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A kind of ph-sensitive artesunate polymer prodrug and its preparation method, and pharmaceutical composition for treating colon cancer

A technology of artesunate and polymer, applied in the field of medicine, can solve the problems of low bioavailability of oral tablets, poor patient tolerance, easy precipitation, etc., achieve good water solubility, enhanced penetration and retention effects, systemic circulation effect of time extension

Active Publication Date: 2022-04-01
INST OF CHINESE MATERIA MEDICA CHINA ACAD OF CHINESE MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Artesunate (ART) is almost insoluble in water, and the oral tablet has low bioavailability and fast metabolism in the body. The powder injection needs 5% sodium bicarbonate to dissolve, and the stability is poor, and precipitation is easy to occur, making it difficult to be effectively transported To the lesion site and cells, the patient's tolerance is poor and the drug effect is low, which greatly limits its clinical application

Method used

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  • A kind of ph-sensitive artesunate polymer prodrug and its preparation method, and pharmaceutical composition for treating colon cancer
  • A kind of ph-sensitive artesunate polymer prodrug and its preparation method, and pharmaceutical composition for treating colon cancer
  • A kind of ph-sensitive artesunate polymer prodrug and its preparation method, and pharmaceutical composition for treating colon cancer

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preparation example Construction

[0043] The present invention also provides a preparation method for the pH-sensitive artesunate polymer prodrug described in the above technical solution, comprising the following steps:

[0044] (1) N-Boc-ethanolamine is mixed with sulfonyl chloride for substitution reaction to obtain Boc-OTS, and the sulfonyl chloride is methanesulfonyl chloride, ethylsulfonyl chloride, p-nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride;

[0045] (2) 2-ethyl-2-oxazoline is mixed with the Boc-OTS to carry out a polymerization reaction to obtain a poly 2-ethyl-2-oxazoline polymer whose terminal is a hydroxyl group;

[0046] (3) Mix the poly 2-ethyl-2-oxazoline polymer whose terminal is a hydroxyl group with D, L-lactide, and polymerize under the condition of the presence of a catalyst to obtain a poly 2-oxazoline polymer containing a terminal hydroxyl group. Ethyl-2-oxazoline-polylactic acid, the catalyst includes one or more of stannous chloride, stannous oxalate, stannous sulfate ...

Embodiment 1

[0078] Preparation of pH-sensitive artesunate polymer prodrug ART-M1:

[0079](1) Mix 10mmol N-Boc-ethanolamine with 11mmol p-toluenesulfonyl chloride, react in an alkaline environment at 0°C for 4h, then continue to react at room temperature for 48h, add deionized water to stop the reaction, and use 50mL lemon Wash with acidic water and 50 mL of saturated brine, dry and spin to a yellow oil drop shape, pass through a silica gel column, precipitate with 200 mL of n-hexane, and dry in vacuo to obtain a white powder product (Bco-OTS).

[0080] (2) Mix 50mmol of 2-ethyl-2-oxazoline with 5mmol of Boc-bond-containing initiator (Bco-OTS), polymerize at 100°C, react for 48h and cool to room temperature with 100mL of 0.1mol The NaOH methanol solution of / L continues to process 4h, dialyzes, lyophilizes, obtains the poly 2-ethyl-2-oxazoline polymer that the terminal is hydroxyl;

[0081] (3) Mix 2g of poly 2-ethyl-2-oxazoline polymer whose terminal is a hydroxyl group with 1.2g of D, ...

Embodiment 2

[0087] Preparation of pH-sensitive artesunate polymer prodrug ART-M2:

[0088] (1) Weigh an appropriate amount of the product of step (4) of Example 1, add 10 molar amounts of 1,4-butanediol diacrylate and 11 times the molar amount of 2-amino-1.3-propanediol, N,N-dimethyl Use methyl formamide as a solvent, react at 50°C for 48 hours, dialyze and freeze-dry to obtain a pH-sensitive polymer material.

[0089] (2) Weigh an appropriate amount of pH-sensitive polymer material, add 5 times the molar amount of artesunate, 5 times the molar amount of DMAP in a branched flask, use DCM as a solvent, and add 10 times the molar amount dropwise through a constant pressure funnel EDAC was reacted at room temperature for 24 hours, dialyzed and freeze-dried to obtain pH-sensitive artesunate polymer prodrug ART-M2, as shown in formula II. Wherein, n=40, m=19, x=7, ART is artesunate, and its molecular weight is 483.42Da.

[0090] use 1 The structure of prodrug ART-M2 was determined by H-NMR ...

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Abstract

The invention provides a pH-sensitive artesunate polymer prodrug, its preparation method and application, a drug for adjuvant treatment of colon cancer, and relates to the field of pharmaceutical technology. The pH-sensitive artesunate polymer prodrug described in the invention Coupling of artesunate to a pH-sensitive polymer via an ester bond. The present invention adopts ester bond to construct the conjugate of artesunate and pH-sensitive polymer, and the obtained pH-sensitive artesunate polymer prodrug has good water solubility, stability, prolonged systemic circulation time, and rapid release characteristics. Compared with artesunate, the pH-sensitive artesunate polymer prodrug provided by the present invention has stronger cytotoxicity and more significant pro-apoptotic effect on mouse colon cancer CT‑26 than free artesunate The anti-tumor effect on mouse colon cancer xenograft model is also significantly better than that of artesunate.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a pH-sensitive artesunate polymer prodrug, a preparation method thereof, and a pharmaceutical composition for treating colon cancer. Background technique [0002] Artesunate (ART) is a derivative of artemisinin, an antimalarial drug with a sesquiterpene structure (the structural formula is shown in formula A), which can treat a variety of malaria, with good curative effect and less toxic side effects. Studies have shown that in addition to antimalarial effects, artemisinin compounds including artesunate also have various pharmacological effects such as immune regulation, anti-virus, anti-inflammatory, antibacterial sensitization, anti-tumor, anti-angiogenesis, and anti-fibrosis. It has a good inhibitory effect on leukemia, liver cancer, colon cancer, lung adenocarcinoma and breast cancer, and has low toxicity to normal tissue cells. At the same time, it has a synergistic effect...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/59A61K31/357A61P35/00C08G73/02C08G63/91C08G63/685C08G63/78
CPCA61K47/593A61K31/357A61P35/00C08G73/02C08G63/912C08G63/78C08G63/6852
Inventor 赵庆贺陈燕军郝单丽
Owner INST OF CHINESE MATERIA MEDICA CHINA ACAD OF CHINESE MEDICAL SCI
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