ISAM - The International Society for Aerosols in Medicine
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The textbook provides comprehensive coverage of a broad range of topics related to aerosol science and clinical applications of aerosol therapy. The textbook has been written by content experts, and provides concise and up-to-date information
on various topics of interest to aerosol scientists and clinicians. The textbook is provided as PDF download (free for ISAM Members) and non members can buy the articles (follow the link below).
Section I
Chapter 1 - Aerosol Medicine in the Past 50 Years and the Role of ISAM
Chapter 2 - Deposition of Aerosols in the Lungs
Chapter 3 - In vitro Testing of Pharmaceutical Aerosols and In Vitro/In Vivo Correlations
Chapter 4 - Imaging Aerosol Deposition and Mucociliary Clearance
Chapter 5 - Pharmacokinetics and Pharmacodynamics of Inhaled Drugs
Section II
Chapter 6 - Drug Delivery Devices (pMDI, DPI, Nebulizers, New Generation Nebulizers)
Chapter 7 - Formulations
Chapter 8 - Inhaled Nanoparticles.
Section III
Chapter 9 - Clinical Application of Aerosols in Ambulatory Patients
Chapter 10 - Clinical Application of Aerosols in Hospitalized Patients
Chapter 11 - Aerosol Therapy in Infants and Children
Chapter 12 - Adherence to Aerosol Therapy
Section IV
Chapter 13 - Inhaled Biotherapeutics and Systemic Therapy
Chapter 14 - Limitations of Pulmonary Drug Delivery
Chapter 15 - Regulatory Issues for Aerosol Therapy.
The textbook provides comprehensive coverage of a broad range of topics related to aerosol science and clinical applications of aerosol therapy. Dr. Rajiv Dhand, MD, the Editor-in-Chief, has been ably supported by 8 associate editors
who are well known authorities in their respective fields. To allow crossover of readership between aerosol scientists and clinicians the book is primarily targeted to clinicians entering a Pulmonary fellowship program and
graduate students starting a research career.
he ISAM Textbook of Aerosol Medicine is an electronic book divided into four sections:
Section 1 deals with aerosol deposition imaging, clearance, and assessment of inhaled products
Section 2 with aerosol devices, formulations, and particulates
Section 3 with clinical applications of aerosol therapy and adherence to inhaled drugs,
Section 4 addresses inhaled biotherapeutics, systemic therapy, limitations of aerosol therapy, regulatory issues with inhaled drugs, and nasal delivery of drugs
Editor
Editor-in-Chief: Dr. Rajiv Dhand, MD, Professor of Medicine (with tenure), Chairman of the Department of Medicine and Associate Dean of Clinical Affairs at the University of Tennessee, Graduate School of Medicine in Knoxville,
Tennessee
ISAM Textbook Chapters
Chapter 1 - Aerosol Medicine in the Past 50 Years and the Role of ISAM
Michael Newhouse, Helger Hauck, and Heinrich Matthys
When Rajiv Dhand, Editor-in-Chief of this Aerosol E-book, asked me to write a history of ISAM and the initial decades of modern aerosol therapy, I felt somewhat daunted by his request, considering the many colleagues that, with their
ideas and the advent of advanced physiological concepts and equipment, had initiated and developed aerosol medicine as a scientific discipline in the “neonatal” years of our sub-sub specialty starting in the 1950s. Many colleagues
started their aerosol research units virtually from scratch, each with their own story of how they were attracted to aerosol research and how they were able to raise the necessary funds from private donors, government grants and
industry. Of course, none of this occurred in a vacuum, and as Newton stated so artfully, we too “stood on the shoulders of giants” as we were trained to ask questions at the bedside and seek answers in the lab for the benefit
of our patients.
Abstract The distribution of particles sizes within an aerosol is essential information for understanding the behavior of that aerosol. The number of particles within certain size ranges is given by distributions specified by a count
distribution if referring to numbers of particles, or a mass distribution if referring to particle mass. The cumulative number, or mass, of particles less than a certain diameter is determined by integrating the relevant distribution,
which allows definition of median diameters. The mass median diameter (MMD) is a commonly specified diameter. For log-normal distributions, the spread of the distribution is given by the geometric standard deviation. While particle
size distributions of actual aerosols are discrete by nature, the use of continuous functions to describe them is a useful conceptual tool.
The success of inhalation therapy is not only dependent upon the pharmacology of the drugs being inhaled but also upon the site and extent of deposition in the respiratory tract. Similarly, the toxicity of environmental and industrial
particulate matter is affected not only by the nature of the dust but also by the amount and spatial distribution of deposited particles in the lung. Aerosol deposition is primarily governed by the mechanisms of inertial impaction,
gravitational sedimentation, Brownian diffusion, and to a lesser extent, by turbulence, electrostatic precipitation and interception. The relative contribution of these different mechanisms is a function of the physical characteristics
of the particles, the lung structure and the flow patterns. Large particles (> 5 μm) tend to deposit mainly in the upper and large airways, limiting the amount of aerosols that can be delivered to the lung.
Chapter 2.3 - Regional Lung Deposition: In vivo Data
Sabine Häußermann, PhD, Knut Sommerer, and Gerhard Scheuch, PhD
The method section of this chapter on in vivo regional lung deposition highlights a nonradioactive method to measure regional deposition, which uses a photometer to quantify inhaled and exhaled particles and in that way is able to
estimate the lung region from which the particles are exhaled and to what amount. The radioactive methods cover the measurement of clearance of the deposited particles as well as different imaging techniques to determine regional
deposition. The result section reviews in vivo trials in human subjects. It also addresses different parameters that influence the regional deposition in the lungs: particle size, inhalation maneuver, carrier gas, disease, and
inhalation device. All of these factors can affect regional deposition significantly.
Modeling particle deposition in the human lung requires information about the morphology of the lung in terms of simple geometric units, e.g. characterizing bronchial airways by straight cylindrical tubes. Five different regional deposition
models are discussed in this section with respect to morphometric lung models and related mathematical modeling techniques: 1) one- dimensional cross-section or “trumpet” model, 2) deterministic symmetric generation or “single-
path” model, 3) deterministic asymmetric generation or “multiple-path” model, 4) stochastic asymmetric generation or “multiple-path” model, and 5) single-path computational fluid and particle dynamics (CFPD) model.
Patterns of regional aerosol deposition within the lungs are known to vary in a predictable manner with a number of factors, most notably aerodynamic particle size and inhalation pattern. Targeting deposition involves the intentional
manipulation of one or more of these factors to promote aerosol deposition in certain locations within the respiratory tract. This section will begin by exploring existing evidence supporting the need to target regional deposition.
Thereafter, various approaches to targeting will be introduced. In addition to control of aerodynamic particle size and inhalation pattern, a collection of approaches are available through which to passively target deposition to
more central or peripheral lung regions.
Of the various particle properties that affect deposition in the respiratory tract, particle diameter and particle density are the most commonly considered, since their effect on deposition is well known and important, as has been
discussed earlier in this chapter. However, there are several other particle properties that can affect particle deposition in the lungs. These include: 1) electrostatic charge on the particle, which can cause electrostatic forces
to enhance deposition; 2) the shape of the particle, which can cause its trajectory to differ from that of a spherical particle and thereby alter its deposition; and 3) volatility of the particle i.e. its ability to condense or
evaporate at its surface, which can change its diameter and in turn affect its deposition. In this section, we examine each of these three factors individually.
Chapter 2.7 - Additional Factors: Carrier Gases and Their Effects on Aerosol Drug Delivery
Tim Corcoran, PhD
Carrier gases provide the medium for delivery of inhaled aerosol therapies. The physical properties of these gases substantially affect both fluid and aerosol mechanics in the lung. Gas density affects both the pressure/flow relationship
in the airways and the extent of turbulence within the flow. These physical properties also affect the operation of some components of respiratory and aerosol drug delivery equipment. The lower resistance associated with breathing
low density gases has prompted many studies of therapeutic applications.
Ventilation and mechanics of breathing are an integral part of respiratory physiology that directly affect aerosol transport and deposition in the lung. Although natural breathing pattern varies widely among individuals, breathing
pattern is controllable, and by using an appropriate breathing pattern, aerosol deposition can be substantially modified for desired purposes. Effects of breathing pattern have been investigated under carefully controlled inhalation
conditions covering a wide range of tidal volumes (VT) and breathing frequencies (f) or respiratory times (T=1/f). The studies have shown that lung deposition can increase or decrease as much as two times by changing the breathing
pattern.
Chapter 2.9 - Effect of Respiratory Tract Disease on Particle Deposition
William D. Bennett, PhD
This chapter describes the effects that respiratory disease has on particle deposition in the lungs. The geometry of airways, breathing patterns, and regional ventilation are all affected by various lung diseases, including COPD, asthma,
and cystic fibrosis, and in turn modify total and regional deposition from normal. Total particle deposition in the lung is increased by airways obstruction and increased ventilation at rest compared to healthy individuals. Regional
particle deposition is 1) shifted from distal to more proximal bronchial airways by airway obstruction, and 2) becomes more heterogeneous due to uneven lung ventilation. The net effect of the changes in total and regional particle
deposition from normal is to greatly enhance bronchial airway surface doses for particle deposition while leaving unventilated lung regions inaccessible to the particles.
Particle size measurement of aerosolized particles from orally inhaled and nasal drug products (OINDPs) can be used to assess likely deposition distribution in the human respiratory tract (HRT). Size is normally expressed in terms
of aerodynamic diameter, since this scale directly relates to the mechanics of particle transport from inhaler to deposition locations. The multistage cascade impactor (CI) is the principal apparatus used to size-fractionate aerosols
in terms of their aerodynamic particle size distributions (APSDs). Clinically meaningful metrics, such as fine and coarse particle mass fractions, can be determined from the cumulative mass-weighted APSD.
Chapter 3.2 - Fine Particle Fraction: The Good and the Bad
Stephen P. Newman, PhD
Fine particle fraction (FPF) is defined in general terms as the fraction or percentage of the drug mass contained in an aerosol cloud that may be small enough to enter the lungs and exert a clinical effect. An aerodynamic diameter
of 5 μm represents the approximate border between “fine” and “coarse” particles, but there is no universally agreed upon definition of FPF in terms of an aerodynamic particle size range. FPF alone does not adequately describe a
heterodisperse aerodynamic particle size distribution, and it needs to be combined with another measure or measures indicating the width of the distribution. When determined using techniques specified in United States and European
Pharmacopeias, FPF is measured by cascade impactors that have straight-sided ninety degree inlets through which air is drawn at a constant rate.
Chapter 3.3 - Use of Airway Replicas in Lung Delivery Applications
Laleh Golshahi, PhD, Warren H. Finlay, PhD, and Herbert Wachtel, PhD
The use of extrathoracic airway replicas in optimization of drug delivery to the lungs with nebulizers, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs) is discussed. Such airway replicas have been useful in
evaluating new pulmonary drug delivery platforms mainly based on the comparison of the total lung dose (TLD) and the aerodynamic particle size distribution (APSD) of the aerosol distal to the physical models. The ability of these
in vitro methods to replicate in vivo results has allowed advancements in respiratory drug delivery and in the accuracy and utility of in vitro-in vivo correlations (IVIVCs).
Traditionally, empirical correlations for predicting respiratory tract deposition of inhaled aerosols have been developed using limited available in vivo data. More recently, advances in medical image segmentation and additive manufacturing
processes have allowed researchers to conduct extensive in vitro deposition experiments in realistic replicas of the upper and central branching airways. This work has led to a collection of empirical equations for predicting regional
aerosol deposition, especially in the upper, nasal and oral airways. The present section reviews empirical correlations based on both in vivo and in vitro data, which may be used to predict total and regional deposition.
In vivo measurements of the deposition of an inhaled radiolabeled pharmaceutic have provided useful information related to the inhaler efficiency for depositing drug in the lung. A number of labeling techniques have been developed
and applied to pharmaceutical aerosols delivered by pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers; the choice of radiotracer depends on the type of imaging study being performed and the equipment
used to image the lung. Preparation, validation and calibration of the radiolabeled pharmaceutical product is key to successful interpretation of the imaging study.
Chapter 4.2 - Design of in vivo Deposition and Clearance Experiments
William D. Bennett, PhD
Experiments designed to image in vivo deposition of radiolabel-drug mixtures are useful for estimating inhaled drug delivery and for assessing bioequivalence of delivery devices. Validation of the radiolabel-drug mixture is vital to
ensure that subsequent imaging is reflective of drug deposition. Application of gamma attenuation corrections allows both total and regional lung deposition of drug to be estimated by two-dimensional (2D) imaging. Imaging methods
are also useful for measuring in vivo mucociliary clearance (MC) function. Such measures allow assessment of the efficacy of drugs designed to improve clearance of airway secretions in airway disease. MC rates can be measured by
controlled inhalation and gamma camera monitoring of radiolabeled aerosols containing non-permeating tracers.
Several imaging modalities have been employed to quantify lung dose and the distribution of the dose of orally inhaled aerosols in vivo. Two-dimensional (2D, or planar) imaging using gamma scintigraphy is the most widely used of these
modalities. Two-dimensional gamma scintigraphy studies are accomplished using a single- or dual-headed gamma camera. The formulation to be tested is admixed with the gamma emitting radioisotope 99mtechnetium, which serves as a
surrogate for the drug. This article provides details as to how 2D gamma scintigraphy images should be acquired and analyzed using recently standardized methods.
Chapter 4.4 - Single Photon Emission Computed Tomography (SPECT)
John S. Fleming, PhD
Imaging of radiolabeled aerosols provides useful in vivo data on both the initial site of deposition and its subsequent transport by mucociliary clearance and epithelial permeability. Single Photon Emission Computed Tomography (SPECT)
uses a gamma camera with multiple rotating heads to produce three-dimensional (3D) images of inhaled radioaerosol labeled with technetium-99m. This enables total lung deposition and its 3D regional distribution to be quantified.
Aligned 3D images of lung structure allow deposition data to be related to lung anatomy. Mucociliary clearance or epithelial permeability can be assessed from a time series of SPECT aerosol images. SPECT is slightly superior to
planar imaging for measuring total lung deposition.
Chapter 4.5 - Measuring Anatomical Distributions of Ventilation and Aerosol Deposition with ET-CT
Jose G. Venegas, PhD
heterogeneity is relevant to aerosol medicine and for quantifying mucociliary clearance from different parts of the lung. In this chapter, we describe positron emission tomography (PET) imaging methods to quantitatively assess the
deposition of aerosol and ventilation distribution within the lung. The anatomical information from computed tomography (CT) combined with the PET- deposition data allows estimates of airway surface concentration and peripheral
tissue dosing in bronchoconstricted asthmatic subjects.
Inhalation is currently used as the preferred method of administering drugs for airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). The principal such agents are beta2-adrenergic agents, antimuscarinic
agents and corticosteroids. Antimicrobial agents are also used for well-circumscribed disorders such as cystic fibrosis and viral pneumonias. However, the advantages of administering agents by this route have led to its use for
other agents such as nicotine and insulin. The inhalational route is being explored for other agents as an alternative to other means of delivering agents to the body.
Chapter 5.2 - The Pharmacokinetics of Inhaled Drugs
Glyn Taylor, BSc, PhD
The pharmacokinetic (PK) profile of a drug after inhalation may differ quite markedly from that seen after dosing by other routes of administration. Drugs may be administered to the lung to elicit a local action or as a portal for
systemic delivery of the drug to its site of action elsewhere in the body. Some knowledge of PK is important for both locally- and systemically-acting drugs. For a systemically-acting drug, the plasma concentration-time profile
shares some similarities with drug given by the oral or intravenous routes, since the plasma concentrations (after the distribution phase) will be in equilibrium with concentrations at the site of action. For a locally-acting drug,
however, the plasma concentrations reflect its fate after it has been absorbed and removed from the airways, and not what is available to its site of action in the lung.
Pharmacodynamics (PD) is discussed in relation to inhalation exposure to inhaled pharmaceutical and toxic agents. Clearly PD is closely related to pharmacokinetics, and this relation is illustrated with reference to inhaled insulin.
PD can be related to pharmacologic responses, and some examples are cited. However, PD can also be thought of as the improvement or deterioration in lung disease state. Some of the major PD endpoints, including histopathology,
pulmonary function, and bronchoalveolar lavage are reviewed. Brief reference is also given to other specialty biomarkers of PD response.
Pressurized metered dose inhalers (pMDIs) have been the most widely used devices for the maintenance therapy of asthma and chronic obstructive pulmonary disease (COPD) for several decades. The pMDI spray is self-powered by propellants
held under pressure in the canister, and a metering valve ensures the delivery of a precise dose on each actuation. The pMDI has many practical advantages, being compact, convenient, portable and multi-dose, but it may give a highly
variable lung dose when used by patients, many of whom cannot use the device correctly. Failure to actuate the pMDI while breathing in slowly and deeply has been identified as the most important error in pMDI technique.
Spacers, primarily valved holding chambers (VHCs), are widely used to overcome some of the problems associated with the use of pressurized metered-dose inhalers (pMDIs). These include the difficulty experienced by patients in trying
to coordinate the initiation of inhalation with the actuation of the pMDI. High oropharyngeal deposition of drug, which may result in both local and systemic side effects, is also a problem. Although the variability in output from
pMDIs under optimized conditions in the laboratory is low, the variability when used in clinical practice is likely to increase considerably. Hence, the dose introduced into a holding chamber may vary significantly depending on
the way in which the pMDI canister is handled before it is actuated. Several studies have shown that various design factors can influence the dose delivered from a holding chamber.
Dry powder inhaler products have played an important role in the treatment and prevention of asthma and more recently chronic obstructive pulmonary disease. The considerations that go into formulation development to support these products
cover a unique range of disciplines including analytical and physical chemistry, aerosol physics, device technology, process engineering and industrial design. An enormous research effort has been expended in the last half century
to provide understanding of this complex dosage form. The guiding principles in considering the development of dry powder inhaler products encompass requirements for disease therapy, advantages and limitations of adopting certain
technological approaches, and desirable features to facilitate patient use, which are all embodied in the target product profile.
Chapter 6.4 - Dry Powder Inhalers—From Bench to Bedside
Henry Chrystyn, BPharm, MSc, PhD, FRPHarmS, FHEA, Wahida Azouz, BSc, PhD, and Walid Tarsin, BSc, PhD
Dry powder inhalers (DPIs) are now widely prescribed and preferred by the majority of patients. These devices have many advantages over the traditional pressurized metered-dose inhaler (pMDI) but they do have disadvantages. The characteristics
of the dose emitted from a DPI are affected by the inhalation maneuvre used by a patient. Each patient is different and the severity of their lung disease varies from mild to very severe. This affects how they use an inhaler and
so determines the type of dose they inhale. An understanding of the pharmaceutical science related to DPIs is important to appreciate the relevance of how patients inhale through these devices.
James B. Fink, RRT, PhD and Kevin W. Stapleton, PhD
inhalers and are used with a broad range of liquid formulations. When the same drug is available in liquid or inhaler form, nebulizers are applicable for use with patients who will not or cannot reliably use a pressurized metered-dosed
inhaler (pMDI) or dry powder inhaler (DPI) due to poor lung function, hand-breath coordination, cognitive abilities (e.g. infants, elderly) or device preference. In a nebulizer, liquid medication is placed in a reservoir and fed
to an aerosol generator to produce the droplets. A series of tubes and channels direct the aerosol to the patient via an interface such as mouthpiece, mask, tent, nasal prongs or artificial airway.
Standard nebulizers are intended for general purpose use and typically are continuously operated jet or ultrasonic nebulizers. Evolutionary developments such as breath-enhanced and breath- triggered devices have improved delivery efficiency
and ease of use, yet are still suitable for delivery of nebulized medications approved in this category. However, recent developments of vibrating membrane or mesh nebulizers have given rise to a significant increase in delivery
efficiency requiring reformulation of former drug products or development of new formulations to match the enhanced delivery characteristics of these new devices. In addition, the electronic nature of the new devices enables tailoring
to specific applications and patient groups, such as guiding or facilitating optimal breathing and improving adherence to the therapeutic regimen.
Hugh Smyth, PhD, Daniel Moraga-Espinoza, BPharm, Tania Bahamondez-Canas, BPharm, Matthew Herpin, BS, Andy Maloney, PhD, Ashkan Yazdi, PharmD, Ping Du, PhD, and Ju Du, PhD
The unique properties and characteristics of pressurized metered-dose inhaler (pMDI) formulations stem from the physicochemical properties of the hydrofluoroalkane (HFA) propellants. The limited number of excipients used in marketed
pMDIs products adds to the complexity of development. In addition to the challenges for formulators, these systems require specialized analytical chemists, regulatory scientists, and pMDI manufacturing expertise. These challenges
highlight the importance of understanding HFA formulations across multiple disciplines. Thus, influence of formulation variables must be appreciated for both formulation design and understanding product performance.
This section aims to provide a concise and contemporary technical perspective and reference resource covering dry powder inhaler (DPI) formulations. While DPI products are currently the leading inhaled products in terms of sales value,
a number of confounding perspectives are presented to illustrate why they are considered surprisingly, and often frustratingly, poorly understood on a fundamental scientific level, and most challenging to design from first principles.
At the core of this issue is the immense complexity of fine cohesive powder systems. This review emphasizes that the difficulty of successful DPI product development should not be underestimated and is best achieved with a well-coordinated
team who respect the challenges and who work in parallel on device and formulation and with an appreciation of the handling environment faced by the patient.
Hui Xin Ong, PhD, Daniela Traini, PhD, and Paul M. Young, PhD
Inhalation of liposomes formulated with phospholipids similar to endogenous lung surfactants and lipids offers biocompatibility and versatility within the pulmonary medicine field to treat a range of diseases such as lung cancer, cystic
fibrosis and lung infections. Manipulation of the physicochemical properties of liposomes enables innovative design of the carrier to meet specific delivery, release and targeting requirements. This delivery system offers several
benefits: improved pharmacokinetics with reduced toxicity, enhanced therapeutic efficacy, increased delivery of poorly soluble drugs, taste masking, biopharmaceutics degradation protection and targeted cellular therapy. This section
provides an overview of liposomal formulation and delivery, together with their applications for different disease states in the lung.
Chapter 8.1 - Overview of Inhaled Nanopharmaceuticals
Sarah Barthold, MSc, Nicole Kunschke, MSc, Xabier Murgia, PhD, Brigitta Loretz, PhD, Cristiane de Souza Carvalho-Wodarz, PhD, and Claus-Michael Lehr, PhD
Nanopharmaceuticals represent a group of nanoparticles engineered for medical purposes. Nowadays, nanotechnology offers several possibilities to improve the safety and efficacy of medicines by designing advanced carrier systems which
have been found to offer particular advantages when formulated in the nanoscale. Some of the initially marketed nano-formulations already demonstrate advantages over conventional formulations. Innovative delivery systems offer
the possibility to not only control drug release but also to overcome biological barriers. For the translation of new drug products from bench to bedside, however, it is pivotal to test and prove their safety.
Chapter 8.2 - Inhaled Nanoparticulate Systems: Composition, Manufacture and Aerosol
Heidi M. Mansour, PhD, Priya Muralidharan, MS and Don Hayes, Jr., MD, MS, MEd
An increasing growth in nanotechnology is evident from the growing number of products approved in the past decade. Nanotechnology can be used in the effective treatment of several pulmonary diseases by developing therapies that are
delivered in a targeted manner to select lung regions based on the disease state. Acute or chronic pulmonary disorders can benefit from this type of therapy, including respiratory distress syndrome (RDS), chronic obstructive pulmonary
disease (COPD), asthma, pulmonary infections (e.g. tuberculosis, Yersinia pestis infection, fungal infections, bacterial infections, and viral infections), lung cancer, cystic fibrosis (CF), pulmonary fibrosis, and pulmonary arterial
hypertension.
Chapter 8.3 - Barriers that Inhaled Particles Encounter
Brijeshkumar Patel, PhD, Nilesh Gupta, PhD, and Fakhrul Ahsan, PhD
Inhalable particulate drug carriers—nano- and micro-particles, liposomes, and micelles—should be designed to promote drug deposition in the lung and engineered to exhibit the desired drug release property. To deposit at the desired
site of action, inhaled particles must evade various lines of lung defense, including mucociliary clearance, entrapment by mucus layer, and phagocytosis by alveolar macrophages. Various physiological, mechanical, and chemical barriers
of the respiratory system reduce particle residence time in the lungs, prevent particle deposition in the deep lung, remove drug-filled particles from the lung, and thus diminish the therapeutic efficacy of inhaled drugs.
Emilie Seydoux, PhD, Kleanthis Fytianos, PhD, Christophe von Garnier, MD, Barbara Rothen-Rutishauser, PhD, and Fabian Blank, PhD
The respiratory tract with its vast surface area and very thin air-blood tissue barrier presents an extremely large interface for potential interaction with xenobiotics such as inhaled pathogens or medicaments. To protect its large
and vulnerable surface, the lung is populated with several different types of immune cells. Pulmonary epithelial cells, macrophages and dendritic cells are key players in shaping the innate and adaptive immune response. Due to
their localization, they represent a frontline of cell populations that are among the first to come in contact with inhaled xenobiotics. Furthermore, depending on the lung compartment they populate, these cells show a large variety
in morphology, phenotype, and function.
Asthma is a chronic inflammatory disease of the airways characterised by reversible airflow obstruction. Current asthma guidelines encourage a “step-up” approach in pharmacological treatment to achieve disease control and a “step-down”
strategy when asthma is under control. In this strategy, inhaled drug therapy remains the foundation in managing patients with asthma. This chapter considers the pathophysiology and clinical assessment of patients with asthma,
the types of inhaler devices used for managing asthma, and the pharmacology of drugs used in treating asthmatic patients.
Ruben D. Restrepo, MD, RRT, FAARC and Andrew Tate, BS, RRT
Inhaled therapy is an important component of the management of patients with chronic obstructive pulmonary disease (COPD). Inhaled agents provide immediate relief of symptoms and aid in restoring the functional capacity of patients
with COPD. Current clinical guidelines are oriented to provide clinicians with a stepwise approach to treating the disease effectively. This manuscript will review the most current evidence regarding the use of inhaled therapy
in the treatment of COPD and summarize some of the emergent inhaled therapies.
Bronchiectasis is a lung disease characterized by irreversible dilatation and destruction of bronchi associated with recurrent infection and inflammation. It is seen in patients with cystic fibrosis (CF) but can also be caused by a
large number of non-CF disorders. Inhaled drugs are a mainstay of chronic therapy for patients with CF and are increasingly used in non-CF bronchiectasis. There is much less evidence, however, about the use of inhaled treatments
in non-CF bronchiectasis, and it cannot be assumed that a therapy effective in CF will also be effective in other types of bronchiectasis. Inhaled mucoactive drugs are used to both liquefy mucus and increase its volume so it can
be cleared from the airways during daily treatments. These include recombinant DNase, hypertonic (7%) saline and mannitol. All of these preparations are used in CF care, although inhaled mannitol has not been as widely approved
by regulatory agencies. Hypertonic saline is recommended for use in non-CF bronchiectasis, but DNase has been found to be harmful. Another growing class of inhaled drugs is that of inhaled antibiotics, primarily aimed at CF patients
who have sputum cultures showing Pseudomonas aeruginosa.
The first effective treatment for pulmonary hypertension was prostacyclin in continuous intravenous infusion, but its lack of pulmonary selectivity, its side effects, and infectious concerns made the inhaled route a viable alternative.
The first inhaled treatment was inhaled nitric oxide (INO), which had the advantage of being selective towards the pulmonary vascular bed but with a huge risk of rebound pulmonary hypertension when discontinued. Inhaled epoprostenol
had the same pulmonary vasodilator potency as intravenous prostacyclin, but it improved ventilation-perfusion matching. An abrupt withdrawal of inhaled epoprostenol caused rebound pulmonary vasoconstriction, and for that reason,
analogues of prostacyclin began to be used, namely, iloprost and treprostinil. INO, epoprostenol and iloprost have similar pulmonary effects but inhaled iloprost is more effective in reducing mean pulmonary arterial pressure (mPAP)and
pulmonary vascular resistance compared with INO. However, inhaled iloprost also produces more side effects. In children with pulmonary hypertension, inhaled iloprost induces a similar pulmonary vasodilator response to INO but with
adverse events such as acute bronchoconstriction.
Chapter 10.1 - Aerosol Therapy in the Emergency Department
Alexander G. Duarte, MD and Rajiv Dhand, MD
Asthma and chronic obstructive pulmonary disease are prevalent conditions associated with sudden, symptomatic decline in respiratory function requiring urgent treatment. Management of acute airflow obstruction includes frequent, thorough
assessments as well as timely administration of supplemental oxygen, corticosteroids and inhalational drug delivery of short- acting bronchodilators. The benefits of inhaled administration of aerosolized short-acting bronchodilators
include rapid symptom relief and improvements in lung function with fewer side effects. To optimize these benefits requires an understanding of the factors concerning aerosol delivery in the acute care setting that include patient
age, severity of airway obstruction, aerosol generating device and the patient and device interface. Treatment strategies have been developed that include increased dosing of short-acting bronchodilators, combined administration
of β-agonist and anticholinergic bronchodilators, continuous drug delivery and the use of helium to enhance lower respiratory tract drug deposition and improve patient outcomes.
Chapter 10.2 - Aerosol Therapy During Noninvasive Ventilation
Dean R. Hess, PhD, RRT
Noninvasive ventilation (NIV) is being used increasingly in patients with acute respiratory failure. The most commonly used interfaces for NIV are oronasal or nasal masks, but other interfaces are also used. Critical care ventilators,
bilevel ventilators designed specifically for NIV, and intermediate ventilators can be used. There are three options for aerosol delivery during NIV. The patient can be removed from NIV and the aerosol administered by nebulizer
or pressurized metered-dose inhaler (pMDI) in the usual manner, a nebulizer placed in-line, or a spacer chamber with metered-dose inhaler in-line. The available evidence suggests that a nebulizer or pMDI can administer a significant
amount of bronchodilator during NIV. The aerosol generator should be placed between the leak port and mask when bilevel ventilators are used. Although current evidence supports that aerosols can be effectively delivered with NIV,
there is not a mature evidence base to suggest that NIV administration of aerosols improves outcomes in patients with acute obstructive lung diseases such as asthma.
Chapter 10.3 - Aerosol Therapy in Mechanically Ventilated Patients
James B. Fink, PhD, RRT and Arzu Ari, PhD
Inhaled medications are an essential component of the treatment of ventilator-dependent patients with pulmonary disorders. However, effective aerosol delivery of drugs to mechanically ventilated patients poses substantial challenges
in critical pulmonary care. There are many issues with selection and use of aerosol devices in patients receiving ventilator support. This chapter reviews aerosol devices used during mechanical ventilation and explains implications
for aerosol administration in different artificial airways and modes of ventilation. Optimum techniques of aerosol administration with various devices and factors affecting aerosol delivery to ventilator- dependent patients are
also discussed.
Chapter 10.4 - Aerosolized Antibiotics for Ventilator–associated Infections
Lucy B. Palmer, MD
With the rapid rise in multi-drug resistant organisms in much of the world, effective treatment for ventilator-associated infections with current systemic antibiotics is increasingly challenging in critically ill patients. Aerosolized
antibiotics provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. This review summarizes current evidence describing the use of aerosolized
antimicrobial therapy for the treatment of bacterial ventilator-associated infections. Inhaled adjunctive therapy has been described in numerous small non-randomized studies and in four recent randomized placebo-controlled trials.
Aerosolized therapy has also been used to treat ventilator-associated tracheobronchitis. These preliminary data suggest aerosolized delivery of antimicrobials may effectively treat resistant pathogens with high minimum inhibitory
concentrations (MICs) when used in time limited protocols and delivered with devices known to deposit antibiotics in the area of infection. Large, multi-site, clinical, randomized placebo-controlled studies are needed to confirm
these data.
Chapter 11.1 - Indications for Aerosol Therapy in Children
André Schultz, PhD, and Peter Le Souëf, MD
Indications for aerosol therapy in children are increasing with robust evidence of benefit and low risk of side effects in an increasing range of conditions. Inhaled treatments offer targeted treatment to the airways with reduced risk
of systemic side effects. The ability to deliver high drug concentrations to the airways can be useful in specific situations. Numerous inhaled therapies have been well studied in children, but many inhaled treatments are still
used in pediatrics based on research findings from studies performed on adults. This chapter focuses on evidence for aerosol therapy from pediatric studies. Specific mention is made when data from adult studies are cited. Diseases
where aerosolized therapies have been well studied will be discussed, followed by conditions where inhaled drugs are used off-label, and novel applications for aerosolized drugs.
Sunalene Devadason, PhD and Mark L. Everard, MB, ChB, DMs
Delivering drugs to infants and children can be a significant challenge. The devices currently available have been developed primarily for adults and have been modified or adapted for young children. As with patients of all age groups,
drugs can have adverse side effects as well as therapeutic effects, and it is important to select devices and accessories that will maximize delivery to the lungs while minimizing extra-pulmonary deposition. Numerous factors influence
pulmonary drug delivery such as characteristics of the aerosol delivery system, use of the device by the patient, variations in airways geometry, and disease of the upper and lower airways. In cooperative subjects, data suggests
the within-subject coefficient of variation is similar to that seen in adults. Many of those dealing with patients are generally aware of the challenges of optimizing drug delivery at the different stages of development, although
unfortunately this is far from universal. For those not dealing directly with patients, it is vital that the impact of developmental physical and mental issues are understood when considering the development of novel devices or
the use of new chemical entities, if reliable delivery of drug to the lungs is to be achieved.
Robert W. Morton, MB, ChB and Mark L. Everard, MB, ChB, DM
There are a variety of methods for recording adherence rates to inhaled medication, with differing objectivity and validity. When objective methods of measurement are used, adherence rates are suboptimal for all major chronic respiratory
diseases and all patient groups. Consequences of suboptimal adherence include poor lung function and poor disease control with increased exacerbations. This results in increased healthcare utilization and associated cost. Intentional
barriers to adherence are based on negative illness and healthcare perceptions, or medication beliefs. Unintentional barriers include forgetting doses and work or social time constraints. An element of suboptimal adherence is also
due to poor device technique, although the extent of this effect is difficult to quantify. Educational interventions alone to increase adherence rates have had limited success, although combined interventions with a behavioral
aspect have had more promising results. Objective adherence feedback and direct reminders such as text messages or alarms have been shown to increase adherence levels, although an associated improvement in disease control has been
more difficult to establish.
The pathway to impaired lung function and death in many pulmonary diseases frequently involves imbalances in immunity. The failure to control bacteria in tuberculosis is an example of a failed response to an antigen. Idiopathic Pulmonary
Fibrosis (IPF) a progressive autoimmune fibrotic lung disease that can lead to respiratory failure and death within three years of diagnosis. Chronic obstructive pulmonary disease (COPD), often triggered by smoke, progresses until
death and in recent years has also been labeled ”autoimmune.” Proposed mechanistic pathways of pathophysiology involve profibrotic cytokines unresponsive to usual anti-inflammatory agents (e.g. corticosteroids). Interferon-γ (IFN-γ)
is a cytokine that can stimulate macrophage function and inhibit fibrotic pathways and therefore has been tried as therapy in tuberculosis and IPF. Unfortunately, for IPF, in several major clinical trials, parenteral IFN-γ failed
to stem disease progression. Dosing in systemic therapy is limited by side effects. In recent studies, our group has approached this problem using inhaled IFN-γ targeted directly to the lung. In a controlled clinical trial, inhaled
IFN-γ was effective in tuberculosis while parenteral IFN-γ was not, indicating that macrophages can be effectively immune-stimulated by aerosol therapy. We are taking a similar approach in IPF. We speculate that the same fibrotic
pathways active in lung parenchyma may be at fault in the airways of COPD. These concepts suggest that clinical trials of inhaled IFN-γ are warranted.
Chapter Chapter 13.2 - Inhaled Biotherapeutics and Systemic Delivery: Aerosol Delivery of Lung Surfactants
Ralph Niven, PhD, MBA
Exogenous lung surfactant is presently administered via intratracheal instillation for the treatment of infants at risk of or exhibiting signs of respiratory distress syndrome. Strong evidence from animal studies suggests that surfactant
should be beneficial in a range of pulmonary conditions including acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary fibrosis and asthma. The utility of surfactant would be extended with the availability
of an aerosol dosage form. In pre-term infants this may reduce the need for intubation and treatment with “rescue” surfactant while for adults, the option of efficient delivery systems in both critical care and ambulatory settings
would be welcomed. Despite the promise of aerosol surfactant therapy, the results of human studies have been of mixed outcome and very few studies have been adequately controlled. Confounding the issue is a less than clear understanding
of the dose received by patients, and in general, development and characterization of delivery systems has been inadequate. Thus, study outcomes may not reflect the potential of aerosolized surfactant. Factors impacting results
differ for the patient population of interest. Designing an efficient delivery system in neonates is complex and is hampered by their rapid, shallow breathing maneuvers and their general fragility.
Cytotoxic chemotherapy remains the cornerstone of treatment for patients diagnosed with advanced stage cancers and is an important component in the multi-disciplinary treatment of several early stage cancers. In the majority of patients
with cancer, cytotoxic chemotherapy is administered intravenously and in some instances by oral administration. Systemic administration of cytotoxic chemotherapy is well known to cause adverse effects, which can be severe and debilitating.
Regional therapy with cytotoxic agents has the potential to reduce the extent of systemic exposure to the drug and reduce the risk of systemic adverse effects. Regional chemotherapy has been successfully employed in the treatment
of certain solid tumors such as hepatocellular carcinoma. However, regional chemotherapy has not been commonly utilized for treatment of lung tumors. Inhaled cytotoxic chemotherapy has the potential to become an effective regional
therapy for both primary lung cancer and metastases to the lung from other primary tumors. Aerosol administration of chemotherapy could potentially avoid some of the adverse effects seen with systemic therapy. In addition, some
chemotherapeutic agents when administered as an aerosol are absorbed directly into the arterial circulation and have therapeutic effects at extrapulmonary sites. Aerosol administration of several different chemotherapeutic agents
is currently under evaluation either in the preclinical setting or in early phase human trials. Some of these studies have shown that inhaled chemotherapy is feasible and effective in treating lung tumors. In this chapter, we review
the published studies and ongoing trials on inhaled chemotherapy to better understand the current status of this field of cancer treatment.
Chapter 13.4 - This chapter has not been edited to date
Chapter 13.5 - Inhaled Biotherapeutics and Systemic Delivery: Aerosol Delivery to the Nasal Cavity– A Tortuous Pathway to Efficacy
Maureen D. Donovan, PhD, Arthur (M-Y) Foo, PhD, and Namita Sawant
Aerosol delivery to the nasal cavity is quite different from delivery to the pulmonary system. The nasal airways are narrow and tortuous, and they provide a myriad of opportunities for particle deposition, yet directing that deposition
to the desired site remains a challenge. A sudden narrowing of the airways in the nasal valve region, along with an accompanying airway direction change, results in the impaction of most aerosols immediately posterior to the nostril
opening rather than within the main nasal cavity. While smaller-sized particles can traverse through the nasal valve and reach the main nasal cavity, their small size also allows them to pass entirely through the nasal cavity and
enter the lungs, significantly limiting the use of < 5 μm particles for nasal delivery. The nasal cavity is compatible with a variety of formulation excipients, resulting in the opportunity to develop formulation/device combinations
that exhibit specific, optimized characteristics for improved deposition and therapeutic efficacy. However, user-based variations in nasal cavity morphology and in administration technique place additional limitations on the efficient
and reproducible delivery of nasal aerosols.
Chapter 13.6 - Inhaled Biotherapeutics and Systemic Delivery: Preclinical Safety
Ronald K. Wolff, PhD and James D. Blanchard, PhD
Several inhaled proteins and peptides have been developed to treat indications in the respiratory tract or systemically with varying degrees of success. This section will summarize the preclinical and clinical studies for inhaled Pulmozyme®
(recombinant human deoxyribonuclease, rhDNase), insulin, human growth hormone (hGH), cyclosporine, alpha-1 antitrypsin, measles vaccine, and anti-immunoglobulin E (IgE). For Pulmozyme® (rhDNase), monkeys had positive serum antibody
titers to rhDNase and allergic/ hypersensitivity (type I) lung lesions in response to foreign protein likely due to differences in homology between monkey and human DNases. However, in patients, the levels of rhDNase antibodies
were low and of no consequence. For inhaled insulin in rats, dogs and monkeys, there were no adverse effects related to insulin or excipients. In clinical trials, over 13,000 patients were safely treated with inhaled insulin for
an average of 1 year. Some patients had higher antibody levels than comparators, but these antibodies did not decrease the effectiveness, safety or tolerability of inhaled insulin over time and/or affect clinical outcomes. Inhaled
hGH had no adverse effects in monkeys, healthy volunteers or pediatric patients, but its absorption from the lungs was too low ( < 5%) in pediatric patients to be successful as a medical product. Inhaled cyclosporine had no
unexpected systemic toxicity or clinically limiting findings in the respiratory tract in rat and dogs; it also had promising Phase 2 clinical data but failed in Phase 3. Inhaled alpha-1 antitrypsin also failed in a recent Phase
2/3 trial. A liquid inhaled measles vaccine was safe, well tolerated and produced an appropriate immune response in Phase 2/3 studies for children ages 10-35 months, but not younger. A dry powder inhaled vaccine in monkeys had
no adverse effects and produced an immune response; Phase 1 trials are underway. Inhaled anti-IgE was well tolerated in monkeys and asthma patients, but systemic delivery had superior results in patients.
Chapter 14 - Limitations of Pulmonary Drug Delivery
Andrew R. Clark, PhD
Delivering drugs to the respiratory tract of patients is a complex undertaking. The maximum dose, regional deposition pattern and delivery consistency are all important limitations that should be considered when contemplating delivery
to the lungs. These performance attributes are influenced by the physiology of the patient and structure of the airways, the performance and type of the delivery modality and the physicochemical properties of the molecules. In
general, current delivery technologies can deliver between a few micrograms to several 100 mgs with differing degrees of difficulty and inconvenience to the patient.
Chapter 15 - Regulatory Considerations for Aerosol Therapy
Svetlana Lyapustina, PhD and David Cipolla, PhD
In all developed and in many developing countries, medicinal products, including medicinal aerosol products, must be approved by an appropriate government agency prior to marketing authorization. Knowing and complying with the requirements
of an appropriate regulatory agency (or agencies) is a prerequisite to successful commercialization of any aerosol therapy. The range of governmental regulatory oversight is broad, including manufacturing site inspections, review
of preliminary data and study protocols before the start of trials in human subjects, review of the sponsor’s clinical and in vitro data for the proposed product, approval of final labeling, review of post-approval changes to any
aspect of the product or manufacturing process, monitoring of adverse event reports, and other areas. The specific regulatory requirements vary by product type and by country, and they also change over time as the science and technology
involved in the development, manufacture and characterization of pharmaceutical and biological products evolve. In general, in order to obtain marketing authorization, the sponsor must demonstrate to regulators, using data from
appropriately designed studies and other relevant documentation that, 1) the product is safe and efficacious for the proposed therapeutic indication in the target patient population; 2) the product’s manufacturing facility follows
current good manufacturing practices (cGMP) and/or quality management systems, as applicable; and 3) appropriate quality control and quality assurance programs are in place, including programs to verify that the product released
to the market, as well as product kept in stability-testing environmental chambers, complies with pre-set quality specifications. For aerosol delivery devices and drug-device or biologic-device combination products, the sponsor
must also assess the influence of human factors, device robustness, and materials’ (bio)compatibility. The sponsor’s responsibility to regulators continues after a product’s approval, in the form of, for example, required compliance
with ongoing quality testing, pharmacovigilance monitoring, any post-approval commitments and qualification of any post-approval changes. This chapter provides an overview of the pertinent organizations and regulatory considerations
for inhalation products.
