Drug-Excipient Interaction-Mediated Supersaturated Emulsion Gel for Enhanced Intradermal Delivery of Tranexamic Acid

The clinical translation of tranexamic acid (TA) for melasma is limited by its hydrophilicity and crystallization tendency, which hinder epidermal drug accumulation in conventional formulations (<5% w/w). We developed a supersaturated emulsion-type gel (TAE Gel) containing 10% (w/w) TA using carbomer 940 (CP) as the matrix. Electrostatic interactions between TA and CP, including hydrogen bonding and ionic pairing, formed a kinetically stabilized TA@CP network that suppressed TA crystallization while enhancing transdermal delivery. The formulation maintained physical stability under stress conditions and showed no visible crystallization. Pharmacokinetic studies demonstrated superior epidermal bioavailability, with a peak dermal concentration 1.91-fold higher than commercial TA cream and minimal irritation. In UV/progesterone-induced melasma models, 10% TAE Gel significantly suppressed tyrosinase activity, restored antioxidant markers (SOD), and reduced lipid peroxidation (MDA), accompanied by normalization of hepatic biomarkers. Histological analysis confirmed melanin clearance and epidermal remodeling without cytotoxicity. Overall, this metastable supersaturation approach offers a promising strategy for high-payload transdermal delivery of hydrophilic actives. The TA@CP-based TAE Gel successfully addresses the formulation trade-off between dose escalation and physical stability, providing a safe and effective platform for topical melasma therapy and potentially other pigmentary disorders.