Inclusion complexes of HP-β-cyclodextrin with agomelatine: Preparation, characterization, mechanism study and in vivo evaluation

Agomelatine (AGM), is efficacious in both the acute phase and the continuation phase of depression. However, its poor water-solubility, low bioavailability and polymorphism limit its pharmacological effects. To address these problems, agomelatine-hydroxypropyl-beta-cyclodextrin inclusion complex (AGM/HP beta-CD) was prepared successfully by freeze-drying. The products was evaluated by structural characterization, solubilization test, in-situ absorption of rat intestinal tract and pharmacokinetic study. In addition, thermodynamic studies were performed, the results indicated that the inclusion process was enthalpy determined and exothermic nature of complexation, signifying the role of steric interactions in complex formation. Molecular docking of AGM with HP beta-CD has been conducted as well to verify the experimental findings and predict the stable molecular structure of the inclusion complex. The in vivo data showed that, AGM was mainly absorbed in duodenum and jejunum by passive diffusion. AGM/HP beta-CD inclusion complex displayed earlier T-max and higher C-max, and the AUC(0-12h) was approximately twice larger than its physical mixture. These results suggested that AGM/HP beta-CD inclusion complex was established with 1:1 stoichiometry through the naphthalene group of AGM and it was deeply inserted into the cavity of HP beta-CD, and the inclusion complex could significantly enhance the oral bioavailability of AGM. (C) 2016 Elsevier Ltd. All rights reserved.