The co-administration of absorption enhancing agents with macromolecular drugs (e.g., protein and peptide drugs) has been identified as a means to improve the oral bioavailability of these drugs. Absorption-enhancing agents of natural origins have received a great deal of attention due to their sustainable production, in support of green chemistry. In previous studies, certain parts of the Aloe vera leaf (e.g., gel and whole leaf extract) have shown a potential to enhance drug permeation across the intestinal epithelial barrier. The mechanism of the drug-absorption-enhancement action and the capacity for absorption-enhancement of the A. vera gel and whole leaf, were investigated in this study. A clear decrease in transepithelial electrical resistance (TEER) of Caco-2 cell monolayers exposed to A. vera gel and wholeleaf extract, in various concentrations, indicated the opening of tight junctions between the epithelial cells. The transport of Fluorescein isothiocyanate (FITC)-dextran, with a molecular weight of 4 kDa (FD-4), could be enhanced across the Caco-2 cell monolayers, by the A. vera gel and whole-leaf extract, but not the FITC-dextran with larger molecular weights (i.e., 10, 20, and 40 kDa), which indicated a limited drug absorption enhancement capacity, in terms of the molecular size. Accumulation of FD-4 between the Caco-2 cells (and not within the cells), after treatment with the A. vera gel and whole-leaf extract was shown with a confocal laser scanning microscopy (CLSM) imaging, indicating that the paracellular transport of FD-4 occurred after the interaction of the A. vera gel and whole-leaf extract, with the epithelial cell monolayers. Furthermore, changes in the F-actin distribution in the cytoskeleton of the Caco-2 cell monolayers was observed by means of a fluorescence staining, which confirmed tight junction modulation as the mechanism of action for the absorption enhancement effect of the A. vera gel and whole-leaf extract.

Background: Besides systemic drug delivery, the intranasal route of administration has shown potential for direct nose-to-brain drug delivery, which has gained popularity because it bypasses the blood-brain barrier. Objective: The region in the nose from which the epithelial tissue membrane is excised to conduct ex vivo permeation studies for nasal drug delivery studies may be of importance, but the permeability of the epithelium from the different nasal regions has not yet been investigated in the sheep model. Method: The permeation of five selected model compounds (i.e., atenolol, caffeine, Rhodamine 123, FITC-dextran, and Lucifer Yellow) was measured across epithelial tissues that were excised from two different areas of the sheep nasal cavity, namely the ventral nasal concha (representing respiratory epithelium) and the ethmoid nasal concha (representing olfactory epithelium). Results: Although the selected compounds' permeation was generally slightly higher across the olfactory epithelial tissues than across the respiratory epithelial tissues, it was not statistically significant except in the case of atenolol. Conclusion: The presence of olfactory nerves and supporting cells and the gaps between them in the olfactory epithelial tissues may have contributed to the higher permeation of atenolol, but this needs to be further investigated to elucidate the precise mechanism.

The intranasal route of administration provides a noninvasive method to deliver drugs into the systemic circulation and/or directly into the brain. Direct nose‐to‐brain drug delivery offers the possibility to treat central nervous system diseases more effectively, as it can evade the blood–brain barrier. In vitro and ex vivo intranasal models provide a means to investigate physiological and pharmaceutical factors that could play a role in drug delivery across the nasal epithelium as well as to determine the mechanisms involved in drug absorption from the nose. The development and implementation of cost‐effective pharmacokinetic models for intranasal drug delivery with good in vitro‐in vivo correlation can accelerate pharmaceutical drug product development and improve economic and ecological aspects by reducing the time and costs spent on animal studies. Special considerations should be made with regard to the purpose of the in vitro/ex vivo study, namely, whether it is intended to predict systemic or brain delivery, source and site of tissue or cell sampling, viability window of selected model, and the experimental setup of diffusion chambers. The type of model implemented should suit the relevant needs and requirements of the project, researcher, and interlaboratory. This review aims to provide an overview of in vitro and ex vivo models that have been developed to study intranasal and direct nose‐to‐brain drug delivery.

Aloe vera gel and whole leaf materials, as well as polysaccharides, precipitated from the gel, have previously been shown to enhance macromolecular drug delivery across epithelial tissues. This study investigated the effectiveness of microparticle formulations prepared from A. vera polysaccharides for nasal delivery of insulin across excised sheep olfactory and respiratory nasal epithelial tissues. An emulsion-solvent evaporation technique was used to prepare two insulin microparticle formulations, namely one containing Eudragit® L100 and A. vera polysaccharides and one containing A. vera polysaccharides only. In addition, an ionic gelation technique was used to prepare an insulin microparticle formulation with A. vera polysaccharides, where calcium chloride was used as a cross-linker. The microparticle formulations were evaluated in terms of drug content (assay), particle size, drug release (dissolution), ex vivo drug permeation, and histology. The microparticle formulations exhibited statistically significantly higher insulin delivery across excised sheep olfactory and respiratory nasal epithelial tissues compared to that of the control group (insulin alone). In conclusion, the use of A. vera polysaccharides in microparticle formulations significantly improved nasal insulin delivery. Therefore, A. vera polysaccharide containing microparticles showed high potential to enhance systemic bioavailability and delivery into the brain of macromolecular drugs such as insulin after intranasal administration.

The intranasal route of drug administration offers an opportunity to bypass the blood–brain barrier and deliver compounds directly into the brain. Scientific evidence exists for medicinal plants (e.g., Centella asiatica and Mesembryanthemum tortuosum) to treat central nervous system conditions such as anxiety and depression. The ex vivo permeation of selected phytochemicals (i.e., asiaticoside and mesembrine) has been measured across excised sheep nasal respiratory and olfactory tissue. Permeation studies were conducted on individual phytochemicals and C. asiatica and M. tortuosum crude extracts. Asiaticoside exhibited statistically significantly higher permeation across both tissues when applied alone as compared to the C. asiatica crude extract, while mesembrine permeation was similar when applied alone or as M. tortuosum crude extract. Permeation of all the phytocompounds was similar or slightly higher than that of the drug atenolol across the respiratory tissue. Permeation of all the phytocompounds was similar to or slightly lower than that of atenolol across the olfactory tissue. In general, the permeation was higher across the olfactory epithelial tissue than across the respiratory epithelial tissue and therefore showed potential for direct nose-to-brain delivery of the selected psychoactive phytochemicals.