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Method for preparing cleavable polyethyleneglycol lipid derivates and application

A technology of polyethylene glycol lipid and polyethylene glycol, applied in the field of medicine, can solve problems such as affecting drug efficacy, being difficult to degrade, and falling off.

Inactive Publication Date: 2009-07-01
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

[0033] Example 1 Synthesis of polyethylene glycol-cholesterol methyl ester (PEG-CHM)

[0034] Put 1.2mmol cholesterol methyl chloromethyl and 0.8mmol monomethyl ether polyethylene glycol (molecular weight 2000) into a three-necked flask, add DMAP (0.4mmol) and triethylamine (1.08mmol) under nitrogen conditions, and add 20mL dichloromethane As the solvent, stir for 1 hour under ice-water bath conditions, remove the ice bath temperature and react for 24 hours. After the crude product is decompressed to recover the reaction solvent, add 100 mL of water, extract three times with dichloromethane, and then wash three times with ice water, saturated with chlorine Washed with sodium chloride 3 times, 2M hydrochloric acid washed 3 times, precipitated with ice 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 the carbonyl absorption peak of CHM is at 1776cm -1 There is a ...

Embodiment 2

[0035] Example 2 Synthesis of polyethylene glycol-α-tocopherol hemisuccinate (PEG-THS)

[0036] 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 an ice water bath, and add 206mg after 15 minutes Dicyclohexylcarbodiimide (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 3 times, then washed 3 times with saturated sodium bicarbonate, washed 3 times with distilled water, dried by rotary evaporation, precipitated with ice 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 the carbonyl absorption peak of THS is at 1753cm -1 And 1714cm -1 There is a carbonyl absorption...

Embodiment 3

[0037] Example 3 Determination of Critical Micelle Concentration (CMC) of PEG Lipid Derivatives

[0038] Due to the hydrophilic group and lipophilic group in the molecular structure, PEG lipid derivatives can spontaneously form micelles in aqueous solution, and the CMC of PEG lipid derivatives is determined by the fluorescent probe method.

[0039] Precisely pipette 0.1mL to a concentration of 1×10 -5 Put several parts of the pyrene working solution of M in a vial, blow dry with nitrogen, accurately weigh out several portions of PEG-CHS, PEG-CHM, and PEG-THS, put them in the vial, add 10 mL of pure water, respectively, to obtain the pyrene solution The 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), ultrasonic 4h at 60 ℃ in a water bath, placed overnight, you will get 10 -5 , 5×10 -5 , 10 -4 , 5×10 -4 , 10 -3 , 5×10 -3 , 10 -2 , 5×10 -2 , 10 -1 , 5×10 -1 , 1,5g / L solution, ready for...

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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, n=5-5000. The molecular weight of PEG is 300-30000. R represents one group selected from hemisuccinate group and carbomethoxy. The liposoluble fragment represented by R comprises one component selected from cholesterol, sitosterol, alpha-tocopherol. According to the invention, polyethylene glycol are 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 specifically relates to a preparation method of a cleavable PEG lipid derivative and its application in a drug delivery system. The adjuvant can be used as a long-circulation adjuvant to be added to the liquid microparticle preparation to prolong the circulation time of the preparation in vivo, increase its stability, and can gradually fall off the PEG chain segment under the action of esterase. Background technique: [0002] When liquid microparticle preparations such as liposomes, vesicles, emulsions, nanoparticles, etc. are used as passive targeted preparations for drug delivery, they are quickly taken up by the reticuloendothelial system (RES) due to the recognition of opsonins in the plasma , And the probability of specific binding with other cancerous tissues and organs is reduced. In order to overcome this shortcoming, the researchers modified the liquid microparticle preparation with lip...

Claims

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Application Information

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Patent Type & Authority Applications(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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