TWI226248B - Aerosolizable particles resistant to hygroscopic growth - Google Patents

Abstract

The present invention is directed to particulate compositions and methods for delivering an active agent to the lung of a human patient. The active agent formulation is in dry powder form and exhibits (i) low moisture sorption, and (ii) a resistance to hygroscopic growth, particularly under simulated lung conditions.

Description

1226248 A7 ---- B7 _ 5. Description of the invention (1) Scope of the invention The present invention relates to an improved delivery of dry powder active agent formulations to the lungs. More specifically, the present invention relates to aerosolizable dry powder particles that are resistant to hygroscopic growth when inhaled. This characteristic of the powder (ie, hygroscopic growth resistance) enables a higher proportion of particles inhaled into the lungs, thereby increasing the bioavailability of the active agent delivered to the lungs. BACKGROUND OF THE INVENTION Methods of delivering active agents via the lung have been shown to be an effective route of administration for topical and systemic administration of drugs. Pulmonary active agent formulations are delivered by the patient inhaling the drug dispersion so that the active agent in the dispersion can reach the lungs. It was found that certain drugs delivered to the lungs are easily absorbed into the blood circulation by the alveolar region directly. However, the percentage of drug inhalation that reaches substantially deep into the lungs is quite low. During pulmonary delivery, an average of about 30% of the drug is lost in the device and about 35% is lost in the oropharynx (upper airway). Of the remaining 35%, about 20% of the drug is lost in the airway, and about 15% is absorbed by the alveolar region. Gonda et al. Pointed out in Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 6, Issue 4 (19 9 0) pages 2 7 3 — 3 1 3 that the absorption of drugs in the distal airways and alveoli should be higher than in the upper airways Quickly, this is due to the thin diffusion barrier and large surface area of such areas. However, 'because the proportion of drugs that substantially reach the surface of the alveoli is low, it is necessary to develop a method to increase the substantial amount of drugs that enter the systemic circulation.

Backstrom et al, U.S. Patent No. This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) (Please read the precautions on the back before filling this page)

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Printed by the Employees 'Cooperatives of the Intellectual Property Bureau of the Ministry of Economics -4- 1226248 A7 B7 Printed by the Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (2) 5 '5 0 6' 2 03 The first is the use of penetration enhancers to increase the epidermal absorption of the lower airway epithelium, thereby increasing the number of systemic circulation that the drug achieves. Backs trom's inhaled compounds are delivered as particles with a diameter of less than 10 microns. Its penetration enhancers include: surfactants, fatty acid salts, bile salts and their derivatives, and others. Wong et al, U.S. Patent No. 5,451,569 have also described the use of similar lung surfactants to promote the absorption of proteins and peptides in the lungs. In order to avoid the use of penetration enhancers, lnterna.tl0nal Publlcatión WO 96/32149 (granted to Inhale Therapeutic Systems) mentions the delivery of aerosolized agents in the form of dispersed dry powders to the lungs. Such agents are easily absorbed by the lungs without the use of penetration enhancers. Interntall0nal Publication W 0 97/44013 (assigned to MIT an d Penn State) also describes similar investigations to improve the bioavailability of inhaled drugs. This announcement uses aerodynamic light particles (density less than 0.4 g / cm3 and a larger average diameter greater than 5 microns) to facilitate the delivery of therapeutic or diagnostic agents to the alveolar region of the lungs. In order to further improve the bioavailability of the drug, International Publication WO98 / 3 1 3 4 6 (to MIT and Penn State) discloses the use of surfactants and aerodynamic light particles to promote drug absorption and improve their biological Effectiveness. In addition to the problem of low absorption of lung active agents through lower airway epithelial cells, another factor that causes inhaled drugs to be low in the depth of the lung is hygroscopic growth. Because it is water-soluble, it is large due to hygroscopic growth (please read the precautions on the back before filling this page).

This paper size applies to Chinese national standards (CNS> A4 size (210 x 297 mm) -5 · 1226248 A7

V. Description of the invention (3) Most aerosol particles deposited on the upper airway increase (Hickey, et Journal of Pharmaceutical Sciences, VOLUME 7 9 ^ (Please read the precautions on the back before filling this page)

Number 1 1, pages 10-9-104). In order to investigate the growth of the powder in a humid environment, fatty acid-coated disodium luciferin powder was prepared using a co-colloid particle adsorption and deposition technique. The coated powder has a M M A D / s of about 4 to 7 microns and exhibits a smaller growth rate than the uncoated powder. Although there are many methods mentioned above, in general, the percentage of drugs inhaled into the alveolar surface of the lungs is still low. Therefore, there is a need to develop a new and improved method to increase the amount of inhaled drugs deposited deep in the lungs, thereby increasing the bioavailability of inhaled active agents. Summary of the invention

The increase in the bioavailability of drugs delivered to the alveolar region of the lungs is related not only to the small particles and density, but also to the ability to absorb water as they pass through the lungs to the alveoli. It was found that relying solely on coated particles was not sufficient to minimize the extent of water absorption in the lungs. The entire particle must have hygroscopic growth-inhibiting properties in order to maintain an appropriate aerosol size distribution when passing through the lungs So that it does not deposit in the upper lung area when it passes through the lungs to the alveolar surface. Accordingly, one of the features of the present invention relates to a particle that delivers an active agent to the alveoli of a human patient. This granule contains active agent and hygroscopic growth inhibitor. Hygroscopic growth inhibitors are incorporated into the particles, and the aerosol particle size distribution of the particles is maintained at less than 3 micrometer M MD when delivered to the alveoli. Other features of the present invention relate to a paper containing active agent and hygroscopic raw paper, which is applicable to China National Standard (CNS) A4 (210 x 297 mm)-6-1226248 A7 B7. 5. Description of the invention (4) The granules of the inhibitor have high dispersibility, and the emission dose is reduced by not more than about 25% in the lung-like state. According to other features, the present invention relates to a particle having low moisture absorption. The granules contain an active agent and a hygroscopic growth inhibitor, and its absorption index is lower than about 6.5. Another feature of the present invention relates to a method for preparing granules capable of delivering active agents to the alveoli of human patients. This method involves preparing a mixture containing a hygroscopic growth inhibitor, an active agent, and a solvent. The mixture is then spray-dried to form homogeneous particles of hygroscopic growth inhibitor and active agent. The particle size distribution of the particles was maintained at less than 3 microns MM A D when delivered by inhalation deep into the lungs. In addition, the resulting particles have a reduced emission dose of no more than about 25% in a pseudo-lung state. In another method, the spray-dried particles have a moisture absorption index of less than about 6,5. Another feature of the present invention relates to a method for delivering an active agent to the alveoli of a human patient, wherein the aerosolized particles having the above characteristics are administered to a human patient by inhalation. Another feature of the invention relates to a method for increasing the amount of inhaled active agent deposited deep in the lungs. This method includes adding hygroscopic growth-inhibiting agents to inhaled dry powder granules containing an active agent, so that after aerosol gelation and inhalation of the granules, at least 20% of the dose is deposited deep in the lungs. These objects and other features of the present invention will be clarified by the following detailed description and the drawings and embodiments. The description of the graphics The paper size applies to the Chinese national standard (CNS> A4 size (210 x 297 mm) (Please read the precautions on the back before filling this page)) Order ---------

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1226248 Α7 Β7 V. Description of the Invention (5) Figure · 1 shows the moisture absorption curve of various spray-dried powder formulations' where moisture uptake (% by weight) is on the vertical axis,% Degree is the horizontal axis. (Round: 20% insulin, 59% sodium citrate, 18% mannitol • 2.6 glycine; square: 100% polydextrose (10K); diamond: 100% hydroxypropylmethyl Cellulose; X: 100% hydroxypropyl-1 / 3-cyclodextrin, and ±: 100% low molecular weight hydroxyethyl starch); Fig. 2 shows the moisture content of 3 different spray-dried powder formulations Absorption curve. (Round: 20% insulin, 59% sodium citrate, 18% mannitol, 2 · 6 glycine; square: 20% insulin, 2 · 6% glycine, 40% hydroxyethyl Starch., 18% mannitol, 19% sodium citrate; rhombus: 100% hydroxyethyl starch). Adding one or more HGIs to a specific formulation to reduce its water and fraction absorption. Figure 3 shows the TAM (Thermal Activity Monitor) results of various insulin dry powder formulations to demonstrate two typical hygroscopic growth inhibitions. The effectiveness of the agent in significantly reducing the hydration properties of such powders; Fig. 4 is the water absorption diagram of three spray-dried formulations, showing the effect of formulations containing hygroscopic growth inhibitors in reducing the rate of water intake and the total content Effectiveness. (Round: 20% insulin, 59% sodium citrate, 18% mannitol, 2.6 glycine; square: 100% spray-dried hydroxypropyl-cyclodextrin, and diamond-shaped 20% insulin '20% leucine, 50% / 3 —cyclodextrin sulfofluorenyl butyl ether, 10% sodium citrate; and this paper uses Chinese National Standard (CNS) A4 specifications ( 210x297 mm) (Please read the notes on the back before filling out this page)

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Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -8- 1226248 A7 _____B7__ V. Description of Invention (6) Fig. 5 is a comparison of the moisture absorption ratios of 5 different spray-dried powder formulations. The graph further shows that formulations containing HGI have a significantly lower water intake rate and total content than formulations without HGI (round: • 20% insulin, 20% leucine, 50% hydroxyethyl starch, 1 〇% sodium citrate; square: 20% insulin, 5% leucine, 50% hydroxyethyl starch, 25% sodium citrate: diamond: 100% hydroxyethyl source powder; 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 an application Microparticle compositions and methods for delivering particles containing active agents and hygroscopic growth inhibitors to the lungs, wherein the particle size distribution of the particles when delivered to the alveoli is less than 3 microns MMAD. The present invention is valuable in that it can increase the bioavailability of the active agent more than the active agent particles containing no hygroscopic growth inhibitor or only adsorbing the hygroscopic growth inhibitor on the surface thereof. It is generally believed that because the hygroscopic growth inhibitor is spread throughout the particles rather than only coated on the surface, when the particle surface is eroded or dissolved by passing through the airway, its new inner coating of hygroscopic growth inhibitor Exposed, thus providing a new coating of particles with hygroscopic growth inhibition. I. Definitions The meanings of the following terms are as explained. Active agent 〃 refers to a pharmacological effect in vivo or in vitro (usually this paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the precautions on the back before filling this page)) Order- -----—

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-9- 1226248 A7 ____________ B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (7) is beneficial) Effects of substances or mixtures, including: pharmaceuticals, drugs, Compound, or composition. This category includes: foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. In this context, and • include any physiologically or pharmacologically active substance that produces a local or systemic effect on the patient. 'Dry powder' means a powder composition containing finely divided solid particles that is free-flowing and (i) easily dispersible in an inhalation device and (ii) is inhaled by a patient so that some particles can reach the lungs and penetrate into In the alveoli. This powder is considered ', suitable for breathing, or suitable for pulmonary transmission. Dry powders generally have a moisture content of less than about 10%, preferably less than 5% moisture, and more preferably less than about 3% moisture. \ 'Hygroscopic growth inhibitor (H G I) means any material added to the particles of the present invention to reduce the rate and / or content of water uptake. When a suitable hygroscopic growth inhibitor is added to the granules of the present invention at an appropriate concentration, compared with HGI-free granules having a considerable particle content content, it can inhibit at least 5%, preferably in a typical environment of the lungs. It is at least 10%, more preferably at least 15% of the hygroscopic growth of the particles. Hygroscopic growth of particles is generally expressed in terms of hygroscopic growth ratio, which is the ratio of the MM A D of the particles to the MM A D of the dry particles before inhalation in a typical environment of the lungs. For example, a particle with a hygroscopic growth ratio of 1 will not change in size when inhaled and exposed in the lung environment. The hygroscopic growth of the particles is determined experimentally. The powder is processed in a chamber in a pseudo-lung state, ie, 3 2-3 7 ° C and 9 5-9 9 · 5% relative humidity. More specifically, the particle dose is aerosolized in the growth chamber described above. Aerosol re-entry (please read the precautions on the back before filling this page)

> n ϋ J lnn I--VW- ^ JI nfn I% This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -10- 1226248 A7 B7 V. Description of the invention (9) '' Pulmonary bioavailability in the lung refers to the amount of active agent that is absorbed after deposition in the lungs and used for systemic circulation in mammals relative to the amount absorbed into the blood from a subcutaneous injection site (% absorption /% deposition) Under the skin •) ° Model systems for measuring lung bioavailability in the lung include: rats, dogs, and non-human primates. Lung bioavailability relative to the lung can be administered directly intratracheally or by inhalation. '' Emission Dose 〃 or E D 〃 provides the distribution of dry powder within the inhaler device after launch or dispersion. E D is defined as the ratio of the emitted dose to a given dose (ie, the mass of powder per unit unit dose in a suitable inhaler device before launch). E D is a parameter measured experimentally, and is generally measured using an in vitro device that simulates the administration of a patient. In order to determine the ED 値, a predetermined dose of dry powder is placed in a suitable dry powder inhaler, and the powder is started and dispersed, and then the aerosol mist formed from the device is evacuated by vacuum, and the remaining Tare the filter membrane. The weight of the powder on the filter constitutes the emitted dose. For example, if a dosage form containing 5 mg of dry powder is placed in an inhalation device, and if the powder is 4 mg of the powder recovered on the weighted filter after dispersion, the emitted dose of the dry powder composition is: 4 mg (emission dose) / 5mg (predetermined dose) x 100 to 80%. For non-homogeneous powders, E D 値 represents the distribution of the drug (not dry powder) in the inhaler device after launch ', which is calculated based on the weight of the drug (not the total weight of the dry powder). 'The degree of reduction of the emitted dose in the pseudo-lung state " refers to the reduction of ED 値 (%) in the environment at that time by E D 値 at 32-37 ° C and 95-9 9 · 5% relative humidity. This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling out this page) H * .ϋ n n n n sip Y i l HI m · ϋ n ·

Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-12- 1226248 A7 B7 V. Description of the invention (12) Medicines, new biological drugs, anti-new biological drugs, hypoglycemic drugs, nutrition and supplements, growth supplements, fats , Anti-enteritis drugs, electrolytes, vaccines and diagnostics. • Examples suitable for the active agent of the present invention include (but are not limited to): calcitonin, erythropoietin (EP0), factor M, factor IX, ceredase, cerezyme, Cyclosporin, granulocyte colony stimulating factor (GCSF), alpha-1 protease inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCS.F), growth hormone, human growth hormone ( (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMVM), interferon alpha, interferon / 3, interferon r, interleukin-2, progesterone releasing hormone (LHRH), insulin, Growth hormone release inhibitors; Analogs of growth hormone release inhibitors, including: octreotide, posterior pituitary hormone analogues, follicle-stimulating hormone (FS Η), insulin-like growth factor, insulin probiotic, interleukin 1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, interleukin-10, macrophage colony stimulating factor (M-CSF), nerve Growth factor, parathyroid hormone (PTT), thymus hormone α 1, Π b / ma inhibitor, α-1 antitrypsin, VLA-4, respiratory fusion cell virus antibody, cystic fibrotic transcellular membrane regulator (CFTR) gene, deoxyribonuclease (Dnase), bactericidal / promoting protein (BPI), anti-CMV antibody, interleukin-1 receptor, 1-3 cis-retinoic acid, Pentamidine, acetic acid, vinegar (a 1 buter ο 1) sulfate, denatured protein alcohol This paper size is applicable to China National Standard (CNS) A4 (210 X 297) (Please read the back Please fill in this page again for the matters needing attention) —Order --------- * Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -15- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 1226248 A7 _ ^ _ B7__ V. Invention Explanation <13) Sulfuric acid vinegar, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, fluticasone, isopropyl bromide Atropine, Flunisolide, Komolin Sodium cromolyn sodium), ergotamine tartrate and the analogues, agonists and antagonists of the above. The active agent can contain nucleic acid, can only contain nucleic acid molecules, viral vectors, combined viral particles, plastid DNA or RNA or other nucleic acid constructs suitable for transfection or transformation of cells (especially cells in the alveolar region of the lung). . The active agent can be in various forms, for example: soluble and insoluble charged or uncharged molecules, molecular complex components or pharmaceutically acceptable salts. The active agent may be a natural molecule or it may be formed recombinantly, or it may be an analogue formed by adding or removing one or more amino acids to a natural or recombinantly formed active agent. In addition, the active agent may contain a live attenuated or killed virus vaccine. The active agent content of the aerosolized particles is an effective therapeutic amount of active agent per unit dose that must be delivered to achieve the desired result. In fact, it depends on the specific agent, its biological activity, the severity of the treatment symptoms, the number of patients, the dosage requirements, and the desired therapeutic effect. Generally, the granules may contain between 1% and about 99% by weight of the active agent, typically between about 2% and about 95% by weight of the active agent, and more typically between about 5% and 85% by weight. Active agent. However, the granules are particularly suitable for active agents that must deliver doses between 0.0001112 / (; 137 to 10011/03; 7, preferably 0.001 mg / day to 50 mg / day This paper size is applicable to Chinese National Standard (CNS) A4 specification (21〇 × 47 mm) (Please read the precautions on the back before filling this page)

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-16- 1226248 A7 B7 V. Description of the invention (14) B · Hygroscopic growth inhibitor (please read the precautions on the back before filling this page) The biggest feature of this kind of granule is that it contains hygroscopic growth inhibitor. Hygroscopic growth inhibitor (H G I) can effectively reduce the rate and / or content of water absorption by the particles by inhalation, so that the MM A D of the particles can be maintained below 3 microns when they are delivered to the alveoli. Materials suitable for H G I are first confirmed by lung screening to determine its moisture absorption curve after spray-drying; low-absorbency materials are more suitable for the present invention, such as the material in Figure 1. Particles containing appropriate amounts of HGI (typically higher than about 5 to 10 percent by weight of the composition) were prepared to further test the suitability of these HG I materials. In some cases, in addition to being contained in the powder, H G I can also form a coating on the surface of the particles. The moisture isotherms of the control group particles containing the same active agent particles as H G I and the same composition but without η G I were determined to determine whether the addition of H G I could effectively reduce the rate and / or content of water absorption by the powder. In general, both high and low HGI are tested to determine the range of additions to which the powder of the present invention is applicable. Hygroscopic growth inhibitors suitable for use by the Consumers ’Cooperatives’ cooperatives in the Intellectual Property Bureau of the Ministry of Economic Affairs include (but not limited to the following: double-chain phospholipids, cyclodextrin and its derivatives, hydroxyethyl starch (HE S), polydextrose, Dextranomer, maltodextrin, starch, hydroxypropyl methyl cellulose (HPMC), cellulose ethyl hydroxyethyl ether, and other cellulose derivatives, such as described in "Cellulosics: Chemical, BioChemical and Material Aspects &quot; (Ellis H or wood Series in Polymer Science and Technology) by JR, B.Sc. Kennedy, GO, B.Sc, Phillips, PA Williams (This paper size applies to China National Standard (CNS) A4 specifications (210x 297mm %) -17- 1226248 A7 ___— B7 _ 5. Explanation of the invention (15)

Editor), and "Comprehensive Cellulose CheπHstry," by D. Klemm (Editor), Bertram Philipp, Ding · Heinze (19 9 8) 0 In some cases, the active agent can also be used as a hygroscopic growth inhibitor. Can be used as the active agent of H G I include: insulin, salmon noretin, and PT. Double-chain phospholipids suitable for use in the present invention include phospholipidylcholine, such as 1,2-dimyristoyl-sn-glycerol-3-phosphocholine (DMPC), 1,2-di Palmitoyl—s η —Glycerol-3—. Choline Phosphate (DPPC), 1,2-distearylphosphonyl-sn-glyceryl-3—choline phosphate (DSPC) —1,2-diole Base-sn—glycerol-3—choline phosphate (DOPC), 1-palmityl-2—oleyl-sn—glycerol-3—choline phosphate (POP C), etc. Suitable for hygroscopic growth inhibitors are phospholipids ethanolamines, for example: 1,2 —dimyristyl — s η — glycerol 3 — phosphate ethanolamine (DMPE), 1, 2 — di almitoyl — sn —Glycerol-3, DPPE, 1, 2 — distearylamine — s η — Glycerol — 3 — Phosphateethanolamine (DS Ρ Ε), 1, 2 — diglycidyl — sn — glycerol— 3-Ethanolamine phosphate (DOPE) and similar phospholipid glycerol and phosphatidic acid derivatives. Cyclodextrins are another suitable class of hygroscopic growth inhibitors. Cyclodextrins (a type of cyclooligosaccharide with a shortened cone and a hydrophobic central cavity) are composed of more than six D-glucosyl groups. The cyclodextrins suitable for the present invention are based on their glucose base numbers, respectively, including: α-cyclodextrin (six glucosyl groups), / 3-cyclodextrin (seven glucosyl groups), and T-cyclodextrin paper size Applicable to China National Standard (CNS) A4 specifications (2) 0 × 297 mm) (Please read the precautions on the back before filling out this page) Order --------- Line i Consumption of Intellectual Property of the Ministry of Economy Cooperative printed purple-18-1226248 A7 B7 V. Description of the invention (17) The derived starches can also be used as hygroscopic growth inhibitors. Hydroxyethyl starch (HES) with a molecular weight between about 70,000 to about 40,000, is an especially preferred hygroscopic growth inhibitor (see, for example: Figure · 2) ° of HES Reviews can be found in intensive Care Med (1 9 9 9) 25-258-268. Suitable hygroscopic growth inhibitors are maltodextrin, a hydrolyzed starch 'and its commercially available derivatives. Preferred is Maltodextnn 40, which has an average molecular weight of about 36,000. The HGI used in the particles and methods of the present invention can minimize the effect of hygroscopic growth and (1) non-toxic in the concentration range and (2) have good powder properties, that is, not sticky or waxy in a solid state . The toxicity of a substance can be tested using standard methods, such as the MTT assay, such as described in Int. J Pharm. 6 5 (199 0), ρ · 249 — 259. The amount of hygroscopic growth inhibitor in the granules should be sufficient to minimize or prevent the hygroscopic growth of the granules so that the size of the granules can be maintained below 3 microns when the aerosol is delivered to the alveoli. The optimal ratio of active agent to H G I for any given H G I can be determined in various ratios using in vitro models as described herein. For example, the active agent is generally in the following w / w ratio with HGI (for example: hydroxyethyl starch): 10/90, 25/75, 50/50, 75/25, and 90 / 10 in combination to determine what ratio can cause a significant reduction in water intake or speed of the powder. From such data, the optimal concentration of H G I can be determined. Different H G I will have different optimal concentrations when used with different active agents (adding excipients as needed), so each H G I must be tested separately. This paper size applies to China National Standard (CNS) A4 specification (21〇 × 297 mm) Clothing — (Please read the precautions on the back before filling out this page) Order printed by S Industrial Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs-20- 1226248 A7 B7 V. Description of the invention (18) Generally speaking, the particles contain at least about 5 to about 20 percent by weight η GI, preferably at least about 20 to 40 percent HGI, and more preferably at least about 40 to about 60% by weight or more of HGI. If the active agent is a protein or a polypeptide, since the protein and the polypeptide can also inhibit hygroscopic growth ', the H G I content required to reduce the water absorption properties of the powder will be less. If the active agent is not a protein or polypeptide, the particles preferably contain at least about 40% HG I, and the amount of HG I contained in the particles is preferably between about 40% and 99% by weight. The inclusion of HG I in the particles maximizes the deposition of aerosolized particles in the lower airways, especially on the surface of the alveoli rather than on the mouth, throat, 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 powder of the present invention can be optionally combined with a pharmaceutical carrier or excipient suitable for respiratory and pulmonary administration. This carrier can be used as a tonic when the concentration of the active agent in the powder to be delivered to the patient is to be reduced. But the 'carrier can also be used to further improve the dispersibility of the powder in the powder dispersing device, so as to make the transfer of the active agent more efficient and reproducible, and improve the operating characteristics of the active agent (such as flowability and viscosity). Promote manufacturing and powder congestion. In particular, excipient materials are commonly used to improve the physical and chemical stability of the particles, minimize the residual moisture content and hinder moisture uptake, and improve particle size, agglutination, surface properties (ie, wrinkle), and inhalation methods. Ease and guides the formed particles deep into the lungs. This paper size applies to China National Standard (CNS) A4 specification (210 x 297 mm) (Please read the precautions on the back before filling this page) ------- Order ------- 丨! Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-21-1226248 V. Description of the invention (19 Such excipients (if contained) are about 1% to about 50% by weight, peptides, amino acids, and Carbohydrates, two, three, four, four, and oligoidonic acids (adonic acids,), exist alone or in combination. Albumin, for example: human hemoglobin albumin (r A), gelatin, casein amino acid / polypeptide components include betaine, histamine, glutamic acid, leucine, isoleucine, Acid, aspartame, dione and trinity A7 B7 in general, including (such as (sugar, sugar; derived esterified sugar, etc.); typical protein protein (HS protein, etc .: alanine,) Asparagine valine acid, methylpeptides, such as, but not limited to, sugars in the composition, including monosaccharides, for example: polysaccharides or sugar excipient packages A), recombinant glycine, buffered glycine, arginine , Cysteine Thiamine, Benzene: Trileucine content, protein sugars, sugar alcohols, polymers including blood glutamates, white amino acids, acids, ionyl propylamines, etc. Consumption by the Intellectual Property Bureau of the Ministry of Economic Affairs Carbohydrate excipients suitable for use in the present invention, such as those produced by Associated Press include monosaccharides: for example: fructose, maltose, galactose, glucose, D-mannose, sorbose; disaccharides, such as: Lactose, sucrose, trehalose, cellulose, etc .; ψ Polysaccharides, such as: raffinose, melezitose, etc .; and sugar alcohols, such as: mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), inositol, etc. The composition also includes a buffer solution or p Η regulator. Representative buffer solutions include organic acid salts such as: citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or Phthalate salts; trimethylolaminomethane, tromethamine hydrogen chloride, or phosphate buffer solution. In addition, the composition of the present invention may further include excipients / additives, for example: f 丨 c 〇m (—species (Polysaccharide), flavoring agent, anti-microbial agent, sweetener This paper size is applicable to Chinese National Standard (CNS) A4 specification (2) 0 X 297 (published) (Please read the precautions on the back before filling this page)

-22- 1226248 Α7 Β7 V. Description of the invention (20) (Please read the precautions on the back before filling this page) Antioxidants, antistatic agents, surfactants (for example: polycyanate, for example, TWEEN 2 0 &quot; and ', TWEEN 8 0 &quot;), and chelator agents (for example: EDTA). Other pharmaceutical excipients and / or additives suitable for the above matrix composition are listed in "Remnigt One: The Science & Practice of Pharmacy", 19lh ed., Williams & Williams, (1995) and `` Physician's Desk Reference &quot;, 52 &quot; d ed ·, Medical Economics, Montvale, NJ (19 9 8), which is hereby incorporated by reference in its entirety. Preferred excipients suitable for this formulation include: mannitol, cottonseed Sugar, and sodium citrate, leucine, isoleucine, valine, sucrose, raffinose, tri-leucine, and mannitol. M. Preparation of powder formulations Prepared by spray-drying under conditions that produce a substantially amorphous powder. Spray-drying formulations are (for example :) such as "Spray Drying Handbook &quot;, 5t 'ed ·, K · Masters, John Wiley &amp; Sons, Inc., NY, NY (1991) and Platz, R., et al., Inernational Patent Publication No. W 0 97/41833 (1997). The full text is consumed by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs. Cooperatives print this entry Literature: Prepare solutions, emulsions, or suspensions containing active agents, hygroscopic growth inhibitors, and other excipients as needed. Spray-drying solutions or suspensions typically contain between about 0.1 To 10% by weight / volume solids. The p Η range of its solution is generally maintained between about 3 and 9, depending on the effect of ρ Η on the stability of the active agent. Because the powder dissolves in the lungs, this paper is suitable for China. National Standard (CNS) A4 specification (2) 0 × 297 mm -23- 1226248 B7 V. Description of the invention (21) P Η helps to maintain the physiological compatibility of the powder, so it should be maintained near neutral ρ Η 値Pre-spray-dried formulations may optionally contain other miscible solvents, such as alcohols or acetone. Representative alcohols are alcohols with lower carbon numbers, such as methanol, ethanol, propanol, isopropanol , Etc. The resulting solution generally contains an active agent concentration between 0.1% (weight / volume) and about 2% (weight / volume), often between 0.1% and 1% (weight / volume). The solution is then spray-dried with a common spray dryer, for example: commercially available Such as: Niro A / S (Denmark), Buchi (Switzerland), etc., forming a stable dry powder. The optimum conditions for a spray-dried formulation depend on the composition of the formulation and are generally determined based on experimental results. The gas used to spray dry the material is usually air, but inert gases such as nitrogen or argon can also be used. In addition, the temperature of the inlet and outlet of the gas used in the spray-dried material should be controlled so as not to cause deactivation / decomposition of the active agent in the spray-dried material. This temperature is generally determined experimentally, but in general, the inlet temperature is between about 50 t: to about 200 ° C, and the outlet temperature is between about 30 ° C and about 150 ° t. In addition, the dry powder can be prepared by freeze-drying, vacuum drying, spray freeze-drying, supercritical liquid processing, or other evaporative drying forms. Under certain conditions, it is desirable to provide a dry powder formulation with improved handling / processability (eg, reduced static electricity, better flowability, low agglomeration, etc.) to prepare a combination containing fine particle aggregates Substances, that is, aggregates or agglomerates of the aforementioned dry powder particles of the matrix, the aggregates of which are easily broken into fine powder components for transmission to the lungs, as described above, for example, Johnson, K., et a]., US This paper size applies China National Standard (CNS) A4 Specification (210 x 297 mm) (Please read the notes on the back before filling out this page) «II — — Line · Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives -24-1226248 A7- ______B7 ____ V. Description of the invention (22)

Patent No. 5,654,007, 1997, the entire contents of which are incorporated herein by reference. In addition, powder can be agglomerated and sieved to obtain agglomerates when powder is prepared. Spheronizing provides more spherical agglomerates, and is coated with glue to form a uniformly screened product, as described above. For example: Ahlneck, c-; et al., International PCT Publication No. WO 9 5 / 〇 96 16,199 5, which is hereby incorporated by reference in its entirety. Dry powder $ can also be mixed, honed, sifted or honed to prepare ingredients in the form of dry powder. The resulting powder is generally in a substantially amorphous form. During manufacturing, processing, and storage, the dry powder should be maintained in a dry (ie, relatively low humidity) state. IV. Characteristics of the powder The powder of the granules of the present invention can maintain an aerodynamic diameter of less than 3 μ when transported to the alveoli. As shown in Example 1, the lack of hygroscopic growth inhibitors and powders starting with MMAD 3.5 micrometers acted like MMAD 5-6 micrometer powders. Detailed calculations show that the powder will grow to 9 μM Μ A D after the lungs are equilibrated. From this data, it can be seen that the addition of a hygroscopic growth inhibitor to the above-mentioned powder formulation can effectively reduce the hygroscopic growth rate and / or content of dry powder particles, thus not only improving the bioavailability of the powder particles containing the active agent, but also Improved dispersion of this formulation. In the powder of the present invention, the MM A D of most of the particles before the administration in the lungs is less than about 3 µ. After lung administration, the particles will grow to a certain degree, but they are still smaller than those without hygroscopic growth inhibitors and their hygroscopic growth ratio is lower than about this paper. Applicable @National Standard (CNS) A4 Specification (210 X 297 mm) (Please read the notes on the back before filling out this page) Order --------- line. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -25- A7 Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the consumer cooperative 1226248 B7_____ V. Description of the invention (23) 2 · 5, preferably less than about 2 · 0, more preferably between about 1.5 to 2 · 0, and the best is less than 1.5. The ratio of hygroscopic growth can be determined experimentally by comparing the M M A D measured at room temperature to the M M A D (M M A D lung / M M D D room temperature) measured in a pseudo-lung state in an ecological room. In addition, the particle M M A D in the lung state can be calculated in the following manner. First, the molecular weight of all components in the particle is used to determine the isotonicity of each component. These isotonicities are then summed to calculate the particle isotonicity. From this number, the volume required for the solution to reach isotonicity can be calculated; this volume is then used as the volume of the sphere. The sphere diameter can be calculated from the sphere volume, which represents the MM A D of the particles calculated in the lung state. This M M A D calculation is then used to determine the above hygroscopic growth ratio. The water uptake characteristics of granules are generally determined by water absorption experiments. Many techniques are available for powder moisture absorption data, such as moisture absorption balance or thermal activity monitoring (TAM). Moisture absorption balance is a measure of the increase or decrease of relative humidity and humidity by weight loss or increase at a fixed temperature. The wet and dry gas-liquid streams are mixed into a carrier gas of known rΗ. This gas is then re-exposed to the sample in a microbalance in a non-hygroscopic sample cup. Depending on the morphology of the sample, it can absorb, adsorb, or desorb water. This absorption is shown by an increase or decrease in weight in the microbalance. A computer program was used to collect all equilibrium data points (usually time, temperature, relative humidity, and weight) specified in the experiment and by the user. The powder of the present invention is qualitatively determined by absorption indices (S I) at a relative humidity of 10%, 20%, 30%, and 40%, that is, the total weight increase of the powder divided by 4. The absorption index is measured with a weight absorption analyzer (for example, the paper size applies the Chinese National Standard (CNS) A4 size (210 x 297 mm) (Please read the precautions on the back before filling this page)

-26- A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1226248 B7 _ Five, Ming Wuming instructions (24) such as. DVS — 1 00 ′ Surface Measurements Systems (London, U.K.)) or manufactured by Water balance (MB 300G, manufactured by VTI Corporation (Hialeah, FL)). The powder of the present invention generally has an absorption 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 6.0. The SI of the powder is shown in Example 2. The preferred powders of the present invention should take up water slowly, that is, with a relative humidity of less than about 0.75% moisture, preferably with a relative humidity of less than 0.550% moisture, and more preferably with relative humidity Below 0.35% moisture, the most preferred is relative humidity below 0.25% moisture (for example, see Fig. 1). In other measurements, the moisture absorbed by the particles under 80% relative humidity should be less than about 60% (wt), preferably less than 30% moisture, preferably less than 25% moisture, and more preferably less At 20 '% moisture, the best is between about 10 and 20% moisture by weight. Figures 1 and 2 show that powders containing hygroscopic growth inhibitors can have lower water uptake rates compared to powder formulations without HGI (lower slope compared to formulations in the control group) ) And lower total water intake. In Fig. 1, at 80% relative humidity, the spray-dried control powder contains 20% insulin, 59% sodium citrate, 18% mannitol, and 2.6% glycine. Absorbed 60% by weight of water, and in the same state, spray-dried polydextrose, via propylmethyl cellulose, hydroxypropyl-3 / 3-cyclodextrin, and hydroxyethyl starch each absorbed 24% , 16%, 16%, and 24% moisture 'thus show the superior hygroscopic growth-inhibiting properties of such materials. The same ‘in the picture · 2 This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page)

-27- A7 1226248 B7___ 5. In the description of the invention (25) at 80% relative humidity, although the control group absorbed 60% moisture under the same conditions, the spray-dried powder contained 20% insulin and 40% hydroxyethyl Based starch, 2.6% glycine, 18% mannitol, 19% • sodium citrate and 100% hydroxyethyl starch 'absorbed 50% and 24% moisture, respectively. In addition, in these two figures, the water uptake rate of the H G I material has been substantially lower than that of the control group. ′ One of the characteristics of the powder of the present invention is that it maintains good dispersibility when exposed to heat and moisture, such as in the lung environment. The powder of the present invention has a reduced emission level (ED) (compared to ED at room temperature) of less than about 30% at 32 ° C and 95% relative humidity (ie, ED ^ minus ED tide port is equal to 3 〇 or less), preferably no more than about 20 to 25%, more preferably no more than about 15%, and the best no more than about 10% 〇 For example, Example 2 shows the evaluation under the ecological room The ED of the powder formulation was only reduced by about 10-15% (60% maltodextrin formulation). At the same time, powder formulations with good E D in the lung state contained 60% hydroxyethyl starch. From the data in Table 1, it can be seen that increasing the hydroxy.ethyl starch from 40% to 60% (samples 2/3 to 4/5) can reduce the ED difference in the ecological room. On average, such formulations show an E D difference of about 20% in the lung state and an E D difference of about 55%. The emitted dose (E D) of the powder containing H G I is greater than 30%, usually greater than 40%, at room temperature. The powders of the present invention have a better emission dose of more than 50%, often more than 60%. The content of the small aerosol particles of the powder of the present invention is generally high, so it is extremely effective when conveyed in aerosolized form. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). (Please read the back Please fill in this page again) Order 丨 丨 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics -28-A7 1226248 B7 _ V. (1) of the description of the invention (26) reached the alveolar region of the lungs, and (ii) spread to Lumen, and (iii) subsequently reach the bloodstream through endothelial cells. (Please read the precautions on the back before filling this page) Generally speaking, the total moisture content of the dry powder of the present invention is less than about 10% by weight at room temperature, usually less than about 5% by weight, preferably less than about 3% by weight. Such low water content solids are more stable than the corresponding ', high water solids. V. Pulmonary inhalation powder The above-mentioned dry powder formulation containing HGI should be delivered by any applicable dry powder inhaler (DP I), that is, a dry powder drug that is conducted by the patient's inhaled breath as a carrier (body) Inhaler device in the lungs. Preferred is a dry powder inhalation device of Inhale Therapeutic Systems, as described in Patton, JS, et al., US Patent No. 5,458,135 (199.5); Smhh, A., et al., US Patent No. 5,74 0,794, (1 9 9 8); and

Smith, A ·, et al ·, U · S · Patent No ·, 5, 7 8 5, 0 4 9, (19 9 8) ° The Intellectual Property Bureau employee consumer cooperative of the Ministry of Economic Affairs printed the In use, the dry powder is contained in a container provided with a perforated lid or other imported surface, preferably a foam packaging or an ejector. The container may contain a single dosage unit or multiple dosage units. Traditionally, a method of penetrating a large number of holes with a metered dose of dry powder medicament is described in, for example, Parks, D. J., et al., International Patent Publication WO 97/410 31, (1997). Another suitable method for conveying the above dry powder is the above dry powder absorbing paper. The paper size applies the Chinese National Standard (CNS) A4 (210 x 297 cm) -29- 1226248 A7 B7 V. Description of the invention (27) Inserter ' For example, Cocozza, S., US Patent No. 3'906, 95, (1974), and Cocozza, S., US ·

Patent No. 4,013,75, (1977) in which a dry powder at an expected dose to be passed to a patient is internally sealed in a hard gelatin capsule. Other dry powder dispersing devices for dry powder for administration to the lungs include the above, for example: Newell, RE ·, et al ·, European Patent No. EP 1 2 9 9 8 5 (1 9 8 8); Hodson ,. PD, etal., European Patent No. EP 472598, (19 9 6), Cocozza, S., et al., European Patent No. EP 467172, (19 9 4), and Lloyd, LJ et al., US

Patent No. 5,522 '3 85, (1996). Other inhalation devices suitable for delivering the base dry powder of the present invention, such as: Astra-Draco iiTURBUHALER &quot;. Such devices are described in detail in Virtanen, R., U: S. Patent No. 4,668,218, (1987); Wetterlin, K., et al, US Patent No. 4, 667, 668, published in May May 26, (1987); Wetterlin, K., et al., US. Patent No. 4, 805, 811, (1989). Other suitable devices are using a piston to supply air to drive the powdered medicine, or release the medicine from the carrier sieve by the air flow through the sieve, or mix the powder medicine with air in the mixing chamber and pass the powder through the device. The mouthpiece is introduced to the patient, for example, as described in Mulhauser, P., et al, US Patent No. 5,388,572, (1997). Dried inhalers containing HGI can also be dosed by inhaler under pressure (this paper size applies to Chinese national standard (CNS> A4 size (210x297 mm)) (Please read the precautions on the back before filling this page) 丨 Order- -------- Line 1 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-30- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1226248 a7 ______B7___ V. Invention Description (28) MDI) Pharmaceutically inert liquid propellants containing pharmaceutical solutions or suspensions, for example, chlorofluorocarbons or fluorocarbons, such as Lanbe, et al., US Patent No. 5, 32, 094, (1994) and Rubs amen , RM, et al, US Patent No. 5 '672, 581 (1994). Before use, dry powder containing HGI is generally stored at room temperature, preferably at about 25 ° C or The temperature below, and the relative humidity (R Η) is between about 30 and 60%. Better relative humidity, for example, is less than about 30%, and can also be used in a second dose pack in dosage form. It is achieved by adding a dehydrating agent. The dry powder of the present invention suitable for breathing has not only good gas solubility Gum effect and good stability. When delivered directly to the lungs after aerosolization, the bioactivity of the active agents contained in the dry powder formulation in the lungs is increased due to the increase of HG Γ powder particles A higher percentage of inhalable particles can be allowed to reach deep into the lungs without being deposited on the upper airway due to hygroscopic growth. Such HGI-containing formulations can provide a smaller unit dose of the drug, without even having to Inhaled multiple times in a single day. In addition, because HGI improves the stability of powder formulations by reducing or preventing water intake, it extends its storage period and the stability of dry powder formulations. Each of the above descriptions The disclosures of documents, patents, or patent applications are incorporated herein by reference in their entirety. 'The entire text of each document, patent, or patent application is deemed to be incorporated individually and individually into a reference. The following examples are not intended to limit the scope of the invention. This paper size applies to China National Standard (CNS) A4 (210 X 297 metric t) c Please read the notes on the back before filling in this page}

-ninnnn II f .. mouth, V fn vn n I -31-1226248 ____ B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ V. Description of the invention (29) Examples of raw materials and methods Salmon calcitonin (sCalcitonin) system Purchased from Bachem (Torrance, CA). Human serum albumin (HSA) was purchased from Miles Inc. (Kankakee, IL). Sodium citrate dihydrate was purchased from J.T. Baker (Phillipsburg, NJ). L, α-Dipalmitoylphospholipid 醯 choline (DPPC) was purchased from Avanti Polar Lipids, Alabama. Example 1 The following active agent-containing granules were prepared to investigate the water uptake and hygroscopic growth properties. A. Production of powder Salmon Calcitonin powder was prepared as follows. Bulk sCalchonin was dissolved in a sodium citrate buffer solution containing mannitol and HAS to produce an aqueous solution with a final solids concentration of 7 · 5 mg / ml and a pH of 6 · 7 ± 0 · 3. The solution was then filtered through a 0.2 2 μm filter and spray-dried using a Buchi 1 900 small sprayer (Buchi Labortechnik. AG, Meierseggstrasse, Switzerland). The sprayer is set to have an inlet temperature between 110 ° C to 120 ° C, a liquid input speed of 5 m 1 / mi η, and an outlet temperature between 70 ° to 80 ° C to collect fine white amorphous Shaped powder. Contains the following hygroscopic growth inhibitors (HG 1 s): DPPC, cyclodextrin, hydroxyethyl starch, polydextrose, dextranomer, malt polydextrose, hydroxypropyl cellulose, hydroxypropyl ( (Please read the precautions on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) -32- 1226248 A7 ____ — B7 V. Description of the invention (30) The powder of methyl methyl cellulose and cellulose ethyl hydroxy ether is based on Prepared in a similar manner. The powder without HG I has a composition of 5% sCalcUonin / 6 · 2 5 SA / 7 3 · 7 5% mannitol / 1 5% citrate weight. The addition of H G I to the powder has the same relative amount as sCalchomn / HSA / mannitol / citrate, and also contains a hygroscopic growth inhibitor between about 10% and 90% by weight. The resulting powder was stored in a sealed container under a dry environment (&lt; 10% RΗ) before being subjected to hygroscopic growth analysis. Β · Powder analysis 5〇21 ^ 〇] ^ 11 The particle size distribution of the powder was measured by dispersing the powder in 36 (^? 6 ^ 6 A-1 I (Micrometrics, Norcross, GA), and then dispersing it in Hon'ba CA-PA -700 Particle Size Analyzer performs liquid centrifugal sedimentation. The moisture content of the sCalcitonin powder is measured by the Mitsubishi CA-06 Moisture Meter using the Carr Fisher method. The aerosol distribution is measured by a series impactor (Graseby Andersen, Smyrna, GA). Flow rate 2 8 1 / mi η was measured, and powder loss at the inlet manifold and the zero-stage ejector was not taken into account. The emitted dose (ED) was evaluated with an Inhale Therapeutic Systems1 aerosol device, as in W09 6/0 9 0 As described in 8 5. The definition of the emitted dose is that after starting the device, it flows out from the aerosol device mouthpiece and stays on the glass fiber filter membrane (G e 1 ma η '4 7 mm diameter) and is vacuum-extracted (3 0 L / m 1 η) The paper size contained in the blister packaging after 2 seconds is applied to the Chinese National Standard (CNS) A4 (210 X 297 mm) (please read the precautions on the back before filling this page) Order- -Line 丨 All employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative A7 1226248 B7_ 5. Description of the invention (31) The percentage of dosage. ED 计算 is calculated by dividing the mass of the powder collected on the filter membrane by the mass of the powder in the blister pack. 5% sCalcitonin The MMAD of 5 2 · 6 and 5 3 · 9% • 〇5% sCalcitonin powder is approximately 3.5-3.6 microns. This similar analysis is performed with sCalcitonin powder containing DPPC. C. The particles grow into the following: The purpose of the study was to investigate the bioavailability of sCalcitonin formulations delivered to the lungs as dry powder aerosols. SCalcitonin granules without HG I were administered to 16 healthy volunteers. Each patient received a dry Powder aerosol dose. The aerosolized dose contains approximately 2.5 mg of powder, approximately 750 I ϋ (125 μg) of salmon calcitonin, and is labeled with 10 μM BQ radioactive 99mTc pertechnitate. The granules were aerosolized using the above-mentioned Inhale Therapeutic Systems 1 aerosol device. The dose of sCalcitonin delivered to the lungs and the lung ends (deep in the lungs) was determined using a modified standard 7 camera technique. Quantitative analysis of sCalcitonin (&quot; Ultra-Sensitive Radioimmunoassay Kit for the Quantitative Radioimmunoassay for the Quantitative Determination of the Quantitative Determination of the Quantitative Radioimmunoassay for the Quantitative Determination of the Quantitative Radioimmunoassay Kit for the Quantitative Radioimmunoassay Kit for the Quantitative Radioimmunoassay for the Quantitative Radioimmunoassay for the Quantitative Radioimmunoassay for the Quantitative Determination of the Quantitative Radioimmunoassay Kit for the Quantitative Radioimmunoassay for the Quantitative Determination of the Quantitative Radioimmunoassay Kit for the Quantitative Radioimmunoassay Kit for the Quantitative Radioimmunoassay for the Quantitative Determination of the Quantitative Radioimmunoassay Kit for the Quantitative Radioimmunoassay for the Quantitative Determination of the Quantitative Radioimmunoassay Kit National Standard (CNS) A4 Specification (21CU297 mm) (Please read the precautions on the back before filling this page) Order --------- line, printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economy -34- A7 1226248 __ B7__ 5. Description of the invention (32) salmon calcitonin in serum and Plasma &quot;, Diagnostic Systems Laboratories Inc.) ° Bioavailability is a dose-corrected • positive AUC (under the curve) compared with peripheral (alveolar) dose estimates region). A U C is determined using a simple irregular quadrilateral product. Relative bioavailability is relative to subcutaneous injection. 7 The statistical analysis of camera deposition data and relative bioavailability data uses the WUcoxon paired symbol evaluation test method. Wilcoon test is a non-parametric test, suitable for small size samples. P 値 0.05 is considered significant. The size distribution of Hg I-free powder plutonium before and after radiolabeling has not changed. When examining the regional deposition pattern after inhalation, 21.6% of the inhaled powder dose reached the peripheral lungs (45.6% reached the entire lung including the peripheral lungs), while the loss at the mouth and oropharynx was Up to 5 4 · 4%. Salmon calcitonin powder has a bioavailability of 28. 0% relative to subcutaneous injection, based on the dose delivered to the surrounding lungs. Despite the large aerosol

The small distribution 値 is 3.5 M M A D. This powder has properties similar to those of M M A D between 5 and 6 microns. It can be concluded that this phenomenon is due to the hygroscopic growth of the particles due to the hygroscopicity of the formulation as they pass through the airway. Evidence for this mechanism is the calculation of the aerodynamically balanced growth ratio of the formulation, with a 値 of 2.53. This ratio shows that in the state of the airway, the particles grow and reach equilibrium. The initial is M MAD 3 · 5 microns' aerosol particles grow to 9 microns M MAD (that is, the particles grow to 2.5 · 3, the original aerodynamic diameter of three Times). Equilibrium growth ratio is used to calculate the powder solution in isotope. The paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page)

-IIIIII * I I --- III Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -35- 1226248 A7 — B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. The solid concentration at the time of the description of the invention (33) The ratio of water), that is, the concentration of liquid droplets when they reach equilibrium in the lungs, and then the M MAD of the isotonic droplets can be calculated. Growth ratio: 5 M droplets such as M M D / powder particles under 'MM ADnis. According to this, sCalcitonin powder that maintains MMA D 3.0 · 0 micron when transported to the alveoli is added to the granules in one or more (concentration between about 10-90%, especially 10, 20, 30, 40, 5 0, 60, 70, 80 and 90% by weight 11 {1) HGI was prepared. The resulting powder is tested again in the lung environment in the manner described above to determine its hygroscopic growth, if any such condition exists. The powder according to the present invention is capable of inhibiting or reducing hygroscopic growth, more specifically, maintaining the particle size distribution below 3.0 micron M MAD when reaching the surrounding lungs, thereby increasing the active agent transmitted by the lungs. Deposits in peripheral lungs and increases their bioavailability in the lungs. Example 2 The powder was measured in an ecological chamber. A spray-dried powder containing one or more hygroscopic growth inhibitors was prepared by the method described in Example 1. The relative weight percentages of the powder components are shown in Table 1 below. To assess the hygroscopicity of aerosol powders, dry inhalable powders were placed in the pseudo-human lungs (32 ° C, 95% R Η) ecological room (Envlr 〇— 室). This room is monitored with a pre-calibrated humidity and temperature probe (Digi-sense). The pre-collected data collected with this pre-calibrated probe showed that 95% R Η and 32 ° C can be stable in the Enviro chamber for a long time. (Please read the notes on the back before filling this page)

-ϋ I— tmmf nn Bn _pn IK n HI% This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) 36- Printed by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs 1226248 A7 B7 V. Description of the invention (34) The emitted dose and particle size are measured under standard (24 ° C and 40%) and humidified (32 ° C and> 95% RΗ) conditions. The samples in the standard state are performed in the ecological room where the system is closed. Data collected under standard conditions are used as baseline for the control group. Filters (47-mm) were used to collect E D and Andersen tandem impactors to measure the particle size distribution. Table 1 Sample No. Lot No. Formulation ED, n = 28 Room temperature ED E-chamber adsorption I R98403 60% maltodextrin 20% insulin 2.6% glycine 4.3% mannitol 13.09% citrate. .13 citric acid pH7.3 76.94 67.12 5.3 2 R98403 same 78.51 65.31 5.3 3 R98414 40% HES-hmw 20% insulin 2.6% glycine 10% mannitol 27.4% citrate PH7.3 72.63 47.52 6.4 4 R98414 Same 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 ρ 7.7.3 75.83 54.55 6 R99041 same 74.23 55.48 * HES-hmw = hydroxyethyl The size of the base starch is based on the Chinese National Standard (CNS) A4 (210 x 297 cm) (Please read the precautions on the back before filling this page)

-37- 1226248 _ ^ _ 5. Description of the invention (35) Table 1 shows that the powder containing HG I is highly dispersible at room temperature and maintains good dispersibility in a pseudo-lung state. This result also shows that the formulation can be optimized after adjusting its HGI quantity, such as sample 3/4 • and sample 5/6, where increasing the percentage of hydroxyethyl starch from 40% to 60% can effectively reduce the Under high humidity conditions (ED room temperature-ED lung) ED decreases. This point demonstrates the resistance of the powder containing H G I to water uptake ′ and its ability to maintain fluidity, even under extremely humid conditions. Μ M A D of powder R 9 8 4 0 3 (samples 1 and 2) was measured at moderate temperature and humidity (70 ° F and 40% relative humidity). The results are as follows. (Please read the precautions on the back before filling this page) Pray weight, mg (dosage form) MMAD, micron% &lt; 5 micron% &lt; 3.3 micron 5 2.9 84 59 5 2.9 84 ___59 2 2.3 96 2 2.4 94 -— ^ 24 — Order --------- line! Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The above results show that this powder retains a small M M A D even at elevated temperature and humidity. Example 3 A spray-dried powder was prepared according to the method described in Example 1. The weight of the paper is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 issued) -38- 1226248 B7 V. Description of the invention (36) Volume absorption analysis VS — I (manufactured by VTI Corporation, Hialeah, FL) Moisture absorption curve of powders containing spray-dried HGI. Spray. The composition of the dry powder is as follows (percent weight). A. 20% insulin, 59% sodium citrate, 18% mannitol, 2.6% glycine B. 10 0% polydextrose C. 100% Hydroxypropyl methylcellulose D. 100% hydroxypropyl-/?-Cyclodextrin E · 100% hydroxyethyl starch (low molecular weight, MW = 2000, 00) F · 20 % Insulin, .4 0% hydroxyethyl starch, 2.6% glycine, 18% mannitol, 19% sodium citrate G. 20% insulin, 20% leucine, 50% — 0 — Cyclodextrin sulfonyl butyl ether, 10% sodium citrate H. 20% insulin, 20% leucine, 50% hydroxyethyl starch, 10% sodium citrate I. 20% insulin, 5% leucine Acid, 50% acetylethyl starch, 25% sodium citrate J. 20% leucine, 50% hydroxyethyl starch, 30% sodium citrate powder A, B, C, D and E moisture absorption curves Figure as shown in Figure 1. The water absorption curves of powders A, F, and E are shown in Figure 2. The water absorption curves of powders A, D, and G are shown in Figure 4. The moisture absorption curves of powders Η, I, E, A, and J are shown in Figure 5. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇χ297297t) (Please read the precautions on the back before filling in this Page) in-line · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -39-1226248 Α7 Β7 V. Description of the invention (37) 〇 As can be seen in the figures, specific formulations have added hygroscopic growth inhibitors. • Effective Reduces its water absorption, which in turn reduces the hygroscopic growth of its particles as it travels through the airways and deep into the lungs. Example 4 The hydration properties of various spray-dried insulin powder formulations were compared using Thermal Activity Monitor, 2277 (Thermometric, Sweden) with T A M (Thermal Activity Monitor). The monitoring conditions are as follows: RH perflusion units are used in the scan mode; and 1.48 SC CM is scanned from 0% RH to 90% RH at 3% RH / hour at .25 ° C. The dry powder formulation has the following composition. A. 20% insulin, 59% sodium citrate, 18% mannitol, 2.6% glycine B. 60% (wt) insulin, 2.6% glycine, 10% mannitol, 27 4% sodium citrate, 2.6% glycine. AcidC. 40% HES — hmw, 20% insulin, 2.6% glycine, 10% mannitol, 27.4% lemon Acid salt D. 60% maltodextrin, 20% insulin, 2.6% glycine, 4.3% mannitol, 13.09% citrate, 0.13% citric acid. The T AM results for each formulation are shown in Figure 3. As can be seen in Figure 3, compared to 20% insulin formulations that do not contain HG I, the paper size applies to China @ 家 standard (CNS) A4 specifications (210x 297 g t) (please read the back first) (Notes to fill out this page)

-VI nn meat en nn I mn mm— mmmm I Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -40-1226248 A7 ___B7_ V. Description of the invention (38) After adding HGI to the formulation, its moisture absorption content and speed are significant Reduced, thus representing that such typical HGIs are effective in reducing the hygroscopic growth of such particles. (Please read the precautions on the back before filling this page) ___ 1 ___ Order · ________. Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is printed in accordance with China National Standard (CNS) A4 (210 X 297 mm) -41 -

Claims (1)

I22S248 A8 B8 C8 D8 repair, qi series. 'See Appendix 6 of the scope of patent application: Patent application No. 881 1 5 876 Chinese application patent scope replaces the Republic of China on April 28, 1993 Amendment 1 · A kind of pass active agent Granules into the alveoli of a human patient, the granules containing 1% to 60% by weight of active agent and 40% to 99% by weight hygroscopic growth inhibitor 'the hygroscopic growth inhibitor is selected from cold-cyclodextrin Essence, transpropyl-cyclodextrin, sulfobutyl ether yS-cyclodextrin, hydroxyethyl starch, dextranomer, and maltodextrin, wherein the hygroscopic growth inhibitor is Added to the granules, and the emission dose of the granules in the pseudo-lung state is reduced by 0% to 25%. 2. The granule according to item 1 of the patent application range, wherein the hygroscopic growth inhibitor is selected from the group consisting of hydroxyethyl starch, polydextrose, and maltodextrin. 3. As for the granules in the scope of patent application item 1, wherein the hygroscopic growth inhibitor is selected from the group consisting of non-cyclodextrin, hydroxypropyl-cold-cyclodextrin, and sulfonate (please read the precautions on the back before filling in (This page) The term T—Η No. 1 in the perpetual wet suction. Fan '1 benefits from ilw, please apply for an application such as ether · 4 butyl printed by the Ministry of Economic Affairs and Intellectual Property Bureau of the Consumers' Cooperatives to print the hydroxyl group as the agent, or as its item-any of the items 4 to 1-1. Envelope powder JIE Dianliji B. The amount of the agent 5 is made. · Ο ο grow to %% ο wet ο absorption · medium ο grain is the size of the medium speed% ο grains so that the wet relative to Take water. Calculate the total, take the grain of the water to take the _ grains of the _ renrenzhong to the full amount of 4 items to contain 1 dose of systemic control Fan Changlisheng specificity, please apply for wet aspiration • Medium 6 capsules -Paper Ns C, one bidder, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country, one country. One centimeter, 7 9 2 1226248, A8, B8, C8, D8. Percent 〇 (Please read the precautions on the back before filling out this page) 7 · For particles in any one of the scope of patent applications, the emission dose is 30% to 78% at room temperature. 8. The granule according to any one of claims 1 to 4 of the patent application scope, which comprises 40 to 60% by weight of a hygroscopic growth inhibitor. 9 _ As for the particles in any of items 1 to 4 of the scope of patent application, when transported by lungs, the amount of particles deposited in the depths of the city of fl is 20% to 100% of the calibrated dose. 10. The particle of any one of claims 1 to 4 in the scope of the patent application, wherein when delivered to the lungs, the biological effect of the active agent delivered to the lungs in the same granules without the hygroscopic growth inhibitor In comparison, the hygroscopic growth inhibitor can effectively improve the bioavailability of the active agent. 1 1. The particle of any one of claims 1 to 4 in the scope of the patent application, wherein the active agent comprises a protein or a polypeptide. 1 2 The granule according to item 11 of the patent application scope, wherein the active agent comprises insulin. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 3 · As for the granules in the scope of patent application No. 11, the active agent contains calcitonin. 1 4 · A spray-dried granule as described in the first item of the patent application. 0 1 5 · A granule that delivers an active agent to the alveoli of a human patient. The particle contains 1% to 60% by weight of the active agent and is added to the particle. The paper size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1226248 A8 B8 C8 D8 6. Scope of patent application (please read the precautions on the back before filling this page) 4 0% by weight to 9 9 weight % Hygroscopic growth inhibitor, the hygroscopic growth inhibitor is selected from / 3-cyclodextrin, hydroxypropyl-1 / 3-cyclodextrin, sulfobutyl ether / 3-cyclodextrin, hydroxyethyl Starch, polydextrose, and maltodextrin, wherein the particles have an absorption index ranging from 0. 0 to 6.5. 16. The granule according to item 15 in the scope of the patent application, wherein the hygroscopic growth inhibitor is selected from the group consisting of hydroxyethyl starch, polydextrose, and maltodextrin. 17 · The granule according to item 15 of the scope of patent application, wherein the hygroscopic growth inhibitor is selected from the group consisting of yS-cyclodextrin, hydroxypropyl- / 9-cyclodextrin and sulfobutyl ether / 3-cyclo dextrin. 18 · The granule according to item 15 of the scope of patent application, wherein the hygroscopic growth inhibitor is hydroxyethyl starch. 19 • As for the particles in any one of items 16 to 18 of the scope of patent application, the emitted dose is 30% to 78% at room temperature. 20 • The granule according to any one of items 16 to 18 of the scope of patent application, which contains 40 to 60% by weight of a hygroscopic growth inhibitor. 2 1 · If any one of the patent application scopes No. 16 to No. 18 is printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the grains are deposited in the depth of the lungs when they are transmitted by the lungs: 20% to 100% of the calibrated dose. 2 2 · The granule according to any one of claims 16 to 18 in the scope of patent application, wherein when delivered to the lungs, the active agent is delivered to the lungs in the same granules as those containing no hygroscopic growth inhibitor. Compared with bioavailability, the hygroscopic growth inhibitor can effectively improve the bioavailability of the active agent. This paper size is applicable to China National Standard (CNS) A4 specification (21 × 297 public directors) 1226248 A8 B8 C8 D8 VI. Patent application scope 2 3 · As for any one of the patent application scope items 16 to 18 Wherein the active agent comprises a protein or polypeptide. (Please read the precautions on the back before filling out this page) 2 4 · As for the granules in the scope of patent application No. 23, the active agent contains insulin. 25. The granules according to item 23 of the patent application, wherein the active agent sentence contains calcitonin. 2 6 · —A kind of spray-dried granules such as item 15 in the scope of patent application. 27 · —a granule for delivering an active agent to the alveoli of a human patient, the granule comprising 1% to 60% by weight of the active agent and 40% to 99% by weight of a hygroscopic growth inhibitor added to the particle The hygroscopic growth inhibitor is selected from the group consisting of / 3-cyclodextrin, hydroxypropyl-cold-cyclodextrin, sulfobutyl ether point-cyclodextrin, hydroxyethyl starch, polydextrose, and wheat. Maltodextrin 'wherein the aerosol particles of the particles are large when delivered to the alveoli. The small distribution is less than 3 micron M MAD (mass median aerodynamic diameter). 2 8 · A method for preparing granules for delivering an active agent to the alveoli of a human patient, comprising: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (1) 40% to 99% by weight selected from / 3 —Cyclodextrin, Shoeylpropyl-Cold-Cyclodextrin, Sulfobutyl Ether, Cyclodextrin, Hydroxyethyl® Powder, Polydextrose, and Maltodextrin (Solid) Hygroscopic Growth Inhibition Agent, (ii) a mixture of 1% to 60% by weight of active agent, and (1i1) a solvent; and spray-dried the mixture to contain a hygroscopic growth inhibitor and a living standard g standard applicable to China (CNS) Eighty-four secrets (21〇χ297 公 董) ^^-1226248 A8 B8 C8 D8 _ 6. Homogeneous particles of a patent-pending scope agent; wherein the emission dose of the particles is reduced by 0 to 25% in a pseudo-lung state . 29. The method of claim 28, wherein the hygroscopic growth inhibitor is selected from the group consisting of hydroxyethyl starch, polydextrose, and maltodextrin. 30. The method according to item 28 of the patent application scope, wherein the hygroscopic growth inhibitor is selected from / 3-cyclodextrin, hydroxypropyl-cyclodextrin, and sulfobutyl ether> 5 -Cyclodextrin. 31. The method of claim 28, wherein the hygroscopic growth inhibitor is hydroxyethyl starch. 32. The method according to any one of claims 28 to 31, wherein the solvent is water. 33. The method according to any one of claims 28 to 31, wherein the homogeneous particles contain 40% to 60% by weight of a hygroscopic growth inhibitor. 34. The method according to any one of claims 28 to 31 in the scope of patent application, wherein the active agent comprises a protein or a polypeptide. 35. The method of claim 34, wherein the active agent comprises insulin. 36. The method of claim 34, wherein the active agent comprises calcitonin. 3 7 ·-A granule prepared by a method such as the scope of patent application No. 28. This paper size applies Chinese National Standard (CNS) M specifications (2) 〇 &gt; &lt; 297mm) -------- ^ ------ Order ----- (Please read first Note on the back, please fill in this page again) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1226248 A8 B8 C8 D8 VI. Patent application scope 3 8. If the patent application scope is 1 to 4, 1 4 to 1 8 '2 6 and The particle of any one of items 27, which is in the form of an aerosol, which is used to deliver the active agent to the lungs of a human patient. 3 9 _ The granules according to any one of claims 1 to 4, 14 to 18, 26, and 27, which are used to deliver active agents to human patients through dry powder inhalers. In the lungs. 4 〇 As for the particles of any one of the scope of patent applications 1 to 4, 14 to 18, 2 6 and 27, wherein the particles are administered by inhalation 0 4 1. As the scope of patent application scope 4 Particles of item 0, wherein the active agent is administered by a dry powder inhaler. 4 2. A method for increasing the content of inhaled active agent deposited deep in the lungs, comprising: adding 40% to 99% by weight of hygroscopic growth to the dry powder particles containing inhaled active agent Inhibitor, the hygroscopic growth inhibitor is selected from the group consisting of me-cyclodextrin, hydroxypropyl-cyclodextrin, sulfobutyl ether / 3-cyclodextrin, hydroxyethyl starch, polydextrose, and wheat Galodextrin, so that when the particles are aerosolized and inhaled, 20% to 100% of the calibrated dose is deposited deep in the lungs. (Please read the “Notes on the back”, and then fill in this item:: Write this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper applies the Chinese National Standard (CNS) A4 (210X297 mm) -6-