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14
A Technological Update onInhalation
Drug Delivery Devices
AnkajKumar, IshwarChandra, V.Rajesh, SourabhJadhav,
HarshitaKrishnatreyya, andArvindGulbake
Abstract
Inhalation drug delivery (IDD) is an effective approach for treating respira-
tory diseases, including asthma, cystic brosis, lung cancer, and chronic
obstructive pulmonary diseases. The advantages of inhalation drug delivery
(IDD) include lowering the dose and dosing frequency, overcoming drug
resistance, increasing in drug’s effectiveness by applying it directly to the
expected site of disease, and lowering the systemic toxicities of the drug.
Inadequate instruction and training in the use of the inhalation device to con-
trol the actuation and aerosol inhalation may lead to the absence of intended
clinical outcomes as well as issues with efcacy or any negative drug effects.
There have been advances in technology- driven novel strategies in the formu-
lation and development of aerosols, nebulizers, metered dose inhalers, and dry
powder inhalers to encounter the problems associated with coordination skills,
dosing frequency, and safety. Formulation advancement involves microparti-
cles and nanomedicine-based approaches for IDD. However, the novel
advancedesigns, structures, and functions of IDD devices make them more
prominent, precise, and effective. The in vitro, in vivo, and ex vivo models that
strengthen and check the possible efcacy of the developed IDDare discussed
in the chapter. This chapter gives insight into the advancement of these IDD,
novel formulation approaches, their evaluation through various preclinical
models, and their benets over previous IDD.
A. Kumar · I. Chandra · V. Rajesh · S. Jadhav · H. Krishnatreyya · A. Gulbake (*)
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research
Guwahati, Kamrup, Assam, India
e-mail: arvind@niperguwahati.in
356
Keywords
Inhalation drug delivery · Microparticles · Inhalation therapy · Drug carriers ·
Nebulizers
14.1 Introduction
It is very fascinating to study the modern approach of inhalation therapy for drug
delivery, especially in the case of lung diseases like chronic obstructive pulmonary
disease, lung cancer, asthma, and many more. Inhalation therapy has a long history
and hundreds of ingenious devices and medications. The word “inhaler” was rst
proposed by John Mudge in late 1778in his book entitled, A Radical and Expeditious
Cure for a Recent Catarrhous Cough (Mudge 1778). Inhalation therapy was prac-
ticed in ancient civilizations such as India, China, and South and Central America.
In India, inhaling the fumes of stramonium and hemp was common, whereas in
China, opium inhalation and ornate metal inhalers were commonly practiced
(Sanders 2007).
The lungs represent the most attractive alternative route for drug delivery, owing
to the larger area for the deposition of pharmaceutical agents and high vasculariza-
tion for the systemic delivery of therapeutic agents. This route of administration
prevents the degradation of active components in the gastrointestinal tract and also
prevents its rst-pass metabolism in the liver (Kuzmov and Minko 2015). The ef-
ciency of IDD mainly depends on lung aerodynamics, the inhaled particle’s size, the
inhalation method, and its delivery devices (Gagnadoux etal. 2008; Lehofer etal.
2014; Chan etal. 2014). Even though this delivery route has advantages, it is still
not used widely due to some limitations, such as high lung toxicity, drug-induced
lung injury, and drug degradation by lung macrophages (Labiris and Dolovich
2003). An ideal IDDdevices should deliver pharmaceutical active components to
the diseased cell without damaging healthy lungs (Kuzmov and Minko 2015).
Several conventional IDD devices and drug carriers have been developed, imple-
mented, and studied in various studies. Nebulizers are one of the most modern and
developed pulmonary drug delivery systems. Recent advancements in nebulizers
are made to optimize the administration of drugs to the lungs by controlling or mea-
suring patient breathing patterns. Jet nebulizers and ultrasonic nebulizers are con-
ventional devices, whereas smart and vibrating mesh nebulizers have recently been
developed and improved in the treatment of lung diseases. Metered dose inhalers
(MDIs) are the most frequently used device for the treatment of lung diseases such
as asthma and chronic obstructive pulmonary disease (Doan etal. 2011). Medihaler
Epi, Riker Laboratories, marketed the world’s rst MDI in late 1956 (Stein etal.
2014). The cost per dose of MDIs is relatively low, which makes it a popular deliv-
ery system among all IDDdevices (Doan etal. 2011). MDI contains dissolved or
suspended drugs in propellant. Though propellant harms the environment, it is still
widely used in devices. The hardware of MDI consists of a canister, a metering
valve, and an actuator mouthpiece (Stein etal. 2014). Dry powder inhalers (DPIs)
are signicant segment of the global pulmonary drug delivery systems market
A. Kumar et al.
357
(Shetty and Srinivasan 2017). The DPI is one of the fastest-growing delivery sys-
tems, with a market size of USD 19.66 billion in 2022 and expected to reach 27.98
billion in upcoming years. DPIs are breath-actuated devices containing particles
with a size of 1-5 μm. The formulation is delivered in the respiratory airways
through oral inhalation (Ashurst et al. 2000). DPIs have more advantages than
metered dose inhalers as these devices are propellant-free, making them eco-
friendly. It also has dose counters that help to calculate the number of doses remain-
ing. It is very user-friendly and easily accessible for patients; hence, it has more
patient compliance (Ashurst et al. 2000; O’Connor 2004; Geller 2005). The
advances in nanotechnology also enhance effective inhalational therapy by offering
sustainability, targetability, dose reduction, and dosing frequency. Polymer-based
nanoparticles, dendrimers, lipid-based nanoparticles, nanospheres, complexes with
nucleic acid, and magnetic nanoparticles are some examples of nanotechnology-
based inhalation drug carriers (Kuzmov and Minko 2015).
The chapter highlights the recent advances in inhalational therapy, with special
emphasis on drug carriers and devices. The possible challenges and solutions are
addressed, making IDD therapy fruitful with broad applications. The study also
included the various preclinical models required to evaluate the performance of
such IDD.The wide applications of IDD in various disease treatments explain the
prominent role of such therapies.
14.2 Challenges andTheir Probable Solutions
Inhalation drug delivery is a very popular route of administration specically for
lung diseases, allowing direct deposition and onset of the drug’s action at the dis-
ease site with a minimal dose. The choice of drug delivery system mainly depends
on drug properties, disease state, patient’s condition, and surrounding atmospheric
conditions. In the last two decades, traditional inhalation devices have been modi-
ed to overcome the problems associated with older inhalers (Sanchis etal. 2013).
14.2.1 Device-Related Challenges
According to Sanchis and colleagues, only 34% of patients adopted adequate inha-
lation techniques (Sanchis et al. 2013). Giraud and Roche subdivided misuse of
inhalers into two categories: either omissions or errors. In omission, improper han-
dling of an inhaler, forced expiration, no expiration, inspiration through the nose,
and no inspiration are included (Giraud and Roche 2002; Lavorini etal. 2015). Any
misuse during the handling of inhalers leads to serious consequences, such as the
risk of hospitalization or emergency department visits (Giraud and Roche 2002).
Omission is signicantly associated with a lack of patient education (AL-Jahdali
etal. 2013). To overcome the misuse of inhalers, the patient should rst be educated
and trained regarding the use of the device. Whenever needed, a physical demon-
stration of how to use inhalers is more benecial than providing just verbal or writ-
ten instruction. If the patient still misuses the device, an alternative inhaler device
14 A Technological Update onInhalation Drug Delivery Devices
358
should be attempted to overcome patient-specic difculties. Respimat soft mist
inhaler is a new type of device that resembles MDI.Advances in devices and carri-
ers have resolved such improper handling and misuse issues. A detailed description
of each advancement and its merits is given in the section below (Giraud and Roche
2002; AL-Jahdali etal. 2013).
The administration of low-potent therapeutics at their higher doses is the main
challenge through IDD.Among all IDD, MDI can deliver a maximum of 100–200μg
active pharmaceutical ingredient (API) per shot (Newman 2005), whereas, in the
case of nebulizers, it requires a long inhalation time even for a small amount of dose
administration (Haque etal. 2016). DPI is the rst choice for high-dose administra-
tion. Generally, it requires a particle size of formulation below 5 μm to reach the
central and peripheral regions of the lungs for therapeutic effect. However, particle
agglomeration is a major concern, leading to poor ow properties (Mangal etal.
2017). To encounter such issues, the possible solution is to blend, exploiting the
adhesion force between micronized drug particles and suitable larger carriers
(Froehlich 2019). A higher carrier amounts can cause serious side effects; thus,
safety must also be considered while designing higher excipient formulations
(Longest etal. 2019).
14.2.2 Biological Barriers
The mucociliary clearance, phagocytosis, and enzymatic degradation in the lungs
are the challenges associated with inhalation drug delivery. There are mucociliary
escalators, alveolar macrophages, and enzymes (cytochrome p450, trypsin, anti-
trypsin, and proteases) that affect the biological performance of the drug carriers.
The presence of lung surfactants is also associated with phagocytosis of inhaled
particles (Pardhi and Jain 2021; Kumar etal. 2024). To overcome the biological bar-
riers, formulation consideration for the use of biocompatible material generally
requires including dipalmitoylphosphatidylcholine (DPPC), 1,2-distearoyl-sn-
glycero-3-phosphoglycerol (DSPG), dioleoylphosphatidylethanolamine (DOPE)
lipids, and lactose (Haque etal. 2016; Mangal etal. 2017; Froehlich 2019).
14.3 Inhalation Drug Delivery andDevices
14.3.1 Nebulizers
14.3.1.1 Conventional Nebulizers
A nebulizer is a device used to make a poly-disperse aerosol mist suitable through
inhalation. It contains liquids and suspensions with a droplet or particlesize range
of 1–5 μm. It benets unconscious, accidental, pediatric, and geriatric patients
(Longest etal. 2019). The signicant and suitable use of nebulizers is in chronic
obstructive pulmonary disease(COPD), asthma, and chest diseases (Waldrep and
Dhand 2008). Compressed air, connection tubing, and patient interface, including
A. Kumar et al.
359
the mouthpiece or facemask, are the components of the nebulizer system. Such
components decide the overall efciency of aerosol drug delivery. Jet and ultrasonic
nebulizers are examples of conventional nebulizers, whereas smart and vibrating
mesh nebulizers are categorized as advanced.
14.3.1.1.1 Jet Nebulizers
In a jet nebulizer, negative pressure is created by compressed air (air stream) passing
through a small orice at high speed. It creates low pressure and makes aerosol from
liquid or suspension (Ibrahim etal. 2015). The solution form is most suitable for
aerosolization owing to higher stability (Dhanani etal. 2016). Overall, nebulization
is based on Ventri’s principle. The pressure range of 2–10L/min generates a spa-
cious range of particle sizes that further reduces size through bafes. The design of
the jet nebulizer is illustrated in Fig. 14.1a. Examples of products administered
through jet nebulizers are antibiotics, mucolytics, liposomal formulations, beta- 2-
agonists, and recombinant products (Pulmozyme) (Dhanani etal. 2016). There are
four categories of jet nebulizers based on the capillary tube, i.e., jet nebulizers with
a corrugated tube, jet nebulizers with a collection bag, breath-enhanced jet nebuliz-
ers, and breath-activated jet nebulizers (Ari 2014). Each type of nebulizer has pros
and cons, as explained in various studies (Ari 2014). The recent modications to jet
nebulizers use a thermostat to overcome the problems with bronchospasm due to a
decrease in the temperature of the liquid (Ochowiak etal. 2019). An example of
such type is described in Table14.1.
14.3.1.1.2 Ultrasonic Nebulizer
This nebulizer uses ultrasonic waves to nebulize the liquid formulation into aerosols
(Fig.14.1b). The piezo-electrical crystals are vibrated to produce ultrasonic wave
frequency in the range of 1–3MHz, producing small particles inside the chamber
for inhalation and larger particles in the reservoir (Longest etal. 2019). The capil-
lary wave and cavitation theories underlie ultrasonic nebulization’s main mecha-
nism (Dhanani et al. 2016). Inhalation therapies include two types of ultrasonic
nebulizers: standard nebulizers and water interface nebulizers. In a standard
nebulizer, the drug has direct contact with a piezo-electric transducer. However, it is
unsuitable for heat-sensitive drugs and products (peptides and proteins) (Longest
etal. 2019). In a water interface nebulizer, water is placed in between the drug for-
mulation reservoir and the piezo-electric transducer. The water decreases heat for-
mation during the principal process of nebulization (Waldrep and Dhand 2008).
Fig. 14.1 Conventional nebulizers: (a) jet nebulizer, (b) ultrasonic nebulizer
14 A Technological Update onInhalation Drug Delivery Devices
360
14.3.1.2 Advances inNebulizers
14.3.1.2.1 Mesh Nebulizer
The nebulizer contains a micropump system to create the aerosols from liquid or
suspension (Fig.14.2a) (Longest etal. 2019). Marketed products in vitro studies are
proving mesh nebulizers are more efcient than conventional nebulizers, and it
takes less time for nebulization (Waldrep and Dhand 2008). The forced formulation,
like liquid or suspension, is passed through various apertures in a mesh placed to
create the aerosols (Ari 2014). Passive and active vibrating mesh nebulizers are two
types of mesh nebulizers. The passive mesh nebulizer includes a piezo-electric ele-
ment positioned near the mesh and a thin uid layer to transmit the vibrations to the
mesh. An active mesh nebulizer attaches a vibration-guided piezo-electric element
nearer the formulation reservoir. Mesh nebulizers have advanced applications in
delivering drug nanocarriers, mRNA, and polymyxin B effectively to the lungs
(Longest etal. 2019). In contrast to conventional nebulizers, it offers deliverability
for higher doses, is suitable for infants and unconscious patients, and does not
require device-patient coordination for inhalation. However, bulkiness and lower
efcacy are the challenges associated with such nebulizer designs (Labiris and
Dolovich 2004).
Table 14.1 Markedly available nebulizer formulations (Waldrep and Dhand 2008)
Types of
marketed
products
Drug
Aerosol
devices
Year
approved Company name
Indications
AeroEclipsell
BAN
Methacholine Breath-
actuated jet
nebulizer
2020 Trudell Medical
International
Asthma, cystic
brosis
AKITA Tobramycin Vibrating
mesh
2007 Activaero
America, Inc.
Cystic brosis
APIXNEB Tobramycin Nebulizer 2007 Activaero
America, Inc.
Cystic brosis
CompAIR Iloprost Jet nebulizer 2020 OMRON Pulmonary
arterial
hypertension
(PAH)
Omron NE
C801
Indocyanine
green
With virtual
value
technology
2014 OMRON Used in lung
cancer
I-neb AAD
system
Alpha-1
antitrypsin
Vibrating
mesh
nebulizer
2011 Respironics
Respiratory
Drug Delivery
(UK) Ltd.
Cystic brosis
MicroAir
NE–U22
Budesonide Vibrating
mesh
nebulizer
2020 HC Med
Innovations,
Co. Ltd.
Persistent
asthma
A. Kumar et al.
361
14.3.1.2.2 Vibrating Mesh Nebulizer (VMN)
This type of nebulizer includes a perforated membrane attached to a piezo element
to assist the vibration mode. Vibrational motion and sound pressure are created
nearer to the membrane, pushing the uid through that membrane to generate the
aerosol (AL-Jahdali et al. 2013). The device is best suitable for intensive care
unit(ICU) settings, as well as the need for low residual drug volume, and is helpful
in attaining deep lung penetration. It can produce the drug particle in a minimal
range of 0.5–3 μm, suitable for alveolar deposition. VMN has a horizontal mesh
containing 1000 holes. The design of VMN is illustrated in Fig.14.2b, c. Total emit-
ted dose studies have proved that VMNs would deliver a higher number of aerosols
than jet nebulizers. Some examples of VMN are breath-activated VMN systems
such as AKITA2, APIXNEB, Aerogen -OnQ
®
, Aerodose
®
, Aeroneb Pro
®
and Solo
®
,
Pari eFlow
®
, and Philips I-Neb
®
nebulizer systems (Table14.1). The novelty here is
the personalized therapies achieved by these VMNs (Mccarthy et al. 2020; Sayed
etal. 2021).
Fig. 14.2 Advancement in nebulizer: (a) mesh nebulizer, (b, c) vibrating mesh nebulizer
14 A Technological Update onInhalation Drug Delivery Devices