| Ornithine aspartate is clinically used to treat elevated blood ammonia and hepatic encephalopathy caused by acute and chronic liver diseases（such as various types of hepatitis,cirrhosis,fatty liver,and post-hepatitis syndrome）.At present,only granules and injections are on the market at home and abroad,but granules are taken frequently,and injections are difficult to store and transport.The purpose of this study is to prepare a sustained-release pellet.It can reduce the number of medications、prolong the action time and make it more convenient for patients to use.At the same time,research on its quality standards to provide guarantee for its safety and effectiveness.Through the pre-prescription study,the aspartic ornithine API was studied to determine its quality to meet the requirements.The compatibility of raw materials and auxiliary materials was studied.All kinds of excipients to be selected were mixed with the API in proportion.Under the conditions of high temperature（60℃±2℃）,high humidity（90%±5%）and strong light（4500 Lx±500 Lx）,the properties of the mixture,the content of related substances and the content of main drugs basically did not change,which met the quality requirements.The excipients have good compatibility with aspartate ornithine.In this project,the ornithine aspartate pill core was prepared by bottom spray coating technology in fluidized bed.The roundness and yield of pellets were used as evaluation indexes of pill core quality,and the prescription and process parameters were investigated by single factor.Orthogonal experimental design was used to screen and optimize the important influencing factors in the prescription and process,and finally the optimal prescription and process conditions were determined as follows:adhesive 8%PVP-K30,drug concentration 30%,air volume 55 m3/h,air inlet temperature 60℃,atomization pressure 0.20 Mpa,liquid inlet speed 1.0 rpm,and the roundness of the pellet core is high,and the yield is qualified.In this project,the fluidized bed bottom spray coating technology is combined with the QbD concept to prepare ornithine aspartate sustained-release pellets.The key quality attribute was determined as cumulative release through the product quality objective,and the amount of slow-release material and plasticizer in the coating solution were determined to have the greatest impact on the key quality attribute through fault analysis,and they were listed as high-risk factors.The design expert software is used to conduct star point design-effect surface analysis to obtain the model fitting equation.The equation has a good linear relationship.At the same time,the measured value is close to the model predicted value.Through the contour map of the effect surface of each factor on the cumulative release rate,the design space predicted by the model is found to be the amount of ethyl cellulose in the coating solution X1:2%-4%,and the amount of stearic acid X2:3%-4.8%,and the amount of polyethylene glycol-4000 X3:0.5%-1%.Take low,medium,and high levels to prepare ornithine aspartate sustained-release pellets to verify the design space.The verification results show that the model fits well,and the control space is determined to be X1:2.2%-3.8%,X2:3.2%-4.6%,X3:0.52%-0.98%.Because the process parameters have little effect on the release degree,the control space is determined by simple testto be air volume:45-50 m3/h,atomization pressure:0.18-0.20 Mpa,air inlet temperature:40-45°C,liquid inlet speed:1.0-1.5 rpm.After optimization,X1:3.205%,X2:3.858%,X3:0.562%were used to prepare three batches of pellets withthis prescription.The cumulative release result was close to the predicted value of the model,powder properties are good and the apparent shape is round,so this was used as the sample for the follow-up quality standard study.Study the quality standards of ornithine aspartate sustained-release pellets.Including properties、identification、content and release degree.Established a comprehensive quality evaluation system.Directly observe and judge its properties by visual inspection;Use chemical methods to identify ornithine aspartate sustained-release pellets;Use high performance liquid chromatography to check its content,related substances,and the method for content and related substances has been verified by methodology;An analytical method for the determination of cumulative release of ornithine aspartate sustained-release pellets by ultraviolet spectrophotometry has been established.The results of all indicators are in line with the standards.At the same time,the quality study was compared with the commercial ornithine aspartate granules to further illustrate its safety and effectiveness.Finally,the preliminary stability of ornithine aspartate sustained-release pellets was investigated.Influencing factors experiments show that ornithine aspartate sustained-release pellets are more sensitive to high temperature conditions,so they are packaged in double aluminum plastic,protected from light,airtight and stored in a cool place.The accelerated test showed that the sustained-release pellets of ornithine aspartate had good stability under the packaging. |
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