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US 20090047336A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0047336A1 Yang et al. (43) Pub. Date: Feb. 19, 2009

(54) NOVEL FORMULATION OF DEHYDRATED Publication Classification LPID VESICLES FOR CONTROLLED (51) Int. Cl. RELEASE OF ACTIVE PHARMACEUTICAL A63/37 (2006.01) INGREDIENT VLANHALATION A6II 47/06 (2006.01) A 6LX 9/27 (2006.01) (75) Inventors: Zhijun Yang, Kowloon (CN); A6IR 9/14 (2006.01) Wenhua Huang, Kowloon (CN); A6IP II/00 (2006.01) Chi Sun Wong, (CN); A6IP II/06 (2006.01) Zhongzhen Zhao, Kowloon (CN) (52) U.S. Cl...... 424/450; 424/489: 514/653: 514/772 Correspondence Address: (57) ABSTRACT LEYDIG VOIT & MAYER, LTD A new formulation of dehydrated lipid vesicles employs a 700 THIRTEENTH ST. NW, SUITE 300 vesicle preserver and permits the control of release and deliv WASHINGTON, DC 20005-3960 (US) ery of active pharmaceutical ingredients into the respiratory system for treatment in particular of . The typical (73) Assignee: HONG KONG BAPTIST formulation provides controlled release of the active pharma UNIVERSITY, Kowloon (CN) ceutical ingredient from 0% to 100% from 0 to 72 hours after inhalation, changes the systemic administration to topical (21) Appl. No.: 11/840,537 administration, allows prolonged therapeutic period for one administration, increased stability, with reduced dose, (22) Filed: Aug. 17, 2007 reduced systemic side effects, reduced toxicity.

S Patent Application Publication US 2009/0047336A1

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--DOPC+1% gly cerin w8m DOTAP+1% glycerin

FIG. 2 US 2009/0047336A1 Feb. 19, 2009

NOVEL FORMULATION OF DEHYDRATED blood pressure. With the advent of selective agents, these side LPD VESCLES FOR CONTROLLED effects have become less common. Patients must becautioned RELEASE OF ACTIVE PHARMACEUTICAL against using these medicines too frequently, as with Such use INGREDIENT VLANHALATION their efficacy may decline, producing desensitization result ing in an exacerbation of symptoms which may lead to refrac FIELD OF THE INVENTION tory asthma and death. Older, less selective recep tor , such as inhaled and epinephrine 0001. The present invention relates to lipid vesicles, and in tablets, have also been used. Cardiac side effects occur with particular to the treatment of asthma and other conditions. these agents at similar rate to albuterol, Hendeles L., Marshik PL, et al. et al. Response to nonprescription epinephrine BACKGROUND OF THE INVENTION inhaler during nocturnal asthma. Ann Allergy Asthma Immu 0002 Asthma is a chronic disease of the respiratory sys mol. December 2005:95(6):530-4, and Rodrigo GJ, Nannini tem in which the airway discontinuously constricts, with L. J. Comparison between nebulized and B-2 ago associated inflammation. This causes symptoms such as nists for the treatment of acute asthma. A meta-analysis of coughing, wheezing, and shortness of breath with chest tight randomized trials. Am J Emerg Med. March 2006: 24(2):217 ness. The symptoms of asthma, which range from mild to life 22. Their use via injection has declined due to related adverse threatening, respond to and can usually be effects. These are typically provided in pocket-sized, controlled with a combination of . In the devel metered-dose inhaler or asthma spacer or nebulizer. oped countries, asthma has been focused upon because of its 0006 Attempts to formulate active pharmaceutical ingre rapidly increasing prevalence, affecting up to one in every dient in appropriate vehicles for targeted use have often been four urban children, see Lilly CM. Diversity of asthma: unsuccessful. Active pharmaceutical ingredient formulated Evolving concepts of pathophysiology and lessons from for inhalation seems to be rapidly absorbed, necessitating genetics. JAllergy Clin Immunol. 2005; 115 (4 Suppl): S526 frequent dosing, which heightens systemic side effects. It 31. may also lead to the mucosal of respiratory tissue damage 0003. Animal models have confirmed a role for A2B caused by a repeated use of fluorocarbon propellants, Sol antagonists in respiratory inflammation, fibrosis and airway vents, or other additives necessary for nasal or oral inhalation remodelling, as in D. Zeng & R. Polosa (2006) European administration. The aerosol droplets carrying the active phar Respiratory Disease. 2006; 26-27, and the causes of asthma maceutical ingredient should avoid multiple dosing while lies in a special type of natural killer cell. That means that providing a maximum therapeutic benefit. It should also pro asthma is often not treated with the right kind of active phar vide a controlled-release of the active pharmaceutical ingre maceutical ingredient. For example, natural killer T cells dient in the respiratory system, while the active pharmaceu seem to be resistant to the corticosteroids in widely used tical ingredient should be released continually over an inhalers, see Cromie, William J. Harvard University Gazette, extended period, providing an effective dose on B-2 agonist in Harvard News Office, Mar. 16, 2006, Retrieved on Sep. 23, the Smooth muscle with the minimum amount of active phar 2006. maceutical ingredient. By developing an appropriate formu 0004 are the most widely used of the lation vehicle for such therapy, the undesirable side effects preventive active pharmaceutical ingredients, such as accompanying active pharmaceutical ingredient therapy of , beclomethasone, , , fluti asthma would be diminished. casone, , , etc. Using corticoster 0007 Bystrom, K., Nilsson, P. in U.S. RE38407 (2001) oids long-term has many side effects, in particular high doses describe pain management with liposome-encapsulated anal of steroids may cause osteoporosis. Currently long acting gesic drugs delivered by the pulmonary route to provide local B-adrenoceptor , including Sustained-release oral or systemic analgesia. Waldrep, J. C., Knight, V., Black, M. B. albuterol, sameterol, , and, are avail in U.S. Pat. No. 5,958,378 (1999) employ about 130-375 able. However, the US Food and Drug Administration (FDA) mg/ml of phospholipids for the liposomal aerosol delivery of released a health advisory in November 2005; alerting that the about 12-30 mg/ml of a active pharmaceutical ingredient via use of long-acting B-2 agonists could lead to a worsening of respiratory system for treatment of diseases. Examples of symptoms, indeed to death in some cases. A study says that further liposomal treatments include those for respiratory three common asthma inhalers containing the active pharma influenza Edwards, D.A., Stone, H.A.: US 200502.20720A1 ceutical ingredient or formoterol may be causing (2005), tumor Jin, T., Zarif, L., Mannino, R.: US four out of five US asthma-related deaths per year and should 2006153217 (2000), local respiratory and cystic be taken off the market, Ramanujan, Krishna (Jun. 9, 2006). fibrosis Hersch, E. M., Petersen, E. A., Profitt, R. T., Cornell Chronicle Online. Cornell News Service. Retrieved Bracken, K.R., Chiang, S-M.: U.S. Pat. No. 5,958,449 (1999) on Sep. 23, 2006. }. Liposome-containing two-phase polymer solution, treated 0005 Bronchodilators are recommended for short-term with Ca" or Zn" etc. cochleate is described in Parmar, M.: relief in all patients with asthma. A higher dose of glucocor US2006 0051406A1 (2006) to achieved efficient delivery of ticoid may be prescribed with a long-acting B-2 agonist, theo pharmaceutical agents. However, the lipids vesicles are not phylline, leukotriene modifier, or mast-cell stabilizer, for per very stable for storage and producing in a great amount sistent disease. Symptomatic control of wheezing and because most of the lipids are easy to disassemble, and the shortness of breath is generally achieved with a fast-acting lipids vesicles are in the hundreds nanometer size, which . The active pharmaceutical ingredients when dispersed in buffer solution must experience Brownian include selective B-2 agonists, such as motion, that may lead to the congregation of the liposome (albuterol), , levalbuterol, and vesicle and leakage of the active pharmaceutical ingredient. . There may also be cardiac side effects at higher 0008 Bystrom, K., Nilsson, P., U.S. Pat. No. 6,045,828 doses due to B-1 agonist activity, such as elevated heart rate or (1996) describes a simple mixed powder of lipids and active US 2009/0047336A1 Feb. 19, 2009 pharmaceutical ingredient developed for inhalation, which is is particularly useful in formulating active pharmaceutical capable of hydration to form liposomes. In that sense the ingredient for inhaled and nebulized inhalation of small aero powder is anhydrous. The manufacturing process of the lipid Sol particles. vesicle powder employs lipids that have a phase transition 0013 The first aspect of this invention is to provide the temperature of below 37° C. Disclosure of phospholipids formulation to form the dehydrated lipids vesicles for deliv powders for rapid absorption of the active pharmaceutical ery of various active pharmaceutical ingredient by nebulizer ingredient is in Weers, J. G., Tarara, T., Clark, A.: US or inhaler into the respiratory system tissue. The dehydrated 20040105820A1 (2004) and in Mezei, M., Hung, O.: U.S. lipids vesicles formed with uniform and controllable particle size enable the active pharmaceutical ingredient to be RE38407 (2004). entrapped or encapsulated, and are Suitable for delivery of 0009 Radhakrishnan, R.: U.S. Pat. No. 5,049,389 (1991) discloses lipid particle formulations that claim prolonged active pharmaceutical ingredient to the respiratory system. release of the active pharmaceutical ingredient, improved 0014. The second aspect of this invention is to provide the therapeutic ratio, reduced toxicity, reduced systemic side formulation, the dehydrated lipids vesicles, with high encap effects, and stability for several months. The formulation is in Sulation efficiencies for encapsulating both water-soluble and particular suitable for treatment of asthma. New steroidal water-insoluble active pharmaceutical ingredients Suitable derivatives obtained by modification of corticosteroids with for inhalation, with lower toxicity and side effects, allowing fatty acid esters were incorporated in the lipid portion of the targeting to and release of active pharmaceutical ingredi liposomes for delivery via inhalation resulting into prolonged ent in a respiratory system tissue, removing need for multiple steroid retention in the respiratory tract of experimental ani dosing, and Sufficiently stable in dried form for long-term mals. In the liposomal active pharmaceutical ingredient pow Storage. der, active pharmaceutical ingredient encapsulated in lipo 0015 The third aspect of this invention is to provide con Some is homogenized, dispersed into carrier and converted trol of release in the respiratory system of the active pharma into dry powder by spray drying and/or freeze drying. On ceutical ingredient from the dehydrated lipid vesicle active inhalation, active pharmaceutical ingredient mixed with lip pharmaceutical ingredient composition; and provide a pro ids get partially rehydrated in the respiratory system and give cess for making the dehydrated lipids vesicles compositions release active pharmaceutical ingredient. The so-called pro for control of release of active pharmaceutical ingredient liposome is only the mixture of the active pharmaceutical delivered by inhalation; and provide a method of treatment of ingredient and lipids, and So it is difficult to maintain the asthma by administering the nebulized or inhaled and inhaled entrapment or encapsulation efficiency because the lipid dehydrated liposome vesicle active pharmaceutical ingredi vesicle may be break or transfigure, and the active pharma ent composition. ceutical ingredient can leak out from the vesicles during the drying and rehydration processes, no matter what the identity BRIEF DESCRIPTION OF THE DRAWINGS of the active pharmaceutical ingredient is, water soluble or water insoluble. Moreover, the active pharmaceutical ingre 0016 FIG. 1 provides TEM (transmission electron micro dient, which once entrapped in the rehydrated liposome Scope) photographs of dehydrated albuterol lipid vesicles. vesicle, must wait for the cells to destroy the vesicle to be (0017 FIG. 2 charts the release of albuterol from dehy released. drated lipid vesicle to buffer solution. 0010 From above, many problems may be seen remaining unresolved with active pharmaceutical ingredient formula DETAILED DISCLOSURE OF THE INVENTION tions using the liposomes or proliposomes. These problems relate to the requirement for proper control of release rate. 0018. According to the present invention, it has been dis covered that albuterol and other active pharmaceutical ingre dients may be successfully retained in dehydrated lipid OBJECTS OF THE INVENTION vesicles for control of release in respiratory system tissues when the liposomes are formulated to contain a stabilizer 0011. It is the primary object of this invention to provide and/or plasticizer Such as glycerin. The stabilizers and/or dehydrated lipid vesicle compositions wherein the active plasticizers act as a vesicle preserver to temporarily maintain pharmaceutical ingredients can be successfully sequestered the liposome vesicle shapeduring the drying processes of within the liposome vesicle without rupture or transfiguring lyophilization or spray drying, and act as a temporary barrier during the drying and rehydration processes, and with con against active pharmaceutical ingredient efflux from the lipo trollable particle size, long-term stability, and effective con Somes vesicle. To design the optimal formulation for high trollable potency of the active pharmaceutical ingredient. A active pharmaceutical ingredient load and the control of related object of the resulting composition is to allow an release of active pharmaceutical ingredient, a number of dif administration of low doses of the active pharmaceutical ferent formulations were developed, studied, and compared ingredient thus reducing toxicity and systemic side effects with compositions comprising components of the invention and in total providing the desired therapeutic effects. in various amounts and ratios as well as conventional lipo somes derived from all kinds of the lipids or their mixtures SUMMARY OF THE INVENTION Such as egg, Soybean, and synthetic phospholipids. 0019. In one preferred form, the present invention pro 0012. The present invention relates to a novel dehydrated vides a pharmaceutical lipid composition for treatment of lipids vesicle formulation suitable for the treatment of asthma by inhalation into the respiratory system, the compo asthma. In particular, the composition provides efficient con sition comprisingdehydrated lipid vesicles of pharmaceuti trol of release of active pharmaceutical ingredient deposited cally acceptable vesicle preserver, pharmaceutically accept in the respiratory system via Small size aerosol particles, and able lipid component and active pharmaceutical ingredient. US 2009/0047336A1 Feb. 19, 2009

0020. The vesicle preserver is chosen from stabilizers and esters of fatty acids, polysorbate, polyoxyethylene polyox plasticizers. Plasticizer is a term for describing the function of ypropylen glycol, macrogol, isopropyl myristate, contton the pharmaceutical excipients, but there is no common physi seed oil-soybean oil mixture, glyceryl monostearate, isopro cal chemistry characteristic and chemical structure. As it is pyllinoleate, petrolatum, etc. These stabilizers and/or plasti common in chemical and pharmaceutical industry, plasticizer cizers can be used as mixtures. is a chemical added to impart flexibility, workability, or 0023 Preferred candidates similar to glycerinare selected stretchability. The most frequently used is glycerol; sorbitol, from the following list: propylene glycol, Sucrose and acacia have been used also. We 0024 2-pyrrolidone, incorporate by reference the relevant disclosure in Michael E (0025 acetytributyl citrate, Aulton, (1988), Pharmaceutics: The science of Dosage Dorm 0026 acetyltriethylcitrate, Design; international student edition (1996), pp.324, Medical (0027 benzyl benzoate, Division of Pearson Professional Ltd, Churchill Livingstone, 0028 butylphthalylbutylglycolate N.Y.. Lactose, acacia, etc are used as the stabilizer or stabi 0029 cellulose acetate phthalate compatible, lizing agents as in pharmaceutical Science. For other plasti 0030 chlorbutanol, cizers and stabilizers we incorporate by reference the relevant 0031 cotton seed oil-soybean oil mixture, disclosure in Raymond C Rowe, Paul J Sheskey, and Sian C 0032 dextrin, Owen, (2006), Handbook of pharmaceutical Excipients, 5" 0033) dibutyl phthalate, edition, Pharmaceutical Press, Publications division of the 0034) dibutyl sebacate, Royal Pharmaceutical Society of Great Britain; and the 0035) diethyl phthalate, American Pharmacists Association, USA., and Japan Phar 0036) dimethyl phthalate, maceutical Excipients Council (2005) Japanese Pharmaceu 0037 dioctyl adipate, tical Excipients Directory, YAKUJI NIPPO LIMITED, 0038 dioctyl phthalate, Tokyo, Japan. 0039 D-sorbitol, 0040 gelatin, 0021. The stabilizers and/or plasticizers can be added 0041 glycerin, before and/or after producing the vesicles. 0042 derivatives of glycerin, 0022 Suitable candidate vesicle preservers are adipic acid 0043 glyceryl monostearate, and its derivatives or salts, ascorbic acid and its derivatives or 0044 hypromellose phthalate compatible salts, aspartic acid and its derivatives or salts, acetyltryp 0045 isopropyllinoleate, tophan and its derivatives or salts, acetanilide and its deriva 0046 isopropyl myristate, tives or salts, aminoethy Sulfonic acid and its derivatives or 0047 karion 83, salts, alanine and its derivatives or salts, acacia, Sodium 004.8 macrogol, bisulfite, Sodium Sulfite, arginine and its derivatives or salts, 0049 , alginic acid and its derivatives or salts, benzoic acid and its 0050 mineral oil and lanolin alcohols, derivatives or salts, isostearic acid and its derivatives or salts, 0051 palmitica acid inositol and its derivatives or salts, ethylenediamine and its 0052 phytosterol derivatives or salts, erythorbic acid and its derivatives or salts, 0053 polyethylene glycol, lysine and its derivatives or salts, cacao butter, castor wax, 0054 polymethacrylate compatible, Xathan gum, Xylitol, citric acid and its derivatives or salts, 0055 polyoxyethylene polyoxypropylen glycol, glycine and its derivatives or salts, glycerin and its deriva 0056 polysorbate, tives, gluconic acid and its derivatives or salts, glutamic acid 0057 polyvinyl acetate phthalate and its derivatives or salts, creatinine, diisopropanolamine 0.058 propylene glycol, and its derivatives, diethanolamine and its derivatives, cyclo 0059 sesame oil, dextrin, cystine, , dibutylhydroxytoluene, tartaric 0060 sobitol acid and its derivatives or salts, sucrose esters of fatty acids, 0061 stearic acid and its derivatives or salts, Stearic acid and its derivatives or salts, gelatin, lanolin, cet 0062 triacetin, anol, gelatin, hydrolyzed gelatin, shellac, D-Sorbitol, Sorbitan 0063 tributyl citrate esters of fatty acid, Sorbica acid and its derivatives or salts, 0064 triethanolamine thioglycolic acid and its derivatives or salts, potassium thio 0065 triethylctrate cyanate, sodium thiomalate, thymol, medium chain fatty acid 0.066 and mixtures thereof. triglyceride, dextran, dextrin, Vitamin E, calcium D-saccha 0067 Preferred candidates similar to lactose are selected rate, tocopherol and its isomer, trometamol, nicotinamide, from the following list: lactic acid and its derivatives or salts, lactose, carbamide, white Soft Sugar, histidine and its derivatives or salts, hydrox 0068 acacia, ypropylcellulose, hyroquinone, phenylalanine, phenacetin, 0069 acetanilide and its derivatives or salts, glucose, fumaric acid and its derivatives or salts, propylene 0070 acetyltryptophan and its derivatives or salts, glycol, heparin sodium, povidone, maleic acid and its deriva (0071 adipic acid tives or salts, malonic acid and its derivatives or salts, man (0072 agar nitol, methionine, sodium lauryl Sulfate, malic acid and its 0073 alanine and its derivatives or salts, derivatives or salts, hydrogenated oil, Sesame oil, karion 83. 0074 albumin diethylenetriaminepentaacetic acid and its derivatives or 0075 alginic acid and its derivatives or salts, salts, dioctyl sodium sulfoSuccinate, polydimethylsiloxane 0076 alginine hydrochloride silicone dioxide mixture, Sorbitan esters offatty acid, triace 0077 aluminum hydroxide gel tin, castor oil, diethyl/dibutyl phthate, butylphtalylbutylgly 0078 aluminum stearate colate, propylene glycol (1,2-propane diol), propylene glycol 0079 aminoethylsulfonic acid and its derivatives or salts, US 2009/0047336A1 Feb. 19, 2009

0080 arginine and its derivatives or salts, 0142 heparin Sodium, 0081 ascorbic acid and its derivatives or salts, 0143 histidine and its derivatives or salts, 0082 ascorbyl palmitate 0144) hydrated silicon dioxide 0083 aspartic acid and its derivatives or salts, (0145 hydrogenated oil, 0084 bentonite 0.146 hydrolyzed gelatin, 0085 benzalkonium chloride 0147 hydroxypropyl cellulose, 0086 benzethonium chloride 0148 hypromellose 0087 benzoic acid and its derivatives or salts, 0149 hyroquinone, 0088 butylated hydroxytoluene O150 inositol and its derivatives or salts, 0089 cacao butter, 0151 invert Sugar 0090 calcium D-saccharate, 0152 isopropyllinoleate, 0091 carbamide, O153 isopropyl myristate, 0092 carbazochrome sodium Sulfonate 0154) isostearic acid and its derivatives or salts, 0093 carboxymethylcellulose and it salts O155 karion 83, 0094) carboxyvinyl polymer 0156 lactic acid and its derivatives or salts, 0095 carmelose calcium O157 lactose, 0.096 carmelose sodium 0158 lanolin, 0097 carrageenan 0159) lecithin 0098 casein peptone (0160 lysine and its derivatives or salts, 0099 castor oil, (0161 macrogol, 01.00 castor Wax, (0162 magnesium aluminum silicate 0101 cellulose acetate phthalate compatible, (0163 maleic acid and its derivatives or salts, 01.02 ceratonia (0164 malic acid and its derivatives or salts, (0103) cetanol, (0165 malonic acid and its derivatives or salts, 0104 chlorbutanol, (0166 mannitol, 01.05 citric acid and its derivatives or salts, (0167 medium chain fatty acid triglyceride, 01.06 colloidal silicon dioxide (0168 methionine, 01.07 cotton seed oil-soybean oil mixture, (0169 microcrystalline cellulose and its derivatives 0108 creatinine, 0170 mineral oil and lanolin alcohols 0109 cyclodextrin, 0171 monoethanolamine 0110 cysteineand and its derivatives or salts, 0172 nicotinamide, 0111 cystine, 0173 pectin 0112 dextran, dextrin, (0174 petrolatum, 0113 dextrin, 0175 phenacetin, 0114 dibutyl phthalate, (0176) phenylalanine, 0115 dibutyl sebacate, 0.177 polacrilin potassium 0116 dibutylhydroxytoluene, 0178 polydimethylsiloxane-silicone dioxide mixture, 0117 diethanolamine and its derivatives, 0179 polyoxyethylene polyoxypropylen glycol, 0118 diethyl phthalate, 0180 polysorbate, 0119) diethyl/dibutyl phthate, butylphtalylbutylglycolate, 0181 polyvinyl alcohol 0120 diethylenetriaminepentaacetic acid and its deriva 0182 potassium chloride tives or salts, 0183) potassium thiocyanate, 0121 diisopropanolamine and its derivatives, 0184 poVidone, 0122 dimethyl phthalate, 0185 propylene gallate 0123. Dioctyl adipate, 0186. propylene glycol (1,2-propane diol), 0.124 dioctyl sodium sulfosuccinate, 0187. propylene glycol alginate, 0.125 disodium glycyrrhizinate 0188 propylene glycol esters of fatty acids, 0.126 D-sorbitol, (0189 propylene glycol, 0127 edetates 0190. raffinose 0128 erythorbic acid and its derivatives or salts, (0191) sesame oil, 0129 ethylcellulose (0192 Schizonepeta spike 0130 ethylene glycol palmitostearate 0.193) shellac, 0131 ethylenediamine and its derivatives or salts, 0.194 silicic acid 0132 fumaric acid and its derivatives or salts, 0195 Sodium acetate, 0.133 fructose (0196) Sodium alginate, 0134 gelatin, 0197) sodium bisulfite, 0135 derivatives or salts of gluconic acid, (0198 Sodium borate, 0.136 glucose, 0199. Sodium carbonate 0.137 derivatives or salts of glutamic acid, (0200 Sodium caprylate 0138 glycerin and its derivatives such as glycerin 0201 Sodium chloride, mono Stearate, (0202 Sodium lauryl Sulfate, 0139 glyceryl monostearate, 0203 Sodium Stearyl fumarate, 0140 glycine and its derivatives or salts, 0204 Sodium Sulfite, 0141 guar gum 0205 Sodium thiomalate, US 2009/0047336A1 Feb. 19, 2009

0206 sorbica acid and its derivatives or salts, respiratory system, for example, the albuterol, terbutalin etc 0207 sorbitan esters of fatty acid, are the medicines used in asthma. We incorporate by refer 0208 sorbitan esters of fatty acid, ence the relevant disclosure in Bertram G. Katzung, (2001). 0209 sorbitol Basic & Clinical Pharmacology, 8" edition, Medical Publish 0210 stearic acid and its derivatives or salts, gelatin, ing Division, McGraw-Hill Companies, Inc. USA. 02.11 stearyl alcohol 0212 sucrose esters of fatty acids, 0233. The mole ratio of active pharmaceutical ingredient 0213 sulfobutylether B-cyclodextrin to the lipid component is usually from 0.1% to 200%. 0214) sulfur 0234. A preferred comopsition employs albuterol present 0215 tartaric acid and its derivatives or salts, in amount between 0.1 to 300 mg/ml of dehydrated lipid 0216) thioglycolic acid and its derivatives or salts, vesicles composition. 0217 thymol, 0235. The composition is preferably one which can be 0218 tocopherol and its isomer, aerosolized into particles predominantly smaller than mass 0219 trehalose, median aerodynamic diameter 10 Jum. 0220 triacetin, 0236. In a related aspect, the invention provides a method 0221 trometamol, of treating asthma by inhalation route of administration to a 0222 vitamin E, person in need of such treatment a therapeutically effective 0223) white soft sugar, amount of plasticized lipid composition consisting essen 0224 white wax, tially of an active pharmaceutical ingredient, a vesivle pre 0225 xanthan gum, server selected from a plasticizer, a stabilizer and mixtures 0226 xylitol, thereof, and lipid component aerosolized into aerosol par 0227 zinc acetate ticles having a mass median aerodynamic diameter Smaller 0228. Zinc chloride than 10 pum and providing a slow or controlled release of the 0229 and mixtures thereof. active pharmaceutical ingredient in the respiratory system. 0230. The ratio of the stabilizers and/or plasticizers to the lipids is suitably from 0.1 to 40 mole % of the stabilizers 0237. In the method the pharmaceutical stabilizers and/or and/or plasticizers; from 99.9 to 60 mole % of the lipids. plasticizers lipid composition form dehydrated lipid vesicles Preferably the ratio of plasticizer to the lipid is 1:5 to 1:50, preferably comprising 0.1 to 40 mole % of the stabilizers such as about 1:10. and/or plasticizer, 99.9 to 60 mole % of lipids, and the active 0231. The active pharmaceutical ingredient is usually pharmaceutical ingredient is from 0.01 to 200 mole % to the selected from the group consisting of ephedrine, ephedrine lipids. hydrochloride, albuterol, theophyline, salbutamol sulfate, 0238 For the method the active pharmaceutical ingredient salmefamol, terbutaline, , , clorprena can be selected from the group consisting of ephedrine, ephe line hydrochloride, clorprenaline glycyrrhizinate, drine hydrochloride, albuterol, theophyline, salbutamol sul , 5-(4-amino-3,5-dichlorophenyl)-3-tert-butylox fate, salmefamol, terbutaline, orciprenaline, fenoterol, clor azole, 5-(4-amino-3,5-dichlorophenyl)-3-tert-butyloxazole prenaline hydrochloride, clorprenaline glycyrrhizinate, hydrochloride, hydrochloride, , salme tulobuterol, 5-(4-amino-3,5-dichlorophenyl)-3-tert-butylox terol, , , formoterol, methoxyphe azole, 5-(4-amino-3,5-dichlorophenyl)-3-tert-butyloxazole namine, , , bitolterol, , reprot hydrochloride, clenbuterol hydrochloride, procaterol, salme erol, , , ipratropine, terol, hexoprenaline, mabuterol, formoterol, methoxyphe isopropylscopolamine, , , cho namine, tretoquinol, rimiterol, bitolterol, protokylol, reprot line theophyllinate, sodium cromoglicate, ketotifen, triproli erol, pirbuterol, fenspiride, ipratropine, dine, tranilast, ammonium chloride, , ace isopropylscopolamine, aminophylline, diprophylline, cho tylcysteine, hydrochloride, , line theophyllinate, sodium cromoglicate, ketotifen, triproli hydrochloride, , , codeine phos dine, tranilast, ammonium chloride, potassium iodide, ace phate, , drotebanol, citrate, chlop tylcysteine, bromhexine hydrochloride, carbocisteine, erastine, phosphate, hydro ambroxol hydrochloride, guaifenesin, codeine, codeine phos bromide, , , , deoxopromethazine phate, pholcodine, drotebanol, pentoxyverine citrate, chlop hydrochloride, , promolate, asverin, , erastine, benproperine phosphate, dextromethorphan hydro , noscactive pharmaceutical ingredient, bromide, oxeladin, eprazinone, Zipeprol, deoxopromethazine beclomethasone, , budesonide, cloprednol, hydrochloride, fominoben, promolate, as verin, benzonatate, cortisone, cortivazol, deoxycortone, desonide, dexametha prenoxdiazine, noscactive pharmaceutical ingredientine, sone, difluorocortolone, fluclorolone, fluorocortisone, flu beclomethasone, betamethasone, budesonide, cloprednol, methasone, flunisolide, fluocinolone, fluocinonide, fluoro cortisone, cortivazol, deoxycortone, desonide, dexametha cortolone, aldosterone, fluorometholone, flurandrenolone. sone, difluorocortolone, fluclorolone, fluorocortisone, flu halcinonide, hydrocortisone, meprednisone, methylpred methasone, flunisolide, fluocinolone, fluocinonide, fluoro nisolone, paramethasone, prednisolone, prednisone, triamci cortolone, aldosterone, fluorometholone, flurandrenolone. nolone, metaproterenol sulfate, isoproterenol, adrenaline, halcinonide, hydrocortisone, meprednisone, methylpred , fluoromethasone, medrysone, , nisolone, paramethasone, prednisolone, prednisone, triamci atropine methyl nitrate, , cromolyn nolone, metaproterenol sulfate, isoproterenol, adrenaline, sodium, or their respective pharmaceutically norepinephrine, fluoromethasone, medrysone, fluticasone, acceptable salts or esters, alone or in combination. atropine methyl nitrate, ipratropium bromide, cromolyn 0232. The active pharmaceutical ingredients that are the sodium, nedocromil or their respective pharmaceutically medicines which are used for treatment of disorders in the acceptable salts or esters, alone or in combination. US 2009/0047336A1 Feb. 19, 2009

0239 When albuterol is present, the amount is preferably 0245 Methods of Dehydrated Lipid Vesicles Formation from 0.1 to 300 mg/ml of dehydrated lipid vesicle composi 0246 The dehydrated lipids vesicles of the invention can tion. be prepared by any of the standard methods for preparing and 0240. In a further aspect, the invention provides an inha sizing liposomes, but formulating with lipids, stabilizers and/ lation method for treatment of respiratory system diseases by or plasticizers and active pharmaceutical ingredients in the treating a person in need of Such treatment with a therapeu beginning. But that is only the liposome vesicles. Before the tically effective amount of aerosolized dehydrated lipid liposome vesicles are formed, the stabilizers and or plasticiz vesicle composition consisting essentially of a active phar ers may be added in/with the lipid solutions to form the lipid maceutical ingredient and lipid components aerosolized into mixed liposome vesicles. The methods for preparing the lipo particles predominantly smaller than 10 um mass median Somes include hydration of lipid films, solvents injection, aerodynamic diameter by the inhalation route of administra reverse-phase evaporation and vesicular phospholipids gels tion. methods, see Brandl, M., Bachmann, D., Reszka, R., and 0241 The active pharmaceutical ingredient is suitably Drechsler, M. Liposomale Zubereitung, ihre Herstellung und selected from the group consisting of ephedrine, ephedrine ihre Verwendung. DE 44 30 592.3 (filed Aug. 18, 1995). hydrochloride, albuterol, theophyline, salbutamol sulfate, PCTWO 96/05808 and see Brandl, M., Tard, C., Drechsler, salmefamol, terbutaline, orciprenaline, fenoterol, clorprena M., Bachmann, D., Reszka, R., Bauer, K. H., et al. (1997). line hydrochloride, clorprenaline glycyrrhizinate, Adv. Drug Deliv. Rev. 24, 161, which are incoproated herein tulobuterol, 5-(4-amino-3,5-dichlorophenyl)-3-tert-butylox by specific reference. Also incoporated by reference is the azole, 5-(4-amino-3,5-dichlorophenyl)-3-tert-butyloxazole detailed information in Ann. Rev. Biophys. Bioeng. 9:467 hydrochloride, clenbuterol hydrochloride, procaterol, salme (1980). Reverse-phase evaporation vesicles (REVs) prepared terol, hexoprenaline, mabuterol, formoterol, methoxyphe by the reverse-evaporation phase method is described in U.S. namine, tretoquinol, rimiterol, bitolterol, protokylol, reprot Pat. No. 4,235,871, incorporated hereby by reference. The erol, pirbuterol, fenspiride, ipratropine, preparation of multilamellar vesicles (MLVs) by thin-film isopropylscopolamine, aminophylline, diprophylline, cho processing of a lipid film or by injection technique is line theophyllinate, Sodium cromoglicate, ketotifen, triproli described in U.S. Pat. No. 4.737.923, incorporated by refer dine, tranilast, ammonium chloride, potassium iodide, ace ence. In the two later procedures, which are generally pre tylcysteine, bromhexine hydrochloride, carbocisteine, ferred, a mixture of liposome-forming lipids dissolved in a ambroXolhydrochloride, guaifenesin, codeine, codeine phos suitable solvent is evaporated in a vessel to form a thin film, phate, pholcodine, drotebanol, pentoxyverine citrate, chlop which is covered by an aqueous buffer solution. The lipid film erastine, benproperine phosphate, dextromethorphan hydro hydrates to form MLVs, typically with sizes between about 0.1 to 10 um. The REVs or MLVs are further treated to bromide, oxeladin, eprazinone, Zipeprol, deoxopromethazine produce a suspension of Smaller, Substantially homogeneous hydrochloride, fominoben, promolate, as verin, benzonatate, liposomes, in the 0.02-2.0 Lim size range, preferably in 0.2- prenoxdiazine, noscactive pharmaceutical ingredientine, 0.4 um range. One effective sizing method involves extruding beclomethasone, betamethasone, budesonide, cloprednol, an aqueous Suspension of the liposomes through a polycar cortisone, cortivaZol, deoxycortone, desonide, dexametha bonate membrane or asymmetric ceramic filter having a sone, difluorocortolone, fluclorolone, fluorocortisone, flu selected uniform pore size, see Ann. Rev. BiophyS. Bioeng, methasone, flunisolide, fluocinolone, fluocinonide, fluoro 9:467 (1980), and U.S. Pat. No. 4.737,323, incorporated by cortolone, aldosterone, fluorometholone, flurandrenolone, reference. The pore size of the polycarbonate membrane is halcinonide, hydrocortisone, meprednisone, methylpred near to the size of the vesicles. Thus, the size of the vesicles nisolone, paramethasone, prednisolone, prednisone, triamci was typically controlled to be from 20 to 5000 nm. Alterna nolone, metaproterenol Sulfate, isoproterenol, adrenaline, tively, the REVs or MLVs can be treated by sonication or norepinephrine, fluoromethasone, medrysone, fluticaSone, extrusion to produce small unilamellar vesicles (SUVs) atropine methyl nitrate, ipratropium bromide, cromolyn which are characterized by sizes 0.02-0.07 Lum. Another pre Sodium, nedocromil or their respective pharmaceutically ferred method for producing SUVs is by homogenizing acceptable salts or esters, alone or in combination. MLVs, using a conventional high pressure homogenizer of 0242. Where albuterol is present the amount is usually the type used commercially for milk homogenization. Here from 0.1-300 mg/ml. the MLVs are cycled through the homogenizer, with periodic 0243 In a yet further aspect, the invention provides a sampling of particle sizes to determine when the MLVs have process of preparing a suspension of inhaleable or nebulize been substantially converted to SUVs. The active pharmaceu able aerosol particles of sizes predominantly smaller than 10 tical ingredient is encapsulated in the liposomes by using for um being particles of dehydrated liposome vesicles, the pro example the procedure described in U.S. Pat. No. 4,752.425, cess comprising providing dehydrated liposome vesicles hav incorporated by reference. After the liposome vesicles are ing sizes less than 10 um in an aqueous Suspension; and formed, some pharmaceutical excipients which may act as inhaling or nebulizing the Suspension under conditions which aerosol carriers, more so the stabilizers and or plasticizers, produce aerosol particles of mass medianaerodynamic diam can be added in the liposome solution, and by immediately to eter predominantly smaller than 10 Jum. cooling to -50° C. the shape and size of liposome vesicles is 0244. The lipid particle comprises dehydrated lipids fixed, then lyophilizing the Solid dispersing cake. vesicles and/or micelle not larger than 1.0 um, which compo 0247. After the moisture in the cake has been dried, the sition for treatment of asthma consisting essentially of lipid dehydrated lipids vesicles are formed with the active pharma components and an active pharmaceutical ingredient or its ceutical ingredient entrapped in the dehydrated lipid vesicles salt or ester, suitable for delivery by inhalation into the res composed of the stabilizers and/or plasticizers but without an piratory system. inner water phase in the lipid vesicles. US 2009/0047336A1 Feb. 19, 2009

0248 Conventional and Dehydrated Lipids Vesicle and similar to DOTAP: 0249 Conventional liposomes are liposomes which con 0265 1,2-Diacyl-3-Trimethylammonium-Propane tain pure lipids, while the dehydrated lipids vesicles of the (TAP)-(Diol) present invention are liposomes which do not contain inner 0266 1,2-Diacyl-3-Dimethylammonium-Propane water but are formed by lipids and stabilizers and/or plasti (DAP)-(Diol) cizers and active pharmaceutical ingredient or, alternatively 0267 DC-Cholesterol (DC-Chol)-(Sterol) by amphipathic lipid components. The stabilizers and/or plas 0268 Dimethyldioctadecylammonium Bromide ticizers act as vesicle preservers, and serve to stabilize the (DDAB)-(Alkyl Amine) lipid vesicles and maintain the shape of the lipid vesicles 0269. The dehydrated lipids vesicles composition may be without water during lyophilization or spray drying. formulated to include minor amounts of fatty alcohols, fatty 0250) Both conventional and dehydrated lipids vesicles acids, and/or stabilizers and/or plasticizers with the proviso can beformed by a variety of standard methods from a variety that these minor lipid components do not significantly reduce of vesicle-forming lipids. For the conventional liposomes the binding affinity of the liposomes for mucosal or respira these lipids include dialiphatic chain lipids, such as phospho tory system tissue, are Substantially unsaturated, are not toxic lipids, diglycerides, dialiphatic glycolipids; the stabilizers or irritating and co-controlling or adjusting the release prop and/or plasticizers are not specialized to keep the shape of the erties of the active pharmaceutical ingredient from the dehy liposome vesicles thereof. The various lipid components are drated lipids vesicles when it rehydrates or contacts with present in an amount between about 99.9-60 mole % of the water or any buffer solutions in vitro or/and in situ or/and in total non-aqueous lipid components in the liposomes; Stabi V1VO. lizers and/or plasticizers are present in amounts between 0.1- 0270 Preparation of Dehydrated Lipid Vesicle Composi 40 mole %. The active pharmaceutical ingredient encapsu tion lated in both kinds of liposomes is in amounts of 0.01-200 0271 According to the present invention, it has been dis mole % to the lipids. The dehydrated lipids vesicles are the covered that albuterol or other active pharmaceutical ingre products which are prepared by lyophilization or spray dry dient may be successfully maintained in lipid vesicle shape the conventional liposome which are formed with lipids and and with retention of the liposome vesicle during and after the stabilizers and/or plasticizers acting to preserve lipid vesicles. processes of lyophilization or spray dray and rehydration, and 0251 Lipids for the present invention include but are not Successfully retained in liposomes vesicles for delayed limited to trimethylammonium-propane (TAP), phosphati release, when the liposomes are formulated to contain a high dylcholine (PC) including their mixture such as egg phos percentage of vesicle preserver stabilizers and/or plasticizers, phatidylcholine (EPC) and lysophosphatidylcholine (LPC), Such as glycerin and Sucrose esters of fatty acids, typically phosphatidylethanolamine (PE), phosphatidylinositol (PI), from 0.1-40 mole. phosphatidylserine (PS), phosphatidic acid (PA) and phos 0272 According to one aspect of the invention, it has been phatidyl glycerol (PG), and their derivatives or mixtures. discovered that the active pharmaceutical ingredient/lipid/ These lipids may be fully saturated or partially saturated. stabilizers and/or pasticizers composition of the invention has They may be naturally occurring or synthetic. much improved properties Such as lesser leakage active phar 0252) DOPC and DOTAP are preferred lipids. Lipids area maceutical ingredient from the liposome vesicles, decreased major component of biological membranes, along with phos toxicity and side effects, controllable release, improved solu pholipids, glycolipids, cholesterol and proteins. Lipids may bility, high encapsulation, active pharmaceutical ingredient be classified in many different ways, and can be subdivided release at the target organ, absence of need for multiple dos into fatty acids and their derivatives (e.g. DOPC and ing, extended stability in that it can be stored long-term in DOTAP), triacylglycerols, wax esters phospholipids (phos dried form without significant leakage of the active pharma phoglycerides e.g. DOPC and sphingomyelin), Sphingolipids ceutical ingredient from the lipids vesicles on rehydration, (molecules other than sphingomyelin that contain the amino and may be nebulized or inhaled to provide a homogeneous alcohol sphingosine), isoprenoids (molecules made up of mixture of aerosol particles having mass median aerody repeating isoprene units, a branched five carbon hydrocar namic diameter Smaller than 10 um. bon). Refer to Trudy McKee and James RMcKee: (2003), 0273 To achieve all the above advantages, the current Biochemistry: the Molecular Bassis of Life, third edition; invention combines the lipid components including stabiliz international edition, pp. 332, McGraw-Hill Companies, Inc., ers and/or plasticizers, providing the hydrophilic group, and (2003) the active pharmaceutical ingredient to be formulated to pro 0253) Following, there is a list of lipids which are similar vide a new, highly efficient liposomal composition for formu to DOPC lation of active pharmaceutical ingredient. The composition (0254 Phosphatidylcholine (PC) is engineered for increased active pharmaceutical ingredient 0255 1,2-Diacyl-sn-Glycero-3-Ethylphosphocholine loading and a controllable release rate of the active pharma (EPC)-(Phospholipid) ceutical ingredient in the respiratory system tissue. It also (0256 Phosphatidylethanolamine (PE) provides a means to Solubilize the active pharmaceutical (0257 Phosphatidylserine (PS) ingredient and incorporate them in Such liposomal composi tion. Further, the formulation can be easily sterilized thus (0258 Phosphatidylinositol (PI & PIP's) meeting an important requirement for pharmaceutical prepa 0259 bis(Monoacylglycero) Phosphate rations, and It is also stable and Suitable for long-term storage. 0260 Phosphatidic Acid (PA) 0274 The dehydrated lipids vesicles compositions con 0261 Phosphatidylglycerol (PG) taining active pharmaceutical ingredient may further contain 0262 Cardiolipin (CA) any Suitable pharmaceutically acceptable additive, diluent 0263. Diacylglycerides (DG) and/or excipient. Examples of Such additives, diluents or 0264 Cholesterol (Plant-Derived) excipients. Such as sodium or potassium chloride, mono or US 2009/0047336A1 Feb. 19, 2009 dibasic sodium phosphates in hydrated or dehydrated form, 0289. The amounts by weight of the components in the water, Saline, etc., are not intended to limit the scope of this products are normally as follows: invention and may be used in any amount needed or necessary which is pharmaceutically acceptable for inhalation formu lations. Pharmaceutically acceptable stabilizers and/or plas range of amounts for preferred range most preferred ticizers and excipients can be used in the formulation. While commercial product of amounts ranges stabilizers and/or plasticizers are preferred, the composition plasticizer O. 1-99.9% 1-99% 10-80% is not restricted to the particular glycerin, and any other Suit stabilizer O. 1-99.9% 1-99% 10-80% able stabilizers and/or plasticizers can be adopted which are lipid O. 1-99.9% 1-99% 10-80% commonly used and pharmaceutically acceptable in pharma active O. 1-99.9% 1-99% 10-80% pharmaceutical ceutical formulations. ingredient 0275 Buffer used in the preparation of the dehydrated lipids vesicles may be any buffer chosen from the group of 0290 The powder will be used to prepare the powder or citrate, carbonate, bicarbonate, acetate, Tris, glycinate, liquid aerosol to treatment the disorder of the respiratory cacodylate, maleate, and Such other, and preferably phos system. phate buffered saline of pH 7.4. 0291. Therapeutic Applications 0276 Any organic solvent such as lower alcohols, 0292. The control of release is very important for success dimethoxyethane, dioxane, tetrahydrofuran, tetrahydropy ful active pharmaceutical ingredient delivery to respiratory ran, diethylether, acetone, dimethylsulfoxide (DMSO), dim system. A list of factors which are known to effect a deposi ethylformamides (DMF), and halogenated hydrocarbons, tion of inhaled particles into respiratory system include char such as Freon, acetonitrile, or mixtures thereof, preferably acteristics of the aerosol or its environment, characteristics of chloroform/methanol can be used in the process of generation the respiratory system structure, characteristics of the inhal of liposomes. ant, and characteristics of the breathing pattern. FIG.2 shows 0277. The preferred method of preparation of dehydrated release profiles of two kinds of dehydrated lipid vesicles lipids vesicles comprises: formulations. 0293. The therapeutic applications and advantages of the 0278 (1) mixing stabilizers and/or plasticizers, and active aerosolizing dehydrated lipids vesicles and micelles in Small pharmaceutical ingredient in dry form, in amounts from particles are numerous. Inhaled aerosolized small particles 0.1-40 mole% of stabilizers and/or plasticizers to the lipids will depositan active pharmaceutical ingredient encapsulated and 0.1-200 mole % of active pharmaceutical ingredient; in dehydrated lipids vesicles in the respiratory tissue in high 0279 (2) dissolving the mixture in a suitable volume of an enough amounts to allow minimal daily dosing with maximal organic solvent, preferably in ethanol; effect extended over a period of time by controlled release. 0280 (3) injecting the ethanol solution into a suitable vol Controlled release of the active pharmaceutical ingredient ume of the buffer at pH 5.6-7.6, then go to (5); or, repeat from the dehydrated lipids vesicles is expected to prolong the edly drying obtained solution under nitrogen and/or therapeutic activity after each administration, reduce the fre quency of administration, further improve the ratio of local Vacuum, and/or, lyophilizing the dry film for Suitable min ized-to-systemic effects, and provide increased and extended utes, at a Suitable temperatures; local therapeutic effect in the respiratory systems. 0281 (4) resuspending the residue in a suitable volume of 0294. In one aspect of this invention, the lipid vesicles buffer at pH 5.6-7.6 preferably in the phosphate-buffered containing active pharmaceutical ingredient are suspended saline, pH 7.4: or/and dissolved or diluted with 0.9% sterile saline and the 0282 (5) forming the liposomes by shaking, stiring or Suspension placed, after mixing, in a nebulizer and the aerosol Sonication, solvent injection or any other Suitable method; is breathed until there is no more liquid in the nebulizer or 0283 (6) sizing the liposomes by extrusion, or by other inhaler. The examples providing the data and evaluating the methods; and new inhalation composition in this application primarily use 0284 (7) sterilizing the liposomes using suitable and the anti inflammatory active pharmaceutical ingredient acceptable methods for sterilization of the liposome albuterol, for inhalation of nebulized or inhaled aerosol par vesicles formulations; ticles into the deep respiratory system. The scope of the invention is not limited to albuterol as an active pharmaceu 0285 (8) lyophilizing or spray-drying the liposome tical ingredient. vesicles formulations to form the dehydrated lipids 0295 Examples of the classes of compounds to be used in vesicles formulations. this composition administered through inhalation therapy 0286 FIG. 1 provides images of TEM pictures of albuterol include, but are not limited to bronchodilators, such as metap dehydrated lipid vesicles prepared by such a method. roterenol sulfate, aminophylline, terbutaline, albuterol, theo 0287 Methods of preparing the composition of the inven phyline, ephedrine, isoproterenol, bitolterol, pirbuterol, tion are not limited to those named above, but other methods adrenaline, norepinephrine, procaterol, and Salmeterol; anti of dehydrated lipid vesicles preparation Such as solvent injec inflammatory active pharmaceutical ingredient, Such as tion, thin film hydration, dehydration-rehydration, and albuterol, dexamethasone, prednisolone, hydrocortisone, reverse evaporation are equally Suitable. fluoromethasone, medrysone, fluticaSone, triamcinolone, and 0288 The size of the preferred dehydrated vesicles is from flunisolide. 20-5000 nm. The moisture content is typically less than 15% 0296 For inhalation, the delivery is achieved by (a) aero by weight, preferably less than 10% by weight, more prefer Solization of a dilute aqueous Suspension by means of a pneu ably less than 9% of the powder. matic or ultrasonic nebulizer, (b) spraying from a self-con US 2009/0047336A1 Feb. 19, 2009 tained atomizer using an air, solvent with Suspended, dried trifugal Filter Devices (Millipore) with a cut-off value of the dehydrated lipids vesicles in a powder, (c) spraying dried 10,000 Dalton. The concentration of albuterol in the centri particles into the respiratory systems with a propellant or (d) fuged solution was determined spectrophotometrically at 276 delivering dried liposomes as a powder aerosol using a Suit nm. This concentration represented the concentration of able device, provided that the aerosol particles generated by albuterol in the continuous phase of the liposome (non-en any of the above means are in the size range from 0.02-20 um. capsulated albuterol). The spectrophotometrical method was The composition of the current invention typically has high also used with the determining of the total concentration of encapsulation values, good Stability, and extended shelf-life. albuterol including in the dispersed phase and the continuous 0297. The following examples illustrate methods of pre phase of liposome. Absolute ethanol was added into the lipo paring dehydrated lipids vesicles for formulation of active Some Suspension to disrupt the liposome completely and the pharmaceutical ingredient and using these dehydrated lipids encapsulated albuterol was completely dissolved in the solu vesicles for treatment of interstitial respiratory system dis tion. The absorbencies were measured by a UV-VIS Varian ease. These examples are in no way intended to limit the Cary 50 instrument equipped with a thermostated Scope of the invention. quartz cell at the wavelengths of 278 nm. The encapsulation EXAMPLES OF THE INVENTION efficiency (EE) was calculated with the formula: 0298. Materials EE(%)=(C- Cree)/Coax 100 0299 Albuterol 2-tert-butylamino-1-(4-hydroxy-3-hy where C is the concentration of unencapsulated albuterol droxy-methylphenyl) ethanol was purchased from the in the continuous phase of liposome dispersion/solution, and Yabang chemical industry Corporation (Changzhou, Jiangsu, C is the total concentration of albuterol in the liposome ). EPC, SPC, DOTAP (1,2-dioleoyl-3-trimethylammo dispersion/solution. The encapsulation efficiencies were nium propane), DOPC (dioleoyl phosphatidylcholine), DSPC (distearoyl phosphotidylcholine), sphingomyelin, 20-30%. ceramide-1-phosphocholine, and DMPC ((dimyristoyl phos phatidylcholine) were purchased from Avanti Polar Lipids, Example 2 Inc (USA). Glycerin and other stabilizers or plasticizers and solvents such as chloroform RDH(Riedel-de Haen) was 0304 Preparation of Liposomes by Solvent Injection purchased from Kou Hing Hong Scientific Supplies Ltd., tris Technique (hydroxymethyl)aminomethane (Tris) (Sigma) was purchase (0305. A mixture of partially DOPC or DOTAP and active from Tin Hang Technology Ltd., and monobasic potassium pharmaceutical ingredient (albuterol, 0.04 mmol) in the mole phosphate (Amersham Biosciences) was purchased from ratio of 1:2 was dissolved in 4 ml of ethanol. Liposomal Amersham Biosciences China Ltd. All of the solvents, solu albuterol dispersion was formed by injecting the lipid/active tions and chemicals were of analytical reagent grade. pharmaceutical ingredient/ethanol solution into 50 ml of the phosphate buffered saline pH 7.4. Liposomes thus formed Example 1 were extruded through a 0.4 or a 0.2 um polycarbonate mem 0300 Preparation of Liposomes By Thin Film Hydration brane to produce uniform size liposome vesicles distribution. 0301 Aqueous multilamellar vesicles (MLV) were pre (0306 Determination of Encapsulation Efficiency pared by conventional lipid membrane hydration method and 0307 150 uL of freshly prepared liposomal sample was subsequent small unilamellar vesicles (SUV) were produced centrifuged with an Avanti J-E centrifuge (type JA-20, by extrusion. Lipid and albuterol were dissolved in chloro 17400xg, 6° C., and 20 min) through Microcon Y-10 Cen form and methanol respectively, and then the solutions were trifugal Filter Devices (Millipore) with a cut-off value of mixed with the indicated molar ratios of lipid and albuterol. The mixture was dried into a homogeneous lipid membrane 10,000 Dalton. The concentration of albuterol in the centri under a stream of nitrogen gas, and then under vacuum over fuged solution was determined spectrophotometrically at 276 night to remove any residual organic solvents. This lipid nm. This concentration represented the concentration of membrane was hydrated in 10 mM Tris-buffered isosmotic albuterol in the continuous phase of the liposome (non-en saline buffer solution (10 mM Tris, 137 mM sodium chloride, capsulated albuterol). The spectrophotometrical method was and pH 7.4 at 25°C.). The final concentration of the lipid was also used with the determining of the total concentration of controlled at 5-20 mg/mL. Then the mixture was maintained albuterol including in the dispersed phase and the continuous at 80°C. (over the transition temperatures of all lipids) for 60 phase of liposome. Absolute ethanol was added into the lipo minutes to anneal the liposome structure. During annealing, it Some Suspension to disrupt the liposome completely and the was stirred 3 times with Vortex at the beginning, middle, and encapsulated albuterol was completely dissolved in the solu ending time points respectively, and each time was stirred tion. The absorbencies were measured by a UV-VIS Varian continually for 5 minutes. The resulting MLV was then Cary 50 Tablet instrument equipped with a thermostated extruded through Whatman 100 nm polycarbonate filters quartz cell at the wavelengths of 278 nm. The encapsulation (Nuclepore, Pleasanton, Calif.) with a diameter of 25 mm, efficiency (EE) was calculated with the formula: using a 10 mL extruder (Lipex Biomembranes Inc., Vancou ver, Canada) with several cycles of extrusion till the sizes EE(%)=(C- Cree)/Coax 100 were within 50-200 nm. where C is the concentration of unencapsulated albuterol 0302 Determination of Encapsulation Efficiency in the continuous phase of liposome dispersion/solution, and 0303 150 uL of freshly prepared liposomal sample was C is the total concentration of albuterol in the liposome centrifuged with an Avanti J-E centrifuge (type JA-20, dispersion/solution. The encapsulation efficiencies were 17400xg, 6° C., and 20 min) through Microcon Y-10 Cen 20-30%. US 2009/0047336A1 Feb. 19, 2009

Example 3 encapsulated liposomes. Before the TEM observation, 10% of glucose and 1% glycerin were added into the vesicle solu 0308 Preparation of Liposomes by Vesicular Phospho tions, and then each of the vesicle Suspensions were diluted to lipid Gels. 100 fold with pure water. The diluted solutions were dropped 0309 1 ml of albuterol saturated water, 0.1 g of glycerin on carbon coated 400 mesh copper electron microscope grids and 2 g of SPC was mixed by high speed homogenizer under (SPI Supplies(R Lot #1110207, Structure probe, Inc. West 50° C. till forming gels; and then the gels diluted in 100 ml of Chester Pa., USA) and the grids were frozen by liquid nitro the phosphate buffered saline pH 7.4 to form the liposome gen. The refrigerated grid with liposome vesicle Suspension vesicles. was lypophilized at -40°C. in the chamber of the lyophilizer 0310 Determination of Encapsulation Efficiency 150 uL (Freezon R. 6 Liter Freeze Dry System, Labconco Corpora offreshly prepared liposomal sample was centrifuged with an tion, USA) for 72 hours. Finally, the grids were sealed into a Avanti J-E centrifuge (type JA-20, 17400xg, 6° C., and 20 10 mL. glass injection vial, and the liposome vesicles on the min) through MicroconY-10 Centrifugal Filter Devices (Mil grids remained to be observed by TEM (FEI, Tecnai G2 20 lipore) with a cut-off value of 10,000 Dalton. The concentra STEM, England). tion of albuterol in the centrifuged solution was determined 0316 Determination of Encapsulation Efficiency spectrophotometrically at 276 mm. This concentration repre 0317. The dehydrated lipid vesicle powder mixture was sented the concentration of albuterol in the continuous phase dissolved and Suspended quantitatively in pure water. Then, of the liposome (non-encapsulated albuterol). The spectro 150 uL of freshly prepared liposomal sample was centrifuged photometrical method was also used with the determining of with an Avanti J-E centrifuge (type JA-20, 17400xg, 6°C., the total concentration of albuterol including in the dispersed and 20 min) through Microcon Y-10 Centrifugal Filter phase and the continuous phase of liposome. Absolute etha Devices (Millipore) with a cut-off value of 10,000 Dalton. nol was added into the liposome Suspension to disrupt the The concentration of albuterol in the centrifuged solution was liposome completely and the encapsulated albuterol was determined spectrophotometrically at 276 mm. This concen completely dissolved in the solution. The absorbencies were tration represented the concentration of albuterol in the con measured by a UV-VIS Varian Cary 50 Tablet instrument tinuous phase of the liposome (non-encapsulated albuterol). equipped with a thermostated quartz cell at the wavelengths The spectrophotometrical method was also used with the of 278 nm. The encapsulation efficiency (EE) was calculated determining of the total concentration of albuterol including with the formula: in the dispersed phase and the continuous phase of liposome. EE(%)=(C- Cree)/Coax 100 Absolute ethanol was added into the liposome Suspension to disrupt the liposome completely and the encapsulated where C is the concentration of unencapsulated albuterol albuterol was completely dissolved in the solution. The absor in the continuous phase of liposome dispersion/solution, and bencies were measured by a UV-VIS Varian Cary 50 Tablet C is the total concentration of albuterol in the liposome instrument equipped with a thermostated quartz cell at the dispersion/solution. The encapsulation efficiencies were wavelengths of 278 nm. The encapsulation efficiency (EE) 50-70%. was calculated with the formula: Example 4 Where C is the concentration of unencapsulated albuterol 0311 Preparation of Dehydrated Lipid Vesicles in the continuous phase of liposome dispersion/solution, and 0312 This example illustrates the method for preparing C is the total concentration of albuterol in the liposome liposomal compositions containing stabilizers and/or plasti dispersion/solution. cizers for controlled release of active pharmaceutical ingre dient. Example 5 0313. A mixture of glycerin, DOPC or DOTAP, and active pharmaceutical ingredient (albuterol, 0.04 mmol) in the mole 0318. The Retention and the Release of Albuterol in Lipo ratio of 1:10:20 was dissolved in 4 ml of ethanol. Liposomal Some during Dialysis Equilibrium albuterol dispersion was formed by injecting the lipid/active 0319. The dehydrated lipids vesicle powder mixture was pharmaceutical ingredient/ethanol solution into 50 ml of the dissolved and Suspended quantitatively in pure water. In order phosphate buffered saline pH 7.4. Liposomes thus formed to evaluate the retention of albuterol in liposome in vitro, the were extruded through a 0.4 or a 0.2 or a 0.1 um polycarbon equilibrium between the dialysis phase, the continuous phase ate membrane to produce uniform size distribution of lipo (dispersion medium) and the dispersion phase (inner of lipo some vesicles. Lactose in the mol ratio of 200% to DOPC or Somes) Suspension were performed by membrane dialysis at DOTAP was added and dissolved into the liposome suspen 25° C. The release medium was Tris-buffered saline buffer Sion, and the temperature immediately decreased by liquid solution (pH 7.4), which was the same buffer solution used to nitrogen. The frozen ice of the liposome Suspension was hydrate lipid-albuterol thin membrane during liposome placed into the -50° C. lyophilizer chamber and vacuum preparation, so as to maintain the osmotic balance between applied to the chamber till the water was dried off, and the the liposome in dialysis tube and the release medium. DOPC dehydrated lipid vesicles were formed with the lactose pow and DOTAP liposomes were chosen for the study, due to their der. relative high encapsulation efficiency. 0314 Transmission Electron Microscope (TEM) Obser 0320 6 mL of each liposome sample was transferred into vation of the Dehydrated Lipid Vesicles dialysis membrane tube (molecular weight 12,000-14,000 0315. The MLV and the SUV liposome solution were pre Dalton cut-off: Spectrum Medical Industries, Los Angeles, pared using the same methods as mentioned above. The lipid Calif.) and placed in the temperature-controlled beaker con concentration of all the liposomes was controlled at 10 taining 150 mL of TBS. The contents of the beaker were mg/mL. The liposome vesicles were the empty and albuterol stirred at 50 rpm at the temperature of 37°C. throughout the US 2009/0047336A1 Feb. 19, 2009 experiment. 5 mL of the dialysis medium was withdrawn its derivatives or salts, potassium thiocyanate, Sodium thi from 150 mL of the medium in total at the time point of 15.30, omalate, thymol, medium chain fatty acid triglyceride, dext 45, 60,90, 120, 150 and 180 min, every hourthereafter for 3 ran, dextrin, vitamin E, calcium D-Saccharate, tocopheroland hand every 3 hour thereafter till 24 h. Each withdrawal was its isomer, trometamol, nicotinamide, lactic acid and its followed by replacement of fresh dialysis medium. The derivatives or salts, lactose, carbamide, white soft Sugar, his samples were assayed by a UV-VIS Varian Cary 50 Tablet tidine and its derivatives or salts, hydroxypropylcellulose, instrument equipped with a thermostat quartz cell at the hydroquinone, phenylalanine, phenacetin, glucose, fumaric wavelength of 278 nm for the concentration of albuterol in the acid and its derivatives or salts, propylene glycol, heparin release medium (C). At the same time point, 300 LL lipo Sodium, povidone, maleic acid and its derivatives or salts, Some in dialysis tubing was pipetted out. 150 uL was centri malonic acid and its derivatives or salts, mannitol, methion fuged with an Avanti J-E centrifuge (type JA-20, 17400xg, 6° ine, sodium lauryl Sulfate, malic acid and its derivatives or C., 20 min) through Microcon Y-10 Centrifugal Filter salts, hydrogenated oil, Sesame oil, karion 83, diethylenetri Devices (Millipore) with a cut-off value of 10 kD. The con aminepentaacetic acid and its derivatives or salts, dioctyl centration of albuterol in the centrifuged solutions was deter Sodium sulfoSuccinate, polydimethylsiloxane-silicone diox mined to be the concentration of albuterol in the continuous ide mixture, Sorbitan esters of fatty acid, triacetin, castor oil, phase of liposomes at the instant time point (C). Another diethyl/dibutyl phthate, butylphtalylbutylglycolate, propy 150 uL liposome was determined to be the total concentration lene glycol (1,2-propane diol), propylene glycol esters of of albuterol in the liposome solutions (C) after appropriate fatty acids, polysorbate, polyoxyethylene polyoxypropylen dilution with ethanol. The difference between C, and C. glycol, macrogol, isopropyl myristate, cotton seed oil-soy was calculated as C, which was regarded as the albuterol bean oil mixture, glyceryl monostearate, isopropyllinoleate, concentrations within the liposome at corresponding Sam petrolatum, and mixtures thereof. pling time point. 3. The composition of claim 2, wherein the composition 0321. The dialysis phase partition coefficient between has a ratio of said vesicle preserver to said lipid component continuous phase and dispersed phase of liposome (K. from 0.1 to 40 mole% of the vesicle preserver and from 99.9 in-C/C) and the dialysis phase partition coefficient to 60 mole % of the lipid commonent. between the continuous phase of the liposome and the release 4. The composition of claim 1, wherein the active pharma medium (K-C/C) were calculated. ceutical ingredient is selected from the group consisting of 0322. After the sinking condition formed to the lipid ephedrine, ephedrine hydrochloride, albuterol, theophyline, vesicles, the K-10; stop the dialysis, and record the time, salbutamol sulfate, salmefamol, terbutaline, orciprenaline, and test the C, and C, following the time, to calculate the fenoterol, clorprenaline hydrochloride, clorprenaline glycyr release of the entrapped albuterol from the lipids vesicle in to rhizinate, tulobuterol, 5-(4-amino-3,5-dichlorophenyl)-3- the buffer. FIG.2 shows the release of the entrapped albuterol tert-butyloxazole, 5-(4-amino-3,5-dichlorophenyl)-3-tert from two kinds of the dehydrated lipids vesicles. butyloxazole hydrochloride, clenbuterol hydrochloride, 1. A pharmaceutical lipid composition for treatment of procaterol, salmeterol, hexoprenaline, mabuterol, formot asthma by inhalation into a respiratory system, said compo erol, , tretoquinol, ririniterol, bitolterol, sition comprising dehydrated lipid vesicles of a pharmaceu protokylol, , pirbuterol, fenspiride, ipratropine, iso tically acceptable vesicle preserver, a pharmaceutically propylscopolamine, aminophylline, diprophylline, choline acceptable lipid component and an active pharmaceutical theophyllinate, sodium cromoglicate, ketotifen, triprolidine, ingredient wherein the pharmaceutically acceptable vesicle tranilast, ammonium chloride, potassium iodide, acetylcys preserver includes plasticizers and/or stabilizers. teine, bromhexine hydrochloride, carbocisteine, ambroxol 2. The composition of claim 1, wherein said vesicle pre hydrochloride, guaifenesin, codeine, codeine phosphate, server is chosen from pharmaceutical stabilizers and plasti pholcodine, drotebanol, pentoxyverine citrate, chloperastine, cizers selected from the group consisting of adipic acid and its benproperine phosphate, dextromethorphan hydrobromide, derivatives or salts, ascorbic acid and its derivatives or salts, oXeladin, eprazinone, Zipeprol, deoxopromethazine hydro aspartic acid and its derivatives or salts, acetyltryptophanand chloride, fominoben, promolate, as verin, benzonatate, its derivatives or salts, acetanilide and its derivatives or salts, prenoxdiazine, noscactive pharmaceutical ingredient, aminoethy Sulfonic acid and its derivatives or salts, alanine beclomethasone, betamethasone, budesonide, cloprednol, and its derivatives or salts, acacia, Sodium bisulfite, sodium cortisone, cortivaZol, deoxycortone, desonide, dexametha Sulfite, arginine and its derivatives or salts, alginic acid and its sone, difluorocortolone, fluclorolone, fluorocortisone, flu derivatives or salts, benzoic acid and its derivatives or salts, methasone, flunisolide, fluocinolone, fluocinonide, fluoro isostearic acid and its derivatives or salts, inositol and its cortolone, aldosterone, fluorometholone, flurandrenolone, derivatives or salts, ethylenediamine and its derivatives or halcinonide, hydrocortisone, meprednisone, methylpred salts, erythorbic acid and its derivatives or salts, lysine and its nisolone, paramethasone, prednisolone, prednisone, triamci derivatives or salts, cacao butter, castor wax, Xathan gum, nolone, metaproterenol Sulfate, isoproterenol, adrenaline, Xylitol, citric acid and its derivatives or salts, glycine and its norepinephrine, fluoromethasone, medrysone, fluticaSone, derivatives or salts, glycerin and its derivatives, gluconic acid atropine methyl nitrate, ipratropiun bromide, cromolyn and its derivatives or salts, glutamic acid and its derivatives or Sodium, nedocromil and their respective pharmaceutically salts, creatinine, diisopropanolamine and its derivatives, acceptable salts or esters, and mixtures thereof. diethanolamine and its derivatives, cyclodextrin, cystine, cys 5. The composition of claim 4, wherein the composition teine, dibutylhydroxytoluene, tartaric acid and its derivatives has a mole ratio of active pharmaceutical ingredient to the or salts. Sucrose esters of fatty acids, Stearic acid and its lipid component from 0.1% to 200%. derivatives or salts, gelatin, lanolin, cetanol, gelatin, hydro 6. The composition of claim 4, wherein albuterol is present lyzed gelatin, shellac, D-sorbitol, sorbitan esters offatty acid, in an amount between 0.1 to 300 mg/ml of the dehydrated Sorbica acid and its derivatives or salts, thioglycolic acid and lipid vesicles composition. US 2009/0047336A1 Feb. 19, 2009

7. The composition of claim 1 which can be aerosolized an active pharmaceutical ingredient and lipid components into particles predominantly smaller than a mass median aerosolized into particles predominantly smaller than a mass aerodynamic diameter of 10 um. median aerodynamic diameter of 10 um by an inhalation 8. A method of treating asthma by an inhalation route of route of administration. administration to a person in need of Such treatment a thera 13. The method of claim 12 wherein said active pharma peutically effective amount of plasticized lipid composition ceutical ingredient is selected from the group consisting of consisting essentially of an active pharmaceutical ingredient, ephedrine, ephedrine hydrochloride, albuterol, theophyline, a vesicle preserver selected from a plasticizer, a stabilizer and salbutamol Sulfate, Salmefarnol, terbutaline, orciprenaline, mixtures thereof, and a lipid component aerosolized into fenoterol, clorprenaline hydrochloride, clorprenaline glycyr aerosol particles having a mass median aerodynamic diam rhizinate, tulobuterol, 5-(4-amino-3,5-dichlorophenyl)-3- eter Smaller than 10 Lum and providing a slow or controlled tert-butyloxazole, 5-(4-amino-3,5-dichlorophenyl)-3-tert release of the active pharmaceutical ingredient into a respi butyloxazole hydrochloride, clenbuterol hydrochloride, ratory system. procaterol, salmeterol, hexoprenaline, mabuterol, formot 9. The method of claim 8 wherein the composition com erol, methoxyphenamine, tretoquinol, rimiterol, bitolterol, prises 0.1 to 40 mole % of said stabilizers and/or plasticizer, protokylol, reproterol, pirbuterol, fenspiride, ipratropine, iso 99.9 to 60 mole % of lipids, and the active pharmaceutical propylscopolamine, aminophylline, diprophylline, choline ingredient is from 0.01 to 200 mole % to the lipids. theophyllinate, sodium cromoglicate, ketotifen, triprolidine, 10. The method of claim 8, wherein said active pharma tranilast, ammonium chloride, potassium iodide, acetylcys ceutical ingredient is selected from the group consisting of teine, bromhexine hydrochloride, carbocisteine, ambroxol ephedrine, ephedrine hydrochloride, albuterol, theophyline, hydrochloride, guaifenesin, codeine, codeine phosphate, salbutamol Sulfate, Salmefamol, terbutaline, orciprenaline, pholcodine, drotebanol, pentoxyverine citrate, chloperastine, fenoterol, clorprenaline hydrochloride, clorprenaline glycyr benproperine phosphate, dextromethorphan hydrobromide, rhizinate, tulobuterol, 5-(4-amino-3,5-dichlorophenyl)-3- oXeladin, eprazinone, Zipeprol, deoxopromethazine hydro tert-butyloxazole, 5-(4-amino-3,5-dichlorophenyl)-3-tert chloride, fominoben, promolate, as verin, benzonatate, butyloxazole hydrochloride, clenbuterol hydrochloride, prenoxdiazine, noscactive pharmaceutical ingredientine, procaterol, salmeterol, hexoprenaline, mabuterol, formot beclomethasone, betamethasone, budesonide, cloprednol, erol, methoxyphenamine, tretoquinol, rimiterol, bitolterol, cortisone, cortivaZol, deoxycortone, desonide, dexametha protokylol, reproterol, pirbuterol, fenspiride, ipratropine, iso sone, difluorocortolone, fluclorolone, fluorocortisone, flu propylscopolamine, aminophylline, diprophylline, choline methasone, flunisolide, fluocinolone, fluocinonide, fluoro theophyllinate, sodium cromoglicate, ketotifen, triprolidine, cortolone, aldosterone, fluorometholone, flurandrenolone, tranilast, ammonium chloride, potassium iodide, acetylcys halcinonide, hydrocortisone, meprednisone, methylpred teine, bromhexine hydrochloride, carbocisteine, ambroxol nisolone, paramethasone, prednisolone, prednisone, triamci hydrochloride, guaifenesin, codeine, codeine phosphate, nolone, metaproterenol Sulfate, isoproterenol, adrenaline, pholcodine, drotebanol, pentoxyverine citrate, chloperastine, norepinephrine, fluoromethasone, medrysone, fluticaSone, benproperine phosphate, dextromethorphan hydrobromide, atropine methyl nitrate, ipratropium bromide, cromolyn oXeladin, eprazinone, Zipeprol, deoxopromethazine hydro Sodium, nedocromil and their respective pharmaceutically chloride, fominoben, promolate, as verin, benzonatate, acceptable salts or esters, and mixtures thereof prenoxdiazine, noscactive pharmaceutical ingredientine, 14. The method of claim 12 which employs albuterol or beclomethasone, betamethasone, budesonide, cloprednol, other active pharmaceutical ingredients in an amount from cortisone, cortivaZol, deoxycortone, desonide, dexametha 0.1 to 300 mg/ml of suspension of the dehydrated lipid vesicle sone, difluorocortolone, fluclorolone, fluorocortisone, flu composition. methasone, flunisolide, fluocinolone, fluocinonide, fluoro 15. A process of preparing a Suspension of inhaleable or cortolone, aldosterone, fluorometholone, flurandrenolone, nebulizeable aerosol particles of sizes predominantly smaller halcinonide, hydrocortisone, meprednisone, methylpred than 10 um, wherein the particles are dehydrated liposome nisolone, paramethasone, prednisolone, prednisone, triamci vesicles, the process comprising providing dehydrated lipo nolone, metaproterenol Sulfate, isoproterenol, adrenaline, Some vesicles having sizes less than 10 um in an aqueous norepinephrine, fluoromethasone, medrysone, fluticaSone, Suspension; and inhaling or nebulizing the Suspension under atropine methyl nitrate, ipratropium bromide, cromolyn conditions which produce aerosol particles of a mass median Sodium, nedocromil and their respective pharmaceutically aerodynamic diameter predominantly smaller than 10 Jum. acceptable salts or esters, and mixtures thereof. 16. The process of claim 15, wherein said particles com 11. The method of claim 8 which employs albuterol in an prise dehydrated lipid vesicles and/or micelles not larger than amount from 0.1 to 300 mg/ml of the dehydrated lipid vesicle 5.0 um, wherein said Suspension is for treatment of asthma composition. and consists essentially of lipid components and an active 12. An inhalation method for treatment of respiratory sys pharmaceutical ingredient or its salt or ester, Suitable for tem diseases by treating a person in need of Such treatment delivery by inhalation into the respiratory system. with a therapeutically effective amount of an aerosolized dehydrated lipid vesicle composition consisting essentially of c c c c c