Preparation And Quality Control Of Entecavir Dispersible Tablets

Entecavir is a deoxyguanosine analog approved of being used for the treatment of chronic Hepatitis B infection and lamivudine-resistant hepatitis B virus. Drugs for the treatment of chronic hepatitis B were divided into two basic categories:interferon and nucleoside(acid) analogues. However, due to the low rate of interferon response and non-lasting efficacy, nucleoside (acid) analogues play an important role in the treatment of HBV, in which entecavir has a distinct advantage with a higher cure rate and lower resistance rate in clinical.Entecavir belongs to insoluble drugs, and ordinary tablet dosage forms have a certain influence on the dissolution of the drug. In this study, entecavir was developed into dispersible tablets, so as to speed its disintegrating, and improve the dissolution rate and bioavailability of the drug.The relevant literature and patent reports home and abroad were referred to grope for formula. According to the result of excipient compat-ibility, the amount of excipients and added method as the study factors in orthogonal test, the optimal match of lactose, microcrystalline cellulose, Carboxymethyl starch Sodium, povidone K30, magnesium stearate, Aspartame, peach essence and entecavir was determined. Respectively110g lactose,80g microcrystalline cellulose, lOg Carboxymethylstarch Sodium,20mL20%povidone solution,2g magnesium stearate,2g aspartame,2g peach flavor and0.5g entecavir were suppressed into1000entecavir dispersible tablets, and the principal agent was over80mesh sieve. Observe the dissolution, uniformity of dosage units, content, related substance and optical isomer by HPLC. Entecavir has three chiral centres so there may be several multiple optical isomers in it, furthermore, pharmaceutical product synthesis process is of complexity and longer synthetic route, so more impurities may be generated.In this study, we researched methodology of related substance in detail by adopting gradient elution and studied the intermediate and four known impurities(Ⅱ、Ⅲ、Ⅳ、 Ⅴ) and whether the degradation product which was destructed by hydrochloric acid, alkali, oxidation, illumination, ultraviolet and high temperature could be separated from entecavir. The optical isomer has not be controlled in any standardization of pharmaceutical product and praeparatum home and abroad. We strictly controlled the content of the impurity A with chiral chromatography to set up methodology. The dispersible tablets prepared in our lab dissolution were much faster than the Entecavir tablets of Bristol-Myers Squibb, and dissolution more than90%among5minutes. The content uniformity was fine, A+1.80S<5. The content exceeded by98%. The related substance could be separated from entecavir and its content was0.12%～0.20%. The optical isomer was not detected.The preparation of Entecavir dispersible tablets is reasonable and the technology is simple. The content and related substance didn’t change obviously and the optical isomer was not checked out of the speedup sample after6months through HPLC methodology verification and stability investigation. In summary, the quality of entecavir dispersible tablets is reliable which possesses favourable application value.