Nanoparticle Technology for Drug Delivery

418 Pages·2006·12.935 MB·English

by  Ram B. Gupta and Uday B. Kompella

DK5687_half-series-title.qxd 11/17/05 8:57 AM Page i
Nanoparticle Technology
for Drug Delivery
edited by
Ram B. Gupta
Auburn University
Auburn, Alabama
Uday B. Kompella
University of Nebraska Medical Center
Omaha, Nebraska
New York London
DK5687_Discl.fm Page 1 Tuesday, November 15, 2005 11:40 AM
Published in 2006 by
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Preface
Products of nanotechnology are expected to revolutionize
modern medicine, as evidenced by recent scientific advances
and global initiatives to support nanotechnology and nano-
medicine research. The field of drug delivery is a direct bene-
ficiary of these advancements. Due to their versatility in
targeting tissues, accessing deep molecular targets, and con-
trolling drug release, nanoparticles are helping address chal-
lenges to face the delivery of modern, as well as conventional
drugs. Since the majority of drug products employ solids,
nanoparticles are expected to have a broad impact on drug
product development. The purpose of this book is to present
practical issues in the manufacturing and biological applica-
tion of nanoparticles. Drug delivery scientists in industry,
academia,andregulatoryagencies,aswellasstudentsinbio-
medical engineering, chemical engineering, pharmaceutical
sciences,and other scienceswithaninterest in drug delivery,
iii
iv Preface
will find this book useful. It can alsobe used as a textbook for
drug delivery courses focusing on nanoparticles.
Thisbookisorganizedintofoursections.Thefirstsection
describes the distinguishing fundamental properties of nano-
particles (Chap. 1) as well as technologies for nanoparticle
manufacturing (Chaps. 2–4). Nanoparticles can be manufac-
tured by either breaking macro-particles using technologies
such as milling and homogenization (Chap. 2) or by building
particles from molecules dissolved in a solution using super-
criticalfluidtechnology(Chap.3).Nanoparticlemanufacturing
and properties can be further optimized by employing poly-
mers or proteins as stabilizers (Chap. 4).
Thesecondsectiondescribesthecharacterizationofnano-
particlesatthematerialorphysicochemicallevel(Chap.5)and
relates these properties to the delivery and effectiveness of
nanoparticles (Chap. 6) as well as toxicological characteristics
(Chap. 7).
The third section presents the various applications of
nanoparticles in drug delivery. Depending on the route and
purposeofdrugdelivery,therequirementsfornanoparticulate
systemscanvary.TheseaspectsarediscussedinChapter8for
injectable delivery, Chapter 9 for oral delivery, Chapter 10for
braindelivery,Chapter11foroculardelivery,andChapter12
forgenedelivery.
Finally, the fourth section provides an overview of the
clinical, ethical, and regulatory issues of nanoparticle-based
drugdelivery. Theseareevolvingareasandthedrugproduct
development experience with nanoparticles is limited. As
more data is gathered on the safety and efficacy of nanoparti-
culate systems, a clearer view will emerge.
Preparation of this book would not have been possible
without the valuable contributions from various experts in
the field. We deeply appreciate their timely contributions.
Also, we are thankful to our colleagues at Auburn University
and the University of Nebraska Medical Center for their
support in preparing this book.
Ram B. Gupta
Uday B. Kompella
Contents
Preface . . . . iii
Contributors . . . . xi
PART I: TECHNOLOGIES FOR NANOPARTICLE
MANUFACTURING
1. Fundamentals of Drug Nanoparticles . . . . . . . . 1
Ram B. Gupta
Introduction . . . . 1
Nanoparticle Size . . . . 2
Nanoparticle Surface . . . . 3
Nanoparticle Suspension and Settling . . . . 4
Magnetic and Optical Properties . . . . 6
Production of Nanoparticles . . . . 6
Biological Transport of Nanoparticles . . . . 12
Conclusions . . . . 17
References . . . . 18
v
vi Contents
2. Manufacturing of Nanoparticles by Milling
and Homogenization Techniques . . . . . . . . . . . 21
Rainer H. Mu€ller, Jan Mo€schwitzer, and
Faris Nadiem Bushrab
Introduction . . . . 21
Pearl/Ball-Milling Technology for the Production of
Drug Nanocrystals . . . . 25
Drug Nanocrystals Produced by
High-Pressure Homogenization . . . . 28
Production of Drug Nanocrystal Compounds by
Spray-Drying . . . . 33
Production in Nonaqueous Liquids . . . . 35
Production in Hot-Melted Matrices . . . . 37
Pelletization Techniques . . . . 41
Direct Compress . . . . 45
References . . . . 47
3. Supercritical Fluid Technology for
Particle Engineering . . . . . . . . . . . . . . . . . . . . . 53
Ram B. Gupta
Introduction . . . . 53
Supercritical CO . . . . 54
2
Solubility in Supercritical CO . . . . 55
2
Rapid Expansion of Supercritical Solution for
Particle Formation . . . . 59
RESS with Solid Cosolvent for Nanoparticle
Formation . . . . 63
Supercritical Antisolvent Process for Particle
Formation . . . . 66
SAS with Enhanced Mass (EM) Transfer
(SAS-EM) Process for Nanoparticle
Formation . . . . 69
Fundamentals Governing Particle Formation with
RESS and SAS . . . . 70
Other Applications of SCFs for
Particle Engineering . . . . 74
Safety and Health Issues . . . . 78
Conclusions . . . . 78
References . . . . 79
Contents vii
4. Polymer or Protein Stabilized Nanoparticles
from Emulsions . . . . . . . . . . . . . . . . . . . . . . . . . 85
Ram B. Gupta
Introduction . . . . 85
Emulsification Solvent Evaporation Process . . . . 86
Emulsification . . . . 87
Nanoparticle Hardening . . . . 93
Residual Solvent and Emulsifier . . . . 97
Protein Stabilized Nanoparticles . . . . 98
Conclusions . . . . 99
References . . . . 101
PART II: NANOPARTICLE CHARACTERIZATION
AND PROPERTIES
5. PhysicalCharacterizationofNanoparticles ... 103
Roy J. Haskell
Introduction . . . . 103
Measurement of Size . . . . 105
Available Methods . . . . 109
In Vitro Release . . . . 119
Example: Particle Size . . . . 121
Conclusions . . . . 130
References . . . . 132
6. Nanoparticle Interface: An Important
Determinant in Nanoparticle-Mediated
Drug/Gene Delivery . . . . . . . . . . . . . . . . . . . . . . 139
Sanjeeb K. Sahoo and Vinod Labhasetwar
Introduction . . . . 139
Influence of Emulsifier on
Pharmaceutical
Properties of Nanoparticles . . . . 140
Implication on Cellular Uptake/Toxicity/Gene
Delivery . . . . 148
Biodistribution . . . . 153
Conclusions . . . . 154
References . . . . 154
viii Contents
7. Toxicological Characterization of Engineered
Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Paul J. A. Borm and Roel P. F. Schins
Introduction . . . . 161
Inhalation of Particles . . . . 164
Effects of Nanoparticles . . . . 170
Screening Engineered NP for Toxicological
Hazards . . . . 178
Conclusion . . . . 187
References . . . . 188
PART III: DRUG DELIVERY APPLICATIONS OF
NANOPARTICLES
8. Injectable Nanoparticles for Efficient Drug
Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Barrett Rabinow and Mahesh V. Chaubal
Introduction: Medical Needs Addressable by
Nanoparticulate Drug Delivery . . . . 199
Types of Carriers . . . . 209
Coating Functionality . . . . 215
External Assistance in Targeting . . . . 215
Drugs Incorporated . . . . 216
Clinical Development . . . . 217
Conclusions . . . . 220
References . . . . 221
9. Polymeric Nanoparticles for Oral Drug
Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Vivekanand Bhardwaj and Majeti Naga Venkata Ravi
Kumar
Introduction . . . . 231
Physiology of GIT with Relevance to Particulate
Uptake . . . . 232
Particle Size and Surface Charge: Critical Factors in
Particle Absorption . . . . 236
Bioadhesion . . . . 237
Tracer Techniques . . . . 241
Contents ix
In Vitro and In Vivo Models . . . . 243
Nanoparticle Formulation . . . . 244
Applications . . . . 253
Future Directions . . . . 260
References . . . . 262
10. Brain Delivery by Nanoparticles . . . . . . . . . . . 273
Svetlana Gelperina
Introduction . . . . 273
Biodistribution Studies . . . . 276
Pharmacological Activity . . . . 289
Mechanisms of Drug Delivery to the Brain by
Means of Polymeric NP . . . . 296
Conclusions . . . . 309
References . . . . 311
11. Nanoparticles for Ocular Drug Delivery . . . . . 319
Aniruddha C. Amrite and Uday B. Kompella
Introduction . . . . 319
Disposition of Nanoparticles in the Eye . . . . 322
Ocular Drug Delivery Enhancement Using
Nanoparticles . . . . 336
Safety and Tolerability of Particulate
Systems . . . . 347
Conclusions . . . . 352
References . . . . 353
12. DNA Nanoparticle Gene Delivery Systems . . . 361
Moses O. Oyewumi and Kevin G. Rice
Gene Delivery Vectors . . . . 361
Polymers Used to Prepare DNA
Nanoparticles . . . . 363
Physical Properties of DNA Nanoparticles . . . . 365
Biodistribution and Trafficking of DNA
Nanoparticles . . . . 371
Conclusions . . . . 372
References . . . . 373