Delivery of drug amines through an inhalation route

• US 8,003,080 B2
• Filed: 05/13/2003
• Issued: 08/23/2011
• Est. Priority Date: 05/13/2002
• Status: Active Grant

• Current Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Original Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Inventors: Zaffaroni, Alejandro C., Rabinowitz, Joshua D.
• Primary Examiner(s): Haghighatian; Mina
• Application Number:
  US10/437,643
• Publication Number:
  US 20040009128A1
• Time in Patent Office: 3,024 Days
• Field of Search: 424/45, 424/46, 424/489, 424/434, 424/499, 424/43, 514/958, 514/284, 514/165, 514/233.5, 128/200.14, 128/200.24, 128/203.15
• US Class Current: 424/45
• 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: A61M 11/001 Particle size control
• CPC Class Codes: A61M 11/041 using heaters
• CPC Class Codes: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04

Abstract

The present invention relates to the delivery of drug amines through an inhalation route. Specifically, it relates to aerosols containing drug amines that are used in inhalation therapy. In one aspect of the present invention, a method of delivering an amine drug in an aerosol form is provided. The method comprises: a) heating a coating, which includes an amine drug salt on a substrate contained in a device to a temperature sufficient to volatilize the amine drug from the coating, b) by said heating, forming an amine drug vapor, and c) during said heating, drawing air through said device, condensing said vapor to form aerosol particles containing less than 10% degradation products of the compound.

Claims

1. A condensation aerosol for delivery of a drug amine formed by heating a coating of a composition comprising a salt of the drug amine on a substrate, to produce a vapor, and cooling the vapor to form a condensation aerosol comprising particles,

wherein the particles comprise at least 10 percent by weight of the drug amine and less than 10 percent by weight of drug amine degradation products,

wherein the condensation aerosol has a mass median aerodynamic diameter of less than 5 μ

m, and

wherein the salt of the drug amine has a decomposition index of less than 0.10.

2. The condensation aerosol of claim 1, wherein the particles comprise less than 5 percent by weight of drug amine degradation products.

3. The condensation aerosol of claim 2, wherein the condensation aerosol has a mass median aerodynamic diameter in the range of 1 to 5 μ

m.

4. The condensation aerosol of claim 3, wherein the condensation aerosol has a mass median aerodynamic diameter in the range of 1 to 3 μ

m.

5. The condensation aerosol of claim 1, wherein the salt of the amine drug is selected from the group consisting of:

brompheniramine maleate, carbinoxamine maleate, chlorpheniramine maleate, cyproheptadine hydrochloride, pyrilamine maleate, buproprion hydrochloride, trimipramine maleate, tranylcypromine hydrochloride, protriptyline hydrochloride, apomorphine diacetate hydrochloride, buprenorphine hydrochloride, nicotine dihydrochloride, nicotine sulfate, apomorphine hydrochloride, diphenhydramine hydrochloride, mexiletine hydrochloride, and nicotine hydrochloride.

6. The condensation aerosol of claim 1, wherein the coating has a thickness within the range of 0.05 μ

m to 50 μ

m.

7. The condensation aerosol of claim 6, wherein the coating has a thickness within the range of 0.2 μ

m to 20 μ

m.

8. The condensation aerosol of claim 1, wherein the drug amine salt has a molecular weight within the range of 200 to 600.

9. The condensation aerosol of claim 1, wherein the condensation aerosol is formed at a rate greater than 10⁹ particles per second.

10. The condensation aerosol of claim 1, wherein the composition that is heated comprises at least 10 percent by weight of the salt of the drug amine.

11. The condensation aerosol of claim 10, wherein the composition that is heated comprises at least 90 percent by weight of the salt of the drug amine.

12. The condensation aerosol of claim 3, wherein the geometric standard deviation around the mass median aerodynamic diameter is less than 3.

13. A method of delivering a condensation aerosol of a drug amine, wherein the method comprises:

a) heating a coating of a composition comprising a drug amine salt on a substrate to produce a drug amine vapor, wherein the drug amine salt has a decomposition index of less than 0.10; and

b) condensing the vapor to form an aerosol,

wherein the aerosol comprises particles comprising less than 10 percent by weight drug amine degradation products, and wherein the condensation aerosol has a mass median aerodynamic diameter of less than 5 μ

m.

14. The method of claim 13, wherein the particles comprise less than 5 percent by weight drug amine degradation products.

15. The method of claim 13, wherein the condensation aerosol has a mass median aerodynamic diameter within the range of 1 to 5 μ

m.

16. The method of claim 15, wherein the condensation aerosol has a mass median aerodynamic diameter within the range of 1 to 3 μ

m.

17. The method of claim 13, wherein the drug amine salt is selected from the group consisting of:

brompheniramine maleate, carbinoxamine maleate, chlorpheniramine maleate, cyproheptadine hydrochloride, pyrilamine maleate, buproprion hydrochloride, trimipramine maleate, tranylcypromine hydrochloride, protriptyline hydrochloride, apomorphine diacetate hydrochloride, buprenorphine hydrochloride, nicotine dihydrochloride, nicotine sulfate, apomorphine hydrochloride, diphenhydramine hydrochloride, mexiletine hydrochloride, and nicotine hydrochloride.

18. The method of claim 13, wherein the coating has a thickness within the range of 0.05 μ

m to 50 μ

m.

19. The method of claim 18, wherein the coating has a thickness within the range of 0.2 μ

m to 20 μ

m.

20. The method of claim 13, wherein the drug amine salt has a molecular weight within the range of 200 to 600.

21. The method of claim 13, wherein the condensation aerosol is formed at a rate greater than 10⁹ particles per second.

22. The method of claim 13, wherein the composition that is heated comprises at least 10 percent by weight of the salt of the drug amine.

23. The method of claim 22, wherein the composition that is heated comprises at least 90 percent by weight of the salt of the drug amine.

24. The method of claim 15, wherein the geometric standard deviation around the mass median aerodynamic diameter is less than 3.

25. A condensation aerosol for delivery of a drug amine formed by heating a coating of a composition comprising a salt of the drug amine on a substrate, to produce a vapor, and cooling the vapor to form a condensation aerosol comprising particles,

wherein the drug amine is liquid in its free base form,

wherein the particles comprise at least 10 percent by weight of the drug amine and less than 10 percent by weight of drug amine degradation products,

wherein the condensation aerosol has a mass median aerodynamic diameter of less than 5 μ

m, and

wherein the salt of the drug amine has a decomposition index of less than 0.10.

26. A condensation aerosol of claim 25, wherein the particles comprise less than 5 percent by weight of drug amine degradation products.

27. A condensation aerosol of claim 26, wherein the condensation aerosol has a mass median aerodynamic diameter in the range of 1 to 5 μ

m.

28. The condensation aerosol of claim 27, wherein the condensation aerosol has a mass median aerodynamic diameter in the range of 1 to 3 μ

m.

29. The condensation aerosol of claim 27, wherein the geometric standard deviation around the mass median aerodynamic diameter is less than 3.

30. The condensation aerosol of claim 25, wherein the salt of the amine drug is selected from the group consisting of:

brompheniramine maleate, carbinoxamine maleate, chlorpheniramine maleate, cyproheptadine hydrochloride, pyrilamine maleate, buproprion hydrochloride, trimipramine maleate, tranylcypromine hydrochloride, protriptyline hydrochloride, apomorphine diacetate hydrochloride, buprenorphine hydrochloride, nicotine dihydrochloride, nicotine sulfate, apomorphine hydrochloride, diphenhydramine hydrochloride, mexiletine hydrochloride, and nicotine hydrochloride.

31. The condensation aerosol of claim 25, wherein the coating has a thickness within the range of 0.05 μ

m to 50 μ

m.

32. The condensation aerosol of claim 31, wherein the coating has a thickness within the range of 0.2 μ

m to 20 μ

m.

33. The condensation aerosol of claim 25, wherein the drug amine salt has a molecular weight within the range of 200 to 600.

34. The condensation aerosol of claim 25, wherein the condensation aerosol is formed at a rate greater than 10⁹ particles per second.

35. The condensation aerosol of claim 25, wherein the composition that is heated comprises at least 10 percent by weight of the salt of the drug amine.

36. The condensation aerosol of claim 35, wherein the composition that is heated comprises at least 90 percent by weight of the salt of the drug amine.

37. A method of delivering a condensation aerosol of a drug amine, wherein the method comprises:

a) heating a coating of a composition comprising a drug amine salt on a substrate to produce a drug amine vapor, wherein the drug amine is a liquid in its free base form, and wherein the drug amine salt has a decomposition index of less than 0.10; and

b) condensing the vapor to form an aerosol,

wherein the aerosol comprises particles comprising less than 10 percent by weight drug amine degradation products, and

wherein the aerosol has a mass median aerodynamic diameter of less than 5 μ

m.

38. The method of claim 37, wherein the particles comprise less than 5 percent by weight drug amine degradation products.

39. The method of claim 38, wherein the condensation aerosol has a mass median aerodynamic diameter within the range of 1 to 5 μ

m.

40. The method of claim 39, wherein the condensation aerosol has a mass median aerodynamic diameter within the range of 1 to 3 μ

m.

41. The method of claim 39, wherein the geometric standard deviation around the mass median aerodynamic diameter is less than 3.

42. The method of claim 37, wherein the drug amine salt is selected from the group consisting of:

brompheniramine maleate, carbinoxamine maleate, chlorpheniramine maleate, cyproheptadine hydrochloride, pyrilamine maleate, buproprion hydrochloride, trimipramine maleate, tranylcypromine hydrochloride, protriptyline hydrochloride, apomorphine diacetate hydrochloride, buprenorphine hydrochloride, nicotine dihydrochloride, nicotine sulfate, apomorphine hydrochloride, diphenhydramine hydrochloride, mexiletine hydrochloride, and nicotine hydrochloride.

43. The method of claim 37, wherein the coating has a thickness within the range of 0.05 μ

m to 50 μ

m.

44. The method of claim 43, wherein the coating has a thickness within the range of 0.2 μ

m to 20 μ

m.

45. The method of claim 37, wherein the drug amine salt has a molecular weight within the range of 200 to 600.

46. The method of claim 37, wherein the condensation aerosol is formed at a rate greater than 10⁹ particles per second.

47. The method of claim 37, wherein the composition that is heated comprises at least 10 percent by weight of the salt of the drug amine.

48. The method of claim 47, wherein the composition that is heated comprises at least 90 percent by weight of the salt of the drug amine.

49. A kit for delivering a condensation aerosol of a drug amine, wherein the kit comprises:

a) a layer containing a salt of the drug amine coated on a solid support; and

b) a device for providing the condensation aerosol, wherein the condensation aerosol is formed by heating the layer to produce a vapor of the drug amine, and condensing the vapor to form a condensation aerosol comprising particles,

wherein the particles comprise less than 10 percent by weight drug amine degradation products,

wherein the aerosol has an MMAD of less than 5 μ

m, and

wherein the salt of the drug amine has a decomposition index of less than 0.10.

50. The kit according to claim 49, wherein the device comprises:

a) a flow-through enclosure containing the solid support;

b) a power source that can be activated to heat the solid support; and

c) at least one portal through which air can be drawn by inhalation,

wherein activation of the power source is effective to produce a vapor of the drug amine, and drawing air through the enclosure is effective to condense the vapor to form the condensation aerosol.

51. The kit according to claim 49, wherein the aerosol has an MMAD within the range of 1 to 5 μ

m.

52. The kit according to claim 49, wherein the aerosol has an MMAD of less than 3 μ

m.

53. The kit according to claim 52, wherein the aerosol has an MMAD within the range of 1 to 3 μ

m.

54. The kit according to claim 49, wherein peak plasma drug amine concentration is reached in less than 0.1 hours.