A consensus research agenda for optimising nasal drug delivery

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors

Proton-dependent oligopeptide transporter (POT)-mediated uptake in the novel blood-brain barrier cell line, hCMEC/D3

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Intracellular localization of human peptide/histidine transporter 1 (hPHT1) in the human gastrointestinal adenocarcinoma cell line HT-29

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Establishment of a hPepT1-stably transfected human cell line: characterization of transporter expression and function

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Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia

Laurent Salade,1 Nathalie Wauthoz,1 Magali Deleu,2 Marjorie Vermeersch,3 Carine De Vriese,1 Karim Amighi,1 Jonathan Goole1 1Laboratoire de Pharmacie Galénique et de Biopharmacie, Université libre de Bruxelles (ULB), Brussels, 2Laboratoire de Biophysique Moléculaire aux Interfaces, Gembloux Agro-Bio Tech, Université de Liège, Gembloux, 3Centre for Microscopy and Molecular Imaging (CMMI), Charleroi, Belgium Abstract: The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose–brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56%) and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone) and carboxylesterase (81.6% vs 17.2% for ghrelin alone). Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with N-(2-hydroxy)propyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9±2.7 to 194±6.1 nm, for uncoated and coated liposomes, respectively. The ζ-potential was similarly increased from -0.3±1.2 mV to 6±0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270) intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4±5.76 and 37.6±5.74 µm, respectively. Overall, the results obtained in this study show that the developed formulation delivered by the VP3 device can be considered as a potential candidate for nose–brain delivery of ghrelin. Keywords: nasal delivery, peptide, liposome, cachexia, brain targeting, enzym

The effects of excipients on transporter mediated absorption.

Traditionally most pharmaceutical excipients used for peroral dosage forms have been considered to be inert, although they have been known to play an important role in governing the release of the active pharmaceutical ingredient (API) required for the desired therapeutic effect. Of considerable interest is the emerging data demonstrating that many of these "inert" excipients may produce subtle changes that could directly or indirectly alter the activity of membrane-spanning proteins such as transporters. In this way, excipients could be altering the overall ADMET properties of an incorporated drug thereby affecting its intended therapeutic efficacy and/or enhancing adverse side effects. Therefore, given this recent evidence, it seems necessary to review what has been reported in the literature on interactions of excipients with human physiological entities, particularly transporters. As of today, safety/toxicity evaluations are typically based on the appearance of gross morphological changes rather than the effects on a cellular level, the ability of excipients in modifying the pharmacological activity of an active drug could lead to toxicity evaluation in routine for each additive used in oral formulations. Further knowledge on this subject will enable formulators to make more rational decisions in dosage form design and will help answer the question of whether certain excipients should be considered active pharmaceutical components of formulations.Journal ArticleReviewSCOPUS: re.jinfo:eu-repo/semantics/publishe

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics.

Our associated microbial communities play a critical role in human health and predisposition to disease, but the degree to which they also shape therapeutic interventions is not well understood. Here, we integrate results from classic and current studies of the direct and indirect impacts of the gut microbiome on the metabolism of therapeutic drugs and diet-derived bioactive compounds. We pay particular attention to microbial influences on host responses to xenobiotics, adding to the growing consensus that treatment outcomes reflect our intimate partnership with the microbial world, and providing an initial framework from which to consider a more comprehensive view of pharmacology and nutrition