Insulin preparations containing NaCl

• US 5,866,538 A
• Filed: 06/20/1997
• Issued: 02/02/1999
• Est. Priority Date: 06/20/1996
• Status: Expired due to Term

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Langkj.ae butted.r, Liselotte, Havelund, Svend, Norup, Elsebeth
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): Borin, Michael
• Application Number:
  US08/879,991
• Time in Patent Office: 592 Days
• Field of Search: 514/3
• 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• 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

Abstract

Insulin preparations of superior chemical stability, comprising human insulin or an analogue or derivative thereof, glycerol and/or mannitol, and 5 to 100 mM of a halogenide are disclosed.

Claims

1. A pharmaceutical formulation comprising:

a polypeptide selected from the group consisting of human insulin, an analogue thereof, a derivative thereof, and combinations of any of the foregoing;

glycerol, mannitol, or glycerol and mannitol; and

5 to 100 mM of a halogenide.

2. A pharmaceutical formulation according to claim 1, wherein the halogenide is an alkali or alkaline earth halogenide.

3. A pharmaceutical formulation according to claim 1, wherein said glycerol or mannitol is present at a concentration of 100 to 250 mM.

4. A pharmaceutical formulation according to claim 1, wherein said polypeptide is an analogue of human insulin selected from the group consisting of:

(i) an analogue wherein position B28 is Asp, Lys, Leu, Val or Ala and position B29 is Lys or Pro; and

(ii) des(B28-B30), des(B27) or des(B30) human insulin.

5. A pharmaceutical formulation according to claim 4, wherein said polypeptide is an analogue of human insulin wherein position B28 is Asp or Lys, and position B29 is Lys or Pro.

6. A pharmaceutical formulation according to claim 4, wherein said polypeptide is des(B30) human insulin.

7. A pharmaceutical formulation according to claim 1, wherein said halogenide is present at a concentration of 5 to 60 mM.

8. A pharmaceutical formulation according to claim 1, wherein said polypeptide is a derivative of human insulin having one or more lipophilic substituents.

9. A pharmaceutical formulation according to claim 8, wherein the insulin derivative is selected from the group consisting of B29-N.sup.ε

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

-palmitoyl-des(B30) human insulin, B29-N.sup.ε

-myristoyl human insulin, B29-N.sup.ε

-palmitoyl human insulin, B28-N.sup.ε

-myristoyl Lys^B28 Pro^B29 human insulin, B28-N.sup.ε

-palmitoyl-Lys^B28 Pro^B29 human insulin, B30-N.sup.ε

-myristoyl-Thr^B29 Lys^B30 human insulin, B30-N.sup.ε

-palmitoyl-Thr^B29 Lys^B30 human insulin, B29-N.sup.ε

-(N-palmitoyl-γ

-glutamyl)-des(B30) human insulin, B29-N.sup.ε

(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin, B29-N.sup.ε

-(ω

-carboxyheptadecanoyl)-des(B30) human insulin and B29-N.sup.ε

-(ω

-carboxyheptadecanoyl) human insulin.

10. A pharmaceutical formulation according to claim 9, wherein the insulin derivative is B29-N.sup.ε

-myristoyl-des(B30) human insulin.

11. A pharmaceutical formulation according to claim 8, wherein said halogenide is present at a concentration of 10 to 100 mM.

12. A pharmaceutical formulation according to claim 1, comprising an insulin analogue as well as an insulin derivative.

13. A pharmaceutical formulation according to claim 1, wherein said polypeptide is present at a concentration of 60 to 3000 nmol/ml.

14. A pharmaceutical formulation according to claim 1, further comprising:

10 to 40 ug Zn/100 U insulin.

15. A pharmaceutical formulation according to claim 1, further comprising:

0 to 5 mg/ml of a phenolic compound.

16. A pharmaceutical formulation according to claim 15, comprising:

18. A pharmaceutical formulation according to claim 1, wherein the halogenide is sodium chloride.

17. 5 to 4.0 mg/ml of m-cresol or 0.5 to 4.0 mg/ml of phenol, or a mixture thereof.