Pharmaceutical compositions and methods for the oral delivery of insulin

• US 8,309,123 B2
• Filed: 12/19/2008
• Issued: 11/13/2012
• Est. Priority Date: 12/19/2007
• Status: Active Grant

• Current Assignee: Farid Bennis
• Original Assignee: Farid Bennis
• Inventors: Bennis, Farid, Serrano, Jean Jacques
• Primary Examiner(s): Russel, Jeffrey E
• Application Number:
  US12/339,310
• Publication Number:
  US 20090176691A1
• Time in Patent Office: 1,425 Days
• Field of Search: None
• US Class Current: 424/464
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/0007 Effervescent A61K9/0065 takes precedence
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention relates to pharmaceutical compositions containing at least one protein active ingredient protected from digestive enzymes. The pharmaceutical compositions contain the at least one protein active ingredient, in free form, as well as, for liquids, a system that buffers them to a pH greater than 4 and less than or equal to 8 or, for solids, a system that exerts, when they are placed in a liquid medium, a buffer effect between a pH greater than 4 and a pH less than or equal to 8.

Claims

1. A pharmaceutical composition, in tablet form, for administration of at least one protein active ingredient sensitive to digestive enzymes, comprising at least one protein active ingredient selected from insulin, Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, and a buffer system capable of protecting the protein active ingredient from digestive enzymes and buffering the composition to a pH greater than, or equal to, 5 and less than, or equal to, 7, wherein the composition is free of any component;

other than the buffer system, that acts to protect the active ingredient from the digestive enzymes.

2. The pharmaceutical composition according to claim 1, wherein the buffer system is selected from phosphate, acetate, maleate, phthalate, succinate, citrate, imidazole, tetrabutylammonium, trihydroxymethylaminomethane, tris-glycine, barbitol, tris-EDTA, BSA, copper sulfate or zwitterionic buffers.

3. The pharmaceutical composition according to claim 1, wherein the composition is formulated in unit form.

4. The pharmaceutical composition according to claim 1, wherein the buffer system is formulated separately from the at least one protein active ingredient.

5. The pharmaceutical composition according to claim 1, wherein the buffer pH is 6.5+/−

0.2.

6. The pharmaceutical composition according to claim 1, wherein the buffer system is a phosphate buffer.

7. The pharmaceutical composition according to claim 1, wherein the at least one protein active ingredient is insulin.

8. The pharmaceutical composition according to claim 1, wherein the at least one protein active ingredient is insulin, the buffer system is a phosphate buffer and the buffer pH is 6.5+/−

0.2.

9. The pharmaceutical composition according to claim 1, wherein the at least one protein active ingredient is insulin, the buffer system is a phosphate buffer and the buffer pH is 6.8.

10. The pharmaceutical composition according to claim 1, wherein the at least one protein active ingredient is Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin.

11. The pharmaceutical composition according to claim 1, wherein the tablet form is in a dispersible tablets form.

12. The pharmaceutical composition according to claim 1, wherein the tablet form is in an effervescent tablets form.

13. The pharmaceutical composition according to claim 1, wherein the at least one protein active ingredient is Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, the buffer system is a phosphate buffer and the buffer pH is 6.5+/−

0.2.

14. A method for administering at least one protein active ingredient, which is sensitive to digestive enzymes, to a patient suffering from diabetes, wherein the at least one protein active ingredient is selected from insulin, Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, the method comprising administering a pharmaceutical composition in tablet form comprising at least one protein active ingredient and a buffer system capable of buffering the composition to a pH greater than, or equal to, 5 and less than, or equal to, 7;

wherein the composition is free of any component, other than the buffer system, that acts to protect the active ingredient from the digestive enzymes.

15. The method according to claim 14, wherein the at least one protein active ingredient is insulin.

16. The method according to claim 14, wherein the at least one protein active ingredient is Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin.

17. The method according to claim 14, wherein the buffer system is selected from phosphate, acetate, maleate, phthalate, succinate, citrate, imidazole, tetrabutylammonium, trihydroxymethylaminomethane, tris-glycine, barbitol, tris-EDTA, BSA, copper sulfate or zwitterionic buffers.

18. The method according to claim 14, wherein the buffer system is a phosphate buffer.

19. The method according to claim 14, wherein the buffer pH is 6.5+/−

0.2.

20. The method according to claim 14, wherein the at least one protein active ingredient is insulin, the buffer system is a phosphate buffer and the buffer pH is 6.5+/−

0.2.

21. The method according to claim 14, wherein the at least one protein active ingredient is Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, the buffer system is a phosphate buffer and the buffer pH is 6.5+/−

0.2.

22. The method according to claim 14, wherein the composition is formulated in unit form.

23. The method according to claim 14, wherein the tablet form is in a dispersible tablets form.

24. The method according to claim 14, wherein the tablet form is in an effervescent tablets form.

25. The method according to claim 14, wherein the buffer system is formulated separately from the at least one protein active ingredient.

26. A method for reducing glycemia in a patient suffering from diabetes, the method comprising administering a pharmaceutical composition in tablet form comprising at least one protein active ingredient which is sensitive to digestive enzymes and is selected from insulin, Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin and a buffer system capable of buffering the composition to a pH greater than, or equal to, 5 and less than, or equal to, 7, wherein the composition is free of any component, other than the buffer system, that acts to protect the active ingredient from the digestive enzymes.

27. The method according to claim 26, wherein the at least one protein active ingredient is insulin.

28. The method according to claim 26, wherein the at least one protein active ingredient is Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin.

29. The method according to claim 26, wherein the buffer system is selected from phosphate, acetate, maleate, phthalate, succinate, citrate, imidazole, tetrabutylammonium, trihydroxymethylaminomethane, tris-glycine, barbitol, tris-EDTA, BSA, copper sulfate or zwitterionic buffers.

30. The method according to claim 26, wherein the buffer system is a phosphate buffer.

31. The method according to claim 26, wherein the buffer pH is 6.5+/−

0.2.

32. The method according to claim 26, wherein the at least one protein active ingredient is insulin, the buffer system is a phosphate buffer and the buffer pH is 6.5+/−

0.2.

33. The method according to claim 26, wherein the at least one protein active ingredient is Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, the buffer system is a phosphate buffer and the buffer pH is 6.5+/−

0.2.

34. The method according to claim 26, wherein the composition is formulated in unit form.

35. The method according to claim 26, wherein the tablet form is in a dispersible tablet form.

36. The method according to claim 35, wherein the tablet form is in an effervescent tablets form.

37. The method of claim 26, wherein the buffer system is formulated separately from the at least one protein active ingredient.

38. A method for treating diabetes comprising administering to a patient a pharmaceutical composition in tablet form comprising at least one protein active ingredient which is sensitive to digestive enzymes and is selected from insulin, Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, and at least one buffer system capable of buffering the composition to a pH greater than, or equal to, 5 and less than, or equal to, 7, wherein the composition is free of any component, other than the buffer system, that acts to protect the active ingredient from the digestive enzymes.

39. A method for orally administering to a patient suffering from diabetes at least one protein active ingredient, the method comprising administering a pharmaceutical composition comprising at least one protein active ingredient, wherein the at least one protein active ingredient is selected from insulin, Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, and a buffer system capable of buffering the composition to a pH greater than, or equal to, 5 and less than, or equal to, 7;

wherein the composition is free of any component, other than the buffer system, that acts to protect the active ingredient from the digestive enzymes.

42. The method according to claim 39, wherein the buffer pH is about 6.5.

43. The method according to claim 39, wherein the buffer pH is about 6.8.

40. A method for reducing glycemia in a patient suffering from diabetes comprising orally administering a pharmaceutical composition comprising at least one protein active ingredient which is sensitive to digestive enzymes and is selected from insulin, Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, and a buffer system capable of buffering the composition to a pH greater than, or equal to, 5 and less than, or equal to, 7;

wherein the composition is free of any component, other than the buffer system, that acts to protect the active ingredient from the digestive enzymes.

44. The method according to claim 40, wherein the buffer pH is about 6.5.

45. The method according to claim 40, wherein the buffer pH is about 6.8.

41. A solid pharmaceutical composition for oral administration of at least one protein active ingredient sensitive to digestive enzymes, comprising at least one protein active ingredient selected from insulin, Lispro insulin, Aspart insulin, Glargine insulin or Detemir insulin, and a buffer system capable of protecting the protein active ingredient from digestive enzymes and buffering the composition to a pH greater than, or equal to, 5 and less than, or equal to, 7, wherein the composition is free of any component, other than the buffer system, that acts to protect the active ingredient from the digestive enzymes.