Bio-derived solvents for in situ forming implants

In situ forming implants (ISFIs) have gained considerable attention over the past decade as minimally invasive long-acting injectable systems for localised and sustained drug delivery. N-Methyl-2-pyrrolidone (NMP) remains the most commonly used solvent for ISFIs; however, concerns regarding its environmental toxicity and teratogenicity have driven the search for alternatives. Therefore, in this study, we investigated bio-derived and bio-renewable solvents - dimethyl isosorbide (DMI) and γ-valerolactone (GVL) - as potential substitutes for NMP. ISFI formulations were individually prepared with each solvent and poly(lactic-co-glycolic acid) (PLGA; L/G 1:1, 10 kDa) at polymer concentrations of 20, 30, and 40% w/w, and containing 1% w/w eosin Y dye as a model hydrophilic drug. ISFIs were subsequently evaluated for their rheological behaviour, injectability, implant morphology, and dye and solvent release. Rheological analyses revealed solvent-dependent differences, with GVL exhibiting flow behaviour comparable to NMP, while DMI showed significantly higher viscosity. These trends translated into injectability performance. Post-injection, NMP- and DMI-based ISFIs formed spherical implants, whereas GVL-based ISFIs produced collapsed and irregular structures. Moreover, in vitro release studies of eosin Y showed that GVL-based ISFIs significantly reduced burst release while exhibiting overall faster release kinetics, which was attributed to rapid polymer solidification and collapsed implant morphology that shortened diffusion path lengths. A two-stage model was developed to fit the release profiles and determine the average diffusion coefficients (D), allowing a quantitative comparison of the different formulations. To compare the performance of the solvents in vivo in rats, ISFI formulations were prepared containing testosterone (2.5% w/w) as a clinically relevant hydrophobic drug. Testosterone release from DMI- and GVL-based ISFIs was comparable to NMP, although NMP formulations resulted in lower overall plasma concentrations. This study highlights the potential of DMI and GVL as alternative solvents for ISFIs, with comparable performance to the traditionally used NMP.