Preparation And Quality Evaluation Of Ligustrazine Phosphate Sustained-release Pellets

Tetramethylpyrazine phosphate（TMPP）is an alkaloid drug,which is mainly used clinically to treat ischemic cardiovascular and cerebrovascular diseases.Because of its short half-life and rapid elimination in the body,it is more suitable for development as a sustained-release preparation.In this paper,ligustrazine phosphate is developed into sustained-release pellets,which can not only maintain the effective blood concentration in the body for a long time,reduce the frequency of taking the drug;but also make the release points more uniformly dispersed,avoiding excessive local drug concentration in conventional immediate-release dosage forms It causes damage to the gastrointestinal tract and improves the effectiveness and safety of the preparation.The research content of this topic mainly includes the following parts:1 Pre-prescription study of ligustrazine phosphate sustained-release pelletsA method for the determination of the content of ligustrazine phosphate sustainedrelease pellets was established,and the methodology was verified.The methodology verification showed that the method can meet the analytical requirements.An in vitro release determination method of ligustrazine phosphate sustained-release pellets was established,which can meet the sink conditions.The particle size and particle size distribution,PH solubility,oil-water partition coefficient,moisture absorption and other physical and chemical properties of the ligustrazine phosphate API were measured and studied.The results showed that the API has a narrow particle size distribution,high solubility under different p H conditions,and good hydrophilicity.The moisture absorption is weak.2 Study on ligustrazine phosphate film-controlled sustained-release pelletsThe ligustrazine phosphate-containing pill core was prepared by extrusion spheronization method,and the key factors and factor levels of the formal experimental design were determined through the study of soft material torque and single factor test.Using the central composite surface design to optimize the formulation process of the pill-containing core,it was determined that the best formulation process was: drug loading: 40%,microcrystalline cellulose: 60%,water: 0.92（the ratio of water to the total material）;Extrusion speed: 30 r/min,spheronization speed: 460 r/min,spheronization time: 8.8 min.The quick-release pellet core prepared by the best prescription technology has high yield,good roundness,narrow particle size distribution,suitable friability and bulk density,and is suitable for fluidized bed coating to prepare sustained-release pellets.Surelease^? water dispersion is selected as the slow-release coating material to coat the pellet core.In order to reduce the loss of pellets during the coating process and reduce the effect of the pellet core drug and the coating liquid,HPMC（E5）is selected as the isolation layer coating The coating material first coats the pill core with an isolation layer,and then carries out a slow-release coating.Taking the release rate of 2 h,6 h,and 12 h as the index,the coating process and the slow-release layer coating prescription were optimized by single factors,and the coating weight gain,type and dosage of porogen were investigated respectively.The influence of polymer concentration and curing process on release was determined,and the optimal coating process and prescription were determined: theoretical coating weight gain: 45%;porogen lactose dosage: 1.5%;coating polymer concentration: 12%;curing Temperature: 40℃;curing time: 0.5 h.The sustained-release pellets with 12-hour slow-release effect were prepared.3 Study on Ligustrazine Phosphate Matrix Sustained Release PelletsThe matrix type sustained-release pellets were prepared by the extrusion spheronization method.The types and dosages of matrix materials,the types and dosages of binders,and the size of the extrusion pore size were screened and investigated.The results showed that it is difficult to achieve the 12-hour sustainedrelease effect..It shows that for drugs with higher solubility such as ligustrazine phosphate,it is more suitable to be developed into film-controlled sustained-release pellets.So finally choose the membrane-controlled route.4 Study on the quality of ligustrazine phosphate sustained-release pelletsThree batches of sustained-release pellets were prepared according to the optimal formulation process optimized by the membrane-controlled process route,and the appearance properties,identification,content determination,and release determination were inspected to control their quality.The in vitro release of sustained-release pellets was fitted according to the zero-order release model,the first-level release model,and the Higuchi release model.The in-vitro drug release fitting results of the ligustrazine phosphate sustained-release pellets conformed to the first-order release equation This shows that the in vitro release of the drug is mainly passive diffusion.The initial stability of the ligustrazine phosphate sustained-release pellets was investigated under high temperature,high humidity and strong light conditions.The results showed that the appearance,content and release curve of the sustained-release pellets did not change significantly under high humidity and light conditions.The content will decrease under high temperature and the release in vitro will be accelerated.It shows that sustainedrelease pellets are greatly affected by high temperature and are not sensitive to high humidity and light.Therefore,in order to prevent the quality of the preparation from changing,high temperature should be avoided as much as possible during storage.In this research,a 12-hour sustained-release ligustrazine phosphate sustainedrelease pellets were prepared,and the quality was studied,which provided a reference for the further research and development of ligustrazine phosphate preparations.