Mechanistically guided development of a high-concentration sustained-release intramuscular depot formulation for...

Poor aqueous solubility and high dose requirements pose significant challenges in the development of sustained-release intramuscular (IM) depot formulations of small-molecule drugs. Fulvestrant, currently formulated as an oil-based IM depot requiring two 5 mL injections to deliver a monthly 500 mg dose, represents a clinically relevant model system for addressing these challenges. Here, we report a mechanistically guided development of a high-concentration sustained-release fulvestrant depot formulation (SYP-1910, 500 mg/5 mL) designed to enable single-site monthly IM administration while preserving the exposure profile of the reference product. Castor oil was selected as the depot matrix based on saturation solubility. Lecithin-based prototypes (a phospholipid surfactant initially included as an interfacial stabilizing agent) exhibited premature in vivo solidification and reduced systemic exposure, particularly in larger species; this limitation was mitigated by incorporation of a low level of polyoxyl 35 castor oil (ELP). ELP, a low-level nonionic surfactant, preserved post-injection depot fluidity and restored sustained systemic exposure to reference-like levels, functioning as a depot-stabilizing excipient rather than a conventional absorption enhancer. In vitro release testing using a dialysis-based method in phosphate-buffered saline containing 4% sodium lauryl sulfate demonstrated release-profile similarity to the reference formulation (f2 = 87.3). Single-dose pharmacokinetics evaluated in rats, rabbits, and beagle dogs showed geometric mean ratios for Cmax and AUClast (0-28 days) within an exploratory 80-125% comparability window across species. Imaging and necropsy findings supported a depot-stabilizing role of the surfactant, preserving depot fluidity and sustained absorption rather than simply accelerating drug uptake. These findings demonstrate that mechanism-informed excipient selection, combined with cross-species biopharmaceutic evaluation, can enable robust high-concentration oil depot formulations for sustained intramuscular delivery of poorly soluble small-molecule drugs.