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Claims for Patent: 7,442,388

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Claims for Patent: 7,442,388

Title:Phospholipid-based powders for drug delivery
Abstract: Phospholipid based powders for drug delivery applications are disclosed. The powders comprise a polyvalent cation in an amount effective to increase the gel-to-liquid crystal transition temperature of the particle compared to particles without the polyvalent cation. The powders are hollow and porous and are preferably administered via inhalation.
Inventor(s): Weers; Jeffry G. (Half Moon Bay, CA), Tarara; Thomas E. (Burlingame, CA), Dellamary; Luis A. (San Marcos, CA), Riess; Jean G. (Falicon, FR), Schutt; Ernest G. (San Diego, CA)
Assignee:
Application Number:09/851,226
Patent Claims: 1. A particulate composition for delivery to the pulmonary system, the composition comprising: particles comprising an active agent, a saturated phospholipid and a polyvalent cation, wherein the molar ratio of polyvalent cation to phospholipid is at least 0.05 and is sufficiently high to increase the gel-to-liquid crystal transition temperature of the particles compared to particles without the polyvalent cation such that the particles have a gel-to-liquid crystal transition temperature that is greater than room temperature by at least 20.degree. C.

2. A particulate composition according to claim 1 wherein said gel-to-liquid crystal transition temperature is greater than room temperature by at least 40.degree. C.

3. A particulate composition according to claim 1 further comprising a surfactant selected from the group consisting of nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof.

4. A particulate composition according to claim 3 wherein the surfactant is selected from the group consisting of sorbitan esters, ethoxylated sorbitan esters, fatty acids, salts, sugar esters, ethylene oxides, and combinations thereof.

5. A particulate composition according to claim 1 wherein the polyvalent cation is a divalent cation.

6. A particulate composition according to claim 5 wherein the divalent cation is selected from the group consisting of calcium, magnesium and zinc.

7. A particulate composition according to claim 5 wherein the molar ratio of divalent cation to phospholipid is 0.05-2.0.

8. A particulate composition according to claim 5 wherein the molar ratio of divalent cation to phospholipid is 0.25-1.0.

9. A particulate composition according to claim 8 wherein the divalent cation is calcium.

10. A particulate composition according to claim 9 wherein the molar ratio of calcium to phospholipid is about 0.50.

11. A particulate composition according to claim 1 wherein the phospholipid comprises a natural or synthetic lung surfactant.

12. A particulate composition according to claim 1 wherein the active agent is selected from the group consisting of nicotine, human growth hormone, parathyroid hormone, leuprolide, budesonide, tobramycin, albuterol, insulin, interferon alpha, interferon beta, amphotericin, fluticasone, salmeterol, formoterol, and salts thereof.

13. A particulate composition according to claim 1 further comprising a polymer selected from the group consisting of polysaccharides, polyvinyl alcohol, polyvinyl pyrrolidone, polylactides, polyglycolides, polyethylene glycol, and mixtures thereof.

14. A particulate composition according to claim 1 comprising particles having a mass median diameter of less than 20 microns.

15. A particulate composition according to claim 14 wherein the mass median diameter is within 0.5-5 microns.

16. A particulate composition according to claim 14 wherein the particles comprise an aerodynamic diameter of less than 10 microns.

17. A particulate composition according to claim 16 wherein the aerodynamic diameter is within 0.5-5 microns.

18. A particulate composition according to claim 1 comprising an emitted dose of at least 40%.

19. A particulate composition according to claim 1 comprising an emitted dose of at least 60%.

20. A particulate composition according to claim 1 comprising an emitted dose of at least 90%.

21. A particulate composition according to claim 1 further comprising a non-aqueous suspension medium.

22. A particulate composition according to claim 1 further comprising an excipient selected from the group consisting of amino acids, carbohydrates, inorganic salts, organic salts, carboxylic acids, and mixtures thereof.

23. A particulate composition according to claim 22 wherein the excipient is selected from the group consisting of hydrophobic amino acids, monosaccharides, disaccharides, polysaccharides, sodium citrate, citric acid, ammonium carbonate, ammonium acetate, and ammonium chloride.

24. A particulate composition according to claim 1 wherein the bulk density of the particulate composition is less than 0.5 g/cm.sup.3.

25. A particulate composition according to claim 24 wherein the bulk density of the particulate composition is less than 0.05 g/cm.sup.3.

26. A particulate composition comprising: particles comprising an active agent, a saturated phospholipid and a polyvalent cation, wherein the molar ratio of polyvalent cation to phospholipid is at least 0.05 and wherein the particles have a gel-to-liquid transition temperature at least 20.degree. C. higher than room temperature.

27. A particulate composition for delivery to the pulmonary system, the composition comprising porous particles comprising: 20-99.9% of a saturated phospholipid; a polyvalent cation; and 0.1-80% active agent; wherein the molar ratio of polyvalent cation to phospholipid is at least 0.05 and is sufficiently high to increase the gel-to-liquid crystal transition temperature of the particles compared to particles without the polyvalent cation such that the particles have a gel-to-liquid crystal transition temperature that is greater than room temperature by at least 20.degree. C.

28. A method of delivering an active agent to a patient in need thereof, the method comprising: administering to the respiratory tract of the patient an effective amount of particles comprising an active agent, a saturated phospholipid and a polyvalent cation, wherein the molar ratio of polyvalent cation to phospholipid is at least 0.05 and is sufficiently high to increase the gel-to-liquid crystal transition temperature of the particles compared to particles without the polyvalent cation such that the particles have a gel-to-liquid crystal transition temperature that is greater than room temperature by at least 20.degree. C.

29. A method according to claim 28 wherein the particulate composition comprises particles having a mass median diameter of less than 20 microns.

30. A method according to claim 29 wherein the mass median diameter is within 0.5-5 microns.

31. A method according to claim 29 wherein the particles comprise an aerodynamic diameter of less than 10 microns.

32. A method according to claim 31 wherein the aerodynamic diameter is within 0.5-5 microns.

33. A method according to claim 28 wherein the particles comprise polyvalent cation at a molar ratio of polyvalent cation:phospholipid of 0.25-1.0.

34. A method according to claim 33 wherein the polyvalent cation comprises calcium.

35. A method according to claim 32 wherein the particles comprise a bulk density of less than 0.5 g/cm.sup.3.

36. A method according to claim 35 wherein the active agent is selected from the group consisting of nicotine, human growth hormone, parathyroid hormone, leuprolide, budesonide, tobramycin, albuterol, insulin, interferon alpha, interferon beta, amphotericin, fluticasone, salmeterol, formoterol, and salts thereof.

37. A particulate composition according to claim 1 wherein the particles are hollow and porous.

38. A particulate composition according to claim 1 comprising 0.1-80% w/w of the active agent.

39. A particulate composition according to claim 26 wherein the particles are hollow and porous.

40. A particulate composition according to claim 26 wherein the particles have a gel-to-liquid transition temperature of at least 40.degree. C. higher than room temperature.

41. A particulate composition according to claim 26 wherein the phospholipid is selected from dipalmitoylphosphatidylcholine or distearoylphosphatidylcholine.

42. A particulate composition comprising: particles comprising a structural matrix comprising a saturated phospholipid and a polyvalent cation, wherein the molar ratio of polyvalent cation to phospholipid is at least 0.05 and is sufficiently high to increase the gel-to-liquid crystal transition temperature of the particles compared to particles without the polyvalent cation such that the particles have a gel-to-liquid crystal transition temperature that is greater than room temperature by at least 20.degree. C., and wherein the particles further comprise an active agent.

43. A particulate composition according to claim 42 wherein the phospholipid comprises dipalmitoylphosphatidylcholine or distearoylphosphatidylcholine.

44. A particulate composition according to claim 42 wherein the polyvalent cation is a divalent cation.

45. A particulate composition according to claim 44 wherein the divalent cation is selected from the group consisting of calcium, magnesium, and zinc.

46. A particulate composition according to claim 42 wherein the molar ratio of polyvalent cation to phospholipid is 0.05-2.0.

47. A particulate composition according to claim 42 wherein the molar ratio of polyvalent cation to phospholipid is 0.25-1.0.

48. A particulate composition according to claim 42 wherein the active agent is selected from the group consisting of nicotine, human growth hormone, parathyroid hormone, leuprolide, budesonide, tobramycin, albuterol, insulin, interferon alpha, interferon beta, amphotericin, fluticasone, salmeterol, formoterol, and salts thereof.

49. A particulate composition according to claim 44 wherein the divalent cation is calcium.

50. A particulate composition according to claim 49 wherein the molar ratio of calcium to phospholipid is about 0.50.

51. A particulate composition according to claim 42 wherein the particles have a gel-to-liquid crystal transition temperature at least 20.degree. C. higher than room temperature.

52. A particulate composition according to claim 42 wherein the particles have a gel-to-liquid crystal transition temperature at least 40.degree. C. higher than room temperature.

53. A particulate composition according to claim 1 wherein the phospholipid is a zwitterionic phospholipid.

54. A particulate composition according to claim 26 wherein the phospholipid is a zwitterionic phospholipid.

55. A particulate composition according to claim 27 wherein the phospholipid is a zwitterionic phospholipid.

56. A particulate composition according to claim 27 wherein the molar ratio of polyvalent cation to phospholipid is effective to increase the gel to liquid crystal transition temperature of the particles compared to particles without the polyvalent cation.

57. A particulate composition according to claim 27 wherein the particles are hollow.

58. A method according to claim 28 wherein the phospholipid is a zwitterionic phospholipid.

59. A particulate composition according to claim 42 wherein the phospholipid is a zwitterionic phospholipid.

60. A particulate composition for delivery to the pulmonary system, the composition comprising: particles comprising an active agent, a saturated phospholipid and a polyvalent cation, wherein the molar ratio of polyvalent cation to phospholipid is at least 0.05 and less than 2, whereby the gel-to-liquid crystal transition temperature of the particles is higher than particles without the polyvalent cation, and is greater than room temperature by at least 20.degree. C.

61. A particulate composition according to claim 60 wherein the molar ratio of divalent cation to phospholipid is from 0.25 to 1.

62. A particulate composition according to claim 60 wherein the polyvalent cation is a divalent cation.

63. A particulate composition according to claim 62 wherein the divalent cation is selected from the group consisting of calcium, magnesium and zinc.

64. A particulate composition according to claim 62 wherein the divalent cation is calcium.

65. A particulate composition according to claim 64 wherein the molar ratio of calcium to phospholipid is about 0.50.

66. A particulate composition according to claim 60 wherein the gel-to-liquid crystal transition temperature is greater than a storage temperature for the particulate composition by at least 20.degree. C.

67. A particulate composition according to claim 60 further comprising a surfactant selected from the group consisting of nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof.

68. A particulate composition according to claim 60 wherein the particles have a mass median diameter of less than 20 microns and an aerodynamic diameter of less than 10 microns.

69. A particulate composition according to claim 60 further comprising an excipient selected from the group consisting of amino acids, carbohydrates, inorganic salts, organic salts, carboxylic acids, and mixtures thereof.

70. A particulate composition according to claim 60 wherein the bulk density of the particulate composition is less than 0.5 g/cm.sup.3.

71. A method of making a temperature stable particulate composition for delivery to the pulmonary system, the method comprising: (a) forming a feedstock comprising a saturated phospholipid emulsion and an active agent; (b) adding a polyvalent cation to the feedstock in an amount sufficient to provide a molar ratio of polyvalent cation to phospholipid in the feedstock that is at least 0.05 and less than 2; and (c) drying the polyvalent cation containing feedstock to form porous particles having a gel-to-liquid crystal transition temperature that is higher than a storage room temperature of the porous particles by at least about 20.degree. C.

72. A method according to claim 71 wherein (b) comprises adding the polyvalent cation to the feedstock in an amount sufficient to provide a molar ratio of polyvalent cation to phospholipid in the feedstock that is from 0.25 to 1.

73. A method according to claim 71 wherein the polyvalent cation is a divalent cation.

74. A method according to claim 73 wherein the divalent cation is selected from the group consisting of calcium, magnesium and zinc.

75. A method according to claim 73 wherein the divalent cation is calcium.

76. A method according to claim 71 further comprising adding to the feedstock, a surfactant selected comprising nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof.

77. A method according to claim 71 further comprising adding to the feedetock a polymer selected from the group consisting of polysaccharides, polyvinyl alcohol, polyvinyl pyrrolidone, polylactides, polyglycolides, polyethylene glycol, and mixtures thereof.

78. A method according to claim 71 comprising drying the polyvalent ion comprising feedstock wherein the particles have a mass median diameter of less than 20 microns and an aerodynamic diameter of less than 10 microns.

79. A method according to claim 71 comprising adding an excipient to the feedstock, the excipient comprising amino acids, carbohydrates, inorganic salts, organic salts, carboxylic acids, and mixtures thereof.

80. A method according to claim 71 comprising drying the polyvalent cation comprising feedstock to provide a bulk density of the porous particles that is less than 0.5 g/cm.sup.3.
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