Preparation And In Vitro Release Evaluation Of Fibriuretinin-resinate Sustained-release Microcapsules

Objective：Bitterness, large dosage volume and frequently taking affect the patientcompliance of Fibriuretinin. Most of present formulation of Fibriuretinin has theproblem of poor oral absorption and low bioavailability. Tablet with Fibriuretinin, asa common used dosage, cause stomach discomfort adverse reactions because of thelong stay instomach and the high local concentration. In this paper, Fibriuretinin wasused as model drug. Through Ion exchange technology, Taste masking and sustainedtechnology, a new sustained drug-resinate microcapsules with Fibriuretinin wasdesigned which can sustained release for12hours. Advantages consist of propertherapeutic value, a stable drug concentration in plasma and least side effect.Methods：Ultra-performance liquid chromatography（UPLC）was first applied to thedetermination of the amount of drug loading, drug release and assaying testing,which was proved sensitive and reliable. The drug-resinate was prepared by batchmethod of ion exchang. The influence of formulation and process on the rate andequilibrium of ion exchang reaction were investigation, and the optimal preparationmethod was definded. The combination mechanism of Fibriuretinin-resinate wasinvestigated by DSC and IR. With IRE as the core material, through solventevaporation and surface modification coating, microencapsulated coating of DRC asmall size (<100μm) was achieved to control drug release better. The use of Drug-resinate along with a suitable coating material was to prepare a prolongedrelease type of microcapsules. Based on the result of single factor tests, the optimumcoating formula was acquired by central composition design method. The surfacemodification coating process parameters and formulation parameters ofFibriuretinin-resinate complexes were optimized with material containing quaternaryammonium group (such as Eudragit RS100, etc.) The quality standard wereestablished to evaluatie the quality of microcapsul preparated by the optimumformulation and technology, and Preliminary study on their release mechanism.Result：1.The UPLC methodology study showed that there was no impact of excipientson Fibriuretinin assay under the established chromatography condition; The systemsuitablility test was good, the exclusive was strong. Berberine, a related substancewith similar structure to Fibrauretine, have been separated very well. The separationbehavior of quaternary ammonium group alkaloids has been obviously improved inband tailing and retention.2. The couples of factors which could influence on the rate and equilibrium of ionexchange reaction were investigation. Ion exchange process of Fibrauretine onAmberlite IRP-88is exothermic, so the lower reaction temperature is conductive tothe progression of ion exchange reaction, enhancing the drug utilization rate and thedrug-loading capacity of drug-resinate complex (DRC). The combination mechanismof DRC was investigation by DSC, infrared analysis, SEM which ascertained that thecombination force between Fibrauretine and resin was ionic bond interaction insteadof physical adsorption interaction. The DRC release dynamics can be defined byViswannathan equation. It shows that the release kinetics is a diffusion process whichis mainly correlated with composition and ionic strength of the release medium, andits diffusion coefficient affects the drug release.3. The Drug-resinate microcapsule was prepared through Solvent evaporation andSurface modification coating technology. Under Light and scanning electronmicroscopy, the microcapsule were smooth, in good balling index and in less adhesionstate. the mean particle sizes of microcapsule prepared by two preparations was 104.9μm and72μm separately. the encapsulation efficiency was72%and71%respectively, drug loadings was19.18±0.53%and20.01±0.45%respectively. Themicrocapsule that preparated by two methods has excellent slow release property, it iscapable to control the release rate in12h. The microcapsules which were prepared bythe most optimum process either in the same batch or batch to batch werehomogeneous, and it was showed that the process was stable and high reproductive.4．The fitting result of release kinetic model of drug-resinate microcapsules wasdescribed as below: after drug-resinate was encapsulated, the release mechanism ofsystem was turn to film diffusion mechanism along with Viswannathan mechanism.Conclusion：In this article Fibriuretinin was used as model drug to make a taste-maskingdrug-resinate microcapsule, which was taken300mg every time and twice in a day. Asa multi-units system, it presented advantages such as steady release rate、littlestomach-empty effect、easiness to divide.