Sethia Sundeep, Squillante Emilio
College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, New York 11439, USA.
J Pharm Sci. 2004 Dec;93(12):2985-93. doi: 10.1002/jps.20199.
In this study improvement in the bioavailability of carbamazepine (CBZ) prepared as solid dispersions by conventional solvent evaporation and supercritical fluid (SCF) processing methods was assessed, along with the elucidation of the mechanism of improved absorption. Solid dispersions of CBZ in polyethylene glycol (PEG) with either Gelucire 44/14 or vitamin E-TPGS (TPGS) were evaluated by intrinsic dissolution. Directional transport through Caco-2 cell monolayers was determined in the presence and absence of TPGS. Cell viability in presence of various concentrations of amphiphilic carriers was seen. In vivo oral bioavailability was determined in rats. The apparent intrinsic dissolution rates (IDR) of both conventional- and SCF-CBZ/PEG 8000/TPGS solid dispersions were increased by 13- and 10.6-fold, respectively, relative to neat CBZ. CBZ was not a substrate of P-glycoprotein. Higher CBZ permeability was seen in presence of 0.1% TPGS. Cell viability studies showed significant cytotoxicity only at or above 0.1% amphiphilic carrier. Supercritical treated formulation (without amphiphilic carrier) displayed oral bioavailability on par with those conventional solid dispersions augmented with amphiphilic carriers. An in vitro-in vivo correlation was seen between IDR and the AUC of the various CBZ solid dispersions. Bioavailability of CBZ was more a function of dissolution as opposed to membrane effects. Although bioavailability from SCF processed dispersions was better than conventionally processed counterparts (except for one formulation containing Gelucire 44/14), an interaction of processing method and inclusion of an amphiphilic carrier, rather by one factor alone contributed to optimal absorption, thus giving contradictory results for Gelucire 44/14 and TPGS formulations.
在本研究中，评估了通过常规溶剂蒸发和超临界流体（SCF）处理方法制备的卡马西平（CBZ）固体分散体的生物利用度改善情况，并阐明了吸收改善的机制。通过特性溶解评估了CBZ在含有Gelucire 44/14或维生素E-TPGS（TPGS）的聚乙二醇（PEG）中的固体分散体。在有和没有TPGS的情况下测定了通过Caco-2细胞单层的定向转运。观察了在各种浓度两亲性载体存在下的细胞活力。在大鼠中测定了体内口服生物利用度。相对于纯CBZ，常规和SCF-CBZ/PEG 8000/TPGS固体分散体的表观特性溶解速率（IDR）分别提高了13倍和10.6倍。CBZ不是P-糖蛋白的底物。在0.1% TPGS存在下观察到更高的CBZ渗透性。细胞活力研究表明，仅在两亲性载体浓度达到或高于0.1%时才具有显著的细胞毒性。超临界处理制剂（无两亲性载体）的口服生物利用度与添加两亲性载体的常规固体分散体相当。在各种CBZ固体分散体的IDR和AUC之间观察到体外-体内相关性。CBZ的生物利用度更多地是溶解的函数，而非膜效应。尽管SCF处理分散体的生物利用度优于常规处理的对应物（含有Gelucire 44/14的一种制剂除外），但加工方法和两亲性载体的加入之间的相互作用，而非单一因素，促成了最佳吸收，因此对于Gelucire 44/14和TPGS制剂给出了相互矛盾的结果。
