Professional Documents
Culture Documents
Nanomaterials For Clinical Applications: Case Studies in Nanomedicines (Micro and Nano Technologies) 1st Edition Costas Demetzos (Editor)
Nanomaterials For Clinical Applications: Case Studies in Nanomedicines (Micro and Nano Technologies) 1st Edition Costas Demetzos (Editor)
Edited by
NATASSA PIPPA
Section of Pharmaceutical Technology, Department of Pharmacy,
School of Health Sciences, National and Kapodistrian University of Athens,
Athens, Greece
COSTAS DEMETZOS
Section of Pharmaceutical Technology, Department of Pharmacy,
School of Health Sciences, National and Kapodistrian University of Athens,
Athens, Greece
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
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.
List of contributors ix
v
vi Contents
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
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.
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 drugloading 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
Solid lipids
Liquid lipid Polymer +
(solid) Solid lipids
(oil) Liquid lipids
(oil)
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. 101122.
Solid lipid nanoparticles in dermaceuticals 5
SLN NLC
(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.
Table 1.2 Marketed products containing lipidic nanoparticles (Müller et al., 2007; Kaul et al., 2018).
Marketed product Active ingredients Intended use
Cutanova Cream Nano Repair Q10, polypeptide, hibiscus Antiaging, smoothes fine
Q10 extract, ginger extract, lines, promotes
ketosugar restructuring
Intensive Serum NanoRepair Q10, polypeptide, mafane Antiaging, antiwrinkle
Q10 extract
Cutanova Cream NanoVital Q10, TiO2, polypeptide, Antiaging
Q10 ursolic acid, oleanolic acid,
sunflower seed extract
SURMER Crème Legère Kukuinut oil, Monoi Tiare Skin-protecting serum
Nano-Protection Tahiti, pseudopeptide, milk,
extract from coconut, wild
indigo, noni extract
SURMER Crème Riche Kukuinut oil, Monoi Tiare Intensely hydrating
Nano-Restructurante Tahiti, pseudopeptide, milk
extract from coconut, wild
indigo, noni extract
SURMER Elixir du Beauté Kukuinut oil, Monoi Tiare Antiaging and moisturizing
Nano-Vitalisant Tahiti, pseudopeptide, milk
extract from coconut, wild
indigo, noni extract
SURMER Masque Crème Kukuinut oil, Monoi Tiare Skin hydration
Nano-Hydratant Tahiti, pseudopeptide, milk
extract from coconut, wild
indigo, noni extract
NanoLipid Restore CLR Black currant seed oil Skin hydration
containing omega 3 and 6
unsaturated fatty acids
Nanolipid Q10 CLR Coenzyme Q10 and black Antiaging
currant seed oil
IOPE Super Vital cream, Coenzyme Q10, omega 3 and Antiaging, moisturizer under
serum, eye cream, extra unsaturated fatty acids eye wrinkles,
moist softener, extra moist face lift
emulsion
NLC Deep Effect Eye Serum Coenzyme Q10, highly active Under eye wrinkles
oligosaccharides
NLC Deep Effect Repair Q10, TiO2, highly active Antiaging
Cream oligosaccharides
NLC Deep Effect Q10, acetyl hexapeptide-3, Antiaging
Reconstruction Cream micronized plant collagen,
high, active oligosaccharides
in polysaccharide matrix
NanoLipid Repair CLR Black currant seed oil and Skin damage repair
manuka oil
(continued)
Solid lipid nanoparticles in dermaceuticals 9
2µm 200 nm
Section:
H2O evaporation
Skin
Top view:
Large pores
Small
''capillary pores''
Application and
Fusion: capillary forces
Figure 1.3 Model of film formation on the skin for lipid 2-mm particles and lipid 200-nm particles
shown as section (upper) and from the top (middle), and a new model of fusion of the nanoparti-
cles to a poreless film (lower). Obtained with permission from Müller, R.H., Radtke, M., Wissing, S.A.,
2002. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermato-
logical preparations. Adv. Drug. Delivery Rev. 54, S131S155.
considerations are also given to osmotic effect of the topical formulation. Change in iso-
tonicity can lead to irritation. NLCs and SLNs show remarkable isotonicity and good
osmotic effect following their application on skin (Souto and Müller, 2008)
Improved chemical stability: Solid matrix of SLNs is stable at room temperature as
well as under physiological conditions. The solid core of SLNs better accommodates
APIs which are prone to hydrolysis and oxidation, protecting them against chemical
degradation from water and oxygen, for example, SLN dispersions of tocopherol, reti-
nol, and coenzyme Q10 are chemically more stable as compared to the corresponding
aqueous dispersions of free or unencapsulated agents (Dingler et al., 1999). It may be
noted that tretinoin incorporated into liposomes was found prone to photodegradation
(Brisaert et al., 2001), while retinol encapsulated within SLNs was chemically
stable (Volkhard and Gohla, 2001). SLNs per se also exhibited high physical stability
during long-term storage (Müller et al., 2007).
of myxœdema,
1272
42
psychic,
19
sensory,
31
trophic,
54-59
of neuralgia,
1213
of neurasthenia,
354
of neuritis,
1191
of neuromata,
1209
952
462
of paralysis agitans,
433
of primary insanity,
152
of progressive unilateral facial atrophy,
694
of sciatica,
1235
of secondary scleroses,
987
862
of spina bifida,
757
of spinal hemorrhage,
809
hyperæmia,
802
meningeal hemorrhage,
754
syphilis,
1024
of symmetrical gangrene,
1258
of tabes dorsalis,
827
of tetanus,
549
661
of the insane temperament,
140
141
653
of thermic fever,
389
of Thomsen's disease,
461
986
of torticollis,
464
of trance,
344
of tremor,
430
of tubercular meningitis,
725
in the adult,
737
1030
1091
1166
of vertigo,
416
of visceral neuralgia,
1215
of writers' cramp,
514
790
Treatment of,
790
783
Syphilis as a cause of disseminated sclerosis,
886
of epilepsy,
471
178
of insanity,
119
749
of tabes dorsalis,
852
of tumors of the brain,
1028
YPHILITIC
FFECTIONS OF THE
ERVE-CENTRES
999
1017
Diagnosis,
1020
1021
Symptoms,
1017
et seq.
1008-1021
1003
Diagnosis,
1012
Pathology,
1014
Prognosis,
1013
Symptoms and clinical history,
1003
Aphasia in,
1009
1010
1003
1003
1005
1003
,
1012
1003
1007-1010
Prodromes,
1003
1004
Psychical symptoms,
1011
1006
Treatment,
1015
1015
Bloodletting, use,
1015
Mercurials, use,
1016
1015
1016
,
1017
“Woods,” use,
1016
1017
Etiology, general,
999
1001
Spinal syphilis,
1022
Diagnosis,
1026
Lesions,
1024
1022
1023
Symptoms,
1024
1025
Pain in,
1024
1025
Syphilitic diseases of brain, in general paralysis of the insane,
197
headaches,
403
886
insanity,
175
1017
T.
Tabes dorsalis,
826
Diagnosis,
857
Etiology,
851
History,
826
840
Physiology of,
840-846
Symptomatology,
827
870
Diagnosis,
870
Etiology,
871
Morbid anatomy,
872
Prognosis,
871
Symptoms,
871
Table of 100 cases of brain tumor,
1069
1107
Taches cérébrales,
1253
223
623
in hemiplegia,
955
in neuralgia,
1213
697
in tumors of brain,
1030
1043
429