Delivery of antihistamines through an inhalation route

• US 20040185000A1
• Filed: 01/29/2004
• Published: 09/23/2004
• Est. Priority Date: 05/24/2001
• Status: Active Grant

• Current Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Original Assignee: Alexza Molecular Delivery Corporation (Grupo Ferrer Internacional SA)
• Inventors: Rabinowitz, Joshua D., Zaffaroni, Alejandro C.
• Granted Patent: US 7,067,114 B2
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/49 Cinchonan derivatives, e.g. quinine
• CPC Class Codes: A61K 31/495 : having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 : Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4985 : Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/501 : not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 : ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 : having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/551 : having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5517 : condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 47/54 : the modifying agent being an organic compound
• CPC Class Codes: A61K 9/007 : Pulmonary tract; Aromatherapy
• CPC Class Codes: A61K 9/0073 : Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/12 : Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: A61M 11/042 : electrical
• CPC Class Codes: A61M 15/06 : Inhaling appliances shaped like cigars, cigarettes or pipes
• CPC Class Codes: A61M 2205/8206 : battery-operated
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: F24V 30/00 : Apparatus or devices using heat produced by exothermal chemical reactions other than combustion

Abstract

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. In a method aspect of the present invention, an antihistamine is delivered to a patient through an inhalation route. The method comprises: a) heating a thin layer of an antihistamine, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% antihistamine drug degradation products. In a kit aspect of the present invention, a kit for delivering an antihistamine through an inhalation route is provided which comprises: a) a thin layer of an antihistamine drug and b) a device for dispensing said thin layer as a condensation aerosol.

Claims

1. A composition for delivery of azatadine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of azatadine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of azatadine and condensing the heated vapor of azatadine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% azatadine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

2. The composition according to claim 1, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

3. The composition according to claim 2, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

4. A composition for delivery of brompheniramine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of brompheniramine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of brompheniramine and condensing the heated vapor of brompheniramine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% brompheniramine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

5. The composition according to claim 4, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

6. The composition according to claim 5, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

7. A composition for delivery of carbinoxamine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of carbinoxamine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of carbinoxamine and condensing the heated vapor of carbinoxamine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% carbinoxamine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

8. The composition according to claim 7, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

9. The composition according to claim 8, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

10. A composition for delivery of chlorpheniramine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of chlorpheniramine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of chlorpheniramine and condensing the heated vapor of chlorpheniramine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% chlorpheniramine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

11. The composition according to claim 10, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

12. The composition according to claim 11, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

13. A composition for delivery of clemastine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of clemastine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of clemastine and condensing the heated vapor of clemastine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% clemastine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

14. The composition according to claim 13, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

15. The composition according to claim 14, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

16. A composition for delivery of cyproheptadine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of cyproheptadine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of cyproheptadine and condensing the heated vapor of cyproheptadine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% cyproheptadine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

17. The composition according to claim 16, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

18. The composition according to claim 17, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

19. A composition for delivery of loratadine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of loratadine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of loratadine and condensing the heated vapor of loratadine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% loratadine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

20. The composition according to claim 19, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

21. The composition according to claim 20, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

22. A composition for delivery of pyrilamine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of pyrilamine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of pyrilamine and condensing the heated vapor of pyrilamine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% pyrilamine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

23. The composition according to claim 22, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

24. The composition according to claim 23, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

25. A composition for delivery of hydroxyzine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of hydroxyzine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of hydroxyzine and condensing the heated vapor of hydroxyzine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% hydroxyzine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

26. The composition according to claim 25, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

27. The composition according to claim 26, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

28. A composition for delivery of promethazine consisting of a condensation aerosol

a. formed by volatilizing a thin layer of promethazine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to produce a heated vapor of promethazine and condensing the heated vapor of promethazine to form condensation aerosol particles,

b. wherein said condensation aerosol particles are characterized by less than 5% promethazine degradation products, and

c. the condensation aerosol has an MMAD of less than 3 microns.

29. The composition according to claim 28, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

30. The composition according to claim 29, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

31. A method of producing azatadine in an aerosol form comprising:

a. heating a thin layer of azatadine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the azatadine to form a heated vapor of the azatadine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the azatadine comprising less than 5% azatadine degradation products, and an aerosol having an MMAD of less than 3 microns.

32. The method according to claim 31, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

33. The method according to claim 32, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

34. A method of producing bromopheniramine in an aerosol form comprising:

a. heating a thin layer of bromopheniramine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the bromopheniramine to form a heated vapor of the bromopheniramine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the bromopheniramine comprising less than 5% bromopheniramine degradation products, and an aerosol having an MMAD of less than 3 microns.

35. The method according to claim 34, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

36. The method according to claim 35, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

37. A method of producing carbinoxamine in an aerosol form comprising:

a. heating a thin layer of carbinoxamine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the carbinoxamine to form a heated vapor of the carbinoxamine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the carbinoxamine comprising less than 5% carbinoxamine degradation products, and an aerosol having an MMAD of less than 3 microns.

38. The method according to claim 37, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

39. The method according to claim 38, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

40. A method of producing chlorpheniramine in an aerosol form comprising:

a. heating a thin layer of chlorpheniramine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the chlorpheniramine to form a heated vapor of the chlorpheniramine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the chlorpheniramine comprising less than 5% chlorpheniramine degradation products, and an aerosol having an MMAD of less than 3 microns.

41. The method according to claim 40, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

42. The method according to claim 41, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

43. A method of producing clemastine in an aerosol form comprising:

a. heating a thin layer of clemastine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the clemastine to form a heated vapor of the clemastine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the clemastine comprising less than 5% clemastine degradation products, and an aerosol having an MMAD of less than 3 microns.

44. The method according to claim 43, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

45. The method according to claim 44, wherein the aerosol particles are formed at a rate of greater than 10 ¹⁰ particles per second.

46. A method of producing cyproheptadine in an aerosol form comprising:

a. heating a thin layer of cyproheptadine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the cyproheptadine to form a heated vapor of the cyproheptadine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the cyproheptadine comprising less than 5% cyproheptadine degradation products, and an aerosol having an MMAD of less than 3 microns.

47. The method according to claim 46, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

48. The method according to claim 47, wherein the aerosol particles are formed at a rate of greater than 10 ¹⁰particles per second.

49. A method of producing loratadine in an aerosol form comprising:

a. heating a thin layer of loratadine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the loratadine to form a heated vapor of the loratadine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the loratadine comprising less than 5% loratadine degradation products, and an aerosol having an MMAD of less than 3 microns.

50. The method according to claim 49, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

51. The method according to claim 50, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

52. A method of producing pyrilamine in an aerosol form comprising:

a. heating a thin layer of pyrilamine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the pyrilamine to form a heated vapor of the pyrilamine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the pyrilamine comprising less than 5% pyrilamine degradation products, and an aerosol having an MMAD of less than 3 microns.

53. The method according to claim 52, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

54. The method according to claim 53, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

55. A method of producing hydroxyzine acid in an aerosol form comprising:

a. heating a thin layer of hydroxyzine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the hydroxyzine to form a heated vapor of the hydroxyzine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the hydroxyzine comprising less than 5% hydroxyzine degradation products, and an aerosol having an MMAD of less than 3 microns.

56. The method according to claim 55, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

57. The method according to claim 56, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

58. A method of producing promethazine in an aerosol form comprising:

a. heating a thin layer of promethazine on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the promethazine to form a heated vapor of the promethazine, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the promethazine comprising less than 5% promethazine degradation products, and an aerosol having an MMAD of less than 3 microns.

59. The method according to claim 58, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

60. The method according to claim 59, wherein the aerosol particles are formed at a rate of greater than 10¹⁰particles per second.