title: Combination of β-cyclodextrin inclusion complex and self-microemulsifying drug delivery system for photostability and enhanced oral bioavailability of methotrexate: novel technique.
abstract: In the present study, we prepared an inclusion complex of methotrexate (MTX) with β-cyclodextrin (β-CD) in order to decrease its photosensitivity and enhance its aqueous solubility. Then we incorporated this inclusion complex in a self-microemulsifying drug delivery system (SMEDDS) overall to increase its oral bioavailability. The inclusion complex has been prepared by freeze drying method and characterized by differential scanning calorimetry (DSC), ultraviolet (UV), and infrared (IR) spectroscopy assays. The proper molecular ratio of MTX/β-CD was found to be of 1:7, and the water-solubility of MTX was increased in an average of 10-fold. The photostability studies showed that the MTX became stable on exposure to light. Construction of pseudoternary diagrams were investigated to prepare a MTX/β-CD inclusion complex loaded SMEDDS which was characterized by measuring the particle size and the zeta-potential. The optimum formulation of SMEDDS was a system consisting of ethyl oleate, tween 80, and propylene glycol with a mean droplet size of 39.42 nm. In vitro drug release in different pH media showed that the release profile of MTX from the MTX/β-CD loaded SMEDDS was influenced by the pH of the release medium and presented the characteristics of a sustained release profile. Finally, in-vivo studies showed an enhancement of the bioavailability of MTX from the MTX/β-CD loaded SMEDDS form of 1.57-fold. We concluded that the β-CD inclusion complex loaded SMEDDS improved the chemical and physiological properties of MTX and could be a promising means for the delivery of MTX and other unstable and lipophilic drugs by oral route.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bourkaib
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Zhengjie
authors.initials: Z
authors.lastname: Fang
authors.forename: Omar
authors.initials: O
authors.lastname: Mezghrani
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004338:Drug Combinations; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D045703:Emulsifying Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D010775:Photic Stimulation / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D045703:Emulsifying Agents; D047392:beta-Cyclodextrins; D008727:Methotrexate