Delivery of nonsteroidal antiinflammatory drugs through an inhalation route

• US 20060269487A1
• Filed: 08/07/2006
• Published: 11/30/2006
• Est. Priority Date: 05/24/2001
• Status: Active Grant

• 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.
• Granted Patent: US 7,510,702 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 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 composition for delivery of indomethacin consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% indomethacin 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 ketoprofen consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% ketoprofen 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 celecoxib consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% celecoxib 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 rofecoxib consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% rofecoxib 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 meclofenamic acid consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% meclofenamic acid 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 fenoprofen consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% fenoprofen 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 diflunisal consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% diflunisal 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 naproxen consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% naproxen 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 ibuprofen consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% ibuprofen 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 flurbiprofen consisting of a condensation aerosol

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

b. wherein said condensation aerosol particles are characterized by less than 5% flurbiprofen 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 composition for delivery of nabumetone consisting of a condensation aerosol

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

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

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

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

33. The composition according to claim 32 wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

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

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

b. during said heating, passing air through the heated vapor to produce aerosol particles of the indomethacin comprising less than 5% indomethacin 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 ketoprofen in an aerosol form comprising:

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

b. during said heating, passing air through the heated vapor to produce aerosol particles of the ketoprofen comprising less than 5% ketoprofen 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 10′

⁰ particles per second.

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

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

b. during said heating, passing air through the heated vapor to produce aerosol particles of the celecoxib comprising less than 5% celecoxib 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 rofecoxib in an aerosol form comprising:

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

b. during said heating, passing air through the heated vapor to produce aerosol particles of the rofecoxib comprising less than 5% rofecoxib 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 10¹⁰ particles per second.

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

a. heating a coating of meclofenamic acid on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the meclofenamic acid to form a heated vapor of the meclofenamic acid, and

b. during said heating, passing air through the heated vapor to produce aerosol particles of the meclofenamic acid comprising less than 5% meclofenamic acid 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 10¹⁰ particles per second.

49. A composition for delivery of tolfenamic acid consisting of a condensation aerosol

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

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

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

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

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

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

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

b. during said heating, passing air through the heated vapor to produce aerosol particles of the fenoprofen comprising less than 5% fenoprofen 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 diflunisal in an aerosol form comprising:

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

b. during said heating, passing air through the heated vapor to produce aerosol particles of the diflunisal comprising less than 5% diflunisal 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 tolfenamic acid in an aerosol form comprising:

a. heating a coating of tolfenamic acid on a solid support, having the surface texture of a metal foil, to a temperature sufficient to volatilize the tolfenamic acid to form a heated vapor of the tolfenamic acid, and

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

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

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

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

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

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

62. The method according to claim 61, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

63. The method according to claim 62, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

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

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

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

65. The method according to claim 65, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

66. The method according to claim 65, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

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

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

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

68. The method according to claim 67, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

69. The method according to claim 69, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

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

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

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

71. The method according to claim 70, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

72. The method according to claim 71, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.