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Preparation method of polyethyleneglycol monomethyl ether-polylactic acid block copolymer

A technology of polyethylene glycol monomethyl ether and block copolymer, which is applied in the directions of non-active ingredients medical preparations, medical preparations containing active ingredients, and pharmaceutical formulas, which can solve the problems of easy agglomeration, solvent residue, large Impurities and other problems, to achieve the effect of good fluidity, reduced molecular weight distribution, and improved hygroscopicity

Inactive Publication Date: 2015-09-09
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent CN102219892 disclosed that the preparation method of the polyethylene glycol monomethyl ether-polylactic acid block copolymer containing the above-mentioned average molecular weight adopts a solvent polycondensation method, and solvents such as isopropanol, xylene, and dimethylformamide are used. , such solvents have high boiling points, which are likely to cause solvent residues and affect the safety of the further prepared drug polymer micelles
At present, the melt polycondensation method that does not use a solvent is the most commonly used method, such as the method disclosed in the preparation example 1 of the Chinese patent CN96197134.7 specification, but the prepared polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared. Polyethylene glycol monomethyl ether-polylactic acid block copolymer has a wide molecular weight distribution, and the product is hygroscopic and easy to agglomerate. It will produce relatively large impurities in the process of preparing paclitaxel polymer micelles with paclitaxel, so it is necessary to prepare Improvement of methods to improve product quality

Method used

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  • Preparation method of polyethyleneglycol monomethyl ether-polylactic acid block copolymer
  • Preparation method of polyethyleneglycol monomethyl ether-polylactic acid block copolymer
  • Preparation method of polyethyleneglycol monomethyl ether-polylactic acid block copolymer

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Reaction stage: put 192g of polyethylene glycol monomethyl ether into the reactor, replace it with nitrogen, and dry it in vacuum at 120°C for 3 hours, then put 1.2g of the catalyst stannous octoate into the reactor, replace it with nitrogen, and continue vacuum drying for 1 hour; put in lactide 208g, evacuate for 1.5min, airtight, after the lactide is completely melted, then evacuate for 5min, heat up to 140°C, react for 12h, after the reaction is completed, cool down to obtain a light yellow clear liquid;

[0037] The first crystallization: dilute with 400ml of dichloromethane, slowly add to 8L of ether, stir and crystallize for 1h, and filter with suction;

[0038] The second crystallization: dilute the filter cake with 1600ml of dichloromethane, wash with 800ml of purified water, dry with 200g of anhydrous magnesium sulfate, filter with suction, remove the dichloromethane by rotary evaporation of the mother liquor, add 200ml of dichloromethane to dissolve, add to 6L ...

Embodiment 2

[0043] Reaction stage: put 192g of polyethylene glycol monomethyl ether into the reactor, replace it with nitrogen, and dry it in vacuum at 120°C for 3 hours, then put 1.2g of the catalyst stannous octoate into the reactor, replace it with nitrogen, and continue vacuum drying for 1 hour; put in lactide 208g, evacuate for 1.5min, airtight, after the lactide is completely melted, then evacuate for 5min, heat up to 140°C, react for 12h, after the reaction is completed, cool down to obtain a light yellow clear liquid;

[0044] The first crystallization: add 3L of dichloromethane to the reaction solution for dilution, wash with 1.5L of purified water, dry with 300g of anhydrous magnesium sulfate, filter with suction, remove the dichloromethane by rotary evaporation of the mother liquor, add 200ml of dichloromethane to dissolve, add to In 6L of ether at 0±5°C, stir and crystallize for 1h, and filter with suction;

[0045] The second crystallization: add 200ml of dichloromethane to t...

Embodiment 3

[0049] Reaction stage: put 192g of polyethylene glycol monomethyl ether into the reactor, replace it with nitrogen, and dry it in vacuum at 120°C for 3 hours, then put 1.2g of the catalyst stannous octoate into the reactor, replace it with nitrogen, and continue vacuum drying for 1 hour; put in lactide 208g, evacuate for 1.5min, airtight, after the lactide is completely melted, then evacuate for 5min, heat up to 140°C, react for 12h, after the reaction is completed, cool down to obtain a light yellow clear liquid;

[0050] The first crystallization: add 200ml of dichloromethane to dilute, slowly add to 6L 0±5°C ether, stir and crystallize for 1h, and filter with suction; the second crystallization: add 1000ml of dichloromethane to dissolve the filter cake, wash with 500ml of purified water, Dry 200g of anhydrous magnesium sulfate, filter with suction, remove dichloromethane by rotary evaporation of the mother liquor, then add 200ml of dichloromethane to dissolve, add to 6L of e...

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Abstract

The invention provides a preparation method of a polyethyleneglycol monomethyl ether-polylactic acid block copolymer, which comprises the following steps: reacting raw materials polyethyleneglycol monomethyl ether and D,L-lactide by melt polycondensation by using stannous octoate as a catalyst; and after the reaction finishes, carrying out after-treatment by a 1-4-time dichloromethane dissolution-aether crystallization process, wherein the product to be purified is dissolved by the dichloromethane and washed with pure water in the first or second crystallization process to remove more low-molecular impurities, thereby obviously narrowing the molecular weight distribution of the product. The hydroscopic property of the product is obviously improved, and the flowability is higher and is more suitable for preservation and use of the product.

Description

technical field [0001] The invention relates to a pharmaceutical preparation auxiliary material, in particular to a preparation method of polyethylene glycol monomethyl ether-polylactic acid block copolymer. Background technique [0002] Paclitaxel is a natural anti-tumor drug isolated from the bark of Taxus brevifolia by WANI in 1971. It is widely used in the treatment of various tumors such as ovarian cancer, breast cancer, and lung cancer. However, paclitaxel is very water-soluble. Low, almost no oral absorption, the main clinical application is paclitaxel injection, but in order to solubilize paclitaxel, the solubilizer used will produce allergic adverse reactions and reduce the curative effect at the same time. In order to improve the efficacy of paclitaxel and reduce adverse reactions, extensive research has been done on its dosage forms and administration methods at home and abroad, among which nano drug delivery system (nDDS) is the current research hotspot. At pres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G63/08C08G63/90A61K9/107A61K9/06A61K31/337A61K47/34
Inventor 罗灿洲吴子强袁庆宝玉荣谢佳琪
Owner 深圳万乐药业有限公司
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