Investigation of New Formulations of Acrylic Bone Cement Containing Antibiotics

266 Pages·2015·56.49 MB·English

UNIVERSIDADE DE LISBOA
FACULDADE DE FARMÁCIA

Investigation of New Formulations of
Acrylic Bone Cement Containing Antibiotics

Ana Cristina Mendes Correia de Matos

Orientadora: Professora Doutora Ana Francisca de Campos Simão Bettencourt
Co-orientadores: Professor Doutor António José Leitão das Neves Almeida e
Professor Doutor Mário Augusto Pires Vaz

Tese especialmente elaborada para a obtenção do grau de Doutor em Farmácia na
especialidade de Tecnologia Farmacêutica

2015

UNIVERSIDADE DE LISBOA
FACULDADE DE FARMÁCIA
DEPARTAMENTO DE CIÊNCIAS TOXICOLÓGICAS E BROMATOLÓGICAS

Investigation of New Formulations of
Acrylic Bone Cement Containing Antibiotics

Ana Cristina Mendes Correia de Matos

Orientadora: Professora Doutora Ana Francisca de Campos Simão Bettencourt
Co-orientadores: Professor Doutor António José Leitão das Neves Almeida e
Professor Doutor Mário Augusto Pires Vaz

Tese especialmente elaborada para a obtenção do grau de Doutor em Farmácia na
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 José Manuel Correia Neves de Sousa Lobo, Professor Catedrático,
Faculdade de Farmácia da Universidade do Porto;
Doutor Fernando Jorge Mendes Monteiro, Professor Catedrático,
Faculdade de Engenharia da Universidade do Porto;
Doutor Mário Augusto Pires Vaz, Professor Associado,
Faculdade de Engenharia da Universidade do Porto; Coorientador;
Doutor Jacinto Manuel de Melo Oliveira Monteiro, Professor Catedrático,
Faculdade de Medicina da Universidade de Lisboa.
Doutor Paulo José Pinto Salústio, Professor Auxiliar,
Faculdade de Farmácia da Universidade de Lisboa.
Doutora Ana Francisca de Campos Simão Bettencourt, Professora Auxiliar,
Faculdade de Farmácia, Universidade de Lisboa; Orientadora

2015

v

“… the dream of yesterday
is the hope of today
and the reality of tomorrow.”
Robert Goddard

Investigation of new formulations of acrylic bone cement containing antibiotics
vi

Investigation of new formulations of acrylic bone cement containing antibiotics
Dedicatee vii

A meus filhos
Gonçalo, Beatriz, Nuno

Investigation of new formulations of acrylic bone cement containing antibiotics
viii

Investigation of new formulations of acrylic bone cement containing antibiotics
Table of Contents ix

Table of Contents

Agradecimentos ........................................................................................................................... xvii

Abstract ........................................................................................................................................ xxv

Resumo ....................................................................................................................................... xxix

List of Figures ............................................................................................................................ xxxiii

List of Tables .............................................................................................................................. xxxix

Abbreviations ................................................................................................................................ xliii

Aims and Organisation of the Thesis ........................................................................................... xlvii

Chapter 1 - General Introduction ..................................................................................................... 1

Foreword ...................................................................................................................................... 3

1.
  The Bone Cement .................................................................................................................. 5

1.1.
  History and Biological Backgrounds of Bone Cement ................................................. 5

1.2.
  Chemical Background of Bone Cement ....................................................................... 7

2.
  Bone cement related infection ............................................................................................. 10

2.1.
  Aetiology and pathogenesis of periprosthetic-joint infection ...................................... 10

2.2.
  Microbiology of periprosthetic-joint infection .............................................................. 12

3.
  Antibiotic-Loaded Bone Cement .......................................................................................... 14

3.1.
  Rationale for ALABC use ........................................................................................... 14

3.2.
  Types of ALABC and Clinical use .............................................................................. 15

3.3.
  The antibiotics ........................................................................................................... 17

Minocycline and Levofloxacin ............................................................................... 20

3.4.
  Importance of bulk and surface of ALABC ................................................................. 21

3.5.
  Antibiotic Release from ALABC ................................................................................. 23

Investigation of new formulations of acrylic bone cement containing antibiotics
x Table of Contents

Antibiotic stability after release ............................................................................ 26

Porosity promoters ............................................................................................... 26

3.6.
  Appraisal of biocompatibility of ALABC ..................................................................... 28

3.7.
  Bioactivity of ALABC ................................................................................................. 29

3.8.
  Mechanical Properties of ALABC .............................................................................. 31

Quasi-static mechanical properties of bone cement as a preliminary evaluation 32

References ................................................................................................................................ 34

Chapter 2 - Incorporation of Antibiotic-Loaded PMMA particles in acrylic bone cement .............. 47

Graphical Abstract ..................................................................................................................... 49

Abstract ..................................................................................................................................... 51

1.
  Introduction ......................................................................................................................... 53

2.
  Materials and Methods ........................................................................................................ 57

2.1.
  Materials ................................................................................................................... 57

2.2.
  Preparation of PMMA particles by DESE method ..................................................... 57

2.3.
  Particles surface morphology .................................................................................... 58

2.4.
  Particle size analysis ................................................................................................. 58

2.5.
  Surface Charge ......................................................................................................... 58

2.6.
  Particle encapsulation efficiency and drug loading ................................................... 59

2.7.
  Antibiotic stability throughout formulation procedure ................................................ 59

2.8.
  Fourier Transform Infrared spectroscopy (FTIR) ...................................................... 60

2.9.
  In vitro release studies .............................................................................................. 60

2.10.
  Preparation of acrylic bone cement specimens ........................................................ 61

3.
  Results ................................................................................................................................ 63

3.1.
  Particle characterisation ............................................................................................ 63

3.2.
  Antibiotic stability throughout formulation procedure ................................................ 64

3.3.
  Fourier Transform Infrared spectroscopy (FTIR) ...................................................... 64

3.4.
  In vitro Release Studies ............................................................................................ 66

4.
  Discussion ........................................................................................................................... 67

5.
  Conclusion .......................................................................................................................... 70

References ................................................................................................................................ 70

Investigation of new formulations of acrylic bone cement containing antibiotics