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Pharmaceutical Inhalation
Aerosol Technology
 DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs

Series Executive Editor

James Swarbrick
Pharmaceutech, Inc.
Pinehurst, North Carolina

Recent Titles in Series

Good Manufacturing Practices for Pharmaceuticals, Seventh Edition, Graham P. Bunn
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Biosimilar Drug Product Development, Laszlo Endrenyi, Paul Declerck, and

Shein-Chung Chow

High Throughput Screening in Drug Discovery, Amancio Carnero

Generic Drug Product Development: International Regulatory Requirements for

Bioequivalence, Second Edition, Isadore Kanfer and Leon Shargel

Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,

Fourth Edition, Linda A. Felton

Good Design Practices for GMP Pharmaceutical Facilities, Second Edition,

Terry Jacobs and Andrew A. Signore

Handbook of Bioequivalence Testing, Second Edition, Sarfaraz K. Niazi

Generic Drug Product Development: Solid Oral Dosage Forms, Second Edition,
edited by Leon Shargel and Isadore Kanfer

Drug Stereochemistry: Analytical Methods and Pharmacology, Third Edition,

edited by Krzysztof Jozwiak, W. J. Lough, and Irving W. Wainer

Pharmaceutical Powder Compaction Technology, Second Edition, edited by Metin Çelik

Pharmaceutical Stress Testing: Predicting Drug Degradation, Second Edition,

edited by Steven W. Baertschi, Karen M. Alsante, and Robert A. Reed

Pharmaceutical Process Scale-Up, Third Edition, edited by Michael Levin

Sterile Drug Products: Formulation, Packaging, Manufacturing, and Quality,

Michael J. Akers
Pharmaceutical Inhalation
Aerosol Technology
Third Edition

Edited by
Anthony J. Hickey
Sandro R.P. da Rocha
CRC Press
Taylor & Francis Group
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© 2019 by Taylor & Francis Group, LLC

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Library of Congress Cataloging‑in‑Publication Data

Names: Hickey, Anthony J., 1955- editor.

Title: Pharmaceutical inhalation aerosol technology
/ [edited by] Anthony J. Hickey, Sandro R.P. da Rocha.
implementing game mechanics, art, design and programming / Penny de Byl.
Description: Third edition. | Boca Raton, Florida : CRC Press, [2019] |
Drugs and the pharmaceutical sciences |
Includes bibliographical references and
index
Identifiers: 2018044344| ISBN 9781138063075 (hardback : alk.paper)
ISBN 9780429055201 (ebook)
Subjects: LCSH: Aerosol therapy.
Classification: LCC RM161 .P55 2019 | DDC 615/.6--dc23
LC record available at https://lccn.loc.gov/2018044344

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Contents

Preface ...................................................................................................................................................... ix
Editors ....................................................................................................................................................... xi
Contributors ............................................................................................................................................xiii

1. Introduction ...................................................................................................................................... 1
Anthony J. Hickey and Sandro R.P. da Rocha

Section I Discovery
2. Physiology of the Airways ................................................................................................................ 5
Anthony J. Hickey and David C. Thompson

3. Drug Targeting to the Lung: Chemical and Biochemical Considerations ............................... 29

Peter A. Crooks, Narsimha R. Penthala, and Abeer M. Al-Ghananeem

Section II Aerosol Critical Attributes

4. Aerosol Physics and Lung Deposition Modeling ......................................................................... 81
Warren H. Finlay

5. Practical Aspects of Imaging Techniques Employed to Study Aerosol Deposition and

Clearance ........................................................................................................................................ 93
Myrna B. Dolovich

6. Pharmacokinetics and Pharmacodynamics of Drugs Delivered to the Lung .........................131

Stefanie K. Drescher, Mong-Jen Chen, Jürgen B. Bulitta, and Günther Hochhaus

Section III Active Pharmaceutical Ingredient/Drug

Product Manufacturing
7. Small Molecules: Process Intensification and Continuous Synthesis ......................................181
Thomas D. Roper

8. Biologic Drug Substance and Drug Product Manufacture ...................................................... 205

Ajit S. Narang, Mary E. Krause, Shelly Pizarro, and Joon Chong Yee

9. Scale-Up Considerations for Orally Inhaled Drug Products .................................................. 233

Jeremy Clarke and S. van den Ban

10. Quality by Control ....................................................................................................................... 249

Helen N. Strickland and Beth Morgan

v
vi Contents

Section IV Particle Engineering/Processing

11. Milling and Blending: Producing the Right Particles and Blend Characteristics for
Dry Powder Inhalation ................................................................................................................ 273
Bernice Mei Jin Tan, Lai Wah Chan, and Paul Wan Sia Heng

12. Engineering Stable Spray-Dried Biologic Powder for Inhalation ............................................291

Nicholas Carrigy and Reinhard Vehring

13. Supercritical Fluid Manufacture ................................................................................................ 327

Ana Aguiar-Ricardo and Eunice Costa

14. Particle Engineering Technology for Inhaled Therapies ......................................................... 349

David Lechuga-Ballesteros, Susan Hoe, and Benjamin W. Maynor

Section V Drug Product Formulation

15. Emerging Pulmonary Delivery Strategies in Gene Therapy: State of the Art and
Future Considerations ................................................................................................................. 365
Gabriella Costabile and Olivia M. Merkel

16. Genome Editing for Genetic Lung Diseases .............................................................................. 389

Ying Zhang and Hao Yin

17. Inhalation Drug Products Containing Nanomaterials ............................................................. 403

Sandro R.P. da Rocha, Rodrigo S. Heyder, Elizabeth R. Bielski, Ailin Guo,
Martina Steinmaurer, and Joshua J. Reineke

Section VI Devices
18. Pressurized Metered-Dose Inhalers ........................................................................................... 427
Sandro R.P. da Rocha, Balaji Bharatwaj, Rodrigo S. Heyder, and Lin Yang

19. Dry Powder Inhalation .................................................................................................................455

Anne H. de Boer and Floris Grasmeijer

20. Nebulizers...................................................................................................................................... 473

John N. Pritchard, Dirk von Hollen, and Ross H.M. Hatley

21. Soft Mist Inhalers ......................................................................................................................... 493

Stefan Leiner, David Cipolla, Joachim Eicher, Wilbur de Kruijf, and Herbert Wachtel

Section VII Drug Product Testing

22. Quality by Design Considerations ...............................................................................................511
William Craig Stagner and Anthony J. Hickey
Contents vii

23. Solid State Testing of Inhaled Formulations ............................................................................. 523

Philip Chi Lip Kwok and Hak-Kim Chan

24. Aerodynamic Particle Size Testing ..............................................................................................541

Jolyon Mitchell

Section VIII Regulatory Considerations

25. Scanning the Intricate Regulatory Landscape and Trying to Peek Over the Horizon .........591
Stephen T. Horhota, Stefan Leiner, and Allen Horhota

26. Pharmacopeial and Regulatory Guidances on Product Quality and Performance .............. 601
Anthony J. Hickey

27. The European Union Regulatory Scene......................................................................................611

Steven C. Nichols and Dennis Sandell

Section IX Preclinical Testing

28. Reconstituted 2D Cell and Tissue Models ................................................................................. 627
Nicole Schneider-Daum, Patrick Carius, Justus C. Horstmann, and Claus-Michael Lehr

29. 3D In Vitro/Ex Vivo Systems........................................................................................................ 653

Bethany M. Young, Alexandria Ritchie, Laleh Golshahi, and Rebecca L. Heise

30. Preclinical Models for Pulmonary Drug Delivery .................................................................... 669

Jibriil P. Ibrahim, Robert J. Bischof, and Michelle P. McIntosh

Section X Clinical Testing

31. Bioequivalence of Orally Inhaled Drug Products: Challenges and Opportunities ............... 687
Jayne E. Hastedt and Elise Burmeister Getz

32. General Conclusions .....................................................................................................................719

Anthony J. Hickey and Sandro R.P. da Rocha

Index .......................................................................................................................................................721
Preface

Two previous editions of the book Pharmaceutical Inhalation Aerosol Technology (PhIAT) were pub-
lished in 1993 and 2004. The first edition appeared at a time when few books on aerosol technology were
available, notably those of WC Hinds (Aerosol Technology, Wiley) and PC Reist (Introduction to Aerosol
Science) that had only been available for a decade. There were few general texts on medical aerosols, and
those were in specialized areas, notably several volumes by Stephen Newman. With this background, the
original PhIAT book was intended to broadly cover all aspects of the field from lung biology (pharmacol-
ogy, physiology, and anatomy) to drug product manufacturing, performance, and clinical applications. In
the intervening decades many new volumes have appeared and much more has been published on aerosol
physics, formulation and device development, and therapeutic strategies, supported by the commercial-
ization of many new drug products.
This edition of PhIAT not only provides an update on many topics addressed in the 2nd edition, but
also expands the “technology” focus of the original volumes to address the title more directly. Since the
major purpose of any book should be its utility to the reader, it is logical to look at the topic from the
perspective of clear unmet needs. The new text covers all aspects of product development and manu-
facturing encompassing the important areas of preformulation, formulation, device selection, and drug
product evaluation. In order to expand the scope to consider previously unaddressed aspects of phar-
maceutical inhalation aerosol technology, considerations of the patient interface have been restricted to
those aspects of aerosol delivery, lung deposition, and clearance that are used as measures of effective
dose delivery.
The introduction of Dr. Sandro da Rocha as co-editor of the new edition reflects the intention to bring
engineering principles to bear on this important topic and to stress the importance of pharmaceutical
engineering as a foundational element of all inhaler products and their application to pulmonary drug
delivery.
We are grateful to the publishing staff, in particular, Hilary LaFoe and Jessica Poile for their assis-
tance in navigating the manuscript through the process.
This book is dedicated in memory of Professor Paul Myrdal, outstanding scientist, educator, family
man, and friend. He is missed by all.

Anthony J. Hickey
Chapel Hill, NC
Sandro R.P. da Rocha
Richmond, VA
September 2018

ix
Editors

Anthony J. Hickey is Distinguished RTI Fellow at the Research Triangle Institute, Emeritus Professor
of Molecular Pharmaceutics of the Eshelman School of Pharmacy (2010–present, Professor 1993–2010),
and Adjunct Professor of Biomedical Engineering in the School of Medicine at the University of
North Carolina at Chapel Hill. He obtained PhD (1984) and DSc (2003) degrees in Pharmaceutical
Sciences from Aston University, Birmingham, United Kingdom. Following postdoctoral positions, at
the University of Kentucky (1984–1988), Dr. Hickey joined the faculty at the University of Illinois
at Chicago (1988–1993). In 1990 he received the AAPS Young Investigator Award in Pharmaceutics
and Pharmaceutical Technology. He is a Fellow of the Royal Society of Biology (2000), the American
Association of Pharmaceutical Scientists (2003), the American Association for the Advancement of
Science (2005), and the Royal Society of Biology (2017). He received the Research Achievement Award
of the Particulate Presentations and Design Division of the Powder Technology Society of Japan (2012),
the Distinguished Scientist Award of the American Association of Indian Pharmaceutical Scientists
(2013); the David W. Grant Award in Physical Pharmacy of the American Association of Pharmaceutical
Scientists (2015); Thomas T. Mercer Joint Prize for Excellence in Inhaled Medicines and Pharmaceutical
Aerosols of the American Association for Aerosol Research and the International Society for Aerosols in
Medicine (2017). He has published numerous papers and chapters (over 250) in the pharmaceutical and
biomedical literature, one of which received the AAPS Meritorious Manuscript Award in 2001. He has
edited five texts on pharmaceutical inhalation aerosols and co-authored three others on “pharmaceutical
process engineering,” “pharmaceutical particulate science,” and “pharmaco-complexity.” He holds 25
United States patents on a variety of inhaler device technologies, pulmonary, and oral drug delivery
formulation technologies. He is founder (1997, and formerly President and CEO, 1997–2013) of Cirrus
Pharmaceuticals, Inc., which was acquired by Kemwell Pharma in 2013; founder (2001, and formerly
CSO, 2002–2007) of Oriel Therapeutics, Inc, which was acquired by Sandoz in 2010; founder and CEO
of Astartein, Inc. (2013–present); member of the Pharmaceutical Dosage Forms Expert Committee of the
United States Pharmacopeia (USP, 2010–2015, Chair of the Sub-committee on Aerosols); and formerly
Chair of the Aerosols Expert Committee of the USP (2005–2010). Dr. Hickey conducts a multidisci-
plinary research program in the field of pulmonary drug and vaccine delivery for treatment and prevention
of a variety of diseases.

Sandro R.P. da Rocha is a full professor in the Department of Pharmaceutics in the School of Pharmacy
and director for Pharmaceutical Engineering—School of Pharmacy at Virginia Commonwealth
University (VCU). He also holds a joint appointment in Chemical and Life Science Engineering and
is a full member of the Massey Cancer Center at VCU. He obtained his BSc and MSc in Chemical
Engineering at USFM and UFSC, respectively, in Brazil, and a PhD in 2000 from the University of Texas
at Austin in Chemical Engineering. After a postdoctoral position in Chemistry and Biochemistry also at
the University of Texas at Austin, Dr. da Rocha joined the faculty at Wayne State University in Detroit,
MI, where he worked until 2015. Professor da Rocha has contributed extensively to the area of pulmonary
drug delivery, particularly through the development of novel pressurized metered dose inhaler formula-
tions and of nanotherapeutics for pulmonary drug delivery, both areas having potential applications in
the treatment of a variety of pulmonary disorders. Professor da Rocha has received numerous awards and
recognition for his work, including visiting appointments at foreign institutions where he has developed
collaborative efforts and taught in the area of nanomedicine and pulmonary drug delivery. Professor
da Rocha has delivered a number of lectures nationally and internationally in the area of pulmonary
nanotherapeutics and has written manuscripts and book chapters with his collaborators that include
visiting faculty, postdoctoral fellows, PhD, undergraduate, graduate, and high-school students, who now
hold key positions in the industry, academia, and government in various areas including pulmonary
pharmaceutics.

xi
Contributors

Ana Aguiar-Ricardo Patrick Carius

LAQV-REQUIMTE Helmholtz Institute for Pharmaceutical
Department of Chemistry Research Saarland (HIPS)
Faculty of Science and Technology Helmholtz Center for Infection Research (HZI)
NOVA University of Lisbon Saarland University
Caparica, Portugal Saarbrücken, Germany
and
Abeer M. Al-Ghananeem Department of Pharmacy
Department of Pharmaceutical Sciences Saarland University
Sullivan University Saarbrücken, Germany
Louisville, Kentucky
Nicholas Carrigy
Balaji Bharatwaj Department of Mechanical Engineering
Merck & Co., Inc., University of Alberta
Rahway, New Jersey Edmonton, Alberta, Canada

Elizabeth R. Bielski Hak-Kim Chan

Department of Pharmaceutics School of Sydney Pharmacy School
Pharmacy Faculty of Medicine and Health
Virginia Commonwealth University The University of Sydney
Richmond, Virginia Camperdown, NSW, Australia

Robert J. Bischof Lai Wah Chan

Hudson Institute of Medical Research Department of Pharmacy
Melbourne, Victoria, Australia National University of Singapore
and Singapore
Allergenix Pty Ltd.
Melbourne, Victoria, Australia Mong-Jen Chen
Department of Pharmaceutics
Jürgen B. Bulitta University of Florida
Department of Pharmaceutics Gainesville, Florida
University of Florida
Gainesville, Florida Jeremy Clarke
GlaxoSmithKline
Elise Burmeister Getz Pharma Supply Chain
Oriel Therapeutics, Inc., a Novartis Company Ware, United Kingdom
Clinical Department
Emeryville, California USA Joon Chong Yee
Bristol-Myers Squibb, Co.
New York City, New York

xiii
xiv Contributors

David Cipolla Laleh Golshahi

Aradigm Department of Mechanical Engineering
Hayward, California Virginia Commonwealth University
Richmond, Virginia
Eunice Costa
Inhalation, R&D Drug Product Development
Floris Grasmeijer
Hovione FarmaCiencia
PureIMS
Lisboa, Portugal
Roden, the Netherlands
Gabriella Costabile University of Groningen
Department of Pharmacy Groningen, the Netherlands
Ludwig-Maximilians-Universität München
Munich, Germany Ailin Guo
Pharmaceutical Sciences
Peter A. Crooks South Dakota State University
University of Arkansas for Medical Sciences Brookings, South Dakota
Little Rock, Arkansas
Jayne E. Hastedt
Sandro R.P. da Rocha
JDP Pharma Consulting, LLC
Department of Pharmaceutics
San Carlos, California
Center for Pharmaceutical Engineering
Virginia Commonwealth University
Richmond, Virginia Ross H.M. Hatley
Respironics Respiratory Drug Delivery (UK) Ltd.
Wilbur de Kruijf A business of Philips Electronics UK Limited
Medspray Chichester, West Sussex, United Kingdom
Enschede, the Netherlands
Rebecca L. Heise
Anne H. de Boer Department of Biomedical Engineering
Department of Pharmaceutical Technology and Virginia Commonwealth University
Biopharmacy Richmond, Virginia
University of Groningen
Groningen, the Netherlands
Paul Wan Sia Heng
Myrna B. Dolovich Department of Pharmacy
Faculty of Health Sciences National University of Singapore
Department of Medicine Singapore
McMaster University
Hamilton, Ontario, Canada Rodrigo S. Heyder
Department of Pharmaceutics
Stefanie K. Drescher Virginia Commonwealth University
Department of Pharmaceutics Richmond, Virginia
University of Florida
Gainesville, Florida
Anthony J. Hickey
Joachim Eicher University of North Carolina
Boehringer Ingelheim Pharma GmbH and Co. KG Chapel Hill, North Carolina
HP Supply Germany and
Ingelheim am Rhein RTI International
Germany Research Triangle Park, North Carolina

Warren H. Finlay Günther Hochhaus

Department of Mechanical Engineering Department of Pharmaceutics
University of Alberta University of Florida
Edmonton, Alberta Gainesville, Florida
Contributors xv

Susan Hoe Stefan Leiner

AstraZeneca Pharmaceuticals LP Boehringer Ingelheim Pharma GmbH and Co. KG
South San Francisco, California Quality & Records Management
Cambridge, United Kingdom Ingelheim am Rhein
Germany
Allen Horhota
Moderna Therapeutics Benjamin W. Maynor
Greater Boston Area Liquidia Technologies
Boston, Massachusetts Research Triangle Park, North Carolina, USA

Stephen T. Horhota
BIND Therapeutics Michelle P. McIntosh
Westford, Massachusetts Monash Institute of Pharmaceutical Sciences
Parkville, Victoria, Australia
Justus C. Horstmann
Helmholtz Institute for Pharmaceutical Bernice Mei Jin Tan
Research Saarland (HIPS) Department of Pharmacy
Helmholtz Center for Infection Research (HZI) National University of Singapore
Saarland University Singapore
Saarbrücken, Germany
and Olivia M. Merkel
Department of Pharmacy Department of Pharmacy
Saarland University Ludwig-Maximilians-Universität München
Saarbrücken, Germany Munich, Germany

Jibriil P. Ibrahim
Monash Institute of Pharmaceutical Sciences Jolyon Mitchell
Parkville, Victoria, Australia Inhaler Consulting Services Inc.
London, Ontario, Canada
Mary E. Krause and
Bristol-Myers Squibb, Co. Affiliate Professor
New York City, New York University of Hawai’i, College of Pharmacy
Hilo, Hawai’i
Philip Chi Lip Kwok
Sydney Pharmacy School Beth Morgan
Faculty of Medicine and Health AstraZeneca Pharmaceuticals
The University of Sydney Research Triangle Park, North Carolina
Camperdown, NSW, Australia
Ajit S. Narang
David Lechuga-Ballesteros Small Molecule Pharmaceutical Sciences
AstraZeneca Pharmaceuticals LP Genentech, Inc.
South San Francisco, California San Francisco, California
Claus-Michael Lehr
Helmholtz Institute for Pharmaceutical Steven C. Nichols
Research Saarland (HIPS) Director
Helmholtz Center for Infection Research (HZI) OINDP Consultancy
Saarland University Rugby, Warwichshire, UK
Saarbrücken, Germany
and Narsimha R. Penthala
Department of Pharmacy Department of Pharmaceutical Sciences
Saarland University University of Arkansas for Medical Sciences
Saarbrücken, Germany Little Rock, Arkansas
xvi Contributors

Shelly Pizarro Helen N. Strickland

Genentech, Inc. GlaxoSmithKline
San Francisco, California Zebulon, North Carolina

John N. Pritchard David C. Thompson

Respironics Respiratory Drug Delivery (UK) Ltd. Department of Clinical Pharmacy
A business of Philips Electronics UK Limited University of Colorado Health Sciences Center
Chichester, West Sussex, United Kingdom Denver, Colorado

S. van den Ban

Joshua J. Reineke GlaxoSmithKline Global Manufacturing
Pharmaceutical Sciences and Supply
South Dakota State University Ware, United Kingdom
Brookings, South Dakota
Reinhard Vehring
Alexandria Ritchie Department of Mechanical Engineering
Department of Biomedical Engineering University of Alberta
Virginia Commonwealth University Edmonton, Alberta, Canada
Richmond, Virginia
Dirk von Hollen
Respironics, Inc.
Thomas D. Roper
A Philips Healthcare Company
Department of Chemical and Life Science
Murrysville, Pennsylvania
Engineering
Virginia Commonwealth University
Herbert Wachtel
Richmond, Virginia
Boehringer Ingelheim Pharma GmbH and Co. KG
Analytical Development
Dennis Sandell Ingelheim am Rhein
S5 Consulting Germany
Blentarp, Sweden
Lin Yang
William Craig Stagner Aurobindo Pharma USA Inc.
Department of Pharmaceutics Durham, North Carolina
Campbell University
Buies Creek, North Carolina Hao Yin
Medical Research Institute
Wuhan University
Nicole Schneider-Daum Wuhan, China
Helmholtz Institute for Pharmaceutical
Research Saarland (HIPS) Bethany M. Young
Helmholtz Center for Infection Research (HZI) Department of Biomedical Engineering
Saarland University Virginia Commonwealth University
Saarbrücken, Germany Richmond, Virginia

Martina Steinmaurer Ying Zhang

Department of Pharmacy Medical Research Institute
Ludwig-Maximilians Universität München Wuhan University
Munich, Germany Wuhan, China
1
Introduction

Anthony J. Hickey and Sandro R.P. da Rocha

A number of outstanding texts on foundational elements of the topics discussed in this book exist, and
the reader is encouraged to familiarize themselves with these materials, as they describe basic principles
(Finlay, 2001), specific (Purewal and Grant, 1997, Srichana, 2016 and Zeng et al, 2000) and general dos-
age forms (Colombo et al., 2013, Hickey, 2007, Newman, 2009, Smyth and Hickey, 2011), and analytical
methods (Tougas et al., 2013).
The advances in pharmaceutical inhalation aerosol technology occurring since the turn of the mil-
lennium have increased the potential of pulmonary drug delivery substantially. While some of the new
developments had their origins in earlier work, we have seen the appearance of new propellants and new
regulations considering the phase out of what we still consider new propellants, new dry powder inhalers,
nebulizers, and a new category of product, soft mist inhalers.
In parallel with these new products, the breadth of application has increased to include the treatment
of chronic obstructive pulmonary disease, a range of infectious diseases, diabetes, idiopathic pulmonary
fibrosis, and pulmonary arterial hypertension. Pre-clinical studies and clinical trials covering yet a range
of other potential applications of orally inhaled products include the use of a broader range of biologics
and also nanomaterials that may help further advance the pulmonary drug delivery market.
Successful aerosol therapy has given research and development a boost, and the prospects of even
greater opportunities for disease management is emerging from patient compliance, adherence tools, and
new classes of drugs for local and systemic delivery through the lungs.
This text is focused on the active pharmaceutical ingredient, formulation development, device design,
process and product engineering, and analytical methods to assess critical quality attributes underpin-
ning safe and efficacious dosage forms.
Figure 1.1 depicts the sequence in which these topics will be presented, which follows the product
development pathway. The conclusion of the volume is a discussion of bioequivalence testing and the
interface between the dosage form and the patient. This reflects the point at which design and engineering
controls, which are embedded in a regulated environment of quality by design, give way to biological
factors.
It is intended that the materials covered in subsequent sections familiarize the reader with the underly-
ing science and engineering associated with the design and characterization of complex dosage forms
required to deliver orally inhaled aerosols. The platform of knowledge will be useful in considering
options for specific applications and is a point from which to launch new technologies that will frame
future developments in the field as described in a companion text (Hickey and Mansour, in press).

1
2 Pharmaceutical Inhalation Aerosol Technology

FIGURE 1.1 Product development themes in pharmaceutical inhalation aerosol technology.

REFERENCES
Colombo P, Traini D, Buttini F. Inhaled Drug Delivery: Techniques and Products. New York: Wiley-Blackwell;
2013.
Finlay W. The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. New York: Academic Press;
2001.
Hickey A. Inhalation Aerosols, Physical and Biological Basis for Therapy. 2nd ed. New York: Informa
Healthcare; 2007.
Hickey A J, Mansour H H, Eds. Inhalation Aerosols, Physical and Biological Basis for Therapy, Third
Edition. Boca Raton, FL: CRC Press; in press.
Newman S. Respiratory Drug Delivery: Essential Theory and Practice. Richmond, VA: RDD Online; 2009.
Purewal T, Grant D. Metered Dose Inhaler Technology. Boca Raton, FL: CRC Press; 1997.
Smyth H, Hickey A. Controlled Pulmonary Drug Delivery. New York: Springer; 2011.
Srichana T. Dry Powder Inhalers: Formulation, Device and Characterization. Hauppauge, NJ: Nova Science
Publishers; 2016.
Tougas T, Mitchell J, Lyapustina S, Eds. Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled
Products. New York: Springer; 2013.
Zeng X, Martin G, Marriott C. Particulate Interactions in Dry Powder Formulations for Inhalation.
New York: CRC Press; 2000.
Section I

Discovery
2
Physiology of the Airways

Anthony J. Hickey and David C. Thompson

CONTENTS
2.1 Introduction ...................................................................................................................................... 5
2.2 Anatomy of the Airways .................................................................................................................. 6
2.2.1 Structure .............................................................................................................................. 6
2.2.1.1 Epithelium ............................................................................................................ 8
2.2.1.2 Smooth Muscle Cells ........................................................................................... 9
2.2.1.3 Gland Cells........................................................................................................... 9
2.2.1.4 Nerves ................................................................................................................ 10
2.2.1.5 Defensive Cells ...................................................................................................11
2.2.1.6 Blood Supply ...................................................................................................... 12
2.2.2 Zones of the Airways .........................................................................................................14
2.2.2.1 Conducting Zone.................................................................................................14
2.2.2.2 Respiratory Zone ................................................................................................14
2.3 Function of the Airways ................................................................................................................. 15
2.3.1 Gas Exchange .................................................................................................................... 15
2.3.2 Acid-Base Balance ............................................................................................................ 15
2.3.3 Endocrine............................................................................................................................16
2.3.4 Metabolism .........................................................................................................................16
2.4 Evaluation of Airway Physiology and Function .............................................................................17
2.4.1 Measures of Pulmonary Volumes ......................................................................................17
2.4.2 Measures of Airway Caliber ..............................................................................................18
2.4.2.1 Peak Flow Measurements .................................................................................. 19
2.4.2.2 Forced Expiratory Flow Measurements ............................................................ 19
2.4.2.3 Airways Resistance and Dynamic Lung Compliance ....................................... 19
2.5 Aerosol Deposition and Airway Physiology .................................................................................. 20
2.6 Conclusion ...................................................................................................................................... 22
References ................................................................................................................................................ 23

2.1 Introduction
The airways represent a unique organ system in the body, their structure allowing air to come into close
contact with blood, is one of the principal adaptions permitting the existence of terrestrial life. This
adaptation also makes the airways a useful route of administration of drugs in the inhaled or aerosol
form. This chapter provides an overview of the physiology of the airways excluding that of the nasopha-
ryngeal regions of the airways. Aspects considered relevant to the practical and theoretical application
of inhaled substances are emphasized.

5
6 Pharmaceutical Inhalation Aerosol Technology

2.2 Anatomy of the Airways

The airways (constituting the lungs) may be viewed as a series of dividing passageways originating at the
trachea and terminating at the alveolar sac. In the context of aerosol design and delivery, such a “static”
overview represents a satisfactorily simple model. However, many factors beyond the anatomy of the
airways are relevant to the therapeutic use of aerosols.

2.2.1 Structure
The airways are often described as the pulmonary tree in that their overall form resembles a tree. The tree
trunk is analogous to the trachea of the airways that bifurcates to form main bronchi. These divide to form
smaller bronchi that lead to individual lung lobes: three lobes on the right side and two on the left side. Inside
each lobe, the bronchi undergo further divisions to form new generations of smaller caliber airways: the
bronchioles. This process continues through the terminal bronchioles (the smallest airway not involved with
an alveolus), the respiratory bronchioles (which exhibit alveoli protruding from their walls), alveolar ducts,
and terminates with the alveolar sacs. In the classic model of the airways, as described by Weibel (1963),
each airway divides to form two smaller “daughter” airways (Figure 2.1), and, as a result, the number of
airways at each generation is double that of the previous generation. The model proposes the existence of
24 airway generations in total, with the trachea being generation 0 and the alveolar sacs being generation 23.
In passing from the trachea to the alveolar sac, two physical changes occur in the airways that are
important in influencing airway function. Firstly, the airway caliber decreases with increasing generations,
for example, tracheal diameter ≈ 1.8 cm versus alveolar diameter ≈ 0.04 cm (Figure 2.2). This permits

FIGURE 2.1 Model of airway. (With kind permission from Taylor & Francis: Morphometry of the Human Lung, Berlin,
Germany, Springer-Verlag, 1963, Weibel, E.)
Physiology of the Airways 7

FIGURE 2.2 Graph of airway diameter and cross-sectional are as a function of airway generation.

adequate penetration of air to the lower airways for a given expansion of the lungs. Secondly, the surface
area of the airways increases with each generation to the extent that the total area at the level of the human
alveolus is in the order of 140 m2 (Gehr et al., 1978). The alveolus is the principal site of gas exchange in
the airways, a function compatible with the increased surface area that promotes extensive and efficient
diffusional gas exchange between the alveolar space and the blood in alveolar capillaries (vide infra). The
relatively small change in cross-sectional area that occurs over the 19 generations of airways between the
trachea and the terminal bronchiole (from 2.5 cm2 to 180 cm2) (Bouhuys, 1974) fosters the rapid, bulk flow
of inspired air down to the terminal bronchiole. By contrast, the cross-sectional area increases greatly in
the four generations between the terminal bronchiole and the alveolar sac (from 180 cm2 to 10,000 cm2)
(Bouhuys, 1974), which results in a significant decrease in the velocity of airflow to the extent that the flow
velocity fails to exceed that of diffusing oxygen molecules (Weibel, 1984). Accordingly, diffusion assumes
a greater role in determining the movement of gases in these peripheral airways.
The various levels of the airways may be categorized functionally as being either conducting or respi-
ratory airways. Those airways not participating in gas exchange constitute the conducting zone of the
airways and extend from the trachea to the terminal bronchioles. This region is the principal site of airway
obstruction in obstructive lung diseases, such as asthma. The respiratory zone includes airways involved
with gas exchange and comprises respiratory bronchioles, alveolar ducts, and alveolar sacs. As such, con-
ducting and respiratory zones of the airways may be distinguished simply by the absence or presence of
alveolar pockets (which confer gas exchange function). Regions within each zone may be classified further
on a histological basis. For example, the contribution of cartilage to the airway wall is one means of dif-
ferentiating the trachea from bronchi and bronchioles because cartilage exists as incomplete rings in the
trachea, regresses to irregularly shaped plates in bronchi, and is absent from bronchioles. Also, respiratory
bronchioles may be discriminated from terminal bronchioles by the presence of associated alveoli.
Other histological changes are evident downward throughout the pulmonary tree, and the cellular
profile of each region has distinctive effect on functional aspects of the airways under physiological and
pathophysiological conditions.
8 Pharmaceutical Inhalation Aerosol Technology

2.2.1.1 Epithelium
The epithelium of the airways is a continuous sheet of cells lining the lumenal surface of the airways.
It separates the internal environment of the body (i.e. subepithelial structures) from the external envi-
ronment (i.e. airway lumen). The lumenal surface of the epithelium is, therefore, exposed to inhaled
substances, such as gases, particulates, or aerosols. Connecting adjacent epithelial cells are specialized
tight junctional processes (Inoue and Hogg, 1974; Williams, 1990) that limit the penetration of inhaled
substances by the intercellular route of administration. Under normal or physiological conditions, larger
molecules must past through the epithelial cell. Therefore, the epithelium serves the important function of
limiting access of inhaled substances to the internal environment of the body. Under pathophysiological
conditions, the epithelium may be damaged, enhancing penetration of substances present in the airway
lumen (Godfrey, 1997).
The airway epithelium comprises a variety of cell types (Table 2.1), the distribution of which confers
different functions on the airways region. The lumenal surface of the airways are lined by ciliated cells
from the trachea to the terminal bronchus. Mucus, a viscous fluid containing mucin glycoproteins and
proteoglycans, floats on a watery layer of periciliary fluid (or sol) and covers the lumenal surface of the
epithelium. The secretions fulfill four important functions. Firstly, it protects the epithelium from becom-
ing dehydrated. Secondly, the water in the mucus promotes saturation of inhaled air. Thirdly, the mucus
contains antibacterial proteins and peptides, such as defensins and lysozyme that suppress microbial colo-
nization of the airways (Finkbeiner, 1999; Schutte and McCray, 2002). Fourthly, the mucus is involved
in airway protection from inhaled xenobiotics or chemicals. Coordinated beating of the epithelial cilia
propels the blanket of mucus towards the upper airways and pharynx where the mucus may either be swal-
lowed or ejected. The rate of mucus propulsion varies according to the airway region such that movement
in the smaller airways is slower than in the larger airways, a situation that arises from the proportionally
larger number of ciliated cells in the larger airways and the higher ciliary beat frequency in the larger
airways (Gail and L’enfant, 1983). Syllogistically, this process is advantageous, given that many small
airways converge on the larger, more central airways whose mucus clearance rate would have to be greater
to accommodate the large volumes of mucus being delivered by the smaller distal airways. This process of

TABLE 2.1
Cells of the Airway Epithelium
Cell Putative Function
Ciliated columnar Mucus movement
Mucous (goblet) Mucus secretion
Serous Periciliary fluid; mucus secretion
Clara (nonciliated epithelial) Xenobiotic metabolism; surfactant
production
Brush Transitional form of ciliated epithelial cell
Basal Progenitor for ciliated epithelial and goblet
cells
Dendritic Immunity
Intermediate Transitional cell in differentiation of basal
cell
Neuroendocrine (Kultschitsky or APUD) Chemoreceptor; paracrine function
Alveolar type I Alveolar gas exchange
Alveolar type II Surfactant secretion; differentiation into
type I cell
Alveolar macrophage Pulmonary defense
Mast Immunoregulation

Sources: Holt, P. et al., Clin. Exp. Allergy, 19, 597–601, 1989; Jeffrey, P., Am. Rev. Respir.
Dis., 128, S14–S20, 1983; Scheuermann, D., Microsc. Res. Tech., 37, 31–42, 1997.
Physiology of the Airways 9

the movement of mucus up the pulmonary tree, known as the mucociliary escalator, serves the defensive
function of clearing inhaled particles that become trapped in the mucus from the lung.
The significance of mucus trapping of aerosolized particles is emphasized by the fact that radiola-
beled aerosols have been used in the measurement of mucociliary transport (Morrow, 1973). Coughing
increases clearance of mucus from the airways, which rapidly propels the mucus towards the pharynx.
Failure to clear mucus from the airways resulting from ciliary dysfunction or mucus hypersecretion
(as may occur in cystic fibrosis or chronic bronchitis) can result in airway obstruction and infection. Such
a situation may adversely affect the therapeutic activity of an inhaled drug by increasing the thickness
of the mucus layer through which the drug must diffuse to reach its site of action and retard penetration
of the aerosolized particles throughout the airways resulting from mucus plugging of the airway lumen.
Goblet cells (and mucous glands) are not present in airways distal to the bronchi (Tyler, 1983), and,
therefore, a mucus layer does not line the peripheral airways.
Alveolar type I cells represent the principal cell type lining the lumenal surface of the alveoli (Crapo
et al., 1983; Gail and L’enfant, 1983), and it is through these cells that gases must diffuse for oxygen and
carbon dioxide exchange to occur with blood in the pulmonary capillaries. Alveolar type II cells are also
present in the alveoli. Cuboidal in nature, these cells possess microvilli and serve the important func-
tion of secreting surfactant (Gail and L’enfant, 1983), a mixture of carbohydrates, proteins, and lipids
essential in reducing alveolar surface tension, which diminishes the work of alveolar expansion during
inspiration. In addition, type II cells serve as progenitor cells in the regeneration of the alveolar epithe-
lium. For example, type II cells differentiate into type I cells after type I cell damage (Gail and L’enfant,
1983; Voelker and Mason, 1989).
Epithelium of the central and peripheral airways have the capacity to produce and release pro-inflammatory
mediators, such as arachidonic acid metabolites, nitric oxide, cytokines, and growth factors, and thereby
modulate the progression of airway diseases (Mills et al., 1999). In addition, substances released from central
airway epithelium can influence the ability of adjacent smooth muscle to contract (Spina, 1998).

2.2.1.2 Smooth Muscle Cells

Smooth muscle is separated from the epithelium by the lamina propria, a region of connective tissue
containing nerves and blood vessels. In the trachea, the smooth muscle connects the open ends of the
incomplete cartilage rings and, therefore, constitutes only a fraction of the circumference of this compo-
nent of the airways. Further down the pulmonary tree, through the bronchi and bronchioles, the contribu-
tion of the smooth muscle to the airway wall increases to the point of completely encircling the airway.
Contraction or relaxation of the smooth muscle has a direct influence on airway caliber and, thereby,
affects airflow in the airways. Bronchoconstriction is the result of smooth muscle contraction and is the
principal cause of airway obstruction in reversible obstructive airway diseases, such as asthma. The tone
or state of contraction of airway smooth muscle is subject to control by neurotransmitters released from
innervating nerves, hormones, or mediators released from activated inflammatory cells.

2.2.1.3 Gland Cells

Located in the submucosa of cartilage-containing airways and in the lamina propria of the trachea
are glands that secrete mucus into the airway lumen (Reid, 1960). Each mucous gland consists of four
regions: the ciliated duct, collecting duct, mucous tubules, and secretory tubules (Meyrick et al., 1960).
The ciliated duct opens to the lumen of the airways and is lined by ciliated epithelial cells. It merges with
the collecting duct, the walls of which comprise columnar cells. Mucous cells line the mucous tubules
that lead from the collecting duct. Serous cells (which contribute to the more liquid component of mucus)
line the blind-ended serous tubules that are located at the distal ends of the mucous tubules. Several
secretory tubules feed into the collecting duct. Mucus is secreted via the collecting and ciliated ducts
into the lumen of the airways. Goblet cells, located in the epithelium of the larger central airways, secrete
mucus directly into the airway lumen (Rogers, 1994). Mucus hypersecretion results from an increase in
the number and/or size of mucous glands and goblet cells in disease states, such as chronic bronchitis
(Finkbeiner, 1999; Rogers, 1994).
10 Pharmaceutical Inhalation Aerosol Technology

2.2.1.4 Nerves
In the central nervous system regulation of airway function, afferent and efferent nerves serving sensory
and effector functions, respectively, innervate the airways (Table 2.2, Figure 2.3) (Widdicombe, 2001).
Slowly adapting receptors (or pulmonary stretch receptors) are located in the smooth muscle of the central
airways (trachea to larger bronchi), respond to airway stretch, and are thought to be involved in the reflex
control of ventilatory drive. Rapidly adapting receptors (or irritant receptors) ramify within the epithe-
lium of the central airways and are sensitive to chemical or irritant stimuli (e.g. inflammatory mediators),
mechanical stimuli, and interstitial edema. Activation of these receptors results in an increase in the rate
or depth of breathing and in bronchoconstriction mediated through a central nervous system reflex in
efferent cholinergic nerve activity. Inhalation of foreign substances, such as particulates, can activate
these receptors to elicit reflex bronchoconstriction. Afferent C-fibers are tachykinin-containing nerves
that ramify within the epithelium and between smooth muscle cells (Lundberg et al., 1984). Chemical
(e.g. inflammatory mediators), particulate, and mechanical stimuli activate afferent C-fibers to cause
rapid, shallow breathing or apnoea and to evoke central reflex bronchoconstriction through increased
efferent cholinergic nerve activity (Coleridge and Coleridge, 1984; Widdicombe, 2001).
Under conditions of cholinoceptor blockade, central reflex bronchodilation through activation of effer-
ent nonadrenergic noncholinergic nerves may be observed (Michoud et al., 1088). Stimulation of afferent
C-fibers can result in the release of tachykinins at the site of stimulation and alter airway function inde-
pendently of the central nervous system, e.g. by inducing mucosal edema (McDonald et al., 1996). These
nerves are thought to be important sensory modalities for conveying retrosternal discomfort induced
by inhaled irritants. Neuroepithelial bodies are located in the epithelium of the central airways and are
intimately associated with the endings of nerves, which are primarily afferent in nature (McDonald
et al., 1996; Widdicombe, 2001). Each neuroepithelial body comprises groups of neuroendocrine cells
that contain biogenic amines, such as serotonin, and peptides, such as calcitonin gene-related peptide
(cGRP) (Cutz and Jackson, 1999). Hypoxia induces the release of these biologically active substances
which can then activate the sensory nerve endings to elicit a central reflex or act locally on adjacent
tissues, such as blood vessels or airway smooth muscle (Cutz and Jackson, 1999; Widdicombe, 2001).
Cholinergic nerves are carried to the airways in the vagus nerve and innervate airway smooth muscle
and submucosal glands. The neurotransmitter, acetylcholine, released from cholinergic nerves promotes
bronchoconstriction (Widdicombe, 1963) and mucus secretion (Baker et al., 1985; Ueki et al., 1980).
Nonadrenergic noncholinergic inhibitory nerves, also carried in the vagus nerve, are the sole bronchodi-
lator innervation of airway smooth muscle (Diamond and Altiere, 1989). These nerves may also inhibit
airway mucus secretion (Rogers, 2000). Adrenergic nerves do not innervate human airway smooth mus-
cle (Richardson, 1977) and have little effect on mucus secretion in human airways (Baker et al., 1985;
Richardson, 1977).

TABLE 2.2
Innervation of the Airways
Nerve Type Putative Function
Afferent
slowly adapting receptor (pulmonary stretch receptor) Breuer-Hering reflex (inhibition of inspiration;
prolongation of expiration)
Rapidly adapting receptor Responds to airway irritants, mechanical
stimuli, Interstitial edema
C-fibers Responds to airway irritants, mechanical stimuli
Neuroepithelial body Responds to hypoxia

Efferent
Adrenergic Vasoconstriction
Cholinergic Bronchoconstriction, mucus secretion
Nonadrenergic noncholinergic inhibitory Bronchodilation, mucus secretion
Physiology of the Airways 11

FIGURE 2.3 Role of afferent and efferent nerves in altering airway function. Stimulation of afferent (or sensory) nerves,
such as afferent C-fibers, rapidly adapting receptors, or slowly adapting receptors, results in an increase in electrical
impulse traffic to the central nervous system. Depending on the afferent nerve activated, processing and integration in
the central nervous system may result in an increase in the activity of: (1) efferent motor nerves governing muscles that
regulate breathing (i.e. affect the rate and depth of ventilation) or (2) efferent autonomic nerves, such as cholinergic and
nonadrenergic noncholinergic inhibitory nerves, that modify mucus secretion or airway caliber through changes in smooth
muscle tone. Afferent C-fibers may also serve an efferent function insofar as impulses can spread throughout the C-fiber
network from the size of C-fiber stimulation to result in the release of tachykinins (such as substance P and neurokinin A).
These released substances may then act on blood vessels to increase permeability or on smooth muscle to increase vascular
permeability and elicit bronchoconstriction, respectively.

2.2.1.5 Defensive Cells

Alveolar macrophages are migrating mononuclear cells present in the interstitium and lumenal surface
of the alveoli (Crapo et al., 1982). These cells phagocytize (envelop and, when possible, enzymatically
degrade) foreign substances, particles, or microorganisms in the alveoli, after which they remain in the
alveolus or migrate to the mucociliary escalator or into lymph tissue. Upon activation, macrophages
release a variety of enzymes and biologically active mediators (Laskin and Laskin, 2001; Sibile and
Reynolds, 1990) that may influence airway function. The synthesis and release of matrix metallopro-
teinases (MMPs) by activated alveolar macrophages can contribute to lung tissue remodeling (Parks and
Shapiro, 2001; Shapiro, 1999).
Mast cells are located in the walls of the central and peripheral airways and may be found free in the
lumen of the airways (Cutz and Orange, 1977). Activation by antigen cross-bridging of surface antibodies
elicits cellular degranulation of the mast cell and the release of biologically active preformed and newly
generated mediators. Also released are proteases, including chymase and tryptase, which can modify
airway function by degrading biologically active proteins and peptides (Caughey, 1991). In addition,
12 Pharmaceutical Inhalation Aerosol Technology

tryptase activates protease-activated receptors, leading a variety of unanticipated biological actions, such
as induction of airway smooth muscle proliferation (Abraham, 2002; Cocks and Moffatt, 2001). Mast
cells serve an important role in the response of the airways to challenge by antigens (or allergens).

2.2.1.6 Blood Supply

The cardiovascular system can be divided into two components (as shown in Figure 2.4): the pulmonary
circulation and the systemic circulation. The pulmonary circulation carries deoxygenated blood from
the right ventricle to the lungs and returns oxygenated blood from the lungs to the left atrium. Emerging
from the right ventricle is the main pulmonary artery, which branches to form smaller pulmonary and
intrapulmonary arteries. This pulmonary arterial tree undergoes further rapid subdivision in parallel
with the pulmonary tree to form pulmonary capillaries, a fine network of blood vessels in intimate
contact with the alveolus. The capillaries drain into postcapillary venules that unite to form small veins
and, distally, larger veins. These drain into the pulmonary vein, which returns blood from the lungs to
the left atrium. The systemic circulation carries oxygenated blood from the left ventricle to the tissues of
the body and returns deoxygenated blood from the body to the right atrium. Arteries and arterioles carry

FIGURE 2.4 Cardiovascular system in the body. Oxygen diffuses from the oxygen-rich environment of the alveolus into
the deoxygenated blood of the pulmonary circulation. The newly oxygenated blood returns by the pulmonary vein to the
left atrium and ventricle: contraction of the latter provides the driving force for circulation of oxygen-rich blood to the
organs and tissues of the body. Cells of the body use oxygen for energy-producing processes that result in the formation of
carbon dioxide. Depleted of oxygen and richer in carbon dioxide, blood leaving the tissues returns by the venous circulation
to the right atrium. The right ventricle pumps the carbon dioxide-rich blood into the pulmonary circulation from whence
the carbon dioxide may diffuse into the alveolus. Arrows indicate the direction of blood flow.
Another random document with
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 BYRON AND WORDSWORTH
Now republished for the first time. See Mr. W. C. Hazlitt’s
Memoirs, etc. I. xxix.

PAG
E Lord Byron’s haste, etc. See Leigh Hunt’s Lord Byron and his
328. Contemporaries, I. 77.
‘A cure,’ etc. Cf. Reflections on the Revolution in France
(Select Works, ed. Payne, II. 164).
329. ‘Ah! voila,’ etc. Confessions, Part I. Liv. VI.
‘Slow,’ etc. Cf. As You Like It, Act II. Sc. 7.
Note. Ada Reis; a Tale, by Lady Caroline Lamb (1785–1828),
published in 1823.
 ON CANT AND HYPOCRISY
This essay and the next were published with some omissions in
Sketches and Essays.

PAG
E ‘If to do,’ etc. The Merchant of Venice, Act I. Sc. 2.
330. Curl. Edmund Curll (1675–1747).

‘The spirit,’ etc. S. Matthew xxvi. 41.

‘Most easily,’ etc. Cf. Hebrews xii. 1.
331. Video, etc. Ovid, Metam., VII. 20–1.

‘Duenna.’ See Act III. Sc. 5.

332. ‘A little round,’ etc. The Castle of Indolence, I. St. 69.

Lord Shaftesbury. See Characteristicks, An Inquiry

333. concerning Virtue, or Merit, Part I. Sect. II.
‘Upon this bank,’ etc. Macbeth, Act I. Sc. 7.
335. ‘Mighty coil,’ etc. Cf. King Lear, Act III. Sc. 2.
 THE SAME SUBJECT CONTINUED

337. ‘Eremites,’ etc. Paradise Lost, III. 474–5.

338. ‘Cant religious,’ etc. See Byron’s Letter to Murray on Bowles’s
Strictures on the Life and Writings of Pope. Letters, etc.,
ed. Prothero, v. 536.
339. Mr. Coleridge, etc. Nearly the whole of this passage from this
point to the end was omitted in Sketches and Essays. In the
Magazine the essay concludes with the words ‘Cetera
desunt.’
Mr. Liberal Snake. See Disraeli’s Vivian Grey.
 POETRY
Now republished for the first time. Some of the essays now first
republished from The Atlas are identified as Hazlitt’s in Mr. W. C.
Hazlitt’s Memoirs, etc. (see I. xxix. and xxx.). The others have been
included on the strength of the internal evidence of authorship. A
short paper, attributed to Hazlitt by Mr. W. C. Hazlitt (Memoirs, I.
xxix.), and entitled ‘Richesse de la Langue,’ had appeared in The
Atlas for Jan. 25, 1829. It runs as follows:—
‘How should one convey by a single word an expression of
face which having arisen from some strong passion, uneasiness
or emotion, is converted into an habitual character, and
remains without any immediate object to excite it? In the
English language there are above thirty ways of doing this, or
else approaching to, and hovering round the point. As for
instance, we may express this look by the following epithets,
more or less pointedly, and with various inflections of meaning
attached to them:—wild, scared, startled, haggard, harassed,
hunted, nervous, agitated, apprehensive, terrified, dismayed,
abstracted, stunned, panick-struck, odd, strange, wayward,
flighty, uncouth, unaccountable, eccentric, embarrassed,
unsettled, uneasy, overconscious, morbid, careworn, blighted,
scare-crow, hang-dog, ghastly, wilful, dogged, staring, fierce,
etc. All these come tolerably near the mark, and differ from
each other; yet none of them is the very word that is wanted to
express the thing in question, though we have no doubt there is
such a word in the English language, and that it might be
suggested by some one who has a greater command of its
resources. The above remarks may serve to guard the student
of English, whether a foreigner or merely a stranger to his
native tongue, against unmeaning synonymes or monotonous
common-place.’

PAG
E ‘Daffodils,’ etc. A Winter’s Tale, Act IV. Sc. 4.
339. ‘That fine madness,’ etc. Cf. Drayton, Elegy, To Henry
340. Reynolds, Esq.

341. ‘Cowslips wan,’ etc. Lycidas, 147.

Lowly children, etc. Cf. ‘With all the lowly children of the
shade.’ Thomson, The Seasons, Spring, 450.
342. ‘To elevate and surprise.’ The Duke of Buckingham, The
Rehearsal, Act I. Sc. 1.
 ENGLISH GRAMMAR
Now republished for the first time. Cf. vol. IV. pp. 231 et seq. and
389 et seq.

‘Foregone conclusion.’ Othello, Act III. Sc. 3.

343. ‘A man of Ind.’ Cf. The Tempest, Act II. Sc. 2.
‘Wise,’ etc. Cf. 1 Corinthians iv. 6.
344. A standard book. Lindley Murray’s English Grammar, no
doubt, the later editions of which were published by
Longmans.
345. Mr. Fearn. Hazlitt’s friend. Anti-Tooke was published in
1824. Cf. vol. VI. (Table-Talk), 63–4.
‘Still, small.’ 1 Kings xix. 12.
 MEMORABILIA OF MR. COLERIDGE
Now republished for the first time. Many of the opinions expressed
are referred to by Hazlitt elsewhere.

PAG
E Barrow. Cf. ante, p. 266, where Hume is said to have
346. borrowed from South.
347. ‘More was meant,’ etc. Cf. Il Penseroso, 120.
348. Dr. Dodd. William Dodd (1729–1777), executed for forgery in
1777. His Thoughts in Prison appeared in the same year.
 PETER PINDAR
Now republished for the first time.

‘Men,’ etc. 2 Henry IV., Act III. Sc. 2.

‘A manly man,’ etc. Chaucer, The Canterbury Tales,
Prologue, 167.
349. ‘Haloo,’ etc. Cf. 2 Henry IV., Act I. Sc. 2.
Viotti. Giovanni Battista Viotti (1753–1824).
‘Making the worse,’ etc. Paradise Lost, II. 113–14.
 LOGIC
Now republished for the first time.

PAG
E ‘That which is,’ etc. Cf. Twelfth Night, Act IV. Sc. 2. The
351. mistake of ‘Cophetua’ for ‘Gorboduc’ is made elsewhere by
Hazlitt.
332. ‘Over shoes, over boots.’ Cf. The Two Gentlemen of Verona,
Act I. Sc. 1.
 THE LATE MR. CURRAN
Now republished for the first time.

353. The late shots at Edinburgh. Hazlitt may refer to the

conviction and execution (Jan. 28, 1829) of the notorious
William Burke. His partner Hare had given evidence
against him and had been released.
 THE COURT JOURNAL—A DIALOGUE
Now republished for the first time. The Court Journal was a
weekly paper founded by Henry Colburn, May 2, 1829.

PAG
E ‘Our withers,’ etc. Hamlet, Act III. Sc. 2.
355.
‘Married a highwayman,’ etc. The Beggar’s Opera, I. 1.
‘The story of Miss ——,’ etc. Cf. vol. XI. (Fugitive Writings), p.
383 note.
356. Mr. C——. Henry Colburn presumably.
 THE LATE DR. PRIESTLEY
Now republished for the first time.

357. ‘His body thought.’ Cf. Donne, An Anatomy of the World, The
Second Anniversary, 245–6.
358. Controversy with Dr. Price. Published in 1778.
‘Dazzling,’ etc. Cf. Comus, 791.
359. ‘Anthropagi,’ etc. Cf. Othello, Act I. Sc. 3.
‘Nay, an you mouth,’ etc. Cf. Hamlet, Act V. Sc. 1.
‘None but a Cobbett,’ etc. See Cobbett’s Observations on
Priestley’s Emigration (Selections, etc. I. 15, et seq.).
 SECTS AND PARTIES
Now republished for the first time.

361. A board of Utility at Charing Cross. Hazlitt may have had in

his mind Francis Place, the radical tailor of Charing Cross,
whose house was well known as a Radical meeting-place,
but the essay attacks the Utilitarian party at large.
362. Mrs. Chatterley. The wife of the actor William Simmonds
Chatterley. It is difficult to understand what Hazlitt’s
innuendo is. The journal he refers to is presumably the
Morning Chronicle.
363. ‘What they are least assured.’ Cf. Measure for Measure, Act
II. Sc. 2,
 CONVERSATIONS AS GOOD AS REAL (1)
These two papers, now republished for the first time, were omitted
for some reason by Hazlitt when he brought out Mr. Northcote’s
Conversations. See vol. VI. note to p. 420. T. is Hazlitt, J., Northcote.
This first Conversation would have followed after Conversation the
Twentieth. See for Hogarth, vol. VIII. (English Comic Writers) 133 et
seq., and Lamb’s essay ‘On the Genius and Character of Hogarth’
(Works, ed. E. V. Lucas, I. 70).

PAG
E That old Mother W. It is not clear to what figure Northcote
364. refers. The procuress in The Harlot’s Progress (Plate I.) was
the notorious Mother Needham who died in 1731.
Fielding has tried, etc. Tom Jones, Book IV. chap. ii.
That remark of his. Cf. ante, p. 268, and vol. VIII. p. 442.
‘With her pie-dish,’ etc. Hazlitt’s phrase. See vol. VIII. p. 137.
367. The ‘Possessed Boy.’ A fresco in the chapel of San Nilo, Grotta
Ferrata. The drawing from this fresco was presumably by
John Bryant Lane (1788–1868), who spent ten years in
Rome (1817–1827).
The late Edinburgh murders. See ante, p. 353 and note.
The group at Ambrose’s. See Wilson’s Noctes Ambrosianæ.
368. One of his tales. Crabbe’s tale ‘The Confidant,’ upon which
Lamb founded The Wife’s Trial; or, the Intruding Widow,
published in Blackwood, 1828.
Tam O’Shanter. Statues of Tam O’Shanter and Souter
Johnny, by Thoms, were exhibited in London in 1829.
Ducrow. Andrew Ducrow (1793–1842), the equestrian
performer.
 CONVERSATIONS AS GOOD AS REAL (2)

369. G. Godwin, probably.

370. A classical education. Cf. vol. I. (The Round Table), p. 5 and
note.
 TRIFLES LIGHT AS AIR
Republished by Mr. W. C. Hazlitt in his edition of The Round
Table (Bohn, 1871). Nos. I.–X. appeared in The Atlas on Sept. 27,
1829; Nos. XI.–XVII. on Oct. 4, 1829. The following additional ‘Trifle’
(XVIII.) appeared in Bohn’s Library, though not in the Magazine: ‘The
French Revolutionists in the “Reign of Terror,” with Robespierre at
their head, made one grand mistake. They really thought that by
getting rid of the patrons and abettors of the ancient régime they
should put an end to the breed of tyrants and slaves; whereas in
order to do this it would be necessary to put an end to the whole
human race.’

PAG
E It was merely a fashion, etc. See Byron’s letter to Murray on
372. Bowles and Pope (Letters, etc., ed. Prothero, V. 553 and
note).
‘Procrastination,’ etc. Young, Night Thoughts, I. 393.
375. ‘Ears polite.’ Pope, Moral Essays, IV. 150.
‘Inconstant moon.’ Romeo and Juliet, II. 2.
 COMMON SENSE
Now republished for the first time.

PAG
E
‘Its price,’ etc. Cf. Job xxviii. 18.
377. ‘Fairly worth the seven.’ Pope, Moral Essays, IV. 44.

‘Comes home,’ etc. Bacon, Essays, Dedication.

‘Fear,’ etc. Cowper, The Task, II. 325.
378. Commodore Trunnion, etc. See Peregrine Pickle, Chap. viii.

‘They have,’ etc. Cf. Julius Cæsar, Act II. Sc. 1.

379.
‘Crack,’ etc. ‘The father cracks of horses, pleughs, and kye.’
380. Burns, Cotter’s Saturday Night, St. VIII.
Phlegmatic C——. Hazlitt probably refers to Cobbett. Cf. a
passage in Table-Talk (vol. VI. p. 102).
 THE SPIRIT OF CONTROVERSY
Now republished for the first time.

381. ‘Envy,’ etc. Cf. ‘From envy, hatred, and malice, and all
uncharitableness.’ The Litany.
383. ‘Root of the matter.’ Job xix. 28.
‘Their hearts,’ etc. Cf. S. Luke xxiv. 32.
‘A coil and pudder.’ See ante, notes to pp. 309 and 335.
Mr. Taylor’s discourses. Robert Taylor (1784–1844), the
notorious deistical clergyman, who, early in 1828, had been
sentenced to a year’s imprisonment for a blasphemous
discourse.
The Duke of Newcastle. The fourth Duke (1785–1851), a
violent opponent of Catholic Emancipation passed by
Wellington’s ministry in 1829.
‘Strange,’ etc. Byrom, On the Feuds between Handel and
Bononcini.
384. ‘Like a thick scarf,’ etc. See ante, note to p. 82.
‘Whose edge,’ etc. Cymbeline, Act III. Sc. 4.
‘Of whatsoe’er descent,’ etc. Dryden, Absalom and
Achitophel, I. 100–3.
 ENVY
Republished in Sketches and Essays.

387. ‘Jealous leer malign.’ Paradise Lost, IV. 503.

388. ‘Phœnix,’ etc. Ibid. v. 272.
‘Though wondering senates,’ etc. Pope, Moral Essays, I. 184–
7.
390. ‘Like to a gate,’ etc. Cf. Troilus and Cressida, Act III. Sc. 3.
391. ‘The learned pate,’ etc. Timon of Athens, Act IV. Sc. 3.