Effects of formulation variables on the in vitro performance of testosterone transdermal gel.

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.

Effect of Isopropyl Myristate on Transdermal Permeation of Testosterone From Carbopol Gel.

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.