Development of novel ketoprofen hydrogels by introducing small molecular ligands for simultaneous release and permeability enhancement

With the development of gels, organic small molecular gels are gradually attracting attention. Could small molecular gels be designed as a new formulation strategy for hydrophobic drugs to realize the release and permeability enhancement? In this study, the nonsteroidal anti-flammatory ingredient ketoprofen (KET) performs restricted treatment application primarily owing to its poor water solubility. Then, an integrated stategy of theory-model-experiment was adopted to design novel KET hydrogels by introducing small molecular ligands, including L-lysine (LYS), arginine (ARG) or meglumine (MEG). The formed KET small molecular hydrogels (i.e., KET-LYS hydrogel, KET-ARG hydrogel and KET-MEG hydrogel) exhibited typical three-dimensional network structures and reasonable rheological properties. Compared with crystalline KET, the solubilities of the KET-LYS hydrogel, KET-ARG hydrogel and KET-MEG hydrogel demonstrated 9.14-, 8.64- and 10.17-fold increases, respectively. Besides, the three KET hydrogels displayed extremely high release rates and extents, and sustained supersaturation over a prolonged period, which was attributed to complexation reaction occurring between KET and ligand components. Furthermore, in comparison to the commercial KET hydrogel, the designed KET hydrogels demonstrated a significant promotion of KET membrane permeability, suggesting their application potential in oral and transdermal delivery systems. Hence, this study answers the question that small molecular gels can become a new formulation strategy of poorly soluble drug for concomitant release and permeability increases.