In vitro drug release testing is an important quality control tool for formulation development. However, the literature has evidence that poly-lactide-co-glycolide (PLGA)-based formulations show a slower in vitro drug release than a real in vivo drug release. Much longer in vitro drug release profiles may not be reflective of real in vivo performances and may significantly affect the timeline for a formulation development. The objective of this study was to develop a surfactant mediated accelerated in vitro drug release method for the PLGA nanoparticles (NPs) of a novel chemotherapeutic agent AC1LPSZG, a model drug with a poor solubility. The Sotax USP apparatus 4 was used to test in vitro drug release in a phosphate buffer with a pH value of 6.8. The sink conditions were improved using surfactants in the order of sodium lauryl sulfate (SLS) < Tween 80 < cetyltrimethylammonium bromide (CTAB). The dissolution efficiency (DE) and area under the dissolution curve (AUC) were increased three-fold when increasing the CTAB concentration in the phosphate buffer (pH 6.8). Similar Weibull release kinetics and good linear correlations (R²~0.99) indicated a good correlation between the real-time in vitro release profile in the phosphate buffer (pH 6.8) and accelerated release profiles in the optimized medium. This newly developed accelerated and discriminatory in vitro test can be used as a quality control tool to identify critical formulation and process parameters to ensure a batch-to-batch uniformity. It may also serve as a surrogate for bioequivalence studies if a predictive in vitro in vivo correlation (IVIVC) is obtained. The results of this study are limited to AC1LPSZG NPs, but a similar consideration can be extended to other PLGA-based NPs of drugs with similar properties and solubility profiles.

Objectives: A thorough understanding of pharmacokinetics and metabolism is critical during early drug development. This study investigates the absorption, distribution, metabolism, and excretion (ADME) profile of R14, a novel compound, using a combination of in vitro and in vivo approaches. Methods: In vitro studies included Caco-2 permeability assays, metabolic stability evaluations in liver microsomes and hepatocytes, and identification of CYP isoforms responsible for R14 metabolism. In vivo pharmacokinetic and metabolic profiling was conducted in rats following oral administration. R14 was quantified using UHPLC-MS/MS. Metabolites were identified using high-resolution UHPLC- QTOF MS/MS, and relative exposure was estimated using peak area-derived AUCs. Results: R14 exhibited low oral bioavailability (13.4%) and high systemic clearance (2.63 L/h/kg), indicating high hepatic extraction. A total of 21 plasma and 38 urine metabolites were identified. Major metabolic pathways included initial hydroxylation and hydrogenation, followed by sequential methylation and Phase II conjugations (glucuronidation and sulfation). Key metabolites (M3, M4, M22, M38) accounted for the majority of systemic exposure. Less than 1% of the unchanged drug was excreted in urine, confirming extensive metabolism. Notably, discrepancies between in vitro and in vivo metabolite profiles suggested rapid further transformation of initial metabolites in vivo, which were not fully captured in vitro. Conclusions: This study demonstrates an efficient and integrated strategy for early-phase ADME characterization. The combined use of in vitro assays and in vivo studies, guided by advanced analytical techniques, provides a robust framework for understanding drug metabolism. These findings can inform drug optimization and help minimize risks in later stages of development.

Promising preliminary clinical data have stimulated research on the use of the mammalian target of rapamycin (mTOR) inhibitors in lung cancer. AC1LPSZG is an mTOR inhibitor that can significantly reduce the viability in lung adenosquamous carcinoma cell line HTB-178 cells, showing potential benefits in effective control of non-small cell lung carcinomas. In this study, a sensitive LC–MS/MS analytical method for quantification of AC1LPSZG has been developed and optimized to a running time of 3 min per sample. A linear dose–response for quantification was observed over the range of 10–5000 ng/mL in rat plasma with required precision and accuracy. High extraction recovery was achieved in the ranges of 86.87–102.51% at QC levels from rat plasma without significant matrix effect. Stability profile of AC1LPSZG in rat plasma and in extract after protein precipitation suggested that samples should be processed within 6 h after collection and stored at −80 °C until analysis within 30 days. The method was successfully applied to plasma pharmacokinetics (PK) study of AC1LPSZG in rat, showing the plasma drug concentration followed a two-compartment model.

Comparing Efficacy and Safety of Olopatadine and Emedastine in Patients with Allergic Conjunctivitis