Acidic insulin preparations having improved stability

• US 20040048783A1
• Filed: 06/13/2003
• Published: 03/11/2004
• Est. Priority Date: 06/18/2002
• Status: Abandoned Application

• Current Assignee: Aventis Pharma Deutschland GmbH (Sanofi )
• Original Assignee: Aventis Pharma Deutschland GmbH (Sanofi )
• Inventors: Lill, Norbert, Brunner-Schwarz, Anette
• Application Number:
  US10/461,740
• Publication Number:
  US 20040048783A1
• Time in Patent Office: Days
• US Class Current: 514/3
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7032 attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
• CPC Class Codes: A61K 38/28 Insulins
• 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
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention relates to a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin metabolite, an insulin analog, an insulin derivative and combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffers or further excipients or combinations thereof, the pharmaceutical formulation having a pH in the acidic range.

Claims

1. A pharmaceutical formulation comprising a polypeptide selected from the group consisting of bovine, porcine or human insulin, an insulin analogue, an insulin derivative, an active insulin metabolite and combinations thereof;

a surfactant or a combination of two or more surfactants;

optionally a preservative or a combination of two or more preservatives;

and optionally an isotonicizing agent, a buffer or buffers or a further excipient or excipients or a combination thereof;

such pharmaceutical formulation being a clear solution having a pH in the range from 1 to 6.8.

2. A pharmaceutical formulation according to claim 1, having a pH in the range from pH 3.5-6.8.

3. A pharmaceutical formulation according to claim 1, having a pH in the range from pH 3.5-4.5.

4. A pharmaceutical formulation according to claim 1 wherein the surfactant is selected from the group consisting of partial and fatty acid esters and ethers of polyhydric alcohols, of glycerol, sorbitol and of sucrose, and polyols.

5. A pharmaceutical formulation according to claim 4, wherein the partial and fatty acid esters and ethers of polyhydric alcohols, of glycerol and sorbitol are selected from the group consisting of Span®

, Tween®

, polysorbate, Myrj®

, Brij®

, Triton®

, and Cremophor®

.

6. A pharmaceutical formulation according to claim 5, wherein the partial and fatty acid esters and ethers of polyhydric alcohols, of glycerol and sorbitol are selected from the group consisting of Tween®

20 and Tween®

80.

7. A pharmaceutical formulation according to claim 4, wherein the polyols are selected from the group consisting of polypropylene glycols, polyethylene glycols, poloxamers, Pluronics®

, and Tetronics®

.

8. A pharmaceutical formulation according to claim 1, wherein the preservative is selected from the group consisting of phenol, cresol, chlorocresol, benzyl alcohol, and parabens.

9. A pharmaceutical formulation according to claim 1, wherein the isotonicizing agent is selected from the group consisting of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.

10. A pharmaceutical formulation according to claim 1 wherein the excipients are selected from the group consisting of TRIS, phosphate, citrate, acetate, and glycylglycine

11. A pharmaceutical formulation according to claim 1 wherein the excipients are selected from the group consisting of acids, alkalis, and salts.

12. A pharmaceutical formulation according to claim 1, wherein the insulin analog is selected from the group consisting of Gly(A21), Arg(B31), Arg(B32)-human insulin, Lys(B3), Glu(B29)-human insulin, Asp(B28)-human insulin, Lys(B28) Pro(B29)-human insulin, and des(B30)-human insulin.

13. A pharmaceutical formulation according to claim 1, wherein the insulin derivative is selected from the group consisting of B29-N-myristoyl-des(B30) human insulin, B29-N-palmitoyl-des(B30) human insulin, B29-N-myristoyl human insulin, B29-N-palmitoyl human insulin, B28-N-myristoyl Lys^B28Pro^B29 human insulin, B28-N-palmitoyl-Lys^B28Pro^B29 human insulin, B30-N-myristoyl-Thr^B29 Lys^B30 human insulin, B30-N-palmitoyl-Thr^B29Lys^B30 human insulin, B29-N-(N-palmitoyl-γ

-glutamyl)-des(B39) human insulin, B29-N-(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin, B29-N-(ω

-carboxy-heptadecanoyl)-des(B30) human insulin and B29-N-(ω

-carboxy-heptadecanoyl) human insulin.

14. A pharmaceutical formulation according to claim 1, wherein the insulin is present in a concentration of 60 to 6000 nmol/ml.

15. A pharmaceutical formulation according to claim 1, wherein the insulin analog is present in a concentration of 60 to 6000 nmol/ml.

16. A pharmaceutical formulation according to claim 1, wherein the insulin derivative is present in a concentration of 60 to 6000 nmol/ml.

17. A pharmaceutical formulation according to claim 14, wherein the insulin is present in a concentration of 240 to 3000 nmol/ml.

18. A pharmaceutical formulation according to claim 15, wherein the insulin analog is present in a concentration of 240 to 3000 nmol/ml.

19. A pharmaceutical formulation according to claim 16, wherein the insulin derivative is present in a concentration of 240 to 3000 nmol/ml.

20. A pharmaceutical formulation according to claim 1 wherein the surfactant is present in a concentration of 5 to 200 μ

g/ml.

21. A pharmaceutical formulation according to claim 20, wherein the surfactant is present in a concentration of 5 to 120 μ

g/ml.

22. A pharmaceutical formulation according to claim 21, wherein the surfactant is present in a concentration of 20 to 75 μ

g/ml.

23. A pharmaceutical formulation according to claim 1, wherein the isotonicizing agent is selected from the group consisting of glycerol and mannitol and wherein the isotonicizing agent is present in a concentration of 100 to 250 mM.

24. A pharmaceutical formulation according to claim 23, wherein NaCl is present in a concentration of 0 to 150 mM.

25. A pharmaceutical formulation according to claim 1, wherein a buffer is present in a concentration of 5 to 250 mM.