Study On Preparation And Drug Release Mechanism Of PH-Responsive Mesoporous Silica/Metoprolol Controlled Release System

Mesoporous silica nanoparticles (MSNs) are widely used in the field of biomedicine, especially as drug carriers for controlled release. MSNs have the advantages of good biocompatibility, large specific surface area,aperture and adjustable channels. The pores of MSNs can be loaded with various types of drug molecules. There are a large number of silicon hydroxyls on the pore surface, which provide the sites to graft other active organic groups for the purpose of modifying carrier properties. Therefore,MSNs are proper choice for controlled drug delivery systems. This thesis studied the pH-responsive mesoporous silica/metoprolol controlled-release systems. We intend to use these systems in prevention and treatment for cardiovascular and cerebrovascular disease which have high incidence in the morning. The primary key is to achieve oral administration at night and delayed release in the next morning. Therefore, the controlled release system requires significant pH-response.that drug is not released or slowly released in the acidic stomach environment, but released sustained in neutral bowel environment. Due to the poor water solubility of metoprolol drug molecules, the forms of metoprolol tartrate (MPT) and metoprolol succinate succinate (MPS) are commonly used. Their molecular sizes are relatively large, reasoably, both the pore size and the pore structure of MSNs have significant impacts on the adsorption and the diffusion of MPT and MPS. In order to obtain the mesoporous silica/metoprolol controlled release system with good pH response, controlled release mechanism of the MSNs for metoprolol molecules and realization of the pH sensitivity of mesoporous silica/metoprolol system are the focuses of this thesis.1. With the development of molecular simulation technology, the research of this technology is also favored by researchers in the field of MSNs. In this thesis, the mechanism of adsorption and drug release of MSN on metoprolol at the atomic level was studied by molecular simulation method. It provided effective theoretical guidance for the design and preparation of the subsequent pH-responsive mesoporous silica/metoprolol controlled-release systems. The specific research method of this study is based on the preliminary results of the laboratory. The MSN samples having pore sizes of 3 nm, 6 nm, 11 nm and 15 nm were selected and modeled by Material Studio software. MPT was used as the drug model. The drug adsorption properties of different pore diameters were calculated. Then, the mean square displacement (MSD) of the whole drug molecules in different pore sizes was calculated by molecular dynamic simulation of each system. The influence of pore size on the diffusion properties of MPT drug molecules was explored. The results showed that the release rate of the drug molecules in the pore channel could be adjusted by changing the pore size of the mesoporous silica, which could affect drug release behaviors.2. Two kinds of metoprolol (MPT and MPS) drugs were loaded in worm-like MSN (pore size:9 nm) and MCF-26 MSN (pore size: 11 nm).The sustained release was tested and the effect of MSN pore size on drug release behavior was verified. The two MSNs were characterized by TEM,XPS, XRD, BET adsorption and desorption. Drug-loaded MSNs were prepared by liquid dipping method and then placed them in simulated intestinal fluid (SIF) and simulated gastric juice (SGJ) for release. The results showed that MCF-26 was superior to the worm-like MSN in facilitating drug release due to its larger pore size, and the drug release rate in the former case was significantly higher than that in the latter case.3. In order to realize th e pH sensitivity of the release system, the effects of the introduction of amino groups grafting the surface of MCF-26 on the release of MPT and MPS in SIF and SGJ were investigated.The method comprises the following steps of: feeding the amino group to the surface of the pore by refluxing in toluene dissolved with 3-aminopropyltri ethoxy silane (APTES), preparing drug-loaded MSN by liquid immersion method, and then placing the amino-modified system into the SIF and SGJ.The results showed that the amino-modified MCF-26 did not show significant pH sensitivity and The release of the outbreak is clear,and the drug release rate decreased with the increase of the amino contents.4. We coated the MCF-26/metoprolol system with acylated gelatin and polyacrylic acid resin ?, both of which have enteric properties. The feasibility of obtaining the pH-responsive mesoporous silica/metoprolol controlled-release system was studied. The method comprised the following steps of suspending MCF-26 loaded with metoprolol in acylated gelatin solution or polyacrylic resin ? solution, adopting emulsion method or precipitation method to obtain polymer coated microspheres, and freeze-drying. The systems were placed in simulated intestinal fluid (SIF)and simulated gastric juice (SGJ) for release. The results revealed that the two systems showed significant pH-sensitive release behavior. Drug release rates slowed down in SGJ, however, were quickly accelerated in SIF. The polyacrylic acid resin ? coating systems almost did not release in the SGJ,but had a stable linear release in the SIF. So, this system was a kind of mesoporous silica/metoprolol controlled release system with significant pH response, which was promising to be applied in clinical practice.