# US 2010/0167990 A1 · Pharmaceutical Formulations Comprising an Insulin Derivative

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- Number: US 2010/0167990 A1
- Document ID: US20100167990A1
- Status: Published application
- Kind: A1
- Application number: 12/664,156
- Filed: 2008-06-12
- Published: 2010-07-01
- Earliest claimed: 2007-06-13
- Assignees: Novo Nordisk A/S
- Inventors: Christian Poulsen; Kasper Huus; Frantisek Hubalek; Dorte Bjerre Steensgaard; Sven Havelund
- Web page: https://patentgrep.com/patent/US20100167990A1

## CPC

- 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)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 31/315: Zinc compounds
- A61K 33/30: Zinc; Compounds thereof
- A61K 38/28: Insulins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07K 14/62: Insulins
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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

### Claim 1

A soluble pharmaceutical formulation comprising an 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.

### Claim 2

A shelf-stable soluble pharmaceutical formulation comprising an insulin derivative wherein the formulation further comprises
a) more than 4 zinc atoms per 6 molecules of 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.

### Claim 3

A soluble pharmaceutical formulation comprising an insulin derivative for the treatment of type 1 diabetes, type 2 diabetes and other states that cause hyperglycaemia in patients in need of such a treatment, 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.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

A pharmaceutical formulation according to claim 1, wherein, wherein at least about 76%, 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.

### Claim 7 (depends on 1)

A pharmaceutical formulation according to claim 1, wherein, 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.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

A pharmaceutical formulation according to claim 1, wherein, 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 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;
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.

### Claim 10 (depends on 1)

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

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13

(canceled)

### Claim 14

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

### Claim 15

A process for preparing a shelf-stable soluble pharmaceutical formulation 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,
mixing the aqueous phase, the zinc ions and the citric acid monohydrate and/or a histidine compound to form a soluble pharmaceutical formulation.