Background: Nearly half of global pregnancies are unplanned, yet condoms are the only male-driven reversible contraceptive available. EP055, a small molecule targeting sperm surface protein epididymal protease inhibitor (EPPIN), recently emerged as a potential non-hormonal male contraceptive following rapid, reversible inhibition of sperm motility in rhesus macaques (Eppin Pharma). Despite promising early efficacy data driven by its accumulation in target tissue, EP055 has a short plasma half-life which affects its dosing frequency. A long-acting delivery system would provide a solution to EP055’s half-life, promote target binding, and foster patient adherence.
Methods: We optimized the release kinetics of in-situ forming implant (ISFI) formulations to sustain EP055 release in vitro for ≥ 30 days by altering the concentration and properties of a biodegradable polymer (polylactic-co-glycolic acid; PLGA) and organic, water miscible solvents (N-methyl-2-pyrrolidone, benzyl benzoate). Formulations were injected into release medium (0.01 M PBS pH 7.4 with 2% Solutol and 0.01% NaN₃) and drug release rates and durations were determined using high-performance liquid chromatography (Figure 1).
Results: Optimized EP055 release kinetics were obtained through drug loading and solvent composition modifications. Release duration was extended by maximizing EP055 loading. Due to the hydrophilicity of EP055, formulations containing small amounts of hydrophobic solvent benzyl benzoate demonstrated a reduction in 24-hour burst release (<25%) that enabled zero order kinetics at target release rates (40 µg/day) over 35 days.
Conclusions: We have successfully formulated the sperm motility inhibitor EP055 in an ISFI system and demonstrated sustained zero order release of EP055 for >30 days in vitro. This success elicits the potential for a long-acting, reversible, non-hormonal male contraceptive.

<b>Figure 1: </b>Overview of ISFI mechanism and cumulative percent release of EP055 from studied formulations.<br /> <b>A)</b> 100 mg EP055/mL 1:2 PLGA:NMP,<br /> <b>B)</b> 100 mg EP055/mL 1:1.5 PLGA:(9:1 NMP:BB),<br /> <b>C)</b> 150 mg EP055/mL 1:1.5 PLGA:(9:1 NMP:BB),<br /> <b>D)</b> 100 mg EP055/mL 1:1.5 PLGA:(4:1 NMP:BB),<br /> <b>E)</b> 150 mg EP055/mL 1:1.5 PLGA:4:1 NMP:BB)

Figure 1: Overview of ISFI mechanism and cumulative percent release of EP055 from studied formulations.
A) 100 mg EP055/mL 1:2 PLGA:NMP,
B) 100 mg EP055/mL 1:1.5 PLGA:(9:1 NMP:BB),
C) 150 mg EP055/mL 1:1.5 PLGA:(9:1 NMP:BB),
D) 100 mg EP055/mL 1:1.5 PLGA:(4:1 NMP:BB),
E) 150 mg EP055/mL 1:1.5 PLGA:4:1 NMP:BB)

Roopali Shrivastava

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