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Monomethoxy polyethylene glycol-dithio-divitamin e succinate and its preparation and application

A polyethylene glycol, monomethoxy technology, applied in gene therapy, medical preparations with inactive ingredients, non-central analgesics, etc., can solve the problems of reducing the efficacy of drugs, hindering the release of drugs, etc. The effect of curative effect, good stability and easy preparation

Active Publication Date: 2015-10-28
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have found that the PEG hydration layer on the surface of micelles can hinder the release of drugs from micelles, thereby reducing the efficacy of drugs and limiting clinical applications.

Method used

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  • Monomethoxy polyethylene glycol-dithio-divitamin e succinate and its preparation and application
  • Monomethoxy polyethylene glycol-dithio-divitamin e succinate and its preparation and application
  • Monomethoxy polyethylene glycol-dithio-divitamin e succinate and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Monomethoxy polyethylene glycol 5000-dithio-ditocopherol succinate block copolymer (P 5k SSLV) and monomethoxy polyethylene glycol 2000-dithio-divitamin E succinate block copolymer (P 2k SSLV) preparation.

[0056] (a) Dissolve 2.1g vitamin E succinate (VES) in dichloromethane, add 1g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI ) and 0.6 g of 1-hydroxybenzotriazole (HOBT) were magnetically stirred in an ice bath at 0 °C for 1 h. 1.3g benzyloxylysine ester hydrochloride sulfonate (OBzl-Lys·HCl·TosOH) was mixed with 3mL triethylamine, then added to the above activation solution, N 2 Under the protection of 30 ℃ magnetic stirring for 24h. After the reaction, wash and dry. After purification, the product (II) is obtained. (b) The product (II) was dissolved in ethyl acetate, and in palladium carbon (Pd / C) and H 2 Under the action of magnetic stirring at 30°C for 6h. Filtrate, collect the filtrate, and rotate to evaporate to obtain the product ...

Embodiment 2

[0067] Preparation of doxorubicin-loaded polymer micelles by film dispersion method

[0068] Weigh 5 mg of doxorubicin hydrochloride, dissolve it in 3 mL of methanol into a 50 mL eggplant-shaped bottle, add 10 μL of triethylamine, stir for 0.5 h, then add 40 mg of monomethoxypolyethylene glycol 5000-diol prepared in Example 1 Sulfur-ditocopherol succinate or monomethoxypolyethylene glycol 2000-dithio-ditocopherol succinate, add 2ml of methanol, shake evenly, 37°C rotary evaporation for 30min, remove the organic solvent. Nitrogen flow (N 2 ) Blow the eggplant-shaped bottle to remove the residual organic solvent, add 5mL of aqueous solution, stir at 37°C for 5h to hydrate. Centrifuge at 1,3000rpm for 20min to remove uncoated drug, and filter through a 0.22μm filter membrane. The encapsulation efficiency of the drug-loaded micelles is above 92%.

[0069] Two kinds of drug-loaded micelles prepared in embodiment 2 are measured the particle size and the shape of micelles by dynam...

Embodiment 3

[0071] Amphipathic P 5k Determination of the critical micelle concentration of SSLV polymers.

[0072] The determination of critical micelle concentration widely adopts pyrene fluorescent probe method. Pyrene is a fat-soluble fluorescent probe with weak fluorescence in polar environment and strong fluorescence in nonpolar environment. When there are micelles or hydrophobic regions in the polar solvent, pyrene will spontaneously transfer from the polar environment to the non-polar environment, resulting in enhanced fluorescence. Usually, this characteristic of pyrene is reflected by the ratio of the intensity of the first excitation peak to the third excitation peak. When this ratio increases significantly, it means that pyrene migrates from a polar environment to a non-polar environment, that is, micelles or hydrophobic region generated.

[0073] will be 5×10 -6 The mol / L pyrene solution in absolute ethanol was added to a 20mL stoppered flask, and the absolute ethanol was ...

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Abstract

The invention relates to a functional polyethylene glycol-disulfo-di-vitamin E succinate derivative and an application thereof in medicine delivery. An amphiphilic block copolymer uses the polyethylene glycol as the hydrophilic end to combine with the hydrophobic lysine di-vitamin E succinate under the bridging of disulfide bonds, so as to obtain the AB 2 type double-arm amphiphilic reduction-sensitive block copolymer. The copolymer has the potential antitumor activity and P-gp inhibitory action, and simultaneously the block copolymer can be self-assembled to form micelles in an aqueous medium, and the micelles can be used as a storage tank of insoluble medicines, protein and genomic medicines and can stably exist in the vivo circulation, and when the micelles enter into tumor, the disulfide bonds break under the effect of a large amount of reducing agents, the micelles are dispersed and the medicines in the micelles are released. The micelles have the characteristics of safety, high stability and high entrapment efficiency, and can be suitable for intravenous injection.

Description

technical field [0001] The invention belongs to the field of new auxiliary materials and new dosage forms of pharmaceutical preparations, and relates to an amphiphilic polyethylene glycol dithiodivitamin E succinate derivative with reduction sensitivity, anti-tumor effect, P-gp inhibition and long-circulation function And the preparation of the carrier, and its application as a drug carrier in drug delivery. Background technique [0002] Nanocarriers are widely used in targeted drug delivery systems because they can improve the efficacy of anticancer drugs and reduce drug side effects. PEGylated nanocarriers can show some unique advantages, such as prolonging the circulation time of nanoparticles; through EPR Effects Increase the accumulation of drugs in tumors; improve drug tolerance and so on. Among many carriers, PEGylated nanomicelles have attracted more attention due to their modifiable chemical structures and self-assembly into core-shell structures in aqueous solutio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48A61K47/34A61K9/107A61K48/00A61P35/00A61P29/00
Inventor 何仲贵孙进艾笑羽
Owner SHENYANG PHARMA UNIVERSITY
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