| Tacrolimus (Taclimous, FK506) is another cytokine synthesis inhibitor after cyclosporin A, the internal and external experiments have confirmed the immunization inhibitory effect of FK506 is 10-100 times of cyclosporine A, FK506 can effectively prevent clinical acute rejection after kidney transplantation, and reverse the refractory rejection, the market application foreground is wide. In order to ensure the safe and effective clinical treatment, we studied quality comprehensively on Tacrolimus Capsules.Objective:to establish a quality control method for Tacrolimus Capsules, and to confirm the package material and packing configuration, storage conditions, specification and product shelf life for the Tacrolimus Capsules.Methods:According to the related guidelines coming from the Chinese Pharmacopoeia appendix and ICHQ1A-F,ICHQ6A-B,ICHQ3A-D, the method and stability study of Tacrolimus Capsules was mainly used the HPLC and other traditional analysis technologies. Because the characteristics of molecular structure of the product and the fermentation process had the complicated influence on its quality, the related substances study was the focal point in the article. The tautomerism of Tacrolimus isomers I and isomer Ⅱ,the stress degradation testing, the related substances structure confirmation, the dissolution condition choice and method comparison were studied in detail too.The stability study of the Tacrolimus Capsules included the accelerated testing (40℃/75%RH) and long-term testing (25℃/60%RH), the package material and packing configuration choice, confirmation the product shelf life. The above choice confirmation was depended on the results of the stability test.Results:when the anhydrous acetonitrile is selected as the solvent, the tautomerism Tacrolimus isomers I and isomer Ⅱ can immediately reach equilibrium, and the solution need not stand, it is more accurate to determination of isomers I and isomer Ⅱ. To make sure the impurities A, C, D and P structure by the IR, NMR,MS apparatus, and define the impurities limits. Method validation parameters include linearity, specificity, precision, recovery, stress degradation testing, filter testing, extraction, solution stability, LOD and LOQ, related substance structure confirmation e.g. Experiments show that the validated method can better separate very well for the related substances produced in acid, alkali, oxidation, light, high temperature and humidity damage. The dissolution use the paddle, the 0.1% SDS and 0.1N hydrochloric acid solution,is the medium, the dissolution speed is 50rpm. the dissolution curve is the same between the generics and RLD.The PVC/PVDC blister with foil sachet and desiccant packing configuration will be as the marked sale package. Tacrolimus Capsules packed in above configuration is stable for the accelerated 6 month and 36 month long term.Conclusion:the validated method is simple, accurate, specific, reproducible, and can test accurately product quality. The test results show that Tacrolimus Capsules packed in PVC/PVDC blister with foil sachet and desiccant is stable at high temperature and high humidity conditions, and to provide the verification for the marked storage condition and shelf life. |
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