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Asiatic acid-chitosan-deoxycholic acid (AA-CS-DCA) micelles and preparation method thereof

A technology of deoxycholic acid and asiatic acid, which can be applied in drug combinations, pharmaceutical formulas, medical preparations of non-active ingredients, etc., and can solve the problems that there is no patent application for asiatic acid micelles

Active Publication Date: 2018-01-30
ZHEJIANG ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] After searching, there is currently no patent application or literature report using deoxycholic acid grafted with chitosan as a carrier to prepare asiatic acid micelles to improve its absorption

Method used

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  • Asiatic acid-chitosan-deoxycholic acid (AA-CS-DCA) micelles and preparation method thereof
  • Asiatic acid-chitosan-deoxycholic acid (AA-CS-DCA) micelles and preparation method thereof
  • Asiatic acid-chitosan-deoxycholic acid (AA-CS-DCA) micelles and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: the synthesis (50KDa) of chitosan deoxycholic acid graft

[0024] Weigh 0.9g of deoxycholic acid and 1.325g of carbodiimide, dissolve them in 50ml of organic solvent (ethanol:acetone=3:7), and activate at 60°C for 1h under magnetic stirring. 1.68g of chitosan with a molecular weight of 50KDa (degree of deacetylation 79.3%) was added to 100ml of deionized water and stirred to dissolve, the above organic solution was added to the aqueous solution, and stirred at 60°C for 8h. The reaction solution was placed in a dialysis bag, dialyzed with deionized water for 24 hours, and the dialysate was freeze-dried to obtain chitosan deoxycholic acid graft. The grafting rate of the synthesized CS-DCA measured by linear potentiometric titration is (6.83±0.10)%; CS-DCA can form self-assembled micelles in water, and its critical micelle concentration is 0.074mg / mL measured by pyrene fluorescence method, The particle size is (34.2±4.3) nm, and the Zeta potential is (43.7±1...

Embodiment 2

[0025] Embodiment 2: the synthesis (126KDa) of chitosan deoxycholic acid graft

[0026] Weigh 0.9g of deoxycholic acid and 1.325g of carbodiimide, dissolve them in 50ml of organic solvent (ethanol:acetone=3:7), and activate at 60°C for 1h under magnetic stirring conditions. Add 1.54 g of chitosan with a molecular weight of 126 KDa (degree of deacetylation: 89.1%), add 100 ml of deionized water and stir to dissolve, add the above organic solution into the aqueous solution, and react with stirring at 60° C. for 8 hours. The reaction solution was placed in a dialysis bag, dialyzed with deionized water for 24 hours, and the dialysate was freeze-dried to obtain chitosan deoxycholic acid graft. The grafting rate of the synthesized CS-DCA measured by linear potentiometric titration is (10.05 ± 0.10)%; CS-DCA can form self-assembled micelles in water, and its critical micelle concentration is 0.158mg / mL measured by pyrene fluorescence method, The particle size is (54.2±2.7) nm, and t...

Embodiment 3

[0027] Embodiment 3: Confirmation of structure of chitosan deoxycholic acid graft

[0028] Under the action of the catalyst, the primary amino group on the chitosan monomer can be used as an active group for chemical grafting reaction, and some functional groups are introduced to obtain a chitosan graft with ideal performance. Considering that DCA is a carboxyl-containing endogenous substance, the physicochemical properties of CS can be significantly improved by grafting DCA onto CS. use 1 The structure of CS-DCA obtained in Example 1 was analyzed by H-NMR.

[0029] The result is as figure 1 As shown, A, B, C are CS, DCA and CS-DCA respectively 1 In the H-NMR spectrum, the peak with a chemical shift of about 12ppm in B is the characteristic peak of DA: the proton peak of -COOH, and this peak is not seen in C (product CS-DCA) and A (CS); C (CS -DCA) appeared in the characteristic peak of DCA (18-CH 3 proton peak), the chemical shift is about 0.6ppm. The above results indi...

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Abstract

The invention discloses AA-CS-DCA micelles and a preparation method of AA-CS-DCA micelles. According to the AA-CS-DCA micelles provided by the invention, CS-DCA is taken as a carrier, and AA is encapsulated, the particle sizes of obtained micelles are smaller than 100nm, the drug loading amount is 4% to 11% and the encapsulation efficiency is 61% to 81%. The preparation method of the AA-CS-DCA micelles comprises the following steps: firstly, synthesizing CS-DCA, then adding CS-DCA to deionized water to be dissolved, and taking AA to be dissolved in methanol, carrying out ultrasound treatment by a probe after mixing the two solutions, carrying out reduced pressure rotary evaporation to remove organic solvents, taking a supernatant to be freeze-dried after performing centrifugation to obtainthe AA-CS-DCA micelles. The micelles can significantly increase intestinal drug absorption and improve oral bioavailability.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations, in particular to asiatic acid chitosan deoxycholic acid graft micelles and a preparation method thereof. Background technique [0002] Asiatic acid (AA) is a ursane-type pentacyclic triterpene acid with multifunctional biological activities. It is the main material basis of the traditional Chinese medicine Centella asiatica L. It effectively promotes the synthesis and metabolism of local collagen, prevents scar hyperplasia, repairs damaged tissues, and has anti-hepatic and renal fibrosis and anti-tumor effects. Generally, long-term oral administration is required in clinical practice. However, AA is poorly soluble in water, has poor absorption, rapid elimination in vivo, and extremely low oral bioavailability: 100mg / kg rat gavage, peak concentration C max About 14ng / ml; beagle dogs orally madecassoside 390mg, the total plasma concentration of asiatic acid is C max =0.74μg / ml...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K31/56A61K47/36A61P17/02A61P1/16A61P13/12A61P35/00C08B37/08
Inventor 尹丽娜张雅雯赵鹏飞王胜浩郑高利
Owner ZHEJIANG ACAD OF MEDICAL SCI
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