Details for Patent: 7,078,019

Title:	Delivery of drug esters through an inhalation route
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.
Inventor(s):	Rabinowitz; Joshua D. (Mountain View, CA), Zaffaroni; Alejandro C. (Atherton, CA)
Assignee:	Alexza Pharmaceuticals, Inc. (Palo Alto, CA)
Filing Date:	Dec 30, 2003
Application Number:	10/749,783
Claims:	1. A method of administering a drug ester condensation aerosol to a patient comprising administering the drug ester condensation aerosol to the patient by inhalation, wherein the drug ester condensation aerosol is formed by heating a thin layer containing the drug ester, on a solid support, to produce a vapor of the drug ester, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug ester degradation products by weight, and an MMAD of less than 5 microns. 2. The method according to claim 1, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns. 3. The method according to claim 1, wherein peak plasma drug ester concentration is reached in less than 0.1 hours. 4. The method according to claim 1, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second. 5. The method according to claim 1, wherein at least 50% by weight of the condensation aerosol is amorphous in form. 6. The method according to claim 1, wherein the therapeutic amount of a drug ester condensation aerosol comprises between 0.1 mg and 100 mg of the drug ester delivered in a single inspiration. 7. A kit for delivering a drug ester condensation aerosol comprising: a. a thin layer containing the drug ester, on a solid support, and b. a device for providing the condensation aerosol, wherein the condensation aerosol is formed by heating the thin layer to produce a vapor of the drug ester, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug ester degradation products by weight, and an MMAD of less than 5 microns. 8. The kit according to claim 7, wherein the device comprises: a. a flow through enclosure containing the solid support, b. a power source that can be activated to heat the solid support, and c. at least one portal through which air can be drawn by inhalation, wherein activation of the power source is effective to produce a vapor of the drug ester, and drawing air through the enclosure is effective to condense the vapor to form the condensation aerosol. 9. The kit according to claim 8, wherein the heat for heating the solid support is generated by an exothermic chemical reaction. 10. The kit according to claim 9, wherein the exothermic chemical reaction is oxidation of combustible materials. 11. The kit according to claim 8, wherein the heat for heating the solid support is generated by passage of current through an electrical resistance element. 12. The kit according to claim 8, wherein the solid support has a surface area dimensioned to accommodate a therapeutic dose of the drug ester. 13. The kit according to claim 7, wherein peak plasma drug ester concentration is reached in less than 0.1 hours. 14. The kit according to claim 7, further including instructions for use. 15. The method according to claim 1, wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns. 16. The method according to claim 1, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to about 3 microns. 17. A method of administering a drug ester condensation aerosol to a patient comprising administering the drug ester condensation to the patient by inhalation, wherein the drug ester condensation aerosol is formed by heating a thin layer containing the drug ester, on a solid support, to produce a vapor of the drug ester, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug ester degradation products by weight, and an MMAD of less than 5 microns, and wherein the drug ester is selected from the group consisting of an ester of 2-pentenylpenicillin, an ester of 4-amino-3-hydroxybutyric acid, an ester of acamprosate, an ester of aceclofenac, an ester of alclofenac, an ester of alminoprofen, an ester of amfenac, an ester of amoxicillin, an ester of ampicillin, an ester of amylpenicillin, an ester of apomorphine, an ester of aspirin, an ester of azidocillin, an ester of baclofen, an ester of benoxaprofen, an ester of benzylpenicillin, an ester of bermoprofen, an ester of betamethasone, an ester of bromfenac, an ester of bucloxate, an ester of bufexamac, an ester of bumadizon, an ester of butibufen, an ester of calcium N-carboamoylaspartate, an ester of carbenicillin, an ester of carbidopa, an ester of carfecillin, an ester of carindacillin, an ester of carprofen, an ester of cefazolin, an ester of cefmetazole, an ester of cefoxitin, an ester of cephacetrile, an ester of cephalexin, an ester of cephaloglycin, an ester of cephaloridine, an ester of a cephalosporin, an ester of cephalotin, an ester of a cephamycin, an ester of cepharin, an ester of cephradine, an ester of chloral betaine, an ester of chlorazepate, an ester of chlorobutin penicillin, an ester of chloroprednisone, an ester of cinchophen, an ester of cinmetacin, an ester of clidanac, an ester of clocortolone, an ester of clometacin, an ester of clometocillin, an ester of clonixin, an ester of clopriac, an ester of cloxacillin, an ester of cortisone, an ester of cyclacillin, an ester of desonide, an ester of desoximetasone, an ester of dexamethasone, an ester of diclofenac, an ester of dicloxacillin, an ester of diflunisal, an ester of difluprednate, an ester of diphenicillin, an ester of estradiol, an ester of ethanedisulfonate, an ester of etodolac, an ester of fenclozate, an ester of fenoprofen, an ester of fexofenadine, an ester of fludrocortisone, an ester of flumethasone, an ester of flunisolide, an ester of fluocortolone, an ester of fluprednisolone, an ester of flurbiprofen, an ester of flutiazin, an ester of gabapentin, an ester of heptylpenicillin, an ester of hetacillin, an ester of hydrocortisone, an ester of ibufenac, an ester of ibuprofen, an ester of indomethacin, an ester of indoprofen, an ester of ketoprofen, an ester of ketorolac, an ester of levodopa, an ester of loxoprofen, an ester of meclofenamate, an ester of meprednisone, an ester of methicillin, an ester of metampicillin, an ester of methylprednisolone, an ester of nafcillin, an ester of naproxen, an ester of oxaprozin, an ester of paramethasone, an ester of a penicillin, an ester of pirprofen, an ester of prednisolone, an ester of prednisone, an ester of pregnan-3-alpha-ol-20-one, an ester of prodolic acid, an ester of S-adenosylmethionine, an ester of salsalate, an ester of sulindac, an ester of testosterone, an ester of thioctate, an ester of tianeptine, an ester of tofenamate, an ester of tolfenamic acid, an ester of tolmetin, an ester of triamcinolone, an ester of valproate and an ester of vigabatrin. 18. The method according to claim 17, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns. 19. The method according to claim 17, wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns. 20. The method according to claim 17, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to about 3 microns. 21. The method according to claim 17, wherein peak plasma drug ester concentration is reached in less than 0.1 hours. 22. The method according to claim 17, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second. 23. The method according to claim 17, wherein at least 50% by weight of the condensation aerosol is amorphous in form. 24. The method according to claim 17, wherein the therapeutic amount of a drug ester condensation aerosol comprises between 0.1 mg and 100 mg of the drug ester delivered in a single inspiration. 25. The kit according to claim 7, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns. 26. The kit according to claim 7, wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns. 27. The kit according to claim 7, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to about 3 microns. 28. The kit according to claim 8, wherein the solid support has a surface to mass ratio of greater than 1 cm.sup.2 per gram. 29. The kit according to claim 8, wherein the solid support has a surface to volume ratio of greater than 100 per meter. 30. The kit according to claim 8, wherein the solid support is a metal foil. 31. The kit according to claim 30, wherein the metal foil has a thickness of less than 0.25 mm. 32. A kit for delivering a drug ester condensation aerosol comprising: a. a thin layer containing the drug ester, on a solid support, and b. a device for providing the condensation aerosol, wherein the condensation aerosol is formed by heating the thin layer to produce a vapor of the drug ester, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug ester degradation products by weight, and an MMAD of less than 5 microns, wherein the drug ester is selected from the group consisting of an ester of 2-pentenylpenicillin, an ester of 4-amino-3-hydroxybutyric acid, an ester of acamprosate, an ester of aceclofenac, an ester of alclofenac, an ester of alminoprofen, an ester of amfenac, an ester of amoxicillin, an ester of ampicillin, an ester of amylpenicillin, an ester of apomorphine, an ester of aspirin, an ester of azidocillin, an ester of baclofen, an ester of benoxaprofen, an ester of benzylpenicillin, an ester of bermoprofen, an ester of betamethasone, an ester of bromfenac, an ester of bucloxate, an ester of bufexamac, an ester of bumadizon, an ester of butibufen, an ester of calcium N-carboamoylaspartate, an ester of carbenicillin, an ester of carbidopa, an ester of carfecillin, an ester of carindacillin, an ester of carprofen, an ester of cefazolin, an ester of cefmetazole, an ester of cefoxitin, an ester of cephacetrile, an ester of cephalexin, an ester of cephaloglycin, an ester of cephaloridine, an ester of a cephalosporin, an ester of cephalotin, an ester of a cephamycin, an ester of cepharin, an ester of cephradine, an ester of chloral betaine, an ester of chlorazepate, an ester of chlorobutin penicillin, an ester of chloroprednisone, an ester of cinchophen, an ester of cinmetacin, an ester of clidanac, an ester of clocortolone, an ester of clometacin, an ester of clometocillin, an ester of clonixin, an ester of clopriac, an ester of cloxacillin, an ester of cortisone, an ester of cyclacillin, an ester of desonide, an ester of desoximetasone, an ester of dexamethasone, an ester of diclofenac, an ester of dicloxacillin, an ester of diflunisal, an ester of difluprednate, an ester of diphenicillin, an ester of estradiol, an ester of ethanedisulfonate, an ester of etodolac, an ester of fenclozate, an ester of fenoprofen, an ester of fexofenadine, an ester of fludrocortisone, an ester of flumethasone, an ester of flunisolide, an ester of fluocortolone, an ester of fluprednisolone, an ester of flurbiprofen, an ester of flutiazin, an ester of gabapentin, an ester of heptylpenicillin, an ester of hetacillin, an ester of hydrocortisone, an ester of ibufenac, an ester of ibuprofen, an ester of indomethacin, an ester of indoprofen, an ester of ketoprofen, an ester of ketorolac, an ester of levodopa, an ester of loxoprofen, an ester of meclofenamate, an ester of meprednisone, an ester of methicillin, an ester of metampicillin, an ester of methylprednisolone, an ester of nafcillin, an ester of naproxen, an ester of oxaprozin, an ester of paramethasone, an ester of a penicillin, an ester of pirprofen, an ester of prednisolone, an ester of prednisone, an ester of pregnan-3-alpha-ol-20-one, an ester of prodolic acid, an ester of S-adenosylmethionine, an ester of salsalate, an ester of sulindac, an ester of testosterone, an ester of thioctate, an ester of tianeptine, an ester of tofenamate, an ester of tolfenamic acid, an ester of tolmetin, an ester of triamcinolone, an ester of valproate and an ester of vigabatrin. 33. The kit according to claim 32, wherein the device comprises: a. a flow through enclosure containing the solid support, b. a power source that can be activated to heat the solid support, and c. at least one portal though which air can be drawn by inhalation, wherein activation of the power source is effective to produce a vapor of the drug ester, and drawing air through the enclosure is effective to condense the vapor to form the condensation aerosol. 34. The kit according to claim 32, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns. 35. The kit according to claim 32 wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns. 36. The kit according to claim 32, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to about 3 microns. 37. The kit according to claim 32, wherein peak plasma drug ester concentration is reached in less than 0.1 hours. 38. The kit according to claim 32, further including instructions for use.