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Volume 8

AAPS Introductions in the

Pharmaceutical Sciences

Series Editor
Claudio Salomon
National University of Rosario, Rosario, Argentina

Founding Editor
Robin Zavod
Chicago College of Pharmacy, Midwestern University, Downers Grove, IL,
USA

The AAPS Introductions in the Pharmaceutical Sciences book series is

designed to support pharmaceutical scientists at the point of
knowledge transition. Springer and the American Association of
Pharmaceutical Scientists (AAPS) have partnered again to produce a
second series that juxtaposes the AAPS Advances in the Pharmaceutical
Sciences series. Whether shifting between positions, business models,
research project objectives, or at a crossroad in professional
development, scientists need to retool to meet the needs of the new
scientific challenges ahead of them. These educational pivot points
require the learner to develop new vocabulary in order to effectively
communicate across disciplines, appreciate historical evolution within
the knowledge area with the aim of appreciating the current limitations
and potential for growth, learn new skills and evaluation metrics so
that project planning and subsequent evolution are evidence-based, as
well as to simply “dust the rust off” content learned in previous
educational or employment settings, or utilized during former scientific
explorations. The Introductions book series will meet these needs and
serve as a quick and easy-to-digest resource for contemporary science.
Editors
Jenny Ka Wing Lam and Philip Chi Lip Kwok

Respiratory Delivery of Biologics,

Nucleic Acids, and Vaccines
First Edition
Editors
Jenny Ka Wing Lam
Department of Pharmaceutics UCL School of Pharmacy, University
College London, Brunswick Square, London, UK

Philip Chi Lip Kwok

Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of
Medicine and Health, The University of Sydney, Camperdown, NSW,
Australia

ISSN 2522-834X e-ISSN 2522-8358

AAPS Introductions in the Pharmaceutical Sciences
ISBN 978-3-031-47566-5 e-ISBN 978-3-031-47567-2
https://doi.org/10.1007/978-3-031-47567-2

Jointly published with American Association of Pharmaceutical

Scientists

© American Association of Pharmaceutical Scientists 2023

This work is subject to copyright. All rights are reserved by the

Publisher, whether the whole or part of the material is concerned,
specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other
physical way, and transmission or information storage and retrieval,
electronic adaptation, computer software, or by similar or dissimilar
methodology now known or hereafter developed.

The use of general descriptive names, registered names, trademarks,

service marks, etc. in this publication does not imply, even in the
absence of a specific statement, that such names are exempt from the
relevant protective laws and regulations and therefore free for general
use.
The publishers, the authors, and the editors are safe to assume that the
advice and information in this book are believed to be true and accurate
at the date of publication. Neither the publishers nor the authors or the
editors give a warranty, express or implied, with respect to the material
contained herein or for any errors or omissions that may have been
made. The publishers remain neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer

Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham,
Switzerland
Preface
Biologics have emerged as an increasingly important class of
therapeutics. Owing to their high specificity and ability to target
specific components of the immune system, biologics are particularly
useful in the treatment of cancers and immune-mediated diseases. In
2022, biologics accounted for over 40% of approvals by the Centre for
Drug Evaluation and Research (CDER) of the United States Food and
Drug Administration, a record high percentage of biologics to date.
Although not classified as biologics, nucleic acids such as small
interfering ribonucleic acid (siRNA) and messenger ribonucleic acid
(mRNA) also gained much attention in recent years. Their capability to
manipulate the expression of virtually any gene makes them
remarkably powerful therapeutic modalities to exploit “undruggable
targets” to treat a wide range of diseases. The COVID-19 pandemic that
began in 2020 has accelerated the development of new vaccine
platforms that prominently feature viral vectors and mRNA vaccines.
The landscape of pharmaceutical development is rapidly evolving, so
biologics are expected to overtake small molecules and dominate the
market in the foreseeable future.
Despite many biologics and vaccines already approved for treating
or preventing lung diseases such as lung cancer, asthma, and
respiratory viral infections, nearly all of them are parenterally
administered. In contrast, administration through inhalation can
directly target therapeutics to the site of action in the airways to
maximise efficacy. This non-invasive route overcomes many drawbacks
associated with parenteral routes, such as the requirement of trained
personnel for administration, sterile formulations, and the risks of
needlestick injuries and blood-borne diseases. Intranasal and orally
inhaled vaccines can trigger mucosal immune response, which is
lacking in conventional injected vaccines, and provide better protection
against respiratory infections. Moreover, the high vascularisation of the
lungs and nasal cavity can serve as an entry portal for the systemic
delivery of small proteins and peptides. The potential of biologics,
nucleic acids, and vaccines could be expanded to benefit more patients
by developing formulations beyond parenteral administration, as the
orally inhaled and nasal routes are already well-established for small
drug molecules against respiratory diseases.
This book consists of nine chapters which give a comprehensive
overview of the challenges and strategies in delivering a wide range of
biologics and macromolecules to the respiratory tract, including
antibodies, proteins, peptides, nucleic acids, and vaccines. It also covers
the respiratory delivery of probiotics and bacteriophages, which have
not yet been extensively studied but have shown promising potentials
in improving health and fighting against infections. The
pharmacokinetics of inhaled biological macromolecules, which is a
poorly understood topic, are also discussed. We hope this book
provides invaluable insights for readers who are working towards the
goal of developing orally inhaled and nasal biologics, nucleic acids, and
vaccines.
Jenny Ka Wing Lam
Philip Chi Lip Kwok
Brunswick Square, London, UK
Camperdown, NSW, Australia
Contents
Design Strategies of Dry Powders for Pulmonary Delivery of
Pharmaceutical Peptides
Hideyuki Sato
Pulmonary Delivery of Antibody for the Treatment of Respiratory
Diseases
Thomas Sécher and Nathalie Heuzé-Vourc’h
Dry Powder Formulation of Monoclonal Antibodies for Pulmonary
Delivery
Kimberly B. Shepard, David Zeigler, W. Brett Caldwell and
Matthew Ferguson
Antimicrobial Peptides and Proteins for Inhalation
Yuncheng Wang, Rachel Y. K. Chang, Warwick J. Britton and Hak-
Kim Chan
Pulmonary Delivery of Nucleic Acids
Gemma Conte, Ivana d’Angelo, Joschka Mü ller, Benjamin Winkeljann,
Simone Carneiro, Olivia M. Merkel and Francesca Ungaro
Intranasal and Inhaled Vaccines
Michael Yee-Tak Chow and Jenny Ka Wing Lam
Respiratory Delivery of Probiotics to Improve Lung Health
Alex Seungyeon Byun, Luis Vitetta, Hak-Kim Chan and
Philip Chi Lip Kwok
Respiratory Delivery of Bacteriophages for the Treatment of Lung
Infections
Alex Seungyeon Byun, Hak-Kim Chan and Philip Chi Lip Kwok
Pharmacokinetics​of Inhaled Medications – What Do We Know
About Biological Macromolecules?​
Audrey Huili Lim, Jinxin Zhao, Nusaibah Abdul Rahim, Jing Zhao,
Haiting Liu, Xiaoyan Yang and Yu-Wei Lin
Index
About the Editors
Jenny Ka Wing Lam
is an Associate Professor of Pharmaceutics at the UCL School of
Pharmacy, University College London. Dr Lam obtained her MPharm
and PhD from The University of Nottingham, UK. In her PhD study, she
investigated the use of non-viral vectors for gene delivery. Dr Lam was
then awarded the Maplethorpe Fellowship and continued her research
in nucleic acid delivery in the Department of Pharmacy at King’s
College London. She then joined the Department of Pharmacology and
Pharmacy in the University of Hong Kong as Assistant Professor, and
returned to the UK in 2022. Dr Lam’s research is focused on the
development of novel delivery system for a wide range of therapeutics
including small molecules, nucleic acids, and biologics, with special
interest in the use of particle engineering methods to produce aerosol
formulations for the treatment/prevention of respiratory diseases. She
is the Principal Investigator of a number of competitive grants. She has
published over 90 peer-reviewed articles and filed a number of patent
applications on pulmonary drug delivery systems. In 2020, she was
awarded the DDL (Drug Delivery to the Lung) Emerging Scientist
Award which recognised her significant accomplishment and
innovation in inhalation science.

Philip Chi Lip Kwok

is a Senior Lecturer in Pharmaceutical Sciences at the School of
Pharmacy, The University of Sydney. He obtained his Bachelor of
Pharmacy degree with First Class Honours in 2002 from this Faculty.
He became a registered pharmacist after one year of training in a
community pharmacy. Dr Kwok then undertook his PhD studies on
pharmaceutical aerosol electrostatics in the Faculty of Pharmacy at The
University of Sydney and graduated in 2007. He was a Research
Associate in the same group until August 2011 and became an Assistant
Professor in the Department of Pharmacology and Pharmacy at The
University of Hong Kong in September 2011. Dr Kwok returned to The
University of Sydney as a Lecturer in Pharmaceutical Sciences at the
end of July 2017. His research is in pulmonary drug delivery. In
particular, he specialises in the engineering, physicochemical
characterisation, and electrostatics of pharmaceutical aerosol
formulations. He has collaborated with academic and industrial
researchers, both locally and internationally, on formulation-focused as
well as interdisciplinary projects.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
J. Lam, P. C. L. Kwok (eds.), Respiratory Delivery of Biologics, Nucleic Acids, and
Vaccines, AAPS Introductions in the Pharmaceutical Sciences 8
https://doi.org/10.1007/978-3-031-47567-2_1

Design Strategies of Dry Powders for

Pulmonary Delivery of Pharmaceutical
Peptides
Hideyuki Sato1
(1) Laboratory of Biopharmacy, School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka, Japan

Hideyuki Sato
Email: h.sato@u-shizuoka-ken.ac.jp

Abstract
Pharmaceutical peptides have gradually become more attractive
therapeutic molecules than small-molecule drugs, since pharmaceutical
peptides are more selective and effective, and have fewer side effects,
compared to small-molecule drugs. Generally, owing to their poor oral
absorbability and gastrointestinal stability, peptides are mainly
administered via intravenous and intramuscular routes, which
adversely affects patient compliance. Pulmonary characteristics, such
as large surface area, abundant capillary network, thin membrane with
adequate permeability for macromolecules, reduced enzymatic
degradation, and lack of first-pass metabolism, facilitate the use of
inhalable formulations to achieve local and systemic actions. Precise
control of powder properties and appropriate design of respirable
particles to stabilize target peptides are necessary for their efficient
pulmonary delivery. This chapter discusses the strategies for
formulation and efficient delivery of peptide-loaded dry powders.
Keywords Dry powders – Particle design – Peptides – Pulmonary
delivery

1 Introduction
Recent advances in formulation development, such as drug engineering
and recombinant DNA technology, facilitate the efficient formulation
and delivery of medium and high molecular weight compounds such as
peptides, nucleic acids, antibodies, and proteins, which have specific
and potent pharmacological actions owing to their high target
selectivity. In 2019, eight biologic drugs were among the top 10 global
sales [10]. Recently, middle molecular weight drugs with a molecular
weight of about 500–6000 Da, peptides and nucleic acids, have
attracted significant interest as they are relatively easy to design,
synthesize, and control, compared with proteins and antibodies.
However, similar to other biologics, the oral bioavailability of peptides
is poor, owing to their molecular size, degradation by digestive enzymes
in the gastrointestinal (GI) tract, low permeability through the
epithelial barriers in the GI tract, and first-pass metabolism. Thus, most
peptide drugs are administered via the parenteral routes, like
subcutaneous, intramuscular, or intravenous injections. Parenteral
administration has several limitations, such as pain, risk of injury at the
injection site, difficulties with self-administration, cold chain storage,
production of needles, syringes, and other waste materials that are
difficult to dispose of. To overcome these drawbacks, safe, effective, and
non-invasive routes and drug delivery technologies are being
developed.
Pulmonary delivery can offer rapid absorption of drugs and higher
systemic exposure because of the extensive vascularization in the lung,
high tissue permeability of epithelial cells, relatively low activity of
metabolic enzymes, and large pulmonary surface area [57], leading to
several advantages over conventional, non-invasive administration
routes in the treatment of systemic diseases. The pulmonary
administration system can deliver a larger amount of drug directly to a
local disease site with minimal systemic exposure. There have been
many reports on achieving efficacious drug delivery to the disease site
for the treatment of asthma, chronic obstructive pulmonary disease,
and respiratory infections [28]. Therefore, pulmonary delivery is a
viable option for effective and safe delivery of therapeutic peptides for
topical and systemic actions, depending on the target disease. Thus,
much attention has been paid to develop and investigate pulmonary
delivery systems for therapeutic peptides. For the systemic actions,
pulmonary delivery of metabolic hormones, including insulin,
calcitonin, growth hormones, somatostatin, thyroid-stimulating
hormone, and follicle-stimulating hormone, to humans and
experimental animals has been reported [1]. For the treatment of
respiratory diseases like asthma, chronic obstructive pulmonary
diseases, and cystic fibrosis and lung infections, applications of
vasoactive intestinal peptide analogues, neuropeptide Y, cyclosporine A,
and colistin have been investigated [7, 16, 79]. However, difficulty in
particle design and formulation strategies limits the practical
applications of pulmonary delivery of therapeutic peptides. Generally,
for orally inhaled particles, aerodynamic particle size between 1 and
5 μm ensures efficient delivery of inhaled particles [13]. Particles with
aerodynamic diameters larger than 10 μm are deposited in the
extrathoracic sites, such as the mouth, pharynx, and larynx, and particle
sizes between 5–10 μm are deposited in the tracheobronchial tree.
Particles that are too small cannot adhere to the surface of the
respiratory tract because they are removed from the respiratory tract
by exhaled airflow. Compared with conventional small-molecule drugs,
therapeutic peptides tend to be at risk of degradation and deactivation,
owing to their poor stability against chemical and physical stress
during the production process and storage [28]. In addition, even after
reaching the respiratory site, some physiological factors cause their
degradation/denaturalization and elimination from the target site [30].
Thus, along with the precise control of particle size, the selection of
appropriate excipients and formulation design are key considerations
for the successful pulmonary delivery of therapeutic peptides.
There are three commonly used systems for inhalation medication:
nebulizers, metered dose inhalers, and dry powder inhalers (DPIs).
Among these, DPIs are the most commonly used inhalation devices in
adults patients due to a lot of practical advantages including ease of
use, portability, and relatively high pulmonary delivery efficiency [70].
Additionally, considering the chemical stability of peptides,
powderization would be one of the options to stabilize the target
molecule, since the presence of water could accelerate the degradation
of peptides. Thus, this chapter mainly focuses on the physicochemical
and biological challenges of therapeutic peptides and particle
design/formulation strategies for DPIs to achieve efficient peptide
delivery by oral inhalation.

2 Factors Affecting Peptide Stability in

Manufacturing Process
During the manufacturing process of inhalable formulations, many
factors cause the degradation, aggregation, and/or deactivation of
target peptides due to preparation conditions and chemical and
physical stresses such as thermal stress, oxidative stress, shear stress,
and pressure. Deamidation, covalent aggregation, oxidation, and
Maillard reaction are the main degradation pathways [77]. Additionally,
in some cases, aggregation is irreversible and reduces the physical
stability of the peptide, not only leading to a loss of activity but also
other critical problems such as toxicity and immunogenicity [54]. Thus,
to prevent the risk of loss of quality and toxicity of the formulation,
appropriate conditions and excipients should be selected. This section
briefly summarizes general information on the potential factors
influencing peptide stability (Table 1).
Table 1 Factors affecting peptide stability in manufacturing process

Factor Comment
pH Solution pH can influence the charge state of dissolved peptide
depending on the isoelectric point (pI), changing the dispersion
state by electric repulsion.
Physical stress Physical stresses in manufacturing process can alter molecular
(heat, pressure, interactions including electrostatic force, hydrophobic
and shear stress) interactions, hydrogen bonding, van der Waals forces, and local
peptide interactions, possibly changing the folding state and
causing aggregations.
Oxidative stress Amino acids with reactive side chain in a peptide (histidine,
methionine, cysteine, tyrosine, and tryptophan) can be
Factor Comment
potentially damaged by reaction with any of a number of
reactive oxygen species during formulation process and storage.
Excipient Buffering agents and salts have potential to influence on peptide
stability due to changing pH and ionic strength of peptide
solution. Some excipients like surfactants and antioxidants can
stabilize peptide.

2.1 pH
Generally, the pH can influence the aggregation and chemical
degradation of peptides. Electrostatic interactions are known to play a
major role in stabilizing the dispersion state. More specifically, a higher
net charge can contribute to the suppression of the aggregation
potential of peptides owing to the electronic repulsion between peptide
molecules [60]. Additionally, the ionic strength and nature of the
cations and anions in solution, and the presence of polyelectrolytes also
have the potential to affect the rate and extent of aggregation. To
estimate the effect of solution conditions on aggregation, the isoelectric
point of peptides, where net charges are essentially zero, is useful
information [38], suggesting the importance of selecting suitable
excipients for stabilizing target peptides in the formulation process and
subsequent products. When the solution pH is significantly different
from the isoelectric point, the protein becomes highly charged,
resulting in electric repulsions.

2.2 Temperature
During the pharmaceutical process, active ingredients experience
physical stress, such as thermal stress, pressure, and shear stress.
Temperature affects the structural stability of peptides via molecular
interactions, conformational stability (secondary structure), solubility,
and chemical degradation. Electrostatic forces, hydrophobic
interactions, hydrogen bonding, van der Waals forces, and local peptide
interactions are responsible for the free energy of the folding state.
Temperature plays a crucial role in reaction kinetics because rate
constants increase exponentially with temperature, i.e., the rate of
aggregation increases at high temperatures because of the rise in global
molecular mobility (kinetic energy) [6]. Therefore, an increase in
temperature accompanies an increase in the probability and number of
collisions with sufficient energy to overcome the activation energies for
the reaction, possibly leading to the acceleration of aggregation
formation. Consequently, they may compromise their therapeutic
efficacy and cause potential safety concerns. The lyophilization/freeze-
drying technique is a very common method to increase both chemical
and physical stability [18] and reduce the thermal stress for
solidification. However, in some cases, these processes result in
conformational changes in peptides, leading to increased aggregation
after reconstitution in water, depending on their physicochemical
characteristics. Considering these points, the thermal stress during
drying and evaporation conditions should be carefully selected to
minimize the risk of aggregation, and even using freeze-drying, the
possible changes in conformational changes and redispersibility of the
peptide should be evaluated by spectroscopic analysis such as circular
dichroism spectroscopy.

2.3 Oxidative Stress

Oxidation of peptides is one of the major problems associated with
chemical and physical instability. It is well known that some amino acid
chains can be oxidatively modified during peptide purification,
formulation, and storage [47, 71]. These peptides included aromatic
amino acids (Tyr, Trp, and His) and sulphur-containing side chains (Met
and Cys). Thus, there have been many reports on the application of
antioxidants, such as ascorbic acid, for stabilization [35]. Methionine,
catalase, sodium thiosulfate, and chelating agents such as
ethylenediaminetetraacetic acid (EDTA) and diethylene triamine
pentaacetic acid (DTPA) have also been used as stabilizers against
oxidative stress [40, 80]. Replacement of these sensitive amino acids
with other chemical moieties may increase the chemical stability of
peptide. In this case, the conformational changes and affinity to the
target site for pharmacological action should be carefully evaluated
after modification of the amino acid sequence and/or chemical
moieties of target peptide.
2.4 Excipients
Different excipients are used in pharmaceutical development of peptide
formulations, including salts, polyols, sugars, surfactants, osmolytes,
chelators, antioxidants, specific ligands, and carbohydrates [77]. As
mentioned above, pH conditions can strongly affect the stability and
potential of aggregation. Therefore, buffering agents such as acetate,
citrate, histidine, phosphate, and Tris can alter stability. Salts also have
a complicated influence on peptide stability by altering both
conformational and colloidal stability [35]. Depending on the difference
in surface charge, the overall effect of a salt on physical stability is a
balance of different and multiple mechanisms by which the salt
interacts with water and biomolecules (Hofmeister effects and Debye–
Hü ckel effects). Using a surfactant, the exposure of the hydrophobic
part of the peptide to water is minimized owing to its amphiphilic
properties, resulting in the stabilization of the peptide. Pharmaceutical
excipients have both positive and negative effects on the stability of
peptides, suggesting the necessity of careful selection depending on the
physicochemical properties of the target peptides.

3 Biological Barriers
Active ingredients can act in the mucus layer or on pathogens for
topical pharmacological actions in the respiratory tract, whereas for
systemic delivery, target drugs have to permeate the bronchial mucus
layer and alveolar epithelial cells to enter systemic circulation (Fig. 1).
The thickness of the mucus layer is between 5 and 55 μm depending on
the depth of the site in the respiratory tract [29] and varies depending
on the physiological conditions [27], resulting in the difficulty of
sufficient delivery of target peptides in obstructive diseases, which
causes increases in mucus production and viscosity of mucus. Thus,
controlling diffusiveness within the mucus layer by mucoadhesive and
mucopenetrating properties of the formulation could contribute to the
enhanced and/or sustained absorbability from the lung (described in
detail in Sect. 5.1 Adjusting mucodiffusiveness). Although pulmonary
mucus is not a significant barrier for macromolecules with sizes less
than 10 nm (−500 kDa), aggregates of peptides and nano/microparticle
formulations (>10 nm) could be trapped by the mucus layer owing to
the mesh-like structure of the mucus layer. They are transported from
the deep lung to the pharynx by mucociliary clearance and are removed
via phagocytosis by macrophages.

Fig. 1 Biological barriers for pulmonary delivery of peptide drugs

For systemic action of the target peptides, they must penetrate the
epithelial layer. For permeation via passive diffusion, there is a suitable
range of lipophilicity (log P value: 2–9) and a cutoff value for molecular
size (above 1000 Da) [4, 48]. Thus, they can permeate the cellular
membrane via transcytosis (which may be receptor-mediated or
carrier-mediated), paracellular routes, and large transitory pores in the
epithelial layer. Proton-coupled peptide transporters (PEPT) are
generally known as the main transporter for the permeation of di-and
tripeptides; however, the contribution of PEPT to the absorption of
inhaled peptides in the pulmonary tract is not significant. If target
peptides can be captured by endocytosis and pinocytosis during the
absorption process, they can be found in lysosomes, possibly leading to
enzymatic degradation by hydrolases in the lysosomes. Therefore,
appropriate strategies are required to avoid inactivation by enzymatic
degradation.
In the respiratory tract, the activities of metabolic enzymes are
lower than those in the gastrointestinal tract and liver tissues, and
molecules absorbed via pulmonary delivery can avoid first-pass
metabolism, suggesting great advantages for peptide delivery via
inhalation systems. However, degradation of peptides and proteins also
occurs in the respiratory tract, and the extent of degradation depends
on the molecular size. Relatively small peptides with molecular sizes of
less than 3 kDa are more sensitive than larger proteins (6–500 kDa)
[73]. In bronchoalveolar lavage fluid, angiotensin-converting enzyme,
cathepsin D, cathepsin H, and dipeptidyl peptidase IV are abundant
enzymes involved in the degradation of peptides and proteins.
Proteins and peptides deposited on ciliated epithelium are not
significantly absorbed owing to mucociliary transportation up the
airways and movement into the gastrointestinal tract, resulting in the
degradation and denaturation of the molecules. The clearance
mechanism in the alveolar region includes phagocytosis by
macrophages, paracellular diffusion through tight junctions, vesicular
endocytosis or pinocytosis, and receptor-mediated transcytosis. For
soluble proteins, clearance via phagocytosis by alveolar macrophages
does not seem important as a clearance system because macrophages
preferentially capture relatively insoluble particles.
Some respiratory diseases, including asthma, chronic obstructive
pulmonary diseases, lung fibrosis, and pulmonary hypertension, cause
physiological changes such as bronchial constriction, emphysema, and
increase of mucus thickness and viscosity. It has also been reported
that the activities of several proteases are altered due to the migration
and accumulation of inflammatory cells at the inflammatory site and
the release of protease from inflammatory cells [22]. Thus, peptide
degradation increases in most lung diseases. An increase in the
thickness of the mucus layer in the diseased state is also a non-
enzymatic barrier for the delivery of peptides to target cells. In patients
with cystic fibrosis, a combination of increased mucus production and
viscosity can be observed, indicating the difficulty of pulmonary drug
delivery compared with the healthy state [27]. Additionally, tissue
remodelling caused by fibrosis in COPD and idiopathic pulmonary
fibrosis evokes an increase in the air-blood barrier thickness due to
tissue hypertrophy.

4 Production and Design of Peptide-Load Inhalable

Particles for DPI
To manufacture inhalable particles with desirable inhalation
performance and sufficient peptide delivery, the production method
and particle design are crucial for determining the potential of the DPI
system. The particle manufacturing approach can be categorized using
an intuitive approach based on whether the starting material is a solid
particle (top-down method) or a liquid (bottom-up method) (Table 2).
The manufacturing approach and composition have a significant impact
on the powder properties and the physical and chemical stability of the
included peptides. Thus, powderization techniques should be carefully
selected based on the physicochemical properties and stability of the
target peptide.

Table 2 Particle production methods for inhalable powders

Category Technique Characteristic Reference

Top-down approaches
Milling Ball/beads milling High shear stress
Necessity of separating
solid milling media
Concerns of
contamination with
foreign particulate
Jet milling Commercially [33, 53,
established method for 78]
small molecular drugs
for inhalation
No solid milling media
No subsequent
separation process
Homogenization High-pressure Necessity of
homogenization evaporation step after
Category Technique Characteristic Reference
micronization
Commercially used for
non-inhalation drugs
Bottom-up approaches
Solvent Spray-drying Commercially [3, 8]
evaporation established method as
single-step particle
formation process
Controlling size,
morphology, density,
surface composition
Spray freeze-drying Variant of spray-drying [58, 59,
process 76]
Two-step process
(freezing and
lyophilization)
Production of fragile
particles with very low
density
No thermal stress, but
poor scalability and
complex process
Supercritical fluid method Use SCF CO2 as [31, 64]
(rapid expansion): atomizing medium
Supercritical fluid-assisted
No use of organic
atomization
solvent
Antisolvent Supercritical fluid method Use SCF CO2 as an anti- [36, 37]
(antisolvent) solvent to precipitate
fine particles

4.1 Preparation Method

4.1.1 Top-Down Method
In top-down approaches, target bulk particles are mechanically broken
down into micron-sized particles or aggregated in the respirable size
range (e.g., milling and high-pressure homogenization). Among the top-
down approaches, jet milling is a well-established method for the
production of DPI systems because it is faster, more scalable, and offers
a better-controlled particle size distribution than homogenization or
ball milling. Additionally, because of the media-less milling process,
there is no requirement for the separation of micronized particles from
the milling media. During jet milling, coarse particles of the raw feed
are injected into the milling chamber with a forceful stream of high-
pressure gas and then pulverized by repetitive inter-particle collisions
and attritions [41]. However, similar to other top-down approaches,
there are stability concerns due to the susceptibility of macromolecules
in the environment, and the heat and mechanical stresses generated by
high-energy conditions and harsh physical grinding. High pressure is
also known to cause denaturation of peptides and proteins [77].
Depending on the operating conditions of jet milling, the milling
process contributes to the loss of potency of target peptides due to the
mechanical stresses of the jet-milling process. Although top-down
approaches are commonly used for the micronization of many types of
small-molecule drugs, optimized micronizing conditions should be
considered in the case of biologics such as peptides.

4.1.2 Bottom-Up Method

In contrast to top-down approaches, there are various bottom-up
approaches, leading to the diversity of starting materials, including
simple solutions, cosolvent solutions, oil in water (O/W) or water in oil
(W/O) emulsions, suspensions, or more complex colloidal fluids,
suggesting flexibility for designing functional particles. The particles
are generated by single-step solvent evaporation, such as spray-drying,
and more complex processes, such as precipitation using an
antisolvent. Compared to top-down approaches, the molecular,
colloidal, or powder nature of bottom-up approaches can be well-
controlled, such as particle morphology and size, surface properties,
and crystallinity. Additionally, the combined use of pharmaceutical
excipients in bottom-up approaches allows further characterization of
the physicochemical, chemical, and physical stability and inhalation
performance of DPI.
 Spray drying is a well-established powderization technology for the
preparation of solid particle formulations [24]. This process consists of
three steps: atomization of the sample solution into fine droplets,
drying by hot air, and collection of the generated powder. This
technique has been used to develop formulations of small-molecule
drugs with poor water solubility; however, it is increasingly used to
provide powder formulations of macromolecules and
biopharmaceuticals [24]. The freeze-drying method is commonly used
for solidification of peptide solutions. Compared with the freeze-drying
method, the spray-drying method can generate fine particles with fine
aerosolization performance for DPI and can control the powder
properties in terms of morphology, size distribution, shape, and surface
texture with scalability. During the spray-drying process, it is possible
to expose some stresses, including mechanical stress, heat stress, and
adsorption at the air-liquid interface during atomization. Although
spray-drying has fewer sources of stress to induce denaturation of
peptides than the mechanical top-down approach, there is still some
possibility of aggregation and denaturation of peptides during the
process. Thus, the atomizing conditions (atomizing pressure, feed
pump, and feed concentration) and drying conditions (temperature of
hot air and flow rate) should be carefully optimized depending on the
target peptides.
Spray-freeze-drying is a variant of the spray-drying process used to
generate highly porous particles, such as freeze-dried cakes. In this
process, the droplets generated from the spray nozzles were directly
frozen using liquid nitrogen and then lyophilized [45]. This process can
be used to prepare inhalable spherical particles with high porosity,
thereby improving inhalation performance. However, the spray-freeze-
drying process is a very complex process with poor scalability; thus, the
applicability might be limited in some cases using highly heat-sensitive
compounds in conventional spray-drying systems.
Supercritical fluid (SCF) technologies have also been applied to
prepare particles for inhalation [75]. Owing to relatively mild
conditions (relatively low critical temperature: 31.1 °C and pressure:
7.38 MPa), SCF carbon dioxide (SC-CO2) is commonly used to develop
the formulations. During the particle production process, SC-CO2 can
act as an anti-solvent to precipitate peptide-loaded particles. This
process has been used to prepare dried protein and peptide
formulations, and to provide the possibility of producing small
microparticles suitable for inhalation. Briefly, an aqueous sample
solution containing peptides, proteins, and ethanol was atomized
through a coaxial nozzle into a pressurized chamber filled with SC-CO2.
The drug-loaded particles were then precipitated from the water
droplet. Among the various SCF-based powderization systems, SCF-
assisted atomization (SAA), where SC-CO2 serves as the atomizing
medium, has been highlighted for its availability in aqueous solutions
without the use of any organic solvents [64]. Although there are still no
products for commercially available DPI manufactured by SCF systems,
some studies on the production of macromolecule-loaded powders,
including insulin, lysozyme, and albumin, have been reported [17, 23,
61, 64]. According to these studies, although biologics-loaded particles
can be successfully developed by the SCF approach, the stability and
inhalation performance of the prepared particles were dependent on
the physicochemical characteristics of the target peptides and process
conditions, such as temperature and pH conditions.
In addition to the conventional technique to prepare uniform
micron-sized particles for inhalation, some unique technologies have
been reported recently. The fine droplet drying (FDD) process is a
powderization technique that employs an inkjet head used in the
printing industry [62, 68]. In this process, the inkjet head uses a piezo
element as an actuator to produce uniform fine droplets, resulting in
uniform particles after drying the generated droplets. The size of the
produced particles could be precisely controlled at the single-micron
scale by changing the size of the nozzle holes. In a previous study,
salmon calcitonin was encapsulated in poly(lactic-co-glycolic acid)
using the FDD process for inhalation to sustain its pharmacological
action [62].

4.2 Excipients to Enhance Stability of Peptides

As mentioned above, there are many possible stresses that induce the
degradation, aggregation, and denaturation of target peptides during
the manufacturing process of inhalable particles. The target
compounds should be protected from such stresses and stabilized
without affecting their biological activity. Immobilization of peptides by
solidification and entrapment within the carrier matrix can simply
contribute to preserving biological action to prevent aggregation and
conformational changes. There are many kinds of excipients, such as
sugars, polyols, salts, amino acids, polymers, and surfactants, which can
be applied as stabilizing agents for peptides during the manufacturing
process (Table 3). However, the use of excipients for stabilization of
peptide-loaded DPI systems is more difficult than that of oral
formulations because only a limited range of compounds is approved as
a pharmaceutical excipient for pulmonary administration.

Table 3 Excipients for using stabilization of peptide and proteins during spray-
drying process
Category Excipient Characteristic Reference
Sugars Glucose, fructose, maltose, sucrose, Water replacement [14, 19, 21,
trehalose, inulin, dextran theory contributes 66]
to the stabilization
of peptide by
molecular
interactions.
Entrapping peptide
into the glassy
matrix structure of
excipients,
stabilizing included
molecules by
restricting mobility.
Polyols Glycerol, mannitol, sorbitol Water replacement
theory contributes
to the stabilization
of peptide by
molecular
interactions.
Entrapping peptide
into the glassy
matrix structure of
excipients,
stabilizing included
molecules by
restricting mobility.
Amino Alanine, arginine, aspartic acid, Forming hydrogen [2, 15, 25,
acids glycine, histidine, leucine, bonding with 26, 32]
isoleucine, lysine, phenylalanine, proteins and
proline peptides.
Inhibition of the
aggregation of
peptides by
competing with
adsorption at the
air–liquid interface.
Improved inhalation
performance and
moisture protection
Category Excipient Characteristic Reference
by hydrophobic
amino acids.
Surfactants Polysorbate 20, polysorbate 80, Inhibition of the [11, 43, 44]
dipalmitoylphosphatidylcholine, aggregation of
sodium glycocholate peptides and
assisting in the
refolding by
preventing
adsorption at the
air–liquid interface.
Sugars and polyols are typically used as pharmaceutical excipients
to improve the flowability and stability of peptides. Sucrose, mannitol,
lactose, trehalose, sorbitol, and inulin are common excipients used for
the production of peptide-loaded particles [21]. These sugars and
polyols can theoretically stabilize the included peptides based on two
theories: (i) water replacement theory and (ii) vitrification theory (Fig.
2). Water replacement theory suggests that during the
solidification/powderization process, these excipients can form
hydrogen bonds with active ingredients by replacing the hydrated
water of protein/peptide, leading to the entrapment of macromolecules
into the matrix structure of excipients. This may reduce the chance of
hydrolysis by removing surrounding water. Vitrification theory
suggests that entrapment of target macromolecules into the glass-
forming matrix former can contribute to the restriction of mobility in a
rigid structure, resulting in the stabilization of highly structured
proteins and peptides. Glassy excipients with a high glass transition
temperature can act as physical barriers to improve thermostability.
Non-reducing sugars, including trehalose and sucrose, are preferable,
and the combined use of sugars, polyols, and other stabilizing
excipients can stabilize proteins and peptides during the manufacturing
process.
Fig. 2 Vitrification and water replacement theories of peptide stabilization by
sugars and polyols
Amino acids are highly biocompatible and this class of compounds
have a wide range of chemical and physicochemical properties,
including hydrophilic, hydrophobic, neutral, cationic, anionic, and
antioxidant effects [32]. Amino acids with relatively small sizes,
including glycine, alanine, leucine, isoleucine, histidine, and arginine,
are typically used as stabilizers in DPI formulations. They can form
hydrogen bonds with proteins and peptides, possibly leading to
stabilization during powderization. Additionally, they can inhibit the
aggregation of peptides by competing with adsorption at the air-liquid
interface. The application of hydrophobic amino acids, L-leucine and
phenylalanine, can also reduce moisture-induced degradation and
improve the inhalation performance of dry powders by acting as
dispersibility enhancers. L-leucine can enhance the aerosolization
efficiency of spray-dried powders by reducing their surface
cohesiveness. Surfactants such as polysorbate 20, polysorbate 80, and
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 V. Persons who tell an artist that he is equal to Claude, or a writer
that he is as great as Bacon, do not add to the satisfaction of their
hearers, but pay themselves a left-handed compliment, by supposing
that their judgment is equivalent to the suffrage of posterity.
VI. A French artist advised young beginners against being too fond
of a variety of colours, which might do very well on a smaller scale,
but when they came to paint a large picture they would find they had
soon lavished all their resources. So superficial writers may deck out
their barren round of common-places in the finest phrases
imaginable; but those who are accustomed to work out a subject by
dint of study, must not use up their whole stock of eloquence at once,
they must bring forward their most appropriate expressions as they
approach nearer to the truth, and raise their style with their
thoughts. A good general keeps his reserve, the élite of his troops, to
charge at the critical moment.
VII. ‘Procrastination is the thief of time.’ It is singular that we are
so often loth to begin what gives us great satisfaction in the progress,
and what, after we have once begun it, we are as loth to leave off. The
reason is, that the imagination is not excited till the first step is taken
or the first blow is struck. Before we begin a certain task, we have
little notion how we shall set about it, or how we shall proceed: it is
like attempting something of which we have no knowledge, and
which we feel we are incapable of doing. It is no wonder, therefore,
that a strong repugnance accompanies this seeming inaptitude: it is
having to make bricks without straw. But after the first effort is over,
and we have turned our minds to the subject, one thing suggests
another, our ideas pour in faster than we can use them, and we
launch into the stream which bears us on with ease and pleasure to
ourselves. The painter who did not like to mix his colours or begin on
a new canvas in the morning, sees the light close in upon him with
unwilling eyes; and the essayist, though gravelled for a thought, or at
a loss for words at the outset of his labours, winds up with alacrity
and spirit.
VIII. Conversation is like a game at tennis, or any other game of
skill. A person shines in one company who makes no figure in
another—just as a tolerably good cricketer, who might be an
acquisition to a country club, would have his wicket struck down at
the first bowl at Lord’s-ground. The same person is frequently dull at
one time and brilliant at another: sometimes those who are most
silent at the beginning of an entertainment are most loquacious at
the end. There is a run in the luck both in cards and conversation.
Some people are good speakers but bad hearers: these are put out,
unless they have all the talk to themselves. Some are best in a tête-à-
tête; others in a mixed company. Some persons talk well on a set
subject, who can hardly answer a common question, still less pay a
compliment or make a repartee. Conversation may be divided into
the personal or the didactic: the one resembles the style of a lecture,
the other that of a comedy. There are as many who fail in
conversation from aiming at too high a standard of excellence, and
wishing only to utter oracles or jeux-d’esprit, as there are who expose
themselves from having no standard at all, and saying whatever
comes into their heads. Pedants and gossips compose the largest
class. Numbers talk on without paying any attention to the effect
they produce upon their audience: some few take no part in the
discourse but by assenting to everything that is said, and these are
not the worst companions in the world. An outcry is sometimes
raised against dull people, as if it were any fault of theirs. The most
brilliant performers very soon grow dull, and we like people to begin
as they end. There is then no disappointment nor false excitement.
The great ingredient in society is good-will. He who is pleased with
what he himself has to say, and listens in his turn with patience and
good-humour, is wise and witty enough for us. We do not covet those
parties where one wit dares not go, because another is expected. How
delectable must the encounter of such pretenders be to one another!
How edifying to the bye-standers!
IX. It was well said by Mr. Coleridge, that people never improve by
contradiction, but by agreeing to differ. If you discuss a question
amicably you may gain a clear insight into it; if you dispute about it
you only throw dust in one another’s eyes. In all angry or violent
controversy, your object is not to learn wisdom, but to prove your
adversary a fool; and in this respect, it must be admitted, both
parties usually succeed.
X. Envy is the ruling passion of mankind. The explanation is
obvious. As we are of infinitely more importance in our own eyes
than all the world beside, the chief bent and study of the mind is
directed to impress others with this self-evident but disputed
distinction, and to arm ourselves with the exclusive signatures and
credentials of our superiority, and to hate and stifle all that stands in
the way of, or obscures, our absurd pretensions. Each individual
looks upon himself in the light of a dethroned monarch, and the rest
of the world as his rebellious subjects and runaway slaves, who
withhold the homage that is his natural due, and burst the chains of
opinion he would impose upon them: the madman in Hogarth (sooth
to say), with his crown of straw and wooden sceptre, is but a type and
common-place emblem of every-day life.
XI. It has been made a subject of regret that in forty or fifty years’
time (if we go on as we have done) no one will read Fielding. What a
falling off! Already, if you thoughtlessly lend Joseph Andrews to a
respectable family, you find it returned upon your hands as an
improper book. To be sure, people read ‘Don Juan’; but that is in
verse. The worst is, that this senseless fastidiousness is more owing
to an affectation of gentility than to a disgust at vice. It is not the
scenes that are described at an alehouse, but the alehouse at which
they take place that gives the mortal stab to taste and refinement.
One comfort is, that the manners and characters which are objected
to as low in Fielding have in a great measure disappeared or taken
another shape; and this at least is one good effect of all excellent
satire—that it destroys ‘the very food whereon it lives.’ The generality
of readers, who only seek for the representation of existing models,
must therefore, after a time, seek in vain for this obvious
verisimilitude in the most powerful and popular works of the kind;
and will be either disgusted or at a loss to understand the
application. People of sense and imagination, who look beyond the
surface or the passing folly of the day, will always read Tom Jones.
XII. There is a set of critics and philosophers who have never read
anything but what has appeared within the last ten years, and to
whom every mode of expression or turn of thought extending beyond
that period has a very odd effect. They cannot comprehend how
people used such out-of-the-way phrases in the time of Shakspeare;
the style of Addison would not do now—even Junius, they think,
would make but a shabby thread-bare figure in the columns of a
modern newspaper—all the riches that the language has acquired in
the course of time, all the idiomatic resources arising from study or
accident, are utterly discarded—sink under-ground: and all that is
admired by the weak or sought after by the vain, is a thin surface of
idle affectation and glossy innovations. Even spelling and
pronunciation have undergone such changes within a short time,
that Pope and Swift require a little modernizing to accommodate
them to ‘ears polite;’ and that a bluestocking belle would be puzzled
in reciting Dryden’s sounding verse with its occasional barbarous,
old-fashioned accenting, if it were the custom to read Dryden aloud
in those serene, morning circles. There is no class more liable to set
up this narrow superficial standard, than people of fashion, in their
horror of what is vulgar and ignorance of what really is so; they have
a jargon of their own, but scout whatever does not fall in with it as
Gothic and outré; the English phrases handed down from the last age
they think come east of Temple-bar, and they perform a sedulous
quarantine against them. The Times, having found it so written in
some outlandish depêche of the Marquis of Wellesley’s, chose as a
mark of the haute literature, to spell dispatch with an e, and for a
long time he was held for a novice or an affected and absolute writer
who spelt it otherwise. The Globe, with its characteristic good sense
and sturdiness of spirit has restored the old English spelling in
defiance of scandal. Some persons who were growing jealous that the
author of Waverley had eclipsed their favourite luminaries may
make themselves easy; he himself is on the wane with those whose
opinions ebb and flow with the ‘inconstant moon’ of fashion, and has
given way (if Mr. Colburn’s advertisements speak true, ‘than which
what’s truer?’) to a set of titled nonentities. Nothing solid is to go
down, or that is likely to last three months; instead of the standing
dishes of old English literature we are to take up with the nicknacks
and whipt syllabubs of modern taste; are to be occupied with a
stream of titlepages, extracts, and specimens, like passing figures in a
camera obscura, and are to be puzzled in a mob of new books as in
the mob of new faces in what was formerly the narrow part of the
Strand.
XIII. Never pity people because they are ill-used. They only wait
the opportunity to use others just as ill. Hate the oppression and
prevent the evil if you can; but do not fancy there is any virtue in
being oppressed, or any love lost between the parties. The
unfortunate are not a jot more amiable than their neighbours,
though they give themselves out so, and our pity takes part with
those who have disarmed our envy.
 XIV. The human mind seems to improve, because it is continually
in progress. But as it moves forward to new acquisitions and
trophies, it loses its hold on those which formerly were its chief boast
and employment. Men are better chemists than they were, but worse
divines; they read the newspapers, it is true, but neglect the classics.
Everything has its turn. Neither is error extirpated so much as it
takes a new form and puts on a more artful disguise. Folly shifts its
ground, but finds its level: absurdity is never left without a
subterfuge. The dupes of dreams and omens in former times, are
now the converts to graver and more solemn pieces of quackery. The
race of the sanguine, the visionary, and the credulous, of those who
believe what they wish, or what excites their wonder, in preference to
what they know, or can have rationally explained, will never wear
out; and they only transfer their innate love of the marvellous from
old and exploded chimeras to fashionable theories, and the terra
incognita of modern science.
XV. It is a curious speculation to take a modern belle, or some
accomplished female acquaintance, and conceive what her great-
great-grandmother was like, some centuries ago. Who was the Mrs.
—— of the year 200? We have some standard of grace and elegance
among eastern nations 3000 years ago, because we read accounts of
them in history; but we have no more notion of, or faith in, our own
ancestors than if we had never had any. We cut the connexion with
the Druids and the Heptarchy; and cannot fancy ourselves (by any
transformation) inmates of caves and woods, or feeders on acorns
and sloes. We seem engrafted on that low stem—a bright, airy, and
insolent excrescence.
XVI. There is this advantage in painting, if there were no other,
that it is the truest and most self-evident kind of history. It shows
that there were people long ago, and also what they were, not in a
book darkly, but face to face. It is not the half-formed clay, the old-
fashioned dress, as we might conceive; but the living lineaments, the
breathing expression. You look at a picture by Vandyke, and there
see as in an enchanted mirror, an English woman of quality two
hundred years ago, sitting in unconscious state with her child playing
at her feet, and with all the dove-like innocence of look, the grace and
refinement that it is possible for virtue and breeding to bestow. It is
enough to make us proud of our nature and our countrywomen; and
dissipates at once the idle, upstart prejudice that all before our time
was sordid and scarce civilised. If our progress does not appear so
great as our presumption has suggested, what does it signify? With
such models kept in view, our chief object ought to be not to
degenerate; and though the future prospect is less gaudy and
imposing, the retrospect opens a larger and brighter vista of
excellence.
XVII. I am by education and conviction inclined to republicanism
and puritanism. In America they have both; but I confess I feel a
little staggered in the practical efficacy and saving grace of first
principles, when I ask myself, ‘Can they throughout the United
States, from Boston to Baltimore, produce a single head like one of
Titian’s Venetian nobles, nurtured in all the pride of aristocracy and
all the blindness of popery?’ Of all the branches of political economy,
the human face is perhaps the best criterion of value.
 COMMON SENSE

The Atlas.]
[October 11, 1829.

Common sense is a rare and enviable quality. It may be truly said

that ‘its price is above rubies.’ How many learned men, how many
wits, how many geniuses, how many dull and ignorant people, how
many cunning knaves, how many well-meaning fools are without it!
How few have it, and how little do they or others know of it, except
from the infallible results—for one of its first requisites is the utter
absence of all pretension! The vulgar laugh at the pedant and
enthusiast for the want of it, while they themselves mistake bigotry
and narrow-minded notions for it. It is not one of the sciences, but
has been well pronounced to be ‘fairly worth the seven.’ It is a kind of
mental instinct, that feels the air of truth and propriety as the fingers
feel objects of touch. It does not consist with ignorance, for we
cannot pronounce on what we do not know; and on the other hand,
the laying in a stock of knowledge, or mastering any art or science,
seems to destroy that native simplicity, and to warp and trammel the
unbiassed freedom of mind which is necessary to its receiving and
giving their due weight to ordinary and casual impressions. Common
sense is neither a peculiar talent nor a laborious acquirement, but
may be regarded as a sound and impartial judgment operating on the
daily practice of life, or on what ‘comes home to the business and
bosoms of men’; combined with great attainments and speculative
inquiries, it would justly earn the title of wisdom; but of the latter we
have never known a single instance, though we have met with a few
of the former; that is, we have known a number of persons who were
wise in the affairs of the world and in what concerned their own
interest, but none who, beyond this, and in judging of general
questions, were not the dupes of some flaw of temper, of some
weakness or vanity, or even striking advantage of their own. To give
an example of two in illustration. A person may be an excellent
scholar, a good mathematician, well versed in law and history, a first-
rate chess-player, a dazzling fencer, in a word, a sort of admirable
Crichton—you are disposed to admire or envy so many talents united
—you smile to see him wanting in common sense, and getting into a
dispute about a douceur to a paltry police-officer, and thinking to
interest all Europe and both Houses of Parliament in his success. It is
true, he has law and reason on his side, has Grotius and Puffendorf
and the statutes at large doubled down in dog-ears for the occasion,
has a vast and lively apparatus of well-arranged premises and
conclusions ready to play off against his adversaries; but he does not
consider that he has to deal with interest and custom, those
impalpable, intangible essences, that ‘fear no discipline of human
wit.’ Does he think to check-mate the police? Will he stop the mouth
of a hungry tide-waiter with a syllogism? Or supersede a perquisite
by the reductio ad absurdum? It is a want of common sense, or the
not distinguishing properly between the definite and the indefinite.
No one can have arrived at years of discretion without knowing or
feeling that he cannot take a single step without some compromise
with existing circumstances; that the path of life is intercepted with
innumerable turnpike-gates, at which he must pay down the toll of
his own convictions and of strict justice; that he cannot walk the
streets but by tacit allowance; and that to disregard all impediments
in the right line of reason and written forms is to imitate the conduct
of Commodore Trunnion, who mistook the land for the sea, and
went to be married by the wind and compass. The proofs of this
occur every hour of the day—they may not be registered, they may
not be remembered, but they are virtually and effectively noted down
by the faculty of common sense, which does not feel its way the less
surely because it proceeds often mechanically and blindly. There may
be exceptions indeed to ordinary rules, on which a man may go to
martyrdom and a stake (such as that of Hampden and ship-money),
but these occur once in a century, and are only met with at the
corners of streets by those who have an excess of logical
discrimination, and have to pay a certain tax for being too clever by
half. It is the fashion at present among the philosophical vulgar to
decry feeling, both the name and the thing. It would be difficult,
however, to do without it: for this word embraces all that mass of
knowledge and of common sense which lies between the extremes of
positive proof or demonstration and downright ignorance; and those
who would pragmatically confine their own convictions or those of
others to what is absolutely known and understood, would at best
become scientific pedants and artificial barbarians. There are some
persons who are the victims of argument; as there are others who are
the slaves of minute details and matters of fact. One class will have a
reason for every thing, and will admit the greatest absurdities that
are formally proposed to them; the other must have facts to support
every conclusion, and can never see an inch beyond their noses. The
last have the organ of individuality largely developed, and are
proportionably deficient in common sense. Their ideas are all local
and literal. To borrow the language of a great but obscure
metaphysician, their minds are epileptic; that is, are in perpetual
throes and convulsions, fasten on every object in their way not to
help but to hinder their progress, and have no voluntary power to let
go their hold of a particular circumstance, to grasp the whole of any
question, or suspend their judgment for an instant. The fact that is
before them is every thing; the rest goes for nothing. They are always
at cross-purposes with themselves, for their decisions are the result
of the last evidence, without any corrective or qualifier in common
sense; in the hunt after proofs, they forget their principles, and gain
their point, though they lose their cause.
The Scotch have much of this matter-of-fact understanding, and
bigotry to personal and actual statistics. They would persuade you
that there is no country but Scotland, nothing but what is Scotch. Mr.
Mac Alpine shifts the discourse from the metropolis, hurries rapidly
over the midland counties, crosses the border, and sits down to an
exordium in praise of the ‘kindly Scot.’ Charity has its home and
hearth by Tweed-side, where he was born and bred, Scotch beggars
were quite different from English beggars: there was none of the
hard-heartedness towards them that was always shown in England.
His mother, though not a rich woman, always received them kindly,
and had a bag of meal out of which she always gave them something,
as they went their rounds. ‘Lord! Mr. Mac Alpine!’ says Mrs. Mac
Alpine, ‘other people have mothers as well as you, and there are
beggars in England as well as Scotland. Why, in Yorkshire, where I
was brought up, common beggars used to come round just as you
describe, and my mother, who was no richer than yours, used to give
them a crust of bread or broken victuals just in the same way; you
make such a fuss about nothing.’ Women are best to set these follies
to rights:—
‘They have no figures nor no fantasies,
Which busy thought draws in the brains of men.’

If no great philosophers, they do not want common sense; and are

only misled in what lies beyond their sphere of feeling and
observation, by taking up the opinions of their better halves. The
common people in like manner do not want common sense in what
falls under their especial cognizance and daily practice. A country-
shoemaker or plough-man understands shoemaking, and can ‘crack
of ploughs and kine,’ though he knows nothing of the Catholic
question. If an old woman in a country-town believes she shall be
burnt at a stake, now that this question is settled, it is because she is
told so by those who ought to know better, and who impose their
prejudices upon her ignorance. Vulgar errors which are taken on
trust, or are traditional, or are the blunders of ignorance on points of
learning, have nothing to do with common sense, which decides only
on facts and feelings which have come under its own notice.
Common sense and common-place are also the antipodes of each
other: the one is a collection of true experiences, the other a routine
of cant phrases. All affectation is the death of common sense, which
requires the utmost simplicity and sincerity. Liars must be without
common sense, for instead of considering what things really are,
their whole time and attention are taken up in imposing false
appearances on themselves and their neighbours. No conceited
person can have the faculty we have been speaking of, since all
objects are tinged and changed from their proper hue by the idle
reflection of their fancied excellence and superiority. Great talkers
are in the same predicament, for they sacrifice truth to a fine speech
or sentiment, and conceal the real consequences of things from their
view by a cloud of words, of empty breath. They look at nature not to
study what it is, but to discover what they can say about it.
Passionate people are generally thought to be devoid of judgment.
They may be so, when their passions are touched to the quick; but
without a certain degree of natural irritability, we do not conceive
truth leaves sufficient stings in the mind, and we judge correctly of
things according to the interest we take in them. No one can be a
physiognomist, for example, or have an insight into character and
expression, without the correspondent germs of these in his own
breast. Phlegmatic C——, with all his husbandry acquirements, is but
half a philosopher, half a clown. Poets, if they have not common
sense, can do very well without it. What need have they to conform
their ideas to the actual world, when they can create a world
according to their fancy? We know of no remedy for want of tact and
insight into human affairs, any more than for the defect of any other
organ. Tom Jones is, we think, the best horn-book for students in
this way; and if the novice should rise up no wiser from its repeated
perusal, at least such an employment of his time will be better than
playing the fool or talking nonsense. After all, the most absurd
characters are those who are so, not from a want of common sense,
but who act in defiance of their better knowledge. The capricious and
fickle who change every moment, the perverse who aim only at what
is placed out of their reach, the obstinate who pursue a losing cause,
the idle and vicious who ruin themselves and every one connected
with them, do it as often with their eyes open as from blind
infatuation; and it is the bias of their wills, not the deficiency of their
understandings, that is in fault. The greatest fools in practice are
sometimes the wisest men in theory, for they have all the advantage
of their own experience and self-reflection to prompt them; and they
can give the best advice to others, though they do not conceive
themselves bound to follow it in their own instance. Video meliora
proboque, etc. Their judgments may be clear and just, but their
habits and affections lie all the wrong way; and it is as useless as it
would be cruel to expect them to reform, since they only delight and
can only exist in their darling absurdities and daily and hourly
escapades from common sense and reason.
 THE SPIRIT OF CONTROVERSY

The Atlas.]
[January 31, 1830.

The Spirit of Controversy has often been arraigned as the source of

much bitterness and vexation, as productive of ‘envy, malice, and all
uncharitableness’: and the charge, no doubt, is too well founded. But
it is said to be an ill wind that blows nobody good; and there are few
evils in life that have not some qualifying circumstance attending
them. It is one of the worst consequences of this very spirit of
controversy that it has led men to regard things too much in a single
and exaggerated point of view. Truth is not one thing, but has many
aspects and many shades of difference; it is neither all black nor all
white; sees something wrong on its own side, something right in
others; makes concessions to an adversary, allowances for human
frailty, and is nearer akin to charity than the dealers in controversy
or the declaimers against it are apt to imagine. The bigot and
partisan (influenced by the very spirit he finds fault with) sees
nothing in the endless disputes which have tormented and occupied
men’s thoughts but an abuse of learning and a waste of time: the
philosopher may still find an excuse for so bad and idle a practice.
One frequent objection made to the incessant wrangling and collision
of sects and parties is, What does it all come to? And the answer is,
What would they have done without it? The pleasure of the chase, or
the benefit derived from it, is not to be estimated by the value of the
game after it is caught, so much as by the difficulty of starting it and
the exercise afforded to the body and the excitement of the animal
spirits in hunting it down: and so it is in the exercises of the mind
and the pursuit of truth, which are chiefly valuable (perhaps) less for
their results when discovered, than for their affording continual
scope and employment to the mind in its endeavours to reach the
fancied goal, without its being ever (or but seldom) able to attain it.
Regard the end, is an ancient saying, and a good one, if it does not
mean that we are to forget the beginning and the middle. By
insisting on the ultimate value of things when all is over, we may
acquire the character of grave men, but not of wise ones. Passe pour
cela. If we would set up such a sort of fixed and final standard of
moral truth and worth, we had better try to construct life over again,
so as to make it a punctum stans, and not a thing in progress; for as
it is, every end, before it can be realised, implies a previous
imagination, a warm interest in, and an active pursuit of, itself, all
which are integral and vital parts of human existence, and it is a
begging of the question to say that an end is only of value in itself,
and not as it draws out the living resources, and satisfies the original
capacities of human nature. When the play is over, the curtain drops,
and we see nothing but a green cloth; but before this, there have
been five acts of brilliant scenery and high-wrought declamation,
which, if we come to plain matter-of-fact and history, are still
something. According to the contrary theory, nothing is real but a
blank. This flatters the paradoxical pride of man, whose motto is, all
or none. Look at that pile of school divinity! Behold where the demon
of controversy lies buried! The huge tomes are mouldy and worm-
eaten:—did their contents the less eat into the brain, or corrode the
heart, or stir the thoughts, or fill up the void of lassitude and ennui in
the minds of those who wrote them? Though now laid aside and
forgotten, if they had not once had a host of readers, they would
never have been written; and their hard and solid bulk asked the
eager tooth of curiosity and zeal to pierce through it. We laugh to see
their ponderous dulness weighed in scales, and sold for waste paper.
We should not laugh too soon. On the smallest difference of faith or
practice discussed in them, the fate of kingdoms hung suspended;
and not merely so (which was a trifle) but Heaven and Hell trembled
in the balance, according to the full persuasion of our pious
forefathers. Many a drop of blood flowed in the field or on the
scaffold, from these tangled briars and thorns of controversy; many a
man marched to a stake to bear testimony to the most frivolous and
incomprehensible of their dogmas. This was an untoward
consequence; but if it was an evil to be burnt at a stake, it was well
and becoming to have an opinion (whether right or wrong) for which
a man was willing to be burnt at a stake. Read Baxter’s Controversial
Works: consider the flames of zeal, the tongues of fire, the heights of
faith, the depths of subtlety, which they unfold, as in a darkly
illuminated scroll; and then ask how much we are gainers by an utter
contempt and indifference to all this? We wonder at the numberless
volumes of sermons that have been written, preached, and printed
on the Arian and Socinian controversies, on Calvinism and
Arminianism, on surplices and stoles, on infant or adult baptism, on
image-worship and the defacing of images; and we forget that it
employed the preacher all the week to prepare his sermon (be the
subject what it would) for the next Lord’s day, with infinite collating
of texts, authorities, and arguments; that his flock were no less
edified by listening to it on the following Sunday; and how many
David Deans’s came away convinced that they had been listening to
the ‘root of the matter’! See that group collected after service-time
and pouring over the gravestones in the churchyard, from whence, to
the eye of faith, a light issues that points to the skies! See them
disperse; and as they take different paths homeward while the
evening closes in, still discoursing of the true doctrine and the glad
tidings they have heard, how ‘their hearts burn within them by the
way’! Then again, we should set down, among other items in the
account, how the schoolboy is put to it to remember the text, and
how the lazy servant-wench starts up to find herself asleep in church-
time! Such is the business of human life; and we, who fancy
ourselves above it, are only so much the more taken up with follies of
our own. We look down in this age of reason on those controverted
points and nominal distinctions which formerly kept up such ‘a coil
and pudder’ in the world, as idle and ridiculous, because we are not
parties to them; but if it was the egotism of our predecessors that
magnified them beyond all rational bounds, it is no less egotism in us
who undervalue their opinions and pursuits because they are not
ours; and, indeed, to leave egotism out of human nature, is ‘to leave
the part of Hamlet out of the play of Hamlet.’ Or what are we the
better with our Utilitarian Controversies, Mr. Taylor’s discourses
(delivered in canonicals) against the evidence of the Christian
religion, or the changes of ministry and disagreements between the
Duke of Wellington and the Duke of Newcastle?
‘Strange! that such difference should be
 ’Twixt Tweedledum and Tweedledee!’

But the prevalence of religious controversy is reproached with

fomenting spiritual pride and intolerance, and sowing heart-
burnings, jealousies, and fears, ‘like a thick scurf o’er life;’ yet, had it
not been for this, we should have been tearing one another to pieces
like savages for fragments of raw flesh, or quarrelling with a herd of
swine for a windfall of acorns under an oak-tree. The world has never
yet done, and will never be able to do, without some apple of discord
—some bone of contention—any more than courts of law can do
without pleadings, or hospitals without the sick. When a thing ceases
to be a subject of controversy, it ceases to be a subject of interest.
Why need we regret the various hardships and persecutions for
conscience-sake, when men only clung closer to their opinions in
consequence? They loved their religion in proportion as they paid
dear for it. Nothing could keep the Dissenters from going to a
conventicle while it was declared an unlawful assembly, and was the
highroad to a prison or the plantations—take away tests and fines,
and make the road open and easy, and the sect dwindles gradually
into insignificance. A thing is supposed to be worth nothing that
costs nothing. Besides, there is always pretty nearly the same
quantity of malice afloat in the world; though with the change of time
and manners it may become a finer poison, and kill by more unseen
ways. When the sword has done its worst, slander, ‘whose edge is
sharper than the sword,’ steps in to keep the blood from stagnating.
Instead of slow fires and paper caps fastened round the heads of the
victims, we arrive at the same end by a politer way of nicknames and
anonymous criticism. Blackwood’s Magazine is the modern version
of Fox’s Book of Martyrs. Discard religion and politics (the two
grand topics of controversy), and people would hate each other as
cordially, and torment each other as effectually about the preference
to be given to Mozart or Rossini, to Malibran or Pasta. We indeed fix
upon the most excellent things, as God, our country, and our King, to
account for the excess of our zeal; but this depends much less upon
the goodness of our cause than on the strength of our passions, and
our overflowing gall and rooted antipathy to whatever stands in the
way of our conceit and obstinacy. We set up an idol (as we set up a
mark to shoot at) for others to bow down to, on peril of our utmost
displeasure, let the value of it be what it may——
 ‘Of whatsoe’er descent his Godhead be,
Stock, stone, or other homely pedigree,
In his defence his servants are as bold
As if he had been born of beaten gold.’

It is, however, but fair to add, in extenuation of the evils of

controversy, that if the points at issue had been quite clear, or the
advantage all on one side, they would not have been so liable to be
contested about. We condemn controversy, because we would have
matters all our own way, and think that ours is the only side that has
a title to be heard. We imagine that there is but one view of a subject
that is right; and that all the rest being plainly and wilfully wrong, it
is a shocking waste of speech, and a dreadful proof of prejudice and
party spirit, to have a word to say in their defence. But this is a want
of liberality and comprehension of mind. For in general we dispute
either about things respecting which we are a good deal in the dark,
and where both parties are very possibly in the wrong, and may be
left to find out their mutual error; or about those points, where there
is an opposition of interests and passions, and where it would be by
no means safe to cut short the debate by making one party judges for
the other. They must, therefore, be left to fight it out as well as they
can; and, between the extremes of folly and violence, to strike a
balance of common sense and even-handed justice. Every sect or
party will, of course, run into extravagance and partiality; but the
probability is, that there is some ground of argument, some
appearance of right, to justify the grossest bigotry and intolerance.
The fury of the combatants is excited because there is something to
be said on the other side of the question. If men were as infallible as
they suppose themselves, they would not dispute. If every novelty
were well founded, truth might be discovered by a receipt; but as
antiquity does not always turn out an old woman, this accounts for
the vis inertiæ of the mind in so often pausing and setting its face
against innovation. Authority has some advantages to recommend it
as well as reason, or it would long ago have been scouted. Aristocracy
and democracy, monarchy and republicanism, are not all pure good
or pure evil, though the abettors or antagonists of each think so, and
that all the mischief arises from others entertaining any doubt about
the question, and insisting on carrying their absurd theories into
practice. The French and English are grossly prejudiced against each
other; but still the interests of each are better taken care of under this
exaggerated notion than if that vast mass of rights and pretensions,
which each is struggling for, were left to the tender mercies and
ruthless candour of the other side. ‘Every man for himself and God
for us all’ is a rule that will apply here. Controversy, therefore, is a
necessary evil or good (call it which you will) till all differences of
opinion or interest are reconciled, and absolute certainty or perfect
indifference alike takes away the possibility or the temptation to
litigation and quarrels. We need be under no immediate alarm of
coming to such a conclusion. There is always room for doubt, food
for contention. While we are engrossed with one controversy, indeed,
we think every thing else is clear; but as soon as one point is settled,
we begin to cavil and start objections to that which has before been
taken for gospel. The Reformers thought only of opposing the
Church of Rome, and never once anticipated the schisms and
animosities which arose among Protestants: the Dissenters, in
carrying their point against the Church of England, did not dream of
that crop of infidelity and scepticism which, to their great horror and
scandal, sprung up in the following age, from their claim of free
inquiry and private judgment. The non-essentials of religion first
came into dispute; then the essentials. Our own opinion, we fancy, is
founded on a rock; the rest we regard as stubble. But no sooner is
one out-work of established faith or practice demolished, than
another is left a defenceless mark for the enemy, and the engines of
wit and sophistry immediately begin to batter it. Thus we proceed
step by step, till, passing through the several gradations of vanity and
paradox, we came to doubt whether we stand on our head or our
heels, alternately deny the existence of spirit and matter, maintain
that black is white, call evil good and good evil, and defy any one to
prove the contrary. As faith is the prop and cement that upholds
society by opposing fixed principles as a barrier against the inroads
of passion, so reason is the menstruum which dissolves it by leaving
nothing sufficiently firm or unquestioned in our opinions to
withstand the current and bias of inclination. Hence the decay and
ruin of states—then barbarism, sloth, and ignorance—and so we
commence the circle again of building up all that it is possible to
conceive out of a rude chaos, and the obscure shadowings of things,
and then pulling down all that we have built up, till not a trace of it is
left. Such is the effect of the ebb and flow and restless agitation of the
human mind.
 ENVY

The Atlas.]
[February 14, 1830.

Envy is the grudging or receiving pain from any accomplishment

or advantage possessed by another. It is one of the most tormenting
and odious of the passions, inasmuch as it does not consist in the
enjoyment or pursuit of any good to ourselves, but in the hatred and
jealousy of the good fortune of others and the debarring and
defrauding them of their due and what is of no use to us, on the dog
in the manger principle; and it is at the same time as mean as it is
revolting, as being accompanied with a sense of weakness and a
desire to conceal and tamper with the truth and its own convictions,
out of paltry spite and vanity. It is, however, but an excess or
excrescence of the other passions (such as pride or avarice) or of a
wish to monopolise all the good things of life to ourselves, which
makes us impatient and dissatisfied at seeing any one else in
possession of that to which we think we have the only fair title. Envy
is the deformed and distorted offspring of egotism; and when we
reflect on the strange and disproportioned character of the parent,
we cannot wonder at the perversity and waywardness of the child.
Such is the absorbing and exorbitant quality of our self-love, that it
represents us as of infinitely more importance in our own eyes than
the whole universe put together, and would sacrifice the claims and
interest of all the world beside to the least of its caprices or
extravagances; need we be surprised then that this little, upstart,
overweening self, that would trample on the globe itself and then
weep for new ones to conquer, should be uneasy, mad, mortified,
eaten up with chagrin and melancholy, and hardly able to bear its
own existence, at seeing a single competitor among the crowd cross
its path, jostle its pretensions, and stagger its opinion of its exclusive
right to admiration and superiority? This it is that constitutes the
offence, that gives the shock, that inflicts the wound, that some poor
creature (as we would fain suppose) whom we had before overlooked
and entirely disregarded as not worth our notice, should of a sudden
enter the lists and challenge comparison with us. The presumption is
excessive; and so is our thirst of revenge. From the moment,
however, that the eye fixes on another as the object of envy, we
cannot take it off; for our pride and self-conceit magnify that which
obstructs our success and lessens our self-importance into a
monster; we see nothing else, we hear of nothing else, we dream of
nothing else, it haunts us and takes possession of our whole souls;
and as we are engrossed by it ourselves, so we fancy that all the rest
of the world are equally taken up with our petty annoyances and
disappointed pride. Hence the ‘jealous leer malign’ of envy, which,
not daring to look that which provokes it in the face, cannot yet keep
its eyes from it, and gloats over and becomes as it were enamoured of
the very object of its loathing and deadly hate. We pay off the score
which our littleness and vanity has been running up, by ample and
gratuitous concessions to the first person that gives a check to our
swelling self-complacency, and forces us to drag him into an
unwilling comparison with ourselves. It is no matter who the person
is, what his pretensions—if they are a counterpoise to our own, we
think them of more consequence than anything else in the world.
This often gives rise to laughable results. We see the jealousies
among servants, hackney-coachmen, cobblers in a stall; we are
amused with the rival advertisements of quacks and stage-coach
proprietors, and smile to read the significant intimation on some
shop window, ‘No connection with the next door;’ but the same folly
runs through the whole of life; each person thinks that he who stands
in his way or outstrips him in a particular pursuit, is the most
enviable, and at the same time the most hateful character in the
world. Nothing can show the absurdity of the passion of envy in a
more striking point of view than the number of rival claims which it
entirely overlooks, while it would arrogate all excellence to itself. The
loftiness of our ambition and the narrowness of our views are equal,
and indeed both depend upon the same cause. The player envies only
the player, the poet envies only the poet, because each confines his
idea of excellence to his own profession and pursuit, and thinks, if he
could but remove some hapless competitor out of his way, he should
have a clear stage to himself, or be a ‘Phœnix gazed by all:’ as if,
though we crushed one rival, another would not start up; or as if
there were not a thousand other claims, a thousand other modes of
excellence and praiseworthy acquirements, to divide the palm and
defeat his idle pretension to the sole and unqualified admiration of
mankind. Professors of every class see merit only in their own line;
yet they would blight and destroy that little bit of excellence which
alone they acknowledge to exist, except as it centres in themselves.
Speak in praise of an actor to another actor, and he turns away with
impatience and disgust: speak disparagingly of the first as an actor in
general, and the latter eagerly takes up the quarrel as his own: thus
the esprit de corps only comes in as an appendage to our self-love. It
is perhaps well that we are so blind to merit out of our immediate
sphere, for it might only prove an additional eye-sore, increase the
obliquity of our mental vision, multiply our antipathies, or end in
total indifference and despair. There is nothing so bad as a cynical
apathy and contempt for every art and science from a superficial
smattering and general acquaintance with them all. The merest
pedantry and the most tormenting jealousy and heart-burnings of
envy are better than this. Those who are masters of different
advantages and accomplishments, are seldom the more satisfied with
them: they still aim at something else (however contemptible) which
they have not or cannot do. So Pope says of Wharton—
‘Though wondering senates hung on all he spoke,
The club must hail him master of the joke.
Shall parts so various aim at nothing new?
He’ll shine a Tully and a Wilmot too.’

The world, indeed, are pretty even with these constellations of

splendid and superfluous qualities in their fastidious estimate of
their own pretensions, for (if possible) they never give any individual
credit for more than one leading attainment. If a man is an artist, his
being a fine musician adds nothing to his fame. When the public
strain a point to own one claim, it is on condition that the fortunate
candidate waives every other. The mind is prepared with a plausible
antithesis in such cases against the formidable encroachments of
vanity: one qualification is regularly made a foil to another. We allow
no one to be two things at a time: it quite unsettles our notions of