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

• US 20040185003A1
• Filed: 01/29/2004
• Published: 09/23/2004
• 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 7,060,255 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 31/192 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 composition for delivery of alprazolam consisting of a condensation aerosol

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

b) wherein said condensation aerosol particles are characterized by less than 5% alprazolam 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. The composition according to claim 1, wherein the condensation aerosol particles are characterized by less than 2.5 percent by weight of alprazolam, degradation products.

5. A composition for delivery of estazolam consisting of a condensation aerosol

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

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

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

6. The composition according to claim 5, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

7. The composition according to claim 6, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

8. The composition according to claim 5, wherein the condensation aerosol particles are characterized by less than 2.5 percent by weight of estazolam, degradation products.

9. A composition for delivery of midazolam consisting of a condensation aerosol

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

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

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

10. The composition according to claim 9, wherein the aerosol particles are formed at a rate of at least 10⁹ particles per second.

11. The composition according to claim 10, wherein the aerosol particles are formed at a rate of at least 10¹⁰ particles per second.

12. The composition according to claim 9, wherein the condensation aerosol particles are characterized by less than 2.5 percent by weight of midazolam, degradation products.

13. A composition for delivery of triazolam consisting of a condensation aerosol

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

b) wherein said condensation aerosol particles are characterized by less than 5% triazolam 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. The composition according to claim 13, wherein the condensation aerosol particles are characterized by less than 2.5 percent by weight of triazolam degradation products.

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

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

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

18. The method according to claim 17, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

19. The method according to claim 18, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second

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

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

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

21. The method according to claim 20, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

22. The method according to claim 21, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

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

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

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

24. The method according to claim 23, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

25. The method according to claim 24, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.

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

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

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

27. The method according to claim 26, wherein the aerosol particles are formed at a rate of greater than 10⁹ particles per second.

28. The method according to claim 27, wherein the aerosol particles are formed at a rate of greater than 10¹⁰ particles per second.