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Oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barriers and preparation method and application of oral nanoparticles

A technology of epithelial cells and nanoparticles, applied in the direction of non-active ingredient medical preparations, medical preparations containing active ingredients, pharmaceutical formulas, etc., can solve the lack of effective drug delivery, weaken nanocarriers and Cell membrane affinity and other issues to achieve the effect of improving the ability

Active Publication Date: 2020-06-30
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is worth noting that the modification of the hydrophilic PEG weakens the affinity between the nanocarrier and the cell membrane, making it lack the ability to overcome the two barriers of the intestinal mucus diffusion layer and the epithelial cell absorption layer at the same time, and cannot really solve the problem of nanocarriers entering the gastrointestinal tract. The problem of effective drug delivery after drug delivery, the effect of improving drug oral absorption is still unsatisfactory

Method used

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  • Oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barriers and preparation method and application of oral nanoparticles
  • Oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barriers and preparation method and application of oral nanoparticles
  • Oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barriers and preparation method and application of oral nanoparticles

Examples

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Embodiment 1

[0041] A method for preparing oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barrier, characterized in that it comprises the following steps:

[0042] (1) Preparation of pH-responsive materials, the synthesis process is as follows figure 1 Shown:

[0043] A: Dissolve 2.50g of stearic acid (SA) in 100ml of dichloromethane (DCM), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the above solution (EDCI) 2.02g, triethylamine (TEA) 1ml and tert-butyl carbazate (boc-hydrazide) 1.39g, react at room temperature for 12h, after the reaction, wash with water 3 times, then wash 3 times with saturated brine, Then dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to obtain 2.77 g of BOC-protected hydrazide SA;

[0044] B: Dissolve 1 g of BOC-protected hydrazide SA in 20 mL of ethyl acetate, add 2 drops of hydrochloric acid to the above solution, and react at room temperature for 2 h. After the reactio...

Embodiment 2

[0049] A method for preparing oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barrier, characterized in that it comprises the following steps:

[0050] (1) Preparation of pH-responsive materials:

[0051] A: Dissolve 1.10 g of stearic acid (SA) in 30 mL of dichloromethane (DCM), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the above solution (EDCI) 1.48g, triethylamine (TEA) 0.2mL and tert-butyl carbazate (boc-hydrazide) 0.61g, react at room temperature for 20h, after the reaction, wash with water 3 times, then wash 3 times with saturated brine , then dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to obtain 1.31 g of BOC-protected hydrazide SA;

[0052] B: Dissolve 0.50 g of BOC-protected hydrazide SA in 15 mL of ethyl acetate, add 3 drops of hydrochloric acid dropwise to the above solution, and react at room temperature for 4 hours. After the reaction, the product is washed with deio...

Embodiment 3

[0057] A method for preparing oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barrier, characterized in that it comprises the following steps:

[0058] (1) Preparation of pH-responsive materials:

[0059] A: Dissolve 1.50 g of stearic acid (SA) in 20 mL of dichloromethane (DCM), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the above solution (EDCI) 1.72g, triethylamine (TEA) 0.2mL and tert-butyl carbazate (boc-hydrazide) 1.04g, react at room temperature for 24h, after the reaction, wash with water 3 times, then wash 3 times with saturated brine , then dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to obtain 1.76 g of BOC-protected hydrazide SA;

[0060] B: Dissolve 0.50 g of BOC-protected hydrazide SA in 20 mL of ethyl acetate, add 3 drops of hydrochloric acid dropwise to the above solution, and react at room temperature for 6 hours. After the reaction, the product is washed with deio...

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Abstract

The invention discloses a preparation method of oral nanoparticles for penetrating gastrointestinal mucus and epithelial cell barriers. The method comprises the following steps: (1) preparing a pH response material: connecting polyethylene glycol to stearic acid through an acylhydrazone bond to obtain the pH response material; (2) preparing a polymer material: connecting chitosan oligosaccharide to stearic acid through an amido bond to obtain the polymer material; and (3) preparing the nanoparticles: mixing the pH response material in the step (1) to the polymer material in the step (2), and performing nano coprecipitation self-assembly to obtain the core-shell oral nanoparticles taking the polymer material as an inner core and the pH response material as an outer shell. According to the nanoparticles prepared by the preparation method provided by the invention, in a mucus microenvironment, the acylhydrazone bond is broken and falls off from a polyethylene glycol shell, and a CSO-SA core is exposed, so that conversion from hydrophilicity to hydrophobicity, conversion from near-neutrality to positive charges and increase of adhesion of the surface of the nanoparticles are realized,the epithelial cell barrier spanning capability of the nanoparticles is enhanced, and the oral absorption rate of drugs is increased.

Description

technical field [0001] The invention relates to the field of drug carrier materials, in particular to an oral nanoparticle for penetrating gastrointestinal mucus and epithelial cell barriers, a preparation method and application thereof. Background technique [0002] At present, the gastrointestinal biological barrier is the main reason for the low oral bioavailability of drugs. Although the entrapment of drugs by nanocarriers can protect them from degradation by gastrointestinal enzymes, for drugs to be effectively absorbed into the blood circulation, nanocarriers must successively pass through the mucus diffusion barrier on the intestinal surface and the epithelial cell absorption barrier. The highly viscoelastic and dynamically renewed mucus layer has a strong ability to capture and quickly remove foreign particles, and is an important gateway for the diffusion of nanocarriers to epithelial cells for further absorption. The force (membrane affinity) between the apical ce...

Claims

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Application Information

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IPC IPC(8): A61K47/16A61K47/26A61K47/36A61K38/28A61P3/10A61K9/50C08B37/08C08G65/333
CPCA61K47/16A61K47/26A61K47/36A61K38/28A61P3/10A61K9/5031C08B37/003C08G65/33324
Inventor 张金洁李建波张振中强弘王帅帅冯天歌蔡慧杰刘志磊
Owner ZHENGZHOU UNIV
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