Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof

A technology of self-emulsification and derivatives, applied in the field of biomedicine, can solve the problems of increased systemic toxicity and achieve the effects of long blood half-life, improved pharmaceutical effects, and high bioavailability

Inactive Publication Date: 2010-01-20
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to achieve a certain dose of CPT and its derivatives, the existing drug delivery system of CPT and its derivatives needs to use a large number of carriers, but repeated use of large doses of carriers will greatly increase the systemic toxicity

Method used

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  • Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof
  • Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof
  • Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Synthesis of a PEG-linked self-emulsifying prodrug (PEG-diCPT) of two CPTs

[0042] (1) Synthesis of PEG-SH

[0043] 4.54g (10mmol) of poly(ethylene glycol) methyl ether acrylate (PEGMEA) was dissolved in 20mL of dry dichloromethane, and 1.92g (2mmol) of 98% 1,2-mercaptoethanol was added, Using 0.1 mL (0.72 mmol) of triethylamine as a catalyst, the reaction was stirred at room temperature for 24 h. After the reaction, the reactant was dialyzed with water to remove small molecules and organic solvents, the aqueous phase was washed with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate and then vacuum-dried to obtain 4.61 g of product PEG-SH with a yield of 83.64%. The structural formula of PEG-SH is as follows:

[0044]

[0045] Among them, n=3-30.

[0046] (2) Synthesis of PEG with diacid at the end

[0047] Dissolve 2.2 g (4 mmol) PEG-SH and 0.52 g (4.5 mmol) fumaric acid in 5 mL dry N,N-dimethylformamide (DMF) with 0.01 mL...

Embodiment 2

[0058] Example 2 Synthesis of self-emulsifying prodrugs based on polyacrylic acid short chains

[0059] (1) Dissolve 1g (2.87mmol) of CPT and 0.34g (3.44mmol) of succinic anhydride in 5mL of DMSO, heat to 60°C, and react for 6 hours. After the reaction, pour the reaction solution into 50mL of acetone to precipitate, and filter through The solid product was collected and dried to give 1.09 g of product I with a yield of 85%. The structural formula of product I is as follows:

[0060]

[0061] (2) Dissolve 0.5g (1.11mmol) of the above product I and 0.154g (1.34mmol) of N-hydroxysuccinimide in DMSO, add 0.276g (1.34mmol) of N, N'-dicyclohexylcarbodi Imine (DCC) and 0.163g (1.34mmol) 4-dimethylamino must (DMAP, react overnight, filter and remove by-product. The filtrate is precipitated in ether, obtains 0.56g product II, and productive rate is 89%. Product II The structural formula is as follows:

[0062]

[0063] (3) 0.5g (0.89mmol) of the above-mentioned product II and ...

Embodiment 3

[0069] Example 3 Synthesis of glucose CPT self-emulsifying prodrug.

[0070] (1) Dissolve 1g (5.12mmol) of gluconic acid and 3.7g (61.6mmol) of ethylenediamine in 10mL of water, add 0.99g (5.12mmol) of 1-ethyl-(3-dimethylaminopropyl)-carbon Diimine (EDC) catalyzed the reaction for 12 hours. After the reaction, the reaction solution was poured into 100 mL of acetone to precipitate, and the solid product was collected by filtration. After drying, 1.11 g of product IV was obtained with a yield of 85%.

[0071] (2) Mix 0.3g (1.17mmol) of the above-mentioned product IV, 0.66g (1.17mmol) of the product II in the second step of Example 2 with 10ml DMSO, react for 3h, and pour the reaction solution into acetone to precipitate after the reaction. The solid product V was collected by filtration.

[0072]

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Abstract

The invention discloses camptothecin and a self-emulsifying medicine precursor of a derivative thereof. The self-emulsifying medicine precursor is prepared by the covalent union of medicine molecules and hydrophilic radicals, wherein the medicine molecules are camptothecin molecules or camptothecin derivative molecules, and the medicine carrying quantity of the precursor is as high as more than 50%. The invention also discloses application of the self-emulsifying medicine precursor. The self-emulsifying medicine precursor can form micelles or vesicles with nano size in water, can be used as a medicine carrier used for loading one or a plurality of other anticancer medicines, such as CPT derivatives, yew alcohol, turmeric essence, methotrexate, irinotecan, danshinolic acid, matrine, doxorubicine and the like, can form a nano medicine carrying a plurality of medicines and can realize the synergic treatment of the medicines.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a self-emulsifying drug precursor of camptothecin and its derivatives and its application. technical background [0002] Camptothecin (CPT for short) and its derivatives act on topoisomerase and are a potential anticancer drug. Currently, topotecan and irinotecan hydrochloride (7-ethyl-10-piperidinocarbonyloxycamptothecin, CPT-11) have been approved by the FDA, and some other derivatives have also entered preclinical trials and clinical trials (Hausheer Frederick H, Haridas Kochat. 11, 7-Substituted camptothecin derivatives and formulations of 11, 7-substituted camptothecin derivatives and methods for uses therefore; US5633260). However, due to the poor solubility of CPT and its derivatives in water, and its lactone ring is easily hydrolyzed in blood, the clinical application is greatly limited. [0003] Drug sustained release technology is one of the methods to solve the p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07H17/04C07D491/22C08G65/48C08F120/06C08F8/30C08F120/28C08F116/06A61K9/00A61K47/48A61K47/58A61K47/60
Inventor 申有青唐建斌隋梅花徐春红
Owner ZHEJIANG UNIV
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