Delivery of beta-blockers through an inhalation route

• US 20040167228A1
• Filed: 02/09/2004
• Published: 08/26/2004
• 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 7,018,620 B2
• Time in Patent Office: Days
• US Class Current: 514/651
• 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 atenolol, pindolol, esmolol, propranolol, or metoprolol through an inhalation route. Specifically, it relates to aerosols containing atenolol, pindolol, esmolol, propranolol, or metoprolol that are used in inhalation therapy. In a method aspect of the present invention, atenolol, pindolol, esmolol, propranolol, or metoprolol is administered to a patient through an inhalation route. The method comprises: a) heating a composition of atenolol, pindolol, esmolol, propranolol, or metoprolol, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% drug degradation products. In a kit aspect of the present invention, a kit for delivering 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 method of treating hypertension, acute myocardial infarction, cardiac arrhythmias or side effects of situational anxiety comprising administering a therapeutic amount of an atenolol, pindolol, esmolol, propranolol, or metoprolol condensation aerosol, having an MMAD less than 3 μ

m and less than 5% atenolol, pindolol, esmolol, propranolol, or metoprolol degradation products, to a patient by inhalation, upon activation by the patient of the formation of, and delivery of, the condensation aerosol.

2. The method of claim 1, wherein said condensation aerosol is formed by

a. volatilizing atenolol, pindolol, esmolol, propranolol, or metoprolol under conditions effective to produce a heated vapor of the atenolol, pindolol, esmolol, propranolol, or metoprolol and

b. condensing the heated vapor of the atenolol, pindolol, esmolol, propranolol, or metoprolol to form condensation aerosol particles.

3. The method according to claim 1, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second.

4. The method according to claim 1, wherein said therapeutic amount of atenolol condensation aerosol comprises between 0.1 mg and 20 mg of atenolol in a single inspiration.

5. The method according to claim 1, wherein said therapeutic amount of pindolol condensation aerosol comprises between 0.1 mg and 20 mg of pindolol in a single inspiration.

6. The method according to claim 1, wherein said therapeutic amount of esmolol condensation aerosol comprises between 4 mg and 100 mg of esmolol delivered in a single inspiration.

7. The method according to claim 1 wherein said therapeutic amount of propranolol condensation aerosol comprises between 0.2 mg and 050 mg of propranolol delivered in a single inspiration.

8. The method according to claim 1 wherein said therapeutic amount of metoprolol condensation aerosol comprises between 1 mg and 30 mg of metoprolol delivered in a single inspiration.

9. The method according to claim 2, wherein said administration results in a peak plasma concentration of said atenolol, pindolol, esmolol, propranolol, or metoprolol in less than 0.1 hours.

10. The method according to claim 1, wherein at least 50% by weight of the condensation aerosol is amorphous in form.

11. A method of administering atenolol, pindolol, esmolol, propranolol, or metoprolol to a patient to achieve a peak plasma drug concentration rapidly, comprising administering to the patient by inhalation an aerosol of atenolol, pindolol, esmolol, propranolol, or metoprolol having less than 5% atenolol, pindolol, esmolol, propranolol, or metoprolol degradation products and an MMAD less than 3 microns wherein the peak plasma drug concentration is achieved in less than 0.1 hours.

20. The kit of claim 11, further including instructions for use.

12. A kit for delivering a drug aerosol comprising:

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.

13. The kit of claim 12, wherein said coating has a thickness between 5.2-6.5 microns.

14. The kit of claim 12, wherein the device for dispensing said coating as a condensation aerosol comprises:

(a) a flow through enclosure,

(b) contained within the enclosure, a metal substrate with a foil-like surface and having a thin coating of atenolol, pindolol, esmolol, propranolol, or metoprolol composition formed on the substrate surface,

(c) a power source that can be activated to heat the substrate to a temperature effective to volatilize the atenolol, pindolol, esmolol, propranolol, or metoprolol composition contained in said coating, and

(d) inlet and exit portals through which air can be drawn through said device by inhalation,

wherein heating the substrate by activation of the power source is effective to form an atenolol, pindolol, esmolol, propranolol, or metoprolol vapor containing less than 5 atenolol, pindolol, esmolol, propranolol, or metoprolol degradation products, and drawing air through said chamber is effective to condense the atenolol, pindolol, esmolol, propranolol, or metoprolol vapor to form aerosol particles wherein the aerosol has an MMAD of less than 3 microns.

15. The kit according to claim 14, wherein the heat for heating the substrate is generated by an exothermic chemical reaction.

16. The kit according to claim 15, wherein said exothermic chemical reaction is oxidation of combustible materials.

17. The kit according to claim 14, wherein the heat for heating the substrate is generated by passage of current through an electrical resistance element.

18. The kit according to claim 14, wherein said substrate has a surface area dimensioned to accommodate a therapeutic dose of atenolol, pindolol, esmolol, propranolol, or metoprolol composition in said coating.

19. The kit according to claim 12, wherein a peak plasma concentration of atenolol, pindolol, esmolol, propranolol, or metoprolol is obtained in less than 0.1 hours after delivery of condensation aerosol to the pulmonary system.