Table Of Contentedited by
“HIV prevention requires a multidisciplinary approach, even when focusing on a particular
biomedical intervention such as anti-HIV microbicides. This book offers a comprehensive, D
José das Neves
integrative, and balanced overview on various aspects of microbicides, including mechanisms
r
of transmission, drug development, and clinical and regulatory aspects, with a special emphasis Bruno Sarmento
u
on formulation. It is therefore equally useful for specialized basic, pharmacological, clinical, o
g
and biotechnological scientists and will hopefully stimulate future interdisciplinary research for f
prevention.”
A D
Prof. Guido Vanham Drug Delivery and
Virology Unit, Institute of Tropical Medicine, Antwerp, Belgium n e
t l
i i
“This treatise offers an insightful analysis on the opportunities that drug delivery technologies can - v
afford in HIV microbicide development. It provides first-of-its-kind comprehensive overview of the H e Development of
challenges in microbicide delivery as well as opportunities to develop novel formulations such as r
I
polymeric implants, stimuli-responsive nanotechnology, and strategies to alter the microbiome. V y
It also addresses the issues of socio-economics, compliance, and regulatory oversight in the a
development of novel microbicides.” M Anti-HIV Microbicides
n
Prof. Mansoor M. Amiji
i d
Distinguished Professor and Chairman, c
Department of Pharmaceutical Sciences, Northeastern University, USA r D
o
The worldwide impact of HIV/AIDS is well recognized. In the absence of a cure, prophylaxis e
b
represents a cornerstone in the battle against infection. One promising strategy comprises the v
i e
use of vaginal/rectal products containing antiviral compounds, termed microbicides, around the c
l
time of sexual intercourse. It is now recognized that the development of specific drug dosage i o
d
forms, drug delivery systems, or both is an indispensable aspect for the success of microbicides.
p
Various groups strived over the past decade to optimize the biophysical and technological e
s m
performance of traditional dosage forms (gels, tablets, and suppositories) in order to fulfill the
specificities of microbicide use, without neglecting users’ preferences and affordability issues. e
n
Moreover, new formulation approaches, such as vaginal rings and films, nanotechnology-based
t
systems, stimuli-sensitive formulations, and targeted drug delivery systems, have been proposed
and are currently undergoing pre-clinical or even clinical testing. This book provides for the first
time a thorough and critical overview of current aspects and recent developments and trends in
the formulation and drug delivery concerning anti-HIV microbicides by leading scientists in the
field. Additionally, it discusses pertinent regulatory aspects and socioeconomic issues related to
the subject.
d
a
José das Neves has a doctorate in pharmaceutical sciences from the University of s
Porto, Portugal. He is researcher at Instituto Superior de Ciências da Saúde-Norte, N
e
Cooperativa de Ensino Superior Politécnico e Universitário, Portugal, and Instituto
v
de Engenharia Biomédica, University of Porto. His current research interests e
include vaginal drug delivery and the development of nanotechnology-based s
solutions for the development of anti-HIV microbicides. |
S
a
Bruno Sarmento has a doctorate in pharmaceutical technology from the
r
University of Porto, Portugal. He is affiliated researcher at Instituto de Engenharia m
Biomédica, University of Porto, and assistant professor of pharmaceutical and e
biopharmaceutical technology at Instituto Superior de Ciências da Saúde- n
t
Norte. His current research focuses on nanomedicines and their application in o
pharmaceutical and biomedical fields.
V408
ISBN 978-981-4463-56-0
Drug Delivery and
Development of
Anti-HIV Microbicides
(cid:49)(cid:66)(cid:79)(cid:1)(cid:52)(cid:85)(cid:66)(cid:79)(cid:71)(cid:80)(cid:83)(cid:69)(cid:1)(cid:52)(cid:70)(cid:83)(cid:74)(cid:70)(cid:84)(cid:1)(cid:80)(cid:79)(cid:1)(cid:51)(cid:70)(cid:79)(cid:70)(cid:88)(cid:66)(cid:67)(cid:77)(cid:70)(cid:1)(cid:38)(cid:79)(cid:70)(cid:83)(cid:72)(cid:90)(cid:1)(cid:137)(cid:1)(cid:55)(cid:80)(cid:77)(cid:86)(cid:78)(cid:70)(cid:1)(cid:19)
Drug Delivery and
Development of
Anti-HIV Microbicides
editors
PrebenMaegaard edited by
AnnaKrenz José das Neves
WolfgangPalz
Bruno Sarmento
The Rise of Modern Wind Energy
Wind Power
for the World
CRC Press
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Contents
Foreword
Preface
xvii
1. Mi crobicides for the Prevention of HIV xx1i
Osmond J. D’Cruz and Fatih M. Uckun
1.1 Introduction 1
1.2 Antiretroviral Microbicides in Development and
Mechanism of Action 2
1.2.1 Virus-Targeting Entry Inhibitors 5
1.2.1.1 C-C chemokine receptor 5
antagonists 6
1.2.1.2 Neutralizing antibodies 8
1.2.1.3 Anti-HIV carbohydrate-binding
agents 9
1.2.1.4 Peptides 10
1.2.2 Reverse Transcriptase Inhibitor-Based
Microbicides 11
1.2.2.1 NtRTI-based microbicide 11
1.2.2.2 NRTIs-based microbicides 12
1.2.2.3 NNRTI-based microbicides 14
1.2.3 RNA Interference-Based Microbicides 18
1.2.4 RNA-Based Aptamer Microbicides 19
1.2.5 Aptamer-siRNA-Based Chimeric Microbicides 20
1.3 Microbicide Efficacy Studies 21
1.3.1 Gel-Based Microbicides 21
1.3.2 Vaginal-Specific Microbicides 22
1.3.3 Rectal-Specific Microbicides 23
1.3.4 Vaginal versus Oral Interventions 25
1.4 Coitally Independent Delivery Systems 27
vi Contents
1.4.1 Intravaginal Rings 27
1.4.2 Lactobacilli Expressing Antiviral Biologics 29
2. HIV Transmission Models: Lessons Learned for Microbicide
1.5 Conclusions 30
Formulation Design 55
Pedro M. M. Mesquita and Betsy C. Herold
2.1 Introduction 55
2.2 Modeling Sexual Transmission 56
2.3 In vitro Models of Microbicide Efficacy 58
2.4 Ex vivo Challenge Models 60
2.5 Impact of Genital Tract Secretions and Semen on
Microbicide Assessments 63
2.6 In vitro and Animal Models of Microbicide Safety 65
2.7 Animal Models for Assessment of PK/PD 67
2.7.1 Murine Models 67
2.7.2 NHP Models 69
2.8 Rationale for Co-Formulations 70
3. 2C.h9a lleCnognesc liuns Mioincsr oabnidci dFeu tDurrueg P Deerslipveecryti:v Iedse ntifying Targets 74
and Evolving Strategies 91
Karolin Hijazi, Constandinos Carserides, and Charles Kelly
3.1 Introduction 91
3.2 HIV Transmission at Mucosal Surfaces 92
3.3 Microbicides: Current State of the Art 94
3.3.1 HIV Fusion 94
3.3.2 Reverse Transcriptase 95
3.3.3 RNase H 96
3.3.4 Integrase 97
3.3.5 Protease 97
3.4 Combination Microbicides 98
3.5 Factors Affecting Drug Distribution in Mucosal
Tissues 99
3.5.1 Drug Transport and Metabolism 99
3.5.2 Mucosal Inflammation 102
Contents vii
3.6 Formulation Strategies 103
4. Safety Aspects of Topical Anti-HIV Microbicides 117
3.7 Conclusions and Future Perspectives 103
Raina N. Fichorova
4.1 Introduction 117
4.2 Vaginal and Rectal Microbicides: Appealing but Also
Finicky 118
4.3 The Birth Pangs of Topical Microbicides 120
Dubium
4.4 TCorepdicoa l Cytokines and Biomarkers of Inflammation
for Microbicide Safety Evaluation: From to
121
Primum non Nocere
4.5 Learning from Failed and Successful Efficacy
Trials: 125
4.6 The Resident Microbiota: The Chapel Master of
Mucosal Immunity 129
4.7 Pre-Clinical Models: From Cells to Function 132
5. Biophysics, Drug Transport Modeling, and Performance of
4.8 Conclusions and Future Perspectives 136
Microbicides 151
David F. Katz
5.1 Introduction 151
5.2 How Modeling Works 153
5.3 Vaginal Coating by Gels: The First Mechanistic
Models for Microbicide Functioning 156
5.3.1 Gel Rheology 156
5.3.2 Effects of Dilution on Gel Rheology 159
5.3.3 Intralumenal Forces Acting on a Gel 159
5.3.4 Geometry of Gel Flow along the Lumen,
Mucosal Surfaces and Ambient Fluid
Contents 160
5.3.5 Examples of Model Predictions for Vaginal
Coating Flows 161
5.3.5.1 Radial flow of a disk of gel: net
squeezing force given 162
5.3.5.2 Channel flow geometry: flat walls,
net squeezing force given 162
viii Contents
5.3.5.3 Flow due to elastic local squeezing
forces by vaginal walls and
incorporating the dynamics of gel
dilution and possible swelling 164
5.3.5.4 Models of gravity and surface tension
driven intravaginal flows 166
5.4 Vaginal Coating by a Film 166
5.5 Interactions between Semen-Borne HIV Virions
and Cyanovirin-N Molecules Delivered by a Gel
Layer: The First Mass Transport Model of
Microbicide Delivery and, Also, of HIV Interaction 168
5.6 Delivery of Dapivirine from an Intravaginal Ring to
Mucosal Surfaces: The First Mass Transport Model
for an Intravaginal Ring 170
5.7 Delivery of Tenofovir from a Gel Layer into the
Mucosal Epithelium and Stroma: The First
Biophysics-Based Compartmental Model of
Microbicide Pharmacokinetics 172
5.8 Design of a Microbicide Gel Using Modeling:
The First Approach 174
5.9 Discussion on Microbicides Modeling 176
5.9.1 The Next Steps in PK Modeling 178
5.9.1.1 Foci for enhanced PK modeling
overall 178
5.9.1.2 Dosage form-specific
improvements 181
5.9.2 Rational Microbicide Design Schemas 182
6. Dosage Forms for Microbicide Formulations:
5.10 Conclusions and Future Perspectives 183
Advantages and Pitfalls 193
Viness Pillay, Pradeep Kumar, Valence M. K. Ndesendo,
Yahya E. Choonara, and Lisa du Toit
6.1 Introduction 193
6.2 Rationale for the Development of Microbicide
Formulations 195
6.2.1 Statement of the Problem 195
