The development of drugs targeting the central nervous system (CNS) is challenging because of the presence of the Blood-Brain barrier (BBB). Developing physiologically relevant in vitro BBB models for evaluating drug permeability and predicting the activity of drug candidates is crucial. The transwell model is one of the most widely used in vitro BBB models. However, this model has limitations in mimicking in vivo conditions, particularly in the absence of shear stress. This study aimed to overcome the limitations of the transwell model using immortalized human endothelial cells (hCMEC/D3) by developing a novel dish design for an orbital shaker, providing shear stress. During optimization, we assessed cell layer integrity using trans-endothelial electrical resistance measurements and the % diffusion of lucifer yellow. The efflux transporter activity and mRNA expression of junctional proteins (claudin-5, occludin, and VE-cadherin) in the newly optimized model were verified. Additionally, the permeability of 14 compounds was evaluated and compared with published in vivo data. The cell-layer integrity was substantially increased using the newly designed annular shaking-dish model. The results demonstrate that our model provided robust conditions for evaluating the permeability of CNS drug candidates, potentially improving the reliability of in vitro BBB models in drug development.

Research on the development of dissolving microneedles (DMNs) has focused on bolus drug delivery, with little attention on sustained release. Here, we evaluated the sustained release, absorption pattern, and effective drug permeation of a novel donepezil-loaded DMN patch through an in vivo investigation on rats. The applications of DMN patches to the shaved skin of rats for 1 week and 1 h were compared with oral donepezil administration to assess their sustained release capabilities. We used a validated liquid chromatography–tandem mass spectrometry method to quantify donepezil in the plasma. We found that the microneedle arrays effectively delivered donepezil across the skin, with dissolution observed within 1 h of application. Furthermore, skin irritation test showed that the patches produced no irritation response. The DMN arrays also effectively increased drug permeation and demonstrated sustained release and absorption of donepezil from DMN patches. These patches allow extended dosing intervals, reduced gastrointestinal adverse effects, and convenient self-administration to mitigate poor drug compliance, making them beneficial for the treatment of elderly patients with Alzheimer’s disease.

Rumex acetosa (R. acetosa) has been used in folk remedies for gastrointestinal disorders and cutaneous diseases. Rumex species, in particular, contain abundant anthraquinones. Anthraquinone glycosides and aglycones show different bioactive effects. However, information on the pharmacokinetics of anthraquinone glycosides is limited, and methods to quantify anthraquinone glycosides in plasma are rarely available. A simple and sensitive liquid chromatography-tandem mass spectrometric bioanalytical method for the simultaneous determination of both anthraquinone glycosides and their aglycones, including emodin, emodin-8-O-β-d-glucoside, chrysophanol, chrysophanol-8-O-β-d-glucoside, physcion, and physcion-8-O-β-d-glucoside , in a low volume of rat plasma (20 µL) was established. A simple and rapid sample preparation was employed using methanol as a precipitating agent with appropriate sensitivity. Chromatographic separation was performed on HPLC by using a biphenyl column with a gradient elution using 2 mM ammonium formate (pH 6) in water and 2 mM ammonium formate (pH 6) in methanol within a run time of 13 min. The anthraquinones were detected on triple-quadrupole mass spectrometer in negative ionization mode using multiple-reaction monitoring. The method was validated in terms of selectivity, linearity, accuracy, precision, recovery, and stability. The values of the lower limit of quantitation of anthraquinones were 1–20 ng/mL. The intra-batch and inter-batch accuracies were 96.7–111.9% and the precision was within the acceptable limits. The method was applied to a pharmacokinetic study after oral administration of R. acetosa 70% ethanol extract to rats at a dose of 2 g/kg.

Herbal drugs are widely used for the auxiliary treatment of diseases. The pharmacokinetics of a drug may be altered when it is coadministered with herbal drugs that can affect drug absorption. The effects of herbal drugs on absorption must be evaluated. In this study, we investigated the effects of Rumex acetosa (R. acetosa) extract on fexofenadine absorption. Fexofenadine was selected as a model drug that is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide 1A2 (OATP1A2). Emodine—the major component of R. acetosa extract—showed P-gp inhibition in vitro and in vivo. Uptake of fexofenadine via OATP1A2 was inhibited by R. acetosa extract in OATP1A2 transfected cells. A pharmacokinetic study showed that the area under the plasma concentration–time curve (AUC) of fexofenadine was smaller in the R. acetosa extract coadministered group than in the control group. R. acetosa extract also decreased aqueous solubility of fexofenadine HCl. The results of this study suggest that R. acetosa extract could inhibit the absorption of certain drugs via intervention in the aqueous solubility and the drug transporters. Therefore, R. acetosa extract may cause drug interactions when coadministered with substrates of drug transporters and poorly water-soluble drugs, although further clinical studies are needed.