目的 采用快速膜乳化-溶剂挥发法制备不含载体辅料的他达拉非微粒，并对其体外释药行为进行评价。方法 采用快速膜乳化-溶剂挥发法制备不含载体辅料的他达拉非微粒，将主药于50℃超声条件下溶解于有机溶剂中作为油相。将聚乙烯醇（PVA）于磁力搅拌加热条件下溶解于去离子水中，趁热用0.45μm的微孔滤膜真空抽滤，得续滤液，作为水相。油相与水相经磁力搅拌混合均匀后得初乳液，将初乳液倒入快速不锈钢膜乳化装置，氮气加压，过膜，收集乳液。将乳液与固化液混合后固化至无有机溶剂气味，离心洗涤，冷冻干燥即得到他达拉非微粒冻干粉。以微粒粒径及焓变值的综合评价为指标，对有机溶剂种类、PVA浓度、药物质量浓度、油水相体积比、过膜次数、固化方式、固化液pH值进行单因素考察，初步筛选出他达拉非微粒最佳制备工艺；采用直接释药法测定并比较他达拉非原料药与微粒在不同时间点的累积释放率，并对其释放行为进行数学模型拟合。结果 经单因素考察，初步确定他达拉非微粒的制备条件为：有机溶剂醋酸乙酯，PVA浓度为3%，油水相体积比为1∶1，油相药物的质量浓度为5mg·mL^-1，固化液pH值为4.5，四级串联不锈钢膜过膜1次，旋转蒸发仪固化。他达拉非微粒平均10%、50%、90%的颗粒尺寸在所测得的尺寸值（D₁₀、D₅₀、D₉₀）分别为30.3、72.0、126μm，扫描电镜下呈现较为均匀的长条片状，差示扫描量热法测定其焓变值为2033.8mJ·mg^-1·s^-1，显示其结晶程度降低；平均药物质量分数为99.07%。他达拉非微粒在4h时累积释放率可达94.00%，而原料药在4h内仅释放54.56%，两者体外释放均符合Logistic方程。结论 快速膜乳化法制备的微粒可使他达拉非粒径更均一，结晶程度降低，溶出度提高，显示该方法可用于提高难溶性药物生物利用度。

Objective To prepare tadalafil microparticles without carrier excipients by rapid membrane emulsification-solvent evaporation method and evaluate their drug release behavior in vitro. Methods Tadalafil microparticles without carrier and excipients were prepared by rapid membrane emulsification solvent volatilization method. The main drug was dissolved in an organic solvent as oil phase under ultrasonic at 50 ℃. The polyvinyl alcohol (PVA) was dissolved in deionized water under the condition of magnetic stirring and heating, and the filtrate was obtained by vacuum pumping with a 0.45 μm microporous filter membrane as the aqueous phase. The oil phase and the water phase were mixed evenly by magnetic stirring to obtain the primary lotion. The primary lotion was poured into the rapid stainless steel membrane emulsifying device, pressurized with nitrogen, and the lotion was collected. After mixing the lotion with the curing liquid, it was cured until there was no smell of organic solvent, centrifugally washed and freeze-dried to obtain the freeze-dried powder of tadalafil microparticles. Taking the comprehensive evaluation of particle size and enthalpy change as the index, the organic solvent, PVA concentration, tadalafil mass concentration, oil-water phase volume ratio, film passing times, curing mode and pH value of curing solution were investigated by single factor method, and the optimal preparation conditions of tadalafil particles was preliminarily determined; The cumulative release rates of tadalafil and its microparticles at different time points were measured and compared by direct release method, and the release behavior was fitted by mathematical model. Results After single factor investigation, the preparation conditions of tadalafil microparticles were preliminarily determined as follows: organic solvent ethyl acetate, PVA concentration of 3%, oil-water phase volume ratio of 1: 1, drug mass concentration of 5 mg·mL^-1, curing liquid pH = 4.5, four-stage series stainless steel membrane passing through the membrane once, and curing by rotary evaporator. The average D₁₀, D₅₀, D₉₀ of tadalafil microparticles were 30.3、 72.0、 126.0 μm, under scanning electron microscope, tadalafil microparticles showed a relatively uniform strip. The enthalpy change value measured by differential scanning calorimetry was 2 033.8 mJ·mg^-1·s^-1. The differential scanning calorimetry showed that the crystallinity of tadalafil microparticles decreased. The average drug mass fraction was 99.07%. The cumulative release rate of tadalafil microparticles was 94.00% at 4 h, while the release of API was only 54.56% at 4 h, the release of both in vitro conforms to the logistic equation. Conclusion The particles prepared by rapid membrane emulsification-solvent evaporation method can make the tadalafil microparticle size more uniform, reduce the degree of crystallization, and improve the dissolution, which shows that this method can be used to improve the bioavailability of insoluble drugs.

R944.2

国家科技重大专项项目（2011ZX09201-201）；北京市科技计划专项研发项目（Z16010101390）