Polypeptide compositions with improved stability

• US 7,022,674 B2
• Filed: 12/05/2000
• Issued: 04/04/2006
• Est. Priority Date: 12/16/1999
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: DeFelippis, Michael Rosario, Sharknas, Alby David, Rinella, Joseph Vincent, Dobbins, Michael Allen, Prokai, Alex Mark
• Primary Examiner(s): Tate, Christopher R.
• Assistant Examiner(s): CORDERO GARCIA, MARCELA M
• Application Number:
  US10/130,836
• Publication Number:
  US 20030207802A1
• Time in Patent Office: 1,946 Days
• Field of Search: 514/12, 514/21, 514/1, 424/455
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/2264 Obesity-gene products, e.g. leptin
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides means to improve the chemical stability of aqueous, parenteral pharmaceutical compositions comprising a polypeptide and glycerin. Reactive aldehydes are identified in commercial glycerins, and means for reducing such are provided. Convenient means are provided to assay for reactive aldehydes in glycerin, and a strong linear correlation between the level of reactive aldehydes in glycerin and chemical stability of compositions comprising a polypeptide and glycerin is demonstrated. The invention includes aqueous compositions comprising a polypeptide and glycerin having improved chemical stability compared to compositions previously known.

Claims

1. An aqueous, parenteral pharmaceutical composition for improving stability of a polypeptide comprising the polypeptide and glycerin, wherein the glycerin comprises propane-1,2,3-triol and reactive aldehyde impurities, the glycerin is derived from a non-animal source, the concentration of propane-1,2,3-triol is less than 500 mg/mL, and the content of reactive aldehyde impurities is less than 33 ppm.

2. The composition according to claim 1, wherein the composition is a solution.

3. The composition according to claim 1, wherein the composition is a suspension.

4. The composition according to claim 1, wherein the glycerin concentration in the pharmaceutical composition is about 1 mg/mL to about 300 mg/mL.

5. The composition according to claim 4, wherein the glycerin concentration is about 3 mg/mL to about 100 mg/mL.

6. The composition according to claim 5, wherein the glycerin concentration is about 10 mg/mL to about 30 mg/mL.

7. The composition according to claim 6, wherein the glycerin concentration is about 15 mg/mL to about 18 mg/mL.

8. The composition according to claim 1, wherein the glycerin is derived from plants or propylene.

9. The composition according to claim 8, wherein the glycerin is derived from propylene.

10. The composition according to claim 1, wherein the glycerin has a reactive aldehyde content of less than 24 ppm.

11. The composition according to claim 10, wherein the glycerin has a reactive aldehyde content of less than 15 ppm.

12. The composition according to claim 11, wherein the glycerin has a reactive aldehyde content of less than 8 ppm.

13. The composition according to claim 12, wherein the glycerin has a reactive aldehyde content of 3 ppm or lower.

14. The composition according to claim 1, wherein the polypeptide is FSH, a FSH analog having deletion of one, two, three or more C-terminal residues of the FSH beta subunit, PTH, a PTH(1–

38) fragment, a PTH(1–

34) fragment, HGH, GLP-1 or an analog or derivative thereof, human insulin or an analog or derivative thereof, or a derivative of a human insulin analog.

15. The composition according to claim 14, wherein the polypeptide is human insulin or an analog or derivative thereof, or a derivative of a human insulin analog.

16. The composition according to claim 15, wherein the polypeptide is human insulin.

17. The composition according to claim 15, wherein the polypeptide is an analog of human insulin.

18. The composition according to claim 17, wherein the analog is Lys(B28)-Pro(B29)-human insulin.

19. The composition according to claim 17, wherein the analog is Asp(B28)-human insulin.

20. The composition according to claim 17, wherein the analog is Gly(A21)Arg(B31)Arg(B32)-human insulin.

21. The composition according to claim 15, wherein the polypeptide is a derivative of human insulin or a derivative of a human insulin analog.

22. The composition according to claim 21, wherein the derivative of a human insulin analog is myristoyl-ε

-Lys(B29)-des(B30)-human insulin.

23. The composition according to claim 21, wherein the derivative of human insulin is palmitoyl-ε

-Lys(B29)-human insulin.