托伐普坦纳米结构脂质载体的制备与药动学研究  

Preparation and pharmacokinetics of tolvaptan loaded nanostructured lipid carriers

作　　者：王丹 任宁君 史步新 WANG Dan;REN Ningjun;SHI Buxin(Department of Pharmacy,Liyang People's Hospital,Liyang 213300,China)

机构地区：[1]溧阳市人民医院药剂科,江苏溧阳213300

出　　处：《药物评价研究》2024年第4期765-775,共11页Drug Evaluation Research

摘　　要：目的制备托伐普坦纳米结构脂质载体(Tol-NLCs),以提高托伐普坦(Tol)的口服生物利用度。方法根据溶解度对辅料进行筛选,包括固体脂质(双硬脂酸甘油酯、山嵛酸甘油酯、聚乙二醇-8山嵛酸甘油酯、单硬脂酸甘油酯和单亚油酸甘油酯)、液体脂质(油酸聚乙二醇甘油酯、单油酸甘油酯、月桂酸聚乙二醇甘油酯和单辛酸丙二醇酯)和表面活性剂(聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇-15羟基硬脂酸酯和泊洛沙姆188),采用乳化超声-低温固化法制备TolNLCs,并使用Box-Behankn效应面法优化处方;分别采用电镜(TEM)观察、粒径分布及Zeta电位测定、差示扫描量热法(DSC)对制备的Tol-NLCs进行表征,同时比较Tol原料药和Tol-NLCs体外药物释放特点、跨膜转运特征;比较Tol混悬液和Tol-NLCs经大鼠ig给药后的体内药动学特征。结果根据溶解度确定以山嵛酸甘油酯作为固体脂质,单油酸甘油酯作为液体脂质,聚乙二醇-15羟基硬脂酸酯作为表面活性剂,通过优化得到Tol-NLCs的最佳处方:总脂质质量浓度为40.0 mg·mL^(−1),表面活性剂质量浓度为25.0 mg·mL^(−1),超声时间为6 min。在透射电镜下可观察到制备的Tol-NLCs呈类球状,分布均匀;Tol-NLCs的平均粒径为(106.2±14.7)nm,PDI为(0.196±0.004),Zeta电位为(−26.6±0.6)mV;药物在Tol-NLCs中以非结晶形式存在。Tol-NLCs在pH 6.8磷酸盐缓冲液中表现为前期药物释放较快,后期药物释放平缓。Caco-2细胞跨膜转运结果显示,Tol-NLCs的Papp(AP→BL)值为(11.16±0.58)×10^(−6) cm·s^(−1),P_(app(BL→AP))值为(4.51±0.46)×10^(−6) cm·s^(−1),与Tol溶液相比,Papp(AP→BL)表现出明显增加趋势,P_(app(BL→AP))表现出明显降低趋势,说明Tol包裹在NLCs中促进了药物吸收,抑制了P-糖蛋白(P-gp)的外排作用。与Tol混悬液相比,大鼠ig Tol-NLCs后,Tol生物利用度提高了2.5倍。结论按优化处方制备的Tol-NLCs,能够显著提高药物的生物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 Papp(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

关 键 词：托伐普坦 纳米结构脂质载体 生物利用度 乳化超声-低温固化法 药动学 细胞跨膜转运 

分 类 号：R969.1[医药卫生—药理学]