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Preparation method of water-soluble paclitaxel anticancer drug

A paclitaxel and drug technology, applied in the field of medicine, can solve the problems of difficult control of reaction conditions, difficult connection of paclitaxel, narrow value range, etc., and achieve good injection safety, reduce in vivo toxicity, and increase the effect of targeting

Inactive Publication Date: 2018-08-31
YANCHENG TEACHERS UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the existing reports on the combination of the prodrug and hyaluronic acid are focused on modifying the COOH of hyaluronic acid and linking it to the prodrug. The carboxylic acid part of hyaluronic acid is the recognition site of the hyaluronic acid receptor CD44 , but the steric hindrance at this place is relatively large, and it is not easy to connect with paclitaxel
The existing methods for modifying HA hydroxyl groups are mostly esterification with alkyl succinic anhydride or methacrylic anhydride, but the reaction conditions are not easy to control
Moreover, the degree of substitution (DS) of MeHA is low, and the value range of DS is also narrow. To a certain extent, insufficient esterification is one of the main reasons for the unsatisfactory mechanical properties of MeHA hydrogels.

Method used

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  • Preparation method of water-soluble paclitaxel anticancer drug
  • Preparation method of water-soluble paclitaxel anticancer drug
  • Preparation method of water-soluble paclitaxel anticancer drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of maleic acid-hyaluronic acid derivatives

[0036] Add 1.0g of hyaluronic acid to 80mL of formamide and stir vigorously at 50°C; , 1.2:0.8, 1.4:0.6, 1.6:0.4) were dissolved in 20mL formamide, added to the hyaluronic acid solution, reacted for 5h and cooled the solution to room temperature. The cooled solution was dissolved in absolute ethanol, stirred vigorously, and precipitated. The precipitate was repeatedly washed with absolute ethanol, and centrifuged at 11000r / min for 3h. Decant and dissolve with distilled water. Adjust the pH value of the above solution to 8-9 with 2mol NaOH solution. Dialyze against deionized water for 24 hours. Freeze at -63°C for 24h, then vacuum dry at -112°C for 48h. Yield: 75-90%.

[0037] Preparation of paclitaxel prodrug 1

[0038] Dissolve 600 mg of maleic acid-hyaluronic acid derivative powder in 5 mL of anhydrous DMSO, and add DCC and DMAP in different molar ratios. The solution was stirred for 1 hour to activate t...

Embodiment 2

[0042] Preparation of phthalic anhydride-hyaluronic acid derivatives

[0043] Add 1.0g of hyaluronic acid into 80mL of dimethyl sulfoxide and stir vigorously at 50°C; 0.8:1.2, 1:1, 1.2:0.8, 1.4:0.6, 1.6:0.4) were dissolved in 20mL dimethyl sulfoxide, added to the hyaluronic acid solution, reacted for 5h and cooled the solution to room temperature. The cooled solution was dissolved in anhydrous methanol, stirred vigorously, and precipitated. The precipitate was repeatedly washed with anhydrous methanol, and centrifuged at 11000r / min for 3h. Decant and dissolve with distilled water. Use 2mol potassium carbonate solution to adjust the pH value of the above solution to 8-9. Dialyze against deionized water for 24 hours. Freeze at -63°C for 24h, then vacuum dry at -112°C for 48h. Yield: 70-91%.

[0044] Preparation of paclitaxel prodrug 2

[0045] Dissolve 600 mg of phthalic anhydride-hyaluronic acid derivative powder in 5 mL of anhydrous DMSO, and add DCC and DMAP in differe...

Embodiment 3

[0049] Succinic Anhydride—Preparation of Hyaluronic Acid Derivatives

[0050] Add 1.0g of hyaluronic acid into 80mL of formamide and stir vigorously at 50°C; , 1.2:0.8, 1.4:0.6, 1.6:0.4) were dissolved in 20mL formamide, added to the hyaluronic acid solution, reacted for 5h and cooled the solution to room temperature. The cooled solution was dissolved in absolute ethanol, stirred vigorously, and precipitated. The precipitate was repeatedly washed with absolute ethanol, and centrifuged at 11000r / min for 3h. Decant and dissolve with distilled water. Adjust the pH value of the above solution to 8-9 with 2mol NaOH solution. Dialyze against deionized water for 24 hours. Freeze at -63°C for 24h, and vacuum dry at -112°C for 48h. Yield: 70-85%.

[0051] Preparation of paclitaxel prodrug 3

[0052] Dissolve 600 mg of succinic anhydride-hyaluronic acid derivative powder in 5 mL of anhydrous DMSO, and add DCC and DMAP in different molar ratios. The solution was stirred for 1 hou...

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Abstract

The invention discloses a preparation method of a water-soluble paclitaxel anticancer drug, and belongs to the field of medicine. A PTX drug precursor has similar antitumor activity to a clinical drugPTX, can be hydrolyzed slowly in vivo, and effectively reduces the in-vivo toxicity. The PTX drug precursor has good solubility in water. The targeting property of the PTX drug precursor is increased. Hyaluronic acid is modified with anhydride and then is grafted to paclitaxel. The polymer has good injection safety, self-aggregation characteristics and drug loading capacity.

Description

technical field [0001] The invention relates to a preparation method of a water-soluble paclitaxel anticancer drug, which belongs to the field of medicine. Background technique [0002] Cancer is a serious threat to human health and life, and the mortality rate of cancer is increasing year by year. Therefore, the task of tumor prevention and treatment is arduous, and currently chemotherapy drugs are the most effective means to treat tumors. [0003] Paclitaxel, also known as paclitaxel, taxol, porphyrin, and special element (structure such as formula 1), is the best natural anticancer drug discovered so far, and has been widely used clinically in breast cancer, ovarian cancer and some head and neck cancers. and lung cancer treatment. As a diterpene alkaloid compound with anticancer activity, paclitaxel has attracted botanists and chemists due to its novel and complex chemical structure, extensive and significant biological activities, new and unique mechanism of action, an...

Claims

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Application Information

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IPC IPC(8): C08B37/08A61K47/61A61K31/337A61P35/00A61P13/08
CPCA61K31/337A61K47/61A61P13/08A61P35/00C08B37/0072
Inventor 顾惠雯纵朝阳陆超龙张威孙雅泉
Owner YANCHENG TEACHERS UNIV
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