Segmented copolymer - docetaxel combination, preparation thereof and preparation method thereof

A technology of block copolymer and docetaxel, which is applied in the field of medicine and chemical industry, can solve the problems of low drug safety and inconvenient clinical drug use, so as to prolong the circulation time, avoid drug burst release, and improve tumor targeting effect Effect

Inactive Publication Date: 2012-08-08
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patients need to pre-administer drugs such as dexamethasone to reduce adverse reactions, which is inconvenient for clinical use and has low drug safety

Method used

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  • Segmented copolymer - docetaxel combination, preparation thereof and preparation method thereof
  • Segmented copolymer - docetaxel combination, preparation thereof and preparation method thereof
  • Segmented copolymer - docetaxel combination, preparation thereof and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] (1) In a 50mL eggplant-shaped bottle, weigh 100mg of docetaxel and dissolve it in 5mL of anhydrous dichloromethane, add succinic anhydride (25mg), 4-dimethylaminopyridine (DMAP, 15mg) in sequence, and nitrogen protection Next, stir at room temperature for 24h. Evaporate dichloromethane to dryness, add 10mL ethyl acetate, fully dissolve, then add 50mL 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 method to obtain carboxylated docetaxel.

[0041] (2) In a 50mL eggplant-shaped bottle, dissolve carboxylated docetaxel (0.3g) in 10mL of anhydrous dichloromethane, and add 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide (EDC) (0.13g), DMAP (0.04g) and Pluronic P123 (1.6g), react...

Embodiment 2

[0052] (1) In a 50mL eggplant-shaped bottle, dissolve 1g of Pluronic P123 and excess succinic anhydride in 10mL of anhydrous dimethylformamide, then add 0.036mL of triethylamine (TEA) and 0.04g of DMAP in sequence, at room temperature Reaction 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.

[0053] (2) In a 50mL eggplant-shaped bottle, dissolve 0.5g of Pluronic P123 with terminal carboxyl groups in anhydrous dimethyl sulfoxide. After the polymer is dissolved, cool to 0°C, and then add 0.035g of dicyclohexylcarbodi Imine (DCC), 0.021g DMAP and 0.103g docetaxel were reacted at room temperature for 48h, and the precipitate generated during the reaction was filtered off. , dialyzed for 72 hours, changed the water every 4 hours, removed dimethyl sulfoxide,...

Embodiment 3

[0057] (1) In a 50 mL eggplant-shaped bottle, weigh 150 mg of docetaxel and dissolve in 8 mL of anhydrous THF, add maleic anhydride (36 mg) and DMAP (45 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 100mL 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 carboxylated docetaxel.

[0058] (2) In a 50mL eggplant-shaped bottle, dissolve carboxylated docetaxel (0.2g) in 10mL of anhydrous 1,4-dioxane, and add N,N'-dioxane in turn under ice bath conditions Isopropylcarbodiimide (DIC) (0.056g), DMAP (0.054g) and Pluronic F127 (2.765g) were reacted at room tem...

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals and discloses segmented copolymer - docetaxel combination, a preparation thereof and a preparation method thereof. The combination is combined by bonding polyoxyethylene - polypropylene oxide - polyoxyethylene (PEO- b - PPO - b - PEO with a product name as Pluronics (BASF company)) triblock copolymer and docetaxel through ester bond, and the Pluronics - docetaxel combination is obtained. By utilizing amphipathy of the combination and adopting physical methods to prepare micelle aqueous solution, a freeze-dried preparation can also be prepared. Nanomicelle is capable of gathering at tumor parts through 'enhanced permeation and retention effects (EPR effects)', and tumor targeting of docetaxel is enhanced. Besides, an active targeting factor is connected on Pluronics polymer so as to have the function of active targeting. The segmented copolymer - docetaxel combination overcomes the defects that existing docetaxel injection is poor in water-solubility and severe in allergic reaction and the like.

Description

technical field [0001] The invention relates to a block copolymer-docetaxel conjugate, a micelle preparation thereof, a freeze-dried micelle preparation and a preparation method thereof, belonging to the technical field of medicine and chemical industry. Background technique [0002] Docetaxel (DTX) is a new type of taxane antineoplastic drug, a precursor compound extracted from the needles of the European yew tree, Taxus baccata L. 10-Deacetylbaccatin III, and then semi-synthesized product, see the attached chemical structure figure 1 . Its mechanism of action is similar to that of paclitaxel. It stimulates the polymerization of cathelicidin, promotes the assembly of tubulin into stable microtubules, inhibits its depolymerization, and causes cell proliferation to stop in the quiescent phase of mitosis (G 2 / M) stage. Its affinity for the microtubule binding site is 2-4 times that of paclitaxel, and has a broad anti-cancer spectrum. It is suitable for the treatment of var...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/337A61K9/19A61K9/10A61P35/00
Inventor 张娜刘志红张娟刘永军
Owner SHANDONG UNIV
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