title: Inclusion complexes of HP-β-cyclodextrin with agomelatine: Preparation, characterization, mechanism study and in vivo evaluation.
abstract: 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-β-cyclodextrin inclusion complex (AGM/HPβ-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 HPβ-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/HPβ-CD inclusion complex displayed earlier Tmax and higher Cmax, and the AUC0-12h was approximately twice larger than its physical mixture. These results suggested that AGM/HPβ-CD inclusion complex was established with 1:1 stoichiometry through the naphthalene group of AGM and it was deeply inserted into the cavity of HPβ-CD, and the inclusion complex could significantly enhance the oral bioavailability of AGM.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Mina
authors.initials: M
authors.lastname: Yan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Yuefang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China. Electronic address: zhaocs@mail.sysu.edu.cn.
authors.forename: Chunshun
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000737:chemistry*; D000081:Acetamides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D002152:Calorimetry, Differential Scanning; D005612:Freeze Drying; D007413:Intestinal Mucosa / Q000378:metabolism; D062105:Molecular Docking Simulation; D051381:Rats; D012995:Solubility; D009281:Naphthalenes
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000081:Acetamides; C084711:agomelatine; D009281:Naphthalenes
keywords: Absorption; Agomelatine; Hydroxypropyl-β-cyclodextrin inclusion complex; Inclusion mechanism; Molecular modeling studies; Pharmacokinetics