Betulin/2-hydroxypropyl-β-cyclodextrin inclusion complex: Physicochemical characterization and hepatoprotective activity

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The thermodynamic and spectroscopic parameters of the betulin/2-hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex and its hepatoprotective activity were investigated in rats with nonalcoholic steatohepatitis (NASH). The pentacyclic triterpene betulin was isolated from birch bark and complexed with HPβCD. The parameters of inclusion complex formation were evaluated by infrared spectroscopy and differential scanning and isothermal titration calorimetries. The aqueous solubility and stability of betulin were significantly increased due to the formation of a stable inclusion complex with a stoichiometry of 1:1. The determined changes in molar enthalpy (ΔH < 0), entropy (ΔS > 0) and free energy (ΔG < 0) values indicate energetically favorable and spontaneous nature of the ligand-receptor interaction. The association constant of the betulin/HPβCD complex formation was equal to 1330 ± 111 M−1, as was determined by a calorimetric method. The complex formation was enthalpy and entropy driven. In rats with NASH induced by a high-fat diet, the oral administration of the betulin/HPβCD complex at 50 mg/kg betulin equivalent resulted in marked liver protective effects exceeding those of a higher dose (100 mg/kg) of betulin alone. Specifically, the betulin/HPβCD complex decreased lipid accumulation, the number of inflammatory foci in the liver, the activities of the serum marker enzymes, and the circulating TNFα level. Therefore, the complexation of betulin with HPβCD, improving aqueous solubility and, in turn, bioavailability, could be a prospective strategy to enhance antioxidative, anti-inflammatory, and hepatoprotective properties of betulin as a promising candidate for treatment of NASH.