Preparation of glutamic acid modified polyethylene glycol monostearate and application of glutamic acid modified polyethylene glycol monostearate in target drug transfer

A technology of polyethylene glycol monostearate and monostearate, applied to the application of targeted materials in active targeted drug delivery systems, glutamic acid-polyethylene glycol monostearate In the field of preparation, it can solve the problems of ignoring the characteristics and advantages of transporters, and achieve good tumor targeting, easy preparation, and good tumor inhibitory effect

Active Publication Date: 2016-02-10
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, more studies have equated the role of transporters with receptors, ignoring the characteristics and advantages of transporters themselves

Method used

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  • Preparation of glutamic acid modified polyethylene glycol monostearate and application of glutamic acid modified polyethylene glycol monostearate in target drug transfer
  • Preparation of glutamic acid modified polyethylene glycol monostearate and application of glutamic acid modified polyethylene glycol monostearate in target drug transfer
  • Preparation of glutamic acid modified polyethylene glycol monostearate and application of glutamic acid modified polyethylene glycol monostearate in target drug transfer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Preparation of glutamic acid-polyethylene glycol monostearate with four different PEG chain lengths.

[0062] N-benzyloxycarbonyl-L-glutamic acid-1-benzyl ester (Z-Glu-OBzl, II), dissolved in an appropriate amount of organic solvents such as dichloromethane and dimethyl sulfoxide, under the action of a catalyst, Such as: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP), keep away from light in ice bath for 1h-2h, and then mix with Different chain length polyethylene glycol monostearate (SP n , Ⅰ) reacted under the protection of N2 at 30°C for 12h-48h, and obtained light yellow solid Ⅲ through separation and purification. Compound Ⅲ undergoes palladium-carbon reduction reaction, removes the protecting group of glutamic acid, and then obtains the final compound-glutamic acid-polyethylene glycol monostearate (SPG) through further separation and purification. n ,Ⅳ). The reaction formula is as follows:

[0063]

[00...

Embodiment 2

[0067] Glutamic acid-polyethylene glycol monostearate modified nanoparticles loaded with paclitaxel or coumarin 6 prepared by emulsification solvent evaporation method

[0068] Weigh 1 mg of paclitaxel or coumarin 6, dissolve in 1 mL of dichloromethane, add 1 mg or 2 mg of glutamic acid-modified polyethylene glycol monostearate or polyethylene glycol with different PEG chain lengths prepared in Example 1 alcohol monostearate, and 20 mg of polylactic polyglycolic acid copolymer. Add it to 5 mL of 1% polyvinyl alcohol aqueous solution, sonicate the probe at 300 W for 10 min, stir overnight, and centrifuge at 3500 rpm for 10 min to remove uncoated drugs.

[0069] The nanoparticles prepared in Example 2 are measured by dynamic light scattering and transmission electron microscopy for particle size and shape of micelles, the results are as follows: Figure 4 . Dynamic light scattering was used to measure glutamic acid-polyethylene glycol monostearate modified nanoparticles with d...

Embodiment 3

[0073] Stability Test of Glutamic Acid-Polyethylene Glycol Monostearate Modified Drug-loaded Nanoparticles in Plasma

[0074] Prepare the drug-loaded nanoparticles modified by glutamic acid-polyethylene glycol monostearate according to Example 2, place the nanoparticles in pH7.4 phosphate buffer containing 10% FBS, and measure the concentration of each nanometer by dynamic light scattering. Particle size at 0h, 1h, 2h, 4h, 6h8h, 10h, 12h and 24h.

[0075] Figure 5 The results showed that the glutamic acid-polyethylene glycol monostearate modified drug-loaded nanoparticles with different ligand modification densities and PEG chain lengths had better plasma stability.

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Abstract

The invention relates to preparation of glutamic acid-polyethylene glycol monostearate and application of the amphipathic target material modified nano-particles in disease target transfer. According to the amphipathic target material, glutamic acid is used as a target head, polyethylene glycol is used for improving the flexibility of the target head, and hydrophobic monostearate is used as an anchoring position with polyglycolic-polylactic acid copolymer. The target material modified nano-particles can be used as a target transfer tool of multiple anti-tumor drugs, and interacts with high-expression big neutral amino acid transporter 1 on a tumor cell membrane by the surface modified glutamic acid, so that the cell uptake and anti-tumor activity of the nano-particles can be effectively improved. The nano-particles have good stability, excellent target performance, can be used in intravenous injection, and have a relatively large market application prospect.

Description

technical field [0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and relates to the preparation of glutamic acid-polyethylene glycol monostearate with different PEG chain lengths and its application as a targeting material in an active targeting drug delivery system . Background technique [0002] The rapid growth and metastasis of tumors are closely related to the high expression of trophic transporters in tumor sites, such as vitamin transporters, amino acid transporters, and glucose transporters. Therefore, these tumor-indispensable trophic transporters can be exploited as new targets for active tumor-targeting therapy. 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, increasing the Ligand flex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K47/34A61K9/51A61K31/337A61P35/00
Inventor 孙进何仲贵李琳狄兴盛仵明瑞
Owner SHENYANG PHARMA UNIVERSITY
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