European Journal of Pharmaceutical Sciences最新文献

In vitro to in vivo extrapolation (IVIVE) methods for hepatic clearance (CL_H) prediction often underpredict, partly due to reliance on mathematical liver disposition models such as the well-stirred model (WSM) or parallel tube model (PTM). The ex vivo isolated perfused rat liver (IPRL) model bridges in vitro and in vivo data, providing mechanistic insights into the predictive accuracy of IVIVE models. This study evaluates the IPRL model across a diverse selection of 16 compounds, and benchmarks results against in vitro and in vivo data to verify the predictive performance of the WSM and PTM. Results demonstrate that both the IPRL and in vivo clearance conflict with assumptions of the WSM (AAFE = 2.85) or PTM (AAFE = 1.74), which consider liver outlet concentration as a driver for hepatic elimination rate. However, except for terfenadine, IPRL clearance predictions were within two-fold (AAFE = 1.59) of in vivo clearance when the liver inlet concentration was utilized to calculate the CL_H. When employing the WSM or PTM for in vitro to ex vivo extrapolation, underpredictions were observed for compounds with high plasma protein binding and subject to sinusoidal hepatic uptake, reflecting model oversimplification compared to in vivo dynamics. Our findings experimentally challenge the theoretical assumptions underlying the use of the WSM and PTM in IVIVE methods. Unique insights from the IPRL model point to the next steps needed to advance IVIVE: refining current liver disposition models through enhanced and next-generation in vitro assays, capturing dynamic in vivo disposition mechanisms, and exploring complementary models.

Coamorphization is an attractive approach to modifying the physicochemical properties of drug molecules, especially the solubility, dissolution, and associated bioavailability. Although these formulations may be advantageous, they exhibit poor physical stability and undergo recrystallisation. To address this limitation, this study investigates the effect of positional isomerism on the coamorphous formation and associated physicochemical properties, to select an optimum solid form with improved stability. Enzalutamide (ENZ), a BCS class II drug, was used as a model compound. Four positional isomers including 2,3-, 2,4-, 2,5- and 2,6-dihydroxybenzoic acid (DHB) were used as coamorphous coformers. Coamorphous formulations were prepared by ball mill in a 2:1 molecular ratio (API:coformer). The solid-state properties of the prepared coamorphous forms were characterised using X-ray powder diffractometer (XRPD), modulated differential scanning calorimetry (mDSC), and Fourier transformed infrared spectrometry (FTIR). Additionally, intra isomer variability in the amorphization kinetics and dissolution enhancement of ENZ, along with physical stability, were evaluated. All coformers formed coamorphous systems, as confirmed by XRPD. mDSC data showed that the glass transition temperature (Tg) varied among the prepared coamorphous forms and was lower than that of pure ENZ. Although there was no significant difference in the dissolution behaviour, the physical stability data reveal a contrast trend. Among the prepared coamorphous forms, ENZ-24DHB^CAM exhibited superior stability, while ENZ-26DHB^CAM exhibited poor stability. This article summarises the similarities and differences between the physicochemical properties of coamorphous forms of Enz because of the change in coformer positional isomerism. Stability studies under different humidity conditions revealed significant differences: at 40% RH, all coamorphous forms remained stable for up to 8 weeks, with minor deviations for ENZ-23DHB^CAM and ENZ-25DHB^CAM. Under 75% RH, the stability varied markedly; ENZ-24DHB^CAM maintained stability for at least 8 weeks, while ENZ-26DHB^CAM became unstable within 1-2 weeks, and ENZ-AMP and ENZ-23DHB^CAM lost stability by week 6. These results demonstrate the careful selection of coformer positional isomer can quantitatively enhance the stability of coamorphous forms, highlighting the importance of positional isomerism associated chemical design space in optimizing solid-state properties.

Bone tissue engineering (BTE) is an attempt to overcome the limitations of conventional grafting through the combination of bioactive scaffolds and regenerative signals. In this study, we prepared an extrusion-based 3D-printed composite scaffold composed of chitosan (CH) combined with dexamethasone (DEX)-loaded mesoporous silica nanoparticle (MSN), (MSN@DEX) in order to compensate for both mechanical insufficiency and temporary osteoinductive signal. MSNs were synthesized by a templated sol-gel method with high drug loading efficiency and biphasic release behavior. Inclusion of MSN@DEX in chitosan resulted in scaffolds with homogeneous and interconnected porosity (310-420 μm), high compressive strength, good swelling profile, and a degradation profile consistent with the time course of bone healing. In vitro experiments with mesenchymal stem cells (MSCs) resulted in a high hemocompatibility, a sustained cell proliferation and a significantly enhanced osteogenic differentiation given by alkaline phosphatase (ALP) activity, calcium deposits and stage-dependent upregulation of RUNX2, ALP, COL1A1 and OCN genes and protein. Together, the hierarchical scaffold architecture, nanostructured reinforcement, and local sustained DEX release provide a cost-effective, stable and clinically adaptable platform for robust osteogenesis with the possibility of enhanced osteogenic induction even with lower dexamethasone release. These findings underscore the potential of CH‑MSN@DEX scaffolds for bone regeneration applications. By combining structural reinforcement with sustained osteoinductive signaling within a single printable construct, this approach represents a clear advancement over previously reported chitosan‑based or DEX‑releasing scaffold systems.

Cyclooxygenase-2 (COX-2) is overexpressed in various cancers and has emerged as a promising target in oncological pharmacotherapy. This study investigates the in vitro antitumor properties and mechanism of action of novel vicinal diaryl-substituted heterocyclic COX-2 inhibitors, with a focus on VA1213, in comparison to celecoxib, a widely marketed COX-2 inhibitor known for its off-target effects. We assessed cytotoxicity, apoptosis induction, cell-cycle distribution, antimetastatic activity, and alterations in key signaling pathways in HT-29 colorectal carcinoma and MDA-MB-231 breast carcinoma cell lines. Among the novel compounds, VA1213 exhibited the most potent growth-inhibitory activity, demonstrating time-dependent cytotoxicity with a lower IC₅₀ after 48-72 hours of treatment compared to VA692 and VA694, and consistent with that observed for celecoxib. Unlike celecoxib, which produced rapid cytotoxic effects, VA1213 required prolonged exposure, suggesting a distinct mechanism of action. VA1213 induced G₀/G₁ phase cell cycle arrest and apoptosis via caspase-3 activation. Furthermore, it impaired EGFR downstream signaling by reducing ERK1/2 and AKT phosphorylation, without directly inhibiting EGFR itself. At sub-cytotoxic concentrations, VA1213 was more effective than celecoxib in inhibiting cell migration and demonstrated a comparable reduction in clonogenic potential. These findings highlight VA1213 as a COX-2 inhibitor with noteworthy in vitro antitumor efficacy, comparable to that of celecoxib. Its ability to interfere with multiple cancer-associated signaling pathways and reduce tumor cell aggressiveness underscores its potential as a promising therapeutic candidate. Further in vivo studies are warranted to confirm its efficacy and assess potential off-target effects.