Acidic Insulin Preparations Having Improved Stability

• US 20090082255A1
• Filed: 12/04/2008
• Published: 03/26/2009
• Est. Priority Date: 06/18/2002
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: Lill, Norbert, Brunner-Schwarz, Anette
• Granted Patent: US 7,713,930 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 Gly(A21), Arg(B31), Arg(B32)-human insulin;

at least one chemical entity chosen from esters and ethers of polyhydric alcohols;

at least one preservative; and

water,

wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.

2. The pharmaceutical formulation as claimed in claim 1, wherein the at least one preservative is chosen from phenols.

3. The pharmaceutical formulation as claimed in claim 1, wherein the at least one preservative is cresol.

4. The pharmaceutical formulation as claimed in claim 3, further including zinc.

5. The pharmaceutical formulation as claimed in claim 1, further including at least one isotonicizing agent.

6. The pharmaceutical formulation as claimed in claim 4, wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 6.8.

8. The pharmaceutical formulation as claimed in claim 1, wherein the at least one preservative is chosen from phenol, cresol, chlorocresol, benzyl alcohol, and parabens.

9. The pharmaceutical formulation as claimed in claim 5, wherein the at least one isotonicizing agent is chosen from mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.

10. The pharmaceutical formulation as claimed in claim 1, further comprising a buffer.

11. The pharmaceutical formulation as claimed in claim 10, wherein the buffer is chosen from TRIS, phosphate, citrate, acetate, and glycylglycine.

12. The pharmaceutical formulation as claimed in claim 1, wherein the Gly(A21), Arg(B31), Arg(B32)-human insulin is present in a concentration of 60-6000 nmol/ml.

13. The pharmaceutical formulation as claimed in claim 12, wherein the Gly(A21), Arg(B31), Arg(B32)-human insulin is present in a concentration of 240-3000 nmol/ml.

14. The pharmaceutical formulation as claimed in claim 1, wherein the at least one chemical entity is present in a concentration of 5-200 μ

g/ml.

15. The pharmaceutical formulation as claimed in claim 14, wherein the at least one chemical entity is present in a concentration of 5-120 μ

g/ml.

16. The pharmaceutical formulation as claimed in claim 15, wherein the at least one chemical entity is present in a concentration of 20-75 μ

g/ml.

17. The pharmaceutical formulation as claimed in claim 9, wherein at least one isotonicizing agent is chosen from glycerol and mannitol and wherein said at least one isotonicizing agent is present in a concentration of 100-250 mM.

18. The pharmaceutical formulation as claimed in claim 1, further comprising one or more excipients chosen from acids, alkalis and salts.

19. The pharmaceutical formulation as claimed in claim 18, wherein the excipient is NaCl which is present in a concentration of up to 150 mM.

20. The pharmaceutical formulation as claimed in claim 10, wherein said buffer is present in a concentration of 5-250 mM.

7. The pharmaceutical formulation as claimed in claimed 6, wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 4.5.