Claims for Patent: 8,114,833

Summary for Patent: 8,114,833

Title:	Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
Abstract:	The present invention relates to pharmaceutical formulations comprising a peptide and propylene glycol, to methods of preparing such formulations, and to uses of such formulations in the treatment of diseases and conditions for which use of the peptide contained in such formulations is indicated. The present invention further relates to methods for reducing the clogging of injection devices by a peptide formulation and for reducing deposits on production equipment during production of a peptide formulation.
Inventor(s):	Pedersen; Tina Bjeldskov (Smorum, DK), Bonde; Claude (Lyngby, DK), Engelund; Dorthe Kot (Holte, DK)
Assignee:	Novo Nordisk A/S (Bagsvaerd, DK)
Application Number:	11/435,977
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,114,833
Patent Claims:	1. A pharmaceutical formulation comprising at least one GLP-1 agonist, a disodium phosphate dihydrate buffer and propylene glycol, wherein said propylene glycol is present in said formulation in a final concentration of from about 1 mg/ml to about 100 mg/ml and wherein said formulation has a pH of from about 7.0 to about 10.0. 2. The formulation according to claim 1, wherein the concentration of propylene glycol is from about 1 mg/ml to about 50 mg/ml. 3. The formulation according to claim 1, wherein the concentration of propylene glycol is from about 5 mg/ml to about 25 mg/ml. 4. The formulation according to claim 1, wherein the concentration of propylene glycol is from about 8 mg/ml to about 16 mg/ml. 5. The formulation according to claim 1, wherein the pH of said formulation is about 7.0 to about 9.5. 6. The formulation according to claim 1, wherein the pH of said formulation is about 7.0 to about 8.3. 7. The formulation according to claim 1, wherein the pH of said formulation is about 7.3 to about 8.3. 8. The formulation according to claim 1, further comprising a preservative. 9. The formulation according to claim 8, wherein said preservative is present in a concentration from 0.1 mg/ml to 20 mg/ml. 10. The formulation according to claim 1, wherein said GLP-1 agonist is selected from the group consisting of GLP-1(7-36)-amide, GLP-1(7-37), a GLP-1(7-36)-amide analogue, a GLP-1(7-37) analogue, or a derivative of any of these. 11. The formulation according to claim 10, wherein said GLP-1 agonist is a derivative of GLP-1(7-36) or GLP-1(7-37) or a GLP-1(7-36)-amide analogue or a GLP-1(7-37) analogue, where said derivative has a lysine residue and a lipophilic substituent attached with or without a spacer to the epsilon amino group of said lysine. 12. The formulation according to claim 11, wherein said lipophilic substituent has from 8 to 40 carbon atoms. 13. The formulation according to claim 12, wherein said spacer is an amino acid. 14. The formulation according to claim 13, wherein said GLP-1 agonist is Arg.sup.34, Lys.sup.26(N-.epsilon.-(.gamma.-Glu(N-.alpha.-hexadecanoyl)))-GLP-1(7-37)- . 15. The formulation according to claim 1, wherein said GLP-1 agonist is selected from the group consisting of Gly.sup.8-GLP-1(7-36)-amide, Gly.sup.8-GLP-1(7-37), Val.sup.8-GLP-1(7-36) amide, Val.sup.8-GLP-1(7-37), Val.sup.8Asp.sup.22-GLP-1(7-36)-amide, Val.sup.8Asp.sup.22-GLP-1(7-37), Val.sup.8Glu.sup.22-GLP-1(7-36) -amide, Val.sup.8Glu.sup.22-GLP-1(7-37), Val.sup.8Lys.sup.22-GLP-1(7-36)-amide, Val.sup.8Lys.sup.22-GLP-1(7-37), Val.sup.8Arg.sup.22-GLP-1(7-36)-amide, Val.sup.8Arg.sup.22-GLP-1(7-37), Val.sup.8His.sup.22-GLP-1(7-36)-amide, Val.sup.8His.sup.22-GLP-1(7-37), Arg.sup.34GLP-1(7-37), Arg.sup.26,34Lys.sup.36GLP-1(7-36), Arg.sup.26GLP-1(7-37), and Gly.sup.8, Arg.sup.26,34Glu.sup.37Lys.sup.38GLP-1(7-38) and derivatives of any of these. 16. A method of preparing a GLP-1 agonist formulation suitable for use in an injection device, said method comprising preparing a formulation containing a GLP-1 agonist, propylene glycol, a disodium phosphate dihydrate buffer, and a preservative, wherein said propylene glycol is present in a concentration from about 1 mg/ml to about 100 mg/ml, and wherein said formulation has a pH from about 7.0 to about 10.0, and wherein said GLP-1 agonist, said propylene glycol and said buffer and preservative are mixed together to produce said formulation as follows: a) preparing a first solution by dissolving preservative, propylene glycol and buffer in water; b) preparing a second solution by dissolving the GLP-1 agonist in water; c) mixing the first and second solutions; and adjusting the pH of the mixture in c) to a pH of from about 7.0 to about 10.0. 17. The method according to claim 16, wherein the concentration of propylene glycol is from about 1 mg/ml to about 50 mg/ml. 18. The method according to claim 16, wherein the concentration of propylene glycol is from about 5 mg/ml to about 25 mg/ml. 19. The method according to claim 16, wherein the concentration of propylene glycol is from about 8 mg/ml to about 16 mg/ml. 20. The method according to claim 16, wherein the pH of said formulation is about 7.0 to about 9.5. 21. The method according to claim 16, wherein the pH of said formulation is about 7.0 to about 8.0. 22. The method according to claim 16, wherein the pH of said formulation is about 7.2 to about 8.0. 23. A method for reducing deposits on production equipment during production of a GLP-1 agonist formulation, said method comprising replacing the isotonicity agent previously utilized in said formulation with propylene glycol at a concentration of between 1-100 mg/ml, and wherein said GLP-1 agonist formulation comprises a disodium phosphate dihydrate buffer. 24. The method according to claim 23, wherein the reduction in deposits on the production equipment during production by the propylene glycol-containing formulation relative to that observed for the formulation containing the previously utilized isotonicity agent is measured by a simulated filling experiment. 25. The method according to claim 23, wherein the isotonicity agent to be replaced by propylene glycol is selected from the group consisting of sorbitol, sucrose, glycine, mannitol, lactose monohydrate, arginin, myo-inositol and dimethylsulfon. 26. A method for reducing deposits in the final product during production of a GLP-1 agonist formulation, said method comprising replacing the isotonicity agent previously utilized in said formulation with propylene glycol at a concentration of between 1-100 mg/ml, and wherein said GLP-1 agonist formulation comprises a disodium phosphate dihydrate buffer. 27. The method according to claim 26, wherein the reduction in deposits in the final product is measured by a reduction in the number of vials and/or cartridges of the propylene glycol-containing formulation that must be discarded due to deposits relative to number of vials and/or cartridges of the formulation containing the previously utilized isotonicity agent that must be discarded due to deposits. 28. The method according to claim 26, wherein the isotonicity agent to be replaced by propylene glycol is selected from the group consisting of sorbitol, glycerol, sucrose, glycine, mannitol, lactose monohydrate, arginin, myo-inositol and dimethylsulfon. 29. A method for reducing the clogging of injection devices by a GLP-1 agonist formulation, said method comprising replacing the isotonicity agent previously utilized in said formulation with propylene glycol at a concentration of between 1-100 mg/ml, and wherein said GLP-1 agonist formulation comprises a disodium phosphate dihydrate buffer. 30. The method according to claim 29, wherein the reduction in clogging of the injection device by the propylene glycol-containing formulation relative to that observed for the formulation containing the previously utilized isotonicity agent is measured in a simulated in use study. 31. The method according to claim 29, wherein the isotonicity agent to be replaced by propylene glycol is selected from the group consisting of inositol, maltose, glycine, lactose and mannitol.