| Fudosteine is the first type of tracheal epithelial secretory cell improving drug developed by SS Pharmaceuticals in Japan.Fudosteine structurally belongs to the amino acid derivative.It not only has a good debonding effect,but also has an inhibitory effect on tracheal inflammation;with less toxic side effects and;good tolerance,which can be used as the first-line medications for chronic respiratory diseases.Fudosteine has occupied an important position in the drug market,so the development of this product has a broad market prospect.We developed a new prescription and process,determined the prescription composition and specific process parameters,and determined the quality of analytical investigations based on the original formula of fudosteine,and according to the requirements of the "Opinions of the General Office of the State Council Concerning the Conformance Assessment of the Quality and Efficacy of Generic Drugs." The main results are listed as follows:(1)We systematically studied the prescription of the original fudosteine tablet and our own.Firstly the formulation of diluents(corn starch,microcrystalline cellulose),adhesives(corn starch,povidone,hypromellose),disintegrants(croscarmellose sodium,cross-linked polypovidone),sodium lauryl sulfate,lubricants(stearic acid,magnesium stearate,talc)were screened.The final prescription was 200 mg of drug substance,7 mg of corn starch as excipient,10 mg of croscarmellose sodium as disintegrant,and 15%?20%of purified water as the wetting agent.The lubricant was stearic acid magnesium and powdered silica gel which are both 2 mg.Core tablet weighs 221 mg and;coating weight gains 3%,and the final products weighs 228 mg.We optimized the binder addition method,the disintegrant addition method,the number of sieve meshes selected during granulation for the process,the granulation method,the tablet hardness,the intermediate moisture and drying temperature,the drying time,and the coating parameters were determined.After such optimization,the final screening results were as follows:wet granulation,binders,and disintegrants were all added while premixing,30-mesh sieve granulation and,and dried at 60? for 2.5 hours during production.The moisture content is controlled below 1,2%and the tableting hardness is between 50 to 70 N.The final process route is:firstly,drug substance was added by the method of equal increment in the corn starch and croscarmellose sodium.Secondly,to ensure that the premixing stage is well performed,15%?20%purified water was added to the above mixture to make the soft material.After granulation,and total mixing,the tablet was coated.We carried out the production of fudosteine tablets in large scale in GMP conditions according to the optimized formulation and process.It proved that the process worked well in GMP conditions and few paramaters were modified.Only the amount of purified water and the drying time of the pellets were adjusted according to the actual production conditions.The prepared pellets had good fluidity,which met the requirements for tablet weight and hardness during the tableting process.The process was stable and the reproducibility was good.(2)The products were produced in large scale and investigated for stability according to the established prescriptions and processes.The three batches of final products were clean,uniform in appearance,color and luster,and the hardness and friability were in compliance with the requirements.Dissolution was within the specified range.The stability of the three batches of products was evaluated by influencing factors,accelerated tests and long-term tests.The main indicators are moisture,dissolution,content uniformity and related substances.The experimental results of the influencing factors showed that the product has no change in appearance and dissolution under high temperature,high humidity and light conditions.Accelerated and long-term experiments of three months indicated that the product was stable and more data are still underway. |
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