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Evaluation de la migration des plastifiants à partir des dispositifs médicaux en polychlorure de vinyle et développement d'un moyen de prévention par procédé Sol-Gel.

Abstract : Plasticizers in medical devices (MD) made of flexible PVC, such as infusion sets of nutrition tubings, are able to migrate into infused solutions and so come in contact with the patient. DEHP (diethylhexylphtalate) was the main plasticizer used in these MD up until 2010. It has been shown to be reprotoxic has been classified as CMR1b chemical and is soon to be banned from tubings used in neonatalogy, and therefore MD’s manufacturers have replaced DEHP by alternative plasticizers named TOTM*, DINP*, DINCH*, DEHA*, DEHT* or ATBC*. However, it is impossible to ascertain that these new plasticizers are harmless because of the lack of migration studies conducted in clinical situations in which MD are used, particularly in « at risk situations » such as infusion, nutrition, ECMO (Extracorporeal Membrane Oxygenation), ECC (Extracoporeal Circulation) in cardiac surgery and haemodialysis. The aim of this thesis is to study this migration, in order to evaluate the risk of exposure to these plasticizers, during clinical practice. Our preliminary bibliographic review allowed us to identify the most appropriate analytical methods to quantify the plasticizers in the MD matrix (direct methods or indirect methods requiring an extraction step), techniques such as GC (Gas Chromatography) and LC (Liquid Chromatography) suitable for the analysis of plasticizers in solutions, drugs or simulants in contact with, and sensitive advanced techniques such as (LC/MS-MS) (Liquid chromatography coupled to tandem mass spectrometry) which are useful to detect and to quantify the plasticizers and their metabolites at trace levels in complex matrices like body fluids.The results of preliminary migration tests carried out in standardized conditions adapted from agrifood methodology show that the plasticizers have different migration abilities, which are 20 times and 3 times lower for TOTM and DEHT compared to DEHP. As regards DINCH, it does release as much as DEHP does after 24 hours of contact. These results formed the basis for the development of an in vitro migration model for infusion and nutrition situations, reflecting a worst case scenario. In this model, which has been validated by a pluridisciplinary task force, the clinical assumption is as follows: « A 60kg-patient is likely to get two litres of infused drugs via 10 dm2 of tubing in flexible PVC ». This model will be used to make the first tests in vitro. At the same time, an inorganic/organic hybrid coating deposited on the PVC surface by dip-coating provides a good protection against the release of the plasticizers, at a level of about 80% during 48 hours of contact, but is insufficient to protect PVC from drug sorption such as diazepam or isosobide dinitrate, which loss is reduced by only 53% and 45% respectively. It is an attractive innovation but has to be necessarily optimized to ensure a risk management concerning MD in flexible PVC.This thesis is part of tasks 1 and 2 of the ARMED research project (Assessment and Risk Management of Medical devices in PolyvinylChloride), directed by Pr Valérie Sautou, and which has received the financial support of the French Medicine Agency (ANSM, Agence Nationale de Sécurité du Médicament et des Produits de Santé) in the framework of call of research proposals in 2012.
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Lise Bernard. Evaluation de la migration des plastifiants à partir des dispositifs médicaux en polychlorure de vinyle et développement d'un moyen de prévention par procédé Sol-Gel.. Médecine humaine et pathologie. Université d'Auvergne - Clermont-Ferrand I, 2015. Français. ⟨NNT : 2015CLF1MM01⟩. ⟨tel-01657409⟩

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