KR20010075063A - Dry powder active agent pulmonary delivery - Google Patents

Abstract

The present invention relates to particulate compositions and methods for delivering an active agent to the lungs of a human patient. The active agent formulations are in dry powder form and exhibit (i) low water sorption and (ii) resistance to hygroscopic growth, especially under simulated lung conditions.

Description

Pulmonary delivery of dry powder actives {DRY POWDER ACTIVE AGENT PULMONARY DELIVERY}

Pulmonary delivery of active agents has been found to be an effective route of administration for local and systemic drug utilization. Pulmonary active formulations are designed such that drug dispersions are delivered inhaled by the patient so that the active agent in the dispersion reaches the lungs. Some drugs delivered to the lungs are readily absorbed into the blood circulation through the alveolar region. However, the proportion of inhaled drugs that actually reach cardiopulmonary is very small. For pulmonary delivery, the drug loses on average about 30% in the device and about 35% in the oropharyngeal (upper airway). Of the remaining 35%, about 20% of the drug is lost in the induced airways and about 15% is absorbed in the alveoli. As pointed out in Gonda et al., Critical Reviwes in Therapeutic Drug Carrier Systems , Vol 6, 4th edition (1990), p 273-313, drug absorption in the distal airways and alveoli is predicted to be faster than in the upper airways. This is because the diffusion barrier in these areas is thinner and the surface area is larger. However, since only a small amount of inhaled drug actually reaches the alveolar surface, new methods are needed to increase the amount of drug that ultimately reaches the systemic circulation.

As a way to solve this problem, US Pat. No. 5,506,203 to Backstrom et al. Employs penetration enhancers that increase absorption through the epithelial cell layer in the lower respiratory tract, ultimately increasing the amount of drug that reaches the systemic circulation. A method is disclosed. According to Backstrom, inhaled compounds are delivered in the form of particles less than 10 microns in diameter. Penetration enhancers used include surfactants, salts of fatty acids, bile salts and derivatives thereof. Similarly, US Pat. No. 5,451,569 to Wong et al. Discloses the use of pulmonary surfactants to enhance lung uptake of proteins and peptides.

In order to eliminate the need for penetration enhancers, International Publication No. WO 96/32149, assigned to Inhale Theraputic Systems, discloses a method of pulmonary delivery of dry powdered and dispersible aerosolized medicaments. Such agents are readily absorbed in the lungs without the use of penetration enhancers. Similar efforts to increase the bioavailability of inhaled drugs are disclosed in International Publication WO 97/44013, assigned to MIT and Penn State. In this publication, aerodynamic hard particles (density less than 0.4 g / cm ³ and large average diameters greater than 5 microns) are used to improve the delivery of therapeutic or diagnostic agents to alveoli. In order to further improve drug bioavailability, International Publication No. WO 98/31346, assigned to MIT and Penn State, discloses the incorporation of surfactants into aerodynamic hard particles to enhance absorption of the formulation and increase bioavailability. Doing.

In addition to the problem of low uptake of active agents delivered through the epithelial cells in the lower respiratory tract, another factor that allows only a small amount of the inhaled drug to reach cardiopulmonary is hygroscopic growth. Due to the water soluble nature, most aerosols increase the deposition of particles in the upper respiratory tract as a result of hygroscopic growth (Hickey et al., Journal of Pharmaceutical Sciences , Vol 79, No. 11, p 1009-1014). In order to investigate the growth rate of powder particles in a humid environment, disodium fluorescein powder coated with fatty acid was prepared by adsorption coacervation technique. The coated powder had a MMAD of about 4-7 microns and exhibited a reduced growth rate compared to the uncoated powder.

In spite of these methods, the proportion of drugs that reach the alveolar surface upon inhalation is generally very low. Accordingly, there is a need for new and improved methods of increasing the amount of inhaled drug deposited on the cardiopulmonary, thereby increasing the bioavailability of the inhalation active agent.

The present invention is directed to an improved method of delivering a dry powder active agent to the deep lungs. More specifically, the present invention relates to aerosolizable dry powder particles that are resistant to hygroscopic growth upon inhalation. Due to the characteristics of this powder (ie hygroscopic growth resistance), a significant amount of inhaled particles reach the cardiopulmonary, thus increasing the bioavailability of the active agent delivered to the lungs.

1 depicts the water sorption profile of various spray dried powder formulations. The vertical axis is moisture absorption (% by weight) and the horizontal axis is relative humidity (%). (○: 20% insulin, 59% sodium citrate, 18% mannitol, 2.6 glycine; □: 100% dextran (10 K); ◇: 100% hydroxypropylmethylcellulose; X: 100% hydroxypropyl-β- Cyclodextrin and ±: 100% low molecular weight hydroxyethyl starch).

2 shows the water sorption profile for three different spray dried powder formulations. (○: 20% insulin, 59% sodium citrate, 18% mannitol, 2.6 glycine; □: 20% insulin, 2.6% glycine, 40% hydroxyethylstarch, 18% mannitol, 19% sodium citrate; and ◇: 100 % Hydroxyethyl starch). Adding one or more HGIs to a particular formulation reduces water sorption.

FIG. 3 shows TAM (thermal activity monitor) results for various insulin dry powder formulations, illustrating the effect of two exemplary hygroscopic growth inhibitors that significantly reduce the hydration properties of the powder.

FIG. 4 is a water sorption plot for three spray dried formulations, illustrating the effect of a formulation containing a hygroscopic growth inhibitor that reduces the rate of water absorption and the overall range. (○: 20% insulin, 59% sodium citrate, 18% mannitol, 2.6 glycine; □: 100% spray dried hydroxypropyl-β-cyclodextrin; and ◇: 20% insulin, 20% leucine, 50% β- Cyclodextrin sulfonylbutyl ether, 10% sodium citrate).

5 is a moisture sorption plot comprising five different spray dried formulations. This plot further illustrates the ability of HGI containing formulations to significantly reduce the rate of water absorption and overall range compared to non-HGI containing formulations. (○: 20% insulin, 20% leucine, 50% hydroxyethyl starch, 10% sodium citrate; □: 20% insulin, 5% leucine, 50% hydroxyethyl starch, 25% sodium citrate; ◇: 100 % Hydroxyethyl starch; X: 20% insulin, 59% sodium citrate, 18% mannitol, 2.6 glycine; ± 20% leucine, 50% hydroxyethyl starch, 30% sodium citrate).

Detailed description of the invention

The present invention provides a particulate composition and method for lung delivery of particles consisting of an active agent and a hygroscopic growth inhibitor, wherein the particle size distribution of the particles is less than 3 micron MMAD upon delivery to the alveoli. The present invention is surprising in that it provides activator particles with increased bioavailability compared to activator particles that have no hygroscopic growth inhibitor or have only hygroscopic growth inhibitors adsorbed on their surface. By having a hygroscopic growth inhibitor distributed throughout the particle rather than being present only as a coating on the surface, a novel inner layer of hygroscopic growth inhibitor is exposed as the surface of the particle is eroded or dissolved as it passes through the airways. Provide a layer to the particles.

I. Definition

The following terms are used herein in the meanings indicated.

By "active agent" as disclosed herein is meant an agent, drug, compound, composition or mixture of agents that provides some advantageous, sometimes advantageous, pharmacological effect that can be demonstrated in vitro or in vivo. Examples thereof are foods, supplements, nutritional supplements, drugs, vaccines, vitamins and other beneficial agents. As used herein, the term further includes any physiological or pharmacologically active substance that produces a local or systemic effect on the patient.

A “dry powder” is a powder that is free flowing and comprises dispersed solid fine particles that (i) are easily dispersed in an inhalation device and (ii) a sample can inhale so that some of the particles can reach the lungs and penetrate into the alveoli. Composition. Such powders are considered to be "breathable" or suitable for pulmonary delivery. The dry powder typically contains less than about 10% moisture, preferably less than 5% moisture, more preferably less than about 3% moisture.

By "Hygroscopic growth inhibitor" (HGI) is meant any material which, when incorporated into the particles of the present invention, reduces the rate and / or range of water absorption. A material suitable for use as a hygroscopic growth inhibitor when added into the particles of the present invention at an appropriate concentration is at least 5%, preferably under conditions typically found in the lungs compared to particles having a relative amount of the same particle component without HGI. Is effective at inhibiting hygroscopic growth of at least 10%, more preferably at least 15%.

Hygroscopic growth of particles is generally described in terms of hygroscopic growth ratio, ie the ratio of MMAD under conditions typically found in the lung to the MMAD of dry particles prior to inhalation. For example, particles with a hygroscopic growth rate of 1 do not change size upon inhalation and exposure to environmental conditions of the lungs. Hygroscopic growth of the particles is determined experimentally by treating the powder in an environmental chamber simulating lung conditions, i.e. 32-37 ° C and 95-99.5% relative humidity. More specifically, the dose of particles is aerosolized in the growth chamber described above. The aerosol is then passed through a cascade paddle to determine the mass median aerodynamic diameter of the particles.

Alternatively, the equilibrium growth rate can be determined by calculating the MMAD of a particular powder composition under simulated lung conditions. The MMAD of aerosolized powder particles in the lung is calculated by calculating the solid concentration (the ratio of powder to water) in which the aqueous solution of the powder is isotonic, ie, the liquid droplets reaching equilibrium in the lung, and then calculating the MMAD of the isotonic droplets. Decide The isotonic droplet MMAD is divided by the MMAD of the powder experimentally measured under ambient conditions to determine the hygroscopic growth ratio.

As described above, particles that incorporate HGI under simulated lung conditions and have a MMAD of less than 3 microns are included in the present invention.

"Mock lung conditions" are 32 to 37 ° C and 95 to 99.5% relative humidity.

“Sorption index” or “SI” is divided by 4 after adding up the weight percent (%) of the dry powder of the invention measured under relative humidity (25 ° C.) of 10%, 20%, 30% and 40%. Sorption indices are measured using a gravimetric sorption analyzer such as DVS-1000 manufactured by Moisture Measurement Systems (London, UK) or a moisture balance made by VTI Corporation (Hiale, FL).

By "active particle" is meant the active agent described above which is present in the form of particles suitable for pulmonary delivery. The particles form a dry powder. It will be appreciated that one or more active agents may be incorporated into the aerosolized active agent formulation, and that the use of the term “formulations” will never exclude the use of two or more such agents.

Particles having "incorporated" hygroscopic growth inhibitory are particles having HGI distributed throughout the particle rather than merely present as a coating on the surface.

"In-lung pulmonary bioavailability" means the amount of active agent used in the systemic circulation of the mammal (subcutaneous absorption) for the amount absorbed after deposition in the lung and absorbed into the bloodstream from the subcutaneous injection site. Amount% / deposited%). Representative model systems for measuring bioavailability in the lung are rats, dogs, and non-human primates. Lung bioavailability in relative lungs can be based on direct intratracheal administration or inhalation.

"Emission amount" or "ED" provides an indication of the distribution of dry powder in a suitable suction device after firing or dispersing. ED is defined as the ratio of the release amount to the nominal dose (ie the mass of powder per unit dose placed in a suitable suction device prior to firing). ED is an experimentally measured variable and is typically measured using an in vitro device instrument that simulates patient administration. In order to measure the ED value, a nominal volume of dry powder is placed in a suitable dry powder inhaler and then started to disperse the powder. The resulting aerosol smoke is evacuated and evacuated from the device, where it is attached to the device mouthpiece. Capture to self-weight filter. The amount of powder that reaches the filter forms the amount of release. For example, if a 5 mg dry powder-containing dosage form is placed in the inhalation device, if 4 mg of powder is recovered in the self-weight filter as described above as a result of the dispersion of the powder, the release amount for the dry powder composition is 4 mg. (Emission amount) / 5 mg (nominal amount) x 100 = 80%. For inhomogeneous powders, the ED value provides an indicator of the distribution of the drug in the inhalation device after firing rather than the distribution of the dry powder and is based on drug weight rather than on total powder weight.

"Drop in the amount of release under simulated lung conditions" is the value of ED at% under ambient conditions minus the value of ED at 32 to 37 ° C and 95 to 99.5% relative humidity.

A "dispersible" powder is a powder having an ED value of at least about 30%, more preferably 40-50%, even more preferably at least about 50-60%.

"Mass median diameter" or "MMD" is a measure of average particle size because the powder of the present invention is generally polydisperse (ie, consists of a range of particle sizes). MMD values as reported herein can be measured by centrifugal sedimentation, but various commonly used techniques can be used to specify average particle size (eg, electron microscopy, light scattering, laser diffraction).

The "mass median aerodynamic diameter" or "MMAD" is a measure of the aerodynamic size of the dispersed particles. Aerodynamic diameter is used to describe aerosolized powders in terms of sedimentation action, and in air, is the diameter of a unit density sphere with the same sedimentation rate as particles. Aerodynamic diameters include particle shape, density and physical size of the particles. As used herein, MMAD means the median or median of the aerodynamic particle size distribution of the aerosolized powder measured by cascade impact unless otherwise indicated.

"Pharmaceutically acceptable excipient or carrier" means an excipient that can be included in the particles of the present invention and absorbed into the lungs with the particles without significant toxicological adverse effects on the subject, particularly the lungs of the subject.

A "pharmacologically effective amount" or "physiologically effective amount of a bioactive agent" means that when the composition is administered pulmonary, it is necessary to provide a predetermined bioactive agent in the bloodstream of the sample to be treated to obtain the expected physiological response. Amount of active agent present in the particulate dry powder composition as such. The exact amount depends on several factors, such as biochemicals, the specific activity of the composition, the delivery device used, the physical properties of the particles, the intended use, patient considerations, etc., and can be readily determined by one skilled in the art based on the information provided herein. will be.

II Ingredients of Inhalable Powder

The particles of the present invention inhibit the hygroscopic growth that typically occurs upon pulmonary administration of dry powder formulations, so that larger amounts of inhaled particles reach the cardiopulmonary. The characteristics of these particles, namely hygroscopic growth inhibitory, are achieved by incorporating a hygroscopic growth inhibitor, ie, the presence thereof, in particular when exposed to environmental conditions of the lung, to reduce the rate of water absorption and / or the extent of absorption by the particles.

A. Active Agent

Active agents for incorporation into the particulate compositions disclosed herein include antibiotics, antiviral agents, anepileptics, analgesics, anti-inflammatory agents and bronchodilators. Active agents include inorganic or organic compounds, including but not limited to peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle, cardiovascular system, flat muscle, blood circulation, synoptic sites, nerve tract organ linkage sites, endocrines and Hormones, immunological systems, reproductive systems, skeletal systems, otacoid systems, digestive system and embryo design, histamine and central nervous system drugs. Suitable agents include, for example, polysaccharides, steroids, hypnotics and sedatives, psychoexciters, neurostabilizers, anticonvulsants, muscle relaxants, antiparkinsonants, analgesics, anti-inflammatory agents, muscle contractors, antimicrobials, antimalarials, hormones such as contraceptives, sympathetics Neurostimulants, polypeptides and proteins that can cause physiological effects, diuretics, lipid modulators, antiandrogens, repellents, neoplasms, antineoplastics, hypoglycemic agents, nutrients and supplements, sexual supplements, fats, enteritis inhibitors, electrolytes, vaccines Diagnostics.

Non-limiting examples of active agents suitable for the present invention include calcitonin, erythropoietin (EPO), factor VIII, factor IX, seredase, serezime, cyclosporin, granulocyte colony stimulating factor (GCSF), alpha-1 proteinase inhibitors, Elkatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, Interleukin-2, luteinizing hormone releasing hormone (LHRH), insulin, growth inhibitory hormone, growth inhibitory hormone analogs such as octreotide, vasopressin analogue, follicle stimulating hormone (FSH), insulin-like growth factor, insulintropin, interleukin- 1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (M-CSF), nerve growth factor, thyroid hormone (PTH), thymosin alpha 1, IIb / IIIa billion Agent, alpha-1 antitrypsin, VLA-4, respiratory syncope virus antibody, cystic fibrosis dura modulator (CFTR) gene, deoxyribonuclease (Dnase), fungicide / penetration enhancing protein (BPI), anti CMV antibody, interleukin-1 receptor, 13-cis retinoic acid, pentamidine isethioate, albuterol sulfate, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, flutica Hand, ipratropium bromide, flunisolid, sodium chromoline, ergotamine tartarate, analogs, agents, and antagonists of the foregoing. Active agents include nucleic acids present as exposed nucleic acid molecules, viral vectors, associative viral particles, plasmid DNA or RNA, or nucleic acid constructs of a kind suitable for transfection or transformation of cells, particularly cells of the alveolar portion. Active agents can exist in various forms, such as water-soluble or insoluble, charged or uncharged molecules, components of molecular complexes, or pharmaceutically acceptable salts. Active agents can be naturally occurring molecules or can be produced recombinantly. Alternatively, it may be a naturally occurring protein, or an analog of a recombinantly produced protein, with one or more amino acids added or deleted. Active agents can also include directed live or savirus suitable for use as a vaccine.

The amount of active agent in the aerosol-type particle is the amount necessary to deliver a therapeutically effective amount of active agent per unit dose to achieve the desired result. In practice, this depends on the particular agent, bioactivity, the severity of the condition to be treated, the patient group, the dosage conditions and the desired therapeutic effect. The particles generally comprise from 1 to about 99 weight percent, typically from about 2 to about 95 weight percent, more typically from about 5 to 85 weight percent of active agent. However, the particles are particularly useful for active agents which must deliver at a dose of 0.001 to 100 mg / day, preferably 0.01 to 50 mg / day.

B. Hygroscopic Growth Inhibitors

An essential feature of the particles is hygroscopic growth inhibitors. Hygroscopic Growth Inhibitors (HGI) are effective in reducing the rate and / or extent that particles absorb moisture upon inhalation, allowing them to maintain an MMAD of less than 3 microns upon delivery to the alveoli.

Materials suitable for use as HGI are first identified by preliminary screening and the water absorption profile measured after spray drying. Low absorbing materials, such as the material of Figure 1, are preferred for use in the present invention. Particles are then prepared that contain an appropriate amount of HGI (typically at least about 5-10 weight percent of the composition) to further test the HGI material for compatibility. In some cases, HGI may form additional coatings on the surface of the particles in addition to being present as part of the bulk powder. The water isotherm is then determined for the control particles containing the same comparative amount of the activator particles comprising HGI and the components without HGI to determine whether the presence of HGI is effective in reducing the extent or rate of water absorption by the powder. Typically, high concentrations of HGI and low concentrations of HGI are tested to determine the useful range for incorporation into the powders of the present invention.

Non-limiting examples of materials that have been found to be useful as hygroscopic growth inhibitors include double-chain phospholipids, cyclodextrins and derivatives thereof, hydroxyethylstarch (HES), dextran, dextranomer, maltodextrin, starch, hydroxide Oxypropylmethylcellulose (HPMC), cellulose ethyl hydroxyethyl ether, and other cellulose derivatives such as "Cellulosics: Chemical, Biochemical and Material Aspects" by Ellis Horwood Series in Polymer Science and Technology, JF, B.Sc. Kennedy, GO, B. Sc. Phillips, P.A. Williams (ed.) And in "Comprehensive Cellulose Chemistry", D. Klemm (ed.), Bertram Philipp, T. Heinze (1998). In some cases, the active agent may function as a hygroscopic growth inhibitor. Active agents that act as HGI include insulin, salmon calcitonin and PTH.

Double-chain phospholipids for use in the present invention include phosphatidylcholine such as 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero- 3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC), and the like. Phosphatidylethanolamines such as 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE ), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), similar Derivatized phosphatidylglycero and phosphatidic acid are also suitable for use as hygroscopic growth inhibitors.

Cyclodextrins are another class of compounds that have been found to be useful as hygroscopic growth inhibitors. Cyclodextrins, truncated cones and cyclic oligosaccharides with a hydrophobic cavity in the center are composed of six or more D-glucose residues. Cyclodextrins for use in the present invention include alpha cyclodextrins (6 glucose residues), beta cyclodextrins (7 glucose residues), gamma cyclodextrins (8 glucose residues), and derivatives such as 2 depending on the number of glucose residues. -Hydroxypropyl-β-cyclodextrin (2-HPβC) and β-cyclodextrin sulfonylbutyl ether. 2-HPβC is a particularly preferred excipient as illustrated in the water sorption profile (FIG. 1). At 80% target relative humidity, 2-HPβC showed only about 16% mass change by water absorption after about 8 hours. Cyclodextrins exhibit a similar profile. Advantageous water sorption profile properties of exemplary formulations containing sulfobutylether-β-cyclodextrin (2-SBEbc) are shown in FIG. 4. Therefore, these materials exhibit (i) excellent resistance to water absorption, and (ii) low speed water absorption, and are suitable for incorporating these materials into the powder of the present invention.

Dextran, a polysaccharide comprising glucose monomers, is also useful as a hygroscopic growth inhibitor. Dextran for use in the present invention has a molecular weight range of about 10,000 to 100,000. Dextran 10, Dextran 40, Dextran 70 and Dextran 75 are preferred. Dextran derivatives such as dextranomers (dextran 2,3-dihydroxypropyl 2-hydroxy-1,3-propanediyl ether), maltodextran and dextran sulfate sodium can also be used. Dextran's resistance to water absorption is illustrated by moisture sorption scale experiments, as shown in Example 3 and FIG. 1, dextran spray-dried at 70% relative humidity absorbs only 19% moisture, while 80 At relative humidity of% dextran exhibited water sorption of 24% by weight.

Derivatized celluloses having a molecular weight of 10,000 to 400,000 such as hydroxypropyl methylcellulose (HPMC), cellulose ethyl hydroxyethyl ether and hydroxypropyl cellulose are useful as hygroscopic growth inhibitors.

Derivatized starch can be used as a hygroscopic growth inhibitor. Particularly preferred hygroscopic growth inhibitors are hydroxyethylstarches (HES) having a molecular weight of about 70,000 to about 400,000 (see eg FIG. 2). A review of HES can be found in Intensive Care Med (1999) 25: 258-268.

Hydrolyzed starch maltodextrin and its commercial derivatives are suitable for use as hygroscopic growth inhibitors. Maltodextrin 40 with an average molecular weight of about 3600 is preferred.

HGI useful in the methods and particles of the present invention combines (1) lack of toxicity at the concentrations used (2) good powder properties, ie lack of cohesive or waxy concentrations in the solid state and effective minimization of hygroscopic growth. Toxicity of provided substances can be found, for example, in Int. J. Pharm. 65 (1990), p249-259, can be tested by standard means such as MTT analysis.

Hygroscopic growth inhibitors are present in the particles in an amount sufficient to minimize or prevent the hygroscopic growth of the particles to maintain the size below 3 microns upon delivery of the particles to the alveoli in aerosol form. Optimal ratios of active agent to HGI can be identified for any given HGI by testing various ratios in the in vitro model as described above. For example, the active agent is typically mixed with HGI such as hydroxyethylstarch in weight ratios of 10/90, 25/75, 50/50, 75/25 and 90/10, so that the water absorption range or absorption in the powder Determine the rate at which the speed is significantly reduced. From these data, the optimal concentration of HGI can be determined. Different HGIs mixed with different active agents and optionally additional excipients have different optimal concentrations, so each HGI must be tested separately.

Generally, the particles comprise at least about 5 to about 20 weight percent, preferably at least about 20 to 40 weight percent, even more preferably at least about 40 to 60 weight percent HGI. If the active agent is a protein or polypeptide, the amount of HGI required to reduce the water absorption properties of the powder is small because the protein and polypeptide act to inhibit hygroscopic growth. Generally, when the active agent is not a protein or polypeptide, the particles preferably comprise at least 40% HGI, and the amount of HGI in the particles ranges from about 40 to 99% by weight. The presence of intracellular HGI maximizes the deposition of aerosol-like particles on the lower airways, especially on the alveolar surface, as opposed to in mice, throats and upper airways, thereby increasing the bioavailability of the active agent delivered to the lungs.

C. Other Excipients

In addition to hygroscopic growth inhibitors, the active agent powders of the present invention may optionally be mixed with pharmaceutical carriers or excipients suitable for respiratory and pulmonary administration. Such carriers can act only as extenders when it is desired to reduce the concentration of active agent in the powder to be delivered to the patient. However, the carrier functions to improve the dispersibility of the powder in the powder dispersing device to provide more effective and reproducible delivery of the active agent, and to improve the handling properties (eg flowability and concentration) of the active agent to facilitate preparation and powder filling. It can act. In particular, excipient materials often improve the physical and chemical stability of the particles, further minimizing residual moisture content and preventing moisture absorption, and for particle size, cohesiveness, surface properties (ie wrinkles), ease of inhalation and cardiopulmonary It can act to improve the targeting of the resulting particles.

These excipients, when present, are present in the composition in an amount of about 1 to about 50% by weight, and non-limiting examples of excipients include proteins, peptides, amino acids, and carbohydrates (eg, monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and Sugars such as oligosaccharides; derivatized sugars such as alditol, aldonic acid, esterified sugars, and the like, and polysaccharides or sugar polymers), and the like, which may be present alone or in combination. Examples of protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein and the like. Representative amino acid / polypeptide components can act as buffering agents such as alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, di Peptides and tripeptides such as trileucine and the like. Carbohydrate excipients suitable for the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; Disaccharides such as lactose, sucrose, trehalose, cellobiose and the like; Polysaccharides such as raffinose, melezitose and the like; Alditol such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glutitol), myoinositol and the like.

The composition may comprise a buffer or pH adjuster. Representative buffers include salts of organic acids such as citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid salts, tris, tromethamine hydrochloride or phosphate buffers and the like. In addition, the compositions of the present invention may contain additional excipients / additives such as picols (polymeric sugars), flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (eg, polysorbates such as “TWEEN 20” and "TWEEN80") and chelating agents (eg, EDTA) and the like. Other pharmaceutical excipients and / or additives suitable for use in the matrix compositions disclosed herein are described in "Remington: The Science & Practice of Pharmacy", 19th edition, Williams & Williams, (1995) and "Physician's Desk Reference", 52nd Edition, Medical Economics, Montvale, New Jersey (1998). Preferred excipients for use in the formulations of the invention include mannitol, raffinose and sodium citrate, leucine, isoleucine, valine, sucrose, raffinose, trileucine and mannitol.

III. Preparation of Powder Formulations

Dry powder formulations are preferably prepared by spray drying under conditions that result in a substantially amorphous powder. Spray drying of formulations is described in international patents such as "Spray Drying Handbook", 5th edition, K.Masters, John Wiley & Sons, Inc., New York, NY (1991), and Platz R. As disclosed in publication WO 97/41833 (1997).

Solutions, emulsions or suspensions containing the active agent, hygroscopic growth inhibitor and optionally other excipients are prepared. Spray dried solutions or suspensions typically contain about 0.1 to 10% by weight per unit volume solids. The pH range of the solution is generally maintained at about 3-9, depending on the effect of pH on the stability of the active agent. A pH near neutral is preferred because it can help maintain the physiological compatibility of the powder after dissolution of the powder in the lungs. The prespray spray dried formulation may comprise additional water miscible solvents such as alcohol or acetone. Representative alcohols include lower alcohols such as methanol, ethanol, propanol, isopropanol and the like. The resulting solution may contain the active agent at a concentration of generally 0.01 to about 2 (weight / volume)%, and generally 0.1 to 1 (weight / volume)%.

The solution is then spray dried in a conventional spray dryer, such as a spray dryer available from Niro A / S (Denmark), Butch (Switzerland) and the like, to form a stable dry powder. Optimum conditions for spray drying the formulation depend on the components of the formulation and are generally determined experimentally. The gas used to spray dry the material is typically air, but inert gases such as nitrogen or argon are also suitable. In addition, the inlet and outlet temperatures of the gases used to dry the sprayed material should not cause deactivation / decomposition of the active agent in the spray dried material. This temperature is usually determined experimentally, but generally the inlet temperature is about 50 to about 200 ° C, while the outflow temperature is about 30 to about 150 ° C.

Dry powders, on the other hand, can be prepared in lyophilization, vacuum drying, spray freeze drying, supercritical liquid processing or other forms of evaporative drying. In some cases, by preparing a composition comprising particulate agglomerates, i.e., agglomerates or agglomerates of the aforementioned matrix dry powder particles, the dry powder formulation is prepared in a form with improved handling / processing properties such as reduced electrostaticity, better flowability, low cohesion. It is desirable to provide. The aggregates can easily be broken down back into fine powder components for lung delivery, as disclosed in US Pat. No. 5,654,007 (1997) to Johnson K. et al., Incorporated herein by reference. Alternatively, condensation of the powder component, as disclosed in International PCT Publication No. WO 95/09616 (1995) to Ahlneck, C et al., Incorporated herein by reference, sieving the material to obtain aggregates, spherical To produce more spherical aggregates, and to classify according to size to obtain a product of uniform size. Dry powders may be prepared by mixing, grinding, sieving or jet milling formulation components in the form of dry powders. The resulting powder is generally in almost amorphous form.

The dry powder is preferably kept under dry (ie, relatively low humidity) conditions during manufacture, processing and storage.

IV. Properties of powder

The powder particles of the present invention retain the ability to keep the aerodynamic diameter below 3 μ when delivered to the alveoli. As can be seen from Example 1, a powder lacking hygroscopic growth inhibitor and having an initial MMAD of 3.5 microns worked like a powder having a MMAD of 5-6 microns. It can be seen from the calculation that at equilibrium in the lung, the powder grows to 9 micron MMAD. From this data, incorporating the hygroscopic growth inhibitor into the powder formulations disclosed herein is effective to significantly reduce the hygroscopic growth rate and / or range of the dry powder particles, thus only increasing the bioavailability of the active agent included in the powder particles. But also increased the dispersibility of these formulations.

In the powders of the invention, in most cases the MMAD of the particles is less than about 3 μ before pulmonary administration. Typically the particles grow somewhat upon pulmonary administration, but have a smaller degree of growth than in the absence of hygroscopic growth inhibitors, and typically have a hygroscopic growth rate of less than about 2.5, preferably less than about 2.0, even more preferably about 1.5 Less than -2.0, most preferably less than 1.5. The hygroscopic growth rate can be determined experimentally by comparing the MMAD of the powder measured under the ambient environment with the MMAD measured under simulated lung conditions in the environmental chamber ( _{around the} MMAD _lung / MMAD). On the other hand, the MMAD of the particles under the closed conditions can be calculated as described above. First, the isotonicity for each component is measured using the molecular weights of all the components of the particles. These isotonicity is added to determine the isotonicity of the particles. From this value, the volume of solution required to reach isotonicity is calculated. This volume is the volume of the sphere. From the volume of this sphere, the diameter of the sphere is calculated to show the calculated MMAD of the particles under the conditions found in the lungs. The calculated MMAD can be used to determine the hygroscopic growth rate as described above.

The water absorption properties of the particles are usually determined by water sorption experiments. Moisture sorption data for powders can be measured with a number of techniques, such as moisture sorption scales or thermal activity monitors (TAMs). Moisture sorption balances are determined by measuring weight gain or loss as a function of increase or decrease in relative humidity at constant temperature. The carrier gas introduced in the known RH is formed by mixing a wet stream and a dry stream of gas. The sample placed in a non-wet sample cup attached to the microbalance is then exposed to this gas. Depending on the form of the sample, moisture can be absorbed, adsorbed or desorbed. Sorption is detected on the balance as an increase or decrease in weight. Data (generally time, temperature, relative humidity and weight) is collected through experimentation using computer programs and at user-defined equilibrium points.

The powders of the present invention can be characterized by the sorption index SI, i.e., the sum of the weight yields of the powders measured at 10%, 20%, 30% and 40% relative humidity divided by 4. Sorption indices are measured using a weight sorption analyzer such as DVS-1000 manufactured by Surface Measurements Systems (London, UK) or a moisture balance using an instrument such as MB300G manufactured by VTI Corporation (Hiale, FL). Powders of the invention typically have a sorption index of less than about 7.5, preferably less than about 7.0, more preferably less than about 6.5, and most preferably less than about 6.0. Powders exhibiting this SI are shown in Example 2.

Preferred powders for the present invention are powders which slowly absorb water, i.e. less than about 0.75% water, preferably less than about 0.50% water, more preferably less than about 0.35% water, most preferably as a function of relative humidity. Is a powder that absorbs at a rate of less than about 0.25% moisture (see, eg, FIG. 1). As another measure, the particles may contain less than about 60 weight percent moisture, preferably less than about 30 weight percent moisture, more preferably less than 25 weight percent moisture, even more preferably, under humid conditions at 80% relative humidity. Less than about 20% by weight of moisture, most preferably about 10-20% by weight of water. 1 and 2 show that the powder containing the hygroscopic growth inhibitor has a somewhat reduced water absorption rate (which can be seen to have a smaller slope compared to the control formulation) and lower moisture compared to the powder formulation lacking HGI. It demonstrates whether the full range of absorption is shown.

As shown in FIG. 1, the spray dried control powder containing 20% insulin, 59% sodium citrate, 18% mannitol and 2.6% glycine under conditions of 80% relative humidity absorbs 60% by weight of water, Dextran, hydroxypropylmethylcellulose, hydroxypropyl-β-cyclodextrin and hydroxyethyl starch spray-dried under the same conditions absorb 24%, 16%, 16% and 24% of water, respectively, Excellent hygroscopic growth inhibition properties are illustrated. Similarly, as shown in FIG. 2, under 80% relative humidity, the control absorbs 60% moisture, while under the same conditions 20% insulin, 40% hydroxyethylstarch, 2.6% glycine, 18% mannitol Spray dried powders containing 19% sodium citrate, and 100% hydroxyethyl starch absorb 50% and 24% moisture, respectively. In addition, in both figures, the rate of absorption was substantially reduced for the HGI material compared to the control.

The powders of the present invention are characterized by maintaining good dispersibility upon exposure to high temperature and high humidity conditions as found in the environment of the lungs. The powders of the invention are generally at or below about 30% (meaning ED _ambient -ED _{humidification} = 30 or less), preferably about 20-25% at 32 ° C. and 95% relative humidity (relative to ED at ambient conditions). Or less, more preferably 15% or less, and most preferably about 10% or less.

As illustrated, Example 2 presents a powder formulation in which ED is reduced by only about 10-15% (60% maltodextrin formulation) when evaluated in an environmental chamber. It was a powder formulation containing 60% hydroxyethyl starch that showed good ED under lung conditions. As can be seen from the data presented in Table 1, increasing the amount of hydroxyethylstarch from 40% to 60% (samples 2/3 vs. 4/5) was effective in reducing the environmental chamber ED drop. On average, these formulations exhibited about 20% drop in ED under lung conditions while maintaining ED values at about 55%.

The emission amount (ED) of the HGI containing powder under ambient conditions is at least 30%, generally at least 40%. More preferably the release amount of the powder of the invention is at least 50%, often at least 60%. The powders of the present invention typically contain large amounts of aerosol particles of small size, and thus aerosol upon (i) reaching the alveolar area, (ii) diffusion into the epilepsy and (iii) subsequent migration into the bloodstream through the endothelium. It is quite effective when delivered in form.

The dry powders of the present invention have a total moisture content of less than about 10%, generally less than about 5%, preferably less than about 3% by weight under ambient conditions. Such low moisture solids tend to be more stable than the corresponding "high moisture" solids.

V. Pulmonary Administration of Powders

The HGI containing dry powder formulations described herein are preferably delivered using any suitable dry powder inhaler (DPI), i.e., an inhalation device that utilizes inhalation of the patient as a vehicle for delivering dry powder drug to the lungs. Patton, J.S. US Patent No. 5,458,135 (1995); US Patent No. 5,740,794 (1998) to Smith A. et al .; And dry powder inhalation devices from Inhale Theraputic Systems, as disclosed in US Pat. No. 5,785,049 (1998) to Smith A. et al.

When administered using this type of device, the dry powder is contained in a receptacle, preferably a blister package or cartridge, having a perforated lid or other access surface, which is a single dose unit or multiple Dosage units may be included. Conventional methods for filling several cavities with a metered dose of dry powder medicament are described, for example, in Parks D.J. International Publication No. WO 97/41031 (1997).

Dry powder inhalers of the kind disclosed in, for example, US Pat. No. 3,906,950 (1974) to Cocozza, S. and US Pat. No. 4,013,075 (1977) to Cocozza, S. are suitable for delivering the dry powders disclosed herein. In this type of dry powder inhaler, pre-measured doses of dry powder are placed in hard gelatin capsules for delivery to the sample.

Other dry powder dispersing devices for dry powder lung administration include, for example, Newell, R.E. European Patent EP 129985 (1988), et al .; Hodson, P.D. European Patent EP 472598 (1996); Cocozza, S. et al., European Patent EP 467172 (1994) and Lloyd, L.J. Et al., US Pat. No. 5,522,385 (1996). Inhalation devices such as Astra-Draco “TURBUHALER” are suitable for delivering the matrix dry powder of the invention. Devices of this kind are described in US Pat. No. 4,668,218 (1987) to Virtanen, R. et al. US Pat. No. 4,667,668 to Wetterlin, K. et al. Issued May 26, 1987; It is described in detail in US Pat. No. 4,805,811 (1989) to Wetterlin, K et al. Appropriate devices are provided for adhering the powdered medicament, for lifting the medicament from the carrier screen by passing air through the screen, or for providing air using a piston to mix the powdered medicament and air in the mixing chamber, Mulhauser The powder is introduced into the patient through the mouthpiece of the device as disclosed in US Pat. No. 5,388,572 (1997) to P., et al.

HGI-containing dry powders are described in US Pat. No. 5,320,094 (1994) to Laube et al. And Rubsamen, R.M. As disclosed in US Pat. No. 5,672,581 (1994), the pressurized metered dose inhaler (MDI) comprising a pharmaceutically inert liquid propellant such as chlorofluorocarbon or drug solution or suspension in fluorocarbon Can be delivered.

Prior to use, the HGI-containing dry powder is generally stored under ambient conditions, preferably at temperatures below about 25 ° C. and at 30-60% relative humidity (RH). More preferred relative humidity conditions, such as less than about 30%, can be achieved by incorporating a desiccant in the dosage form of the second packaging. The respirable dry powder of the present invention not only has excellent aerosol performance but also excellent stability.

When aerosolized for direct delivery to the lungs, the active agents contained in the dry powder formulations disclosed herein increase bioavailability in the lungs due to the presence of HGI contained in the powder particles, resulting in a greater proportion of inhaled particles In the upper respiratory tract, due to hygroscopic growth, the cardiopulmonary is reached without first being deposited. Thus, such HGI containing formulations can be administered in small amounts per drug dose and do not even need to be inhaled multiple times per day. In addition, the presence of HGI reduces or prevents water absorption to improve stability for powder formulations, thus improving the shelf life and transport stability of dry powder formulations.

Each publication, patent, or patent application mentioned in this specification is herein incorporated by reference to the same extent as they have been shown to be specifically and individually incorporated by reference.

Summary of the Invention

An important variable that increases the bioavailability of the drug delivered to the alveolar area is the particle's size and density, as well as the particle's ability to absorb water as it passes through the lungs to the alveoli. The inventors have found that simply coating the particles is insufficient to minimize the absorption of water in the lungs, but rather that the complete particles retain hygroscopic growth inhibition properties and are not pre-deposited in the upper lung area and pass through the alveolar surface through the lungs. It has been found that it is possible to maintain an appropriate particle size distribution of the aerosol.

Thus, in one aspect, the invention relates to particles for delivering an active agent to alveoli of a human patient. This particle includes an active agent and a hygroscopic growth inhibitor. Hygroscopic growth inhibitors are incorporated into the particles and the particles maintain an aerosol particle size distribution of less than 3 microns MMAD upon delivery to the alveoli.

In another aspect, the invention relates to particles containing an active agent and a hygroscopic growth inhibitor, wherein the particles are highly dispersible and exhibit a drop of up to about 25% of the release capacity under simulated lung conditions.

According to another aspect, the present invention relates to particles having low water absorption. This particle comprises an active agent and a hygroscopic growth inhibitor, and is further characterized by a sorption index of less than about 6.5.

In another aspect, the invention relates to a method of making particles for delivering an active agent to alveoli of a human patient. This method involves preparing a mixture of hygroscopic growth inhibitors, active agents and solvents. The mixture is then spray dried to obtain homogeneous particles of the hygroscopic growth inhibitor and the active agent. The particle size distribution of the resulting particles is less than 3 micron MMAD upon inhalation delivery to cardiopulmonary. Alternatively, the resulting particles are characterized by a drop of 25% or less of the release capacity under simulated lung conditions. As another alternative, the spray dried particles are characterized by a water sorption index of less than about 6.5.

In another aspect, the invention relates to a method of delivering an active agent to the lungs of a human patient, wherein the aerosol-like particles having the aforementioned characteristics are administered by inhalation to the human patient.

Another aspect of the invention relates to a method of increasing the amount of inhaled active agent deposited on cardiopulmonary. The method includes the step of incorporating a hygroscopic growth inhibitor into the inhalation active agent-containing dry powder such that at least 20% of the nominal amount is deposited in the cardiopulmonary upon aerosolization and inhalation of the particles.

These and other objects and features of the present invention will become more apparent from the following detailed description taken in conjunction with the accompanying drawings and examples.

The following examples are illustrative only and should not be construed as limiting the scope of the invention.

Example

Materials and methods

Salmon calcitonin (sCalcitonin) was purchased from Bachem (Torrance, CA).

Human serum albumin (HSA) was purchased from Miles Incorporated, Kankake, Illinois.

Sodium citrate dihydrate was obtained from J. T. Bakker (Phillipsburg, NJ).

L, α-dipalmitoylphosphatidylcholine (DPPC) is available from Avanti Polar Lipid, Alabama.

Example 1

Particles containing the following active agents were prepared to investigate moisture absorption and hygroscopic growth properties.

A. Producing Powder

Salmon calcitonin powder was prepared as follows. A large amount of sCalcitonin was dissolved in sodium citrate buffer containing mannitol and HSA to give an aqueous solution with a final solids concentration of 7.5 mg / ml and a pH of 6.7 ± 0.3. This aqueous solution was passed through a 0.22 μm filter and then spray dried using a material in a Butch 190 mini spray dryer (Buchi Lavortecnik AG, Myerskstrasse, Switzerland). The spray dryer was operated at an inlet temperature of 110 to 120 ° C., a liquid feed rate of 5 ml / min, and an outlet temperature of 70 to 80 ° C. to collect fine white microcrystalline powder.

Hygroscopic growth inhibitors (HGI), i.e. containing DPPC, cyclodextrin, hydroxyethylstarch, dextran, dextranomer, maltodextran, hydroxypropylcellulose, hydroxypropylmethylcellulose and cellulose ethyl hydroxyethyl ether Powders are similarly prepared.

The composition of the powder without HGI was 5% by weight salmon calcitonin / 6.25% by weight HSA / 73.75% by weight mannitol / 15% by weight citrate. Powders containing HGI retain salmon calcitonin / HSA / mannitol / citrate in equal relative amounts but contain about 10-90% by weight of hygroscopic growth inhibitors.

The resulting powder is stored in a hermetically closed container in a dry environment (<10% RH) prior to hygroscopic growth analysis.

B. Powder Analysis

The particle size distribution of salmon calcitonin powder was measured by liquid centrifugation sedimentation on a Horiba CAPA-700 particle size analyzer after dispersion of the powder in Sedisperse A-11 (Micrometrics, Norcross, GA).

The moisture content of salmon calcitonin powder was measured by the Karl Fischer technique using a Mitsubishi CA-06 moisture meter.

The aerosol particle size distribution was measured using a cascade bomber (Grassby Anderson, Smina, GA) at a flow rate of 28 L / min, ignoring powder loss in the inlet manifold and stage 0 jet plate.

The amount of release (ED) was evaluated using an Inhale Terrafutic Systems aerosol device similar to that disclosed in WO 96/09085. Emission amount is the ratio of the nominal amount contained in the blister package that is released from the mouthpiece of the aerosol device and collected in a glass fiber filter (gelman, 47 mm diameter) by vacuum (30 L / min) for 2.5 seconds after device activation. define. ED is calculated by dividing the amount of powder collected on the filter by the mass of the powder in the blister pack.

The ED of 5% salmon calcitonin powder is 52.6-53.9%.

The MMAD of the 5% salmon calcitonin powder was approximately 3.5-3.5 microns.

These analyzes are similarly performed for DPPC-containing salmon powders.

C. Particle Growth

The following study was performed to investigate the bioavailability of salmon calcitonin formulations delivered to the lungs as dry powder aerosols.

Non-HGI-salmon calcitonin particles were administered to 16 healthy volunteers. Each sample was given a dry powder aerosol dose. The aerosolized dose comprises about 2.5 mg of a powder containing about 750 IU (125 μg) of salmon calcitonin radiolabeled with 10 MBq ^99m Tc pertechnate. Particles were aerosolized using an Inhale Terrafutic Systems aerosol device as described above.

The dose of salmon calcitonin delivered to the lungs and peri-pulmonary (cardiopulmonary) was measured using standard gamma camera modification techniques. Quantification of salmon calcitonin reaching the systemic circulatory system was performed by radioimmunoassay of serum samples taken 6 hours after administration. Supersensitive radioimmunoassay kit for quantitative radioimmunoassay ").

Bioavailability was measured by comparison with dose corrected AUC (area curve) estimates using peripheral (alveolar) doses. AUC was measured using a simple inequilateral integration. Relative bioavailability was measured compared to subcutaneous injection. Statistical analysis of gamma camera deposition data and relative bioavailability data was performed using the Wilcoxon matched pair labeled ranking test. The Wilcoxon test is a nonparametric test suitable for small sample sizes. P values of ≦ 0.05 were considered significant.

There was little change in the size distribution of the powder without HGI before and after the radiolabeling treatment. After inhalation, the deposition pattern was examined by site and 21.6% of the inhaled powder dose reached the peripheral lung (45.6% reached the entire lung, including the peripheral lung), while the loss in the oral cavity and oropharyngeal was 54.4%. .

The bioavailability of salmon calcitonin powder compared to subcutaneous injection was 28.0% of the dose delivered to the surrounding lungs. Despite the 3.5 MMAD values obtained for the aerosol size distribution, the powder behaved like a powder of 5-6 micron MMAD. This can be explained as the result of the hygroscopic growth of the particles as the powder passes through the airways due to the hygroscopic properties of the formulation.

This mechanism was supported by calculating the aerodynamic equilibrium growth ratio for the formulation, 2.53. This ratio suggests that the particles grow under airway conditions, starting with 3.5 micron MMAD in equilibrium and aerosol particles growing to 9 micron MMAD (ie, the particle's original aerodynamic diameter grows to 2.53 times). The equilibrium growth ratio is determined by calculating the solid concentration (powder to powder ratio) at which the aqueous powder solution is isotonic, i.e. the concentration at which liquid droplets reach equilibrium in the lungs, and then calculating the MMAD of the isotonic droplets. Growth ratio is MMAD _{isotonic droplets} / MMAD _{peripheral powder particles} .

Thus, salmon calcitonin powder, which maintains 3.0 microns of MMAD when delivered to the alveoli, is present in the particles at a concentration of about 10-90%, in particular 10, 20, 30, 40, 50, 60, 70, 80 and 90% by weight HGI. Prepared by incorporating one or more HGI. The resulting powder is then tested as described above to determine if there is hygroscopic growth upon exposure to environmental conditions in the lungs. The powders of the present invention are powders that exhibit inhibition or reduction of hygroscopic growth, and more specifically, maintain a particle size distribution of less than 3.0 microns MMAD upon delivery to the surrounding lungs to increase deposition in the surrounding lungs and increase the activity of the lung delivered actives. Increase bioavailability in the lungs.

Example 2

Powder Measurement in Environmental Chambers

Spray dried powders containing one or more hygroscopic growth inhibitors were prepared as disclosed in Example 1. The relative weight ratios of the powder components are shown in Table 1 below.

To assess the hygroscopic action of aerosol powders, dry inhalable powders were placed in an environmental chamber (Enviro-chamber) that simulates the physiological conditions of the human lung (32 ° C. and 95% RH). The chamber was monitored with a predetermined humidity and temperature probe (Digi-Sense). From the data collected in advance by a predetermined probe, it was confirmed that 95% RH and 32 ° C. were constantly maintained by the Enviro-chamber for a long time.

Emission amounts and particle sizes were measured under standard conditions (24 ° C. and 40%) and high humidity conditions (32 ° C. and> 95% RH). Sampling under standard conditions made the system large and inside the environmental chamber. Data collected under standard conditions was used as control baseline. Membrane filters (47 mm) were used for ED collection and an Andersen Cascade Impactor for particle size distribution measurements.

Sample number Lot number combination ED, n = 28 EDE-chamber Sorption Index One R98403 60% maltodextrin 20% insulin 2.6% glycine 4.3% mannitol 13.09% citrate 0.013 citric acid, pH 7.3 76.94 67.12 5.3 2 R98403 Same as above 78.51 65.31 5.3 3 R98414 40% HES-hmw 20% Insulin 2.6% Glycine 10% Mannitol 27.4% Citrate pH 7.3 72.63 47.52 6.4 4 R98414 Same as above 77.23 49.39 6.4 5 R99041 60% HES-hmw 20% Insulin 2.6% Glycine 4.3% Mannitol 13.09% Citrate 0.013% Citric Acid pH 7.3 75.83 54.55 - 6 R99041 Same as above 74.23 55.48 * HES-mhw = hydroxyethyl starch

The results presented in Table 1 illustrate that the powder containing HGI is highly dispersible under ambient conditions and maintains good dispersibility under simulated lung conditions. This result illustrates how to optimize the formulation by adjusting the amount of HGI, as can be seen for sample 3/4 compared to sample 5/6. Increasing the hydroxyethyl starch from 40% to 60% is effective in reducing the ED drop (per ED _surrounding -ED _lung ) under high humidity conditions. This illustrates the ability of the HGI containing powders to resist fluid absorption and maintain fluidity even under extreme high humidity conditions.

MMAD of Powder R98403 (Samples 1 and 2 above) was measured under normal temperature and humidity conditions (70 ° F. and 40% relative humidity). The results are summarized below.

Fill weight (mg) (dose form) MMAD (micron) <5 microns (%) <3.3 micron (%) 5 2.9 84 59 5 2.9 84 59 2 2.3 96 77 2 2.4 94 74

As evidenced from the above results, this powder maintains low MMAD even under high temperature and high humidity conditions.

Example 3

Spray dried powders were prepared as disclosed in Example 1. Moisture sorption profiles were measured on spray dried HGI containing powders using gravimetric sorption analyzer DVS-1 manufactured by VTI Corporation (Hiale, FL). The spray dried powder has the following composition (% by weight).

A. 20% insulin, 59% sodium citrate, 18% mannitol, 2.6% glycine

B. 100% Dextran

C. 100% hydroxypropylmethylcellulose

D. 100% hydroxypropyl-β-cyclodextrin

E. 100% hydroxyethyl starch (low molecular weight, MW = 200,000)

F. 20% insulin, 40% hydroxyethylstarch, 2.6% glycine, 18% mannitol, 19% sodium citrate

G. 20% insulin, 20% leucine, 50% β-cyclodextrin sulfonylbutyl ether, 10% sodium citrate

H. 20% insulin, 20% leucine, 50% hydroxyethyl starch, 10% sodium citrate

I. 20% insulin, 5% leucine, 50% hydroxyethyl starch, 25% sodium citrate

J. 20% Leucine, 50% Hydroxyethyl Starch, 30% Sodium Citrate

Water sorption profiles for Powders A, B, C, D and E are shown graphically in FIG. 1.

Water sorption profiles for Powders A, F and E are shown in FIG. 2.

Water sorption profiles for Powders A, D and G are shown in FIG. 4.

Water sorption profiles for powders H, I, E, A and J are shown in FIG. 5.

As can be seen from each figure, the addition of a hygroscopic growth inhibitor to certain formulations is effective in significantly reducing the water sorption profile, thereby reducing the hygroscopic growth of the particles as they are delivered through the airways into the cardiopulmonary.

Example 4

Hydration characteristics of various spray dried insulin powder formulations were compared by thermal activity monitoring (TAM) using thermal activity monitor model 2277 (Sweden Thermometrics). The operating conditions are as follows. Gradient mode using RH perflusion units; Sterilize from 0% RH to 90% RH at 25 ° C., 3% RH / hr using a nitrogen stream of 1.48 SCCM. The dry powder formulations used were as follows.

A. 20% insulin, 59% sodium citrate, 18% mannitol, 2.6% glycine

B. 60% by weight insulin, 2.6% glycine, 10% mannitol, 27.4% sodium citrate, 2.6% glycine

C. 40% HES-hmw, 20% Insulin, 2.6% Glycine, 10% Mannitol, 27.4% Citrate

D. 60% maltodextrin, 20% insulin, 2.6% glycine, 4.3% mannitol, 13.09% citrate, 0.13% citric acid

TAM results for each formulation are shown in FIG. 3. As shown in FIG. 3, the incorporation of HGI into the 20% insulin formulation significantly reduced the water adsorption range and rate compared to the 20% insulin formulation without HGI, which indicates the hygroscopic growth range of the particles. To reduce the HGI effect.

Claims (23)

A particle for delivering an active agent to an alveoli of a human patient comprising an active agent and a hygroscopic growth inhibitor, wherein the hygroscopic growth inhibitor is incorporated into the particle and the particle exhibits a release drop of less than 25% under simulated lung conditions. The hygroscopic growth inhibitor according to claim 1, wherein the hygroscopic growth inhibitor is a double-chain phospholipid, cyclodextrin, hydroxyethyl starch, dextran, dextranomer, maltodextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose and cellulose ethyl hydroxyethyl ether Particles for delivering the active agent to the alveoli of a human patient, characterized in that it is selected from the group consisting of. The hygroscopic growth inhibitor according to claim 1 or 2, wherein the hygroscopic growth inhibitor is β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether β-cyclodextrin, dextran, hydroxypropylmethylcellulose, hydroxyethyl starch. And particles for delivering the active agent to the alveoli of a human patient, characterized in being selected from the group consisting of maltodextrin. The human patient of claim 1, wherein the hygroscopic growth inhibitory agent is present in the powder in an amount sufficient to provide a powder exhibiting a water absorption rate of less than about 0.50% as a function of relative humidity. For delivering the active agent to the alveoli of the patient. 5. The hygroscopic growth inhibitor of claim 1, wherein the hygroscopic growth inhibitory agent is present in the powder in an amount sufficient to provide a powder exhibiting an overall moisture absorption range of up to about 30% by weight at 80% relative humidity. 6. Particles for delivering an active agent to the alveoli of a human patient. 6. Particles according to any one of the preceding claims, characterized in that the amount of release is at least 60% under ambient conditions. The particle for delivering an active agent to the alveoli of a human patient according to any one of claims 1 to 6, comprising about 20 to about 99% by weight of a hygroscopic growth inhibitor. 8. A method according to any one of the preceding claims for the delivery of an active agent to the alveoli of a human patient characterized in that it is deposited in the deep lungs in the range of 20% or more of the nominal dose upon delivery of the lungs. particle. The method according to any one of claims 1 to 8, wherein the hygroscopic growth inhibitor is applied to the lung when compared to the bioavailability observed for the active agent contained in the same particle without the hygroscopic growth inhibitor and delivered to the lung. A particle for delivering an active agent to the alveoli of a human patient characterized by being effective at increasing bioavailability by at least about 5%. A particle for delivering an active agent to the alveoli of a human patient comprising an active agent incorporated into the particle and a hygroscopic growth inhibitor, characterized by a sorption index of less than about 6.5. 11. The hygroscopic growth inhibitor according to claim 10, wherein the hygroscopic growth inhibitor is a double-chain phospholipid, cyclodextrin, hydroxyethyl starch, dextran, dextranomer, maltodextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose and cellulose ethyl hydroxyethyl ether Particles for delivering the active agent to the alveoli of a human patient, characterized in that it is selected from the group consisting of. The hygroscopic growth inhibitor according to claim 10 or 11, wherein the hygroscopic growth inhibitor is β-cyclodextrin, hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfobutylether, dextran, hydroxypropylmethylcellulose, hydroxyethyl starch. And particles for delivering the active agent to the alveoli of a human patient, characterized in being selected from the group consisting of maltodextrin. The particle for delivering an active agent to the alveoli of a human patient according to claim 10, wherein the amount of release is at least 60% under ambient conditions. The particle for delivering an active agent to the alveoli of a human patient according to any one of claims 10 to 13, comprising about 20 to about 99% by weight of a hygroscopic growth inhibitor. A particle for delivering an active agent to the alveoli of a human patient comprising an active agent incorporated into the particle and a hygroscopic growth inhibitor, characterized by maintaining an aerosol particle size distribution at less than 3 microns MMAD upon delivery to the alveoli. Preparing a mixture of hygroscopic growth inhibitor, active agent and solvent; And Spray drying the mixture to obtain homogeneous particles of the hygroscopic growth inhibitor and the active agent, wherein the particles exhibit an emission drop of less than about 25% under simulated lung conditions, to deliver the active agent to the alveoli of a human patient. Method for producing the particles for. 17. The hygroscopic growth inhibitor of claim 16, wherein the hygroscopic growth inhibitor is a double-chain phospholipid, cyclodextrin, hydroxyethylstarch, dextran, dextranomer, maltodextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose and cellulose ethyl hydroxyethyl ether A method for producing particles for delivering an active agent to alveoli of a human patient, characterized in that it is selected from the group consisting of: The method of claim 17, wherein the hygroscopic growth inhibitors are β-cyclodextrin, hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfonylbutylether, dextran, hydroxypropylmethylcellulose, hydroxyethylstarch and maltodextrin. Method for producing a particle for delivering the active agent to the alveoli of a human patient, characterized in that it is selected from the group consisting of. 19. The method of any one of claims 16-18, wherein the solvent is water. 20. The method of claim 16, wherein the homogeneous particles comprise from about 20 to about 99 weight percent hygroscopic growth inhibitory agent. 21. A method of delivering an active agent to a lung of a human patient, comprising inhaling and administering the aerosolized active particle of any one of claims 1 to 15. The method of claim 21, wherein the active agent is administered by a dry powder inhaler. Incorporating a hygroscopic growth inhibitor into the inhaled active agent-containing dry powder particles such that at least 20% of the nominal amount is deposited in the cardiopulmonary upon aerosolization and inhalation of the particles.