title: Modified Release and Improved Stability of Unstable BCS II Drug by Using Cyclodextrin Complex as Carrier To Remotely Load Drug into Niosomes.
abstract: In answering to the challenge of enzymatic unstability of Biopharmaceutics Classification System (BCS) class II drugs, an effective remote loading strategy was developed to successfully incorporate the drug-cyclodextrin (CD) complex into niosomes to modify the release and stability of a drug candidate, pseudolaric acid B (PAB). Judged by binding constants, and combined solubilization effects of pH and CD complexation on PAB at different pH, the complex internalization driven by a transmembrane pH gradient (from 2.0 to 7.4) and the dynamic shifting of PAB-CD complexation equilibrium at this gradient were introduced. The transfer of PAB-CD complex into the internal aqueous phase of niosomes at 60 °C was primarily verified by synchrotron radiation Fourier transform infrared spectroscopy. The remote loading samples behaved as retarded release at pH 5.8, 6.8, and 7.4, for which the stability of PAB in rat plasma was significantly enhanced (about 8.1-fold), in comparison with niosomes prepared by the passive and lipid bilayer loading of PAB. The drug-carrier interaction based release modeling was further fitted, and the convection rate constant (ks) and free energy difference between free and bound states (ΔG) indicated the strongest PAB-carrier interactions in remote loading niosomes. The remote loading strategy also reduced the CD-cholesterol interaction and provided better physical stability of the system. In conclusion, the remote loading of drug-CD complex into niosomes provides advantages to modify the release and enhance the stability of unstable BCS class II drug.
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201210, China.
authors.forename: Liandi
authors.initials: L
authors.lastname: Chi
authors.affiliation: School of Pharmaceutical Sciences, Anhui University of Chinese Medicine , Hefei 230038, China.
authors.forename: Delin
authors.initials: D
authors.lastname: Wu
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201210, China.|School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hongchun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201210, China.
authors.forename: Caifen
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Anhui University of Chinese Medicine , Hefei 230038, China.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Gui
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201210, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201210, China.|School of Pharmaceutical Sciences, Anhui University of Chinese Medicine , Hefei 230038, China.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D003505:Cyclodextrins / Q000737:chemistry*; D004224:Diterpenes / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry*; D051381:Rats
chemical_list: D003505:Cyclodextrins; D004224:Diterpenes; D004337:Drug Carriers; D008081:Liposomes; C058391:pseudolaric acid B
keywords: enzymatic stability; niosomes; pH gradient; pseudolaric acid B; remote loading; retarded release