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14.3.2 Dry Powder Inhalers
Dry powder inhalers are devices of medical origin containing formulations like dry
powders (Telko and Hickey 2005). Historically, DPIs devices were intended for
low-dose medicines to treat lung-related diseases, such as asthma and COPD (de
Boer etal. 2016). However, non-respiratory diseases like migraine and diabetes are
also the newly targeted areas for recently developed DPIs (Ashurst etal. 2000). The
current DPIs market includes more than 20 FDA-approved products. Table 14.2
summarizes the marketed DPI products. The DPI is favored over the nebulizer and
the pressurized MDIs (Telko and Hickey 2005; Shetty and Srinivasan 2017). Some
MDI devices are breath-actuated single-dose, multidose, and active devices (Cheng
etal. 2020). The background of each type is the deliverable dosage quantity, the
patient’s involvement in forming a colloidal suspension of a powder dispersed in air,
and the methods by which the powder is dispersed. Each type is subdivided into
single-unit dose inhalers, multi-unit dose inhalers, and multidose reservoir inhalers.
The DPI is preferable owing to it offering high stability in comparison to dosage
forms consisting of liquid, the smaller size of the device makes it easier to carry and
use, andit is propellant-free design for delivery of API to the target site (Rattanupatam
and Srichana 2014; Onoue etal. 2008). Regardless of the device’s design and for-
mulation, deep and forceful inhalations are required to break the powder into breath-
able size (5μm) that reaches the target site (Zheng etal. 2021). The whole dose is
lost if a patient unexpectedly exhales into the device. Hence, it is not the best choice
in emergencies (Gaikwad etal. 2023). The conventional design of such IDD devices
is given in Fig.14.3a, b.
Table 14.2 Marketed DPI products (Hebbink etal. 2022)
Manufacturer
Device
name API/drug
Device
type Indication
Year of
approval
GlaxoSmithKline
(GSK)
Ellipta
®
Relvar
®
Incruse
®
Blister Asthma/COPD 2017
Teva Armonair
®
Digihaler
®
Fluticasone
propionate
Reservoir Asthma 2017
Mylan
Pharmaceuticals
Wixela
®
Inhub
®
Fluticasone
propionate
Salmeterol
xinafoate
Blister Asthma/COPD 2019
Pzer Exubera Insulin Blisters Type 2 diabetes
mellitus
2006
Novartis Airmax™ Foradil
(formoterol)
Mionide
(budesonide)
Reservoir Asthma,
bronchitis
Bronchospasm
2007
(delay due
to lawsuit)
Orion Easyhaler
®
Budesonide
Formoterol
Reservoir Asthma/COPD 2018
A. Kumar et al.
363
14.3.2.1 Challenges ofConventional Dry Powder Inhalers
(Need forAdvancement)
There are a few challenges for the DPIs in general for delivering the drug to the
target site. To achieve effective and reproducible dose delivery, the patient must
produce sufcient inspiratory airow, which is determined by DPI’s internal resis-
tance. DPIs are not ideal for patients with considerable airow blockage since it
takes more effort to produce the inspiratory airow (Colthorpe etal. 2013). The
single unit dose requires emptying all the capsule contents into the device before
starting the inhalation procedure. Inhalation should be continued until no remaining
powder is left in the device to avoid any signicant degree of dose variability. Dose
variability is also caused by changes in device (brand) by patients, knowingly or
unknowingly. The temperature may affect the capsule, making it soft and hard to
break in the device before inhalation. Particle agglomeration due to high tempera-
ture and humidity causes changes in drug release, leading to dose variability in
DPIs. Some of the multidose DPI devices are complex, costly for production, and
user-friendly for some patients (O’Connor 2004). The challenges can be encoun-
tered by employing advanced IDD devices and formulation.
Fig. 14.3 Schematic representation of (a, b) conventional DPI, (c) advancement in DPI
(Aspirair device)
14 A Technological Update onInhalation Drug Delivery Devices
364
14.3.2.2 Advancements inDPI Devices
In extension to developments in DPI formulation design, advancements in the
design of the devices are ongoing with the introduction of new designs and digital
technologies. With the digitalization of many devices, there has been a massive
improvement in the product’s performance and a decrease in errors. This has
improved product usage and execution, along with patient acceptance, compliance,
adherence, and clinical results (Xiroudaki et al. 2021). The active and passive
devices have been studied more in advancing the DPI device design.
14.3.2.2.1 Active Devices
Most DPIs are referred to as “passive” inhalers since powder aerosolization occurs
exclusively because of the energy of air pulled through the device by a patient. The
powder dose is preloaded in three different ways: capsules, blisters, and reservoirs.
Powder particle deagglomeration in all passive inhalers is often generated by iner-
tial effects caused by airow patterns and aerosol impaction on the grid and mouth-
piece walls. Hence, these passive devices are ow-dependent. To overcome these
problems, active DPI devices were introduced, e.g., Exubera (single dose) and
Airmax (multidose). Although active devices have a more complicated design and
high cost, it is necessary to produce powder aerosolization, which can give the func-
tional advantage of being independent of airow intensity (Gradoń and Sosnowski
2014). The active device implements energy from additional sources like com-
pressed gas, motor-driven impellers, or electronic vibration for dispersing the API
in the formulation, hence making them easy to use for geriatric patients (Young
etal. 2004). The active devices are made to deliver drugs without relying on the
patient’s inspiration; however, the physical or electrical mechanisms are necessary
for powder dispersion. Several methods, including priming the device with com-
pressed air, high- frequency piezoelectric vibrators, and battery-powered motors, are
used by active DPIs to get around issues caused by dependence on inspiratory air-
ow (Newman 2004). One example of an active device is Aspirair
®
(Fig.14.3c). To
optimize drug delivery to the lungs, the Aspirair
®
device uses a vortex separation
chamber and compressed air supply that an airow sensor activates (Tobyn
etal. 2004).
14.3.2.2.2 Digital/Smart Devices
Administration of drugs at the right time, with proper technique, is often a problem
for a large population of patients (mostly seen in older people). To overcome such
issues, one can arrange a physical timer or diary to keep track of the doses, along
with following the proper procedure for drug delivery. This hassle can be overcome
by incorporating technology into the device or digitalizing the device to keep all the
steps in check. The technique is known as the digital/smart device technique, i.e.,
add-on devices (the monitor is placed on the exterior part of the device) and inte-
grated devices, where technology is incorporated into the very fabric of the device
(Xiroudaki etal. 2021).
A. Kumar et al.
365
14.3.3 Metered Dose Inhaler (MDI)
An MDI is a multidose, compact, and portable device, basically a pressurized reser-
voir system consisting of a canister (generally made of aluminum) inside a plastic
actuator. The drug is released from the chamber at the end of the actuator with the
help of an orice. The canister contains the solution of drug and co-solvent or a
suspension of micronized drug crystals within a propellant (becomes gaseous under
the atmospheric pressure)/propellant mixture (Janssens et al. 2008). During the
1950s, the rst propellant-based, pressurized metered-dose inhalers (pMDIs) came
into existence, starting a new age of portable, compact modern inhalers with very
effective aerosolization engines (Laube et al. 2011). The pMDIs, estimated to
account for more than 80% of the global market, have dominated the pulmonary
drug delivery market for the past 30years (O’Connor 2004). Table14.3 explained
the various marketed formulations for MDI.Respiratory diseases are one of the
Table 14.3 Marketed formulations for MDI devices
Brand name
API Type Company Indication
Year of
approval
Atrovent Ipratropium
bromide
Solution Boehringer
Ingelheim
Limited
Bronchospasm,
emphysema
2004
Serevent Salmeterol Suspension GSK Long-term airway
obstruction in
asthma
1998
Flovent
HFA
Fluticasone
propionate
Suspension GSK Prophylactic
therapy in asthma
2004
Pulmicort Budesonide Suspension AstraZeneca Prophylactic
therapy in asthma
in patients older
than 6years of
age
2000
Bevespi
aerosphere
Glycopyrrolate Suspension AstraZeneca COPD 2016
Qvar Dipropionate Solution Teva
Pharmaceutical
Industries Ltd.
Prophylactic
therapy in asthma
2000
Ventolin Albuterol
sulfate
Suspension GSK Bronchospasm 2001
Primatene
mist
Epinephrine Solution Amphastar
Pharmaceuticals
Intermittent
asthma, including
wheezing and
shortness of
breath
2018
Alvesco Ciclesonide Solution Covis Pharma Prophylactic
therapy in asthma
in patients older
than 12years of
age
2008
14 A Technological Update onInhalation Drug Delivery Devices
366
signicant causes of mortality and morbidity to the health of the general public all
over the world. Amid all mentioned devices, the fascinating rst choice of the clini-
cian is MDI over the others (Kumar etal. 2022). The formulation or the components
of MDI are well protected from any degradation, as well as from environmental
factors like moisture, light, oxygen, and microbial contamination due to being
packed inside a closed pressurized reservoir within a canister (Janssens etal. 2008).
MDIs are relevant options/devices of choice for patients with insufcient negative
inspiratory airow, intubated, or on ventilators, avoid rst-pass metabolism, and
give quick onset of action. It delivers low concentrations of drugs locally to the
lungs for systemic circulation, decreasing the chances of side effects. Despite the
positive consequences, various limitations are also associated with MDIs. The
inhalers consist of propellants such as chlorouorocarbons, which are toxic to the
environment and should be avoided (Ashurst etal. 2000). The coordination between
activation and inhalation is essential while using an MDI.Ineffective therapeutic
delivery is the result of poor coordination and is a topic of concern related to the
proper use of MDI.The failure to shake before usage will result in non-uniformity
in doses and inefcient drug delivery (O’Connor 2004). Keeping track of the daily
dose is often a challenge for the patientsand decreasing patient compliance (Geller
2005). The MDI can also cause local side effects due to oropharyngeal deposits. In
order to overcome these obstacles, various advancements have been made in MDI
formulations and devices, as stated below.
14.3.3.1 Recent Advances inMDI Devices
Conventional MDI devices consist of ve major components for their successful
applications. The actuator/mouthpiece, canister, metering valve, and nozzle are
basic device components. The advancement of MDI has been done based on nozzle
geometry, extra-ne particle atomization, and the addition of spacers in drug-
delivery devices. A brief description of each type is given in Table14.3.
14.3.3.1.1 Modified Design Based onNozzle Geometry
Pressurized metered dose inhaler’s aerosol properties and output can be impacted
by subtle modications to the actuator design and geometry (Fig. 14.4a) (Dalby
etal. 2004). One example is the Respimat
®
inhaler, which combines the benets of
pMDIs and nebulizers, as shown in Fig.14.4d. It operates by uniblock, a design
nozzle that creates two tiny liquid jets at precisely appropriate angles and this con-
vergence is what causes the soft mist to develop. It can operate at a moderate inhala-
tion ow rate to slowly aerosolize propellant-free drug solutions as a ne mist,
similar to nebulizers, reducing the likelihood of oropharyngeal deposition, which is
frequently seen with pMDIs (Leach etal. 2005).
14.3.3.1.2 Extra-Fine Particle Atomization
New pMDIs that create aerosols with extra-ne particles have been developed
thanks to advancements in drug formulation. With the longer duration of aerosol
emission and less impact of inspiratory ow and coordination on lung deposition,
these newer formulations are said to be less dependent on inhaler technique than
A. Kumar et al.
367
other MDIs (Leach etal. 2005). The addition of dissolved CO
2
to a mixture ofhydro-
uoroalkanes ( HFA)-134 and ethanol was suggested as a novel approach to mini-
mize the size of droplets after emission from the pMDIs (Ibrahim etal. 2015).
14.3.3.1.3 Addition of“Spacers”
pMDIs can be equipped with spacers that serve as reservoirs into which drug aero-
sol can be produced (Fig. 14.4b). This allows the patient to administer the drug
without coordinating the inhalation and actuation (Capstick and Clifton 2012). The
benets of utilizing a spacer device include better drug inhalation from pMDIs,
especially for people who have trouble using a pMDI by themselves, such as
AeroChamber Plus
®
andFlow-Vu
®
as shown in Fig.14.4c (Ho etal. 2004).
14.3.3.2 Advancement inMDI Formulations
Technological advances have driven the use of advanced formulation strategies
through MDI.It includes the induction of newer propellants and various micro- and
nano-drug carriers. Using newer propellants as substitutes for older ones is an
advance in one of the formulation strategies through MDI.The hydrouoroalkanes
(HFA) 134a and 227 were found to be the only HFAs that could effectively
replacechlorouorocarbons (CFC) propellants in pMDIs after signicant investiga-
tion. HFAs 134a and 227 have numerous traits in common as both propellants
exhibit very little impurity, are above 99.9% pure, and are chemically stable under
Fig. 14.4 Advancement in MDI: (a) Respimat soft mist inhaler, (b) spacer added MDI, (c)
AeroChamber Plus
®
Flow-Vu
®
, and (d) Respimat
®
inhaler
14 A Technological Update onInhalation Drug Delivery Devices
368
typical storage conditions. HFAs can produce sufcient vapor pressure even at
lower temperatures, which helps in the effective delivery of API due to their lower
boiling points (BP) (Morton 2001). Salbutamol and uticasone propionate are the
two drugs tested for dosage uniformity and particle size distribution in pMDIs that
use HFA 134a as a propellant. Cripps etal. (2000) conducted a study on replacing
CFCs with HFAs in pMDI for reproducibility and regulatory requirements. The
investigation was conducted on pMDI for dose uniformity, particle size distribution
(PDI), single actuation reproducibility, and content uniformity. The ndings from
the study showed that products (pMDI) provided an emitted dose within ±25% of
the mean value, indicating consistent dosing of salbutamol (100μg per actuation) or
uticasone propionate (125 and 250/μg per actuation) using HFA 134a. The results
didn’t differ signicantly from that of CFCs; hence HFAs were suitable replace-
ments for CFCs without any decrease in therapeutic efcacy (Cripps etal. 2000).
Another study by Pickering etal. (2001) uses HFA 227in pMDI to deliver mometa-
sone furoate (MF). Gamma scintigraphy was used to determine respiratory tract
deposition pattern and efciency of the delivery of formulation containing HFA
227in a total of 11 patients. It was concluded that lung deposition via HFA 227
pMDI was 10–20% compared to other corticosteroid suspensions, has shown effec-
tiveness in the treatment of asthma, and was a suitable replacement for the CFCs
(Pickering etal. 2001).
14.3.3.2.1 Nano- andMicroformulations
Despite the availability of pMDIs commercially, deaths due to pulmonary diseases
are increasing every year; hence there is a constant search for effective drug delivery
systems and advanced pMDIs. Nanotechnology, biotechnology, particle engineer-
ing, etc. have shown improvements in MDIs. The different microparticles (MPs)
(nanocomposite, porous) and nanoparticles [liposomes, solid lipid nanoparticles
(SLN), dendrimers, and polymer hybrid NPs] are tested with MDIs for improve-
ments in the delivery process and therapeutic outcomes for the treatment of pulmo-
nary diseases (Kumar etal. 2017).
14.4 Applications ofInhalational Drug Delivery
There are several advantages of using inhalation medicines over other administra-
tion routes for treating pulmonary and systemic diseases. In contrast to oral ther-
apy, this route of administration eliminates the poor absorption of the drug and
drug degradation in the GI tract and avoids rst-pass metabolism in the liver.
However, in contrast to the parenteral route of administration, pain and patient
discomfort are overcome by the inhalational route. Systemic toxicities or organ-
specic toxicities are also associated with the systemic route of drug administra-
tion (Anderson etal. 2022; Okuda and Okamoto 2020). The possible advantages
offered by IDDs produce wide applications to deliver drugs, genes, peptides, and
vaccines for various diseases (Saleem etal. 2017). Pulmonary drug administration
is the prominent route of drug administration to acquire disease specicity by
A. Kumar et al.
369
localized targeting. After the publication of the rst clinical trial in 1968, the evo-
lution of various IDDs has been raised. Broadly, lung diseases (lung cancer,
asthma, COPD, cystic brosis, lung injury, etc.) are attractive pathological condi-
tions for the drug-oriented applications of IDD.It offers a non-invasive delivery
route for self-medications, can deliver high doses to acquire rapid onset of action,
and has low enzymatic degradation, thus increasing effectiveness. Various studies
have explained the importance of IDD in pulmonary diseases (Kunde etal. 2022;
Chang etal. 2021). The route is suitable for delivering vaccines that induce immu-
nological responses more effectively than the parenteral route (De Castro etal.
2005; Wong-Chew et al. 2006; Henao-Restrepo et al. 2010; Smith et al. 2003;
Dilraj etal. 2007). The inhalation route of insulin administration also helped to
treat diabetes, as discussed in various studies (Laube etal. 1993, 1998; Cefalu
etal. 2001; Beth 2005). The developed IDD devices for insulin Nektar, Aradigam,
and Aerogen explained the success of such biopharmaceuticals (Beth 2005). The
IDD is also found to be used or delivering genes, proteins, and peptides to treat
various diseases (Griesenbach etal. 2006). It has already been explained that pro-
teins or peptides are delicate molecules easily ruptured by gastric juice, high tem-
perature, or enzymatic degradation (Mehta 2016). Most literature favor using
DPIs for the pulmonary delivery of protein owing to their inexpensive, propellant-
free, and stable formulation properties throughout the shelf life (Hak-Kim and
Andy 1997).
14.5 Evaluation ofInhalation Drug Delivery Devices
The fundamental goal of inhalation therapy is to administer medication topically to
the lungs. The characteristic features of the device (e.g., the aerosolization system,
internal resistance, speed of the aerosol plume, oral/nasal inhalation, and inhaled
carrier gas) and formulation (e.g., lipophilicity, particle charge, and hygroscopicity)
affect the lung deposition of molecules and their ability to reach the small airways.
Each inhaler device includes distinctive instructions for preparing the dose, deliver-
ing medication into the airways, and determining the density and size of the aerosol-
ized particulates (Rogliani etal. 2017). Additionally, the qualities and intensity of
the respiratory condition and the simplicity with which patients can use the device
have a role in the correct delivery of inhalational medication (Hirsh et al. 2008;
Laube etal. 2011).
According to Froehlich (2019), the repeatability of aerosol distribution is a cru-
cial factor in determining how well an inhalation device works. Higher doses of
ethanol slow the evaporation, causing bigger droplets and oropharyngeal deposi-
tion. The possibility of generating turbulences that amplify lung deposition and the
interaction between plume velocity and inhalation airow is complicated. Aerosol
deposition for dry powder inhalers (DPIs) is inuenced by emitted dose (ED), aero-
dynamic particle size distribution (APSD), and device resistance (Froehlich 2019).
There are various preclinical models (in vitro, ex vivo, and invivo) to assess the
performance of IDD devices.
14 A Technological Update onInhalation Drug Delivery Devices
370
14.5.1 In Vitro Evaluation ofInhalation Devices
Chrystyn (2007), state that the performance characteristics of inhalers vary consid-
erably based on the wide variation in design characteristics, which impacts their
suitability for use in different patient populations. The ne particle fraction (FPF)
and total emitted dose (TED) from the IDD devices decide the deposition and actual
performance of the therapeutics. Therefore, it is essential to consider its suitability
before prescribing a DPI for an individual patient (Chrystyn 2007). The TED is
dened as the amount of drug emitted by the inhaler during a single actuation. The
quantity of drug particles in the TED that are tiny enough to enter the airways when
inhaled provide the therapeutic effect. FPF is the mass of particles produced in an
actuation with an aerodynamic diameter of less than 5μm (Davies 1979). The likeli-
hood of these particles depositing on the airways during inhalation is highest. The
oropharynx is where larger aerosol particles usually settle before being swallowed.
In vitropharmacopoeial procedures are used in the laboratory to measure the
TED and FPF delivered by inhalers. Boshra etal. (2018), used a DPI sampling
method to determine the TED given by Diskus or Aerolizer inhalers containing
200mg salbutamol (Boshra etal. 2018). These techniques have shown that the ef-
cacy of the various inhalation systems is highly variable and that they provide help-
ful information on probable aerosol deposit locations within the airways (Chrystyn
2007). In practice, the airow capacity of a DPI during use is adaptable and is
affected by the patient’s inhaling capacity. A patient’s inspiratory capacity varies,
inuenced by parameters including airway obstruction, lung size, and inspiratory
musculature (Chrystyn 2007). According to Boehr etal. (2002), a typical consider-
ation during the formulation and characterization of drug inhalation systems is the
measurement of the APSD from the aerosol mist as a function of constant inspira-
tory ow rate. To effectively deposit the dosage at the site of action within the respi-
ratory tract, evaluating the TED and whether it has the necessary size range is
essential. The sizes of aerodynamic particles have been measured using a variety of
methods. With equipment like cascade impactors, Aerosizers, elutriators, spiral cen-
trifuge aerosol spectrometers, electrical mobility analyzers, etc., direct cloud mea-
surement from an inhaler is possible (Froehlich 2019; de Boer etal. 2003). According
to Ho etal. (1986), laser diffraction techniques produce size distributions for nebu-
lized aqueous drug solutions that are more accurate than those produced by inertial
impaction methods (Ho etal. 2011). The application of the laser diffraction tech-
niques for particle size characterization in the plumes released from MDIs was
described in detail by Ranucci (1992). The apparent permeability (AP) of the
inhaled therapeutics is another important property that affects the biological perfor-
mance of the IDDs. AP is the rate of drug molecule transport through the cell mono-
layer made up of Calu 3 cells, NCL-H441, HAEVi cells, and human primary cells
(Ehrmann et al. 2020; Sakagami 2020; Cidem et al. 2020). The advantages and
disadvantages of such are discussed in Table14.4.
A. Kumar et al.
371
Table 14.4 In vitro and ex vivo preclinical models to evaluate the IDD
Models (Ehrmann
etal. 2020; Sakagami
2020; Cidem etal.
2020; Secher etal.
2020)
Advantages
Disadvantages
Air liquid interface • Controllable dose
• Carry out effectively through
impactor machines
• Reaction for drugs like a
respiratory tract of the lung
• Challenges in holding inserts
• It has specicity to particular
cell lines
• Some restrictions in cell
culturing (primary cell lines)
Organoids • It exactly replicates the
heterogenic nature of the lung
• Capable of screening
personalized medicines in this
method
• Mimic-like lung micro-level
environment
• Not able to predict the
bio-pharmacokinetics of inhaled
particles in the pathway at the
mouth to airways
Lung on chip • Capability of representing
barriers in the lung for drug
absorption
• Having the capacity to
recreate mechanical and shear
forces brought on by cyclical
breathing
• Giving the same
heterogenicity and ow rates as
the in vivo environment of the
lung
• Capable of creating respiratory
airways
• It recreates the alveolar-
capillary airways
• In situ aerosol exposure
• Less to optimum throughput
• Relatively time-consuming
• Moving elements that could be
complicated—inconsistent
production processes
Precision-cut lung
slices (PCLS)
• High platform repeatability
• An accurate portrayal of the
structural response of the lungs to
experimental stimuli is made
possible by preserving the lung
architecture
• Maintain effective cell-cell
communication for a multicellular
reaction
• The experimental design is
more controllable than the use of
animals in studies
• Exact modeling of the upper
airway concerning the distal
airway
• Lack of clinical inhalation
applicability and dosage estimation
based on therapy
• Failure to replicate muscular
stretch, circulation, or airow seen
in the human lung
(continued)
14 A Technological Update onInhalation Drug Delivery Devices