Delivery of physiologically active compounds through an inhalation route

• US 7,033,575 B2
• Filed: 01/30/2004
• Issued: 04/25/2006
• 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:
  US10/769,051
• Publication Number:
  US 20040185002A1
• Time in Patent Office: 816 Days
• Field of Search: 424/45, 424/43, 424/434, 424/46, 424/489, 424/499, 128/208.17, 128/200.14, 128/200.24, 514/958
• 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 physiologically active compounds through an inhalation route. Specifically, it relates to aerosols containing physiologically active compounds that are used in inhalation therapy. In a method aspect of the present invention, the physiologically active compound is delivered to a patient through an inhalation route. The method comprises: a) heating a coating of a physiologically active compound, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% physiologically active compound degradation products. In a kit aspect of the present invention, a kit for delivering a physiologically active compound through an inhalation route is provided which comprises: a) a thin coating of a physiologically active compound, and b) a device for dispensing said thin coating as a condensation aerosol.

Claims

1. A condensation aerosol for delivery of a drug selected from the group consisting of chlordiazepoxide, betahistine, clonidine, testosterone, a conjugated estrogen, an estrogen ester, estradiol, an estradiol ester, ethinyl estradiol, an ethinyl estradiol ester and hyoscyamine,

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 about 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 1, 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 chlordiazepoxide.

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

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

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

17. The condensation aerosol according to claim 1, wherein the drug is a conjugated estrogen.

18. The condensation aerosol according to claim 1, wherein the drug is an estrogen ester.

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

20. The condensation aerosol according to claim 1, wherein the drug is an estradiol ester.

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

22. The condensation aerosol according to claim 1, wherein the drug is an ethinyl estradiol ester.

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

4. A method of producing a drug selected from the group consisting of chlordiazepoxide, betahistine, clonidine, testosterone, a conjugated estrogen, an estrogen ester, estradiol, an estradiol ester, ethinyl estradiol, an ethinyl estradiol ester and hyoscyamine 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 0.1 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 about 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 chlordiazepoxide.

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

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

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

34. The method according to claim 4, wherein the drug is a conjugated estrogen.

35. The method according to claim 4, wherein the drug is an estrogen ester.

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

37. The method according to claim 4, wherein the drug is an estradiol ester.

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

39. The method according to claim 4, wherein the drug is an ethinyl estradiol ester.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

56. A method of producing a conjugated estrogen in an aerosol form comprising:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

61. A method of producing an ethinyl estradiol ester in an aerosol form comprising:

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

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

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

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

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