Development of a bio-relevant in vitro release testing method for subcutaneous and intramuscular oil depot formulations

Oil depot formulations constitute a class of long-acting injectables with clinical and commercial precedence used to prolong exposure for hydrophobic compounds. The development of long-acting injectable formulations can be guided by the use of in vitro release testing methods that simulate in vivo drug release under bio-relevant conditions. However, the development of such methods for oil depot formulations has been limited. This study presents a single-use in vitro release (IVR) cartridge holding a size exclusion chromatography (SEC) matrix for emulating subcutaneous or intra-muscular tissue. Utilizing rat in vivo data from literature as guidance, the aim was to explore development of an in vitro drug release testing approach for injectable oil depot formulations. Release of p-hydroxyazobenzene (PHAB) was investigated upon injection of oil solutions into the IVR cartridge followed by intermittent elution with 1 mL release medium by gravity flow. The in vitro release profiles were described by first-order kinetics and consistent with previously published in vivo release observations. Bovine serum albumin solution was the preferred release medium since it provided higher release rates than sodium dodecyl sulfate solutions. In contrast to in vivo studies, the in vitro PHAB release from sesame oil was concentration-dependent as a decreasing PHAB fraction may be bound to albumin at increasing PHAB concentrations (range 1-20 mg/mL). The SEC matrix confined the oil solution at the injection site; leading to a decreasing PHAB release rate with increasing injection volume similar to the in vivo situation. In vitro release of PHAB decreased with increasing oil-buffer distribution coefficients, exhibiting similar ranking as was observed in vivo in rats. The in vitro release cartridge used in this study was able to capture in vivo release observed for subcutaneously and intramuscularly injected oily PHAB solutions in rats and holds promise as an in vitro release testing approach for injectable depots.