Influence of injection volume on the release kinetics of liposomal chloroquine administered subcutaneously or intramuscularly to mice

Abstract

Encapsulation of chloroquine in liposomes has proven to reduce toxicity and to improve therapeutic efficacy against malaria parasites in mice. In this study the influence of the injection volume on the kinetics of chloroquine containing ‘gel’ state liposomes after intramuscular (im) and subcutaneous (sc) injection was investigated. Mice were given 0.6 mg liposome-encapsulated chloroquine dispersed in different injection volumes (20,40, 60, 80 and 100μl) either im or sc. Blood samples were taken at regular time intervals and chloroquine concentrations were determined with HPLC. Chloroquine concentrations were also measured in heart, liver, spleen and kidney at several time intervals after injection (24 h, 8 days or 22 days). Chloroquine-containing liposomes act as a local depot and provide prolonged release. In most cases chloroquine concentrations in blood were measurable up to 8 days after injection depending on the injection volume. In the case of sc injection of 80 or 100μl, detectable chloroquine concentrations could be found for a period of 4 days. Mean absorption rate constants ( k a ) after the injection of 20,40,60, 80 or 100 μl were 0.10,0.17,0.23,0.31 and 0.66 h −1 respectively after im administration and 0.06, 0.05, 0.10, 0.18 and 0.35 h −1 respectively after sc injection. A positive correlation (Kendall's rank order test, α = 0.05) was found between k a, and injection volume. This might be related to differences in spreading behaviour of the vehicle and differences in caking of the remaining depot by the muscle tonus. Mean peak chloroquine concentrations in blood were higher after im injection than after subcutaneous injection and increased with larger injection volumes. No correlation was found between AUC 0–1 (area under the curve from start to the time of last measurement above detection limit) and injection volume within each administration route. In all cases mean AUC value after im injection was significantly higher than after sc injection. Chloroquine concentrations in spleen increased in time. This was ascribed to the tendency of chloroquine to accumulate in red blood cells and the subsequent clearance of these cells by the spleen.