A RIGOROUS THEORY OF REMOTE LOADING OF DRUGS INTO LIPOSOMES

Various gradients have been used to actively load molecules into prefo rmed colloidal particles separated from a medium by a semipermeable me mbrane. Therapeutic applications of liposomes have predominantly utili zed pH and ammonium sulfate gradient methods to load drug molecules, w hich are weak bases or acids, into preformed liposomes. Except for the influence of a few simple parameters in the case of the pH gradient l oading, the influences of many variables, involving different mechanis ms and processes affecting the loading, are not well understood. Here we present a rigorous theoretical treatment to explain these phenomena and simulate loading processes as a function of any given variable. F irstly, taking into account acid/base equilibria, we develop an Ansatz to calculate the pH of any solution as well as concentration of any s pecies under given conditions, We use this concept to explain pH gradi ent loading and exchange gradient loading in the cases of simple or co upled redistribution of species across a semipermeable membrane in one or two directions. Finally we add the interaction of permeated specie s with the bilayer or with the liposome preencapsulated material and e valuate both concepts of loading for the case of drug binding to the m embrane and formation of precipitate in the liposome. As a result, som e examples of possible drug loading systems are simulated, discussed, and represented in the form of families of curves, showing the most si gnificant parameters in the equilibrated liposome systems after loadin g. In general, the mathematical methodology presented in this article can be used to simulate physical and chemical processes which occur in any two compartment system separated by a semipermeable membrane.