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NANOMATERIALS FOR
CLINICAL APPLICATIONS
NANOMATERIALS FOR
CLINICAL APPLICATIONS
Case Studies in Nanomedicines

Edited by
NATASSA PIPPA
Section of Pharmaceutical Technology, Department of Pharmacy,
School of Health Sciences, National and Kapodistrian University of Athens,
Athens, Greece

Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation,

Athens, Greece

COSTAS DEMETZOS
Section of Pharmaceutical Technology, Department of Pharmacy,
School of Health Sciences, National and Kapodistrian University of Athens,
Athens, Greece
Elsevier
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The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
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Copyright © 2020 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center
and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they
should be mindful of their own safety and the safety of others, including parties for whom they have a professional
responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability
for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or
from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

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A catalogue record for this book is available from the British Library
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A catalog record for this book is available from the Library of Congress
ISBN: 978-0-12-816705-2

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Publisher: Matthew Deans

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Typeset by MPS Limited, Chennai, India
CONTENTS

List of contributors ix

1. Solid lipid nanoparticles in dermaceuticals 1

Indu Pal Kaur, Garima Sharma, Mandeep Singh, Mohhammad Ramzan, Joga Singh,
Simarjot Kaur Sandhu and Jaspreet Singh Gulati
1.1 General introduction 1
1.2 Why solid lipid nanoparticles? 2
1.3 Evolution of lipidic nanoparticles from solid lipid nanoparticles to nanostructured
lipid carriers 3
1.4 Cosmetic and topical applications of solid lipid nanoparticles 5
1.5 Skin penetration with solid lipid nanoparticles 11
1.6 Mechanism of drug penetration with solid lipid nanoparticles 12
1.7 Incorporation into semisolid vehicle 13
1.8 Case studies of successful topical delivery with lipidic nanoparticles 13
1.9 Delivery of agents for other skin diseases 15
1.10 Conclusions 22
References 22

2. Cyclodextrin-based drug delivery systems 29

Mario Jug
2.1 Cyclodextrins—structure, physiochemical properties, and toxicological profile 29
2.2 Cyclodextrin inclusion complexes—formation, stability, and application in drug delivery 31
2.3 Cyclodextrin-based products in clinical practice 33
References 60

3. Lipid vesicles for (trans)dermal administration 71

Silvia Franzè, Umberto M. Musazzi and Francesco Cilurzo
3.1 (Trans)dermal drug-delivery systems 71
3.2 Lipid vesicles for breaching the skin barrier 74
3.3 Liposomal formulation in clinics 88
3.4 Final remarks 92
References 92

4. Stimuli-responsive nanocarriers for drug delivery 99

Maria Chountoulesi, Nikolaos Naziris, Natassa Pippa, Stergios Pispas and Costas Demetzos
4.1 Introduction 99
4.2 Types of stimuli 100
4.3 Development of chimeric stimuli-responsive liposomes with incorporated
stimuli-responsive polymers 103

v
vi Contents

4.4 Thermotropic behavior of stimuli-responsive liposomes 106

4.5 Physicochemical properties of stimuli-responsive liposomes 110
4.6 Development of stimuli-responsive lyotropic liquid crystalline nanosystems 112
4.7 Conclusion and future directions 116
References 117

5. Biodegradable nanomaterials 123

Katerina Anagnostou, Minas Stylianakis, Sotiris Michaleas and Athanasios Skouras
5.1 Introduction 123
5.2 Natural polymers 125
5.3 Synthetic polymers 130
5.4 Polymeric nanoparticles 136
5.5 Clinical applications of biodegradable nanoparticles 145
5.6 Future perspectives 151
Acknowledgments 152
References 153
Further reading 157

6. Modulating the immune response with liposomal delivery 159

David Nardo, David Henson, Joe E. Springer and Vincent J. Venditto
6.1 Introduction 159
6.2 Liposomal immune modulation with small-molecule therapeutics 164
6.3 Liposomal immune modulation with liposomal gene vectors 174
6.4 Immune stimulation with liposomal vaccines 184
6.5 Conclusions and future directions 193
List of abbreviations 194
Acknowledgments 195
References 195

7. Recent advances in solid lipid nanoparticles formulation and clinical

applications 213
Helena Rouco, Patricia Diaz-Rodriguez, Carmen Remuñán-López and Mariana Landin
7.1 Lipid nanoparticles 213
7.2 Formulation components 214
7.3 Preformulation studies 220
7.4 Formulation procedures 221
7.5 Characterization techniques 225
7.6 Drug incorporation models 231
7.7 Administration routes 233
7.8 Solid lipid nanoparticles and nanostructured lipid carriers case studies in humans
for medical applications 239
Self-assessment questions 241
References 242
Contents vii

8. Biopolymers, liposomes, and nanofibers as modified peroral drug release

formulants 249
Marilena Vlachou and Angeliki Siamidi
8.1 Introduction 249
8.2 Mathematical models for drug release 252
8.3 Release profiles comparison 260
8.4 Biopolymers in modified peroral drug delivery 261
8.5 Nanofibers in modified peroral drug delivery 263
8.6 Examples of liposomal-modified release formulations in clinical use 264
8.7 Conclusion 265
Self-assessment questions 266
References 267

9. Grafted polymethacrylate nanocarriers in drug delivery 271

Dorota Neugebauer
9.1 Graft poly(meth)acrylates, including molecular brushes 271
9.2 Carriers based on poly(ethylene glycol) poly(meth)acrylate brushes 273
9.3 Carriers based on poly(ethylene glycol) grafted poly(meth)acrylates 275
9.4 Poly(ethylene glycol) and biodegradable polyester nonlinear amphiphilics 281
9.5 Other thermoresponsive graft polymethacrylate nanocarriers 283
9.6 Heterografted Janus-type carriers 284
9.7 Core shell graft copolymers 287
9.8 Graft polymers containing disulfide linkers 289
9.9 Summary 291
References 291

Index 297
LIST OF CONTRIBUTORS

Katerina Anagnostou
Department of Electrical & Computer Engineering, Hellenic Mediterranean University Heraklion, Crete,
Greece
Maria Chountoulesi
Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National
and Kapodistrian University of Athens, Athens, Greece
Francesco Cilurzo
Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
Costas Demetzos
Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National
and Kapodistrian University of Athens, Athens, Greece
Patricia Diaz-Rodriguez
R+D Pharma Group (GI-1645), Department of Pharmacology, Pharmacy and Pharmaceutical
Technology, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain
Silvia Franzè
Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
Jaspreet Singh Gulati
Hitech Formulations Pvt Ltd, Industrial Area 1, Chandigarh, India
David Henson
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States
Mario Jug
Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
Indu Pal Kaur
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Mariana Landin
R+D Pharma Group (GI-1645), Department of Pharmacology, Pharmacy and Pharmaceutical
Technology, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain
Sotiris Michaleas
Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
Umberto M. Musazzi
Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
David Nardo
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States
Nikolaos Naziris
Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National
and Kapodistrian University of Athens, Athens, Greece

ix
x List of contributors

Dorota Neugebauer
Silesian University of Technology, Faculty of Chemistry, Department of Physical Chemistry and
Technology of Polymers, Gliwice, Poland
Natassa Pippa
Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National
and Kapodistrian University of Athens, Athens, Greece; Theoretical and Physical Chemistry Institute,
National Hellenic Research Foundation, Athens, Greece
Stergios Pispas
Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens, Greece
Mohhammad Ramzan
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Carmen Remuñán-López
NanoBiofar Group (GI-1643), Department of Pharmacology, Pharmacy and Pharmaceutical Technology,
Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain
Helena Rouco
R+D Pharma Group (GI-1645), Department of Pharmacology, Pharmacy and Pharmaceutical
Technology, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain
Simarjot Kaur Sandhu
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Garima Sharma
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Angeliki Siamidi
Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National
and Kapodistrian University of Athens, Athens, Greece
Joga Singh
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Mandeep Singh
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Athanasios Skouras
Department of Electrical & Computer Engineering, Hellenic Mediterranean University Heraklion, Crete,
Greece; Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
Joe E. Springer
Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, United States
Minas Stylianakis
Department of Electrical & Computer Engineering, Hellenic Mediterranean University Heraklion, Crete,
Greece
Vincent J. Venditto
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States
Marilena Vlachou
Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National
and Kapodistrian University of Athens, Athens, Greece
 CHAPTER ONE

Solid lipid nanoparticles in

dermaceuticals
Indu Pal Kaur1, Garima Sharma1, Mandeep Singh1, Mohhammad Ramzan1,
Joga Singh1, Simarjot Kaur Sandhu1 and Jaspreet Singh Gulati2
1
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
2
Hitech Formulations Pvt Ltd, Industrial Area 1, Chandigarh, India

1.1 General introduction

World Health Organization has included skin diseases as the most common
noncommunicable diseases in hot and humid countries, including India; prevalence of
these diseases is on the rise, world over. Skin being the largest organ that interfaces
with the environment is exposed to a variety of physical [ultraviolet (UV) radiations],
chemical, and microbial insults that affect its structure and function. Since significant
part of skin is visible to others, any disfigurement of skin is often associated with social
and psychological implications much beyond the actual disease symptoms. Global
Burden of Disease survey reported skin and subcutaneous diseases as 18th leading cause
of global disability-adjusted life years and 4th leading cause of nonfatal burden
(Karimkhani et al., 2017). Years lived with disability from these diseases (36.4 million)
are more than those caused by diabetes mellitus (29.5 million) and migraines (28.9
million) (Karimkhani et al., 2017). The global dermaceutical market (over the counter
and prescription) is huge and evolving quickly indicating a global market of USD
91.40 billion in 2028 from USD 49.22 billion in 2018.
The treatments available at present are unable to completely cure various diseases
of the skin and meet the expectations of patients. This is attributed to either a lack of
suitable treatment/agents or poor delivery of drug agent to the appropriate layer of
the skin. The outermost part (15
20 μm) of the epidermis, namely stratum corneum
(SC), is the major barrier to drug absorption into the skin. The resistant envelopes of
SC corneocytes and keratin microfibrils are considered as bricks, and the lipidic layers
found between these cells are called as mortar. This unique arrangement is responsible
for basic skin permeation resistance and reduces the passage of molecules (larger than
500 Da) through skin (Erdogan, 2009). Although drugs may diffuse into the skin via
hair follicles, sebaceous glands, or sweat glands, permeation through the multiple lipid

Nanomaterials for Clinical Applications. © 2020 Elsevier Inc.

DOI: https://doi.org/10.1016/B978-0-12-816705-2.00001-1 All rights reserved. 1
2 Indu Pal Kaur et al.

bilayers of SC remains the main pathway (Ting et al., 2004) because the former
comprise only a small area of the skin. The inability of drug molecules to penetrate
the SC and reach the deeper dermis layer of the skin in sufficient concentration can
usually result in recurrence of several skin diseases including infections that are often
not limited to the SC.
Small-sized carriers including liposomes, niosomes, aquasomes, transfersomes, elasto-
somes, microemulsions, nanoemulsions, self microemulsifying drug delivery system, self
nanoemulsifying drug delivery system, and solid lipid nanoparticles (SLNs) are currently
being explored extensively for their ability to permeate the SC and reach the lower skin
layers including dermis and at times the subcutaneous tissue too. Both micrometer- and
nanometer-range carriers were found effective in improving the delivery to skin. Since
the drug is released gradually and over a prolonged period of time, irritancy or other
side effects associated with the active ingredients, when applied in conventional formu-
lations, are significantly reduced when incorporated into these systems, without
compromising the efficacy (Castro and Ferreira, 2008). These systems not only mask the
irritation and side effects of the selected agent to be delivered but also invariably
improve its solubility and permeability.

1.2 Why solid lipid nanoparticles?

In 1990 the lipidic nanoparticles were invented as an alternative to traditional
drug carriers such as polymeric nanoparticles and liposomes. Many questions of ability
to produce at industrial level, regulatory status of excipients, and nanotoxicity rose
regarding the use of these conventional nanocarriers. Such questions were addressed
with the development of SLNs as an alternative. Various advantages of SLNs over
polymeric nanoparticles and liposomes are elaborated later.

1.2.1 Formulation aspects

• SLNs can be prepared without employing organic solvents. Residues of these sol-
vents have toxic effects (Kaur et al., 2014).
• High drug loading (B10% or more) can be achieved with SLNs versus a low drug
loading of , 5% in case of polymeric nanoparticles (Singh et al., 2010).
• SLNs are reported to be stable for up to 3 years (Kakkar et al., 2011). This is an
important advantage over other colloidal carrier systems.
• Remarkable scalability and reproducibility of important properties namely, particle
size and encapsulation efficiency in large (Liu et al., 2007) batches using a
Solid lipid nanoparticles in dermaceuticals 3

cost-effective high-pressure homogenization technique as the preparation proce-

dure is again an exclusive advantage with SLNs (Albanese et al., 2012).
• SLNs can be sterilized by autoclaving. Other nano colloidal systems are sterilized
by gamma irradiation, which is not only costly and a specialized technique but may
possibly lead to the formation of free radicals and subsequently toxic reaction pro-
ducts (Kaur et al., 2014).
• Quantification of SLN in creams is simplified as compared to other particles. Many
cream bases do not exhibit a melting peak below 100 C, which means the content
of SLN in a cream can be quantified by their melting peak determined by differen-
tial scanning calorimetry.

1.2.2 Physiological aspects

• SLNs act as drug reservoirs in various skin layers (Vyas et al., 2014) by variety of
uptake mechanisms like entering into a shunt such as hair follicle, accumulating
between corneocytes, and intermingling with skin lipids, or by disintegrating and
merging with lipidic layers (Toll et al., 2004; Bseiso et al., 2015).
• Depending on the produced SLN type, controlled release of the active ingredients
is possible. SLNs with a drug-enriched shell show burst release characteristics
whereas SLNs with a drug-enriched core lead to sustained release (Wissing and
Müller, 2003b).
• SLNs act as occlusives, that is, they can increase the water content of the skin mak-
ing it more hydrated and thus more permeable (Wissing et al., 2001).
• SLNs show a UV-blocking potential, that is, they act as physical sunscreens on
their own and can be combined with molecular sunscreens to achieve improved
photoprotection (Wissing and Müller, 2003b).
• The components used to formulate SLNs are safe as compared to polymeric nano-
and microparticles which may cause systemic toxicity by impairment of the reticu-
loendothelial system due to slow degradation of its components up to 4 weeks
(Cavalli et al., 2000).

1.3 Evolution of lipidic nanoparticles from solid lipid

nanoparticles to nanostructured lipid carriers
The most important parameters for evaluation of lipid nanoparticles are particle
size and size distribution, zeta potential, polymorphism, degree of crystallinity, drug
loading, entrapment efficiency, and drug release.
4 Indu Pal Kaur et al.

The first generation of lipidic nanoparticles, that is, SLNs, necessarily comprise
high-melting point lipid(s) which are heated at least once to melt and consecutively
cooled. Latter results in the recrystallization of the lipid matrix leading to high possibil-
ity of polymorphism occurrence. Lipid particles crystallize in a higher energy modifica-
tion (α or β0 ) which during storage transform to the low-energy, more-ordered
modification (β).
Drug molecules in SLNs, oriented between the fatty acid chains or glycerides, can
be potentially expelled during transformation of the lipid from α to β form on storage.
This happens due to the formation of more-ordered structure or reduced number of
imperfections in the crystal lattice (Guimarães and Ré, 2011). Moreover because of
their perfect crystalline structure, SLNs exhibit a low drug
loading efficiency
(Ghasemiyeh and Mohammadi, 2018).
To overcome these potential challenges faced by SLNs, the second-generation
lipidic nanoparticles called nanostructured lipid carriers (NLCs) were introduced in
1999. Evolution of lipidic nanoparticles from emulsion to NLCs is shown in Fig. 1.1
(Guimarães and Ré, 2011).
NLCs are composed of blends of solid and liquid lipids resulting in imperfections
in the lattice which can accommodate a greater amount of the active ingredient. The
less-ordered structure is due to inhibition of crystallization by liquid lipids. This
enables a significant increase in loading capacity and also minimizes premature active
ingredient expulsion. The structural comparison of SLN and NLC is depicted in Fig. 1.2

Traditional carriers Innovative carriers

1950 s 1970 s 1991 1999/2000

Solid lipids
Liquid lipid Polymer +
(solid) Solid lipids
(oil) Liquid lipids
(oil)

Polymeric SLN NLC

o/w emulsion
nanoparticles 1st generation 2nd generation

Lipid nanoparticles

Figure 1.1 Evolution of lipid nanoparticle concept in comparison with the conventional technolo-
gies till the beginning of the 1990s. NLC, Nanostructured lipid carrier; SLN, solid lipid nanoparticle.
Obtained with permission from Guimarães, K.L., Ré, M.I., 2011. Lipid nanoparticles as carriers for cosmetic
ingredients: the first (SLN) and the second generation (NLC). In: Beck, R., Guterres, S., Pohlmann, A. (Eds.),
Nanocosmetics and Nanomedicines, Springer, Berlin, Heidelberg, pp. 101
122.
Solid lipid nanoparticles in dermaceuticals 5

SLN NLC

“Brick wall” structure Unstructure matrix

Low drug load High drug load

Drug expulsion Long-term drug

during storage stability
Figure 1.2 “Symmetric brick wall” and “Welsh natural stone wall” model depicting difference
between particle matrix structure of SLNs and NLCs, respectively. NLCs, Nanostructured lipid carriers;
SLNs, solid lipid nanoparticles. Obtained with permission from Beloqui, A., Solinís, M.A., Rodríguez-
Gascón, A., Almeida, A.J., Préat, V., 2016. Nanostructured lipid carriers: promising drug delivery systems
for future clinics. Nanomed. Nanotechnol. Biol. Med., 12, 143
161.

(Beloqui et al., 2016). Different patented and marketed products using SLN/NLC tech-
nology are given in Tables 1.1 and 1.2, respectively (Müller et al., 2007; Kaul et al.,
2018), respectively.

1.4 Cosmetic and topical applications of solid

lipid nanoparticles
Occlusion: Epidermal layer of skin has 20% water content and play principal
role as the barrier of topical absorption of foreign particles. Occlusion process can
enhance hydration of SC layer which influence topical absorption. SLNs have the
ability to form a hydrophobic monolayered film, which has attraction for the epi-
dermal layer of skin. The occlusive nature of this film retards the water loss due to
Table 1.1 Important patents concerning the use of lipidic nanoparticles for topical dermal administration.
Patent number Title Medical condition Reference
US8715736B2 Nanoparticle formulations for skin Skin inflammation Singh and Patlolla (2009)
delivery
ES2384060B1 Capsules lipid nanoparticles Hormone replacement Viladot Petit et al. (2010)
therapy
RU2602171C2 Composition containing lipid Atopic dermatitis Bastholm and Peterson
nanoparticles and corticosteroid (2012)
or vitamin D derivative
EP2919756B1 Solid lipid nanoparticles of Hair loss or acne Cal and Frackowiak
roxithromycin for hair loss or (2012)
acne
CN102670484B Mannose-modified solid lipid Immuno booster and Jianqing Chen and Ping
nanoparticle plural gel and antiinflammatory (2012)
preparation method thereof
KR101860555B1 Solid lipid nanoparticles Skin whitening Jin et al. (2016)
composition for skin-whitening
effect comprising MHY498 and
preparation method thereof
CN102342914A Calcipotriol solid lipid nanoparticle Psoriasis and Minmin and Haijun
and preparation method of same ichthyosis (2011)
RU2491911C1 Moisturizing cream with solid lipid Moisturizing cream Omelyanchuk and
nanoparticles Vilinskaya (2012)
KR101810695B1 Peptides used in the treatment and/ Skin care Sanz et al. (2009)
or care of skin, mucous
membranes, and/or scalp and
their use in cosmetic or
pharmaceutical compositions
WO2010112749A1 Solid lipid nanoparticles Hair loss Padois et al. (2009)
encapsulating minoxidil and
aqueous suspension containing
same
WO2017143421A1 Nanoscale system for the sustained Insect repellent De Paula et al. (2017)
release of active cosmetic and/or
repellent substances
WO2008041116A2 Formulations of active principles Transdermal delivery Gasco (2006)
incorporated in SLNs suitable for of drugs with short
transdermal administration half life
US6875438B2 Preparations for topical Androgenic alopecia Kraemer et al. (2003)
administration of substances
having antiandrogenic activity
US20180296493A1 Lipid nanoparticle compositions and Antiinflammatory Kaufman (2015)
methods as carriers of
cannabinoids in standardized
precision-metered dosage forms
JP2018521052A Lipid and lipid nanoparticles Diseases related to Du and Ansell (2016)
formulations for delivery of a deficiency of
nucleic acids a protein and
enzymes
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