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Docetaxel micelle drug load system and preparation method thereof

A technology of docetaxel and drug-carrying system, which is applied in the direction of pharmaceutical formulations, antineoplastic drugs, drug combinations, etc., can solve the problems of poor drug stability, no increase in tolerated dose, and low injection utilization, and achieve an increase effect The effect of strong power and good industrial application prospects

Inactive Publication Date: 2015-08-26
CHANGZHOU TARGET MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many disadvantages in this type of solubilization method: (1) it is easy to cause allergic reactions, so patients need anti-allergic treatment before medication; (2) poor drug stability and low injection availability: the above-mentioned preparations are easily precipitated after dilution , need to go through a special filter device when administering the drug, and the injection dilution process needs to be carried out slowly, often resulting in inconsistent degrees of drug precipitation due to different operators, resulting in inaccurate drug doses entering the body, resulting in differences in curative effect; (3) High hematological toxicity: Tween 80 can cause hematological toxicity, which becomes the main factor limiting the increase of therapeutic dose
The micelles quickly disintegrate after entering the body, and the drug is then combined with proteins in the blood (such as albumin), so the EPR effect of the micelles cannot be exerted. The results of animal experiments show that the drug effect is no different from that of docetaxel injection. , the tolerated dose did not increase, so the advantage is not obvious

Method used

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  • Docetaxel micelle drug load system and preparation method thereof
  • Docetaxel micelle drug load system and preparation method thereof
  • Docetaxel micelle drug load system and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 Polymer excipient mPEG 2000 -PLA 1800 -Synthesis of Phe (Boc)

[0036] 20g (10mmol) of mPEG (number average molecular weight is 2000) was added to the polymerization flask, heated to 130°C and vacuum dehydrated for 3h before use. 1.28g (10mmol) of naphthalene dissolved in 20ml of tetrahydrofuran, add 390mg (10mmol) of potassium metal and stir at room temperature until the potassium metal is completely dissolved to obtain a dark green potassium naphthalene solution. Add the above solution to the dry mPEG, stir at room temperature for 5 minutes and then add 25g D,L Lactide / Tetrahydrofuran solution (1g / mL), stirred at room temperature under nitrogen protection for 30 minutes, vacuumed out the solvent, and then dissolved the reactants in ethanol. The resulting solution was cooled to -20°C and the precipitated polymer was filtered. MPEG 2000 -PLA 1800 Block copolymer.

[0037] 6.65g Boc-L-phenylalanine was dissolved in 50ml of anhydrous ethyl acetate, 4.2ml of triethyl...

Embodiment 2

[0040] Example 2 Preparation of docetaxel micelles

[0041] Take 100mg docetaxel and 1.9g mPEG 2000 -PLA 1800 -Phe(Boc) was dissolved in 25ml absolute ethanol, organic solvent was removed by rotary evaporation at 45℃, 25ml physiological saline was added to dissolve the drug film, 400mg mannitol was added and the solution was filtered through 0.22μm sterile film and then freeze-dried. Thaxa micellar freeze-dried powder. The LC-MS / MS analysis showed that the drug encapsulation efficiency was 100%, the drug loading was 5%, the particle size was 16nm, and the dispersion coefficient PDI was 0.02. Its resolubility is good, the particle size distribution changes little before and after resolubilization, the detailed results are attached figure 2 And image 3 .

[0042] Test Example 3 Pharmacokinetic test

[0043] A. Experimental animals:

[0044] Male SD rats, weighing 240±20g, were randomly divided into five groups, each with 6 rats, and spare.

[0045] B. Experimental preparation:

[0046...

Embodiment 4

[0057] Example 4 Pharmacodynamic test

[0058] 4.1 The inhibitory effect of docetaxel micelles for injection on xenograft tumors of prostate cancer PC-3A adriamycin-resistant cells in nude mice

[0059] Male BALB / c nude mice were inoculated subcutaneously on the ventral side of 5×10 6 PC-3A cells. About a week later, the average tumor size of the tumor-bearing mice reached 100mm 3 At the above, 30 tumor-bearing mice were randomly stratified and grouped according to the tumor volume, namely: vehicle group, docetaxel micelles for injection (10 mg / kg, from Example 2), docetaxel injection ( Taxotere, 10mg / kg), administered intravenously, once every 3 days for a total of 3 times. During the experiment, the animal tumor volume was measured every week (calculation formula ab 2 / 2, a and b are the length and width of the tumor respectively) and weight. The result is Figure 5 As shown, the micelle inhibition rate of docetaxel for equal-dose injection was significantly higher than that of...

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Abstract

The invention relates to a novel micelle drug load system formed by an amphiphilic segmented copolymer and docetaxel. The amphiphilic segmented copolymer comprises a hydrophilic chain segment and a hydrophobic chain segment, the hydrophilic chain segment is polyethylene glycol monomethyl ether, the hydrophobic chain segment is polycaprolactone, and the end group of the hydrophobic chain segment is terminated by a hydrophobic group. The hydrophobic group is tertbutyloxycarbonyl phenylalanine, so the compatibility of a drug molecule with the hydrophobic chain segment in the segmented copolymer is improved, the interaction between the drug molecule and the segmented copolymer is increased, a large space is provided for accommodating the drug molecule, and a prepared micelle can effectively restrict the drug molecule in the core of the micelle to make the drug molecule difficultly dissolved out, thereby a drug loaded micelle with high stability is obtained.

Description

Technical field [0001] The invention relates to a drug-carrying system formed by an amphiphilic block copolymer and docetaxel and a preparation method thereof, and belongs to the field of nano-medicinal preparations. Background technique [0002] Tumor is a type of disease that seriously threatens the safety of human life. The research on safe and effective anti-tumor drugs is of great significance for improving the quality of human life. [0003] Docetaxel (DTX) is a very effective and broad-spectrum anti-tumor drug. Its mechanism of action is mainly to polymerize and stabilize microtubules, which can cause fast-dividing tumor cells to be fixed in the mitotic stage, so that cancer cells can replicate Blocked and died. [0004] [0005] In vitro experiments have proved that: Docetaxel has a significant radiosensitization effect, which can stop cells in G2 and M phases that are sensitive to radiotherapy. However, due to its high hydrophobicity, oral absorption is poor, and currently...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K9/19A61K31/337A61K47/34C08G63/91C08G63/664A61P35/00
Inventor 刘珂郎跃武许卉范华英其他发明人请求不公开姓名
Owner CHANGZHOU TARGET MEDICINE TECH CO LTD
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