US 2008O175887A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0175887 A1 Wang (43) Pub. Date: Jul. 24, 2008

(54) TREATMENT OF ASTHMA AND CHRONIC Mar. 2, 2007, provisional application No. 60/981,380, OBSTRUCTIVE PULMONARY DISEASE filed on Oct. 19, 2007, provisional application No. WITH ANT-PROLIFERATE AND 60/981,384, filed on Oct. 19, 2007. ANTI-NFLAMMATORY DRUGS Publication Classification (76) Inventor: Lixiao Wang, Medina, MN (US) (51) Int. Cl. A6IR 9/12 (2006.01) Correspondence Address: A63L/436 (2006.01) FINNEGAN, HENDERSON, FARABOW, GAR A6IP II/00 (2006.01) RETT & DUNNER A6M I5/00 (2006.01) LLP A6IF 2/82 (2006.01) 901 NEW YORKAVENUE, NW A6M 25/10 (2006.01) WASHINGTON, DC 20001-4413 A6M II/00 (2006.01) A63L/337 (2006.01) (21) Appl. No.: 11/942,459 (52) U.S. Cl...... 424/434; 514/291; 514/449; 424/43; 128/200.23; 128/203.15; 604/103.02; 623/1.42 (22) Filed: Nov. 19, 2007 (57) ABSTRACT Embodiments of the present invention provide a method for Related U.S. Application Data treatment of respiratory disorders such as asthma, chronic (60) Provisional application No. 60/860,084, filed on Nov. obstructive pulmonary disease, and chronic sinusitis, includ 20, 2006, provisional application No. 60/880,742, ing cystic fibrosis, interstitial fibrosis, chronic bronchitis, filed on Jan. 17, 2007, provisional application No. emphysema, bronchopulmonary dysplasia and neoplasia. 60/897.427, filed on Jan. 25, 2007, provisional appli The method involves administration, preferably oral, nasal or cation No. 60/903.529, filed on Feb. 26, 2007, provi pulmonary administration, of anti-inflammatory and anti sional application No. 60/926,850, filed on Apr. 30, proliferative drugs (rapamycin or paclitaxel and their ana 2007, provisional application No. 60/904,473, filed on logues). US 2008/0175887 A1 Jul. 24, 2008

TREATMENT OF ASTHMIA AND CHRONIC emphysema localized to the upper lung lobes are candidates OBSTRUCTIVE PULMONARY DISEASE for lung Volume reduction Surgery, where the upper lobes are WITH ANT-PROLIFERATE AND Surgically removed to restore the natural concavity and func ANTI-NFLAMMATORY DRUGS tion of the diaphragm. 0006 Acute exacerbation of asthma are often caused by CROSS REFERENCE TO RELATED spasm of the airways, or bronchoconstriction, causing Symp APPLICATIONS toms including Sudden shortness of breath, wheezing, and cough. Bronchospasm is treated with inhaled bronchodilators 0001. This application claims the benefit of priority under (anticholinergics such as ipratropium and beta-agonists Such 35 U.S.C. S 119 of U.S. Provisional Application No. 60/860, as albuterol). Patients inhale these medications into their 084, filed on Nov. 20, 2006, U.S. Provisional Application No. lungs as a mist, produced by either a nebulizer or a hand-held 607880,742, filed Jan. 17, 2007, U.S. Provisional Application meter dose (MDI) or dry powder (DPI) inhaler. Patients with No. 60/897,427, filed on Jan. 25, 2007, U.S. Provisional acute episodes may also be treated with oral or intravenous Application No. 60/903.529 filed on Feb. 26, 2007, U.S. steroids that serve to reduce the inflammatory response that Provisional Application No. 60/926,850 filed Apr. 30, 2007, exacerbates the condition. U.S. Provisional Application No. 60/904,473 filed Mar. 2, 0007 Asthma is a chronic respiratory disease character 2007, U.S. Provisional Application No. 60/981,380 filed Oct. ized by inflammation of the airways, excess mucus produc 19, 2007, and U.S. Provisional Application 60/981,384 filed tion and airway hyperresponsiveness, and a condition in Oct. 19, 2007, the disclosures of all of which are incorporated which airways narrow excessively or too easily respond to a by reference herein. stimulus. Asthma episodes or attacks cause narrowing of the airways, which make breathing difficult. Asthma attacks can FIELD OF THE INVENTION have a significant impact on a patient’s life, limiting partici 0002 The present invention relates to a method for treat pation in many activities. In severe cases, asthma attacks can ment of respiratory disorders such as asthma and chronic be life threatening. Presently, there is no know cure for obstructive pulmonary disease, including cystic fibrosis, asthma. interstitial fibrosis, chronic bronchitis, emphysema, bron 0008 According to the American Lung Association, there chopulmonary dysplasia and neoplasia. The method involves are approximately 20 million Americans with asthma in 2002. administration, preferably oral, nasal or pulmonary adminis Fourteen million of them were adults. Asthma resulted in tration, of anti-inflammatory and anti-proliferate drugs (rapa approximately 1.9 million emergency room visits in 2002. mycin or paclitaxel and their analogues). The estimated direct cost of asthma in the U.S. is S11.5 billions, which is spent on asthma medications, physician BACKGROUND OF THE INVENTION office visits, emergency room visits and hospitalizations. 0003 Chronic obstructive pulmonary disease (COPD) is a 0009. The causes of coronary heart disease and asthma are term used to classify two major airflow obstruction disorders: neointimal proliferation of Smooth muscle in arterial vessels chronic bronchitis and emphysema. Approximately 16 mil and in walls of airways. One aspect of the invention is to lion Americans have COPD, 80-90% of them were smokers deliverpaclitaxel or rapamycin and their analogues to the wall throughout much of their lives. COPD is a leading cause of of airways to treat the asthma and COPD. Drug coated stents death in the U.S., accounting for 122.283 deaths in 2003. The with these drugs have been approved for inhibiting the growth cost to the USA for COPD was approximately $20.9 billion in of the Smooth muscle cells in vascular arterial vessels. direct health care expenditures in 2003. Chronic bronchitis is 0010 Chronic sinusitis is an inflammation of the mem inflammation of the bronchial airways. The bronchial airways brane lining of one or more paranasal sinuses. Chronic sinusi connect the trachea with the lungs. When inflamed, the bron tis lasts longer than three weeks and often continues for chial tubes Secrete mucus, causing a chronic cough. Emphy months. In cases of chronic sinusitis, there is usually tissue sema is an overinflation of the alveoli, or air sacs in the lungs. damage. According to the Center for Disease Control (CDC), This condition causes shortness of breath. thirty seven million cases of chronic sinusitis are reported 0004. In emphysema, the alveolar sacs are overinflated as annually. a result of damage to the elastin skeleton of the lung. Inflam 0011 Chronic sinusitis is often difficult to treat success matory cells in emphysematous lung release elastase fully, however, as some symptoms persist even after pro enzymes, which degrade or damage elastin fibers within the longed courses of antibiotics. Steroid nasal sprays and pre lung matrix. Emphysema has a number of causes, including scribed Steroids are commonly used to treat inflammation in Smoking, exposure to environmental pollutants, alpha-one chronic sinusitis. When medical treatment fails, Surgery may antitrypsin deficiency, and aging. be the only alternative in treating chronic sinusitis. Presently, 0005. There are no therapies available today to halt the the most common Surgery done is functional endoscopic progression of COPD. Inhaled steroids have recently been sinus Surgery, in which the diseased and thickened tissues studied (Lung Health Study II) as a potential therapy to pre from the sinuses are removed to allow drainage. However, vent loss of lung function in emphysema patients. The study there is a need for better medicine for chronic sinusitis. concluded, however, that inhaled steroids failed to alter the 0012. The present invention provides a new method for decline in lung function over time. As patients lose lung treatment of respiratory disorders such as asthma, chronic function over time, they may become dependent on oxygen, obstructive pulmonary disease, and chronic sinusitis. The and eventually end up onventilators to assist with respiration. method involves administration, preferably oral, nasal or pull A relatively new treatment for patients with emphysema is monary administration, of anti-inflammatory and anti-prolif lung Volume reduction Surgery. Emphysema patients Suffer erate drugs (rapamycin or paclitaxel and their analogues). from air trapping in the lungs. This flattens the diaphragm, Embodiments of the present invention provides a pharmaceu impairing the ability to inhale and exhale. Patients with tical formulation comprising a drug for treatment of the res US 2008/0175887 A1 Jul. 24, 2008 piratory system, and an additive that enhances absorption of Sally, intrabronchially, transdermally, rectally, or via an the drug into tissue of body passages. impregnated vascular stent or balloon catheter into a body passage, wherein said drug is chosen from rapamycin and SUMMARY OF THE INVENTION analogues thereof and paclitaxel and analogues thereof. In 0013 Embodiments of the present invention are directed one aspect of this embodiment, the asthma and chronic to the treatment of respiratory disorders by intratracheal obstructive pulmonary disease to be treated is selected from administration of an effective amount of anti-inflammatory the group consisting of chronic bronchitis, cystic fibrosis, and anti-proliferate drugs (rapamycin or paclitaxel and their interstitial fibrosis, nasal and sinus dysplasia, bronchopulmo analogues). Respiratory disorders such as asthma, chronic nary dysplasia and neoplasia, and emphysema. In another obstructive pulmonary disease, and chronic sinusitis include aspect of this embodiment, the administering comprises cystic fibrosis, interstitial fibrosis, chronic bronchitis, emphy delivery via a mist route selected from the group consisting of sema, nasal and sinus dysplasia, bronchopulmonary dyspla aerosol inhalation, dry powder inhalation, liquid inhalation, sia and neoplasia. The treatment is intended for a variety of and liquid instillation. In one embodiment, the mist is pro animals, such as premature neonates to adult humans. Admin duced by either a nebulizer, a hand-held meter dose inhaler istration of rapamycin or paclitaxel may be performed by (MDI), or dry powder (DPI) inhaler. aerosol, which can be generated by a nebulizer, by inhalation 0018. In one embodiment of the method, the additive or by instillation. The rapamycin or paclitaxel may be admin enhances absorption of the drug into tissue of the body pas istered alone or with an additive carrier in solution Such as sage of the respiratory and sinus system. In another embodi saline solution, DMSO, alcohol, or water. It may also be used ment of the method, the additive comprises a hydrophilic part as combinations with inhaled bronchodilators (anticholin and a hydrophobic part. In another embodiment, the drug is ergics Such as ipratropium and beta-agonists such as not enclosed in micelles or encapsulated in polymer particles. albuterol) and oral or intravenous steroids. Patients inhale In yet another embodiment, the pharmaceutical formulation these medications into their lungs as a mist, produced by does not include oil, a lipid, or a polymer. either a nebulizer or a hand-held meter dose (MDI) or dry 0019. In one embodiment of the method, the additive is powder (DPI) inhaler. chosen from PEG fatty esters and alcohols, glycerol fatty 0014. The additive has a lipophilic or hydrophobic part esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG and a hydrophilic part. The hydrophobic part may include Sorbitan fatty esters, Sugar fatty esters, PEG sugar esters, aliphatic and aromatic organic hydrocarbon compounds, Vitamins and derivatives, aminoacids, multiaminoacids and Such as benzene, toluene, and alkanes, among others. These derivatives, peptides, polypeptides, proteins, quaternary parts are not water soluble. They have no covalently bonded ammonium salts, organic acids, salts and anhydrides. In iodine. The hydrophilic part may include hydroxyl groups, another embodiment, the additive is chosen from amine groups, amide groups, carbonyl groups, carboxylic p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, acid and anhydrides, ethyl oxide, ethylglycol, polyethylene PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, glycol, ascorbic acid, amino acid, amino alcohol, glucose, PEG glyceryl Stearate, polyglyceryl laurate, plyglyceryl ole Sucrose, Sorbitan, glycerol, polyalcohol, phosphates, Sulfates, ate, polyglyceryl myristate, polyglyceryl palmitate, PEG sor organic salts and their Substituted molecules, among others. bitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan These parts can dissolve in water and polar solvents. These monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG additives are not oils, lipids, or polymers. The therapeutic laurayl ether, octoxynol, monoxynol, tyloxapol; cystine, agent is not enclosed in micelles or liposomes or encapsulated tyrosine, tryptophan, leucine, isoleucine, phenylalanine, in polymer particles. asparagine, aspartic acid, glutamic acid, and methionine 00.15 Embodiments of the present invention provide a (Aminoacids); acetic anhydride, benzoic anhydride, ascorbic method for treating the lung during an acute episode of acid, 2-pyrrolidone-5-carboxylic acid, Sodium pyrrolidone reversible chronic obstructive pulmonary disease is provided. carboxylate, ethylenediaminetetraacetic dianhydride, maleic The coronary and peripheral diseases result from Smooth and anhydride, Succinic anhydride, diglycolic anhydride, glu muscle cell proliferation. Asthma includes episodes or taric anhydride, acetiamine, benfotiamine, pantothenic acid attacks of the airway narrowing, contracting and thickening (organic acids and anhydrides); cetotiamine; cyclothiamine, via Smooth muscle cell proliferation. The rapamycin, pacli dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phos taxel, and their analogues can be used for treating asthma in phate, nicotinamide ascorbate, riboflavin, riboflavin phos the lung. phate, thiamine, folic acid, menadiol diphosphate, menadi 0016 Embodiments of the present invention provide a one sodium bisulfite, menadoxime, vitamin B12, vitamin K5, method of treating respiratory disorders such as asthma, vitamin K6, vitamin K6, and vitamin U (vitamins); albumin, chronic obstructive pulmonary disease and chronic sinusitis immunoglobulins, caseins, hemoglobins, lysozymes, immu in a mammal comprises administrating an antiproliferative noglobins, a-2-macroglobulin, fibronectins, vitronectins, and anti-inflammatory effective amount of rapamycin, or firbinogens, lipases, benzalkonium chloride, benzethonium paclitaxel or their analogues to said mammal orally, parenter chloride, docecyl trimethyl ammonium bromide, sodium ally, intravascularly, intranasally, intrabronchially, transder docecylsulfates, dialkyl methylbenzyl ammonium chloride, mally, rectally, or via an impregnated vascular stent or bal and dialkylesters of Sodium Sulfonsuccinic acid. loon catheter. 0020. In another embodiment of the method, the additive 0017. In one embodiment, the present invention relates to is a Surfactant. In one aspect of this embodiment, the Surfac a method for treating at least one of asthma, chronic obstruc tant is an ionic Surfactant. In another aspect of this embodi tive pulmonary disease, and chronic sinusitis in a mammal ment, the ionic Surfactant is chosen from benzalkonium chlo comprising administering a pharmaceutical formulation ride, benzethonium chloride, cetylpyridinium chloride, comprising an effective amount of a drug and an additive to docecyl trimethyl ammonium bromide, Sodium docecylsul said mammal orally, parenterally, intravascularly, intrana fates, dialkyl methylbenzyl ammonium chloride, edropho US 2008/0175887 A1 Jul. 24, 2008 nium chloride, domiphen bromide, dialkylesters of sodium monolaurate, decanoyl-N-methylglucamide, n-decyl-B-D- Sulfonsuccinic acid, sodium dioctyl sulfoSuccinate, sodium glucopyranoside, n-decyl-B-D-maltopyranoside, n-dodecyl cholate, and sodium taurocholate. B-D-glucopyranoside, n-dodecyl-3-D-maltoside, heptanoyl 0021. In one embodiment of the method, he additive is N-methylglucamide, n-heptyl-B-D-glucop-yranoside, chosen from PEG-fatty acids and PEG-fatty acid mono and n-heptyl-B-D-thioglucoside, n-hexyl-D-glucopyranoside, diesters, polyethylene glycol glycerol fatty acid esters, alco nonanoyl-N-methylglucamide, n-noyl-B-D-glucopyrano hol-oil transesterification products, polyglyceryl fatty acids, side, octanoyl-N-methylglucamide, n-octyl-B-D-glucopyra propylene glycol fatty acid esters, sterols and derivatives noside, and octyl-B-D-thioglucopyranoside. thereof, polyethylene glycol Sorbitan fatty acid esters, poly ethylene glycol alkyl ethers, Sugars and derivatives thereof, 0025. In another embodiment of the method, the additive polyethylene glycol alkyl phenols, polyoxyethylene-polyox is chosen from PEG-10-100 nonyl phenol, PEG-15-100 octyl ypropylene block copolymers, Sorbitan fatty acid esters, fat phenol ether, Tyloxapol, octoxynol, and nonoxynol. In soluble vitamins and salts thereof, water-soluble vitamins and another embodiment of the method, the additive is chosen amphiphilic derivatives thereof, amino acid and salts thereof, from poloxamer 108, poloxamer 188, poloxamer 217, polox oligopeptides, peptides and proteins, and organic acids and amer 238, poloxamer 288, poloxamer 338, and poloxamer esters and anhydrides thereof. 407. In another embodiment of the method, the additive is 0022. In another embodiment of the method, the additive chosen from poloxamer 124, poloxamer 182, poloxamer 183, is chosen from esters of lauric acid, oleic acid, and Stearic poloxamer 212, poloxamer 331, and poloxamer 335. In acid, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 another embodiment of the method, the additive is chosen oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, from Sorbitan monolaurate, Sorbitan monopalmitate, Sorbitan PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and PEG-20 monooleate, and Sorbitan monostearate. In another embodi oleate. In another embodiment, the additive is chosen from ment of the method, the additive is chosen from alpha-toco PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, pherol, beta-tocopherol, gamma-tocopherol, delta-toco PEG-32 dilaurate and PEG-32 dioleate. In another embodi pherol, tocopherol acetate, ergosterol, 1-alpha ment of the method, the additive is chosen from PEG-20 hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl carotene, beta-carotene, gamma-carotene, Vitamin A, laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. fursultiamine, methyloiriboflavin, octotiamine, prosul In another embodiment of the method, the additive is chosen tiamine, riboflavine, vintiamol, dihydroVitamin K1, menadiol from PEG-35 castor oil, PEG-40 hydrogenated castor oil, diacetate, menadiol dibutyrate, menadiol disulfate, menadiol. PEG-25 trioleate, PEG-60 corn glycerides, PEG-60 almond Vitamin K1, Vitamin K1 oxide, Vitamins K2, and vitamin oil, PEG-40 palm kernel oil, PEG-50 castor oil, PEG-50 K S(II), and folic acid. hydrogenated castor oil, PEG-8 caprylic?capric glycerides, 0026. In another embodiment of the method, the additive and PEG-6 caprylic/capric glycerides, PEG-7 hydrogenated is chosen from acetiamine, benfotiamine, pantothenic acid, castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil, cetotiamine, cyclothiamine, dexpanthenol, niacinamide, PEG-6 almond oil, PEG-6 apricotkernel oil, PEG-6 olive oil, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascor PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, bate, riboflavin, riboflavin phosphate, thiamine, folic acid, PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG menadiol diphosphate, menadione sodium bisulfite, mena 20 corn glycerides, and PEG-20 almond glycerides. doxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, 0023. In another embodiment of the method, the additive and vitamin U. In another embodiment of the method, the is chosen from polyglyceryl oleate, polyglyceryl-2 dioleate, additive is chosen from alanine, arginine, asparagines, aspar polyglyceryl-10 trioleate, polyglyceryl Stearate, polyglyceryl tic acid, cysteine, glutamic acid, glutamine, glycine, histi laurate, polyglyceryl myristate, polyglyceryl palmitate, and dine, proline, isoleucine, leucine, lysine, methionine, pheny polyglyceryl linoleate, polyglyceryl-10 laurate, polyglyc lalanine, serine, threonine, tryptophan, tyrosine, and valine, eryl-10 oleate, polyglyceryl-10 mono, dioleate, polyglyceryl and salts of any of the foregoing. In another embodiment of 10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 the method, the additive is albumin. In another embodiment myristate, polyglyceryl-10 palmitate, polyglyceryl-10 of the method, the additive is chosen from benzalkonium linoleate, polyglyceryl-6 Stearate, polyglyceryl-6 laurate, chloride, n-octyl-B-D-glucopyranoside, octoxynol-9, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and Polysorbates, Tyloxapol, Octoxynol, nonoxynol, polyglyceryl-6 linoleate, and polyglyceryl polyricinoleate. In isononylphenylpolyglycidol, PEG glyceryl monooleate, Sor another embodiment of the method, the additive is chosen bitan monolaurate, Sorbitan monopalmitate, Sorbitan from propylene glycol monolaurate, propylene glycol ricino monooleate, Sorbitan monostearate, polyglyceryl-10 oleate, leate, propylene glycol monooleate, propylene glycol dica polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyg prylate/dicaprate, and propylene glycol dioctanoate. In lyceryl-10 Stearate, L-ascorbic acid, thiamine, maleic anhy another embodiment of the method, the additive is PEG-24 dride, niacinamide, and 2-pyrrolidone-5-carboxylic acid. cholesterol ether. In another embodiment of the method, the 0027. In another embodiment of the method, the additive additive is chosen from sterol polyethylene glycol deriva is chosen from riboflavin, riboflavin-phosphate sodium, Vita tives. min D3, folic acid, vitamin 12, diethylenetriaminepentaacetic 0024. In another embodiment of the method, the additive acid dianhydride, ethylenediaminetetraacetic dianhydride, is chosen from PEG-20 sorbitan monolaurate, PEG-20 sorbi maleic acid and anhydride. Succinic acid and anhydride, dig tan monopalmitate, PEG-20 sorbitan monostearate, and lycolic anhydride, glutaric anhydride, L-ascorbic acid, thia PEG-20 sorbitan monooleate. In another embodiment of the mine, nicotinamide, nicotinic acid, 2-pyrrolidone-5-carboxy method, the additive is chosen from PEG-3 oleyl ether and lic acid, cystine, tyrosine, tryptophan, leucine, isoleucine, PEG-4 lauryl ether. In another embodiment of the method, the phenylalanine, asparagine, aspartic acid, glutamic acid, and additive is chosen from Sucrose monopalmitate. Sucrose methionine. US 2008/0175887 A1 Jul. 24, 2008

0028. In another embodiment of the method, the additive castor oil, PEG-25 trioleate, PEG-60 corn glycerides, PEG is chosen from isononylphenylpolyglycidol, PEG glyceryl 60 almond oil, PEG-40 palm kernel oil, PEG-50 castor oil, monooleate, Sorbitan monolaurate, Sorbitan monopalmitate, PEG-50 hydrogenated castor oil, PEG-8 caprylic/capric glyc Sorbitan monooleate, Sorbitan monostearate, polyglyceryl-10 erides, PEG-6 caprylic/capric glycerides, PEG-5 hydroge oleate, polyglyceryl-10 laurate, polyglyceryl-10 palmitate, nated castor oil, PEG-7 hydrogenated castor oil, PEG-9 and polyglyceryl-10 stearate. In another embodiment of the hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, method, the additive is chosen from L-ascorbic acid, thia PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, mine, maleic acids, niacinamide, and 2-pyrrolidone-5-car PEG-6 hydrogenated palm kernel oil, PEG-6 palm kernel oil, boxylic acid. In another embodiment of the method, the addi PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides, and tive is chosen from Vitamin D2 and D3. PEG-20 almond glycerides. 0029. In another embodiment of the method, the pharma 0034. In one embodiment of the pharmaceutical formula ceutical formulation comprising a drug and an additive fur tion, the additive is chosen from polyglyceryl oleate, polyg ther comprises an additional drug. In one aspect of this lyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl embodiment, the additional drug is selected from the group Stearate, polyglyceryl laurate, polyglyceryl myristate, polyg consisting of corticosteroids, anticholinergics, beta-agonists, lyceryl palmitate, and polyglyceryl linoleate, polyglyceryl non-steroidal anti-inflammatory drugs, macrollide antibiotics, 10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono, bronchodilators, leukotriene receptor inhibitors, cromolyn dioleate, polyglyceryl-10 Stearate, polyglyceryl-10 laurate, Sulfate, and combinations thereof. polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyg 0030. In one embodiment, the present invention relates to lyceryl-10 linoleate, polyglyceryl-6 Stearate, polyglyceryl-6 a pharmaceutical formulation comprising an effective laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, amount of a drug for treatment of a respiratory or sinus and polyglyceryl-6 linoleate, and polyglyceryl polyricino system, and an additive that enhances absorption of the drug leate. In another embodiment of the pharmaceutical formu into tissue of the respiratory system. In one aspect of this lation, the additive is chosen from propylene glycol mono embodiment, the additive comprises a hydrophilic part and a laurate, propylene glycol ricinoleate, propylene glycol hydrophobic part. In another aspect of this embodiment, the monooleate, propylene glycol dicaprylate/dicaprate, and pro drug is not enclosed in micelles or encapsulated in polymer pylene glycol dioctanoate. particles. In another aspect of this embodiment, the formula 0035. In one embodiment of the pharmaceutical formula tion does not include oil, a lipid, or a polymer. In yet another tion, the additive is PEG-24 cholesterol ether. In another aspect of this embodiment, the formulation is an aqueous embodiment of the pharmaceutical formulation, the additive aerosol formulation, a dry powder aerosol formulation, or a is chosen from sterol polyethylene glycol derivatives. In propellant-based formulation. another embodiment of the pharmaceutical formulation, the 0031. In one embodiment of the pharmaceutical formula additive is chosen from PEG-20 sorbitan monolaurate, PEG tion, the drug is chosen from paclitaxel and analogues thereof 20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, and rapamycin and analogues thereof. In one aspect of this and PEG-20 sorbitan monooleate. In another embodiment of embodiment, the drug is present in a concentration of about the pharmaceutical formulation, the additive is chosen from 0.05 mg/ml to about 600 mg/ml. PEG-3 oleyl ether and PEG-4 lauryl ether. 0032. In one embodiment of the pharmaceutical formula 0036. In one embodiment of the pharmaceutical formula tion, the additive is chosen from PEG-fatty acids and PEG tion, the additive is chosen from Sucrose monopalmitate, fatty acid mono and diesters, polyethylene glycol glycerol Sucrose monolaurate, decanoyl-N-methylglucamide, n-de fatty acid esters, alcohol-oil transesterification products, cyl-B-D-glucopyranoside, n-decyl-3-D-maltopyranoside, polyglyceryl fatty acids, propylene glycol fatty acid esters, n-dodecyl-3-D-glucopyranoside, n-dodecyl-B-D-maltoside, sterol and derivatives thereof, polyethylene glycol sorbitan heptanoyl-N-methylglucamide, n-heptyl-B-D-glucop-yrano fatty acid esters, polyethylene glycol alkyl ethers, Sugars and side, n-heptyl-B-D-thioglucoside, n-hexyl-B-D-glucopyra derivatives thereof, polyethylene glycol alkyl phenols, poly noside, nonanoyl-N-methylglucamide, n-noyl-B-D-glucopy oxyethylene-polyoxypropylene block copolymers, Sorbitan ranoside, octanoyl-N-methylglucamide, n-octyl-B-D- fatty acid esters, fat-soluble vitamins and salts thereof, water glucopyranoside, and octyl-B-D-thioglucopyranoside. In soluble vitamins and amphiphilic derivatives thereof, amino another embodiment of the pharmaceutical formulation, the acid and salts thereof, oligopeptides, peptides and proteins, additive is chosen from PEG-10-100 nonyl phenol, PEG-15 and organic acids and esters and anhydrides thereof. In 100 octyl phenol ether, Tyloxapol, octoxynol, and nonoxynol. another embodiment of the pharmaceutical formulation, the In another embodiment of the pharmaceutical formulation, additive is chosen from esters of lauric acid, oleic acid, and the additive is chosen from poloxamer 108, poloxamer 188, stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, poloxamer 217, poloxamer 238, poloxamer 288, poloxamer PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 lau 338, and poloxamer 407. In another embodiment of the phar rate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and maceutical formulation, the additive is chosen from poloX PEG-20 oleate. amer 124, poloxamer 182, poloxamer 183, poloxamer 212, 0033. In one embodiment of the pharmaceutical formula poloxamer 331, and poloxamer 335. tion, the additive is chosen from PEG-20 dilaurate, PEG-20 0037. In one embodiment of the pharmaceutical formula dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 tion, the additive is chosen from Sorbitan monolaurate, Sor dioleate. In another embodiment of the pharmaceutical for bitan monopalmitate, Sorbitan monooleate, and Sorbitan mulation, the additive is chosen from PEG-20 glyceryl lau monostearate. In another embodiment of the pharmaceutical rate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG formulation, the additive is chosen from alpha-tocopherol, 20 glyceryl oleate, and PEG-30 glyceryl oleate. In another beta-tocopherol, gamma-tocopherol, delta-tocopherol, toco embodiment of the pharmaceutical formulation, the additive pherol acetate, ergosterol, 1-alpha-hydroxycholecal-ciferol, is chosen from PEG-35 castor oil, PEG-40 hydrogenated Vitamin D2, Vitamin D3, alpha-carotene, beta-carotene, US 2008/0175887 A1 Jul. 24, 2008 gamma-carotene, Vitamin A, fursultiamine, methylolribofla wherein the particles comprise a water insoluble drug and an vin, octotiamine, prosultiamine, riboflavine, Vintiamol, dihy additive that enhances absorption of the drug into tissue of the drovitamin K1, menadiol diacetate, menadiol dibutyrate, respiratory system, and (2) administering the aerosol to the menadiol disulfate, menadiol, Vitamin K1, Vitamin K1 oxide, respiratory system of the mammal. In one aspect of this vitamins K2, and vitamin K S(II), and folic acid. embodiment, the additive comprises a hydrophilic part and a 0038. In another embodiment of the pharmaceutical for hydrophobic part. In another aspect of this embodiment, the mulation, the additive is chosen from acetiamine, benfo drug is not enclosed in micelles or encapsulated in polymer tiamine, pantothenic acid, cetotiamine, cyclothiamine, dex particles. In another aspect of this embodiment, the disper panthenol, niacinamide, nicotinic acid, pyridoxal sion does not include oil, a lipid, or a polymer. In another 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin aspect of this embodiment, the dispersion does not include a phosphate, thiamine, folic acid, menadiol diphosphate, purely hydrophobic additive. In another aspect of this menadione sodium bisulfite, menadoxime, vitamin B12, Vita embodiment, the dispersion does not include a dye. In another min K5, vitamin K6, vitamin K6, and vitamin U. In another aspect of this embodiment, the additive is chosen from PEG embodiment of the pharmaceutical formulation, the additive fatty acids and PEG-fatty acid mono and diesters, polyethyl is chosen from alanine, arginine, asparagines, aspartic acid, ene glycol glycerol fatty acid esters, alcohol-oil transesteri cysteine, cystine, glutamic acid, glutamine, glycine, histi fication products, polyglyceryl fatty acids, propylene glycol dine, proline, isoleucine, leucine, lysine, methionine, pheny fatty acid esters, sterol and derivatives thereof, polyethylene lalanine, serine, threonine, tryptophan, tyrosine, and valine, glycol sorbitan fatty acid esters, polyethylene glycol alkyl and salts of any of the foregoing. In another embodiment of ethers, Sugars and derivatives thereof, polyethylene glycol the pharmaceutical formulation, the additive is albumin. alkyl phenols, polyoxyethylene-polyoxypropylene block 0039. In one embodiment of the pharmaceutical formula copolymers, Sorbitan fatty acid esters, fat-soluble vitamins tion, the additive is chosen from benzalkonium chloride, and salts thereof, water-soluble vitamins and amphiphilic n-octyl-B-D-glucopyranoside, octoxynol-9, PolySorbates, derivatives thereof, amino acid and salts thereof, oligopep Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglyci tides, peptides and proteins, and organic acids and esters and dol, PEG glyceryl monooleate, sorbitan monolaurate, sorbi anhydrides thereof. In yet another aspect of this embodiment, tan monopalmitate, Sorbitan monooleate, Sorbitan the water insoluble drug is chosen from paclitaxel and ana monostearate, polyglyceryl-10 oleate, polyglyceryl-10 lau logues thereof and rapamycin and analogues thereof. rate, polyglyceryl-10 palmitate, polyglyceryl-10 Stearate, 0043. In one embodiment, the present invention relates to L-ascorbic acid, thiamine, maleic anhydride, niacinamide, anaerosol device for delivering a drug to a respiratory system, and 2-pyrrolidone-5-carboxylic acid. In another embodiment the device comprising a pharmaceutical formulation com of the pharmaceutical formulation, the additive is chosen prising a water insoluble drug and an additive, wherein the from riboflavin, riboflavin-phosphate sodium, Vitamin D3, additive enhances absorption of the drug into tissue of the folic acid, vitamin 12, diethylenetriaminepentaacetic acid respiratory system. In one aspect of this embodiment, the dianhydride, ethylenediaminetetraacetic dianhydride, maleic pharmaceutical formulation is an aqeuous, propellant based, acid and anhydride, Succinic acid and anhydride, diglycolic or dry powder formulation. In another aspect of this embodi anhydride, glutaric anhydride, L-ascorbic acid, thiamine, ment, the additive comprises a hydrophilic part and a hydro nicotinamide, nicotinic acid, 2-pyrrolidone-5-carboxylic phobic part. In another aspect of this embodiment, the drug is acid, cystine, tyrosine, tryptophan, leucine, isoleucine, phe not enclosed in micelles or encapsulated in polymer particles. nylalanine, asparagine, aspartic acid, glutamic acid, and In another aspect of this embodiment, the formulation does methionine. not include oil, a lipid, or a polymer. In another aspect of this 0040. In one embodiment of the pharmaceutical formula embodiment, the additive is chosen from PEG-fatty acids and tion, the additive is chosen fromisononylphenylpolyglycidol. PEG-fatty acid mono and diesters, polyethylene glycol glyc PEG glyceryl monooleate, sorbitan monolaurate, sorbitan erol fatty acid esters, alcohol-oil transesterification products, monopalmitate, Sorbitan monooleate, Sorbitan monostearate, polyglyceryl fatty acids, propylene glycol fatty acid esters, polyglyceryl-10 oleate, polyglyceryl-10 laurate, polyglyc sterol and derivatives thereof, polyethylene glycol sorbitan eryl-10 palmitate, and polyglyceryl-10 Stearate. In another fatty acid esters, polyethylene glycol alkyl ethers, Sugars and embodiment of the pharmaceutical formulation, the additive derivatives thereof, polyethylene glycol alkyl phenols, poly is chosen from L-ascorbic acid, thiamine, maleic acids, niaci oxyethylene-polyoxypropylene block copolymers, Sorbitan namide, and 2-pyrrolidone-5-carboxylic acid. In another fatty acid esters, fat-soluble vitamins and salts thereof, water embodiment of the pharmaceutical formulation, the additive soluble vitamins and amphiphilic derivatives thereof, amino is chosen from Vitamin D2 and D3. acid and salts thereof, oligopeptides, peptides and proteins, 0041. In one embodiment of the pharmaceutical formula and organic acids and esters and anhydrides thereof. In tion, the drug is present in a concentration of about 0.05 mg/g another aspect of this embodiment, the water insoluble drug is to about 990 mg/g. In another embodiment of the pharmaceu chosen from paclitaxel and analogues thereof and rapamycin tical formulation, the formulation further comprises an addi and analogues thereof. In yet another aspect of this embodi tional drug. In one aspect of this embodiment, the additional ment, the aerosol device is one of a nebulizer, a hand-held drug is selected from the group consisting of corticosteroids, meter dose inhaler, or a dry powder inhaler. anticholinergics, beta-agonists, non-steroidal anti-inflamma 0044. In one embodiment, the present invention relates to tory drugs, macrollide antibiotics, bronchodilators, leukot a device sized and configured for insertion into a passage of a riene receptor inhibitors, cromolyn Sulfate, and combinations respiratory system, the device comprising a layer overlying thereof. an exterior Surface of the device, the layer comprising a water 0042. In one embodiment, the present invention relates to insoluble drug for the treatment of the respiratory system and a method for treating a respiratory system in a mammal com an additive that enhances absorption of the drug into tissue of prising (1) forming an aerosol of a dispersion of particles, the respiratory system. In one aspect of this embodiment, the US 2008/0175887 A1 Jul. 24, 2008 additive comprises a hydrophilic part and a hydrophobic part. 0046. It is understood that both the foregoing general In another aspect of this embodiment, the drug is not enclosed description and the following detailed description are exem in micelles or encapsulated in polymer particles. In another plary and explanatory only and are not restrictive of the aspect of this embodiment, the layer does not include oil, a present invention as claimed. lipid, or a polymer. In another aspect of this embodiment, the DETAILED DESCRIPTION OF EXEMPLARY layer does not include a purely hydrophobic additive. In EMBODIMENTS another aspect of this embodiment, the layer does not include a dye. In another aspect of this embodiment, the device is a 0047 Embodiments of the present invention provide a balloon catheter or a stent. In another aspect of this embodi method for treatment of respiratory disorders such as asthma, chronic obstructive pulmonary disease and chronic sinusitis, ment, the water insoluble drug is chosen from paclitaxel and including cystic fibrosis, interstitial fibrosis, chronic bronchi analogues thereof and rapamycin and analogues thereof. In tis, emphysema, nasal and sinus dysplasia, bronchopulmo another aspect of this embodiment, the additive is chosen nary dysplasia and neoplasia. According to embodiments, the from PEG-fatty acids and PEG-fatty acid mono and diesters, method involves administration, preferably oral or pulmo polyethylene glycol glycerol fatty acid esters, alcohol-oil nary administration, of anti-inflammatory and anti-prolifer transesterification products, polyglyceryl fatty acids, propy ate drugs (rapamycin or paclitaxel and their analogues). lene glycol fatty acid esters, sterol and derivatives thereof, 0048. The anti-inflammatory and anti-proliferate drugs polyethylene glycol Sorbitan fatty acid esters, polyethylene intended for intranasal delivery (systemic and local) for treat glycol alkyl ethers, Sugars and derivatives thereof, polyethyl ment of respiratory disorders such as asthma, COPD and ene glycol alkyl phenols, polyoxyethylene-polyoxypropy chronic sinusitis can be, administered as aqueous solutions or Suspensions, as Solutions or Suspensions in halogenated lene block copolymers, sorbitan fatty acid esters, fat-soluble hydrocarbon propellants (pressurized metered-dose inhal Vitamins and salts thereof, water-soluble vitamins and ers), or as dry powders. Metered-dose spray pumps for aque amphiphilic derivatives thereof, amino acid and salts thereof, ous formulations, pMDIs, and DPIs for nasal delivery, are oligopeptides, peptides and proteins, and organic acids and available from, for example, Valois of America or Pfeiffer of esters and anhydrides thereof. America. 0045. In one embodiment, the present invention relates to 0049. The drugs intended for pulmonary delivery can also a method for treating a respiratory system comprising insert be administered as aqueous formulations, as Suspensions or ing a balloon catheter comprising a coating layer into an solutions in halogenated hydrocarbon propellants, or as dry airway, wherein the coating layer comprises a drug and an powders. Aqueous formulations must be aerosolized by liq uid nebulizers employing either hydraulic or ultrasonic additive, inflating the balloon catheter and releasing the drug atomization, propellant-based systems require Suitable pres to a wall of the airway, deflating the balloon; and withdrawing surized metered-dose inhalers (pMDIs), and dry powders the balloon catheter from the airway. In one aspect of this require dry powder inhaler devices (DPIs), which are capable embodiment, the additive enhances absorption of the drug of dispersing the drug Substance effectively. For aqueous and into tissue of the respiratory or sinus system. In another aspect other non-pressurized liquid systems, a variety of nebulizers of this embodiment, the additive comprises a hydrophilic part (including Small Volume nebulizers) are available to aero and a hydrophobic part. In another aspect of this embodiment, solize the formulations. Compressor-driven nebulizers incor the drug is not enclosed in micelles or encapsulated in poly porate jet technology and use compressed air to generate the mer particles. In another aspect of this embodiment, the liquidaerosol. Such devices are commercially available from, cocating layer does not include oil, a lipid, or a polymer. In for example, Healthdyne Technologies, Inc., Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.; another aspect of this embodiment, the coating layer does not Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss include a purely hydrophobic additive. In another aspect of Health Care, Inc.; and Hospitak, Inc. Ultrasonic nebulizers this embodiment, the coating layer does not include a dye. In rely on mechanical energy in the form of vibration of a piezo another aspect of this embodiment, the drug is chosen from electric crystal to generate respirable liquid droplets and are paclitaxel and analogues thereof and rapamycin and ana commercially available from, for example, Omron Health logues thereof. In another aspect of this embodiment, the care, Inc. and DeVilbiss Health Care, Inc. additive is chosen from PEG-fatty acids and PEG-fatty acid 0050 A propellant driven inhaler (pMDI) releases a mono and diesters, polyethylene glycol glycerol fatty acid metered dose of medicine upon each actuation. The medicine esters, alcohol-oil transesterification products, polyglyceryl is formulated as a suspension or solution of a drug Substance fatty acids, propylene glycol fatty acid esters, sterol and in a Suitable propellant such as a halogenated hydrocarbon. pMDIs are described in, for example, Newman, S. P., Aero derivatives thereof, polyethylene glycol sorbitan fatty acid sols and the Lung, Clarke et al., eds., pp. 197-224 (Butter esters, polyethylene glycol alkyl ethers, Sugars and deriva worths, London, England, 1984). tives thereof, polyethylene glycol alkyl phenols, polyoxyeth 0051 Dry powder inhalers (DPIs), which involve ylene-polyoxypropylene block copolymers, Sorbitan fatty deaggregation and aerosolization of dry powders, normally acid esters, fat-soluble vitamins and salts thereof, water rely upon a burst of inspired air that is drawn through the unit soluble vitamins and amphiphilic derivatives thereof, amino to deliver a drug dosage. Such devices are described in, for acid and salts thereof, oligopeptides, peptides and proteins, example, U.S. Pat. No. 4,807,814, which is directed to a and organic acids and esters and anhydrides thereof. In yet pneumatic powder ejector having a Suction stage and an injec another aspect of this embodiment, the drug can be released to tion stage; SU 628930 (Abstract), describing a hand-held the wall of the airway prior to, during, or after an asthma powder disperser having an axial air flow tube; Fox et al., attack. Powder and Bulk Engineering, pages 33-36 (March 1988), US 2008/0175887 A1 Jul. 24, 2008 describing a venturi eductor having an axial air inlet tube mg/ml up to about 600 mg/ML. Such formulations provide upstream of a venturi restriction; EP 347 779, describing a effective delivery to appropriate areas of the lung. In addition, hand-held powder disperser having a collapsible expansion the more concentrated aerosol formulations (i.e., for aqueous chamber; and U.S. Pat. No. 5,785,049 directed to dry powder aerosol formulations, about 10 mg/ml up to about 600 mg/ml) delivery devices for drugs. have the additional advantage of enabling large quantities of 0052 Droplet/particle size determines deposition site. In drug substance to be delivered to the lung in a very short developing the therapeutic aerosol of the anti-inflammatory period of time. and anti-proliferate drugs, the aerodynamic size distribution 0058 B. Dry Powder Aerosol Formulations of the inhaled particles is the single most important variable in 0059 Another embodiment of the invention is directed to defining the site of droplet or particle deposition in the dry powder aerosol formulations comprising anti-inflamma patient; in short, it will determine whether drug targeting tory and anti-proliferate drug particles for pulmonary and succeeds or fails. See P. Byron, “Aerosol Formulation, Gen nasal administration. Dry powders, which can be used in both eration, and Delivery Using Nonmetered Systems.” Respira DPIs and pMDIs, can be made by spray drying aqueous drug tory Drug Delivery, 144-151,144 (CRC Press, 1989). Thus, a dispersions. Alternatively, dry powders containing anti-in prerequisite in developing a therapeutic aerosol is a preferen flammatory and anti-proliferate drug can be made by freeze tial particle size. The deposition of inhaled aerosols involves drying drug dispersions. Combinations of spray-dried and different mechanisms for different size particles. D. Swift freeze-dried drug powders can be used in DPIs and pMDIs. (1980); Parodi et al., “Airborne Particles and Their Pulmo For dry powder aerosol formulations, the anti-inflammatory nary Deposition in Scientific Foundations of Respiratory and anti-proliferate drug may be presentata concentration of Medicine, Scaddings et al. (eds.), pp. 545-557 (W.B. Saun about 0.05 mg/g up to about 990 mg/g. ders, Philadelphia, 1981); J. Heyder, “Mechanism of Aerosol 0060) 1. Spray-Dried Powders Containing Anti-Inflam Particle Deposition.” Chest, 80:820–823 (1981). matory and Anti-Proliferate Drug 0053 Generally, inhaled particles are subject to deposi 0061 Powders comprising anti-inflammatory and anti tion by one of two mechanisms: impaction, which usually proliferate drug can be made by spray-drying aqueous dis predominates for larger particles, and sedimentation, which is persions of a drug and an additive to form a dry powder which prevalent for Smaller particles. Impaction occurs when the consists of aggregated drug particles. The aggregates can momentum of an inhaled particle is large enough that the have a size of about 1 to about 2 microns, which is suitable for particle does not follow the air stream and encounters a physi deep lung delivery. The aggregate particle size can be ological surface. In contrast, sedimentation occurs primarily increased to target alternative delivery sites, such as the upper in the deep lung when very small particles which have trav bronchial region or nasal mucosa by increasing the concen eled with the inhaled air stream encounter physiological Sur tration of drug in the spray-dried dispersion or by increasing faces as a result of random diffusion within the air stream. For the droplet size generated by the spray dryer. intranasally administered drug compounds which are inhaled 0062 Alternatively, the aqueous dispersion of the anti through the nose, it is desirable for the drug to impact directly inflammatory and anti-proliferate drug and additive can con on the nasal mucosa; thus, large (ca. 5 to 100 microns) par tain a dissolved diluent such as lactose or mannitol which, ticles or droplets are generally preferred for targeting of nasal when spray dried, forms respirable diluent particles, each of delivery. which contains at least one embedded drug particle and addi 0054 Pulmonary drug delivery of the anti-inflammatory tive. The diluent particles with embedded drug can have a and anti-proliferative drugs is accomplished by inhalation of particle size of about 1 to about 2 microns, suitable for deep an aerosol through the mouth and throat. Particles having lung delivery. In addition, the diluent particle size can be aerodynamic diameters of greater than about 5 microns gen increased to target alternate delivery sites, such as the upper erally do not reach the lung; instead, they tend to impact the bronchial region or nasal mucosa by increasing the concen back of the throat and are swallowed and possibly orally tration of dissolved diluent in the aqueous dispersion prior to absorbed. Particles having diameters of about 2 to about 5 spray drying, or by increasing the droplet size generated by microns are small enough to reach the upper- to mid-pulmo the spray dryer. nary region (conducting airways), but are too large to reach 0063 Spray-dried powders can be used in DPIs orpMDIs, the alveoli. Even smaller particles, i.e., about 0.5 to about 2 either alone or combined with freeze-dried particulate pow microns, are capable of reaching the alveolar region. Particles der. In addition, spray-dried powders containing drug par having diameters Smaller than about 0.5 microns can also be ticles can be reconstituted and used in either jet or ultrasonic deposited in the alveolar region by sedimentation, although nebulizers to generate aqueous dispersions having respirable very small particles may be exhaled. droplet sizes, where each droplet contains at least one drug 0055 Embodiments of the present invention are directed particle. Concentrated particulate dispersions may also be to aqueous, propellant-based, and dry powder aerosols of used in these aspects of the invention. anti-inflammatory and anti-proliferate drug compositions, for 0064. 2. Freeze-Dried Powders Containing Anti-Inflam pulmonary delivery, in which essentially every inhaled par matory and Anti-Proliferative Particulate Drug ticle contains at least one anti-inflammatory and anti-prolif 0065. The particulate drug dispersions can also be freeze erate drug particle. The drug is highly water-insoluble. Pref dried to obtain powders suitable for nasal or pulmonary deliv erably, the anti-inflammatory and anti-proliferate drug has an ery. Such powders may contain aggregated particulate drug effective average particle size of about 5 micron or less. particles having an additive. Such aggregates may have sizes 0056 A. Aqueous Aerosol Formulations within a respirable range, i.e., about 2 to about 5 microns. 0057 Embodiments of the present invention encompass 0.066 Freeze dried powders of the appropriate particle size aqueous formulations containing drug particles. For aqueous can also be obtained by freeze drying aqueous dispersions of aerosol formulations, the anti-inflammatory and anti-prolif the anti-inflammatory and anti-proliferative drug and addi erate drug may be present at a concentration of about 0.05 tive, which additionally contain a dissolved diluent such as US 2008/0175887 A1 Jul. 24, 2008

lactose or mannitol. In these instances the freeze dried pow 0074 E. Methods of Using Particulate Aerosol Formula ders consist of respirable particles of diluent, each of which tions contains at least one embedded drug particle. 0075. In yet another aspect of the invention, there is pro 0067 Freeze-dried powders can be used in DPIs or vided a method of treating asthma and COPD of mammals pMDIs, either alone or combined with spray-dried particulate comprising: (1) forming an aerosol of a dispersion (either powder. In addition, freeze-dried powders containing drug aqueous or powder) of the anti-inflammatory and anti-prolif erate drug particles, wherein the particles comprise an particles can be reconstituted and used in either jet or ultra insoluble drug having an additive on the Surface thereof, and Sonic nebulizers to generate aqueous dispersions having (2) administering the aerosol to the pulmonary or nasal cavi respirable droplet sizes, where each droplet contains at least ties of the mammal. Concentrated aerosol formulations may one drug particle. Concentrated particulate dispersions may also be used in Such methods. also be used in these aspects of the invention. 0076 Drugs and Drug Combinations 0068 C. Propellant-Based Formulations 0077. The therapeutic drug or agent in the invention com 0069. Yet another embodiment of the invention is directed prises one or more drugs or agents selected from the group to a process and composition for propellant-based systems consisting of an anti-thrombosis agent, an anti-proliferate comprising anti-inflammatory and anti-proliferative drug agent, an anti-inflammatory agent, an anti-coagulant, an particles and an additive. Such formulations may be prepared agent affecting extra cellular matrix production and organi by wet milling the coarse drug Substance and additive in Zation, and a vasodilating agent. liquid propellant, either at ambient pressure or under high 0078 Examples of the therapeutic agents or drugs that are pressure conditions. Alternatively, dry powders containing suitable for use in accordance with the present invention drug particles may be prepared by spray-drying or freeze include sirolimus, everolimus, actinomycin D (ActD), taxol. drying aqueous dispersions of drug particles and the resultant paclitaxel, or derivatives and analogs thereof. Examples of powders dispersed into Suitable propellants for use in con agents include other antiproliferative Substances as well as ventional pMDIs. Such particulate pMDI formulations can be antineoplastic, antiinflammatory, antiplatelet, anticoagulant, used for either nasal or pulmonary delivery. For pulmonary antifibrin, antithrombin, antimitotic, antibiotic, and antioxi dant Substances. Examples of antineoplastics include taxol administration, Such formulations afford increased delivery (paclitaxel and docetaxel). Further examples of therapeutic to the deep lung regions because of the Small (i.e., about 1 to drugs or agents include antiplatelets, anticoagulants, antifi about 2 microns) particle sizes available from these methods. brins, antiinflammatories, antithrombins, and antiprolifera Concentrated aerosol formulations can also be employed in tives. Examples of antiplatelets, anticoagulants, antifibrins, pMDIs. and antithrombins include, but are not limited to, sodium 0070) D. Methods of Making Aerosol Formulations heparin, low molecular weight heparin, hirudin, argatroban, 0071. In embodiments, the invention also provides meth forskolin, vapiprost, prostacyclin and prostacyclin analogs, ods for making an aerosol of anti-inflammatory and anti dextran, D-phe-pro-arg-chloromethylketone (synthetic anti proliferate drug particulate compositions. The particulate dis thrombin), dipyridamole, glycoprotein IIb/IIIa platelet mem persions used in making aqueous aerosol compositions can be brane receptor antagonist, recombinant hirudin, thrombin made by wet milling or by precipitation methods known in the inhibitor (available from Biogen located in Cambridge, art. Dry powders containing the drug particles can be made by Mass.), and 7E-3B.RTM. (An antiplatelet drug from Cento spray-drying or freeze-drying aqueous dispersions of the cor located in Malvern, Pa.). Examples of antimitotic agents anti-inflammatory and anti-proliferate drug particles. The include methotrexate, azathioprine, Vincristine, vinblastine, fluorouracil, adriamycin, and mutamycin. Examples of cyto dispersions used in these systems may or may not contain static orantiproliferative agents include angiopeptin (a Soma dissolved diluent material prior to drying. Additionally, both to statin analog from Ibsen located in the United Kingdom), pressurized and non-pressurized milling operations can be angiotensin converting enzyme inhibitors such as Captopril. employed to make particulate drug compositions in non RTM. (available from Squibb located in New York, N.Y.), aqueous Systems. Cilazapril.RTM. (available from Hoffman-LaRoche located 0072. In a non-aqueous, non-pressurized milling system, a in Basel, Switzerland), or Lisinopril.RTM. (available from non-aqueous liquid which has a vapor pressure of 1 atm or Merck located in Whitehouse Station, N.J.); calcium channel less at room temperature is used as a milling medium and may blockers (such as Nifedipine), colchicine, fibroblast growth be evaporated to yield dry particulate drug and additive. The factor (FGF) antagonists, fish oil (omega 3-fatty acid), hista non-aqueous liquid may be, for example, a high-boiling halo mine antagonists, Lovastatin. RTM. (an inhibitor of HMG genated hydrocarbon. The dry particulate drug composition CoA reductase, a cholesterol lowering drug from Merck), thus produced may then be mixed with a suitable propellantor methotrexate, monoclonal antibodies (such as PDGF recep propellants and used in a conventional pMDI. tors), nitroprusside, phosphodiesterase inhibitors, prostag 0073. Alternatively, in a pressurized milling operation, a landin inhibitor (available from GlaxoSmithKline located in non-aqueous liquid which has a vapor pressure >1 atm at United Kingdom), Seramin (a PDGF antagonist), serotonin room temperature is used as a milling medium for making a blockers, steroids, thioprotease inhibitors, triazolopyrimidine particulate drug and additive composition. Such a liquid may (a PDGF antagonist), and nitric oxide. Other therapeutic be, for example, a halogenated hydrocarbon propellant which drugs or agents which may be appropriate include alpha has a low boiling point. The resultant particulate composition interferon, genetically engineered epithelial cells, and dex can then be used in a conventional pMDI without further amethasone. modification, or can be blended with other suitable propel 0079 An anti-thrombosis agent, an anti-proliferate agent, lants. Concentrated aerosols may also be made via Such meth an anti-inflammatory agent, especially rapamycin or pacli ods. taxel and their analogues, as discussed above, can be used in US 2008/0175887 A1 Jul. 24, 2008

combination with other drugs, such as inhaled corticoster compound includes polar or charged hydrophilic moieties as oids, inhaled anticholinergics Such as ipratropium and beta well as non-polar hydrophobic (lipophilic) moieties. agonists such as albuterol, inhaled leukotriene inhibitors, and I0087 An empirical parameter commonly used in medici inhaled epinephrine. nal chemistry to characterize the relative hydrophilicity and 0080 Some drugs that are considered particularly suitable hydrophobicity of pharmaceutical compounds is the partition for the combination are inhaled corticosteroids such as, coefficient, P, the ratio of concentrations of unionized com Budesonide, Flunisolide, Triamcinolone, Beclomethasone, pound in the two phases of a mixture of two immiscible Fluticasone, MometaSone, Dexamethasone, Hydrocortisone, solvents, usually octanol and water, such that P=(solute Methylprednisolone, Prednisone, Cotisone, Betamethasone, octanol/solute water). Compounds with higher log PS are or the like. Some other suitable drugs are bronchodilators more hydrophobic, while compounds with lower log Ps are such as Terbutaline, Albuterol, Ipratropium, Pirbuterol, Epi more hydrophilic. Lipinski's rule Suggests that pharmaceuti nephrine, Salmeterol, Levalbuterol, Formoterol, or the like. cal compounds having log P-5 are typically more membrane 0081. Other drugs that are also considered to be suitably permeable. While a compound's octanol-waterpartition coef administered in the combinations include, but are not limited ficient P or log P is useful as a measurement of relative to, Leukotriene inhibitors such as Montelukast, Zafirlukast, hydrophilicity and hydrophobicity, it is merely a rough guide Zileuton, or the like; antihistamines such as Loratadine, Ceti that may be useful in defining suitable additives for use in rizine or the like: Anti-Tuberculosis drugs for MTB or atypi embodiments of the present invention. cal mycobacteria Such as, Isoniazid, Ethambutol, PyraZina 0088 Suitable additives that can be used in embodiments mide, Rifamycin; Rifampin, Streptomycin, Clarithromycin, of the present invention include, without limitation, organic or the like; other drugs; such as the Serine lung protease and inorganic pharmaceutical recipients, natural products inhibitors Azelastine, and Theophylline; and other peptides, and their derivatives (such as Sugars, vitamins, amino acids, Such as those that relate to Allergy Immunotherapy for indoor peptides, proteins, fatty acids), low molecular weight oligo and outdoor allergens, or the like. Additionally, amikacin, mers, Surfactants (anionic, cationic, non-ionic, and ionic), gentamicin, tobramicin, rifabutin, rifapentine, sparfloxacin, and mixtures thereof. The following detailed list of additives ciprofloxacin, quinolones, azithromycin, erythromycin, iso useful in the present invention is provided for exemplary niazid, or the like, can be considered to be useful. purposes only and is not intended to be comprehensive. Many 0082. According to embodiments of the invention pre other additives may be useful for purposes of the present ferred, fagonists in the combinations according to the inven invention. tion are selected from the group consisting of albuterol, bam 0089. Surfactants buterol, bitolterol, broXaterol, carbuterol, clenbuterol, 0090 The surfactant can be any surfactant suitable for use fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, in pharmaceutical compositions. Such surfactants can be isoprenaline, levosalbutamol, mabuterol, meluadrine, metap anionic, cationic, Zwitterionic or non-ionic. Mixtures of Sur roterenol, orciprenaline, pirbuterol, procaterol, reproterol, factants are also within the scope of the invention, as are TD 3327, ritodrine, salmeterol, salmefamol, soterenot, sul combinations of surfactant and other additives. The surfac phonterol, tiaramide, terbutaline, and tolubuterol. tants often have one or more long aliphatic chains such as 0083. Additive fatty acids. They insert directly into the lipid structures to 0084. The additive of the present invention has two parts. form part of the lipid structure of the cells, and the other One part is hydrophilic and the other part is hydrophobic or structure parts of the Surfactants results in loosening the lipid lipophilic. The hydrophobic or lipophilic part of the additive structure to enhance the drug penetration and absorption. The may bind the lipophilic drug, Such as rapamycin or paclitaxel. iopromide will not do the same. The hydrophilic portion accelerates diffusion and increases 0091 An empirical parameter commonly used to charac permeation of the drug into tissue. It may facilitate rapid terize the relative hydrophilicity and hydrophobicity of Sur movement of drug off the medical device during deployment factants is the hydrophilic-lipophilic balance (“HLB' value). and into interstitial space and through polar headgroups to the Surfactants with lower HLB values are more hydrophobic, lipid bilayer of cell membranes of target tissues. and have greater solubility in oils, while surfactants with 0085. The additive has a lipophilic or hydrophobic part higher HLB values are more hydrophilic, and have greater and a hydrophilic part. The hydrophobic part may include solubility in aqueous solutions. Using HLB values as a rough aliphatic and aromatic organic hydrocarbon compounds, guide, hydrophilic Surfactants are generally considered to be Such as benzene, toluene, and alkanes, among others. These those compounds having an HLB value greater than about 10, parts are not water soluble. They have no covalently bonded as well as anionic, cationic, or Zwitterionic compounds for iodine. The hydrophilic part may include hydroxyl groups, which the HLB scale is not generally applicable. Similarly, amine groups, amide groups, carbonyl groups, carboxylic hydrophobic Surfactants are compounds having an HLB acid and anhydrides, ethyl oxide, ethylglycol, polyethylene value less than about 10. glycol, ascorbic acid, amino acid, amino alcohol, glucose, 0092. It should be understood that the HLB value of a Sucrose, Sorbitan, glycerol, polyalcohol, phosphates, Sulfates, Surfactant is merely a rough guide generally used to enable organic salts and their Substituted molecules, among others. formulation of industrial, pharmaceutical and cosmetic emul These parts can dissolve in water and polar solvents. These sions, for example. For many important Surfactants, including additives are not oils, lipids, or polymers. The therapeutic several polyethoxylated surfactants, it has been reported that agent is not enclosed in micelles or liposomes or encapsulated HLB values can differ by as much as about 8 HLB units, in polymer particles. depending upon the empirical method chosen to determine I0086. As is well known in the art, the terms “hydrophilic' the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 and “hydrophobic' are relative terms. To function as an addi (1990)). Keeping these inherent difficulties in mind, and tive in exemplary embodiments of the present invention, the using HLB values as a guide, Surfactants may be identified US 2008/0175887 A1 Jul. 24, 2008 that have suitable hydrophilicity or hydrophobicity for use in phobic surfactants include polyglyceryl oleate (Plurol Ole embodiments of the present invention, as described herein. ique), polyglyceryl-2 dioleate (Nikkol DGDO), polyglyc 0093 PEG-Fatty Acids and PEG-Fatty Acid Mono and eryl-10 trioleate, polyglyceryl Stearate, polyglyceryl laurate, Diesters polyglyceryl myristate, polyglyceryl palmitate, and polyg 0094. Although polyethylene glycol (PEG) itself does not lyceryl linoleate. Preferred hydrophilic surfactants include function as a surfactant, a variety of PEG-fatty acid esters polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyc have useful surfactant properties. Among the PEG-fatty acid eryl-10 oleate (Nikkol Decaglyn 1-0), and polyglyceryl-10 monoesters, esters of lauric acid, oleic acid, and Stearic acid mono, dioleate (Caprol.RTM. PEG 860), polyglyceryl-10 are most useful in embodiments of the present invention. Stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, Preferred hydrophilic surfactants include PEG-8 laurate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyg PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, lyceryl-6 Stearate, polyglyceryl-6 laurate, polyglyceryl-6 PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 ole myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 ate, PEG-20 laurate and PEG-20 oleate. The HLB values are linoleate. Polyglyceryl polyricinoleates (Polymuls) are also in the range of 4-20. preferred surfactants. 0095 Polyethylene glycol fatty acid diesters are also suit (0103 Propylene Glycol Fatty Acid Esters able for use as Surfactants in the compositions of embodi 0104 Esters of propylene glycol and fatty acids are suit ments of the present invention. Most preferred hydrophilic able surfactants for use in embodiments of the present inven surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG tion. In this Surfactant class, preferred hydrophobic Surfac 20 distearate, PEG-32 dilaurate and PEG-32 dioleate. The tants include propylene glycol monolaurate (Lauroglycol HLB values are in the range of 5-15. FCC), propylene glycol ricinoleate (Propymuls), propylene 0096. In general, mixtures of surfactants are also useful in glycol monooleate (My verol P-06), propylene glycol dica embodiments of the present invention, including mixtures of prylate/dicaprate (Captex.RTM. 200), and propylene glycol two or more commercial Surfactants as well as mixtures of dioctanoate (Captex.RTM. 800). surfactants with another additive or additives. Several PEG 0105 Sterol and Sterol Derivatives fatty acid esters are marketed commercially as mixtures or 0106 Sterols and derivatives of sterols are suitable surfac mono- and diesters. tants for use in embodiments of the present invention. Pre 0097 Polyethylene Glycol Glycerol Fatty Acid Esters ferred derivatives include the polyethylene glycol derivatives. 0098 Preferred hydrophilic surfactants are PEG-20 glyc A preferred surfactant in this class is PEG-24 cholesterol eryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl lau ether (Solulan C-24). rate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. 0107 Polyethylene Glycol Sorbitan Fatty Acid Esters 0099 Alcohol-Oil Transesterification Products 0108) A variety of PEG-sorbitan fatty acid esters are avail 0100. A large number of surfactants of different degrees of able and are suitable for use as surfactants in embodiments of hydrophobicity or hydrophilicity can be prepared by reaction the present invention. Among the PEG-sorbitan fatty acid of alcohols or polyalcohol with a variety of natural and/or esters, preferred surfactants include PEG-20 sorbitan mono hydrogenated oils. Most commonly, the oils used are castor laurate (Tween-20), PEG-20 sorbitan monopalmitate oil or hydrogenated castor oil, or an edible vegetable oil Such (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and as corn oil, olive oil, peanut oil, palm kernel oil, apricotkernel PEG-20 sorbitan monooleate (Tween-80). oil, or almond oil. Preferred alcohols include glycerol, pro 0109 Polyethylene Glycol Alkyl Ethers pylene glycol, ethylene glycol, polyethylene glycol, Sorbitol, 0110 Ethers of polyethylene glycol and alkyl alcohols are and pentaerythritol. Among these alcohol-oil transesterified suitable surfactants for use in embodiments of the present surfactants, preferred hydrophilic surfactants are PEG-35 invention. Preferred ethers include PEG-3 oleyl ether (Volpo castor oil (Incrocas-35), PEG-40 hydrogenated castor oil 3) and PEG-4 lauryl ether (Brij 30). (Cremophor RH 40), PEG-25 trioleate (TAGAT.RTM. TO), 0111 Sugar and its Derivatives PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil 0112 Sugar derivatives are suitable surfactants for use in (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG embodiments of the present invention. Preferred surfactants 50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil in this class include Sucrose monopalmitate. Sucrose mono (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labra laurate, decanoyl-N-methylglucamide, n-decyl-B-D-glu sol), and PEG-6 caprylic/capric glycerides (Softigen 767). copyranoside, n-decyl-B-D-maltopyranoside, n-dodecyl-B- Preferred hydrophobic surfactants in this class include PEG-5 D-glucopyranoside, n-dodecyl-B-D-maltoside, heptanoyl-N- hydrogenated castor oil, PEG-7 hydrogenated castor oil, methylglucamide, n-heptyl-B-D-glucopyranoside, n-heptyl PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil. B-D-thioglucoside, n-hexyl-B-D-glucopyranoside, RTM. M. 2125 CS), PEG-6 almond oil (Labrafil.RTM. M nonanoyl-N-methylglucamide, n-nonyl-B-D-glucopyrano 1966 CS), PEG-6 apricot kernel oil (Labrafil.RTM. M. 1944 side, octanoyl-N-methylglucamide, n-octyl-B-D-glucopyra CS), PEG-6 olive oil (Labrafil.RTM. M. 1980 CS), PEG-6 noside, and octyl-B-D-thioglucopyranoside. peanut oil (Labrafil.RTM. M. 1969 CS), PEG-6 hydrogenated 0113 Polyethylene Glycol Alkyl Phenols palm kernel oil (Labrafil.RTM. M. 2130 BS), PEG-6 palm 0114 Several PEG-alkyl phenol surfactants are available, kernel oil (Labrafil.RTM. M. 2130 CS), PEG-6 triolein (La such as PEG-10-100 nonyl phenol and PEG-15-100 octyl brafil.RTM.b M 2735 CS), PEG-8 corn oil (Labrafil.RTM. phenol ether, Tyloxapol, octoxynol, nonoxynol, and are Suit WL 2609 BS), PEG-20 corn glycerides (Crovol M40), and able for use in embodiments of the present invention. PEG-20 almond glycerides (Crovol A40). 0115 Polyoxyethylene-Polyoxypropylene (POE-POP) 0101 Polyglyceryl Fatty Acids Block Copolymers 0102 Polyglycerol esters of fatty acids are also suitable 0116. The POE-POP block copolymers are a unique class Surfactants for use in embodiments of the present invention. of polymeric Surfactants. The unique structure of the Surfac Among the polyglyceryl fatty acid esters, preferred hydro tants, with hydrophilic POE and hydrophobic POP moieties US 2008/0175887 A1 Jul. 24, 2008 in well-defined ratios and positions, provides a wide variety pherol, tocopherol acetate, ergosterol, 1-alpha-hydroxyc of surfactants suitable for use in embodiments of the present holecal-ciferol, vitamin D2, vitamin D3, alpha-carotene, invention. These surfactants are available under various trade beta-carotene, gamma-carotene, Vitamin A, fursultiamine, names, including Symperonic PE series (ICI); Pluronic.RTM. methylolriboflavin, octotiamine, prosultiamine, riboflavine, series (BASF), Emkalyx, Lutrol (BASF), Supronic, Mono Vintiamol, dihydroVitamin K1, menadiol diacetate, menadiol lan, Pluracare, and Plurodac. The generic term for these poly dibutyrate, menadiol disulfate, menadiol, Vitamin K1, Vita mers is “poloxamer' (CAS 9003-11-6). These polymers have min K1 oxide, vitamins K2, and vitamin K—S(II). Folic acid the formula: HO(CHO)(CHO)(CHO)H where “a is also of this type, and although it is water-soluble at physi and “b' denote the number of polyoxyethylene and polyox ological pH, it can be formulated in the free acid form. Other ypropylene units, respectively. derivatives of fat-soluble vitamins useful in embodiments of 0117 Preferred hydrophilic surfactants of this class include Poloxamers 108, 188, 217, 238,288,338, and 407. the present invention may easily be obtained via well known Preferred hydrophobic surfactants in this class include Polox chemical reactions with hydrophilic molecules. amers 124, 182, 183,212, 331, and 335. 0.126 Water-Soluble Vitamins and their Amphiphilic 0118 Sorbitan Fatty Acid Esters Derivatives 0119 Sorbitan esters offatty acids are suitable surfactants I0127 Vitamins B, C, U. pantothenic acid, folic acid, and for use in embodiments of the present invention. Among these Some of the menadione-related vitamins/provitamins in many esters, preferred hydrophobic surfactants include sorbitan of their various forms are considered water-soluble vitamins. monolaurate (Arlacel 20), Sorbitan monopalmitate (Span These may also be conjugated or complexed with hydropho 40), sorbitan monooleate (Span-80), sorbitan monostearate. bic moieties or multivalent ions into amphiphilic forms hav 0120. The sorbitan monopalmitate, an amphiphilic deriva ing relatively high octanol-water partition coefficients and tive of Vitamin C (which has Vitamin C activity), can serve polar groups. Again, such compounds can be of low toxicity two important functions in Solubilization systems. First, it and high benefit to risk ratio, making them useful as additives possesses effective polar groups that can modulate the in embodiments of the present invention. Salts of these can microenvironment. These polar groups are the same groups also be useful as additives in the present invention. Examples that make vitamin C itself (ascorbic acid) one of the most water-soluble organic Solid compounds available: ascorbic of water-soluble vitamins and derivatives include, without acid is soluble to about 30 wit/wt % in water (very close to the limitation, acetiamine, benfotiamine, pantothenic acid, ceto solubility of sodium chloride, for example). And second, tiamine, cyclothiamine, dexpanthenol, niacinamide, nico when the pH increases so as to convert a fraction of the tinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, ascorbyl palmitate to a more soluble salt, such as sodium riboflavin, riboflavin phosphate, thiamine, folic acid, mena ascorbyl palmitate. diol diphosphate, menadione sodium bisulfite, menadoxime, 0121 Ionic Surfactants vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vita 0122 Ionic Surfactants, including cationic, anionic and min U. Also, as mentioned above, folic acidis, over a wide pH Zwitterionic Surfactants, are suitable hydrophilic Surfactants range including physiological pH, water-soluble, as a salt. for use in embodiments of the present invention. Preferred I0128 Compounds in which an amino or other basic group ionic Surfactants include quaternary ammonium salts, fatty is present can easily be modified by simple acid-base reaction acid salts and bile salts. Specifically, preferred ionic surfac with a hydrophobic group-containing acid such as a fatty acid tants include benzalkonium chloride, benzethonium chloride, (especially lauric, oleic, myristic, palmitic, Stearic, or 2-eth cetylpyridinium chloride, docecyl trimethyl ammonium bro ylhexanoic acid), low-solubility amino acid, benzoic acid, mide, Sodium docecylsulfates, dialkyl methylbenzyl ammo salicylic acid, or an acidic fat-soluble vitamin (such as ribo nium chloride, edrophonium chloride, domiphen bromide, flavin). Other compounds might be obtained by reacting Such dialkylesters of Sodium sulfonsuccinic acid, Sodium dioctyl an acid with another group on the vitamin Such as a hydroxyl SulfoSuccinate, sodium cholate, and sodium taurocholate. group to form a linkage Such as an ester linkage, etc. Deriva These quaternary ammonium salts are preferred additives. tives of a water-soluble vitamin containing an acidic group They can be dissolved in both organic solvents (such as etha can be generated in reactions with a hydrophobic group nol, acetone, and toluene) and water. This is especially useful containing reactant Such as Stearylamine or riboflavine, for for medical device coatings because it simplifies the prepa example, to create a compound that is useful in embodiments ration and coating process and has good adhesive properties. of the present invention. The linkage of a palmitate chain to Water insoluble drugs are commonly dissolved in organic vitamin C yields ascorbyl palmitate. Solvents. 0129. Amino Acids and Their Salts (0123 Fat-Soluble Vitamins and Salts. Thereof 0.130 Alanine, arginine, asparagines, aspartic acid, cys 0.124 Vitamins A, D, E and K in many of their various teine, cystine, glutamic acid, glutamine, glycine, histidine, forms and provitamin forms are considered as fat-soluble proline, isoleucine, leucine, lysine, methionine, phenylala Vitamins and in addition to these a number of other vitamins nine, serine, threonine, tryptophan, tyrosine, Valine, and their and vitamin Sources or close relatives are also fat-soluble and derivatives are other useful additives in embodiments of the have polar groups, and relatively high octanol-water partition invention. coefficients. Clearly, the general class of such compounds has 0131 Certain amino acids, in their Zwitterionic form and/ a history of safe use and high benefit to risk ratio, making or in a salt form with a monovalent or multivalention, have them useful as additives in embodiments of the present inven polar groups, relatively high octanol-water partition coeffi tion. cients, and are useful in embodiments of the present inven 0.125. The following examples of fat-soluble vitamin tion. In the context of the present disclosure we take “low derivatives and/or sources are also useful as additives: Alpha solubility amino acid' to mean an amino acid which has tocopherol, beta-tocopherol, gamma-tocopherol, delta-toco solubility in unbuffered water of less than about 4% (40 US 2008/0175887 A1 Jul. 24, 2008 mg/ml). These include Cystine, tyrosine, tryptophan, leucine, in the coating solution, and the polar groups of alcohols and isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acids accelerate drug permeation of tissue. acid, and methionine. 0.141. Other preferred additives that may be useful in 0132 Amino acid dimers, Sugar-conjugates, and other embodiments of the present invention include riboflavin, derivatives are also useful, such as dopamine hydrochloride, riboflavin-phosphate sodium, Vitamin D3, folic acid (vitamin DOPA, LOVADOPA, and carbidopa. Through simple reac B9), vitamin 12, diethylenetriaminepentaacetic acid dianhy tions well known in the art hydrophilic molecules may be dride, ethylenediaminetetraacetic dianhydride, maleic acid joined to hydrophobic amino acids, or hydrophobic mol and anhydride, Succinic acid and anhydride, diglycolic anhy ecules to hydrophilic amino acids, to make additional addi dride, glutaric anhydride, L-ascorbic acid, thiamine, nicoti tives useful in embodiments of the present invention. namide, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, cys 0.133 Oligopeptides, Peptides and Proteins tine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, 0134 Oligopeptides and peptides are useful as additives, asparagine, aspartic acid, glutamic acid, and methionine. since hydrophobic and hydrophilic amino acids may be easily These additives are often compatible with water insoluble coupled and various sequences of amino acids may be tested drugs (such as paclitaxel and rapamycin) from structure point to maximally facilitate permeation of tissue by drug. of view. They often contain double bonds such as C—C, 0135 Proteins are also useful as additives in embodiments C—N, C=O in aromatic or aliphatic structure. They also of the present invention. Serum albumin, for example, is a contains amine, alcohol, ester, amide, anhydride, carboxylic particularly preferred additive since it is water soluble and acid, and hydroxyl group on their structure. Those molecules contains significant hydrophobic parts to bind drug: pacli containing multiple hydroxyl groups are especially useful. taxel is 89% to 98% protein-bound after human intravenous They can have good affinity to vessel wall. These molecules infusion, and rapamycin is 92% protein bound, primarily are polyglyceryl fatty esters, ascorbic ester of fatty acids, (97%) to albumin. Furthermore, paclitaxel solubility in PBS Sugar ester, alcohol and ether of fatty acids. The fatty chains increases over 20-fold with the addition of BSA. Albumin is can insert into the lipid structure to form part of the lipid structure. Some of the aminoacids, vitamins and organic acids naturally present at high concentrations in serum and is thus have aromatic C=N. amino, hydroxyl, and carboxylic group very safe for human intravascular use. on their structure. These structure can bind or complex with 0136. Other useful proteins include, without limitation, paclitaxel or rapamycin. They are very compatible with pacli other albumins, immunoglobulins, caseins, hemoglobins, taxel and rapamycin because of the similar structure. They lysozymes, immunoglobins, a-2-macroglobulin, fibronec can penetrate into tissue to loosen lipid structure of the cells. tins, vitronectins, firbinogens, lipases, and the like. 0.142 For example, isononylphenylpolyglycidol (Olin-10 0.137 Organic Acids and Their Esters and Anhydrides G and Surfactant-10G), PEG glyceryl monooleate, sorbitan 0138 Examples are acetic acid and anhydride, benzoic monolaurate (Arlacel 20), Sorbitan monopalmitate (Span acid and anhydride, acetylsalicylic acid, diflunisal, 2-hy 40), sorbitan monooleate (Span-80), sorbitan monostearate, droxyethyl salicylate, diethylenetriaminepentaacetic acid polyglyceryl-10 oleate, polyglyceryl-10 laurate, polyglyc dianhydride, ethylenediaminetetraacetic dianhydride, maleic eryl-10 palmitate, and polyglyceryl-10 Stearate, these mol acid and anhydride, Succinic acid and anhydride, diglycolic ecules have more than four hydroxyl groups in their hydro anhydride, glutaric anhydride, ascorbic acid, citric acid, tar philic part. These hydroxyl groups have very good affinity to taric acid, lactic acid, oxalic acid aspartic acid, nicotinic acid, the vessel wall. At the same time they have long chain offatty 2-pyrrolidone-5-carboxylic acid, and 2-pyrrolidone. acid, alcohol, ether and ester they can insert into the lipid 0.139. These esters and anhydrides are soluble in organic structure of the cells to form the part of the lipid structure. Solvents such as ethanol, acetone, methylethylketone, ethy This results in the deformed or loosen lipid structure, leading lacetate. The water insoluble drugs can be dissolved in to drug absorption and penetration in the tissue. organic solvent with these esters and anhydrides, then coated 0.143 For another example, L-ascorbic acid, thiamine, easily on to the medical device, then hydrolyzed under high maleic acids, niacinamide, and 2-pyrrolidone-5-carboxylic pH conditions. The hydrolyzed anhydrides or esters are acids acid, these molecules have a very high water and ethanol or alcohols, which are water soluble and can effectively carry solubility, a low molecular weight and small size; therefore the drugs off the device into the vessel walls. they can penetrate into the tissue easily. They also have the 0140 Preferred additives include benzalkonium chloride, chemical structure of aromatic C=N. amino, hydroxyl, and n-octyl-f-D-glucopyranoside, octoxynol-9 (Triton X-100), carboxylic groups. These structures have very good compat Polysorbates (such as 20, 21, 40, 60, 80 and 81), Tyloxapol, ibility with paclitaxel and rapamycin. They can increase the octoxynol, nonoxynol, isononylphenylpolyglycidol (Olin-10 solubility of the water-insoluble drugs in water. These will G and Surfactant-10G), PEG glyceryl monooleate, sorbitan enhance the absorption of the drug in the tissues. monolaurate (Arlacel 20), Sorbitan monopalmitate (Span 0144 Representative examples of additives include cetyl 40), sorbitan monooleate (Span-80), sorbitan monostearate, pyridinium chloride, gelatin, casein, lecithin (phosphatides), polyglyceryl-10 oleate, polyglyceryl-10 laurate, polyglyc dextran, glycerol, gum acacia, cholesterol, tragacanth, Stearic eryl-10 palmitate, polyglyceryl-10 Stearate, L-ascorbic acid, acid, benzalkonium chloride, calcium Stearate, glycerol thiamine, maleic anhydride, niacinamide, 2-pyrrolidone-5- monostearate, cetostearyl alcohol, cetomacrogolemulsifying carboxylic acid, and the like. These additives are both water wax, Sorbitan esters, polyoxyethylene alkyl ethers (e.g., mac soluble and organic solvent soluble. They have good adhesive rogol ethers such as cetomacrogol 1000), polyoxyethylene properties and adhere to the Surface of polyamide medical castor oil derivatives, polyoxyethylene sorbitan fatty acid devices, such as balloon catheters. They may therefore be esters (e.g., the commercially available Tweens. RTM. Such as used in both the adherent layer and in the drug layer of e.g., Tween 20.RTM. and Tween 80.RTM. (ICI Specialty embodiments of the present invention. The aromatic and ali Chemicals); polyethylene glycols (e.g., Carbowaxs 3350. phatic groups increase the solubility of water insoluble drugs RTM. and 1450.RTM., and Carbopol 934.RTM. (Union Car US 2008/0175887 A1 Jul. 24, 2008 bide)), dodecyl trimethyl ammonium bromide, polyoxyeth substituted with two or three additional hydrophilic groups. ylene Stearates, colloidal silicon dioxide, phosphates, sodium In the case of biliary contrast agents (compounds that are dodecylsulfate, carboxymethylcellulose calcium, hydrox taken up by the liver and excreted mainly by the biliary tract), ypropyl cellulose (HPC, HPC-SL, and HPC-L), hydroxypro two hydrophilic groups are introduced. For angiographic? pyl methylcellulose (HPMC), carboxymethylcellulose urographic agents (compounds that stay within the extravas sodium, methylcellulose, hydroxyethylcellulose, hydrox cular distribution volume and that are excreted by the kid ypropylcellulose, hydroxypropylmethyl-cellulose phthalate, neys), three hydrophilic groups are introduced. The noncrystalline cellulose, magnesium aluminum silicate, tri monomers are exclusively derived from aminoisophathalic ethanolamine, polyvinyl alcohol (PVA), polyvinylpyrroli acid. They only differ by their side-chains, which determine done (PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer their physiochemical characteristics such as solubility, with ethylene oxide and formaldehyde (also known as tylox hydrophilicity, Viscosity and osmolality. The aqueous solu apol, Superione, and triton), poloxamers (e.g., Pluronics F68. bility of X-ray contrast agents is generally extremely high RTM. and F108.RTM., which are block copolymers of eth being in the order of 1000 mg/ml. Most preparations of X-ray ylene oxide and propylene oxide); poloxamines (e.g., contrast agents are over-saturated Solutions. Tetronic 908. RTM., also known as Poloxamine 908. RTM., 0.148. The relative amount of drug and additive can vary which is a tetrafunctional block copolymer derived from widely and the optimal amount of the additive can depend sequential addition of propylene oxide and ethylene oxide to upon, for example, the particular drug and additives selected, ethylenediamine (BASF Wyandotte Corporation, Parsippany, the critical micelle concentration of the additive if it forms N.J.)); a charged phospholipid such as dimyristoyl phophati micelles, the hydrophilic-lipophilic-balance (HLB) of the dylglycerol, dioctylsulfosuccinate (DOSS); Tetronic 1508. additive, the melting point of the additive, the water solubility RTM. (T-1508) (BASF Wyandotte Corporation), dialkylest of the additive and/or drug, the surface tension of water solu ers of sodium sulfosuccinic acid (e.g., Aerosol OTRTM., tions of the additive, etc. which is a dioctyl ester of sodium Sulfo Succinic acid (Ameri 0149. In embodiments of the present invention, the opti can Cyanamid)); Duponol PRTM., which is a sodium lauryl mal ratio of drug to additive is about 1% to about 99% drug, sulfate (DuPont); Tritons X-200.RTM., which is an alkylaryl more preferably about 30% to about 90% drug. polyether sulfonate (Rohm and Haas); Crodestas F-110. 0150. Adherent Layer RTM., which is a mixture of sucrose stearate and sucrose 0151. The adherent layer, which is an optional layer under distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), lying the drug coating layer, improves the adherence of the also known as Olin-10G.RTM. or Surfactant 10-G.RTM. drug coating layer to the exterior surface of the medical (Olin Chemicals, Stamford, Conn.); Crodestas SL-40.RTM. device. Such as a balloon catheter or stent, and protects coat (Croda, Inc.); and SA9OHCO, which is CH-CH(CON ing integrity. If drug and additive differ in their adherence to (CH)CH (CHOH)(CHOH), (Eastman Kodak Co.); the medical device, the adherent layer may prevent differen decanoyl-N-methylglucamide; n-decyl B-D-glucopyrano tial loss (during transit) or elution (at the target site) of drug side; n-decyl B-D-maltopyranoside; n-dodecyl B-D-glucopy layer components in order to maintain consistent drug-to ranoside; n-dodecyl B-D-maltoside; heptanoyl-N-methylglu additive ratio delivery at the target site of therapeutic inter camide; n-heptyl-B-D-glucopyranoside; n-heptyl B-D- vention. Furthermore, the adherent layer may function to thioglucoside; n-hexyl B-D-glucopyranoside; nonanoyl-N- facilitate release of coating layer components which other methylglucamide; n-nonyl B-D-glucopyranoside; octanoyl wise might adhere too strongly to the device for elution dur N-methylglucamide; n-octyl-B-D-glucopyranoside; octyl ing brief contact with tissues at the target site. For example, in B-D-thioglucopyranoside; and the like. Tyloxapol is a par the case where a particular drug binds the medical device ticularly preferred additive for the pulmonary or intranasal tightly, more hydrophilic components are incorporated into delivery of steroids, even more so for nebulization therapies. the adherent layer in order to decrease affinity of the drug to 0145 Some of the additives are characterized by rapid the device surface. extracellular distribution followed by renal excretion by 0152 The adherent layer comprises a polymer or an addi glomerular filtration. It has been reported (Topic in Current tive or mixtures of both. The polymers that are particularly Chemistry, Vol. 222, P 150) that these additives are extrava useful for forming the adherent layer are ones that are bio sated to a massive extent on the first pass and extraction of the compatible and avoid irritation of body tissue. Some nonionic additives averaged 33% in normally perfused myo examples of polymers that are useful for forming the adherent cardial area and 50% in stenotic area. In another model, layer are polymers that are biostable. Such as polyurethanes, approximately 80% of the myocardial content of 1-iothala silicones, and polyesters. Other polymers that are useful for mate was found in the extravascular space 1 minute after forming the adherent layer include polymers that can be dis intravenous injection in rats. solved and polymerized on the medical device. 0146 Some of the X-ray contrast agents can be used as the 0153. Some examples of polymers that are useful in the additives in embodiments of the invention. Iodinated contrast adherent layer of embodiments of the present invention agents are widely used in X-ray diagnostic procedure such as include polyolefins, polyisobutylene, ethylene-C-olefin angiography, urography and computed tomography. X-ray copolymers, acrylic polymers and copolymers, polyvinyl contrast agents have been moved historically from inorganic chloride, polyvinyl methyl ether, polyvinylidene fluoride and iodide, to organic mono-iodine compounds (Uroselectan A), polyvinylidene chloride, polyacrylonitrile, polyvinyl bis-iodine (Uroselectan B) and tris-iodine substances (diatri ketones, polystyrene, polyvinyl acetate, ethylene-methyl Zoate), from lipophilic to hydrophilic agents from ionic (dia methacrylate copolymers, acrylonitrile-styrene copolymers, trizoate) to non-ionic drugs (iopromide) and from monomers ABS resins, Nylon 12 and its block copolymers, polycapro (iopromide) to dimmers (iotrolan). lactone, polyoxymethylenes, polyethers, epoxy resins, poly 0147 All presented available X-ray contrast agents for urethanes, rayon-triacetate, cellulose, cellulose acetate, cel intravascular injection are based upon the triiodobenzene ring lulose butyrate, cellophane, cellulose nitrate, cellulose US 2008/0175887 A1 Jul. 24, 2008

propionate, cellulose ethers, carboxymethyl cellulose, 0158. The pulmonary balloon catheters and stents are chitins, polylactic acid, polyglycolic acid, polylactic acid similar to vascular balloon catheters and stents. The diam polyethylene oxide copolymers, polyethylene glycol, eters of the pulmonary balloon catheters and stents are 8, 10. polypropylene glycol, polyvinyl alcohol, and mixtures and 12, 14, 16, 18, 20, 22 mm with lengths of 20, 30, 40, 50, 60, block copolymers thereof. 70, 80 mm. It is designed to pass over a 0.035 in guidewire through its guidewire lumen. The balloon can also be passed 0154 Since medical devices such as balloon catheters and through a minimum 5.0 mm working channel bronchoscope. stents undergo mechanical manipulation, i.e., expansion and The diameters of the sinus balloon catheters are 2.0, 3.0, 3.0, contraction, examples of polymers that are useful in the 4.0 mm and 10 mm with lengths of 10, 12, 15, 18, 20, and 30 adherent layer include elastomeric polymers, such as sili . cones (e.g., polysiloxanes and Substituted polysiloxanes), 0159. The paclitaxel or rapamycin and their analogues can polyurethanes, thermoplastic elastomers, ethylene vinyl be used for treatments of respiratory disorders such as acetate copolymers, polyolefinelastomers, and EPDM rub asthma, chronic obstructive pulmonary disease and chronic bers. Due to the elastic nature of these polymers, when these sinusitis. A method of treating respiratory disorders com polymers are used, the coating better adheres to the Surface of prises administrating an anti-proliferate and anti-inflamma the medical device when the device is subjected to forces or tory effective amount of rapamycin, or paclitaxel or their StreSS. analogues to said mammal orally, parenterally, intravascu 0155 The adherent layer may also comprise one or more larly, intranasally, intrabronchially, transdermally, rectally, or of the additives previously described, or other components, in via an impregnated vascular stent or balloon catheters. order to maintain the integrity and adherence of the coating 0160 The paclitaxel or rapamycin and their analogues can layer to the device and to facilitate both adherence of drug and be used in combinations with inhaled corticosteroids, inhaled additive components during transit and rapid elution during atrovent, inhaled leukotriene inhibitors, inhaled epinephrine, deployment at the site of therapeutic intervention. long acting & selective beta agonists for treatments of asthma 0156 Inasthma and COPD, many of the clinical signs and and COPD. A method of treating asthma and COPD in the symptoms are due to airway obstruction resulting from lung comprises administrating an anti-proliferate and anti Smooth muscle constriction. The magnitude of the obstruc inflammatory effective amount of rapamycin, or paclitaxel or tive response observed for a given degree of Smooth muscle their analogues in combinations with inhaled corticosteroids, activation reflects the contractile capacity of the airway inhaled atrovent, inhaled leukotriene inhibitors, inhaled epi smooth muscle and the resistance to airway deformation. The nephrine, long acting & selective beta agonists to said mam airway Smooth muscle plays a central role in asthma. The mal orally, parenterally, intravascularly, intranasally, intra luminal folding or buckling as a consequence of airway bronchially, transdermally, rectally, or via an impregnated Smooth muscle constriction has been observed in asthma. vascular stent or balloon catheters. Such bucking has also been observed in arteries, blood ves 0.161 Embodiments of the present invention also pertain sels in the myocardium, and the gastrointestinal tract (J. Appl. to a method for treating the disease state, especially nasal and Physiol. 83(6): 1814-1821, 1977). Studies also show that sinus dysplasia in mammals caused by mammalian nasal and airway Smooth muscle cell, in addition to its contractile func sinus cells involved in the inflammatory response and com tion, can participate in and coordinate the inflammatory positions useful in the method. The method for treating the response. The inflammatory Smooth muscle produces excess disease state in mammals caused by mammalian nasal and thick and Sticky mucus, which causes asthma attack by block sinus cells involved in the inflammatory response comprises: ing airways. The Smooth muscle hyperplasia has been linked contacting the mammalian nasal and sinus cells participating to airway hyperresponsiveness that is a critical phenotypic in the inflammatory response with the anti-proliferate and characteristic of asthma. anti-inflammatory drugs. 0157. The causes of the coronary heart diseases and 0162 Embodiments of the present invention also pertain asthma may be the neointimal proliferation of smooth muscle to compositions for reducing and treating the disease state in in arterial vessels and in walls of airways. The one aspect of mammals caused by undesired inflammatory response of the invention is to deliver paclitaxel or rapamycin and their nasal and sinus cells comprising an anti-proliferate and anti analogues to the wall of airways to treat the asthma. The drug inflammatory drug a carrier, and an additive composition, coated stents with the two drugs have been approved for wherein the drugs are paclitaxel, rapamycin and their ana inhibiting the growth of the Smooth muscle cells in vascular logues. arterial vessels. Drug coated balloon has been approved to 0163. In a preferred embodiment, the therapeutic compo achieve similar results as the drug coated stent. Therefore, the sitions are administered by nasal inhalation. In another pre drug coated Stent and drug coated balloon used for vascular ferred embodiment, the therapeutic compositions are admin diseases can be adapted in the obstructive airway for the istered by nose drops. The therapeutic compositions may be treatment of asthma. The method comprises inserting the first nebulized by any suitable means. The therapeutic com therapeutic-agent-delivery balloon catheter into the airway in positions may be in liquid or Solid form with liquid droplets or the lung, inflating the balloon catheter, releasing drug to an particle size being Small enough to facilitate access to nasal airway wall of an airway Such that a diameter of the airway is and sinus tissue by inhalation or nose drops. increased, deflating the balloon, withdrawing the balloon 0164. In one embodiment, the ratio by weight of the addi catheter from the airway. The drug may be released to the tive to the therapeutic agent in the layer is from about 0.05 to airway wall prior to, during, or after an asthma attack. The 100, for example, from about 0.1 to 5, from 0.5 to 2, and drug may be released in an amount Sufficient to temporarily or further for example, from about 0.8 to 1.2. permanently increase the diameter of the airway. The method 0.165 Although various embodiments are specifically may be performed while the airway is open, closed, or par illustrated and described herein, it will be appreciated that tially closed. modifications and variations of the present invention are cov US 2008/0175887 A1 Jul. 24, 2008

ered by the above teachings and are within the purview of the menadiol diphosphate, menadione sodium bisulfite, mena appended claims without departing from the spirit and doxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, intended scope of the invention. and vitamin U (vitamins); albumin, immunoglobulins, What is claimed is: caseins, hemoglobins, lysozymes, immunoglobins, a-2-mac 1. A method for treating at least one of asthma, chronic roglobulin, fibronectins, vitronectins, firbinogens, lipases, obstructive pulmonary disease, and chronic sinusitis in a benzalkonium chloride, benzethonium chloride, docecyl tri mammal comprising: methyl ammonium bromide, Sodium docecylsulfates, dialkyl administering a pharmaceutical formulation comprising an methylbenzyl ammonium chloride, and dialkylesters of effective amount of a drug and an additive to said mam Sodium sulfonsuccinic acid. mal orally, parenterally, intravascularly, intranasally, 11. The method according to claim 1, wherein the additive intrabronchially, transdermally, rectally, or via an is a Surfactant. impregnated vascular stent or balloon catheter into a 12. The method according to claim 11, wherein the surfac body passage, wherein said drug is chosen from rapa tant is an ionic Surfactant. mycin and analogues thereof and paclitaxel and ana 13. The method according to claim 12, wherein the ionic logues thereof. surfactant is chosen from benzalkonium chloride, benzetho 2. The method according to claim 1, wherein said admin nium chloride, cetylpyridinium chloride, docecyl trimethyl istering comprises delivery via a mist route selected from the ammonium bromide, Sodium docecylsulfates, dialkyl meth group consisting of aerosol inhalation, dry powder inhalation, ylbenzyl ammonium chloride, edrophonium chloride, domi liquid inhalation, and liquid instillation. phen bromide, dialkylesters of Sodium sulfonsuccinic acid, 3. The method according to claim 2, wherein the mist is Sodium dioctyl Sulfo Succinate, Sodium cholate, and sodium produced by either a nebulizer, a hand-held meter dose taurocholate. inhaler (MDI), or dry powder (DPI) inhaler. 14. The method according to claim 1, wherein the additive 4. The method according to claim 1, wherein the asthma is chosen from PEG-fatty acids and PEG-fatty acid mono and and chronic obstructive pulmonary disease to be treated is diesters, polyethylene glycol glycerol fatty acid esters, alco selected from the group consisting of chronic bronchitis, hol-oil transesterification products, polyglyceryl fatty acids, cystic fibrosis, interstitial fibrosis, nasal and sinus dysplasia, propylene glycol fatty acid esters, sterols and derivatives bronchopulmonary dysplasia and neoplasia, and emphy thereof, polyethylene glycol Sorbitan fatty acid esters, poly SCa. ethylene glycol alkyl ethers, Sugars and derivatives thereof, 5. The method according to claim 1, wherein the additive polyethylene glycol alkyl phenols, polyoxyethylene-polyox enhances absorption of the drug into tissue of the body pas ypropylene block copolymers, Sorbitan fatty acid esters, fat sage of the respiratory and sinus system. soluble vitamins and salts thereof, water-soluble vitamins and 6. The method according to claim 1, wherein the additive amphiphilic derivatives thereof, amino acid and salts thereof, comprises a hydrophilic part and a hydrophobic part. oligopeptides, peptides and proteins, and organic acids and 7. The method according to claim 1, wherein the drug is not esters and anhydrides thereof. enclosed in micelles or encapsulated in polymer particles. 15. The method according to claim 14, wherein the additive 8. The method according to claim 1, wherein the pharma is chosen from esters of lauric acid, oleic acid, and Stearic ceutical formulation does not include oil, a lipid, or a poly acid, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 C. oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, 9. The method according to claim 1, wherein the additive is PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and PEG-20 chosen from PEG fatty esters and alcohols, glycerol fatty oleate. esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG 16. The method according to claim 14, wherein the additive Sorbitan fatty esters, Sugar fatty esters, PEG sugar esters, is chosen from PEG-20 dilaurate, PEG-20 dioleate, PEG-20 Vitamins and derivatives, aminoacids, multiaminoacids and distearate, PEG-32 dilaurate and PEG-32 dioleate. derivatives, peptides, polypeptides, proteins, quaternary 17. The method according to claim 14, wherein the additive ammonium salts, organic acids, salts and anhydrides. is chosen from PEG-20 glyceryl laurate, PEG-30 glyceryl 10. The method according to claim 1, wherein the additive laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, is chosen from p-isononylphenoxypolyglycidol, PEG lau and PEG-30 glyceryl oleate. rate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG 18. The method according to claim 14, wherein the additive glyceryl oleate, PEG glyceryl Stearate, polyglyceryl laurate, is chosen from PEG-35 castor oil, PEG-40 hydrogenated plyglyceryl oleate, polyglyceryl myristate, polyglyceryl castor oil, PEG-25 trioleate, PEG-60 corn glycerides, PEG palmitate, PEG sorbitan monolaurate, PEG sorbitan mono 60 almond oil, PEG-40 palm kernel oil, PEG-50 castor oil, laurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG-50 hydrogenated castor oil, PEG-8 caprylic/capric glyc PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, erides, and PEG-6 caprylic/capric glycerides, PEG-7 hydro tyloxapol; cystine, tyrosine, tryptophan, leucine, isoleucine, genated castor oil, PEG-9 hydrogenated castor oil, PEG-6 phenylalanine, asparagine, aspartic acid, glutamic acid, and corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 methionine (Aminoacids); acetic anhydride, benzoic anhy olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel dride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, oil, PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil, Sodium pyrrolidone carboxylate, ethylenediaminetetraacetic PEG-20 corn glycerides, and PEG-20 almond glycerides. dianhydride, maleic and anhydride, Succinic anhydride, dig 19. The method according to claim 14, wherein the additive lycolic anhydride, glutaric anhydride, acetiamine, benfo is chosen from polyglyceryl oleate, polyglyceryl-2 dioleate, tiamine, pantothenic acid (organic acids and anhydrides); polyglyceryl-10 trioleate, polyglyceryl Stearate, polyglyceryl cetotiamine; cyclothiamine, dexpanthenol, niacinamide, laurate, polyglyceryl myristate, polyglyceryl palmitate, and nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascor polyglyceryl linoleate, polyglyceryl-10 laurate, polyglyc bate, riboflavin, riboflavin phosphate, thiamine, folic acid, eryl-10 oleate, polyglyceryl-10 mono, dioleate, polyglyceryl US 2008/0175887 A1 Jul. 24, 2008

10 stearate, polyglyceryl-10 laurate, polyglyceryl-10 line, isoleucine, leucine, lysine, methionine, phenylalanine, myristate, polyglyceryl-10 palmitate, polyglyceryl-10 serine, threonine, tryptophan, tyrosine, and valine, and salts linoleate, polyglyceryl-6 Stearate, polyglyceryl-6 laurate, of any of the foregoing. polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and 33. The method according to claim 14, wherein the additive polyglyceryl-6 linoleate, and polyglyceryl polyricinoleate. is albumin. 20. The method according to claim 14, wherein the additive 34. The method according to claim 14, wherein the additive is chosen from propylene glycol monolaurate, propylene gly is chosen from benzalkonium chloride, n-octyl-B-D-glucopy col ricinoleate, propylene glycol monooleate, propylene gly ranoside, octoxynol-9, PolySorbates, Tyloxapol, octoxynol, col dicaprylate/dicaprate, and propylene glycol dioctanoate. nonoxynol, isononylphenylpolyglycidol, PEG glyceryl 21. The method according to claim 14, wherein the additive monooleate, Sorbitan monolaurate, Sorbitan monopalmitate, is PEG-24 cholesterol ether. Sorbitan monooleate, Sorbitan monostearate, polyglyceryl-10 22. The method according to claim 14, wherein the additive oleate, polyglyceryl-10 laurate, polyglyceryl-10 palmitate, is chosen from sterol polyethylene glycol derivatives. polyglyceryl-10 Stearate, L-ascorbic acid, thiamine, maleic anhydride, niacinamide, and 2-pyrrolidone-5-carboxylic 23. The method according to claim 14, wherein the additive acid. is chosen from PEG-20 sorbitan monolaurate, PEG-20 sorbi 35. The method according to claim 14, wherein the additive tan monopalmitate, PEG-20 sorbitan monostearate, and is chosen from riboflavin, riboflavin-phosphate sodium, Vita PEG-20 sorbitan monooleate. min D3, folic acid, vitamin 12, diethylenetriaminepentaacetic 24. The method according to claim 14, wherein the additive acid dianhydride, ethylenediaminetetraacetic dianhydride, is chosen from PEG-3 oleyl ether and PEG-4 lauryl ether. maleic acid and anhydride. Succinic acid and anhydride, dig 25. The method according to claim 14, wherein the additive lycolic anhydride, glutaric anhydride, L-ascorbic acid, thia is chosen from Sucrose monopalmitate. Sucrose monolaurate, mine, nicotinamide, nicotinic acid, 2-pyrrolidone-5-carboxy decanoyl-N-methylglucamide, n-decyl-B-D-glucopyrano lic acid, cystine, tyrosine, tryptophan, leucine, isoleucine, side, n-decyl-B-D-maltopyranoside, n-dodecyl-B-D-glu phenylalanine, asparagine, aspartic acid, glutamic acid, and copyranoside, n-dodecyl-B-D-maltoside, heptanoyl-N-meth methionine. ylglucamide, n-heptyl-B-D-glucop-yranoside, n-heptyl-B-D- 36. The method according to claim 14, wherein the additive thioglucoside, n-hexyl-B-D-glucopyranoside, nonanoyl-N- is chosen from isononylphenylpolyglycidol, PEG glyceryl methylglucamide, n-noyl-3-D-glucopyranoside, octanoyl monooleate, Sorbitan monolaurate, Sorbitan monopalmitate, N-methylglucamide, n-octyl-3-D-glucopyranoside, and sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 octyl-B-D-thioglucopyranoside. oleate, polyglyceryl-10 laurate, polyglyceryl-10 palmitate, 26. The method according to claim 14, wherein the additive and polyglyceryl-10 Stearate. is chosen from PEG-10-100 nonyl phenol, PEG-15-100 octyl 37. The method according to claim 14, wherein the additive phenol ether, Tyloxapol, octoxynol, and nonoxynol. is chosen from L-ascorbic acid, thiamine, maleic acids, niaci 27. The method according to claim 14, wherein the additive namide, and 2-pyrrolidone-5-carboxylic acid. is chosen from poloxamer 108, poloxamer 188, poloxamer 38. The method according to claim 14, wherein the additive 217, poloxamer 238, poloxamer 288, poloxamer 338, and is chosen from Vitamin D2 and D3. poloxamer 407. 39. The method according to claim 1, wherein the pharma 28. The method according to claim 14, wherein the additive ceutical formulation further comprises an additional drug. is chosen from poloxamer 124, poloxamer 182, poloxamer 40. The method according to claim 39, wherein the addi 183, poloxamer 212, poloxamer 331, and poloxamer 335. tional drug is selected from the group consisting of corticos 29. The method according to claim 14, wherein the additive teroids, anticholinergics, beta-agonists, non-steroidal anti is chosen from Sorbitan monolaurate, Sorbitan monopalmi inflammatory drugs, macrollide antibiotics, bronchodilators, tate, Sorbitan monooleate, and Sorbitan monostearate. leukotriene receptor inhibitors, cromolyn Sulfate, and combi 30. The method according to claim 14, wherein the additive nations thereof. is chosen from alpha-tocopherol, beta-tocopherol, gamma 41. A pharmaceutical formulation comprising an effective tocopherol, delta-tocopherol, tocopherol acetate, ergosterol, amount of a drug for treatment of a respiratory or sinus 1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, system, and an additive that enhances absorption of the drug alpha-carotene, beta-carotene, gamma-carotene, Vitamin A, into tissue of the respiratory system. fursultiamine, methylolriboflavin, octotiamine, prosul 42. The formulation according to claim 41, wherein the tiamine, riboflavine, vintiamol, dihydroVitamin K1, menadiol additive comprises a hydrophilic part and a hydrophobic part. diacetate, menadiol dibutyrate, menadiol disulfate, menadiol. 43. The formulation according to claim 41, wherein the Vitamin K1, Vitamin K1 oxide, Vitamins K2, and Vitamin drug is not enclosed in micelles or encapsulated in polymer K—S(II), and folic acid. particles. 31. The method according to claim 14, wherein the additive 44. The formulation according to claim 41, wherein the is chosen from acetiamine, benfotiamine, pantothenic acid, formulation does not include oil, a lipid, or a polymer. cetotiamine, cyclothiamine, dexpanthenol, niacinamide, 45. The formulation according to claim 41, wherein the nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascor formulation is an aqueous aerosol formulation, a dry powder bate, riboflavin, riboflavin phosphate, thiamine, folic acid, aerosol formulation, or a propellant-based formulation. menadiol diphosphate, menadione sodium bisulfite, mena 46. The formulation according to claim 41, wherein the doxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, drug is chosen from paclitaxel and analogues thereof and and vitamin U. rapamycin and analogues thereof. 32. The method according to claim 14, wherein the additive 47. The formulation according to claim 41, wherein the is chosen from alanine, arginine, asparagines, aspartic acid, drug is present in a concentration of about 0.05 mg/ml to cysteine, glutamic acid, glutamine, glycine, histidine, pro about 600 mg/ml. US 2008/0175887 A1 Jul. 24, 2008

48. The formulation according to claim 41, wherein the 58. The formulation according to claim 48, wherein the additive is chosen from from PEG-fatty acids and PEG-fatty additive is chosen from PEG-3 oleyl ether and PEG-4 lauryl acid mono and diesters, polyethylene glycol glycerol fatty ether. acid esters, alcohol-oil transesterification products, polyglyc 59. The formulation according to claim 48, wherein the eryl fatty acids, propylene glycol fatty acid esters, Sterol and additive is chosen from Sucrose monopalmitate. Sucrose derivatives thereof, polyethylene glycol sorbitan fatty acid monolaurate, decanoyl-N-methylglucamide, n-decyl-B-D- esters, polyethylene glycol alkyl ethers, Sugars and deriva glucopyranoside, n-decyl-B-D-maltopyranoside, n-dodecyl tives thereof, polyethylene glycol alkyl phenols, polyoxyeth B-D-glucopyranoside, n-dodecyl-3-D-maltoside, heptanoyl ylene-polyoxypropylene block copolymers, Sorbitan fatty N-methylglucamide, n-heptyl-B-D-glucop-yranoside, acid esters, fat-soluble vitamins and salts thereof, water n-heptyl-B-D-thioglucoside, n-hexyl-B-D-glucopyranoside, soluble vitamins and amphiphilic derivatives thereof, amino nonanoyl-N-methylglucamide, n-noyl-B-D-glucopyrano acid and salts thereof, oligopeptides, peptides and proteins, side, octanoyl-N-methylglucamide, n-octyl-B-D-glucopyra and organic acids and esters and anhydrides thereof. noside, and octyl-B-D-thioglucopyranoside. 49. The formulation according to claim 48, wherein the 60. The formulation according to claim 48, wherein the additive is chosen from esters of lauric acid, oleic acid, and additive is chosen from PEG-10-100 nonyl phenol, PEG-15 stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, 100 octyl phenol ether, Tyloxapol, octoxynol, and nonoxynol. PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 lau 61. The formulation according to claim 48, wherein the rate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and additive is chosen from poloxamer 108, poloxamer 188, PEG-20 oleate. poloxamer 217, poloxamer 238, poloxamer 288, poloxamer 50. The formulation according to claim 48, wherein the 338, and poloxamer 407. additive is chosen from PEG-20 dilaurate, PEG-20 dioleate, 62. The formulation according to claim 48, wherein the PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. additive is chosen from poloxamer 124, poloxamer 182, 51. The formulation according to claim 48, wherein the poloxamer 183, poloxamer 212, poloxamer 331, and polox additive is chosen from PEG-20 glyceryl laurate, PEG-30 amer 335. glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl 63. The formulation according to claim 48, wherein the oleate, and PEG-30 glyceryl oleate. additive is chosen from Sorbitan monolaurate, Sorbitan mono 52. The formulation according to claim 48, wherein the palmitate, Sorbitan monooleate, and Sorbitan monostearate. additive is chosen from PEG-35 castor oil, PEG-40 hydroge 64. The formulation according to claim 48, wherein the nated castor oil, PEG-25 trioleate, PEG-60 corn glycerides, additive is chosen from alpha-tocopherol, beta-tocopherol, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-50 castor gamma-tocopherol, delta-tocopherol, tocopherol acetate, oil, PEG-50 hydrogenated castor oil, PEG-8 caprylic/capric ergosterol, 1-alpha-hydroxycholecal-ciferol, Vitamin D2, glycerides, PEG-6 caprylic/capric glycerides, PEG-5 hydro Vitamin D3, alpha-carotene, beta-carotene, gamma-carotene, genated castor oil, PEG-7 hydrogenated castor oil, PEG-9 Vitamin A, fursultiamine, methyloiriboflavin, octotiamine, hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, prosultiamine, riboflavine, vintiamol, dihydroVitamin K1, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, menadiol diacetate, menadiol dibutyrate, menadiol disulfate, PEG-6 hydrogenated palm kernel oil, PEG-6 palm kernel oil, menadiol, Vitamin K1, Vitamin K1 oxide, Vitamins K2, and PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides, and vitamin K—S(II), and folic acid. PEG-20 almond glycerides. 65. The formulation according to claim 48, wherein the 53. The formulation according to claim 48, wherein the additive is chosen from acetiamine, benfotiamine, pan additive is chosen from polyglyceryl oleate, polyglyceryl-2 tothenic acid, cetotiamine, cyclothiamine, dexpanthenol, dioleate, polyglyceryl-10 trioleate, polyglyceryl Stearate, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotina polyglyceryl laurate, polyglyceryl myristate, polyglyceryl mide ascorbate, riboflavin, riboflavin phosphate, thiamine, palmitate, and polyglyceryl linoleate, polyglyceryl-10 lau folic acid, menadiol diphosphate, menadione sodium rate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, polyglyceryl-10 Stearate, polyglyceryl-10 laurate, polyglyc vitamin K6, and vitamin U. eryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl 66. The formulation according to claim 48, wherein the 10 linoleate, polyglyceryl-6 Stearate, polyglyceryl-6 laurate, additive is chosen from alanine, arginine, asparagines, aspar polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and tic acid, cysteine, cystine, glutamic acid, glutamine, glycine, polyglyceryl-6 linoleate, and polyglyceryl polyricinoleate. histidine, proline, isoleucine, leucine, lysine, methionine, 54. The formulation according to claim 48, wherein the phenylalanine, serine, threonine, tryptophan, tyrosine, and additive is chosen from propylene glycol monolaurate, pro Valine, and salts of any of the foregoing. pylene glycol ricinoleate, propylene glycol monooleate, pro 67. The formulation according to claim 48, wherein the pylene glycol dicaprylate/dicaprate, and propylene glycol additive is albumin. dioctanoate. 68. The formulation according to claim 48, wherein the 55. The formulation according to claim 48, wherein the additive is chosen from benzalkonium chloride, n-octyl-f-D- additive is PEG-24 cholesterol ether. glucopyranoside, octoxynol-9, Polysorbates, Tyloxapol, 56. The formulation according to claim 48, wherein the octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG additive is chosen from sterol polyethylene glycol deriva glyceryl monooleate, Sorbitan monolaurate, Sorbitan mono tives. palmitate, Sorbitan monooleate, Sorbitan monostearate, 57. The formulation according to claim 48, wherein the polyglyceryl-10 oleate, polyglyceryl-10 laurate, polyglyc additive is chosen from PEG-20 sorbitan monolaurate, PEG eryl-10 palmitate, polyglyceryl-10 Stearate, L-ascorbic acid, 20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, thiamine, maleic anhydride, niacinamide, and 2-pyrrolidone and PEG-20 sorbitan monooleate. 5-carboxylic acid. US 2008/0175887 A1 Jul. 24, 2008

69. The formulation according to claim 48, wherein the 83. The method according to claim 76, wherein the water additive is chosen from riboflavin, riboflavin-phosphate insoluble drug is chosen from paclitaxel and analogues sodium, Vitamin D3, folic acid, vitamin 12, diethylenetri thereof and rapamycin and analogues thereof. aminepentaacetic acid dianhydride, ethylenediaminetet 84. An aerosol device for delivering a drug to a respiratory raacetic dianhydride, maleic acid and anhydride, Succinic system, the device comprising a pharmaceutical formulation acid and anhydride, diglycolic anhydride, glutaric anhydride, comprising a water insoluble drug and an additive, wherein L-ascorbic acid, thiamine, nicotinamide, nicotinic acid, the additive enhances absorption of the drug into tissue of the 2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryp respiratory system. tophan, leucine, isoleucine, phenylalanine, asparagine, aspar 85. The device according to claim 84, wherein the pharma tic acid, glutamic acid, and methionine. ceutical formulation is an aqeuous, propellant based, or dry 70. The formulation according to claim 48, wherein the powder formulation. additive is chosen from isononylphenylpolyglycidol, PEG 86. The device according to claim 84, wherein the additive glyceryl monooleate, Sorbitan monolaurate, Sorbitan mono comprises a hydrophilic part and a hydrophobic part. palmitate, Sorbitan monooleate, Sorbitan monostearate, 87. The device according to claim 84, wherein the drug is polyglyceryl-10 oleate, polyglyceryl-10 laurate, polyglyc not enclosed in micelles or encapsulated in polymer particles. eryl-10 palmitate, and polyglyceryl-10 Stearate. 88. The device according to claim 84, wherein the formu 71. The formulation according to claim 48, wherein the lation does not include oil, a lipid, or a polymer. additive is chosen from L-ascorbic acid, thiamine, maleic 89. The device according to claim 84, wherein the additive acids, niacinamide, and 2-pyrrolidone-5-carboxylic acid. is chosen from PEG-fatty acids and PEG-fatty acid mono and 72. The formulation according to claim 48, wherein the diesters, polyethylene glycol glycerol fatty acid esters, alco additive is chosen from Vitamin D2 and D3. hol-oil transesterification products, polyglyceryl fatty acids, propylene glycol fatty acid esters, Sterol and derivatives 73. The formulation according to claim 41, wherein the thereof, polyethylene glycol Sorbitan fatty acid esters, poly drug is present in a concentration of about 0.05 mg/g to about ethylene glycol alkyl ethers, Sugars and derivatives thereof, 990 mg/g. polyethylene glycol alkyl phenols, polyoxyethylene-polyox 74. The formulation according to claim 41, wherein the ypropylene block copolymers, Sorbitan fatty acid esters, fat formulation further comprises an additional drug. soluble vitamins and salts thereof, water-soluble vitamins and 75. The formulation according to claim 74, wherein the amphiphilic derivatives thereof, amino acid and salts thereof, additional drug is selected from the group consisting of cor oligopeptides, peptides and proteins, and organic acids and ticosteroids, anticholinergics, beta-agonists, non-steroidal esters and anhydrides thereof. anti-inflammatory drugs, macrollide antibiotics, bronchodila 90. The device according to claim 84, wherein the water tors, leukotriene receptor inhibitors, cromolyn Sulfate, and insoluble drug is chosen from paclitaxel and analogues combinations thereof. thereof and rapamycin and analogues thereof. 76. A method for treating a respiratory system in a mammal 91. The device according to claim 84, wherein the aerosol comprising: device is one of a nebulizer, a hand-held meter dose inhaler, or (1) forming an aerosol of a dispersion of particles, wherein a dry powder inhaler. the particles comprise a water insoluble drug and an 92. A device sized and configured for insertion into a pas additive that enhances absorption of the drug into tissue sage of a respiratory system, the device comprising a layer of the respiratory system; and overlying an exterior Surface of the device, the layer compris (2) administering the aerosol to the respiratory system of ing a water insoluble drug for the treatment of the respiratory the mammal. system and an additive that enhances absorption of the drug 77. The method according to claim 76, wherein the additive into tissue of the respiratory system. comprises a hydrophilic part and a hydrophobic part. 93. The device according to claim 92, wherein the additive 78. The method according to claim 76, wherein the drug is comprises a hydrophilic part and a hydrophobic part. not enclosed in micelles or encapsulated in polymer particles. 94. The device according to claim 92, wherein the drug is 79. The method according to claim 76, wherein the disper not enclosed in micelles or encapsulated in polymer particles. sion does not include oil, a lipid, or a polymer. 95. The device according to claim 92, wherein the layer 80. The method according to claim 76, wherein the disper does not include oil, a lipid, or a polymer. sion does not include a purely hydrophobic additive. 96. The device according to claim 92, wherein the layer 81. The method according to claim 76, wherein the disper does not include a purely hydrophobic additive. sion does not include a dye. 97. The device according to claim 92, wherein the layer 82. The method according to claim 76, wherein the additive does not include a dye. is chosen from PEG-fatty acids and PEG-fatty acid mono and 98. The device according to claim 92, wherein the device is diesters, polyethylene glycol glycerol fatty acid esters, alco a balloon catheter or a stent. hol-oil transesterification products, polyglyceryl fatty acids, 99. The device according to claim 92, wherein the water propylene glycol fatty acid esters, sterol and derivatives insoluble drug is chosen from paclitaxel and analogues thereof, polyethylene glycol Sorbitan fatty acid esters, poly thereof and rapamycin and analogues thereof. ethylene glycol alkyl ethers, Sugars and derivatives thereof, 100. The device according to claim 92, wherein the addi polyethylene glycol alkyl phenols, polyoxyethylene-polyox tive is chosen from PEG-fatty acids and PEG-fatty acid mono ypropylene block copolymers, Sorbitan fatty acid esters, fat and diesters, polyethylene glycol glycerol fatty acid esters, soluble vitamins and salts thereof, water-soluble vitamins and alcohol-oil transesterification products, polyglyceryl fatty amphiphilic derivatives thereof, amino acid and salts thereof, acids, propylene glycol fatty acid esters, Sterol and derivatives oligopeptides, peptides and proteins, and organic acids and thereof, polyethylene glycol Sorbitan fatty acid esters, poly esters and anhydrides thereof. ethylene glycol alkyl ethers, Sugars and derivatives thereof, US 2008/0175887 A1 Jul. 24, 2008

polyethylene glycol alkyl phenols, polyoxyethylene-polyox 106. The method according to claim 101, wherein the ypropylene block copolymers, Sorbitan fatty acid esters, fat coating layer does not include a purely hydrophobic additive. soluble vitamins and salts thereof, water-soluble vitamins and 107. The method according to claim 101, wherein the amphiphilic derivatives thereof, amino acid and salts thereof, coating layer does not include a dye. oligopeptides, peptides and proteins, and organic acids and 108. The method according to claim 101, wherein the drug esters and anhydrides thereof. is chosen from paclitaxel and analogues thereof and rapamy 101. A method for treating a respiratory system compris cin and analogues thereof. 1ng: 109. The method according to claim 101, wherein the inserting a balloon catheter comprising a coating layer into additive is chosen from PEG-fatty acids and PEG-fatty acid an airway, wherein the coating layer comprises a drug mono and diesters, polyethylene glycol glycerol fatty acid and an additive; esters, alcohol-oil transesterification products, polyglyceryl inflating the balloon catheter and releasing the drug to a fatty acids, propylene glycol fatty acid esters, sterol and wall of the airway; derivatives thereof, polyethylene glycol sorbitan fatty acid deflating the balloon; and esters, polyethylene glycol alkyl ethers, Sugars and deriva withdrawing the balloon catheter from the airway. tives thereof, polyethylene glycol alkyl phenols, polyoxyeth 102. The method according to claim 101, wherein the ylene-polyoxypropylene block copolymers, Sorbitan fatty additive enhances absorption of the drug into tissue of the acid esters, fat-soluble vitamins and salts thereof, water respiratory or sinus system. soluble vitamins and amphiphilic derivatives thereof, amino 103. The method according to claim 101, wherein the acid and salts thereof, oligopeptides, peptides and proteins, additive comprises a hydrophilic part and a hydrophobic part. and organic acids and esters and anhydrides thereof. 104. The method according to claim 101, wherein the drug 110. The method according to claim 101, wherein the drug is not enclosed in micelles or encapsulated in polymer par can be released to the wall of the airway prior to, during, or ticles. after an asthma attack. 105. The method according to claim 101, wherein the cocating layer does not include oil, a lipid, or a polymer. c c c c c