【作者】 隋红；

【导师】 李三鸣；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2003， 硕士

【摘要】 盐酸万乃洛韦（Valaciclovir Hydrochloride，简称VACV），是阿昔洛韦（ACV）的前体药物，进入体内经酶水解成为ACV而发挥抗病毒作用。 本文考察了VACV的理化特性：37℃时VACV水中溶解度为466.64mg／mL；摩尔熔解热为35.16kJ／mol；饱和VACV溶液的渗透压摩尔浓度为2.222 Osmol／kg；表观油水分配系数为0.487，且随温度升高而增加。 对Eudragit RS粉末和游离膜的性质进行了考察：Eudragit RS干燥失重为0.85％；特性粘度为27.33mL／g；玻璃转化温度为226.63℃；粉末松密度为0.575g／cm³；粉末休止角为35.04°；通过测定聚合物溶度参数及透湿性，确定乙醇为良溶剂；通过测定游离膜的玻璃转化温度、透湿性，确定DBP为良好的增塑剂；通过电镜扫描确定水溶性增塑剂PEG-400还同时起到致孔剂的作用。 选用HPMC为填充剂；分别以醋酸纤维素、PEG-400、DBP的丙酮溶液（Ⅰ）、Eudragit RS PO、PEG-400、DBP的乙醇溶液（Ⅱ）为包衣材料；制备了VACV微孔渗透泵（Micro-Porous Osmotic Pump，简称MPOP）控释片。通过正交设计，以2、6、10hr的药物释放度及直线拟合相关系数r为评价指标，优化筛选出最佳包衣液处方和包衣工艺。 研究结果表明膜内外渗透压差是影响药物释放的关键。药物在相同渗透压的不同溶出介质中具有相同的释药速率；不同渗透压的同种溶出介质中，其释药速率随渗透压差减小而成比例减小，证明释药机制为渗透释药。对其曲线进行拟合，符合零级释放规律。该制剂在40℃、RH75％环境下密封放置三个月，外观、释放度和含量均无明显变化，表现出良好的稳定性。 以市售普通片为对照，采用HPLC法研究了VACV MPOP片狗体内相对生物利用度和药代动力学。结果表明，普通片的C_max、T_max分别为沈川药科大学硕士学位论文 摘 要3546．gng加L和 Zhr：MPOP片的 Cm肌、Tin皿分另为 1659 卫＂g／mL和 6hr。＊＊＊P片与普通片的相对生物利用度为108．＊％。＊＊＊P片具有出峰时间晚、峰值低、血药浓度平稳的缓控释特征。＊P＊P片的体外释药特性与体内吸收有较好的相关性。更多还原

【Abstract】 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.更多还原