Abstract
Context: The intramuscular (IM) injection is an important route of drug administration. Some researchers have suggested that the erratic rate of drug absorption from oil-based IM injections is due to variability in the spread of the formulations from the injection site. Recently, the application of ultrasound (US) has been investigated as a possible strategy to enhance the spread of IM injected formulations and thereby reduce variability in drug absorption.
Objective: The aim of the research reported in this thesis was to investigate the effects of US on the spread of IM injected formulations.
Methods: For in vitro experiments, transparent agarose gel was used as the matrix. Both Nile blue(aqueous) solution (0.001% w/w) and Nile red(oily) solutions (0.01% w/w) were prepared and injected into gels. The area of spread of injected formulations was photographically recorded and measured immediately after injection. US (1.1 MHz, 3 W/cm2) was then applied to the injection site using a 6 min on-off working cycle for 60 min after which the area of spread was measured again. Areas of spread determined as mean ± standard deviation before and after US treatment were compared. For in vivo experiments, three Wether lambs (6 to 8 months old, 32 kgs approx.) were subjected to IM injections post-mortem. Three different types of formulation (Lipiodol: ethyl esters of iodized fatty acid of poppy seed oil, 48% w/v iodine; oily suspension: barium sulfate in Miglyol 812, 30% w/w; and a self-emulsifying drug delivery system (SEDDS): mixture of Lipiodol, Maisine and Miglyol, 40:20:40%, w/w)) were prepared and two different injection volumes (1.5 and 4.5 mL) injected into muscle. US (1.1 MHz, 3 W/cm2, 100% working cycle) was applied for 0, 5 and 10 min at the injection site and the spread of formulations visualized by CT scan and measured before and after US application. The collected data was analysed using two-way ANOVA and Tukey test for post -hoc statistical analysis. Muscle tissue containing injected formulations was frozen in liquid nitrogen and subsequently examined by dissection.
Results: In the in vitro study, 60 minutes after injection, the spread of both aqueous and oily solutions remained unchanged after application of US. In the post-mortem study, the initial spread showed no significant difference between either type of formulation or injection volume. After application of US for 5 min, a significant increase in spread was observed for the oily suspension and SEDDS using an injection volume of 4.5 mL; after exposure to US for 10 min, significant increases in spread were found for the oily suspension and SEDDS at both 1.5 and 4.5 mL injection volumes. The subsequent dissection revealed a large amount of injected formulation outside the injected muscle bundle resulting from spread along the fat layer and into the inter-muscle space.
Conclusion: There is no effect of US on the spread of formulations injected into agarose gel. In the post-mortem study, the CT scan proved to be suitable to visualize the spread of IM injected formulations. The initial spread of the IM injected oil formulations showed high variation. US-induced spread was observed for the oil suspension and SEDDS. The mechanism behind the enhanced spread needs further investigation but could be related to the ability of applied US to reduce the viscosity of the injected formulations or to the transfer of the mechanical energy of US to surface energy.