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Amphoteric ion-based charge reversal chitosan derivative and application thereof in medicament

A technology of chitosan derivatives and polymer glue, applied in the field of polymer chemistry, can solve the problems of large physiological toxicity, fast plasma clearance rate, difficult application, etc.

Active Publication Date: 2012-06-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, cationic nanocarriers carry positive charges, resulting in greater physiological toxicity and faster plasma clearance, and are difficult to be practically applied in humans (Ma SF, Nishikawab M, Katsumi H, et al.Cationic charge-dependentthepatic delivery of amidated serum albumin. Journal of Controlled Release 2005, 102: 583-594. Fischera D, Li Y, Ahlemeyer B, et al. In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials 2003, 24: 112 1131.)

Method used

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  • Amphoteric ion-based charge reversal chitosan derivative and application thereof in medicament
  • Amphoteric ion-based charge reversal chitosan derivative and application thereof in medicament
  • Amphoteric ion-based charge reversal chitosan derivative and application thereof in medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 1. Preparation of N-octyl chitosan (NOC)

[0048] Add 4g of chitosan to a 500mL three-necked bottle, add 105mL of anhydrous methanol to the three-necked bottle, heat up to 30°C, and keep stirring for 2h. Add 10.6mL octanal, react at room temperature for 12h, slowly add 5g KBH 4 , reduced reaction at room temperature for 24 hours, adjusted the pH of the reaction solution to 7, filtered, washed twice with water, four times with methanol, twice with ether, and dried to obtain 4.6 g of yellow powder (octyl substitution degree 25%).

[0049] 2. Preparation of N-succinyl histidine methyl ester

[0050] Suspend 15.5g (0.1mol) of L-histidine in 320ml of anhydrous methanol, cool in an ice bath to 0°C-5°C, and slowly add 10.9ml (0.15mol) of thionyl chloride dropwise. After the dropwise addition was completed, the temperature was raised to 68° C., and the reaction was refluxed for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain a whi...

Embodiment 2

[0060] 1. N-octyl-N'-tert-butoxycarbonyl lysyl chitosan (NONLB)

[0061] Chitosan reacted with octanal, using KBH 4 Reduction, NOC was prepared according to the preparation method of NOC in Example 1. Take 1g of N-octyl chitosan (NOC) and swell in 50ml of dimethyl sulfoxide at room temperature for 12h. Add 3g (0.009mol) N, N ε - Boc-L-lysine and 1.92g (0.017mol) NHS, cooled to 0°C in an ice bath. Dissolve 3.3g (0.017mol) of EDC·HCl in 10ml of methanol and slowly drop into the reaction system. The reaction was continued for 24 h at room temperature. Reaction solution is poured in 250ml acetone, filters, filter cake water successively, water-acetone mixed liquor, acetone washing, dry to obtain 1.8g yellow powder N-octyl-N'-tert-butoxycarbonyl lysyl chitosan.

[0062]Suspend 1 g of NONLB in 20 ml of methanol and stir at room temperature for 1 h, add 20 ml of formic acid under ice-cooling, react at 0-5°C for 8 h, adjust the pH to neutral with 1 mol / L NaOH solution, dialyze fo...

Embodiment 3

[0070] 1. N-octyl-N'-citraroyl-N"-lysyl chitosan (NONLC)

[0071] Use citric anhydride to react with NONL, and the preparation method follows the preparation of NONLS in Example 2.

[0072] FT-IR: 3423, 2956, 2863, 1729, 1668, 1549, 1420, 1381, 1236, 1158, 1112, 1066, 1033cm -1 .

[0073] 1 H NMR (500MHz, D 2 O): 6.4-5.9 (-C H =C(CH 3 )-), 4.6-4.5 (HαLys, H 1 ), 4.0-3.3 (H 3 , H 4 , H 5 , H 6 ), 3.2 (-NH-C H 2 -(CH 2 ) 10 -CH 3 ), 3.0 (H 2 )2.5-2.2 (HεLys), 2.0 (NH-CO-C H 3 ), 1.7 (HβLys), 1.6-1.0 (-NH-CH 2 -(C H 2 ) 10 -CH 3 , HγLys, HδLys), 0.8(-NH-CH 2 -(CH 2 ) 10 -C H 3 ).

[0074] According to the elemental analysis data, according to the elemental analysis data, it can be calculated that the N-octyl-N'-succinyl-N"-lysyl chitosan octyl substitution degree is 27%; according to 1 The integrated area of ​​H in H NMR can be calculated to be 49% and 41% for citroyl and lysyl, respectively.

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Abstract

The invention relates to the fields of macromolecular chemistry and medicinal adjuvant, in particular to an amphoteric ion-based charge reversal chitosan derivative and application thereof in a medicament. The chitosan derivative is characterized in that chitosan is used as a framework, and 2-NH2 of the chitosan is grafted with hydrophilic succinyl group, histidine and hydrophobic long-chain octyl; or 2-NH2 of the chitosan is grafted with hydrophilic lysine and hydrophobic chain octyl, and then succinyl group or citryl playing a role in charge reversal is introduced into the 2-NH2 of the chitosan and the -NH2 of the lysine. The chitosan derivative of the invention has the effect of solubilizing insoluble medicaments; and the surface of the charge reversal chitosan derivative carries negative charges in long circulation in vivo, and the charges are reversed to form positive charges by responding to the weak acid environment condition after reaching the outside of tumor cells or the inside of lysosome, so the chitosan derivative can promote the cells to take in nano carriers and promote escape from the lysosome, improve the delivery efficiency of the medicament and reduce the toxic or side effect of the medicament.

Description

technical field [0001] The invention relates to the field of polymer chemistry and the field of pharmaceutical auxiliary materials. Specifically related to amino acid modified chitosan derivatives with charge reversal function, including N-octyl-N'-succinyl-N"-lysyl chitosan capable of forming amphiphilic polymers, N-octyl Base-N'-citraroyl-N"-lysyl chitosan, N-octyl-N'-succinyl-N"-histidyl chitosan and its preparation method, and water-soluble polymer N-succinyl-N'-lysyl chitosan, N-citraroyl-N'-lysyl chitosan, N-succinyl-N'-histidyl chitosan derivatives and preparation thereof The method. The present invention also relates to the solubilization of amphiphilic polymers forming micelle materials to insoluble drugs, and the modification of hydrophilic polymers to carriers such as liposomes and nanoparticles. Background technique [0002] The targets of most chemotherapeutic drugs or gene drugs are located in the cytoplasm, organelles or nuclei of tumor cells, and the role o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/36A61K31/4745A61K31/337A61K31/35A61K38/13A61K31/7048A61K31/475A61K31/4422A61K31/435C08B37/08A61P35/00
Inventor 张灿平其能丁崧鞠曹云莫然
Owner CHINA PHARM UNIV
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