Aerosol formulation containing particulate formoterol, propellant and polar cosolvent

• US 6,919,069 B2
• Filed: 04/30/2003
• Issued: 07/19/2005
• Est. Priority Date: 12/12/1991
• Status: Expired due to Fees

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Wyatt, David Andrew, Taylor, Anthony James, Akehurst, Rachel Ann
• Primary Examiner(s): Dodson, Shelley A.
• Assistant Examiner(s): George, Konata M.
• Application Number:
  US10/425,839
• Publication Number:
  US 20030198600A1
• Time in Patent Office: 811 Days
• Field of Search: 424/45, 424/46
• US Class Current: 424/45
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• 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 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/4741 condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Abstract

A pharmaceutical aerosol formulation comprising (i) particulate medicament, (ii) 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3,-heptafluoro-n-propane or a mixture thereof as propellant, and (iii) 0.01 to 5% w/w based upon the propellant of a polar cosolvent, the particulate medicament being present in an amount from 0.005% to 5% w/w relative to the total weight of the formulation and having a particle size of less than 100 microns, and which formulation contains less than 0.0001% w/w surfactant based upon the weight of medicament.

Claims

1. A pharmaceutical aerosol formulation which comprises two or more particulate medicaments, a fluorocarbon or hydrogen-containing fluorocarbon propellant and up to 5% w/w based upon propellant of a polar co-solvent, which formulation is substantially free of surfactant and is free of chlorofluorocarbons.

2. A formulation as claimed in claim 1 wherein said medicaments are selected from the group consisting of an anti-allergic, a bronchodilator and an anti-inflammatory steroid.

3. A formulation as claimed in claim 1 wherein said medicaments are selected from the group consisting of salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof.

4. A formulation as claimed in claim 1 which comprises a particulate bronchodilatory medicament and a particulate anti-inflammatory medicament.

5. A formulation as claimed in claim 1 which comprises salmeterol or a physiologically acceptable salt thereof in combination with fluticasone propionate.

6. A formulation as claimed in claim 1 which comprises salmeterol xinafoate in combination with fluticasone propionate.

7. A formulation according to claim 1 wherein the propellant comprises 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.

8. A formulation according to claim 1 wherein the polar co-solvent is ethanol.

9. A formulation according to claim 1 wherein the medicament is present in an amount of 0.005-5% w/w based on the total weight of the formulation.

10. A formulation according to claim 1 which has a respirable fraction of 20% or more based on the total weight of the formulation.

11. A formulation according to claim 1 wherein said particulate medicament is surface modified.

13. A formulation according to claim 1 wherein the polar co-solvent is present in an amount of 0.01 to 5% w/w based upon propellant of a polar co-solvent.

14. A formulation according to claim 1 wherein the polar co-solvent is present in an amount of 0.05 to 3% w/w based upon propellant of a polar co-solvent.

15. A formulation according to claim 1 wherein one of said medicaments is triamcinoline acetonide.

16. A formulation according to claim 1 wherein one of said medicaments is formoterol or a physiologically acceptable salt thereof.

17. A formulation according to claim 13 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

18. A formulation according to claim 14 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

19. A formulation according to claim 15 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

20. A formulation according to claim 16 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

21. A formulation according to claim 4 wherein the anti-inflammatory medicament is a steroidal anti-inflammatory medicament.

12. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation which comprises two or more particulate medicaments a fluorocarbon or hydrogen-containing fluorocarbon propellant and up to 5% w/w based upon propellant of a polar co-solvent, which formulation is substantially free of surfactant.

22. A method according to claim 12 wherein the respiratory disorder is asthma.

23. A method according to claim 12 wherein the polar co-solvent is present in an amount of 0.01 to 5% w/w based upon propellant of a polar co-solvent.

24. A method according to claim 12 wherein the polar co-solvent is present in an amount of 0.05 to 3% w/w based upon propellant of a polar co-solvent.

25. A method according to claim 12 wherein one of said medicaments is triamcinoline acetonide.

26. A method according to claim 12 wherein one of said medicaments is formoterol or a physiologically acceptable salt thereof.

27. A method according to claim 12 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

28. A method according to claim 23 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

29. A method according to claim 24 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

30. A method according to claim 25 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

31. A method according to claim 26 wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

32. A pharmaceutical aerosol formulation which comprises (a) a particulate bronchodilatory medicament (b) a particulate steroidal anti-inflammatory medicament (c) a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof and (d) 0.05-3% w/w based upon propellant of ethanol, which formulation is substantially free of surfactant and is free of chlorofluorocarbons.

34. A formulation according to claim 32 wherein the bronchodilatory medicament is formoterol or a physiologically acceptable salt thereof.

36. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation according to claim 32.

38. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation according to claim 34.

40. A method according to claim 36 wherein the respiratory disorder is asthma.

42. A method according to claim 38 wherein the respiratory disorder is asthma.

33. A pharmaceutical aerosol formulation which consists essentially of (a) a particulate bronchodilatory medicament (b) a particulate steroidal anti-inflammatory medicament (c) a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof and (d) 0.05-3% w/w based upon propellant of ethanol, which formulation is substantially free of surfactant and is free of chlorofluorocarbons.

35. A formulation according to claim 33 wherein the bronchodilatory medicament is formoterol or a physiologically acceptable salt thereof.

37. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation according to claim 33.

39. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation according to claim 35.

41. A method according to claim 37 wherein the respiratory disorder is asthma.

43. A method according to claim 39 wherein the respiratory disorder is asthma.