Purpose To enable the practical application of a novel transdermal therapeutic system (TTS) that combines the achievement of supersaturation by the pH-shift method and user activated system (UAS), for more than 24 h for the expected period of TTS utilization, we investigated the supersaturation achievement conditions for permeation enhancement. Methods Supersaturation was achieved using the pH-shift method. After achieving supersaturation, the skin permeation-enhancing properties of flurbiprofen (FP) and ketoconazole (KCZ) with different crystallization properties were evaluated by in vitro permeation test using excised skin. Additionally, we investigated the conditions for achieving supersaturation of KCZ through a 54-h in vitro permeation test using a silicone membrane, which showed a reliable enhancement in permeation for more than 24 h. Results Compared to FP, the skin permeability of KCZ, which exhibits slow crystallization, was significantly increased at 50 mu g/mL supersaturation. Furthermore, hydroxypropyl methylcellulose (HPMC), an anti-nucleant polymer, was added to maintain the most stable kinetic solubility increase of KCZ for approximately 54 h with supersaturation at 500 mu g/mL. This result could be explained by the strong crystal growth inhibition effect of HPMC on KCZ. Conclusion KCZ, which has a slow crystallization rate, increases skin permeability by achieving supersaturation. The combination of KCZ and HPMC provides stable supersaturation and permeation enhancement for approximately 54 h after achieving supersaturation via the pH-shift method. In addition, this combination can be expected to be used as the novel TTS that combines the achievement of supersaturation by the pH-shift method and UAS.
