Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route

• US 7,060,255 B2
• Filed: 01/29/2004
• Issued: 06/13/2006
• 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): Padmanabhan, Sreeni
• Assistant Examiner(s): Haghighatian, Mina
• Application Number:
  US10/769,157
• Publication Number:
  US 20040185003A1
• Time in Patent Office: 866 Days
• Field of Search: 424/45, 424/46, 424/489, 424/499, 424/43, 424/434, 424/789, 424/165, 424/200.14, 424/200.12, 514/220, 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 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• 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 31/422 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 31/49 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 31/517 : ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• 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: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• 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 alprazolam, estazolam, midazolam or triazolam through an inhalation route. Specifically, it relates to aerosols containing alprazolam, estazolam, midazolam or triazolam that are used in inhalation therapy. In a method aspect of the present invention, alprazolam, estazolam, midazolam or triazolam is administered to a patient through an inhalation route. The method comprises: a) heating a thin layer of alprazolam, estazolam, midazolam or triazolam, on a solid support to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% drug degradation products. In a kit aspect of the present invention, a kit for delivering alprazolam, estazolam, midazolam or triazolam through an inhalation route is provided which comprises: a) a thin coating of an alprazolam, estazolam, midazolam, or triazolam composition 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 alprazolam, estazolam, midazolam and triazolam, 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 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 thin layer has a thickness between 0.2 and 4.8 microns.

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

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

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

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

4. A method of producing a drug selected from the group consisting of alprazolam, estazolam, midazolam and triazolam 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.

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

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

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

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

22. The method according to claim 21, wherein the condensation aerosol is characterized by less than 2.5% drug degradation products by weight.

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

24. The method according to claim 4, wherein the thin layer has a thickness between 0.2 and 4.8 microns.

25. The method according to claim 4, wherein the drug is alprazolam.

26. The method according to claim 4, wherein the drug is estazolam.

27. The method according to claim 4, wherein the drug is midazolam.

28. The method according to claim 4, wherein the drug is triazolam.

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

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

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

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

33. A method of producing alprazolam in an aerosol form comprising:

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

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

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

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

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

35. A method of producing midazolam in an aerosol form comprising:

a. heating a thin layer containing midazolam, on a solid support, to produce a vapor characterized by less than 5% midazolam degradation products by weight, and an MMAD of about 0.2 to 3 microns.

36. A method of producing triazolam in an aerosol form comprising:

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

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