Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.
J Pharm Sci. 2012 Feb;101(2):616-26. doi: 10.1002/jps.22791. Epub 2011 Oct 11.
The aim of the present study was to evaluate and improve the in vitro transcorneal permeability characteristics of Δ(9) -tetrahydrocannabinol (THC) through prodrug derivatization and formulation approaches. In vitro corneal permeability of THC and its hemisuccinate (THC-HS) and hemiglutarate (THC-HG) ester prodrugs and WIN 55-212-2 (WIN), a synthetic cannabinoid, was determined using isolated rabbit cornea. The formulations studied included hydroxypropyl beta cyclodextrin (HPβCD) or randomly methylated beta cyclodextrin (RMβCD), as well as prodrug-ion-pair complexes with l-arginine or tromethamine. Corneal permeability of WIN was found to be two-fold higher than THC in the presence of HPβCD. THC-HS and THC-HG exhibited pH-dependent permeability. In the presence of HPβCD, at pH 5 (donor solution pH), both prodrugs exhibited six-fold higher permeability compared with THC. However, permeability of the prodrugs was about three-fold lower than that of THC at pH 7.4. RMβCD, at pH 7.4, led to a significant improvement in permeability. Formation of ion-pair complexes markedly improved the solubility and permeability of THC-HG (sevenfold and threefold greater permeability compared with THC and WIN, respectively) at pH 7.4. The in vitro results demonstrate that the use of an ion-pair complex of THC-HG could be an effective strategy for topical delivery of THC.
本研究旨在通过前药衍生化和制剂方法评估和改善 Δ(9)-四氢大麻酚（THC）的体外角膜透过特性。采用离体兔角膜法测定 THC 及其半琥珀酸酯（THC-HS）和半戊二酸酯（THC-HG）酯前药以及合成大麻素 WIN 55-212-2（WIN）的体外角膜透过性。研究的制剂包括羟丙基-β-环糊精（HPβCD）或随机甲基-β-环糊精（RMβCD），以及与精氨酸或三甲胺形成的前药-离子对复合物。在 HPβCD 存在下，WIN 的角膜透过性是 THC 的两倍。THC-HS 和 THC-HG 表现出 pH 依赖性通透性。在 HPβCD 存在下，在 pH5（供体溶液 pH）时，两种前药的透过性比 THC 高 6 倍。然而，在 pH7.4 时，前药的透过性比 THC 低约 3 倍。在 pH7.4 时，RMβCD 显著提高了透过性。在 pH7.4 时，THC-HG 形成离子对复合物可显著提高其溶解度和透过性（与 THC 和 WIN 相比，透过性分别增加了 7 倍和 3 倍）。体外研究结果表明，THC-HG 离子对复合物的应用可能是局部递送 THC 的有效策略。
