W5 Pulmonary Drug Delivery l ll and lll

Question 1

Why delivery drugs via the respiratory route?

Answer 1

• 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

Question 2

How are drugs delivered to the lungs?

Answer 2

– 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

Question 3

How do you measure particle size?

Answer 3

da = dp (p/po)^1/2

Where;
dp= physical diameter
p= particle density
po= unit density

Question 4

What is the aerodynamic diameter (da)?

Answer 4

The diameter of a sphere of which settles
through air with a velocity equal to that of the particle in question

Question 5

What is inertial impaction

Question 6

What is sedimentation?

Question 7

What is diffusion?

Question 8

Structure of the airways
The lungs are made up of an extensive network.
What do Gen 0 and Gen 23 stand for?

Answer 8

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

Question 9

State the Pulmonary Drug Delivery Devices.

Answer 9

– Pressurised metered-dose inhalers (pMDIs)
– Dry powder inhalers (DPIs)
– Nebulisers
– Electronic cigarettes

Many medical gases (including medical oxygen) are regulated as medicinal products

Question 10

Pressurised metered-dose inhalers (pMDIs)
What type of drug is salbutamol?

Answer 10

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

Question 11

What are the components of pMDIs:

Answer 11

Canister: typically aluminium
Metering valve: controls the volume delivered
Propellant:hydrofluoroalkanes
(HFA) e.g. HFA-134a,HFA-227 (liquified gases)

Question 12

Filling of pMDI canisters:
What is the cold filling method?

Answer 12

1. Drug + excipients + propellant
   chilled to 60 °C and added to canister
2. Further (chilled) propellant added and canister sealed (with the valve)
3. QC: leak tested – placed in water bath and then weighed

Question 13

Filling of pMDI canisters:
What is the pressure filling method?

Answer 13

• 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

Question 14

Formulation of pMDIs (for info 1/2)

Answer 14

• 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

Question 15

Formulation of pMDIs (for info 2/2)

Answer 15

• 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

Question 16

pMDIs and formulation (for info)

Answer 16

• 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

Question 17

Ventolin vs Salamol
Which is better economically?

Answer 17

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

Question 18

Advantages & Disadvantages of pMDIs

Answer 18

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

Question 19

How are pMDI sustainable?

Answer 19

They are bulky dosage forms that use plastics and aluminium. Both are recyclable but no national recycling schemes exist.

Question 20

pMDIs and special patient groups
(for info)

Answer 20

• 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

Question 21

pMDIs and special patient groups

Answer 21

• 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

Question 22

Dry powder inhalers (DPIs)

Answer 22

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)

Question 23

What are the advantages and disadvantages of DPIs?

Answer 23

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

Question 24

Formulation of DPIs:

Answer 24

• 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)

Question 25

Drug in hard capsule DPIs

Answer 25

• 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

Question 26

Multidose DPIs
Multidose DPIs can be broadly divided into two categories called..?
What are the brand name examples?

Answer 26

1. Multiple unti dose device
   * Diskhaler and Accuhaler
2. Reservoir based device
   * Turbohaler and Clickhaler

*
– Multiple unit dose device
– Reservoir-based device

Question 27

Smart inhalers

Answer 27

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)

Question 28

Nebulizers
What are they?
What are the adv and disadv?

Answer 28

• 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)

Question 29

What is the formulation of Nebules?

Answer 29

• 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

Question 30

What are the 3 types of nebuliser?

Answer 30

1. Jet Nebulizers
2. Ultrasonic Nebulizer
3. Mesh Nebuliser

Question 31

Jet Nebulizers

Answer 31

• 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

Question 32

Ultrasonic Nebulizers

Answer 32

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

Question 33

Mesh Nebulizers

Answer 33

• 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

Question 34

Pulmonary delivery for a systemic effect
(for info)

Answer 34

• 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

Question 35

Pulmonary delivery for a systemic effect

AER-501 insulin formulation from AERAMI Therapeutics is under development

Answer 35

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

Question 36

Electronic cigarettes

Answer 36

• 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

Question 37

Medical Gases Administration

Answer 37

• 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

Question 38

What is Scintigraphy?

What can Lung scintigraphy be used for?

Answer 38

• 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)