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Page 1: ENGINEERING POLYMER DRUG DELIVERY€¦ · Engineering polymer systems for improved drug delivery / edited by Rebecca A. Bader, David A. Putnam. pages cm Includes bibliographical references
Page 2: ENGINEERING POLYMER DRUG DELIVERY€¦ · Engineering polymer systems for improved drug delivery / edited by Rebecca A. Bader, David A. Putnam. pages cm Includes bibliographical references
Page 3: ENGINEERING POLYMER DRUG DELIVERY€¦ · Engineering polymer systems for improved drug delivery / edited by Rebecca A. Bader, David A. Putnam. pages cm Includes bibliographical references

ENGINEERING POLYMERSYSTEMS FOR IMPROVED

DRUG DELIVERY

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ENGINEERING POLYMERSYSTEMS FOR IMPROVED

DRUG DELIVERY

Edited by

Rebecca A. BaderDavid A. Putnam

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Cover Design: WileyCover Image: © Horst von Recum and Andrew Fu/Courtesy of Rebecca A. Bader and David A. Putnam

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form orby any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except aspermitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the priorwritten permission of the Publisher, or authorization through payment of the appropriate per-copy fee tothe Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax(978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should beaddressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts inpreparing this book, they make no representations or warranties with respect to the accuracy orcompleteness of the contents of this book and specifically disclaim any implied warranties ofmerchantability or fitness for a particular purpose. No warranty may be created or extended by salesrepresentatives or written sales materials. The advice and strategies contained herein may not be suitablefor your situation. You should consult with a professional where appropriate. Neither the publisher norauthor shall be liable for any loss of profit or any other commercial damages, including but not limited tospecial, incidental, consequential, or other damages.

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Wiley also publishes its books in a variety of electronic formats. Some content that appears in print maynot be available in electronic formats. For more information about Wiley products, visit our web site atwww.wiley.com.

Library of Congress Cataloging-in-Publication Data:Engineering polymer systems for improved drug delivery / edited by Rebecca A. Bader, David A. Putnam.

pages cmIncludes bibliographical references and index.ISBN 978-1-118-09847-9 (cloth)

1. Polymeric drug delivery systems. 2. Polymeric drugs. 3. Polymers in medicine. 4. Drug deliverysystems. I. Bader, Rebecca A., 1977- editor of compilation. II. Putnam, David A., 1966- editor ofcompilation.

RS201.P65E54 2013615.1—dc23

2013016292

Printed in the United States of America.

10 9 8 7 6 5 4 3 2 1

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CONTENTS

FOREWORD xi

PREFACE xiii

CONTRIBUTORS xv

PART I INTRODUCTION 1

1 FUNDAMENTALS OF DRUG DELIVERY 3Rebecca A. Bader

1.1 Introduction: History and Future of Drug Delivery 3

1.2 Terminology 5

1.3 Basic Pharmacokinetics 8

1.4 Basic Pharmacodynamics 12

1.5 Mass Transfer 13

1.6 Key Points 23

1.7 Homework Problems 23

2 CHALLENGES OF DRUG DELIVERY 29Patricia R. Wardwell and Rebecca A. Bader

2.1 Introduction 29

2.2 History and Challenges of Drug Delivery 30

2.3 Physical Barriers 31

2.4 Metabolic and Chemical Concerns 39

2.5 Physical Properties of Therapeutics 42

2.6 Polymer Carriers as a Solution to Challenges 45

2.7 Key Points 50

2.8 Homework Problems 50

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vi CONTENTS

PART II INJECTABLE POLYMERIC DRUG DELIVERYSYSTEMS 55

3 POLYMER–DRUG CONJUGATES 57Cristina Fante and Francesca Greco

3.1 Introduction 57

3.2 Historical Perspective 58

3.3 Polymer–Drug Conjugates: Biological Rationale 59

3.4 Structural Features of Polymer–Drug Conjugates 62

3.5 Making a Polymer–Drug Conjugate 68

3.6 Current Challenges and Future Perspectives 71

3.7 Key Points 75

3.8 Worked Example 76

3.9 Homework Problems 76

4 POLYMERIC MICROPARTICLES 85Noelle K. Comolli and Colleen E. Clark

4.1 Introduction 85

4.2 The Rationale for Microparticles 86

4.3 Defining the Design Criteria 87

4.4 Polymer Selection 89

4.5 Microparticle Synthesis 91

4.6 Microparticle Characterization Methods 96

4.7 Drug Release from Microparticles 100

4.8 Microparticle Design Examples 108

4.9 Key Points 110

4.10 Worked Example 110

4.11 Homework Problems 111

5 POLYMERIC NANOPARTICLES 117Andrew L. Vasilakes, Thomas D. Dziubla, and Paritosh P. Wattamwar

5.1 Introduction 117

5.2 PNP Design 124

5.3 PNP Formulation Methods and Targeting 128

5.4 Nanoparticle Targeting Overview 133

5.5 PNP Characterization 139

5.6 Major Clinical Achievements 147

5.7 Key Points 148

5.8 Worked Example 149

5.9 Homework Problems 150

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CONTENTS vii

6 BLOCK COPOLYMER MICELLES AND VESICLES FOR DRUGDELIVERY 163James D. Robertson, Nisa Patikarnmonthon, Adrian S. Joseph, andGiuseppe Battaglia

6.1 Introduction 163

6.2 Drug Encapsulation and Release 165

6.3 Bioavailability and Biodistribution 166

6.4 Stimuli Responsiveness 170

6.5 The Immune System 174

6.6 Gene Therapy 177

6.7 Cancer Therapy 180

6.8 Conclusions 182

6.9 Key Points 182

6.10 Homework Problems 183

PART III IMPLANTABLE POLYMERIC DRUGDELIVERY SYSTEMS 189

7 IMPLANTABLE DRUG DELIVERY SYSTEMS 191Luis Solorio, Angela Carlson, Haoyan Zhou, and Agata A. Exner

7.1 Introduction 191

7.2 Nondegradable Polymeric Implants 193

7.3 Biodegradable Polymeric Implants 198

7.4 Conclusions and Future Perspectives 215

7.5 Key Points 216

7.6 Homework Problems 216

8 POLYMERIC DRUG DELIVERY SYSTEMS IN TISSUEENGINEERING 227Matthew Skiles and James Blanchette

8.1 Introduction 227

8.2 Wound Healing as a Prototype for Adult Tissue Generation 228

8.3 Bioactive Factors in Tissue Engineering and RegenerativeMedicine 232

8.4 Delivery of Growth Factors in Tissue Engineering andRegenerative Medicine 248

8.5 Key Points 268

8.6 Worked Example 269

8.7 Homework Problems 270

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viii CONTENTS

PART IV ORAL POLYMERIC DRUG DELIVERYSYSTEMS 283

9 ORAL CONTROLLED-RELEASE POLYMERIC DRUG DELIVERYSYSTEMS 285James W. McGinity, James C. DiNunzio, and Justin M. Keen

9.1 Introduction 285

9.2 Release Mechanisms of Oral Polymeric Dosage Forms 288

9.3 Oral Polymeric Release Modifiers 295

9.4 Manufacturing Technologies and Industrial Applications ofControlled Release 297

9.5 Worked Example 311

9.6 Key Points 314

9.7 Homework Problems 314

10 MUCOADHESIVE DRUG DELIVERY SYSTEMS 319Srinath Muppalaneni, David Mastropietro, and Hossein Omidian

10.1 Introduction 319

10.2 Factors Affecting Mucoadhesion 320

10.3 Polymer–Mucus Interactions 320

10.4 Mucoadhesion Mechanisms 322

10.5 Mucoadhesive Polymers 324

10.6 Novel Mucoadhesive Materials 327

10.7 Mucoadhesion Testing 330

10.8 Drug Release Studies 332

10.9 Mucoadhesive Dosage Forms 332

10.10 Conclusion 334

10.11 Key Points 334

10.12 Homework Questions 337

11 ENHANCED ORAL DRUG DELIVERY THROUGH METABOLICPATHWAYS 343Gregory Russell-Jones

11.1 Introduction 343

11.2 Uptake of Nutrients from the Intestine 344

11.3 Nutrient Transport in the Intestine 349

11.4 Use of Nutrient Transporters for Drug Delivery 352

11.5 Case Study: The Use of the Vitamin B2 Uptake System forDrug Delivery 352

11.6 Key Points 365

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CONTENTS ix

11.7 Worked Example 365

11.8 Homework Problems 366

PART V ADVANCED POLYMERIC DRUG DELIVERY 375

12 STIMULI-RESPONSIVE POLYMER DELIVERY SYSTEMS 377Amy Van Hove, Zhanwu Cui, and Danielle S.W. Benoit

12.1 Introduction 377

12.2 Temperature-Responsive Polymers for Drug Delivery 378

12.3 pH-Responsive Polymers for Drug Delivery 387

12.4 Reduction/Oxidation (Redox)-Responsive Polymers 397

12.5 Enzymatically Responsive Drug Delivery 403

12.6 Key Points 415

12.7 Homework Questions 416

13 AFFINITY-BASED DRUG DELIVERY 429Andrew S. Fu and Horst A. von Recum

13.1 Introduction 429

13.2 Association Constant 430

13.3 Worked Example 432

13.4 Affinity-Based Drug Delivery Systems 437

13.5 Mathematical Modeling of Affinity-Based Systems 444

13.6 Challenges and Future Directions 448

13.7 Key Points 448

13.8 Homework Problems 449

INDEX 453

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FOREWORD

The body is made up of tens of trillions of human cells and an even greater numberof microorganisms, each of which impact health in ways that scientists, physicians,and engineers are still trying to fully comprehend. Overall, the amount of informationencoded in each of these cells and their surroundings is staggering, leading to theorganization of approximately 7 octillion atoms (a 7 followed by 27 zeros) into a well-oiled, living, breathing, and reproducing machine. Importantly, the myriad of cells inthe body do not act in isolation, but rather in concert with one another, sometimeswith subsecond precision and timing, forming a countless network of signals andinteractions that is nothing short of awe-inspiring.

In contrast, the current state of medicine is somewhat less impressive. Even themost modern medicine is still administered in a way so as to expose a drug to all cellsin the body indiscriminately, even though that drug’s goal is to elicit a specific responsefrom a specific cell type. In the few instances where this is not the case, any observedcell-specific localization could be completely accidental. Consequently, the total coststo the US Healthcare system associated with side effects from these kinds of drugs(including costs associated with deleterious effects from patients not properly takingthese drugs) currently exceeds the amount of money spent on treating both cancerand heart disease combined. It may be surprising to hear that a solution to theseproblems was described four decades ago with the first demonstration of polymersfor the controlled and localized release of biologic molecules. Using polymers thatare extremely safe (some of which can completely disappear in the body followingaction), it was envisioned that it was not only possible to limit a drug’s effects to aspecific location or specific cell population, but also quite possible to achieve effectsover extremely long durations of time, making the common, daily dosing of drugsobsolete. Yet, only a handful of these advanced drug delivery systems have ever beentranslated to clinical practice given a slower than anticipated learning curve in theunderstanding of the nature of polymeric delivery systems and the engineering oftheir behavior.

Most recently, however, there have been exciting advances in understandingand practice in the field of polymeric drug delivery systems so as to increase theeffectiveness of new drugs while minimizing (or even completely eliminating) theirtoxicity and side effects. These advances are built on the foundations laid by thefounders and luminaries in the field by the next generation of leaders, many of whomwere personally trained by these founders and luminaries.

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xii FOREWORD

It is for this reason that I could not have been more excited to hear thatDr. Rebecca Bader and Dr. David Putnam (who are both outstanding teachers andwell-respected scholars in the field) have taken on the task of bringing together animpressive team of these next generation leaders to contribute to the book that youare reading right now and to provide an overview of the state of the art in the fieldof polymeric drug delivery. Also, as expected, Dr. Bader and Dr. Putnam provideexcellent historical and topical context in this work as well as a well-groundedunderstanding of the important current problems in the field. The following chapters(arranged by mode of administration) cover an extremely broad array of advancesranging from micro and nano particulate systems to implantable matrices, to ratecontrolling membranes, to advanced, stimuli responsive and affinity-based systems.Importantly, each of these chapters has been carefully composed by individualswho have each contributed to the modern understanding of the respective polymericdrug delivery systems. I am excited to have this extremely valuable resource on mybookshelf.

It is also important to mention that given the expected impacts that the informationcontained in this book will have on the field, I am sure that this volume could not havecome at a better time. It is my opinion that we will soon pass a critical point in timewhere our understanding will lead to drug delivery systems that enable the scores ofpromising drugs that would have otherwise been discarded. It is also my strong beliefthat we are extremely close to this critical point. If that is true, the person readingthis text right now may very well be one of the ones who will use this information tocreate the next generation of medical treatments that will improve the quality of lifeand the cost of healthcare for our children and our grandchildren. Now is indeed avery exciting time in the field, one that has the potential to redefine medicine forever.

Steven Little

Chairman, Department of Chemical Engineering University of Pittsburgh

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PREFACE

Pharmaceutical treatment of disease has evolved from “the botanical era,” when herbalremedies were the mainstay, to the present “age of biologics,” marked by the useof nucleic acid- and protein-based drugs to alter disease pathology. Although theseexciting, new therapeutics offer the possibility of curing diseases that were previouslythought to be incurable, a myriad of problems have arisen that have prevented transla-tion to widespread clinical use. Of primary concern is the unwanted delivery of thesecompounds to normal, healthy tissue, rather than the disease site, which can resultin unexpected and/or severe adverse side effects (see Fig. 1). For example, in 2006,TGN1412, a monoclonal antibody that activates T cells, caused multiple organ fail-ure in all six human volunteers recruited for the Phase I clinical trial, despite provenpreclinical safety and efficacy. The antibody was intended to target only regulatoryT cells to suppress, rather than induce, inflammation, thereby providing an effectivetreatment for those who suffer from autoimmune diseases such as rheumatoid arthri-tis. However, TGN1412 instead is thought to have indiscriminately activated T cellsthroughout the body, leading to an abnormal immune response as well as destructionof healthy tissue [1].

In this example, the question remains as to whether this drug could have beenformulated in such a way so as to have enhanced specificity and efficacy, therebypreventing the horrific outcome that was observed. The goal of Engineering PolymerSystems for Improved Drug Delivery is to provide an overview of how polymers canbe used to control not only what the drug does to the body but also what the bodydoes to the drug. In so doing, polymers provide the key to maximizing the potentialof old and new therapeutics alike, including those that would previously be eliminatedfrom consideration as nonviable drug candidates. The cooperation of pharmaceuticalscientists and polymer engineers may mark the beginning of an era in which diseasescan be treated with increased certainty of a positive outcome.

This book, intended for undergraduate or graduate student instruction, begins withthe basics of drug delivery (Chapters 1 and 2), continues through injectable (Chapters3–6), implantable (Chapters 7 and 8), and oral polymer-based drug delivery systems(Chapters 9–11), and concludes with advanced polymeric drug delivery techniques(Chapters 12 and 13). Each chapter is written so as to give a broad overview of atopic and is concluded with key points, worked problem(s), and homework problems.By taking this approach, we are hopeful that we will inspire the next generation ofscientists to make meaningful contributions to the field of drug delivery.

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xiv PREFACE

Figure 1. The advent of new therapeutic treatments has been accompanied by an increase

an adverse side effects. Our hope is that polymeric drug delivery can help eliminate some of

these side effects.

We would like to thank all the authors for their valuable contributions. Specialthanks are due to Patricia Wardwell for her help in organizing the chapters, obtainingpermissions, and for providing assistance in general.

Rebecca A. Bader and David A. Putnam

REFERENCE

1. Attarwala H. TGN1412: from Discovery to Disaster. J Young Pharm 2010;2(3):332–6.

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CONTRIBUTORS

Rebecca A. Bader Syracuse Biomaterials Institute, Syracuse University, Syracuse,NY, USA

Giuseppe Battaglia Department of Chemistry, University College London, London,UK

Danielle S.W. Benoit Department of Biomedical Engineering, University ofRochester, Rochester, NY, USA

James Blanchette Department of Biomedical Engineering, University of South Car-olina, Columbia, SC, USA

Angela Carlson Department of Radiology, Case Western Reserve University, Cleve-land, OH, USA

Colleen E. Clark Department of Chemical Engineering, Villanova University,Philadelphia, PA, USA

Noelle K. Comolli Department of Chemical Engineering, Villanova University,Philadelphia, PA, USA

Zhanwu Cui Department of Biomedical Engineering, University of Rochester,Rochester, NY, USA

James C. DiNunzio Pharmaceutics Division, College of Pharmacy, The University ofTexas at Austin, Austin, TX, USA; Hoffmann-La Roche, Inc., Nutley, NJ, USA

Thomas D. Dziubla Department of Chemical and Materials Engineering, Universityof Kentucky, Lexington, KY, USA

Agata A. Exner Department of Radiology, Case Western Reserve University, Cleve-land, OH, USA

Cristina Fante School of Pharmacy, University of Reading, Reading, UK

Andrew S. Fu Department of Biomedical Engineering, Case Western Reserve Uni-versity, Cleveland, OH, USA

Francesca Greco School of Pharmacy, University of Reading, Reading, UK

Adrian S. Joseph Department of Biomedical Science, The University of Sheffield,Sheffield, UK

Justin M. Keen Pharmaceutics Division, College of Pharmacy, The University ofTexas at Austin, Austin, TX, USA

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xvi CONTRIBUTORS

David Mastropietro Department of Pharmaceutical Sciences, College of Pharmacy,Nova Southeastern University, Fort Lauderdale, FL, USA

James W. McGinity Pharmaceutics Division, College of Pharmacy, The Universityof Texas at Austin, Austin, TX, USA

Srinath Muppalaneni Department of Pharmaceutical Sciences, College of Pharmacy,Nova Southeastern University, Fort Lauderdale, FL, USA

Hossein Omidian Department of Pharmaceutical Sciences, College of Pharmacy,Nova Southeastern University, Fort Lauderdale, FL, USA

Nisa Patikarnmonthon Department of Biomedical Science, The University ofSheffield, Sheffield, UK

David A. Putnam Department of Biomedical Engineering, Cornell University, Ithaca,NY, USA

Horst A. von Recum Department of Biomedical Engineering, Case Western ReserveUniversity, Cleveland, OH, USA

James D. Robertson Department of Biomedical Science, The University of Sheffield,Sheffield, UK

Gregory Russell-Jones Mentor Pharmaceutical Consulting Pty Ltd, Middle Cove,Australia

Matthew Skiles Department of Biomedical Engineering, University of South Carolina,Columbia, SC, USA

Luis Solorio Department of Radiology, Case Western Reserve University, Cleveland,OH, USA

Amy Van Hove Department of Biomedical Engineering, University of Rochester,Rochester, NY, USA

Andrew L. Vasilakes Department of Chemical and Materials Engineering, Universityof Kentucky, Lexington, KY, USA

Patricia R. Wardwell Syracuse Biomaterials Institute, Syracuse University, Syracuse,NY, USA

Paritosh P. Wattamwar Teva Pharmaceutical Industries Ltd., West Chester, PA, USA

Haoyan Zhou Department of Radiology, Case Western Reserve University, Cleveland,OH, USA

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PART I

INTRODUCTION

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1

FUNDAMENTALS OF DRUGDELIVERY

Rebecca A. Bader

Syracuse Biomaterials Institute, Syracuse University, Syracuse, NY, USA

1.1 INTRODUCTION: HISTORY AND FUTURE OF DRUG DELIVERY

As depicted in Fig. 1.1, as drug discovery has evolved, the need for innovate meth-ods to effectively deliver therapeutics has risen. In the early 1900s, there began ashift away from the traditional herbal remedies characteristic of the “age of botani-cals” toward a more modern approach based on developments in synthetic chemistry[1, 2]. Through the 1940s, drug discovery needs were directed by the needs of themilitary, that is, antibiotics were developed and produced to treat injured soldiers[3]. As more pharmaceuticals were rapidly identified by biologists and chemists alike,people became more cognizant of the impact therapeutics could have on everyday life.During the late 1940s to the early 1950s, drugs were, for the first time, formulatedinto microcapsules to simplify administration and to facilitate a sustained, controlledtherapeutic effect [4]. For example, Spansules®, microcapsules containing drug pel-lets surrounded by coatings of variable thickness to prolong release, were developedby Smith Kline and French Laboratories and rapidly approved for use [5]. Many ofthese early microencapsulation techniques, particularly the Wurster process, wherebydrug cores are spray coated with a polymer shell, are still in use today [6, 7].

Engineering Polymer Systems for Improved Drug Delivery, First Edition.Edited by Rebecca A. Bader and David A. Putnam.© 2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.

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4 FUNDAMENTALS OF DRUG DELIVERY

Figure 1.1. Drug delivery (a) and drug discovery (b) have followed similar trajectories with

the need for drug delivery rising with the identification of new therapeutic compounds.

Although a number of advanced methods for controlled and/or targeted drug deliv-ery were proposed in the 1960s, building on the conventional drug delivery methodof microencapsulation, these techniques were not fully implemented until the 1970s[8, 9]. During this decade, biotechnology and molecular biology began to play a sig-nificant role in the drug discovery process, culminating in an increased understandingof the etiology of numerous diseases and the development of protein-based therapeu-tics. Likewise, computer screening, predictive software, combinatorial chemistry, andhigh throughput screening significantly accelerated the rate at which lead compoundsfor new therapeutic compounds could be identified [1, 4]. As is discussed further inChapter 2, drug carrier systems, such as implants, coatings, micelles, liposomes, andpolymer conjugates, were proposed to address the growing need to deliver the newlyidentified therapeutic compounds with maximum efficacy and minimal risk of negativeside effects [8, 9] (Fig. 1.2).

In sum, over time, as technology has advanced for drug discovery, there has beena paradigm shift in drug delivery from simplifying the administration of old drugsto creating systems that can make new drugs work. This is particularly true as wecontinue to identify and develop therapeutics based on proteins and nucleic acids thatare difficult to administer in a patient-friendly manner and/or with the necessary site-specificity to reverse adverse consequences. However, as drug delivery technologyhas advanced for new drugs, many of the old drugs have likewise benefited throughincreased predictability of pharmacokinetic/pharmacodynamic profiles, decreased sideeffects, and enhanced efficacy. This text is intended to explain how these advanceddrug delivery techniques, particularly those related to the application of polymers, have

Conventionaldosage forms

The wurster process:microencapsulation of

drug particles

Introduction of polymer-drug conjugates

("nanotherapeutics")

Drug-elutingcoronary stents

approved

<1900 1930s 1940s 1950s 1960s 1970s 1980s 1990s >2000

<1900 1930s 1940s 1950s 1960s 1970s 1980s 1990s >2000

"Age ofchemical synthetic

discovery"

Emergence ofcomputer technology

"Age of biotechnology"

"Antibiotic era""Age ofbotanicals"

Approval offirst monoclonal

antibody

Approval of thespansule

Introduction ofdrug-loaded depots

and liposomes

Development of PEGylated liposomes

and micelles

Developmentof protein-

based drugs

Development ofcombinatorial

chemistry & HTS

Delivery systems thatsimulate physiologicalpatternsOral delivery ofpeptides/proteinsGene therapy

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TERMINOLOGY 5

Figure 1.2. The temporal and spatial distribution of drugs is impacted by absorption, distri-

bution, metabolism, and excretion (ADME).

improved the efficacy of old and new drugs alike. Chapter 1 serves as the foundationfor all subsequent chapters, defining the necessary terminology related to drug deliveryand pharmaceutics.

1.2 TERMINOLOGY

1.2.1 Pharmacology

Pharmacology, the science of drugs, is composed of two primary branches, pharma-codynamics and pharmacokinetic. In broad terms, pharmacokinetics refers to what thebody does to the drug whereas pharmacodynamics describes what the drug does to thebody. In the subsequent sections, a brief overview of these two branches of study aregiven in order to highlight some of the basic pharmacological terminology frequentlyencountered in both drug discovery and delivery

1.2.1.1 Pharmacokinetics. Pharmacokinetics tracks the time course of drugsand drug delivery systems through the body. The processes that impact the tempo-ral and spatial distribution of drugs are absorption, distribution, metabolism, excre-tion (ADME). Following administration, the drugs are absorbed by the bloodstream,

METABOLISMMetabolite formation

EXCRETION EXCRETION

ABSORPTION

PLASMA

Cp (bound) Cp(unbound) Ct (bound) Ct(unbound)

DISTRIBUTION TISSUE

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6 FUNDAMENTALS OF DRUG DELIVERY

TABLE 1.1. Pharmacokinetic Parameters

Process Parameter Definition

Absorption Absorption rate constant (ka) First-order rate constant forabsorption

Bioavailability (F ) The extent of drug absorptionDistribution Plasma drug concentration (Cp) The concentration of drug in the

plasmaVolume of distribution (Vd) The mass amount of drug given

(dose) divided by the plasmaconcentration (Cp). Vd is anapparent volume with nodirect physiological relevance

Unbound fraction The fraction of drug not boundto protein, that is,pharmaceutically active

Elimination(metabolism andexcretion)

Metabolism rate constant (km) First-order rate constant forelimination by metabolism

Excretion rate constant (kex) First-order rate constants forelimination by excretion

Elimination rate constant (ke) ke = kex + kmExtrarenal (metabolic) clearance The volume of plasma cleared

of drug per unit time bymetabolism

Renal clearance The volume of plasma clearedof drug per unit time bymetabolism

Total clearance Total clearance = renalclearance + extrarenalClearance

Half-life (t1/2) The time necessary for theplasma drug concentration tobe reduced 50%

distributed to tissues and organs throughout the body, and eventually eliminated bymetabolism or excretion. Although a summary of these processes with associatedparameters is provided in Table 1.1, each of these terms are described in further detailin Section 1.3 [10, 11].

1.2.1.2 Pharmacodynamics. Because pharmacodynamics broadly refers towhat the drug does to the body, pharmacodynamics measurements involve lookingat toxicity, as well as therapeutic efficacy. These measurements frequently involveexamining dose–response curves to determine the optimal range over which drugscan be administered with maximum therapeutic impact and minimal negative sideeffects. Pharmacodynamics also involves examining the mechanism by which drugsact, that is, drug–receptor interactions. Typically, these studies are used to identify

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TERMINOLOGY 7

the amount of drug necessary to reduce interactions of endogenous agonists with thereceptor [12]. These concepts related to pharmacodynamics will be explored in greaterdetail in Section 1.4.

1.2.2 Routes of Administration

The route by which drugs are administered can have a profound impact on the phar-macokinetic properties given in Table 1.1. One of the goals of drug delivery is tofacilitate administration by routes that normally have an adverse impact on the asso-ciated therapeutic pharmacokinetic properties. For example, as is discussed further inChapter 2, effective oral administration of numerous drugs is not feasible because ofpoor uptake through the mucosal epithelial barrier of the intestine and a low resultantbioavailability. Furthermore, orally administered drugs are subject to what is referredto as the first pass effect, whereby the bioavailability is reduced by metabolism withinthe liver and/or gut wall. Carrier systems have been designed to (i) increase intercel-lular transport by disrupting the epithelial barrier, (ii) facilitate intracellular transportthrough targeting of the absorptive epithelial cells, and/or (iii) reduce the destructionof drugs by liver enzymes [13–16].

The most explored routes of drug administration are summarized in Table 1.2.Although 90% of drugs are administered orally due to convenience and high patientcompliance, oral drug delivery is associated with low and/or variable bioavailabilityas a result of the harsh environment of the gastrointestinal tract and the impermeablenature of the mucosal epithelial barrier. In contrast, parenteral forms of adminis-tration (intravenous, subcutaneous, and intramuscular) yield rapid effects and highbioavailability (100% for intravenous); however, patient compliance is extremelylow as a result of the discomfort because of the injection. Transdermal delivery is

TABLE 1.2. Routes of Administration for Drug Delivery

Route ofAdministration

Advantages Limitations

Parenteral Immediate effectsReproducibleHigh bioavailability

Low patient complianceOften requires a clinician

Oral ConvenientHigh patient compliance

Highly variableHarsh environmental conditionsLow absorption of many drugs

Transdermal Continuous delivery Limited to lipophilic drugsPulmonary High absorptive surface area

Rapid absorption of small moleculedrugs

The morphology of the lung tissuemakes systemic delivery difficult

Limited absorption ofmacromolecules

Nasal Rapid absorption of lipophilic drugsHigh bioavailability of lipophilic

drugs

Limited absorption of polarmolecules

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8 FUNDAMENTALS OF DRUG DELIVERY

a favorable route of administration because of high patient acceptability and readyaccess to the site of absorption; however, this method has historically been limitedto small, lipophilic drugs that can passively diffuse through the skin barrier [17, 18].New techniques are currently being developed to extend transdermal delivery to polarand/or macromolecular compounds. For example, ultrasound and iontophoresis pro-vide a driving force for the passage of small, charged drugs, while electroporation andmicroneedles disrupt the outermost layer of the skin for delivery of macromolecules,particularly peptides and proteins [19]. Nasal and pulmonary drug deliveries are alsoattractive routes of administration because of the high potential surface area availablefor drug absorption; however, as with transdermal delivery, the nature of the epithelialbarriers in both regions limits this to lipophilic compounds [17, 18].

1.2.3 Drug Delivery

1.2.3.1 Controlled Release. Controlled drug delivery systems, also referredto as prolonged and sustained release systems, aim to minimize dosing frequency bymaintaining the local and/or systemic concentrations of drugs for extended periodsof time. Although difficult to achieve, ideal release of drugs from controlled releasedelivery systems follow zero-order release kinetics, whereby the rate of drug releasedoes not change with time until no drug remains. As a result, constant drug levelswithin the body can be maintained. A variable release rate with drugs provided to thebody at a nonconstant, time-dependent rate is more common. If first-order kineticsare followed, the release rate decreases exponentially with time until the majority ofthe drug has been released, at which time zero-order release kinetics are approached(Fig. 1.4) [9, 20–23].

1.2.3.2 Active Versus Passive Targeting. Inflammatory tissue and solidtumors both possess an increased vascular permeability that can be exploited forimproved drug delivery. The diseased tissue can be passively targeted by developingsystems (such as liposomes, micelles, and nanoparticles) with a hydrodynamic radiuslarge enough to prevent renal filtration, but small enough to pass through the leakyvasculature. In cancer, the change in vasculature is accompanied by a reduction inlymphatic drainage, thereby increasing the passive targeting capacity of carrier systemsthrough “enhanced permeation and retention” [24–26]. The site-specificity of drugdelivery systems can be further improved through the addition of a ligand, such as anantibody, polysaccharide, or peptide, that will actively target receptors overexpressedin the diseased region [27–30]. The concepts of active and passive targeting will arisethroughout this book.

1.3 BASIC PHARMACOKINETICS

1.3.1 Compartment Models

Compartment models are used as a simple method to describe the time course of adrug through a physiological system on administration. One and two compartment

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BASIC PHARMACOKINETICS 9

models are depicted in Fig. 1.3. The simplest pharmacokinetic model is the one com-partment open model for drugs administered by intravenous (IV) bolus with first-orderelimination, that is, the rate at which the amount of drug in the body changes is pro-portional to the amount of drug remaining in the body. To apply a one compartmentopen model, the assumption must be made that the drugs are instantaneously, homoge-nously distributed between tissues on administration, thereby allowing the body to bedescribed as a unit from which drugs are cleared. While the one compartment modelfor IV bolus administration will be presented herein, more complicated models, suchas those required when drugs are not instantaneously distributed, are beyond the scopeof this text. Readers are encouraged to look at several excellent textbooks on basicpharmacokinetics for additional information [10, 11, 31]

As mentioned in brief above, elimination after IV bolus administration can bedescribed using a first-order kinetic equation when applying a one compartment model.This equation can be derived by assessing the rate of change for either drug concen-tration (Eq. 1.1) or drug amount (Eq. 1.2)

dCp

dt= −keCp (1.1)

dM

dt= −keM (1.2)

where Cp is the plasma concentration of drug, M is the mass amount of drug, and keis a first-order elimination rate constant. Although an identical analysis can be appliedto the rate of change of drug amount, all subsequent pharmacokinetic parameters willbe derived using the rate of change of drug concentration (Eq. 1.1). Thus, integrationof Eq. 1.1 gives:

Cp,t = Cp,0e−ket (1.3)

Equation 1.3 in conjunction with the area under the curve (AUC) described inSection 1.3.2, serves as a spring board from which other pharmacokinetic parametersare derived. Note that Cp is not equal to the concentration of drug in other tissues;

Figure 1.3. (a) One and (b) two compartment models can be used to describe the time course

of drugs in the body after administration.

(a) (b)

DOSE DOSE

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10 FUNDAMENTALS OF DRUG DELIVERY

however, changes in drug concentration within the plasma are directly proportionalto those in other tissues as a consequence of describing the body as a homogenous,single compartment.

1.3.2 Bioavailability and Area Under the Curve (AUC)

Bioavailability refers to the rate and extent to which a drug has reached the systemiccirculation for delivery to the site of action. Thus, the most common indicator ofbioavailability is Cp. From a plot of Cp versus time, the AUC provides a quantitativemeasure of how much drug stays in the body and for how long [10, 31].

For an IV bolus with first-order elimination kinetics, an exact solution for theAUC can be obtained by analytical integration [10, 31]. For example, consider theCp versus time plot shown in Fig. 1.4. As derived in Section 1.3.1, Cp at a giventime can be determined from Eq. 1.3. Using calculus, the AUC is equal to the inte-gral from t = 0 to an infinite time point. Therefore, taking the integral of Eq. 1.3gives

AUC =∫ ∞

0Cp,tdt (1.4)

AUC =∫ ∞

0Cp,0e−ke tdt = Cp,0

[e−ket

−ke

]∞

0(1.5)

AUC = Cp,0

[e−ke∞ − e−ke0

−ke

](1.6)

AUC = Cp,0

ke(1.7)

Figure 1.4. After IV bolus administration, elimination can be described using a first-order

kinetic equation if a one compartment model is assumed.

Cp,1

Cp

Cp,2

t1 t2 Time

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BASIC PHARMACOKINETICS 11

Alternatively, Cp,0 if and/or ke are unknown, the AUC can be found using the trape-zoidal rule. Using Fig. 1.4, the AUC for the highlighted segment can be found with

AUC1−2 = Cp,1 + Cp,2

2(t2 − t1) (1.8)

Extrapolating the first segment to determine Cp,0, assuming the last points follow anexponential decay that defines ke, adding all possible segments together yields.

AUC = AUC0−1 + AUC1−last + AUClast−∞ (1.9)

AUC = Cp,0 + Cp,1

2t1 + Cp,1 + Cp,2

2(t2 − t1) + · · · + Cp,last

ke(1.10)

1.3.3 Elimination Rate Constant and Half-Life

The elimination rate constant, ke, introduced above can be found by converting Eq. 1.3to natural logarithmic form to give

Ln(Cp,t) = Ln(Cp,0) − ket (1.11)

Thus, ke is the slope of a plot of Ln(Cp) versus time:

ke = Ln(Cp,1) − Ln(Cp,2)

t2 − t1(1.12)

Note that the elimination rate constant includes both excretion and metabolism. Fromke, the half-life, that is, the time necessary to decrease Cp to one half of Cp,0, canbe determined. Considering Eq. 1.12 and solving for the time when Cp,2 = Cp,1/2gives

t1/2 = Ln2

ke= 0.693

ke(1.13)

Equation 1.13 shows that the half-life is independent of drug concentration. Thus,regardless of Cp,0, the half-life can be used to describe when most of the drug hasbeen eliminated from the body. For example, after five half-lives, Cp = Cp,0/32 and96.875% of the initial amount of drug in the body has been lost [10, 31].

1.3.4 Volume of Distribution

Despite the importance of this parameter in pharmacokinetics, the volume of distribu-tion, Vd, does not have any direct physiological relevance and does not correlate witha true volume. Vd can be defined as the ratio of dose, D, to the plasma concentrationat t = 0

Vd = D

Cp,0(1.14)

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12 FUNDAMENTALS OF DRUG DELIVERY

Likewise, Vd can be obtained by taking the ratio of the mass amount to theconcentration of drug at any given time point. If Vd is high, the drug is highly dis-tributed to tissues/organs throughout the body, rather than being confined primarily tothe plasma; while if Vd is low, the drug is not well distributed to tissue/organs andresides, for the most part, in the plasma [10, 31].

1.3.5 Clearance

Drug clearance (CL) is a proportionality constant relating the elimination rate, dM/dt ,to the plasma concentration Cp[10, 31].

CL = dM

dt· 1

Cp(1.15)

Substituting in Eq. 1.2 and noting that volume of distribution is equal to the amountof drug divided by the concentration of drug gives

CL = keVd (1.16)

Half-life is related to ke through Eq. 1.13. Thus,

CL = 0.693Vd

t1/2(1.17)

1.4 BASIC PHARMACODYNAMICS

1.4.1 Therapeutic Index and Therapeutic Window

The goal in the development of new therapeutic agents, as well as drug delivery sys-tems, is to maximize efficacy while minimizing the potential for adverse drug events.Thus, dose–response curves, will examine both therapeutic response and toxicity, asshown in Fig. 1.5. The ratio of the median toxic dose (TD50), that is, the dose thatcauses toxicity in 50% of the population, to the median effective dose (EC50), that is,the dose required to elicit a response in 50% of the population, is referred to as thetherapeutic index (TI). A drug with a high TI can be used over a wide range of doses,referred to as the therapeutic window, without adverse side effects. In contrast, a lowTI suggests a narrow therapeutic window [12, 32].

1.4.2 Ligand-Receptor Binding

Although some drugs act through chemical reactions or physical associations withmolecules within the body, a number of other drugs are used to elicit, change, or pre-vent a cellular response via ligand-receptor binding interactions. For this mechanismof action, the drug serves as an exogenous ligand that either (i) prevents interactions