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Pegylated, Extended Insulins

a technology of pegylated and extended insulin, applied in the direction of peptide/protein ingredients, drug compositions, metabolic disorders, etc., can solve the problems of ineffective insulin absorption, psychological and physical pain of therapy type, and many diabetics are unwilling to undertake intensive therapy, etc., to achieve the effect of sufficient chemical stability

Inactive Publication Date: 2009-12-10
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]Another aspect of this invention deals with the furnishing of a medicament which can conveniently be administered pulmonary to treat diabetic patients and to reduce the risk of some of or all of the late complications often associated with diabetes.

Problems solved by technology

Unfortunately, many diabetics are unwilling to undertake intensive therapy due to the discomfort associated with the many injections required to maintain close control of glucose levels.
This type of therapy can be both psychologically and physically painful.
Thus far, however, these routes of administration have not resulted in effective insulin absorption.
This technology leads to reduced clearance in man and animals of a hormone polypeptide compared to the native polypeptide.
However, this technique is often hampered by reduced potency of the hormone polypeptides subjected to this technique (Hinds, K., et al., Bioconjugate Chem.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

General Procedure (A)

[0238]A22K(Nε-mPEG2000-Propionyl), B29R, desB30 Human Insulin

Step 1: Preparation and Purification of the Insulin Precursor LysA22 ArqB29 B29R desB30 B′A

[0239]The insulin precursor A22K, B29R, desB30, B′A single chain insulin can be purified as described in the purification steps A to C below.

Purification step A: Capture

[0240]In step A, 10.75 litres of cleared culture media is diluted by addition of 4.5 litres of 99% ethanol, to give a total volume of 15.25 litres containing 30 vol % ethanol (conductivity 2.7 mS / cm, pH=3.4). A 300 ml SP Big Beads Sepharose column (100-300 μm, Amersham Biosciences) was equilibrated with 1 litre of 0.1 M citric acid pH 3.5 (flow app. 20 ml / min), before loading the 15.25 litres of prepared culture media over night (flow app. 10 ml / min). After loading the column was again washed with 1 litre of 0.1 M citric acid pH 3.5 followed by 1 liter of 40 vol % ethanol (flow app. 20 ml / min). The bound insulin precursor A22K, B29R, desB30, B′A s...

example 2

General Procedure (B)

[0245]A22K(NεmPEG2000-propionyl), B29R, desB30 Human Insulin

[0246]A22K, B29R, desB30 human insulin (125 mg) was dissolved in 0.1 M Na2CO3 (2.8 ml). mPEG-SPA 2000 (50 mg) dissolved in acetonitrile (1.25 ml) was added. pH was adjusted from 10.2 to 10.4 with 0.1 N NaOH. After 50 min more mPEG-SPA 2000 (25 mg) dissolved in acetonitrile (1.25 ml) was added. After slow stirring for 80 min, water (4.5 ml) was added and pH was adjusted to 5 with 1 N HCl. The mixture was lyophilized. The title compound was obtained by preparative HPLC purification. Column: C4, 2 cm. A-Buffer: 0.1% TFA in MiliQ Water; B-buffer: 0.1% TFA in acetonitrile. Gradient 30-65% B over 30 min. Yield 43 mg.

[0247]MALDI-MS (matrix: sinapinic acid); m / z: 8114.

example 3

General Procedure (B)

[0248]A22K(NεmPEG750-Propionyl, B29R, desB30 Human Insulin

[0249]MALDI-MS (matrix: sinapinic acid); m / z: 5862.

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PUM

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Abstract

PEGylated, extended insulins are insulins which, compared with human insulin, has one or more extensions extended from the A1, B1, A21 and / or B30 position(s), said extension(s) consist(s) of amino acid residue(s) and wherein a PEG moiety, via a linker, is attached to one or more of the amino acid residues in the extension(s). PEG is polyethyleneglycol. Such PEGylated, extended insulins have higher bioavailability and a longer time-action profile than regulär insulin and are in particular suited for pulmonary administration and can, conveniently, be used to treat diabetes.

Description

FIELD OF THIS INVENTION[0001]The present invention is related to PEGylated, extended insulins which have insulin activity and can be used for the treatment of diabetes. The PEGylated, extended insulins have higher bioavailability and a longer time-action profile than regular insulin and are in particular suited for pulmonary administration. They will also have a high physical stability and a low tendency to fibrillation and will be soluble at neutral pH. This invention is also related to pharmaceutical compositions containing the PEGylated, extended insulins.BACKGROUND OF THIS INVENTION[0002]The inherited physical and chemical stability of the insulin molecule is a basic condition for insulin therapy of diabetes mellitus. These basic properties are fundamental for insulin formulation and for applicable insulin administration methods, as well as for shelf-life and storage conditions of pharmaceutical preparations. Use of solutions in administration of insulin exposes the molecule to ...

Claims

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Application Information

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IPC IPC(8): C07K14/62
CPCA61K47/48215A61K38/28A61K47/60A61P3/10A61P3/08A61P5/48
Inventor MADSEN, PETERKJELDSEN, THOMAS BORGLUMTAGMOSE, TINA MOLLERJAKOBSEN, PALLE
Owner NOVO NORDISK AS
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