Administration par voie intranasale d’un principe actif hydrophile d’intérêt thérapeutique potentiel pour le traitement de la maladie d’Alzheimer

This study aimed at preparing and characterizing thermosensitive gel formulations based on a mixture of two hydrophilic polymers (Poloxamer 407 and 188) for a sustained delivery via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer’s disease through nasal route. API was characterized as being a selective inhibitor of butyrylcholinesterase but presents a low permeability through brain blood barrier model. The osmolarity and the gelation temperature (T°sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. At the issue of assays, a mixture composed of p407/p188 (15/1 %, w/w) was selected, being compatible with intranasal administration in terms of (T°sol-gel = 34,5°c ± 0,3) and with the olfactory mucosal (280 ± 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. various parameters such as lipid ratio, concentration and lipid to drug ratio were investigated to obtain acceptable entrapment efficiency (EE). Formulations were evaluated for vesicle size granulometry, zeta potential, and EE determined after purification. Mucoadhesion studies were performed, and showed that in situ gel formulations present good natural mucoadhesive characteristics, that could be increased with liposomes. Drug release studies showed the API was successfully and completely released with a controlled rate, and slower than with API-loaded solutions or gels. The study demonstrated successful formulation of a promising API-loaded liposomes in a thermosensitive hydrogel for nasal delivery.Cette étude visait à préparer et caractériser des formulations de gels thermosensibles à base de poloxamères (p407 et p188) en vue d’une délivrance prolongée, par le biais de liposomes, d’un principe actif (PA) pharmaceutique présentant un intérêt potentiel pour la maladie d’Alzheimer par voie nasale. Le PA a été caractérisé comme étant un inhibiteur sélectif de la butyrylcholinestérase, mais présente une faible perméabilité à travers le modèle de barrière hémato-encéphalique. L'osmolarité et la température de gélification (T°sol-gel) des formulations, définies dans un diagramme ternaire, ont été étudiées par analyse rhéologique et détermination visuelle. Des liposomes charges en PA ont été préparés par la méthode d'hydratation du film lipidique. Leurs propriétés ont été évaluées en termes de granulométrie, de potentiel zêta et de taux d’encapsulation. À l’issue de ces essais, un mélange composé de P407/188 15/1 (%, masse/masse) a été choisi, compatible avec l’administration intranasale et la muqueuse olfactive en termes de T°sol-gel (34,5°c ± 0,3), d’osmolarité (280 ± 20 mosmol) et de pH (6). Des études de mucoadhésion ont établi que ce gel présentait de bonnes caractéristiques mucoadhésives naturelles, et augmentées en présence de liposomes. Les cinétiques de libération ont montré que la formulation composite permettait une libération prolongée et complète du PA. Ce travail de thèse a permis le développement d’une formulation innovante, administrable par voie intranasale, assurant un temps de résidence prolongé dans la cavité nasale et libérant de façon maitrisée un PA d’intérêt thérapeutique pour le traitement d’une maladie neurodégénérative incurable à ce jour

Discovery of an earliest Pliocene relic tropical fish fauna in a newly detected cliff section (Sabratah Basin, NW Libya)

International audienc

A national population-based study of patients, bystanders and contextual factors associated with resuscitation in witnessed cardiac arrest: insight from the french RéAC registry

International audienceBackground: In out-of-hospital cardiac arrest (OHCA), bystander initiated cardiopulmonary resuscitation (CPR) increases the chance of return of spontaneous circulation and survival with a favourable neurological status. Socioeconomic disparities have been highlighted in OHCA field. In areas with the lowest average socioeconomic status, OHCA incidence increased, and bystander CPR decreased. Evaluations were performed on restricted geographical area, and European evaluation is lacking. We aimed to analyse, at a national level, the impact of area-level social deprivation on the initiation of CPR in case of a witnessed OHCA. Methods: We included all witnessed OHCA cases with age over 18 years from July 2011 to July 2018 form the OHCA French national registry. We excluded OHCA occurred in front of rescue teams or in nursing home, and patients with incomplete address or partial geocoding. We collected data from context, bystander and patient. The area-level social deprivation was estimated by the French version of the European Deprivation Index (in quintile) associated with the place where OHCA occurred. We assessed the associations between Utstein variables and social deprivation level using a mixed-effect logit model with bystander-initiated CPR. Results: We included 23,979 witnessed OHCA of which 12,299 (51%) had a bystander-initiated CPR. More than one third of the OHCA (8,326 (35%)) occurred in an area from the highest quintile of social deprivation. The higher the area-level deprivation, the less the proportion of bystander-initiated CPR (56% in Quintile 1 versus 48% in Quintile 5). The In the multivariable analysis, bystander less often began CPR in areas with the highest deprivation level, compared to those with the lowest deprivation level (OR=0.69, IC95%: 0.63-0.75). Conclusions: The level of social deprivation of the area where OHCA occurred was associated with bystander-initiated CPR. It decreased in the more deprived areas although these areas also concentrate more younger patients

Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer’s Disease Treatment

Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer’s disease. The osmolarity and the gelation temperature (T° sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. Regarding the issue of assays, a mixture composed of P407/P188 (15/1%, w/w) was selected for intranasal administration in terms of T° sol-gel and for the compatibility with the olfactory mucosal (280 ± 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. Mucoadhesion studies were performed by using mucin disc, and they showed the good natural mucoadhesive characteristics of in situ gel formulations, which increased when liposomes were added. The study demonstrated successful pharmacotechnical development of a promising API-loaded liposomes in a thermosensitive hydrogel intended for nasal Alzheimer’s disease treatment