Conjugates of hydroxyalkyl starch and a protein

A technology of hydroxyalkyl starch and conjugates, which is applied in the field of conjugates of hydroxyalkyl starches and proteins, and can solve problems such as not being very clear about the metabolic pathway of non-natural polymer PEG

Inactive Publication Date: 2012-01-04
FRESENIUS KABI DEUT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Despite advances in conjugation methods and applications of monofunctional PEG-molecules, a common disadvantage of PEGylated drugs is that the metabolic pathways of non-natural polymer PEGs are not well understood.

Method used

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  • Conjugates of hydroxyalkyl starch and a protein
  • Conjugates of hydroxyalkyl starch and a protein
  • Conjugates of hydroxyalkyl starch and a protein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0327] Example 1: Synthesis of functionalized HES:

[0328] Example 1.1 Synthesis of Amino-HES from Oxidized HES

[0329] 5.122 g of HES (MW=14,500 D, DS=0.41, Supramol Parenteral Colloids GmbH, Rosbach-Rodheim, D) selectively oxidized at its reducing end groups according to the description of DE 19628705 A1 were heated at 80° C. under vacuum for 15.5 hours And it was dissolved in 25 mL dry DMSO (Fluka, Sigma-Aldrich Chemie GmbH, Taufkirchen, D) under nitrogen. To the resulting solution was added 51.22 mmol of 1,4-diaminobutane (Fluka, Sigma-Aldrich Chemie GmbH, Taufkirchen, D). After it was incubated at 40° C. for 17 hours, the reaction mixture was added to 150 mL of ice-cold 1:1 ethanol (DAB, Sonnenberg, Braunschweig, D) and acetone (Carl Roth GmbH+Co.KG, Karlsruhe, D). (v / v) mixture and incubated at -20°C for 1 hour. The precipitated product was collected by centrifugation at 4°C, washed with 40 ml of the same mixture, redissolved in 80 mL of water, and dialyzed against ...

Embodiment 2

[0336] Example 2 Synthesis of protein-HES conjugates by chemical ligation:

Embodiment 21

[0337] Example 2.1 Synthesis of peptide-thioester A-HES conjugates from H-Cys(S-tBu)-HES and peptide-thioester A

[0338] At 22°C, add 5 μL of 10 mg / mL peptide-thioester A (GBF, Braunschweig, D, amino acid sequence: H-SPFGADTTVCCFNYSVRKLPQNHVKDYFYTSSK-ethyl thiopropionate; MW=3,920 g / mol) at 1:1 ( v / v) N, N-dimethylformamide (peptide synthesis grade, Biosolve, Valkenswaard, NL) and 0.1M sodium phosphate buffer (pH 7.2) in the solution of the mixture, add 5 μ L 255mg / mL as in Example H-Cys(S-tBu)-HES solution synthesized as described in 1.2 and 5 μL of 1.5M catalyst solution in DMF. As a catalyst, thiophenol ( figure 1 , lane B) or benzylthiol ( figure 1 , lane C). As a reaction control, 5 μL of buffer instead of catalyst solution was added to the mixture of HES-derivative and peptide ( figure 1 , lane E).

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Abstract

The present invention relates to an active substance and hydroxyalklyl starch, preferably hydroxyalkyl starch, wherein the conjugates are prepared by native chemical ligation via covalently linking the hydroxyalkyl stach and the active substance by reacting a thioester group with an alpha-X beta-amino group, wherein X is selected from the group consisting of -SH and NH-N. The present invention also relates to the method of producing these conjugates and the use of the conjugates.

Description

[0001] This application is a divisional application of the international application filed on March 11, 2005 with the application number PCT / EP2005 / 002640 and the title of the invention "Conjugates of Hydroxyalkyl Starch and Protein". The international application was filed in September 2006 It entered the Chinese national phase on the 11th, with the application number 200580007791.x. technical field [0002] The present invention relates to conjugates of active substances and hydroxyalkyl starches, preferably hydroxyethyl starches, wherein said conjugates are produced by native chemical linkages covalently linking hydroxyalkyl starches and active substances, said The covalent attachment of is carried out by reacting a thioester group with an α-Xβ-amino group, where X is selected from -SH and The invention also relates to methods for the preparation of these conjugates and to the use of said conjugates. Background technique [0003] Native chemical ligation is a very effic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48C08B31/18C08H1/00C07K1/13A61K47/36
CPCC07K1/13A61K47/4823C08H1/00C08B31/185A61K47/61A61P7/06A61P43/00
Inventor N·桑德尔R·弗兰克
Owner FRESENIUS KABI DEUT GMBH
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