Study On Valaciclovir Hydrochloride Micro-porous Osmotic Pump Tablets

The paper focused on the antiviral prodrug: the 1-valyl ester of acyclovir, valaciclovir(VACV). The compound was rapidly and extensively converted to acyclovir after oral administration.Equilibrium solubility of VACV in water under 37 C was 466.64mg/mL; Osmolality of saturated VACV solution was inferred 2.222 Osmol/kg. Apparent n-octanol/water partition coefficient was 0.487, and swelled with the increasing of temperature.Properties of Eudragit RS powder and film were evaluated for selection of formulation of good preparation. Loss on dry of powder was 0.85%; intrinsic viscosity was 27.33mL/g; glass transition temperature(Tg) was 226.63 C; bulk density was 0.575g/cm3; angle of repose was 35.04 ;Ethanol was a good solvent for Eudragit RS by investigating solubility parameter( 5 ) and water permeability; DBP was a good plasticizer by investigating Tg and water permeability; PEG-400 was a good pore former by scanning electronic micrographs.In the paper, VACV micro-porous osmotic pump (MPOP) tablets were prepared. Based on the comprehensive research, HPMC was used to make the part of tablet core. Cellulose acetate(CA), Polyethylene glyco1400(PEG-400), Dibutyl phthalate (DBP)and acetone were selected as the coating solution(I); Eudragit RS PO, PEG-400, DBP and ethanol were employed as the coatingsolution(II). The coating formulation and process were optimized by orthogonal design, having the linear correlation coefficient and the accumulative release amount of 2hn 6hr and 10hr as the evaluation target.The effect of the osmotic pressure difference across the membrane on release rate was studied. It was proved that the drug release rates were similar on the similar osmotic pressure difference of different mediums, and that the drug release rate decreased in proportion of the osmotic pressure difference. The linear correlation coefficient of the accumulative release amount mostly conformed to the model of zero order, which proved its osmotic principle. The study showed that the drug release characterisecs, appearance and the content of the well packaged preparation did not change after stored under 40 C and RH75% environment for three months.By HPLC with UV detection for determining VACV concentration in plasma and using commercial conventional tablets as the reference, pharmacokinetics of VACV MPOP tablets were performed in three healthy dogs . Cmax and Tmax of reference tablets were 3546.9ng/mL and 2hr. Cmax and Tmax of MPOP tablets were 1659.2ng/mL and 6hr. The relative bioavailability of MPOP tablets was 108.2%. MPOP tablets had the controlled-release characteristics of delayed Tmax,lower Cmax and smoother plasma concentration. Obvious correlation was observed between absorption percentage in vivo and release rate in vitro.