European Journal of Pharmaceutical Sciences最新文献

Ocular drug delivery presents significant challenges due to the unique anatomical and physiological barriers of the human eye, with the rapid precorneal elimination, limiting the bioavailability of conventional eye drops. Thermosensitive in situ gels have emerged as a promising delivery system to overcome these limitations by undergoing a reversible sol-to-gel transition upon contact with ocular surface temperature, which facilitates ease of administration as a liquid and subsequent transformation into a gel, thereby enhancing precorneal residence time, prolonging the drug release, and improving therapeutic efficacy. This review provides a comprehensive overview of thermos-responsive polymer-based ocular delivery systems, with a specific focus on poloxamers, poly(N-isopropylacrylamide), and cellulose derivatives. Particular attention is given to the physicochemical mechanisms of thermogelation, such as poloxamer micellization and micelle packing, as well as the role of auxiliary polymers in enhancing mucoadhesion, mechanical strength, and gel retention. Additionally, the review synthesizes findings from multiple experimental studies to highlight the critical formulation parameters essential for developing effective in situ gels, including sol-gel transition temperature and time, clarity, rheological behavior, gelling capacity, isotonicity, and ocular biocompatibility. By selecting an optimized thermosensitive in situ gel formulation with suitable characteristics, it becomes possible to develop effective delivery systems targeting both the anterior and posterior segments of the eye.

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.