目的 制備托伐普坦納米結(jié)構(gòu)脂質(zhì)載體（Tol-NLCs），以提高托伐普坦（Tol）的口服生物利用度。方法 根據(jù)溶解度對輔料進(jìn)行篩選，包括固體脂質(zhì)（雙硬脂酸甘油酯、山崳酸甘油酯、聚乙二醇-8山崳酸甘油酯、單硬脂酸甘油酯和單亞油酸甘油酯）、液體脂質(zhì)（油酸聚乙二醇甘油酯、單油酸甘油酯、月桂酸聚乙二醇甘油酯和單辛酸丙二醇酯）和表面活性劑（聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇-15羥基硬脂酸酯和泊洛沙姆188），采用乳化超聲-低溫固化法制備TolNLCs，并使用Box-Behankn效應(yīng)面法優(yōu)化處方；分別采用電鏡（TEM）觀察、粒徑分布及Zeta電位測定、差示掃描量熱法（DSC）對制備的Tol-NLCs進(jìn)行表征，同時(shí)比較Tol原料藥和Tol-NLCs體外藥物釋放特點(diǎn)、跨膜轉(zhuǎn)運(yùn)特征；比較Tol混懸液和Tol-NLCs經(jīng)大鼠ig給藥后的體內(nèi)藥動(dòng)學(xué)特征。結(jié)果 根據(jù)溶解度確定以山崳酸甘油酯作為固體脂質(zhì)，單油酸甘油酯作為液體脂質(zhì)，聚乙二醇-15羥基硬脂酸酯作為表面活性劑，通過優(yōu)化得到Tol-NLCs的最佳處方：總脂質(zhì)質(zhì)量濃度為40.0 mg·mL^-1，表面活性劑質(zhì)量濃度為25.0 mg·mL^-1，超聲時(shí)間為6 min。在透射電鏡下可觀察到制備的Tol-NLCs呈類球狀，分布均勻；Tol-NLCs的平均粒徑為（106.2±14.7）nm，PDI為（0.196±0.004），Zeta電位為（-26.6±0.6）mV；藥物在Tol-NLCs中以非結(jié)晶形式存在。Tol-NLCs在pH 6.8磷酸鹽緩沖液中表現(xiàn)為前期藥物釋放較快，后期藥物釋放平緩。Caco-2細(xì)胞跨膜轉(zhuǎn)運(yùn)結(jié)果顯示，Tol-NLCs的P_{app（AP→BL）}值為（11.16±0.58）×10^-6 cm·s^-1，P_{app（BL→AP）}值為（4.51±0.46）×10^-6 cm·s^-1，與Tol溶液相比，P_{app（AP→BL）}表現(xiàn)出明顯增加趨勢，P_{app（BL→AP）}表現(xiàn)出明顯降低趨勢，說明Tol包裹在NLCs中促進(jìn)了藥物吸收，抑制了P-糖蛋白（P-gp）的外排作用。與Tol混懸液相比，大鼠ig Tol-NLCs后，Tol生物利用度提高了2.5倍。結(jié)論 按優(yōu)化處方制備的Tol-NLCs，能夠顯著提高藥物的生物利用度。

Objective To prepare tolvaptan loaded nanostructured lipid carriers (Tol-NLCs) for improving the oral bioavailability of tolvaptan. Methods Based on solubility, excipients were screened, including solid lipids (precirol ATO 5, campriitol 888 ATO, compritol HD5 ATO, glycerol monostearate, maisine CC), liquid lipids (labrafil M 1944 CS, peceol, gelucire 44/14, capryol 90) and surfactants (tween 80, cremophore EL, solutol HS15, poloxamer 188). Tol-NLCs were prepared using an emulsified ultrasound lowtemperature curing method and the formulation was optimized using Box-Behankn effect surface methodology. The prepared TolNLCs were characterized by electron microscopy (TEM) observation, particle size distribution and Zeta potential measurement, and differential scanning calorimetry (DSC). At the same time, the in vitro drug release characteristics and transmembrane transport characteristics of Tol raw materials and Tol-NLCs were compared. Compare the in vivo pharmacokinetic characteristics of Tol suspension and Tol-NLCs after ig administration in rats. Results Based on the solubility, the optimal formula for Tol-NLCs was determined using glycerol valerate as a solid lipid, glycerol monooleate as a liquid lipid, and polyethylene glycol 15 hydroxystearate as a surfactant. Through optimization, the total lipid concentration was 40.0 mg·mL^?1, the surfactant concentration was 25.0 mg·mL^?1, and the ultrasound time was six minutes. Under transmission electron microscopy, the prepared Tol-NLCs can be observed to be spherical in shape and evenly distributed. The average particle size of Tol-NLCs is (106.2 ± 14.7) nm, PDI is (0.196 ± 0.004), and Zeta potential is (?26.6 ± 0.6) mV. The drug exists in an amorphous form in Tol-NLCs. Tol-NLCs exhibit faster drug release in the early stage and slower drug release in the later stage in pH 6.8 phosphate buffer. The results of Caco-2 cell transmembrane transport showed that the P_{app（AP→BL）} value of Tol-NLCs was (11.16 ± 0.58) × 10^?6 cm·s^?1, and the P_app(BL→AP) value was (4.51 ± 0.46) × 10^?6 cm·s^?1. Compared with Tol solution, P_app(AP→BL) showed a significant increase trend, while P_app(BL→AP) showed a significant decrease trend, indicating that Tol encapsulation in NLCs promoted drug absorption and inhibited the efflux of P-glycoprotein (P-gp). Compared with Tol suspension, the bioavailability of Tol increased by 2.5 times after ig of Tol-NLCs in rats. Conclusion Tol-NLCs prepared according to optimized prescription can significantly improve the bioavailability of drugs and have important value for the development of Tol dosage forms.

R969.1