SLOW-ACTING INSULIN PREPARATIONS

• US 20120232002A1
• Filed: 07/02/2010
• Published: 09/13/2012
• Est. Priority Date: 07/06/2009
• Status: Abandoned Application

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: Hauck, Gerrit, Schoettle, Isabell, Fuerst, Christiane, Siefke-Henzler, Verena, Kamm, Walter, Schnieders, Julia, Carls, Jutta, Wolf, Gert
• Application Number:
  US13/382,772
• Publication Number:
  US 20120232002A1
• Time in Patent Office: Days
• US Class Current: 514/6.2
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 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
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Aqueous pharmaceutical formulations with an insulin analog, 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
  whose pH is 5 or less, and also their preparation, use for treating diabetes mellitus, and a medicament for treating diabetes mellitus.

Claims

1. Aqueous An aqueous pharmaceutical formulations formulation comprising an insulin analog of the formula I

2. The pharmaceutical formulation as claimed in claim 1, in which the insulin analog is selected from the group containing:

Arg (A0), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Arg (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Arg (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Lys (B32)-NH₂human 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)—

NH₂human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His(A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Arg (B32)-NH₂human insulin,

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

Arg (A0), His (A8), Glu (A5), 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)-NH₂human 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)-NH₂human 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)-NH₂human 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)-NH₂human insulin,

Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B0), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B0), Arg (B31), Arg (B32)-NH₂human insulin,

Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B0), Arg (B31), Lys (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Arg (B32)-NH₂human insulin,

Arg (A0), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Lys (B32)-NH₂human insulin,

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

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

3. The pharmaceutical formulation as claimed in claim 1, wherein the preservative is selected from a group containing phenol, m-cresol, chlorocresol, benzyl alcohol, and parabens.

4. The pharmaceutical formulation as claimed in claim 1, wherein the isotonicity agent is selected from a group containing mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.

5. The pharmaceutical formulation as claimed in claim 1, wherein said formulation has a pH in the range of pH 2.5-4.5.

6. The pharmaceutical formulation as claimed in claim 1, wherein said formulation has having a pH in the range of pH 3.0-4.0.

7. The pharmaceutical formulation as claimed in claim 1, wherein said formulation has a pH in the region of pH 3.75.

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

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

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

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

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

14. The pharmaceutical formulation as claimed in claim 1, further comprising a glucagon-like peptide-1 (GLP1) or an analog or derivative thereof, or exendin-3 and/or -4 or an analog or derivative thereof.

15. The pharmaceutical formulation as claimed in claim 14, further comprising exendin-4.

16. The pharmaceutical formulation as claimed in claim 14, wherein said analog of exendin-4 is selected from a group containing

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

17. The pharmaceutical formulation as claimed in claim 14, wherein said analog of exendin-4 is selected from a group containing

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

18. The pharmaceutical formulation as claimed in claim 17, wherein peptide Lys₆-NH₂ is attached to the C-termini of the analogs of exendin-4.

19. The pharmaceutical formulation as claimed in claim 14, wherein said analog of exendin-4 is selected from the group containing

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

des Asp²⁸Pro³⁶, Pro³⁷, Pro³⁸exendin-4(1-39)-NH₂,

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

H-Asn-(Glu)₅des 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 Asp²⁸Pro³⁶, 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)¹⁴Asp²⁸Pro ³⁶, Pro³⁷, Pro³⁸exendin-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)₅des 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 Asp²⁸Pro³⁶, Pro³⁷, Pro³⁸[Met(O)¹⁴, Trp(O₂)²⁵]exendin-4(1-39)-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,

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

20. The pharmaceutical formulation as claimed in claim 14, further comprising Arg³⁴, Lys²⁶(N^ε

(γ

-glutamyl(N^α

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

21. The pharmaceutical formulation as claimed in claim 1, comprising methionine.

22. The pharmaceutical formulation as claimed in claim 21, comprising methionine in the concentration range of up to 10 mg/ml.

23. The pharmaceutical formulation as claimed in claim 22, comprising methionine in the concentration range of up to 3 mg/ml.

24. A process for preparing the pharmaceutical formulation of claim 1, comprising

(a) introducing the components into an aqueous solution and

(b) adjusting the pH.

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

8. The pharmaceutical formulation as claimed in wherein said insulin, insulin analog and/or insulin derivative are present in a concentration of 240-3000 nmol/ml.

26. (canceled)