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USOO681.4955B2 (12) United States Patent (10) Patent No.: US 6,814,955 B2 Rabinowitz et al. (45) Date of Patent: Nov. 9, 2004

(54) DELIVERY OF PHYSIOLOGICALLY ACTIVE WO WOOO/662O6 11/2000 COMPOUNDS THROUGH AN INHALATION WO WO OO/76673 12/2000 ROUTE WO WO 01/O5459 1/2001 WO WO 01/13957 3/2001 (75) Inventors: Joshua D. Rabinowitz, Mountain View, WO WO 01/41732 6/2001 CA (US); Alejandro C. Zaffaroni, OTHER PUBLICATIONS Atherton, CA (US) Office Action mailed Aug. 13, 2003 for U.S. application (73) Assignee: Alexza Molecular Delivery 10/153,313 filed May 21, 2002 “Delivery of Benzodiaz Corporation, Palo Alto, CA (US) epines through an Inhalation Route'. Bennett, R.L. et al. (1981). “Patient-Controlled Analgesia: A (*) Notice: Subject to any disclaimer, the term of this New Concept of Postoperative Pain Relief.” Annual Surg. patent is extended or adjusted under 35 195(6):700–705. U.S.C. 154(b) by 10 days. Carroll, M.E. et al. (1990), “Cocaine-base smoking in rhesus monkeys: reinforcing and physiological effects,” (21) Appl. No.: 10/154,765 Psychopharmacology (Berl). 102:443-450. Clark, A. and Byron, P. (1986). “Dependence of Pulmonary (22) Filed: May 23, 2002 Absorption Kinetics on Aerosol Particle Size, Z. Erkrank. (65) Prior Publication Data 166:13–24. US 2003/0017114A1 Jan. 23, 2003 (List continued on next page.) Related U.S. Application Data Primary Examiner Michael G. Hartley (60) Provisional application No. 60/294.203, filed on May 24, Assistant Examiner Mina Haghighatian 2001, and provisional application No. 60/317,479, filed on (74) Attorney, Agent, or Firm-Elaine C. Stracker Sep. 5, 2001. (57) ABSTRACT (51) Int. Cl...... A61K 9/12; A61K 9/14 The present invention relates to the delivery of physiologi (52) U.S. Cl...... 424/45; 424/46; 128/200.24; cally active compounds through an inhalation route. 128/200.23; 125/203.17 Specifically, it relates to aerosols containing physiologically (58) Field of Search ...... 424/45, 46, 489; active compounds that are used in inhalation therapy. In a 128/200.24, 200.23, 200.14; 125/203.17 composition aspect of the present invention, the aeroSol (56) References Cited comprises particles comprising at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, , U.S. PATENT DOCUMENTS conjugated , , , estradiol 3,982,095 A 9/1976 Robinson esters, ethinyl estradiol, ethinyl estradiol esters, or hyOS 4,121,583. A 10/1978 Chen cyamine. In a method aspect of the present invention, RE30.285 E 5/1980 Babington chlordiazepoxide, betahistine, clonidine, testosterone, con 4,303.083. A 12/1981 Burruss, Jr. jugated estrogens, estrogen esters, estradiol, estradiol esters, 4,474,191 A 10/1984 Steiner ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine is 4,683.231 A 7/1987 Glassman delivered to a through an inhalation route. The 4,693,868 A 9/1987 Katsuda et al. method comprises: a) heating a composition, wherein the (List continued on next page.) composition comprises at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, con FOREIGN PATENT DOCUMENTS jugated estrogens, estrogen esters, estradiol, estradiol esters, EP O 358 114 3/1990 ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine, to WO WO 91/07947 6/1991 form a vapor; and, b) allowing the vapor to cool, thereby WO WO 96/09846 4/1996 forming a condensation aerosol comprising particles, which WO WO 96/1.3161 5/1996 is inhaled by the mammal. In a kit aspect of the present WO WO 96/13290 5/1996 invention, a kit for delivering chlordiazepoxide, betahistine, WO WO 96/13291 5/1996 WO WO 96/13292 5/1996 clonidine, testosterone, , estrogen WO WO 96/300.68 10/1996 esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl WO WO 97/27804 8/1997 estradiol esters, or hyoscyamine through an inhalation route WO WO 98/22170 5/1998 to a mammal is provided which comprises: a) a composition WO WO 98/31346 7/1998 comprising at least 5 percent by weight of chlordiazepoxide, WO WO 98/36651 8/1998 betahistine, clonidine, testosterone, conjugated estrogens, WO WO 98/37896 9/1998 estrogen esters, estradiol, estradiol esters, ethinyl estradiol, WO WO 99/16419 4/1999 ethinyl estradiol esters, or hyoscyamine; and, b) a device WO WO 99/64094 12/1999 that forms a chlordiazepoxide, betahistine, clonidine, WO WO OO/OO176 1/2000 testosterone, conjugated estrogens, estrogen esters, WO WO OO/OO215 1/2000 WO WO OO/29053 5/2000 estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol WO WO OO/47203 8/2000 esters, or hyoscyamine containing aerosol from the WO WO OO/47203 9/2000 composition, for inhalation by the mammal. WO WO OO/64940 11/2000 WO WOOO/66084 11/2000 5 Claims, 1 Drawing Sheet US 6,814,955 B2 Page 2

U.S. PATENT DOCUMENTS Gonda.I. (1991). “Particle Deposition in the Human Respi 4,708,151 A 11/1987 Shelar ratory Tract,” Chapter 176, The Lung. Scientific Founda 4,714,082 A 12/1987 Banerjee et al. tions. Crystal R.G. and West, J.B. (eds.), Raven Publishers, 4,734,560 A 3/1988 Bowen New York. pp. 2289–2294. 4,735,217 A 4f1988 Gerth et al. Hatsukami D, et al. (May 1990) “A method for delivery of 4,753,758 A 6/1988 Miller precise doses of Smoked cocaine-base to humans.” Phar 4,756,318 A 7/1988 Clearman et al. macology Biochemistry & Behavior. 36(1):1-7. 4,771,795. A 9/1988 White et al. Heyder, J. et al., (1986). “Deposition of Particles in the 4,793,365 A 12/1988 Sensabaugh, Jr. et al. Human Respiratory Tract in the Size Range 0.005-15 um.” 4,819,665 A 4f1989 Roberts et al. 4,848,374. A 7/1989 Chard et al. J. Aerosol Sci. 17(5):811-822. 4.853,517 A 8/1989 Bowen et al. Huizer, H., “Analytical studies on illicit heron. V. Efficacy of 4,854,331 A 8/1989 Banerjee et al. Volatilization during heroin Smoking.” Pharmaceutisch 4,858,630 A 8/1989 Banerjee et al. Weekblad Scientific Edition (1987). 9(4):203-211. 4.881,556 A 11/1989 Clearman et al. Hurt, R.D., MD and Robertson, C.R., PhD, (Oct. 1998). 4,895,719 A 1/1990 Radhakrishnan et al. “Prying Open the Door to the Tobacco Industry’s Secrets 4,906,417 A 3/1990 Gentry About Nicotine: The Minnesota Tobacco Trial,” JAMA 4,917,119 A 4/1990 Potter et al. 280(13): 1173–1181. 4,922.901 A 5/1990 Brooks et al. Lichtman, A.H. et al. (1996). “Inhalation Exposure to Vola 4,928,714 A 5/1990 Shannon tilized Opioids Produces Antinociception in Mice,” Journal 4.941,483 A 7/1990 Ridings et al. of Pharmacology and Experimental Therapeutics. 4.947.874 A 8/1990 Brooks et al. 4.947.875 A 8/1990 Brooks et al. 279(1):69–76. 4,989,619 A 2/1991 Clearman et al. Matrin, B.R. and Lue, L.P. (May/Jun. 1989). “Pyrolysis and 5,099,861 A 3/1992 Clearman et al. Volatilization of Cocaine,” Journal of Analytical Toxicology 5,388,574. A * 2/1995 Ingebretsen ...... 125/2O3.17 13:158-162. 5,457,100 A 10/1995 Daniel Mattox, A.J. and Carroll, M.E., (1996). “Smoked heroin 5,544,646 A 8/1996 Lloyd et al. Self-administration in rhesus monkeys,” Psychopharmacol 5,655,523 A 8/1997 Hodson et al. ogy, 125:195-201. 5,694,919 A 12/1997 Rubsamen et al. 5,735,263 A 4/1998 Rubsamen et al. Meng, Y. et al. Inhalation Studies With Drugs of Abuse, 5,738,865 A 4/1998 Baichwal et al. NIDA Research Monograph, (1997) 173:201-224. 5,758,637 A 6/1998 Ivri et al. Meng, Y., et al. (1999). “Pharmacological effects of meth 5,915,378 A 6/1999 Lloyd et al. amphetamine and other Stimulants via inhalation exposure,” 5,934.272 A 8/1999 Lloyd et al. Drug and Alcohol Dependence. 53:111-120. 5,957,124 A 9/1999 Lloyd et al. Pankow, J.F. et al. (1997). “Conversion of Nicotine in 5,960,792 A 10/1999 Lloyd et al. Tobacco Smoke to Its Volatile and Available Free-Base 6,041.777 A * 3/2000 Faithfull et al...... 128/200.24 Form Through the Action of Gaseous Ammonia, Environ. 6,095,134 A 8/2000 Sievers et al. Sci. Technol. 3 1:2428-2433. 6,095,153 A 8/2000 Kessler et al. 6,102,036 A 8/2000 Slutsky et al. Pankow, J. (Mar. 2000). ACS Conference-San Francisco 6,299,900 B1 10/2001 Reed et al. Mar. 26, 2000. Chemistry of Tobacco Smoke. pp. 1-8. 6,306.431 B1 10/2001 Zhang et al. Seeman, J. et al. (1999). “The Form of Nicotine in Tobacco. 6,514,482 B1 2/2003 Bartus et al...... 424/45 Thermal Transfer of Nicotine and Nicotine Acid Salts to 6,591839 B2 7/2003 Meyer et al. Nicotine in the Gas Phase,” J. Agric. Food Chem. 2002/0058009 A1 5/2002 Bartus et al. 47(12):5133–5145. 2003/0032638 A1 2/2003 Kim et al. Sekine, H. and Nakahara, Y. (1987). “Abuse of Smoking OTHER PUBLICATIONS Methamphetamine Mixed with Tobacco: 1. Inhalation Effi ciency and Pyrolysis Products of Methamphetamine,” Jour Darquenne, C. et al. (1997). “Aerosol Dispersion in Human nal of Forensic Science 32(5):1271–1280. Lung: Comparison Between Numerical Simulations and Vapotronics, Inc. (1998) located at http://www.vapotronics. Experiments for Bolus Tests,” American Physiological Soci com.au/banner.htm., 11 pages, (visited on Jun. 5, 2000). ety. 966–974. Ward, M.E. MD, et al. (Dec. 1997). “Morphine Pharmaco Davies, C.N. et al. (May 1972). “Breathing of Half-Micron kinetics after Pulmonary Administration from a Novel Aero Aerosols,” Journal of Applied Physiology. 32(5):591-600. Sol Delivery System,” Clinical Pharmacology & Therapeu Dershwitz, M., M.D., et al. (Sep. 2000). “Pharmacokinetics tics 62(6):596–609. and of Inhaled versus Intravenous Mor Wood, R.W. et al. (1996). “Generation of Stable Test Atmo phine in Healthy Volunteers,” Anesthesiology. 93(3): spheres of Cocaine Base and Its Pyrolyzate, Methylecgoni 619-628. dine, and Demonstration of Their Biological Activity.” Finlay, W.H. (2001). “The Mechanics of Inhaled Pharma Pharmacology Biochemistry & Behavior. 55(2):237-248. ceutical Aerosols”, Academic Press: San Diego Formula 2.39. pp. 3-14 (Table of Contents). pp. v.-viii. * cited by examiner U.S. Patent Nov. 9, 2004 US 6,814,955 B2

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2 US 6,814,955 B2 1 2 DELIVERY OF PHYSIOLOGICALLY ACTIVE Typically, the aerosol particles comprise less than 90 COMPOUNDS THROUGH AN INHALATION percent by weight of water. Preferably, the particles com ROUTE prise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 This application claims priority to U.S. provisional appli percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 cation Ser. No. 60/294,203 entitled “Thermal Vapor Deliv percent, or 5 percent by weight of water. ery of Drugs,” filed May 24, 2001, Rabinowitz and Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up leSS Zaffaroni, the entire disclosure of which is hereby incorpo than 50 percent by weight of the total aerosol weight, rated by reference. This application further claims priority to regardless of the nature of individual particles. Preferably, at U.S. provisional application Ser. No. 60/317,479 entitled least 75 percent by weight of the aerosol is amorphous in “Aerosol Drug Delivery,” filed Sep. 5, 2001, Rabinowitz and form. More preferably, at least 90 percent by weight of the Zaffaroni, the entire disclosure of which is hereby incorpo aeroSol is amorphous in form. rated by reference. Typically, where the aerosol comprises chlordiazepoxide, FIELD OF THE INVENTION the aerosol has an inhalable aerosol drug mass density of 15 between 1 mg/L and 40 mg/L. Preferably, the aerosol has an The present invention relates to the delivery of physi inhalable aerosol drug mass density of between 2 mg/L and ologically active compounds through an inhalation route. 30 mg/L. More preferably, the aerosol has an inhalable Specifically, it relates to aerosols containing physiologically aeroSol drug mass density of between 3 mg/L and 20 mg/L. active compounds that are used in inhalation therapy. Typically, where the aerosol comprises betahistine, the aeroSol has an inhalable aeroSol drug mass density of BACKGROUND OF THE INVENTION between 0.5 mg/L and 50 mg/L. Preferably, the aerosol has It is desirable to provide a new route of administration for an inhalable aerosol drug mass density of between 2 mg/L physiologically active compounds that rapidly produces and 30 mg/L. More preferably, the aerosol has an inhalable peak plasma concentrations of the compound. The provision aeroSol drug mass density of between 5 mg/L and 20 mg/L. of Such a route is an object of the present invention. 25 Typically, where the aerosol comprises clonidine, the aeroSol has an inhalable aeroSol drug mass density of SUMMARY OF THE INVENTION between 0.02 mg/L and 2 mg/L. Preferably, the aerosol has The present invention relates to the delivery of physi an inhalable aerosol drug mass density of between 0.03 ologically active compounds through an inhalation route. mg/L and 1.5 mg/L. More preferably, the aerosol has an Specifically, it relates to aerosols containing physiologically inhalable aerosol drug mass density of between 0.05 mg/L active compounds that are used in inhalation therapy. and 1 mg/L. In a composition aspect of the present invention, the Typically, where the aerosol comprises testosterone, the aeroSol comprises particles comprising at least 5 percent by aeroSol has an inhalable aeroSol drug mass density of weight of chlordiazepoxide, betahistine, clonidine, 35 between 0.1 mg/L and 20 mg/L. Preferably, the aerosol has testosterone, conjugated estrogens, estrogen esters, an inhalable aeroSol drug mass density of between 0.2 mg/L estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol and 10 mg/L. More preferably, the aerosol has an inhalable esters, or hyoscyamine. Preferably, the particles comprise at aeroSol drug mass density of between 0.5 mg/L and 5 mg/L. least 10 percent by weight of chlordiazepoxide, betahistine, Typically, where the aerosol comprises conjugated estro clonidine, testosterone, conjugated estrogens, estrogen 40 gens or estrogen esters, the aerosol has an inhalable aeroSol esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl drug mass density of between 0.05 mg/L and 5 mg/L. estradiol esters, or hyoscyamine. More preferably, the par Preferably, the aerosol has an inhalable aerosol drug mass ticles comprise at least 20 percent, 30 percent, 40 percent, 50 density of between 0.1 mg/L and 2 mg/L. More preferably, percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 the aerosol has an inhalable aerosol drug mass density of percent, 97 percent, 99 percent, 99.5 percent or 99.97 45 between 0.15 mg/L and 1.5 mg/L. percent by weight of chlordiazepoxide, betahistine, Typically, where the aerosol comprises conjugated clonidine, testosterone, conjugated estrogens, estrogen estradiol, estradiol esters, ethinyl estradiol, or ethinyl estra esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl diol esters, the aerosol has an inhalable aerosol drug mass estradiol esters, or hyoscyamine. density of between 0.001 mg/L and 0.2 mg/L. Preferably, the Typically, the aerosol has a mass of at least 1 lug. 50 aeroSol has an inhalable aeroSol drug mass density of Preferably, the aerosol has a mass of at least 10 ug. More between 0.002 mg/L and 0.1 mg/L. More preferably, the preferably, the aerosol has a mass of at least 20 ug. aeroSol has an inhalable aeroSol drug mass density of Typically, the aerosol particles comprise less than 10 between 0.004 mg/L and 0.05 mg/L. percent by weight of chlordiazepoxide, betahistine, Typically, where the aeroSol comprises hyoscyamine, the clonidine, testosterone, conjugated estrogens, estrogen 55 aeroSol has an inhalable aeroSol drug mass density of esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl between 0.01 mg/L and 1 mg/L. Preferably, the aerosol has estradiol esters, or hyoscyamine degradation products. an inhalable aerosol drug mass density of between 0.025 Preferably, the particles comprise less than 5 percent by mg/L and 0.75 mg/L. More preferably, the aerosol has an weight of chlordiazepoxide, betahistine, clonidine, inhalable aerosol drug mass density of between 0.05 mg/L testosterone, conjugated estrogens, estrogen esters, 60 and 0.5 mg/L. estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol Typically, the aerosol has an inhalable aerosol particle esters, or hyoscyamine degradation products. More density greater than 10 particles/mL. Preferably, the aerosol preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or has an inhalable aerosol particle density greater than 107 0.03 percent by weight of chlordiazepoxide, betahistine, particles/mL. More preferably, the aerosol has an inhalable clonidine, testosterone, conjugated estrogens, estrogen 65 aerosol particle density greater than 10 particles/mL. esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl Typically, the aerosol particles have a mass median aero estradiol esters, or hyoscyamine degradation products. dynamic diameter of less than 5 microns. Preferably, the US 6,814,955 B2 3 4 particles have a mass median aerodynamic diameter of leSS esters, or hyoscyamine degradation products. More than 3 microns. More preferably, the particles have a mass preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or median aerodynamic diameter of less than 2 or 1 micron(s). 0.03 percent by weight of chlordiazepoxide, betahistine, Typically, the geometric Standard deviation around the clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl mass median aerodynamic diameter of the aerosol particles estradiol esters, or hyoscyamine degradation products. is less than 3.0. Preferably, the geometric standard deviation Typically, the particles of the delivered condensation is less than 2.85. More preferably, the geometric standard aeroSol have a mass median aerodynamic diameter of leSS deviation is less than 2.7. than 5 microns. Preferably, the particles have a mass median Typically, the aerosol is formed by heating a composition aerodynamic diameter of less than 3 microns. More containing chlordiazepoxide, betahistine, clonidine, preferably, the particles have a mass median aerodynamic testosterone, conjugated estrogens, estrogen esters, diameter of less than 2 or 1 micron(s). estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol Typically, the geometric Standard deviation around the esters, or hyoscyamine to form a vapor and Subsequently mass median aerodynamic diameter of the aerosol particles allowing the vapor to condense into an aeroSol. is less than 3.0. Preferably, the geometric standard deviation In a method aspect of the present invention, 15 is less than 2.85. More preferably, the geometric standard chlordiazepoxide, betahistine, clonidine, testosterone, con deviation is less than 2.7. jugated estrogens, estrogen esters, estradiol, estradiol esters, Typically, the particles of the delivered condensation ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine is aeroSol comprise less than 90 percent by weight of water. delivered to a mammal through an inhalation route. The Preferably, the particles comprise less than 80 percent by method comprises: a) heating a composition, wherein the weight of water. More preferably, the particles comprise leSS composition comprises at least 5 percent by weight of than 70 percent, 60 percent, 50 percent, 40 percent, 30 chlordiazepoxide, betahistine, clonidine, testosterone, con percent, 20 percent, 10 percent, or 5 percent by weight of jugated estrogens, estrogen esters, estradiol, estradiol esters, Water. ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine; Typically, at least 50 percent by weight of the aerosol is and, b) allowing the vapor to cool, thereby forming a 25 amorphous in form, wherein crystalline forms make up leSS condensation aeroSol comprising particles, which is inhaled than 50 percent by weight of the total aerosol weight, by the mammal. Preferably, the composition that is heated regardless of the nature of individual particles. Preferably, at comprises at least 10 percent by weight of chlordiazepoxide, least 75 percent by weight of the aerosol is amorphous in betahistine, clonidine, testosterone, conjugated estrogens, form. More preferably, at least 90 percent by weight of the estrogen esters, estradiol, estradiol esters, ethinyl estradiol, aeroSol is amorphous in form. ethinyl estradiol esters, or hyoscyamine. More preferably, Typically, where the aerosol comprises chlordiazepoxide, the composition comprises 20 percent, 30 percent, 40 the delivered aerosol has an inhalable aeroSol drug mass percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 density of between 1 mg/L and 40 mg/L. Preferably, the percent, 95 percent, 97 percent, 99 percent, 99.5 percent, delivered aerosol has an inhalable aerosol drug mass density 99.9 percent or 99.97 percent by weight of 35 of between 2 mg/L and 30 mg/L. More preferably, the chlordiazepoxide, betahistine, clonidine, testosterone, con delivered aerosol has an inhalable aerosol drug mass density jugated estrogens, estrogen esters, estradiol, estradiol esters, of between 3 mg/L and 20 mg/L. ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. Typically, where the aerosol comprises betahistine, the Typically, the delivered aerosol particles comprise at least 40 delivered aerosol has an inhalable aerosol drug mass density 5 percent by weight of chlordiazepoxide, betahistine, of between 0.5 mg/L and 50 mg/L. Preferably, the delivered clonidine, testosterone, conjugated estrogens, estrogen aeroSol has an inhalable aeroSol drug mass density of esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl between 2 mg/L and 30 mg/L. More preferably, the deliv estradiol esters, or hyoscyamine. Preferably, the particles ered aerosol has an inhalable aerosol drug mass density of comprise at least 10 percent by weight of chlordiazepoxide, 45 between 5 mg/L and 20 mg/L. betahistine, clonidine, testosterone, conjugated estrogens, Typically, where the delivered aerosol comprises estrogen esters, estradiol, estradiol esters, ethinyl estradiol, clonidine, the aerosol has an inhalable aerosol drug mass ethinyl estradiol esters, or hyoscyamine. More preferably, density of between 0.02 mg/L and 2 mg/L. Preferably, the the particles comprise at least 20 percent, 30 percent, 40 delivered aerosol has an inhalable aerosol drug mass density percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 50 of between 0.03 mg/L and 1.5 mg/L. More preferably, the percent, 95 percent, 97 percent, 99 percent, 99.5 percent, delivered aerosol has an inhalable aerosol drug mass density 99.9 percent or 99.97 percent by weight of of between 0.05 mg/L and 1 mg/L. chlordiazepoxide, betahistine, clonidine, testosterone, con Typically, where the aerosol comprises testosterone, the jugated estrogens, estrogen esters, estradiol, estradiol esters, delivered aerosol has an inhalable aerosol drug mass density ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. 55 of between 0.1 mg/L and 20 mg/L. Preferably, the delivered Typically, the delivered aerosol has a mass of at least 1 lug. aeroSol has an inhalable aeroSol drug mass density of Preferably, the aerosol has a mass of at least 10 ug. More between 0.2 mg/L and 10 mg/L. More preferably, the preferably, the aerosol has a mass of at least 20 ug. delivered aerosol has an inhalable aerosol drug mass density Typically, the delivered aerosol particles comprise leSS of between 0.5 mg/L and 5 mg/L. than 10 percent by weight of chlordiazepoxide, betahistine, 60 Typically, where the aerosol comprises conjugated estro clonidine, testosterone, conjugated estrogens, estrogen gens or estrogen esters, the delivered aerosol has an inhal esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl able aerosol drug mass density of between 0.05 mg/L and 5 estradiol esters, or hyoscyamine degradation products. mg/L. Preferably, the delivered aerosol has an inhalable Preferably, the particles comprise less than 5 percent by aeroSol drug mass density of between 0.1 mg/L and 2 mg/L. weight of chlordiazepoxide, betahistine, clonidine, 65 More preferably, the delivered aerosol has an inhalable testosterone, conjugated estrogens, estrogen esters, aeroSol drug mass density of between 0.15 mg/L and 1.5 estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol mg/L. US 6,814,955 B2 S 6 Typically, where the aerosol comprises conjugated preferably, between 0.15 mg and 1.5 mg of conjugated estradiol, estradiol esters, ethinyl estradiol, or ethinyl estra estrogens or estrogen esterS is delivered to the mammal in a diol esters, the delivered aerosol has an inhalable aeroSol Single inspiration. drug mass density of between 0.001 mg/L and 0.2 mg/L. Typically, where the aerosol comprises conjugated Preferably, the delivered aerosol has an inhalable aerosol estradiol, estradiol esters, ethinyl estradiol, or ethinyl estra drug mass density of between 0.002 mg/L and 0.1 mg/L. diol esters, between 0.001 mg and 0.2 mg of conjugated More preferably, the delivered aerosol has an inhalable conjugated estradiol, estradiol esters, ethinyl estradiol, or aerosol drug mass density of between 0.004 mg/L and 0.05 ethinyl estradiol esterS is delivered to the mammal in a Single mg/L. inspiration. Preferably, between 0.002 mg and 0.1 mg of conjugated estradiol, estradiol esters, ethinyl estradiol, or Typically, where the aerosol comprises hyoscyamine, the ethinyl estradiol esterS is delivered to the mammal in a Single delivered aeroSol has an inhalable aeroSol drug mass density inspiration. More preferably, between 0.004 mg and 0.05 mg of between 0.01 mg/L and 1 mg/L. Preferably, the delivered of conjugated estradiol, estradiol esters, ethinyl estradiol, or aeroSol has an inhalable aeroSol drug mass density of ethinyl estradiol esterS is delivered to the mammal in a Single between 0.025 mg/L and 0.75 mg/L. More preferably, the inspiration. delivered aeroSol has an inhalable aeroSol drug mass density 15 Typically, where the aeroSol comprises hyoscyamine, of between 0.05 mg/L and 0.5 mg/L. between 0.01 mg and 1 mg of hyoscyamine is delivered to Typically, the delivered aerosol has an inhalable aeroSol the mammal in a single inspiration. Preferably, between particle density greater than 10° particles/mL. Preferably, 0.025 mg and 0.75 mg of hyoscyamine is delivered to the the aerosol has an inhalable aerosol particle density greater mammal in a Single inspiration. More preferably, between than 107 particles/mL. More preferably, the aerosol has an 0.05 mg and 0.5 mg of hyoscyamine is delivered to the inhalable aerosol particle density greater than 10 particles/ mammal in a single inspiration. mL. Typically, the delivered condensation aerosol results in a Typically, the rate of inhalable aeroSol particle formation peak plasma concentration of chlordiazepoxide, betahistine, of the delivered condensation aerosol is greater than 10 clonidine, testosterone, conjugated estrogens, estrogen particles per Second. Preferably, the aerosol is formed at a 25 esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine in the mammal in less than rate greater than 10 inhalable particles per second. More 1 h. Preferably, the peak plasma concentration is reached in preferably, the aerosol is formed at a rate greater than 10' less than 0.5 h. More preferably, the peak plasma concen inhalable particles per Second. tration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or Typically, the delivered aerosol is formed at a rate greater 0.005 h (arterial measurement). than 0.25 mg/second. Preferably, the aerosol is formed at a In a kit aspect of the present invention, a kit for delivering rate greater than 0.5 mg/second. More preferably, the aerosol chlordiazepoxide, betahistine, clonidine, testosterone, con is formed at a rate greater than 1 or 2 mg/second. jugated estrogens, estrogen esters, estradiol, estradiol esters, Typically, where the aerosol comprises chlordiazepoxide, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine between 1 mg and 40 mg of chlordiazepoxide is delivered to through an inhalation route to a mammal is provided which the mammal in a Single inspiration. Preferably, between 2 35 comprises: a) a composition comprising at least 5 percent by mg and 30 mg of chlordiazepoxide is delivered to the weight of chlordiazepoxide, betahistine, clonidine, mammal in a Single inspiration. More preferably, between 3 testosterone, conjugated estrogens, estrogen esters, mg and 20 mg of chlordiazepoxide is delivered to the estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol mammal in a single inspiration. esters, or hyoscyamine; and, b) a device that forms a 40 chlordiazepoxide, betahistine, clonidine, testosterone, con Typically, where the aerosol comprises betahistine, jugated estrogens, estrogen esters, estradiol, estradiol esters, between 0.5 mg and 50 mg of betahistine is delivered to the ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine mammal in a Single inspiration. Preferably, between 2 mg containing aerosol from the composition, for inhalation by and 30 mg of betahistine is delivered to the mammal in a the mammal. Preferably, the composition comprises at least Single inspiration. More preferably, between 5 mg and 20 mg 45 10 percent by weight of chlordiazepoxide, betahistine, of betahistine is delivered to the mammal in a Single clonidine, testosterone, conjugated estrogens, estrogen inspiration. esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl Typically, where the aerosol comprises clonidine, estradiol esters, or hyoscyamine. More preferably, the com between 0.02 mg and 2 mg of clonidine is delivered to the position comprises at least 20 percent, 30 percent, 40 mammal in a single inspiration. Preferably, between 0.03 mg 50 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 and 1.5 mg of clonidine is delivered to the mammal in a percent, 95 percent, 97 percent, 99 percent, 99.5 percent, single inspiration. More preferably, between 0.05 mg and 1 99.9 percent or 99.97 percent by weight of mg of clonidine is delivered to the mammal in a Single chlordiazepoxide, betahistine, clonidine, testosterone, con inspiration. jugated estrogens, estrogen esters, estradiol, estradiol esters, Typically, where the aerosol comprises testosterone, 55 ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. between 0.1 mg and 20 mg of testosterone is delivered to the Typically, the device contained in the kit comprises: a) an mammal in a single inspiration. Preferably, between 0.2 mg element for heating the chlordiazepoxide, betahistine, and 10 mg of testosterone is delivered to the mammal in a clonidine, testosterone, conjugated estrogens, estrogen Single inspiration. More preferably, between 0.5 mg and 5 esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl mg of testosterone is delivered to the mammal in a Single 60 estradiol esters, or hyoscyamine composition to form a inspiration. vapor; b) an element allowing the vapor to cool to form an Typically, where the aerosol comprises conjugated estro aerosol, and, c) an element permitting the mammal to inhale gens or estrogen esters, between 0.05 mg and 5 mg of the aeroSol. conjugated estrogens or estrogen esterS is delivered to the mammal in a single inspiration. Preferably, between 0.1 mg 65 BRIEF DESCRIPTION OF THE FIGURE and 2 mg of conjugated estrogens or estrogen esters is FIG. 1 shows a device used to deliver chlordiazepoxide, delivered to the mammal in a Single inspiration. More betahistine, clonidine, testosterone, conjugated estrogens, US 6,814,955 B2 7 8 estrogen esters, estradiol, estradiol esters, ethinyl estradiol, "Estradiol degradation product” refers to a com ethinyl estradiol esters, or hyoscyamine containing aerosols pound resulting from a chemical modification of an estradiol to a mammal through an inhalation route. ester. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reac DETAILED DESCRIPTION OF THE tions include, without limitation, oxidation and hydrolysis. INVENTION “” refers to an ester derived from the Definitions esterification of an alcohol moiety of estrogen. “Aerodynamic diameter of a given particle refers to the "Estrogen ester degradation product” refers to a com diameter of a spherical droplet with a density of 1 g/mL (the pound resulting from a chemical modification of an estrogen density of water) that has the same Settling Velocity as the ester. The modification, for example, can be the result of a given particle. thermally or photochemically induced reaction. Such reac “AeroSol' refers to a of Solid or liquid par tions include, without limitation, oxidation and hydrolysis. ticles in a gas. “Ethinyl estradiol” refers to 19-nor-17C.-pregna-1,3,5 “AeroSol drug mass density' refers to the mass of (10)-trien-20-yne-3,17-diol. chlordiazepoxide, betahistine, clonidine, testosterone, con “Ethinyl estradiol degradation product” refers to a com jugated estrogens, estrogen esters, estradiol, estradiol esters, 15 pound resulting from a chemical modification of ethinyl ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine per estradiol. The modification, for example, can be the result of unit volume of aeroSol. a thermally or photochemically induced reaction. Such reac “AeroSol mass density' refers to the mass of particulate tions include, without limitation, oxidation and hydrolysis. matter per unit volume of aerosol. “Ethinyl estradiol ester” refers to an ester derived from “Aerosol particle density” refers to the number of par the esterification of an alcohol moiety of ethinyl estradiol. ticles per unit volume of aerosol. “Ethinyl estradiol ester degradation product” refers to a "Amorphous particle' refers to a particle that does not compound resulting from a chemical modification of an contain more more than 50 percent by weight of a crystalline ethinyl estradiol ester. The modification, for example, can be form. Preferably, the particle does not contain more than 25 the result of a thermally or photochemically induced reac percent by weight of a crystalline form. More preferably, the 25 tion. Such reactions include, without limitation, oxidation particle does not contain more than 10 percent by weight of and hydrolysis. a crystalline form. “Hyoscyamine” refers to C.-(hydroxymethyl) “Betahistine” refers to N-methyl-2-pyridineethanamine. benzeneacetic acid 8-methyl-8-azabicyclo3.2.1]oct-3-yl “Betahistine degradation product” refers to a compound eSter. resulting from a chemical modification of betahistine. The “Hyoscyamine degradation product” refers to a com modification, for example, can be the result of a thermally or pound resulting from a chemical modification of hyOS photochemically induced reaction. Such reactions include, cyamine. The modification, for example, can be the result of without limitation, oxidation and hydrolysis. a thermally or photochemically induced reaction. Such reac “Chlordiazepoxide” refers to 7-chloro-N-methyl-5- tions include, without limitation, oxidation and hydrolysis. phenyl-3H-1,4-benzodiazepin-2-amine 4-oxide. 35 “Inhalable aerosol drug mass density” refers to the aerosol “Chlordiazepoxide degradation product” refers to a com drug mass density produced by an inhalation device and pound resulting from a chemical modification of chlordiaz delivered into a typical patient tidal Volume. epoxide. The modification, for example, can be the result of “Inhalable aerosol mass density” refers to the aerosol a thermally or photochemically induced reaction. Such reac mass density produced by an inhalation device and delivered tions include, without limitation, oxidation and hydrolysis. 40 into a typical patient tidal Volume. “Clo nidine” refers to 2,6-dichloro-N-2- “Inhalable aerosol particle density” refers to the aerosol imidazolidinylidene-benzeneamine. particle density of particles of size between 100 nm and 5 “Clonidine degradation product” refers to a compound microns produced by an inhalation device and delivered into resulting from a chemical modification of clonidine. The a typical patient tidal Volume. modification, for example, can be the result of a thermally or 45 “Mass median aerodynamic diameter” or “MMAD” of an photochemically induced reaction. Such reactions include, aerosol refers to the aerodynamic diameter for which half without limitation, oxidation and hydrolysis. the particulate mass of the aerosol is contributed by particles “Condensation aerosol refers to an aerosol formed by with an aerodynamic diameter larger than the MMAD and Vaporization of a Substance followed by condensation of the half by particles with an aerodynamic diameter Smaller than Substance into an aeroSol. 50 the MMAD. “Conjugated estrogen' refers to estrogen Sulfates. This "Rate of aerosol formation” refers to the mass of aero includes a blend of estrogen Sulfates containing , Solized particulate matter produced by an inhalation device , and 17 C-dihydroequilin. per unit time. “Conjugated estrogen degradation product” refers to a “Rate of inhalable aerosol particle formation” refers to the compound resulting from a chemical modification of a 55 number of particles of size between 100 nm and 5 microns conjugated estrogen. The modification, for example, can be produced by an inhalation device per unit time. the result of a thermally or photochemically induced reac “Rate of drug aerosol formation” refers to the mass of tion. Such reactions include, without limitation, oxidation aerosolized chlordiazepoxide, betahistine, clonidine, and hydrolysis. testosterone, conjugated estrogens, estrogen esters, “Estradiol” refers to estra-1,3,5(10)-triene-3,17-diol. 60 estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol "Estradiol degradation product” refers to a compound esters, or hyoscyamine produced by an inhalation device per resulting from a chemical modification of estradiol. The unit time. modification, for example, can be the result of a thermally or “Settling velocity” refers to the terminal velocity of an photochemically induced reaction. Such reactions include, aeroSol particle undergoing gravitational Settling in air. without limitation, oxidation and hydrolysis. 65 “Testosterone” refers to 17 B-hydroxyandrost-4-en-3-one. "Estradiol ester” refers to an ester derived from the "Testosterone degradation product” refers to a compound esterification of an alcohol moiety of estradiol. resulting from a chemical modification of testosterone. The US 6,814,955 B2 9 10 modification, for example, can be the result of a thermally or A number of different materials are used to construct the photochemically induced reaction. Such reactions include, Solid Supports. Classes of Such materials include, without without limitation, oxidation and hydrolysis. limitation, metals, inorganic materials, carbonaceous mate “Typical patient tidal volume” refers to 1 L for an adult rials and . The following are examples of the patient and 15 mL/kg for a pediatric patient. material classes: aluminum, Silver, gold, Stainless Steel, "Vapor refers to a gas, and “vapor phase' refers to a gas copper and tungsten; Silica, glass, Silicon and alumina; phase. The term “thermal vapor refers to a vapor phase, graphite, porous , yams and carbon felts, aeroSol, or mixture of aeroSol-vapor phases, formed prefer polytetrafluoroethylene and polyethylene glycol. Combina ably by heating. tions of materials and coated variants of materials are used Formation of Physiologically Active Compound Containing as well. AeroSols Where aluminum is used as a Solid Support, aluminum foil Any suitable method is used to form the aerosols of the is a Suitable material. Examples of Silica, alumina and present invention. A preferred method, however, involves silicon based materials include amphorous silica S-5631 heating a composition comprising chlordiazepoxide, (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined betahistine, clonidine, testosterone, conjugated estrogens, 15 Surface area greater than 2 m/g from Aldrich, St. Louis, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, Mo.) and a Silicon wafer as used in the Semiconductor ethinyl estradiol esters, or hyoscyamine to form a vapor, industry. Carbon yams and felts are available from American followed by cooling of the vapor Such that it condenses to Kynol, Inc., New York, N.Y. resins such as provide an chlordiazepoxide, betahistine, clonidine, octadecycl Silane chemically bonded to porous Silica are testosterone, conjugated estrogens, estrogen esters, exemplary coated variants of Silica. estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol The heating of the chlordiazepoxide, betahistine, esters, or hyoscyamine comprising aerosol (condensation clonidine, testosterone, conjugated estrogens, estrogen aeroSol). The composition is heated in one of four forms: as esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl pure active compound (i.e., pure chlordiazepoxide, estradiol esters, or hyoscyamine compositions is performed betahistine, clonidine, testosterone, conjugated estrogens, 25 using any Suitable method. Examples of methods by which estrogen esters, estradiol, estradiol esters, ethinyl estradiol, heat can be generated include the following: passage of ethinyl estradiol esters, or hyoscyamine) as a mixture of current through an electrical resistance element; absorption active compound and a pharmaceutically acceptable excipi of electromagnetic radiation, Such as microwave or laser ent, as a Salt form of the pure active compound; and, as a light; and, exothermic chemical reactions, Such as exother mixture of active compound Salt form and a pharmaceuti mic Solvation, hydration of pyrophoric materials and oxida cally acceptable . tion of combustible materials. Salt forms of chlordiazepoxide, betahistine, clonidine, Delivery of Physiologically Active Compound Containing testosterone, conjugated estrogens, estrogen esters, AeroSols estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol Chlordiazepoxide, betahistine, clonidine, testosterone, esters, or hyoscyamine are either commercially available or 35 conjugated estrogens, estrogen esters, estradiol, estradiol are obtained from the corresponding free base using well esters, ethinyl estradiol, ethinyl estradiol esters, or hyOS known methods in the art. A variety of pharmaceutically cyamine containing aerosols of the present invention are acceptable Salts are Suitable for aeroSolization. Such Salts delivered to a mammal using an inhalation device. Where include, without limitation, the following: hydrochloric acid, the aerosol is a condensation aeroSol, the device has at least hydrobromic acid, , maleic acid, formic acid, and 40 three elements: an element for heating a chlordiazepoxide, fumaric acid Salts. betahistine, clonidine, testosterone, conjugated estrogens, Pharmaceutically acceptable may be volatile or estrogen esters, estradiol, estradiol esters, ethinyl estradiol, nonvolatile. Volatile excipients, when heated, are concur ethinyl estradiol esters, or hyoscyamine containing compo rently volatilized, aerosolized and inhaled with the antihis Sition to form a vapor; an element allowing the vapor to cool, tamine. Classes of Such excipients are known in the art and 45 thereby providing a condensation aerosol, and, an element include, without limitation, gaseous, Supercritical fluid, liq permitting the mammal to inhale the aeroSol. Various Suit uid and solid solvents. The following is a list of exemplary able heating methods are described above. The element that carriers within the classes: water, terpenes, Such as menthol; allows cooling is, in it Simplest form, an inert passageway alcohols, Such as ethanol, propylene glycol, glycerol and linking the heating means to the inhalation means. The other similar alcohols, dimethylformamide; dimethylaceta 50 element permitting inhalation is an aerosol exit portal that mide, waX; Supercritical carbon dioxide, dry ice; and mix forms a connection between the cooling element and the tures thereof. mammal’s respiratory System. Solid Supports on which the composition is heated are of One device used to deliver a chlordiazepoxide, a variety of shapes. Examples of Such shapes include, betahistine, clonidine, testosterone, conjugated estrogens, without limitation, cylinders of less than 1.0 mm in diameter, 55 estrogen esters, estradiol, estradiol esters, ethinyl estradiol, boxes of less than 1.0 mm thickneSS and Virtually any shape ethinyl estradiol esters, or hyoscyamine containing aeroSol permeated by Small (e.g., less than 1.0 mm-sized) pores. is described in reference to FIG.1. Delivery device 100 has Preferably, Solid Supports provide a large Surface to Volume a proximal end 102 and a distal end 104, a heating module ratio (e.g., greater than 100 per meter) and a large Surface to 106, a power source 108, and a mouthpiece 110. A mass ratio (e.g., greater than 1 cm per gram). 60 chlordiazepoxide, betahistine, clonidine, testosterone, con A Solid Support of one shape can also be transformed into jugated estrogens, estrogen esters, estradiol, estradiol esters, another shape with different properties. For example, a flat ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine sheet of 0.25 mm thickness has a Surface to volume ratio of composition is deposited on a Surface 112 of heating module approximately 8,000 per meter. Rolling the sheet into a 106. Upon activation of a user activated Switch 114, power hollow cylinder of 1 cm diameter produces a Support that 65 source 108 initiates heating of heating module 106 (e.g., retains the high Surface to mass ratio of the original sheet but through ignition of combustible fuel or passage of current has a lower surface to volume ratio (about 400 per meter). through a resistive heating element). The chlordiazepoxide, US 6,814,955 B2 11 12 betahistine, clonidine, testosterone, conjugated estrogens, Analysis of Physiologically Active Compound Containing estrogen esters, estradiol, estradiol esters, ethinyl estradiol, AeroSols ethinyl estradiol esters, or hyoscyamine composition vola Purity of a chlordiazepoxide, betahistine, clonidine, tilizes due to the heating of heating module 106 and con testosterone, conjugated estrogens, estrogen esters, denses to form a condensation aerosol prior to reaching the estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol mouthpiece 110 at the proximal end of the device 102. Air esters, or hyoscyamine containing aerosol is determined flow traveling from the device distal end 104 to the mouth using a number of methods, examples of which are piece 110 carries the condensation aerosol to the mouthpiece described in Sekine et al., Journal of Forensic Science 32:1271–1280 (1987) and Martin et al., Journal of Analytic 110, where it is inhaled by the mammal. Toxicology 13:158-162 (1989). One method involves form Devices, if desired, contain a variety of components to ing the aerosol in a device through which a gas flow (e.g., facilitate the delivery of chlordiazepoxide, betahistine, air flow) is maintained, generally at a rate between 0.4 and clonidine, testosterone, conjugated estrogens, estrogen 60 L/min. The gas flow carries the aeroSol into one or more esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl traps. After isolation from the trap, the aerosol is Subjected estradiol esters, or hyoscyamine containing aeroSols. For 15 to an analytical technique, Such as gas or liquid instance, the device may include any component known in chromatography, that permits a determination of composi the art to control the timing of drug aeroSolization relative to tion purity. inhalation (e.g., breath-actuation), to provide feedback to A variety of different traps are used for aerosol collection. patients on the rate and/or Volume of inhalation, to prevent The following list contains examples of Such traps: filters, excessive use (i.e., "lock-out” feature), to prevent use by glass wool; impingers, Solvent traps, Such as dry ice-cooled unauthorized individuals, and/or to record dosing histories. ethanol, methanol, acetone and dichloromethane traps at Dosage of Physiologically Active Compound Containing various pH values, Syringes that Sample the aerosol, empty, low-pressure (e.g., vacuum) containers into which the aero AeroSols Sol is drawn; and, empty containers that fully Surround and The dosage amount of chlordiazepoxide, betahistine, 25 enclose the aerosol generating device. Where a Solid Such as clonidine, testosterone, conjugated estrogens, estrogen glass wool is used, it is typically extracted with a Solvent esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl Such as ethanol. The Solvent extract is Subjected to analysis estradiol esters, or hyoscyamine in aerosol form is generally rather than the Solid (i.e., glass wool) itself. Where a Syringe no greater than twice the Standard dose of the drug given or container is used, the container is similarly extracted with orally. The following dosage amounts are typical for the a Solvent. respective compounds: chlordiazepoxide, 10 mg, The gas or liquid chromatograph discussed above con betahistine, 16 mg, clonidine, 0.1 mg testosterone, 5 mg, tains a detection system (i.e., detector). Such detection conjugated estrogens and estrogen esters, 0.625 mg, Systems are well known in the art and include, for example, estradiol, estradiol esters, ethinyl estradiol and ethinyl estra flame ionization, photon absorption and mass spectrometry diol esters, 0.02 mg, and, hyoscyamine, 0.15 mg. AS 35 detectors. An advantage of a mass spectrometry detector is aeroSols, doses are generally provided as follows for the that it can be used to determine the Structure of Same indications: chlordiazepoxide, 1 to 40 mg, betahistine, chlordiazepoxide, betahistine, clonidine, testosterone, con 0.5 to 50 mg; clonidine, 0.02 to 2 mg; testosterone, 0.1 to 20 jugated estrogens, estrogen esters, estradiol, estradiol esters, mg, conjugated estrogens and estrogen esters, 0.05 to 5 mg, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine estradiol, estradiol esters, ethinyl estradiol and ethinyl estra 40 degradation products. diol esters, 0.001 mg to 0.2 mg; and, hyoscyamine, 0.01 to Particle size distribution of a chlordiazepoxide, 1 mg. A typical dosage of a chlordiazepoxide, betahistine, betahistine, clonidine, testosterone, conjugated estrogens, clonidine, testosterone, conjugated estrogens, estrogen estrogen esters, estradiol, estradiol esters, ethinyl estradiol, esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl ethinyl estradiol esters, or hyoscyamine containing aeroSol estradiol esters, or hyoscyamine aerosol is either adminis 45 is determined using any Suitable method in the art (e.g., tered as a Single inhalation or as a Series of inhalations taken cascade impaction). An Andersen Eight Stage Non-viable within an hour or less (dosage equals Sum of inhaled Cascade Impactor (Andersen Instruments, Smyrna, Ga.) amounts). Where the drug is administered as a Series of linked to a furnace tube by a mock throat (USP throat, inhalations, a different amount may be delivered in each Andersen Instruments, Smyrna, Ga.) is one system used for inhalation. 50 cascade impaction Studies. One can determine the appropriate dose of a Inhalable aerosol maSS density is determined, for chlordiazepoxide, betahistine, clonidine, testosterone, con example, by delivering a drug-containing aeroSol into a jugated estrogens, estrogen esters, estradiol, estradiol esters, confined chamber via an inhalation device and measuring ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine the mass collected in the chamber. Typically, the aerosol is containing aerosol to treat a particular condition using 55 drawn into the chamber by having a pressure gradient methods Such as animal experiments and a dose-finding between the device and the chamber, wherein the chamber (Phase I/II) . One animal experiment involves is at lower pressure than the device. The volume of the measuring plasma concentrations of drug in an animal after chamber should approximate the tidal Volume of an inhaling its exposure to the aerosol. Such as dogs or patient. primates are typically used in Such studies, Since their 60 Inhalable aerosol drug mass density is determined, for respiratory Systems are Similar to that of a human. Initial example, by delivering a drug-containing aeroSol into a dose levels for testing in humans is generally less than or confined chamber via an inhalation device and measuring equal to the dose in the mammal model that resulted in the amount of active drug compound collected in the cham plasma drug levels associated with a therapeutic effect in ber. Typically, the aerosol is drawn into the chamber by humans. Dose escalation in humans is then performed, until 65 having a preSSure gradient between the device and the either an optimal therapeutic response is obtained or a chamber, wherein the chamber is at lower preSSure than the dose-limiting toxicity is encountered. device. The volume of the chamber should approximate the US 6,814,955 B2 13 14 tidal Volume of an inhaling patient. The amount of active ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine drug compound collected in the chamber is determined by containing aerosol comprises a pharmaceutically acceptable extracting the chamber, conducting chromatographic analy excipient, multiplying the rate of aeroSol formation by the sis of the extract and comparing the results of the chromato percentage of chlordiazepoxide, betahistine, clonidine, graphic analysis to those of a Standard containing known testosterone, conjugated estrogens, estrogen esters, amounts of drug. estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol Inhalable aerosol particle density is determined, for esters, or hyoscyamine in the aerosol provides the rate of example, by delivering aerosol phase drug into a confined drug aeroSol formation. chamber via an inhalation device and measuring the number Utility of Physiologically Active Compound Containing of particles of given size collected in the chamber. The AeroSols number of particles of a given size may be directly measured Chlordiazepoxide containing aerosols are typically used based on the light-Scattering properties of the particles. for the treatment of anxiety. Betahistine containing aerosols Alternatively, the number of particles of a given size may be are typically used for the treatment of vertigo (Meniere's determined by measuring the mass of particles within the disease). Clonidine containing aerosols are typically used given size range and calculating the number of particles 15 for the treatment of alcohol withdrawal, nicotine based on the mass as follows: Total number of particles= withdrawal, Sedation, or hot flashes. Testosterone containing Sum (from size range 1 to size range N) of number of aerosols are typically used for testosterone replacement particles in each size range. Number of particles in a given therapy. Conjugated estrogens and estrogen ester containing Size range=Mass in the Size range/Mass of a typical particle aerosols are typically used for hormone replacement therapy in the size range. Mass of a typical particle in a given size (menopause). Estradiol, estradiol ester, ethinyl estradiol, and range=TL*D*q/6, where D is a typical particle diameter in ethinyl estradiol ester containing aerosols are typically used the size range (generally, the mean boundary MMADS for hormone replacement therapy (estradiol and esters) and defining the size range) in microns, p is the particle density the prevention of pregnancy (ethinyl estradiol and esters). (in g/mL) and mass is given in units of picograms (g'). Hyoscyamine containing aerosols are typically used for the Rate of inhalable aerosol particle formation is determined, 25 treatment of peptic ulcers. for example, by delivering aeroSol phase drug into a con The following examples are meant to illustrate, rather fined chamber via an inhalation device. The delivery is for than limit, the present invention. a set period of time (e.g., 3 s), and the number of particles Chlor diazepoxide hydrochloride, beta histine of a given size collected in the chamber is determined as dihydrochloride, clonidine hydrochloride, testosterone, outlined above. The rate of particle formation is equal to the estradiol, certain estradiol esters, and hyoscyamine are com number of 100 nm to 5 micron particles collected divided by mercially available from Sigma (www.sigma-aldrich.com). the duration of the collection time. Obtaining a free base from a Salt or esterifying an alcohol are done according to Standard methods in the art. Compounds Rate of aerosol formation is determined, for example, by Such as ethinyl estradiol are isolated from commercially delivering aerosol phase drug into a confined chamber via an available pharmaceutical preparations or Synthesized using inhalation device. The delivery is for a set period of time 35 (e.g., 3 s), and the mass of particulate matter collected is Standard methods in the art. determined by weighing the confined chamber before and EXAMPLE 1. after the delivery of the particulate matter. The rate of aeroSol formation is equal to the increase in mass in the General Procedure for Volatilizing Compounds chamber divided by the duration of the collection time. 40 A Solution of drug in approximately 120 u, dichlo Alternatively, where a change in mass of the delivery device romethane is coated on a 3 cm x8 cm piece of aluminum foil. or component thereof can only occur through release of the The dichloromethane is allowed to evaporate. The coated aeroSol phase particulate matter, the mass of particulate foil is wrapped around a 300 watt halogen tube (Feit Electric matter may be equated with the mass lost from the device or Company, Pico Rivera, Calif.), which is inserted into a glass component during the delivery of the aerosol. In this case, 45 tube sealed at one end with a rubber stopper. Running 60 V the rate of aerosol formation is equal to the decrease in mass (45 V for chlordiazepoxide) of alternating current (driven by of the device or component during the delivery event line power controlled by a variac) through the bulb for 5 to divided by the duration of the delivery event. 15 S affords thermal vapor (including aerosol), which is Rate of drug aerosol formation is determined, for collected on the glass tube walls. Reverse-phase HPLC example, by delivering a chlordiazepoxide, betahistine, 50 analysis with detection by absorption of 225 nm light is used clonidine, testosterone, conjugated estrogens, estrogen to determine the purity of the aerosol. (When desired, the esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl System is flushed through with argon prior to volatilization.) estradiol esters, or hyoscyamine containing aerosol into a The following aerosol purities were obtained using this confined chamber via an inhalation device over a Set period method: chlordiazepoxide (99% purity, 1.3 mg); estradiol of time (e.g., 3 s). Where the aerosol is pure 55 17-acetate (98.6% purity, 0.59 mg); estradiol-3,17-diacetate chlordiazepoxide, betahistine, clonidine, testosterone, con (96.9% purity, 1.07 mg); testosterone (100% purity, 0.93 jugated estrogens, estrogen esters, estradiol, estradiol esters, mg); and, hyoscyamine (95.9% purity, 1.07 mg). ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine, To obtain higher purity aerosols, one can coat a lesser the amount of drug collected in the chamber is measured as amount of drug, yielding a thinner film to heat. A linear described above. The rate of drug aerosol formation is equal 60 decrease in film thickness is associated with a linear to the amount of chlordiazepoxide, betahistine, clonidine, decrease in impurities. testosterone, conjugated estrogens, estrogen esters, What is claimed is: estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol 1. A composition for delivery of chlordiazepoxide, esters, or hyoscyamine collected in the chamber divided by betahistine, clonidine, testosterone, conjugated estrogens, the duration of the collection time. Where the 65 estrogen esters, estradiol, estradiol esters, ethinyl estradiol, chlordiazepoxide, betahistine, clonidine, testosterone, con etbinyl estradiol esters, or hyoscyamine comprising a con jugated estrogens, estrogen esters, estradiol, estradiol esters, densation aeroSol US 6,814,955 B2 15 16 a) formed by volatilizing chlordiazepoxide, betahistine, chiordiazepoxide, betahistine, clonidine, testosterone, clonidine, testosterone, conjugated estrogens, estrogen conjugated estrogens, estrogen esters, estradiol, estra esters, estradiol, estradiol esters, ethinyl estradiol, ethi- diol esters, ethinyl estradiol, ethinyl estradiol esters, or nyl estradiol esters, or hyoscyamine under conditions hyoscyaxnine, and effective to produce a heated Vapor of 5 b) during said volatilizing, passing air through the heated chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estra Vapor to produce aerosol particles of chlordiazepoxide, diol esters, ethinyl estradiol, ethinyl estradiol esters, or betahistine, clonidine, testosterone, conjugated hyoscyamine and condensing the heated vapor to form estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyOS condensation aeroSol particles, 1O cyamine comprising less than 5% chlordiazepoxide, b) wherein said condensation aerosol particles are char betahistine, clonidine, testosterone, conjugated acterized by less than 5% chlordiazepoxide, estrogens, estrogen esters, estradiol, estradiol esters, betahistine, clonidine, testosterone, conjugated ethinyl estradiol, ethinyl estradiol esters, or hyOS s ten t sh estradiol s 15 cyamine degradation products and an aerosol having an ethinyl estradiol, ethinyl estradiol esters, or hyOS- MMAD less than 3 lum. cyamine degradation products, and 4. The method according to claim 3, wherein Said vola c) wherein the aerosol MMAD is less than 3 microns. tilizing includes heating a thin layer which includes 2. The composition-according to claim 1, wherein the chlordiazepoxide, betahistine, clonidine, testosterone, con condensation aerosol particles comprise at least 90 percent jugated estrogens, estrogen esters, estradiol, estradiolesters, by weight of chiordiazepoxide, betahistine, clonidine, 2O ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine, testosterone, conjugated estrogens, estrogen esters, which is on a Solid Support having the Surface texture of a estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol metal foil, to a temperature Sufficient to volatilize the esters, or hyoscyamine. chlordiazepoxide, betahistine, clonidine, testosterone, con 3. A method of producing chlordiazepoxide, betahistine, 25 jugated estrogens, estrogen esters, estradiol, estradiol esters, clonidine, testosterone, conjugated estrogens, estrogen ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl from the thin layer. estradiol esters, or hyoscyamine in an aerosol form com- 5. The method according to claim 4, wherein the aerosol pr1SIng: particles comprise at least 90 percent by weight of a) volatilizing chlordiazepoxide, betahistine, clonidine, 3O chlordiazepoxide, betahistine, clonidine, testosterone, con testosterone, conjugated estrogens, estrogen esters, jugated estrogens, estrogen esters, estradiol, estradiol esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. estradiol esters, or hyoscyamine under conditions effective to produce a heated Vapor of k . . . .