Concepts and Models for Drug Permeability Studies

Cell and Tissue based In Vitro Culture Models
 
 
Woodhead Publishing
  • 1. Auflage
  • |
  • erschienen am 30. September 2015
  • |
  • 408 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
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978-0-08-100114-1 (ISBN)
 

This book intends to be an updated compilation of the most important buccal, gastric, intestinal, pulmonary, nasal, vaginal, ocular, skin and blood-brain barrier in vitro models for predicting the permeability of drugs. Concepts and Models for Drug Permeability Studies focuses on different approaches and comprises of various models. Each model describes the protocol of seeding and conservation, the application for specific drugs, and takes into account the maintenance of physiologic characteristics and functionality of epithelium, from the simplest immortalized cell-based monoculture to the most complex engineered-tissue models. Chapters also discuss the equivalence between in vitro cell and tissue models and in vivo conditions, highlighting how each model may provisionally resemble a different drug absorption route.


  • Updated information regarding the most recent in vitro models to study the permeability of drugs
  • Short and concise chapters covering all the biological barriers with interest in drug permeability
  • A combination of bibliographic information related with individual models and footnote instructions of technical procedures for construction of cell and tissue-based models
  • Simple and clear scientific content, adaptable for young scientists and experimented researchers


Bruno Sarmento is an Affiliated Investigator at the INEB-Instituto de Engenharia Biomédica, based at the University of Porto, Portugal and is Assistant Professor of Pharmaceutical Technology in the Department of Pharmaceutical Sciences, at ISCS-N, Gandra, Portugal. His current research is focused on the study of nanomedicines and their application in the pharmaceutical and biomedical fields, as well as the use of in vitro cell models as a tool to correlate the transport of biopharmaceuticals and nanoparticles across human mucosa. Bruno has been involved with more than two hundred publications, including three edited books in the field of Pharmaceutical Technology and Nanomedicine, more than one hundred papers in international peer-review journals and several conference proceedings. He also serves as an editorial board member for several international journals and an evaluator of research projects form international agencies. He is an active member of several international associations (AAPS, CRS, EUFEPS, EFSD, FIP) and works on biotechnology and health post-graduate programs at national and international level.
  • Englisch
Elsevier Science
  • 13,28 MB
978-0-08-100114-1 (9780081001141)
0081001142 (0081001142)
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  • Front Cover
  • Related titles
  • Concepts and Models for Drug Permeability Studies
  • Copyright
  • Contents
  • List of contributors
  • List of figures
  • List of tables
  • 1 - Introduction
  • 1.1 Introduction
  • References
  • 2 - Importance and applications of cell- and tissue-based in vitro models for drug permeability screening in early stages o ...
  • 2.1 Introduction
  • 2.2 General considerations
  • 2.3 Drug transport
  • 2.3.1 Transport mechanisms
  • 2.4 Permeability-absorption models
  • 2.4.1 Physicochemical methods
  • 2.4.1.1 Physicochemical factors
  • 2.4.1.2 Immobilized artificial membrane chromatography
  • 2.4.1.3 Parallel artificial membrane permeability assay
  • 2.4.2 In vitro cell and tissue methods
  • 2.4.2.1 Cell-based methods
  • 2.4.2.2 Tissue-based methods
  • Diffusion chambers
  • Franz cells
  • Everted sacs
  • Isolated membrane vesicles
  • 2.5 Methods for permeability calculation
  • 2.6 Standardization of protocols for in vitro methods
  • 2.7 The "three Rs" principle
  • 2.8 Biosecurity systems
  • References
  • 3.1 - Cell-based in vitro models for buccal permeability studies
  • 3.1.1 Introduction
  • 3.1.2 Physiology of the buccal mucosa
  • 3.1.3 Different in vitro models
  • 3.1.3.1 Hamster cheek pouch cells
  • 3.1.3.2 TR146 cell line
  • 3.1.3.2.1 Protocol
  • Cell culture conditions
  • Permeability studies
  • 3.1.3.3 Human oral keratinocytes
  • 3.1.3.3.1 Protocol
  • Oral keratinocyte culture conditions
  • Culturing on dead de-epidermized dermis (DDED)
  • Permeability studies
  • 3.1.3.4 MatTek EpiOralT
  • 3.1.3.4.1 Protocol
  • Cell culture conditions
  • Permeability studies
  • 3.1.4 Conclusions
  • References
  • 3.2 - Cell-based in vitro models for gastric permeability studies
  • 3.2.1 The stomach as a natural barrier to absorption
  • 3.2.2 Gastric drug delivery
  • 3.2.2.1 Molecular absorption in the stomach
  • 3.2.2.2 Physicochemical factors mediating stomach absorptive permeability
  • 3.2.3 Cellularized models of gastric permeability
  • 3.2.3.1 Protocol for establishing cellularized artificial models of the gastric wall
  • 3.2.4 Conclusions
  • Acknowledgments
  • References
  • 3.3 - Cell-based in vitro models for intestinal permeability studies
  • 3.3.1 Anatomy and physiology of human small intestine
  • 3.3.1.1 Stromal-epithelial cross-talk
  • 3.3.2 Mechanisms of transport
  • 3.3.3 Intestinal barriers
  • 3.3.4 Intestinal in vitro models
  • 3.3.4.1 Caco-2 model
  • 3.3.4.1.1 Accelerated Caco-2 models
  • 3.3.4.1.2 Alternatives to the Caco-2 model
  • 3.3.4.2 Caco-2/HT29-MTX model
  • 3.3.4.3 Caco-2/Raji B model
  • 3.3.4.4 Caco-2/HT29-MTX/Raji B
  • 3.3.4.5 Novel 3D in vitro models
  • 3.3.5 Validation studies
  • 3.3.6 Conclusions
  • References
  • 3.4 - Cell-based in vitro models for nasal permeability studies
  • 3.4.1 Introduction
  • 3.4.2 Nasal primary cell culture models
  • 3.4.2.1 Sampling approaches and procedures
  • 3.4.2.2 HNE cell preparation and culture initiation
  • 3.4.3 Immortalized nasal cell lines
  • 3.4.3.1 RMPI 2650 cell line
  • 3.4.3.2 BT cell line
  • 3.4.3.3 Human lung carcinoma cell line
  • 3.4.3.4 Human normal bronchial epithelium of male heart-lung transplant patient 16HBE14o- cell line
  • 3.4.4 Nasal permeability studies
  • 3.4.4.1 Culture conditions
  • 3.4.4.2 Cell-based permeation studies
  • 3.4.5 Conclusions
  • References
  • 3.5 - Cell-based in vitro models for pulmonary permeability studies
  • 3.5.1 Introduction
  • 3.5.2 Mechanisms involved in pulmonary absorption of drugs
  • 3.5.3 Cell-based models of immortalized cells
  • 3.5.3.1 Bronchial cell lines
  • 3.5.3.2 Alveolar cell lines
  • 3.5.4 Primary cell cultures
  • 3.5.5 Conclusions
  • References
  • 3.6 - Cell-based in vitro models for vaginal permeability studies
  • 3.6.1 Introduction
  • 3.6.2 Anatomy of the female genital tract and mucosa
  • 3.6.3 Human primary cells
  • 3.6.3.1 Isolation and cultivation of human ectocervical epithelia cells
  • 3.6.3.2 Seeding of hECE on filter inserts
  • 3.6.3.3 Transepithelial electrical resistance
  • 3.6.3.4 Permeability assessment using hECE
  • 3.6.3.5 Limitations of primary cell cultures
  • 3.6.4 Immortalized human cells forming monolayers (bi-/tri-layers)
  • 3.6.4.1 Cultivation, maintenance, and permeability setup using CaSki cells
  • 3.6.4.2 Cultivation, maintenance, and permeability setup using HEC-1A cells
  • 3.6.4.3 Cultivation, maintenance, and permeability setup using C-33A cells
  • 3.6.4.4 Dual-chamber model as a screening tool
  • 3.6.5 Commercially available three-dimensional culture of nontransformed human vaginal-ectocervical epithelial cells
  • 3.6.5.1 Need for in vitro human tissue models
  • 3.6.5.2 EpiVaginalT cell-based tissue model
  • 3.6.5.3 Available EpiVaginalT tissue types
  • 3.6.5.4 Maintenance and use
  • 3.6.6 Concluding remarks
  • References
  • 3.7 - Cell-based in vitro models for ocular permeability studies
  • 3.7.1 Introduction
  • 3.7.2 Ocular anatomy
  • 3.7.3 Ocular pharmacokinetics in the anterior segment
  • 3.7.3.1 Rapid removal from the eye surface
  • 3.7.3.2 Low permeability in ocular structures
  • 3.7.4 Ocular pharmacokinetics in the posterior segment
  • 3.7.5 In vitro eye cellular models for drug permeability
  • 3.7.5.1 Corneal epithelium models
  • 3.7.5.2 Conjunctiva epithelium models
  • 3.7.5.3 Blood-ocular barrier models
  • 3.7.5.3.1 Blood-aqueous humor models
  • 3.7.5.3.2 Blood-retina models
  • 3.7.5.3.3 Retinal pigment epithelium
  • 3.7.5.3.4 Retinal capillary endothelium
  • 3.7.6 Conclusions
  • References
  • 3.8 - Cell-based in vitro models for dermal permeability studies
  • 3.8.1 Introduction
  • 3.8.2 Human skin and dermal permeability
  • 3.8.3 Drug permeability in in vitro models
  • 3.8.3.1 Two-dimensional models
  • 3.8.3.2 Three-dimensional models
  • 3.8.4 Reconstructed dermal equivalents
  • 3.8.4.1 EpiSkinT
  • 3.8.4.2 EpiDermT
  • 3.8.4.3 SkinEthicT
  • 3.8.5 Reconstructed full-thickness models
  • 3.8.5.1 StrataTestT
  • 3.8.5.2 EpiDerm FT
  • 3.8.5.3 EpiCS®
  • 3.8.6 Conclusions and future perspectives
  • References
  • 3.9 - Cell-based in vitro models for studying blood-brain barrier (BBB) permeability
  • 3.9.1 Blood-brain barrier: structure, importance, and difficulties to overcome
  • 3.9.2 BBB in vitro models
  • 3.9.2.1 Cell types
  • 3.9.2.2 Cell culture
  • 3.9.2.2.1 Monoculture models
  • 3.9.2.2.2 Co-culture models
  • Co-culture of ECs with glial cells/astrocytes
  • Co-culture of ECs with pericytes
  • Co-culture of ECs with other cells
  • 3.9.2.2.3 Triple co-culture
  • 3.9.2.3 BBB apparatus
  • 3.9.2.3.1 Static BBB models
  • 3.9.2.3.2 DIV models
  • 3.9.2.3.3 Microfluidic models
  • 3.9.3 Permeability of drugs: how to screen and study
  • 3.9.4 Comparison of BBB models
  • 3.9.4.1 Perfect BBB in vitro model
  • 3.9.4.2 Qualitative comparison of BBB models
  • Acknowledgments
  • References
  • 4.1 - Tissue-based in vitro and ex vivo models for buccal permeability studies
  • 4.1.1 Introduction
  • 4.1.2 Porcine buccal mucosa
  • 4.1.2.1 Harvest and preparation of porcine buccal mucosa
  • 4.1.2.2 Transport of porcine buccal mucosa
  • 4.1.2.3 Preservation of porcine buccal mucosa
  • 4.1.3 Diffusion cells
  • 4.1.4 Permeation assay using porcine buccal mucosa
  • 4.1.5 Tissue integrity and viability assessment
  • 4.1.6 Porcine esophageal mucosa
  • 4.1.7 Conclusions and future prospects
  • References
  • 4.2 - Tissue-based in vitro and ex vivo models for intestinal permeability studies
  • 4.2.1 Introduction
  • 4.2.1.1 Anatomy, histology, and physiology of the intestine
  • 4.2.1.2 Transport mechanisms across the intestinal mucosa
  • 4.2.1.3 Factors governing intestinal permeability
  • 4.2.2 Current tissue-based methodologies for intestinal permeability studies
  • 4.2.2.1 Diffusion chambers
  • 4.2.2.1.1 Ussing chamber
  • Practical aspects
  • Tissue preparation
  • Incubation buffer
  • Viability markers
  • Tissue viability
  • 4.2.2.2 Franz cell
  • 4.2.2.3 Everted intestinal sac
  • 4.2.2.3.1 Practical aspects
  • 4.2.2.4 Everted intestinal ring
  • 4.2.2.4.1 Practical aspects
  • 4.2.3 Animal versus human intestinal tissue
  • 4.2.4 In vivo versus in vitro correlations
  • 4.2.5 New trends in permeability studies using tissue-based models
  • 4.2.6 Conclusions
  • References
  • 4.3 - Tissue-based in vitro and ex vivo models for nasal permeability studies
  • 4.3.1 Brief description of the structure of the nose
  • 4.3.2 Nasal administration of drugs
  • 4.3.3 Limitations of in vivo models
  • 4.3.4 In vitro models of nasal permeability
  • 4.3.5 Ex vivo models of nasal permeability
  • 4.3.6 Conclusions
  • References
  • 4.4 - Tissue-based in vitro and ex vivo models for pulmonary permeability studies
  • 4.4.1 Introduction
  • 4.4.2 Lung physiology and tissue biology
  • 4.4.2.1 Nasal cavity
  • 4.4.2.2 Tracheobronchial tree
  • 4.4.2.3 Alveolar tissue and air-blood barrier
  • 4.4.3 Isolated perfused lung
  • 4.4.3.1 Lung surgical isolation and preservation
  • 4.4.3.2 IPL as model to study absorption of compounds
  • 4.4.3.3 Lung tissue preparation
  • 4.4.4 Conclusions
  • References
  • 4.5 - Tissue-based in vitro and ex vivo models for vaginal permeability studies
  • 4.5.1 Introduction
  • 4.5.2 Vaginal permeability and absorption
  • 4.5.3 In vitro 3D organotypic models
  • 4.5.3.1 Gorodeski model
  • 4.5.3.2 EpiVaginalT model
  • 4.5.3.3 Other potential models
  • 4.5.4 Ex vivo mucosal models
  • 4.5.4.1 General considerations for mucosal tissue handling and experimental setup
  • 4.5.4.2 Nonhuman mucosal models
  • 4.5.4.2.1 Rabbit
  • 4.5.4.2.2 Guinea pig
  • 4.5.4.2.3 Sheep
  • 4.5.4.2.4 Pig
  • 4.5.4.2.5 Cow
  • 4.5.4.2.6 Nonhuman primates
  • 4.5.4.3 Human mucosal model
  • 4.5.5 Conclusions
  • Acknowledgments
  • References
  • 4.6 - Tissue-based in vitro and ex vivo models for ocular permeability studies
  • 4.6.1 Introduction
  • 4.6.2 Requirements for a valid corneal cell culture model for in vitro drug absorption studies
  • 4.6.3 Methods to obtain corneal cells
  • 4.6.4 Methods to verify cultivated cell layers in the construct
  • 4.6.5 3D reconstructed cornea models
  • 4.6.5.1 Cornea constructs based on animal cells
  • 4.6.5.2 Cornea constructs based on human cells
  • 4.6.6 Discussions
  • 4.6.7 Conclusions
  • References
  • 4.7 - Tissue-based in vitro and ex vivo models for dermal permeability studies
  • 4.7.1 Introduction
  • 4.7.2 Structure and function of the skin
  • 4.7.3 Mechanisms of skin absorption
  • 4.7.4 Mathematical principles of skin absorption
  • 4.7.5 Conducting in vitro dermal absorption tests
  • 4.7.5.1 Guidelines
  • 4.7.5.2 Diffusion cells
  • 4.7.5.3 Skin preparations
  • 4.7.5.3.1 Animal skin
  • 4.7.5.3.2 Human skin
  • 4.7.5.3.3 Preparation of skin membranes
  • 4.7.5.3.4 Skin preparation integrity
  • 4.7.5.4 Interpretation of results
  • References
  • 4.8 - Tissue-based in vitro and ex vivo models for blood-brain barrier permeability studies
  • 4.8.1 Introduction
  • 4.8.2 Structure and function of BBB
  • 4.8.3 Cerebral microvessels and their characteristics
  • 4.8.4 Methods for cell isolation and immortalization
  • 4.8.5 Cell-based in vitro BBB models and their properties necessary for drug permeability estimation
  • 4.8.6 Immortalized endothelial cell lines
  • 4.8.7 Static and dynamic models of BBB compared
  • 4.8.8 Measurements of drug permeability
  • 4.8.9 Conclusions and future developments
  • References
  • 5 - Correlation between cell- and tissue-based in vitro models for drug permeability screening with in vivo situation: mode ...
  • 5.1 Introduction
  • 5.2 Empirical correlations
  • 5.2.1 Orally administered drugs
  • 5.2.2 Pulmonary administration
  • 5.2.3 Blood-brain barrier
  • 5.2.4 Topical application
  • 5.3 Physiologically based pharmacokinetic models
  • 5.3.1 Oral absorption
  • 5.3.2 Pulmonary absorption
  • 5.3.3 Blood-brain barrier
  • 5.3.4 Dermal absorption
  • 5.4 Conclusions
  • References
  • Index
  • A
  • B
  • C
  • D
  • E
  • F
  • G
  • H
  • I
  • K
  • L
  • M
  • N
  • O
  • P
  • R
  • S
  • T
  • U
  • V
  • Z
  • Back Cover

List of contributors


João Albuquerque,     University of Porto, Porto, Portugal

Isabel Almeida,     University of Porto, Porto, Portugal

Fernanda Andrade

Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain

Francisca Araújo

Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal

Marival Bermejo Sanz,     Universidad Miguel Hernández, San Juan de Alicante, Alicante, España

Malgorzata Burek,     Department of Anaesthesia and Critical Care, University of Wurzburg, Wurzburg, Germany

Miguel Ángel Cabrera Pérez

Universidad Central Marta Abreu de Las Villas, Santa Clara, Villa Clara, Cuba

Universidad Miguel Hernández, San Juan de Alicante, Alicante, España

Pedro Castro,     CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa/Porto, Porto, Portugal

Luise Chaves,     UCIBIO/REQUIMTE-Laboratory of Applied Chemistry, University of Porto, Porto, Portugal

João Coentro

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

Faculdade de Engenharia da Universidade do Porto (FEUP), Porto, Portugal

Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

Ana Costa

Instituto de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal

CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra PRD, Portugal

Joana Costa

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

FEUP-Faculdade de Engenharia da Universidade do Porto, Porto, Portugal

Paulo Costa,     University of Porto, Porto, Portugal

Sara Baptista da Silva

Faculty of Pharmacy, University of Porto, Porto, Portugal

CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa/Porto, Porto, Portugal

José das Neves

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Tiago dos Santos,     INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

Domingos Ferreira,     Faculty of Pharmacy, University of Porto, Porto, Portugal

Carola Y. Förster,     Department of Anaesthesia and Critical Care, University of Wurzburg, Wurzburg, Germany

Isabel González Álvarez,     Universidad Miguel Hernández, San Juan de Alicante, Alicante, España

Marta González-Álvarez,     Universidad Miguel Hernández, San Juan de Alicante, Alicante, España

Luís Gouveia,     iMed.UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Pedro L. Granja

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

Faculdade de Engenharia da Universidade do Porto (FEUP), Porto, Portugal

Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

Jouni Hirvonen,     Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

Maria João Gomes

INEB-Instituto de Engenharia Biomédica, Universisdade do Porto, Porto, Portugal

ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal

Instituto de Investigação e Inovação em Saude, Universidade do Porto, Porto, Portugal

Christian Kölln,     Institut für Pharmazeutische Technologie, Technische Universität Braunschweig, Braunschweig, Germany

Bianca N. Lourenço

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

Faculdade de Engenharia da Universidade do Porto (FEUP), Porto, Portugal

Alexandra Machado

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Raquel Madureira,     CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa/Porto, Porto, Portugal

Victor Mangas Sanjuan,     Universidad Miguel Hernández, San Juan de Alicante, Alicante, España

Sara Marques,     CIBIO/InBIO-UP-Centro de Investigação em Biodiversidade e Recursos Genéticos, University of Porto, Campus Agrário, Vairão, Portugal

Susana Martins,     University of Southern Denmark, Odense, Denmark

Bárbara Mendes

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

Instituto de Investigação e Inovação em Saude, Universidade do Porto, Porto, Portugal

José Augusto Guimarães Morais,     iMed.UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Rute Nunes,     INEB-Instituto de Engenharia Biomédica, University of Porto, Porto, Portugal

Maria Beatriz P.P. Oliveira,     Requimte, Faculty of Pharmacy, University of Porto, Porto, Portugal

Paulo Paixão,     iMed.UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Carla Pereira

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

FEUP-Faculdade de Engenharia da Universidade do Porto, Porto, Portugal

Manuela Pintado,     CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa/Porto, Porto, Portugal

Stephan Reichl,     Institut für Pharmazeutische Technologie, Technische Universität Braunschweig, Braunschweig, Germany

Francisca Rodrigues

Requimte, Faculty of Pharmacy, University of Porto, Porto, Portugal

Fourmag Lda, Parque Industrial do Cruzeiro, Moreira de Cónegos, Portugal

Ellaine Salvador,     Department of Anaesthesia and Critical Care, University of Wurzburg, Wurzburg, Germany

Hélder A. Santos,     Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

Bruno Sarmento

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Superior de Ciências da Saúde-Norte, Departamento de Ciências Farmacêuticas, Gandra-PRD, Portugal

Neha Shrestha,     Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

Cátia Silva,     CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra PRD, Portugal

Nuno Silva,     iMed.UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Natasa Skalko-Basnet,     University of Tromsø The Arctic University of Norway, Tromsø, Norway

Alejandro Sosnik,     Technion-Israel Institute of Technology, Technion City, Haifa, Israel

Flávia Sousa,     CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Superior de Ciências da Saúde-Norte, Gandra PRD, Portugal

Ingunn Tho,     University of Oslo, Oslo, Norway

Ana Vanessa Nascimento

University of Porto, Porto, Portugal

IINFACTS, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, CESPU, Cooperativa...

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