Kogan Anna, Kesselman Ellina, Danino Dganit, Aserin Abraham, Garti Nissim
Casali Institute of Applied Chemistry, The Institute of Chemistry, Givat Ram, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Colloids Surf B Biointerfaces. 2008 Oct 1;66(1):1-12. doi: 10.1016/j.colsurfb.2008.05.006. Epub 2008 May 18.
The purpose of this study was to evaluate the viability and permeability of carbamazepine (CBZ) solubilized in fully dilutable non-ionic microemulsions across Caco-2 cells used as a model for intestinal epithelium. Maximum solubilization capacity (SC) of CBZ was determined within water-in-oil (W/O), bicontinuous and oil-in-water (O/W) structures formed upon dilution. The effect of the nature of the oil phase, surfactant type, and the ratio between the oil phase and surfactant on the quantity of solubilized CBZ, droplets size, the viability of the cells and drug permeability was elucidated. We found that: (1) several fully dilutable microemulsions based on pharma-grade ingredients can be loaded with very significant amounts of CBZ, (2) W/O microemulsions (10wt% water) exhibit up to 3-fold higher solubilization capacity over the drug's solubility in oil (triacetin), (3) CBZ in the O/W microemulsions (80wt% water) exhibit up to 29-fold higher solubilization than in water, (4) the O/W droplets of the examined systems are 9-11nm in size, (5) the highest permeability was obtained in systems containing triacetin/alpha-tocopherol acetate/ethanol in 3/1/4wt% ratio as oil phase and Tween 60 as surfactant, (6) the replacement of alpha-tocopherol acetate by alpha-tocopherol inhibits CBZ release, (7) replacement of a saturated chain of Tween 60 by an unsaturated (Tween 80) or shorter chain (Tween 40) inhibited drug release, (8) the decrease in the oil phase to surfactant ratio leads to enhancement of drug release (dilution line 64>dilution line 73).
本研究的目的是评估溶解在完全可稀释非离子微乳液中的卡马西平（CBZ）通过用作肠上皮模型的Caco-2细胞的活力和渗透性。在稀释形成的油包水（W/O）、双连续和水包油（O/W）结构中测定了CBZ的最大增溶能力（SC）。阐明了油相性质、表面活性剂类型以及油相与表面活性剂之间的比例对溶解的CBZ量、液滴大小、细胞活力和药物渗透性的影响。我们发现：（1）几种基于药用级成分的完全可稀释微乳液可以负载非常大量的CBZ，（2）W/O微乳液（10wt%水）的增溶能力比药物在油（三醋精）中的溶解度高3倍，（3）O/W微乳液（80wt%水）中的CBZ增溶能力比在水中高29倍，（4）所研究体系的O/W液滴尺寸为9-11nm，（5）在以3/1/4wt%比例的三醋精/α-生育酚醋酸酯/乙醇作为油相和吐温60作为表面活性剂的体系中获得了最高的渗透性，（6）用α-生育酚替代α-生育酚醋酸酯会抑制CBZ释放，（7）用不饱和（吐温80）或较短链（吐温40）的链替代吐温60的饱和链会抑制药物释放，（8）油相与表面活性剂比例的降低导致药物释放增强（稀释线64>稀释线73）。
