INSULIN PREPARATIONS CONTAINING METHIONINE

• US 20120252724A1
• Filed: 07/02/2010
• Published: 10/04/2012
• Est. Priority Date: 07/06/2009
• Status: Active Application

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis (Sanofi-Synthélabo SA)
• Inventors: Schoettle, Isabell, Hagendorf, Annika, Fuerst, Christiane, Hauck, Gerrit, Siefke-Henzler, Verena, Kamm, Walter, Schnieders, Julia
• Application Number:
  US13/382,442
• Publication Number:
  US 20120252724A1
• Time in Patent Office: Days
• US Class Current: 514/6.2
• 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 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/00 Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
• 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 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• 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: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The invention relates to an aqueous pharmaceutical formulation having insulin, an insulin analog, or an insulin derivative, and methionine; and to the production thereof, to the use thereof for treating diabetes mellitus, and to a medication for treating diabetes mellitus.

Claims

1. An aqueous pharmaceutical formulation comprising an insulin, insulin analog or insulin derivative, or a pharmacologically tolerable salt thereof, and methionine.

2. The pharmaceutical formulation as claimed in claim 1, the insulin being selected from the group consisting of human insulin, porcine insulin, and bovine insulin.

3. The pharmaceutical formulation as claimed in claim 1, the insulin analog being 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, Des(B30) human insulin and an insulin analog of the formula I

4. The pharmaceutical formulation as claimed in claim 3, in which the insulin analog is selected from the group consisting of:

Arg (A0), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu(A5), Glu (A15), Gly (A21), Arg (B31), Arg (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A5), Glu (A15), Gly (A21), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His(A8), Glu (A5), Gly (A21), Asp (B3), Arg (B31), Arg (B32)-NH₂human insulin,

Arg (A0), His(A8), Glu (A5), Gly (A21), Asp (B3), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His(A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (AS), Gly (A21), Glu (B4), Arg (B31), Arg (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B4), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B0), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B0), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B0), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B0), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B0), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B0), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A

     15), Gly (A21), Asp (B

     1), Arg (B31), Arg(B32)-NH₂ human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Asp (B1), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B1), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B1), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Gly (A21), Glu (B0), Asp (B1), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Glu (B0), Asp (B1), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Arg (B31)-NH₂ human insulin, and

Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Lys (B31)-NH₂ human insulin.

5. The pharmaceutical formulation as claimed in claim 1, the insulin analog being selected from the group consisting of an insulin analog of the formula II

6. The pharmaceutical formulation as claimed in claim 5, in which the insulin analog is selected from the group consisting of:

Arg (A-1), Arg (A0), Glu (A5), His (A8), Gly (A21), Arg (B30)-NH₂ human insulin,

Arg (A-1), Arg (A0), Glu (A5), His (A8), Gly (A21), Lys (B30)-NH₂ human insulin,

Arg (A-1), Arg (A0), Glu (A15), His (A8), Gly (A21), Arg (B30)-NH₂ human

Arg (A-1), Arg (A0), Glu (A15), His (A8), Gly (A21), Lys (B30)-NH₂ human insulin,

Arg (A-1), Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B30)-NH₂human insulin,

Arg (A-1), Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B30)-NH₂human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B0), Arg (B30)-NH₂human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B0), Lys (B30)-NH₂human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Asp (B3), Arg (B30)-NH₂ human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Asp (B3), Lys (B30)-NH₂human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B30)-NH₂ human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B4), Lys (B30)-NH₂human insulin,

Arg (A0), His (A8), Gly (A21), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), Glu (A5), His (A8), Gly (A21), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), Glu (A5), His (A8), Gly (A21), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), Glu (A15), His (A8), Gly (A21), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), Glu (A15), His (A8), Gly (A21), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Asp (B3), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Asp (B3), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Glu (B0), Arg (B31), Arg (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Glu (B0), Arg (B31), Lys (B32)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Arg (B30)-NH₂ human insulin,

Arg (A0), His (A8), Gly (A21), Lys (B30)-NH₂ human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Arg (B30)-NH₂ human insulin,

Arg (A-1), Arg (A0), His (A8), Gly (A21), Lys (B30)-NH₂ human insulin,

Arg (A0), Arg (A1), His (A8), Gly (A21), Arg (B30)-NH₂ human insulin,

Arg (A0), Arg (A1), His (A8), Gly (A21), Lys (B30)-NH₂ human insulin, and

His (A8), Gly (A21), Arg (B31), Arg (B32)-NH₂ human insulin.

7. The pharmaceutical formulation as claimed in claim 1, the insulin derivative being 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^B29Lys^B30 human insulin, B30-N-palmitoyl-Thr^B29Lys^B30 human insulin, B29-N-(N-palmitoyl-Y-glutamyl)-des(B39) human insulin, B29-N—

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

-carboxyheptadecanoyl)-des(B30) human insulin, and B29-N-(ω

-carboxyheptadecanoyl) human insulin,

8. The pharmaceutical formulation as claimed in claim 1, further comprising

0.001 to 0.2 mg/ml of zinc,

0.1 to 5.0 mg/ml of a preservative, and

5.0 to 100 mg/ml of an isotonicity agent, and

having a pH of 5 or less.

9. The pharmaceutical formulation as claimed in claim 1 one, further comprising a preservative selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, and parabens.

10. The pharmaceutical formulation as claimed in claim 1, further comprising an isotonicity agent selected from the group consisting of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.

11. The pharmaceutical formulation as claimed in claim 1, having a pH in the range of pH 2.5-4.5.

12. The pharmaceutical formulation as claimed in claim 1, having a pH in the range of pH 3.0-4.0.

13. The pharmaceutical formulation as claimed in claim 1, having a pH in the region of pH 3.75.

14. The pharmaceutical formulation as claimed in claim 1, wherein the insulin, insulin analog and/or insulin derivative is present in a concentration of 240-3000 nmol/ml.

15. The pharmaceutical formulation as claimed in claim 1, further comprising glycerol at a concentration of 20 to 30 mg/ml.

16. The pharmaceutical formulation as claimed in claim 1, further comprising glycerol at a concentration of 25 mg/ml.

17. The pharmaceutical formulation as claimed in claim 1, further comprising m-cresol at a concentration of 1 to 3 mg/ml.

18. The pharmaceutical formulation as claimed in claim 1, further comprising m-cresol at a concentration of 2 mg/ml.

19. The pharmaceutical formulation as claimed in claim 1, further comprising zinc at a concentration of 0.01 or 0.03 or 0.08 mg/ml.

20. The pharmaceutical formulation as claimed in claim 1, further comprising a glucagon-like peptide-1 (GLP 1) or an analog or derivative thereof, or exendin-3 and/or -4 or an analog or derivative thereof.

21. The pharmaceutical formulation as claimed in claim 20, further comprising exendin-4.

22. The pharmaceutical formulation as claimed in claim 20, in which an analog of exendin-4 is selected from the group consisting of

H-desPro³⁶-exendin-4-Lys₆-NH₂,

H-des(Pro^36,37)-exendin-4-Lys₄-NH₂ and

H-des(Pro^36,37)-exendin-4-Lys₅-NH₂,

or a pharmacologically tolerable salt thereof.

23. The pharmaceutical formulation as claimed in claim 20, in which an analog of exendin-4 is selected from the group consisting of

desPro³⁶ [Asp²⁸]exendin-4 (1-39),

desPro³⁶ [IsoAsp²⁸]exendin-4 (1-39),

desPro³⁶ [Met(O)¹⁴, Asp²⁸]exendin-4 (1-39),

desPro³⁶ [Met(O)¹⁴, IsoAsp²⁸]exendin-4 (1-39),

desPro³⁶ [Trp(O₂)²⁵, Asp²⁸]exendin-2 (1-39),

desPro³⁶ [Trp(O₂)²⁵, IsoAsp²⁸]exendin-2 (1-39),

desPro³⁶ [Met(O)¹⁴Trp(O₂)²⁵, Asp²⁸]exendin-4 (1-39) and

desPro³⁶ [Met(O)¹⁴Trp(O₂)²⁵, IsoAsp²⁸]exendin-4 (1-39),

or a pharmacologically tolerable salt thereof.

24. The pharmaceutical formulation as claimed in claim 23, in which the peptide Lys₆-NH₂ is attached to the C-termini of the analogs of exendin-4.

25. The pharmaceutical formulation as claimed in claim 20, in which an analog of exendin-4 is selected from the group consisting of

H-(Lys)₆-des Pro³⁶ [Asp²⁸]exendin-4(1-39)-Lys₆-NH₂

des Asp²⁸Pro³⁶, Pro³⁷, Pro³⁸ exendin-4(1-39)-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-NH₂,

H-Asn-(Glu);

des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-NH₂,

des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-(Lys)₆-des Pro³⁶ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,

H-des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵]exendin-4(1-39)-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-NH₂,

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-NH₂,

des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-(Lys)₆-des Pro³⁶ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,

des Met(O)¹⁴ Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ exendin-4(1-39)-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-NH₂,

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39)-NH₂,

des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,

H-Asn-(Glu)₅ des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39)-(Lys)₆-NH₂,

H-(Lys)₆-des Pro³⁶ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,

des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²1exendin-4(1-3

     9)-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-NH₂,

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39)-NH₂,

des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂, and

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)₂₅, Asp²⁸] exendin-4(1-39)-(Lys)₆-NH₂,

or a pharmacologically tolerable salt thereof.

26. The pharmaceutical formulation as claimed in claim 20, further comprising Arg³⁴, Lys²⁶ (N^ε

(γ

-glutamyl(N^α

-hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof.

27. The pharmaceutical formulation as claimed in claim 1, comprising methionine in the concentration range of up to 10 mg/ml.

28. The pharmaceutical formulation as claimed in claim 27, comprising methionine in the concentration range of up to 3 mg/ml.

29. A process for preparing the pharmaceutical formulation as claimed in claim 1 comprising

(a) introducing the components into an aqueous solution and

(b) adjusting the pH.

30. A method of treating diabetes mellitus in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the aqueous pharmaceutical formulation of claim 1.

31. (canceled)