Sustained-release delayed gels

• US 20030072803A1
• Filed: 11/20/2002
• Published: 04/17/2003
• Est. Priority Date: 05/16/1997
• Status: Abandoned Application

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Beekman, Alice C., Goldenberg, Merrill Seymour, Gu, Jian Hua
• Application Number:
  US10/301,360
• Publication Number:
  US 20030072803A1
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• 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

Abstract

The present invention relates to sustained-release formulations using alginate delayed gels and methods thereof.

Claims

1. A sustained-release delayed gel composition, comprising:

a) a hydrophilic polymer;

b) a biologically active agent; and

c) at least one bound polyvalent metal ion.

2. The sustained-release composition of claim 1 further comprising (d) at least one proton donor capable of freeing the bound polyvalent metal ion.

3. The sustained-release composition of claim 1 or 2 wherein the bound polyvalent metal ion is a mixture of bound and unbound polyvalent metal ion.

4. The sustained-release composition of claim 1 or 2 further comprising excipients for stabilizing the biologically active agent or the hydrophilic polymer.

5. The composition of claim 1 or 2 wherein the bound polyvalent metal ion is a salt selected from the group consisting of acetates, phosphates, lactates, tartrates, citrates, chlorides, sulfates, carbonates, hydroxides or fatty acid anions thereof.

6. The composition of claim 5 wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, copper, aluminum or zinc.

7. The composition of claim 6 wherein the metal ion is calcium.

8. The composition of claim 1 or 2 wherein the hydrophilic polymer is a polyanion.

9. The composition of claim 1 or 2 wherein the hydrophilic polymer is a polysaccharide.

10. The composition of claim 9 wherein the polysaccharide is an acidic polysaccharide.

11. The composition of claim 10 wherein the polysaccharide is alginate.

12. The composition of claim 11 wherein the alginate contains at least 30% guluronic acid.

13. The composition of claim 11 wherein the alginate consists of at least 0.05% by weight.

14. The composition of claim 1 or 2 wherein the biologically active agent comprises a protein.

15. The composition of claim 14 wherein the protein consists of at least 0.001 mg/ml.

16. The composition of claim 14 wherein the protein is selected from the group consisting of hematopoetic factors, colony stimulating factors, anti-obesity factors, growth factors, trophic factors, and antiinflammatory factors.

17. The composition of claim 14 wherein the protein is selected from the group consisting of leptin, G-CSF, SCF, BDNF, GDNF, NT3, GM-CSF, IL-1ra, IL2, TNF-bp, MGDF, OPG, interferons, erythropoietin, KGF, insulin and analogs or derivatives thereof.

18. The composition of claim 1 or 2 wherein the biologically active agent is a complexed biologically active agent.

19. The composition of claim 18 wherein the complexed biologically active agent is a precipitated protein.

20. The composition of claim 19 wherein the precipitated protein is a zinc leptin precipitate.

21. The composition of claim 2 wherein the proton donor is from an acid source.

22. The composition of claim 21 wherein the acid source is selected from the group consisting of buffers, esters, slowly dissolving acids or lactones.

45. A pharmaceutical formulation comprising the sustained-release composition according to claims 1 or 2 in a pharmaceutically acceptable carrier, diluent or adjuvant.

46. The pharmaceutical formulation of claim 45, wherein the formulation is in a syringe.

47. A method of treating an indication with a sustained-release composition according to claims 1 or 2 in a pharmaceutically acceptable carrier, diluent or adjuvant.

48. A method of treatment of a disorder selected from the group consisting of excess weight, diabetes, high blood lipid level, artherial sclerosis, artherial plaque, the reduction or prevention of gall stones formation, insufficient lean tissue mass, insufficient sensitivity to insulin, and stroke, with a sustained-release composition according to claims 1 or 2 in a pharmaceutically acceptable carrier, diluent, or adjuvant wherein the biologically active agent is leptin, an analog or derivative thereof.

49. A method of treating a disorder selected from the group consisting of hematopoietic cell deficiencies, infection, and neutropenia with a sustained-release composition according to claims 1 or 2 in a pharmaceutically acceptable carrier, diluent, or adjuvant wherein the biologically active agent is GCSF, an analog or derivative thereof.

50. A method of treating inflammation with a sustained-release composition according to claims 1 or 2 in a pharmaceutically acceptable carrier, diluent, or adjuvant, wherein the biologically active agent is IL-1ra, an analog or derivative thereof.

23. A method of producing a sustained-release delayed gel composition, comprising the steps of:

a) mixing a biologically active agent and a hydrophilic polymer in a solvent to form a first mixture; and

b) mixing to the first mixture at least one bound polyvalent metal ion to form a second mixture.

24. The method of claim 23 further comprising the step of c) mixing to the second mixture at least one proton donor capable of releasing the bound polyvalent metal ion.

25. The method of claim 23 or 24 wherein the bound polyvalent metal ion is a salt selected from the group consisting of acetates, phosphates, lactates, citrates, sulfates, tartrates, chlorides, carbonates, hydroxides or fatty acid anions thereof.

26. The method of claim 25 wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, copper, aluminum or zinc.

27. The method of claim 26 wherein the metal ion is calcium.

28. The method of claim 23 or 24 wherein the hydrophilic polymer is a polyanion.

29. The method of claim 23 or 24 wherein the hydrophilic polymer is a polysaccharide.

30. The method of claim 29 wherein the polysaccharide is an acidic polysaccharide.

31. The method of claim 30 wherein the polysaccharide is alginate.

32. The method of claim 31 wherein the alginate contains at least 30% guluronic acid.

33. The method of claim 31 wherein the alginate consists of at least 0.05% by weight.

34. The method of claim 23 or 24 wherein the biologically active agent comprises a protein.

35. The method of claim 34 wherein the protein consists of at least 0.001 mg/ml.

36. The method of claim 34 wherein the protein is selected from the group consisting of hematopoetic factors, colony stimulating factors, anti-obesity factors, growth factors, trophic factors, and antiinflammatory factors.

37. The method of claim 34 wherein the protein is selected from the group consisting of leptin, G-CSF, SCF, BDNF, GDNF, NT3, GM-CSF, IL-1ra, IL2, TNF-bp, MGDF, OPG, interferons, erythropoietin, KGF and analogs or derivatives thereof.

38. The method of claim 23 or 24 wherein the biologically active agent is a complexed biologically active agent.

39. The method of claim 38 wherein the complexed biologically active agent is a precipitated protein.

40. The method of claim 39 wherein the precipitated protein is a zinc leptin precipitate.

41. The method of claim 23 or 24 further comprising the step of isolating the sustained-release composition.

42. The method of claim 24 wherein the proton donor is from an acid source.

43. The method of claim 42 wherein the acid source is selected from the group consisting of buffers, esters, slowly dissolving acids or lactones.

44. The sustained-release composition produced by the method of claims 23, 24 or 41.