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In the recent years, with the advent of transdermal formulations which delivers the drug through the skin directed to systemic circulation is considered to be a most desirable alternative to the oral drug delivery system. Transdermal route can maintain a constant, prolonged and therapeutically effective drug levels by using intact skin as a port of drug administration. However, the skin permeability of most drugs is low but can be enhanced by physical techniques or chemical method using penetration enhancers. Among the transdermal formulations, gels and patches are frequently used for the treatment various diseases. It is always challenging to formulate and then optimize appropriate formulation from a number of experimental trials. Thus, the need of the hour for pharmaceutical sector is to design drug delivery systems with a minimum number of trials in order to obtain the appropriate formulations with target goals in minimum time. Therefore, the present work is based on the combination of design and optimization of experiments (using Design Expert software), and then the incorporation of novel penetration enhancers to develop thermosensitive transdermal gel.