Loading drugs into liposomes by temperature up-down cycle procedure with controllable results fitting prediction by mathematical and thermodynamic process

Abstract

Liposomes are a useful carrier for delivering drugs but rarely make a poorly water-soluble drug (PWSD) realize its therapeutic potential. A key barrier lies in that, by conventional methods, PWSD is mainly loaded just in liposome bilayer membranes, which rarely provide sufficient room to accommodate drugs satisfying clinical therapy. In this investigation, a novel procedure of temperature up-down cycle (TUDC) was developed for loading PWSDs into the liposome interiors instead of bilayer membranes to hold enough agents. In particular, the TUDC procedure renders PWSDs such as curcumin (Cur) entrapment purposely controllable, as evidenced by the encapsulation efficiency (EE) of Cur varies nearly from 0% to 100% in response to changes the determinant factors of the procedure. In addition, several mathematical equations that could calculate the loading efficiency by TUDC were established and proved, when combined with thermodynamic process, able to successfully predict the loading results through including thermodynamic parameters, such as temperature and deduced drug solubility, thus remarkably cutting down the laborious experiments and enhancing liposome development efficiency. Cryo-TEM, SAXS, XRD and DSC tests proved that TUDC is feasible to load a PWSD into PEG-liposomes but rendering the drug in the amorphous state. Thus, the novel TUDC procedure and the established mathematical and thermodynamic process may provide a useful tool to promote the development of liposome products.

Keywords: Cyclic operation; Drug solubility; Liposome entrapment; Loading capacity; PEGylation; Temperature fluctuation.