US007067114B2

(12) United States Patent (10) Patent No.: US 7,067,114 B2 Rabinowitz et al. (45) Date of Patent: *Jun. 27, 2006

(54) DELIVERY OF ANTIHISTAMINES 4,848,374. A 7, 1989 Chard et al. THROUGH AN INHALATION ROUTE 4,853,517 A 8, 1989 Bowen et al. 4,895,719 A 1/1990 Radhakrishnan et al. (75) Inventors: Joshua D. Rabinowitz, Mountain View, 4,906,417 A 3/1990 Gentry CA (US); Alejandro C. Zaffaroni, 4,917,119 A 4, 1990 Potter et al. Atherton, CA (US) 4,924,883. A 5/1990 Perfetti et al. 4.941,483. A 7/1990 Ridings et al. (73) Assignee: Alexza Pharmaceuticals, Inc., Palo 4,963,289 A 10, 1990 Ortiz et al. Alto, CA (US) 5,042,509 A 8/1991 Banerjee et al. 5,049,389 A 9, 1991 Radhakrishnan (*) Notice: Subject to any disclaimer, the term of this 5,060.671 A 10, 1991 Counts et al. patent is extended or adjusted under 35 5,099,861 A 3, 1992 Clearman et al. 5,135,009 A 8, 1992 Muller et al. U.S.C. 154(b) by 0 days. 5,144.962 A 9, 1992 Counts et al. This patent is Subject to a terminal dis 5,146,915 A 9/1992 Montgomery claimer. 5,224,498 A 7/1993 Deevi et al. 5,345,951 A 9, 1994 Serrano et al. 5,366,770 A 11/1994 Wang (21) Appl. No.: 10/768,293 5,388,574 A 2/1995 Ingebrethsen 5,455,043 A 10, 1995 Fischel-Ghodsian (22) Filed: Jan. 29, 2004 5,456,247 A 10/1995 Shilling et al. (65) Prior Publication Data 5,457,100 A 10, 1995 Daniel 5,511,726 A 4/1996 Greenspan et al. US 2004/O185OOO A1 Sep. 23, 2004 5,544,646 A 8/1996 Lloyd et al. 5,564,442 A 10, 1996 MacDonald et al. Related U.S. Application Data 5,592,934 A 1/1997 Thwaites (63) Continuation of application No. 10/749,536, filed on 5,605,146 A 2, 1997 Sarella Dec. 30, 2003, which is a continuation of application No. 10/153,831, filed on May 21, 2002, now Pat. No. (Continued) 6,740,308. FOREIGN PATENT DOCUMENTS (60) Provisional application No. 60/317,479, filed on Sep. EP O 358 114 3, 1990 5, 2001, provisional application No. 60/294.203, filed on May 24, 2001. (Continued) (51) Int. Cl. OTHER PUBLICATIONS A6 IK 9/12 (2006.01) A6 IK 9/14 (2006.01) U.S. Appl. No. 10/633,876, filed Aug. 4, 2003, Hale et al. A6M I5/00 (2006.01) (52) U.S. Cl...... 424/45; 424/46; 424/489: (Continued) 424/499; 514/958: 128/200.14; 128/200.24; Primary Examiner Sreeni Padmanabhan 128/2O3.15 Assistant Examiner Mina Haghighatian (58) Field of Classification Search ...... 424/45, (74) Attorney, Agent, or Firm—Swanson & Bratschun LLC; 424/46, 489, 499; 128/200.14, 200.24, 203.15; William L. Leschensky 514/958 See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention relates to the delivery of antihista U.S. PATENT DOCUMENTS mines through an inhalation route. Specifically, it relates to 3,219,533 A 11/1965 Mullins aerosols containing antihistamines that are used in inhalation 3,560,607 A 2/1971 Hartley et al. therapy. In a method aspect of the present invention, an 3,949,743 A 4, 1976 Shanbrom 3,982,095 A 9, 1976 Robinson antihistamine is delivered to a patient through an inhalation 4,141,369 A 2f1979 Burruss route. The method comprises: a) heating a thin layer of an 4,183,912 A 1, 1980 Rosenthale antihistamine, on a solid Support, to form a vapor, and, b) RE30,285 E 5/1980 Babington passing air through the heated vapor to produce aerosol 4,232,002 A 11/1980 Nogrady particles having less than 5% antihistamine drug degradation 4,303,083. A 12/1981 Burruss, Jr. products. In a kit aspect of the present invention, a kit for 4,474,191 A 10, 1984 Steiner delivering an antihistamine through an inhalation route is 4.484,576 A 11, 1984 Albarda provided which comprises: a) a thin layer of an antihista 4,566,451 A 1, 1986 Badewien mine drug and b) a device for dispensing said thin layer as 4,708,151 A 11, 1987 Shelar a condensation aerosol. 4,734,560 A 3, 1988 Bowen 4,735,217 A 4, 1988 Gerth et al. 4,819,665 A 4, 1989 Roberts et al. 58 Claims, 1 Drawing Sheet US 7,067,114 B2 Page 2

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Meng, Y. et al. “Inhalation Studies With Drugs of Abuse.” .S. Appl. No. 10/814,690, filed Mar. 31, 2004, Rabinowitz NIDA Research Monograph, (1997) 173:201-224. t a 1. Meng, Y., et al. (1999). “Pharmacological effects of .S. Appl. No. 10/814,998, filed Mar. 31, 2004, Rabinowitz methamphetamine and other stimulants via inhalation expo t a 1. sure.” Drug and Alcohol Dependence. 53:111-120. .S. Appl. No. 10/815,527, filed Apr. 1, 2004, Rabinowitz et Office Action mailed Aug. 13, 2003 for U.S. Appl. No. 1 10/153,313, filed May 21, 2002 “Delivery of .S. Appl. No. 10/816,407, filed Apr. 1, 2004, Rabinowitz et Benzodiazepines Through an Inhalation Route'. 1 Pankow, J.F. et al. (1997). “Conversion of Nicotine in .S. Appl. No. 10/816,492, filed Apr. 1, 2004, Rabinowitz et Tobacco Smoke to Its Volatile and Available Free-Base Form Through the Action of Gaseous Ammonia. Environ. .S. Appl. No. 10/816,567, filed Apr. 1, 2004, Rabinowitz et Sci. Technol. 3 1:2428-2433. a 1 Pankow, J. (Mar. 2000). 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O US 7,067,114 B2 1. 2 DELIVERY OF ANTHISTAMINES ably, the particles comprise less than 70 percent, 60 percent, THROUGH AN INHALATION ROUTE 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water. This application is a continuation of U.S. patent applica Typically, at least 50 percent by weight of the aerosol is tion Ser. Nos. 10/153,831 and 10/749,536 entitled “Delivery amorphous in form, wherein crystalline forms make up less of Antihistamines Through an Inhalation Route, filed May than 50 percent by weight of the total aerosol weight, 21, 2002, now U.S. Pat. No. 6,740,308, and Dec. 30, 2003, regardless of the nature of individual particles. Preferably, at respectively, Rabinowitz and Zaffaroni, which claims prior least 75 percent by weight of the aerosol is amorphous in ity to U.S. provisional application Ser. No. 60/294.203 form. More preferably, at least 90 percent by weight of the entitled “Thermal Vapor Delivery of Drugs.” filed May 24, 10 aerosol is amorphous in form. 2001, Rabinowitz and Zaffaroni, and to U.S. provisional Typically, the aerosol has an inhalable aerosol particle application Ser. No. 60/317,479 entitled “Aerosol Drug density greater than 10° particles/mL. Preferably, the aerosol Delivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the has an inhalable aerosol particle density greater than 107 entire disclosures of which are hereby incorporated by particles/mL. More preferably, the aerosol has an inhalable reference. 15 aerosol particle density greater than 10 particles/mL. Typically, the aerosol particles have a mass median aero FIELD OF THE INVENTION dynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less The present invention relates to the delivery of antihista than 3 microns. More preferably, the particles have a mass mines through an inhalation route. Specifically, it relates to median aerodynamic diameter of less than 2 or 1 micron(s). aerosols containing antihistamines that are used in inhalation Typically, the geometric standard deviation around the therapy. mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation BACKGROUND OF THE INVENTION is less than 2.85. More preferably, the geometric standard 25 deviation is less than 2.7. There are a number of antihistamine containing compo Typically, the aerosol is formed by heating a composition sitions currently marketed for the treatment of allergy Symp containing an antihistamine to form a vapor and Subse toms. The compositions contain at least one active ingredi quently allowing the vapor to condense into an aerosol. ent that provides for observed therapeutic effects. Among the In another composition aspect of the present invention, active ingredients in Such compositions are azatadine, bro 30 the aerosol comprises particles comprising at least 5 percent mpheniramine, carbinoxamine, chlorpheniramine, clemas by weight of azatadine, brompheniramine, carbinoxamine, tine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, chlorpheniramine, clemastine, cyproheptadine, loratadine, and promethazine. pyrilamine, hydroxyzine, or promethazine. Preferably, the It is desirable to provide a new route of administration for particles comprise at least 10 percent by weight of azatadine, antihistamines that rapidly produces peak plasma concen 35 brompheniramine, carbinoxamine, chlorpheniramine, clem trations of the compound. The provision of such a route is an astine, cyproheptadine, loratadine, pyrilamine, hydroxy Zine, object of the present invention. or promethazine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 SUMMARY OF THE INVENTION percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 40 percent, 99 percent, 99.5 percent or 99.97 percent by weight The present invention relates to the delivery of antihista of azatadine, brompheniramine, carbinoxamine, chlorphe mines through an inhalation route. Specifically, it relates to niramine, clemastine, cyproheptadine, loratadine, pyril aerosols containing antihistamines that are used in inhalation amine, hydroxyzine, or promethazine. therapy. Typically, the aerosol has a mass of at least 0.10 ug. In a composition aspect of the present invention, the 45 Preferably, the aerosol has a mass of at least 100 lug. More aerosol comprises particles comprising at least 5 percent by preferably, the aerosol has a mass of at least 200 ug. weight of an antihistamine. Preferably, the particles com Typically, the aerosol particles comprise less than 10 prise at least 10 percent by weight of an antihistamine. More percent by weight of azatadine, brompheniramine, carbinox preferably, the particles comprise at least 20 percent, 30 amine, chlorpheniramine, clemastine, cyproheptadine, lora percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 50 tadine, pyrilamine, hydroxy Zine, or promethazine degrada percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 tion products. Preferably, the particles comprise less than 5 percent or 99.97 percent by weight of an antihistamine. percent by weight of azatadine, brompheniramine, carbinox Typically, the antihistamine is not one of the following amine, chlorpheniramine, clemastine, cyproheptadine, lora antihistamines: dexmedetomidine, diphenhydramine, doxy tadine, pyrilamine, hydroxy Zine, or promethazine degrada lamine, loratidine, and promethazine. 55 tion products. More preferably, the particles comprise less Typically, the aerosol has a mass of at least 0.10 ug. than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of azatadine, Preferably, the aerosol has a mass of at least 100 lug. More brompheniramine, carbinoxamine, chlorpheniramine, clem preferably, the aerosol has a mass of at least 200 ug. astine, cyproheptadine, loratadine, pyrilamine, hydroxy Zine, Typically, the aerosol particles comprise less than 10 or promethazine degradation products. percent by weight of antihistamine degradation products. 60 Typically, the aerosol particles comprise less than 90 Preferably, the particles comprise less than 5 percent by percent by weight of water. Preferably, the particles com weight of antihistamine degradation products. More prefer prise less than 80 percent by weight of water. More prefer ably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 ably, the particles comprise less than 70 percent, 60 percent, percent by weight of antihistamine degradation products. 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or Typically, the aerosol particles comprise less than 90 65 5 percent by weight of water. percent by weight of water. Preferably, the particles com Typically, at least 50 percent by weight of the aerosol is prise less than 80 percent by weight of water. More prefer amorphous in form, wherein crystalline forms make up less US 7,067,114 B2 3 4 than 50 percent by weight of the total aerosol weight, Typically, the geometric standard deviation around the regardless of the nature of individual particles. Preferably, at mass median aerodynamic diameter of the aerosol particles least 75 percent by weight of the aerosol is amorphous in is less than 3.0. Preferably, the geometric standard deviation form. More preferably, at least 90 percent by weight of the is less than 2.85. More preferably, the geometric standard aerosol is amorphous in form. 5 deviation is less than 2.7. Typically, where the aerosol comprises azatadine, the Typically, the aerosol is formed by heating a composition aerosol has an inhalable aerosol drug mass density of containing azatadine, brompheniramine, carbinoxamine, between 0.2 mg/L and 2.5 mg/L. Preferably, the aerosol has chlorpheniramine, clemastine, cyproheptadine, loratadine, an inhalable aerosol drug mass density of between 0.35 pyrilamine, hydroxy Zine, or promethazine to form a vapor mg/L and 2 mg/L. More preferably, the aerosol has an 10 and Subsequently allowing the vapor to condense into an inhalable aerosol drug mass density of between 0.5 mg/L aerosol. and 1.5 mg/L. In a method aspect of the present invention, an antihis Typically, where the aerosol comprises clemastine, the tamine is delivered to a mammal through an inhalation route. aerosol has an inhalable aerosol drug mass density of The method comprises: a) heating a composition, wherein between 0.25 mg/L and 6 mg/L. Preferably, the aerosol has 15 the composition comprises at least 5 percent by weight of an an inhalable aerosol drug mass density of between 0.35 antihistamine; and, b) allowing the vapor to cool, thereby mg/L and 4 mg/L. More preferably, the aerosol has an forming a condensation aerosol comprising particles, which inhalable aerosol drug mass density of between 0.5 mg/L is inhaled by the mammal. Preferably, the composition that and 3.5 mg/L. is heated comprises at least 10 percent by weight of an Typically, where the aerosol comprises chlorpheniramine, antihistamine. More preferably, the composition comprises the aerosol has an inhalable aerosol drug mass density of 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 between 0.5 mg/L and 5 mg/L. Preferably, the aerosol has an percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 inhalable aerosol drug mass density of between 0.75 mg/L percent, 99.5 percent, 99.9 percent or 99.97 percent by and 4 mg/L. More preferably, the aerosol has an inhalable weight of an antihistamine. aerosol drug mass density of between 1 mg/L and 3 mg/L. 25 Typically, the antihistamine is not one of the following Typically, where the aerosol comprises brompheniramine, antihistamines: dexmedetomidine, diphenhydramine, doxy carbinoxamine or cyproheptadine, the aerosol has an inhal lamine, loratidine, and promethazine. able aerosol drug mass density of between 0.8 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug In certain embodiments, the composition that is heated 30 comprises at least 15 percent by weight of an antihistamine mass density of between 1.4 mg/L and 8 mg/L. More pharmaceutically acceptable salt. Preferably, the salt is a preferably, the aerosol has an inhalable aerosol drug mass hydrochloric acid salt, hydrobromic acid salt, acetic acid density of between 2 mg/L and 6 mg/L. salt, maleic acid salt, formic acid salt or fumaric acid salt. Typically, where the aerosol comprises loratadine, the Typically, the delivered aerosol particles comprise at least aerosol has an inhalable aerosol drug mass density of 35 5 percent by weight of an antihistamine. Preferably, the between 2 mg/L and 25 mg/L. Preferably, the aerosol has an particles comprise at least 10 percent by weight of an inhalable aerosol drug mass density of between 3.5 mg/L antihistamine. More preferably, the particles comprise at and 20 mg/L. More preferably, the aerosol has an inhalable least 20 percent, 30 percent, 40 percent, 50 percent, 60 aerosol drug mass density of between 5 mg/L and 15 mg/L. percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 Typically, where the aerosol comprises promethazine, the 40 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 60 mg/L. Preferably, the aerosol has an percent by weight of an antihistamine. inhalable aerosol drug mass density of between 10 mg/L and Typically, the delivered aerosol has a mass of at least 10 47.5 mg/L. More preferably, the aerosol has an inhalable ug. Preferably, the aerosol has a mass of at least 100 ug. aerosol drug mass density of between 15 mg/L and 35 mg/L. More preferably, the aerosol has a mass of at least 200 ug. Typically, where the aerosol comprises pyrilamine, the 45 Typically, the delivered aerosol particles comprise less aerosol has an inhalable aerosol drug mass density of than 10 percent by weight of antihistamine degradation between 6 mg/L and 70 mg/L. Preferably, the aerosol has an products. Preferably, the particles comprise less than 5 inhalable aerosol drug mass density of between 13 mg/L and percent by weight of antihistamine degradation products. 55 mg/L. More preferably, the aerosol has an inhalable More preferably, the particles comprise less than 2.5, 1, 0.5, aerosol drug mass density of between 20 mg/L and 40 mg/L. 0.1 or 0.03 percent by weight of antihistamine degradation Typically, where the aerosol comprises hydroxy Zine, the products. aerosol has an inhalable aerosol drug mass density of Typically, the particles of the delivered condensation between 2 mg/L and 100 mg/L. Preferably, the aerosol has aerosol have a mass median aerodynamic diameter of less an inhalable aerosol drug mass density of between 5 mg/L 55 than 5 microns. Preferably, the particles have a mass median and 75 mg/L. More preferably, the aerosol has an inhalable aerodynamic diameter of less than 3 microns. More prefer aerosol drug mass density of between 10 mg/L and 50 mg/L. ably, the particles have a mass median aerodynamic diam Typically, the aerosol has an inhalable aerosol particle eter of less than 2 or 1 micron(s). density greater than 10° particles/mL. Preferably, the aerosol Typically, the geometric standard deviation around the has an inhalable aerosol particle density greater than 107 60 mass median aerodynamic diameter of the aerosol particles particles/mL. More preferably, the aerosol has an inhalable is less than 3.0. Preferably, the geometric standard deviation aerosol particle density greater than 10 particles/mL. is less than 2.85. More preferably, the geometric standard Typically, the aerosol particles have a mass median aero deviation is less than 2.7. dynamic diameter of less than 5 microns. Preferably, the Typically, the particles of the delivered condensation particles have a mass median aerodynamic diameter of less 65 aerosol comprise less than 90 percent by weight of water. than 3 microns. More preferably, the particles have a mass Preferably, the particles comprise less than 80percent by median aerodynamic diameter of less than 2 or 1 micron(s). weight of water. More preferably, the particles comprise less US 7,067,114 B2 5 6 than 70 percent, 60 percent, 50 percent, 40 percent, 30 erably, the particles comprise at least 10 percent by weight percent, 20 percent, 10 percent, or 5 percent by weight of of azatadine, brompheniramine, carbinoxamine, chlorphe Water. niramine, clemastine, cyproheptadine, loratadine, pyril Typically, at least 50 percent by weight of the aerosol is amine, hydroxyzine, or promethazine. More preferably, the amorphous in form, wherein crystalline forms make up less particles comprise at least 20 percent, 30 percent, 40 percent, than 50 percent by weight of the total aerosol weight, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 regardless of the nature of individual particles. Preferably, at percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or least 75 percent by weight of the aerosol is amorphous in 99.97 percent by weight of azatadine, brompheniramine, form. More preferably, at least 90 percent by weight of the carbinoxamine, chlorpheniramine, clemastine, cyprohepta aerosol is amorphous in form. 10 dine, loratadine, pyrilamine, hydroxyzine, or promethazine. Typically, the delivered aerosol has an inhalable aerosol Typically, the delivered aerosol has a mass of at least 10 particle density greater than 10° particles/mL. Preferably, the ug. Preferably, the aerosol has a mass of at least 100 ug. aerosol has an inhalable aerosol particle density greater than More preferably, the aerosol has a mass of at least 200 ug. 107 particles/mL. More preferably, the aerosol has an inhal Typically, the delivered aerosol particles comprise less able aerosol particle density greater than 10 particles/mL. 15 than 10 percent by weight of azatadine, brompheniramine, Typically, the rate of inhalable aerosol particle formation carbinoxamine, chlorpheniramine, clemastine, cyprohepta of the delivered condensation aerosol is greater than 10 dine, loratadine, pyrilamine, hydroxy Zine, or promethazine particles per second. Preferably, the aerosol is formed at a degradation products. Preferably, the particles comprise less rate greater than 10 inhalable particles per second. More than 5 percent by weight of azatadine, brompheniramine, preferably, the aerosol is formed at a rate greater than 10" carbinoxamine, chlorpheniramine, clemastine, cyprohepta inhalable particles per second. dine, loratadine, pyrilamine, hydroxy Zine, or promethazine Typically, the delivered aerosol is formed at a rate greater degradation products. More preferably, the particles com than 0.25 mg/second. Preferably, the aerosol is formed at a prise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of rate greater than 0.5 mg/second. More preferably, the aerosol aZatadine, brompheniramine, carbinoxamine, chlorphe is formed at a rate greater than 1 or 2 mg/second. 25 niramine, clemastine, cyproheptadine, loratadine, pyril Typically, the delivered condensation aerosol results in a amine, hydroxy Zine, or promethazine degradation products. peak plasma concentration of the antihistamine in the mam Typically, the particles of the delivered condensation mal in less than 1 h. Preferably, the peak plasma concen aerosol have a mass median aerodynamic diameter of less tration is reached in less than 0.5 h. More preferably, the than 5 microns. Preferably, the particles have a mass median peak plasma concentration is reached in less than 0.2, 0.1. 30 aerodynamic diameter of less than 3 microns. More prefer 0.05, 0.02, 0.01, or 0.005 h (arterial measurement). ably, the particles have a mass median aerodynamic diam Typically, the delivered condensation aerosol is used to eter of less than 2 or 1 micron(s). treat allergy symptoms. Typically, the geometric standard deviation around the In another method aspect of the present invention, azata mass median aerodynamic diameter of the aerosol particles dine, brompheniramine, carbinoxamine, chlorpheniramine, 35 is less than 3.0. Preferably, the geometric standard deviation clemastine, cyproheptadine, loratadine, pyrilamine, hydrox is less than 2.85. More preferably, the geometric standard yZine, or promethazine is delivered to a mammal through an deviation is less than 2.7. inhalation route. The method comprises: a) heating a com Typically, the particles of the delivered condensation position, wherein the composition comprises at least 5 aerosol comprise less than 90 percent by weight of water. percent by weight of azatadine, brompheniramine, carbinox 40 Preferably, the particles comprise less than 80 percent by amine, chlorpheniramine, clemastine, cyproheptadine, lora weight of water. More preferably, the particles comprise less tadine, pyrilamine, hydroxy Zine, or promethazine; and, b) than 70 percent, 60 percent, 50 percent, 40 percent, 30 allowing the vapor to cool, thereby forming a condensation percent, 20 percent, 10 percent, or 5 percent by weight of aerosol comprising particles, which is inhaled by the mam Water. mal. Preferably, the composition that is heated comprises at 45 Typically, at least 50 percent by weight of the aerosol is least 10 percent by weight of azatadine, brompheniramine, amorphous in form, wherein crystalline forms make up less carbinoxamine, chlorpheniramine, clemastine, cyprohepta than 50 percent by weight of the total aerosol weight, dine, loratadine, pyrilamine, hydroxyzine, or promethazine. regardless of the nature of individual particles. Preferably, at More preferably, the composition comprises 20 percent, 30 least 75 percent by weight of the aerosol is amorphous in percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 50 form. More preferably, at least 90 percent by weight of the percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 aerosol is amorphous in form. percent, 99.9 percent or 99.97 percent by weight of azata Typically, where the aerosol comprises azatadine, the dine, brompheniramine, carbinoxamine, chlorpheniramine, aerosol has an inhalable aerosol drug mass density of clemastine, cyproheptadine, loratadine, pyrilamine, hydrox between 0.2 mg/L and 2.5 mg/L. Preferably, the aerosol has yZine, or promethazine. 55 an inhalable aerosol drug mass density of between 0.35 In certain embodiments, the composition that is heated mg/L and 2 mg/L. More preferably, the aerosol has an comprises at least 15 percent by weight of an azatadine, inhalable aerosol drug mass density of between 0.5 mg/L brompheniramine, carbinoxamine, chlorpheniramine, clem and 1.5 mg/L. astine, cyproheptadine, loratadine, pyrilamine, hydroxy Zine, Typically, where the aerosol comprises clemastine, the or promethazine pharmaceutically acceptable salt. Prefer 60 aerosol has an inhalable aerosol drug mass density of ably, the salt is a hydrochloric acid salt, hydrobromic acid between 0.25 mg/L and 6 mg/L. Preferably, the aerosol has salt, acetic acid salt, maleic acid salt, formic acid salt or an inhalable aerosol drug mass density of between 0.35 fumaric acid salt. mg/L and 4 mg/L. More preferably, the aerosol has an Typically, the delivered aerosol particles comprise at least inhalable aerosol drug mass density of between 0.5 mg/L 5 percent by weight of azatadine, brompheniramine, carbi 65 and 3.5 mg/L. noxamine, chlorpheniramine, clemastine, cyproheptadine, Typically, where the aerosol comprises chlorpheniramine, loratadine, pyrilamine, hydroxy Zine, or promethazine. Pref the aerosol has an inhalable aerosol drug mass density of US 7,067,114 B2 7 8 between 0.5 mg/L and 5 mg/L. Preferably, the aerosol has an mammal in a single inspiration. More preferably, between 1 inhalable aerosol drug mass density of between 0.75 mg/L mg and 3 mg of chlorpheniramine is delivered to the and 4 mg/L. More preferably, the aerosol has an inhalable mammal in a single inspiration. aerosol drug mass density of between 1 mg/L and 3 mg/L. Typically, where the aerosol comprises brompheniramine, Typically, where the aerosol comprises brompheniramine, carbinoxamine or cyproheptadine, between 0.8 mg and 10 carbinoxamine or cyproheptadine, the aerosol has an inhal mg of brompheniramine, carbinoxamine or cyproheptadine able aerosol drug mass density of between 0.8 mg/L and 10 is delivered to the mammal in a single inhalation. Preferably, mg/L. Preferably, the aerosol has an inhalable aerosol drug between 1.4 mg and 8 mg of brompheniramine, carbinox mass density of between 1.4 mg/L and 8 mg/L. More amine or cyproheptadine is delivered to the mammal in a preferably, the aerosol has an inhalable aerosol drug mass 10 single inhalation. More preferably, between 2 mg and 6 mg density of between 2 mg/L and 6 mg/L. of brompheniramine, carbinoxamine or cyproheptadine is Typically, where the aerosol comprises loratadine, the delivered to the mammal in a single inhalation. aerosol has an inhalable aerosol drug mass density of Typically, where the aerosol comprises loratadine, between 2 mg/L and 25 mg/L. Preferably, the aerosol has an between 2 mg and 25 mg or loratadine is delivered to the inhalable aerosol drug mass density of between 3.5 mg/L 15 mammal in a single inhalation. Preferably, between 3.5 mg and 20 mg/L. More preferably, the aerosol has an inhalable and 20 mg of loratadine is delivered to the mammal in a aerosol drug mass density of between 5 mg/L and 15 mg/L. single inspiration. More preferably, between 5 mg and 15 mg Typically, where the aerosol comprises promethazine, the of loratadine is delivered to the mammal in a single inspi aerosol has an inhalable aerosol drug mass density of ration. between 5 mg/L and 60 mg/L. Preferably, the aerosol has an Typically, where the aerosol comprises promethazine, inhalable aerosol drug mass density of between 10 mg/L and between 5 mg and 60 mg of promethazine is delivered to the 47.5 mg/L. More preferably, the aerosol has an inhalable mammal in a single inspiration. Preferably, between 10 mg aerosol drug mass density of between 15 mg/L and 35 mg/L. and 47.5 mg of promethazine is delivered to the mammal in Typically, where the aerosol comprises hydroxy Zine, the a single inspiration. More preferably, between 15 mg and 35 aerosol has an inhalable aerosol drug mass density of 25 mg of promethazine is delivered to the mammal in a single between 2 mg/L and 100 mg/L. Preferably, the aerosol has inspiration. an inhalable aerosol drug mass density of between 5 mg/L Typically, where the aerosol comprises hydroxyzine, and 75 mg/L. More preferably, the aerosol has an inhalable between 2 mg and 100 mg of hydroxyzine is delivered to the aerosol drug mass density of between 10 mg/L and 50 mg/L. mammal in a single inspiration. Preferably, between 5 mg Typically, where the aerosol comprises pyrilamine, the 30 and 75 mg of hydroxyzine is delivered to the mammal in a aerosol has an inhalable aerosol drug mass density of single inspiration. More preferably, between 10 mg and 50 between 6 mg/L and 70 mg/L. Preferably, the aerosol has an mg of hydroxyzine is delivered to the mammal in a single inhalable aerosol drug mass density of between 13 mg/L and inspiration. 55 mg/L. More preferably, the aerosol has an inhalable Typically, where the aerosol comprises pyrilamine, aerosol drug mass density of between 20 mg/L and 40 mg/L. 35 between 6 mg and 70 mg of pyrilamine is delivered to the Typically, the delivered aerosol has an inhalable aerosol mammal in a single inspiration. Preferably, between 13 mg particle density greater than 10° particles/mL. Preferably, the and 55 mg of pyrilamine is delivered to the mammal in a aerosol has an inhalable aerosol particle density greater than single inspiration. More preferably, between 20 mg and 40 107 particles/mL. More preferably, the aerosol has an inhal mg of pyrilamine is delivered to the mammal in a single able aerosol particle density greater than 10 particles/mL. 40 inspiration. Typically, the rate of inhalable aerosol particle formation Typically, the delivered condensation aerosol results in a of the delivered condensation aerosol is greater than 10 peak plasma concentration of azatadine, brompheniramine, particles per second. Preferably, the aerosol is formed at a carbinoxamine, chlorpheniramine, clemastine, cyprohepta rate greater than 10 inhalable particles per second. More dine, loratadine, pyrilamine, hydroxy Zine, or promethazine preferably, the aerosol is formed at a rate greater than 10' 45 in the mammal in less than 1 h. Preferably, the peak plasma inhalable particles per second. concentration is reached in less than 0.5 h. More preferably, Typically, the delivered aerosol is formed at a rate greater the peak plasma concentration is reached in less than 0.2, than 0.25 mg/second. Preferably, the aerosol is formed at a 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement). rate greater than 0.5 mg/second. More preferably, the aerosol Typically, the delivered condensation aerosol is used to is formed at a rate greater than 1 or 2 mg/second. 50 treat allergy symptoms. Typically, where the aerosol comprises azatadine, In a kit aspect of the present invention, a kit for delivering between 0.2 mg and 2.5 mg of azatadine is delivered to the an antihistamine through an inhalation route to a mammal is mammal in a single inspiration. Preferably, between 0.35 mg provided which comprises: a) a composition comprising at and 2 mg of azatadine is delivered to the mammal in a single least 5 percent by weight of an antihistamine; and, b) a inspiration. More preferably, between 0.5 mg and 1.5 mg of 55 device that forms an antihistamine containing aerosol from aZatadine is delivered to the mammal in a single inspiration. the composition, for inhalation by the mammal. Preferably, Typically, where the aerosol comprises clemastine, the composition comprises at least 10 percent by weight of between 0.25 mg and 6 mg of clemastine is delivered to the an antihistamine. More preferably, the composition com mammal in a single inspiration. Preferably, between 0.35 mg prises at least 20 percent, 30 percent, 40 percent, 50 percent, and 4 mg of clemastine is delivered to the mammal in a 60 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 single inspiration. More preferably, between 0.5 mg and 3.5 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 mg of clemastine is delivered to the mammal in a single percent by weight of an antihistamine. inspiration. Typically, the device contained in the kit comprises: a) an Typically, where the aerosol comprises chlorpheniramine, element for heating the antihistamine composition to form a between 0.5 mg and 5 mg of chlorpheniramine is delivered 65 vapor; b) an element allowing the vapor to cool to form an to the mammal in a single inspiration. Preferably, between aerosol; and, c) an element permitting the mammal to inhale 0.75 mg and 4 mg of chlorpheniramine is delivered to the the aerosol. US 7,067,114 B2 10 In another kit aspect of the present invention, a kit for “AZatadine' refers to 6,11-dihydro-11-(1-methyl-4-pip delivering azatadine, brompheniramine, carbinoxamine, eridinylidene)-5H-benzo 5,6cyclohepta 1.2-bipyridine. chlorpheniramine, clemastine, cyproheptadine, loratadine, “AZatadine degradation product” refers to a compound pyrilamine, hydroxyZine, or promethazine an inhalation resulting from a chemical modification of azatadine. The route to a mammal is provided which comprises: a) a 5 modification, for example, can be the result of a thermally or composition comprising at least 5 percent by weight of photochemically induced reaction. Such reactions include, aZatadine, brompheniramine, carbinoxamine, chlorphe without limitation, oxidation and hydrolysis. niramine, clemastine, cyproheptadine, loratadine, pyril “Brompheniramine” refers to 1-(p-bromophenyl)-1-(2- amine, hydroxyzine, or promethazine; and, b) a device that pyridyl)-3-N,N-dimethylaminopropane. forms a azatadine, brompheniramine, carbinoxamine, chlo 10 “Brompheniramine degradation product” refers to a com rpheniramine, clemastine, cyproheptadine, loratadine, pyril pound resulting from a chemical modification of bromphe amine, hydroxy Zine, or promethazine containing aerosol niramine. The modification, for example, can be the result of from the composition, for inhalation by the mammal. Pref a thermally or photochemically induced reaction. Such reac erably, the composition comprises at least 10 percent by tions include, without limitation, oxidation and hydrolysis. weight of azatadine, brompheniramine, carbinoxamine, 15 “Carbinoxamine” refers to 2-p-chloro-O-(2-dimethy chlorpheniramine, clemastine, cyproheptadine, loratadine, laminoethoxy)benzyl-pyridine. pyrilamine, hydroxyzine, or promethazine. More preferably, “Carbinoxamine degradation product” refers to a com the composition comprises at least 20 percent, 30 percent, 40 pound resulting from a chemical modification of carbinox percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 amine. The modification, for example, can be the result of a percent, 95 percent, 97 percent, 99 percent, 99.5 percent, thermally or photochemically induced reaction. Such reac 99.9 percent or 99.97 percent by weight of azatadine, tions include, without limitation, oxidation and hydrolysis. brompheniramine, carbinoxamine, chlorpheniramine, clem “Chlorpheniramine” refers to 1-(p-chlorophenyl)-1-(2- astine, cyproheptadine, loratadine, pyrilamine, hydroxy Zine, pyridyl)-3-N,N-dimethylaminopropane. or promethazine. “Chlorpheniramine degradation product” refers to a com Typically, the device contained in the kit comprises: a) an 25 pound resulting from a chemical modification of chlorphe element for heating the azatadine, brompheniramine, carbi niramine. The modification, for example, can be the result of noxamine, chlorpheniramine, clemastine, cyproheptadine, a thermally or photochemically induced reaction. Such reac loratadine, pyrilamine, hydroxy Zine, or promethazine com tions include, without limitation, oxidation and hydrolysis. position to form a vapor; b) an element allowing the vapor An example of a degradation product is a compound of to cool to form an aerosol, and, c) an element permitting the 30 molecular formula C2HNOCl. mammal to inhale the aerosol. “Clemastine' refers to 2-2-1-(4-chlorophenyl)-1-phe nyl-ethoxyethyl-1-methylpyrrolidine. BRIEF DESCRIPTION OF THE FIGURE "Clemastine degradation product” refers to a compound resulting from a chemical modification of clemastine. The FIG. 1 shows a device used to deliver antihistamine 35 modification, for example, can be the result of a thermally or containing aerosols to a mammal through an inhalation photochemically induced reaction. Such reactions include, rOute. without limitation, oxidation and hydrolysis. An example of a degradation product is CHOCl (removal of sidechain DETAILED DESCRIPTION OF THE from oxygen, yielding an alcohol). INVENTION 40 “Condensation aerosol refers to an aerosol formed by vaporization of a substance followed by condensation of the Substance into an aerosol. Definitions “Cyproheptadine' refers to 4-(5H-dibenzoa.dcyclohep “Aerodynamic diameter of a given particle refers to the ten-5-ylidene)-1-methylpiperidine. diameter of a spherical droplet with a density of 1 g/mL (the 45 density of water) that has the same settling velocity as the “Cyproheptadine degradation product” refers to a com given particle. pound resulting from a chemical modification of cyprohep tadine. The modification, for example, can be the result of a “Aerosol refers to a suspension of solid or liquid par thermally or photochemically induced reaction. Such reac ticles in a gas. tions include, without limitation, oxidation and hydrolysis. “Aerosol drug mass density refers to the mass of anti 50 An example of a degradation product is the N-oxide of histamine per unit volume of aerosol. cyproheptadine (CHNO). “Aerosol mass density' refers to the mass of particulate “Hydroxyzine' refers to 2-2-4-(4-chlorophenyl)phe matter per unit volume of aerosol. nylmethyl-1-peoperazinyl-ethoxyethanol. “Aerosol particle density' refers to the number of par 55 “Hydroxyzine degradation product” refers to a compound ticles per unit volume of aerosol. resulting from a chemical modification of hydroxy Zine. The “Amorphous particle' refers to a particle that does not modification, for example, can be the result of a thermally or contain more than 50 percent by weight of a crystalline photochemically induced reaction. Such reactions include, form. Preferably, the particle does not contain more than 25 without limitation, oxidation and hydrolysis. An example of percent by weight of a crystalline form. More preferably, the 60 a degradation product is a compound of molecular formula particle does not contain more than 10 percent by weight of CHOCl (a chloro benzophenone). a crystalline form. "Inhalable aerosol drug mass density' refers to the aerosol "Antihistamine degradation product” refers to a com drug mass density produced by an inhalation device and pound resulting from a chemical modification of an antihis delivered into a typical patient tidal volume. tamine. The modification, for example, can be the result of 65 "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. into a typical patient tidal Volume. US 7,067,114 B2 11 12 "Inhalable aerosol particle density' refers to the aerosol Salt forms of antihistamines (e.g., azatadine, bromphe particle density of particles of size between 100 nm and 5 niramine, carbinoxamine, chlorpheniramine, clemastine, microns produced by an inhalation device and delivered into cyproheptadine, loratadine, pyrilamine, hydroxy Zine, or a typical patient tidal Volume. promethazine) are either commercially available or are “Loratadine' refers to ethyl 4-(8-chloro-5,6-dihydro-11H- 5 obtained from the corresponding free base using well known benzo 5,6cyclohepta 1,2-bipyridine-11-ylidene)-1-pip methods in the art. A variety of pharmaceutically acceptable eridinecarboxylate salts are suitable for aerosolization. Such salts include, "Loratadine degradation product” refers to a compound without limitation, the following: hydrochloric acid, hydro resulting from a chemical modification of loratadine. The bromic acid, acetic acid, maleic acid, formic acid, and modification, for example, can be the result of a thermally or 10 photochemically induced reaction. Such reactions include, fumaric acid salts. without limitation, oxidation and hydrolysis. Pharmaceutically acceptable excipients may be volatile or “Mass median aerodynamic diameter' or “MMAD” of an nonvolatile. Volatile excipients, when heated, are concur aerosol refers to the aerodynamic diameter for which half rently volatilized, aerosolized and inhaled with the antihis the particulate mass of the aerosol is contributed by particles 15 tamine. Classes of Such excipients are known in the art and with an aerodynamic diameter larger than the MMAD and include, without limitation, gaseous, Supercritical fluid, liq half by particles with an aerodynamic diameter Smaller than uid and solid solvents. The following is a list of exemplary the MMAD. carriers within the classes: water, terpenes, such as menthol; “Promethazine' refers to 10-(2-dimethylaminopropyl) alcohols, such as ethanol, propylene glycol, glycerol and phenothiazine. other similar alcohols; dimethylformamide; dimethylaceta “Promethazine degradation product” refers to a com mide; wax; Supercritical carbon dioxide; dry ice; and mix pound resulting from a chemical modification of promet tures thereof. hazine. The modification, for example, can be the result of Solid supports on which the composition is heated are of a thermally or photochemically induced reaction. Such reac a variety of shapes. Examples of Such shapes include, tions include, without limitation, oxidation and hydrolysis. 25 An example of a degradation product is a compound of without limitation, cylinders of less than 1.0 mm in diameter, molecular formula C2HNOS (a sulfoxide). boxes of less than 1.0 mm thickness and virtually any shape “Pyrilamine” refers to N-(4-methoxyphenyl)methyl-N', permeated by Small (e.g., less than 1.0 mm-sized) pores. N'-dimethyl-N-2-pyridinyl-1,2-ethanediamine. Preferably, solid supports provide a large surface to volume “Pyrilamine degradation product” refers to a compound 30 ratio (e.g., greater than 100 per meter) and a large Surface to resulting from a chemical modification of pyrilamine. The mass ratio (e.g., greater than 1 cm per gram). modification, for example, can be the result of a thermally or A solid support of one shape can also be transformed into photochemically induced reaction. Such reactions include, another shape with different properties. For example, a flat without limitation, oxidation and hydrolysis. An example of sheet of 0.25 mm thickness has a surface to volume ratio of a degradation product is 4-methoxy-benzaldehyde. 35 approximately 8,000 per meter. Rolling the sheet into a "Rate of aerosol formation” refers to the mass of aero hollow cylinder of 1 cm diameter produces a Support that Solized particulate matter produced by an inhalation device retains the high Surface to mass ratio of the original sheet but per unit time. has a lower surface to volume ratio (about 400 per meter). "Rate of inhalable aerosol particle formation” refers to the A number of different materials are used to construct the number of particles of size between 100 nm and 5 microns 40 Solid Supports. Classes of Such materials include, without produced by an inhalation device per unit time. limitation, metals, inorganic materials, carbonaceous mate "Rate of drug aerosol formation” refers to the mass of rials and polymers. The following are examples of the aerosolized antihistamine produced by an inhalation device material classes: aluminum, silver, gold, stainless steel, per unit time. copper and tungsten; silica, glass, silicon and alumina; “Settling velocity' refers to the terminal velocity of an 45 graphite, porous carbons, carbon yarns and carbon felts; aerosol particle undergoing gravitational settling in air. polytetrafluoroethylene and polyethylene glycol. Combina “Typical patient tidal volume' refers to 1 L for an adult tions of materials and coated variants of materials are used patient and 15 mL/kg for a pediatric patient. as well. "Vapor refers to a gas, and “vapor phase' refers to a gas 50 Where aluminum is used as a Solid Support, aluminum foil phase. The term “thermal vapor refers to a vapor phase, is a suitable material. Examples of silica, alumina and aerosol, or mixture of aerosol-vapor phases, formed prefer silicon based materials include amphorous silica S-5631 ably by heating. (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined Formation of Antihistamine Containing Aerosols surface area greater than 2 mg from Aldrich, St. Louis, Any suitable method is used to form the aerosols of the 55 Mo.) and a silicon wafer as used in the semiconductor present invention. A preferred method, however, involves industry. Carbon yarns and felts are available from American heating a composition comprising an antihistamine to form Kynol, Inc., New York, N.Y. Chromatography resins such as a vapor, followed by cooling of the vapor such that it octadecycl silane chemically bonded to porous silica are condenses to provide an antihistamine comprising aerosol exemplary coated variants of silica. (condensation aerosol). The composition is heated in one of 60 The heating of the antihistamine compositions is per four forms: as pure active compound (e.g., pure azatadine, formed using any Suitable method. Examples of methods by brompheniramine, carbinoxamine, chlorpheniramine, clem which heat can be generated include the following: passage astine, cyproheptadine, loratadine, pyrilamine, hydroxy Zine, of current through an electrical resistance element; absorp or promethazine); as a mixture of active compound and a tion of electromagnetic radiation, Such as microwave or laser pharmaceutically acceptable excipient; as a salt form of the 65 light; and, exothermic chemical reactions, such as exother pure active compound; and, as a mixture of active compound mic Solvation, hydration of pyrophoric materials and oxida salt form and a pharmaceutically acceptable excipient. tion of combustible materials. US 7,067,114 B2 13 14 Delivery of Antihistamine Containing Aerosols primates are typically used in Such studies, since their Antihistamine containing aerosols of the present inven respiratory systems are similar to that of a human. Initial tion are delivered to a mammal using an inhalation device. dose levels for testing in humans is generally less than or Where the aerosol is a condensation aerosol, the device has equal to the dose in the mammal model that resulted in at least three elements: an element for heating an antihista plasma drug levels associated with a therapeutic effect in mine containing composition to form a vapor, an element humans. Dose escalation in humans is then performed, until allowing the vapor to cool, thereby providing a condensation either an optimal therapeutic response is obtained or a aerosol; and, an element permitting the mammal to inhale dose-limiting toxicity is encountered. the aerosol. Various suitable heating methods are described Analysis of Antihistamine Containing Aerosols above. The element that allows cooling is, in it simplest 10 form, an inert passageway linking the heating means to the Purity of an antihistamine containing aerosol is deter inhalation means. The element permitting inhalation is an mined using a number of methods, examples of which are aerosol exit portal that forms a connection between the described in Sekine et al., Journal of Forensic Science cooling element and the mammals respiratory system. 32:1271–1280 (1987) and Martin et al., Journal of Analytic One device used to deliver an antihistamine containing 15 Toxicology 13:158—162 (1989). One method involves form aerosol is described in reference to FIG. 1. Delivery device ing the aerosol in a device through which a gas flow (e.g., 100 has a proximal end 102 and a distal end 104, a heating air flow) is maintained, generally at a rate between 0.4 and module 106, a power source 108, and a mouthpiece 110. An 60 L/min. The gas flow carries the aerosol into one or more antihistamine composition is deposited on a surface 112 of traps. After isolation from the trap, the aerosol is subjected heating module 106. Upon activation of a user activated to an analytical technique, Such as gas or liquid chromatog switch 114, power source 108 initiates heating of heating raphy, that permits a determination of composition purity. module 106 (e.g. through ignition of combustible fuel or A variety of different traps are used for aerosol collection. passage of current through a resistive heating element). The The following list contains examples of Such traps: filters; antihistamine composition volatilizes due to the heating of glass wool; impingers; solvent traps, such as dry ice-cooled heating module 106 and condenses to form a condensation 25 ethanol, methanol, acetone and dichloromethane traps at aerosol prior to reaching the mouthpiece 110 at the proximal various pH values; Syringes that sample the aerosol, empty, end of the device 102. Air flow traveling from the device low-pressure (e.g., vacuum) containers into which the aero distal end 104 to the mouthpiece 110 carries the condensa Sol is drawn; and, empty containers that fully Surround and tion aerosol to the mouthpiece 110, where it is inhaled by the enclose the aerosol generating device. Where a solid Such as mammal. 30 glass wool is used, it is typically extracted with a solvent Devices, if desired, contain a variety of components to Such as ethanol. The solvent extract is Subjected to analysis facilitate the delivery of antihistamine containing aerosols. rather than the solid (i.e., glass wool) itself. Where a syringe For instance, the device may include any component known or container is used, the container is similarly extracted with in the art to control the timing of drug aerosolization relative a solvent. 35 The gas or liquid chromatograph discussed above con to inhalation (e.g., breath-actuation), to provide feedback to tains a detection system (i.e., detector). Such detection patients on the rate and/or Volume of inhalation, to prevent systems are well known in the art and include, for example, excessive use (i.e., “lock-out” feature), to prevent use by flame ionization, photon absorption and mass spectrometry unauthorized individuals, and/or to record dosing histories. detectors. An advantage of a mass spectrometry detector is Dosage of Antihistamine Containing Aerosols 40 that it can be used to determine the structure of antihistamine The dosage amount of antihistamine in aerosol form is degradation products. generally no greater than twice the standard dose of the drug Particle size distribution of an antihistamine containing given orally. For instance, for the treatment of allergy aerosol is determined using any suitable method in the art symptoms azatadine, brompheniramine, carbinoxamine, (e.g., cascade impaction). An Andersen Eight Stage Non chlorpheniramine, clemastine, cyproheptadine, loratadine, 45 viable Cascade Impactor (Andersen Instruments, Smyrna, pyrilamine, hydroxyZine and promethazine are typically Ga.) linked to a furnace tube by a mock throat (USP throat, provided orally at the following respective strengths: 1 mg, Andersen Instruments, Smyrna, Ga.) is one system used for 4 mg. 4 mg, 2 mg, 1.34 mg. 4 mg, 10 mg. 30 mg, 25 mg, and cascade impaction studies. 25 mg. As aerosols, the compounds are generally provided Inhalable aerosol mass density is determined, for in the following amounts per inspiration for the same 50 example, by delivering a drug-containing aerosol into a indication: azatadine, 0.2 mg to 2.5 mg; clemastine, 0.25 mg confined chamber via an inhalation device and measuring to 6 mg; chlorpheniramine, 0.5 mg to 5 mg; bromphe the mass collected in the chamber. Typically, the aerosol is niramine, 0.8 mg to 10 mg carbinoxamine, 0.8 mg to 10 mg: drawn into the chamber by having a pressure gradient cyproheptadine, 0.8 mg to 10 mg; loratadine, 2 mg to 25 mg: between the device and the chamber, wherein the chamber promethazine, 5 mg to 60 mg: hydroxy Zine, 2 mg to 100 mg: 55 is at lower pressure than the device. The volume of the and, pyrilamine, 6 mg to 70 mg. A typical dosage of an chamber should approximate the tidal Volume of an inhaling antihistamine aerosol is either administered as a single patient. inhalation or as a series of inhalations taken within an hour Inhalable aerosol drug mass density is determined, for or less (dosage equals Sum of inhaled amounts). Where the example, by delivering a drug-containing aerosol into a drug is administered as a series of inhalations, a different 60 confined chamber via an inhalation device and measuring amount may be delivered in each inhalation. the amount of active drug compound collected in the cham One can determine the appropriate dose of an antihista ber. Typically, the aerosol is drawn into the chamber by mine containing aerosol to treat a particular condition using having a pressure gradient between the device and the methods such as animal experiments and a dose-finding chamber, wherein the chamber is at lower pressure than the (Phase I/II) clinical trial. One animal experiment involves 65 device. The volume of the chamber should approximate the measuring plasma concentrations of drug in an animal after tidal Volume of an inhaling patient. The amount of active its exposure to the aerosol. Mammals such as dogs or drug compound collected in the chamber is determined by US 7,067,114 B2 15 16 extracting the chamber, conducting chromatographic analy hydrochloride are commercially available from Sigma (ww sis of the extract and comparing the results of the chromato w.sigma-aldrich.com). Antihistamines can also be isolated graphic analysis to those of a standard containing known from compositions such as RYNATANR), DIMETANER, amounts of drug. RONDECR, SINUTAB(R, TAVISTR), PERIACTINR, Inhalable aerosol particle density is determined, for CLARITINR, RYNA-12TM, and PHENERGANR) using example, by delivering aerosol phase drug into a confined standard methods in the art. chamber via an inhalation device and measuring the number of particles of given size collected in the chamber. The EXAMPLE 1. number of particles of a given size may be directly measured based on the light-scattering properties of the particles. 10 General Procedure for Obtaining Free Base of an Alternatively, the number of particles of a given size may be Antihistamine Salt determined by measuring the mass of particles within the given size range and calculating the number of particles Approximately 1 g of salt (e.g., mono hydrochloride) is based on the mass as follows: Total number of dissolved in deionized water (-30 mL). Three equivalents of particles-Sum (from size range 1 to size range N) of number 15 sodium hydroxide (1 N NaOH) is added dropwise to the of particles in each size range. Number of particles in a given solution, and the pH is checked to ensure it is basic. The size range-Mass in the size range/Mass of a typical particle aqueous solution is extracted four times with dichlo in the size range. Mass of a typical particle in a given size romethane (~50 mL), and the extracts are combined, dried range TD*p/6, where D is a typical particle diameter in (Na2SO4) and filtered. The filtered organic solution is con the size range (generally, the mean boundary MMADs centrated using a rotary evaporator to provide the desired defining the size range) in microns, p is the particle density free base. If necessary, purification of the free base is (in g/mL) and mass is given in units of picograms (g'). performed using standard methods such as chromatography Rate of inhalable aerosol particle formation is determined, or recrystallization. for example, by delivering aerosol phase drug into a con fined chamber via an inhalation device. The delivery is for 25 EXAMPLE 2 a set period of time (e.g., 3 s), and the number of particles of a given size collected in the chamber is determined as General Procedure for Volatilizing Compounds outlined above. The rate of particle formation is equal to the number of 100 nm to 5 micron particles collected divided by A solution of drug in approximately 120 uL dichlo the duration of the collection time. 30 romethane is coated on a 3 cm x8 cm piece of aluminum foil. Rate of aerosol formation is determined, for example, by The dichloromethane is allowed to evaporate. The coated delivering aerosol phase drug into a confined chamber via an foil is wrapped around a 300 watt halogen tube (Feit Electric inhalation device. The delivery is for a set period of time Company, Pico Rivera, Calif.), which is inserted into a glass (e.g., 3 s), and the mass of particulate matter collected is tube sealed at one end with a rubber stopper. Running 60 V determined by weighing the confined chamber before and 35 of alternating current (driven by line power controlled by a after the delivery of the particulate matter. The rate of variac) through the bulb for 5–11 s affords thermal vapor aerosol formation is equal to the increase in mass in the (including aerosol), which is collected on the glass tube chamber divided by the duration of the collection time. walls. Reverse-phase HPLC analysis with detection by Alternatively, where a change in mass of the delivery device absorption of 225 nm light is used to determine the purity of or component thereof can only occur through release of the 40 the aerosol. (When desired, the system is flushed through aerosol phase particulate matter, the mass of particulate with argon prior to volatilization.) matter may be equated with the mass lost from the device or Table 1, which follows, provides data from drugs vola component during the delivery of the aerosol. In this case, tilized using the above-recited general procedure. Current is the rate of aerosol formation is equal to the decrease in mass typically run for 5s after an aerosol is first noticed. To obtain of the device or component during the delivery event 45 higher purity aerosols, one can coat a lesser amount of drug, divided by the duration of the delivery event. yielding a thinner film to heat. A linear decrease in film Rate of drug aerosol formation is determined, for thickness is associated with a linear decrease in impurities. example, by delivering an antihistamine containing aerosol into a confined chamber via an inhalation device over a set TABLE 1 period of time (e.g., 3 s). Where the aerosol is pure antihis 50 tamine, the amount of drug collected in the chamber is Compound Aerosol Purity Argon Used measured as described above. The rate of drug aerosol AZatadine 99.6% No formation is equal to the amount of antihistamine collected Brompheniramine 99.0% No in the chamber divided by the duration of the collection Brompheniramine 99.3% Yes 55 Brompheniramine 99.6% No time. Where the antihistamine containing aerosol comprises Maleate a pharmaceutically acceptable excipient, multiplying the Brompheniramine 100% Yes rate of aerosol formation by the percentage of antihistamine Maleate Carbinoxamine 94.8% Yes in the aerosol provides the rate of drug aerosol formation. Carbinoxamine 99.0% No Utility of Antihistamine Containing Aerosols Maleate 60 Carbinoxamine 100% Yes Antihistamine containing aerosols are typically used for Maleate the treatment of allergy symptoms. Chlorpheniramine 98.4% No The following examples are meant to illustrate, rather Chlorpheniramine 99.6% No Maleate than limit, the present invention. Chlorpheniramine 100% Yes Hydroxyzine dihydrochloride, brompheniramine maleate, 65 Clemastine 94.3% No carbinoxamine maleate, clemastine fumarate, cyprohepta Cyproheptadine 100% No dine hydrochloride, pyrilamine maleate, and promethazine US 7,067,114 B2 17 18

TABLE 1-continued TABLE 1-continued Compound Aerosol Purity Argon Used Determination of the characteristics of a loratadine condensation aerosol by cascade impaction using an Andersen 8-stage Cyproheptadine 99.6% No non-viable cascade impactor run at 1 cubic foot per Hydroxyzine 98.6% No minute air flow. Loratadine 99.0% No Loratadine 99.6% Yes Mass Pyrilamine 98.8% No Particle size Average particle collected Number of Pyrilamine 99.5% Yes Stage range (microns) size (microns) (mg) particles Promethazine 94.5% Yes 10 3 33-47 4.0 O.1 3.0 x 10° 4 2.1-33 2.7 O6 5.8 x 107 5 1.1-2.1 1.6 O.O O EXAMPLE 3 6 O.7-1.1 O.9 0.4 1.1 x 10 7 O4. O.7 0.55 O.3 3.4 x 109 8 0–0.4 O.2 O.2 4.8 x 109 Particle Size, Particle Density, and Rate of 15 Inhalable Particle Formation of Loratadine Aerosol A solution of 12.1 mg loratadine in 200 uL EXAMPLE 4 dichioromethane was spread out in a thin layer on the central portion of a 3.5 cmx7 cm sheet of aluminum foil. The Drug Mass Density and Rate of Drug Aerosol dichloromethane was allowed to evaporate. Assuming a Formation of Loratadine Aerosol drug density of about 1 g/cc, the calculated thickness of the loratadine thin layer on the 24.5 cm aluminum solid sup A solution of 10.4 mg loratadine in 200 uL port, after solvent evaporation, is about 4.9 microns. The dichioromethane was spread out in a thin layer on the central aluminum foil was wrapped around a 300 watt halogen tube, 25 portion of a 3.5 cmx7 cm sheet of aluminum foil. The which was inserted into a T-shaped glass tube. Both of the dichioromethane was allowed to evaporate. Assuming a openings of the tube were left open and the third opening drug density of about 1 g/cc, the calculated thickness of the was connected to a 1 liter, 3-neck glass flask. The glass flask loratadine thin layer on the 24.5 cm aluminum solid sup was further connected to a large piston capable of drawing port, after solvent evaporation, is about 4.2 microns. The 1.1 liters of air through the flask. Alternating current was run 30 aluminum foil was wrapped around a 300 watt halogen tube, through the halogen bulb by application of 90 V using a which was inserted into a T-shaped glass tube. Both of the variac connected to 110 V line power. Within 1 s, an aerosol openings of the tube were left open and the third opening appeared and was drawn into the 1 L flask by use of the was connected to a 1 liter, 3-neck glass flask. The glass flask piston, with collection of the aerosol terminated after 6 s. was further connected to a large piston capable of drawing The aerosol was analyzed by connecting the 1 L flask to an 35 1.1 liters of air through the flask. Alternating current was run eight-stage Andersen non-viable cascade impactor. Results through the halogen bulb by application of 90 V using a are shown in table 1. MMAD of the collected aerosol was variac connected to 110 V line power. Within seconds, an 1.1 microns with a geometric Standard deviation of 2.6. Also aerosol appeared and was drawn into the 1 L flask by use of shown in table 1 is the number of particles collected on the the piston, with formation of the aerosol terminated after 6 various stages of the cascade impactor, given by the mass 40 s. The aerosol was allowed to sediment onto the walls of the collected on the stage divided by the mass of a typical 1 L flask for approximately 30 minutes. The flask was then particle trapped on that stage. The mass of a single particle extracted with acetonitrile and the extract analyzed by of diameter D is given by the volume of the particle, td/6, HPLC with detection by light absorption at 225 nm. Com multiplied by the density of the drug (taken to be 1 g/cm). parison with standards containing known amounts of lora The inhalable aerosol particle density is the sum of the 45 tadine revealed that 1.0 mg of >99% pure loratadine had numbers of particles collected on impactor stages 3 to 8 been collected in the flask, resulting in an aerosol drug mass divided by the collection volume of 1 L, giving an inhalable density of 1.0 mg/L. The aluminum foil upon which the aerosol particle density of 5.2x10 particles/mL. The rate of loratadine had previously been coated was weighed follow inhalable aerosol particle formation is the sum of the num ing the experiment. Of the 10.4 mg originally coated on the bers of particles collected on impactor stages 3 through 8 aluminum, 3.8 mg of the material was found to have divided by the formation time of 6 s, giving a rate of aerosolized in the 6 s time period, implying a rate of drug inhalable aerosol particle formation of 8.7x10 particles/ aerosol formation of 0.6 mg/s. second. The invention claimed is: 55 1. A condensation aerosol for delivery of a drug selected TABLE 1. from the group consisting of azatadine, brompheniramine, Determination of the characteristics of a loratadine condensation carbinoxamine, chlorpheniramine, clemastine, cyprohepta aerosol by cascade impaction using an Andersen 8-stage dine, loratadine, pyrilamine, hydroxy Zine and promethazine, non-viable cascade impactor run at 1 cubic foot per wherein the condensation aerosol is formed by heating a minute air flow. 60 thin layer containing the drug, on a solid Support, to Mass produce a vapor of the drug, and condensing the vapor Particle size Average particle collected Number of to form a condensation aerosol characterized by less Stage range (microns) size (microns) (mg) particles than 10% drug degradation products by weight, and an MMAD of less than 5 microns. O 9.0-10.O 9.5 O.O O 1 5.8 9.0 7.4 O.1 4.7 x 10 65 2. The condensation aerosol according to claim 1, wherein 2 4.7-5.8 5.25 O.O O the condensation aerosol is formed at a rate greater than 10 particles per second. US 7,067,114 B2 19 20 3. The condensation aerosol according to claim 2, wherein 27. The method according to claim 26, wherein the the condensation aerosol is formed at a rate greater than 10' condensation aerosol is characterized by less than 2.5% drug particles per second. degradation products by weight. 4. A method of producing a drug selected from the group 28. The method according to claim 4, wherein the solid consisting of azatadine, brompheniramine, carbinoxamine, Support is a metal foil. chlorpheniramine, clemastine, cyproheptadine, loratadine, 29. The method according to claim 4, wherein the drug is pyrilamine, hydroxy Zine and promethazine in an aerosol aZatadine. form comprising: 30. The method according to claim 4, wherein the drug is a. heating a thin layer containing the drug, on a solid brompheniramine. Support, to produce a vapor of the drug, and 10 31. The method according to claim 4, wherein the drug is b. providing an air flow through the vapor to form a carbinoxamine. condensation aerosol characterized by less than 10% 32. The method according to claim 4, wherein the drug is drug degradation products by weight, and an MMAD chlorpheniramine. of less than 5 microns. 33. The method according to claim 4, wherein the drug is 5. The method according to claim 4, wherein the conden clemastine. sation aerosol is formed at a rate greater than 10 particles 15 34. The method according to claim 4, wherein the drug is per second. cyproheptadine. 6. The method according to claim 5, wherein the conden 35. The method according to claim 4, wherein the drug is sation aerosol is formed at a rate greater than 10' particles loratadine. per second. 36. The method according to claim 4, wherein the drug is 7. The condensation aerosol according to claim 1, wherein pyrilamine. the condensation aerosol is characterized by an MMAD of 37. The method according to claim 4, wherein the drug is 0.1 to 5 microns. hydroxy Zine. 8. The condensation aerosol according to claim 1, wherein 38. The method according to claim 4, wherein the drug is the condensation aerosol is characterized by an MMAD of promethazine. less than 3 microns. 25 39. A condensation aerosol for delivery of azatadine, wherein the condensation aerosol is formed by heating a thin 9. The condensation aerosol according to claim 1, wherein layer containing azatadine, on a solid Support, to produce a the condensation aerosol is characterized by an MMAD of vapor of azatadine, and condensing the vapor to form a about 0.2 to about 3 microns. condensation aerosol characterized by less than 5% azata 10. The condensation aerosol according to claim 1, dine degradation products by weight, and an MMAD of wherein the condensation aerosol is characterized by less 30 than 5% drug degradation products by weight. about 0.2 to 3 microns. 40. A condensation aerosol for delivery of bromphe 11. The condensation aerosol according to claim 10, niramine, wherein the condensation aerosol is formed by wherein the condensation aerosol is characterized by less heating a thin layer containing brompheniramine, on a solid than 2.5% drug degradation products by weight. Support, to produce a vapor of brompheniramine, and con 12. The condensation aerosol according to claim 35 densing the vapor to form a condensation aerosol charac wherein the solid support is a metal foil. terized by less than 5% brompheniramine degradation prod 13. The condensation aerosol according to claim ucts by weight, and an MMAD of about 0.2 to 3 microns. wherein the drug is azatadine. 41. A condensation aerosol for delivery of carbinoxamine, 14. The condensation aerosol according to claim wherein the condensation aerosol is formed by heating a thin wherein the drug is brompheniramine. 40 layer containing carbinoxamine, on a solid Support, to 15. The condensation aerosol according to claim produce a vapor of carbinoxamine, and condensing the wherein the drug is carbinoxamine. vapor to form a condensation aerosol characterized by less 16. The condensation aerosol according to claim than 5% carbinoxamine degradation products by weight, and wherein the drug is chlorpheniramine. an MMAD of about 0.2 to 3 microns. 17. The condensation aerosol according to claim 45 42. A condensation aerosol for delivery of chlorphe wherein the drug is clemastine. niramine, wherein the condensation aerosol is formed by 18. The condensation aerosol according to claim heating a thin layer containing chlorpheniramine, on a solid wherein the drug is cyproheptadine. Support, to produce a vapor of chlorpheniramine, and con 19. The condensation aerosol according to claim densing the vapor to form a condensation aerosol charac wherein the drug is loratadine. 50 terized by less than 5% chlorpheniramine degradation prod 20. The condensation aerosol according to claim ucts by weight, and an MMAD of about 0.2 to 3 microns. wherein the drug is pyrilamine. 43. A condensation aerosol for delivery of clemastine, 21. The condensation aerosol according to claim wherein the condensation aerosol is formed by heating a thin wherein the drug is hydroxy Zine. layer containing clemastine, on a solid Support, to produce 22. The condensation aerosol according to claim 1, a vapor of clemastine, and condensing the vapor to form a wherein the drug is promethazine. 55 condensation aerosol characterized by less than 5% clem 23. The method according to claim 4, wherein the con astine degradation products by weight, and an MMAD of densation aerosol is characterized by an MMAD of 0.1 to 5 about 0.2 to 3 microns. microns. 44. A condensation aerosol for delivery of cyprohepta 24. The method according to claim 4, wherein the con dine, wherein the condensation aerosol is formed by heating densation aerosol is characterized by an MMAD of less than 60 a thin layer containing cyproheptadine, on a solid Support, to 3 microns. produce a vapor of cyproheptadine, and condensing the 25. The method according to claim 4, wherein the con vapor to form a condensation aerosol characterized by less densation aerosol is characterized by an MMAD of about 0.2 than 5% cyproheptadine degradation products by weight, to about 3 microns. and an MMAD of about 0.2 to 3 microns. 26. The method according to claim 4, wherein the con 65 45. A condensation aerosol for delivery of loratadine, densation aerosol is characterized by less than 5% drug wherein the condensation aerosol is formed by heating a thin degradation products by weight. layer containing loratadine, on a Solid Support, to produce a US 7,067,114 B2 21 22 vapor of loratadine, and condensing the vapor to form a chlorpheniramine degradation products by weight, and condensation aerosol characterized by less than 5% lorata an MMAD of about 0.2 to 3 microns. dine degradation products by weight, and an MMAD of 53. A method of producing clemastine in an aerosol form about 0.2 to 3 microns. comprising: 46. A condensation aerosol for delivery of pyrilamine, 5 wherein the condensation aerosol is formed by heating a thin a. heating a thin layer containing clemastine, on a solid layer containing pyrilamine, on a solid Support, to produce Support, to produce a vapor of clemastine, and a vapor of pyrilamine, and condensing the vapor to form a b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% pyril condensation aerosol characterized by less than 5% amine degradation products by weight, and an MMAD of clemastine degradation products by weight, and an about 0.2 to 3 microns. 10 MMAD of about 0.2 to 3 microns. 47. A condensation aerosol for delivery of hydroxyzine, 54. A method of producing cyproheptadine in an aerosol wherein the condensation aerosol is formed by heating a thin form comprising: layer containing hydroxy Zine, on a Solid Support, to produce a. heating a thin layer containing cyproheptadine, on a a vapor of hydroxy Zine, and condensing the vapor to form Solid Support, to produce a vapor of cyproheptadine, a condensation aerosol characterized by less than 5% is hydroxy Zine degradation products by weight, and an and MMAD of about 0.2 to 3 microns. b. providing an air flow through the vapor to form a 48. A condensation aerosol for delivery of promethazine, condensation aerosol characterized by less than 5% wherein the condensation aerosol is formed by heating a thin cyproheptadine degradation products by weight, and an layer containing promethazine, on a solid Support, to pro MMAD of about 0.2 to 3 microns. duce a vapor of promethazine, and condensing the vapor to 55. A method of producing loratadine in an aerosol form form a condensation aerosol characterized by less than 5% comprising: promethazine degradation products by weight, and an a. heating a thin layer containing loratadine, on a solid MMAD of about 0.2 to 3 microns. Support, to produce a vapor of loratadine, and 49. A method of producing azatadine in an aerosol form 25 b. providing an air flow through the vapor to form a comprising: condensation aerosol characterized by less than 5% a. heating a thin layer containing azatadine, on a solid loratadine degradation products by weight, and an Support, to produce a vapor of azatadine, and b. providing an air flow through the vapor to form a MMAD of about 0.2 to 3 microns. condensation aerosol characterized by less than 5% 56. A method of producing pyrilamine in an aerosol form aZatadine degradation products by weight, and an compr1S1ng: MMAD of about 0.2 to 3 microns. a. heating a thin layer containing pyrilamine, on a solid 50. A method of producing brompheniramine in an aero Support, to produce a vapor of pyrilamine, and Sol form comprising: b. providing an air flow through the vapor to form a a. heating a thin layer containing brompheniramine, on a condensation aerosol characterized by less than 5% Solid Support, to produce a vapor of brompheniramine, 35 pyrilamine degradation products by weight, and an and MMAD of about 0.2 to 3 microns. b. providing an air flow through the vapor to form a 57. A method of producing hydroxyzine in an aerosol condensation aerosol characterized by less than 5% form comprising: brompheniramine degradation products by weight, and a. heating a thin layer containing hydroxy Zine, on a solid an MMAD of about 0.2 to 3 microns. 40 Support, to produce a vapor of hydroxyZine, and 51. A method of producing carbinoxamine in an aerosol b. providing an air flow through the vapor to form a form comprising: condensation aerosol characterized by less than 5% a. heating a thin layer containing carbinoxamine, on a hydroxy Zine degradation products by weight, and an Solid Support, to produce a vapor of carbinoxamine, and MMAD of about 0.2 to 3 microns. b. providing an air flow through the vapor to form a 58. A method of producing promethazine in an aerosol condensation aerosol characterized by less than 5% form comprising: carbinoxamine degradation products by weight, and an MMAD of about 0.2 to 3 microns. a. heating a thin layer containing promethazine, on a solid 52. A method of producing chlorpheniramine in an aero Support, to produce a vapor of promethazine, and Sol form comprising: 50 b. providing an air flow through the vapor to form a a. heating a thin layer containing chlorpheniramine, on a condensation aerosol characterized by less than 5% Solid Support, to produce a vapor of chlorpheniramine, promethazine degradation products by weight, and an and MMAD of about 0.2 to 3 microns. b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5%