Biol. Pharm. Bull. 28(9) 1684—1688 (2005)

poor skin penetration. To improve the cutaneous absorption of drugs, various methods have been developed such as chemical penetration enhancers, novel vehicle systems and physical enhancement techniques including iontophoresis, sonophoresis, and electroporation. Supersaturated formulations are one of the vehicle systems, and its potential benefit has been examined by many investigators. Supersaturation is hypothesized to act directly on the drug and to increase skin permeation without structural alternation of the stratum corneum. The mechanism of permeation enhancement by supersaturation systems is based on increased thermodynamic activity of the drug in the formulation. A supersaturated state can be prepared by various methods just before or during application. Generally, the following three methods are available to obtain a supersaturated system: (1) by water uptake from the skin, (2) through evaporation of a volatile formulation component during application, and (3) by using the method of mixed cosolvent systems wherein vehicle changes are produced immediately prior to administration of the formulation. In the third method, two miscible solvents are chosen, and drugs are stored as a subsaturated solution in the solvent with the higher solubility for the drug. Before use, the other solvent with the lower solubility is added into the subsaturated solution to decrease the overall solubility in the cosolvent mixture. Application of this supersaturated system for hydrocortisone acetate, piroxicam, ibuprofen, oestradiol, and some lipophilic compounds has been investigated but not for ketoprofen (KP). As a limiting factor for drug permeation from the supersaturated system, optimization of the degree of saturation (DS) in the basal formulation is very important. For instance, the DS can increase by increasing the drug concentration or by decreasing the overall solubility of drugs in the cosolvent mixture. Both approaches can enhance the thermodynamic activity of drugs in the supersaturated systems and thus force drugs out of the vehicle and into the membrane. However, such solutions are thermodynamically unstable and can result in the recrystallization of drugs in the short term. As one technique to stabilize the supersaturated systems, the addition of antinucleant polymers such as polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), and hydroxypropyl-b-cyclodextrin has been attempted. In some conditions, however, these polymers may decrease the release of drugs from the applied formulation into the target membrane due to high stability in the vehicle. Therefore, the effects of antinucleant polymers on the stability to avoid recrystallization and the permeability of supersaturated drugs should be evaluated. In the present study, the applicability of the supersaturated system and antinucleant polymers for the permeation enhancement of KP was investigated. A silicone membrane was used as a skin (the stratum corneum) model because its merit in transmembrane study has already been demonstrated by other researchers. Supersaturated solutions were prepared in cosolvent mixtures of water and propylene glycol (PG). The effects of the antinucleant polymers HPMC, PVP and SCMC on the supersaturated KP were also examined. Finally, the importance of optimization of the physical stability and permeability of KP is discussed.