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Application of Response Surface Methodology for Design and Optimization of Reservoir-type Transdermal Patch of Simvastatin.

The objective of the present investigation was to develop and optimize reservoir-type of transdermal drug delivery system of Simvastatin using response surface methodology. A total of 17 experimental runs were conducted according to three-factor, three-level Box-Behnken design employing Design expert®2 software to determine the effect of independent variables (simvastatin concentration, percentage of poloxamer 407, and concentration of D-limonene) on cumulative amount of simvastatin permeation through human cadaver skin in 48 h (dependent variable). The experimental data was fitted to different response surface models using multiple regression analysis and observed quadratic model was the best fit model with significant p-value (p꞊0.0003) and coefficient of determination value of 0.9949. The second-order polynomial equation and response surface plots indicated the significant influence of concentration of simvastatin and D-limonene on the simvastatin permeation in 48 h. The highest simvastatin permeation value of 76.94 μg/cm2 was observed in case of experimental number 10 with 1.5% (w/w) of simvastatin, 25% (w/w) of poloxamer 407, and 10% (w/w) of D-limonene. Using Derringer's desirability functional tool for optimization, the highest simvastatin permeation value of 78.7684 μg/cm2 in 48 h was predicted under optimum condition of; simvastatin concentration of 1.4893% (w/w), poloxamer 407 percentage of 22.43% (w/w), and D-limonene concentration of 9.8541% (w/w) with optimum desirability value. The in-vivo hypolipidemic study conducted for 14 days in hyperlipidemia induced Sprague-Dawley rats revealed that the optimized patch exhibited significant lowering of blood lipid profile. Finally, histology study was performed on skin sample used in permeation study of optimized formulation and compared with untreated skin sample. The treated skin sample showed a significant distortion in stratum corneum, which supported the ex-vivo permeation result. Thus, the patch may serve as an alternative therapy to oral dosage form of simvastatin with outmost patient compliance.