SIMULTANEOUS-OPTIMIZATION FOR SEVERAL CHARACTERISTICS CONCERNING PERCUTANEOUS-ABSORPTION AND SKIN DAMAGE OF KETOPROFEN HYDROGELS CONTAINING D-LIMONENE

A simultaneous optimization technique for multi-objective problems was applied for the designing of a formulation for a gel ointment of ketoprofen (KPF) containing d-limonene and ethanol as absorption enhancers. The generalized distance function was employed for dealing with all the responses simultaneously. Pharmacokinetic parameters of KPF percutaneously absorbed from model formulations were determined in rats as prime response variables. The skin damage evoked by each formulation was microscopically judged and graded as the response variable concerned with safety to the skin. These response variables were predicted by multiple regression equations composed of a combination of the concentrations of d-limonene and ethanol as formulation factors. The regression equations for response variables were assembled as a simultaneous optimization problem. Experimental results obtained for the optimum formulation agreed well with the predictions, suggesting the usefulness and reliability of the optimization techniques based on a generalized distance function in which the impartiality among the responses was considered.