Delivery of Drug Esters Through an Inhalation Route

• US 20080175796A1
• Filed: 03/27/2008
• Published: 07/24/2008
• Est. Priority Date: 05/24/2001
• Status: Active Grant

• 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.
• Granted Patent: US 7,988,952 B2
• Time in Patent Office: Days
• 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 the delivery of drug esters through an inhalation route. Specifically, it relates to aerosols containing drug esters that are used in inhalation therapy. In a method aspect of the present invention, a drug ester is delivered to a patient through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises a drug ester, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% drug ester degradation product. In a kit aspect of the present invention, a kit for delivering a drug ester through an inhalation route is provided which comprises: a) a thin coating of a drug ester composition and b) a device for dispensing said thin coating as a condensation aerosol.

Claims

1. A condensation aerosol for delivery of drug ester,

wherein the drug ester is an ester of a drug selected from the group consisting of aceclofenac, alclofenac, alminoprofen, amfenac, aspirin, benoxaprofen, bermoprofen, bromfenac, bufexamac, butibufen, bucloxate, carprofen, cinchophen, cinmetacin, clidanac, clopriac, clometacin, diclofenac, diflunisal, etodolac, fenclozate, fenoprofen, flutiazin, flurbiprofen, ibuprofen, ibufenac, indomethacin, indoprofen, ketoprofen, ketorolac, loxoprofen, meclofenamate, naproxen, oxaprozin, pirprofen, prodolic acid, salsalate, sulindac, tofenamate, tolmetincoated, apomorphine, baclofen, levodopa, carbidopa, and thioctate;

wherein the aerosol is formed by heating a composition containing the drug ester coated on a solid support to produce a vapor and cooling the vapor to form a condensation aerosol comprising particles;

wherein the particles comprise at least 10 percent by weight of the drug ester and less than 5 percent by weight of drug ester degradation products; and

wherein the condensation aerosol has an MMAD between 0.2 and 5 microns.

2. The condensation aerosol according to claim 1, wherein the condensation aerosol has an MMAD between 1 and 3 microns.

3. The condensation aerosol according to claim 1, wherein the geometric standard deviation around the MMAD is less than 2.0.

4. The condensation aerosol according to claim 1, wherein the composition further comprises a pharmaceutically acceptable excipient.

5. The condensation aerosol according to claim 1, wherein the drug ester is an ester of a drug selected from the group consisting of indomethacin, ketoprofen, ketorolac, and apomorphine.

6. The condensation aerosol according to claim 5, wherein the condensation aerosol has an MMAD between 1 and 3 microns.

7. The condensation aerosol according to claim 5, wherein the geometric standard deviation around the MMAD is less than 2.0.

8. The condensation aerosol according to claim 5, wherein the composition further comprises a pharmaceutically acceptable excipient.

9. The condensation aerosol according to claim 5, wherein the drug ester is selected from the group consisting of indomethacin methyl ester, indomethacin ethyl ester, and indomethacin norcholine ester.

10. The condensation aerosol according to claim 5, wherein the drug ester is selected from the group consisting of ketoprofen methyl ester, ketoprofen ethyl ester, and ketoprofen norcholine ester.

11. The condensation aerosol according to claim 5, wherein the drug ester is selected from the group consisting of ketorolac methyl ester, ketorolac ethyl ester, and ketorolac norcholine ester.

12. The condensation aerosol according to claim 5, wherein the drug ester is apomorphine diacetate.

13. A method of producing a drug ester aerosol comprising:

a. coating a composition containing the drug ester on a solid support, wherein the drug ester is an ester of a drug selected from the group consisting of aceclofenac, alclofenac, alminoprofen, amfenac, aspirin, benoxaprofen, bermoprofen, bromfenac, bufexamac, butibufen, bucloxate, carprofen, cinchophen, cinmetacin, clidanac, clopriac, clometacin, diclofenac, diflunisal, etodolac, fenclozate, fenoprofen, flutiazin, flurbiprofen, ibuprofen, ibufenac, indomethacin, indoprofen, ketoprofen, ketorolac, loxoprofen, meclofenamate, naproxen, oxaprozin, pirprofen, prodolic acid, salsalate, sulindac, tofenamate, tolmetincoated, apomorphine, baclofen, levodopa, carbidopa, and thioctate;

b. heating the coated composition to form a vapor; and

c. allowing the vapor to cool to produce a condensation aerosol comprising particles, wherein the particles comprise less than 5 percent by weight of drug ester degradation products and wherein the condensation aerosol has an MMAD between 0.2 and 5 microns.

14. The method according to claim 13, wherein the condensation aerosol has an MMAD between 1 and 3 microns.

15. The method according to claim 13, wherein the coated composition comprises at least 10 percent by weight of the drug ester.

16. The method according to claim 13, wherein the composition further comprises a pharmaceutically acceptable excipient.

17. The method according to claim 13, wherein the drug ester is an ester of a drug selected from the group consisting of indomethacin, ketoprofen, ketorolac, and apomorphine.

18. The method according to claim 17, wherein the condensation aerosol has an MMAD between 1 and 3 microns.

19. The method according to claim 17, wherein the coated composition comprises at least 10 percent by weight of the drug ester.

20. The method according to claim 17, wherein the composition further comprises a pharmaceutically acceptable excipient.

21. The method according to claim 17, wherein the drug ester is selected from the group consisting of indomethacin methyl ester, indomethacin ethyl ester, and indomethacin norcholine ester.

22. The method according to claim 17, wherein the drug ester is selected from the group consisting of ketoprofen methyl ester, ketoprofen ethyl ester, and ketoprofen norcholine ester.

23. The method according to claim 17, wherein the drug ester is selected from the group consisting of ketorolac methyl ester, ketorolac ethyl ester, and ketorolac norcholine ester.

24. The method according to claim 17, wherein the drug ester is apomorphine diacetate