W5 Pulmonary Drug Delivery l ll and lll Flashcards
Why delivery drugs via the respiratory route?
- Rapid onset of activity when given for a local affect, e.g. bronchodilators such as salbutamol
- Smaller doses of drug are required which is more economical and leads to lower side effects
- Useful if there are bioavailability issues, e.g. high first-pass metabolism
- High lung surface area and good blood supply makes provides potential for systemic delivery
But the lungs are designed for gaseous
exchange and have evolved to reduce
the inspiration of particles
How are drugs delivered to the lungs?
– Solid particles suspended in the air
– Liquid particles suspended in the air
- Gases are also sometimes administered via the pulmonary route, e.g. oxygen, anaesthetic
How do you measure particle size?
da = dp (p/po)^1/2
Where;
dp= physical diameter
p= particle density
po= unit density
What is the aerodynamic diameter (da)?
The diameter of a sphere of which settles
through air with a velocity equal to that of the particle in question
What is inertial impaction
What is sedimentation?
What is diffusion?
Structure of the airways
The lungs are made up of an extensive network.
What do Gen 0 and Gen 23 stand for?
Gen 0- Trachea
Gen 1- Mainstem bronchus
Generation 23- when drugs reach the alveoli
There are up to 6 × 10^8 alveoli in the lungs
State the Pulmonary Drug Delivery Devices.
– Pressurised metered-dose inhalers (pMDIs)
– Dry powder inhalers (DPIs)
– Nebulisers
– Electronic cigarettes
Many medical gases (including medical oxygen) are regulated as medicinal products
Pressurised metered-dose inhalers (pMDIs)
What type of drug is salbutamol?
Medihaler launched in 1956 for the
delivery of adrenalin or isoprenaline
* Allen & Hanburys launched the first
selective β2-receptor agonist salbutamol (Ventolin) in the 1960s
* Drug is dispersed in the liquid propellant – may be in solution or a suspension
* Dose (set volume) released on actuation of a metering valve
What are the components of pMDIs:
Canister: typically aluminium
Metering valve: controls the volume delivered
Propellant:hydrofluoroalkanes
(HFA) e.g. HFA-134a,HFA-227 (liquified gases)
Filling of pMDI canisters:
What is the cold filling method?
- Drug + excipients + propellant
chilled to 60 °C and added to canister - Further (chilled) propellant added and canister sealed (with the valve)
- QC: leak tested – placed in water bath and then weighed
Filling of pMDI canisters:
What is the pressure filling method?
- Ethanol can also be added
BEFORE the valve crimped in
place
1. Drug + excipients + propellant
added to the canister under pressure (through the valve
2. Further propellant (under
pressure) added
3. QC: leak tested – placed in water bath and then weighed
Formulation of pMDIs (for info 1/2)
- pMDIs originally contained chlorofluorocarbons (CFCs) but
discovered in the 1980s that these damaged the ozone layer - CFCs removed from pMDIs during the late 1990s/ early 2000s
and replaced with hydrofluoroalkanes (HFAs) - HFAs still greenhouse gases and will need to be phased out
Formulation of pMDIs (for info 2/2)
- Drug may be dispersed in the propellant as a solution (two-phase system) or a suspension (three-phase system)
- HFA-134a and HFA-227 exhibit low relative permittivity values so are not good solvents for many drugs (or excipients)
- Surfactants may be required as suspending agents and/or valve lubricants
Surfactants:
* Lecithin
* Oleic acid
* Sorbitan trioleate
=Previously used at 0.1% to 2.0%
w/w in CFC-based inhalers
=Solubility <0.02% w/w in HFAs hence
requires cosolvent (ethanol)
Co-solvents, e.g. ethanol, 2-propanol, can be added to aid solubility of drugs and excipients = can increase droplet size
pMDIs and formulation (for info)
- HFA salbutamol pMDIs were largely bioequivalent to CFC inhalers but beclometasone pMDIs not interchangeable
- From the BNF:
- QVAR has extra-fine particles, is more potent than traditional beclometasone diproprionate CFC-containing inhalers and is approx 2x as potent as Clenil Modulite
- When beclometasone dissolved in the propellant this can lead to very small particles (more potent)
- Some formulations include a less
volatile solvent, e.g. Clenil Modulite
Inhaler needs to be prescribed by brand
Ventolin vs Salamol
Which is better economically?
Ventolin brand salbutamol inhaler is not included in the All Wales Adult Asthma Management and Prescribing Guideline
Excipients:
Ventolin- HFA 134a
Salamol- Ethanol, anhydrous; Norfluane (Propellant HFA-134a)
Ventolin MDI has been omitted from the guidelines as it is an MDI with a very high carbon footprint. Salamol in comparison has a lower carbon footprint although it is still classed as a high global warming potential inhaler
Advantages & Disadvantages of pMDIs
Advantages:
- Portable
- Low cost
- Drug protected from environment in canister
- Multiple doses in one device
- Reproducible dose
- Efficient at drug delivery (cf. oral route)
- Disposable
Disadvantages
- Incorrect use by patients
- Greenhouse gases
- Inefficient at drug delivery!
- Disposable
How are pMDI sustainable?
They are bulky dosage forms that use plastics and aluminium. Both are recyclable but no national recycling schemes exist.
pMDIs and special patient groups
(for info)
- 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
- 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
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
Dry powder inhalers (DPIs)
DPIs use no propellant and rely on the force of the patient’s
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)
What are the advantages and disadvantages of DPIs?
Advantages
* Propellant-free, i.e. better for the
environment than pMDIs DPIs require inspiratory flow rates of 30-90 L/minute
* Being breath-actuated they avoid inspiration and actuation coordination issues
* Can deliver larger doses of drug than pMDIs
Disadvantages
* Sometimes a higher upfront cost
* DPIs more exposed to ambient air which may cause stability issues
* Route Adm is not always suitable for patient compared to pMDI
Formulation of DPIs:
- Drug particles should be <5 m for biopharmaceutical reasons
need to be micronized - 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 - Lactose typically used for carrier particles
Formulation of DPIs
Micronization: process of reducing drug particle size to micron size ranges
(typically <5
m in diameter)
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
Multidose DPIs
Multidose DPIs can be broadly divided into two categories called..?
What are the brand name examples?
- Multiple unti dose device
* Diskhaler and Accuhaler - Reservoir based device
* Turbohaler and Clickhaler
*
– Multiple unit dose device
– Reservoir-based device
Smart inhalers
Smart inhalers use sensors in the
device to detect and record on
the use of the inhaler
* The inhaler connects via
Bluetooth to a smartphone or other device and (should the
patient choose to) their data can be shared with the prescriber/
asthma specialist
* GoResp Digihaler (Teva) was launched in the UK in July 2023
* DPI containing budesonide (steroid), formoterol fumarate
dihydrate (long-acting β2-agonist)
* Data gathered can include:
– How often the device is use
– Inspiratory flow rate (important for a DPI)
Nebulizers
What are they?
What are the adv and disadv?
- 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 - Nebulizers are used in hospital and
domiciliary settings - Generally not very portable due to
their size and power requirements
Nebulizers
Nebule contents emptied into nebulizer
and inhaled over an extended time period
A nebulizer mask (James Heilman MD)
What is the 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
- Can be a solution or suspension
Saline-based nebules can also usually be
diluted with normal saline if required
What are the 3 types of nebuliser?
- Jet Nebulizers
- Ultrasonic Nebulizer
- Mesh Nebuliser
Jet Nebulizers
- These require compressed air from a cylinder, hospital air line
or electrical compressor
Jet Nebulizers
Jet nebulizer (adapted from Aulton’s Pharmaceutics)
Compressed air passed through
the Venturi nozzle – low pressure
created draws liquid up from the
reservoir through a feed tube
Baffle ensures that (larger) non-
respirable particles are not
inhaled and can be recycled
Aerosol out
Aerosol droplet size and drug
delivery is determined by the
compressed gas flow rate
Ultrasonic Nebulizers
Energy to generate aerosol comes from a vibrating piezoelectric crystal
Large aerosol droplets are emitted from the apex and smaller droplets from the
lower areas
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 transfers energy to the mesh via a transducer
Newer designs are able to coincide aerosol release with the patient’s breathing= reducing drug wastage
Pulmonary delivery for a systemic effect
(for info)
- Pfizer’s Exubera dry powder insulin formulation was launched in the UK in 2006 (but withdrawn in 2007)
- Significant challenges overcame including the development of an insulin formulation stable at room temperature
- Insulin deagglomerates in the chamber prior to inhalation
- Referred to (in Aulton) as a breath-assisted DPI
- Compressed air generated
by movement of the handle on the device - Sanofi launched MannKind’s Afrezza inhaled insulin device
in 2015 (“withdrawn” in 2016) - Another dry powder formulation: insulin + Technosphere
aggregates (2 – 5 m) which rapidly dissolve in the lung - Overcame some of the issues with Exubera but 25% of all
Afrezza® users experienced cough and sales were
ultimately disappointing
Pulmonary delivery for a systemic effect
AER-501 insulin formulation from AERAMI Therapeutics is under development
AER-501 is a liquid formulation of human insulin and is
inhaled using a small, smart inhalation device
* Similar principle to that of a mesh nebuliser, i.e. vibrating
mesh technology
Pulmonary delivery for a systemic effect
AER-501 is delivered with the AFINA Inhaler
Image from AERAMI Therapeutics
Liquid insulin formulation is
added dropwise (by the patient)
into the inhaler
Electronic cigarettes
- In widespread public usage and MHRA have recently
published guidance for licensing electronic cigarettes - Multiple designs available (disposable / refillable)
- Formulation: cartridge typically contains nicotine,
propylene glycol, glycerine (glycerol), flavourings
Aerosols contain fewer numbers
(and lower levels) of toxicants
than cigarettes
Evidence emerging that usage
indoors increases concentration
of nicotine / particulate matter in
the air
Medical Gases Administration
- Medical gases may be delivered in cylinders or generated in situ, e.g. using an oxygen concentrator
- Hospital uses and domiciliary care
- Oxygen gas is under pressure in a
cylinder and the flow is controlled with a regulated tap (central pipelines often used) - Continuous positive airway pressure
ventilation (CPAP) – O2 enriched air
delivered via mask/ hood/ nasal cannula - Ventilator – machine that helps with
breathing; air or O2 enriched air delivered via a breathing tube
What is Scintigraphy?
What can Lung scintigraphy be used for?
- Scintigraphy = radiation emitting substances are administered to a patient and the subsequent emissions are captured by a gamma camera and an image produced
Lung scintigraphy can be used as a diagnostic tool and also to
evaluate new respiratory formulations
* Diagnostic: patient inhales nebulized radionuclide-containing
solution and/or has radiopharmaceutical injected iv
* Formulation: drug-carrier aggregates are radiolabelled (Tc99m) and loaded into the device. Participants would inhale from the
device and deposition of drug would be imaged
(can assess bioavailability)
