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The oral uptake of intact nanocarriers through Peyer’s patches is an important uptake pathway. We report Rifampicin Lipid-Polymer hybrid nanoparticles (RIF-LIPOMER) using glyceryl monostearate as lipid and the mucoadhesive polymer, Gantrez, with the objective of balancing hydrophobicity and mucoadhesion for enhanced Peyer’s patch uptake. RIF-LIPOMER was optimized for size, hydrophobicity, and mucoadhesion using Box-Behnken. Designed RIF-LIPOMER (RIF-LIPO-120) exhibited average particle size in the range 300–400 nm with drug loading >12%. DSC and XRD confirmed complete amorphization. Contact angle and mucoadhesion force revealed that RIF-LIPO-120 exhibited greater hydrophobicity and lower mucoadhesion compared to Gantrez nanoparticles (RIF-GzNP). Comparative uptake of fluorescent labelled RIF-LIPO-120 and RIF-GzNP, through Peyer’s patch following intraduodenal administration in rats, revealed the high accumulation of RIF-GzNP at the villi border, and high Peyer’s patch uptake of RIF-LIPO-120. Furthermore, lower accumulation of RIF-LIPO-120 in the liver, compared to RIF-GzNP, suggested bypass of the portal circulation and lymphatic uptake through Peyer’s patches. Significantly higher lung: plasma concentration ratio exhibited by RIF-LIPO-120 compared to RIF-GzNP confirmed the same (p < 0.05). Our study demonstrated that optimization of hydrophobicity and mucoadhesion of nanoparticles could favor Peyer’s patch uptake, which in turn could enable enhanced drug accumulation in the lungs with advantage in the therapy of pulmonary afflictions. [ABSTRACT FROM AUTHOR]

This article reviews the field of oral uptake of nanoparticles across the gastrointestinal epithelium for the period 2006–2016. Analysis is conducted from the viewpoint of i) M-cell genetics and model development, ii) drug targeting to Peyer's patches and M-cells, and iii) physicochemical interactions of nanoparticles in the intestinal milieu. In light of these recent developments, regulatory considerations in the development of orally-absorbable nanoparticle drug products are discussed and focused on Module 3.2.P sub-sections of the Common Technical Document. Particular attention is paid to novel excipients, ligands and the non-standard method of manufacture. The novelty of this drug delivery system demands not only a multi-disciplinary scientific and regulatory approach but also a risk-adjusted consideration for a system defined by both processes and specifications. Given the current state of scientific development in the field it is suggested (in the author's personal opinion) that the design of nanoparticulate drug delivery systems should be kept as simple as possible (from a regulatory and manufacturing perspective) and to target the entire gastrointestinal epithelium. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate the cellular electrophysiological effects of ranolazine on action potential characteristics. The experiments were carried out in dog and human cardiac preparations using the conventional microelectrode technique. In dog Purkinje fibres ranolazine produced a concentration- and frequency-dependent depression of the maximum rate of depolarization (Vmax) while action potential duration (APD) was shortened. In dog and human right ventricular papillary muscle ranolazine exerted no significant effect on APD, while it produced, like mexiletine, use-dependent depression of Vmax with relatively fast onset and offset kinetics. In dog midmyocardial preparations the drug did not exert statistically significant effect on repolarization at 10μM, although a tendency toward prolongation was observed at 20μM. A moderate lengthening of APD90 by ranolazine was noticed in canine atrial preparations obtained from dogs in sinus rhythm and in tachypacing induced remodelled preparations. Use-dependent depression of Vmax was more pronounced in atria from dogs in sinus rhythm than those in remodelled atria or in the ventricle. These findings indicate that ranolazine, in addition to its known late sodium current blocking effect, also depresses peak INa with class I/B antiarrhythmic characteristics. Although peak INa inhibition by ranolazine is stronger in the atria, it is also substantial (at fast stimulation frequencies) in ventricular preparations. Ranolazine also decreased the dispersion of ventricular repolarization (the difference in APD90 values between Purkinje fibres and papillary muscles), which can contribute to the antiarrhythmic property of the drug. [Copyright &y& Elsevier]

Abstract: Antigen uptake has been shown to occur in the teleost intestine, but so far, limited information is available on the distribution and nature of cells involved in the process, and M cells, known for their antigen-sampling abilities in mammals, have not been identified. Here, different intestinal segments from salmonid fish were exposed to gold-BSA to identify antigen-sampling cells. Sections from exposed intestine were examined by light and electron microscopy. Uptake of gold-BSA was restricted to very few dendritic-like cells and to a limited number of epithelial cells located in the mucosal folds in the second segment of the mid-intestine. Gold-positive epithelial cells displayed diverging and electron-dense microvilli with channels intruding into the cytoplasm. A lectin binding experiment demonstrated the presence of cells with mammalian M-cell characteristics in the identical regions. As the identified epithelial cells shared some morphological similarities with immature mammalian M cells, this phenotype may represent evolutionary early antigen-sampling enterocytes. [Copyright &y& Elsevier]

Abstract: The paired palatine tonsils, located at the junction of the nasopharynx and oropharynx, are ideally positioned to sample antigens entering through the nasal cavity or oral cavity. Entering antigens will first contact tonsilar epithelium. To better understand the cellular composition of this important epithelial layer, palatine tonsils were collected from six, 7-month-old calves and examined by light microscopy, immunohistochemistry and electron microscopy. Morphometric analysis showed that epithelium overlying lymphoid follicles (reticular epithelium) contained more B-cells, CD4+, CD8+, CD11c+, CD172a+ and γ/δ TCR+ cells than non-reticular epithelium, with B-cells, CD4+ cells and CD11c+ cells being most numerous. Scanning and transmission electron microscopy of reticular epithelium identified an interrupted basement membrane and vascular elements within the epithelium, as well as cells with characteristics morphologically consistent with cells identified as M-cells in other species. Bovine palatine tonsilar reticular epithelium contains key immune cells, as well as potential M-cell-like cells; elements essential for antigen uptake, antigen processing and initiation of immune responses. [Copyright &y& Elsevier]

Abstract: Neuraminidases act as a virulence factors for several pathogens that invade the human body through Peyer''s patch M-cells. Because of the structural similarity of Aleuria aurantia lectin (AAL) to neuraminidases, we hypothesized that AAL might also target human M-cells. In an in vitro human M-cell co-culture model significantly more particles were transported across the epithelium when microparticles were functionalized with AAL versus those that were not. Moreover, high concentrations of AAL induced no detectable cytotoxic effects on the related intestinal epithelial cell cultures, epithelial Caco2- and HT29-MTX-E12-cells. Upon incubation with AAL, PBMCs of allergic volunteers proliferated in response to AAL and secreted the cytokines, IL-2, IFN-γ, IL-10 and IL-5 in a concentration-dependent manner, indicating immune-stimulatory properties of the lectin. We conclude that AAL-coated microparticles may have the potential to target entrapped antigens to human M-cells for oral vaccination. [Copyright &y& Elsevier]