Aerosol formulations containing P134A and/or P227 and particulate medicament

• US 5,916,540 A
• Filed: 04/06/1998
• Issued: 06/29/1999
• Est. Priority Date: 10/24/1994
• Status: Expired due to Term

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Wyatt, David Andrew, Taylor, Anthony James, Akehurst, Rachel Ann
• Primary Examiner(s): Bawa, Raj
• Application Number:
  US09/055,253
• Time in Patent Office: 449 Days
• Field of Search: 424/45, 424/46, 514/937
• 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 consisting essentially of (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.

2. A formulation as claimed in claim 1 wherein the polar cosolvent is present in an amount from 0.05 to 3% w/w based upon the propellant.

3. A formulation as claimed in claim 1 wherein the polar cosolvent is present in an amount of 0.05 to 5% w/w based upon the propellant.

4. A formulation as claimed in claim 2 wherein said medicament is an anti-allergic, a bronchodilator or an anti-inflammatory steroid.

5. A formulation as claimed in claim 2 wherein said medicament is selected from the group consisting of salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof.

6. A formulation as claimed in claim 2 wherein said medicament is beclomethasone dipropionate or a physiologically acceptable solvate thereof.

7. A formulation as claimed in claim 2 wherein said medicament is selected from the group consisting of ephedrine, adrenaline, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, rimiterol, terbutaline, (-)4-amino-3,5-dichloro-α

- 6- 2-(2-pyridinyl)ethoxy!hexyl!-amino!methyl!benzene-methanol and physiologically acceptable salts thereof.

8. A formulation as claimed in claim 2 wherein said medicament is selected from the group consisting of pirbuterol and physiologically acceptable salts thereof.

9. A formulation as claimed in claim 2 wherein said medicament is selected from the group consisting of formoterol and physiologically acceptable salts thereof.

10. A formulation as claimed in claim 2 wherein said medicament is selected from the group consisting of fenoterol, reproterol, isoetharine and tolubuterol.

11. A formulation as claimed in claim 2 which contains two or more particulate medicaments.

12. A formulation as claimed in claim 2 which contains a particulate bronchodilatory medicament and a particulate anti-inflammatory medicament.

13. A formulation as claimed in claim 2 which contains salmeterol xinafoate in combination with fluticasone propionate.

14. A formulation as claimed in claim 2 which is free of surfactant.

15. A formulation as claimed in claim 2 wherein the medicament is present in an amount from 0.01 to 1% w/w relative to the total weight of the formulation.

16. A formulation as claimed in claim 2 which has a respirable fraction of 20% or more by weight of the medicament.

17. A formulation as claimed in claim 2 wherein said medicament is an anti-allergic medicament selected from the group consisting of ketotifen, nedocromil and physiologically acceptable salts thereof.

18. A formulation as claimed in claim 2 wherein said medicament is selected from the group consisting of cromoglycate and physiologically acceptable salts thereof.

19. A formulation as claimed in claim 2 wherein said medicament is an anti-inflammatory medicament selected from the group consisting of budesonide and triamcinolone acetonide.

20. A formulation as claimed in claim 2 wherein said medicament is flunisolide.

21. A formulation as claimed in claim 2 wherein said medicament is an anti-cholinergic medicament selected from the group consisting of ipratropium, atropine, oxitropium, and physiologically acceptable salts thereof.

22. A formulation as claimed in claim 2 wherein said medicament is a xanthine selected from the group consisting of aminophylline, choline theophyllinate, lysine theophyllinate, theophylline and physiologically acceptable salts thereof.

75. A formulation as claimed in claim 9 wherein the polar cosolvent is ethanol.

78. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as claimed in claim 1.

82. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as claimed in claim 9.

84. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 2.

92. A formulation as claimed in claim 1 wherein the polar cosolvent is ethanol.

96. A formulation as claimed in claim 1 wherein the propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.

23. A pharmaceutical aerosol formulation consisting of (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.

24. A formulation as claimed in claim 23 wherein the polar cosolvent is present in an amount from 0.05 to 3% w/w based upon the propellant.

25. A formulation as claimed in claim 24 wherein said medicament is selected from the group consisting of salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof.

26. A formulation as claimed in claim 24 wherein said medicament is beclomethasone dipropionate or a physiologically acceptable solvate thereof.

27. A formulation as claimed in claim 24 wherein said medicament is selected from the group consisting of ephedrine, adrenaline, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, rimiterol, terbutaline, orciprenaline, (-)4-amino-3,5-dichloro-α

- 6- 2-2(-pyridinyl)ethoxy!hexyl!-amino!methyl!benzene-methanol and physiologically acceptable salts thereof.

28. A formulation as claimed in claim 24 wherein said medicament is selected from the group consisting of pirbuterol and physiologically acceptable salts thereof.

29. A formulation as claimed in claim 24 wherein said medicament is selected from the group consisting of formoterol and physiologically acceptable salts thereof.

30. A formulation as claimed in claim 24 wherein said medicament is selected from the group consisting of fenoterol, reproterol, isoetharine and tolubuterol.

31. A formulation as claimed in claim 24 which contains two or more particulate medicaments.

32. A formulation as claimed in claim 24, which contains a particulate bronchodilatory medicament and a particulate anti-inflammatory medicament.

33. A formulation as claimed in claim 24, which contains salmeterol xinafoate in combination with fluticasone propionate.

34. A formulation as claimed in claim 24 wherein said medicament is an anti-allergic, a bronchodilator or an anti-inflammatory steroid.

35. A formulation as claimed in claim 24 wherein the medicament is present in an amount from 0.01 to 1% w/w relative to the total weight of the formulation.

36. A formulation as claimed in claim 24 which has a respirable fraction of 20% or more by weight of the medicament.

37. A formulation as claimed in claim 24 wherein said medicament is an anti-allergic medicament selected from the group consisting of ketotifen, nedocromil and physiologically acceptable salts thereof.

38. A formulation as claimed in claim 24 wherein said medicament is an anti-inflammatory medicament selected from the group consisting of budesonide and triamcinolone acetonide.

39. A formulation as claimed in claim 24 wherein said medicament is an anti-cholinergic medicament selected from the group consisting of ipratropium, atropine, oxitropium, and physiologically acceptable salts thereof.

40. A formulation as claimed in claim 24 wherein said medicament is a xanthine selected from the group consisting of aminophylline, choline theophyllinate, lysine theophyllinate, theophylline and physiologically acceptable salts thereof.

76. A formulation as claimed in claim 29 wherein the polar cosolvent is ethanol.

79. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as claimed in claim 23.

85. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 24.

93. A formulation as claimed in claim 23 wherein the polar cosolvent is ethanol.

95. A formulation as claimed in claim 35 wherein the polar cosolvent is ethanol.

97. A formulation as claimed in claim 23 wherein the propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.

41. A pharmaceutical aerosol formulation consisting essentially of (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) 0.05 to 5% w/w based upon the propellant of a polar cosolvent, the particulate medicament being present in an amount from 0.01 to 1 % 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.

42. A formulation as claimed in claim 41 which is free of surfactant.

43. A formulation as claimed in claim 41 which contains 0.05 to 3% w/w based upon the propellant of a polar cosolvent.

44. A formulation as claimed in claim 42 which contains 0.05 to 3% w/w based upon the propellant of a polar cosolvent.

45. A formulation as claimed in claim 42 wherein said medicament is flunisolide.

46. A formulation as claimed in claim 42 wherein said medicament is formoterol or a physiologically acceptable salt thereof.

47. A formulation as claimed in claim 42 wherein said medicament is selected from the group consisting of ephedrine, adrenaline, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, rimiterol, terbutaline, (-)-4-amino-3,5-dichloro-α

- 6- 2-(2-pyridinyl)ethoxy!hexyl!-amino!methyl!benzene-methanol and physiologically acceptable salts thereof.

48. A formulation as claimed in claim 42 wherein said medicament is selected from the group consisting of pirbuterol and physiologically acceptable salts thereof.

49. A formulation as claimed in claim 42 wherein said medicament is selected from the group consisting of fenoterol, reproterol, isoetharine and tolubuterol.

50. A formulation as claimed in claim 42 wherein said medicament is an anti-allergic medicament selected from the group consisting of ketotifen or nedocromil and physiologically acceptable salts thereof.

51. A formulation as claimed in claim 42 wherein said medicament is selected from the group consisting of cromoglycate and physiologically acceptable salts thereof.

52. A formulation as claimed in claim 42 wherein said medicament is an anti-inflammatory medicament selected from the group consisting of budesonide and triamcinolone acetonide.

53. A formulation as claimed in claim 42 wherein said medicament is an anti-cholinergic medicament selected from the group consisting of ipratropium, atropine, oxitropium, and physiologically acceptable salts thereof.

54. A formulation as claimed in claim 42 wherein said medicament is a xanthine selected from the group consisting of aminophylline, choline theophyllinate, lysine theophyllinate, theophylline and physiologically acceptable salts thereof.

77. A formulation as claimed in claim 46 wherein the polar cosolvent is ethanol.

80. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as claimed in claim 41.

86. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 43.

89. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 46.

94. A formulation as claimed in claim 41 wherein the polar cosolvent is ethanol.

98. A formulation as claimed in claim 41 wherein the propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.

55. A pharmaceutical aerosol formulation consisting of (i) particulate medicament, (ii) 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3,-heptafluoro-n-propane or a mixture as propellant and (iii) 0.05 to 5% w/w based upon the propellant of a polar cosolvent, the particulate medicament being present in an amount from 0.01 to 1% w/w relative to the total weight of the formulation and having a particle size of less than 100 microns.

56. A formulation as claimed in claim 55 which contains 0.05 to 3% w/w based upon the propellant of a polar cosolvent.

57. A formulation as claimed in claim 56 wherein said medicament is an anti-allergic medicament selected from the group consisting of ketotifen, nedocromil and physiologically acceptable salts thereof.

58. A formulation as claimed in claim 56 wherein said medicament is selected from the group consisting of cromoglycate and physiologically acceptable salts thereof.

59. A formulation as claimed in claim 56 wherein said medicament is an anti-inflammatory medicament selected from the group consisting of budesonide and triamcinolone acetonide.

60. A formulation as claimed in claim 56 wherein said medicament is flunisolide.

61. A formulation as claimed in claim 56 wherein said medicament is an anti-cholinergic medicament selected from the group consisting of ipratropium, atropine, oxitropium, and physiologically acceptable salts thereof.

62. A formulation as claimed in claim 56 wherein said medicament is a xanthine selected from the group consisting of aminophylline, choline theophyllinate, lysine theophyllinate, theophylline and physiologically acceptable salts thereof.

63. A formulation as claimed in claim 56 wherein said medicament is selected from the group consisting of ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tolubuterol, (-)4-amino-3,5-dichloro-α

- 6- 2-(2-pyridinyl)ethoxy!hexyl!-amino!methyl!benzene-methanol and physiologically acceptable salts thereof.

81. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as claimed in claim 55.

87. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 56.

99. A formulation as claimed in claim 55 wherein the propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.

64. A pharmaceutical aerosol formulation consisting of (i) a particulate medicament which is triamcinalone acetonide (ii) 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3,-heptafluoro-n-propane or a mixture as propellant and (iii) 0.05 to 3% w/w based upon the propellant of a polar cosolvent, the particulate medicament being present in an amount from 0.01 to 1% w/w relative to the total weight of the formulation and having a particle size of less than 100 microns.

65. A formulation as claimed in claim 64 wherein the polar cosolvent is ethanol.

66. A formulation as claimed in claim 64 wherein the propellant is 1,1,1,2-tetrafluoroethane.

67. A formulation as claimed in claim 65 wherein the propellant is 1,1,1,2-tetrafluoroethane.

88. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 65.

101. A formulation as claimed in claim 64 wherein the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane.

68. 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 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.

70. A formulation as claimed in claim 68 wherein the polar cosolvent is present in an amount from 0.05% to 5% w/w based upon the propellant.

71. A formulation as claimed in claim 70 wherein the polar cosolvent is ethanol.

72. A formulation as claimed in claim 70 wherein the medicament is formoterol or a physiologically acceptable salt thereof.

83. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 68.

100. A formulation as claimed in claim 68 wherein the propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.

102. A formulation as claimed in claim 68 wherein the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane.

69. A formulation as claimed in claimed 68 wherein the polar cosolvent is present in an amount of from 0.05% to 3% w/w based upon the propellant.

73. A formulation as claimed in claim 69 wherein the medicament is formoterol or a physiologically acceptable salt thereof.

74. A formulation as claimed in claim 73 wherein the polar cosolvent is ethanol.

90. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 69.

91. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as a claimed in claim 74.