Claims for Patent: 6,524,557

Summary for Patent: 6,524,557

Title:	Aerosol formulations of peptides and proteins
Abstract:	A pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C.sub.8 -C.sub.16 fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide, which surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract. The invention also relates to methods of manufacturing such formulations and the use of such formulations in treating patients.
Inventor(s):	Backstrom; Kjell (Lund, SE), Dahlback; Magnus (Lund, SE), Johansson; Ann (Lund, SE), Kallstrand; Goran (Bjarred, SE), Lindqvist; Elisabet (Lund, SE)
Assignee:	AstraZeneca AB (Sodertalje, SE)
Application Number:	08/624,504
Patent Claims:	1. A pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C.sub.8 -C.sub.16 fatty acid salt, a bile salt, a single-chain phospholipid, or an alkyl saccharide, which surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract. 2. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the surfactant is a C.sub.8 -C.sub.16 fatty acid salt. 3. A pharmaceutical aerosol formulation as claimed in claim 2, wherein the fatty acid salt is selected from the sodium, potassium and lysine salts of caprylate (C.sub.8), caprate (C.sub.10), laurate (C.sub.12) and myristate (C.sub.14). 4. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the surfactant is a trihydroxy bile salt. 5. A pharmaceutical aerosol formulation as claimed in claim 4, wherein the bile salt is selected from the salts of cholic, glycocholic and taurocholic acids. 6. A pharmaceutical aerosol formulation as claimed in claim 5, wherein the bile salt is selected from the sodium and potassium salts of cholic, glycocholic and taurocholic acids. 7. A pharmaceutical aerosol formulation as claimed in claim 6, wherein the bile salt is sodium taurocholate. 8. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the surfactant is a single-chain phospholipid. 9. A pharmaceutical aerosol formulation as claimed in claim 8, wherein the surfactant is selected from lysophosphatidylcholines, lysophosphatidylglycerols, lysophosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylserines. 10. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the sufactant is selected from alkyl glucosides and alkyl maltosides. 11. A pharmaceutical aerosol formulation as claimed in claim 10, wherein the surfactant is selected from decyl glucoside and dodecyl maltoside. 12. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the propellant comprises 1,1,1,2-tetrafluoroethane (P134a); 1,1,1,2,3,3,3-heptafluoropropane (P227) or 1,1-difluoroethane (P152a). 13. A pharmaceutical aerosol formulation as claimed in claim 12, wherein the propellant comprises 1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227). 14. A pharmaceutical aerosol formulation as claimed in claim 13, wherein the propellant comprises a density-matched mixture of 1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227). 15. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the polypeptide is of molecular weight up to 40 kD. 16. A pharmaceutical aerosol formulation as claimed in claim 15, wherein the polypeptide is of molecular weight up to 30 kD. 17. A pharmaceutical aerosol formulation as claimed in claim 16, wherein the polypeptide is of molecular weight up to 25 kD. 18. A pharmaceutical aerosol formulation as claimed in claim 17, wherein the polypeptide is of molecular weight up to 15 kD. 19. A pharmaceutical aerosol formulation as claimed in claim 18, wherein the polypeptide is of molecular weight up to 10 kD. 20. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the polypeptide is a peptide hormone. 21. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the polypeptide is selected from the group consisting of insulin, glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing hormone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotropin, calcitonin, parathyroid hormone (PTH), bioactive fragments of PTH, growth hormone (GH), growth hormone releasing hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropin releasing hormone (TRH), deoxyribonuclease (DNase), prolactin, and follicle stimulating hormone (FSH), and biologically active analogues thereof. 22. A pharmaceutical aerosol formulation as claimed in claim 21, wherein the polypeptide is insulin. 23. A pharmaceutical aerosol formulation as claimed in claim 1, including ethanol in an amount of up to 20% by weight of propellant and surfactant. 24. A pharmaceutical aerosol formulation as claimed in claim 1, including ethanol in an amount of up to 5% by weight of propellant and surfactant. 25. A pharmaceutical aerosol formulation as claimed in claim 1, additionally comprising an additive selected from the group consisting of adjuvants, carriers, flavouring agents, buffers, antioxidants and chemical stabilisers. 26. A pharmaceutical aerosol formulation as claimed in claim 25, wherein the additive is selected from the group consisting of lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, a hydrate of any of the aforementioned carbohydrates, alanine, glycine, betaine, and albumen. 27. A pharmaceutical aerosol formulation as claimed in claim 26, wherein the additive is melezitose. 28. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the surfactant is present in a surfactant:polypeptide ratio in the range of 1:10 to 1:0.2. 29. A pharmaceutical aerosol formulation as claimed in claim 28, wherein the surfactant is present in a surfactant:polypeptide ratio in the range of 1:4 to 1:1. 30. A pharmaceutical aerosol formulation as claimed in claim 1, wherein at least 50% of the polypeptide consists of particles having a diameter of 0.01-10 microns. 31. A pharmaceutical aerosol formulation as claimed in claim 30, wherein at least 50% of the polypeptide consists of particles having a diameter of 0.1-6 microns. 32. A pharmaceutical aerosol formulation as claimed in claim 30, wherein at least 50% of the polypeptide consists of particles having a diameter of 0.1-5 microns. 33. A pharmaceutical aerosol formulation as claimed in claim 30, wherein at least 70% of the polypeptide consists of particles having a diameter of 0.01-10 microns. 34. A pharmaceutical aerosol formulation as claimed in claim 31, wherein at least 70% of the polypeptide consists of particles having a diameter of 0.1-6 microns. 35. A pharmaceutical aerosol formulation as claimed in claim 32, wherein at least 70% of the polypeptide consists of particles having a diameter of 0.1-5 microns. 36. A pharmaceutical aerosol formulation as claimed in claim 30, wherein at least 90% of the polypeptide consists of particles having a diameter of 0.01-10 microns. 37. A pharmaceutical aerosol formulation as claimed in claim 32, wherein at least 90% of the polypeptide consists of particles having a diameter of 0.1-5 microns. 38. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the concentration of polypeptide is 0.1 mg/ml to 25 mg/ml of the formulation. 39. A method for the manufacture of a pharmaceutical aerosol formulation as claimed in claim 1, comprising the steps of: mixing the polypeptide and the surfactant in an aqueous buffer; drying to give a solid powder; and mixing the powder and the propellant in a vessel. 40. A method as claimed in claim 39, wherein said mixing step is carried out by first mixing a portion of the propellant with the powder in the vessel, and then adding the remaining propellant to the vessel. 41. A method for the treatment of a patient in need of therapy with a given polypeptide, comprising administering to said patient a therapeutically effective amount of the pharmaceutical aerosol formulation of claim 1, provided that the pharmaceutically active polypeptide in the formulation is said given polypeptide. 42. A method as claimed in claim 41, wherein the surfactant is a C.sub.8 -C.sub.16 fatty acid salt. 43. A method as claimed in claim 41, wherein the fatty acid salt is selected from the sodium, potassium and lysine salts of caprylate (C.sub.8), caprate (C.sub.10), laurate (C.sub.12) and myristate (C.sub.14). 44. A method as claimed in claim 41, wherein the surfactant is a trihydroxy bile salt. 45. A method as claimed in claim 41, wherein the bile salt is selected from the salts of cholic, glycocholic and taurocholic acids. 46. A method as claimed in claim 41, wherein the bile salt is sodium taurocholate. 47. A method as claimed in claim 41, wherein the surfactant is a single-chain phospholipid. 48. A method as claimed in claim 41, wherein the surfactant is selected from alkyl glucosides and alkyl maltosides. 49. A method as claimed in claim 41, wherein the propellant comprises 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) or 1,1-difluoroethane (P152a). 50. A method as claimed in claim 41, wherein the propellant comprises a density-matched mixture of 1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227). 51. A method as claimed in claim 41, wherein the polypeptide is of molecular weight up to 40 kD. 52. A method as claimed in claim 41, wherein the polypeptide is of molecular weight up to 20 kD. 53. A method as claimed in claim 41, wherein the polypeptide is of molecular weight up to 10 kD. 54. A method as claimed in claim 41, wherein the polypeptide is a peptide hormone. 55. A method as claimed in claim 41, wherein the polypeptide is selected from insulin, glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing hormone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotropin, calcitonin, parathyroid hormone (PTH), bioactive fragments of PTH, growth hormone (GH), growth hormone releasing hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropin releasing hormone (TRH), deoxyribonuclease (DNase), prolactin, and follicle stimulating hormone (FSH), and biologically active analogues thereof. 56. A method as claimed in claim 41, wherein the polypeptide is insulin. 57. A method as claimed in claim 41, wherein the formulation further comprises ethanol in an amount of up to 20% by weight of propellant and surfactant. 58. A method as claimed in claim 41, wherein the formulation further comprises an additive selected from the group consisting of lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, a hydrate of any of the aforementioned carbohydrates, alanine, glycine, betaine, and albumen. 59. A method as claimed in claim 58, wherein the additive is melezitose. 60. A method as claimed in claim 41, wherein the surfactant is present in a surfactant:polypeptide ratio in the range of 1:10 to 1:0.2. 61. A method as claimed in claim 41, wherein at least 50% of the polypeptide is in the form of particles having a diameter of 0.01-10 microns. 62. A pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C.sub.8 -C.sub.16 fatty acid salt, a bile salt, a phospholipid, or an alkyl saccharide, wherein the surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract and the surfactant is dispersed in the propellant as solid particles. 63. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the surfactant is a C.sub.8 -C.sub.16 fatty acid salt. 64. A pharmaceutical aerosol formation as claimed in claim 63, wherein the fatty acid salt is selected from the sodium, potassium and lysine salts of caprylate (C.sub.8), caprate (C.sub.10), laurate (C.sub.12) and myristate (C.sub.14). 65. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the surfactant is a trihydroxy bile salt. 66. A pharmaceutical aerosol formulation as claimed in claim 65, wherein the bile salt is selected from the salts of cholic, glycocholic and taurocholic acids. 67. A pharmaceutical aerosol formulation as claimed in claim 66, wherein the bile salt is selected from the sodium and potassium salts of cholic, glycocholic and taurocholic acids. 68. A pharmaceutical aerosol formulation as claimed in claim 67, wherein the bile salt is sodium taurocholate. 69. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the surfactant is a single-chain phospholipid. 70. A pharmaceutical aerosol formulation as claimed in claim 69, wherein the surfactant is selected from lysophosphatidylcholines, lysophosphatidylglycerols, lysophosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylserines. 71. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the surfactant is a double-chain phospholipid. 72. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the surfactant is selected from the group consisting of diacylphosphatidylcholines, diacylphosphatidylglycerols, diacylphosphatidylethanolamines, diacylphosphatidylinositols and diacylphosphatidylserines. 73. A pharmaceutical aerosol formulation as claimed in claim 72, wherein the surfactant is selected from dioctanoylphosphatidylglycerol and dioctanoylphosphatidylcholine. 74. A pharmaceutical aerosol formulation as claimed in claim 72, wherein the surfactant is selected from alkyl glucosides and alkyl maltosides. 75. A pharmaceutical aerosol formulation as claimed in claim 74, wherein the surfactant is selected from decyl glucoside and dodecyl maltoside. 76. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the propellant comprises 1,1,1,2-tetrafluoroethane (P134a); 1,1,1,2,3,3,3-heptafluoropropane (P227) or 1,1-difluoroethane (P152a). 77. A pharmaceutical aerosol formulation as claimed in claim 76, wherein the propellant comprises 1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227). 78. A pharmaceutical aerosol formulation as claimed in claim 77, wherein the propellant comprises a density-matched mixture of ,1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227). 79. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the polypeptide is of molecular weight up to 40 kD. 80. A pharmaceutical aerosol formulation as claimed in claim 79, wherein the polypeptide is of molecular weight up to 30 kD. 81. A pharmaceutical aerosol formulation as claimed in claim 80, wherein the polypeptide is of molecular weight up to 25 kD. 82. A pharmaceutical aerosol formulation as claimed in claim 81, wherein the polypeptide is of molecular weight up to 15 kD. 83. A pharmaceutical aerosol formulation as claimed in claim 82, wherein the polypeptide is of molecular weight up to 10 kD. 84. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the polypeptide is a peptide hormone. 85. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the polypeptide is selected from the group consisting of glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing hormone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotropin, calcitonin, parathyroid hormone (PTH), bioactive fragments of PTH, growth hormone (GH), growth hormone releasing hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropin releasing hormone (TRH), deoxyribonuclease (DNase), prolactin, and follicle stimulating hormone (FSH), and biologically active analogues thereof. 86. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the polypeptide is insulin. 87. A pharmaceutical aerosol formulation as claimed in claim 62, including ethanol in an amount of up to 20% by weight of propellant and surfactant. 88. A pharmaceutical aerosol formulation as claimed in claim 62, including ethanol in an amount of up to 5% by weight of propellant and surfactant. 89. A pharmaceutical aerosol formulation as claimed in claim 62, additionally comprising an additive selected from the group consisting of adjuvants, carriers, flavouring agents, buffers, antioxidants and chemical stabilisers. 90. A pharmaceutical aerosol formulation as claimed in claim 89, wherein the additive is selected from the group consisting of lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, a hydrate of any of the aforementioned carbohydrates, alanine, glycine, betaine, and albumen. 91. A pharmaceutical aerosol formulation as claimed in claim 90, wherein the additive is melezitose. 92. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the surfactant is present in a surfactant:polypeptide ratio in the range of 1:10 to 1:0.2. 93. A pharmaceutical aerosol formulation as claimed in claim 92, wherein the surfactant is present in a surfactant:polypeptide ratio in the range of 1:4 to 1:1. 94. A pharmaceutical aerosol formulation as claimed in claim 62, wherein at least 50% of the polypeptide consists of particles having a diameter of 0.01-10 microns. 95. A pharmaceutical aerosol formulation as claimed in claim 94, wherein at least 50% of the polypeptide consists of particles having a diameter of 0.1-6 microns. 96. A pharmaceutical aerosol formulation as claimed in claim 94, wherein at least 50% of the polypeptide consists of particles having a diameter of 0.1-5 microns. 97. A pharmaceutical aerosol formulation as claimed in claim 94, wherein at least 70% of the polypeptide consists of particles having a diameter of 0.01-10 microns. 98. A pharmaceutical aerosol formulation as claimed in claim 95, wherein at least 70% of the polypeptide consists of particles having a diameter of 0.1-6 microns. 99. A pharmaceutical aerosol formulation as claimed in claim 96, wherein at least 70% of the polypeptide consists of particles having a diameter of 0.1-5 microns. 100. A pharmaceutical aerosol formulation as claimed in claim 94, wherein at least 90% of the polypeptide consists of particles having a diameter of 0.01-10 microns. 101. A pharmaceutical aerosol formulation as claimed in claim 96, wherein at least 90% of the polypeptide consists of particles having a diameter of 0.1-5 microns. 102. A pharmaceutical aerosol formulation as claimed in claim 62, wherein the concentration of polypeptide is 0.1 mg/ml to 25 mg/ml of the formulation. 103. A method for the manufacture of a pharmaceutical aerosol formulation as claimed in claim 62, comprising the steps of: mixing the polypeptide and the surfactant in an aqueous buffer; drying to give a solid powder; and mixing the powder and the propellant in a vessel. 104. A method as claimed in claim 103, wherein said mixing step is carried out by first mixing a portion of the propellant with the powder in the vessel, and then adding the remaining propellant to the vessel. 105. A method for the treatment of a patient in need of therapy with a given polypeptide, comprising administering to said patient a therapeutically effective amount of the pharmaceutical aerosol formulation of claim 62, provided that the pharmaceutically active polypeptide in the formulation is said given polypeptide. 106. A method as claimed in claim 104, wherein the surfactant is a C.sub.8 -C.sub.16 fatty acid salt. 107. A method as claimed in claim 104, wherein the fatty acid salt is selected from the sodium, potassium and lysine salts of caprylate (C.sub.8), caprate (C.sub.10), laurate (C.sub.12) and myristate (C.sub.14). 108. A method as claimed in claim 104, wherein the surfactant is a trihydroxy bile salt. 109. A method as claimed in claim 104, wherein the bile salt is selected from the salts of cholic, glycocholic and taurocholic acids. 110. A method as claimed in claim 104, wherein the bile salt is sodium taurocholate. 111. A method as claimed in claim 104, wherein the surfactant is a single-chain phospholipid. 112. A method as claimed in claim 104, wherein the surfactant is a double-chain phospholipid. 113. A method as claimed in claim 104, wherein the surfactant is selected from dioctanoylphosphatidylglycerol and dioctanoylphosphatidylcholine. 114. A method as claimed in claim 105, wherein the surfactant is selected from alkyl glucosides and alkyl maltosides. 115. A method as claimed in claim 105, wherein the propellant comprises 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) or 1,1-difluoroethane (P152a). 116. A method as claimed in claim 105, wherein the propellant comprises a density-matched mixture of 1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227). 117. A method as claimed in claim 105, wherein the polypeptide is of molecular weight up to 40 kD. 118. A method as claimed in claim 105, wherein the polypeptide is of molecular weight up to 20 kD. 119. A method as claimed in claim 105, wherein the polypeptide is of molecular weight up to 10 kD. 120. A method as claimed in claim 105, wherein the polypeptide is a peptide hormone. 121. A method as claimed in claim 105, wherein the polypeptide is selected from glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing hormone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotropin, calcitonin, parathyroid hormone (PTH), bioactive fragments of PTH, growth hormone (GH), growth hormone releasing hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropin releasing hormone (TRH), deoxyribonuclease (DNase), prolactin, and follicle stimulating hormone (FSH), and biologically active analogues thereof. 122. A method as claimed in claim 105, wherein the polypeptide is insulin. 123. A method as claimed in claim 105, wherein the formulation further comprises ethanol in an amount of up to 20% by weight of propellant and surfactant. 124. A method as claimed in claim 105, wherein the formulation further comprises an additive selected from the group consisting of lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, a hydrate of any of the aforementioned carbohydrates, alanine, glycine, betaine, and albumen. 125. A method as claimed in claim 124, wherein the additive is melezitose. 126. A method as claimed in claim 105, wherein the surfactant is present in a surfactant:polypeptide ratio in the range of 1:10 to 1:0.2. 127. A method as claimed in claim 105, wherein at least 50% of the polypeptide is in the form of particles having a diameter of 0.01-10 microns.

Details for Patent 6,524,557

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2014-12-22