Patent EA-002880-B1 (EA)
Title: Stable insulin formulations
Inventor: DEFELIPPIS MICHAEL ROSARIO
IPC: A61K38/28
Filed: 1998-06-11
Abstract: 1. A solution formulation comprising: a) a physiologically tolerated buffer selected from the group consisting of TRIS and arginine; b) a monomeric human insulin analog, selected from the group, consisting of human insulin, wherein Pro in position B28 is substituted with Asp, Lys, Leu, Val or Ala; and wherein Lys in position B29 is Lys or is substituted with Pro; Ala<B26>- human insulin, dez-(B28-B30) human insulin and dez-(B27) human insulin, c) zinc and d) a phenolic preservative. 2. The formulation of Claim 1, wherein the monomeric insulin analog is Lys<B28>Pro<B29>-human insulin and the buffer is TRIS. 3. The formulation of Claim 2 further comprising an isotonicity agent and wherein the pH of the formulation is between pH 7.0 and pH 8.0 when measured at a temperature of 22 degree C. 4. The formulation of Claim 3, wherein the concentration of Lys<B28>Pro<B29>-human insulin is between about 1,2 mg/mL and about 50 mg/mL. 5. The formulation of Claim 4, wherein the concentration of Lys<B28>Pro<B29>-human insulin is between about 3,0 mg/mL and about 35 mg/mL. 6. The formulation of Claim 5, wherein TRIS is present at a concentration of about 2 mg/mL; glycerol is the isotonicity agent and is present at a concentration of about 16 mg/mL; and m-cresol is present at a concentration of about 1.76 mg/mL and phenol is present at a concentration of about 0.715 mg/mL. 7. A stable, soluble formulation of a monomeric insulin analog for use in a continuous infusion system, consisting essentially of: a) an isotonicity agent; b) a buffer selected from the group consisting of TRIS and arginine; c) a monomeric insulin analog selected from the group, consisting of human insulin, wherein Pro in position B28 is substituted with Asp, Lys, Leu, Val or Ala; and wherein Lys in position B29 is Lys or is substituted with Pro; Ala<B26>- human insulin, dez-(B28-B30) human insulin and dez-(B27) human insulin; d) zinc; and e) a phenolic preservative. 8. The insulin analog formulation of Claim 1, which further comprises protamine. 9. The formulation of Claim 8, wherein the insulin analog is Lys<B28>Pro<B29>- human insulin. 10. The formulation of any one of Claims 8 and 9 wherein the buffer is arginine. 11. The formulation of any one of Claims 1 through 7 for use in a continuous infusion system. 12. A method for treating diabetes comprising administering an effective dose of the formulation of any one of Claims 1 through 10 to a patient in need thereof. 13. A method for treating diabetes comprising administering an effective dose of the formulation of any, one of Claims 1 through 7, wherein the formulation is administered using a continuous infusion system. 14. A method for treating hyperglycemia comprising administering an effective dose of the formulation of any one of Claims 1 through 10 to a patient in need thereof. 15. A method for treating hyperglycemia comprising administering an effective dose of the formulation of any one of Claims 1 through 7 to a patient in need thereof, wherein the formulation is administered using a continuous infusion system. 16. The formulation of monomeric insulin analog as described in any one of Claims 1 through 10 for use as a medicament for the treatment of diabetes. 17. The formulation of monomeric insulin analog as described in any one of Claims 1 through 10 for use as a medicament for the treatment of hyperglycemia. 18. A process for preparing the monomeric insulin analog formulation of Claim 1 comprising the steps of mixing: a) a physiologically-tolerated buffer selected from the group consisting of TRIS and arginine with b) a monomeric human insulin analog selected from the group, consisting of human insulin, wherein Pro in position B28 is substituted with Asp, Lys, Leu, Val or Ala; and wherein Lys in position B29 is Lys or is substituted with Pro; Ala<B26>- human insulin, dez-(B28-B30) human insulin and dez-(B27) human insulin; d) zinc; and e) a phenolic preservative. 19. The formulation of Claim 18, wherein the monomeric insulin analog is Lys<B28>Pro<B29>-human insulin and the buffer is TRIS. 20. A process for preparing the monomeric insulin analog based formulation of Claim 1 comprising the steps of mixing: a) a buffer selected from the group consisting of TRIS and arginine with b) a monomeric insulin analog selected from the group, consisting of human insulin, wherein Pro in position B28 is substituted with Asp, Lys, Leu, Val or Ala; and wherein Lys in position B29 is Lys or is substituted with Pro; Ala<B26>- human insulin, dez-(B28-B30) human insulin and dez(B27) human insulin; c) zinc; d) protamine; and e) a phenolic preservative. 21. The process of Claim 20, wherein the monomeric insulin analog is Lys<B28>Pro<B29> human insulin.