Stable glucagon formulations
View Patent ↗Stabilized formulations containing a peptide, such as a glucagon, are described herein. The formulations are in the form of a solution or suspension, which exhibit little or no chemical degradation and/or aggregation of the peptide over an extended period of time. In some embodiments, the formulations are in the form of a solution containing the peptide, a solvent such as glycerin, and one or more thermal stabilizers. In other embodiments, the formulation is in the form of a suspension containing nano- and/or microparticles containing the peptide suspended in a non-aqueous, non-solvent. The nano- and/or microparticles can be prepared by micronizing the peptide with one or more humectants, such as salts, sugars, water-soluble polymers, and combinations thereof which increase the rate of dissolution of the peptide upon administration.
1. A stabilized glucagon formulation comprising glucagon dissolved in glycerin, wherein the formulation contains less than 5%, 1%, 0.5%, 0.25%, 0.1%, or 0.05%, weight by volume of water and an effective amount of a di-arginine piperazine to increase the stability of the glucagon.
2. The formulation of claim 1 , wherein the concentration of glucagon is from about 1.0 mg/ml of glucagon to about 10 mg/ml of glucagon.
3. The formulation of claim 2 , wherein the concentration of glucagon is about 1 mg/ml.
4. The formulation of claim 2 , wherein the concentration of glucagon is about 5 mg/mi.
5. The formulation of claim 1 , wherein the di-arginine piperazine has the formula:
6. The formulation of claim 5 , wherein the concentration of the di-arginine piperazine is from about 5 mg/ml of di-arginine piperazine to about 100 mg/ml of di-arginine piperazine.
7. The formulation of claim 6 , wherein the concentration of the di-arginine piperazine is about 10 mg/ml.
8. The formulation of claim 6 , wherein the concentration of the di-arginine piperazine is about 20 mg/ml.
9. The formulation of claim 1 wherein the formulation is a solution, wherein the solution further comprises a pH-altering agent.
10. The formulation of claim 9 , wherein the pH-altering agent is sodium bicarbonate.
11. The formulation of claim 10 , wherein the pH of the formulation is adjusted to between 7 and 8.5.
12. The formulation of claim 10 , wherein the pH of the formulation is adjusted to between 8 and 8.5.
13. The formulation of claim 10 , wherein the concentration of sodium bicarbonate is from about 5 mg/ml of sodium bicarbonate to about 20 mg/ml of sodium bicarbonate.
14. The formulation of claim 10 , wherein the concentration of sodium bicarbonate is about 10 mg/mi.
15. The formulation of claim 10 , wherein the concentration of sodium bicarbonate is about 20 mg/ml.
16. The formulation of claim 1 , wherein the formulation further comprises a sugar.
17. The formulation of claim 16 , wherein the sugar is a disaccharide.
18. The formulation of claim 17 , wherein the disaccharide is sucrose.
19. The formulation of claim 18 , wherein the concentration of sucrose is from about 5 mg/ml of sucrose to about 15 mg/ml of sucrose.
20. The formulation of claim 18 , wherein the concentration of sucrose is about 10 mg/ml.
21. The formulation of claim 17 , wherein the disaccharide is trehalose.
22. The formulation of claim 21 , wherein the concentration of trehalose is from about 5 mg/ml of trehalose to about 15 mg/ml of trehalose.
23. The formulation of claim 22 , wherein the concentration of trehalose is about 10 mg/ml.
24. The formulation of claim 1 , wherein the formulation further comprises an antimicrobial agent.
25. The formulation of claim 24 , wherein the antimicrobial agent is metacresol (m-cresol).
26. The formulation of claim 25 , wherein the concentration of m-cresol is from about 0.5 mg/ml of m-cresol to about 3.0 mg/ml of m-cresol.
27. The formulation of claim 26 , wherein the concentration of m-cresol is about 1.5 mg/ml.
28. The formulation of claim 26 , wherein the concentration of m-cresol is about 2 mg/ml.
29. The formulation of claim 1 , wherein the formulation further comprises a non-aqueous cosolvent.
30. The formulation of claim 29 , wherein the non-aqueous cosolvent is ethanol.
31. The formulation of claim 30 , wherein the concentration of ethanol is from about 1 to about 50.
32. The formulation of claim 30 , wherein the concentration of ethanol is from about 10 to about 40 volume percent.
33. The formulation of claim 30 , wherein the concentration of ethanol is from about 20 to about 30 volume percent.
34. A unit dosage form comprising the stabilized glucagon formulation of claim 1 .
35. The unit dosage form of claim 34 , wherein the dosage form is a syringe or a cartridge.
36. A method of treating diabetes or hypoglycemia in a patient in need thereof comprising administering a stabilized glucagon formulation comprising a glucagon dissolved in glycerin, wherein the formulation contains less than 5%, 1%, 0.5%, 0.25%, 0.1%, or 0.05%, weight by volume of water, and an effective amount of a di-arginine piperazine to increase the stability of the glucagon.