| Valaciclovir is the L-valyl ester of acyclovir, and it is characterized by its good water solubility and high bioavailability. Valaciclovir Hydrochloride is often used in the treatment of varicella, herpes zoster, herpes simplex type I (HSV-1) and herpes simplex type II (HSV-2) , including incipient and recrudescent genital herpes.Valaciclovir Hydrochloride (VCV)is often formed into traditional tablets and it is dosed 300mg each time and twice per day. It should be used continuously for 10 days to treat herpes zoster and 7 days to treat herpes simplex. In order to reduce dosing frequency, improve patients' compliance and minish the adverse effect caused by high plasma concentration of Valaciclovir Hydrochloride, we developed Valaciclovir Hydrochloride sustained release tablets(VHSRT) for one dose per day. Till now, we have finished it's pre-clinical. pharmacokinetics, bioavailability and clinical research.Because Valaciclovir Hydrochloride could be easily dissolved in water and be absorbed in the whole gastrointestinal tract, we formed it into frame tablets with hydrophilic hydrogel. According to the results of dissolution tests, we selected the proper base material and bioadhesive material, and optimized the components of the sustained tablets. Using the homogeneous design , we studied the cumulated release-time profile of the tablets. The results showed that the cumulated release-time profile fitted Hixon-Crowell equation best. Its correlation coefficient r was maximal and MSE error was minimal. The results demonstratedthat during the dissolution, Valaciclovir Hydrochloride was dissolved with the erosion of frame structure, and its dissolution and diffusion rate from the frame structure was the speed limiting process of the release of ValaciclovirHydrochloride.Using traditional Valaciclovir Hydrochloride tablets(VHT) as control group,the single-dose and multi-dose bioavailability of VHSRT was studied with 6 dogs, and the data was processed with 3p97 program. Compared with the control group, the single-dose relative bioavailability of VHSRT was 97.02%. The results proved that VHSRT and VHT had same bioavailability. The Cmax and Tmax of VHT were 4.24ug/mL and 2.33h respectively, and The Cmax and Tmax of VHSRT were 3.81ug/mL and 3.50h respectively. VHSRT demonstrated a obvious prolonged release. After the stable state of muliti-dosage was reached, The mean bathyphase plasma concentration and fluctuation range of VHT were 0.58ug/mL and 483.1 respectively, and the mean bathyphase plasma concentration and fluctuation range of VHSRT were 1.20ug/mL and 135.2 respectively. The mean bathyphase plasma concentration of VHSRT was 2.07 folds higher than that of VHT and the fluctuation range of VHT was 3.56 folds larger than that of VHSRT. The results showed that compared with VHT, VHSRT could maintain more stable plasma drug concentration, and the VHSRT could promote the efficacy and safety of Valaciclovir Hydrochloride.In clinical bioavailability studies, 19 healthy volunteers were selected in single-dose group and 22 healthy volunteers were selected in multi-dose group. In single-dose group, the AUCo_Tn,AUCo-^0,Tniax,CIliax,t,/2 and MRT of VHSRT and Lizhuwei R were 16.13±2.94ugxh/ml W(i I7.48±3.62ugxh/ml, 19.45±3.86ugxh/ml and 19.45±3.69ugxh/ml, 3.4±0.4h and 1.9±0.4h,1.84±0.41 fig/ml and 3.85±0.74ug/ml, 5.9±2.1h and 2.8±0.9h, 9.9±2.7h and 4.8±1.0h respectively. Compared with LizhuweiS, the O-Tn and O-oo relative bioavailability of VHSRT were 93.09±6.92% and 100.49±10.41% respectively. In multi-dose group, the Q?* C^55, T^ AUCV?. DP/o and MRT of VHSRT and LizhuweiB. were 1.37±0.5lug/ml and 0.74±0.37ug/m, 3.24±0.56 ug/ml and 4.55±0.76 ug/ml, 4.57±0.66h and 2.09±0.33h, 53.50±12.10ugxh/ml and 28.93±6.92ugxh/ml,87.46±26.44% and 163.44±32.20% respectively. F{0.T) was 93.66±11.87%. The analysis of variance and two-sided t test proved that VHSRT and Lizhuweifi have same bioavailbility. Compared with LizhuweiB, VHSRT has lower 0^ longer T^, lesser fluctuation range. VHSRT exhibited significant prolonged release. The efficacy and safety of VHSRT for the treatment of dermopathic herpesvirus disease were studied by multicenter, random, double blind, double simulated and positively parallel comparable clinical researches. The results showed that compared with VHT, VHSRT was safe and efficient in the treatment of herpes zoster, herpes simplex, its clinical curative effect and adverse effect had no significant difference statistically.When we brought forward the concept of novel VHSRT, it was not reported abroad. The frame structure of VHSRT was composed with HPMC and bioadhesive material C. 24h prolonged release of Valaciclovir Hydrochloride was achieved by VHSRT and its efficacy and safety was approved by clinical research. VHSRT enriched the research of antibiotic sustained delivery systems. It is supposed that VHSRT will contribute to the society and make good profits.
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