| PSS (Propylene glycol alginate sodium sulfate), the first marine sulfated polysaccharide drug that chinese has researched and developmented independently, mianly used for the treatment of ischemic cardiovascular and cerebrovascular disease.However, the pharmaceutical formulation of PSS now are just ordinary tablets and injections, and their quality standards are so backward that we unable to control their quality effectively; especially the deficiency of the evaluation of PSS Solid preparation’s drug release in vitro, which can not meet the increasing clinical needs,.It is urgent to improve the quality standard.Meanwhile, PSS tablets have many problems.Like requiring multiple dosing, fluctuation of blood drug concentration, poor patients compliance issues, et al.Therefore, it is necessary to develop the PSS sustained-release tablets to solve these problems.PSS sustained-release tablets were prepared by melting granulation method and wet granulation method using HPMC, CMC-Na and octadecanol as matrix materials; evaluating the two methods in the tablet weight difference, hardness difference, the actual operation and other aspects, The results show that the melting granulation method is better than the wet granulation method.According to the structure and physicochemical characteristics of PSS, gel permeation high performance liquid chromatography(HPGPC) method and precolumn derivatization high performance liquid chromatography (PC-HPLC) method was used to study the content and determination of in vitro release of PSS sustained-release tablets.PSS and excipients could not be separated completely by using HPGPC method in a variety of gel chromatography column, there is some overlap with the chromatographic peak of PSS and excipients, but make the Shodex OHpak SB-806 HQ and TSK gel G3000 PWXL in series could improve the separation of PSS and excipients obviously, and comparing to using peak area to determine content, using peak height to determine content has a better linearity, can effectively reduce the impact of the overlap of peaks; PSS sustained-release tablets was determined by PC-HPLC method, the specificity is good, all excipients did not disturb the determination of release rate of PSS, the concentration and peak aera showed a good linearity in 0.3-12 mg/mL range(r=0.9983), The RSD of precision test was 1.4%(n=5), the RSD of repeatability test was 3.4%(n=5), the precision and reproducibility are Satisfied.The PC-HPLC method can meet most of the analytical requirements that PSS sustained-release tablets need.Evaluating the effects of the dosage of HPMC, CMC-Na and octadecanol on the in vitro drug release through single factor test, the prescription was optimized by using orthogonal design method, Using the commonly drug release kinetics model to evaluate release rate in vitro of sustained-release tablets. The optimum prescription was determined by orthogonal design as follows:the weight percents of HPMC, CMC-Na, and octadecanolin PSS sustained-release tablets were 15%,10%,10%, respectively.The release rates of PSS sustained-release tablets were 30.3%,70.9% and 95.5% within 2 h,6 h,12 h, respectively. The drug release behavior in vitro conforms to the first-order kinetics equations, releasing drug by fickian diffusion and skeleton dissolution synergistically.Preparation process, excipients effect on the drug release and the prescription optimization of PSS sustained-release tablets has been studied systematically, succeeded to prepare the PSS sustained-release tablets which drug release behavior conform to the first-order equation; and the PC-HPLC method on the content of PSS sustained-release tablets and determination of in vitro release was established. These findings provide a basis and reference for the application and development of PSS and other marine polysaccharide drugs sustained-release preparation, playing an important role in reducing the adverse reaction of PSS in clinical application, improving the compliance of patients. |
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