Stabilized insulin compositions

• US 6,174,856 B1
• Filed: 01/07/1999
• Issued: 01/16/2001
• Est. Priority Date: 01/09/1998
• Status: Expired due to Term

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Norup, Elsebeth, Langballe, Peter
• Primary Examiner(s): Moezie, F. T.
• Application Number:
  US09/227,053
• Time in Patent Office: 740 Days
• Field of Search: 514/3, 514/4, 514/12, 530/303, 530/304, 530/305
• US Class Current: 514/6.3
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

An aqueous insulin composition with improved chemical and physical stability comprising human insulin or an analogue or derivative thereof, a buffer selected from glycylglycine, citrate or TRIS, in particular glycylglycine, and metal ions, in particular calcium or magnesium ions.

Claims

1. An aqueous insulin composition comprising human insulin or an analogue or derivative thereof, glycylglycine buffer, and metal ions selected from the group consisting of calcium and magnesium ions.

2. The composition of claim 1, comprising 0.1-10 metal ions per hexamer of insulin or insulin analogue or derivative.

3. The composition of claim 2, comprising 0.5-5 metal ions per hexamer of insulin or insulin analogue or derivative.

4. The composition of claim 3, comprising 1-4 metal ions per hexamer of insulin or insulin analogue or derivative.

5. The composition of claim 1, wherein the metal ions are calcium ions.

6. The composition of claim 1, wherein the concentration of glycylglycine is in the range of 1-20 mM.

7. The composition of claim 6, wherein the concentration of glycylglycine is in the range of 3-15 mM.

8. The composition of claim 7, wherein the concentration of glycylglycine is in the range of 4-10 mM.

9. The composition of claim 5, wherein the concentration of glycylglycine is in the range of 4-10 mM.

10. The composition of claim 1, comprising a derivative of human insulin or an analogue thereof having at least one lipophilic substituent.

11. The composition of claim 10, comprising an acylated insulin derivative.

12. The composition of claim 11, comprising an insulin derivative wherein the ε

-amino group of Lys^B29 contains an acyl substituent comprising at least 6 carbon atoms.

13. The composition of claim 11, wherein the insulin derivative is selected from the group consisting of N^ε

B29-myristoyl-des(B30) human insulin, N<sup>ε

B29</sup>-palmitoyl-des(B30) human insulin, N<sup>ε

B29</sup>-myristoyl human insulin, N<sup>ε

B29</sup>-palmitoyl human insulin, N<sup>ε

B28</sup>-myristoyl Lys^B28 Pro^B29 human insulin, N<sup>ε

B28</sup>-palmitoyl Lys^B28 Pro^B29 human insulin, N<sup>ε

B30</sup>-myristoyl-Thr^B29Lys^B30 human insulin, N<sup>ε

B30</sup>-palmitoyl-Thr^B29Lys^B30 human insulin, N<sup>ε

B29</sup>-(N-palmitoyl-γ

-glutamyl)-des(B30) human insulin, N<sup>ε

B29</sup>-(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin, N<sup>ε

B29</sup>(ω

-carboxyheptadecanoyl)-des(B30) human insulin, and N<sup>ε

B29</sup>-(ω

-carboxyheptadecanoyl) human insulin.

14. The composition of claim 13, wherein the insulin derivative is N^ε

B29-myristoyl-des(B30) human insulin.

15. The composition of claim 9, wherein the insulin derivative is selected from the group consisting of N^ε

B29-myristoyl-des(B30) human insulin, N<sup>ε

B29</sup>-palmitoyl-des(B30) human insulin, N<sup>ε

B29</sup>-myristoyl human insulin, N<sup>ε

B29</sup>-palmitoyl human insulin, N<sup>ε

B28</sup>-myristoyl Lys^B28 Pro^B29 human insulin, N<sup>ε

B28</sup>-palmitoyl Lys^B28 Pro^B29 human insulin, N<sup>ε

B30</sup>-myristoyl-Thr^B29Lys^B30 human insulin, N<sup>ε

B30</sup>-palmitoyl-Thr^B29Lys^B30 human insulin, N<sup>ε

B29</sup>-(N-palmitoyl-γ

-glutamyl)-des(B30) human insulin, N<sup>ε

B29</sup>-(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin, N<sup>ε

B29</sup>-(ω

-carboxyheptadecanoyl)-des(B30) human insulin, and N<sup>ε

B29</sup>-(ω

-carboxyheptadecanoyl) human insulin.

16. The composition of claim 10, comprising a derivative of human insulin having Lys at position B28 and wherein the ε

-amino group of Lys^B28 contains an acyl substituent comprising at least 6 carbon atoms.

17. The composition of claim 16, wherein the insulin derivative is N^ε

B28-myristoyl Lys^B28 Pro^B29 human insulin or N<sup>ε

B28</sup>-palmitoyl Lys^B28 Pro^B29 human insulin.

18. A parenteral pharmaceutical formulation comprising an insulin composition of claim 1 and a preservative.

19. A method for improving the stability of an insulin composition comprising human insulin or an analogue or a derivative thereof, which method comprises adding to said composition a glycylglycine buffer and metal ions selected from the group consisting of calcium and magnesium ions.