AU2002303868B2 - Delivery of antihistamines through an inhalation route - Google Patents

Description

WO 02/094245 PCT/US02/16463 DELIVERY OF ANTIHISTAMINES THROUGH AN INHALATION ROUTE [0001] This application claims priority to U.S. provisional application Ser. No.

60/294,203 entitled "Thermal Vapor Delivery of Drugs," filed May 24, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference. This application further claims priority to U.S. provisional application Ser. No. 60/317,479 entitled "Aerosol Drug Delivery," filed September 5, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference.

Field of the Invention [0002] The present invention relates to the delivery of antihistamines through an inhalation route. Specifically, it relates to aerosols containing antihistamines that are used in inhalation therapy.

Background of the Invention [0003] There are a number of antihistamine containing compositions currently marketed for the treatment of allergy symptoms. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients in such compositions are azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, and promethazine.

[0004] It is desirable to provide a new route of administration for antihistamines that rapidly produces peak plasma concentrations of the compound. The provision of such a route is an object of the present invention.

Summary of the Invention [0005] The present invention relates to the delivery of antihistamines through an inhalation route. Specifically, it relates to aerosols containing antihistamines that are used in inhalation therapy.

[0006] In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of an antihistamine. Preferably, the particles comprise WO 02/094245 PCT/US02/16463 at least 10 percent by weight of an antihistamine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of an antihistamine.

[0007] Typically, the antihistamine is not one of the following antihistamines: dexmedetomidine, diphenhydramine, doxylamine, loratidine, and promethazine.

[0008] Typically, the aerosol has a mass of at least 0.10 pg. Preferably, the aerosol has a mass of at least 100 pg. More preferably, the aerosol has a mass of at least 200 Gg.

[0009] Typically, the aerosol particles comprise less than 10 percent by weight of antihistamine degradation products. Preferably, the particles comprise less than 5 percent by weight of antihistamine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of antihistamine degradation products.

[0010] Typically, the aerosol particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, percent, 20 percent, 10 percent, or 5 percent by weight of water.

[0011] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.

[0012] Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 10 s particles/mL.

[0013] Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).

WO 02/094245 PCT/US02/16463 [0014] Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.85. More preferably, the geometric standard deviation is less than 2.7.

[0015] Typically, the aerosol is formed by heating a composition containing an antihistamine to form a vapor and subsequently allowing the vapor to condense into an aerosol.

[0016] In another composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine. Preferably, the particles comprise at least 10 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.

[0017] Typically, the aerosol has a mass of at least 0.10 pg. Preferably, the aerosol has a mass of at least 100 ug. More preferably, the aerosol has a mass of at least 200 pg.

[0018] Typically, the aerosol particles comprise less than 10 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine degradation products. Preferably, the particles comprise less than 5 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine degradation products.

[0019] Typically, the aerosol particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More WO 02/094245 PCT/US02/16463 preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, percent, 20 percent, 10 percent, or 5 percent by weight of water.

[0020] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.

[0021] Typically, where the aerosol comprises azatadine, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.35 mg/L and 2 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 1.5 mg/L.

100221 Typically, where the aerosol comprises clemastine, the aerosol has an inhalable aerosol drug mass density of between 0.25 mg/L and 6 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.35 mg/L and 4 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 3.5 mg/L.

[0023] Typically, where the aerosol comprises chlorpheniramine, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 4 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 3 mg/L.

[0024] Typically, where the aerosol comprises brompheniramine, carbinoxamine or cyproheptadine, the aerosol has an inhalable aerosol drug mass density of between 0.8 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 1.4 mg/L and 8 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 6 mg/L.

[0025] Typically, where the aerosol comprises loratadine, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 25 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 3.5 mg/L and 20 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 15 mg/L.

WO 02/094245 PCT/US02/16463 10026] Typically, where the aerosol comprises promethazine, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 60 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 47.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and mg/L.

[0027] Typically, where the aerosol comprises pyrilamine, the aerosol has an inhalable aerosol drug mass density of between 6 mg/L and 70 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 13 mg/L and 55 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 40 mg/L.

[0028] Typically, where the aerosol comprises hydroxyzine, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 50 mg/L.

[0029] Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.

[0030] Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).

[0031] Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.85. More preferably, the geometric standard deviation is less than 2.7.

[0032] Typically, the aerosol is formed by heating a composition containing azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine to form a vapor and subsequently allowing the vapor to condense into an aerosol.

WO 02/094245 PCT/US02/16463 [00331 In a method aspect of the present invention, an antihistamine is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of an antihistamine; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least percent by weight of an antihistamine. More preferably, the composition comprises percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of an antihistamine.

[0034] Typically, the antihistamine is not one of the following antihistamines: dexmedetomidine, diphenhydramine, doxylamine, loratidine, and promethazine.

[0035] In certain embodiments, the composition that is heated comprises at least percent by weight of an antihistamine pharmaceutically acceptable salt. Preferably, the salt is a hydrochloric acid salt, hydrobromic acid salt, acetic acid salt, maleic acid salt, formic acid salt or fumaric acid salt.

[00361 Typically, the delivered aerosol particles comprise at least 5 percent by weight of an antihistamine. Preferably, the particles comprise at least 10 percent by weight of an antihistamine. More preferably, the particles comprise at least 20 percent, 30 percent, percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of an antihistamine.

[00371 Typically, the delivered aerosol has a mass of at least 10 pg. Preferably, the aerosol has a mass of at least 100 pg. More preferably, the aerosol has a mass of at least 200 jtg.

[0038] Typically, the delivered aerosol particles comprise less than 10 percent by weight of antihistamine degradation products. Preferably, the particles comprise less than percent by weight of antihistamine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of antihistamine degradation products.

[00391 Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass WO 02/094245 PCT/US02/16463 median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).

[0040] Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.85. More preferably, the geometric standard deviation is less than 2.7.

[0041] Typically, the particles of the delivered condensation aerosol comprise less than percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.

[0042] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.

[0043] Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL,. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.

[00441 Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 10 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.

[0045] Typically, the delivered aerosol is formed at a rate greater than 0.25 mg/second.

Preferably, the aerosol is formed at a rate greater than 0.5 mg/second. More preferably, the aerosol is formed at a rate greater than 1 or 2 mg/second.

[0046] Typically, the delivered condensation aerosol results in a peak plasma concentration of the antihistamine in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

WO 02/094245 PCT/US02/16463 [0047] Typically, the delivered condensation aerosol is used to treat allergy symptoms.

[0048] In another method aspect of the present invention, azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine. More preferably, the composition comprises 20 percent, 30 percent, 40 percent, 50 percent, percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyprohcptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.

[0049] In certain embodiments, the composition that is heated comprises at least percent by weight of an azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine pharmaceutically acceptable salt. Preferably, the salt is a hydrochloric acid salt, hydrobromic acid salt, acetic acid salt, maleic acid salt, formic acid salt or fumaric acid salt.

[0050] Typically, the delivered aerosol particles comprise at least 5 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine. Preferably, the particles comprise at least 10 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of azatadine, brompheniramine, carbinoxamine, WO 02/094245 PCT/US02/16463 chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.

[0051] Typically, the delivered aerosol has a mass of at least 10 pg. Preferably, the aerosol has a mass of at least 100 pg. More preferably, the aerosol has a mass of at least 200 pg- [0052] Typically, the delivered aerosol particles comprise less than 10 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine degradation products.

Preferably, the particles comprise less than 5 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine degradation products.

[0053] Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).

[0054] Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.85. More preferably, the geometric standard deviation is less than 2.7.

[0055] Typically, the particles of the delivered condensation aerosol comprise less than percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.

[0056] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the WO 02/094245 PCT/US02/16463 aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.

[0057] Typically, where the aerosol comprises azatadine, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.35 mg/L and 2 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 1.5 mg/L.

[00581 Typically, where the aerosol comprises clemastine, the aerosol has an inhalable aerosol drug mass density of between 0.25 mg/L and 6 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.35 mg/L and 4 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 3.5 mg/L.

[0059] Typically, where the aerosol comprises chlorpheniramine, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 4 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 3 mg/L.

[0060] Typically, where the aerosol comprises brompheniramine, carbinoxamine or cyproheptadine, the aerosol has an inhalable aerosol drug mass density of between 0.8 mg/L and 10 mg/L. Preferably, the aerosol has an inhalablc aerosol drug mass density of between 1.4 mg/L and 8 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 6 mg/L.

[0061] Typically, where the aerosol comprises loratadine, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 25 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 3.5 mg/L and 20 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 15 mg/L.

[0062] Typically, where the aerosol comprises promethazine, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 60 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 47.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and mg/L.

WO 02/094245 PCT/US02/16463 [0063] Typically, where the aerosol comprises hydroxyzine, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 50 mg/L.

[0064] Typically, where the aerosol comprises pyrilamine, the aerosol has an inhalable aerosol drug mass density of between 6 mg/L and 70 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 13 mg/L and 55 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 40 mg/L.

[0065] Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10 7 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 10 8 particles/mL.

[0066] Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 10 9 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.

[0067] Typically, the delivered aerosol is formed at a rate greater than 0.25 mg/second.

Preferably, the aerosol is formed at a rate greater than 0.5 mg/second. More preferably, the aerosol is formed at a rate greater than 1 or 2 mg/second.

[0068] Typically, where the aerosol comprises azatadine, between 0.2 mg and 2.5 mg of azatadine is delivered to the mammal in a single inspiration. Preferably, between 0.35 mg and 2 mg of azatadine is delivered to the mammal in a single inspiration. More preferably, between 0.5 mg and 1.5 mg of azatadine is delivered to the mammal in a single inspiration.

[0069] Typically, where the aerosol comprises clemastine, between 0.25 mg and 6 mg ofclemastine is delivered to the mammal in a single inspiration. Preferably, between 0.35 mg and 4 mg of clemastine is delivered to the mammal in a single inspiration. More preferably, between 0.5 mg and 3.5 mg ofclemastine is delivered to the mammal in a single inspiration.

[0070] Typically, where the aerosol comprises chlorpheniramine, between Q.5 mg and mg of chlorpheniramine is delivered to the mammal in a single inspiration. Preferably, between 0.75 mg and 4 mg of chlorpheniramine is delivered to the mammal in a single WO 02/094245 PCT/US02/16463 inspiration. More preferably, between 1 mg and 3 mg of chlorpheniramine is delivered to the mammal in a single inspiration.

[0071] Typically, where the aerosol comprises brompheniramine, carbinoxamine or cyproheptadine, between 0.8 mg and 10 mg of brompheniramine, carbinoxamine or cyproheptadine is delivered to the mammal in a single inhalation. Preferably, between 1.4 mg and 8 mg of brompheniramine, carbinoxamine or cyproheptadine is delivered to the mammal in a single inhalation. More preferably, between 2 mg and 6 mg of brompheniramine, carbinoxamine or cyproheptadine is delivered to the mammal in a single inhalation.

[0072] Typically, where the aerosol comprises loratadine, between 2 mg and 25 mg or loratadine is delivered to the mammal in a single inhalation. Preferably, between 3.5 mg and mg of loratadine is delivered to the mammal in a single inspiration. More preferably, between 5 mg and 15 mg of loratadine is delivered to the mammal in a single inspiration.

[0073] Typically, where the aerosol comprises promethazine, between 5 mg and 60 mg of promethazine is delivered to the mammal in a single inspiration. Preferably, between 10 mg and 47.5 mg ofpromethazine is delivered to the mammal in a single inspiration. More preferably, between 15 mg and 35 mg of promethazine is delivered to the mammal in a single inspiration.

[0074] Typically, where the aerosol comprises hydroxyzine, between 2 mg and 100 mg ofhydroxyzine is delivered to the mammal in a single inspiration. Preferably, between 5 mg and 75 mg ofhydroxyzine is delivered to the mammal in a single inspiration. More preferably, between 10 mg and 50 mg of hydroxyzine is delivered to the mammal in a single inspiration.

[0075] Typically, where the aerosol comprises pyrilamine, between 6 mg and 70 mg of pyrilamine is delivered to the mammal in a single inspiration. Preferably, between 13 mg and mg of pyrilamine is delivered to the mammal in a single inspiration. More preferably, between 20 mg and 40 mg of pyrilamine is delivered to the mammal in a single inspiration.

[0076] Typically, the delivered condensation aerosol results in a peak plasma concentration of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More WO 02/094245 PCT/US02/16463 preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

[0077] Typically, the delivered condensation aerosol is used to treat allergy symptoms.

[0078] In a kit aspect of the present invention, a kit for delivering an antihistamine through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of an antihistamine; and, b) a device that forms an antihistamine containing aerosol from the composition, for inhalation by the mammal.

Preferably, the composition comprises at least 10 percent by weight of an antihistamine. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of an antihistamine.

[0079] Typically, the device contained in the kit comprises: a) an element for heating the antihistamine composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.

[0080] In another kit aspect of the present invention, a kit for delivering azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine; and, b) a device that forms a azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine containing aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 10 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine.

WO 02/094245 PCT/US02/16463 [0081] Typically, the device contained in the kit comprises: a) an element for heating the azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.

Brief Description of the Figure [0082] Fig. 1 shows a device used to deliver antihistamine containing aerosols to a mammal through an inhalation route.

Detailed Description of the Invention Definitions [0083] "Aerodynamic diameter" of a given particle refers to the diameter of a spherical droplet with a density of 1 g/mL (the density of water) that has the same settling velocity as the given particle.

[0084] "Aerosol" refers to a suspension of solid or liquid particles in a gas.

[0085] "Aerosol drug mass density" refers to the mass of antihistamine per unit volume of aerosol.

[0086] "Aerosol mass density" refers to the mass of particulate matter per unit volume of aerosol.

[0087] "Aerosol particle density" refers to the number of particles per unit volume of aerosol.

[0088] "Amorphous particle" refers to a particle that does not contain more than percent by weight of a crystalline form. Preferably, the particle does not contain more than percent by weight of a crystalline form. More preferably, the particle does not contain more than 10 percent by weight of a crystalline form.

[0089] "Antihistamine degradation product" refers to a compound resulting from a chemical modification of an antihistamine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.

WO 02/094245 PCT/US02/16463 [00901 "Azatadine" refers to 6,11-dihydro-1 l-(1-methyl-4-piperidinylidene)-5Hbenzo[5,6]cyclohepta[1,2-b]pyridine.

[0091] "Azatadine degradation product" refers to a compound resulting from a chemical modification of azatadine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.

[0092] "Brompheniramine" refers to -(p-bromophenyl)-1 -(2-pyridyl)-3-N,Ndimethylaminopropane.

[0093] "Brompheniramine degradation product" refers to a compound resulting from a chemical modification of brompheniramine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.

[0094] "Carbinoxamine" refers to 2-[p-chloro-a-(2-dimethylaminoethoxy)benzyl]pyridine.

[0095] "Carbinoxamine degradation product" refers to a compound resulting from a chemical modification of carbinoxamine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.

[0096] "Chlorpheniramine" refers to 1-(p-chlorophenyl)-1-(2-pyridyl)-3-N,Ndimethylaminopropane.

[00971 "Chlorpheniramine degradation product" refers to a compound resulting from a chemical modification of chlorpheniramine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis. An example of a degradation product is a compound of molecular formula C 1 2 HNOC1.

[00981 "Clemastine" refers to 2-[2-[1-(4-chlorophenyl)-l -phenyl-ethoxy]ethyl]- 1methylpyrrolidine.

[0099] "Clemastine degradation product" refers to a compound resulting from a chemical modification of clemastine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, WO 02/094245 PCT/US02/16463 oxidation and hydrolysis. An example of a degradation product is C 14

H

13 0C1 (removal of sidechain from oxygen, yielding an alcohol).

"Condensation aerosol" refers to an aerosol formed by vaporization of a substance followed by condensation of the substance into an aerosol.

[0100] "Cyproheptadine" refers to 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1methylpiperidine.

[0101] "Cyproheptadine degradation product" refers to a compound resulting from a chemical modification of cyproheptadine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis. An example of a degradation product is the N-oxide of cyproheptadine (C 21

H

21

NO).

[0102] "Hydroxyzine" refers to 2-[2-[4-[(4-chlorophenyl)phenylmethyl]- 1piperazinyl]-ethoxy]ethanol.

[0103] "Hydroxyzine degradation product" refers to a compound resulting from a chemical modification of hydroxyzine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis. An example of a degradation product is a compound of molecular formula C 3

H

9 0C1 (a chloro benzophenone).

[0104] "Inhalable aerosol drug mass density" refers to the aerosol drug mass density produced by an inhalation device and delivered into a typical patient tidal volume.

[0105] "Inhalable aerosol mass density" refers to the aerosol mass density produced by an inhalation device and delivered into a typical patient tidal volume.

[0106] "Inhalable aerosol particle density" refers to the aerosol particle density of particles of size between 100 nm and 5 microns produced by an inhalation device and delivered into a typical patient tidal volume.

[0107] "Loratadine" refers to ethyl 4-(8-chloro-5,6-dihydro-11Hbenzo[5,6]cyclohepta[l ,2-b]pyridine- l -ylidene)-l -piperidinecarboxylate [0108] "Loratadine degradation product" refers to a compound resulting from a chemical modification of loratadine. The modification, for example, can be the result of a WO 02/094245 PCT/US02/16463 thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.

[0109] "Mass median aerodynamic diameter" or "MMAD" of an aerosol refers to the aerodynamic diameter for which half the particulate mass of the aerosol is contributed by particles with an aerodynamic diameter larger than the MMAD and half by particles with an aerodynamic diameter smaller than the MMAD.

[0110] "Promethazine" refers to 10-(2-dimethylaminopropyl)phenothiazine.

[0111] "Promethazine degradation product" refers to a compound resulting from a chemical modification of promethazine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis. An example of a degradation product is a compound of molecular formula C 12

H

9 NOS (a sulfoxide).

[0112] "Pyrilamine" refers to N-[(4-methoxyphenyl)methyl]-N',N'-dimethyl-N-2pyridinyl-1,2-ethanediamine.

[0113] "Pyrilamine degradation product" refers to a compound resulting from a chemical modification of pyrilamine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis. An example of a degradation product is 4-methoxy-benzaldehyde.

[0114] "Rate of aerosol formation" refers to the mass of aerosolized particulate matter produced by an inhalation device per unit time.

[0115] "Rate of inhalable aerosol particle formation" refers to the number of particles of size between 100 nm and 5 microns produced by an inhalation device per unit time.

[0116] "Rate of drug aerosol formation" refers to the mass of aerosolized antihistamine produced by an inhalation device per unit time.

[0117] "Settling velocity" refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.

[0118] "Typical patient tidal volume" refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient.

WO 02/094245 PCT/US02/16463 [0119] "Vapor" refers to a gas, and "vapor phase" refers to a gas phase. The term "thermal vapor" refers to a vapor phase, aerosol, or mixture of aerosol-vapor phases, formed preferably by heating.

Formation of Antihistamine Containing Aerosols [0120] Any suitable method is used to form the aerosols of the present invention. A preferred method, however, involves heating a composition comprising an antihistamine to form a vapor, followed by cooling of the vapor such that it condenses to provide an antihistamine comprising aerosol (condensation aerosol). The composition is heated in one of four forms: as pure active compound pure azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine); as a mixture of active compound and a pharmaceutically acceptable excipient; as a salt form of the pure active compound; and, as a mixture of active compound salt form and a pharmaceutically acceptable excipient.

[0121] Salt forms of antihistamines azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, or promethazine) are either commercially available or are obtained from the corresponding free base using well known methods in the art. A variety of pharmaceutically acceptable salts are suitable for aerosolization. Such salts include, without limitation, the following: hydrochloric acid, hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaric acid salts.

[0122] Pharmaceutically acceptable excipients may be volatile or nonvolatile. Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with the antihistamine. Classes of such excipients are known in the art and include, without limitation, gaseous, supercritical fluid, liquid and solid solvents. The following is a list of exemplary carriers within the classes: water; terpenes, such as menthol; alcohols, such as ethanol, propylene glycol, glycerol and other similar alcohols; dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide; dry ice; and mixtures thereof.

[0123] Solid supports on which the composition is heated are of a variety of shapes.

Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small WO 02/094245 PCT/US02/16463 less than 1.0 mm-sized) pores. Preferably, solid supports provide a large surface to volume ratio greater than 100 per meter) and a large surface to mass ratio greater than 1 cm 2 per gram).

[0124] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).

[0125] A number of different materials are used to construct the solid supports.

Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite, porous carbons, carbon yarns and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well.

[0126] Where aluminum is used as a solid support, aluminum foil is a suitable material.

Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, MO), BCR171 (an alumina of defined surface area greater than 2 m 2 /g from Aldrich, St. Louis, MO) and a silicon wafer as used in the semiconductor industry. Carbon yarns and felts are available from American Kynol, Inc., New York, NY. Chromatography resins such as octadecycl silane chemically bonded to porous silica are exemplary coated variants of silica.

[0127] The heating of the antihistamine compositions is performed using any suitable method. Examples of methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic solvation, hydration of pyrophoric materials and oxidation of combustible materials.

WO 02/094245 PCT/US02/16463 Delivery of Antihistamine Containinn Aerosols [0128] Antihistamine containing aerosols of the present invention are delivered to a mammal using an inhalation device. Where the aerosol is a condensation aerosol, the device has at least three elements: an element for heating an antihistamine containing composition to form a vapor; an element allowing the vapor to cool, thereby providing a condensation aerosol; and, an element permitting the mammal to inhale the aerosol. Various suitable heating methods are described above. The element that allows cooling is, in it simplest form, an inert passageway linking the heating means to the inhalation means. The element permitting inhalation is an aerosol exit portal that forms a connection between the cooling element and the mammal's respiratory system.

[01291 One device used to deliver an antihistamine containing aerosol is described in reference to Fig. 1. Delivery device 100 has a proximal end 102 and a distal end 104, a heating module 106, a power source 108, and a mouthpiece 110. An antihistamine composition is deposited on a surface 112 of heating module 106. Upon activation of a user activated switch 114, power source 108 initiates heating of heating module 106 through ignition of combustible fuel or passage of current through a resistive heating element). The antihistamine composition volatilizes due to the heating of heating module 106 and condenses to form a condensation aerosol prior to reaching the mouthpiece 110 at the proximal end of the device 102. Air flow traveling from the device distal end 104 to the mouthpiece 110 carries the condensation aerosol to the mouthpiece 110, where it is inhaled by the mammal.

[0130] Devices, if desired, contain a variety of components to facilitate the delivery of antihistamine containing aerosols. For instance, the device may include any component known in the art to control the timing of drug aerosolization relative to inhalation breathactuation), to provide feedback to patients on the rate and/or volume of inhalation, to prevent excessive use "lock-out" feature), to prevent use by unauthorized individuals, and/or to record dosing histories.

WO 02/094245 PCT/US02/16463 Dosage of Antihistamine Containing Aerosols [0131] The dosage amount of antihistamine in aerosol form is generally no greater than twice the standard dose of the drug given orally. For instance, for the treatment of allergy symptoms azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine and promethazine are typically provided orally at the following respective strengths: 1 mg, 4 mg, 4 mg, 2 mg, 1.34 mg, 4 mg, 10 mg, mg, 25 mg, and 25 mg. As aerosols, the compounds are generally provided in the following amounts per inspiration for the same indication: azatadine, 0.2 mg to 2.5 mg; clemastine, 0.25 mg to 6 mg; chlorpheniramine, 0.5 mg to 5 mg; brompheniramine, 0.8 mg to 10 mg; carbinoxamine, 0.8 mg to 10 mg; cyproheptadine, 0.8 mg to 10 mg; loratadine, 2 mg to 25 mg; promethazine, 5 mg to 60 mg; hydroxyzine, 2 mg to 100 mg; and, pyrilamine, 6 mg to 70 mg.

A typical dosage of an antihistamine aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts).

Where the drug is administered as a series of inhalations, a different amount may be delivered in each inhalation.

[0132] One can determine the appropriate dose of an antihistamine containing aerosol to treat a particular condition using methods such as animal experiments and a dose-finding (Phase I/II) clinical trial. One animal experiment involves measuring plasma concentrations of drug in an animal after its exposure to the aerosol. -Mammals such as dogs or primates are typically used in such studies, since their respiratory systems are similar to that of a human.

Initial dose levels for testing in humans is generally less than or equal to the dose in the mammal model that resulted in plasma drug levels associated with a therapeutic effect in humans. Dose escalation in humans is then performed, until either an optimal therapeutic response is obtained or a dose-limiting toxicity is encountered.

Analysis of Antihistamine Containing Aerosols [0133] Purity of an antihistamine containing aerosol is determined using a number of methods, examples of which are described in Sekine et al., Journal ofForensic Science 32:1271-1280 (1987) and Martin et al., Journal ofAnalytic Toxicology 13:158-162 (1989).

WO 02/094245 PCT/US02/16463 One method involves forming the aerosol in a device through which a gas flow air flow) is maintained, generally at a rate between 0.4 and 60 L/min. The gas flow carries the aerosol into one or more traps. After isolation from the trap, the aerosol is subjected to an analytical technique, such as gas or liquid chromatography, that permits a determination of composition purity.

[0134] A variety of different traps are used for aerosol collection. The following list contains examples of such traps: filters; glass wool; impingers; solvent traps, such as dry icecooled ethanol, methanol, acetone and dichloromethane traps at various pH values; syringes that sample the aerosol; empty, low-pressure vacuum) containers into which the aerosol is drawn; and, empty containers that fully surround and enclose the aerosol generating device.

Where a solid such as glass wool is used, it is typically extracted with a solvent such as ethanol. The solvent extract is subjected to analysis rather than the solid glass wool) itself. Where a syringe or container is used, the container is similarly extracted with a solvent.

[0135] The gas or liquid chromatograph discussed above contains a detection system detector). Such detection systems are well known in the art and include, for example, flame ionization, photon absorption and mass spectrometry detectors. An advantage of a mass spectrometry detector is that it can be used to determine the structure of antihistamine degradation products.

[0136] Particle size distribution of an antihistamine containing aerosol is determined using any suitable method in the art cascade impaction). An Andersen Eight Stage Nonviable Cascade Impactor (Andersen Instruments, Smyrna, GA) linked to a furnace tube by a mock throat (USP throat, Andersen Instruments, Smyrna, GA) is one system used for cascade impaction studies.

[0137] Inhalable aerosol mass density is determined, for example, by delivering a drugcontaining aerosol into a confined chamber via an inhalation device and measuring the mass collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient.

WO 02/094245 PCT/US02/16463 [0138] Inhalable aerosol drug mass density is determined, for example, by delivering a drug-containing aerosol into a confined chamber via an inhalation device and measuring the amount of active drug compound collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient. The amount of active drug compound collected in the chamber is determined by extracting the chamber, conducting chromatographic analysis of the extract and comparing the results of the chromatographic analysis to those of a standard containing known amounts of drug.

[0139] Inhalable aerosol particle density is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device and measuring the number of particles of given size collected in the chamber. The number of particles of a given size may be directly measured based on the light-scattering properties of the particles.

Alternatively, the number of particles of a given size may be determined by measuring the mass of particles within the given size range and calculating the number of particles based on the mass as follows: Total number of particles Sum (from size range I to size range N) of number of particles in each size range. Number of particles in a given size range Mass in the size range/Mass of a typical particle in the size range. Mass of a typical particle in a given size range 7*D 3 where D is a typical particle diameter in the size range (generally, the mean boundary MMADs defining the size range) in microns, p is the particle density (in g/mL) and mass is given in units of picograms (g-12).

[0140] Rate of inhalable aerosol particle formation is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device. The delivery is for a set period of time 3 and the number of particles of a given size collected in the chamber is determined as outlined above. The rate of particle formation is equal to the number of 100 nm to 5 micron particles collected divided by the duration of the collection time.

101411 Rate of aerosol formation is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device. The delivery is for a set period of time 3 and the mass of particulate matter collected is determined by weighing the confined chamber before and after the delivery of the particulate matter. The rate of aerosol WO 02/094245 PCT/US02/16463 formation is equal to the increase in mass in the chamber divided by the duration of the collection time. Alternatively, where a change in mass of the delivery device or component thereof can only occur through release of the aerosol phase particulate matter, the mass of particulate matter may be equated with the mass lost from the device or component during the delivery of the aerosol. In this case, the rate of aerosol formation is equal to the decrease in mass of the device or component during the delivery event divided by the duration of the delivery event.

[0142] Rate of drug aerosol formation is determined, for example, by delivering an antihistamine containing aerosol into a confined chamber via an inhalation device over a set period of time 3 Where the aerosol is pure antihistamine, the amount of drug collected in the chamber is measured as described above. The rate of drug aerosol formation is equal to the amount of antihistamine collected in the chamber divided by the duration of the collection time. Where the antihistamine containing aerosol comprises a pharmaceutically acceptable excipient, multiplying the rate of aerosol formation by the percentage of antihistamine in the aerosol provides the rate of drug aerosol formation.

Utility of Antihistamine Containing Aerosols [0143] Antihistamine containing aerosols are typically used for the treatment of allergy symptoms.

[0144] The following examples are meant to illustrate, rather than limit, the present invention.

[01451 Hydroxyzine dihydrochloride, brompheniramine maleate, carbinoxamine maleate, clemastine fumarate, cyproheptadine hydrochloride, pyrilamine maleate, and promethazine hydrochloride are commercially available from Sigma (www.sigmaaldrich.com). Antihistamines can also be isolated from compositions such as RYNATAN®, DIMETANE®, RONDEC®, SINUTAB®, TAVIST®, PERIACTIN®, CLARITIN®, RYNA- 12TM, and PHENERGAN® using standard methods in the art.

WO 02/094245 PCT/US02/16463 EXAMPLE 1 General Procedure for Obtaining Free Base of an Antihistamine Salt [0146] Approximately 1 g of salt mono hydrochloride) is dissolved in deionized water (-30 mL). Three equivalents of sodium hydroxide (1 N NaOHaq) is added dropwise to the solution, and the pH is checked to ensure it is basic. The aqueous solution is extracted four times with dichloromethane (-50 mL), and the extracts are combined, dried (Na 2

SO

4 and filtered. The filtered organic solution is concentrated using a rotary evaporator to provide the desired free base. If necessary, purification of the free base is performed using standard methods such as chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds [0147] A solution of drug in approximatelyl20 aL dichloromethane is coated on a 3 cm x 8 cm piece of aluminum foil. The dichloromethane is allowed to evaporate. The coated foil is wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, CA), which is inserted into a glass tube sealed at one end with a rubber stopper. Running 60 V of alternating current (driven by line power controlled by a variac) through the bulb for 5-11 s affords thermal vapor (including aerosol), which is collected on the glass tube walls. Reversephase HPLC analysis with detection by absorption of 225 nm light is used to determine the purity of the aerosol. (When desired, the system is flushed through with argon prior to volatilization.) [0148] Table 1, which follows, provides data from drugs volatilized using the aboverecited general procedure. Current is typically run for 5 s after an aerosol is first noticed. To obtain higher purity aerosols, one can coat a lesser amount of drug, yielding a thinner film to heat. A linear decrease in film thickness is associated with a linear decrease in impurities.

WO 02/094245 WO 02/94245PCT/US02/16463 TABLE 1 Compound Aerosol Purity Argon Used Azatadine 99.6% No Brompheniramine 99.0% No Brompheniramine 99.3% Yes Brompheniramine 99.6% No Maleate Brompheniramine 100% Yes Maleate Carbinoxamine 94.9% Yes Carbinoxamine 99.0% No Maleate Carbinoxamine 100% Yes Maleate Chlorpheniramine 98.4% No Chiorpheniramine 99.6% No Maleate Chiorpheiiiramine 100% Yes Clemastine 94.3% No Cyproheptadine 100% No Cyproheptadine 99.6% No Hydroxyzine 98.6% No Loratadine 99.0% No Loratadine 99.6% Yes Pyrilamine 98.8% No Pyrilamine, 99.5% Yes Promnethazine 94.5% Yes WO 02/094245 PCT/US02/16463 EXAMPLE 3 Particle Size, Particle Density, and Rate oflnhalableParticle Formation ofLoratadine Aerosol [0149] A solution of 12.1 mg loratadine in 200 [tL dichloromethane was spread out in a thin layer on the central portion of a 3.5 cm x 7 cm sheet of aluminum foil. The dichloromethane was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. Both of the openings of the tube were left open and the third opening was connected to a 1 liter, 3-neck glass flask. The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within 1 s, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with collection of the aerosol terminated after 6 s. The aerosol was analyzed by connecting the 1 L flask to an eight-stage Andersen non-viable cascade impactor. Results are shown in table 1. MMAD of the collected aerosol was 1.1 microns with a geometric standard deviation of 2.6. Also shown in table 1 is the number of particles collected on the various stages of the cascade impactor, given by the mass collected on the stage divided by the mass of a typical particle trapped on that stage. The mass of a single particle of diameter D is given by the volume of the particle, 1TD 3 multiplied by the density of the drug (taken to be 1 g/cm 3 The inhalable aerosol particle density is the sum of the numbers of particles collected on impactor stages 3 to 8 divided by the collection volume of 1 L, giving an inhalable aerosol particle density of 5.2 x 10 7 particles/mL. The rate of inhalable aerosol particle formation is the sum of the numbers of particles collected on impactor stages 3 through 8 divided by the formation time of 6 s, giving a rate of inhalable aerosol particle formation of 8.7 x 109 particles/second.

WO 02/094245 PCT/US02/16463 Table 1: Determination of the characteristics of a loratadine condensation aerosol by cascade impaction using an Andersen 8-stage non-viable cascade impactor run at 1 cubic foot per minute air flow.

Stage Particle size Average particle Mass Number of range (microns) size (microns) collected particles (mg) 0 9.0-10.0 9.5 0.0 0 1 5.8-9.0 7.4 0.1 4.7 x 2 4.7-5.8 5.25 0.0 0 3 3.3-4.7 4.0 0.1 3.0 x 106 4 2.1-3.3 2.7 0.6 5.8 x 1.1-2.1 1.6 0.0 0 6 0.7-1.1 0.9 0.4 1.1 x 10 9 7 0.4-0.7 0.55 0.3 3.4 x 10 9 8 0-0.4 0.2 0.2 4.8 x 10"1 EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofLoratadine Aerosol [0150] A solution of 10.4 mg loratadine in 200 gL dichloromethane was spread out in a thin layer on the central portion of a 3.5 cm x 7 cm sheet of aluminum foil. The dichloromethane was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. Both of the openings of the tube were left open and the third opening was connected to a 1 liter, 3-neck glass flask. The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within seconds, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with formation of the aerosol terminated after 6 s. The aerosol was allowed to sediment onto the walls of the 1 L flask for approximately 30 minutes.

The flask was then extracted with acetonitrile and the extract analyzed by HPLC with detection by light absorption at 225 nm. Comparison with standards containing known amounts of loratadine revealed that 1.0 mg of> 99% pure loratadine had been collected in the flask, P NOPERHPMle.xu Ph a=iacclsls23647Mmawdcd Pago doc9/1 If2007 -29z resulting in an aerosol drug mass density of 1.0 mg/L. The aluminium foil upon which the loratadine had previously been coated was weighed following the experiment. Of the 10.4 mg originally coated on the aluminium, 3.8 mg of the material was found to have aerosolized in the 6 s time period, implying a rate of drug aerosol formation of 0.6 mg/s.

IND 00 SThroughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (24)

1. A condensation aerosol containing an antihistamine compound selected from the 0O group consisting of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, 0 clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyine, and promethazine wherein: ,I a) said condensation aerosol comprises particles comprising less than 0percent by weight antihistamine compound degradation products; and b) said condensation aerosol has an MMAD of less than 5 p[m.

2. A condensation aerosol according to Claim 1, formed by volatilizing the antihistamine compound under conditions effective to produce a vapor of the antihistamine compound and condensing the vapor to form said particles.

3. A condensation aerosol according to Claim 2, wherein said volatilizing includes heating a solid support coated with a composition comprising the antihistamine compound to volatilize the antihistamine compound from the coated composition.

4. A condensation aerosol according to Claim 2 or 3, wherein said condensing includes allowing the vapor to cool.

A condensation aerosol according to any one of Claims 1 to 4, wherein said particles comprise less than 5 percent by weight antihistamine compound degradation products.

6. A condensation aerosol according to any one of Claims 1 to 4, wherein said particles comprise less than 2.5 percent by weight antihistamine compound degradation products.

7. A condensation aerosol according to any one of Claims 1 to 6, wherein said condensation aerosol comprises at least 5 percent by weight of the antihistamine P \OPER\NPMAkc7,a Pha-amuclaW2147M~mm8nded Pago dws-RA8/2()08 00 O -31- Scompound.

8. A condensation aerosol according to any one of Claims 1 to 6, wherein said 0O condensation aerosol comprises at least 90 percent by weight of the antihistamine 0 compound. O N

9. A condensation aerosol according to any one of Claims 1 to 8, wherein said Scondensation aerosol has an MMAD of less than 3 pm.

A condensation aerosol according to any one of Claims 1 to 9 for use in inhalation therapy.

11. A composition for delivery of an antihistamine compound, the composition comprising a condensation aerosol according to any one of Claims 1 to

12. A method of producing an antihistamine compound in an aerosol form comprising: a) volatilizing an antihistamine compound selected from the group consisting of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyine, and promethazine under conditions effective to produce a vapor of the antihistamine compound, wherein said volatilizing comprises heating a composition comprising at least 5 percent by weight of the antihistamine compound; and b) condensing the vapor thereby providing a condensation aerosol comprising particles comprising less than 10 percent by weight antihistamine compound degradation products and having an MMAD of less than 5 pm.

13. A method according to Claim 12, wherein step a) comprises heating a solid support coated with a composition comprising the antihistamine compound to volatilize the antihistamine compound from the coated composition.

14. A method according to Claim 12, wherein step a) comprises heating a solid support P OPER\HPMxAICez Phjmi&cMII"II\t 2364?MAmn,,d\cn d Paga dom.MA)r(x X 00 O -32- Z on which a composition comprising the antihistamine compound is deposited to volatilize t the antihistamine compound from the deposited composition. 00

15. A method according to any one of Claims 12 to 14, wherein step b) comprises Sallowing the vapor to cool thereby providing the condensation aerosol. O 0 M

16. A method according to any one of Claims 12 to 15, wherein said particles comprise less than 5 percent by weight antihistamine compound degradation products.

17. A method according to any one of Claims 12 to 15, wherein said particles comprise less than 2.5 percent by weight antihistamine compound degradation products.

18. A method according to any one of Claims 12 to 17, wherein said condensation aerosol comprises at least 90 percent by weight of the antihistamine compound.

19. A method according to any one of Claims 12 to 18, wherein said particles are formed at a rate of greater than 0.5 mg/sec.

A method according to any one of Claims 12 to 18, wherein said particles are formed at a rate of greater than 1 mg/sec.

21. A method according to any one of Claims 12 to 20, wherein said condensation aerosol has an MMAD of less than 3 pm.

22. A method according to any one of Claims 12 to 21, wherein the condensation aerosol is for use in inhalation therapy.

23. A kit when used for delivering an antihistamine compound selected from the group consisting of azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, loratadine, pyrilamine, hydroxyzine, and promethazine, wherein the kit comprises: P \OPERIMPMUAle-, -IsCa12\3i647RAcmded PagedocAhV2E1 -33- a) a composition comprising the antihistamine compound; and b) a device that forms an antihistamine compound containing aerosol from the composition; wherein the device comprises: 1) an element for heating the antihistamine compound composition to form a vapour; 2) an element allowing the vapour to cool to form an aerosol; and 3) an element permitting inhalation of the aerosol.

24. A condensation aerosol according to any one of Claims 1 to 10 or a composition for delivery according to Claim 11 or a method according to any one of Claims 12 to 22 or a kit according to Claim 23 substantially as hereinbefore described with reference to the Figures and Examples.