Kircik Leon, Okumu Franklin, Kandavilli Sateesh, Sugarman Jeffrey
Icahn School of Medicine at Mount Sinai, New York, New York.
Promius Pharma LLC, Princeton, New Jersey.
J Clin Aesthet Dermatol. 2017 Feb;10(2):12-19. Epub 2017 Feb 1.
To design a topical vehicle that provided the optimal balance of betamethasone dipropionate penetration and retention in the skin, with minimal systemic absorption. Six test formulations of betamethasone dipropionate 0.05% in vehicles contained the following penetration enhancers: elaidyl alcohol (Formulation-1), hexanol (Formulation-2), dodecanol (Formulation-3), octadecanol (Formulation-4), docosanol (Formulation-5), or oleyl alcohol (Formulation-6). Test agents were applied to human cadaver skin in static Franz-cell chambers containing receptor fluid. Betamethasone absorption into the receptor fluid was measured over 24 hours. The distribution of betamethasone and its metabolites in the stratum corneum, epidermis, and dermis was analyzed using LC-MS/MS. The formulation with the optimal balance of penetration, permeation, retention, and minimal absorption was selected for a similar study comparing its penetration and absorption versus several commercially available betamethasone formulations. Formulation-3 resulted in the highest retention of betamethasone in the skin as well as the highest steroid levels in the receptor fluid at 12 and 24 hours. Formulation-6 had the second highest retention of betamethasone in total skin, with relatively low absorption into the receptor fluid. All other variants had both lower steroid retention in the skin and lower absorption into the receptor fluid, with the exception of Formulation-2 which had higher absorption at 24 hours. Formulation-6/DFD-01 was selected for further development. Comparison of Formulation-6/DFD-01 with commercially available formulations of betamethasone dipropionate showed it had the highest steroid levels in the epidermis and dermis combined, with relatively low levels in the receptor fluid. Formulation-6/DFD-01 had the optimal balance of betamethasone retention in the skin, with low systemic absorption. This designed vehicle ensured retention of the corticosteroid in skin layers to maximize local efficacy while minimizing potential for hypothalamic-pituitary-adrenal suppression.
设计一种局部用药载体，使其在丙酸倍他米松的皮肤渗透与滞留之间达到最佳平衡，同时使全身吸收降至最低。六种含0.05%丙酸倍他米松的载体测试制剂含有以下渗透促进剂：反油酸醇（制剂1）、己醇（制剂2）、十二烷醇（制剂3）、十八烷醇（制剂4）、二十二烷醇（制剂5）或油醇（制剂6）。将测试制剂应用于装有受体液的静态弗兰兹细胞室中的人体尸体皮肤。在24小时内测量丙酸倍他米松进入受体液的吸收情况。使用液相色谱-串联质谱法分析丙酸倍他米松及其代谢产物在角质层、表皮和真皮中的分布。选择在渗透、透过、滞留和最低吸收方面达到最佳平衡的制剂，进行一项类似研究，比较其与几种市售丙酸倍他米松制剂的渗透和吸收情况。制剂3在12小时和24小时时导致丙酸倍他米松在皮肤中的滞留量最高，同时受体液中的类固醇水平也最高。制剂6在全皮肤中丙酸倍他米松的滞留量排第二，进入受体液的吸收相对较低。所有其他变体在皮肤中的类固醇滞留量和进入受体液的吸收都较低，除了制剂2在24小时时吸收较高。制剂6/DFD - 01被选中进行进一步研发。将制剂6/DFD - 01与市售丙酸倍他米松制剂进行比较，结果显示其在表皮和真皮中的类固醇水平最高，而受体液中的水平相对较低。制剂6/DFD - 01在皮肤中丙酸倍他米松的滞留达到了最佳平衡，全身吸收较低。这种设计的载体确保了皮质类固醇在皮肤层中的滞留，以最大限度地提高局部疗效，同时将下丘脑 - 垂体 - 肾上腺抑制的可能性降至最低。
