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Polysaccharide conjugate of carboxylic acid drug, preparation method thereof and application thereof

A technology of carboxylic acid drugs and conjugates, which can be used in pharmaceutical formulations, medical preparations without active ingredients, and medical preparations containing active ingredients, etc. Low, difficult to achieve the dosage and other issues, to achieve the effects of good stability, excellent biodegradability, and excellent biocompatibility

Inactive Publication Date: 2010-06-23
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some polysaccharide-drug conjugates are now in the research stage, but these conjugates still have the following defects: the inherent difficulties in the chemical reaction of the polymer make the synthesis conditions relatively harsh and the yield is low; When other functional groups are directly condensed, the linking arms used are more complex, such as amino acids or polypeptides; the grafting rate of some hydrophobic drugs is low, and the drug loading capacity is not high, making it difficult to achieve the dosage and affect the therapeutic effect, etc.

Method used

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  • Polysaccharide conjugate of carboxylic acid drug, preparation method thereof and application thereof
  • Polysaccharide conjugate of carboxylic acid drug, preparation method thereof and application thereof
  • Polysaccharide conjugate of carboxylic acid drug, preparation method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: the synthesis of all-trans retinoic acid-heparin

[0050] Take 10mmol all-trans retinoic acid, 12mmol dicyclohexylcarbodiimide (DCC), 15mmol hydroxysuccinimide (NHS), dissolve in 30ml N,N-dimethylformamide, protect from light and nitrogen , reacted in ice bath for 30min, and then rose to room temperature for 24h. After the reaction, the precipitate was filtered off, and a large amount of ethyl acetate was added to wash the precipitate. The filtrate was extracted, the ethyl acetate layers were combined, and the solvent was removed by rotary evaporation to obtain the activated intermediate ester of all-trans retinoic acid. Dissolve 1mmol of all-trans retinoic acid activated intermediate ester in 10ml of dichloromethane, slowly drop into 3mmol / ml of ethylenediamine in dichloromethane solution under ice-bath conditions, and monitor the reaction by thin layer chromatography (TLC method) After completion, the reaction liquid is extracted, the organic layers ar...

Embodiment 2

[0051] Embodiment 2: the synthesis of baicalin-chondroitin

[0052] Take 10mmol baicalin, 16mmol dicyclohexylcarbodiimide (DCC), 16mmol hydroxysuccinimide (NHS), dissolve in 25ml tetrahydrofuran, keep away from light, under the protection of nitrogen, react in ice bath for 45min, then rise to room temperature for reaction After 24 hours, the precipitate was filtered off, and a large amount of ethyl acetate was added to wash the precipitate. The filtrate was extracted, the ethyl acetate layers were combined, and the solvent was removed by rotary evaporation to obtain the activated intermediate ester of baicalin. Dissolve 2mmol of baicalin activated intermediate ester in 20ml of dichloromethane, and slowly drop into 6mmol / ml of ethylenediamine in dichloromethane solution under ice-bath conditions. After TLC monitors the reaction until complete, extract the reaction solution and combine organic layer, and separate and purify the resulting product to obtain the active intermediat...

Embodiment 3

[0053] Embodiment 3: the synthesis of baicalin-carboxymethyl chitosan

[0054] Take 10mmol baicalin, 16mmol dicyclohexylcarbodiimide (DCC), 16mmol hydroxysuccinimide (NHS), dissolve in 25ml tetrahydrofuran, keep away from light, under the protection of nitrogen, react in ice bath for 45min, then rise to room temperature for reaction After 24 hours, the precipitate was filtered off, and a large amount of ethyl acetate was added to wash the precipitate. The filtrate was extracted, the ethyl acetate layers were combined, and the solvent was removed by rotary evaporation to obtain the activated intermediate ester of baicalin. Dissolve 2mmol of baicalin activated intermediate ester in 20ml of dichloromethane, and slowly drop into 6mmol / ml of ethylenediamine in dichloromethane solution under ice-bath conditions. After TLC monitors the reaction until complete, extract the reaction solution and combine organic layer, and separate and purify the resulting product to obtain the active ...

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Abstract

The invention discloses a polysaccharide conjugate of carboxylic acid drug, a preparation thereof and application thereof. In the technical scheme, sub-alkyl diamine with 2-12 carbon atoms is used as a connecting arm, and a carboxylic acid drug and polysaccharide carboxyl are connected with each other through an amido link. Compared with the original carboxylic acid drug, the conjugate enhances the pharmacological effect, reduces the adverse effect and improve the safety. In addition, the conjugate can have the amphipathic performance through using the hydrophobic carboxylic acid drug, so as to be used as a carrier of a slightly soluble or sparingly soluble drug. The preparation method of the invention is simple, the process is mature, the yield is high, and the preparation method is applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a carboxylic acid drug-polysaccharide conjugate with good physiological activity and biodegradability as a drug carrier or a polymer prodrug, and the invention also relates to a preparation method of the conjugate and its application. Background technique [0002] In drug research, it is found that nearly 40% of drugs are insoluble in water, which easily leads to problems such as difficult preparation of preparations and low bioavailability. A hot and difficult point. [0003] In the preparation process, technologies such as microemulsion, liposome and solid dispersion are often used, or methods such as preparing the drug into a salt, adding a latent solvent, adding a co-solvent, and adding a surfactant are used to solubilize. However, as a drug carrier, liposomes still have disadvantages such as low encapsulation efficiency, unsatisfactory target distribution, and poor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K45/00A61K47/61
Inventor 周建平姚静侯琳
Owner CHINA PHARM UNIV
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