Preparation Based On Extrusion Spheronization Process Isosorbide Mononitrate Sustained Release Capsules

Objective: Based on the research on the reference preparation of isosorbide mononitrate sustained-release capsules,preliminarily established the prescription and preparation process of the self-made product,and carried out the optimization of the prescription,the investigation of the durability of the prescription,and the exploration of the parameters of the preparation process.The similarity of the release curve is the evaluation index to determine the final formulation composition,preparation process and process parameters of key steps of the self-made product.Methods: 1.Determine the content and release determination method of this product,and carry out methodological verification.2.Through the project information research,understand the basic physical and chemical properties of the raw materials and excipients,examine the stability of the raw materials under the conditions of influencing factors,and examine the compatibility between the raw materials and excipients under accelerated conditions.3.Investigate project information and conduct reverse analysis of reference preparations to determine the preliminary prescription and process for the preparation of self-made products.4.Screening of self-made prescriptions,preparing the first batch of prescription samples,testing the content,related substances,moisture,release curve,analyzing the reasons according to the test results,and optimizing the prescription and preparation process.5.In the small-scale production stage,enlarge the feeding batch,investigate the similarity of the release behavior of the self-made product and the reference preparation,and optimize the process parameters of each process.6.In the pilot scale-up stage,scale up the batch in the small-scale production stage,produce 3 batches continuously,and strictly control the process parameters of the production process to ensure the similarity of the in vitro release behavior of the homemade product and the research product,and package the finished product.Take packaged samples for stability studies.7.Human bioequivalence trial,using a single-center,open-label,single-dose,two-period,randomized crossover design to evaluate bioequivalence in 18 healthy subjects.Results: 1.The content determination method was determined as: HPLC method,using octadecylsilane bonded silica gel as filler,methanol-water(25:75)as mobile phase,and the detection wavelength was 210 nm.The release rate detection method is: the second method(paddle method),50 rpm,the standard medium is water,the medium volume is 1000 m L,and the release rate is determined by HPLC.2.Through the project information research,the API of this product is a soluble drug,and its solubility in water,p H1.2 medium,p H4.0 medium,and p H6.8 medium is basically the same,and has no p H dependence;Good stability under factor conditions(high temperature,high humidity,light),no incompatibility of raw and auxiliary materials under accelerated conditions(40℃/75%RH).3.Through the investigation of the basic information of the original drug and the reverse analysis of the reference preparation,the prescription composition and preparation process of the original drug were determined.This product has a patented preparation process,and the patent is protected until March 15,2039.In order to circumvent patents and combine the composition of the original research product,consider using the extrusion-spheronization method to prepare the pill-containing core,and the outer layer of the pill-containing core is covered with a sustained-release layer(the sustained-release material is ethyl cellulose),and the outer layer of the sustained-release layer is It comprises a drug layer,namely an immediate release layer,the immediate release layer is coated with a protective layer(film coat),and the protective layer materials are polyvinyl alcohol polyethylene glycol copolymer and talcum powder.The unit prescription ratio of the pill core and the immediate release layer is 7:3.4.After the prescription screening,the final prescription of this product is determined.The pill core contains: isosorbide mononitrate 35 mg,sucrose 16.34 mg,lactose monohydrate 13.42 mg,corn starch 10.00 mg,hydroxypropyl cellulose 0.68 mg;sustained-release layer: 95% ethyl cellulose ethanol solution to increase the weight to 8%;immediate-release layer: containing 15 mg of API per unit prescription,that is,the weight gain is about 18.4%;Film coating material:polyvinyl alcohol polyethylene glycol copolymer,talc 1250 mesh,coating weight increase to about 5%.5.The final formulation is scaled up and produced in a small test.The product meets the quality standard and is basically similar to the reference preparation in vitro release behavior.The similarity factor f2>50.After 6 months of stability test,the sample still meets the quality standard.The prescription is scaled up to the pilot batch.6.The three batches of samples in the pilot test meet the quality standards and have a good similarity to the in vitro release behavior of the reference preparation,and the stability of the homemade product has been investigated.Due to the time relationship,this product is only stable for 6 months.Good,consistent with the change behavior of the reference product.7.According to the results of the pre-BE test,it is believed that the in vivo release behavior of the self-made product and the reference preparation is consistent with 90% confidence.Conclusion: The preparation process adopted in this study is feasible,the product quality is controllable,the in vitro release degree is similar to the reference preparation,and there is no significant difference between batches.Samples tested for longer periods of time are for further study.The in vivo release behavior of the self-made product and the reference preparation was equivalent in the fasting state and the postprandial state.