Cannabidiol-Loaded Hyaluronic Acid Hydrogels: Solubilization via β-Cyclodextrin Micelles

Objective: Cannabidiol (CBD) possesses considerable anti-inflammatory and antioxidant activities; however, its pharmaceutical application is hindered by its extremely low aqueous solubility (<0.1 μg/mL). This study aimed to improve the solubility of CBD through β-cyclodextrin (β-CD) inclusion complexation combined with polymeric micelles formation and to develop a CBD-loaded hyaluronic acid (HA) hydrogel delivery system.Materia and Methods: Water-soluble CBD formulations were prepared through β-CD inclusion complexation combined with poloxamer 407-based polymeric micelle formation, followed by lyophilization. The resulting powder was subsequently incorporated into HA-based hydrogels. Solid-state characteristics were investigated using differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, and powder X-ray diffraction (PXRD). Physicochemical properties, including particle size, polydispersity index (PDI), and zeta potential, were determined. Rheological properties and gelation were evaluated using a stress-controlled rheometer. In vitro CBD release was assessed using a dialysis bag diffusion method in phosphate buffer solution (PBS, pH 7.4) at 35±1 °C.Results: The aqueous solubility of CBD was markedly enhanced to 2.5 mg/mL, representing a 4,275-fold increase compared with native CBD. Solid-state characterization confirmed the transformation of crystalline CBD and the formation of a new phase. The developed hydrogels exhibited particle sizes ranging from 558.6 to 2,905.3 nm and showed a more negative zeta potential than the blank hydrogel formulation. All formulations demonstrated shear-thinning rheological behavior, whereas gelation at 15.9 °C was observed only in the blank hydrogel. In vitro release studies revealed that most formulations released CBD within 45–60 minutes.Conclusion: The β-CD–poloxamer system effectively enhanced the aqueous solubility of CBD and enabled its stable incorporation into an HA-based hydrogel matrix. The developed formulation demonstrates promising potential as a versatile platform for CBD-based drug delivery applications.