Abstract

Background: Baicalein (BA) is a poorly soluble flavonoid with limited oral bioavailability. This study aimed to enhance the solubility and nasal absorption of the compound using a dual-carrier system that combines cyclodextrin inclusion complexes and thermosensitive hydrogels.Methods: The inclusion complexes of BA with hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutyl-β-cyclodextrin (SBE-β-CD), namely BA-HP-β-CD and BA-SBE-β-CD, were prepared via solution stirring and characterized by solubility, dissolution, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis-differential scanning calorimetry (TG-DSC), and Madin-Darby canine kidney (MDCK) cell permeation. The optimal complexes were incorporated into chitosan/β-glycerophosphate thermosensitive hydrogels (BA/HP-Gel and BA/SBE-Gel), followed by evaluations of gelation properties, in vitro release, and in vivo pharmacokinetics in rats.Results: The water solubility of BA-HP-β-CD and BA-SBE-β-CD increased 572 and 582 times, with MDCK permeability enhanced by 5.3 and 2.9 times, respectively. Both hydrogels showed rapid solution-gel transition at nasal temperature and sustained release. Following intranasal administration, BA/HP-Gel and BA/SBE-Gel achieved relative bioavailabilities of 623.5% and 697.8%, respectively, compared with BA-Gel.Conclusions: The dual-carrier platform effectively improved BA solubility, permeability, and nasal bioavailability, offering a promising strategy for nasal delivery of poorly soluble drugs.