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Deoxycholic acid modified nano compound and preparation method and application thereof

A technology of nanocomposite and deoxycholic acid is applied in the field of loading insoluble active ingredients of traditional Chinese medicine, can solve problems such as poor affinity of nanocomposite, and achieve the effects of improving oral absorption, realizing oral delivery, and simple and easy preparation method.

Active Publication Date: 2019-06-21
ZHEJIANG CHINESE MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the poor affinity between hydrophilic nanocomposites and cell membranes, their use in oral delivery of drugs is still limited to a certain extent.

Method used

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  • Deoxycholic acid modified nano compound and preparation method and application thereof
  • Deoxycholic acid modified nano compound and preparation method and application thereof
  • Deoxycholic acid modified nano compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 1. Synthesis and characterization of DOCA-LMWC conjugates

[0031] (1) Weigh 31mg (0.078mmol) of deoxycholic acid (DOCA) and dissolve it in 2mL of dimethyl sulfoxide (DMSO) to make a DOCA solution. Dissolve 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) 30mg (0.156mmol) and N-hydroxysuccinimide (NHS) 18mg (0.156mmol) respectively Make an EDC / NHS solution in 1 mL DMSO. Mix all the EDC / NHS solution and DOCA solution, and react at room temperature (25-30° C.) for 2 hours to obtain activated DOCA.

[0032] (2) 60 mg of low-molecular-weight chitosan (LMWC) was dissolved in 5 mL of 90% DMSO aqueous solution to prepare LMWC solution. The activated DOCA (0.078mmol as carboxyl group) obtained in step (1) was slowly dropped into the LMWC solution (0.312mmol as amino group) under stirring, reacted at room temperature for 24h, and dialyzed with deionized water (molecular weight cut-off 3500Da) for 3d, The retentate was taken and freeze-dried at -50°C for 48 ho...

Embodiment 2

[0079] The preparation of DOCA-LMWC conjugates is the same as in Example 1, and the preparation of deoxycholic acid-modified nanocomposites is as follows: Weigh 6 mg of DOCA-LMWC conjugates and dissolve them in 2 mL of 0.2% CH 3 DOCA-LMWC acetic acid solution was made in COOH aqueous solution; 12mg CMCs was dissolved in 2ml deionized water to make CMCs solution. Add the CMCs solution dropwise to the DOCA-LMWC acetic acid solution under stirring, react at 25°C for 30 minutes until the solution appears blue opalescence, stop the reaction, and obtain the deoxycholic acid-modified nanocomposite (DOCA-LMWC / CMCs NCs) About 4ml. The particle size of the obtained nanocomposite is 230.4±1.5nm, the PDI is 0.29±0.01, and the Zeta: is 32.5±0.5mV. The preparation of nanocomposite-wrapped rhein is the same as in Example 1.

Embodiment 3

[0081] The preparation of DOCA-LMWC conjugates is the same as in Example 1, and the preparation of deoxycholic acid-modified nanocomposites is as follows: Weigh 12 mg of DOCA-LMWC conjugates and dissolve them in 2 mL of 0.2% CH 3DOCA-LMWC acetic acid solution was made in COOH aqueous solution; 6mg CMCs was dissolved in 2ml deionized water to make CMCs solution. Add the CMCs solution dropwise to the DOCA-LMWC acetic acid solution under stirring, react at 25°C for 30 minutes until the solution appears blue opalescence, stop the reaction, and obtain the deoxycholic acid-modified nanocomposite (DOCA-LMWC / CMCs NCs) About 4ml. The particle size of the obtained nanocomposite is 166.3±1.0nm, the PDI is 0.15±0.02, and the Zeta: is 42.3±0.7mV. The preparation of nanocomposite-wrapped rhein is the same as in Example 1.

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Abstract

The invention discloses a deoxycholic acid modified nano compound and a preparation method and application thereof. The preparation method includes: adopting carbodiimide condensation reaction to prepare a deoxycholic acid-low-molecular chitosan conjugate, and then preparing a deoxycholic acid modified low-molecular chitosan / carboxymethyl chitosan nano compound through an ion crosslinking process.The nano compound is high in encapsulation rate and drug loading capacity which are 90.7+ / -0.73% and 6.5+ / -0.29% respectively; in-vitro drug release has pH sensitivity, and intake rate (increased by2 times) of Caco-2 cells can be remarkably increased through mutual action of transporter-ligand; pharmacokinetic experiments show that the nano compound can remarkably improve oral absorption of RH,and oral delivery of rheinic acid can be realized effectively. The preparation method is simple and easy to implement, and modification of DOCA enables the nano compound to be effectively combined with small intestine cholic acid transporter to be efficiently taken by epithelial cells, so that oral absorption of drug is facilitated.

Description

[0001] (1) Technical field [0002] The invention relates to a loading method of insoluble active ingredients of traditional Chinese medicine, in particular to a deoxycholic acid-low molecular weight chitosan / carboxymethyl chitosan nanocomposite and its role in improving the uptake efficiency of small intestinal epithelial cells and increasing the oral administration of drugs. applications in absorption. [0003] (2) Background technology [0004] Low molecular weight chitosan (LMWC) is a biodegradable material widely used in the preparation of nanoparticles. However, as a cationic polymer, LMWC is easily damaged by the gastric acid environment for oral delivery, resulting in drug burst and leakage. Carboxymethyl chitosan (CMCs) is an anionic polymer that can self-assemble with low-molecular-weight chitosan through electrostatic adsorption to form a nanocomposite with pH-responsive properties, thereby avoiding degradation in the low pH environment of gastric acid and maintaini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K47/28A61K47/36A61K31/192
Inventor 魏颖慧罗静雯陈丹飞李范珠孙蒋姚文杰
Owner ZHEJIANG CHINESE MEDICAL UNIVERSITY
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