Pharmaceutical formulations comprising an insulin derivative

• US 9,034,818 B2
• Filed: 06/12/2008
• Issued: 05/19/2015
• Est. Priority Date: 06/13/2007
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Hubalek, Frantisek, Havelund, Svend, Poulsen, Christian, Huus, Kasper, Steensgaard, Dorte Bjerre
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US12/664,156
• Publication Number:
  US 20100167990A1
• Time in Patent Office: 2,532 Days
• US Class Current: 514/6.4
• 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 31/315 Zinc compounds
• CPC Class Codes: A61K 33/30 Zinc; Compounds thereof
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• 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 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The invention concerns a soluble pharmaceutical formulation comprising an insulin derivative wherein the formulation further comprises more than 4 zinc atoms per 6 molecules of the insulin derivative, and a citric acid monohydrate and/or a histidine compound used in an amount sufficient to increase the tendency of the insulin derivative to self-associate into dodecamers. The invention further comprises a process for preparing the soluble pharmaceutical formulation.

Claims

1. A soluble pharmaceutical formulation comprising dodecamers of insulin derivative wherein the formulation further comprises

a) more than 4 zinc atoms per 6 molecules of the insulin derivative,

b) citric acid monohydrate and/or a histidine compound used in an amount sufficient to increase the tendency of the insulin derivative to self-associate into dodecamers,

wherein the insulin derivative is a parent insulin with an ε

-amino group of a Lys residue present in the B chain of the parent insulin acylated and wherein the insulin derivative can be modified from the parent insulin by up to one further modification selected from the group consisting of the addition of one amino acid to the parent insulin, deletion of one amino acid from the parent insulin or the exchange of one amino acid from the parent insulin, wherein at least about 76% of the insulin derivative molecules are present as dodecamers when measured by SEC with phenol after storage at 37°

C. for 4 weeks.

2. A pharmaceutical formulation according to claim 1, wherein the molar ratio between the citric acid monohydrate and/or a histidine compound and zinc ions is from about 0.05 to about 10, from about 0.1 to about 2, from about 0.1 to about 1 or from about 0.2 to about 1.

3. A pharmaceutical formulation according to claim 1, wherein the citric acid monohydrate or the histidine compound is present in an amount from about 0.05 mM to about 4 mM, from about 0.1 mM to about 2 mM, from about 0.1 to about 1.8 mM, from about 0.05 mM to about 0.95 mM, from about 0.1 mM to about 0.9 mM, from about 0.1 mM to about 0.8 mM, from about 0.1 mM to about 0.7 mM, from about 0.1 mM to about 0.6 mM, from about 0.2 mM to about 0.9 mM or from about 0.2 mM to about 0.8 mM.

4. A pharmaceutical formulation according to claim 1, wherein at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.8% of the insulin derivative molecules are present as dodecamers when measured by SEC with phenol after storage at 37°

C. for 4 weeks.

5. A pharmaceutical formulation according to claim 1, wherein up to about 5%, up to about 4.5%, up to about 4%, up to about 3.5%, up to about 3.0%, up to about 2.5%, up to about 2.0% or up to about 1.5% of the insulin derivative molecules are present as monomers when measured by SEC without phenol after storage at 37°

C. for 4 weeks.

6. A pharmaceutical formulation according to claim 1, wherein the formulation comprises a histidine compound.

7. A pharmaceutical formulation according to claim 1, wherein the insulin derivative has a substituent —

W—

X—

Y—

Z attached to the ε

-amino group of a Lys residue present in the B chain of the parent insulin, the substituent being of the general formula;

—

W—

X—

Y—

Z

wherein W is;

an α

-amino acid residue having a carboxylic acid group in the side chain which residue forms, with one of its carboxylic acid groups, an amide group together with e ε

-amino group of a Lys residue present in the B chain of the parent insulin;

a chain composed of two, three or four α

-amino acid residues linked together via amide carbonyl bonds, which chain—

via an amide bond—

is linked to an ε

-amino group of a Lys residue present in the B chain of the parent insulin, the amino acid residues of W being selected from the group of amino acid residues having a neutral side chain and amino acid residues having a carboxylic acid group in the side chain so that W has at least one amino acid residue which has a carboxylic acid group in the side chain;

or

a covalent bond from X to an ε

-amino group of a Lys residue present in the B chain of the parent insulin;

X is;

—

CO—

;

—

CH(COOH)CO—

;

—

CO—

N(CH₂COOH)CH₂CO—

;

—

CO—

N(CH₂COOH)CH₂CON(CH₂COOH)CH₂CO;

—

CO—

N(CH₂CH₂COOH)CH₂CH₂CO—

;

—

CO—

N(CH₂CH₂COOH)CH₂CH₂CON(CH₂CH₂COOH)CH₂CH₂CO—

;

—

CO—

NHCH(COOH)(CH₂)₄NHCO;

—

CO—

N(CH₂CH₂COOH)CH₂CO—

;

or

—

CO—

N(CH₂COOH)CH₂CH₂CO;

that

a) when W is an amino acid residue or a chain of amino acid residues, via a bond from the underscored carbon forms an amide bond with an amino group in W, or

b) when W is a covalent bond, via a bond from the underscored carbonyl carbon forms an amide bond with an ε

-amino group of a Lys residue present in the B chain of the parent insulin;

Y is;

—

(CH₂)_m—

where m is an integer in the range of 6 to 32;

or

a divalent hydrocarbon chain comprising 1, 2 or 3 —

CH═

CH—

groups and a number of —

CH₂—

groups sufficient to give a total number of carbon atoms in the chain in the range of 10 to 32; and

Z is;

—

COOH;

—

CO-Asp;

—

CO-Glu;

—

CO-Gly;

—

CO-Sar;

—

CH(COOH)₂;

—

N(CH₂COOH)₂;

—

SO₃H;

or

—

PO₃H

provided that when W is a covalent bond and X is —

CO—

, then Z is different from —

COOH.

8. A pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation further comprises a rapid-acting insulin.

9. A process for preparing a soluble pharmaceutical formulation of claim 1 comprising

a) Providing an aqueous phase comprising an insulin derivative,

b) Providing more than about 4 zinc ions per 6 molecules of the insulin derivative,

c) Providing citric acid monohydrate and/or a histidine compound to increase the tendency of the insulin derivative to self-associate to dodecamer form, and

mixing the aqueous phase, the zinc ions and the citric acid monohydrate and/or the histidine compound to form a soluble pharmaceutical formulation.

10. The process of claim 9 wherein the resulting soluble pharmaceutical formulation is shelf stable.

11. A pharmaceutical composition according to claim 1, wherein the ε

-amino group of the Lys B29 insulin derivative is acylated.

12. A pharmaceutical composition according to claim 1, where the insulin derivative is LysB29Nε

-hexadecandioyl-γ

-Glu desB30 human insulin.

13. A method of treatment of type 1 diabetes, type 2 diabetes, and other disease states or conditions that cause hyperglycaemia, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a pharmaceutical formulation according to claim 1.

14. A soluble pharmaceutical formulation according to claim 1, wherein the formulation is shelf stable.