Pulmonary Drug Delivery II

Drugs and Medicines (PMP201)

Professor Andrew Morris
(a.p.morris@swansea.ac.uk)
Lecture outline
• pMDIs and special patient groups
• Dry powder inhalers (DPIs)
– Drug in hard gelatin capsules
– Multidose DPIs
• Nebulizers
– Jet nebulizers
– Ultrasonic nebulizers
– Mesh nebulizers
pMDIs and special patient groups
• Ability of a patient to use a pulmonary drug delivery device
needs to be considered – particularly coordination
• A valved holding chamber (spacers) +/- facemask is often used
with young children
pMDIs and special patient groups
• Spacers do not require the patient to coordinate their breathing
with the actuation of the pMDI
• Reduces the initial droplet velocity and allows time for
propellant to evaporate
AeroChamber Plus spacer

One-way pMDI
valve mouthpiece
goes here

Cap removed and

There are multiple brands of spacer so
patient inhales through
pharmacists must be familiar with all
(facemask may be
attached here)
pMDIs and special patient groups
• Spacers + facemasks are often not suitable for young infants
and a nebulizer + mask may be used – nebulizers covered later
• Other patient groups may face issues using inhalers
– Patients with limited dexterity, e.g. arthritis
– Partially-sighted patients or with reduced vision
– Patients with cognitive impairment
– Elderly – lung function reduces over time (a problem for DPI use)
• Such patients may benefit from a pMDI + spacer or potentially
breath-actuated pMDIs or nebulizer therapy
pMDIs and special patient groups
• Breath-actuated pMDIs, e.g. Autohaler, Easi-Breathe, assist
with coordination of inspiration and actuation
• Inspiration by the patient triggers the release of the drug, i.e.
opening of the metering chamber
Dry powder inhalers (DPIs)
• DPIs use no propellant and rely on the force of the patients
inspiration to carry the drug (as a dry powder) into the lungs
• Two common categories:
1. Drug in hard capsule DPIs
2. Multidose DPIs (multiple unit dose OR reservoir type)

Advantages
Propellant free, i.e. better for the
environment than pMDIs
Being breath-actuated they avoid
inspiration and actuation
coordination issues
Can deliver larger doses of drug
than pMDIs
Disadvantages
DPIs require inspiratory flow rates
of 30-90 L/minute
Sometimes a higher upfront cost
DPIs more exposed to ambient air
which may cause stability issues
Formulation of DPIs
• Drug particles should be <5 m for biopharmaceutical reasons
→ need to be micronized

Micronization: process of reducing drug particle size to micron size ranges

(typically <5 m in diameter)

Milling / Supercritical
grinding Spray Spray fluid
drying freeze- processes
drying

• Micronized particles often have poor flow properties due to

static / cohesive / adhesive nature
• Drug (micronized) particles mixed with much larger (30 m to
150 m) carrier particles to improve flow
Carrier
• Lactose typically used for carrier particles particle
Micronized drug
Formulation of DPIs
• Formulated so that micronized drug particles adhere to
the larger lactose particles
• Leads to more uniform device filling and improved
liberation of drug from the DPI
Schematic representation of drug-
carrier aggregates in a generic DPI

Turbulent airflow causes the drug particles and carrier particles to disaggregate
(1) Drug in hard capsule DPIs
• Drug (+ carrier) is loaded into a hard-shelled gelatin capsule
• Capsule is loaded into the device by the patient
• Punctured by two metal needles inside the device
• Inspiration by the patient causes a rotor to rotate and
this causes a turbovibratory air pattern to disrupt the
powder in the capsule
 (2) Multidose DPIs
• Multidose DPIs can be broadly divided into two categories
– Multiple unit dose device
– Reservoir-based device

Diskhaler
Accuhaler

Schematic representation of a multiple unit dose device

Turbohaler
Clickhaler

Schematic representation of a reservoir-based device

Diagrams adapted from N. Islam, M.J. Cleary / Medical Engineering & Physics 34 (2012) 409–427
Nebulizers
• Nebulizers are much larger pulmonary delivery devices that
generate aerosols from the contents of unit dose nebules
• Large volumes of drug solution (and
therefore doses) can be administered
• Drug inhaled during normal breathing
usually via a mask
Nebule contents emptied into nebulizer
• Nebulizers are used in hospital and and inhaled over an extended time period

domiciliary settings
• Generally not very portable due to
their size and power requirements

A nebulizer mask (James Heilman MD)

Formulation of Nebules
• Nebule formulations can be quite simple and are often just the
drug dissolved in “normal saline”
• Normal saline is a 0.9% w/v NaCl aqueous solution

Solution Suspension

Saline-based nebules can also usually be

diluted with normal saline if required
Image: Kays Medical Image: Breatheazy
 Jet Nebulizers
• These require compressed air from a cylinder, hospital air line
or electrical compressor
Aerosol out
Aerosol droplet size and drug
delivery is determined by the
compressed gas flow rate

Baffle ensures that (larger) non-

respirable particles are not
inhaled and can be recycled

Compressed air passed through

the Venturi nozzle – low pressure
created draws liquid up from the
reservoir through a feed tube

Jet nebulizer (adapted from Aulton’s Pharmaceutics)

 Ultrasonic Nebulizers
• Energy to generate aerosol comes from a vibrating piezoelectric
crystal
Aerosol out

. . Large aerosol droplets are

.. . .. .. . emitted from the apex and

smaller droplets from the
Carrier gas in
. .. Aerosol chamber lower areas

Diaphragm

Sound waves

Piezoelectric
transducer

Ultrasonic nebulizer (adapted from Florence & Attwood)

 Mesh Nebulizers
• These are more recently developed devices and involve aerosol
being generated by a vibrating mesh
• Mesh (perforated plate) may have up to 7000 holes etched with
a laser
Vibrational energy due to a
piezoelectric crystal which
Liquid reservoir Piezoelectric transfers energy to the mesh
transducer via a transducer

Newer designs are able to

coincide aerosol release with
the patient’s breathing →
reducing drug wastage

Ultrasonic nebulizer (adapted from Florence & Attwood)

Summary
• pMDIs can be adapted to take into account the needs of
special patient groups
• There are a diverse range of DPIs and whilst these
overcome some challenges (e.g. coordination) and
environmental issues they also have disadvantages
• Nebulizers (which can be of several different designs) can
be used to administer higher doses of drug
Directed Study
• Aulton's Pharmaceutics: The Design and
Manufacture of Medicines (2021), 6th Edition.
Kevin M.G. Taylor, Michael E. Aulton (Eds.)
– Pages: 647 – 653

• Aulton's Pharmaceutics: The Design and

Manufacture of Medicines (2017), 5th Edition.
Kevin M.G. Taylor, Michael E. Aulton (Eds.)
– Pages: 660 – 666