Delivery of beta-blockers through an inhalation route

• US 7,048,909 B2
• Filed: 02/09/2004
• Issued: 05/23/2006
• 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:
  US10/775,586
• Publication Number:
  US 20040161385A1
• Time in Patent Office: 834 Days
• Field of Search: 424/45, 424/46, 424/489, 424/43, 424/434, 424/789, 424/499, 514/220, 514/252, 514/958, 128/200.14, 128/200.24, 128/203.15, 128/200.12
• 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 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 condensation aerosol for delivery of a drug selected from the group consisting of atenolol, pindolol, esmolol, propranolol, and metoprolol

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 and 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 drug is atenolol.

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

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

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

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

4. A method of producing a drug selected from the group consisting of atenolol, pindolol, esmolol, propranolol, and metoprolol, 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 0.1 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 drug is atenolol.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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