Zidan Ahmed S, Kamal Nahid, Alayoubi Alaadin, Seggel Mark, Ibrahim Sarah, Rahman Ziyaur, Cruz Celia N, Ashraf Muhammad
Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland 20993.
Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Maryland 20993.
J Pharm Sci. 2017 Jul;106(7):1805-1813. doi: 10.1016/j.xphs.2017.03.016. Epub 2017 Mar 21.
The objective of the present study was to investigate the effect of isopropyl myristate (IPM) on the in vitro permeation of testosterone through human cadaver skin from carbopol gels. Six testosterone gel formulations were prepared using different IPM contents of 0%, 0.4%, 0.7%, 1%, 2%, and 3%. The gels were characterized for drug permeation, matrix morphology, pH, kinetics of ethanol evaporation, and viscosity. Mass balance studies were performed to estimate testosterone distribution among the compartments of diffusion cells. All formulations exhibited pH values of 5.1 and viscosities of 1.25-1.75 Pa.s depending on IPM contents. Under occlusive condition, testosterone flux was found to increase significantly (p < 0.05) by increasing IPM content. Gels containing 2% IPM exhibited 11-fold increase in flux compared with formulation devoid of IPM. Ethanol was found to have a synergistic effect with IPM in enhancing testosterone flux. Mass balance analysis showed that testosterone was in a saturated state in the skin. Conducting permeation experiments under nonocclusive condition was nondiscriminating because of the evaporation of alcohol and consequent precipitation of drugs. Based on demonstrated effect of IPM on product performance, the final IPM concentration should be controlled with minimal variation during manufacturing and shelf life of drug product.
本研究的目的是调查肉豆蔻酸异丙酯（IPM）对睾酮从卡波姆凝胶透过人体尸体皮肤的体外渗透作用。使用0%、0.4%、0.7%、1%、2%和3%的不同IPM含量制备了六种睾酮凝胶制剂。对凝胶进行了药物渗透、基质形态、pH值、乙醇蒸发动力学和粘度等方面的表征。进行了质量平衡研究以估计睾酮在扩散池各隔室中的分布。所有制剂的pH值均为5.1，粘度为1.25 - 1.75 Pa·s，具体取决于IPM含量。在封闭条件下，发现随着IPM含量的增加，睾酮通量显著增加（p < 0.05）。与不含IPM的制剂相比，含有2% IPM的凝胶通量增加了11倍。发现乙醇与IPM在增强睾酮通量方面具有协同作用。质量平衡分析表明，睾酮在皮肤中处于饱和状态。在非封闭条件下进行渗透实验没有区分性，因为酒精蒸发会导致药物沉淀。基于IPM对产品性能的已证实作用，在药品生产和保质期内，最终IPM浓度应控制在最小变化范围内。
