Partitioning of an homologous series of alkylp-aminobenzoates within liposomes.

Abstract

The purpose of this study was to elucidate the effect of various physicochemical factors on drug partitioning into multilamellar liposomes (MLV). Knowledge of how these factors affect drug partitioning in liposomes is essential in the development of liposomal drug delivery systems. This research tested the hypothesis if the entrapment of a water soluble compound in liposomes and its release from liposomes could be controlled by the use of more lipophilic prodrugs. An homologous series of the n-alkyl p-aminobenzoates was used to study homolog partitioning effects in dipalmitoylphosphatidylcholine (DPPC) MLV. An ultracentrifugation procedure was developed to determine the (bilayer/water) distribution coefficient (DC) of these compounds. The relationship between the DC of these compounds and their in vitro release from MLV was also investigated. The results can be summarized as follows: (1) Drug partitioning into DPPC MLV is highly dependent on the physical state of the lipid bilayer and not the mode of drug addition. The temperature at which these liposomes are to be used is the critical factor that determines how solute partitions between the bilayer and aqueous compartments. Higher distribution coefficients are achieved when the bilayer is in the liquid-crystalline state as compared to the gel state. Partitioning studies also revealed that increasing alkyl chain length increases drug partitioning into the bilayer. (2) The partitioning of these esters into the lipid bilayer is dependent on bilayer composition and type. Inclusion of cholesterol in the DPPC bilayer at 23$\sp\circ$C or extrusion of DPPC MLV increases the partitioning of these esters into the bilayer because of a decrease in the surface density of the bilayer. (3) Release of these esters from DPPC MLV is a diffusion-controlled process. The diffusion constant was found to be inversely proportional to the DC of the esters. These results suggest that drug release from liposomes can be controlled by modifying either the structure of the drug and/or liposome composition. (4) Comparison of the DC of these esters and their respective distribution coefficients in various organic solvent/water systems suggests that the DC is dependent on a relationship between solute structure and the structural organization of the bilayer.