Studies On Topiroxostat Loaded Sustained-Release Pellet Capsule

Topiroxostat is a kind of non-purine xanthine oxidase inhibitor with high selectivity, and could be used to inhibite the effects of reducing and oxidizing xanthine oxidases. It could be used for the treatment of gout patient with hyperuricemia. The conventional tablet of topiroxostat was approved for marketing in Japan in 2013, but there was no raw material of topiroxostat, production or import of tablet at present in China. The conventional tablet of topiroxostat was administrated in each morning and evening with the dosage of 20 mg. The dosage could be increased according to the treatment needs, resulting in the long taking cycle of conventional tablet. The sustained-release dosage form was chosen in this research to achieve the sustained-releasing, infrequent administration and improved compliance. In recent years, sustained-release pellet has attracted much attention due to the advantages including wide range of drug loading, controllable drug release rate and easily available materials.There are several methods for the preparation of sustained-release pellet. The fluidized bed spray drying method is one of the widely used technologies since the pellet preparation is performed in a containment system to obtain the pellet with round shape, no adhesion., equal size and narrow distribution of particle size. The sustained-release coating material is very important for the design and preparation of sustained-release pellet. Eudragit NE30D is widely used since it is safe, non-toxic and tasteless, not easily to be absorpted or metabolismed in vivo and make effect without plasticizer added during preparation.Thus in this research, the fluidized bed spray drying blank pellet coating technology was used to prepare the topiroxostat loaded sustain-release pellet. The Eudragit NE30D was selected as the sustained-release coating material. The drug release test and the quality research were carried out. Then the sustained-release pellet was loaded into capsule to prepare topiroxostat sustain-release pellet capsule. The characterization of topiroxostat loaded sustain-release pellet capsule was studied.The main research contents in this reseach include: ①The method of quality analysis and measurement of release degree in vitro was studied to provide the basis for the selection of formulation and preparation technology.②The formulation and preparation technology was screened for the topiroxostat loaded sustained-release pellet;③ The sustained-release pellet capsule was prepared and the characterizated. The main methods and results are shown as follows:1.The establishment of topiroxostat analysis methodUV-VIS spectrophotometry was used for the research on measurement of release degree in vitro. The detecting wavelength was determined within the range from 200 nm to 400 nm. The topiroxostat solution in different solvents with different concentrations (from 3.2 μg/ml to 9.6 μg/ml) was prepared, and the absorbance was measured at the wavelength of 279 nm. Additionally, the linear regression analysis on absorbance and concentration and standard curve were made, coupled with good linear relationship. The equilibrium solubility of topiroxostat in sodium dodecyl sulfonate (SDS) solvent at different pH was measured, and the results showed that there was no obvious increase in the solubility of topiroxostat when the concentration of SDS≥0.5%, thus 0.5% SDS was chosen as the solution. The stability of topiroxostat within 8 h in different solvents was measured, and the result indicated that topiroxostat was stable in 8 h. The recovery rate of 50%,80% and 100%(100% means the concentration of topiroxostat is 6 μg/ml) was determined, and the mean recycling rate was 99.79%. High performance liquid chromatography (HPLC) was used for the methodology research of content determination and related material research. The methodology research of content determination included specific test and stability test within 8 h. No peak of blank adjuvant was found in specific test, so the measurement of main drug won’t be interfered by the adjuvant. The results of the stability test within 8 h showed that the solution was stable. The standard curve with peak area of topiroxostat as vertical axis and concentration as horizontal axis was drawn (concentration ranged from 60% to 140%), showing good linear relationship, and the recycling rate of topiroxostat (70%,100% and 130%) was 99.79%. The limit of quantitation and inspection test were made for related material research and the RSD value were all less than 5%, the results indicated that the production met the requirement. The result of the solution stability test showed the solution was stable within 8 hours. The contrast solution was measured for 6 times in precision test, and the results showed that the retention time of main peak was the same and the precision degree was good.Thus it’s feasible to use UV method for the measurement of release degree of Topiroxostat loaded sustained-release pellets and to use HPLC method for the content measurement of Topiroxostat loaded sustained-release pellets.2.The blank core pellet coating method for the preparation of topiroxostat loadedsustained-release pelletsThe active ingredients topiroxostat was mixed with different accessories such as pellet core fines, PVPK30 and HPMC in a certain proportion, the stabilities were measured under high temperature or high humidity. The compatibility studies of raw materials were carried out, and the results showed that the compatibility of raw adjuvant material was good. Core pellet fluidized bed spray was selected asthe releasing layer for the preparation of sustained-releasing pellet. Firstly, the observation of isolated layer of core pellet was made for the preparation of pellet with different particle sizes. The test results indicated that it’s uneasy to adhere on the wall when P3 (500-700um) was used for pellet coating. Therefore, P3 is often chosen as the core of Topiroxostat loaded sustained-release pellet. Secondly, the drug-loaded solution was screened with the concentration of topiroxostat as 5%. After that, crushing-disposal treatment of raw materials was made. When D90 is≤20μm, the main drug is added into 5% povidone K30 and 70% ethanol solution to prepare the suspension as the drug-loaded solution. Quality evaluation of topiroxostat pellet was made after coating and drug-loading. After 1% HPMC being chosen as the isolated layer, the coating weigh and release degree in the different solvents was determained, and the release curve was drawn. Finally, Eudragit(?) NE30D was chosen as the sustain-release material. L9 (33) orthogonal design of coat weight, talcum powder addition and drying time was made. Thus the Topiroxostat loaded sustained-release pellet was prepared with coating weight gain of 8%, add amount of talcum powder of 50% and drying time of 24 h. Three batches of scale-up of small test according to the initially identified prescription and technology, showing good reproducibility.3.The preparation and quality research of topiroxostat loaded sustained-release pellet0# capsule was selected. Three batches of topiroxostat loaded sustained-release pellets were prepared to capsules with the specification of 40 mg. Quality research was made for three batches of pellet capsules. The product should be white to off-white pellets. Identifications:The solution of test sample should have an absorption peak at the wavelength of 279nm. The topiroxostat (C13H8N6) content of this product should be 90.0%-110.0% of labeled amount. Release degree:At 2 h,6 h and 12 h, the dissolved quantity of topiroxostat should be 25%-35%,60%-70%, and more than 85% of labeled amount respectively. Formula one of drug release kinetics equation and Higuchi equation were used to match Topiroxostat loaded sustained-release pellet capsule. The topiroxostat loaded sustained-release pellets conform to Higuchi equation releasing model. No obvious changes could be found in appearance, content and release degree of the product after 6 month observation under accelerated and long term condition, which showed the product was stable.In this research, Topiroxostat loaded sustained-release pellets and sustained-release capsules were prepared. The reproducibility of the prescription of pellet and sustained-release capsule was verified by the scale-up of small test. According to the results of quality research of sustained-release pellet and sustained-release capsule, the capsule we prepared met the requirement of preset objective and could be used to provide experimental basis for the industrial production of Topiroxostat loaded sustained-release pellet capsule.