Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements.
Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements.
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DOI：
10.1021/mp300083e
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发表时间：
2012-09
影响因子：
4.9
通讯作者：
Keisuke Ueda;K. Higashi;W. Limwikrant;Shuichi Sekine;T. Horie;Keiji. Yamamoto;K. Moribe
中科院分区：
文献类型：
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作者：
Keisuke Ueda;K. Higashi;W. Limwikrant;Shuichi Sekine;T. Horie;Keiji. Yamamoto;K. Moribe
采用喷雾干燥法制备了卡马西平（CBZ）与琥珀酸羟丙基甲基纤维素乙酸酯（HPMC-AS）的固体分散体（SPD）。用SPD观察到的CBZ的表观溶解度（37°C, pH 7.4）比未处理的CBZ的溶解度高3倍以上。过饱和溶液稳定7天。通过与poloxam407 (P407)（一种增溶剂）混合，也可以在水介质中获得更高浓度的CBZ。通过Caco-2单层膜和透析膜对CBZ的渗透研究，我们观察到CBZ/HPMC-AS SPD过饱和溶液中CBZ穿过膜的渗透率提高。与此相反，CBZ溶解的P407溶液对CBZ的渗透性较差。与HPMC-AS共存后，CBZ/HPMC-AS SPD溶液(1)H NMR谱上的化学位移没有明显改变。相比之下，在CBZ/P407溶液中观察到CBZ的前场位移。自旋-晶格弛豫时间(T(1)) /自旋-自旋弛豫时间（T(2)）表明CBZ在HPMC-AS溶液中的迁移率远低于在水中的迁移率。同时，CBZ在P407溶液中的迁移率显著高于在水中的迁移率。核磁共振数据表明，CBZ与HPMC-AS没有强烈的相互作用。由于CBZ周围的自缔合和微粘度，CBZ的迁移率受到抑制，但不影响渗透行为。CBZ/P407溶液中的大部分CBZ分子被溶解在P407的疏水性核心中，少数CBZ分子自由地渗透到膜中。通过核磁共振测量评估，CBZ的分子状态与渗透行为直接相关。
A solid dispersion (SPD) of carbamazepine (CBZ) with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was prepared by the spray drying method. The apparent solubility (37 °C, pH 7.4) of CBZ observed with the SPD was over 3 times higher than the solubility of unprocessed CBZ. The supersaturated solution was stable for 7 days. A higher concentration of CBZ in aqueous medium was also achieved by mixing with Poloxamer 407 (P407), a solubilizing agent. From permeation studies of CBZ using Caco-2 monolayers and dialysis membranes, we observed improved CBZ permeation across the membrane in the supersaturated solution of CBZ/HPMC-AS SPD. On the contrary, the CBZ-solubilized P407 solution exhibited poor permeation by CBZ. The chemical shifts of CBZ on the (1)H NMR spectrum from CBZ/HPMC-AS SPD solution were not altered significantly by coexistence with HPMC-AS. In contrast, an upfield shift of CBZ was observed in the CBZ/P407 solution. The spin-lattice relaxation time (T(1)) over spin-spin relaxation time (T(2)) indicated that the mobility of CBZ in the HPMC-AS solution was much lower than that in water. Meanwhile, the mobility of CBZ in P407 solution was significantly higher than that in water. NMR data indicate that CBZ does not strongly interact with HPMC-AS. CBZ mobility was suppressed due to self-association and microviscosity around CBZ, which do not affect permeation behavior. Most of the CBZ molecules in the CBZ/P407 solution were solubilized in the hydrophobic core of P407, and a few were free to permeate the membrane. The molecular state of CBZ, as evaluated by NMR measurements, directly correlated with permeation behavior.