Modified Release and Improved Stability of Unstable BCS II Drug by Using Cyclodextrin Complex as Carrier To Remotely Load Drug into Niosomes

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.