Oral transmucosal delivery of eletriptan for neurological diseases.

Migraine is a highly prevalent neurological disease affecting circa 1 billion patients worldwide with severe incapacitating symptoms, which significantly diminishes the quality of life. As self-medication practice, oral administration of triptans is the most common option, despite its relatively slow therapeutic onset and low drug bioavailability. To overcome these issues, here we present, to the best of our knowledge, the first study on the possibility of oral transmucosal delivery of one of the safest triptans, namely eletriptan hydrobromide (EB). Based on a comprehensive set of in vitro and ex vivo experiments, we highlight the conditions required for oral transmucosal delivery, potentially giving rise to similar, or even higher, drug plasma concentrations expected from conventional oral administration. With histology and tissue integrity studies, we conclude that EB neither induces morphological changes nor impairs the integrity of the mucosal barrier following 4 h of exposure. On a cellular level, EB is internalized in human oral keratinocytes within the first 5 min without inducing toxicity at the relevant concentrations for transmucosal delivery. Considering that the pKa of EB falls within the physiologically range, we systematically investigated the effect of pH on both solubility and transmucosal permeation. When the pH is increased from 6.8 to 10.4, the drug solubility decreases drastically from 14.7 to 0.07 mg/mL. At pH 6.8, EB gave rise to the highest drug flux and total permeated amount across mucosa, while at pH 10.4 EB shows greater permeability coefficient and thus higher ratio of permeated drug versus applied drug. Permeation experiments with model membranes confirmed the pH dependent permeation profile of EB. The distribution of EB in different cellular compartments of keratinocytes is pH dependent. In brief, high drug ionization leads to higher association with the cell membrane, suggesting ionic interactions between EB and the phospholipid head groups. Moreover, we show that the chemical permeation enhancer DMSO can be used to enhance the drug permeation significantly (i.e., 12 to 36-fold increase). Taken together, this study presents important findings on transmucosal delivery of eletriptan via the oral cavity and paves the way for clinical investigations for a fast and safe migraine treatment.

Polyphenol-hydrogen peroxide reactions in skin: In vitro model relevant to study ROS reactions at inflammation.

Antioxidants are important to protect and maintain biological barriers, such as the skin. Antioxidant effects are often assessed using clinical trials, however these tests are costly and time consuming. In this work we introduce a skin membrane-covered oxygen electrode (SCOE) as an in vitro tool for monitoring H2O2 and antioxidant reactions in skin. The SCOE gives amperometric response to H2O2 concentrations down to 0.05 mM. More importantly, the electrode allows measurements of polyphenol penetration and reaction with H2O2 in skin. Measurements with SCOE show that lipophilic polyphenols such as quercetin, piceatannol, resveratrol, and plant extract from Plantago major impose their antioxidant effect in skin within 2-20 min. Rutin is however too hydrophilic to penetrate into stratum corneum and therefore cannot deliver its antioxidant effect during similar time interval. The measurements are interpreted considering polyphenol partition-penetration through stratum corneum and the reaction with the H2O2-catalase system in the skin. The contribution of other enzymes will be addressed in the future.