Technology Servier

Orléans, France

Technology Servier

Orléans, France
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Moroy G.,University Paris Diderot | Martiny V.Y.,University Paris Diderot | Vayer P.,Technology Servier | Villoutreix B.O.,University Paris Diderot | Miteva M.A.,University Paris Diderot
Drug Discovery Today | Year: 2012

Quantitative structure-activity relationship (QSAR) methods and related approaches have been used to investigate the molecular features that influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. As the three-dimensional structures of several major ADMET proteins become available, structure-based (docking-scoring) computations can be carried out to complement or to go beyond QSAR studies. Applying docking-scoring methods to ADMET proteins is a challenging process because they usually have a large and flexible binding cavity; however, promising results relating to metabolizing enzymes have been reported. After reviewing current trends in the field we applied structure-based methods in the context of receptor flexibility in a case study involving the phase II metabolizing sulfotransferases. Overall, the explored concepts and results suggested that structure-based ADMET profiling will probably join the mainstream during the coming years. © 2011 Elsevier Ltd.


Gendre C.,University Paris - Sud | Gendre C.,French National Center for Scientific Research | Boiret M.,Technology SERVIER | Genty M.,Technology SERVIER | And 2 more authors.
International Journal of Pharmaceutics | Year: 2011

The aim of this work was to carry out real-time near infrared (NIR) predictions of drug release from sustained release coated tablets and to determine end point of coating operation. In-line measurements were ensured by implementation of a NIR probe inside a pan coater. Tablets were coated using a functional aqueous dispersion of ethylcellulose blended with PVA-PEG graft copolymer to obtain a controlled drug release dosage form over 16 h. Samples were collected at regular intervals and subjected to a standardized curing step. Percentages of released drug at 4 h, 8 h and 12 h were selected to describe the controlled drug release of cured tablets. These dissolution criteria were used as reference values to calibrate NIR spectral information and to develop three partial least squares regressions. Low predictive errors of 1.7%, 1.9% and 1.5%, respectively, were obtained. The coating operation was stopped while desired dissolution criteria were achieved, corresponding to a coating level around 10%. The present study demonstrated that real-time NIR measurements could be performed on non-finished drug products to predict dissolution properties of cured coated tablets. This novel and innovative approach fulfils the expectations of ICH Q8 guideline on pharmaceutical development, in terms of process understanding and process analytical technology (PAT) control strategy. This approach should be however adapted to curing operation to allow a real-time release testing. © 2011 Elsevier B.V. All rights reserved.


Shepard T.,Medicines and Healthcare Products Regulatory Agency MHRA | Scott G.,Takeda Development Center Europe | Cole S.,Medicines and Healthcare Products Regulatory Agency MHRA | Nordmark A.,Swedish Medical Products Agency MPA | Bouzom F.,Technology Servier
CPT: Pharmacometrics and Systems Pharmacology | Year: 2015

Under the remit of the Ministerial Industry Strategy Group (MISG), the Association of the British Pharmaceutical Industry (ABPI) and Medicines and Healthcare products Regulatory Agency (MHRA) hosted a meeting to explore physiologically based pharmacokinetic modeling and simulation, focusing on the clinical component of regulatory applications. The meeting took place on 30 June 2014 with international representatives from industry, academia, and regulatory agencies. Discussion topics were selected to be complementary to those discussed at an earlier US Food and Drug Administration (FDA) meeting. This report summarizes the meeting outcomes, focusing on the European regulatory perspective. © 2015 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.


Hamm G.,ImaBiotech | Bonnel D.,ImaBiotech | Legouffe R.,ImaBiotech | Pamelard F.,ImaBiotech | And 3 more authors.
Journal of Proteomics | Year: 2012

In order to quantify small molecules at the early stage of drug discovery, we developed a quantitation approach based on mass spectrometry imaging (MSI) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) without the use of a labeled compound. We describe a method intended to respond to the main challenges encountered in quantification through MALDI imaging dedicated to whole-body or single heterogeneous organ samples (brain, eye, liver). These include the high dependence of the detected signal on the matrix deposition, the MALDI ionization yield of specific target molecules, and lastly, the ion suppression effect on the tissue. To address these challenges, we based our approach on the use of a normalization factor called the TEC (Tissue Extinction Coefficient). This factor takes into account the ion suppression effect that is both tissue- and drug-specific. Through this protocol, the amount of drug per gram of tissue was determined, which in turn, was compared with other analytical techniques such as Liquid Chromatography-Mass spectrometry (LC-MS/MS).This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research. © 2012 Elsevier B.V.


Gravel E.,CEA Saclay Nuclear Research Center | Ogier J.,Technology Servier | Arnauld T.,Technology Servier | MacKiewicz N.,French Atomic Energy Commission | And 2 more authors.
Chemistry - A European Journal | Year: 2012

This concept article summarizes our recent findings regarding photopolymerized micelles obtained from the self-assembly of diacetylene-containing amphiphiles. Their synthesis and characterization are presented as well as some biomedical applications, such as tumor imaging and drug delivery. Finally, ongoing studies and future challenges are briefly discussed. Photopolymerized micelles obtained from the self-assembly of diacetylene-containing amphiphiles have been developed for biomedical applications in the fields of imaging and drug delivery (see figure). Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Boiret M.,Technology Servier | Meunier L.,Technology Servier | Ginot Y.-M.,Technology Servier
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

A near infrared (NIR) method was developed for determination of tablet potency of active pharmaceutical ingredient (API) in a complex coated tablet matrix. The calibration set contained samples from laboratory and production scale batches. The reference values were obtained by high performance liquid chromatography (HPLC) and partial least squares (PLS) regression was used to establish a model. The model was challenged by calculating tablet potency of two external test sets. Root mean square errors of prediction were respectively equal to 2.0% and 2.7%. To use this model with a second spectrometer from the production field, a calibration transfer method called piecewise direct standardisation (PDS) was used. After the transfer, the root mean square error of prediction of the first test set was 2.4% compared to 4.0% without transferring the spectra. A statistical technique using bootstrap of PLS residuals was used to estimate confidence intervals of tablet potency calculations. This method requires an optimised PLS model, selection of the bootstrap number and determination of the risk. In the case of a chemical analysis, the tablet potency value will be included within the confidence interval calculated by the bootstrap method. An easy to use graphical interface was developed to easily determine if the predictions, surrounded by minimum and maximum values, are within the specifications defined by the regulatory organisation. © 2010 Elsevier B.V.


Bouzom F.,Technology Servier | Ball K.,Technology Servier | Perdaems N.,Technology Servier | Walther B.,Technology Servier
Biopharmaceutics and Drug Disposition | Year: 2012

In 2005, a survey compared a number of commercial PBPK software available at the time, mainly focusing on 'ready to use' modelling tools. Since then, these tools and software have been further developed and improved to allow modellers to perform WB-PBPK modelling including ADME processes at a high level of sophistication. This review presents a comparison of the features, values and limitations of both the 'ready to use' software and of the traditional user customizable software that are frequently used for the building and use of PBPK models, as well as the challenges associated with the various modelling approaches regarding their current and future use. PBPK models continue to be used more and more frequently during the drug development process since they represent a quantitative, physiologically realistic platform with which to simulate and predict the impact of various potential scenarios on the pharmacokinetics and pharmacodynamics of drugs. The 'ready to use' PBPK software has been a major factor in the increasing use of PBPK modelling in the pharmaceutical industry, opening up the PBPK approach to a broader range of users. The challenge is now to educate and to train scientists and modellers to ensure their appropriate understanding of the assumptions and the limitations linked both to the physiological framework of the 'virtual body' and to the scaling methodology from in vitro to in vivo (IVIVE). Copyright © 2012 John Wiley & Sons, Ltd.


Boiret M.,Technology Servier | Rutledge D.N.,Agro ParisTech | Gorretta N.,IRSTEA | Ginot Y.-M.,Technology Servier | Roger J.-M.,IRSTEA
Journal of Pharmaceutical and Biomedical Analysis | Year: 2014

Independent component analysis (ICA) was used as a blind source separation method on a Raman image of a pharmaceutical tablet. Calculations were performed without a priori knowledge concerning the formulation. The aim was to extract the pure signals from the initial data set in order to examine the distribution of actives and major excipients within the tablet. As a method based on the decomposition of a matrix of mixtures of several components, the number of independent component to choose is a critical step of the analysis. The ICA_by_blocks method, based on the calculation of several models using an increasing number of independent components on initial matrix blocks, was used. The calculated ICA signals were compared with the pure spectra of the formulation compounds. High correlations between the two active principal ingredient spectra and their corresponding calculated signals were observed giving a good overview of the distributions of these compounds within the tablet. Information from the major excipients (lactose and avicel) was found in several independent components but the ICA approach provides high level of information concerning their distribution within the tablet. However, the results could vary considerably by changing the number of independent components or the preprocessing method. Indeed, it was shown that under-decomposition of the matrix could lead to better signal quality (compared to the pure spectra) but in that case the contributions due to minor components or effects were not correctly identified and extracted. On the contrary, over-decomposition of the original dataset could provide information about low concentration compounds at the expense of some loss of signal interpretability for the other compounds. © 2013 Elsevier B.V.


Croixmarie V.,Technology Servier
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Mechanisms involved in induction processes have been investigated using fresh human hepatocytes in culture as a cellular model and using mass spectrometry-based metabonomics as a global investigation tool. Sample preparation to data analysis have been detailed in an approach enabling to separate drug-induced (endogenous metabolites) and drug-related (drug metabolites) biomarkers for reference inducers. Rifampicin, a nuclear pregnane X receptor (PXR) ligand; CITCO, a nuclear constitutive androstane receptor (CAR) ligand; and phenobarbital, which activates both CAR and PXR, have been used. Specific intra-cellular metabolites have been isolated for rifampicin and CITCO as potential endogenous biomarkers of their respective induction mechanism. A mixture of these two types of biomarkers modified in the same way after treatment with either rifampicin or CITCO on the one hand and with phenobarbital on the other hand has been found.


Boiret M.,Technology Servier | Chauchard F.,Indatech
Analytical and Bioanalytical Chemistry | Year: 2016

Near-infrared (NIR) spectroscopy is a non-destructive analytical technique that enables better-understanding and optimization of pharmaceutical processes and final drug products. The use in line is often limited by acquisition speed and sampling area. This work focuses on performing a multipoint measurement at high acquisition speed at the end of the manufacturing process on a conveyor belt system to control both the distribution and the content of active pharmaceutical ingredient within final drug products, i.e., tablets. A specially designed probe with several collection fibers was developed for this study. By measuring spectral and spatial information, it provides physical and chemical knowledge on the final drug product. The NIR probe was installed on a conveyor belt system that enables the analysis of a lot of tablets. The use of these NIR multipoint measurement probes on a conveyor belt system provided an innovative method that has the potential to be used as a new paradigm to ensure the drug product quality at the end of the manufacturing process and as a new analytical method for the real-time release control strategy. [Figure not available: see fulltext.] © 2016 Springer-Verlag Berlin Heidelberg

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