Protease Stabilized, Pegylated Insulin Analogues

a technology of pegylated insulin and protease, which is applied in the direction of peptide/protein ingredients, drug compositions, metabolic disorders, etc., can solve the problems that the administration of therapeutic peptides or proteins is often limited to parenteral routes rather than the preferred oral administration, and achieves high potential, high degree of bioavailability, and high apparent potency and/or bioavailability.

Inactive Publication Date: 2010-08-26
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0048]It has been discovered that insulins that are stabilised towards proteolytic degradation (by specific mutations) and PEGylated at the B29-lysine are efficacious and protracted and possess high potential as protracted insulins that can be administered pulmonary or orally. Furthermore, after oral administration, these PEGylated insulins of this invention have a higher degree of bioavailability than similar known PEGylated insulins, that are not stabilised towards proteolytic degradation and wherein the insulin backbone is not stabilised towards proteolytic degradation. Hence, these PEGylated insulin analogues of this invention

Problems solved by technology

Administration of therapeutic peptides or proteins is however often limited to parenteral routes rather than the preferred oral administration due to several barriers such as enzymatic degrada

Method used

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  • Protease Stabilized, Pegylated Insulin Analogues
  • Protease Stabilized, Pegylated Insulin Analogues
  • Protease Stabilized, Pegylated Insulin Analogues

Examples

Experimental program
Comparison scheme
Effect test

example 1

General Procedure (A)

[0278]A14E, B25H, B29K(M-3-mdPEG24-Propionyl), desB30 Human Insulin

[0279]A14E, B25H desB30 human insulin (1.5 g) was dissolved in 0.1 M Na2CO3 (34 ml) and pH was adjusted to 10 with 1N NaOH. mdPEG24-SPA (0.45 g, Quanta BioDesign Ltd.) dissolved in MeCN (16.8 ml) was added and the mixture was slowly stirred for 1 hour. Water (25 ml) was added, pH was adjusted to 5.5 with 1N HCl and the mixture was lyophilised. The title compound was obtained by preparative HPLC purification. Column: C18, 3 cm. A-Buffer: 0.1% TFA in MiliQ Water; B-buffer: 0.1% TFA in acetonitrile. Gradient 10-55% B over 45 min. Yield: 650 mg.

[0280]MALDI-MS (matrix: HCCA); m / z: 6762, calcd: 6762.

[0281]This compound has substantial protracted pulmonary efficacy.

[0282]The compound of example 1 (i.e. A14E, B25H, B29K(Nε-3-mdPEG24-propionyl), desB30 human insulin) and insulin aspart were tested by rat intratracheal drop instillation by the procedure described in example 10 below. The number of animals ...

example 2

General Procedure (A)

[0283]A14E, B25H, B29K(M-3-mPEG2.000-Propionyl), desB30 Human Insulin

[0284]MALDI-MS (matrix: sinapinic acid); m / z: 7850 (broad).

example 3

General Procedure (A)

[0285]A14E, B25H, B29K(Ar3-{mPEG750}Propionylcarbamoyl), desB30 Human Insulin

[0286]MALDI-MS (matrix: sinapinic acid); m / z: 6570 (broad).

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Abstract

Novel PEGylated insulin analogues exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogues contain B25H and A14E or A14H. The PEGylation is at B29K.

Description

FIELD OF THIS INVENTION[0001]The present invention relates to novel PEGylated insulin analogues exhibiting resistance towards proteases, a method for the preparation of such insulin analogues, insulin preparations containing the insulin analogues of the invention and a method of treating diabetes mellitus using these insulin analogues.BACKGROUND OF THIS INVENTION[0002]Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes and the disorder approaches epidemic proportions. Since the introduction of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus. Since people suffering from diabetes are subject to chronic treatment over several decades, there is a major need for safe, convenient and life quality improving insulin formulations.[0003]Human insulin consists of two polypeptide chains, the so-called A and B chains which contain 21 and 3...

Claims

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Application Information

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IPC IPC(8): A61K38/28C07K14/62A61P3/10A61P3/04
CPCA61K38/28C07K14/62A61K47/48215A61K47/60A61P3/00A61P3/04A61P3/06A61P3/08A61P3/10
Inventor MADSEN, PETER
Owner NOVO NORDISK AS
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