Molecular Modeling-Based Inclusion Mechanism and Stability Studies of Doxycycline and Hydroxypropyl-?-Cyclodextrin Complex for Ophthalmic Delivery

• Published in: AAPS PharmSciTech Vol. 14; no. 1; pp. 10 - 18
• Main Authors: Zhang, Haohao, Chen, Meiwan, He, Zixin, Wang, Zhouhua, Zhang, Meimei, He, Zhouyang, Wan, Qian, Liang, Dan, Repka, Michael A, Wu, Chuanbin
• Format: Journal Article
• Language: English
• Published: 01.03.2013
• ISSN: 1530-9932
• DOI: 10.1208/s12249-012-9877-1

The aim of the present study was to prepare a stable complex of doxycycline (Doxy) and hydroxypropyl-?-cyclodextrin (HP?CD) for ophthalmic delivery and investigate the inclusion mechanism and the inclusion effects on the stability of Doxy. The Doxy/HP?CD complex was prepared by solution stirring and then characterized by scanning electron microscopy and ultraviolet spectroscopy. Based on results of nuclear magnetic resonance, molecular model of Doxy/HP?CD complex was established using computational simulation of PM3 method implemented in Gaussian 03. Stabilities of Doxy/HP?CD complex in both aqueous solution and solid state at 25ADGC were evaluated by HPLC. Finally, in vitro antibacterial activity of the Doxy/HP?CD complex was evaluated by disk diffusion test. It was found that the stabilities of Doxy/HP?CD complex in both aqueous solution and solid state were improved obviously as compared with Doxy alone. This stability enhancement is consistent with the inclusion mechanism between HP?CD and Doxy, which showed that the unstable site of Doxy molecule at 6-CH3 was protected in the hydrophobic cavity of HP?CD, additionally, the chelation of Mg2+ provided a synergetic protection of the other unstable site of Doxy at 4-N(CH3)2. The antibacterial activity results indicated that Doxy/HP?CD complex might have potential for clinical applications.