Delivery of beta-blockers through an inhalation route

• US 20040161385A1
• Filed: 02/09/2004
• Published: 08/19/2004
• 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 7,048,909 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 aerosols containing of atenolol, pindolol, esmolol, propranolol, or metoprolol that are used in inhalation therapy. In a method aspect of the present invention, of atenolol, pindolol, esmolol, propranolol, or metoprolol is administered to a patient through an inhalation route. The method comprises: a) heating a thin layer of atenolol, pindolol, esmolol, propranolol, or metoprolol, 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 of atenolol, pindolol, esmolol, propranolol, or metoprolol through an inhalation route is provided which comprises: a) a thin coating of an atenolol, pindolol, esmolol, propranolol, or metoprolol composition and b) a device for dispensing said thin coating as a condensation aerosol.

Claims

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

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

b) wherein said condensation aerosol particles are characterized by less than 5% atenolol 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 pindolol consisting of a condensation aerosol

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

b) wherein said condensation aerosol particles are characterized by less than 5% pindolol 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 esmolol consisting of a condensation aerosol

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

b) wherein said condensation aerosol particles are characterized by less than 5% esmolol 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 propranolol consisting of a condensation aerosol

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

b) wherein said condensation aerosol particles are characterized by less than 5% propranolol 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 propranolol consisting of a condensation aerosol

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

b) wherein said condensation aerosol particles are characterized by less than 5% propranolol 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 method of producing atenolol in an aerosol form comprising:

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

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

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

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

19. A method of producing pindolol in an aerosol form comprising:

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

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

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

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

22. A method of producing esmolol in an aerosol form comprising:

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

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

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

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

25. A method of producing propranolol in an aerosol form comprising:

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

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

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

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

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

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

28. A method of producing metoprolol in an aerosol form comprising:

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

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