Delivery of opioids through an inhalation route

• US 7,169,378 B2
• Filed: 01/29/2004
• Issued: 01/30/2007
• Est. Priority Date: 05/24/2001
• Status: Expired due to Term

• 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): Richter; Johann
• Assistant Examiner(s): Haghighatian; Mina
• Application Number:
  US10/768,281
• Publication Number:
  US 20040202617A1
• Time in Patent Office: 1,097 Days
• Field of Search: 424/45, 424/46, 424/489, 424/499, 514/958, 128/200.14, 128/200.24, 128/203.15
• 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 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 condensation aerosol for delivery of a drug selected from the group consisting of naltrexone, buprenorphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, sufentanil, nalbuphine and fentanyl

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 0.2 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 claim 1, wherein the condensation aerosol is characterized by an MMAD of 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 naltrexone.

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

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

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

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

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

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

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

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

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

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

4. A method of producing a drug selected from the group consisting of naltrexone, buprenorphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, sufentanil, nalbuphine and fentanyl 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.

24. The method according to claim 4, wherein the condensation aerosol is characterized by an MMAD of 0.2 to 5 microns.

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

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

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

28. The method according to claim 27, wherein the condensation aerosol is characterized by less than 2.5% drug degradation products by weight.

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

30. The method according to claim 4, wherein the drug is naltrexone.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

53. A method of producing buprenorphine in an aerosol form comprising:

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

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

54. A method of producing naloxone in an aerosol form comprising:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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