Respiratory drug condensation aerosols and methods of making and using them

• US 7,550,133 B2
• Filed: 11/20/2003
• Issued: 06/23/2009
• Est. Priority Date: 11/26/2002
• Status: Expired due to Fees

• Current Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Original Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Inventors: Hale, Ron L., Lloyd, Peter M., Rabinowitz, Joshua D., Wensley, Martin J., Lu, Amy T.
• Primary Examiner(s): Haghighatian; Mina
• Application Number:
  US10/719,899
• Publication Number:
  US 20040105819A1
• Time in Patent Office: 2,042 Days
• Field of Search: 424/45, 424/46, 424/489, 424/499, 424/434, 514/958, 128/200.14, 128/200.24, 128/203.15
• US Class Current: 424/45
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• 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

Abstract

Described herein are respiratory drug condensation aerosols and methods of making and using them. Kits for delivering condensation aerosols are also described. The respiratory drug aerosols typically comprise respiratory drug condensation aerosol particles. In some variations the respiratory drug compound is selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators and pharmaceutically acceptable analogs, derivatives, and mixtures thereof. Methods of treating a respiratory ailment using the described aerosols are also described. In general, the methods typically comprise the step of administering a therapeutically effective amount of respiratory drug condensation aerosol to a person with a respiratory ailment. Methods of forming a respiratory drug condensation aerosol are also described. The methods comprise the steps of vaporizing and condensing a respiratory drug composition.

Claims

1. A composition for delivery of a drug, the compostion comprising a condensation aerosol

a) wherein the condensation aerosol is formed by heating a thin film of a drug composition to produce a vapor, and condensing the vapor to form a condensation aerosol comprising the drug,

b) wherein the condensation aerosol comprises particles that are characterized by less than 10% drug degradation products by weight,

c) wherein the condensation aerosol has an MMAD of less than 5 microns, and

d) wherein the drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, and treprostinil.

2. The composition of claim 1, wherein the condensation aerosol particles are characterized by less than 5% drug degradation products.

3. The composition of claim 2, wherein the condensation aerosol particles are characterized by less than 1% drug degradation products.

4. The composition of claim 1, wherein the drug composition comprises a drug that is in a free base form.

5. The composition of claim 1, wherein the drug composition comprises a drug that is in a free acid form.

6. The composition of claim 1, wherein the drug composition comprises at least two drugs.

7. The composition of claim 1, wherein the drug composition comprises a pharmaceutically acceptable excipient.

8. The composition of claim 1, wherein the condensation aerosol is devoid of excipients.

9. The composition of claim 1, wherein the condensation aerosol is devoid of propellants and organic solvents.

10. The composition of claim 1, wherein the condensation aerosol particles are characterized by increasing percentages of drug degradation products with increasing film thicknesses.

11. The composition of claim 1, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns.

12. The composition of claim 1, wherein the condensation aerosol is characterized by an MMAD of 1 to 5 microns.

13. The composition of claim 1, wherein the condensation aerosol is characterized by an MMAD of 10 to 100 nm.

14. The composition of claim 12, wherein the condensation aerosol is characterized by an MMAD of 1 to 3 microns.

15. The composition of claim 14, wherein the condensation aerosol particles are characterized by less than 5% drug degradation products.

16. The composition of claim 15, wherein the condensation aerosol particles are characterized by less than 1% drug degradation products.

17. The composition of claim 1, wherein the thin film has a thickness between 0.05 and 20 microns.

18. The composition of claim 17, wherein the thin film has a thickness between 0.5 and 5 microns.

32. The composition of claim 14, wherein the drug composition comprises a drug that is in a free base form.

33. The composition of claim 14, wherein the drug composition comprises a drug that is in a free acid form.

34. The composition of claim 14, wherein the drug composition comprises at least two drugs.

35. The composition of claim 14, wherein the drug composition comprises a pharmaceutically acceptable excipient.

36. The composition of claim 14, wherein the condensation aerosol is devoid of excipients.

37. The composition of claim 14, wherein the condensation aerosol is devoid of propellants and organic solvents.

38. The composition of claim 14, wherein the condensation aerosol particles are characterized by increasing percentages of drug degradation products with increasing film thicknesses.

39. The composition of claim 14, wherein the thin film has a thickness between 0.05 and 20 microns.

40. The composition of claim 39, wherein the thin film has a thickness between 0.5 and 5 microns.

41. The composition of claim 14, wherein the condensation aerosol is formed at a rate greater than 0.01 mg/s.

42. The composition of claim 41, wherein the condensation aerosol is formed at a rate greater than 0.9 mg/s.

43. The composition of claim 42, wherein the condensation aerosol is formed at a rate greater than 2.5 mg/s.

44. The composition of claim 1, wherein the condensation aerosol is formed at a rate greater than 0.01 mg/s.

45. The composition of claim 44, wherein the condensation aerosol is formed at a rate greater than 0.9 mg/s.

46. The composition of claim 45, wherein the condensation aerosol is formed at a rate greater than 2.5 mg/s.

19. A kit for delivering a condensation aerosol, the kit comprising:

a) a thin film of a drug composition comprising a drug, on a solid support, and

b) a device for providing the condensation aerosol,

wherein the condensation aerosol is formed by heating the drug composition to produce a vapor, and condensing the vapor to form a condensation aerosol comprising the drug,

wherein the condensation aerosol comprises particles that are characterized by less than 10% drug degradation products by weight,

wherein the condensation aerosol has an MMAD of less than 5 microns, and

wherein the drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, and treprostinil.

20. The kit of claim 19, wherein the thin film has a thickness between 0.05 and 20 microns.

21. The kit of claim 19, wherein the thin film has a thickness between 0.5 and 5 microns.

22. The kit of claim 19, wherein the device comprises a heating element configured to heat the thin film to produce a vapor, and an enclosure allowing the vapor to condense to form a condensation aerosol.

23. The kit of claim 19, wherein the condensation aerosol comprises more than one drug.

24. The kit of claim 19, wherein the drug composition further comprises a pharmaceutically acceptable excipient.

25. The kit of claim 19, wherein the condensation aerosol has an MMAD of less than 3 microns.

26. The kit of claim 19, wherein the condensation aerosol has an MMAD of 1 to 5 microns.

27. The kit of claim 19, wherein the condensation aerosol has an MMAD of 10 to 100 nm.

28. The kit of claim 26, wherein the condensation aerosol has an MMAD of 1 to 3 microns.

29. The kit of claim 19, wherein the solid support is a metal foil.

30. The kit of claim 19, wherein the condensation aerosol particles are characterized by less than 5% drug degradation products.

31. The kit of claim 30, wherein the condensation aerosol particles are characterized by less than 1% drug degradation products.