Preparation and Characterization of Ternary Complexes to Improve the Solubility and Dissolution Performance of a Proteolysis-Targeting Chimera Drug.

Proteolysis-targeting chimeras (PROTACs) have shown significant potential in the treatment of intractable diseases. However, their clinical applications are limited by poor water solubility and permeability. In this study, the cyclodextrin inclusion method was employed for the first time to prepare the PROTAC-CD complex with the aim of improving the dissolution of a PROTAC drug (LC001). Initially, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was selected to improve the solubility of LC001. The polymer TPGS was screened based on the phase solubility method to enhance the efficiency of complexation and solubilization capacity, and its ratio with SBE-β-CD was optimized. The ternary complex was prepared by lyophilization with an SBE-β-CD/TPGS molar ratio of 1:0.03. Differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy results confirmed the formation of an amorphous complex. Fourier-transform infrared and molecular docking simulations indicated the formation of hydrogen bond interactions between components. The results showed that the ternary complexes significantly improved the dissolution rate and release amount of LC001 in PBS (pH 6.8) and were unaffected by changes in gastric pH compared to the binary complexes and physical mixtures. The lack of crystal structure in the lyophilized particles and the formation of nano aggregates in solution may be the reasons for the improved dissolution of the ternary complex. In conclusion, the addition of TPGS to the LC001-SBE-β-CD binary system has a synergistic effect on improving the solubility and dissolution of LC001. This ternary complex is a promising formulation for enhancing the dissolution of LC001.