Enhancing the Solubility and Oral Bioavailability of Trimethoprim Through PEG-PLGA Nanoparticles: A Comprehensive Evaluation of In Vitro and In Vivo Performance

<b>Background/Objectives:</b> Trimethoprim (TMP), a sulfonamide antibacterial synergist, is widely used in antimicrobial therapy owing to its broad-spectrum activity and clinical efficacy in treating respiratory, urinary tract, and gastrointestinal infections. However, its application is limited due to poor aqueous solubility, a short elimination half-life (t_1/2), and low bioavailability. In this study, we proposed TMP loaded by PEG-PLGA polymer nanoparticles (NPs) to increase its efficacy. <b>Methods:</b> We synthesized and thoroughly characterized PEG-PLGA NPs loaded with TMP using an oil-in-water (O/W) emulsion solvent evaporation method, denoted as PEG-PLGA/TMP NPs. Drug loading capacity (LC) and encapsulation efficiency (EE) were quantified by ultra-performance liquid chromatography (UPLC). Comprehensive investigations were conducted on the stability of PEG-PLGA/TMP NPs, in vitro drug release profiles, and in vivo pharmacokinetics. <b>Results:</b> The optimized PEG-PLGA/TMP NPs displayed a high LC of 34.0 ± 1.6%, a particle size of 245 ± 40 nm, a polydispersity index (PDI) of 0.103 ± 0.019, a zeta potential of -23.8 ± 1.2 mV, and an EE of 88.2 ± 4.3%. The NPs remained stable at 4 °C for 30 days and under acidic conditions. In vitro release showed sustained biphasic kinetics and enhanced cumulative release, 86% at pH 6.8, aligning with first-order models. Pharmacokinetics in rats revealed a 2.82-fold bioavailability increase, prolonged half-life 2.47 ± 0.19 h versus 0.72 ± 0.08 h for free TMP, and extended MRT 3.10 ± 0.11 h versus 1.27 ± 0.11 h. <b>Conclusions:</b> PEG-PLGA NPs enhanced the solubility and oral bioavailability of TMP via high drug loading, stability, and sustained-release kinetics, validated by robust in vitro-in vivo correlation, offering a promising alternative for clinical antimicrobial therapy.