Delivery of muscle relaxants through an inhalation route

• US 20040186130A1
• Filed: 03/31/2004
• 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 7,063,832 B2
• Time in Patent Office: Days
• US Class Current: 514/305
• 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 muscle relaxants through an inhalation route. Specifically, it relates to aerosols containing muscle relaxants that are used in inhalation therapy. In a method aspect of the present invention, a muscle relaxant is delivered to a patient through an inhalation route. The method comprises: a) heating a coating of a muscle relaxant, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% muscle relaxant degradation products. In a kit aspect of the present invention, a kit for delivering a muscle relaxant through an inhalation route is provided which comprises: a) a coating of a muscle relaxant and b) a device for dispensing said coating a muscle relaxant as a condensation aerosol.

Claims

1. A method of treating musculoskeletal pain or restless leg syndrome comprising administering a therapeutic amount of a muscle relaxant condensation aerosol, having an MMAD less than 3 μ

m and less than 5% muscle relaxant 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 a muscle relaxant under conditions effective to produce a heated vapor of the muscle relaxant;

and

b. condensing the heated vapor of the muscle relaxant to form condensation aerosol particles.

3. The method according to claim 2, wherein said administration results in a peak plasma concentration of said muscle relaxant in less than 0.1 hours.

4. The method of claim 2, wherein the muscle relaxant is selected from the group consisting of quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

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

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

7. The method according to claim 4, wherein said therapeutic amount of quinine condensation aerosol comprises between 50 mg and 500 mg of quinine delivered in a single inspiration.

8. The method according to claim 4, wherein said therapeutic amount of chlorzoxazone condensation aerosol comprises between 50 mg and 400 mg of chlorzoxazone delivered in a single inspiration.

9. The method according to claim 4, wherein said therapeutic amount of carisprodol condensation aerosol comprises between 70 mg and 500 mg of carisprodol delivered in a single inspiration.

10. The method according to claim 4, wherein said therapeutic amount of cyclobenzaprine condensation aerosol comprises between 2 mg and 25 mg of cyclobenzaprine delivered in a single inspiration.

11. A method of treating musculoskeletal pain or restless leg syndrome comprising administering a therapeutic amount of a quinine, chlorzoxazone, carisprodol or cyclobenzaprine condensation aerosol, having an MMAD less than 3 μ

m and less than 5% quinine, chlorzoxazone, carisprodol or cyclobenzaprine degradation products, to a patient by inhalation, upon activation by the patient of the formation of, and delivery of, the condensation aerosol.

12. The method of claim 11, wherein said condensation aerosol is formed by

a. volatilizing quinine, chlorzoxazone, carisprodol or cyclobenzaprine under conditions effective to produce a heated vapor of quinine, chlorzoxazone, carisprodol or cyclobenzaprine;

and

b. condensing the heated vapor of quinine, chlorzoxazone, carisprodol or cyclobenzaprine to form condensation aerosol particles.

13. The method according to claim 11, wherein said administration results in a peak plasma concentration of quinine, chlorzoxazone, carisprodol or cyclobenzaprine in less than 0.1 hours.

14. The method according to claim 11, wherein at least 50% by weight of the condensation aerosol is amorphous in form.

15. A method of administering a muscle relaxant to a patient to achieve a peak plasma drug concentration rapidly, comprising administering to the patient by inhalation an aerosol of a muscle relaxant having less than 5% muscle relaxant degradation products and an MMAD less than 3 microns wherein the peak plasma concentration of the muscle relaxant is achieved in less than 0.1 hours.

16. A method of administering quinine, chlorzoxazone, carisprodol or cyclobenzaprine to a patient to achieve a peak plasma drug concentration rapidly, comprising administering to the patient by inhalation an aerosol of quinine, chlorzoxazone, carisprodol or cyclobenzaprine having less than 5% quinine, chlorzoxazone, carisprodol or cyclobenzaprine degradation products and an MMAD less than 3 microns wherein the peak plasma drug concentration of quinine, chlorzoxazone, carisprodol or cyclobenzaprine is achieved in less than 0.1 hours.

17. A kit for delivering a drug aerosol comprising:

a) a coating of a muscle relaxant composition and

b) a device for dispensing said coating as a condensation aerosol.

18. The kit of claim 17, wherein the muscle relaxant in the composition is selected from the group consisting quinine, chlorzoxazone, carisprodol or cyclobenzaprine.

19. The kit of claim 17, wherein the device for dispensing said coating of a muscle relaxant composition as an aerosol comprises

(a) a flow through enclosure,

(b) contained within the enclosure, a metal substrate with a foil-like surface and having a coating of an muscle relaxant 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 muscle relaxant 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 a muscle relaxant vapor containing less than 5% muscle relaxant degradation products, and drawing air through said chamber is effective to condense the muscle relaxant to form aerosol particles wherein the aerosol has an MMAD of less than 3 microns.

20. The kit according to claim 19, wherein the heat for heating the substrate is generated by an exothermic chemical reaction.

21. The kit according to claim 20, wherein said exothermic chemical reaction is oxidation of combustible materials.

22. The kit according to claim 19, wherein the heat for heating the substrate is generated by passage of current through an electrical resistance element.

23. The kit according to claim 19, wherein said substrate has a surface area dimensioned to accommodate a therapeutic dose of a muscle relaxant composition in said coating.

24. The kit according to claim 17, wherein a peak plasma concentration of muscle relaxant is obtained in less than 0.1 hours after delivery of the condensation aerosol to the pulmonary system.

25. The kit of claim 17, further including instructions for use.