Pluronics-PTX (Paclitaxel) amphiphilic macromolecular prodrug and micelle preparation thereof

A paclitaxel and macromolecular technology, applied in the field of medicine and chemical industry, can solve the problems of low solubility of taxane drugs and increase drug safety, and achieve the effects of improving bioavailability, avoiding drug burst release, and good safety

Inactive Publication Date: 2014-10-15
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The prodrug can self-assemble in water to form micelles with paclitaxel as the hydrophobic core and Pluronics as the hydrophilic shell, which not only increases the content of paclitaxel in the preparation, but also solves the problem of low solubility of taxanes in water. Moreover, the final preparation does not contain solubilizers and organic solvents, which increases the safety of medication

Method used

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  • Pluronics-PTX (Paclitaxel) amphiphilic macromolecular prodrug and micelle preparation thereof
  • Pluronics-PTX (Paclitaxel) amphiphilic macromolecular prodrug and micelle preparation thereof
  • Pluronics-PTX (Paclitaxel) amphiphilic macromolecular prodrug and micelle preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1 prepares Pluronics-paclitaxel amphiphilic macromolecular prodrug and micellar preparation thereof (synthetic route such as figure 2 shown)

[0045] (1) In a 50mL eggplant-shaped bottle, weigh 300mg paclitaxel and dissolve it in 10mL anhydrous dichloromethane, add succinic anhydride (48mg) and 4-dimethylaminopyridine (DMAP, 30mg) in sequence, under nitrogen protection, room temperature Stir for 24h. Evaporate dichloromethane to dryness, add 10mL ethyl acetate, fully dissolve, then add 10mL dilute hydrochloric acid (mass concentration 10.5%) for pickling, stir for 10min, extract and collect the organic phase, and repeat acid washing twice. The ethyl acetate layer containing the product was dried overnight (12 h) with anhydrous magnesium sulfate, concentrated by rotary evaporation, and the product was separated and purified on a silica gel column by dry loading to obtain carboxy-modified paclitaxel.

[0046] (2) In a 50mL eggplant-shaped bottle, dissolve ca...

Embodiment 2

[0057] (1) In a 50mL eggplant-shaped bottle, dissolve 2g Pluronic P123 and 34mg succinic anhydride in 15mL anhydrous dimethylformamide, then add 0.072mL triethylamine (TEA) and 0.08g DMAP in sequence, and react at room temperature 24h. Put the reaction solution into a treated dialysis bag (molecular weight cut-off 3500Da), put it in 500mL distilled water, dialyze for 48h, change the water every 4h, remove dimethylformamide, and freeze-dry to obtain the carboxyl-terminated Pluronic P123 solid product.

[0058] (2) In a 50mL eggplant-shaped bottle, dissolve 0.5g of Pluronic P123 with terminal carboxyl groups in anhydrous dimethyl sulfoxide, and after the polymer is dissolved, add 0.036g of dicyclohexylcarbodi Imine (DCC), 0.023g DMAP and 0.071g paclitaxel were reacted at room temperature for 48h, and the precipitate generated during the reaction was filtered off. After 72 hours, the water was changed every 4 hours to remove dimethyl sulfoxide, and freeze-dried to obtain the so...

Embodiment 3

[0061] (1) In a 50 mL eggplant-shaped bottle, weigh 100 mg paclitaxel and dissolve in 5 mL anhydrous THF, add maleic anhydride (17 mg) and DMAP (10 mg) in sequence, and stir at room temperature for 36 h under nitrogen protection. Evaporate THF to dryness and remove, add 15mL ethyl acetate, fully dissolve, then add 20mL dilute hydrochloric acid solution for pickling, stir for 30min, extract and collect the organic phase, and repeat acid washing twice. The ethyl acetate layer containing the product was dried overnight with anhydrous magnesium sulfate, concentrated by rotary evaporation, and the product was separated and purified on a silica gel column by dry loading to obtain carboxyl-modified paclitaxel.

[0062] (2) In a 50mL eggplant-shaped bottle, dissolve carboxy-modified paclitaxel (0.2g) in 10mL of anhydrous 1,4-dioxane, and add N,N'-diisopropyl Carbodiimide (DIC) (0.056g), DMAP (0.031g) and Pluronic F68 (2.065g) were reacted at room temperature for 48h. Dialyzed for 72 ...

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Abstract

The invention discloses a Pluronics-PTX (Paclitaxel) amphiphilic macromolecular prodrug which is prepared by bonding Pluronics and PTX through an ester bond. The prodrug can be self-assembled in water to form micelle which takes PTX as a hydrophobic core and takes Pluronics as a hydrophilic shell, the content of a PTX drug in a preparation is increased, the problem of low solubility of the PTX drugs in water is solved, and further, the final preparation is free of a solubilizer and an organic solvent, so that the safety of drug use is improved. An active targeting factor can be connected to a Pluronics-terminated hydroxyl to provide the drug with an active targeting function. Further, the defects of poor water solubility, serious allergic reaction and the like of the conventional PTX injection are overcome.

Description

technical field [0001] The invention relates to a Pluronics-paclitaxel amphiphilic macromolecular prodrug and a micelle preparation thereof, as well as a preparation method thereof, belonging to the technical field of medicine and chemical industry. Background technique [0002] Paclitaxel (PTX) was originally a tetracyclic diterpenoid compound extracted from the bark of Pacific yew. It is one of the first-choice anti-cancer drugs. See the chemical structure figure 1 . The anti-tumor mechanism of paclitaxel is: increase the number and polymerization speed of microtubule dimers during cell mitosis, promote the polymerization of microtubules, and at the same time inhibit the depolymerization of cytoplasmic microtubules, thereby inhibiting cell mitosis and making cancer cells stop at G2 phase and M phase to achieve the purpose of inhibiting the growth of tumor cells. Currently, paclitaxel is the drug of choice for the clinical treatment of ovarian cancer and breast cancer, wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K9/107A61K31/337A61P35/00
Inventor 张娜李敏刘永军刘凤喜
Owner SHANDONG UNIV
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