nanoparticulate drug delivery systems, 2007, p.382

Nanoparticulate
Drug Delivery Systems
DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
Executive Editor
James Swarbrick
PharmaceuTech, Inc.
Pinehurst, North Carolina
Advisory Board
Larry L. Augsburger
University of Maryland
Baltimore, Maryland
Jennifer B. Dressman
Johann Wolfgang Goethe University
Frankfurt, Germany
Jeffrey A. Hughes
University of Florida College of
Pharmacy
Gainesville, Florida
Trevor M. Jones
The Association of the
British Pharmaceutical Industry
London, United Kingdom
Vincent H. L. Lee
University of Southern California
Los Angeles, California
Jerome P. Skelly
Alexandria, Virginia
Geoffrey T. Tucker
University of Sheffield

Royal Hallamshire Hospital
Sheffield, United Kingdom
Harry G. Brittain
Center for Pharmaceutical Physics
Milford, New Jersey
Anthony J. Hickey
University of North Carolina School of
Pharmacy
Chapel Hill, North Carolina
Ajaz Hussain
Sandoz
Princeton, New Jersey
Hans E. Junginger
Leiden/Amsterdam Center
for Drug Research
Leiden, The Netherlands
Stephen G. Schulman
University of Florida
Gainesville, Florida
Elizabeth M. Topp
University of Kansas School of
Pharmacy
Lawrence, Kansas
Peter York
University of Bradford School of
Pharmacy
Bradford, United Kingdom
1. Pharmacokinetics, Milo Gibaldi and Donald Perrier
2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Sidney H. Willig, Murray M. Tuckerman,

and William S. Hitchings IV
3. Microencapsulation, edited by J. R. Nixon
4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa
and Peter Jenner
5. New Drugs: Discovery and Development, edited by Alan A. Rubin
6. Sustained and Controlled Release Drug Delivery Systems, edited by
Joseph R. Robinson
7. Modern Pharmaceutics, edited by Gilbert S. Banker
and Christopher T. Rhodes
8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz
9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney
10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner
and Bernard Testa
11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by
James W. Munson
12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphan Drugs, edited by Fred E. Karch
14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,
Biomedical Assessments, Yie W. Chien
15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi
and Donald Perrier
16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Second Edition, Revised and Expanded, Sidney H. Willig,
Murray M. Tuckerman, and William S. Hitchings IV
17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger
18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry
19. The Clinical Research Process in the Pharmaceutical Industry, edited by
Gary M. Matoren
20. Microencapsulation and Related Drug Processes, Patrick B. Deasy
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe

and T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus
and Robert A. Nash
24. Anticancer and Interferon Agents: Synthesis and Properties, edited by
Raphael M. Ottenbrite and George B. Butler
25. Pharmaceutical Statistics: Practical and Clinical Applications,
Sanford Bolton
26. Drug Dynamics for Analytical, Clinical, and Biological Chemists,
Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr.,
and Michael J. Gudzinowicz
27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos
28. Solubility and Related Properties, Kenneth C. James
29. Controlled Drug Delivery: Fundamentals and Applications, Second
Edition,
Revised and Expanded, edited by Joseph R. Robinson and Vincent H.
Lee
30. New Drug Approval Process: Clinical and Regulatory Management,
edited by Richard A. Guarino
31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien
32. Drug Delivery Devices: Fundamentals and Applications, edited by
Praveen Tyle
33. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives,
edited by Peter G. Welling and Francis L. S. Tse
34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato
35. Transdermal Drug Delivery: Developmental Issues and Research
Initiatives, edited by Jonathan Hadgraft and Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,
edited by James W. McGinity
37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-

Sellassie
38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch
39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su,
and Shyi-Feu Chang
40. Modern Pharmaceutics: Second Edition, Revised and Expanded,
edited by Gilbert S. Banker and Christopher T. Rhodes
41. Specialized Drug Delivery Systems: Manufacturing and Production
Technology, edited by Praveen Tyle
42. Topical Drug Delivery Formulations, edited by David W. Osborne
and Anton H. Amann
43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications,
Second Edition, Revised and Expanded, Sanford Bolton
45. Biodegradable Polymers as Drug Delivery Systems, edited by
Mark Chasin and Robert Langer
46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S. Tse
and James J. Jaffe
47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong
and Stanley K. Lam
48. Pharmaceutical Bioequivalence, edited by Peter G. Welling,
Francis L. S. Tse, and Shrikant V. Dinghe
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded,
Yie W. Chien
51. Managing the Clinical Drug Development Process, David M. Cocchetto
and Ronald V. Nardi
52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Third Edition, edited by Sidney H. Willig
and James R. Stoker
53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan

54. Pharmaceutical Inhalation Aerosol Technology, edited by
Anthony J. Hickey
55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by
Adrian D. Nunn
56. New Drug Approval Process: Second Edition, Revised and Expanded,
edited by Richard A. Guarino
57. Pharmaceutical Process Validation: Second Edition, Revised
and Expanded, edited by Ira R. Berry and Robert A. Nash
58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra
59. Pharmaceutical Skin Penetration Enhancement, edited by
Kenneth A. Walters and Jonathan Hadgraft
60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck
61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited by
Alain Rolland
62. Drug Permeation Enhancement: Theory and Applications, edited by
Dean S. Hsieh
63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan
64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls
65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie
66. Colloidal Drug Delivery Systems, edited by Jörg Kreuter
67. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives,
Second Edition, edited by Peter G. Welling and Francis L. S. Tse
68. Drug Stability: Principles and Practices, Second Edition, Revised
and Expanded, Jens T. Carstensen
69. Good Laboratory Practice Regulations: Second Edition, Revised
and Expanded, edited by Sandy Weinberg
70. Physical Characterization of Pharmaceutical Solids, edited by
Harry G. Brittain
71. Pharmaceutical Powder Compaction Technology, edited by
Göran Alderborn and Christer Nyström

72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by
Gilbert S. Banker and Christopher T. Rhodes
73. Microencapsulation: Methods and Industrial Applications, edited by
Simon Benita
74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone
75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt
and Michael Montagne
76. The Drug Development Process: Increasing Efficiency and Cost
Effectiveness, edited by Peter G. Welling, Louis Lasagna,
and Umesh V. Banakar
77. Microparticulate Systems for the Delivery of Proteins and Vaccines,
edited by Smadar Cohen and Howard Bernstein
78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Fourth Edition, Revised and Expanded, Sidney H. Willig
and James R. Stoker
79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms:
Second Edition, Revised and Expanded, edited by James W. McGinity
80. Pharmaceutical Statistics: Practical and Clinical Applications,
Third Edition, Sanford Bolton
81. Handbook of Pharmaceutical Granulation Technology, edited by
Dilip M. Parikh
82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded,
edited by William R. Strohl
83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts
and Richard H. Guy
84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpé
85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by
John A. Bontempo
86. Pharmaceutical Project Management, edited by Tony Kennedy
87. Drug Products for Clinical Trials: An International Guide to Formulation •

Production • Quality Control, edited by Donald C. Monkhouse
and Christopher T. Rhodes
88. Development and Formulation of Veterinary Dosage Forms:
Second Edition, Revised and Expanded, edited by Gregory E. Hardee
and J. Desmond Baggot
89. Receptor-Based Drug Design, edited by Paul Leff
90. Automation and Validation of Information in Pharmaceutical Processing,
edited by Joseph F. deSpautz
91. Dermal Absorption and Toxicity Assessment, edited by Michael S.
Roberts
and Kenneth A. Walters
92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu,
and Roger Phan-Tan-Luu
93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III
94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR
Spectroscopy, David E. Bugay and W. Paul Findlay
95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain
96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products,
edited by Louis Rey and Joan C. May
97. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Third Edition, Revised and Expanded, edited by Robert L. Bronaugh
and Howard I. Maibach
98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches,
and Development, edited by Edith Mathiowitz, Donald E. Chickering III,
and Claus-Michael Lehr
99. Protein Formulation and Delivery, edited by Eugene J. McNally
100. New Drug Approval Process: Third Edition, The Global Challenge,
edited by Richard A. Guarino
101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid
102. Transport Processes in Pharmaceutical Systems, edited by

Gordon L. Amidon, Ping I. Lee, and Elizabeth M. Topp
103. Excipient Toxicity and Safety, edited by Myra L. Weiner
and Lois A. Kotkoskie
104. The Clinical Audit in Pharmaceutical Development, edited by
Michael R. Hamrell
105. Pharmaceutical Emulsions and Suspensions, edited by Francoise
Nielloud
and Gilberte Marti-Mestres
106. Oral Drug Absorption: Prediction and Assessment, edited by
Jennifer B. Dressman and Hans Lennernäs
107. Drug Stability: Principles and Practices, Third Edition, Revised
and Expanded, edited by Jens T. Carstensen and C. T. Rhodes
108. Containment in the Pharmaceutical Industry, edited by James P. Wood
109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control from Manufacturer to Consumer, Fifth Edition, Revised
and Expanded, Sidney H. Willig
110. Advanced Pharmaceutical Solids, Jens T. Carstensen
111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition,
Revised and Expanded, Kevin L. Williams
112. Pharmaceutical Process Engineering, Anthony J. Hickey
and David Ganderton
113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer
and Rachel F. Tyndale
114. Handbook of Drug Screening, edited by Ramakrishna Seethala
and Prabhavathi B. Fernandes
115. Drug Targeting Technology: Physical • Chemical • Biological Methods,
edited by Hans Schreier
116. Drug–Drug Interactions, edited by A. David Rodrigues
117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian
and Anthony J. Streeter

118. Pharmaceutical Process Scale-Up, edited by Michael Levin
119. Dermatological and Transdermal Formulations, edited by
Kenneth A. Walters
120. Clinical Drug Trials and Tribulations: Second Edition, Revised
and Expanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III
121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edited by
Gilbert S. Banker and Christopher T. Rhodes
122. Surfactants and Polymers in Drug Delivery, Martin Malmsten
123. Transdermal Drug Delivery: Second Edition, Revised and Expanded,
edited by Richard H. Guy and Jonathan Hadgraft
124. Good Laboratory Practice Regulations: Second Edition, Revised
and Expanded, edited by Sandy Weinberg
125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package
Integrity Testing: Third Edition, Revised and Expanded, Michael J. Akers,
Daniel S. Larrimore, and Dana Morton Guazzo
126. Modified-Release Drug Delivery Technology, edited by
Michael J. Rathbone, Jonathan Hadgraft, and Michael S. Roberts
127. Simulation for Designing Clinical Trials: A Pharmacokinetic-
Pharmacodynamic Modeling Perspective, edited by Hui C. Kimko
and Stephen B. Duffull
128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharma-
ceutics,
edited by Reinhard H. H. Neubert and Hans-Hermann Rüttinger
129. Pharmaceutical Process Validation: An International Third Edition,
Revised and Expanded, edited by Robert A. Nash and Alfred H. Wachter
130. Ophthalmic Drug Delivery Systems: Second Edition, Revised
and Expanded, edited by Ashim K. Mitra
131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland
and Sean M. Sullivan
132. Biomarkers in Clinical Drug Development, edited by John C. Bloom

and Robert A. Dean
133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie
and Charles Martin
134. Pharmaceutical Inhalation Aerosol Technology: Second Edition,
Revised and Expanded, edited by Anthony J. Hickey
135. Pharmaceutical Statistics: Practical and Clinical Applications,
Fourth Edition, Sanford Bolton and Charles Bon
136. Compliance Handbook for Pharmaceuticals, Medical Devices,
and Biologics, edited by Carmen Medina
137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products:
Second Edition, Revised and Expanded, edited by Louis Rey
and Joan C. May
138. Supercritical Fluid Technology for Drug Product Development, edited by
Peter York, Uday B. Kompella, and Boris Y. Shekunov
139. New Drug Approval Process: Fourth Edition, Accelerating Global
Registrations, edited by Richard A. Guarino
140. Microbial Contamination Control in Parenteral Manufacturing, edited by
Kevin L. Williams
141. New Drug Development: Regulatory Paradigms for Clinical Pharmacology
and Biopharmaceutics, edited by Chandrahas G. Sahajwalla
142. Microbial Contamination Control in the Pharmaceutical Industry, edited
by Luis Jimenez
143. Generic Drug Product Development: Solid Oral Dosage Forms, edited by
Leon Shargel and Izzy Kanfer
144. Introduction to the Pharmaceutical Regulatory Process, edited by
Ira R. Berry
145. Drug Delivery to the Oral Cavity: Molecules to Market, edited by
Tapash K. Ghosh and William R. Pfister
146. Good Design Practices for GMP Pharmaceutical Facilities, edited by
Andrew Signore and Terry Jacobs

147. Drug Products for Clinical Trials, Second Edition, edited by Donald
Monkhouse, Charles Carney, and Jim Clark
148. Polymeric Drug Delivery Systems, edited by Glen S. Kwon
149. Injectable Dispersed Systems: Formulation, Processing, and
Performance,
edited by Diane J. Burgess
150. Laboratory Auditing for Quality and Regulatory Compliance,
Donald Singer, Raluca-Ioana Stefan, and Jacobus van Staden
151. Active Pharmaceutical Ingredients: Development, Manufacturing,
and Regulation, edited by Stanley Nusim
152. Preclinical Drug Development, edited by Mark C. Rogge and David R. Taft
153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by
Steven W. Baertschi
154. Handbook of Pharmaceutical Granulation Technology: Second Edition,
edited by Dilip M. Parikh
155. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach
156. Pharmacogenomics: Second Edition, edited by Werner Kalow,
Urs A. Meyer and Rachel F. Tyndale
157. Pharmaceutical Process Scale-Up, Second Edition, edited by
Michael Levin
158. Microencapsulation: Methods and Industrial Applications, Second
Edition,
edited by Simon Benita
159. Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta
and Uday B. Kompella
160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain
161. Dose Optimization in Drug Development, edited by Rajesh Krishna
162. Herbal Supplements-Drug Interactions: Scientific and Regulatory
Perspectives, edited by Y. W. Francis Lam, Shiew-Mei Huang,

and Stephen D. Hall
163. Pharmaceutical Photostability and Stabilization Technology, edited by
Joseph T. Piechocki and Karl Thoma
164. Environmental Monitoring for Cleanrooms and Controlled Environments,
edited by Anne Marie Dixon
165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited
by Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young
166. Nanoparticulate Drug Delivery Systems, edited by Deepak Thassu,
Michel Deleers, and Yashwant Pathak
167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition,
edited by Kevin L. Williams
168. Good Laboratory Practice Regulations, Fourth Edition, edited by
Sandy Weinberg
169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition,
edited by Joseph D. Nally
Nanoparticulate
Drug Delivery Systems
edited by
Deepak Thassu
UCB Pharma, Inc.
Rochester, New York, U.S.A.
Michel Deleers
UCB Pharma, Chemin du Foriest
Braine l'Alleud, Belgium
Yashwant Pathak
UCB Manufacturing, Inc.
Rochester, New York, U.S.A.
New York London
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Library of Congress Cataloging‑in‑Publication Data
Nanoparticulate drug delivery systems / edited by Deepak Thassu, Michel Deleers,
Yashwant Pathak.
p. ; cm. ‑‑ (Drugs and the pharmaceutical sciences ; v. 166)
Includes bibliographical references and index.
ISBN‑13: 978‑0‑8493‑9073‑9 (alk. paper)
ISBN‑10: 0‑8493‑9073‑7 (alk. paper)

1. Drug delivery systems. 2. Nanoparticles. I. Thassu, Deepak. II. Deleers, Michel.
III. Pathak, Yashwant. IV. Series.
[DNLM: 1. Drug Delivery Systems‑‑methods. 2. Nanostructures. 3. Drug Carriers.
W1 DR893B v.166 2007 / WB 340 N184 2007]
RS199.5.N36 2007
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iii
Foreword
The use of molecular or macromolecular entities and superstructures derived
thereof for the delivery of drugs has a long history. Antibodies, for instance, were
suggested early last century as a means to direct anticancer drugs to tumor cells in
the body expressing the corresponding antigen. Their use in the form of monoclonals
is now at the forefront of targeted therapy. Following advances in the discovery of
cell receptors, receptor-binding macromolecules were added to the armamentarium
of systems for the targeting of drugs. Parallel to these developments has been, since
the early 1970s, the exploitation of liposomes as a delivery system for drugs and
vaccines. These superstructures, formed spontaneously from amphipathic lipid
molecules, together with a diverse collection of other promising superstructures
derived from a huge variety of natural and synthetic monomeric or polymeric units,
have evolved to sophisticated versions through the incorporation onto their surface
of macromolecules that contribute to optimal pharmacokinetics of actives and their
delivery to where they are needed. An ever increasing number of drug- and vaccine-
delivery systems are being tested clinically, with many already marketed.
Recently, drug-delivery systems have been rediscovered as the biological dimen-
sion of nanotechnology. A leading article in a prestigious scientific journal tells us
that “biologists are embracing nanotechnology—the engineering and manipulation

of entities in the 1 to 100 nm range—and are exploiting its potential to develop new
therapeutics and diagnostics.” What else is new?, you might say! Nonetheless, the
prefix
nano
(from the Greek word for
dwarf
) is a useful one because it helps define
drug-delivery systems of a certain size range. Reflecting this trend of size definition,
Nanoparticulate Drug Delivery Systems is a worthy attempt to bring together a wide
range of drug-delivery systems for the delivery (targeted or otherwise), through a
variety of routes of administration, of drugs, diagnostics, and vaccines in the
treatment or prevention of disease, now encapsulated in the term “nanomedicine.”
Importantly, the book includes a wealth of the latest advances in the technology of
nanoparticulates, including electrospinning, formation of microcrystals, production
of liquid crystalline phases, and, last but not least, the technology of metallic
nanoparticles. The editors, Deepak Thassu, Michel Deleers, and Yashwant Pathak,
are to be complimented for both their judicial selection of nanosystems and choice
of the international panel of contributors.
Gregory Gregoriadis
The School of Pharmacy
University of London
London, U.K.

Preface
v
Preface
For many decades, the interest in modifying drug-delivery systems has been a
prominent thrust of pharmaceutical research. In recent years, due to tremendous
expansion in the different scientific domains and skill sets, the scope has been wid-
ened to incorporate many faculties in the drug-delivery research covering physics,

polymer sciences, electrical engineering, bioelectronics, genetics, biotechnology,
and molecular pharmaceutics.
Pharmaceutical industry research culture is facing an uncertain future. Higher
clinical development cost coupled with declining drug-discovery process and lower
clinical success rates is decreasing the flow of new chemical entities in the research
and development pipeline.
Due to the advent of analytical techniques and capabilities to measure the
particle sizes in nanometer ranges, particulate drug-delivery systems research and
development has been moving from the micro- to the nanosize scale. Significant
research interests are geared towards utilizing the techniques where the particles
can be reduced almost to nanometer ranges, thus reducing the dose and reactive
nature of the molecule. This can deliver the drug at the targeted sites.
The book presented herewith is an attempt to describe the research efforts
being done in this direction by the global scientific community. Nanoparticulate
drug-delivery systems are a challenging area, and there are pulsating changes hap-
pening almost every day. This is an attempt to cover the recent trends and emerging
technologies in the area of nanoparticulate drug-delivery systems.
The first chapter covers a complete overview of the nanoparticulate drug-
delivery system, covering wide applications and evaluation of the nanoparticulate
drug-delivery system in various fields. Chapter 2 encompasses formulations of
nanosuspensions for parenteral delivery. The third chapter covers the polymer-
based nanoparticulate drug-delivery systems. Chapters 4 to 6 focus on nanofibers,
nanocrystals, and lipid-based nanoparticulate drug-delivery systems, respectively.
Chapters 7 to 10 discuss the engineering aspects and different techniques used
for nanoparticulate drug-delivery systems, including nanoengineering, aerosol flow
reactor, supercooled smectic nanoparticles, and metallic nanoparticles, respectively.
Chapters 11 and 12 focus on biological requirements and the role of nanobiotechnol-
ogy in the development of nanomedicines. Chapters 13 to 21 extensively cover the
applications of nanoparticulate drug-delivery systems, including lipid nanoparti-
cles for dermal applications; gene carriers for restenosis; ocular, central nervous

system, gastrointestinal applications; adjuvant for vaccine development; and trans-
dermal systems.
It is our hope that this multiauthored book on nanoparticulate drug-delivery
systems will assist and enrich the readers in understanding the diverse types of
nanoparticulate drug- delivery systems available or under development, as well as
highlight their applications in the future development of nanomedicines. This book
is equally relevant to academic, industrial, as well as scientists working in pharma-
ceutical drug delivery worldwide. The text is planned in such a way that each
chapter represents an independent area of research and can be easily followed with-
out referring to other chapters.
We would like to express our sincere thanks to Tony Benfonte for the figures in
Chapters 1 and 13 and to Linda Glather for reading the manuscript and suggesting
corrections and punctuation. Special thanks to our editors, Stevan Zolo, Yvonne
Honigsberg, and Sherri Niziolek, who helped us to get through the project
successfully.
Last, but not least, we would like to express our sincere gratitude to all the
authors who have taken time from their busy schedules to be part of this project and
written wonderful chapters that added both the depth and value to this book.
Deepak Thassu
Michel Deleers
Yashwant Pathak
vi Preface
vii
Contents
Foreword Gregory Gregoriadis . . . . iii
Preface . . . . v
Contributors . . . . ix
1. Nanoparticulate Drug-Delivery Systems: An Overview 1
Deepak Thassu, Yashwant Pathak, and Michel Deleers
2. Nanosuspensions for Parenteral Delivery 33

Barrett E. Rabinow
3. Nanoparticles Prepared Using Natural and Synthetic Polymers 51
Sudhir S. Chakravarthi, Dennis H. Robinson, and Sinjan De
4. Nanofiber-Based Drug Delivery 61
Matthew D. Burke and Dmitry Luzhansky
5. Drug Nanocrystals—The Universal Formulation Approach for Poorly Soluble
Drugs 71
Jan Möschwitzer and Rainer H. Müller
6. Lipid-Based Nanoparticulate Drug Delivery Systems 89
Jun Wu, Xiaobin Zhao, and Robert J. Lee
7. Nanoengineering of Drug Delivery Systems 99
Ashwath Jayagopal and V. Prasad Shastri
8. Aerosol Flow Reactor Method for the Synthesis of Multicomponent Drug
Nano- and Microparticles 111
Janne Raula, Hannele Eerikäinen, Anna Lähde, and Esko I. Kauppinen
9. Supercooled Smectic Nanoparticles 129
Heike Bunjes and Judith Kuntsche
10. Biological and Engineering Considerations for Developing Tumor-Targeting
Metallic Nanoparticle Drug-Delivery Systems 141
Giulio F. Paciotti and Lawrence Tamarkin
11. Biological Requirements for Nanotherapeutic Applications 159
Joseph F. Chiang
12. Role of Nanobiotechnology in the Development of Nanomedicine 173
K. K. Jain
13. Pharmaceutical Applications of Nanoparticulate Drug-Delivery Systems 185
Yashwant Pathak, Deepak Thassu, and Michel Deleers
14. Lipid Nanoparticles (Solid Lipid Nanoparticles and Nanostructured Lipid
Carriers) for Cosmetic, Dermal, and Transdermal Applications 213
Eliana B. Souto and Rainer H. Müller
15. Nano-Carriers of Drugs and Genes for the Treatment of Restenosis 235

Einat Cohen-Sela, Victoria Elazar, Hila Epstein-Barash, and Gershon Golomb
16. Ocular Applications of Nanoparticulate Drug-Delivery Systems 271
Annick Ludwig
17. Nanoparticulate Systems for Central Nervous System Drug Delivery 281
Jean-Christophe Olivier and Manuela Pereira de Oliveira
18. Nanoparticles for Gene Delivery: Formulation Characteristics 291
Jaspreet K. Vasir and Vinod Labhasetwar
19. Gastrointestinal Applications of Nanoparticulate Drug-Delivery Systems 305
Maria Rosa Gasco
20. Nanoparticles as Adjuvant-Vectors for Vaccination 317
Socorro Espuelas, Carlos Gamazo, María José Blanco-Prieto, and Juan M. Irache
21. Transdermal Applications of Nanoparticulates 327
Jongwon Shim
Index . . . . 339
viii
Contents
ix
Contributors
María José Blanco-Prieto Department of Pharmacy and Pharmaceutical Technology,
University of Navarra, Pamplona, Spain
Heike Bunjes Department of Pharmaceutical Technology, Institute of Pharmacy,
Friedrich Schiller University Jena, Jena, Germany
Matthew D. Burke Department of Pharmaceutical Development, GlaxoSmithKline,
Research Triangle Park, North Carolina, U.S.A.
Sudhir S. Chakravarthi Department of Pharmaceutical Sciences, University of
Nebraska Medical Center, Omaha, Nebraska, U.S.A.
Joseph F. Chiang Department of Chemistry and Biochemistry, State University of New
York at Oneonta, Oneonta, New York, U.S.A., and Department of Chemistry, Tsinghua
University, Beijing, China
Einat Cohen-Sela Department of Pharmaceutics, School of Pharmacy, The Hebrew

University of Jerusalem, Jerusalem, Israel
Sinjan De Research and Development, Perrigo Company, Allegan, Michigan, U.S.A.
Michel Deleers Global Pharmaceutical Technology and Analytical Development
(GPTAD), UCB, Braine l’Alleud, Belgium
Hannele Eerikäinen Pharmaceutical Product Development, Orion Corporation
Orion Pharma, Espoo, Finland
Victoria Elazar Department of Pharmaceutics, School of Pharmacy, The Hebrew
University of Jerusalem, Jerusalem, Israel
Hila Epstein-Barash Department of Pharmaceutics, School of Pharmacy, The Hebrew
University of Jerusalem, Jerusalem, Israel
Socorro Espuelas Department of Pharmacy and Pharmaceutical Technology,
University of Navarra, Pamplona, Spain
Carlos Gamazo Department of Microbiology, University of Navarra, Pamplona, Spain
Maria Rosa Gasco Nanovector srl, Torino, Italy
Gershon Golomb Department of Pharmaceutics, School of Pharmacy, The Hebrew
University of Jerusalem, Jerusalem, Israel
Juan M. Irache Department of Pharmacy and Pharmaceutical Technology,
University of Navarra, Pamplona, Spain
K. K. Jain Jain PharmaBiotech, Basel, Switzerland
Ashwath Jayagopal Biomaterials, Drug Delivery, and Tissue Engineering Laboratory,
Department of Biomedical Engineering, Vanderbilt University, Nashville,
Tennessee, U.S.A.
Esko I. Kauppinen NanoMaterials Group, Laboratory of Physics and Center for New
Materials, Helsinki University of Technology, and VTT Biotechnology, Helsinki, Finland
Judith Kuntsche Department of Pharmaceutical Technology, Institute of Pharmacy,
Friedrich Schiller University Jena, Jena, Germany
Vinod Labhasetwar Department of Pharmaceutical Sciences, University of Nebraska
Medical Center, Omaha, Nebraska, U.S.A.
Anna Lähde NanoMaterials Group, Laboratory of Physics and Center for
New Materials, Helsinki University of Technology, Helsinki, Finland

Robert J. Lee Division of Pharmaceutics, College of Pharmacy, NCI Comprehensive
Cancer Center, NSF Nanoscale Science and Engineering Center for Affordable
Nanoengineering of Polymeric Biomedical Devices, The Ohio State University,
Columbus, Ohio, U.S.A.
Annick Ludwig Department of Pharmaceutical Sciences, University of Antwerp,
Antwerp, Belgium
Dmitry Luzhansky Department of Corporate Technology, Donaldson Company, Inc.,
Minneapolis, Minnesota, U.S.A.
Rainer H. Müller Department of Pharmaceutical Technology, Biotechnology, and
Quality Management, Freie Universität Berlin, Berlin, Germany
Jan Möschwitzer Department of Pharmaceutical Technology, Biotechnology, and
Quality Management, Freie Universität Berlin, Berlin, Germany
Jean-Christophe Olivier Pharmacologie des Médicaments Anti-Infectieux, Faculty of
Medicine and Pharmacy, and INSERM, ERI 023, Poitiers, France
Giulio F. Paciotti CytImmune Sciences, Inc., Rockville, Maryland, U.S.A.
Yashwant Pathak UCB Manufacturing, Inc., Rochester, New York, U.S.A.
Manuela Pereira de Oliveira Pharmacologie des Médicaments Anti-Infectieux,
Faculty of Medicine and Pharmacy, and INSERM, ERI 023, Poitiers, France
Janne Raula NanoMaterials Group, Laboratory of Physics and Center for
New Materials, Helsinki University of Technology, Helsinki, Finland
Barrett E. Rabinow Baxter Healthcare Corporation, Round Lake, Illinois, U.S.A.
Dennis H. Robinson Department of Pharmaceutical Sciences, University of Nebraska
Medical Center, Omaha, Nebraska, U.S.A.
V. Prasad Shastri Biomaterials, Drug Delivery, and Tissue Engineering Laboratory,
Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, U.S.A.
Jongwon Shim Nanotechnology Research Team, Skin Research Institute, R&D
Center, Amorpacific Corporation, Kyounggi, South Korea
Eliana B. Souto Department of Pharmaceutical Technology, Biotechnology, and
Quality Management, Freie Universität Berlin, Berlin, Germany
Lawrence Tamarkin CytImmune Sciences, Inc., Rockville, Maryland, U.S.A.

Deepak Thassu UCB Pharma, Inc., Rochester, New York, U.S.A.
Jaspreet K. Vasir Department of Pharmaceutical Sciences, University of Nebraska
Medical Center, Omaha, Nebraska, U.S.A.
Jun Wu Division of Pharmaceutics, College of Pharmacy, The Ohio State University,
Columbus, Ohio, U.S.A.
Xiaobin Zhao Division of Pharmaceutics, College of Pharmacy, The Ohio State
University, Columbus, Ohio, U.S.A.
x
Contributors
1
Nanoparticulate Drug-Delivery
Systems: An Overview
Deepak Thassu
UCB Pharma, Inc., Rochester, New York, U.S.A.
Yashwant Pathak
UCB Manufacturing, Inc., Rochester, New York, U.S.A.
Michel Deleers
Global Pharmaceutical Technology and Analytical Development (GPTAD),
UCB, Braine l’Alleud, Belgium
INTRODUCTION
Nanotechnology and nanoscience are widely seen as having a great potential to bring
benefits to many areas of research and applications. It is attracting increasing invest-
ments from governments and private sector businesses in many parts of the world.
Concurrently, the application of nanoscience is raising new challenges in the safety,
regulatory, and ethical domains that will require extensive debates on all levels.
The prefix nano is derived from the Greek word dwarf. One nanometer (nm) is
equal to one-billionth of a meter, that is, 10
−9
m. The term “nanotechnology” was first
used in 1974, when Norio Taniguchi, a scientist at the University of Tokyo, Japan,

referred to materials in nano meters. The size range that holds so much interest is typi-
cally from 100 nm down to the atomic level approximately 0.2 nm, because in this
range materials can have different and enhanced properties compared with the same
material at a larger size. Figure 1 shows the nanometer in context (1). Nanotechnologies
have been used to create tiny features on computer chips for the last 25 years. The
natural world also contains many examples of nanoscale structures, from milk (a
nanoscale colloid) to the sophisticated nanosized and nanostructured proteins that
control a range of biological activities, such as flexing muscles, releasing energy, and
repairing cells. Nanoparticles (NPs) occur naturally and have been in existence for
thousands of years as products of combustion and cooking of food.
Nanomaterials differ significantly from other materials due to the following
two major principal factors: the increased surface area and quantum effects. These
factors can enhance properties such as reactivity, strength, electrical characteristics,
and in vivo behavior. As the particle size decreases, a greater proportion of atoms are
found at the surface compared to inside. For example, a particle size of 30 nm has 5%
of its atoms on the surface, at 10 nm 20%, and at 3 nm 50% of the atoms are on surface
(1). Thus, an NP has a much greater surface area per unit mass compared with larger
particles, leading to greater reactivity. In tandem with surface area effects, quantum
effects can begin to dominate the properties of matter as size is reduced to the nanos-
cale. These can affect the optical, electrical, and magnetic behavior of materials. Their
in vivo behavior can be from increased absorption to high toxicity of nanomaterials.
METHODS OF MEASUREMENTS AND CHARACTERIZATION
OF NANOMATERIALS
Nanometrology is the science of measurements at the nanoscale, and its application
underlies all the nanoscience and nanotechnology. The ability to measure and
1
2 Thassu et al.
FIGURE 1 (See color insert.) Length scale showing the nanometer in context. The length scale of interest for nanoscience and nanotech-
nologies is from 100 nm down to the atomic scale approximately 0.2 nm. Source: From Ref. 1.
Nanoparticulate Drug-Delivery Systems 3

characterize materials, as well as determine their shape, size, and physical pro-
perties at the nanoscale is vital for nanomaterials and devices. These need to be
produced to a high degree of accuracy and reli ability, to realize the applications
of nanotechnologies. Nanometrology includes length and/or size (where dimen-
sions are typically in nanometers) as well as measurement of force, mass, electrical,
and other properties. Four commonly used techniques are: transmission
electron microscopy (TEM), scanning electron microscopy (SEM), scanning probe
techniques [scanning probe microscopy (SPM)], and optical tweezers (single-beam
gradient trap).
Transmission Electron Microscopy
TEM is used to investigate the internal structure of micro- and nanostructures. It works
by passing electrons through the samples and then using magnetic lenses to focus the
image of the structure. TEM can reveal the finest details of the internal structure, in
some cases the individual atoms. TEM with high-resolution transmission electron
microscopy is the important tool for the study of NP.
Scanning Electron Microscopy
SEM uses the basic technology developed for TEM, but the beam of electrons is
focused to a diameter spot of approximately 1 nm on the surface of the specimen and
scanned repetitively across the surface. It reveals that the surface topography of the
sample with the best spatial resolution currently achieved is on the order of 1 nm.
Scanning Probe Techniques (Scanning Probe Microscopy)
SPM uses the interaction between a sharp tip and a surface to obtain the image. The
sharp tip is held very close to the surface to be examined and is scanned back and
forth. As the tip is scanned across the sample, the displacement of the end of the
cantilever is measured, using a laser beam. This can image insulating materials
simply because the signal corresponds to the force between the tip and the sample,
which reflects the topography being scanned. The scanning tunneling microscope
brought a Noble prize for physics to Gerd Binnig and Heinrich in 1986. The atomic
force microscope uses this SPM technique, which reflects the surface topography of
the samples.

Optical Tweezers (Single-Beam Gradient Trap)
Optical tweezers use a single laser beam (focused by a high-quality microscope
objective) to a spot on the specimen plane. The radiation pressure and gradient
forces from the spot create an optical trap, which holds a particle at its center. Small
interatomic forces and displacements can be measured by this technique. Samples
that can be analyzed range from single atoms to micrometer-sized spheres to strands
of DNA and living cells. Numerous traps can be used simultaneously with other
optical techniques, such as scalpels, which can cut the particle being studied. Various
analytical techniques utilized in nanometrology are enumerated in Table 1.
MANUFACTURE OF NANOMATERIALS
There are a wide variety of techniques that are capable of creating nanostructures
with various degrees of quality, speed, and cost. These manufacturing approaches
4 Thassu et al.
fall under two categories: bottom-up and top-down. Figure 2 illustrates the types of
materials and products which can be manufactured using these two approaches (1).
Bottom-Up Manufacturing
Bottom-up manufacturing involves the building of nanostructures atom by atom or
molecule by molecule. This can be done in three ways: chemical synthesis, self-
assembly, and positional assembly.
Chemical synthesis is a method of producing raw materials, such as molecules or
particles, which can then be used either directly in products in their bulk-disordered
form or as the building blocks of more advanced ordered materials. Figure 3 repre-
sents the generic processes that are involved in the production of NPs (1):
1. Self-assembly is a production technique in which atoms or molecules arrange
themselves into ordered nanoscale structures by physical or chemical interactions
within the smaller units. The formation of salt crystals and snowflakes with their
intricate structure are examples of the self-assembly process. Although self-
assembly occurs in nature, in industry it is relatively new and not a well-
established process (1).
TABLE 1 Analytical Techniques Used for Characterization of Nanoparticles

Name of the technique Reference
Laser diffraction
Photon correlation spectroscopy
Wide-angle X-ray scattering
Differential scanning colorimetry
Proton nuclear magnetic resonance spectroscopy
Electron spin resonance
(2)
Electron transmission microscopy (3)
Sedimentation velocity analysis and EM (4)
DLS and cryo-TEM (5)
DLS and TEM (6)
Flow cytometry and ELISA method (7)
Fluorometry (8)
Fluorescence and TEM (9)
Abbreviations: DLS, dynamic light scattering; ELISA, enzyme-linked immunosorbent assay; EM,
electron microscopy; NP, nanoparticle; TEM, transmission electron microscopy.
FIGURE 2 The use of bottom-up and top-down techniques in manufacturing nanoparticles.
Abbreviation: MEMS, microelectromechanical system. Source: From Ref. 1.