Investigation of the Enhancement Effect of Coloading of Compounds with Different Hydrophobicities on the Stability of a Phospholipid/Bile Salt Mixed Micellar System

Bile acid salt (BAS) micellar structures containing phospholipids (PPLs) have many important applications in the field of drug delivery on account of their biocompatibility, but improving their structural stability is a crucial issue for further development. Combined with our previous findings, we hypothesized that coloading of drugs with different hydrophobicities can enhance the structural stability of the micelles. Puerarin (PUE) and tanshinone IIA (TSA) from the Chinese couplet medicines, Radix Puerariae-Salvia miltiorrhiza, were chosen as the model hydrophobic compound pair to be encapsulated into mixed micelles composed of BAS and PPL (BPMM), to form four mixed micellar systems, including blank BPMM, single-drug-carrying BPMM (namely, PUE-loaded BPMM (P-BPMM) and TSA-loaded BPMM (T-BPMM)), and coloaded BPMM (PT-BPMM). The hypothesis was confirmed by comparing the stability of blank BPMM with those of drug-loaded BPMM, single-drug-carrying and drug-cocarrying BPMM, by utilizing molecular dynamics (MD) simulations combined with various experimental observations. Moreover, it is found that the drug distribution preference in the system is not significant when a single drug is loaded. However, when coloaded, the distribution preference of different hydrophobic drugs in the same space is reflected, that is, a more appropriate spatial distribution of drugs in the micellar system can effectively improve the drug-loading stability of the system. The strategy to improve the stability of mixed micelles in this investigation avoids the complex processes associated with modifying the structure of micellar carrier materials and offers the advantages of the use of biosurfactants for drug delivery.