Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
Int J Pharm. 2020 Nov 30;590:119951. doi: 10.1016/j.ijpharm.2020.119951. Epub 2020 Oct 6.
The variation in the critical formulation variables during life-cycle of the drug product may result in undesirable changes in product performance. The current study aimed at evaluating the effects of formulation variables on the in vitro performance of carbopol-loaded testosterone gel. The formulation variables included concentrations of permeation enhancers, testosterone, ethanol, carbopol and sodium hydroxide. In vitro evaluation of the product performance included assessment of the rheological and morphological properties, kinetics of ethanol evaporation, and drug permeation through human cadaver skin. The results revealed that carbopol, sodium hydroxide and testosterone concentrations increased the viscosity of the gels significantly (p < 0.05). However, carbopol concentration was the only critical variable to affect the yield stress of the gel. The concentration of ethanol was critical to metamorphosis of the gel due to solvent evaporation upon application to skin with minor contributions from other formulation variables. The increase in concentration of isopropyl myristate or isopropyl palmitate to 5%, ethanol to 70%, and testosterone to 2%, enhanced the testosterone permeation across the skin by ten-folds. Synergistic effects of ethanol and permeation enhancers on testosterone permeation was observed. In conclusion, strict control over the critical formulation variables should be exercised during manufacturing to ensure desired product performance.
药物产品生命周期中关键配方变量的变化可能导致产品性能的不理想变化。本研究旨在评估配方变量对载有卡波姆的睾酮凝胶的体外性能的影响。配方变量包括渗透增强剂、睾酮、乙醇、卡波姆和氢氧化钠的浓度。产品性能的体外评估包括评估流变学和形态特性、乙醇蒸发动力学以及药物通过人体尸体皮肤的渗透。结果表明，卡波姆、氢氧化钠和睾酮浓度显著增加了凝胶的粘度（p < 0.05）。然而，卡波姆浓度是唯一影响凝胶屈服应力的关键变量。由于应用于皮肤时溶剂蒸发，乙醇浓度是凝胶变形的关键变量，而其他配方变量的贡献较小。将肉豆蔻异丙酯或棕榈酸异丙酯的浓度增加到 5%，乙醇增加到 70%，睾酮增加到 2%，可使睾酮在皮肤中的渗透增加十倍。观察到乙醇和渗透增强剂对睾酮渗透的协同作用。总之，在制造过程中应严格控制关键配方变量，以确保所需的产品性能。
