目的 采用快速膜乳化-溶劑揮發(fā)法制備不含載體輔料的他達(dá)拉非微粒，并對(duì)其體外釋藥行為進(jìn)行評(píng)價(jià)。方法 采用快速膜乳化-溶劑揮發(fā)法制備不含載體輔料的他達(dá)拉非微粒，將主藥于50℃超聲條件下溶解于有機(jī)溶劑中作為油相。將聚乙烯醇（PVA）于磁力攪拌加熱條件下溶解于去離子水中，趁熱用0.45μm的微孔濾膜真空抽濾，得續(xù)濾液，作為水相。油相與水相經(jīng)磁力攪拌混合均勻后得初乳液，將初乳液倒入快速不銹鋼膜乳化裝置，氮?dú)饧訅海^(guò)膜，收集乳液。將乳液與固化液混合后固化至無(wú)有機(jī)溶劑氣味，離心洗滌，冷凍干燥即得到他達(dá)拉非微粒凍干粉。以微粒粒徑及焓變值的綜合評(píng)價(jià)為指標(biāo)，對(duì)有機(jī)溶劑種類(lèi)、PVA濃度、藥物質(zhì)量濃度、油水相體積比、過(guò)膜次數(shù)、固化方式、固化液pH值進(jìn)行單因素考察，初步篩選出他達(dá)拉非微粒最佳制備工藝；采用直接釋藥法測(cè)定并比較他達(dá)拉非原料藥與微粒在不同時(shí)間點(diǎn)的累積釋放率，并對(duì)其釋放行為進(jìn)行數(shù)學(xué)模型擬合。結(jié)果 經(jīng)單因素考察，初步確定他達(dá)拉非微粒的制備條件為：有機(jī)溶劑醋酸乙酯，PVA濃度為3%，油水相體積比為1∶1，油相藥物的質(zhì)量濃度為5mg·mL^-1，固化液pH值為4.5，四級(jí)串聯(lián)不銹鋼膜過(guò)膜1次，旋轉(zhuǎn)蒸發(fā)儀固化。他達(dá)拉非微粒平均10%、50%、90%的顆粒尺寸在所測(cè)得的尺寸值（D₁₀、D₅₀、D₉₀）分別為30.3、72.0、126μm，掃描電鏡下呈現(xiàn)較為均勻的長(zhǎng)條片狀，差示掃描量熱法測(cè)定其焓變值為2033.8mJ·mg^-1·s^-1，顯示其結(jié)晶程度降低；平均藥物質(zhì)量分?jǐn)?shù)為99.07%。他達(dá)拉非微粒在4h時(shí)累積釋放率可達(dá)94.00%，而原料藥在4h內(nèi)僅釋放54.56%，兩者體外釋放均符合Logistic方程。結(jié)論 快速膜乳化法制備的微?？墒顾_(dá)拉非粒徑更均一，結(jié)晶程度降低，溶出度提高，顯示該方法可用于提高難溶性藥物生物利用度。

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

國(guó)家科技重大專(zhuān)項(xiàng)項(xiàng)目（2011ZX09201-201）；北京市科技計(jì)劃專(zhuān)項(xiàng)研發(fā)項(xiàng)目（Z16010101390）