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Drug delivery systems 3rd ed Edition Cannon Digital
Instant Download
Author(s): Cannon, John B.; Ranade, Vasant V
ISBN(s): 9781439806197, 1439806195
Edition: 3rd ed
File Details: PDF, 23.63 MB
Year: 2011
Language: english
DRUG
DELIVERY
SYSTEMS
T h i r d E d i t i o n
DRUG
DELIVERY
SYSTEMS
T h i r d E d i t i o n
Vasant V. Ranade
John B. Cannon
Boca Raton London New York
CRC Press is an imprint of the

Taylor & Francis Group, an informa business
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This book is dedicated
to our families.
Vasant V. Ranade
John B. Cannon
Contents
Preface to the Third Edition..................................................................................... xv
Authors....................................................................................................................xvii
Chapter 1 Site-Specific Drug Delivery Using Liposomes and Emulsions

as Carriers............................................................................................. 1
Introduction........................................................................................... 1
Liposomes in Drug Delivery.................................................................2
Regional Drug Delivery...................................................................2
Chemical Characteristics of Liposomes........................................... 3
Liposome-Drug Concept.......................................................................5
Liposome Size.................................................................................. 5
Targeting Ligands............................................................................. 6
Problems and Advantages of Liposomal Drug Delivery.................. 6
Manufacturing Methods and Issues.................................................8
Liposomes as Carriers of Therapeutic Agents.................................... 12
Application..................................................................................... 12
Liposomal Products and Manufacturers........................................ 15
Parenteral Emulsions........................................................................... 18
Recent Advances and Future Prospects..............................................20
Highlights of Current Research......................................................20
Concluding Remarks........................................................................... 32
References........................................................................................... 32
Chapter 2 Site-Specific Drug Delivery Utilizing Monoclonal Antibodies.......... 47

Introduction......................................................................................... 47
Chemistry....................................................................................... 47
Polyclonals vs. Monoclonals........................................................... 47
Conjugation of Antibodies.............................................................. 48
Production of Monoclonal Antibodies................................................ 48
Continuously Proliferating Cell Lines............................................ 49
Human–Human Hybridomas......................................................... 49
Large-Scale Production.................................................................. 50
Drug–Monoclonal Antibody Conjugates for Drug Targeting............. 50
Principles........................................................................................ 50
Drug Antibody Bonding................................................................. 51
In Vitro and In Vivo Testing........................................................... 51
Recent Studies with Monoclonal Antibodies...................................... 54
Highlights of Current Research...................................................... 54
Conclusion and Basis for Future Trends............................................. 70
References........................................................................................... 71
vii
viii Contents
Chapter 3 Role of Polymers in Drug Delivery..................................................... 79

Introduction......................................................................................... 79
Currently Available Polymers............................................................. 79
Diffusion-Controlled Systems........................................................ 79
Solvent-Activated Systems.............................................................80
Chemically Controlled Systems.....................................................80
Magnetically Controlled Systems..................................................80
Soluble Polymers as Drug Carriers..................................................... 81
Pinocytosis...................................................................................... 81
Ideal Soluble Polymers................................................................... 82
Biodegradable or Bioerodible Polymers..............................................84
Drug Release by Matrix Solubilization..........................................90
Erodible Diffusional Systems......................................................... 91
Monolithic Systems........................................................................ 91
Mucoadhesive Polymers......................................................................94
Polymers Containing Pendant Bioactive Substituents........................ 98
Matrix Systems.................................................................................. 101
Heparin-Releasing Polymers............................................................. 103
Ionic Polymers................................................................................... 104
Oligomers.......................................................................................... 109
Miscellaneous.................................................................................... 109
Recent Advances............................................................................... 111
Conclusion......................................................................................... 122
References......................................................................................... 124
Chapter 4 Implants in Drug Delivery................................................................ 137

Introduction....................................................................................... 137
Insulin Delivery as a Model Implant Pump System......................... 138
Peristaltic Pumps.......................................................................... 141
Fluorocarbon Propellant-Driven Pumps...................................... 143
Osmotic Pumps............................................................................. 144
Miniosmotic Pumps: Systemic Delivery...................................... 146
Miniosmotic Pumps: Local Delivery........................................... 146
Miniosmotic Pumps: Patterned Delivery..................................... 147
Positive-Displacement Pumps...................................................... 148
Controlled-Release Micropump................................................... 148
Other Devices............................................................................... 150
Implants for Contraception................................................................ 150
Biodegradable............................................................................... 150
Nonbiodegradable......................................................................... 151
Delivery of Chemotherapeutic Agents Using Implants.................... 152
Recent Advances in Implants and Related Devices
(Excluding Inserts)............................................................................ 154
Contents ix
Future Prospects................................................................................ 161

References......................................................................................... 162
Chapter 5 Oral Drug Delivery........................................................................... 169

Controlled-Release Formulations...................................................... 169
Introduction.................................................................................. 169
Features of the GI Tract................................................................ 171
Targeting of Drugs in the GI Tract............................................... 172
Mathematical Models for Controlled-Release Kinetics............... 173
Design and Fabrication of Oral Delivery Systems....................... 174
Dissolution-Controlled Release............................................... 174
Osmotically Controlled Release.............................................. 176
Diffusion-Controlled Release.................................................. 179
Chemically Controlled Release............................................... 184
Miscellaneous Forms of Controlled Release........................... 184
Survey of Oral Controlled-Release Products............................... 198
Recent Advances.......................................................................... 198
Current Development of Oral Drug Delivery Systems................205
Conclusion....................................................................................209
References......................................................................................... 210
Enhancing Oral Bioavailability......................................................... 215
Introduction.................................................................................. 215
Increasing Bioavailability of Water-Insoluble Drugs................... 216
General Approaches for Water-Insoluble Drugs: Salt
Formation, Cosolvents, and Particle Size Reduction............... 216
Lipid-Based and Micellar Formulations.................................. 217
Solid Dispersions and Related Technologies........................... 231
Cyclodextrins and Complexation Techniques......................... 234
Increasing Bioavailability of Proteins, Peptides,
and Other Drugs with Absorption Problems................................ 235
Recent Advances and Future Prospects....................................... 236
References......................................................................................... 238
Chapter 6 Transdermal Drug Delivery.............................................................. 243

Introduction....................................................................................... 243
Theoretical Aspects of Transdermal Drug Delivery......................... 245
Structure of Human Skin.............................................................. 245
Mechanisms of Penetration..........................................................246
Optimization of Percutaneous Absorption and Effects
of Penetration Enhancers.............................................................. 253
Development of the Transdermal Therapeutic System..................... 257
Types of Transdermal Patches...................................................... 257
Formulation.................................................................................. 259
x Contents
Adhesion.......................................................................................260
Bioactivity and Metabolism.......................................................... 261
Polymers in Transdermal Delivery Systems................................ 262
Examples of Transdermal Applications............................................ 262
Diseases for Which TDD Is Used................................................ 262
Current Transdermal Products and Devices................................ 263
“Minimally Invasive” Technologies............................................. 265
Iontophoresis Systems............................................................. 267
Microneedle Systems............................................................... 270
Other Minimally Invasive and Combination Systems............. 272
Other Transdermal Controlled-Release Products and Devices.... 273
Recent Advances and Future Prospects............................................ 274
Conclusion......................................................................................... 287
References......................................................................................... 288
Chapter 7 Transmucosal and Ocular Drug Delivery......................................... 305

Introduction: Transmucosal and Ocular Drug Delivery................... 305
Pulmonary Drug Delivery................................................................. 305
Introduction.................................................................................. 305
Lung Physiology and Pulmonary Drug Administration.............. 305
Pulmonary Drug Delivery Devices..............................................306
Recent Advances.......................................................................... 317
Intranasal Drug Delivery.................................................................. 322
Introduction.................................................................................. 322
Nasal Physiology and Intranasal Drug Administration............... 323
Nasal Drug Delivery Devices....................................................... 325
Examples of Intranasal Drug Delivery Systems.......................... 327
Recent Advances.......................................................................... 332
Buccal and Sublingual Drug Delivery.............................................. 333
Introduction.................................................................................. 333
Examples of Buccal and Sublingual Drug Delivery Systems...... 335
Recent Advances.......................................................................... 335
Rectal, Vaginal, and Other Forms of Transmucosal Drug Delivery..... 337
Intravaginal Delivery.................................................................... 337
Rectal Delivery............................................................................. 341
Ocular Drug Delivery........................................................................ 347
Introduction.................................................................................. 347
Relevant Anatomy and Physiology of the Eye..............................348
Examples of Ocular Drug Delivery Systems............................... 352
Recent Advances.......................................................................... 357
Conclusions and Future Outlook for Transmucosal
and Ocular Drug Delivery................................................................. 359
References......................................................................................... 361
Contents xi
Chapter 8 Miscellaneous Forms of Drug Delivery............................................ 373

Introduction....................................................................................... 373
Pro-Drugs.......................................................................................... 373
Infusion Devices................................................................................ 382
Pumps�� 382
Mechanical Pumps.................................................................. 382
Closed- and Open-Loop Systems............................................ 382
Programmable and Manual Systems....................................... 383
Implantable and External Systems.......................................... 383
Syringe Pumps......................................................................... 383
Piston Pumps........................................................................... 383
Peristaltic Pumps..................................................................... 383
Balloon Pumps......................................................................... 384
Gas-Pressure Pumps................................................................ 384
Portable Infusion Pumps......................................................... 384
Controllers............................................................................... 384
Other External Infusion Systems................................................. 385
Percutaneous Catheters............................................................ 385
Totally Implantable Pump and Reservoir Systems.................. 386
Totally Implantable Portal and Catheter Systems................... 387
Insulin Delivery................................................................................. 388
Parenteral Prolonged-Action Dosage Forms..................................... 391
Complex Formation and Addition of Macromolecules................ 392
Salts of Low Solubility and Slowly Hydrolyzable Esters............. 392
Aqueous Suspensions................................................................... 392
Oleaginous Suspensions and Emulsions....................................... 393
Precipitation of Drug in Tissue.................................................... 393
Implants........................................................................................ 393
SC Drug Delivery Systems........................................................... 394
Intravenous Delivery................................................................ 395
Magnetically Modulated Systems................................................ 397
Intrauterine Delivery.................................................................... 399
Microspheres................................................................................403
Hydrogels......................................................................................406
Microcapsules and Microencapsulation....................................... 411
Microparticles—Nanoparticles.................................................... 414
Colloids and Microemulsions....................................................... 417
Hollow Fibers............................................................................... 421
Ultrasonically Controlled............................................................. 422
Liquid-Crystalline Phases............................................................ 423
Time-Controlled “Explosion Systems”........................................ 423
Mammalian Cells......................................................................... 423
Sutures�� 424
Microsealed Drug Delivery.......................................................... 425
xii Contents
Recent Advances............................................................................... 426

Summary........................................................................................... 436
References......................................................................................... 436
Chapter 9 Nanoscience and Nanotechnology for Drug Delivery...................... 451

Introduction....................................................................................... 451
Nanotechnologies.............................................................................. 451
Fundamentals............................................................................... 453
Biopharmaceutical, Physiological, and Clinical
Considerations.............................................................................. 453
Delivery of Small Molecules, Proteins, and Nucleic Acids......... 463
Nanoethics, Safety, and Risk Assessment.................................... 467
Nanomaterial Characterization.................................................... 467
FDA Regulations and Manufacturers...........................................468
Building Business and Trends...................................................... 470
Miscellaneous Applications of Nanomaterials................................. 471
Nano-oncology............................................................................. 471
Nanoneurology and Nanoneurosurgery........................................ 478
Nanodermatology, Nanopulmonology, Nanogeriatrics,
Nanoimmunology, and Nanodentistry.......................................... 479
Nano-orthopedics.........................................................................480
Nanomicrobiology........................................................................480
Nanodevices for Medicine and Surgery.......................................480
Nanocardiology............................................................................ 481
Nano-ophthalmology.................................................................... 481
Nanobiotechnology for Regenerative Medicine and Tissue
Engineering.................................................................................. 482
Nanomolecular Diagnostics.......................................................... 482
Nanotechnology for Gene and Vaccine Delivery.........................484
Nanoparticles and Nanostructures.................................................... 485
Nanoparticles................................................................................ 487
Nanocomposites........................................................................... 493
Nanotubes, Nanorods, Nanofibers, and Nanohorns..................... 493
Nanocarriers............................................................................ 499
Nanochips................................................................................500
Nanosized Colloids..................................................................500
Nanoemulsions......................................................................... 501
Nanocrystals............................................................................ 501
Nanostructures......................................................................... 501
Nanomaterials.......................................................................... 502
Nanomedicine and Nanopharmaceuticals......................................... 507
Worldwide Development.............................................................. 507
Future Prospects........................................................................... 511
References......................................................................................... 513
Contents xiii
Chapter 10 Regulatory Considerations for Drug Delivery Systems.................... 525

Introduction....................................................................................... 525
Current Status of Drug Delivery Technology................................... 528
Regulatory Requirements............................................................. 528
Bioavailability Data...................................................................... 532
The Reference Standard............................................................... 533
Requirements to Demonstrate Drug Controlled-Release............. 533
In Vitro Drug Release Data..................................................... 533
In Vivo Bioavailability Data.................................................... 533
Bioequivalence.............................................................................540
Stability Testing............................................................................ 542
Submission of Documents for Manufacture and Quality..................546
Control of Drug Products.............................................................546
Drug Product (NDAs and ANDAs).........................................546
Regulatory Specifications and Methods for Drug Products...... 548
Methods of Manufacturing and Packaging............................. 550
Current FDA Draft Guidelines and Regulations..................... 551
Implants�� 555
Monoclonal Antibodies........................................................... 556
Computer Access and Security Requirements........................ 558
References......................................................................................... 559
Chapter 11 Drug Delivery Industry and the Global Outlook.............................. 563

Basis for the Recent Trend................................................................ 569
References......................................................................................... 572
Preface to the Third Edition
A few years ago, Dr. Mannfred Hollinger passed away unexpectedly. He will be
missed and remembered by his colleagues for his expertise in the pharmacological
and toxicological sciences and, in particular, drug delivery.
During the preparation of the third edition of this book, I was fortunate to receive
timely help form Dr. John Cannon, who agreed to offer his views and comments on
various forms of drug delivery systems, especially oral, transdermal, transmucosal,
and liposomal forms of drug delivery. In this edition, we have attempted to include
relevant information regarding drug delivery systems that was published through the
end of 2009. A new chapter on nanoscience and nanotechnology for drug delivery
has been included. In a short, concise volume on drug delivery such as this one, it is
almost impossible to include every detail on the subject. However, we have made an
honest attempt to include research and development work so that the reader will be
adequately informed about the current trend and the future prospects of the science
of drug delivery.
We would like to thank our colleagues, especially Dr. John Somberg and Ms. Susan
Somberg, for their continued support. We would also like to express our deep sense
of gratitude to our wives, Usha and Charlene, for their constant encouragement and
assistance. Also we would like to thank staff of CRC Press/Taylor & Francis Group
for their patience, understanding and help during preparation of this book.
Finally, as an interesting note, Dr. Stephen R. Covey in his bestseller book,
The 7 Habits of Highly Effective People, mentioned that “I did not invent them and
take no credit for them. I have simply identified and organized them into a sequential
framework.” This scenario is also applicable to our endeavor of presentation of the
science of drug delivery in this edition.
xv
Authors
Vinayak (Vasant) V. Ranade, PhD, is director of chemical sciences for Academic
Pharmaceuticals Inc. in Lake Bluff, Illinois. He also holds a faculty position in the
Department of Pharmacology at Rush University Medical Center in Chicago, Illinois.
Dr. Ranade received his PhD in organic chemistry from Bombay University in
1965 and his postdoctoral training in the College of Pharmacy at the University of
Michigan, Ann Arbor, Michigan. He has worked as a research chemist for Abbott
Laboratories, Mallinckrodt Inc., and DuPont Critical Care. Dr. Ranade is a member
of the American Chemical Society; APhA Academy of Pharmaceutical Sciences;
and the honorary society, Sigma Xi. He was awarded the Council of Scientific and
Industrial Research Fellowship and was elected fellow of the American Institute of
Chemists. He was the corecipient of the Genia Czerniak Prize for Nuclear Medicine
and Radiopharmacology.
Over the past 40 years, Dr. Ranade has been a reviewer for a number of scien-
tific journals and has presented research work at the American Chemical Society,
the APhA Academy of Pharmaceutical Sciences, and the American College of
Cardiology and Pharmacology meetings. He has published more than 200 papers,
including original and review articles, book chapters, book reviews, and abstracts
for presentation. He is the recipient of several U.S. patents and his research work has
also been included in Canadian, European, and International patents. He coauthored
the first and second editions of the book titled Drug Delivery Systems published
by CRC Press. He also developed and directed courses on drug delivery technolo-
gies for the Center of Business Intelligence (Massachusetts) and the Center for
Professional Advancement (New Jersey) for presentation in Europe and the United
States. Dr. Ranade is on the editorial board of the American Journal of Therapeutics
and his biography is listed in American Men and Women of Science and Who’s Who
in Technology Today’s (Chemistry and Biotechnology).
Dr. Ranade’s significant contributions to pharmaceutical research and develop-
ment for marketed products include radiosynthesis, formulations, and chiral chro-
matographic separations. He also worked as a consultant in the areas of chemical
and pharmaceutical technology for some industrial organizations, securities market
analysis companies, and research organizations in the United States.
John B. Cannon, PhD, Trinity International University, Deerfield, Illinois, is cur-

rently a visiting assistant professor of chemistry at Trinity International University
in Deerfield, Illinois, and is also president of his own drug delivery and pharma-
ceutics consulting firm, Targeted Drug Solutions, Inc., in Grayslake, Illinois. He
received his BS in chemistry from Duke University and his PhD in organic chemis-
try from Princeton University; his dissertation research focused on organo-transition
metal chemistry. After a postdoctoral fellowship at the University of California at
San Diego investigating hemoglobin model compounds, Dr. Cannon served in fac-
ulty positions at Northern Illinois University and Cleveland State University (Ohio),
xvii
xviii Authors
as well as in visiting scientist research positions at Scripps Clinic and Research

Foundation (California) and at Cornell University Medical College (New York). He
made significant contributions to understanding the interaction of metalloporphy-
rins and heme proteins with biological membranes and liposomes. This was fol-
lowed by a research chemist position at American Cyanamid Company’s Veterinary
Research Division investigating parenteral controlled release formulations of protein
and peptide hormones. He recently retired from a 20 year career as a pharmaceu-
tical scientist at Abbott Laboratories, where he focused on oral lipid-based drug
delivery systems, water-insoluble drug formulations, liposomes, emulsions, topical/
transdermal drug delivery, preformulation/basic pharmaceutics, and Phase I formu-
lation development. He is a member of the American Association of Pharmaceutical
Scientists, the American Scientific Affiliation, the American Chemical Society,
and Sigma Xi. Dr. Cannon has published over 30 papers in peer-reviewed journals,
12 book chapters, and 4 patents. He has also made about 15 presentations with pub-
lished abstracts at meetings of various scientific societies and has been a reviewer for
a number of scientific journals.
1 Site-Specific Drug
Delivery Using
Liposomes and
Emulsions as Carriers*
INTRODUCTION
Over the past three decades, significant advances have been made in drug delivery
technology. This effort, pioneered by Alza Laboratories of Palo Alto, California,1,2
among others, has been accelerated in recent years due to a decline in the devel-
opment of new drug entities. Drug delivery has now become a multidisciplinary
science consisting of biopharmaceutics and pharmacokinetics. Great strides have
also been made by physical biochemists, pharmacists, and other pharmaceutical
research scientists working in university and industrial laboratories.3–6
The underlying principle that drug delivery technology, per se, can bring both
therapeutic and commercial value to health care products has been widely accepted.
Recently, large pharmaceutical companies have been losing their market share to
generic competitors with increasing rapidity after their patents expire. This has created
an intense need for presenting “old” drugs in new forms and utilizing novel forms of
delivery. As a result, companies developing new drug delivery systems seem to enjoy
a good return on their investment in the form of increased revenues and market share.7
In the United States, the Drug Price Competition and Patent Term Restoration
Act (also known as ANDA-Exclusivity Provisions Act) was passed in 1984. This
provided new incentives to manufacturers who can distinguish their products from
competition, with features such as longer dosage schedules, improved safety profiles,
new indications for existing drugs, and new combinations.8
The following chapters, which focus on the area of research and development in
the drug delivery field, have been divided into five sections:
1. Site-specific drug delivery

2. Polymers and implantable drug delivery systems
3. Oral drug delivery
4. Transdermal, transmucosal, ocular, and miscellaneous drug delivery systems
5. Regulatory considerations and global outlook
* Adapted in part from Ranade, V.V., Drug delivery systems. 1. Site specific drug delivery using lipo-
somes as carriers, J. Clin. Pharmacol., 29, 685, 1989. With permission of the J. Clin. Pharmacol., and
J.B. Lippincott Publishing Company, Philadelphia, PA.
1
2 Drug Delivery Systems
Drug delivery, which takes into consideration the carrier, the route, and the target, has
evolved into a strategy of processes or devices designed to enhance the efficacy of ther-
apeutic agents through controlled release. This may involve enhanced bioavailability,
improved therapeutic index, or improved patient acceptance or compliance. Drug deliv-
ery, or controlled release, has been defined by Flynn as “the use of whatever means
possible, be it chemical, physiochemical, or mechanical, to regulate a drug’s access rate
to the body’s central compartment or, in some cases, directly to the involved tissues.”9
Tomlinson10 has emphasized features such as exclusive delivery to specific com-
ponents, access to primarily inaccessible sites, protection of body from unwanted
deposition, controlled rate and modality of delivery to pharmacological receptors,
and reduction in the amount of active principal employed. Tomlinson10,11 has also
described the properties that are needed for site-specific carriers, as well as proper-
ties that are biological, drug related, and carrier related.
LIPOSOMES IN DRUG DELIVERY

Regional Drug Delivery
Most efforts to make drug therapy more efficient by direct delivery of drugs to affected
tissues have focused on local or regional injection techniques, such as intra-arterial or
infusions into body cavities, such as the peritoneum. The benefits of regional therapy
include reducing systemic toxicity and achieving peak drug levels directly at the tar-
get site. However, these methods of administration have met with limited success.
For example, although intra-arterial injections effectively concentrate drugs at certain
tumor sites, in others the drug is cleared from the system so rapidly that the benefits are
not realized. Currently, pharmaceutical researchers are trying to design drug delivery
systems that will localize drugs and affect only the afflicted tissues. A carrier system
that has received considerable attention in this regard is liposomes.12–17 Emulsions
have received somewhat less attention as carriers of therapeutic agents, but they also
have the potential for delivery of water-insoluble drugs, which will be discussed later.
Liposomes consist of a bilayer of amphipathic lipid molecules (usually phospho-
lipids) encapsulating an aqueous space.18 The lipid molecules arrange themselves
into layers, referred to as lamellae, by exposing their polar “head” groups toward
the water phase. The hydrophobic hydrocarbon “tail” groups adhere together in the
bilayer, thus forming close, concentric, bimolecular lipid leaflets separating aqueous
compartments. Liposomes vary in charge and size, ranging from 20 nm to 10 μm,
depending on the method of preparation and the lipids used.
Drug molecules can be either encapsulated in the aqueous space or intercalated
into the bilayer (see Figures 1.1 and 1.2).265 The exact location of the drug in the lipo-
some depends upon the physiochemical characteristics of the drug and the composi-
tion of the constituent lipids.19 Stable liposomes from phospholipids are formed only
at temperatures above the “gel to liquid-crystalline” phase transition temperature
(Tc). This represents the melting point of the acyl chains. All phospholipids have
a characteristic Tc, which depends upon the nature of the polar head group and on
the length and degree of unsaturation of the acyl chains.19,20 Above the transition
temperature, phospholipids form a liquid-crystalline phase that constitutes increased
Site-Specific Drug Delivery Using Liposomes and Emulsions as Carriers 3
Amphiphatic Polar solute in

molecule aqueous phase
Polar head
of lipid
Lipophilic
molecule
Nonpolar tail
of lipid
(A)
SUV MLV LUV MVV
(a)
<Tc
(b)
>Tc
(B)
FIGURE 1.1 Schematic of a bilayer vesicle or liposome. (A) Multilamellar liposome showing
interaction with drugs. (Weiner, A.L., Cannon, J.B., and Tyle, P.: Commercial Approaches to
the delivery of Macrmolecular drugs with liposomes, in Rossoff, M., Ed., Controlled Release
of Drugs: Polymers and Aggregate Systems, p. 225, 1989. Copyright Wiley-VCH GmbH & Co,
KGaA. Reproduced with permission.) (B) Schematic showing (a) differences between SUV,
MLV, LUV, and MVV; and (b) gel to liquid crystalline phase transition of a lipid bilayer at the
transition temperature, Tc. (From Kadir, F. et al., In Injectable Drug Development, Gupta, P.K.
and Brazeau, G.A., Eds., Interpharm Press, Englewood, CO, 1999, p. 339. With permission.)
mobility of the acyl chains. A reduction in temperature below the Tc creates a transi-
tion to a more rigid gel state. This results in restrained mobility of the tightly packed
acyl chains. When the liquid molecules arrange themselves to form closed bilayer
structures containing water and solutes, drugs are trapped between the adjacent
planes of the polar head groups. This compartmentalization has been discussed in
detail by Roerdink et al.14
Chemical Characteristics of Liposomes

Liposomal affinity for various tissues can be modified by synthesizing liposomes con-
taining phospholipids with various fatty-acid chain configurations. These substances
1 μm
FIGURE 1.2 Micrograph view of a liposome. (Weiner, A.L., Cannon, J.B., and Tyle, P.:
Commercial Approaches to the delivery of Macrmolecular drugs with liposomes, in
Rossoff, M., Ed., Controlled Release of Drugs: Polymers and Aggregate Systems, p. 225,
1989. Copyright Wiley-VCH GmbH & Co, KGaA. Reproduced with permission.)
may have either solid, gel, fluid, or liquid crystalline character dependent on tempera-
ture and conditions.21,22 Also, altering the charge on the liposome vesicle can greatly
influence its distribution in the body. Negatively charged vesicles, for example, can enter
the cell by fusion, allowing the drug to be discharged into the cell cytoplasm. Neutral
vesicles, on the other hand, are more likely to be incorporated into the cell by phago-
cytosis, exposing the drug to the lysosomal hydrolytic system of the cells. Positive- and
neutral-liposomal vesicles are cleared more slowly than negatively charged ones.
A variety of phospholipids can be used to prepare liposomes. The lipid most
widely used is phosphatidylcholine (PC),23,24 which has been used individually or in
combination with cholesterol. Cholesterol is known to condense the packing of phos-
pholipids in bilayers above the Tc and modulates the fluidity of the bilayer. Cholesterol
also reduces the permeability of the bilayers to encapsulated compounds. Structures
of these lipids are shown in Figure 1.3.
Negatively charged lipids such as phosphatidic acid, phosphatidylglycerol (PS) are
usually used in order to provide a surface charge to the liposomes. For drug molecules
encapsulated in the aqueous space, the bilayer serves as a diffusion barrier, permit-
ting the liposomes to serve as a rate-controlling input device. Papahadjopoulos and
coworkers have done pioneering research in trying to establish and develop the lipo-
somal delivery system from experimental therapeutics to clinical applications.25–29
The introduction of this delivery system directly to the target site (such as the eye,
lung, or bladder) is a well-established approach for treating local diseases, and lipo-
somes have been shown to play a beneficial role when applied in this way. Positively
charged lipids such as stearylamine (STA) can also be used to provide a charge to the
lipid bilayer, but these are generally more toxic than negatively charged lipids.
O R
O P O– Phosphatidic acid:
R=H
O
H 2C CH CH2 Phosphatidylcholine:
R = CH2CH2N(CH3)3+
O O
O O
Phosphatidylethanolamine:
R = CH2CH2NH3+
Phosphatidylglycerol:
R= CH2 CH CH2
OH OH
H3C CH3
CH3
H
CH3
CH3 H
H H
HO
Cholesterol
FIGURE 1.3 Structures of phospholipids and cholesterol used in liposomes.
LIPOSOME-DRUG CONCEPT
Liposome Size
While liposomes have been used via a variety of administration routes, including
intramuscular, intraperitoneal, pulmonary, nasal, and oral,30–32 intravenous (IV)
injection is the most widely utilized route. The half-life of liposomes in the vascular
system can range from a few minutes to many hours, depending on the size and lipid
composition of the vesicles.
Following IV administration, small liposomes (0.1–1.0 μm) are taken up prefer-
entially by cells of the reticuloendothelial system (RES), located principally in the
liver and spleen,33 whereas liposomes larger than 3.0 μm are deposited in the lungs.34
This preferential uptake of smaller-size liposomes by cells of the RES system has
been utilized to deliver chemotherapeutic agents to macrophages and tumors of the
liver.14 Alternative physical approaches based upon the ability to destabilize the
liposome bilayer have led to the design of heat-sensitive, light-sensitive, and pH-
sensitive liposomes, which allow release of the liposomal drug contents at specific
target locations.35–37
Targeting Ligands
The chemical approach to achieving site-specific delivery requires that the liposome
has a targeting ligand bound to its surface, thereby enabling it to attach preferentially
to the target site. A variety of targeting ligands have been proposed for this purpose,
including antitumor monoclonal antibodies (MAb), carbohydrates, vitamins, and
transport proteins.38 Only carbohydrate and MAb-modified liposomes have thus far
shown promise in achieving targeting specificity.
Successful targeting of liposomes to cells other than those belonging to the RES is
fairly restricted but appears to include hepatocytes and circulating red blood cells.39
A high degree of specific liposome–cell association has been obtained in vitro by
coating the vesicles with cell-specific ligands, such as MAbs or F(ab1)2 fragments (see
Figure 1.4).40–42,266 Targeting can also be accomplished by attaching specific peptides
(Figure 1.5),267 folate (Figure 1.6)268 or other ligands to the liposome surface.
Problems and Advantages of Liposomal Drug Delivery

In vivo, the obstacles to successful targeting that have to be overcome are substantial.
First, the liposomes have to escape nonspecific clearance by the RES cells. Second, the
vesicles have to cross the capillary endothelium and the basement membrane. Third,
many cell types, including most tumor cells, display a low endocytotic capacity. Since
it has been found that endocytosis is the dominant mechanism of liposome–cell inter-
action, this is a serious limitation to the successful application of liposomes as a drug
delivery system.14
Small-size liposomes may serve as drug carriers to liver parenchymal cells
by virtue of their capacity to penetrate the liver’s fenestrated endothelium. Once
taken up by the cells, liposomes may be degraded in the lysosomal compartment.
Antigen combining sites
S S Pepsin DTT +
SS SH HS
F(ab΄)2 2 Fab΄
IgG
O O O O
H
pH 6.5
NH C (CH2)3 N NH C (CH2)3 N
S
O O
MPB-PE vesicle Fab΄-vesicle
FIGURE 1.4 Illustration of the chemical-coupling methodology for antibody/liposomes.

(From Conference Proceedings: The Latest Developments in Drug Delivery Systems, Pharm.
Technol., October 1985.)
Hydrated
(b) (c)
oligosaccharide (a)
interface
Encapsulated
volume
Covalently
Coupled peptides
80–100 nm
(A) (B)
FIGURE 1.5 Molecular schematic of a surface-modified liposomal drug delivery vehicle for
intravascular targeting. (A) The liposome surface consists of a glycocalyx-like oligosaccha-
ride layer to minimize nonspecific interactions and peptide ligands to mediate selective recep-
tor targeting. (B) Composite molecular model showing glycolipids hydrating the surface of the
phospholipid bilayer (a), an RGD peptide coupled to the liposome through a poly(ethylene oxide)
spacer (b), and a hypothetical coagulation factor VII peptide for targeting endothelial TF (c).
(Reprinted from J. Control. Release, 78, Lestini, B.J., Sagnella, S.M., Xu, J., Shive, M.S., Ritcher,
N.J., Jayascharan, J., Case, A.J., et al., Surface modification of liposomes for selective cell target-
ing in cardiovascular drug delivery, 235–247, Copyright (2002), with permission from Elsevier.)
Folate
PEG3350
Liposomes
entrapping
araC
Folate receptor
Released araC
+
+ +
+ H
+
+
H
FIGURE 1.6 Possible mechanism of intracellular araC delivery by FR-targeted, cationic,

lipid-based, pH-sensitive liposomes. At first, the folate-derivatized liposomes are taken into
the cell by binding to the FRs on the plasma membrane and FR-mediated endocytosis. This
is followed by acidification of the endosome, which results in protonation of the anionic lipid
component and generation of a net positive surface charge on the liposomes. Finally, the elec-
trostatic interactions between the liposomal and endosomal membranes result in bilayer fusion
and the cytosolic delivery of the encapsulated araC. (Reprinted from J. Control. Release, 80,
Lestini, B.J., Shi, G., Guo, W., Stephenson, S.M., and Lee, R.J., Efficient intracellular drug
and gene delivery using folate receptor-targeted pH-sensitive liposomes composed of cationic/
anionic lipid combinations, 309–319, Copyright (2002), with permission from Elsevier.)
Drug entrapped
in carrier
Lysosome
Fusion and
release of
drug from
the carrier
Endocytosis
Endocytic
vesicles
Macrophage Drug release
FIGURE 1.7 Schematic of phagocytosis of particulate carriers by macrophages.

Macrophages take up the carriers by the process of endocytosis. Drugs are released from the
carriers following intralysosomal degradation of the carriers. (Reprinted from J. Control.
Release, 79, Ahsan, F., Rivas, I.P., Khan, M.A., and Torres Suarez, A.I., Targeting to
macrophages: role of physicochemical properties of particulate carriers—liposomes and
m icrospheres—on the phagocytosis by macrophages, 29–40, Copyright (2002), with permis-
sion from Elsevier.)
Liposome-encapsulated drugs, when resistant to the intralysosomal environment,
may slowly leak out of the lysosomes into the cytosol and may become available to
exert their therapeutic action. Drugs may also be released from liposomes phagocy-
tized by macrophages (see Figure 1.7).269
An important advantage of the liposome–drug relationship involves reducing
toxicity of the liposome-encapsulated agent. This is particularly important for anti-
neoplastic agents with low therapeutic indices such as doxorubicin (adriamycin) or
antimicrobial drugs such as Amphotericin B.43–45
Manufacturing Methods and Issues

Several methods are used to make liposomal systems for drug incorporation. The
most common method deals with hydration of a lipid followed by high-intensity agi-
tation using a sonicator, a high-shear propeller, or a homogenizer. Liposomes are sub-
sequently sized by filtration or high-pressure membrane extrusion. As an initial step,
lipids and lipophilic drugs are dissolved in an organic solvent; most commonly used
are chloroform, methylene chloride, methanol, ethanol, ether, or mixtures of these
solvents. Next, the solution is evaporated down onto the sides of the flask or onto a
solid support. Then the dried film is hydrated by addition of an aqueous medium fol-
lowed by agitation until the lipid film has been completely dispersed, forming lipid
bilayers. Generally, this method yields liposomes with multiple lamellae (see Figure
1.1). Batch size can be made as small as 5 mL and as large as up to 20 L when using
rotary evaporators with different sizes. Entrapment of water-soluble substances using
this method is often low, but entrapping water-insoluble compounds in the lipophilic
lipid bilayers is efficient. Another disadvantage is that the liposome size distribution
is heterogeneous; particles as large as 30 μm and as small as 0.050 μm can exist in

the system.46 This method is difficult to scale up but has nevertheless been used to
manufacture liposomes for clinical use.
After formation of the liposomes, a particle size reduction or homogenization step
must be used to reduce the particle size to the desired range, especially if they are to
be used for parenteral administration and must be small enough to pass through an
aseptic filter. Probe sonication is a common laboratory method, producing small and
homogeneously distributed small unilamellar vesicle (SUV), but may introduce metal
contamination from the sonicator probe. Laboratory bath sonicators normally do not
impart enough energy to reduce liposome sizes, but “cup-horn” type sonicators are
available, for example, from Branson that are powerful enough to reduce liposome
size. Sonication is generally limited to small quantities (<100 mL) of material. There
are several homogenizers capable of generating sufficient high shear forces to pro-
duce both unilamellar and multilamellar vesicles with defined size distributions.47,48
The Microfluidizer® (Microfluidics, Inc.) pumps fluid at a very high pressure (up to
18,000 psi) through an interaction chamber containing defined microchannels which
direct two streams of fluid to collide at right-angles with very high velocities. The
fluid collected can be recycled through the pump and the interaction chamber until
vesicles of the required dimensions are obtained. Other commercial homogenizers
(e.g., Five-Star, Manton-Gaulin, and Rannie homogenizers) that operate similarly
with high shear forces and high liquid pressures are adaptable for large-scale particle
size reduction of liposomes. Membrane extrusion is another homogenization method
for the reduction of the particle size of liposomes.49
In a variation of the above method lipids are dried down onto a finely divided
particulate support such as powdered sorbitol, sodium chloride, lactose, or poly-
saccharide, giving a product known as “pro-liposomes.” When hydrating the dry
powder while mixing with a whirl mixer, the phospholipids swell while the support
rapidly dissolves to give a liposomal suspension of MLVs in an aqueous solution.
The equipment used to prepare small scale pro-liposomes are the same as the “thin
film” method described above, except that some modifications have been made to the
rotary evaporator, so that the lipid solution is introduced into the flask as a fine spray
until all the solution is sprayed onto the core materials. The temperature and spray rate
must be monitored closely to ensure that the components remain in a finely dried
form and the lipids and drug are evenly dispersed onto the particles. If microporous
sorbitol granules are used as the solid support, surface area of the granule alone
could be approximately 33.1 m2/g, and loading is typically about 1 g of lipid for 5 g of
sorbitol. Because of the high surface area, liposomes are formed much more rapidly
by this method compared to the thin-film method, and a higher proportion of smaller
vesicles is obtained.50 Like the thin-film method, the pro-liposome method has the
low entrapment efficiency for hydrophilic compounds. However, it has advantages
that the dry pro-liposome product which can be stored for long periods and hydrated
immediately before use. Large-scale production can be accomplished using a fluid-
bed dryer or spray dryer.
In another method, called reverse phase evaporation vesicles (REV), a phospho-
lipid is first dissolved in an organic solvent and then added to an aqueous medium by
vigorous agitation. The organic solvent is removed under vacuum, and the resulting
liposomal dispersion or emulsion is sized by filtration or extrusion. A variation is

the ether infusion method, introduced by Deamer and Bangham,51 in which the lipid
are dissolved in ether and injected into an aqueous solution above the boiling point
of ether, resulting in liposomes after the ether evaporates. An advantage of these
methods is that they can produce liposomes that have a high proportion of large unil-
amellar vesicles (LUV) and thus high encapsulation efficiencies for water-soluble
drugs. However, removal of residual solvents to acceptable levels for clinical use may
be problematic, and scale-up is also difficult. Even if they are mostly unilamellar,
liposomes from these injection processes are found to exhibit a broad size distribu-
tion in the range of 0.2–1.5 μm; particle size reduction generally results in a loss
of encapsulated water-soluble materials. An alternative method involves the extru-
sion of a heterogeneous population of fairly large liposomes through polycarbonate
membranes under moderate pressures. This technique can reduce a heterogeneous
population to a suspension of vesicles that exhibit a mean particle size near that of
the pores through which they are extruded.
Incorporation of drugs into liposomes is achieved by using one of the three pri-
mary mechanisms: encapsulation, partitioning, and reverse loading. Encapsulation
is useful for water-soluble drugs, and it involves hydration of a lipid with an aqueous
solution of a drug. The dissolved drug remains in the intralamellar spaces. If a size
reduction technique is used, the encapsulation efficiency will likely decrease.
In the partitioning method, the drug is dissolved along with the phospholipids
in a suitable organic solvent. It is then dried first (e.g., if using the thin film or pro-
liposome manufacturing technique) or added directly to the aqueous phase before
removing the residual solvent in a vacuum (e.g., if using a reverse-phase evaporation
or solvent injection manufacturing technique). The drug will then partition between
the lipid bilayers and aqueous portion of the liposome, depending upon its aqueous
solubility and lipid affinity. High encapsulation will result for lipid-soluble drugs.
The reverse-loading (or remote-loading) process is an elegant technique used
for weakly acidic drugs that exist in both charged and uncharged forms, depend-
ing on the pH of the environment.52 Liposomes are first prepared by the techniques
described above, and an aqueous solution of the drug is added to permeate into lipo-
somes. The pH is then adjusted to create a trans-membrane pH gradient charge on the
drug molecule. The drugs will be redistributed across the lipid bilayers in response
to the pH gradient, since the charged drug molecule will not pass through the lipid
bilayer and return to the external medium. Entrapment efficiencies of almost 100%
can potentially be achieved using this method with lipophilic amines such as doxo-
rubicin and dopamine. Another advantage is that this technique allows the drug to
be encapsulated just prior to use, which eliminates the stability problems associated
with the post-encapsulation processing and long-term storage. Any lipids or mixture
of lipids can be used as long as they form liposomes capable of maintaining a stable
transmembrane pH gradient.
Another method is the freeze-drying (or dehydration-rehydration) method, devel-
oped by Ohsawa et al.53 and Kirby and Gregoriadis.54 In this method, small “empty”
unilamellar vesicles are first prepared and combined with an aqueous solution con-
taining the drug. The mixture is dehydrated by freeze drying, and the powder thus
obtained is rehydrated under controlled conditions. Large multilamellar vesicle
(MLV) liposomes usually result initially; particle size reduction, for example, by
microfluidization, can then be carried out, which, however, may reduce the encap-
sulation efficiency. Relatively homogenous and physically stable suspensions can
be obtained by carefully controlling the complex conditions. The liposome will be
generated by adding an aqueous phase, followed by shaking. This method often
produces liposomes with high entrapment efficiency; the product can be stored in
the lyophilized state and rehydrated immediately before use. The drawbacks of the
method are possible particle size instability of the liposome during the freeze-drying
process, and the high cost of the freeze-drying process.
Unless sterile raw materials are used and all stages of liposome manufacture are
carried out under aseptic conditions, aseptic filtration is necessary for parenteral
formulations. In addition, when the drug or formulation does not have adequate shelf
life in the liquid state, liposomes manufactured by any of the above methods may
be freeze-dried (lyophilized) and reconstituted immediately before use. In order to
preserve the liposome structures during the freeze-drying process, lyoprotectants
such as lactose, sucrose, or trehalose are added in the liposomal formulation. Certain
polymers are also known to retard or suppress ice crystal growth.
After manufacture, liposomes are typically characterized by the measurement of
concentrations of the drug and lipids in the vesicles, measurements of captured vol-
ume, size distribution, and lamellarity of lipid vesicles. Mean vesicle size and size
distribution are important parameters for the physical properties and biological fate
of liposomes and their entrapped substances in vivo. One of the most commonly used
methods to determine size and size distribution is light scattering analysis, preferably
using a newer apparatus based on laser light scattering to provide accurate estimate of
the size–frequency distribution. Encapsulation efficiency is a measure of the propor-
tion of drug entrapped in the liposome. First the total concentration of drug (free and
entrapped) is measured by a suitable method such as high performance liquid chrom-
agraphy (HPLC). Then another sample is used to separate the free drug from entrapped
drug and the concentration of free drug is measured. Ultrafiltration is a convenient
method to do this, as long as a suitable molecular weight cutoff (MWCO) membrane
is used so that all liposomes are retained by the filter and free (unencapsulated) drug
passes through the membrane. Molecular sieve (gel filtration) chromatography is also
used, but lipid-soluble soluble drugs often partition and re-equilibrate as they pass
through the column, resulting in inaccurate results. Encapsulation efficiency (%) is
then calculated from the concentration of free drug divided by the total concentration.
Monitoring stability of a liposomal drug formulation must consider both chemical
and physical stability. Like other colloidal systems, liposomes can undergo fusion,
phase changes, and aggregation upon storage. Physically stable formulations pre-
serve both liposomal size distribution and the quantity of the material entrapped;
thus size as well as encapsulation efficiency must be monitored. Stability depends
on the mechanical properties of the liposomal membranes, their thermodynamics,
and colloidal properties of the system. Liposomal phospholipids can also undergo
chemical degradation, primarily by hydrolysis and/or peroxidation. Hydrolysis
will liberate free fatty acids; thus, monitoring change in pH is an important part
of a stability protocol. Changes in surface charge (measured by zeta potential) may
also occur over time. Measuring peroxide value or another assay of peroxidation
DSPE-PEG(2000)-Biotin
Lipid
Lipid
vesicle
vesicle
NeutrAvidinTM
PEG-Biotin
Poly (ethylenimine)
Acetaldehyde plasma polymer
FIGURE 1.8 Schematic drawing (not to scale) of the multilayer construct used for immobi-
lizing PEG-biotinylated liposomes onto solid polymeric carrier materials via NeutrAvidin™
binding. (Reprinted from J. Control. Release, 80, Vermette, P., Meagher, L., Gagnon, E.,
Griesser, H.J., and Doillon, C.J., Immobilized liposome layers for drug delivery applications:
Inhibition of angiogenisis, 179–195, Copyright (2002), with permission from Elsevier.)
should be considered. Accelerated (high-temperature) testing greater than 25°C is

frequently used for heterogeneous products. However, a variety of phase transitions
occur in liposome bilayers, and accelerated stability studies are not always predictive
of stability at normal storage conditions. In summary, for liposomal formulations,
each test condition indicating stability of the vesicles should express conditions for
microscopic observation (e.g., flocculation), particle-size profiles, rheological pro-
files, extent of leakage, and chemical and physical stability. Other newer methods
such as atomic force microscopy (AFM) have also been used to characterize lipo-
somes; for example, AFM was used to study immobilized liposomes bound to a
surface by biotin–avidin binding (see Figure 1.8).270
LIPOSOMES AS CARRIERS OF THERAPEUTIC AGENTS

Application
Since 1972, when Gregoriadis proposed the use of liposomes as carriers of enzymes
in the treatment of lysosomal storage diseases, the application of liposomes has
been extended to a variety of drugs, such as antineoplastic agents,16,55,56 antimicro-
bial compounds,42,57 and immunomodulators.58–61 In addition to utilizing liposomes
as drug carriers in the treatment of intracellular infections,62 liposomes have also
been used as carriers of Amphotericin B in the treatment of mycotic infections,
such as histoplasmosis,63 cryptococcosis, and candidiasis.63 Lopez-Berestein et al.64
reported that liposomal Amphotericin B is effective in the treatment of candida and
aspergillus infections in leukemia patients who have not responded to the nonencap-
sulated drug. The increase in amphotericin’s efficacy by encapsulation in liposomes
is associated with reduced toxicity.65
Incorporation of lipophilic amphotericin within liposomes might result in a facilitated
transfer of the drug to fungal cells. In turn, this selective transfer of amphotericin from
liposomes to fungal cells may form the molecular basis of the reduced toxicity. Other
factors, such as altered kinetics or tissue distribution, may also play an important role.66
Antibacterial activity with liposome encapsulation has been reported by Sunamoto
et al. (in experimental Legionnaires’ disease).67 They showed that uptake of IV-injected
liposomes by circulating monocytes and alveolar macrophages can be increased by
coating the vesicles with a palmitoyl derivative of amylopectin. After IV injection, the
amylopectin-modified liposomes were found to preferentially distribute in the lungs.
Macrophages have an affinity for liposomes, and this property has been utilized
in the use of these vesicles as carriers of immunomodulators to create macrophages
cytotoxic to metastatic tumor cells. As a result, macrophages serve as an important
barrier against the proliferation and metastatic spread of tumor cells. Activation of
macrophages to induce tumor cytotoxicity occurs as a result of exposure to a variety
of immunomodulating substances, such as lymphokines,68 γ-interferon, and mur-
amyl dipeptide (MDP).69–72
Liposomes are known to increase the adjuvant activity of MDP. Adjuvants are
nonspecific immune stimulants that boost immunoresponses to weak antigenic mol-
ecules. MDP micelles, for example, are highly potent adjuvants in tests for vaccina-
tion against bovine viral diarrhea. Although it is unknown how this process occurs,
activated macrophages can selectively kill tumor cells. Activated macrophages have
been considered in the management of metastatic cancer, which is often seriously
hampered by the biological heterogeneity of tumor cells with respect to growth rate
and sensitivity to various cytotoxic drugs.
Although preliminary results with liposome-encapsulated immunomodulators
are encouraging, successful application in the treatment of patients with liver metas-
tasis may be hampered by unfavorable macrophage-to-tumor cell ratios in many
metastatic tumors.73 Therefore, it would appear that therapeutic regimens designed to
stimulate macrophage-mediated tumor cytotoxicity will have to be used in combina-
tion with other treatment modalities.74–76
Successful targeting of liposomes, at least to solid tumors located outside the main
circulatory system, faces numerous challenges. As described by Roerdink et al.14 selec-
tive introduction of antineoplastic drugs into tumor cells in vivo by means of liposomes
is currently a difficult task. However, application of liposomes as a drug delivery system
for antitumor drugs may be of great benefit in diminishing toxicity of encapsulated com-
pounds by altering their pharmacokinetics or tissue distribution. In addition, liposomes
can serve as a sustained- or controlled-release system for cytostatic drugs, such as cyto-
sine arabinoside. The therapeutic effect of this cell-cycle-specific drug is enhanced by
liposomal encapsulation, possibly by maintaining therapeutically favorable drug levels
for a prolonged period of time following leakage from the liposomes, or, alternatively,
from macrophages that have phagocytosed the drug-loaded liposomes.
A promising example of a liposomal delivery system for an antitumor drug has
been the use of doxorubicin in liposome-encapsulated form.14 Doxorubicin, an
anthracycline antibiotic, is useful in the treatment of a variety of solid neoplasms,

lymphomas, and leukemias. Its clinical use, however, is limited by its cardiotoxicity.
Several investigators have shown that entrapment of doxorubicin within liposomes
greatly reduces its cardiotoxicity without loss of antitumor activity.77–80 The mecha-
nism responsible for doxorubicin’s increased therapeutic index is not fully under-
stood, but may involve low uptake of the liposomal drug by the myocardium14 or
prolonged release of the drug from macrophage depots.81
While in the bloodstream, liposomes may be susceptible to destabilizing effects
of serum proteins, resulting in the escape of encapsulated water-soluble compounds.
In addition, high-density lipoproteins (HDL) have been found to penetrate lipo-
somal bilayers. This process is accompanied by loss of PC from the liposomes to
the HDL.82,83 High susceptibility to PC loss was found at the gel-to-liquid phase-
transition temperatures of the liposomal lipids, while both above and below those
temperatures the liposomes were relatively stable.84 Net loss of phospholipid can be
prevented by incorporation of cholesterol into the liposomal membranes, thereby
causing obstruction to penetration of serum lipoproteins and increasing the stabil-
ity of liposomes.85 Cholesterol does not form bilayer structures by itself, but can
be incorporated into phospholipid membranes at very high concentrations (up to
2:1 molar ratios of cholesterol to phospholipid). In the presence of cholesterol, the
freedom of molecular motion of the bilayer above the phase transition is decreased,
but below the phase transition mobility is increased. Thus cholesterol broadens the
phase transition of the bilayer and moderates the differences between gel and liquid
crystalline phases. Some of the benefits that may result from the use of cholesterol in
a liposomal formulation are decreased permeability of the bilayer, smaller and more
uniform size distribution, and prevention of phase separation.
Opsonins adsorb onto the surface of the vesicles; the resulting opsonin–liposome
complexes, along with the entrapped drug, fall prey to the phagocyte cells of the
RES.86 Recently there has been a great deal of interest in liposomes whose surfaces
have been derivatized or modified to prevent their uptake by the RES and prolong
their circulating lifetime. There have been several approaches to this modification:
the earliest utilized incorporation of sialic acids (e.g., ganglioside GM1) into the
bilayer.87–89 More recently, incorporating 10–20 mol% polyethylene glycol (PEG)-
derivatized phospholipids into liposomes, have become the method of choice for
preparing long-circulating liposomes.90 The surface modification can increase the
circulating half-life from 2–3 h for conventional liposomes to over 24 h for sterically
stabilized (“Stealth”) liposomes due to reduced RES uptake. For example, an 18-fold
increase in half-life was observed when PEG–lipid was included in small distearoyl-
phosphatidylcholine (DSPC) liposomes.91 The marked reduction in RES uptake of
sterically stabilized liposomes leads to an increased uptake in other target areas, for
example, tumors. Although the mechanism by which the surface modification alters
the pharmacokinetics is not yet fully understood, the primary effect seems to be that
the PEG “masks” the surface charge of the phospholipids and provides a steric bar-
rier, reducing the recognition and binding of the opsinizing agents and reducing RES
uptake.92 Other possible factors may be PEG’s role in imparting a greater degree of
hydrophilicity to the liposome surface,90 and the flexibility of the polymer chain.93 If
a prolonged drug circulating half-life is a formulation goal and/or RES uptake is a
problem, the use of sterically stabilized liposomes should be considered and evalu-
ated in appropriate models. On the other hand, if solubilization of the drug is the
primary function of the liposomal formulation, and/or drug is removed more rapidly
by plasma proteins from the liposome liposomes uptake by the RES, pegylated lipo-
somes would have little value. Similarly, if liver or spleen is the primary targets of
the drug’s action, sterically stabilized liposomes would have little use.
Liposomal Products and Manufacturers

Table 1.1 presents a list of liposome technology-based research and develop-
ment firms, their products, and indications for their usage.94 The antifungal drug
Amphotericin B is normally toxic, causing hemolysis, nephrotoxicity, and other
severe adverse reactions. Liposomes were shown to ameliorate these effects, and
thus there are several liposomal-type Amphotericin B products now marketed.
Ambisome, originally developed by Nexstar (now Gilead Sciences), is composed
of hydrogenated soy PC/distearoyl phosphatidylglycerol/cholesterol/Amphotericin B
(2:0.8:1:0.4 molar ratio). It is the only true liposomal formulation, comprising small
unilamellar liposome within a size range of 45–80 nm.95 Amphotericin B destabi-
lizes liposome bilayers, and the Abelcet formulation developed by the Liposome
Company (now part of Elan), with a lower phospholipid/drug ratio, is characterized
as a “lipid complex” with ribbon-like structures rather than liposomes. The third
Amphotericin B formulation, Amphotec, developed by Sequus (now Alza, part of
Johnson and Johnson), is composed of cholesterol sulfate vesicles. Doxorubicin is an
anticancer drug with cardiotoxic effects; liposomes, by increasing uptake of the drug
by tumors relative to other tissues, can reduce its toxicity. Doxil® is a sterically stabi-
lized formulation of doxorubicin prepared by the remote loading technique; this IV
formulation showed a circulating half-life of 40–60 h in humans.92 Daunorubicin has
similar effects to doxorubicin; DaunoXome is a liposomal formulation of daunorubi-
cin used in cancer treatment. Visudyne is a photodynamic therapy agent, liposomal
verteporfin. Originally developed and tested for cancer treatment, it is now used to
treat macular degeneration.
Cancer remains the area in which there is the most intense interest in liposomal
applications. For example, paclitaxel is an antineoplastic drug with powerful anti-
tumor activity with poor water solubility. The current clinical dosage form consists
of 0.3–1.2 mg/mL of Paclitaxel dispersed in an ethanol/polyethoxylated castor oil
(Cremophor EL)96 vehicle. Some of the side-effects, such as severe hypersensitiv-
ity reactions, have been attributed to the Cremophor EL.96 Accordingly, there have
been a number of research and clinical studies examining liposomal formulations
of paclitaxel. Results of a Phase I clinical study of liposome-entrapped paclitaxel
easy-to-use (LEP-ETU) indicated that it would have an improved therapeutic index
compared to the current formulation.97 Liposomal formulations of a related com-
pound, docetaxel (DT), are also being developed, for example, LE-DT in Phase I
trials. Liposomal formulations of camptothecin (CPT) and its analogs, topotecan and
irinotecan, have been found promising in clinical trials.
In addition to those presented in Tables 1.1 and 1.2, the following industrial estab-
lishments are also involved in liposome delivery research and development (either
TABLE 1.1
Summary of Liposomal Marketed and Developmental Products
Corporation Product Indications Status
Gilead/Astellas AmBisome: liposomal formulation of Systemic fungal infections Marketed
Amphotericin B
Gilead DaunoXome: liposomal daunorubicin Cancer Marketed
MiKasome—aminoglycoside Drug-resistant tuberculosis; Phase II
antibiotic, amikacin serious bacterial infections
NX 211: liposomal lurtotecan Ovarian and lung cancer Phase II
GS7904L: liposomal thymidylate Cancer Phase I
synthase inhibitor
Vescan: liposomal Indium-111 imaging MRI enhancer in tumors Phase II/
agent III
Alza/InterMune Amphotec: Amphotericin B colloidal Systemic fungal infections; Marketed
dispersion Leishmaniasis
Alza/Ortho Doxil: stealth liposomal doxorubicin Kaposi’s sarcoma, ovarian Marketed
cancer
QLT, Inc. Visudyne: liposomal verteporfin Photodynamic therapy of Marketed
macular degeneration
The Liposome Abelcet: Amphotericin B lipid complex Fungal infections in AIDS Marketed
Company (Elan) and cancer patients
TLC G-65 Mycobacterium avium Phase I
intracellulare (MAI)
infections in AIDS patients
TLC I-16, nonionic, iodinated contrast Liver imaging in CT scans Phase I
agent for liver metastases
TLC A-60: liposomal adjuvant system Human influenza vaccine Phase I
TLC C-53: prostaglandin E Acute inflammatory and Phase I
veso-occlusive conditions
Neopharm LEP-ETU: liposomal paclitaxel Metastatic breast cancer Phase I
LE-DT: liposomal docetaxel Metastatic solid cancer Phase I
LErafAON: liposomal antisense Pancreatic cancer Preclinical
oligonucleotide
Celator CPX-351: Liposomal Acute myeloid leukemia Phase II
Pharmaceuticals Cytarabine:Daunorubicin
CPX-1: Liposome Irinotecan Colorectal cancer Phase II
HCl:Floxuridine
CPX-571: liposomal irinotecan/ Small-cell lung cancer Preclinical
cisplatin
Hermes Anti-HER2 Immunoliposomal HER-2 overexpressing Preclinical
Biosciences Doxorubicin cancers
Nanoliposomal Vinorelbine Non-small cell lung cancer, Phase II
breast cancer
Nanoliposomal Irinotecan Gastric cancer, malignant Phase II
(camptothecin pro-drug CPT-11 gliomas, lung cancer
Ciba-Geigy Muramyl tripeptide Cancer therapy, metastatic Phase II
melanoma
TABLE 1.2
Summary of Investigational Liposomal Products
Corporation Product Indications
The Liposome Defensins, potent antifungal and Cryptococcal infections in AIDS
Company (Elan) antiviral peptides isolated from patients
human neutrophils
Vescan MRI enhancer in animal tumors
Cyclosporine Multidrug resistance to cancer
chemotherapy
Liposomes linked to specific Affinity for sites on diseased cells
proteins
Boron isotope of mass 10 Cancer therapy
Liposomes coated with a specific AIDS and other viral diseases
viral receptor protein
Hemoglobin Blood substitute
Alza/Ortho Plasminogen streptokinase reversed In canines, encapsulated local ischemia
(5,12-naphthacenedione) Advanced cancer patients
doxorubicin (Lip-Dox)
Teijin-Taisho Epoprostanol derivatives Myocardial infarction
Isocarbacyclin Cerebrovascular orders, chronic arterial
obstruction in rats
ImmunoTherapeutics Glucosamyl muramyl analog Delivery to the monocyte/macrophage
system in cancer chemotherapy
Genset Development of liposomes For antisense delivery aspergillosis
infections
Liposome inhalation Albuterol, Salbutamol (inhaled Respiratory and systemic diseases; Beta
products liposomal formulations) 2 adrenoreceptor agonist (asthma)
Univax & Micro Gentamicin—(aminoglycoside
antibiotic)
Vesicular Systems Novasome liposome technology for Bacterial and viral vaccines (e.g., for
vaccines pseudomonas, HIV)
in liposome development or as phospholipid suppliers): American Bioproducts,

American Lecithin Co., Applied Genetics, Argus Pharmaceuticals, Becton
Dickinson & Co., Bristol-Myers Squibb, Brocades Pharma ESCA Agenetics Corp.,
Fountain Pharmaceuticals, Genzyme Corp., IGI, Inc., Nichiyu Liposome Co.,
Pharmos Ltd., RibiImmunochem Research, Inc., Schering AG, Schering-Plough
Corp., Somatogen, Inc., Structure Probe, and Vical, Inc. According to FIND/SVP’s
report on the total market for liposomal pharmaceuticals and diagnostics for 1995,
anti-infectives will occupy 75.2% of the market, followed by anticancers (18.8%),
diagnostics (5.0%), and respiratory (1.0%). The total market for pharmaceutical and
diagnostic liposomes reached an estimated $18 million in 1991, and this is expected
to grow dramatically as new products gain regulatory approval. The overall market
for drug delivery systems was observed to reach $399 million in 1995.
TABLE 1.3
Comparison of Liposomal and Conventional
Amphotericin B Formulations
Formulation
Parameter Liposomal Conventional
Number of patients 29 29
Graft lossesa 6/11 (55%) 14/16 (88%)
Mean duration of 21.3 days 21 days
antifungal treatment
Adverse reaction reports 3 in 3 patients
Deaths 9 17
Survival Rates
Liver transplant 71.4% (n = 7) 20.0% (n = 5)
Kidney transplant 72.7% (n = 11) 62.5% (n = 16)
Bone marrow transplant 63.6% (n = 11) 12.5% (n = 8)
a Kidney or pancreas transplant only
In Table 1.3, liposomal and conventional formulations of Amphotericin B are

compared in transplant recipients with systemic fungal infections.98
PARENTERAL EMULSIONS
Compared to liposomes, there has been somewhat less interest in using emulsions
as a pharmaceutical vehicle for parenteral drug delivery. An emulsion is defined as
a mixture of two immiscible phases (viz., water and oil) with an emulsifier added to
stabilize the dispersed droplets.99 Emulsions for parenteral use should be “submicron
emulsions,” that is, have droplet size less than 1 μm and be 100–1000 nm. Emulsions
have been used for some time as IV total parenteral nutrition mixtures to supply
high-caloric lipids. Examples are Liposyn® and Intralipid®, which are emulsions of
soybean, sesame, or safflower oil (10%–20%) emulsified with egg lecithin contain-
ing 60%–70% PC. Hydrophobic drugs can be incorporated into the oil phase of the
emulsion, or at the interface, depending upon its solubility in oil. Formulating in
emulsions can thus aid in solubilization of the drug, and sometimes reduce toxic
effects. As summarized in Table 1.4, examples of drugs formulated as emulsions
formulations are diazepam, propofol, prostaglandin E1, etomidate, vitamins A, D, E,
and K, dexamethazone palmitate, flubiprofen, perflurodecalin, and cyclosporine.
Analogous to those with liposomes described above, experimental studies have
also been carried out on Amphotericin B. PC/oil Amphotericin B emulsions pre-
pared de novo have shown reduced toxicity in cell culture and animal studies.99–101
Amphotericin B has also been formulated extemporaneously as an emulsion by addi-
tion of the commercial product Fungizone® to Intralipid® 20% and examined clini-
cally. Although some reports indicate that the emulsion reduces renal toxicity while
TABLE 1.4
A Representative List of Marketed Intravenous Emulsion Products
Containing Water-Insoluble Drugs
Drug
Drug Product Name Company Activity Product Status Reference
Diazepam Diazemuls ® Braun Sedation Marketed: Europe, [100]
Diazepam®-Lipuro Melsungen Canada, Australia
Stesolid Dumex Sedation Marketed in Europe [100]
(Denmark)
Etomidate Etomidat®-Lipuro Braun Anesthesia Marketed in Europe
Melsungen
Prostaglandin Liple Green Cross Vasodilator Marketed in Japan [109]
E1
Propofol Propofol Baxter Anesthesia Marketed in the [110]
Anesthesia United States
Diprivan® AstraZeneca Anesthesia Marketed [111]
worldwide
Propofol®-Lipuro Braun Anesthesia Marketed in Europe [112]
Vitamins A, Vitalipid® Kabi Nutrition Marketed in Europe [100]
D, E and K
Flurbiprofen Lipfen® Green Cross Analgesia Marketed in Japan [109]
Source: Adapted from Cannon, J. et al., In Water-Insoluble Drug Formulation, 2nd edn., Liu, R., Ed.,
CRC Press, Boca Raton, FL, 2008, 200. With permission.
maintaining efficacy,102,103 there is other evidence that there is incomplete incorpora-

tion of the drug into the emulsion droplets and precipitation of drug.104 TOCOSOL®
Paclitaxel is a tocopherol-based emulsion formulation of paclitaxel currently in
Phase III clinical trial for the treatment of cancers.105 Antitumor activity of the for-
mulation has been demonstrated in clinical trials in bladder, ovarian, and non-small
cell lung cancers.106 Another hydrophobic drug examined clinically in emulsions is
etoposide. A Phase I clinical study was carried out in four ovarian cancer patients
to investigate the drug targeting ability of cholesterol-rich emulsions to low density
lipoprotein (LDL) receptors of tumor cells. Uptake of [3H] oleate and [14C] choles-
terol oleate were 4.1 and 4.9 times, respectively, greater than that in contralateral
normal ovaries, indicating the ability of the cholesterol-rich emulsions to concentrate
in ovarian carcinomas.107 A number of other drugs have been examined in animal
studies. Suggested benefits included reduced pain on injection (etomidate, diazepam,
clarithromycin); reduced thrombophlebitis (etomidate); reduced toxicity (cyclospo-
rine, Amphotericin b, vincristine); improved stability (sodium phenobarbital, oxathiin
carboxanilide, physostigmine); prolonged activity (somatotropin, physostigmine, eto-
poside); drug targeting (bleomycin, titanocene dichloride, mitomycin c); and vaccine
adjuvants (MDP).108
RECENT ADVANCES AND FUTURE PROSPECTS

Despite the promise that resulted from early research on liposomes, there have been
only a handful of products that have come to fruition from these efforts. Although
some products in current clinical trials may enter the market, it is now clear that
liposomes will likely remain a niche platform for drug delivery rather than a panacea
for a wide range of drug delivery goals. Nevertheless, there are several cases where
liposomes should be considered in choosing a drug delivery system for a new or
existing drug. The use of liposomes to solubilize a parenteral poorly soluble drug
could have some advantages over other alternatives, since the components are gener-
ally nontoxic, and formulations of acceptable size range (<500 nm) can be prepared.
Although no products have yet resulted, the potential to actively target drug-laden
liposomes by means of a MAb or other agent also offers promise. Through increas-
ing uptake of liposomes by tumors, cancer treatment will likely continue to be a
fruitful area for investigation of liposomal drug delivery.
Recent studies and examples of liposomal formulations containing various
entrapped ingredients are as follows113–115: L-NDDP (liposomal cis-bis-neodecanoato-
trans-(R,R)-1,2-diaminocyclohexane platinum), vincristine (in stealth liposome),
cytochalasin B, vaginal antifungal agents, such as miconazole, steroidal liposomes
from sterols, such as cholesterol, vitamin D, steroid hormones and fluorinated steroids,
benzylpenicillin, topical and in-aerosol devices for anti-inflammatories, beclometha-
sone dipropionate, dexamethasone palmitate, bronchodilators, such as metaproterenol
(Metasome) and terbutaline, indomethacin, daunorubicin (Cerbudine), radiophar-
maceutical VS-101, cisplatin (Platinol), minoxidil, calcitonin, CPT, indium-111,
cephalothin, nystatin, a-tocopherol, a-tocopherol nicotinate (TN), vitamins A and E,
tin mesoporphyrin, cyclosporin A (CsA) (aerosol formulation), apolipoprotein B,
5-fluoro-2′-deoxyuridine and its pro-drug, 3–5′-O-dipalmitoyl derivative, (dpFUdR)
corticosteroids, 14-O-palmitoyl-hydroxyrubicin, plasmid DNA, glutathione, idarubi-
cin, dideoxyinosine triphosphate, bovine somatotropin, antimonial drug meglumine
antimonate for leishmaniasis, hamycin, Novasome vaccines, 2–133-Interleukin 2,
imidazolidines, and dyphylline.94
Highlights of Current Research

Sterical stabilization by modification with PEG or similar substances continue to
be a preferred method to produce long-circulating liposomes to avoid uptake by the
RES and increase uptake by desired targets such as tumors. PEG-modified lipo-
somes loaded with topotecan increased the area-under-the-curve (AUC)0–∞ in rats
by 52-fold compared to free drug.116 Pegylated paclitaxel liposomes had a circulating
half-life of 17.8 h in rats compared to 5 h for conventional liposomes, and greater
tumor growth inhibition.117 Pegylated liposomal recombinant human Factor VIII
injected into animals showed 40% higher AUC compared to conventional liposomes
as well as reduced Factor VIII antibody titers.118 A variety of coatings similar to
pegylation have been examined in order to prolong the circulation half-life of lipo-
somes. Chitosan and gelatin were investigated as coatings for liposomes with the
CPT pro-drug Irinotecan HCl, prepared by a modified ethanol injection method to
increase circulation longevity.119 A sustained release thermosensitive formulation

of cytarabine liposomes was prepared by coating the liposomes with chitosan-β-
glycerophosphate.120 Polyamino acid-coated liposomes showed long circulation
when injected intravenously to rats.121 Phosphatidylethanolamine normally serves
as the anchor to which PEG is attached for steric stabilization of liposomes, but
several studies122 have successfully utilized cholesterol for this purpose; the target-
ing moiety folate was also conjugated to cholesterol. Shehata et al.123 prepared lipo-
somes modified with 4% PEG/1% polyvinylalcohol (PVA), which were shown to
have longer systemic circulating residence time compared to those modified with
5% PEG. The difference was attributed to decreased adsorption of opsonins such as
complement C3 and immunoglobulin G on the PEG/PVA liposomes. Conjugation
of human serum albumin along with PEG to the surface of liposomes led to greater
tumor uptake compared to liposomes modified with PEG alone.124 Similar results
were reported by Furumoto et al.125 who showed that the longer circulation of
albumin-PEG liposomes was due to reduced adsorption of opsonizing proteins on
their surface. Liposomes coated with silk fibroin showed increased retention of drug
(emodin, a tyrosine kinase inhibitor) in breast cancer cells.126 Animal studies have
shown that repeated injections of polymer-coated liposomes can cause them to lose
their long-circulating ability; this has been shown to be due to an unexpected immu-
nogenic response to the polymer coating after subsequent injections.127
Various methods to target liposomes by coupling species such as MAb to the
liposome surface have been explored. Targeting liposomes with MAbs was recently
reviewed by Torchilin128 and by Sofou and Sgouros.129 Pattillo et al.130 prepared
immunoliposomes conjugated with anti-E-selectin containing the antivascular drug
combretastatin disodium phosphate. Mice bearing transplanted mammary tumors
were injected with the liposomes, and tumor growth was retarded. Herceptin was
conjugated to paclitaxel-loaded Pegyylated liposomes; the liposomes were taken up
efficiently in vitro by breast cancer cells.131 Liposomes containing a plasmid DNA
were conjugated to MAb specific for transferrin receptor; encapsulation efficiency
of the plasmid DNA was 71%, the in vivo terminal half-life in mice reached 23.9 h,
and transfection to neuroblastoma cells was mediated by the antibody–receptor
binding.132 Liposomes with anti-GD2 antibodies, using a sterol PEG 1300 as anchor,
selectively bound to GD2 expressing cells.133 In vitro studies of Simard and Leroux134
demonstrated that pH-sensitive immunoliposomes with anti-CD33 antibody could
selectively release encapsulated cytosine arabinoside into leukemic cells. PEG
liposomes containing doxorubicin were coupled to antibodies against membrane
type-1 matrix metalloproteinase (MT1-MMP); cellular uptake into HT1080 can-
cer cells was significantly enhanced, and tumor growth in mice was suppressed.135
Doxorubicin long-circulating liposomes were modified with a nucleosome-specific
MAb, 2C5, leading to a five to eightfold reduction in IC50 values with various murine
and human cancer cell lines relative to Doxil.136 Immunoliposomes conjugated to
a cytoskeletal-antigen specific antibody targeted to heart were evaluated in an in
vivo rabbit model of acute myocardial infarction; myocardial infarct size of rabbits
treated with the targeted liposomes were five times smaller than those of controls.137
Despite the promise of antibody targeting of liposomes, only one clinical trial test-
ing the concept has been reported. MCC-465, a PEG immunoliposome containing
doxorubicin was examined in a Phase I study in 23 patients with metastatic stomach

cancer as a 1 h infusion every 3 weeks for up to 18 weeks. MCC-465 was well toler-
ated up to about 20 mg/m2; while no antitumor response was observed, stable disease
was observed in 10 out of 18 evaluable patients, and the pharmacokinetic profile was
similar to Doxil.138
Besides MAbs, other species have been explored as liposomal targeting agents.
Pegylated liposomes containing a novel cationic lipid, TRX-20, were shown to bind
preferentially to human mesangial cells, and thus have potential for long circula-
tion time and targeted therapy for glomerulonephritis.139 Targeting strategies to
the brain have been reviewed recently by Pardridge140; insulin and transferrin can
facilitate liposome crossing the blood–brain barrier by receptor-mediated trans-
port. Pegylated doxorubicin liposomes with surface-conjugated transferrin showed
increased uptake in tumors and decreased uptake by heart and kidney in mice.141
Similarly, pegylated liposomes containing the cis-platin derivative oxaliplatin with
surface-conjugated transferrin led to increased circulation time, increased extrava-
sation, and suppression of tumor growth in vivo relative to nontargeted pegylated
liposomes.142 Kobayashi et al.143 performed studies that suggested that transferrin-
bearing liposomes mediated inhibition of drug efflux by PgP, which is overex-
pressed in cancer cells and confers multidrug resistance; liposomes apparently need
to be targeted and must have the proper physicochemical properties for adequate
internalization and release of the drug. A pentappeptide conjugated to liposomes
containing an angiogenesis inhibitor, SU1498, decreased tumor microvessel den-
sity and tumor growth in mice.144 Targeting liposomes via folate was recently
reviewed by Zhao et al.145 A lipophilic folate derivative, folate–PEG–cholesterol
hemisuccinate, was evaluated as a targeting ligand for liposomal doxorubicin; these
folate-targeted liposomes showed increased in vitro cytotoxicity relative to con-
trol doxorubicin liposomes.146 An enzymatically cleavable poly(amino acid)-lipid
conjugate was used to modify the surface of liposomes; enzymatic degradation of
the poly(amino acid) moiety triggered release of the liposomal contents.147 Magnetic
liposomes illustrate another targeting strategy: for example, maghemite nanocrys-
tals were encapsulated in PEG-coated liposomes148 and surfactant-treated magne-
tite ferrofluid was encapsulated in liposomes,149 suggesting potential for targeting.
Pegylated liposomes were conjugated to PR_b peptide, which mimics the cell adhe-
sion domain of fibrinonectin, to target colon cancer cells; in vitro studies demon-
strated that the targeted liposomes were efficiently internalized by the cells and
were cytotoxic.150 Schiffelers and Storm151 recently reviewed targeting strategies
for cancer therapy, focusing on targeting the supporting cells required for metas-
tasis rather than the tumor cells themselves. A novel peptide ligand, GE11, was
conjugated to liposomes to target epidermal growth factor receptor; the liposomes
extravasated and accumulated preferentially at the tumor site in vivo in a H1299
xenograft mouse model.152 Taking advantage of differing pH values in tumors is
another strategy to achieve targeting; pH-sensitive liposomes can be prepared using
dioleoylphosphatidyl-ethanolamine (DOPE), as reviewed by Karanth and Murthy.153
The potential of targeting liposomes to bone was shown by incorporating cholester-
yltrisoxyethylene-bisphosphonic acid into liposome bilayers, which has high affinity
to hydroxyapatite of bone.154
There has been renewed interest in liposomes recently due to their potential for
gene therapy and delivery of oligonucleotides, short-interfering RNA (siRNA), and
nucleic acids. Positively charged liposomal or micellar structures, composed of
lipids, such as N,N-dioctadecylamidoglycylspermine (DOGS), dimethyldioctadecy-
lammonium bromide (DDAB), or 1,2 dioleyloxy-3-(trimethylammonium)propane
(DOTAP), form complexes with these negatively charged oligonucleotide/nucleic
acid species. At higher ratios of lipid to nucleotide, liposome bilayers are disrupted
and “lipoplexes” form, which can transfect cells and transfer the nucleotide or
nucleic acid species into the cell. Recent examples of applications include the fol-
lowing: An immunostimulatory nucleic acid, CpG DNA, was complexed with either
conventional or mannosylated cationic liposomes and was found to yield effective
inhibition of hepatic metastasis in mice.155 Delivery of glial-derived neurotrophic
factor plasmid DNA gene therapy was evaluated in rats with liposomes targeted with
a MAb to the transferrin receptor; nearly complete reduction of neurotoxin effects
are achieved after repeated IV administration of the liposomes, indicating promise
in treatment of Parkinson’s disease.156 Lyophilized liposome–DNA complexes were
prepared with sucrose as a croprotectant, and could be stored at 25°C–50°C up to
50 days without large loss of transfection efficiency.157 Octaarginine-modified lipo-
somes can be used in gene therapy; the peptide leads to enhanced cellular uptake
and controlled intracellular trafficking.158 Two positively charged cholesterol deriva-
tives, cholesteryloxypropan-1-amine and cholesteryl-2-aminoethylcarbamate, were
incorporated into liposomes, and their ability to increased apoptosis of Hepa1-6,
A549, and Hela cells was demonstrated.159 A liposome based on DOGS and DOPE
was developed for nuclear delivery of negatively charged antisense oligonucleotides,
and exhibited efficient in nuclear targeting in vitro.160 Sterically stabilized liposomes
containing siRNA were taken up by Hela cells; release was mediated by phospho-
lipase A2, which acted as a site-specific enzymatic trigger in inflamed tissue, and
hence showed potential in treatment of rheumatoid arthritis.161 Liposomal and other
delivery vehicles for siRNA were recently reviewed by de Fougerolles.162 A cationic
emulsion containing DOTAP formed a complex with plasmid DNA and showed a
high transfection efficiency and minimal cytotoxicity in vitro, as well as prolonged
high-level gene expression for 1 week after IV injection into Balb/c mice.163 Similarly,
cationic emulsions of oligonucleotides were prepared from medium chain triglycer-
ides, egg lecithin, and either oleylamine or DOTAP as the cationic lipid.164
A number of clinical trials have evaluated liposomal and lipoplex delivery of
genes, oligonucleotides, siRNA, and nucleic acids. Valentis Inc. has developed for-
mulations of a plasmid encoding human IL-2 complexed with DOTMA/cholesterol
liposomes and has initiated clinical studies of intratumoral injection in head and
neck cancer patients165; results, however, have apparently been disappointing. In a
Phase I clinical trial, cationic liposome-mediated interferon-beta gene transfer was
examined in patients with high-grade glioma; autopsy and histological examina-
tions revealed patterns of altered gene expression and changes in the tumor tissues
after therapy in all patients.166 In a Phase I clinical study of liposome-encapsulated
c-raf antisense oligodeoxyribonucleotide in combination with radiation therapy
in 17 patients with advanced malignancies, intact oligonucleotide was detected in
plasma for 30 min to several hours. Eight patients had partial response or stable disease;
inhibition of c-raf-1 mRNA was observed in three of evaluable five patients, and
Raf-1 protein was inhibited in four of five patients.167 However, another Phase I trial
of liposome c-raf antisense oligonucleotide in 22 patients without radiation showed
no objective response, and only two patients with stable disease.168 In a Phase II
trial, 28 patients with coronary heart disease received vascular endothelial growth
factor (VEGF) DNA plasmid liposomes composed of DOTMA:DOPE (1:1) through
catheter-based intracoronary gene transfer. The intracoronary gene transfer was well
tolerated, but myocardial perfusion improvement was inferior to that in 37 patients
who received VEGF adenovirus.169 A plasmid DNA, allovectin-7, complexed with
a cationic lipid mixture was evaluated in a Phase II clinical study of 52 patients
with metastatic melanoma by direct intratumoral injections. Treatment was well
tolerated, and regression of the injected lesion was observed in 18% of patients.170
A phase I clinical trial evaluated intracavitary (thoracic or peritoneal) injection of
E1A gene complexed with cationic liposome in 18 patients with breast and ovarian
cancers; E1A gene expression in tumor cells was detected, which was accompanied
by HER-2/neu down-regulation, increased apoptosis, and reduced proliferation,
providing proof of concept and warranting further clinical studies.171
Novel methods to manufacture and characterize liposomal formulations are also
needed. Drummond et al.172 has reviewed strategies to optimize liposome formula-
tions with respect to drug encapsulation, retention, and release in order to maximize
therapeutic benefit. Ferulic acid was incorporated into liposomes by remote loading
using an optimized calcium acetate gradient method to achieve a high solubility in
the intraliposomal buffer relative to the extraliposomal buffer; stable unilamellar
liposomes resulted in an 80% entrapment efficiency.173 Topotecan liposomes were
prepared by a double emulsion freeze-drying method; the dry products were
stable for at least 6 months, and upon rehydration formed unilamellar liposomes
with encapsulation efficiency of up to 80% and a mean diameter below 200 nm.174
Pegylated liposomes were prepared by membrane extrusion and loaded with fla-
vopiridol by a pH-gradient remote loading procedure, resulting in liposomes with
diameter of 120 nm, entrapment efficiency of 70%, and improved pharmacokinetics
in mice.175 A novel method for encapsulating irinotecan into liposomes was reported
by Dicko et al.176; copper gluconate/triethanolamine at pH 7.0 was encapsulated into
liposomes, and added irinotecan was loaded into the liposomes as a result of com-
plex formation between the drug and copper gluconate, apparently by an antiport
exchange mechanism between irinotecan and triethanolamine. Nanoscale multicom-
partment liposomes have been reported by Al-Jamal and Kostarelos,177 with poten-
tial applications for combination drug delivery. De Rosa et al.178 reported the use of
cold field emission gun-scanning electron microscopy to acquire detailed images
of liposome surfaces, as a method to gain detailed information on morphology and
surface ultrastructures of liposomes. A novel fluorescence method was developed
to monitor intravesicular pH in liposomal formulations of a CPT antitumor agent,
DB-67; this can potentially be used to optimize remote loading methods and monitor
drug partitioning between bilayer and aqueous regions as a function of pH.179
The use of emulsions and microemulsions in drug delivery studies has also
expanded. Parenteral drug delivery and targeting using emulsions and related
lipid nanodisoersions has been reviewed by Constantinides et al.180 while
parenteral microemulsion formulation and application has been reviewed by Date

and Nagarsenker.181 Lipid emulsions containing a water insoluble and unstable drug,
2-(allylthio)pyrazine, have been prepared; they showed enhanced drug stability
(up to 8 weeks) and liver targeting after IV administration in rats.182 A submicron
lipid emulsion of DT was prepared as a potentially less toxic alternative to current
micellar formulations; the optimal formulation was physically and chemically stable
at 4°C and 25°C for 6 months and had significantly AUC and Cmax in rats compared
to a micellar solution.183 Paclitaxel emulsions were prepared with vitamin E as the
oil phase, and a freeze-drying technique produced reconstitutible emulsions with
25 mg drug/g Vitamin E without crystal formation; the mean emulsion droplet size
remained <200 nm for 430 days at 4°C.184 Optimal methods to prepare emulsions by
“low-energy” methods were explored by Anton and Vandamme;185 suitable ternary
water/nonionic surfactant/oil systems were designed to form emulsions upon spon-
taneous emulsification, or by a phase inversion temperature method. Incorporation
of cinnarizine into emulsions, in which of the drug was localized in the interfacial
lecithin layer, significantly improved the chemical stability of the drug; estimated
shelf-life was 1472 days at 4°C (compared with 20 days in aqueous solution), and the
final products could withstand 121°C steam sterilization for 15 min.186 A chloram-
bucil emulsion had significantly greater AUC, mean residence time, and anticancer
activity in mice with colon-38 adenocarcinoma.187 Some parenteral emulsions (viz.,
those based on triglycerides and phospholipids) have been characterized as “syn-
thetic chylomicrons.” An analogous approach therefore would be to use lipoprotein-
based formulations as delivery vehicles; this delivery system, using both native and
synthetic lipoprotein carriers for hydrophobic anticancer drugs, has been reviewed
by Lacko et al.188
Liposome products to deliver medication to the eye (e.g., dry eye syndrome)189,190
or gastrointestinal tract have been described.94,191 Animal studies have been carried
out using liposomes and heat application to deliver anticancer drugs. Anticancer
drug-containing liposomes are injected into the bloodstream. At temperatures a few
degrees above normal, the liposomes melt, allowing drugs to leak out.192
Primaquin (an antimalarial agent) has been coupled to a liver cell-targeting pep-
tide to form a complex that can be encapsulated.193,194
Multivesicular liposomes for the administration of anticancer agents have been
developed. These liposomes are composed of multiple, nonconcentric, aqueous
chambers, allowing more efficient drug entrapment and improved incorporation of
drugs, including cytarabine and bleomycin.14
Battelle has developed a process to dehydrate drug-encapsulated liposomes,
allowing storage as a stable powder that can be reconstituted when required for drug
delivery.94
Macromolecular carriers and liposomes have been covalently coupled to MAbs
targeted against cardiac myosin heavy chain. Deferoxamine-modified polymers
were bound tightly with 67Ga and 68Ga radioisotopes.195
The penetration behavior of liposomes (prepared from NAT-106) incorporated
with proteins has been investigated in vivo utilizing MAbs. Within 20 min of topi-
cal application to young pig skin, an even distribution through all skin layers was
demonstrated.196
Dioleoyl-N-(monoethoxy polyethyleneglycol succinyl)-phosphatidylethanol-

amine (PGE-PE) (mol. wt. of PEG = 5000), an amphipathic polymer, can be incor-
porated into the liposome membrane and significantly prolong the blood circulation
time of the liposome.197
Two rat MAbs, 34A and 201B, that specifically bind to a surface glycoprotein
(gp112) of the pulmonary endothelial cell surface, have been coupled to unilamellar
liposomes (immunoliposomes) of approximately 0.25 mm in diameter. Time-course
studies reveal that 34A liposomes bind to lung antigens within 1 min after injection,
indicating that binding takes place during the first few passages through the lung
capillary bed.198
The MAb DAL K29 against a human renal cell carcinoma associated cell surface
antigen has been covalently linked to small unilamellar lipid vesicles (SUV) contain-
ing the antifolate methotrexate, with full retention of antibody activity.199
Two T lymphocyte cell surface molecules, CD4 and CD7, have been studied as
targets for the specific delivery of drugs from antibody-directed liposomes. The effi-
ciency of uptake by peripheral lymphocytes, thymocytes, and two CEM sublines
(CEM.MRS and CEM-T4) of anti-CD4 and anti-CD7 liposomes containing metho-
trexate have been evaluated by methotrexate-mediated inhibition of the incorpora-
tion of d-[3H]Urd into DNA. This was compared with similar liposomes targeted to
MHC-encoded HLA Class I molecules, which are known to be taken up efficiently
by T cells.200
Generation of cytotoxic T lymphocytes (CTLs) in vitro and tumor-rejection
responses by sensitization of semisyngenic mice with tumor antigen reconsti-
tuted liposomes has been investigated. Liposomes were prepared from a crude
butanol extract of BALBRVD leukemia cells and egg PC: 1,2-Dimyristoylamido-
1,2-Deoxyphosphatidylcholine (DDPC) (3:2), or dimyristoylphosphatidylcholine
(DMPC):DDPC (1:4).201
A new method for the elimination of mononuclear phagocytic cells from cell
suspensions has been described. By making use of liposome-encapsulated dichlo-
romethylene diphosphonate, macrophages were effectively removed from spleen
cell suspensions. This effect was not observed when using the free-drug or control
liposomes.202
Comparative studies of the preparation of immunoliposomes with the use of two
bifunctional coupling agents and investigation of in vitro immunoliposome target
cell binding by cytofluorometry and electron microscopy have been carried out. The
specificity of the binding of B8–24.3-liposomes to EL4 target cells was visualized
by scanning electron microscopy. Antibody-mediated endocytic uptake of immuno-
liposomes was demonstrated.203
The potential of small unilamellar liposomes coupled to antitumor MAbs to
accumulate in solid tumor tissue has been tested in two systems: a human malig-
nant melanoma xenografted into nude mice and a syngeneic murine lymphoma ESb.
Mp exhibiting spontaneous metastasis to the liver. Both MAbs tested were partly
released from immunoliposomes within a few hours and produced a constant level
of circulating antibody.204
A differentiation inducer, sodium butyrate (SB), encapsulated in liposomes conju-
gated covalently to an MAb directed to CD19 antigen has been successfully targeted
Exploring the Variety of Random
Documents with Different Content
Az Eszter mosolygása eltünt.
– Tekintetes úr, – kérdezte gyorsan – mit akar csinálni?
A kasznár örömtől részegen harsogott, krákogott, röhögött; fogta
az oldalát és ordított:
– Megkoppasztani!… Munkára, emberek. Megkoppasztani, úgy
kihajítani az utcára… hadd lássák… Munkára, emberek.
– Tekintetes úr, – szólt Eszter remegő hangon – azt én nem
engedem meg.
– Csiba, jérce – szólt a kasznár. – Munkára, emberek!
A kocsis, a kertész és a béres rávetette magát a Lőrinczi-
gyerekre. A Lőrinczi-gyerek félig ájultan védekezett.
Belekapaszkodott annak a széknek a karfájába, amelyet megfogott
és szótlanul, görcsösen szorította a fát bele a markába. Nem lehetett
a kezét a székről lefejteni.
Eszter megmozdult; segítségére akart menni. A kasznár elébe
állott, föltartotta és közben uszította az embereit.
– Ki az utcára… Ki vele az utcára…
Eszter sápadtan nézte egy másodpercig ezt a harcot, azután
fölsikoltott és begörbített karmokkal ugrott neki a kasznár duzzadt,
vörös arcának. A kasznár védekezett, de az első rohamot már nem
tudta kivédeni. Az Eszter körme nyomán repedt a bőr és szakadt a
hús; a kasznár duzzadt arcán kis vérpatakok csordultak lefelé.
Nem bírt Eszterrel. Eszter tépte, vágta és ütötte. Megszökött előle
a folyosóra, Eszter utána ment. Innen is szöknie kellett.
– Csak ki az utcára! – ordította be a szobába, és ő is szaladni
kezdett az utca felé.
Az utcán ott volt a Zöldkoszoru egész társasága, a kunszállási
fiatalság. A kasznár törölgette az arcáról a vért és nevetve, ugatva,
bufogva kiabálta nekik:
– Hozzák már! Hozzák már… Várjatok csak, hozzák már!
Hozták. Egyikük Eszterrel harcolt, a másik kettő hozta a Lőrinczi-
gyereket. A Lőrinczi-gyerek nem védekezett; úgy feküdt a karjukon
lehunyt szemmel, fehér arccal, mintha elájult volna. Hozták.
– Lökjétek ki, hajítsátok ki; ide hajítsátok – üvöltötte a kasznár.
A két ember nem lökte ki a Lőrinczi-gyereket. Óvatosan
megfogták, ijedten nézték a fehér arcát és – szinte gyöngéden –
megpróbálták talpra állítani.
A Lőrinczi-gyerek egészen meztelen volt.
A két ember megpróbálta talpra állitani, de a Lőrinczi-gyereknek
megrogyott a térde. A kunszállási fiatalság csendes, édes nevetéssel
fogadta már a megjelenését is, mikor a lába megrogyott, akkor a
csendes nevetés viharos kacagássá alakult át. A fiatalság tréfálózott,
nevetett, röhögött, hahotázott, hejahujázott és a szomszédban
kíváncsian nyíltak föl az ablakok. A kasznár csapkodta az oldalát és
bugyborékolt ki belőle a boldog röhej…
– Hohoho! Huhuhu! A szent pap… a kis kakas… no nézze meg az
ember… ide nézzenek… No paraszt, no paraszt.
A Lőrinczi-gyerek most kinyitotta a szemét és egy elborult,
fájdalmas tekintettel végignézett a kunszállási fiatalságon és a
szomszédban kinyílt ablakokon. A térde még egyszer megroggyant,
úgy tetszett, össze fog esni. De nem esett össze. A szeme nem
csukódott újra be, hanem tágra lobbanva kinyílt és visszatért a
kasznárhoz, aki vonaglott a röhögéstől és boldog vonaglásban
törölgette a vért az arcáról. Visszatért a kasznárhoz és megállapodott
nála, megállapodott rajta.
A Lőrinczi-gyerek lobogó szemmel nézte a kasznárt. Csend lett. A
Lőrinczi-gyerek kiegyenesedett. Meztelen, szép, fiatal teste
kihuzódott, kifeszült; ökölbe szorította a kezét és a karján
megfeszültek az izmok; boltozatos melle földuzzadva szítta be a
levegőt. A kasznár is elhallgatott; hiába igyekezett nevetni, most már
csak fujni tudott.
– No paraszt – mondta pöfögve. – No paraszt.
A Lőrinczi-gyerek előre lépett egyet. Elfelejtette, hogy meztelen;
nem törődött többé a meztelenségével és a meztelensége nem is
volt már nevetséges, hanem pompás és félelmes volt. Előrelépett
egyet. Még egyet. A kasznár védelemre kapta föl a kezét, de mielőtt
még védekezhetett volna és mielőtt a meghökkent, az elámult
kunszállási ifjuság közbeléphetett volna, a Lőrinczi-gyerek fölemelte
az öklét és mint egy irtózatos csontbuzogánnyal, úgy csapott bele a
kasznár duzzadt, véres arcába. A kasznár birokra akart vele menni,
egy fejjel volt nagyobb nála, de a Lőrinczi-gyerek pompás, acélos,
gyönyörü, meztelen teste úgy dolgozott, mint egy gép. A kasznár
még két irtózatos ütést kapott a fejére; támolyogni kezdett. Még egy
harmadikat; összeesett, mint egy csomó rongy.
A meztelen Lőrinczi-gyerek lenézett rá. Tiszta szép feje most
lobogó pirosságban égett; fölszegte a fejét, undorodva pillantott le
még egyszer a kasznárra, azután világító és bátor szemmel
körülnézett. Senki sem nézett szembe vele.
A Lőrinczi-gyerek nyugodtan, szégyenkezés nélkül megfordult,
bement a házba, felöltözködött és a kerten keresztül hazament.
Otthon levetette a reverendáját és soha többé nem vette föl. Másnap
reggel kiment a földre és inaszakadtáig, boldogan, mámorosan
dolgozott együtt az apja aratóival. Omlott és énekelt a kaszája előtt
a búza.
Zólyomi Jeanette.
Zólyomy Jeanette volt pár évig – pontosan: hat esztendeig – a
legszebb leány Kunszálláson. (Ami nem csekélység, mert
Kunszálláson sok szép lány van.) Hat évig Kunszállás egyhangu
itélete szerint ő volt a legszebb lány nem csupán Kunszálláson,
hanem az egész vármegyében. Ez a hat év terjedt a Zólyomy
Jeanette huszonharmadik évétől a huszonkilencedikig.
Huszonhárom éves volt ez a délceg, bársonyos szemü, nagyon
fekete haju, nagyon fehér arcu, büszke száju lány, amikor
Kunszállásra került a postához. Pár évvel azelőtt még Budapesten
bálozott és úgy volt, hogy milliomosnak vagy grófnak, de lehetőleg
milliomosnak és grófnak kell lennie annak, akihez feleségül megy. Az
apja azután meghalt, és kiderült, hogy éppen csak annyiuk maradt,
– neki meg az anyjának – hogy egy évig szükösen megélhetnek. A
milliomosok és a grófok elmaradtak tőlük, kisebb ember soha
közeledni sem mert feléjük, – Jeanette tehát sietve elvégezte a
postás tanfolyamot és lejött Kunszállásra postáskisasszonynak.
Kunszálláson nagy föltünést keltett a megjelenése. Nem csupán a
gyér kunszállási ifjúság, hanem a feleséges emberek is csapatostul
tódultak a postára, ahol Zólyomy Jeanette márványarccal ült a rács
mögött és adta a bélyegeket és írta a recepiszeket. Az ismerkedési
kisérletek azonban ferdén végződtek. Zólyomy Jeanette nem volt
gőgös, – oh, azt nem lehet mondani, hogy gőgös lett volna – hanem
olyan módon volt udvarias, azt lehet mondani: olyan módon volt
alázatos, hogy az emberek megdermedtek tőle és a szolgabirónak
csak úgy a torkán akadt a szó, mint a fiatal Bergernek, aki a
legnagyobb rőföskereskedő volt és így nőbarát és női szakértő.
Zólyomy Jeanette megsértett és megalázott fejedelemasszony volt;
királyné számüzetésben. Igazán az volt ez a királyi teremtés, és
Kunszállásnak becsületére válik, hogy ezt elég gyorsan megértette. A
fiatalság hamar tisztába jött vele, hogy ezt a lányt nem lehet
feleségnek elvinni még a zsindelyes kunszállási házakba sem,
nemhogy a zsupfedelüekbe (pedig a legtöbb kunszállási ház
zsupfedelü volt akkoriban még), kezdeni pedig éppen nem lehet
vele… A ki Zólyomy Jeanettebe mégis szerelmes lett, – és sorra
szerelmesek lettek bele az ifjak jóformán mindnyájan – az eleve
tudta, hogy reménytelenül szerelmes. Ha a Lojzi bandája nagyon
keserves nótákat rikoltozott a Zöld koszorú-ban, akkor tudni lehetett,
hogy a kunszállási ifjúságból megint reménytelenül szerelmes valaki
Zólyomy Jeanettebe. Olyan volt ez a szerelem Kunszálláson, mint
másutt a versírás, vagy a világfájdalom: a fiatalságnak át kellett rajta
esnie. Zólyomy Jeanette volt a messzeség, az elérhetetlen, az ideál,
a szürke élet egyetlen nagy föllendülése a kunszállási porból valami
más, tisztább levegőbe: a végtelen felé.
Lassanként mindenkivel megismerkedett Zólyomy Jeanette,
barátságot azonban senkivel sem kötött. (A férfiakkal nem akart, a
nőkkel nem lehetett.) Barátságot az emberekkel csak az anyja kötött.
Az anyja tudniillik gőgös volt, vele tehát lehetett barátkozni. Az anyja
gőgös volt: gondosan ápolta teintjét, néha-néha fölvette a régi
ruháit és mindenkinek elmondta, aki érdeklődött iránta, milyen
előkelő család ők, mennyire nincs – bocsássanak meg, de igazán
nincs – Kunszálláson egyetlen család sem, amelyet hozzájuk lehetne
hasonlítani, elmondta, kikkel vannak rokonságban, kik jártak
hozzájuk és végül, hogy ők úgy sem maradnak sokáig Kunszálláson,
mert Jeanette vagy alapítványi hölgy lesz, vagy valami fényes, valami
– közelebbről soha meg nem határozott, de – fényes állást kap,
olyant, amely példátlan a magyar posta történetében. Mindennap
várják már a levelet…
Az idő mult, eltelt egy-két év, de a levél csak nem jött. A
kunszállásiak, akik Jeanettehez soha egy tiszteletlen szóval sem
közeledtek, szelíd gunnyal kezdték kérdezgetni az öreg asszonyt, mi
van azzal a bizonyos levéllel. A kinevezéssel? A fényes állással, amely
páratlan a magyar posta történetében? (Az öreg asszonnyal lehetett
csufolódni, – ő gőgös volt.) Az öreg asszony buzgón, szorgalmasan,
hadarva válaszolt minden kérdésre. Hogy a dolog már megindult.
Már útban van. A miniszter már legközelebbre igérte. Mikor a
harmadik év is eltelt és a kinevezés mégsem jött, akkor az öreg
asszony egy napon így válaszolt a kérdezősködésre:
– Ugyan kérem, tudhatná, hogy a király mostanában mennyire el
van foglalva. Most nem ér rá. De mihelyt ráér…
E mellett azután meg is maradt egy félévig. Egy félév múlva
meghalt. A szívével volt valami baj. A halála napjáig ragaszkodott
ahhoz az állításához, ahhoz a hitéhez, hogy mihelyt a király ráér egy
kicsit, rögtön kinevezi Jeanettet valami fényes állásra, amely páratlan
a magyar posta történetében és amely az ő magyarázatai – az ő hite
– szerint valami olyanféle állás lett volna, hogy annak a jövedelméből
nagy házat, négy lovat lehet tartani Budapesten is…
Zólyomy Jeanette a gyászruhában még szebb volt, mint azelőtt.
Megrendítően szép volt. Így látta meg őt először és így értékelte a
szépségét Drágffy Péter is, aki akkor öt esztendő óta először jött
haza Kunszállásra. Drágffy Péter ekkor harminc éves volt; öt
esztendővel ezelőtt elvett egy nagyon gazdag leányt, azzal két
esztendeig elég jól élt; de három év óta csak éppen hogy együtt
laktak. Voltaképpen unalmukban vetődtek haza a kunszállási
kastélyukba és megnézték egy kicsit a birtokukat. Ezenközben, nyár
elején jött Drágffy Péter a postára is.
Megrendült, amikor Zólyomy Jeanettet meglátta. A leány a rács
mögött volt; állott és éppen lehajolt egy postacsomagért; és olyan
szép volt és a mozdulata olyan különös volt, az egész testének az
acélos és bódító szépsége annyira benne volt ebben az egy
mozdulatban, hogy Drágffy Péter megremegett a vágyódástól, amely
hirtelen föllobbant benne. De ő tudta, hogyan kell ehhez a leányhoz
közeledni. Előbb nagyon korrekt volt, tökéletesen, de hidegen
udvarias; azután lassan elejtegetett egypár baráti szót, végül
fölfedezett egy nagyon távoli rokonságot. A kunszállási tartózkodását
pedig, amelyet egy hónapra tervezett, meghosszabbította őszig.
A kunszállási ifjúság ekkortájt fogadta el végképpen azt a
megállapítást, hogy Zólyomy Jeanette nem csupán a kunszállási
szerelmeket utasítja vissza, hanem általában hideg teremtés.
Betegesen, természetellenesen hideg. És ekkortájt voltak Zólyomy
Jeanettenek életében először olyan éjszakái, amikor vergődött a
vágyódástól, amikor sírt és reggelig hánykolódott attól a forró
szomjúságtól, amely kínozta. Szerelmes volt Drágffy Péterbe.
Szerette őt magát, az erejét, a tüzes és szép férfiasságát és szerette
benne a távoli előkelőséget, a gazdagságot, a nagyúri életet is,
amely után évek óta síró nosztalgiát érzett.
Drágffy Péter juliusban elküldte a feleségét tenger mellé és
éjszakánkét bejárt a postához, a Zólyomy Jeanette ablaka alá. Csak
az ablaka alá; és még ezzel is nagyon kellett vigyázni, mert
Kunszálláson egy lépést sem lehetett ellenőrizetlenül tennie senkinek
és Drágffy Péter meg éppen tudhatta, hogy minden mozdulatáról
értesül másnap egész Kunszállás. Nyáron még az éjszaka sem adott
semmiféle biztosságot és csak éjfél után egy és két óra között
lehetett egy-egy félóra hosszat zavartalanul beszélgetni. Félegy
tájban tehát Zólyomy Jeanette csendesen kinyitotta az ablakát;
ugyanekkor elindúlt Drágffy Péter a Felvégről, ahol a kastélya volt és
– óvatosan kikerülve a néha még ilyentájban is kalandok után járó
kunszállási ifjakat – odalopózott a Zólyomy Jeanette ablaka alá. Ő ott
állott az utcán; a leány kikönyökölt az ablakon; egy poros, nagy
ákácfa rájuk hajolt; forró kézszorítások, eszeveszett csókok, heves
könyörgések és reszkető vonakodások egy félóra hosszat; akkor
rendesen jött már valaki az utcán és a leány visszahúzódott a
szobájába és Drágffy Péter ment haza a Felvégre, a kastélyába.
Ez így tartott szeptember elejéig. Szeptember elején egy napon
Drágffy Péter megmondta, hogy ma korábban jön. Ott volt már
féltizenkettőkor. A leány várta.
– Jeanette, – suttogta neki Drágffy Péter – ma sok mindenről
akarok veled beszélni. Vagy gyere el a templomkertbe sétálni, vagy
eressz be.
A leány a templomkertbe nem akart menni. De beereszteni? –
nem, azt sem lehet.
– De megigérek mindent… Esküszöm!
A leány nem akarta. Tiz perce tartott már a vita, amikor az utcán
messziről közeledő hangok hallatszottak. Drágffy Péter ekkor
félretolta a leányt az ablakból, a védekező két kezét összefogta a
jobb markába, a ballal megfogta az ablakpárkányt, fölugrott rá és
bent volt a szobában.
– Szent Isten, – mondta a leány – és odakint jönnek…
– Hát csukd be az ablakot.
A leány gyorsan becsukta az ablakot. Egy ideig mozdulatlanul
álltak. A beszélgető emberek végre elhaladtak az ablak alatt. Drágffy
ekkor a leány keze után nyúlt.
– Nem! – mondta a leány vacogó foggal és halkan sikoltott egyet.
– De hiszen nem bántalak – mondta Drágffy. – Hozzád sem
nyúlok. Csak le akartalak ültetni, mert beszélni akarok veled. Nézd,
elmegyek tőled… ilyen messzire… Hát ülj le végre.
A leány leült és ekkor a sötét szobában suttogva, kétségbeesett
harcot víva, hajnalig beszélgettek. Drágffy elmondta a leánynak azt,
amit odakint az utcán állva nem tudott elmondani. Gyöngéden és
óvatosan kellett ezt elmondani. Arról van szó, hogy ők ketten – ugy-
e – szeretik egymást. Két ember még így nem szerette egymást. De
neki – Drágffynak – felesége van, akitől nem válhat el száz nagy
okból. Házasság tehát nem lehetséges. De nem volna-e esztelenség,
ostobaság és bűn, ha ők ketten megtagadnák maguktól azt, ami a
legfőbb vágyuk, ami az életük értelme – csak azért, mert az emberi
ostobaság úgy kivánja? Nem volna-e bűn megölni az életüket? A
leánynak itt kell hagynia ezt a nyomorult fészket, ezt a hozzá
méltatlan piszkos életet; föl kell jönnie Budapestre; megint
szépségben és kényelemben kell élnie és szeretnie kell őt; ő
gondoskodik róla; biztosítja a jövőjét is; hát szabad mind ezt ostoba
babonák miatt föláldozni?…
A leány válaszolt, tiltakozott és védekezett és hajnalban, amikor
Drágffynak mennie kellett, még eldöntetlen volt az egész kérdés.
Majd holnap…
Lett ebből a holnapból holnapután is; szeptember vége volt,
amikor Zólyomy Jeanette kínzó töprengések és gyötrő ingadozások
után még mindig nem tudta magát az igenre rászánni. Ekkor egy
már hűvös szeptemberi estén Drágffy ismét félretolta az ablakból és
beugrott a szobájába.
– Holnap velem jössz, – mondta neki.
– Nem.
A férfi megölelte és az ajkát kereste. A leány egy félpercre
elbágyadt és átadta az ajkát, de azután megrázkódott, megvonaglott
és szabadulni akart. A férfi nem engedte.
– Te őrült, te őrült! – lihegte neki. – Ne akard megölni magadat.
A leány védekezett, teljes erejéből, makacs elszántsággal, foggal,
körömmel védekezett; minden királynői indulata most lázadt föl
benne; nem tudta eltürni, hogy így próbálja valaki – még ha ő
epedve szereti is – zsákmányul ejteni; és amikor az ereje fogyóban
volt, akkor lihegve suttogta:
– Menjen el… én segítségért kiáltok…
– Nem bánom! Kiálts!
A leány egy végső erőfeszítéssel kiszabadította magát és a sötét
szoba másik végébe surrant. Drágffy tapogatózva kereste. A leány
egy fiókot nyitott ki és a kezében megcsörrent valami.
– Jeanette! – mondta Drágffy halkan.
A leány suttogva felelte:
– Menjen el. Revolver van nálam.
Drágffy izgatottan, halkan nevetett és tapogatózva lépett előre
egyet.
– Ne jőjjön ide – lihegte a leány. – Menjen el. Ha még egy lépést
tesz, én lövök. Szavamra mondom!
Drágffy megmozdult, a leány fölemelte a revolvert és a sötétbe
belevillant, beledördült egy revolverlövés. Utána két másodpercig
megdermedt, rémült csend volt. Azután a leány megrettenten
elsikoltotta magát; ez a sikoltás a saját cselekedete vakmerőségének
szólt. Azután még egy ujjongó sikoltás tört ki a torkán, amikor
Drágffy megmozdult és látszott, hogy semmi baja. Kint mozgolódás
támadt. Drágffy odaugrott az ablakhoz, fölrántotta, kiszökött az
utcára, eltünt; és másnap reggel elutazott.
Zólyomy Jeanette a revolverlövést valami szép hazugsággal
megmagyarázta és aggódva, szégyenkezve, dacosan és vágyódva
várta a Drágffy látogatását. Amikor az elutazását meghallotta,
természetesnek találta, hogy most el kell telnie egy darab időnek,
amíg ők megint beszélgethetnek egymással. Amikor Drágffy az egész
télen nem jött haza, – tavaszra várta; tavasszal nyárra várta; nyáron
őszre. Amikor ősszel sem jött, levelet akart neki irni; a levélirást
azonban szégyelte. Néha megutálta a gyengeségét, a vágyódását is
és azt gondolta: neki kell jönnie, ő könyörögjön… Azután megint
levelet akart irni és megint elhalasztotta.
Így múlt el megint harmadfél év és a harmadfél év elmúltával
letelt az a hat esztendő is, amely hat esztendő alatt Zólyomy
Jeanette volt a legszebb leány Kunszálláson. A változás egészen
hirtelenül történt. A kunszállásiak fölébredtek egy napon és ezen a
napon a legszebb leány Kunszálláson kétségtelenül Viczay Ili volt
már. Zólyomy Jeanette-en semmi különös változás nem történt;
senki sem tudta volna megmondani, hogy az arca vagy a termete, az
ajka vagy a szeme más-e, mint tegnap volt; egy volt egészen,
véglegesen, mindenki számára bizonyos: az, hogy nem a legszebb
leány többé. A kunszállási fiatalság ettől a naptól kezdve nem volt
többé szerelmes belé; Zólyomy Jeanette nem pótolta többé a
versírást és a világfájdalmat Kunszálláson; az emberek kezdtek vele
nem törődni és egy-két év alatt – a fejedelmi elvonúltságában, a
királyi zárkózottságában olyanná vált a számukra, mintha mindig ott
ült volna a rács mögött és mintha hozzátartoznék a mátra-kunszállási
postahivatal berendezéséhez.
Zólyomy Jeanette azonban – királyi elzárkózottságában – ezalatt
is tovább vívta a maga nagy lelki harcát és amint teltek az évek és
amint még mindig nem tudta a levélírásra rászánni magát, egyre
türelmetlenebbül várta haza Drágffy Pétert és egyre inkább
bizonyosnak érezte, hogy a hazajövetele mindent, mindent
megváltoztat majd, mindenért, oh mindenért kárpótlást hoz majd.
Tíz esztendő telt el azóta, mióta Zólyomy Jeanette Kunszállásra
jött és ennek a tizedik esztendőnek a nyarán Drágffy Péter
csakugyan hazaérkezett végre. Zólyomy Jeanette fölujjongott,
megborzongott és fölfrissült erre a hírre. Mikor jön el? Megvárja-e
vajjon, míg ő hívja? Kell-e, hogy írjon neki? – Nem kellett. Drágffy
Péter jelentkezett. Egyelőre nem jött, csak írt. Nagyon vágyódik az
után, hogy beszélgessenek egy kicsit; – mikor jöhetne? Zólyomy
Jeanette remegő kézzel írta meg a választ: holnap, vasárnap
délután, ha úgy tetszik. Igen, vasárnap délután. Nyiltan. Kunszállás
beszélhet most már, amit akar…
Vasárnap délután be volt csukva a posta. Tisztára ki volt söpörve,
szépen föl volt locsolva a ház eleje; a kis kertben rendesen,
megöntözötten, szerényen álltak a georginák és a fuksziák; és a
homályos, hűvös szobában dobogó szívvel várakozott Zólyomy
Jeanette. Nem kellett sokáig várnia; Drágffy Péter korán jött; sietett
és neki is dobogott a szíve. Elfogultan és fölindultan nyitott be a
homályos, hűvös szobába és az első szavai remegőek voltak. Hogy
nagyon vágyódott; évek óta; hiszen, ugy-e, nekik sok minden
mondanivalójuk van egymás számára. De amikor a szeme lassan
hozzászokott a félhomályhoz és amikor a tekintete meghökkenve és
idegesen kutatta végig újra meg újra a leányt, akkor a szavai nem
remegtek többé, csak meghűvösödtek, el-elakadtak, ide-oda
billentek.
Persze, sok beszélni valójuk van… igen, igen… Hát – hogy van
Jeanette? Mit csinál? Mit csinált azóta? Remélem, egészséges volt?
És mi ujság itt Kunszálláson? Hiszen ez a város épül, a végén még
igazán város lesz. Megérjük, hogy jól lehet mulatni benne. Az ember
egészen jól érezheti magát itt ugy-e? No, majd beszélgetünk róla
máskor is. Milyen kedves, hogy megengedte, hogy eljöjjek. Hát a
viszontlátásra.
Zólyomy Jeanette fölállott. Egy édes fölindulás szorongatta a
torkát, egy nagy áldozatkészség gyulladt föl benne, soha nem ismert
alázatosság és bűnbánat. Igen, neki kell megtennie az első lépést…
– Péter, – mondta dideregve – amikor mi… utoljára
beszélgettünk, akkoriban maga… maga hívott engem… Budapestre
hívott… Én…
Drágffy Péter közbevágott.
– Oh, – mondta udvariasan – most már belátom, milyen
helytelenül tettem. Igaza volt: méltatlan lett volna magához.
– De én…
Drágffy Péter ismét közbevágott:
– Nem, nem, én teljesen beláttam azóta, hogy ez lehetetlen.
Most már szó sincs róla többé. Eszembe se jutna… Isten ments!
Sietve búcsúzott is.
– Viszontlátásra, – mondta – viszontlátásra.
Miközben a kalapját vette és kiment az ajtón, folyton beszélt,
hogy elhárítson minden ujrakezdést. Kint volt. A léptei elhangzottak.
A kocsija elrobogott.
Zólyomy Jeanette pedig ezen az éjszakán, a vasárnapról hétfőre
virradó éjszakán fölakasztotta magát. Úgy találta meg reggel a
levélhordó a postahivatalban holtan. A revolvere – a régi hivatali
revolvere – ott volt az asztalon; előbb nyilván ehhez akart
folyamodni, de azután meggondolta a dolgot és ezzel a revolverrel
nem akart véget vetni az életének. A kunszállásiak ezt nagyon
ostobának találták, mert nyilvánvaló, hogy revolverrel egyszerűbb és
fájdalomtalanabb az öngyilkosság, mint kötéllel, úriember nem
akasztja föl magát, hanem főbelövi magát és vén kisasszonynak kell
hozzá lenni, hogy valaki a kötelet válassza, mikor ott van a
kényelmes revolver is.
András csendőr lett.
Csendes, szép őszi nap. Sós András csendőrkáplár ül annak a
bérelt nagy parasztháznak az udvarán, amely a csendőrlaktanya
nevet viseli; a puskáját a lábához ereszti és komoran nézi a puskája
tövében a földet. Bentről, a laktanyából egy-egy elfojtott kiáltás
hallatszik ki néha. András tudja, hogy az őrmester vallat odabent.
Délelőtt négy embert hoztak be. Valami „mozgalom“ volt már
megint, pedig ősz van és most már nyughatnának.
Az őrmester odabent most megáll az embere előtt, az előtt, aki
soron van; fölemeli a csizmás lábát és a szeges csizmájával rálép a
paraszt meztelen lábára. Rálép. Ránehezedik. Hozzá mosolyog és
egyelőre atyai jóindulattal kérdezősködik a „mozgalom“ felől;
egyelőre atyai jóindulattal, mert ez még csak a kezdet. A folytatása
pofonzuhogás; megvasalás, hogy ropog a csont, szakad az in és
csordul a vér.
András sötéten bámulja a földet, de ekkor kijön belülről Daróczi
Gergely, öreg csendőr.
– No – mondja Andrásnak.
András fölkel, veszi a puskáját, odaáll Daróczi elé, megbillenti a
fejét, azután mind a ketten indulnak kifelé. Zsadányra indulnak; a
rendes őrjáratuk ez. Kiérnek az utcára és lekanyarodnak a zsadányi
út felé. Az út közepén mennek mindenütt, a teljes fölszerelésükben,
tollasan, kardosan, a szuronyuk csillog az őszi napfényben, a
ragyogó kakastoll meg-meglibben a kalapjukon. A parasztok kitérnek
előlük és utánuk néznek; a két csendőr komolyan, keményen,
szótlanul halad előre.
Elhagyják az utolsó kunszállási házat, András ekkor a gallérjához
nyul, tágít rajta egyet; nem kapcsolja ki, inkább csak megcsavarja
benne a nyakát; a fegyverét kényelmesebbre ereszti, szinte
meglóbálja, azután kiszabadított nyakán gyors mozdulattal magasra
szegi a fejét és azt mondja, nem is a másiknak, inkább csak maga
elé az őszi levegőbe:
– Azokat is csak anya szülte.
Daróczi ránéz. Megérti. Nem válaszol. Komor, öreg csendőr ez,
nagyon kevésbe veszi fiatal társát. András alig huszonkét éves még;
korán lett katona, a huszároktól jött ide, egyenesen csendőrnek. Az
arca piros, mint valami lányé, még meg sem barnult igazán a
huszároknál.
András érzi, hogy a szavát semmibe sem veszik, a keserüség
még jobban elárasztja; csendes harag lobog föl benne, de egyelőre
nem is igen tudja, ki ellen. Összeharapja a fogát; hallgat; szótlanul
mennek előre.
Megérkeznek Zsadányba. A dolgukat elvégzik, öt órára jár az idő,
indulnak hazafelé. A falu végén betérnek egy korcsmába, András
bort iszik, Daróczi pálinkát, negyedóra mulva otthagyják a korcsmát
és újra kint vannak az országúton.
András nem szólna, de Daróczinak most már jobb kedve van attól
a pálinkától, amelyet megivott – sokat iszik, de birja – és ő szólal
meg.
– Hát – mondja – azokat azóta megnyúzta az őrmester.
Ez válasz Andrásnak, válasz arra, amit ő négy órával ezelőtt
mondott. Az András tompa haragja rögtön elmulik, szinte
elérzékenyül, hogy szóltak hozzája; meglágyul a szíve; annyi a
mondanivalója, hogy nem tudja hol kezdeni; ki kell öntenie a lelkét.
– Pogány dolog ez, – mondja végül szinte dadogva – ha… ha…
ha én nekem őrsöm lesz, én nem…
Azt akarja mondani, hogyha ő egy ilyen kis csendőrőrsnek a
parancsolója lesz, nem kínozza majd az embereket. A szavát
azonban elakasztja a Daróczi tekintete. Az öreg csendőr komor
lenézéssel méri végig fiatal társát, a sötét ajka körül egy mérges
mosolygás is megjelenik.
– Gyerek vagy még te öcsém – mondja a szája szegletéből. –
Sokat kell még neked tanulnod.
András nem tud válaszolni. Sokféle mondanivalója volna, de ami
a fiatalságot illeti, ő csakugyan fiatal még. Nem szól; ránéz az öreg
csendőrre, mint aki bővebb magyarázatot vár. Az öreg csendőr
megadja a magyarázatot. Komoran bólintgat néhányat.
– Ölni kell a népet, öcsém – mondja felsőbbséges, nyugodt,
tanító hangon. – Ölni kell a népet, mert különben nem bir magával
és azt hiszi, övé a világ.
András megriadtan rázza meg a fejét. Az öreg csendőr fölemeli
keztyüs mutatóujját:
– Vágni kell a parasztot, öcsém, mint a répát, mert különben rád
kap.
András nem bir magával. Dacosan megrángatja a vállát.
– Hiszen én is paraszt voltam, – fakad ki elkeseredetten.
Az öreg csendőr megáll. Ránéz.
– ’Sz én is – feleli hangosan.
Tovább megy.
– De most már nem vagyok az – mondja nyugodtan, a hangját
leeresztve.
András megint nem tud szólni. Daróczi tovább beszél. Most
beszélő kedve van. Amikor elindultak, nem akart beszélni. Nem is
Ő
válaszolt. Ő akkor beszél, amikor neki van rá kedve, nem akkor,
amikor másnak van rá.
– Csendőr vagyok – mondja nyugodtan, csendesen, gőgösen.
A jobb szemével hunyorít egyet fiatal társa felé.
– De te még nem vagy az – szól halkan és várja a hatást.
András meghökkenve áll meg. De Daróczi tovább megy; ő is
utána siet; meg van zavarodva.
– Hogy én ne volnék?…
– Nem vagy hát – feleli Daróczi nyugodtan. – Csirke vagy. Most
bujtál ki a tojásból. Zöldfülü. Bundás.
András elpirul haragjában és szégyenkezésében.
– Már tavaly ilyenkor is öreg csont voltam én – mondja
elkeseredetten. – Nem bakáéknál – teszi hozzá kihivóan.
– Hát hol, öcsém?
Az András hangja recseg, mint a trombita:
– A huszas huszároknál. Cugszfirer.
Az öreg csendőr baka volt valamikor. De az András válaszára a
szempillája sem rezdül meg.
– Hát aztán mit csináltál ott a huszároknál, öcsém? – kérdezi
nyugodtan. – Nyergeltél? Abrakoltattál? Istállót takarítottál?
András nem válaszolt.
– Karabélyt hordtál a hátadon? – kérdezi nyugodtan az öreg
csendőr. – Hát azzal a karabéllyal mit csináltál? Sajbára lövöldöztél
vele? Visszalőtt-e a sajba? Nem ijedtél-e meg tőle?
András kezdi megérteni, merre tart az öreg csendőr és elhallgat.
Az öreg csendőr látja, hogy András nem válaszol; az ő hangja sem
éles már; nyugodtan magyaráz:
– Én, öcsém, ezzel a fegyverrel itt e, öt embernek oltottam ki az
életét… csak golyó által. Pedig mi a golyó a szuronyhoz képest!
Mikor megfogod a fegyvert, előre szegzed a szuronyt, azután
meglódítod… Csak meg kell lódítani, – úgy megy az bele az
emberbe, mintha nem csontból meg húsból volna, hanem vajból.
Csak olyan hangot ad az egész, mintha selymet szakítanának. Nem
kell hozzá nagy erő, csak szív kell hozzá. De az kell.
András nem felel. Megilletődve hallgat.
– Én, öcsém, – mondja az öreg csendőr – már három emberbe
eresztettem bele ezt a szuronyt. Hát te hányba a tiedet?
András hallgat.
– Addig pedig, öcsém, nem vagy csendőr, amig bele nem
ereszted vagy kettőbe. Zöldfülü vagy.
András még mindig hallgat.
– Hát addig, öcsém, ne beszélj – mondja az öreg csendőr. –
Addig nem tudsz semmit. Majd csak azután leszel csendőr.
András megrendülten hallgat. Beérnek Kunszállásra. Itt az utcán
mind a ketten hallgatnak. Tollasan, kardosan, komolyan, keményen
mennek előre. Hazaérkeznek a laktanyába. A börtönszobában
sebesen, megkínzottan nyögnek a parasztok. András nem tőrödik
velük. Levágja magát az ágyára és szótlanul bámul a levegőbe.
András éjszaka nyugtalanul alszik. Másnap vasárnap van. Szüret
utáni, szép, őszi vasárnap; ilyenkor verekszenek a korcsmában a
legények. Ahány kunszállási korcsma van, abba mindbe csendőr
kellene ilyenkor. De mindegyikbe nem jut, hát a csendőrök egy része
sorra járja a korcsmákat, a másik része a laktanyában várja, nem
hívják-e valahová.
Délután hat órakor vágtatva jön egy suhancgyerek. Hogy a
csendőr urak jöjjenek a Hegyesbe, mert a legények agyonverik a
Bagi-gyereket. András sietve elindul; utána majd jön még két
csendőr.
A Hegyes ajtaja előtt egy csomó sivalkodó öregasszony áll. A
legények vasárnaponként isznak bent, az anyák pedig kint várják
reszketve, kinek a gyerekét kell hazavinni, vértől tisztára mosni. Az
öregasszonyok sivalkodnak kint; bent a korcsmában nagy zenebona.
András berugja az ajtót. A Bagi-gyereket nem verték agyon. A
Bagi-gyerek áll a szoba egyik végében; a vér csurog az arcáról; a
kezében sebesen forgatja a – véres – ólmos botját; a szoba másik
végében pedig állanak a többi legények és uj rohamra készülnek.
Mikor András belép, csend támad. András ránéz a Bagi-gyerekre. Ez
a véres fickó, ez a híres verekedő elmarta őt valamikor egy lánytól. A
Bagi-gyerek most vele is farkasszemet néz.
András intézkedni akar, de mielőtt még szólhatna, ott terem
előtte a Bagi-gyerek anyja. Az öreg asszony félti a fiát és berohant a
korcsmába. András el akarja tolni maga elől, de az öreg asszony
sivalkodik és belekapaszkodik a karjába. András lerázza magáról;
hátralép; a hóna alá kapja a fegyverét.
– Félre előlem – mondja az öregasszonynak.
Az öregasszony félig őrült az ijedelemtől. Belekapaszkodik a
fegyverbe, le akarja nyomni, el akarja kapni, ki akarja csavarni a
csendőr kezéből. Sivalkodik. Hadonászik. A magzata! Ne bántsák!
Igérje meg András!
András meglöki a fegyverével az asszonyt. Az asszony
megtántorodik, de azután újra ráesik a fegyverre. A háta mögött
fenyegetően közeledik a Bagi-gyerek. Andrásnak elborul a szeme.
Hivatalos hangon elhadarja a figyelmeztetést, az öreg asszony
rángatja a fegyvert, mögötte ott van a Bagi-gyerek.
András hátrakapja a fegyvert, azután előre lódítja. Az éles
szurony úgy megy bele az öreg asszonyba, mintha nem csontból
meg húsból volna, hanem vajból. Olyan hangot ad az egész, mintha
selymet hasítanának.
András visszahúzza a fegyvert, az öreg asszony melléből
kibuggyan a vér. Az öreg asszony megtántorodik. Mögötte ordítva
kapja föl a Bagi-gyerek a véres ólmos botot. A többi bot is
megmozdul. András villámgyorsan emeli vállhoz a fegyverét, a
fegyver eldördül…
András csendőr lett.
TARTALOM.
A vércse 3
Köböl József 13
Gyürky-Hajdu Ádám 26
Pacséry Flórián 35
Gábor és Brigitta 44
Fehér Péter 56
Matyi 64
Tarányi Sándor 79
A Teréz 91
Pufi bácsi pofonjai 101
Csermák Antalné 110
Kürth Pista 118
A Hlavathy-gyerekek 130
Frank Éva 140
Orvosok 151
A Lőrinczy-gyerek 160
Zólyomi Jeanette 169
András csendőr lett 182
Javítások.
Az eredeti szöveg helyesírásán nem változtattunk.

A nyomdai hibákat javítottuk. Ezek listája:
43 ingerlő kiváncsiágnak ingerlő kiváncsiságnak

57 lehetet megérezni lehetett megérezni
61 akarta-csak akarta, csak
72 jutottt már jutott már
105 nem tuda nem tudta
136 változáson men át változáson ment át
176 velm jössz velem jössz
183 Daróczi nánéz Daróczi ránéz
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Novel Delivery Systems for Transdermal and Intradermal

CISA certified information systems auditor study guide 3rd

Handbook of Polyester Drug Delivery Systems 1st Edition

Ocular Drug Delivery Systems Barriers and Application of

Bioinspired and Biomimetic Polymer Systems for Drug and

Drug Delivery 1st Edition Maria A. Popescu

Enhancement in Drug Delivery 1st Edition Elka Touitou

Polymers in Drug Delivery 1st Edition Ijeoma F. Uchegbu

Boca Raton London New York

CRC Press is an imprint of the

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper

International Standard Book Number-13: 978-1-4398-0619-7 (Ebook-PDF)

Chapter 1 Site-Specific Drug Delivery Using Liposomes and Emulsions

Chapter 2 Site-Specific Drug Delivery Utilizing Monoclonal Antibodies.......... 47

Chapter 3 Role of Polymers in Drug Delivery..................................................... 79

Chapter 4 Implants in Drug Delivery................................................................ 137

Future Prospects................................................................................ 161

Chapter 5 Oral Drug Delivery........................................................................... 169

Chapter 6 Transdermal Drug Delivery.............................................................. 243

Chapter 7 Transmucosal and Ocular Drug Delivery......................................... 305

Chapter 8 Miscellaneous Forms of Drug Delivery............................................ 373

Recent Advances............................................................................... 426

Chapter 9 Nanoscience and Nanotechnology for Drug Delivery...................... 451

Chapter 10 Regulatory Considerations for Drug Delivery Systems.................... 525

Chapter 11 Drug Delivery Industry and the Global Outlook.............................. 563

John B. Cannon, PhD, Trinity International University, Deerfield, Illinois, is cur-

as well as in visiting scientist research positions at Scripps Clinic and Research

1. Site-specific drug delivery

LIPOSOMES IN DRUG DELIVERY

Amphiphatic Polar solute in

SUV MLV LUV MVV

Chemical Characteristics of Liposomes

FIGURE 1.3 Structures of phospholipids and cholesterol used in liposomes.

Problems and Advantages of Liposomal Drug Delivery

FIGURE 1.4 Illustration of the chemical-coupling methodology for antibody/liposomes.

FIGURE 1.6 Possible mechanism of intracellular araC delivery by FR-targeted, cationic,

Macrophage Drug release

FIGURE 1.7 Schematic of phagocytosis of particulate carriers by macrophages.

Manufacturing Methods and Issues

is heterogeneous; particles as large as 30 μm and as small as 0.050 μm can exist in

liposomal dispersion or emulsion is sized by filtration or extrusion. A variation is

should be considered. Accelerated (high-temperature) testing greater than 25°C is

LIPOSOMES AS CARRIERS OF THERAPEUTIC AGENTS

anthracycline antibiotic, is useful in the treatment of a variety of solid neoplasms,

Liposomal Products and Manufacturers

in liposome development or as phospholipid suppliers): American Bioproducts,

a Kidney or pancreas transplant only

In Table 1.3, liposomal and conventional formulations of Amphotericin B are

maintaining efficacy,102,103 there is other evidence that there is incomplete incorpora-

RECENT ADVANCES AND FUTURE PROSPECTS

Highlights of Current Research

increase circulation longevity.119 A sustained release thermosensitive formulation

doxorubicin was examined in a Phase I study in 23 patients with metastatic stomach

parenteral microemulsion formulation and application has been reviewed by Date

Dioleoyl-N-(monoethoxy polyethyleneglycol succinyl)-phosphatidylethanol-

Az eredeti szöveg helyesírásán nem változtattunk.