CN-121987573-A - Ginsenoside-loaded double-network crosslinked microsphere and preparation method and application thereof

Abstract

A ginsenoside-loaded double-network crosslinked microsphere and a preparation method and application thereof belong to the technical field of oral drug delivery and biomedical microsphere materials. The microsphere is formed by a first network formed by polysaccharide-multivalent cation crosslinking and a second network containing dynamic disulfide bonds formed by lipoic acid under illumination, so as to form an interpenetrating double-network structure. The preparation method comprises mixing polysaccharide, lipoic acid, photoinitiator and ginsenoside to form precursor solution, and performing light treatment after multivalent cation crosslinking into balls to obtain the double-crosslinked microsphere. The method has mild process and simple operation. The microsphere can reduce the early release of the drug in the stomach environment, improve the adhesion and retention capacity of the drug at the inflammatory part of the intestinal tract, has the characteristic of responsive release in the inflammation-related oxidation-reduction abnormal environment, and is suitable for oral delivery of the inflammatory diseases of the intestinal tract such as inflammatory bowel diseases.

Inventors

• SONG LINGJIE
• WU ZHONGQI
• LI WEI
• LIU JIA
• LI CHAOQUN
• ZHANG JINGTIAN
• HU JUNNAN
• CHEN LONG

Assignees

• 吉林农业大学

Dates

Publication Date

20260508

Application Date

20260408

Claims (8)

1. 1. A ginsenoside-loaded double-network crosslinked microsphere, wherein the microsphere comprises: a first network of an ionomer network formed by alginate and/or an ionically crosslinkable carboxyl-containing polysaccharide and a polyvalent cation; a second network, namely a polymerization crosslinking network containing a dynamic disulfide bond structure and formed by lipoic acid under the illumination condition; The medicine component is ginsenoside dispersed, entrapped or dissolved in the double-network structure; wherein the first network and the second network spatially form an interpenetrating dual network (IPN) structure.
2. 2. The double-network crosslinked microsphere according to claim 1, wherein the alginate is one or more selected from sodium alginate, potassium alginate and ammonium alginate, the carboxyl group-containing polysaccharide is one or more selected from pectin, hyaluronic acid and carboxymethyl cellulose, and the multivalent cation is one or more selected from Ca 2+ 、Ba 2+ 、Sr 2+ 、Zn 2+ .
3. 3. The dual network crosslinked microsphere of claim 1, wherein the second crosslinked network is formed by inducing polymerization and/or crosslinking of lipoic acid by light having a wavelength of 320-400 nm, a photoinitiator selected from the group consisting of LAP, irgacure 2959, and combinations thereof, 0.1-5 wt% by mass of lipoic acid in the microsphere precursor system, 0.01-0.5 wt% by mass of photoinitiator in the microsphere precursor system, a light intensity of 10-50 mW/cm2, an irradiation time of 60-600 s, and the light is performed while the microsphere is in a wet or aqueous dispersion state.
4. 4. The dual network crosslinked microsphere of claim 1, wherein the second crosslinked network comprises a dynamic disulfide structure, thereby enhancing interactions between the microsphere and intestinal mucus layers, and wherein the dual network crosslinked microsphere exhibits increased release rate responsive characteristics in an inflammation-related redox abnormal environment.
5. 5. The double-network crosslinked microsphere according to claim 1, wherein the ginsenoside comprises one or more ginsenoside monomers, the mass fraction of the ginsenoside in a microsphere precursor system is 0.01-2 wt%, the ginsenoside can be directly present in the precursor system in a dissolved form, cyclodextrin inclusion compounds and/or pharmaceutically acceptable solubilization forms can be adopted for the ginsenoside with lower solubility to be introduced into the precursor system, and the particle size of the microsphere is 10-2000 μm.
6. 6. A method of preparing the double crosslinked microsphere of any one of claims 1 to 5, comprising the steps of: a) Preparing a microsphere precursor system containing alginate and/or carboxyl-containing polysaccharide, lipoic acid, a photoinitiator and ginsenoside; b) Contacting the microsphere precursor system with a multivalent cation to form ionically crosslinked microspheres, thereby obtaining a first crosslinked network; C) And (3) carrying out light treatment on the microsphere obtained in the step (B) to form a lipoic acid dynamic disulfide cross-linked network, thereby obtaining the interpenetrating double-network double-cross-linked microsphere.
7. 7. The method according to claim 6, wherein the ionic crosslinking in the step B is achieved by exogenous diffusion crosslinking or endogenous release crosslinking, and when exogenous diffusion crosslinking is adopted, the microsphere precursor system is added into CaCl 2 aqueous solution to form ionic crosslinking microspheres, and the mass fraction of the CaCl 2 aqueous solution is 0.5-5 wt%.
8. 8. Use of the double cross-linked microspheres according to any one of claims 1-5 for the preparation of an oral ginsenoside delivery formulation for local delivery at the site of intestinal inflammation and/or for delivery of an inflammatory microenvironment response, said inflammatory microenvironment being an intestinal inflammatory microenvironment, said microspheres being suitable for use in an inflammatory bowel disease related intestinal inflammatory microenvironment.

Description

Ginsenoside-loaded double-network crosslinked microsphere and preparation method and application thereof Technical Field The invention belongs to the technical field of oral drug delivery and biomedical microsphere materials, and particularly relates to a ginsenoside-loaded double-network crosslinked microsphere, and a preparation method and application thereof. The microsphere is composed of a first network formed by polysaccharide-multivalent cation crosslinking and a dynamic disulfide network formed by Lipoic Acid (LA) under the illumination condition, so as to form an Interpenetrating Polymer Network (IPN) structure. The microsphere can be loaded with ginsenoside, and a controllable drug release system is formed by a preparation method. The microspheres are suitable for inflammatory microenvironment responsive delivery, preferably for adhesion enhancement and adaptive controlled release at sites of intestinal inflammation. Background Inflammatory bowel disease (Inflammatory Bowel Disease, IBD) is a group of diseases characterized by chronic recurrent inflammation of the gut, principally including ulcerative colitis and crohn's disease. The diseases are often accompanied by damage to the intestinal mucosa barrier, enhancement of local oxidative stress and abnormal expression of inflammatory factors. The existing treatment modes mostly adopt oral administration or systemic administration, but the local enrichment efficiency of the medicine at the focus of intestinal inflammation is limited, and part of the medicine is easy to be released or degraded in advance in the gastrointestinal tract transportation process, thereby influencing the treatment effect. Therefore, it is of great importance to develop a drug carrier system that is capable of achieving stable delivery and local action at the site of intestinal inflammation after oral administration. Ginsenoside (such as Rg3, rb1, rd and metabolites/total saponins thereof) is an important active component of ginseng, has various pharmacological activities such as anti-inflammatory, immunoregulation and antioxidation, and has good application prospect in the intervention of related diseases of intestinal inflammation (Phytomedicine, 2024, 130, 155476). However, the ginsenoside has the problems of insufficient stability, limited local residence time, insufficient effective exposure of focus parts and the like in the gastrointestinal environment when the ginsenoside is directly taken orally, so that the full play of the drug effect is limited. Currently, oral enteric delivery vehicles mainly include ionomer polysaccharide microspheres, hydrogel particles, pH-responsive vehicles, adhesive materials, and the like. Wherein, the ion crosslinking microsphere formed by carboxyl-containing polysaccharide such as alginate and multivalent cations such as Ca 2+ is widely applied to the construction of an oral delivery system due to mild preparation conditions, better biocompatibility and lower cost. However, single-ion crosslinked networks generally have the problems of relatively loose structure, easy drug-carrying leakage, early release of gastric segments, limited release behavior regulation capability, lack of inflammatory microenvironment response and the like, and are difficult to simultaneously meet the requirements of gastric segment protection, intestinal segment delivery and on-demand release of focal sites. Furthermore, effective treatment of the focal site of IBD depends not only on drug release behavior, but also on the local retention capacity of the carrier on the intestinal wall and mucosal surfaces. The intestinal mucus layer is mainly composed of mucins, and its structure can significantly affect adhesion, migration and removal of particles. The existing adhesion strategy depends on weak interactions such as electrostatic interaction, hydrogen bonding interaction and the like, and under the conditions of intestinal fluid flushing, intestinal peristalsis and continuous mucous renewal, the carrier is easy to desorb from the surface of a focus, so that stable retention is difficult to realize. Studies have shown that materials with thiol-or disulfide-exchange capability enhance interactions with mucins, thereby increasing adhesion strength and retention capacity (Advanced drug DELIVERY REVIEWS, 2005, 57 (11): 1569-1582). Therefore, the introduction of a dynamic disulfide bond-related adhesion mechanism into an oral IBD delivery system is expected to improve the problem that the carrier is easy to wash and clear, and improve the local residence effect of the carrier at the intestinal inflammation site. Lipoic Acid (LA) has both antioxidant activity and disulfide dynamic exchange potential as a small molecule containing a cyclic disulfide bond, and is widely used for constructing dynamic materials or drug carrier systems in recent years. However, the related art of LA is mainly focused on the fields of hydrogel, material adhesion or dynamic material constru