US 2004O105819A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0105819 A1 Hale et al. (43) Pub. Date: Jun. 3, 2004

(54) RESPIRATORY DRUG CONDENSATION Publication Classification AEROSOLS AND METHODS OF MAKING AND USING THEM 5 1. Int.nt. Cl.C.7 ...... A61L 9/04 ; A61K 31/573;5 A61K 31/522 (75) Inventors: Ron L. Hale, Woodside, CA (US); (52) U.S. Cl...... 424/45; 514/179; 514/263.34; Peter M. Lloyd, Walnut Creek, CA 514/291 (US); Amy T. Lu, Los Altos, CA (US); Joshua D. Rabinowitz, Mountain View, (57) ABSTRACT CA (US); Martin J. Wensley, San Described herein are respiratory drug condensation aerosols Francisco, CA (US) and methods of making and using them. Kits for delivering condensation aerosols are also described. The respiratory Correspondence Address: drug aerosols typically comprise respiratory drug conden ALEXZAMOLECULAR DELIVERY sation aerosol particles. In Some variations the respiratory CORPORATION drug compound is Selected from the group consisting of 1001 EAST MEADOW CIRCLE B-adrenergics, methylxanthines, anticholinergics, corticos PALO ALTO, CA 94.303 (US) teroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin (73) Assignee: Alexza Molecular Delivery Corpora drugs, proStacyclin drugs, ion channel or pump inhibitors, tion, Palo Alto, CA (US) enhancers, or modulators and pharmaceutically acceptable (21) Appl. No.: 10/719,899 analogs, derivatives, and mixtures thereof. Methods of treat ing a respiratory ailment using the described aerosols are (22) Filed: Nov. 20, 2003 also described. In general, the methods typically comprise the Step of administering a therapeutically effective amount Related U.S. Application Data of respiratory drug condensation aerosol to a person with a respiratory ailment. Methods of forming a respiratory drug condensation aerosol are also described. The methods com (60) Provisional application No. 60/429,364, filed on Nov. prise the Steps of vaporizing and condensing a respiratory 26, 2002. drug composition. Patent Application Publication Jun. 3, 2004 Sheet 1 of 5 US 2004/0105819 A1

s Patent Application Publication Jun. 3, 2004 Sheet 2 of 5 US 2004/0105819 A1

air 200 2O6 /

air

Patent Application Publication Jun. 3, 2004 Sheet 3 of 5 US 2004/0105819 A1

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312

, S. S. ". i. i. Patent Application Publication Jun. 3, 2004 Sheet 4 of 5 US 2004/0105819 A1

albuterol 100 SS. 98 e to 96 A s 94 3s 92 (vs 90 O.O O.5 1.0 1.5 2.0 film thickness (micrometers) Patent Application Publication Jun. 3, 2004 Sheet 5 of 5 US 2004/0105819 A1

ciclesonide 100

an 99 A. SS > 98

C 97 V 9 96 A AA

O 0.5 1 15 2 2.5 film thickness (micrometers)

Fig. 5 US 2004/0105819 A1 Jun. 3, 2004

RESPRATORY DRUG CONDENSATION disease, pulmonary fibrosis (most notably idiopathic pulmo AEROSOLS AND METHODS OF MAKING AND nary fibrosis), pulmonary hypertension, and cystic fibrosis. USING THEM Many of these diseases, especially chronic obstructive pull monary disease, may be improved by the medications CROSS REFERENCE TO RELATED described above for use in asthma. APPLICATIONS 0007 Chronic obstructive pulmonary disease (COPD) is 0001. This application claims priority to U.S. Provisional a common and Serious disease Strongly associated with Application Serial No. 60/429,364 entitled, “Delivery of cigarette Smoking and characterized by chronic productive Asthma Drugs through an Inhalation Route,” which was cough or abnormal permanent enlargement of the alveolar filed on Nov. 26, 2002 and is hereby incorporated by (deep lung) airspaces, accompanied by difficulty moving air reference in its entirety. in and out of the lungs. This difficulty moving air results ShortneSS of breath on exertion and expiratory wheezes or decreased breath Sounds on chest examination. The disease BACKGROUND is generally progressive, with Severe blood oxygen defi 0002 Asthma is a chronic lung disease affecting millions ciency and carbon dioxide overload occurring in the late of people. It is thought to involve three major factors: Stages. Despite the Serious and progressive nature of the Swelling of the airways, constriction of the muscles around underlying pathology of COPD, the disease also frequently the airways, and inflammation. Symptoms of asthma differ involves an airway hyperreactivity (asthma-like) component widely among Sufferers. While Some people experience that may be reversible, resulting in the total obstruction to tightness of the chest, wheezing, and difficulty breathing airflow being partially reversible. COPD is thus sometimes only intermittently, (e.g., with exercise), others experience hard to differentiate from unremitting asthma, and the these Symptoms daily. asthma treatments described above are among of the most 0003. The precise cause of asthma is not known, but important treatments for COPD. genetic predisposition appears to be an important factor. The 0008 Pulmonary fibrosis generally involves chronic most typical triggers of asthma attacks are cold air, exercise, inflammation of the alveolar walls with progressive fibrosis. infection, common viruses, irritants, and allergens (e.g., Clinical manifestations include shortneSS of breath on exer pollen, pet dander, etc.). When the airways come in contact tion, nonproductive cough, crackles on chest examination, with one of these triggers, the tissue inside the bronchi and and, at later Stages, digital clubbing and cyanosis. Pulmo bronchioles becomes inflammed and the muscles on the nary hypertension is an obliterative disease of medium and outside of the airways constrict, causing them to narrow. Small pulmonary arteries resulting in heart failure. The key Mucus enters the airways, causing them to Swell, and narrow clinical manifestation is progressive exertional shortneSS of further. Sometimes avoiding the trigger is all that is neces breath. Both of the above diseases have very poor prognosis, Sary to prevent an asthma attack. However, avoiding asthma frequently resulting in death within 2 to 7 years of diagnosis. triggers in all instances is Seldom possible, So asthma Nevertheless, certain respiratory agents, Such as anti-endot typically requires medical treatment. helin drugs and proStacyclin drugs, provide Some Survival 0004. There are two primary types of medicines used to and/or quality of life benefits. treat asthma: the “relievers” and the “controllers” (some 0009 Cystic fibrosis is an inherited disease of secretory times also referred to as the “preventers”). Reliever medi glands, affecting multiple body organs, with a strong respi cines are typically bronchodilators. They are used to provide ratory component. It is the most common life-shortening immediate relief of asthma Symptoms (e.g., wheezing, genetic disease in the U.S., and is caused by a genetic defect coughing, tightness in the chest, shortness of breath, etc.). in a particular chloride-transporting protein, the cystic fibro Bronchodilators function by dilating, or opening up, the sis transmembrane regulator. Its respiratory Symptoms gen bronchi (i.e., the larger airways delivering air inside the erally include those of chronic pulmonary obstruction. lungs). Most commonly prescribed are the f-adrenoceptor Beyond the treatments described above, which may be agonists, also referred to as the f-adrenergics (e.g., epineph effective in treating the obstructive pulmonary Symptoms of rine, isoproterenol, albuterol, Salmeterol, Salbutamol, terb cystic fibrosis, other treatments may also be useful, in utaline, isoprenaline, isoetharine, metaproterenol, etc.) and particular ion channel or pump inhibitors, enhancers, or the Xanthines (e.g., caffeine, theophylline, etc.). modulators. 0005 Controllers or preventers, on the other hand, are 0010 While agents for the treatment of respiratory dis typically anti-inflammatory medicines. They are medicines ease may be delivered by many routes, including Systemic taken on a regular basis, even when the asthmatic is not routes, many agents effective for the treatment of respiratory Suffering from any Symptoms. The goal of these medicines disease, e.g., relievers and controllers, are delivered in is to prevent asthma Symptoms from developing. Controllers aeroSol form via inhalers. Currently, there are three basic function by decreasing the inflammation (e.g., fluid and types of inhalers available: nebulizers (jet and ultrasonic), cellular debris) inside the airways. They are divided into metered dose inhalers, (“MDIs,” including MDIs with spac Several classes of medications, the most common of which ers), and dry powder inhalers (“DPIs”). These inhalers are are the corticosteriods. Mediator-release inhibitors, and leu used for both aeroSol generation and aeroSol delivery of kotriene modifier agents are also anti-inflammatories used to asthma drugs. control asthma. These medicines may also be useful in 0011 Nebulizers aerosolize liquids and produce a mist of treating certain respiratory diseases or ailments. drug-containing water particles for inhalation. There are two 0006 Beyond asthma, other common and/or important basic types of nebulizers, the jet nebulizer, and the ultrasonic respiratory diseases include chronic obstructive pulmonary nebulizer. Jet nebulizers are more common than ultrasonic US 2004/0105819 A1 Jun. 3, 2004

nebulizers, because they are leSS expensive. Typically, with Such as nebulizers is that delivery of liquids other than a jet nebulizer, compressed gas flows from an inlet tube over neutral pH Saline to the lungs may irritate the lungs, whereas the top of a tube whose end is immersed in a drug Solution. Saline may provide a vehicle that carries bacteria or other The Venturi effect creates a pressure drop, which Sucks up pathogens into the lungs. Also, many important drugs are not the liquid and causes it to enter the air Stream where it is soluble in neutral pH Saline. For dry powder inhalers, rapidly dispersed into droplets. The Stream of air and water undesirably large particle Size is again a problem. The droplets is directed against a baffle, which breaks the drop problem is particularly Severe for patients who cannot inhale lets into Small particles. The Small particles are then carried with much vigor, because vigorous inhalation is generally out of the nebulizer Suspended in air, and the remaining required to disperse the powder. Because respiratory patients droplets re-enter the solution. With ultrasonic nebulizers, in need of inhaled medications frequently have impaired particles are produced by mechanical vibration of a plate or abilities to inhale, the above problem of Strong inhalation mesh using a piezoelectric crystal. being required to disperse dry powderS is particularly clini 0012. With MDIs, a measured (i.e., metered) dose of cally significant. Another problem with dry powderS is that medicine is dispensed into the user's mouth using a Small they contain additives Such as lactose, generally in quantities amount of pressurized gas (i.e., a propellant). Sometimes a exceeding the quantity of drug in the inhaler. Such additives Spacer is placed between the drug reservoir and the user's may irritate or otherwise damage the lung, while providing mouth in order to control the amount of aeroSol that is no therapeutic benefits. inhaled. The aerosol of a MDI is created when a valve is 0015 Accordingly, it would be desirable to provide opened (usually by pressing down on a propellant canister), improved respiratory drug aerosols and improved inhalation allowing liquid propellant to Spray out by cavitation. The devices for administering Such aeroSols. drug is usually contained in Small particles Suspended in the liquid propellant, but in Some formulations the drug is SUMMARY dissolved in the propellant. In either case, the propellant evaporates rapidly as the aeroSol leaves the device, resulting 0016 Described herein are respiratory drug condensation aerosols and methods of making and using them. Kits for in Small drug particles that are inhaled. Prior to the mid delivering a condensation aeroSol are also described. The 1990s, MDIs used various chlorofluorocarbons (“CFCs”) as respiratory drug aerosols described herein typically com their propellant, but with the elimination of CFCs in industry prise respiratory drug condensation aerosol particles. In due to OZone depletion concerns, the propellants in new Some variations the particles comprise a respiratory drug MDIs typically use hydrofluoroalkanes (“HFAs”). Selected from the group consisting of B-adrenergics, meth 0013 Unlike the aerosols discussed above, the aerosols ylxanthines, anticholinergics, corticosteroids, mediator-re produced by DPIs are in the form of a powder. Typically the lease inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma drugs of DPIS are manufactured in powder form as asthma antagonists, anti-endothelin drugs, proStacyclin Small powder particles of a few micrometers in diameter. drugs, ion channel or pump inhibitors, enhancers, or modu The asthma drug is then typically mixed with larger Sugar lators and pharmaceutically acceptable analogs, derivatives, particles, for example, lactose monohydrate, (e.g., typically and mixtures thereof. In other variations, the respiratory 50-100 micrometers in diameter). The asthma drug particles drug is Selected from the group consisting of albuterol, attach to the excipient lactose particles. The increased aero epinephrine, metaproterenol, terbutaline, pseudoephedrine dynamic forces on the lactose/drug agglomerates are thought hydrochloride, bambuterol, bitolterol, carbuterol, clen to improve entrainment of the Small drug particles upon buterol, clorprenalin, dioxethedrine, eproZinol, etefiedrine, inhalation. Upon inhalation, the powder is broken into its ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, constituent particles with the aid of turbulence and, in Some isoetharine, isoproterenol, mabuterol, methoxyphenamine, instances, mechanical devices Such as Screens or Spinning pirbuterol, procaterol, protokylol, rimiterol, Salmeterol, Surfaces. Dry powder formulations, while offering advan Soterenol, tretoquinol, tulobuterol, caffeine, theophylline, tages over the cumberSome liquid nebulizer formulations, aminophylline, acefylline, bamifylline, doxofylline, dyphyl and the propellant-driven formulations, are prone to aggre line, etamiphyllin, etofylline, proxyphylline, reproterol, gation and low flowability phenomena which considerably theobromine-1-acetic acid, atropine, ipratropium bromide, diminish the efficiency of the dry powder-based inhalation flutropium bromide, OXitropium bromide, tiotropium bro therapies. mide, budesonide, beclomethasone, cicleSonide, dexametha 0.014. Despite the variety of inhalation devices available, Sone, flunisolide, fluticaSone propionate, triamcinolone these devices are Suboptimal in numerous respects. For acetonide, prednisolone, methylprednisolone, hydrocorti example, MDIs need to be shaken prior to use. Many users Sone, cromolyn Sodium, nedocromil Sodium, montelukast, fail to shake the MDIs and therefore receive inconsistent Zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumi amounts of medication. Other times, the MDI ejects the drug last, pumafentrine, domitroban, israpafant, ramatroban, with Such a great exit Velocity or in Such a large particle size Seratrodast, tiaramide, Zileuton, ambrisentan, boSentan, that the drug collides with the back of the throat and does not enrasentan, SitaXSentan, teZoSentan, iloprost, treprostinil, reach the lung in Substantial quantity. For nebulizers, unde and pharmaceutically acceptable analogs, derivatives, and Sirably large particle size is also a common problem, as is mixtures thereof. Slow aeroSolization of the drug. Because of Slow aeroSol 0017. In some variations, the aerosol comprises at least generation, nebulizer treatments often require a patient to 50% by weight of a respiratory drug. In other variations the inhale on the nebulizer for minutes to hours to receive a aerosol comprises at least 75% or 95% by weight of the therapeutic amount of medication, disrupting the patient's respiratory drug. Similarly, in Some variations, the aerosol is other life activities or providing unacceptably Slow relief of Substantially free of thermal degradation products, and in an acute asthma attack. Another problem with liquid inhalers Some variations, the respiratory drug condensation aeroSol US 2004/0105819 A1 Jun. 3, 2004

has a MMAD in the range of 2-4 um. In some variations, the theophylline, aminophylline, acefylline, bamifylline, dox respiratory drug condensation aerosol has a MMAD in the ofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, range of 10 nm-100 nm. In Some variations, the aeroSol reproterol, theobromine-1-acetic acid, atropine, ipratropium comprises two or more therapeutically active respiratory bromide, flutropium bromide, oxitropium bromide, tiotro drugs. In Some variations, the aerosol comprises both B-adr pium bromide, budeSonide, beclomethasone, ciclesonide, energic drug and a corticosteroid. dexamethasone, flunisolide, fluticasone propionate, triamci nolone acetonide, prednisolone, methylprednisolone, hydro 0.018. The kit for delivering a respiratory drug conden cortisone, cromolyn Sodium, nedocromil Sodium, mon sation aerosol typically comprises a composition comprising telukast, Zafirlukast, pirfenidone, CPX, IBMX, cilomilast, a respiratory drug, and a device for forming a respiratory roflumilast, pumafentrine, domitroban, israpafant, rama drug aeroSol. The device for forming a respiratory drug troban, Seratrodast, tiaramide, Zileuton, ambrisentan, bosen aeroSol typically comprises an element configured to heat tan, enrasentan, SitaXSentan, teZoSentan, iloprost, treprosti the composition to form a vapor, an element allowing the nil, and pharmaceutically acceptable analogs, derivatives, Vapor to condense to form a condensation aeroSol, and an and mixtures thereof. element permitting a user to inhale the condensation aeroSol. The composition may further comprise a pharmaceutically acceptable excipient, and the device may further comprise BRIEF DESCRIPTION OF THE DRAWINGS features Such as breath-actuation or lockout elements. 0022 FIG. 1 is an illustration of an exemplary device 0.019 Methods of treating respiratory ailments using the that may be used to form and administer the aeroSols aerosols described herein are also provided. In general, the described herein. method comprises the Step of administering a therapeutically 0023 FIGS. 2A and 2B are illustrations of other exem effective amount of a respiratory drug condensation aeroSol plary devices that may be used to form and administer the to a person with a respiratory ailment. In Some variations, aerosols described herein. the method for treating a respiratory ailment comprises the Step of administering a therapeutically effective amount of a 0024 FIGS. 3A and 3B illustrate solid supports suitable respiratory drug aerosol to a perSon with the respiratory for use with the devices and methods described herein. ailment, wherein the respiratory drug aerosol comprises a 0025 FIG. 4 is a plot depicting the effects of film respiratory drug and has a MMAD in the range of about 2-4 thickness on aerosol purity for albuterol. tim. The respiratory drug condensation aerosol may be administered in a single inhalation, or may be administered 0026 FIG. 5 is a plot depicting the effects of film in more than one inhalation. In Some variations, the respi thickness on aerosol purity for ciclesonide. ratory drug condensation aerosol has a purity greater than 90%. In Some variations, the respiratory drug condensation DETAILED DESCRIPTION aeroSol comprises two or more therapeutically active respi 0027 Definitions ratory drugs. In Some variations, the drug condensation aeroSol comprising two or more respiratory drugs has a 0028. As defined herein, the following terms shall have purity of greater than 90%. In some variations, the purity of the following meanings when reference is made to them each of the respiratory drugs present in the aerosol is greater throughout the Specification. than 90%. 0029. “Condensation aerosol” refers to an aerosol that 0020 Methods of forming a respiratory drug condensa has been formed by the vaporization and Subsequent cooling tion aerosol are also described. The methods of forming a of the vapor, Such that the vapor condenses to form particles. respiratory drug condensation aerosol typically comprise the 0030) “Controllers” or “preventers” are used herein inter Steps of providing a respiratory drug composition in a unit changably and refer to drugs that are anti-inflammatory dose form, vaporizing the respiratory drug composition, and medicines. condensing the respiratory drug composition. The Step of Vaporizing the respiratory drug composition typically com 0031) “Heat stable drug” refers to a drug that has a prises the Step of heating the composition to form a vapor. TSR29 when vaporized from a film of some thickness between 0.05 um and 20 lum. 0021. The composition typically comprises one or more respiratory drug Selected from the group consisting of B-adr 0032 “Mass median aerodynamic diameter” or energics, methylxanthines, anticholinergics, corticosteroids, “MMAD” of an aerosol refers to the aerodynamic diameter mediator-release inhibitors, anti-leukotriene drugs, asthma for which half the particulate mass of the aerosol is con inhibitors, asthma antagonists, anti-endothelin drugs, proS tributed by particles with an aerodynamic diameter larger tacyclin drugs, ion channel or pump inhibitors, enhancers, or than the MMAD and half by particles with an aerodynamic modulators and pharmaceutically acceptable analogs, diameter Smaller than the MMAD. derivatives, and mixtures thereof. In other variations, the 0033 “Purity” as used herein, with respect to the aerosol asthma drug is Selected from the group consisting of purity, means (the fraction of drug in the aerosol/the fraction albuterol, epinephrine, metaproterenol, terbutaline, pseu of drug in the aerosol plus drug degradation products in the doephedrine hydrochloride, bambuterol, bitolterol, car aeroSol). In the case where an aerosol contains more than buterol, clenbuterol, clorprenalin, dioxethedrine, eproZinol, one drug, purity may be reported as the fraction of drug etefiedrine, ethylnorepinephrine, fenoterol, fenspiride, heXo composition (Summed for all of the drugs in the aerosol)/the prenaline, isoetharine, isoproterenol, mabuterol, methoX fraction of the drug composition in the aerosol plus drug yphenamine, pirbuterol, procaterol, protokylol, rimiterol, degradation products in the aerosol (Summed for all of the Salmeterol, Soterenol, tretoquinol, tulobuterol, caffeine, drugs in the aerosol). Alternatively, if it is known which US 2004/0105819 A1 Jun. 3, 2004

parent drug gives rise to each of the drug degradation well as other inhibitors or antagonists. Other classes of products present in the aerosol in Significant amounts, the respiratory drugs Suitable for use with the described methods purity may be reported for each drug in the aerosol as (the and devices include anti-endothelin drugs and proStacyclin fraction of the Specific drug in the aeroSol/the fraction of that drugs, which are particularly useful in the treatment of drug plus that drug's degradation products) in the aerosol. pulmonary fibrosis or hypertension, and ion channel or pump inhibitors, enhancers, and modulators, which are 0034) “Reliever” refers to a drug that is a bronchodilator. particularly useful in the treatment of cystic fibrosis. Exem 0.035 “Substantially free of thermal degradation prod plary B-adrenergicS include, without limitation, albuterol, ucts' means that the aerosol is at least 50% free of thermal epinephrine, metaproterenol, terbutaline, pseudoephedrine degradation products. hydrochloride, bambuterol, bitolterol, carbuterol, clen 0.036 “Therapeutically effective amount’ means the buterol, clorprenalin, dioxethedrine, eproZinol, etefiedrine, amount required to achieve a therapeutic effect. The thera ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, peutic effect could be any therapeutic effect ranging from isoetharine, isoproterenol, mabuterol, methoxyphenamine, prevention, Symptom amelioration, Symptom treatment, to pirbuterol, procaterol, protokylol, rimiterol, Salmeterol, disease termination or cure. Soterenol, tretoquinol, tulobuterol, and pharmaceutically 0037 “Thermal degradation product” means any byprod acceptable analogs, derivatives, and mixtures thereof. uct, which results from heating the respiratory drug com Exemplary methylxanthines include, without limitation, caf position and is not responsible for producing a therapeutic feine, theophylline, aminophylline, acefylline, bamifylline, effect. doxofylline, dyphylline, etamiphyllin, etofylline, proxy phylline, reproterol, theobromine-1-acetic acid, and phar 0038 “Thermal stability ratio” or “TSR' means the % maceutically acceptable analogs, derivatives, and mixtures purity/(100%–9% purity) if the % purity is <99.9%, and 1000 thereof. Exemplary anticholinergics include, without limi if the % purity is 299.9%. For example, a respiratory drug tation, atropine, ipratropium bromide, flutropium bromide, vaporizing at 90% purity would have a TSR of 9. An OXitropium bromide, tiotropium bromide, and pharmaceuti example of how to determine whether a respiratory drug is cally acceptable analogs, derivatives, and mixtures thereof. heat stable is provided below. 0039) “Vapor” refers to a gas, and “vapor phase” refers to 0044 Similarly, exemplary corticosteroids include, with a gas phase. The term “thermal vapor refers to a vapor out limitation, budeSonide, beclomethasone, cicleSonide, phase, aerosol, or mixture of aerosol-vapor phases, formed dexamethasone, flunisolide, fluticasone propionate, triamci preferably by heating. nolone acetonide, prednisolone, methylprednisolone, hydro cortisone, and pharmaceutically acceptable analogs, deriva 0040 Respiratory Drug Compositions tives, and mixtures thereof. Exemplary mediator-release 0041. The respiratory drug compositions described inhibitors include, without limitation, cromolyn Sodium, herein typically comprise at least one asthma drug, chronic nedocromil Sodium, and pharmaceutically acceptable ana obstructive pulmonary disease drug, pulmonary hyperten logs, derivatives, and mixtures thereof. Exemplary anti Sion drug, pulmonary fibrosis drug, and/or cystic fibrosis leukotrienes include, without limitation, montelukast, drug. It should be understood that when reference is made Zafirlukast, and pharmaceutically acceptable analogs, herein to a “respiratory drug” it is intended that this phrase derivatives, and mixtures thereof. Other suitable respiratory includes those drugs described herein, which may also be drugs include, without limitation, pirfenidone, CPX, IBMX, useful in treating asthma, as well as certain respiratory cilomilast, roflumilast, pumafentrine, domitroban, isra ailments or diseases (e.g., chronic obstructive pulmonary pafant, ramatroban, Seratrodast, tiaramide, Zileuton, disease, pulmonary hypertension, pulmonary fibrosis, cystic ambrisentan, boSentan, enrasentan, SitaXSentan, teZoSentan, fibrosis, and the like). The respiratory drug compositions iloprost, treprostinil, and pharmaceutically acceptable ana may comprise other compounds as well. For example, the respiratory drug composition may comprise a mixture of logs, derivatives, and mixtures thereof. respiratory drugs, a mixture of a respiratory drug and a 004.5 Tables providing chemical structures and some pharmaceutically acceptable excipient, or a mixture of a physical properties for a few of these illustrative compounds respiratory drug with other compounds having useful or are provided below. desirable properties. The respiratory drug composition may comprise a pure respiratory drug as well. TABLE 1. 0.042 Any suitable respiratory drug may be used. In SUITABLE B-ADRENERGIC DRUGS general, we have found that Suitable respiratory drugs have properties that make them acceptable candidates for use with AIbuterol the devices and methods herein described. For example, the respiratory drug is typically one that is, or can be made to be, OH Vaporizable. HO C(CH3)3 0.043 Classes of bronchodilator drugs suitable for use with the described methods and devices include the B-adr energics, the methylxanthines, and the anticholinergics. HO Classes of anti-inflammatory drugs Suitable for use with the MW: 239 described methods and devices include the corticosteroids, MP: 158° C. the mediator-release inhibitors, the anti-leukotriene drugs, as US 2004/0105819 A1 Jun. 3, 2004

TABLE 1-continued TABLE 1-continued

SUITABLE B-ADRENERGIC DRUGS SUITABLE B-ADRENERGIC DRUGS Epinephrine Bitolterol

OH O YCH, HC O CH O CH MW: 165 MP: 40° C. O -C(CH3)3 Metaproterenol NH OH OH H MW: 462 HO N N CH Carbuterol CH OH

OH HN,2. N r n C(CH3)3 MW: 211 O MP: 100° C. HO Terbutaline

MW: 267 OH MP: 174 HO n ClenbuterolCeO C(CH3)3 o

OH

C OH YC(CH3),

MW: 225 MP: 122° C. HN Pseudoephedrine Hydrochloride Cl

gh MW: 277 NaH Clorprenalin CH o

CH OH H HCI N N CH MW: 2O2 CH MP: 184° C. C Bambuterol MW: 214 CH CH Dioxethedrine H,C1 r YCH, OH O O HO CH N1 3 H Nn CH HO C(CH3)3 HO

MW: 367 MW: 211 US 2004/0105819 A1 Jun. 3, 2004

TABLE 1-continued TABLE 1-continued

SUITABLE B-ADRENERGIC DRUGS SUITABLE B-ADRENERGIC DRUGS Eprozinol Hexoprenaline

OH OH H OCH r HO N 2

HO

MW: 421 MW: 354 MP: 12 C. Etefedrine Isoetharine

OH th OH N N-1'-'3CH CH CH HN CH HO

OH CH MW: 193 Ethylnorepinephrine o MW: 239 OH Isoproterenol

HO CH OH H NH2 HO N CH HO N CH MW: 197 HO Fenoterol MW: 211 OH MP: 155° C. HO NH Mabuterol

CH OH OH FC NaH OH C(CH3)3

MW:303 HN Fenspiride Cl -(O MethoxyphenamineMW: 311 NH

N YCH, CH OCH3

MW: 260 MW: 179 US 2004/0105819 A1 Jun. 3, 2004

TABLE 1-continued TABLE 1-continued

SUITABLE B-ADRENERGIC DRUGS SUITABLE B-ADRENERGIC DRUGS Pirbuterol Soterenol

OH OH N HO 21 n H H HC Ns1 N N CH N HO 4. \, NCH HO MW: 240 Procaterol MW: 288 Tretoquinol

OCH OCH

OCH3

NH

HO MW: 290

Protokylol MW: 345 Tulobuterol OH H HO N C

CH HO

MW: 331 OH Rimiterol MW: 228 OH MP: 89° C. H N OH 0046) OH TABLE 2

MW: 223 SUITABLE METHYLXANTHINE DRUGS MP: 2O3° C. Theophylline Salmeterol

OH

HO Y(CH3)-O

HO ---CH

MW: 416 MW: 18O MP: 76 MP: 274° C. US 2004/0105819 A1 Jun. 3, 2004

TABLE 2-continued TABLE 2-continued

SUITABLE METHYLXANTHINE DRUGS SUITABLE METHYLXANTHINE DRUGS Acefylline o Etamiphyllin

O -cool O 1N HCN, N r N CH3 AX H3CN N lisCH O N N 1. M 21 n1 N CH CH MW: 238 MP: 271° C. MW: 279 Bamifylline MP: 75° C. Etofylline CH o O r O H3CN N 1N1 N N1 No ?\, N HC n N

O N O1. N NM CH hi,

MW: 385 MW: 222 MP: 80° C. MP: 158° C. Doxofylline Proxyphylline O s OH O O O HC CH 3 es Ny "),es N CH hi,

MW: 266 MW: 238 MP: 144° C. Dyphylline MP: 135° C. o Reproterol

OH OH OH H O N OH O

HCN, N HC3 n Nr

Oall? N N 1. AX OH O N N CH CH MW: 254 MP: 158° C. MW: 389 US 2004/0105819 A1 Jun. 3, 2004

TABLE 2-continued TABLE 3-continued

SUITABLE METHYLXANTHINE DRUGS SUTABLE ANTICHOLINERGIC DRUGS

Theobromine-1-acetic Acid Oxitropium Bromide

O y H. H3C- +/NCHN 3 Hooc1N NX

O1. N NA O 1. OH Br O CH

O MW: 238 MP:260° C. MW: 412 MP: 2O3° C. 0047 TiotropiumOtropium BromidBronde

TABLE 3 HCS-CH SUTABLE ANTICHOLINERGIC DRUGS

Ipratropium Bromide O Br CH

HC n -- 1N N CH

Br MW: 472 MP: 218 C.

O OH

O 0048)

TABLE 4

SUTABLE CORTICOSTEROID DRUGS MW: 412 MP: 232° C. Budesonide Flutropium Bromide

H3C n N1+ Nchi,

HO Br O

O O

MW: 431 MP: 192 C. MP: 232° C. US 2004/0105819 A1 Jun. 3, 2004

TABLE 4-continued TABLE 4-continued

SUITABLE CORTICOSTEROID DRUGS SUTABLE CORTICOSTEROID DRUGS Ciclesonide Triamcinolone Acetonide O

O

MW: 434 MP: 294° C. O

MW: 541 Dexamethasone 0049)

TABLE 5

SUTABLE INHIBITOR OR ANTAGONIST DRUGS Pirfenidone

HC N

O N O MW: 392 MP: 271° C. Flunisolide

MW: 185 MP: 102° C. CPX

O

N 1s, NX-( MW: 431 N

MW: 304 MP: 191° C. IBMX

O Dry1s, \

MW: 5O1 MP: 272 C. MW: 222 US 2004/0105819 A1 Jun. 3, 2004 11

TABLE 5-continued TABLE 5-continued

SUITABLE INHIBITOR OR ANTAGONST DRUGS SUTABLE INHIBITOR OR ANTAGONIST DRUGS Cillomilast Ramatroban CH O COOH

HCO H

MW: 343 MP: 157° C. Rofluimilast N

Cl COOH - O NN MW: 416 MP: 134° C. Seratrodast All-FCH-O NH C21

Pumafentrine HC CH

HC COOH

MW: 354 Domitroban MP: 128° C. Tiaramide CCY” MW: 378 MP: 60° C. Israpafant

MW: 356 Zileuton

HO O V S N / NH2 CH

MW: 236 MW: 489 MP: 157° C. MP: 130° C. US 2004/0105819 A1 Jun. 3, 2004 12

0050 0051) TABLE 6 TABLE 7

SUITABLE ANT-ENDOTHELIN DRUGS SUITABLE ANTI-LEUKOTRENE DRUGS Bosentan

Montelukast O. O o V/

Sn 1xico NH OCH3 C (H3C)3C O r 21 N Ns O CH N-N Nuo MW: 552 Ambrisentan

CO2H MW: 586 MeO Zafirlukast O

Ph Ph 1. ---. MW: 378 Sitaxsentan

O S OCH / y IN-SO2 Me O

O N C NS

MW: 576 Me MP: 140° C. MW:455 Pranlukast

O 0052

TABLE 8 NH HN-N W SUITABLE PROSTACYCLIN DRUGS O N -N O N Treprostinil

O

MW: 482 MP: 244 C. N1 US 2004/0105819 A1 Jun. 3, 2004

bonaceous materials, and polymers. Illustrative materials TABLE 8-continued within these classes are aluminum, Silver, iron, gold, Stain leSS Steel, copper and tungsten; Silica, glass, Silicon and SUTABLE PROSTACYCLIN DRUGS alumina, graphite, ceramics, and polytetrafluoroethylene. In Iloprost one variation, the Solid Support is StainleSS Steel. Combina tions of materials and coated variants of materials may be used as well. HOOC 0059 When it is desirable to use aluminum as a solid Support, aluminum foil is a Suitable material. Examples of alumina and silicon based materials include BCR171 (an alumina of defined surface area greater than 2 m/g from Aldrich, St. Louis, Mo.) and a silicon wafer as used in the Semiconductor industry. Chromatography resins Such as octadecycl Silane chemically bonded to porous Silica are exemplary coated variants of Silica.

MW: 361 0060 Typically it is desirable that the solid support have relatively few, or Substantially no, Surface irregularities. Although a variety of Supports may be used, Supports that 0.053 Typically, the respiratory drug is in its free base, have an impermeable Surface, or an impermeable Surface free acid or ester form. However, it is not without possibility coating, are typically desirable. Illustrative examples of Such that the respiratory drug can be vaporizable from its Salt Supports include metal foils, Smooth metal Surfaces, nonpo form as well. Indeed, a variety of pharmaceutically accept rous ceramics, and the like. able Salts are Suitable for aeroSolization. Illustrative Salts 0061 The respiratory drug composition is typically include, without limitation, the following: Sodium, potas coated on the solid support in the form of a film. The film sium, or other alkali metal Salts, and ammonium or Substi may be coated on the Solid Support using any Suitable tuted ammonium Salts, hydrochloric acid, hydrobromic acid, method. The method Suitable for coating is often dependent acetic acid, maleic acid, formic acid, and fumaric acid Salts. upon the physical properties of the respiratory drug and the Salt forms of respiratory drugs can be obtained from their desired film thickness. One exemplary method of coating a corresponding free base or free acid forms using well known respiratory drug composition on a Solid Support is by pre methods in the art. paring a Solution of respiratory drug (alone or in combina 0.054 Suitable pharmaceutically acceptable excipients tion with other desirable compounds) in a Suitable Solvent, may be volatile or nonvolatile. Volatile excipients, when applying the Solution to the exterior Surface of the Solid heated, are concurrently volatilized, aeroSolized and inhaled Support, and then removing the Solvent (e.g., via evapora with the asthma drug. Classes of Such excipients are known tion, etc.) thereby leaving a film on the Support Surface. in the art and include, without limitation, gaseous, Super 0062 Common solvents include methanol, dichlo critical fluid, liquid and solid solvents. The following is a list romethane, methyl ethyl ketone, diethyl ether, 3:1 chloro of exemplary carriers within these classes: water, terpenes, form:methanol mixture, 1:1 dichloromethane: methyl ethyl Such as menthol; alcohols, Such as ethanol, propylene gly ketone mixture, dimethylformamide, and deionized water. col, glycerol and other Similar alcohols, dimethylforma Sonication may also be used as necessary to dissolve the mide; dimethylacetamide, waX; Supercritical carbon diox respiratory drug. ide; dry ice; and mixtures thereof. 0063. The respiratory drug composition may also be 0055 Solid Support coated on the Solid Support by dipping the Support into a respiratory drug composition Solution, or by Spraying, 0056 Typically, the respiratory drug composition is brushing or otherwise applying the Solution to the Support. coated on a Solid Support and the Solid Support is heated to Alternatively, a melt of the drug can be prepared and applied Vaporize the asthma drug composition. The Support may be to the Support. For drugs that are liquids at room tempera of any geometry and a variety of different sizes. It is often ture, thickening agents can be mixed with the drug to permit desirable that the Solid Support provide a large Surface to application of a Solid drug film. Volume ratio (e.g., greater than 100 per meter) and a large Surface to mass ratio (e.g., greater than 1 cm per gram). 0064. Formation of Respiratory Drug Condensation AeroSols 0057. A solid support of one shape can also be trans formed into another shape with different properties. For 0065. Any suitable method may be used to form the example, a flat sheet of 0.25 mm thickness has a Surface to respiratory drug aerosols described herein. One Such method volume ratio of approximately 8,000 per meter. Rolling the involves the heating of a respiratory drug composition to sheet into a hollow cylinder of 1 cm diameter produces a form a vapor, followed by cooling of the vapor So that it Support that retains the high Surface to mass ratio of the forms an aerosol (i.e., a condensation aeroSol). Exemplary original sheet but has a lower Surface to volume ratio (about methods of heating include the passage of current through an 400 per meter). electrical resistance element, absorption of electromagnetic radiation (e.g., microwave or laser light) and exothermic 0.058 A number of different materials may be used to chemical reactions (e.g., exothermic Salvation, hydration of construct the Solid Supports. Classes of Such materials pyrophoric materials, and oxidation of combustible materi include, without limitation, metals, inorganic materials, car als). Heating of the Substrate by conductive heating is also US 2004/0105819 A1 Jun. 3, 2004

Suitable. One exemplary heating Source is described in U.S. unit time) the drug aerosol may be formed at a rate in the patent application for SELF-CONTAINED HEATING range of from about 0.03 mg/second to about 2 mg/Second. UNIT AND DRUG-SUPPLY UNITEMPLOYING SAME, Alternatively or in addition, the rate of drug aerosol forma U.S. Serial No. 60/472,697 filed May 21, 2003. The descrip tion may be greater than 0.01 mg/S, 0.03 mg/S, 0.05 mg/S, tion of the exemplary heating Source disclosed therein, is 0.09 mg/s, 0.15 mg/s, 0.25 mg/s, 0.4 mg/s, 0.6 mg/s, 0.9 hereby incorporated by reference. mg/s, 1.3 mg/s, 1.9 mg/S, or 2.5 mg/S. 0.066 Heat sources or devices that contain a chemically 0072 Typically, the delivered aerosol has an inhalable reactive material are also Suitable. Typically the chemically aerosol particle density greater than 10° particles/mL. More reactive material undergoes an exothermic reaction upon typically, the aerosol has an inhalable aeroSol particle den actuation, e.g., by a Spark or other heat element, Such as a sity greater than 107 particles/mL, and most typically, the flashbulb type heater, or other heaters such as described in aeroSol has an inhalable aeroSol particle density greater than U.S. patent application for SELF-CONTAINED HEATING 10 particles/mL. UNIT AND DRUG-SUPPLY UNITEMPLOYING SAME. 0073. Typically, where the aerosol comprises albuterol, In particular, heat Sources that generate heat by exothermic the aerosol has an inhalable aerosol drug mass density of reaction, where the chemical "load” of the Source is con between 10 ug/L and 200 tug/L. More typically, the aerosol Sumed in a period of between 50-500 msec or less are has an inhalable aeroSol drug mass density of between 17.5 generally Suitable, assuming good thermal coupling between tug/L and 75 lug/L, and most typically, the aeroSol has an the heat Source and Substrate. inhalable aerosol drug mass density of between 25 ug/L and 0067. In one method, the heating of the respiratory drug 50 tug/L. composition involves heating a thin film of the composition 0074 Typically, where the aerosol comprises metaprot having a thickness between about 0.05 um-20 um to form a erenol, the aerosol has an inhalable aerosol drug mass Vapor. In yet other variations, the composition has a film density of between 0.1 mg/L and 1.5 mg/L. More typically, thickness between about 0.5 um-10 um. Most typically, the the aerosol has an inhalable aerosol drug mass density of film thickness vaporized is between 0.5 um-5 um. between 0.15 mg/L and 1.25 mg/L, and most typically, the 0068. In some variations, the respiratory drug condensa aeroSol has an inhalable aeroSol drug mass density of tion aerosol comprises at least 5% by weight of asthma drug between 0.2 mg/L and 1 mg/L. condensation aerosol particles. In other variations, the aero 0075 Typically, where the aerosol comprises terbutaline, sol comprises at least 10%, 20%, 30%, 40%, 50%, 60%, or the aerosol has an inhalable aerosol drug mass density of 75% by weight of asthma drug condensation aerosol par between 0.01 mg/L and 1 mg/L. More typically, the aerosol ticles. In Still other variations, the aerosol comprises at least has an inhalable aerosol drug mass density of between 0.03 95%, 99%, or 99.5% by weight of respiratory drug conden mg/L and 0.75 mg/L. Most typically, the aerosol has an sation aeroSol particles. inhalable aerosol drug mass density of between 0.05 mg/L 0069. In some variations, the respiratory drug condensa and 0.5 mg/L. tion aerosol particles comprise less than 10% by weight of 0076 Typically, where the aerosol comprises tramcino a thermal degradation product. In other variations, the lone acetonide, the aerosol has an inhalable aerosol drug respiratory drug condensation aeroSol particles comprise mass density of between 10 ug/L and 200 tug/L. More less than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight of a typically, the aerosol has an inhalable aerosol drug mass thermal degradation product. density of between 20 tug/L and 175 ug/L. Most typically, the 0070. In some variations the respiratory drug condensa aeroSol has an inhalable aeroSol drug mass density of tion aerosol has a MMAD in the range of about 1-5 um, between 30 tug/L and 150 lug/L. 1.5-4.5 um, 1.5-4 um, 1.8-4 tim, 1-3 lum, or 2-3 um. In other 0.077 Delivery Device variations the respiratory drug condensation aerosol has a 0078. The delivery devices described herein for admin MMAD in the range of about 10-100 nm, 10-200 nm or of istering a respiratory drug condensation aerosol typically about 10-300 nm. In some variations the geometric standard comprise an element for heating the asthma drug composi deviation around the MMAD of the respiratory drug con tion to form a vapor, an element allowing the vapor to cool, densation aerosol particles is less than 3.0. In other varia thereby forming a condensation aeroSol, and an element tions, the geometric standard deviation around the MMAD permitting a user to inhale the aeroSol. The delivery device of the respiratory drug condensation aerosol particles is leSS may be combined with a composition comprising a respi than 2.5, or less than 2.0. ratory drug in unit dose form, for use as a kit. 0071. The aerosol particles for administration can typi cally be formed using any of the described methods at a rate 0079. One suitable device is illustrated in FIG. 1. Deliv of greater than 10 inhalable particles per second. In some ery device 100 has a proximal end 102 and a distal end 104, variations, the aerosol particles for administration are a solid support 106, a power source 108, and a mouthpiece formed at a rate of greater than 10” or 10" inhalable 110. In this depiction, solid support 106 also comprises a particles per Second. With respect to the rate of aeroSol heating module. An asthma drug composition is deposited formation (i.e., the mass of aerosolized particulate matter on solid support 106. Upon activation of a user activated produced by a delivery device per unit time) the aerosol may Switch 114, power source 108 initiates heating of heating be formed at a rate greater than 0.25 mg/second, greater than module (e.g., through ignition of combustible fuel or passage 0.5 mg/second, or greater than 1 or 2 mg/second. Similarly, of current through a resistive heating element, etc.). with respect to the rate of drug aerosol formation (i.e., the 0080. The respiratory drug composition vaporizes and mass of aeroSolized drug produced by a delivery device per condenses to form a condensation aerosol prior to reaching US 2004/0105819 A1 Jun. 3, 2004

the mouthpiece 110 at the proximal end of the device 102. the upper and lower housing members are slotted, as Seen Air flow traveling from the device distal end 104 to the best in the figure in the upper housing member at 222, to mouthpiece 110 carries the condensation aerosol to the provide for air intake when a user inhales. The upper and mouthpiece 110, where it is inhaled by a user. lower housing members when fitted together define a cham ber 224. Positioned within chamber 224 is a solid support 0081. The devices described herein may additionally 226, shown in a partial cut-away view. contain a variety of components to facilitate aeroSol deliv ery. For instance, the device may include any component 0087 As shown in FIG. 2B, the solid support shown known in the art to control the timing of drug aeroSolization there is of a Substantially cylindrical configuration having a relative to inhalation (e.g., breath-actuation). Similarly, the Slight taper. However, as described above the Solid Support device may include a component to provide feedback to may be of any desirable configuration. At least a portion of patients on the rate and/or Volume of inhalation, or a the Solid Support Surface 228 is coated with a respiratory component to prevent excessive use (i.e., "lock-out” fea drug composition film 230. Visible in the cutaway portion of ture). In addition, the device may further include a compo the Solid Support is an interior region 232, which comprises nent to prevent use by unauthorized individuals, and a a Substance Suitable to generate heat. The Substance may be, component to record dosing histories. These components for example, a Solid chemical fuel, chemical reagents that may be used alone, or in combination with other compo mix exothermically, an electrically resistive wire, or the like. nentS. A power Supply Source, if needed for heating, and any necessary Valving for the inhalation device may be con 0082 The element that allows cooling may be of any configuration. For example, it may be an inert passageway tained in end piece 234. linking the heating means to the inhalation means. Similarly, 0088. The device may also include a gas-flow control the element permitting inhalation by a user may be of any Valve disposed upstream of the Solid Support, for limiting configuration. For example, it may be an exit portal that gas-flow rate through the condensation region. The gas-flow forms a connection between the cooling element and the Valve may, for example, include an inlet port communicating user's respiratory System. with the chamber, and a deformable flap adapted to divert or restrict air flow away from the port increasingly, with 0.083. Other suitable devices for use with the aerosols increasing pressure drop acroSS the valve. Similarly, the described herein are shown in FIGS. 2A and 2B. As shown gas-flow valve may include an actuation Switch. In this in FIG. 2A, there is a device 200 comprising an element for variation, the valve movement would be in response to an air heating an asthma drug composition to form a vapor, an preSSure differential acroSS the valve, which for example, element allowing the vapor to cool, thereby forming a could function to close the Switch. The gas-flow valve may condensation aeroSol, and an element permitting a user to also include an orifice designed to limit airflow rate into the inhale the aerosol. Device 200 also comprises a housing 202 chamber. with a tapered end 204 for insertion into the mouth of a user. On the end opposite tapered end 204, the housing has one or 0089. The device may also include a bypass valve com more openings, Such as slots 206, for air intake when a user municating with the chamber downstream of the unit for places the device in the mouth and inhales a breath. Within offsetting the decrease in airflow produced by the gas-flow housing 202 is a solid support 208, visible in the cut-away control valve, as the user draws air into the chamber. In this portion of the figure. At least a portion of the Solid Support way, the bypass valve could cooperate with the gas-control is coated on a surface 210 with a film 212 of an asthma drug Valve to control the flow through the condensation region of composition. the chamber as well as the total amount of air being drawn through the device. Thus the total volumetric airflow 0084 Typically, the solid support 208 is heated to a through the device in this variation would be the sum of the temperature Sufficient to vaporize all or a portion of the film Volumetric airflow rate through the gas-control valve and the 212, So that the respiratory drug composition forms a vapor Volumetric airflow rate through the bypass valve. that becomes entrained in a Stream of air during inhalation. As noted above, heating of the solid support 208 may be 0090 The gas control valve could, for example, function accomplished using, for example, an electrically-resistive to limit air drawn into the device to a preselected level, e.g., wire embedded or inserted into the Substrate and connected 15 L/minute. In this way, air flow for producing particles of to a battery disposed in the housing. The heating can be a desired size may be preselected and produced. For actuated, for example, with a button on the housing or via example, once this Selected airflow level is reached, addi breath actuation, as is known in the art. tional air drawn into the device would create a pressure drop acroSS the bypass valve, which in turn would accommodate 0085 FIG. 2B shows another device that may be used to airflow through the bypass valve into the downstream end of form and deliver the aerosols described herein. The device, the device adjacent the user's mouth. Thus, the user Senses 214 comprises an element for heating a respiratory drug a full breath being drawn in, with the two valves distributing composition to form a vapor, an element allowing the vapor the total airflow between desired airflow rate and bypass to cool, thereby forming a condensation aeroSol, and an airflow rate. element permitting a user to inhale the aeroSol. The device 0091. These valves may be used to control the gas also comprises an upper external housing member 216 and Velocity through the condensation region of the chamber and a lower external housing member 218 that fit together. hence to control the particle size of the aeroSol particles 0086) Shown in the depiction of FIG. 2B, the down produced. Typically, the faster the airflow, the smaller the Stream end of each housing member is gently tapered for particles. Thus, to achieve Smaller or larger particles, the gas insertion into a user's mouth, as best Seen on upper housing Velocity through the condensation region of the chamber member 216 at downstream end 220. The upstream end of may be altered by modifying the gas-flow control valve to US 2004/0105819 A1 Jun. 3, 2004

increase or decrease the Volumetric airflow rate. For 0098. For example, if the purity of the particles is less example, to produce condensation particles in the Size range than that which is desired, or if the percent yield is less than of about 2-4 um MMAD, a chamber having substantially that which is desired, the thickness of the drug film is Smooth-Surfaced walls would have a Selected gas-flow rate adjusted to a thickness different from the initial film thick in the range of 4-50 L/minute. neSS. The purity and yield are then determined at the adjusted film thickness, and this proceSS is repeated until the 0092 Additionally, as will be appreciated by one of skill desired purity and yield are achieved. After Selection of an in the art, particle size may be altered by modifying the appropriate film thickness, the area of Substrate required to croSS-Section of the chamber condensation region to increase provide a therapeutically effective dose, is determined. or decrease linear gas Velocity for a given volumetric flow rate, and/or the presence or absence of Structures that 0099 Solid Support Surface Area produce turbulence within the chamber. Thus, for example 0100. As noted above, the surface area of the solid to produce condensation particles in the size range 10-100 Support is Selected Such that it is Sufficient to yield a nm MMAD, the chamber may provide gas-flow barriers for therapeutically effective dose. The amount of respiratory creating air turbulence within the condensation chamber. drug required to provide a therapeutically effective dose is These barriers are typically placed within a few thousands of generally known in the art, and is discussed in more detail an inch from the Substrate Surface. Particle size is discussed below. The Substrate area may then be determined using the in more detail below. following equation: 0093 FIGS. 3A and 3B provide exploded views of solid Supports that may be used in combination with the devices described herein. As shown in FIG. 3A, there is a Solid film thickness (cm) X drug density Support 300 having a respiratory drug composition coating 302 at least a portion of the upper surface 304. While the (gfcm3) X substrate area (cm2) = dose (g) coating 302 is shown on upper surface 304 in FIG. 3A, it OR should be understood that it need not be so. Indeed, the coating may be placed on any Suitable Surface, Such as substrate area (cm2) = Surfaces 306 and 308. dose (g)ffilm thickness (cm) X drug density (gfcm3) 0094 FIG. 3B provides a perspective, cut-away view of another solid support 310 that may be used with the methods and devices herein described. AS shown there, the Solid 0101 The drug mass can be determined by weighing the support 310 comprises a cylindrically-shaped substrate 312. substrate before and after formation of the drug film or by This substrate may be formed from a heat-conductive mate extracting the drug and measuring the amount analytically. rial, for example. The exterior surface 314 of substrate 312 Drug density can be determined experimentally by a variety is coated with an asthma drug composition. AS shown in the of well known techniques, or may be found in the literature cut-away portion, there is a heating element 316 disposed in or in reference texts, Such as in the CRC. An assumption of the substrate. The Substrate can be hollow with a heating unit density is acceptable if an actual drug density is not element inserted into the hollow Space or Solid with a known. heating element incorporated into the Substrate. 0102 Dosage of Respiratory Drug Containing Aerosols 0.095 The illustrative heating element shown in FIG. 3B 0103) The dosage amount of respiratory drugs in aerosol is shown as an electrical resistive wire that produces heat form is generally less than the Standard dose of the drug when a current flows through it, but as noted above, a given orally. For instance, albuterol, metaproterenol, or number of different heating methods and corresponding terbutaline given at Strengths of 2 mg to 4 mg, 10 mg to 20 devices are acceptable. For example, acceptable heat Sources mg, and 2.5 mg to 5 mg respectively for the treatment of can Supply heat to the Solid Support at rates that rapidly asthma. AS aerosols, 10 ug to 200 ug of albuterol, 0.1 mg to achieve a temperature Sufficient to completely vaporize the 1.5 mg metaproterenol, 0.01 mg to 1 mg terbutaline, and 10 asthma drug composition from the Support Surface. For tug to 200 ug of triamcinolone acetonide are generally example, heat Sources that achieve a temperature of 200 C. provided per inhalation for the same indication. to 500 C. within a period of 2 seconds, although it should be appreciated that the temperature chosen will be depen 0104. A dosage of respiratory drug aerosol may be dent upon the vaporization properties of the asthma drug administered in a Single inhalation or may be administered composition. in more than one inhalation, Such as a Series of inhalations. Where the drug is administered as a Series of inhalations, the 0.096 Respiratory Drug Composition Film Thickness inhalations are typically taken within an hour or less (dosage equals Sum of inhaled amounts). When the drug is admin 0097. Typically, the respiratory drug composition film istered as a Series of inhalations, a different amount may be coated on the Solid Support has a thickness of between about delivered in each inhalation. 0.05-20 um, and typically a thickness between 0.1-15 lum. More typically, the thickness is between about 0.2-10 um; 0105 Typically, in the respiratory drug containing aero even more typically, the thickness is between about 0.5-10 Sol, between 0.005 mg and 10 mg of a respiratory drug is tim, and most typically, the thickness is between about 0.5-5 delivered to the mammal in a single inspiration. More tim. The desirable film thickneSS for any given respiratory typically, between 0.01 mg and 3 mg of a respiratory drug drug composition is typically determined by an iterative is delivered to the mammal in a single inspiration, and most proceSS in which the desired yield and purity of the con typically, between 0.02 mg and 1.5 mg of a respiratory drug densation aeroSol composition are Selected or known. is delivered to the mammal in a Single inspiration. US 2004/0105819 A1 Jun. 3, 2004

0106. One can determine the appropriate dose of respi sation particles in the size range 10-100 nm MMAD, the ratory drug aerosol to treat a particular condition using chamber may provide gas-flow barriers for creating air methods Such as animal experiments and a dose-finding turbulence within the condensation chamber. These barriers (Phase I/II) clinical trial. Typically, studies are first con are typically placed within a few thousands of an inch from ducted to determine dose limiting toxicity in a mammal. the Substrate Surface. Initial dose levels for testing in humans are generally leSS 0111 Analysis of Respiratory Drug Aerosols than or equal to one-tenth of the dose on a body Surface area basis that resulted in dose-limiting toxicity in the mammal. 0112 Purity of a respiratory drug aerosol may be deter Dose escalation in humans is then performed, until either an mined using a number of different methods. Examples of optimal therapeutic response is obtained or a dose-limiting Suitable methods for determining aerosol purity are toxicity is encountered. described in Sekine et al., Journal of Forensic Science 32:1271-1280 (1987) and in Martin et al., Journal of Ana 01.07 Particle Size lytic Toxicology 13:158-162 (1989). 0108) Efficient aerosol delivery to the lungs requires that 0113. One suitable method involves the use of a trap. In the particles have certain penetration and Settling or diffu this method, the aeroSol is collected in a trap in order to Sional characteristics. Deposition in the Small airways of the determine the percent or fraction of thermal degradation lungs may occur by either gravitational Settling or diffusion, product. Any Suitable trap may be used. Suitable traps and can only occur if the delivered particles are able to pass include filters, glass wool, impingers, Solvent traps, cold from the mouth through the larynx to the airways and lungs. traps, and the like. Filters are often most desirable. The trap Avoiding impaction in the mouth and upper respiratory tract is then typically extracted with a Solvent, e.g. acetonitrile, requires particles in the Size range between about 10 nm and and the extract Subjected to analysis by any of a variety of 5 um, because particles much smaller than 10 nm (e.g., analytical methods known in the art, for example, gas, vapors) diffuse So rapidly that they are lost in the mouth and liquid, and high performance liquid chromatography par upper-most airways, and particles larger than 5 um tend to ticularly useful. inertially impact in the back of the throat and larynx. To avoid impaction, particles Smaller than 4 um or even 3 um 0114. The gas or liquid chromatography method typically are preferred. Once in the airways, for the treatment of includes a detector System, Such as a mass spectrometry airway disease (e.g., asthma), particle sizes that either dif detector or an ultraViolet absorption detector. Ideally, the fuse or Settle due to gravity into the airway walls are detector System allows determination of the quantity of the preferred. This contrasts with treatment of alveolar disease components of the drug composition and of the byproduct, or Systemic disease (where alveolar absorption of drug into by weight. This is achieved in practice by measuring the the blood is desirable), in that particle sizes that pass through Signal obtained upon analysis of one or more known the airways and Settle or diffuse into the deepest-most lung mass(es) of components of the drug composition or byprod tissues of the alveoli (e.g., 1-3 um or 10 nm -100 nm uct (standards) and then comparing the signal obtained upon particles) are preferred. Thus, for treatment of airway dis analysis of the aerosol to that obtained upon analysis of the ease, when deposition by gravitational Settling is desired, Standard(s), an approach well known in the art. aerosols characterized by a mass median aerodynamic diam 0.115. In many cases, the structure of a thermal degrada eter (MMAD) in the about 1.5 um to 4 um size range are tion product may not be known or a Standard for it may not preferred, and aerosols with a 2 um to 3 um MMAD are be available. In Such cases, one may calculate the weight more preferred. For treatment of airway disease, when fraction of the thermal degradation product by assuming it deposition of particles by diffusion is desired, aerosols has an identical response coefficient (e.g. for ultraviolet characterized by a mass median aerodynamic diameter absorption detection, identical extinction coefficient) to the (MMAD) in the about 10 nm to 300 nm size range are drug component or components in the respiratory drug preferred, and aerosols with a 10 nm to 200 nm or 10 nm to composition. When conducting Such analysis, thermal deg 100 nm MMAD are more preferred. Typically, in order to radation products present in less than a very Small fraction produce particles having a desired MMAD, gas or air is of the drug compound, e.g. less than 0.2% or 0.1% or 0.03% passed over the Solid Support at a certain flow rate. of the drug compound, are typically excluded. Because of the frequent necessity to assume an identical response 0109 Typically, the higher the flow rate, the Smaller the coefficient between drug and byproduct in calculating a particles that are formed. Therefore, in order to achieve weight percentage of thermal degradation product, it is often Smaller or larger particles, the flow rate through the con more desirable to use an analytical approach in which Such densation region of the delivery device may be altered. This an assumption has a high probability of validity. In this may be done, for example, by modifying a gas-flow control respect, high performance liquid chromatography with Valve to increase or decrease the Volumetric airflow rate. To detection by absorption of ultraviolet light at 225 nm is illustrate, condensation particles in the size range 1.5-4 um typically desirable. UV absorption at 250 nm may be used MMAD may be produced by selecting the gas-flow rate to for detection of compounds in cases where the compound be in a range of 4-50 L/minute. absorbs more strongly at 250 nm or for other reasons one 0110. Additionally, as will be appreciated by one of skill skilled in the art would consider detection at 250 nm the in the art, particle size may also be altered by modifying the most appropriate means of estimating purity by weight using croSS-Section of the chamber condensation region to increase HPLC analysis. In certain cases where analysis of the drug or decrease linear gas Velocity for a given volumetric flow by UV are not viable, other analytical tools such as GC/MS rate. In addition, particle size may also be altered by the or LC/MS may be used to determine purity. presence or absence of Structures that produce turbulence 0116. It is possible that modifying the form of the drug within the chamber. Thus, for example to produce conden may impact the purity of the aerosol obtained. Although not US 2004/0105819 A1 Jun. 3, 2004

always the case, the free base or free acid form of the drug of number of particles in each size range. Number of as opposed to the Salt, generally results in either a higher particles in a given size range=Mass in the size range/Mass purity or yield of the resultant aeroSol. Therefore, in certain of a typical particle in the size range. Mass of a typical circumstances, it may be more desirable to use the free base particle in a given size range=TC D*(p/6, where D is a typical or free acid forms of the compounds used. Similarly, it is particle diameter in the size range (generally, the mean possible that changing the gas under which vaporization of boundary MMADS defining the size range) in microns, p is the composition occurs may also impact the purity. the particle density (in g/mL) and mass is given in units of picograms (g'). 0117. Other Analytical Methods 0121 Rate of inhalable aerosol particle formation may be 0118 Particle size distribution of a respiratory drug aero determined, for example, by delivering aerosol phase drug Sol may be determined using any Suitable method in the art into a confined chamber via an inhalation device. The (e.g., cascade impaction). An Andersen Eight Stage Non delivery is for a set period of time (e.g., 1s), and the number viable Cascade Impactor (Andersen Instruments, Smyrna, of particles of a given size collected in the chamber is Ga.) linked to a furnace tube by a mock throat (USP throat, determined as outlined above. The rate of particle formation Andersen Instruments, Smyrna, Ga.) is one system used for is equal to the number of 100 nm to 5 micron particles cascade impaction Studies. For most pharmaceutical aeroSol collected divided by the duration of the collection time. testing the Anderson Cascade Impactor (ACI) is a gold Standard instrument. The ACI inertially Separates the aeroSol 0122) Rate of aerosol formation may be determined, for into 7 stages with progressively Smaller cutoff diameters example, by delivering aerosol phase drug into a confined from 9.0 um to 0.4 um. However, when testing particle size chamber via an inhalation device. The delivery is for a set distribution of aerosols that have a Substantial fraction leSS period of time (e.g., 1s), and the mass of particulate matter than 1 um aerodynamic diameter, or aerosols with a MMAD collected is determined by weighing the confined chamber less than 1 micrometer, the ACI is does not provide optimal before and after the delivery of the particulate matter. The resolution at that Size range. The ACI has only one stage rate of aeroSol formation is equal to the increase in mass in with a cutoff diameter less than 1 um, at 0.4 mm and thus the chamber divided by the duration of the collection time. cannot provide much information about the size distribution Alternatively, where a change in mass of the delivery device of an aerosol below 1 lum. A better alternative is the Micro or component thereof can only occur through release of the Orifice Uniform Deposit Impactor (MOUDI) designed and aeroSol phase particulate matter, the mass of particulate distributed by MSP Corporation in Shoreview, Minn. The matter may be equated with the mass lost from the device or MOUDI model 110 has eleven stages, five with cutoff component during the delivery of the aerosol. In this case, diameters less than 1.0 lim. The Stage 0 cut diameter is 18 the rate of aerosol formation is equal to the decrease in mass lum and below 1 um the cutoffs are 0.56, 0.32, 0.18, 0.1, and of the device or component during the delivery event 0.056 um. If additional resolution is required below 0.056 divided by the duration of the delivery event. um, the nano-MOUDI model 115 provides cutoffs of 0.032, 0123 Rate of drug aerosol formation may be determined, 0.018 and 0.010 um. The performance of these devices has for example, by delivering an asthma drug aeroSol into a been documented by Virgil Marple, Kenneth Rubow, and confined chamber via an inhalation device over a Set period Steven Behm (see Marple et al., Aerosol Science and of time (e.g., 1s). Where the aerosol is pure asthma drug, the Technology 14:434-446, 1991). amount of drug collected in the chamber is measured as 0119 Inhalable aerosol drug mass density may be deter described above. The rate of drug aerosol formation is equal mined, for example, by delivering a drug-containing aeroSol to the amount of asthma drug collected in the chamber into a confined chamber via an inhalation device and mea divided by the duration of the collection time. Where the Suring the amount of active drug compound collected in the asthma drug aerosol comprises a pharmaceutically accept chamber. Typically, the aerosol is drawn into the chamber by able excipient, multiplying the rate of aeroSol formation by having a preSSure gradient between the device and the the percentage of asthma drug in the aerosol provides the chamber, wherein the chamber is at lower preSSure than the rate of drug aerosol formation. device. The volume of the chamber should approximate the 0.124 General Procedure for Determining Whether a Res tidal Volume of an inhaling patient. The amount of active piratory Drug is a “Heat Stable Drug drug compound collected in the chamber is determined by extracting the chamber, conducting chromatographic analy 0125 Drug is dissolved or suspended in a solvent (e.g., sis of the extract and comparing the results of the chromato dichloromethane or methanol). The Solution or Suspension is graphic analysis to those of a Standard containing known coated to about a 4 micron thickness on a stainless Steel amounts of drug. substrate of about 8 cm surface area. The substrate may either be a Standard Stainless Steel foil or a heat-passivated 0120 Inhalable aerosol particle density may be deter Stainless Steel foil. The Substrate is heated to a temperature mined, for example, by delivering aerosol phase drug into a sufficient to generate a thermal vapor (generally ~350° C.) confined chamber via an inhalation device and measuring but at least to a temperature of 200 C. with an air flow the number of particles of given size collected in the typically of 20 L/min (1 m/s) passing over the film during chamber. The number of particles of a given size may be heating. The heating is done in a volatilization chamber directly measured based on the light-Scattering properties of fitted with a trap (Such as described in the Examples above). the particles. Alternatively, the number of particles of a After vaporization is complete, airflow is discontinued and given size may be determined by measuring the mass of the resultant aerosol is analyzed for purity using the methods particles within the given size range and calculating the disclosed herein. If the resultant aerosol contains less than number of particles based on the mass as follows: Total 10% drug degradation product, i.e., the TSR 29, then the number of particles=Sum (from Size range 1 to size range N) drug is a heat Stable drug. If, however, at about 4 micron US 2004/0105819 A1 Jun. 3, 2004 thickness, greater than 10% degradation is determined, the cm were dip-coated approximately 4.5 to 5 cm on the Strip experiment is repeated at the same conditions, except that with an asthma drug Solution prepared as described above. film thicknesses of about 1.5 microns, and of about 0.5 The foil was then partially dipped three times into solvent to micron, respectively, are used. If a decrease in degradation rinse drug off of the last 2-3 cm of the dipped end of the foil. products relative to the 4 micron thickness is seen at either Alternatively, the drug-coating from this bottom 2-3 cm area of these thinner film thicknesses, a plot of film thickneSS was carefully taken off with a razor blade. The final coated Versus purity is graphed and extrapolated out to a film area was between 2.0-2.5 cm by 1.3 cm on both sides of the thickness of 0.05 microns. The graph is used to determine if foil, for a total area of between 5.2-6.5 cm. Foils were there exists a film thickness where the purity of the aeroSol prepared as Stated above and then Some were extracted with would be Such that it contains less than 10% drug degrada methanol or acetonitrile as Standards. The amount of drug tion products. If Such a point exists on the graph, then the was determined from quantitative HPLC analysis. Using the drug is defined as a heat Stable drug. known drug-coated Surface area, the thickneSS was then 0.126 Methods of Treating Respiratory Ailments calculated. 0127. Also described herein are methods for treating a 0.136. After drying, the drug-coated foil was placed into respiratory ailment. Typically the methods comprise the Step a volatilization chamber constructed of a Delrin block (the of administering a therapeutically effective amount of a airway) and brass bars, which served as electrodes. The respiratory drug condensation aerosol to a person with a dimensions of the airway were 1.3 cm high by 2.6 cm wide respiratory ailment. Typically the Step of administering the by 8.9 cm long. The drug-coated foil was placed into the respiratory drug condensation aerosol comprises the Step of Volatilization chamber Such that the drug-coated Section was administering an orally inhalable respiratory drug conden between the two sets of electrodes. After Securing the top of the Volatilization chamber, the electrodes were connected to sation aerosol to the person with the respiratory ailment. a 1 Farad capacitor (Phoenix Gold). The back of the vola 0128. The respiratory drug aerosol may be administered tilization chamber was connected to a two micron Teflon(E) in a single inhalation, or in more than one inhalation, as filter (Savillex) and filter housing, which were in turn described above. The respiratory drug condensation aeroSol connected to the house vacuum. Sufficient airflow was may comprise a respiratory drug composition as described initiated (typically 30 L/min=1.5 m/sec), at which point the above. The respiratory drug composition typically com capacitor was charged with a power Supply, typically to prises at least one respiratory drug Selected from the group between 14-17 Volts. consisting of B-adrenergics, methyl Xanthines, anti-cholin ergics, corticosteroids, mediator-release inhibitors, anti-leu 0.137 The circuit was closed with a switch, causing the kotriene drugs, asthma inhibitors, asthma antagonists, and drug-coated foil to resistively heat to temperatures of about pharmaceutically acceptable analogs, derivatives, and mix 280-430° C. (as measured with an infrared camera (FLIR tures thereof. In Some variations, the asthma drug conden Thermacam SC3000)), in about 200 milliseconds. After the sation aerosol has a MMAD in the range of about 2-4 lum. drug had vaporized, airflow was stopped and the Teflon(E) filter was extracted with acetonitrile. Drug extracted from 0129. In some variations, the method for treating a res the filter was analyzed generally by HPLC UV absorbance piratory ailment comprises the Step of administering a generally at 225 nm using a gradient method aimed at therapeutically effective amount of a respiratory drug aero detection of impurities to determine percent purity. Also, the Sol to a person with the respiratory ailment, wherein the extracted drug was quantified to determine a percent yield, respiratory drug aerosol comprises a respiratory drug and based on the mass of drug initially coated onto the Substrate. has a MMAD in the range of about 2-4 um, and wherein the A percent recovery was determined by quantifying any drug aerosol has a purity of greater than 90%. remaining on the Substrate and chamber walls, adding this to 0130 Working Examples the quantity of drug recovered in the filter and comparing it to the mass of drug initially coated onto the Substrate. 0131 The following working examples are meant to be illustrative, and are in no way intended to limit the Scope of 0.138 Volatilization Using Aluminum Foil and Halogen the invention. Albuterol, metaproterenol hemisulfate, terb Bulb utaline Sulfate, and triamcinolone acetonide are commer 0.139. A substrate of aluminum foil (3.5 cmx7cm; 0.0005 cially available from Sigma-Aldrich (www.sigma-aldrich inches thick) was precleaned with acetone. A Solution of .com). drug in a minimal amount of Solvent was coated onto the foil 0132) Preparation of Drug-Coating Solution substrate. The solvent was allowed to evaporate. The coated foil was wrapped around a 300 watt halogen tube (Felt 0.133 Drug was dissolved in an appropriate solvent. Electric Company, Pico Rivera, Calif.), which was inserted Common Solvent choices included methanol, dichloromet into a T-shaped glass tube Sealed at two ends with parafilm. ane, methyl ethyl ketone, diethyl ether, 3:1 chloroform The parafilm was punctured with ten to fifteen needles for air :methanol mixture, 1:1 dichlorormethane:methyl ethyl flow. The third opening was connected to a 1 liter, 3-neck ketone mixture, dimethylformamide, and deionized water. glass flask. The glass flask was further connected to a piston Sonication and/or heat were used as necessary to dissolve capable of drawing 1.1 liters of air through the flask. Ninety the compound. The drug concetration was typically between volts of alternating current (driven by line power controlled 50-200 mg/mL. by a Variac) was run through the bulb for 6-7 seconds to generate a thermal vapor (including aeroSol) which was 013.4 Volatilization Using Stainless Steel Foil drawn into the 1 liter flask. The aerosol was allowed to 0135) Strips of clean 304 stainless steel foil (0.0125 cm sediment onto the walls of the 1 liter flask for 30 minutes. thick, Thin Metal Sales) having dimensions 1.3 cm by 7.0 The material collected on the flask walls was recovered and US 2004/0105819 A1 Jun. 3, 2004 20 the following determinations were made: (1) the amount quantify the recovery. Some Samples were further analyzed emitted, (2) the percent emitted, and (3) the purity of the by LC/MS to confirm the molecular weight of the drug and aerosol by reverse-phase HPLC analysis with detection by any degradants. typically by absorption of 225 nm light. Additionally, any material remaining on the Substrate was collected and quan EXAMPLE 1A tified. 0144 Volatilization of Albuterol 0140 Volatilization Using Stainless Steel Cylinder 0145 About 1.2 mg of albuterol was dip coated onto the 0.141. A hollow stainless steel cylinder with thin walls, Stainless Steel Surface of a flashbar apparatus. (The flashbar typically 0.12 mm wall thickness, a diameter of 13 mm, and is a cylinder 3.5 cm long and 1.3 cm in diameter consisting a length of 34 mm was cleaned in dichloromethane, metha of a hollow tube of 0.005" thick stainless steel). Brass nol, and acetone, then dried, and fired at least once to remove electrodes were connected to either end of the Steel cylinder. any residual volatile material and to thermally passivate the The coated flashbar was Secured in an electrical mount, Stainless Steel Surface. The Substrate was then dip-coated which connected to two 1.0 Farad capacitors in parallel. An with a drug coating Solution (prepared as described above). airway was provided by a 2 cm diameter glass Sleeve placed The dip-coating was done using a computerized dipcoating around the flashbar. 15 L/min of room air were pulled by a machine to produce a thin layer of drug on the outside of the house vacuum through the vaporization chamber and a filter Substrate Surface. The Substrate was lowered into the drug housing, which contained a two-micron Teflon filter. A Solution and then removed from the solvent at a rate of power Supply charged the capacitors to 20.5 volts, at which typically 5-25 cm/sec. (To coat larger amounts of material point the circuit was closed with a Switch and the Stainless on the Substrate, the Substrate was removed more rapidly steel flashbar was resistively heated to about 400 C. within from the Solvent or the Solution used was more concen about 200 milliseconds. The drug aerosolized and flowed trated.) The Substrate was then allowed to dry for 30 minutes through the airway and into the filter. The Teflon filter was inside a fume hood. If either dimethylformamide (DMF) or extracted with 5 mL of acetonitrile, and the Sample was run a water mixture was used as a dip-coating Solvent, the through an HPLC for purity analysis. Purity analysis indi Substrate was vacuum dried inside a desiccator for a mini cated that the aerosol was 94.4% albuterol. mum of one hour. The drug-coated portion of the cylinder 0146 To obtain higher purity aerosols, one can coat a generally has a Surface area of 8 cm. By assuming a unit lesser amount of drug, yielding a thinner film to heat. A density for the drug, the initial drug coating thickneSS was linear decrease in film thickness is associated with a linear calculated. The amount of drug coated onto the Substrates decrease in impurities. was determined in the same manner as that described above: the Substrates were coated, then extracted with methanol or EXAMPLE 1B acetonitrile and analyzed with quantitative HPLC methods, to determine the mass of drug coated onto the Substrate. 0147 Volatilization of Albuterol 0142. The drug-coated Substrate was placed in a Sur 0148 Albuterol (MW 239, melting point 158°C., MDI rounding glass tube connected at the exit end via Tygon(E) inhalation dose 0.18 mg), a bronchodilator, was coated onto tubing to a filter holder fitted with a Teflon(R) filter (Savillex). six stainless steel foil Substrates (5 cm) according to the The junction of the tubing and the filter was sealed with method “Volatilization Using Stainless Steel Foil” described paraffin film. The Substrate was placed in a fitting for above. The calculated thickness of the drug film on each connection to two 1 Farad capacitors wired in parallel and substrate ranged from about 0.4 um to about 1.6 lum. The controlled by a high current relay. The capacitors were Substrates were heated as described above by charging the charged by a separate power Source to about 18-22 Volts and capacitors to 15 V. Purity of the drug aerosol particles from most of the power was channeled to the Substrate by closing each Substrate was determined and the results are shown in a Switch and allowing the capacitors to discharge into the FIG. 4. Substrate. The Substrate was heated to a temperature of between about 300-500 C. in about 100 milliseconds. The EXAMPLE 2 heating process was done under an airflow of 15 L/min, 0149 Volatilization of Ephedrine which Swept the vaporized drug aeroSol into a 2 micron Teflon(E) filter. 0150. About 8.0 mg was coated onto an aluminum foil substrate as described above in “Volatilization Using Alu 0143. After volatilization, the aerosol captured on the minum Foil and Halogen Bulb,” for a calculated drug film filter was recovered for quantification and analysis. The thickness of about 4.0 lum. The substrate was heated as quantity of material recovered in the filter was used to described above. The purity of the drug-aerosol particles determine a percent yield, based on the mass of drug coated was determined to be about 99%. onto the Substrate. The material recovered in the filter was also analyzed generally by HPLC UV absorbance at typi EXAMPLE 3 cally 225 nm using a gradient method aimed at detection of impurities, to determine purity of the thermal vapor. Any 0151 Volatilization of Metaproterenol material deposited on the glass sleeve or remaining on the 0152 About 1.35 mg of metaproterenol was dip coated Substrate was also recovered and quantified to determine a onto the stainless Steel Surface of a flashbar apparatus. (The percent total recovery (mass of drug in filter+mass of drug flashbar is a cylinder 3.5 cm long and 1.3 cm in diameter remaining on Substrate and glass sleeve)/mass of drug consisting of a hollow tube of 0.005" thick stainless steel). coated onto substrate). For compounds without UV absorp Brass electrodes were connected to either end of the Steel tion GCMS or LC/MS was used to determine purity and to cylinder. The coated flashbar was Secured in an electrical US 2004/0105819 A1 Jun. 3, 2004

mount, which connected to two 1.0 Farad capacitors in EXAMPLE 6A parallel. An airway was provided by a 2 cm diameter glass sleeve placed around the flashbar. 15 L/min of room air were 0157 Volatilization of Ciclesonide pulled by a house vacuum through the vaporization chamber 0158) About 0.204 mg ciclesonide (MW 541, melting and a filter housing, which contained a two-micron Teflon point 206.5-207 C., MDI inhalation dose 0.2 mg) was filter. A power Supply charged the capacitors to 20.5 volts, at coated onto a stainless steel foil Substrate (5 cm) according which point the circuit was closed with a switch and the to the method “Volatilization Using Stainless Steel Foil” Stainless Steel flashbar was resistively heated in the range of described above. The calculated thickness of the drug film about 380-420 C. within about 200 milliseconds. The drug was about 0.4 um. The substrate was heated as described aeroSolized and flowed through the airway and into the filter. above by charging the capacitor to 15 V. Purity analysis The Teflon filter was extracted with 5 mL of acetonitrile, and indicated that the aerosol was 99.03% ciclesonide. A total the sample was run through an HPLC for purity analysis. mass of 0.2 mg was recovered from the test apparatus and Purity analysis indicated that the aerosol was 99.1% metap substrate, for a total recovery of 100%. roterenol. A total mass of 1.2 mg was recovered from the test apparatus and substrate, for a total recovery of 88.9%. EXAMPLE 6B EXAMPLE 4 0159) Volatilization of Ciclesonide 0160 Ciclesonide (MW 541, melting point 206.5-207 0153 Volatilization of Terbutaline C., oral dose 0.2 mg) was coated on stainless Steel foil 0154) About 2.32 mg of terbutaline was dip coated onto substrates (6 cm ) according to the method “Volatilization the stainless Steel Surface of a flashbar apparatus. (The Using Stainless Steel Foil” described above. Eight Substrates flashbar is a cylinder 3.5 cm long and 1.3 cm in diameter were prepared, with the drug film thickness ranging from consisting of a hollow tube of 0.005" thick stainless steel). about 0.4 um to about 2.4 um. The substrates were heated as Brass electrodes were connected to either end of the Steel described above, with the capacitors charged with 15.0 or cylinder. The coated flashbar was Secured in an electrical 15.5 V. Purity of the drug-aerosol particles from each mount, which connected to two 1.0 Farad capacitors in Substrate was determined and the results are shown in FIG. parallel. An airway was provided by a 2 cm diameter glass 5. sleeve placed around the flashbar. 15 L/min of room air were pulled by a house vacuum through the vaporization chamber EXAMPLE 7A and a filter housing, which contained a two-micron Teflon filter. A power supply charged the capacitors to 20.5 volts, at 0161 Volatilization of Flunisolide which point the circuit was closed with a switch and the 0162 About 0.3 mg flunisolide (MW 435, MDI inhala stainless steel flashbar was resistively heated to about 400 tion dose 0.25 mg) was coated onto a stainless Steel foil C. within about 200 milliseconds. The drug aerosolized and substrate (5 cm ) according to the method “Volatilization flowed through the airway and into the filter. The Teflon Using Stainless Steel Foil” described above. The calculated filter was extracted with 5 mL of acetonitrile, and the sample thickness of the drug film was about 0.6 tum. The substrate was run through an HPLC for purity analysis. Purity analysis was heated as described above by charging the capacitor to indicated that the aerosol was 99.3% terbutaline. A total 15 V. Purity analysis indicated that the aerosol was 94.9% mass of 1.9 mg was recovered from the test apparatus and flunisolide. A total mass of 0.3 mg was recovered from the substrate, for a total recovery of 83.5%. test apparatus and substrate, for a total recovery of 100%. EXAMPLE 5 EXAMPLE 7B 0155 Volatilization of Budesonide 0163 Volatilization of Flunisolide 0156. About 1.46 mg of budesonide was dip coated onto 0164. About 0.5 mg of flunisolide was dip coated onto the the stainless Steel Surface of a flashbar apparatus. (The Stainless Steel Surface of a flashbar apparatus. (The flashbar flashbar is a cylinder 3.5 cm long and 1.3 cm in diameter is a cylinder 3.5 cm long and 1.3 cm in diameter consisting consisting of a hollow tube of 0.005" thick stainless steel). of a hollow tube of 0.005" thick stainless steel). Brass Brass electrodes were connected to either end of the Steel electrodes were connected to either end of the Steel cylinder. cylinder. The coated flashbar was Secured in an electrical The coated flashbar was Secured in an electrical mount, mount, which connected to two 1.0 Farad capacitors in which connected to two 1.0 Farad capacitors in parallel. An parallel. An airway was provided by a 2 cm diameter glass airway was provided by a 2 cm diameter glass Sleeve placed sleeve placed around the flashbar. 15 L/min of room air were around the flashbar. 15 L/min of room air were pulled by a pulled by a house vacuum through the vaporization chamber house vacuum through the vaporization chamber and a filter and a filter housing, which contained a two-micron Teflon housing, which contained a two-micron Teflon filter. A filter. A power Supply charged the capacitors to 20.5 volts, at power Supply charged the capacitors to 20.5 volts, at which which point the circuit was closed with a switch and the point the circuit was closed with a Switch and the Stainless stainless steel flashbar was resistively heated to about 400 steel flashbar was resistively heated to about 400 C. within C. within about 200 milliseconds. The drug aerosolized and about 200 milliseconds. The drug aerosolized and flowed flowed through the airway and into the filter. The Teflon through the airway and into the filter. The Teflon filter was filter was extracted with 5 mL of acetonitrile, and the sample extracted with 5 mL of acetonitrile, and the Sample was run was run through an HPLC for purity analysis. Purity analysis through an HPLC for purity analysis. Purity analysis indi indicated that the aerosol was 70.5% budesonide. A total cated that the aerosol was 97.6% flunisolide. A total mass of mass of 0.6 mg was recovered from the test apparatus and 0.5 mg was recovered from the test apparatus and Substrate, substrate, for a total recovery of 41.2%. for a total recovery of 100%. US 2004/0105819 A1 Jun. 3, 2004 22

EXAMPLE 8 EXAMPLE 11 0.165 Volatilization of Fluticasone Propionate 0171 Volatilization of CPX 0166 About 0.3 mg fluticasone propionate (MW 501, 0172. About 0.64 mg. CPX (MW 304) was coated onto a MDI inhalation dose 0.044 mg) was coated onto a stainless stainless steel foil substrate (5 cm) according to the method steel foil substrate (5 cm) according to the method “Vola “Volatilization Using Stainless Steel Foil” described above. tilization Using Stainless Steel Foil” described above. The The calculated thickness of the drug film was about 1.1 um. calculated thickness of the drug film was about 0.6 tum. The The Substrate was heated as described above by charging the Substrate was heated as described above by charging the capacitor to 15 V. Purity analysis indicated that the aerosol capacitor to 15 V. Purity analysis indicated that the aerosol was 99.8% CPX. A total mass of about 0.6 mg was recovered was 91.6% fluticasone propionate. A total mass of about 0.2 from the test apparatus and Substrate, for a total recovery of mg was recovered from the test apparatus and Substrate, for about 98.0%. a total recovery of about 71.4%. EXAMPLE 12 EXAMPLE 9 0173 Volatilization of IBMX 0167 Volatilization of Triamcinolone Acetonide 0.174. About 0.66 mg IBMX (MW 222) was coated onto 0168 About 0.2 mg of triamcinolone acetonide was dip a stainless steel foil Substrate (5 cm) according to the coated onto the StainleSS Steel Surface of a flashbar appara method “Volatilization Using Stainless Steel Foil” described tus. (The flashbar is a cylinder 3.5 cm long and 1.3 cm in above. The calculated thickness of the drug film was about diameter consisting of a hollow tube of 0.005" thick stain 1.2 tum. The substrate was heated as described above by less Steel). Brass electrodes were connected to either end of charging the capacitor to 15 V. Purity analysis indicated that the Steel cylinder. The coated flashbar was Secured in an the aerosol was 99.9% IBMX. A total mass of about 0.66 mg electrical mount, which connected to two 1.0 Farad capaci was recovered from the test apparatus and Substrate, for a tors in parallel. An airway was provided by a 2 cm diameter total recovery of about 100%. glass sleeve placed around the flashbar. 15 L/min of room air were pulled by a house vacuum through the vaporization EXAMPLE 13 chamber and a filter housing, which contained a two-micron 0175 Volatilization of a Mixture of Albuterol and Teflon filter. A power Supply charged the capacitors to 20.5 Flunisolide volts, at which point the circuit was closed with a Switch and 0176). A solution of about 0.20 mg flunisolide (MW 435, the stainless steel flashbar was resistively heated to about oral dose 0.25 mg) and about 0.16 mg albuterol (MW 239, 400 C. within about 200 milliseconds. The drug aerosolized melting point 158 C., oral dose 0.18 mg) was coated onto and flowed through the airway and into the filter. The Teflon a stainless steel foil Substrate (5 cm) according to the filter was extracted with 5 mL of acetonitrile, and the sample method “Volatilization Using Stainless Steel Foil” described was run through an HPLC for purity analysis. Purity analysis above. The calculated thickness of the drug film was about indicated that the aerosol was about 92.0% triamcinolone 0.64 um. The substrate was heated as described above by acetonide. A total mass of about 0.1 mg was recovered from charging the capacitor to 15.5 V. Purity analysis indicated the test apparatus and Substrate, for a total recovery of about that the aerosol was composed of albuterol (97.2% purity) 50%. and flunisolide (94.5%) along with their associated impuri ties. A total mass of 0.36 mg was recovered from the test EXAMPLE 10 apparatus and substrate, for a total recovery of 100%. 0169 Volatilization of Theophylline 0177. While the present invention has been described 0170 About 0.86 mg of theophylline was dip coated onto with reference to one or more particular variations, those the stainless Steel Surface of a flashbar apparatus. (The skilled in the art will recognize that many changes may be flashbar is a cylinder 3.5 cm long and 1.3 cm in diameter made hereto without departing from the Spirit and Scope of consisting of a hollow tube of 0.005" thick stainless steel). the devices and methods herein described and claimed. Brass electrodes were connected to either end of the Steel What we claim is: cylinder. The coated flashbar was Secured in an electrical 1. A method for treating a respiratory ailment comprising mount, which connected to two 1.0 Farad capacitors in parallel. An airway was provided by a 2 cm diameter glass the step of: sleeve placed around the flashbar. 15 L/min of room air were administering a therapeutically effective amount of a pulled by a house vacuum through the vaporization chamber respiratory drug condensation aerosol to a perSon with and a filter housing, which contained a two-micron Teflon the respiratory ailment, wherein the Step of adminis filter. A power Supply charged the capacitors to 20.5 volts, at tering comprises the Step of administering an orally which point the circuit was closed with a switch and the inhalable respiratory drug condensation aerosol to the stainless steel flashbar was resistively heated to about 400 person with the respiratory ailment, and wherein the C. within about 200 milliseconds. The drug aerosolized and aerosol comprises at least 50% by weight of a respira flowed through the airway and into the filter. The Teflon tory drug. filter was extracted with 5 mL of acetonitrile, and the sample 2. The method of claim 1 wherein the respiratory drug is was run through an HPLC for purity analysis. Purity analysis Selected from the group consisting of B-adrenergics, meth indicated that the aerosol was about 99.5% theophylline. A ylxanthines, anticholinergics, corticosteroids, mediator-re total mass of about 0.86 mg was recovered from the test lease inhibitors, anti-leukotriene drugs, asthma inhibitors, apparatus and substrate, for a total recovery of about 100%. asthma antagonists, anti-endothelin drugs, proStacyclin US 2004/0105819 A1 Jun. 3, 2004

drugs, ion channel or pump inhibitors, enhancers, or modu fenspiride, hexoprenaline, isoetharine, isoproterenol, lators and pharmaceutically acceptable analogs, derivatives, mabuterol, methoxyphenamine, pirbuterol, procaterol, pro and mixtures thereof. tokylol, rimiterol, Salmeterol, Soterenol, tretoquinol, 3. The method of claim 2 wherein the respiratory drug is tulobuterol, caffeine, theophylline, aminophylline, acefyl Selected from the group consisting of albuterol, epinephrine, line, bamifylline, doxofylline, dyphylline, etamiphyllin, metaproterenol, terbutaline, pseudoephedrine hydrochlo etofylline, proxyphylline, reproterol, theobromine-1-acetic ride, bambuterol, bitolterol, carbuterol, clenbuterol, clorpre acid, atropine, ipratropium bromide, flutropium bromide, nalin, dioxethedrine, eproZinol, etefiedrine, ethylnorepineph OXitropium bromide, tiotropium bromide, budesonide, rine, fenoterol, fenspiride, heXoprenaline, isoetharine, beclomethasone, cicleSonide, dexamethasone, flunisolide, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, fluticasone propionate, triamcinolone acetonide, predniso procaterol, protokylol, rimiterol, Salmeterol, Soterenol, tre lone, methylprednisolone, hydrocortisone, cromolyn toquinol, tulobuterol, caffeine, theophylline, aminophylline, Sodium, nedocromil Sodium, montelukast, Zafirlukast, pir acefylline, bamifylline, doxofylline, dyphylline, etamiphyl fenidone, CPX, IBMX, cilomilast, roflumilast, pumafen lin, etofylline, proxyphylline, reproterol, theobromine-1- trine, domitroban, israpafant, ramatroban, Seratrodast, tiara acetic acid, atropine, ipratropium bromide, flutropium bro mide, Zileuton, ambrisentan, boSentan, enrasentan, mide, OXitropium bromide, tiotropium bromide, budeSonide, SitaXSentan, teZosentan, iloprost, treprostinil, and pharma beclomethasone, cicleSonide, dexamethasone, flunisolide, ceutically acceptable analogs, derivatives, and mixtures fluticasone propionate, triamcinolone acetonide, predniso thereof. lone, methylprednisolone, hydrocortisone, cromolyn 11. The method of claim 8 wherein the respiratory drug Sodium, nedocromil Sodium, montelukast, Zafirlukast, pir composition further comprises a pharmaceutically accept fenidone, CPX, IBMX, cilomilast, roflumilast, pumafen able excipient. trine, domitroban, israpafant, ramatroban, Seratrodast, tiara 12. The method of claim 8 wherein the respiratory drug mide, Zileuton, ambrisentan, boSentan, enrasentan, condensation aerosol comprises at least 50% by weight of a SitaXSentan, teZosentan, iloprost, treprostinil, and pharma respiratory drug. ceutically acceptable analogs, derivatives, and mixtures 13. A respiratory drug condensation aerosol comprising: thereof. respiratory drug condensation aerosol particles, wherein 4. The method of claim 1 wherein the respiratory drug the respiratory drug aerosol particles comprise a respi condensation aerosol has a MMAD in the range of about ratory drug Selected from the group consisting of 1.5-4 um. B-adrenergics, methylxanthines, anticholinergics, cor 5. The method of claim 1 wherein the respiratory drug ticosteroids, mediator-release inhibitors, anti-leukot condensation aerosol has a MMAD in the range of about riene drugs, asthma inhibitors, asthma antagonists, anti 10-100 nm. endothelin drugs, prostacyclin drugs, ion channel or 6. The method of claim 1 wherein the step of adminis pump inhibitors, enhancers, or modulators, and phar tering the respiratory drug condensation aerosol comprises maceutically acceptable analogs, derivatives, and mix the Step of administering the respiratory drug condensation tures thereof, and wherein the respiratory drug conden aeroSol in a single inhalation. sation aerosol has a MMAD in the range of about 2-4 7. The method of claim 1 wherein the step of adminis plm. tering the respiratory drug condensation aerosol comprises 14. The respiratory drug condensation aerosol of claim 13 the Step of administering the respiratory drug condensation wherein the respiratory drug is Selected from the group aeroSol in more than one inhalation. consisting of albuterol, epinephrine, metaproterenol, terb 8. A method for forming a respiratory drug condensation utaline, pseudoephedrine hydrochloride, bambuterol, aeroSol comprising the Steps of: bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethe providing a respiratory drug composition in a unit dose drine, eproZinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, form; and mabuterol, methoxyphenamine, pirbuterol, procaterol, pro Vaporizing the respiratory drug composition, wherein the tokylol, rimiterol, Salmeterol, Soterenol, tretoquinol, Step of vaporizing the respiratory drug composition tulobuterol, caffeine, theophylline, aminophylline, acefyl comprises the Step of heating the composition to form line, bamifylline, doxofylline, dyphylline, etamiphyllin, a Vapor. etofylline, proxyphylline, reproterol, theobromine-1-acetic 9. The method of claim 8 wherein the respiratory drug acid, atropine, ipratropium bromide, flutropium bromide, composition comprises a respiratory drug Selected from the OXitropium bromide, tiotropium bromide, budesonide, group consisting of B-adrenergics, methylxanthines, anti beclomethasone, cicleSonide, dexamethasone, flunisolide, cholinergics, corticosteroids, mediator-release inhibitors, fluticasone propionate, triamcinolone acetonide, predniso anti-leukotriene drugs, asthma inhibitors, asthma antago lone, methylprednisolone, hydrocortisone, cromolyn nists, anti-endothelin drugs, proStacyclin drugs, ion channel Sodium, nedocromil Sodium, montelukast, Zafirlukast, pir or pump inhibitors, enhancers, or modulators, and pharma fenidone, CPX, IBMX, cilomilast, roflumilast, pumafen ceutically acceptable analogs, derivatives, and mixtures trine, domitroban, israpafant, ramatroban, Seratrodast, tiara thereof. mide, Zileuton, ambrisentan, boSentan, enrasentan, 10. The respiratory drug condensation aerosol of claim 9 SitaXSentan, teZosentan, iloprost, treprostinil, and pharma wherein the respiratory drug is Selected from the group ceutically acceptable analogs, derivatives, and mixtures consisting of albuterol, epinephrine, metaproterenol, terb thereof. utaline, pseudoephedrine hydrochloride, bambuterol, 15. The respiratory drug condensation aerosol of claim 13 bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethe wherein the aerosol comprises at least 50% by weight of a drine, eproZinol, etefedrine, ethylnorepinephrine, fenoterol, respiratory drug. US 2004/0105819 A1 Jun. 3, 2004 24

16. The respiratory drug condensation aerosol of claim 13 23. The method of claim 22 wherein the respiratory drug wherein the aeroSol is Substantially free of thermal degra is Selected from the group consisting of B-adrenergics, dation products. methylxanthines, anticholinergics, corticosteroids, media 17. A kit for delivering a respiratory drug condensation tor-release inhibitors, anti-leukotriene drugs, asthma inhibi aeroSol comprising: tors, asthma antagonists, endothelin antagonists, prostacy lins, and pharmaceutically acceptable analogs, derivatives, a composition comprising a respiratory drug in a unit dose and mixtures thereof. form; and 24. The method of claim 23 wherein the respiratory drug a device for forming a respiratory drug aeroSol, wherein is Selected from the group consisting of albuterol, epineph the device for forming the respiratory drug aeroSol rine, metaproterenol, terbutaline, pseudoephedrine hydro chloride, bambuterol, bitolterol, carbuterol, clenbuterol, clo comprises an element configured to heat the composi rprenalin, dioxethedrine, eprozinol, etefiedrine, tion to form a vapor, an element allowing the vapor to ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, condense to form a condensation aeroSol, and an ele isoetharine, isoproterenol, mabuterol, methoxyphenamine, ment permitting a user to inhale the condensation pirbuterol, procaterol, protokylol, rimiterol, Salmeterol, aeroSol. Soterenol, tretoquinol, tulobuterol, caffeine, theophylline, 18. The kit of claim 17 wherein the composition further aminophylline, acefylline, bamifylline, doxofylline, dyphyl comprises a pharmaceutically acceptable excipient. line, etamiphyllin, etofylline, proxyphylline, reproterol, 19. The kit of claim 17 wherein the respiratory drug theobromine-1-acetic acid, atropine, ipratropium bromide, condensation aerosol comprises at least 50% by weight of a flutropium bromide, OXitropium bromide, tiotropium bro respiratory drug. mide, budesonide, beclomethasone, cicleSonide, dexametha 20. The kit of claim 17 wherein the respiratory drug is Sone, flunisolide, fluticaSone propionate, triamcinolone Selected from the group consisting of B-adrenergics, meth acetonide, prednisolone, methylprednisolone, hydrocorti ylxanthines, anticholinergics, corticosteroids, mediator-re Sone, cromolyn Sodium, nedocromil Sodium, montelukast, lease inhibitors, anti-leukotriene drugs, asthma inhibitors, Zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumi asthma antagonists, anti-endothelin drugs, proStacyclin last, pumafentrine, domitroban, israpafant, ramatroban, drugs, ion channel or pump inhibitors, enhancers, or modu Seratrodast, tiaramide, Zileuton, ambrisentan, boSentan, lators, and pharmaceutically acceptable analogs, derivatives, enrasentan, SitaXSentan, teZoSentan, iloprost, treprostinil, and mixtures thereof. and pharmaceutically acceptable analogs, derivatives, and 21. The kit of claim 20 wherein the respiratory drug is mixtures thereof. Selected from the group consisting of albuterol, epinephrine, 25. A composition for delivery of a drug comprising a metaproterenol, terbutaline, pseudoephedrine hydrochlo respiratory drug condensation aeroSol ride, bambuterol, bitolterol, carbuterol, clenbuterol, clorpre nalin, dioxethedrine, eproZinol, etefiedrine, ethylnorepineph a) formed by volatilizing a heat Stable drug composition rine, fenoterol, fenspiride, heXoprenaline, isoetharine, comprising a respiratory drug Selected from the group isoproterenol, mabuterol, methoxyphenamine, pirbuterol, consisting of B-adrenergics, methylxanthines, anticho procaterol, protokylol, rimiterol, Salmeterol, Soterenol, tre linergics, corticosteroids, mediator-release inhibitors, toquinol, tulobuterol, caffeine, theophylline, aminophylline, anti-leukotriene drugs, asthma inhibitors, asthma acefylline, bamifylline, doxofylline, dyphylline, etamiphyl antagonists, anti-endothelin drugs, prostacyclin drugs, lin, etofylline, proxyphylline, reproterol, theobromine-1- ion channel or pump inhibitors, enhancers, or modula acetic acid, atropine, ipratropium bromide, flutropium bro tors under conditions effective to produce a heated mide, OXitropium bromide, tiotropium bromide, budeSonide, Vapor of Said drug composition and condensing the beclomethasone, cicleSonide, dexamethasone, flunisolide, heated vapor of the drug composition to form conden fluticasone propionate, triamcinolone acetonide, predniso sation aerosol particles and wherein the respiratory lone, methylprednisolone, hydrocortisone, cromolyn drug condensation aeroSol has a MMAD in the range of about 2-4 um. Sodium, nedocromil Sodium, montelukast, Zafirlukast, pir 26. The composition of claim 25, wherein the heat stable fenidone, CPX, IBMX, cilomilast, roflumilast, pumafen drug is Selected from the group consisting albuterol, epi trine, domitroban, israpafant, ramatroban, Seratrodast, tiara nephrine, metaproterenol, terbutaline, pseudoephedrine mide, Zileuton, ambrisentan, boSentan, enrasentan, hydrochloride, bambuterol, bitolterol, carbuterol, clen SitaXSentan, teZosentan, iloprost, treprostinil, and pharma buterol, clorprenalin, dioxethedrine, eproZinol, etefiedrine, ceutically acceptable analogs, derivatives, and mixtures ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, thereof. isoetharine, isoproterenol, mabuterol, methoxyphenamine, 22. A method for treating a respiratory ailment comprising pirbuterol, procaterol, protokylol, rimiterol, Salmeterol, the step of: Soterenol, tretoquinol, tulobuterol, caffeine, theophylline, administering a therapeutically effective amount of a aminophylline, acefylline, bamifylline, doxofylline, dyphyl respiratory drug condensation aerosol to a person with line, etamiphyllin, etofylline, proxyphylline, reproterol, the respiratory ailment, wherein the respiratory drug theobromine-1-acetic acid, atropine, ipratropium bromide, aeroSol comprises a respiratory drug and has a MMAD flutropium bromide, OXitropium bromide, tiotropium bro in the range of about 1.5-4 um and a purity of at least mide, budesonide, beclomethasone, cicleSonide, dexametha Sone, flunisolide, fluticaSone propionate, triamcinolone 90%, and acetonide, prednisolone, methylprednisolone, hydrocorti wherein the Step of administering comprises the Step of Sone, cromolyn Sodium, nedocromil Sodium, montelukast, administering an orally inhalable respiratory drug aero Zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumi Sol to the person with the respiratory ailment. last, pumafentrine, domitroban, israpafant, ramatroban, US 2004/0105819 A1 Jun. 3, 2004

Seratrodast, tiaramide, Zileuton, ambrisentan, boSentan, drug condensation aerosol to the perSon with the res enrasentan, SitaXSentan, teZoSentan, iloprost, treprostinil, piratory ailment, and wherein the aerosol comprises at and pharmaceutically acceptable analogs, derivatives, and least 50% by weight of a respiratory drug. mixtures thereof. 34. A method of producing a heat Stable respiratory drug 27. The composition of claim 25, wherein the condensa in an aeroSol form comprising: tion aerosol particles are characterized by less than 5% drug degradation products a) volatilizing a heat stable respiratory drug under con 28. The composition of claim 25, wherein said drug ditions effective to produce a heated vapor of the drug composition comprises at least two drugs. and 29. The composition of claim 28, wherein at least one b) during said volatilizing, passing through the heated drug of the drug composition is a reliever and another drug Vapor to produce aerosol particles of the drug and an of the drug composition is a controller. aerosol having an MMAD in the range of 1.5-4. 30. The composition of claim 29, wherein the reliever is 35. The method of claim 34, wherein the aerosol particles a f-adrenergic. comprise less than 5% compound degradation products. 31. The composition of claim 30, wherein the controller 36. The method of claim 34, wherein said volatilizing is a corticosteriod. includes heating a coating of the respiratory drug, which is 32. The composition of claim 29, wherein the controller formed on a Solid Support having the Surface texture of a is a corticosteriod. metal foil, to a temperature Sufficient to volatized the com 33. A method for treating a respiratory ailment comprising pound from the coating. the step of: 37. The method of claim 36, wherein said coating com administering a therapeutically effective amount of a prises at least two respiratory drugs. respiratory drug condensation aerosol comprising a 38. The method of claim 37, wherein at least one drug is heat Stable respiratory drug to a person with the respi a reliever and another drug is a controller. ratory ailment, wherein the Step of administering com prises administering an orally inhalable respiratory