Propellant-based microparticle formulations

• US 20030064033A1
• Filed: 08/16/2002
• Published: 04/03/2003
• Est. Priority Date: 08/16/2001
• Status: Abandoned Application

• Current Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Inventors: Brown, Larry R., Scott, Terrence L., McGeehan, John K., Rashba-Step, Julia
• Application Number:
  US10/222,200
• Publication Number:
  US 20030064033A1
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

Pulmonary formulations containing microparticles and a propellant are provided. The microparticles, preferably microspheres, contain protein and exhibit a fine particle fraction in the range of 25 to 100%.

Claims

1. A composition comprising:

(a) a plurality of microparticles, said microparticles containing a protein; and

(b) a propellant;

wherein the composition has a fine particle fraction in the range of 25% to 100%.

2. The composition of claim 1, wherein the microparticles have a density in the range of 0.06 gm/cc to 2.5 gm/cc.

3. The composition of claim 2, wherein the microparticles have a density in the range of 0.6 gm/cc to 1.8 gm/cc.

4. The composition of claim 1, wherein the microparticles have a narrow particle size distribution.

5. The composition of claim 1, wherein the microparticles are microspheres.

6. The composition of claim 1, wherein the propellant is a hydrofluoroalkane propellant.

7. The composition of claim 1 wherein the microparticles have a mean diameter in the range of from about 0.1 microns to about 10.0 microns.

8. The composition of claim 1 wherein the microparticles have a mean diameter in the range of from about 0.1 microns to about 5.0 microns.

9. The composition of claim 1 wherein the microparticles have a mean diameter in the range of from about 0.1 microns to about 3.0 microns.

10. The composition of claim 1 further comprising a polymer.

11. The composition of claim 10, wherein the polymer is water soluble or soluble in a water miscible solvent.

12. The composition of claim 10, wherein the polymer is selected from the group consisting of carbohydrate-based polymers, polyaliphatic alcohols, poly(vinyl) polymers, polyacrylic acids, polyorganic acids, polyamino acids, polyethers, naturally occurring polymers, polyimids, polyesters, polyaldehydes, co-polymers, block co-polymers, tertpolymers, surfactants, branched polymers, cyclo-polymers, and mixtures thereof.

13. The composition of claim 10, wherein the polymer is selected from the group consisting of dextran, polyethylene glycol, polyvinyl pyrrolidone, co-polymers of polyethylene glycol and polyvinyl pyrrolidone, polyvinyl alcohol, co-polymers of polyoxyethylene and polyoxypropylene, and mixtures thereof.

14. The composition of claim 10 wherein the polymer is a co-polymer of polyethylene glycol and polyvinyl pyrrolidone, and a co-polymer of polyoxyethylene and polyoxypropylene.

15. The composition of claim 1, wherein the microparticles are microspheres comprising greater than about 90% protein by weight.

16. The composition of claim 1, wherein the microparticles are microspheres comprising greater than about 95% protein by weight.

17. The composition of claim 1, wherein the microparticles are microspheres comprising greater than about 99% protein by weight.

18. The composition of claim 1, wherein the protein is selected from the group consisting of:

leuprolide acetate, luteinizing hormone releasing hormone (LHRH), (D-Tryp6)-LHRH, nafarelin acetate, insulin, sodium insulin, zinc insulin, proinsulin, C-peptide of insulin of insulin, a mixture of insulin and C-peptide of insulin, hybrid insulin cocrystals, protamine, lysozyme, alpha-lactalbumin, basic fibroblast growth factor (bFGF), beta-lactoglobulin, trypsin, carbonic anhydrase, ovalbumin, bovine serum albumin (BSA), human serum albumin (HSA), phosphorylase b, alkaline phosphatase, beta -galactosidase, IgG, fibrinogen, poly-L-lysine, IgM, DNA, desmopressin acetate™

, growth hormone releasing factor (GHRF), somatostatin, antide, Factor VIII, G-CSF/GM-CSF, human growth hormone (hGH), beta interferon, antithrombin III, alpha interferon, alpha interferon 2b, parathyroid hormone, and calcitonin.

19. The composition of claim 1, wherein the propellant is HFA P134a.

20. The composition of claim 1, wherein the propellant is HFA P227.

21. The composition of claim 1, wherein the composition does not comprise a surfactant.

22. The composition of claim 1, wherein the fine particle fraction is at least 40%.

23. The composition of claim 1, wherein the microparticles are in suspension.

24. The composition of claim 23, wherein the microparticles remain in suspension for at least 10 seconds following agitation.

25. The composition of claim 1, wherein the microparticles further comprise a therapeutic molecule.

26. The composition of claim 25, wherein the therapeutic molecule is selected from the group consisting of:

albuterol, fluticazone, ipratropium bromide, beclamethasone, and other beta-agonists and steroids.

27. The composition of claim 25, wherein the therapeutic molecule is selected from the group consisting of:

betaxolol™

, diclofenac™

, doxorubicin, and rifampin™

.

28. The composition of claim 1, wherein the microparticles comprise a carbohydrate-based polymer.

29. The composition of claim 28, wherein the carbohydrate-based polymer comprises hetastarch.

30. The composition of claim 28, wherein the carbohydrate-based polymer comprises dextran sulfate.

67. A method of administering a protein to the pulmonary system of a subject, comprising:

administering to the respiratory tract of a subject in need of treatment, an effective amount of the composition of any of claims 1-61.

68. A method of manufacture, comprising:

dispersing one, two or more therapeutic doses into a pulmonary delivery device, each of said therapeutic doses containing a therapeutically effective amount of a composition of any of claims 1-61.

69. A pulmonary delivery device comprising one, two, or more therapeutic doses containing a therapeutically effective amount of a composition of any of claims 1-61.

70. The device of claim 69, which is a metered dose inhaler.

71. A composition comprising:

a package comprising;

a container having contents, said container comprising one, two or more therapeutic doses of the composition of any of claims 1-61; and

instructions for using the container to deliver the contents to a pulmonary delivery device.

31. A composition comprising:

a plurality of microparticles, said microparticles containing a protein; and

a propellant;

wherein the composition does not comprise a surfactant.

32. The composition of claim 31, wherein the microparticles remain in suspension for at least 10 seconds following agitation.

33. The composition of claim 31, wherein the composition has a fine particle fraction in the range of 25% to 100%.

34. The composition of claim 31, wherein the microparticles have a density in the range of 0.06 gm/cc to 2.5 gm/cc.

35. The composition of claim 34, wherein the microparticles have a density in the range of 0.6 gm/cc to 1.8 gm/cc.

36. The composition of claim 31, wherein the microparticles have a narrow particle size distribution.

37. The composition of claim 31, wherein the microparticles are microspheres.

38. The composition of claim 31, wherein the propellant is a hydrofluoroalkane propellant.

39. The composition of claim 31 wherein the microparticles have a mean diameter in the range of from about 0.1 microns to about 10.0 microns.

40. The composition of claim 31 wherein the microparticles have a mean diameter in the range of from about 0.1 microns to about 5.0 microns.

41. The composition of claim 31 wherein the microparticles have a mean diameter in the range of from about 0.1 microns to about 3.0 microns.

42. The composition of claim 31 further comprising a polymer.

43. The composition of claim 42, wherein the polymer is water soluble or soluble in a water miscible solvent.

44. The composition of claim 42, wherein the polymer is selected from the group consisting of carbohydrate-based polymers, polyaliphatic alcohols, poly(vinyl) polymers, polyacrylic acids, polyorganic acids, polyamino acids, polyethers, naturally occurring polymers, polyimids, polyesters, polyaldehydes, co-polymers, block co-polymers, tertpolymers, branched polymers, cyclo-polymers, and mixtures thereof.

45. The composition of claim 42, wherein the polymer is selected from the group consisting of dextran, polyethylene glycol, polyvinyl pyrrolidone, co-polymers of polyethylene glycol and polyvinyl pyrrolidone, polyvinyl alcohol, co-polymers of polyoxyethylene and polyoxypropylene, and mixtures thereof.

46. The composition of claim 42 wherein the polymer is a co-polymer of polyethylene glycol and polyvinyl pyrrolidone, and a co-polymer of polyoxyethylene and polyoxypropylene.

47. The composition of claim 42, wherein the microparticles are microspheres comprising greater than about 90% protein by weight.

48. The composition of claim 31, wherein the microparticles are microspheres comprising greater than about 95% protein by weight.

49. The composition of claim 31, wherein the microparticles are microspheres comprising greater than about 99% protein by weight.

50. The composition of claim 31, wherein the protein is selected from the group consisting of:

leuprolide acetate, luteinizing hormone releasing hormone (LHRH), (D-Tryp6)-LHRH, nafarelin acetate, insulin, sodium insulin, zinc insulin, proinsulin, C-peptide of insulin, a mixture of insulin and C-peptide of insulin, hybrid insulin cocrystals, protamine, lysozyme, alpha-lactalbumin, basic fibroblast growth factor (bFGF), beta-lactoglobulin, trypsin, carbonic anhydrase, ovalbumin, bovine serum albumin (BSA), human serum albumin (HSA), phosphorylase b, alkaline phosphatase, beta -galactosidase, IgG, fibrinogen, poly-L-lysine, IgM, DNA, desmopressin acetate™

, growth hormone releasing factor (GHRF), somatostatin, antide, Factor VIII, G-CSF/GM-CSF, human growth hormone (hGH), beta interferon, antithrombin III, alpha interferon, alpha interferon 2b, parathyroid hormone, and calcitonin.

51. The composition of claim 31, wherein the propellant is HFA P134a.

52. The composition of claim 31, wherein the propellant is HFA P227.

53. The composition of claim 31, wherein the fine particle fraction is at least 40%.

54. The composition of claim 31, wherein the microparticles are in suspension.

55. The composition of claim 54, wherein the microparticles remain in suspension for at least 10 seconds following agitation.

56. The composition of claim 31, wherein the microparticles further comprise a therapeutic molecule.

57. The composition of claim 56, wherein the therapeutic molecule is selected from the group consisting of:

albuterol, fluticazone, ipratropium bromide, beclamethasone, and other beta-agonists and steroids.

58. The composition of claim 56, wherein the therapeutic molecule is selected from the group consisting of:

betaxolol™

, diclofenac™

, doxorubicin, and rifampin™

.

59. The composition of claim 31, wherein the microparticles comprise a carbohydrate-based polymer.

60. The composition of claim 59, wherein the carbohydrate-based polymer comprises hetastarch.

61. The composition of claim 59, wherein the carbohydrate-based polymer comprises dextran sulfate.

62. A method for preparing a pulmonary preparation, comprising:

selecting a propellant having a known density, ρ

_propellant;

selecting a microparticle having a microparticle density ρ

_{microparticle} such that the ratio of ρ

_{microparticle} to ρ

_propellant is in the range of 0.05 to 30; and

contacting a plurality of the microparticles with the propellant to form the pulmonary preparation.

63. The method of claim 62, wherein the propellant is a hydrofluoroalkane propellant.

64. The method of claim 63, wherein the propellant is HFA P134a.

65. The method of claim 63, wherein the propellant is HFA P227.

66. The method of claim 62, wherein the ratio ρ

_{microparticle} to ρ

_propellant is in the range of 0.5 to 3.0.