Mechanistic Differences in Permeation Behavior of Supersaturated and Solubilized Solutions of Carbamazepine Revealed by Nuclear Magnetic Resonance Measurements

作者：Ueda Keisuke; Higashi Kenjirou; Limwikrant Waree; Sekine Shuichi; Horie Toshiharu; Yamamoto Keiji; Moribe Kunikazu^*

来源：Molecular Pharmaceutics, 2012, 9(11): 3023-3033.

DOI：10.1021/mp300083e

• solid dispersion
• HPMC-AS
• supersaturated solution
• Caco-2 permeation
• H-1 NMR spectroscopy
• NMR relaxation time

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 degrees 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 H-1 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.

• 出版日期2012-11