FORMULATIONS FOR DELIVERING INSULIN

• US 20100151009A1
• Filed: 04/12/2007
• Published: 06/17/2010
• Est. Priority Date: 04/12/2006
• Status: Active Grant

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Levchik, Halina
• Granted Patent: US 8,927,015 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2063 Proteins, e.g. gelatin
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00

Abstract

Oral insulin formulations and processes for preparing oral insulin formulations are provided.

Claims

1. A solid oral dosage form comprising

(a) sodium 4-CNAB;

(b) about 150 Units of insulin;

wherein the dosage form exhibits an average Cmax of insulin greater than 5 μ

U/ml after oral administration in a human.

2. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 7 μ

U/ml after oral administration in a human.

3. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 10 μ

U/ml after oral administration in a human.

4. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 12 μ

U/ml after oral administration in a human.

5. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 15 μ

U/ml after oral administration in a human.

6. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 20 μ

U/ml after oral administration in a human.

7. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 25 μ

U/ml after oral administration in a human.

8. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 30 μ

U/ml after oral administration in a human.

9. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 35 μ

U/ml after oral administration in a human.

10. The solid dosage form of claim 1, wherein the dosage form exhibits an average Cmax greater than 40 μ

U/ml after oral administration in a human.

61. The solid dosage form of any one of claims 1-60 wherein the 4-CNAB and insulin are lyophilized together.

62. The solid dosage form of any one of claims 1-60 wherein the 4-CNAB and insulin are rotary evaporated together.

63. The solid dosage form of any one of claims 1-60 wherein the dosage form is in the form of a gel prior to being tableted or filled in a capsule.

64. The solid dosage form of claim 63 wherein the dosage form comprises a gelatin.

82. The pharmaceutical compositions of any one claims 1-70 prepared by the process of any one of claims 71-80.

11. A solid oral dosage form comprising

(a) sodium 4-CNAB;

(b) about 75 Units of insulin;

wherein the dosage form exhibits an average Cmax of insulin greater than 3 μ

U/ml after oral administration in a human.

12. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 4 μ

U/ml after oral administration in a human.

13. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 5 μ

U/ml after oral administration in a human.

14. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 6 μ

U/ml after oral administration in a human.

15. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 8 μ

U/ml after oral administration in a human.

16. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 10 μ

U/ml after oral administration in a human.

17. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 13 μ

U/ml after oral administration in a human.

18. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 15 μ

U/ml after oral administration in a human.

19. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 13 μ

U/ml after oral administration in a human.

20. The solid dosage form of claim 11, wherein the dosage form exhibits an average Cmax greater than 20 μ

U/ml after oral administration in a human.

21. A solid oral dosage form comprising

(a) sodium 4-CNAB;

(b) insulin;

wherein the dosage form exhibits an average Cmax greater than 0.033 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

22. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.0466 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

23. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.0666 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

24. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.08 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

25. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.1 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

26. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.13331 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

27. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.1666 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

28. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.2 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

29. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.2333 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

30. The solid dosage form of claim 21, wherein the dosage form exhibits an average Cmax greater than 0.2666 μ

U/ml per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

31. A solid oral dosage form comprising

(a) sodium 4-CNAB;

(b) about 150 Units of insulin;

wherein the dosage form exhibits an average insulin AUC greater than 100 μ

U/ml*min after oral administration in a human.

32. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 200 μ

U/ml*min after oral administration in a human.

33. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 300 μ

U/ml*min after oral administration in a human.

34. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 400 μ

U/ml*min after oral administration in a human.

35. The solid dosage form of claim 31 wherein the dosage form exhibits an average insulin AUC greater than 500 μ

U/ml*min after oral administration in a human.

36. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 550 μ

U/ml*min after oral administration in a human.

37. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 600 μ

U/ml*min after oral administration in a human.

38. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 650 μ

U/ml*min after oral administration in a human.

39. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 700 μ

U/ml*min after oral administration in a human.

40. The solid dosage form of claim 31, wherein the dosage form exhibits an average insulin AUC greater than 750 μ

U/ml*min after oral administration in a human.

41. A solid oral dosage form comprising

(a) sodium 4-CNAB;

(b) about 75 Units of insulin;

wherein the dosage form exhibits an average insulin AUC greater than 50 μ

U/ml*min after oral administration in a human.

42. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 100 μ

U/ml*min after oral administration in a human.

43. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 150 μ

U/ml*min after oral administration in a human.

44. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 200 μ

U/ml*min after oral administration in a human.

45. The solid dosage form of claim 41 wherein the dosage form exhibits an average insulin AUC greater than 250 μ

U/ml*min after oral administration in a human.

46. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 275 μ

U/ml*min after oral administration in a human.

47. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 300 μ

U/ml*min after oral administration in a human.

48. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 325 μ

U/ml*min after oral administration in a human.

49. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 350 μ

U/ml*min after oral administration in a human.

50. The solid dosage form of claim 41, wherein the dosage form exhibits an average insulin AUC greater than 375 μ

U/ml*min after oral administration in a human.

51. A solid oral dosage form comprising

(a) sodium 4-CNAB;

(b) insulin;

wherein the dosage form exhibits an average insulin AUC greater than 0.666 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

52. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 1.333 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

53. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 2 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

54. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 2.666 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

55. The solid dosage form of claim 51 wherein the dosage form exhibits an average insulin AUC greater than 3.333 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

56. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 3.666 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

57. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 4 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

58. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 4.333 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

59. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 4.666 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

60. The solid dosage form of claim 51, wherein the dosage form exhibits an average insulin AUC greater than 5 μ

U/ml*min per Unit of orally administered insulin after oral administration of the solid dosage form in a human.

65. A solid dosage form wherein a delivery agent is lyophilized with insulin.

70. The compositions of any one of claims 65-69 wherein the delivery agent is 4-CNAB.

66. A solid dosage form wherein a delivery agent is rotary evaporated with insulin.

67. A composition wherein a delivery agent and insulin is in the form of a gel.

68. A solid dosage form wherein a delivery agent and insulin is in the form of a gel prior to being tableted or filled in a capsule.

69. The solid dosage form of claim 68 comprising a gelatin.

71. A process to prepare an oral insulin pharmaceutical formulation comprising

(a) introducing insulin to an aqueous solution that contains a delivery agent compound,

(b) drying the solution to obtain an insulin/delivery agent powder,

(c) optionally granulating the powder with intragranular excipients,

(d) optionally adding extragranular excipients to the powder or granules, and

(e) forming a unit dosage form from the resulting composition.

72. The process of claim 71 wherein forming a unit dosage form comprises compressing the composition into tablets.

73. The process of claim 71 wherein forming a unit dosage form comprises filling capsules with the resulting composition.

79. The process of any one of claim 71-78 wherein the delivery agent is 4-CNAB or a salt therof.

80. The process of claim 79 wherein the delivery agent is sodium 4-CNAB.

74. A process for preparing an oral insulin pharmaceutical composition comprising the steps of

(a) preparing an insulin/delivery agent solution;

(b) freeze-drying the insulin/delivery agent solution;

(c) milling the insulin/delivery agent colyophilized powder obtained by freeze-drying the insulin/delivery agent solution;

(d) mixing the milled co-lyophilized powder with intragranular excipients;

(e) performing dry granulation,

(f) adding extragranular excipients; and

(g) forming a unit dosage form from the resulting composition.

75. A process for preparing an oral insulin pharmaceutical compositions comprising the steps of

(a) preparing an insulin/delivery agent solution;

(b) performing rotary evaporation on the insulin/delivery agent solution; and

(c) forming a unit dosage form from the rotary evaporated insulin/delivery agent solution.

76. The process of claim 75 further comprising at least one of the steps of (c) milling the insulin/delivery agent powder obtained by rotary evaporation of the insulin/delivery agent solution;

(d) mixing the milled powder with intragranular excipients;

(e) granulating the milled powder and intragranular excipients; and

(f) adding extragranular excipients.

77. A process for preparing an oral insulin pharmaceutical compositions comprising the step of mixing a gelling agent with (a) a delivery agent compound and (b) insulin or an insulin analog.

78. The process of claim 77 wherein the gelling agent is gelatin.

81. A a pharmaceutical composition comprising (a) insulin or an insulin analog, (b) a delivery agent and (c) gelatin.

83. A method for solubilizing a biologically active agent without subtantially degrading the biologically active agent comprising adding the biologically active agent to a solution containing a delivery agent.

84. The method of claim 83 wherein the biologically active agent is selected from acyclovir, BIBN-4096BS, growth hormones, human growth hormones recombinant human growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone releasing hormones, growth hormone releasing factor, glucagon, interferons, α

-interferon, β

-interferon, γ

-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin;

erythropoietin (EPO), atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoeitin, filgrastim. postaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), fragments of PTH, glucagon-like peptide 1 (GLP-1), antimicrobials, anti-fungal agents, vitamins;

analogs, fragments, mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds;

gallium or gallium salts;

glucagons;

zanamivir, sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, caspofungin acetate and any combination thereof.

85. The method of claim 84 wherein the biologically active agent is a protein.

86. The method of claim 85 wherein the protein is larger than 4000 daltons.

87. The method of claim 85 wherein the protein is larger than 5500 daltons.

88. The method of claim 85 wherein the protein is larger than 10,000 daltons.

89. The method of claim 85 wherein the protein is larger than 15,000 daltons.

90. The method of claim 84 wherein the biologically active agent is insulin.

91. The method of claim 84 wherein the biologically active agent is acyclovir.