Table Of ContentUNIVERSIDADE DE LISBOA
FACULDADE DE FARMÁCIA
DEPARTAMENTO DE FARMÁCIA GALÉNICA E TECNOLOGIA
FARMACÊUTICA
New polyurethane nail lacquers for the delivery of
antifungal drugs
Bárbara Susana Gregorí Valdés
Orientadores: Prof. Doutora Helena Margarida de Oliveira Marques Ribeiro
Prof. Doutor João Moura Bordado
Tese especialmente elaborada para a obtenção do grau de Doutor em Farmácia,
especialidade de Tecnologia Farmacêutica.
2017
UNIVERSIDADE DE LISBOA
FACULDADE DE FARMÁCIA
DEPARTAMENTO DE FARMÁCIA GALÉNICA E TECNOLOGIA
FARMACÊUTICA
New polyurethane nail lacquers for the delivery of antifungal drugs
Bárbara Susana Gregorí Valdés
Orientadores: Prof. Doutora Helena Margarida de Oliveira Marques Ribeiro
Prof. Doutor João Moura Bordado
Tese especialmente elaborada para a obtenção do grau de Doutor em Farmácia, especialidade
de Tecnologia Farmacêutica.
Júri:
Presidente:
Doutora Matilde da Luz dos Santos Duque da Fonseca e Castro, Professora
Catedrática e Diretora da Faculdade de Farmácia da Universidade de Lisboa.
Vogais:
- Doutor Francisco Javier Otero Espinar, Titular de Universidad Facultad de
Farmacia da Universidade Santiago de Compostela, Espanha;
- Doutora Maria Eugénia Soares Rodrigues Tavares de Pina, Professora
Associada com Agregação Faculdade de Farmácia da Universidade de
Coimbra;
- Doutora Ana Paula Rocha Duarte, Professora Auxiliar Convidada
Universidade Atlântica;
- Doutor Rui Miguel Galhano dos Santos Lopes, Bolseiro de Pós-Doutoramento
Instituto Superior Técnico da Universidade de Lisboa;
- Doutora Helena Margarida de Oliveira Marques Ribeiro, Professora Associada
Faculdade de Farmácia da Universidade de Lisboa, Orientadora;
- Doutora Joana Marques Marto, Professora Auxiliar Convidada Faculdade de
Farmácia da Universidade de Lisboa.
Fundação para a Ciência e a Tecnologia. Grant (SFRH/BD/78962/2011)
2017
To my daughter
v
vi
“Competition breeds excellence
and whoever says otherwise,
is still hurting from a loss in the past.
Victory is around the corner if you keep competing.”
— Patrick Bet-David
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viii
Table of Contents
Acknowledgements .................................................................................................................. xvi
Abstract ................................................................................................................................. xviii
Resumo ...................................................................................................................................... xx
List of figures ........................................................................................................................... xxv
List of Tables .......................................................................................................................... xxix
Abbreviations & Symbols ...................................................................................................... xxxii
Chapter 1: General Introduction ............................................................................................... 1
1.Onychomycosis ........................................................................................................................ 5
1.1 Epidemiology ................................................................................................................... 5
1.2 Risk factors ....................................................................................................................... 6
1.3 Clinical classification ....................................................................................................... 7
2.Transungual delivery ............................................................................................................... 9
2.1 Nail structure and transungual permeation ....................................................................... 9
2.2 Mathematical description of nail permeability ............................................................... 12
3.Onychomycosis topical therapy ............................................................................................ 13
3.1 Drug delivery enhancers ................................................................................................. 14
3.2 Examples of antifungal drugs ......................................................................................... 20
3.3 Examples of topical pharmaceutical forms .................................................................... 25
4. Nail Lacquer in onychomycosis therapy .............................................................................. 32
5. Polyurethane a potential excipient in therapeutic nail lacquer ........................................... 42
5.1 Synthesis of Polyurethane .............................................................................................. 42
5.2 Monomers for the synthesis of polyurethanes ................................................................ 43
5.3 Methods for synthesis of polyurethanes ......................................................................... 47
ix
5.4 Synthesis of polyurethanes from carbohydrates ............................................................. 48
5.5 Application of polyurethane in Biomedical Industry ..................................................... 49
5.6 Application of polyurethane in drug delivery system. ................................................... 50
6. References ............................................................................................................................ 53
Chapter 2: Synthesis and characterization of polyurethanes employing carbohydrates ......... 69
1.Introduction ........................................................................................................................... 71
2. Materials and methods ......................................................................................................... 72
2.1 Materials ......................................................................................................................... 72
2.2 Methods .......................................................................................................................... 72
2.2.1 Synthesis of the polyurethane quasi-prepolymers ....................................................... 72
2.2.2 Synthesis of polyurethanes .......................................................................................... 73
2.3 Characterization of polyurethane quasi-prepolymers .................................................... 74
2.3.1 Determination of viscosity .......................................................................................... 74
2.3.2 Free isocyanate content ............................................................................................... 74
2.3.3 FTIR ............................................................................................................................ 74
2.4 Polyurethane characterization ........................................................................................ 74
2.4.1 Solubility studies for polyurethanes ............................................................................ 74
2.4.2 FTIR ............................................................................................................................ 74
2.4.3 NMR ........................................................................................................................... 74
2.4.4 Thermoanalytical measurements ................................................................................. 75
2.4.5 Cytotoxicity assay ....................................................................................................... 75
2.4.5.1 Preparation of sample ............................................................................................... 75
2.4.5.2 Direct contact assay .................................................................................................. 75
3. Results and discussion .......................................................................................................... 76
3.1 Syntheses of polyurethane quasi-prepolymers ............................................................... 76
x
Description:between sexes, leading to a difference in the capacity to inhibit the growth of dermatophytes. (18). It is also considered that the use of occlusive footwear and nail injuries may contribute to a higher incidence in males (2). Recent studies had stated that onychomycosis may have a genetic basis, w
