Suivi de l’opération d’enrobage pour le développement d’une forme posologique facile à avaler pour des fins pédiatriques : étude du procédé et développement d’outils pour un suivi en temps réel

Malgré les mesures récentes des organismes de réglementation, il y a encore des lacunes dans la mise en œuvre de formulations adaptées à l'âge à l’intention de la population pédiatrique. Les différences au sein de cette population, conjuguées à la non-adhésion thérapeutique due au mauvais goût des médicaments, présentent de grands défis pour la formulation de médicaments pris par voie orale. Des formulations orales solides souples, comme les microsphères, ont été proposées comme solutions de rechange aux formulations déjà commercialisées, comme les comprimés ou les formes posologiques orales liquides. Les microsphères sont des systèmes matriciels dans lesquels le principe actif (PA) est dispersé. Le PA est donc subdivisé en plusieurs petites unités posologiques. De plus, les microsphères peuvent être enrobées afin de masquer le goût. La stratégie consiste à appliquer une barrière protectrice à la microsphère qui empêchera la libération du médicament dans la cavité buccale, tout en maintenant une libération immédiate dès que le produit médicamenteux atteint le site d’absorption, pour ainsi obtenir un profil neutre sur le plan du goût sans affecter la biodisponibilité du PA. Les lits d’air fluidisé avec : Wurster sont utilisés depuis plusieurs années dans l’industrie pharmaceutique pour enrober les petites particules, car ils produisent des particules uniformément enrobés. La nécessité d’acquérir une meilleure compréhension des procédés conventionnels utilisés dans l’industrie pharmaceutique est connue. Les organismes de réglementation favorisent l’utilisation des principes de qualité par la conception, ainsi que des nouvelles technologies, comme les outils de la technologie d’analyse des procédés (PAT), dans le but d’élaborer une stratégie pour transformer un procédé de fabrication qui se rapproche davantage d’une forme d’art en procédé basé sur des données scientifiques. La présente thèse porte spécifiquement sur cette question et plus particulièrement sur une meilleure compréhension de la relation entre la formulation de la solution d’enrobage et le procédé d’enrobage pour la dissolution du PA. Dans le cadre de ces travaux, un plan d’expérience D-optimal couplé à la mise en œuvre de trois outils PAT en ligne a permis d’identifier les paramètres critiques du procédé et les attributs critiques du matériau (formulation de la solution d’enrobage) qui influencent la libération in-vitro du PA au pH buccal. Le niveau de l’enrobage, le niveau de plastifiant, le débit, la température du lit et le durcissement sont les paramètres critiques identifiés pour une formation complète du film. La criticité de la morphologie de l’enrobage sur la dissolution dans la salive simulée est également démontrée. La performance en ligne de la spectroscopie Raman, de la spectroscopie proche infrarouge et de la mesure de la réflectance du faisceau focalisé, ainsi que les données du procédé et les attributs des matières premières sont évalués et comparés pour faire le suivi du procédé d’enrobage des microsphères. En recourant à une analyse multiblock partial least squares, il est démontré que la spectroscopie Raman a une performance supérieure pour assurer le suivi du procédé et obtenir ainsi un enrobage constant pour la membrane barrière à couche mince, essentielle à l'observance du patient.Abstract: Despite recent incentives provided by regulatory agencies there is still a gap in the implementation of age-appropriate formulations for the pediatric population. The differences within this population, coupled with the non-compliance due to poor taste, present great challenges for oral drug formulation. Flexible solid oral formulations, such as microspheres, have been proposed as alternatives to existing marketed formulations such as tablets or liquid oral dosage forms. Microspheres are matrix systems where the Active Pharmaceutical Ingredient (API) is dispersed. The API is thus subdivided into a plurality of small dosage units. Additionally, microspheres can be coated as a strategy to achieve taste masking. It consists in applying a protective barrier to the microsphere that will prevent the release of drug in the oral cavity, while maintaining an immediate release once the drug product reaches the absorption site, thereby achieving a taste neutral profile without adversely affect the bioavailabity of the API. To coat small particles Wurster fluid bed coaters have been used for many years in the pharmaceutical industry, as they produce uniformly coated particles. There is a recognized need to better understand conventional processes used within the pharmaceutical industry. The regulatory agencies have encouraged the employment of quality by design principles, together with new technologies, such as Process Analytical Technology (PAT) tools, with the aim of developing a strategy to transform, what is generally considered an art form, into sound science based processes. This thesis specifically concerns this issue by focusing on better understanding the relation between both coating formulation and coating process to dissolution of the API. In this work, a D-optimal design coupled with the implementation of three in-line PAT tools helped identify the critical process parameters and critical material attributes (coating formulation) influencing in-vitro API release at mouth pH. Coating level, plasticizer level, spray rate and product bed temperature and curing are the identified critical parameters for a complete film formation. The criticality of coating morphology on the dissolution in simulated saliva is also demonstrated. The in-line performance of Raman spectroscopy, near infrared spectroscopy and focused beam reflectance measurement, together with process data and raw material attribute is evaluated and compared to monitor the microsphere coating process. By resorting to multiblock partial least squares it is shown that Raman has superior performance to ensure consistent coating performance for thin film barrier membrane, essential to patient compliance

“It won’t work here”: Lessons for just nature-based stream restoration in the context of urban informality

Nature-Based Solutions (NBS) have been advocated for their potential to contribute to the making of sustainable and just cities. However, a growing body of research shows that NBS cannot inherently provide just outcomes and might instead (re)produce environmental injustices. This research explores NBS for stream/river restoration in ‘informal’ areas, showing how riparian margins have become spaces of conflict. It draws lessons from two linear parks integrated into neighbourhood regeneration strategies in São Paulo. Data were collected from household surveys and focus group discussions to examine local populations’ values towards stream restoration. They provide understandings of residents’ perceptions towards multiple health and safety risks and concerns over contested responsibilities, notably revealing that local preferences for stream burial have been shaped by persisting waste dumping issues. An environmental justice lens helps highlight the limited integration of plural social and cultural values into project plans. This further helps draw lessons on ways to address local conflicts and integrate multiple socio-environmental values into NBS planning, with support from policy tools that allow stronger community engagement. Findings also support the identification of justice pathways for NBS in informal settings. The analysis of material and interpretative human-environment relationships provides evidence of opportunities for NBS to be integrated into everyday uses of local space and pre-existing environmental caring practices. For this, communities need to have stronger influence over decisions affecting them. The research thereby demonstrates that NBS will only become a mechanism for ecological recovery with city-wide benefits if marginalised groups are better included in their planning

ALIMENTOS QUE SON FUENTES DE HIERRO Y VITAMINA C CONSUMIDOS ENTRE LACTENTES DE LA ATENCIÓN BÁSICA A LA SALUD

Objetivo: evaluar el consumo de alimentos que son fuentes de hierro y vitamina C entre niños de 0 a 24 meses. Métodos: estudiotransversal realizado con 357 niños durante campaña de vacunación en noviembre de 2014 en Montes Claros, MG. Se evaluó el consumo dealimentos ricos en hierro y vitamina C por medio de cuestionario de frecuencia alimentar. Se realizó análisis descriptivo simple. Resultados: severificó amamantamiento en 140 (93%) niños con menos de seis meses. En la alimentación complementar entre los alimentos ricos en hierro, elconsumo de carne cocida/molida fue frecuente en 80 (38,2%) y de vísceras fue bajo o inexistente en 147 (70,6%). Todos los niños consumían frijolde forma moderada o frecuente. El consumo a menudo de naranja fue apuntado en 74 (35,5%). Conclusión: el consumo de alimentos ricos en hierroy vitamina C de los niños en la Atención Básica a la Salud tiene baja frecuencia y presenta riesgo para anemia ferropriva.Objetivo: avaliar o consumo de alimentos fontes de ferro e vitamina C entre crianças de 0 a 24 meses. Métodos: trata-se de estudo transversal realizado com 357 crianças durante campanha de vacinação em novembro de 2014 em Montes Claros, MG. O consumo de alimentos fontes de ferro e vitamina C foi avaliado com questionário de frequência alimentar. Realizou-se análise descritiva simples. Resultados: a amamentação foi verificada em 140 (93%) crianças menores de seis meses. Na alimentação complementar entre os alimentos fontes de ferro, o consumo de carne cozida/moída foi frequente em 80 (38,2%) e de vísceras foi baixo ou ausente em 147 (70,6%). Todas as crianças consumiam feijão moderadamente ou frequentemente. O consumo frequente de laranja foi relatado em 74 (35,5%). Conclusão: o consumo de alimentos fontes de ferro e vitamina C das crianças na Atenção Primária à Saúde é de baixa frequência, apresentando risco para anemia ferropriva.Objective: to evaluate the consumption of food sources of iron and vitamin C among children from 0 to 24 months. Methods: Thiscross-sectional study was carried out with 357 children during the vaccination campaign in November 2014 in Montes Claros, Minas Gerais, Brazil.The consumption of food sources of iron and vitamin C was evaluated using a food frequency questionnaire. A simple descriptive analysis wasperformed. Results: Breastfeeding was verified in 140 (93%) children younger than 6 months. Regarding the supplementary feeding of iron sourcefoods, the consumption of cooked/ground meat was frequent in 80 (38.2%) children and the consumption of offal was low or absent in 147 (70.6%).All the children moderately or frequently consumed beans. Frequent consumption of oranges was reported in 74 (35.5%) children. Conclusion: Theconsumption of food sources of iron and vitamin C by children in Primary Healthcare presented a low-frequency, with a risk for iron deficiencyanemia

UMA REVISÃO DE LITERATURA SOBRE A ERRADICAÇÃO DA VARÍOLA

A varíola foi uma doença infecciosa causada pelo vírus da varíola. O último caso real da doença foi diagnosticado em outubro de 1977, o que levou a OMS ( Organização Mundial de Saúde) a certificar-se que houve realmente a erradicação da doença em 1980. O risco de morte logo após contrair a doença  era por volta de 30%, sendo muito superior em bebês. Entre os que conseguiam sobreviver as sequelas mais comuns desenvolvidas eram uma extensa cicatrização da pele acompanhada de cegueira

Maternal Toxoplasma gondii infection affects proliferation, differentiation and cell cycle regulation of retinal neural progenitor cells in mouse embryo

BackgroundToxoplasmosis affects one third of the world population and has the protozoan Toxoplasma gondii as etiological agent. Congenital toxoplasmosis (CT) can cause severe damage to the fetus, including miscarriages, intracranial calcification, hydrocephalus and retinochoroiditis. Severity of CT depends on the gestational period in which infection occurs, and alterations at the cellular level during retinal development have been reported. In this study, we proposed a mouse CT model to investigate the impact of infection on retinal development.MethodsPregnant females of pigmented C57BL/6 strain mice were infected intragastrically with two T. gondii cysts (ME49 strain) at embryonic day 10 (E10), and the offspring were analyzed at E18.ResultsInfected embryos had significantly smaller body sizes and weights than the PBS-treated controls, indicating that embryonic development was affected. In the retina, a significant increase in the number of Ki-67-positive cells (marker of proliferating cells) was found in the apical region of the NBL of infected mice compared to the control. Supporting this, cell cycle proteins Cyclin D3, Cdk6 and pChK2 were significantly altered in infected retinas. Interestingly, the immunohistochemical analysis showed a significant increase in the population of β-III-tubulin-positive cells, one of the earliest markers of neuronal differentiation.ConclusionsOur data suggests that CT affects cell cycle progression in retinal progenitor cells, possibly inducing the arrest of these cells at G2/M phase. Such alterations could influence the differentiation, anticipating/increasing neuronal maturation, and therefore leading to abnormal retinal formation. Our model mimics important events observed in ocular CT

Mutation of the surface layer protein SlpB has pleiotropic effects in the probiotic propionibacterium freudenreichii CIRM-BIA 129

Propionibacterium freudenreichii is a beneficial Gram-positive bacterium, traditionally used as a cheese-ripening starter, and currently considered as an emerging probiotic. As an example, the P. freudenreichii CIRM-BIA 129 strain recently revealed promising immunomodulatory properties. Its consumption accordingly exerts healing effects in different animal models of colitis, suggesting a potent role in the context of inflammatory bowel diseases. This anti-inflammatory effect depends on surface layer proteins (SLPs). SLPs may be involved in key functions in probiotics, such as persistence within the gut, adhesion to host cells and mucus, or immunomodulation. Several SLPs coexist in P. freudenreichii CIRM-BIA 129 and mediate immunomodulation and adhesion. A mutant P. freudenreichii CIRM-BIA 129ΔslpB (CB129ΔslpB) strain was shown to exhibit decreased adhesion to intestinal epithelial cells. In the present study, we thoroughly analyzed the impact of this mutation on cellular properties. Firstly, we investigated alterations of surface properties in CB129ΔslpB. Surface extractable proteins, surface charges (ζ-potential) and surface hydrophobicity were affected by the mutation. Whole-cell proteomics, using high definition mass spectrometry, identified 1,288 quantifiable proteins in the wild-type strain, i.e., 53% of the theoretical proteome predicted according to P. freudenreichii CIRM-BIA 129 genome sequence. In the mutant strain, we detected 1,252 proteins, including 1,227 proteins in common with the wild-type strain. Comparative quantitative analysis revealed 97 proteins with significant differences between wild-type and mutant strains. These proteins are involved in various cellular process like signaling, metabolism, and DNA repair and replication. Finally, in silico analysis predicted that slpB gene is not part of an operon, thus not affecting the downstream genes after gene knockout. This study, in accordance with the various roles attributed in the literature to SLPs, revealed a pleiotropic effect of a single slpB mutation, in the probiotic P. freudenreichii. This suggests that SlpB may be at a central node of cellular processes and confirms that both nature and amount of SLPs, which are highly variable within the P. freudenreichii species, determine the probiotic abilities of strains.Fil: do Carmo, Fillipe L. R.. Institut National de la Recherche Agronomique; Francia. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Marques Da Silva, Wanderson. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tavares, Guilherme C.. Universidade Federal de Minas Gerais; BrasilFil: Ibraim, Izabela C.. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Cordeiro, Barbara F.. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Oliveira, Emiliano R.. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Rabah, Houem. Institut National de la Recherche Agronomique; FranciaFil: Cauty, Chantal. Institut National de la Recherche Agronomique; FranciaFil: da Silva, Sara H.. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Canário Viana, Marcus V.. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Caetano, Ana C. B.. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: dos Santos, Roselane G.. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: de Oliveira Carvalho, Rodrigo D.. Instituto de Ciencias Da Saúde; BrasilFil: Jardin, Julien. Institut National de la Recherche Agronomique; FranciaFil: Pereira, Felipe L.. Universidade Federal de Minas Gerais; BrasilFil: Folador, Edson L.. Universidade Estadual da Paraiba; BrasilFil: Le Loir, Yves. Institut National de la Recherche Agronomique; FranciaFil: Figueiredo, Henrique C. P.. Universidade Federal de Minas Gerais; BrasilFil: Jan, Gwénaël. Institut National de la Recherche Agronomique; FranciaFil: Azevedo, Vasco. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; Brasi