Stabilized glucagon solutions and uses therefor

• US 8,636,711 B2
• Filed: 06/14/2011
• Issued: 01/28/2014
• Est. Priority Date: 06/14/2010
• Status: Active Grant

• Current Assignee: Indiana University Research & Technology Corporation (Indiana University), Legacy Emanuel Hospital and Health Center
• Original Assignee: Indiana University Research & Technology Corporation (Indiana University), Legacy Emanuel Hospital and Health Center
• Inventors: Ward, W. Kenneth, DiMarchi, Richard D.
• Primary Examiner(s): Lucchesi, Nicholas
• Assistant Examiner(s): Snyder, Melissa A
• Application Number:
  US13/160,349
• Publication Number:
  US 20120071817A1
• Time in Patent Office: 959 Days
• Field of Search: 604 65- 67, 600/365
• US Class Current: 604/504
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• 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 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61M 5/145 using pressurised reservoirs, e.g. pressurised by means of pistons
• CPC Class Codes: A61M 5/1723 using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Stabilized glucagon solutions, methods of storing and using the stabilized glucagon solutions, and drug delivery devices containing the stabilized glucagon solutions. In some embodiments, the glucagon solutions may be alkaline, such as with a pH of at least about 9. The glucagon solutions may be resistant to aggregation of glucagon when the solutions are stored for a prolonged period, such as at least about three days, at room temperature and/or physiological temperature.

Claims

1. A method of treating a glucagon-responsive medical condition, comprising:

providing an aqueous solution of glucagon at a pH of greater than about 9;

storing the solution in liquid form at a pH of greater than about 9 for at least three days at room temperature or higher without substantial aggregation of the glucagon; and

delivering at least a portion of the solution into a subject after the step of storing.

2. The method of claim 1, wherein the glucagon is present at a concentration of at least about 0.5 mg/mL.

3. The method of claim 1, wherein the solution is stored at a pH of about 9.5 to 10.5.

4. The method of claim 1, wherein the solution includes a buffering agent comprising an ampholyte.

5. The method of claim 4, wherein the ampholyte is glycine.

6. The method of claim 1, wherein the solution is substantially free of detergent.

7. The method of claim 1, wherein the step of storing is performed in a drug delivery device, and wherein the step of delivering is performed with the drug delivery device.

8. The method of claim 1, wherein the step of delivering is performed by injection intravenously, intramuscularly, or subcutaneously.

9. The method of claim 1, wherein the subject is hypoglycemic.

10. The method of claim 1, wherein the step of delivering is controlled by a processor that is in communication with at least one glucose sensor that monitors glucose concentration of the subject.

11. The method of claim 10, wherein the processor is programmed to cause delivery of the solution based on a proportional error and/or a derivative error of the glucose concentration.

12. The method of claim 11, wherein the timing and amount of glucagon delivered is based on the proportional error and the derivative error.

13. The method of claim 11, wherein the processor is programmed to use a fading memory proportional derivative algorithm to determine the timing and amount of glucagon delivered, based on a signal from the at least one glucose sensor.

19. The method of claim 1, wherein the step of storing is performed at a pH of greater than about 9 for at least three days at a physiological temperature.

14. A drug delivery system, comprising:

a drug delivery device including a container holding an aqueous solution of glucagon that has been stored in the container at a pH of greater than about 9 and at room temperature or higher for at least three days, the glucagon being substantially non-aggregated, the device also including an outlet through which the solution is configured to be driven from the container for delivery into a subject.

15. The drug delivery system of claim 14, further comprising a pressure source operatively disposed to drive the solution from the container through the outlet.

16. The drug delivery system of claim 15, further comprising at least one glucose sensor and a processor programmed to control operation of the pressure source based on a signal received from the glucose sensor.

17. The drug delivery system of claim 16, wherein the processor is programmed to control operation of the pressure source based on a proportional error and/or a derivative error of glucose concentration measured by the glucose sensor.

18. The drug delivery system of claim 17, wherein the processor is programmed to control the timing and amount of glucagon delivered based on the proportional error and the derivative error.

20. The system of claim 14, wherein the solution of glucagon has been stored in the container at a pH of greater than about 9 for at least three days at a physiological temperature.