Delivery of nonsteroidal antiinflammatory drugs through an inhalation route

• US 7,087,217 B2
• Filed: 01/27/2004
• Issued: 08/08/2006
• Est. Priority Date: 05/24/2001
• Status: Expired due to Fees

• Current Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Original Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Inventors: Rabinowitz, Joshua D., Zaffaroni, Alejandro C.
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Haghighatian, Mina
• Application Number:
  US10/766,279
• Publication Number:
  US 20040184996A1
• Time in Patent Office: 924 Days
• Field of Search: 424/45, 424/46, 424/43, 424/434, 424/489, 424/499, 514/220, 514/420, 514/958, 128/200.14, 128/203.15, 128/200.24
• US Class Current: 424/45
• 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 nonsteroidal antiinflammatory drugs (NSAIDs) through an inhalation route. Specifically, it relates to aerosols containing NSAIDs that are used in inhalation therapy. In a method aspect of the present invention, an NSAID is delivered to a patient through an inhalation route. The method comprises: a) heating a coating of an NSAID, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particle having less than 5% NSAID degradation products. In a kit aspect of the present invention, a kit for delivering an NSAID through an inhalation route is provided which comprises: a) a coating of an NSAID composition and b) a device for dispensing said coating as a condensation aerosol.

Claims

1. A condensation aerosol for delivery of a drug selected from the group consisting of indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen and nabumetone, wherein the condensation aerosol is formed by heating a thin layer containing the drug, on a solid support, to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and an MMAD of less than 5 microns.

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

3. The condensation aerosol according to claim 2, wherein the condensation aerosol is formed at a rate greater than 10¹⁰ particles per second.

7. The condensation aerosol according to claim 1, wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns.

8. The condensation aerosol according to claim 1, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns.

9. The condensation aerosol according to claim 1, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to 3 microns.

10. The condensation aerosol according to claim 1, wherein the condensation aerosol is characterized by less than 5% drug degradation products by weight.

11. The condensation aerosol according to claim 10, wherein the condensation aerosol is characterized by less than 2.5% drug degradation products by weight.

12. The condensation aerosol according to claim 1, wherein the solid support is a metal foil.

13. The condensation aerosol according to claim 1, wherein the drug is indomethacin.

14. The condensation aerosol according to claim 1, wherein the drug is ketoprofen.

15. The condensation aerosol according to claim 1, wherein the drug is celcoxib.

16. The condensation aerosol according to claim 1, wherein the drug is rofecoxib.

17. The condensation aerosol according to claim 1, wherein the drug is meclofenamic acid.

18. The condensation aerosol according to claim 1, wherein the drug is fenoprofen.

19. The condensation aerosol according to claim 1, wherein the drug is diflunisal.

20. The condensation aerosol according to claim 1, wherein the drug is tolfenamic acid.

21. The condensation aerosol according to claim 1, wherein the drug is naproxen.

22. The condensation aerosol according to claim 1, wherein the drug is ibuprofen.

23. The condensation aerosol according to claim 1, wherein the drug is flurbiprofen.

24. The condensation aerosol according to claim 1, wherein the drug is nabumetone.

4. A method of producing a drug selected from the group consisting of indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen and nabumetone in an aerosol form comprising:

a. heating a thin layer containing the drug, on a solid support, to produce a vapor of the drug, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and an MMAD of less than 5 microns.

5. The method according to claim 4, wherein the condensation aerosol is formed at a rate greater than 10⁹ particles per second.

6. The method according to claim 5, wherein the condensation aerosol is formed at a rate greater than 10¹⁰ particles per second.

25. The method according to claim 4, wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns.

26. The method according to claim 4, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns.

27. The method according to claim 4, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to 3 microns.

28. The method according to claim 4, wherein the condensation aerosol is characterized by less than 5% drug degradation products by weight.

29. The method according to claim 28, wherein the condensation aerosol is characterized by less than 2.5% drug degradation products by weight.

30. The method according to claim 4, wherein the solid support is a metal foil.

31. The method according to claim 4, wherein the drug is indomethacin.

32. The method according to claim 4, wherein the drug is ketoprofen.

33. The method according to claim 4, wherein the drug is celcoxib.

34. The method according to claim 4, wherein the drug is rofecoxib.

35. The method according to claim 4, wherein the drug is meclofenamic acid.

36. The method according to claim 4, wherein the drug is fenoprofen.

37. The method according to claim 4, wherein the drug is diflunisal.

38. The method according to claim 4, wherein the drug is tolfenamic acid.

39. The method according to claim 4, wherein the drug is naproxen.

40. The method according to claim 4, wherein the drug is ibuprofen.

41. The method according to claim 4, wherein the drug is flurbiprofen.

42. The method according to claim 4, wherein the drug is nabumetone.

43. A condensation aerosol for delivery of indomethacin, wherein the condensation aerosol is formed by heating a thin layer containing indomethacin, on a solid support, to produce a vapor of indomethacin, and condensing the vapor to form a condensation aerosol characterized by less than 5% indomethacin degradation products by weight, and an MMAD of about 0.2 to 3 microns.

44. A condensation aerosol for delivery of ketoprofen, wherein the condensation aerosol is formed by heating a thin layer containing ketoprofen, on a solid support, to produce a vapor of ketoprofen, and condensing the vapor to form a condensation aerosol characterized by less than 5% ketoprofen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

45. A condensation aerosol for delivery of celcoxib, wherein the condensation aerosol is formed by heating a thin layer containing celcoxib, on a solid support, to produce a vapor of celcoxib, and condensing the vapor to form a condensation aerosol characterized by less than 5% celcoxib degradation products by weight, and an MMAD of about 0.2 to 3 microns.

46. A condensation aerosol for delivery of rofecoxib, wherein the condensation aerosol is formed by heating a thin layer containing rofecoxib, on a solid support, to produce a vapor of rofecoxib, and condensing the vapor to form a condensation aerosol characterized by less than 5% rofecoxib degradation products by weight, and an MMAD of about 0.2 to 3 microns.

47. A condensation aerosol for delivery of meclofenamic acid, wherein the condensation aerosol is formed by heating a thin layer containing meclofenamic acid, on a solid support, to produce a vapor of meclofenamic acid, and condensing the vapor to form a condensation aerosol characterized by less than 5% meclofenamic acid degradation products by weight, and an MMAD of about 0.2 to 3 microns.

48. A condensation aerosol for delivery of fenoprofen, wherein the condensation aerosol is formed by heating a thin layer containing fenoprofen, on a solid support, to produce a vapor of fenoprofen, and condensing the vapor to form a condensation aerosol characterized by less than 5% fenoprofen degradation products by weight, and an MMAD of 0.2 to 3 microns.

49. A condensation aerosol for delivery of diflunisal, wherein the condensation aerosol is formed by heating a thin layer containing diflunisal, on a solid support, to produce a vapor of diflunisal, and condensing the vapor to form a condensation aerosol characterized by less than 5% diflunisal degradation products by weight, and an MMAD of about 0.2 to 3 microns.

50. A condensation aerosol for delivery of tolfenamic acid, wherein the condensation aerosol is formed by heating a thin layer containing tolfenamic acid, on a solid support, to produce a vapor of tolfenamic acid, and condensing the vapor to form a condensation aerosol characterized by less than 5% tolfenamic acid degradation products by weight, and an MMAD of about 0.2 to 3 microns.

51. A condensation aerosol for delivery of naproxen, wherein the condensation aerosol is formed by heating a thin layer containing naproxen, on a solid support, to produce a vapor of naproxen, and condensing the vapor to form a condensation aerosol characterized by less than 5% naproxen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

52. A condensation aerosol for delivery of ibuprofen, wherein the condensation aerosol is formed by heating a thin layer containing ibuprofen, on a solid support, to produce a vapor of ibuprofen, and condensing the vapor to form a condensation aerosol characterized by less than 5% ibuprofen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

53. A condensation aerosol for delivery of flurbiprofen, wherein the condensation aerosol is formed by heating a thin layer containing flurbiprofen, on a solid support, to produce a vapor of flurbiprofen, and condensing the vapor to form a condensation aerosol characterized by less than 5% flurbiprofen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

54. A condensation aerosol for delivery of nabumetone, wherein the condensation aerosol is formed by heating a thin layer containing nabumetone, on a solid support, to produce a vapor of nabumetone, and condensing the vapor to form a condensation aerosol characterized by less than 5% nabumetone degradation products by weight, and an MMAD of about 0.2 to 3 microns.

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

a. heating a thin layer containing indomethacin, on a solid support, to produce a vapor of indomethacin, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% indomethacin degradation products by weight, and an MMAD of about 0.2 to 3 microns.

56. A method of producing ketoprofen in an aerosol form comprising:

a. heating a thin layer containing ketoprofen, on a solid support, to produce a vapor of ketoprofen, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% ketoprofen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

57. A method of producing celcoxib in an aerosol form comprising:

a. heating a thin layer containing celcoxib, on a solid support, to produce a vapor of celcoxib, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% celcoxib degradation products by weight, and an MMAD of about 0.2 to 3 microns.

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

a. heating a thin layer containing rofecoxib, on a solid support, to produce a vapor of rofecoxib, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% rofecoxib degradation products by weight, and an MMAD of about 0.2 to 3 microns.

59. A method of producing meclofenamic acid in an aerosol form comprising:

a. heating a thin layer containing meclofenamic acid, on a solid support, to produce a vapor of meclofenamic acid, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% meclofenamic acid degradation products by weight, and an MMAD of about 0.2 to 3 microns.

60. A method of producing fenoprofen in an aerosol form comprising:

a. heating a thin layer containing fenoprofen, on a solid support, to produce a vapor of fenoprofen, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% fenoprofen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

61. A method of producing diflunisal in an aerosol form comprising:

a. heating a thin layer containing diflunisal, on a solid support, to produce a vapor of diflunisal, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% diflunisal degradation products by weight, and an MMAD of about 0.2 to 3 microns.

62. A method of producing tolfenamic acid in an aerosol form comprising:

a. heating a thin layer containing tolfenamic acid, on a solid support, to produce a vapor of tolfenamic acid, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% tolfenamic acid degradation products by weight, and an MMAD of about 0.2 to 3 microns.

63. A method of producing naproxen in an aerosol form comprising:

a. heating a thin layer containing naproxen, on a solid support, to produce a vapor of naproxen, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% naproxen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

64. A method of producing ibuprofen in an aerosol form comprising:

a. heating a thin layer containing ibuprofen, on a solid support, to produce a vapor of ibuprofen, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% ibuprofen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

65. A method of producing flurbiprofen in an aerosol form comprising:

a. heating a thin layer containing flurbiprofen, on a solid support, to produce a vapor of flurbiprofen, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% flurbiprofen degradation products by weight, and an MMAD of about 0.2 to 3 microns.

66. A method of producing nabumetone in an aerosol form comprising:

a. heating a thin layer containing nabumetone, on a solid support, to produce a vapor of nabumetone, and

b. providing an air flow through the vapor to form a condensation aerosol characterized by less than 5% nabumetone degradation products by weight, and an MMAD of about 0.2 to 3 microns.