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Method for preparing cleavable polyethyleneglycol lipid derivates and application

A technology of polyethylene glycol lipids and derivatives, which is applied in the field of medicine and can solve problems such as affecting drug efficacy, falling off, and not easy to degrade

Inactive Publication Date: 2012-06-27
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, traditional long-circulation materials are not easy to degrade in vivo. Although they can prolong the circulation time of the formulation in vivo, they may cause liposome content to be released when the formulation reaches the target site because the PEG chain is still attached to the surface of the liposome. The delay affects the efficacy of the drug. Therefore, some researchers have hoped that by changing the chemical bond between PEG and lipids, human physiological or pathological conditions can be used to make the PEG chain fall off from the liposome surface during circulation or after reaching the target site. , increase the amount of drug carried by liposomes into cells

Method used

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  • Method for preparing cleavable polyethyleneglycol lipid derivates and application
  • Method for preparing cleavable polyethyleneglycol lipid derivates and application
  • Method for preparing cleavable polyethyleneglycol lipid derivates and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The synthesis of embodiment 1 polyethylene glycol-cholesterol methyl ester (PEG-CHM)

[0037] Put 1.2mmol cholesteryl chloromethyl ester and 0.8mmol monomethyl ether polyethylene glycol (molecular weight 2000) into a three-neck flask, add DMAP (0.4mmol) and triethylamine (1.08mmol) under nitrogen, and add 20mL dichloromethane As a solvent, stir for 1 hour in an ice-water bath, remove the ice bath and react for 24 hours. After the crude product is recovered from the reaction solvent under reduced pressure, 100 mL of water is added, extracted three times with dichloromethane, washed three times with ice water, saturated with chlorine Washed three times with sodium chloride, washed three times with 2M hydrochloric acid, precipitated with glacial ether, and recrystallized from absolute ethanol to obtain a white waxy polymer. The product obtained is PEG-CHM, IR (KBr) (cm -1 ): PEG has no carbonyl absorption peak, and CHM has a carbonyl absorption peak at 1776cm -1 There is ...

Embodiment 2

[0038] Example 2 Synthesis of polyethylene glycol-α-tocopheryl hemisuccinate (PEG-THS)

[0039] Put 1mmol α-tocopherol hemisuccinate and 0.6mmol monomethyl ether polyethylene glycol (molecular weight 2000) into a round bottom flask, use 20mL dichloromethane as the reaction solvent, add 44mg DMAP in ice-water bath, add 206mg dichloromethane after 15 minutes Cyclohexylcarbodiimide (DCC) was used as a catalyst, reacted at room temperature for 4 hours, and filtered with suction to obtain a crude product solution. The crude product was washed 3 times with 2M hydrochloric acid and extracted three times, then washed 3 times with saturated sodium bicarbonate, washed 3 times with distilled water, dried by rotary evaporation, precipitated with glacial ether, and recrystallized from absolute ethanol to obtain a white waxy polymer. The product is PEG-THS, IR(KBr)(cm -1 ): PEG has no carbonyl absorption peak, and THS has a carbonyl absorption peak at 1753cm -1 and 1714cm -1 There is a c...

Embodiment 3

[0040] The mensuration of embodiment 3PEG lipid derivative critical micelle concentration (CMC)

[0041] Due to the hydrophilic and lipophilic groups in the molecular structure, PEG lipid derivatives can spontaneously form micelles in aqueous solution, and the CMC of PEG lipid derivatives was determined by fluorescent probe method.

[0042] Precisely pipette 0.1mL with a concentration of 1×10 -5 Several parts of the pyrene working solution of M were placed in vials, blown dry with nitrogen gas, accurately weighed several parts of PEG-CHS, PEG-CHM, and PEG-THS, put them in the aforementioned vials, and added 10 mL of pure water respectively to obtain the pyrene solution. Concentration is 10 -7 M (the saturated solubility of pyrene in pure water is 7×10 -7 M, the value is slightly lower than the saturated solubility), ultrasonicated in a water bath at 60°C for 4h, and left overnight to obtain 10 -5 , 5×10 -5 , 10 -4 , 5×10 -4 , 10 -3 , 5×10 -3 , 10 -2 , 5×10 -2 , 10 -...

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Abstract

The present invention belongs to technical field of medicine, and relates to the preparing of cleavable polyethylene glycol (PEG) lipid derivative and an application thereof in the liquid particle preparation. The general formula is as follows: CH3O(CH2CH2O)n-R-O-R<1>, wherein n=5-5000, the molecular weight of PEG is 300-30000, R represents one group selected from hemisuccinate group and carbomethoxy, and the liposoluble fragment represented by R<1> comprises one component selected from cholesterol, sitosterol, alpha-tocopherol. According to the invention, polyethylene glycol is connected with lipoid derivatives such as cholesterol, alpha-tocopherol, etc. through ester linkage. The cleavable PEG lipid derivative can be applied to the modification of liquid particle preparation. On one hand, the PEG lipid derivative has appropriate adhesive force of the surface of liquid particle preparation and guarantees enough holding time of PEG lipid derivative in blood. On the other hand, the PEG lipid derivative can gradually break away from the surface of preparation in the circulation process. The particle preparation which only comprises a few polyethylene glycol on the surface can combine and phagocytose the pathological cell. The medicine is delivered into the cell and therefore has the function of selectively killing the pathological cell.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a class of cleavable PEG lipid derivatives and an application in a drug delivery system. The auxiliary material can be added to the liquid particle preparation as a long-circulation auxiliary material to extend the circulation time of the preparation in vivo, increase its stability, and gradually shed the PEG chain segment under the action of esterase. Background technique: [0002] When liquid particle preparations such as liposomes, vesicles, emulsions, nanoparticles, etc. are used as passive targeting agents for drug delivery, they are quickly absorbed by the reticuloendothelial system (RES) due to the recognition of opsonins in plasma , while the probability of specific binding to other cancerous tissues and organs is reduced. In order to overcome this defect, the researchers modified the liquid particle preparation with lipid derivative...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/34A61K47/48A61K47/14A61K47/22A61K47/28
Inventor 邓意辉徐缓王绍宁陈大为
Owner SHENYANG PHARMA UNIVERSITY
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