  • This example compares the bronchodilator and cardiovascular effects of a microcrystalline suspension of albuterol free base (ProventilTM inhaler, Schering) and a suspension of spray-dried liposomal albuterol sulfate (MDL-ABS).
  • a metered-dose inhaler form of albuterol was provided by a commercial preparation (ProventilTM Inhaler,
  • This product contained albuterol in its base form, and provided nominal delivery of 90 ⁇ g albuterol free base
  • a metered-dose inhaler form of liposomal albuterol sulfate (MDI-L-ABS) was prepared in several steps.
  • Liposome-entrapped albuterol sulfate (LP-water) was produced as in Example 2.1 with the exception that .alpha.-tocopherol was omitted.
  • the concentrate was then diluted in aqueous buffer and spray dried to obtain a free-flowing liposomal powder.
  • the albuterol sulfate was 273 mg/g, and the phospholipid concentration was 709 ⁇ mol/g (total lipid concentration being 1180 ⁇ mol/g).
  • This powder was formulated with propellant and filled into metered-dose vials (3M/Riker). Delivery of albuterol sulfate from the metered-dose inhaler valve was determined spectrophotometrically to be 111 ⁇ g per actuation.
  • mice Male Hartley strain guinea pigs (Cavia porcellus), 4-7 weeks old, weighing 350-500 g, were supplied by Harlan Sprague Dawley, Inc. After delivery from the vendor they were weighed and quarantined in pairs for at least 3 days and reweighed. Water and Purina Guinea Pig Chow were given and the animals were allowed to feed ad libitum. Animals showing weight loss or overt signs of disease were not used in the studies. They were assigned to test groups on a random basis.
  • Pulmonary and Cardiac Function were measured as follows.
  • the guinea pigs were anesthetized with an intramuscular injection of xylazine: ketamine (2.5:75 mg/kg).
  • the trachea, esophagus, left common carotid artery, and left jugular vein were exposed and cannulated with polyethylene tubing.
  • the guinea pigs were then placed in a supine position in a whole body plethysmograph.
  • the tracheal cannula was connected to the exterior to allow breathing from the room air. Changes in thoracic volume produced airflow into or out of the plethysmograph. This flow was measured with a
  • Validyne MP-45 differential transducer which detected the pressure drop across the plethysmograph's constant resistance element. The flow signal was automatically integrated to produce a measurement of tidal volume. Thoracic pressure was measured indirectly with the esophageal cannula and a Statham P23Dc fluid-filled transducer. Systemic arterial blood pressure (diastolic) was measured from the catheter in the common carotid artery via a Statham P23Db transducer. All transducers were attached via Validyne carrier demodulators to a buxco Model 6 Pulmonary Mechanics Analyzer.
  • the analyzer used the airflow and esophageal pressure to compute pulmonary resistance (R L ) at points of equal tidal volume. Data were converted from analogue to digital form and recorded on a Texas Instrument Data terminal. 4.3 Administration of the Metered Dose Albuterol Sulfate
  • MDI metered-dose inhaler
  • a cylindrical dosing chamber (3.8 cm diameter by 13.5 cm length, approximately 150 cc volume) was inserted between a Harvard rodent respirator and the approximately 10 cm of 1/4" Tygon tubing leading to the animal in the plethysmograph. at the tracheal cannula.
  • MDI vials were actuated four times into the dosing chamber. The dosing was followed by adjustment of the respirator to produce a stroke volume of 2 mL/100 g body weight and 60 breaths per minute. Actuation of the solenoid valves closed the normal breathing path (to room air) and opened the alternate path to the ventilator/nebulizer. Exposure to the aerosol in this fashion was carried out for two minutes. Atomized saline was used as a control.
  • test animal was placed in the whole body plethysmograph, and basal date on pulmonary mechanics and cardiovascular state were collected. Then, the responses to an intravenous injection of histamine (10 ⁇ g/kg) were determined as follows. Fifteen minutes after the initial histamine challenge, the animal was exposed to the aerosolized test substance (ProventilTM or MDI-L-albuterol sulfate) for two minutes, with the mechanical ventilation described above. Following this administration (designated the zero time point), the animal was given additional histamine challenges as above at 15 minutes, 1, 2, 3, and 4 hours. 4.4 Analysis of Results
  • R L lung resistance responses
  • ANOVA was also used to test for significant differences in means for R L between each time point within each group, and between each group at each time point.
  • ANOVA indicated a difference
  • a Student's t test was performed to locate the data sets showing the differences.
  • the cardiovascular responses were assessed by comparing the cardiovascular data directly before drug administration (after the first baseline histamine challenge) with the data collected during the following 10-minute period (before the second histamine challenge). The significance of any alteration was tested using ANOVA and post hoc Least Significant Difference (LSD) tests.

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Abstract

Procédé de séchage par pulvérisation directe d'une solution de lipides et de médicament soluble dans l'eau afin de produire une poudre constituant une alternative au séchage de liposomes préformés. Selon le procédé de l'invention, les lipides sont dissous dans un solvant et le médicament soluble dans l'eau est dissous dans un solvant aqueux. On combine les deux solutions afin de former une solution d'alimentation exempte de précipité, laquelle est ensuite séchée par pulvérisation afin de produire la poudre en vrac. Lors de la réhydratation la poudre forme spontanément des liposomes présentant une efficacité d'encapsulation de médicament élévée d'approximativement 70 %. La poudre séchée par pulvérisation directe est particulièrement utile dans l'administration de médicament par inhalation.
PCT/US1991/003092 1990-05-08 1991-05-06 Composition de medicament/lipides en poudre sechee par pulverisation directe WO1991016882A1 (fr)

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EP0527940A1 (fr) 1993-02-24
CA2081474A1 (fr) 1991-11-09
JPH05507090A (ja) 1993-10-14
AU7908791A (en) 1991-11-27

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