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Combretastatin A4 derivative and preparation thereof

A technology of combretastatin and derivatives, applied in the field of combretastatin A4 derivatives and preparations thereof, to achieve the effects of solving poor lipid solubility, high drug concentration and improving chemical stability

Active Publication Date: 2017-04-26
SHANGHAI WEI ER BIOPHARM TECH CO LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] From the perspective of the druggability of nano-preparations, combretastatin A4 fatty acid esters with different carbon chain lengths from C2 to C18 can basically prepare good nano-preparations, and there is no essential difference

Method used

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  • Combretastatin A4 derivative and preparation thereof
  • Combretastatin A4 derivative and preparation thereof
  • Combretastatin A4 derivative and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Comparative evaluation of series of different combretastatin A4 fatty acid esters in vivo and in vitro

[0057] The international patent (WO 2007059118 A1) records that the carbon chain length of fatty acids is in the range of C2-C21, basically covering all common fatty acids, but does not clearly record the corresponding substantial effects. For this reason, in a parallel comparative experiment, we randomly designed and synthesized 10 combretastatin A4 esters with different fatty acid carbon chains within this range, that is, combretastatin A4 acetate, butyrate, hexanoate, caprylate , caprate, laurate, myristate, palmitate, stearate, oleate, including combretastatin A4 esters of saturated fatty acids and unsaturated fatty acids, which were evaluated in vivo and in vitro.

[0058] (1) Preparation of a series of different combretastatin A4 fatty acid esters

[0059] 1. Preparation of combretastatin A4 acetate

[0060] Add 250 mg of combretastatin A4 to the r...

Embodiment 2

[0159] Example 2: Comparative study on the preparation process of combretastatin A4 stearate nano-preparation injection

[0160]Generally, there are three methods for preparing nano-preparations for injection, namely, melting high-pressure homogenization method, thin-film high-pressure homogenization method and injection high-pressure homogenization method. feasibility study.

[0161] (1) Melting high pressure homogenization method

[0162] The melting high-pressure homogenization method is to mix the drug or the drug with the lipid material, make it in a molten or semi-molten state at a certain temperature, emulsify it in water under the action of a surfactant, and then further reduce it through a high-pressure homogenizer. particle size to obtain nano-preparations. According to its principle, we use this method to prepare combretastatin A4 stearate nano-preparation with the most conservative drug loading of 0.5mg / ml, and conduct quality evaluation.

[0163] 1. Preparation...

Embodiment 3

[0186] Example 3: Research on the preparation process of combretastatin A4 stearate nano-preparation injection

[0187] A large number of tests have shown that the commonly used nano-preparation method is not suitable for the preparation of combretastatin A4 stearate nano-preparation. But in comparison, the nanoparticles prepared by injecting high-pressure homogeneous method are relatively the best. In order to investigate the reason, we repeatedly conducted decomposition tests on injection high-pressure homogenization method, and unexpectedly found that a relatively good nano-preparation has been formed at the moment when the lipid solution is injected into water for injection, and then it is processed by conventional thinking. On the contrary, the high-pressure homogenization will make the distribution of nanoparticles uneven, and even cause damage to the nanoparticles.

[0188] Regarding this conclusion, we have carried out many comparative experiments to confirm it, and a...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a combretastatin A4 derivative preparation, wherein the derivative is obtained through the reaction between combretastatin A4 and stearyl chloride under the substitution reaction condition and under the condition that an acid-binding agent exits, and the structural formula of the derivative is as follows (shown in the description). The invention further provides a nanometer preparation of the derivative. The preparation has the advantages of improving the anti-tumor effect of medicines, enhancing the stability of the medicines, reducing the toxic and side effects of the medicines, etc.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a combretastatin A4 derivative and a preparation thereof. Background technique [0002] Combretastatin A4 (Combretastatin A4, referred to as CA4, the structural formula is shown in formula A) is a natural and powerful small molecule anti-mitotic agent isolated from the bark of the South African shrub willow. The polymerization of tubulin can inhibit the depolymerization of tubulin and the accumulation of mitogens in cells (Shang Hai, et al. Research progress of tubulin inhibitors[J]. Acta Pharmaceutica Sinica, 20l0,45(9):1078 -1088). In 1991, G.R.Pettit determined its chemical structure and applied for a US patent (US4,996,237). A series of structure-activity relationship studies have shown that combretastatin A4 can selectively inhibit the binding of tumor tubulin by utilizing the physiological difference between tumor tissue and normal tissue endothelial cells, change the sk...

Claims

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Application Information

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IPC IPC(8): A61K31/23A61K9/19A61K9/08A61K47/24A61K47/28A61K47/34C07C69/24C07C67/08A61P35/00
CPCA61K9/08A61K9/19A61K31/23A61K47/24A61K47/28C07C67/08C07C69/24
Inventor 周琴琴单彬
Owner SHANGHAI WEI ER BIOPHARM TECH CO LTD
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