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Mono-modified polyethyleneglycol-insulin complexes and preparation method thereof

A technology of polyethylene glycol and amino polyethylene glycol, applied in the field of biomedicine, can solve the problems of difficult separation of modified products, increased cost of industrial production and the like

Inactive Publication Date: 2008-10-15
DALIAN NATIONALITIES UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some people use chemical methods to protect the N-terminal of the A chain, and modify the N-terminal of the B chain and the ε-amino group of the lysine of B29. Although most of the activity of insulin can be retained, the separation of the single-site modified product causes It is very difficult, and it also increases the cost of industrial production; there are also some people who can selectively modify the activity of the reagent by changing the activity of the reagent. For example, the aldehyde derivatives of PEG can selectively modify the N-terminal amino group at low pH. This still needs to protect the N-terminus of the A chain; in short, the current modification method cannot completely avoid the influence of the above four factors, and cannot obtain satisfactory modification results

Method used

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  • Mono-modified polyethyleneglycol-insulin complexes and preparation method thereof
  • Mono-modified polyethyleneglycol-insulin complexes and preparation method thereof
  • Mono-modified polyethyleneglycol-insulin complexes and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Preparation of an insulin-PEG complex whose end is connected to a PEG chain with a molecular weight of 5000

[0039] Step 1: Preparation of aminopolyethylene glycol with molecular weight of 5000

[0040] Get 20 grams (4 millimoles) of monomethoxy polyethylene glycol with a relative molecular weight of 5000, add in a 500 milliliter round bottom flask with 300 milliliters of toluene, heat and steam 100 milliliters of toluene to take out the moisture in the alcohol . The remaining solution was added with equimolar pyridine to reflux, and 2 times the molar amount of thionyl chloride (SOCl 2 ), after the dropwise addition, the temperature was lowered to 90°C to continue the reaction for 4 hours, cooled, filtered to remove the crystals, then evaporated toluene under reduced pressure, the residue was precipitated with ether, vacuum-dried by suction filtration to obtain 19 grams of product, which had a molecular weight of 5000 PEG-Cl. Dissolve this product in a sm...

Embodiment 2

[0051] Example 2: Preparation of an insulin-PEG complex whose end is connected to a PEG chain with a molecular weight of 10,000

[0052] Step 1: Preparation of aminopolyethylene glycol with molecular weight of 10000

[0053] Take 20 grams (2 mmol) of monomethoxypolyethylene glycol with a relative molecular weight of 10000, add it to a 500 milliliter round bottom flask filled with 300 milliliters of toluene, heat and steam 100 milliliters of toluene to take out the moisture in the alcohol . The remaining solution was added with equimolar pyridine to reflux, and 2 times the molar amount of thionyl chloride (SOCl 2 ), after the dropwise addition, the temperature was lowered to 90°C to continue the reaction for 4 hours, cooled, filtered to remove the crystals, then evaporated toluene under reduced pressure, the residue was precipitated with ether, vacuum-dried by suction filtration to obtain 19 grams of product, which had a molecular weight of 10000 PEG-Cl. Dissolve this produc...

Embodiment 3

[0064]Example 3: Preparation of an insulin-PEG complex with a PEG chain with a molecular weight of 20,000 at the end

[0065] Step 1: Preparation of aminopolyethylene glycol with molecular weight of 20000

[0066] Take 20 grams (1 mmol) of monomethoxypolyethylene glycol with a relative molecular weight of 20,000, add it to a 500-milliliter round-bottomed flask filled with 300 milliliters of toluene, heat and steam 100 milliliters of toluene to take out the moisture in the alcohol . The remaining solution was added with equimolar pyridine to reflux, and 2 times the molar amount of thionyl chloride (SOCl 2 ), after the dropwise addition, the temperature was lowered to 90°C to continue the reaction for 4 hours, cooled, filtered to remove the crystals, then evaporated toluene under reduced pressure, the residue was precipitated with ether, vacuum-dried by suction filtration to obtain 19 grams of product, which had a molecular weight of 20000 PEG-Cl. Dissolve this product in a s...

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Abstract

The invention relates to the field of bio-medicine. The formula of a polyethylene glycol-modified insulin composite is RNH-X-D, wherein R represents CH3O-(CH2CH2O)nCH2CH2, n is equal to 50-500, X is natural amino acid outside proline of genetic encode or non-natural amino acid of mono-amino mono-carboxyl, and D is B30 amino acid residue-removed natural pork insulin or human insulin. In PEG modification, carboxyl instead that amino is modified, and polyethylene glycol chain is linked to alpha carboxyl on B30 amino acid residue of insulin via amide bond at high yield and high stability. The polyethylene glycol-modified insulin composite has important application prospect in long acting aspect, and substantially is chemically modified insulin. The polyethylene glycol-modified insulin composite has potential long acting function.

Description

1. Technical field: [0001] The invention relates to the field of biomedicine, in particular to insulin for diabetes, and also provides a preparation method thereof. 2. Background technology: [0002] Diabetes mellitus is a common multiple metabolic disease, and its incidence is on the rise both at home and abroad. According to incomplete statistics, there are more than 30 million people with diabetes in the country, and the incidence of diabetes is as high as 3.2%. Although many diseases can kill people, diabetes is the third leading cause of death. [0003] Insulin is a specific peptide hormone compound for the treatment of diabetes, and there is no more effective alternative drug so far. However, since insulin is a protein that is easily hydrolyzed by proteases in the gastrointestinal tract and loses its activity, it can only be used by injection and cannot be administered in other ways. For insulin-dependent patients, to maintain the normal metabolism of life, frequent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K38/28A61P3/10A61K47/60
Inventor 何明磊
Owner DALIAN NATIONALITIES UNIVERSITY
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