Delivery of opioids through an inhalation route

• US 20040202617A1
• Filed: 01/29/2004
• Published: 10/14/2004
• 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 7,169,378 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 opioids through an inhalation route. Specifically, it relates to aerosols containing opioids that are used in inhalation therapy. In a method aspect of the present invention, an opioid is delivered to a patient through an inhalation route. The method comprises: a) heating a thin layer of an opioid, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% opioid degradation products. In a kit aspect of the present invention, a kit for delivering an opioid through an inhalation route is provided which comprises: a) a thin layer of an opioid and b) a device for dispensing said thin layer as a condensation aerosol.

Claims

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

b. wherein said condensation aerosol particles are characterized by less than 5% fentanyl 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 naltrexone in an aerosol form comprising:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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