R18 - Inhaler technologies 1

Which classes of drugs are delivered to the lungs?

The main classes of drugs delivered to the lungs by inhalation are:

1. β₂-adrenoceptor agonists (bronchodilators)

• Examples: Salbutamol (SABA), salmeterol (LABA).

• Relax airway smooth muscle, causing bronchodilation.

2. Muscarinic receptor antagonists (bronchodilators)

• Examples: Ipratropium (SAMA), tiotropium (LAMA).

• Block muscarinic receptors, preventing airway smooth muscle contraction.

3. Inhaled corticosteroids (ICS)

• Examples: Beclometasone, budesonide, fluticasone.

• Reduce airway inflammation and swelling.

4. Inhaled antibiotics

• Examples: Tobramycin, colistin methanesulfonate sodium.

• Treat bacterial lung infections, particularly in cystic fibrosis or bronchiectasis.

5. Mucolytics

• Example: Dornase alfa.

• Break down components of thick mucus, making it easier to clear from the lungs.

Key point for exams: The three main inhaled drug classes used to manage asthma and COPD are β₂-agonists, muscarinic antagonists and inhaled corticosteroids.

Why are drugs delivered to the lungs?

Drugs are delivered directly to the lungs by inhalation because:

1. Rapid onset of action – Drugs reach the airways quickly, producing a faster therapeutic effect.

2. Direct delivery to the site of action – Drugs act directly on the lungs, where they are needed to treat conditions such as asthma and COPD.

3. Lower doses required – A smaller dose can produce the desired effect because the drug is delivered directly to the target site.

4. Fewer systemic side effects – Less drug may enter the bloodstream compared with oral administration, reducing unwanted effects elsewhere in the body.

5. Avoids first-pass metabolism – The drug absorbed through the lungs enters the bloodstream without initially passing through the liver.

6. Large surface area – The lungs have a large surface area and good blood supply, allowing rapid absorption of drugs intended for systemic delivery.

How are drugs delivered to the lungs?

As an aerosol = dispersion of solid particles or liquid droplets in a gas
▪ Source of energy required to form an aerosol
▪ Specialised inhalation devices are used
▪ Nebulisers
▪ Pressurised metered dose inhalers (pMDI)
▪ Dry powder inhalers (DPI)
▪ Soft mist inhalers (SMI

What are the challenges?

Drug particles must deposit in the right area of the airways;
▪ The lungs act as a filter to keep particles out
▪ Drug particle size is critical
▪ Only particles < 5 μm enter the lungs
▪ Small particles are very cohesive

How does the anatomy of the Lungs affect drug delivery?

Trachea and bronchi
▪ Branching system
▪ Main function: filter and condition inspired air
▪ 100% humidity in airspaces
Bronchioles and alveoli
▪ Main function: gas exchange

What are the biological barriers in the lungs?

Airways
▪ Epithelium is ciliated and
covered in mucus
Alveoli
▪ Epithelium is very thin and permeable
▪ No cilia or mucus

What is the mucociliary clearance?

Airway epithelium covered by a viscoelastic mucus layer
▪ Composed mainly of water, glycoproteins and cell debris
▪ Biphasic:
→ Low-viscosity layer in contact with epithelium
→ Upper, more viscous gel layer
▪ Protects epithelium from dehydration, inhaled particles,
microbiological infection

▪ Particles trapped in mucus, propelled to the oropharynx
by the action of cilia and swallowed
▪ Thinner mucus layer, lower cilia density and lower ciliary
beating frequency in lower airways
▪ Particles cleared within 15-20 min

How do drug particles deposit in the lungs?

Three main mechanisms:
▪ Inertial impaction
▪ Sedimentation
▪ Brownian diffusion

Depending on:
▪ Particle properties (size, density, shape, charge…)
▪ Patient’s respiratory tract morphology
▪ Patient’s inhalation technique

What is inertial impact?

Due to inertia, large particles (> 10 μm) are unable to remain in the streamline when air changes direction:
▪ Particles impinge on airway walls
▪ Affects particles with high mass and velocity
▪ Occurs in the oropharynx and large airways → Particles are swallowed

What is sedimentation?

Particles deposit in the respiratory tract due to gravity
▪ Increases with residence time in the lungs
▪ In lower airways or alveoli depending on size and density

What is brownian diffusion ?

• Particles < 1μm are propelled in random directions by collision with gas molecules until they strike a surface
  ▪ Favoured by long residence time
  ▪ Occurs in alveoli
  → Particles may accumulate in alveoli
  → Drug may be absorbed in bloodstream

What are the consequences for drug delivery to the lungs?

Inhalation devices must deliver drug particles
▪ to the small bronchi
▪ in the 1-5 μm size range
▪ in a controlled and reproducible manner
▪ The mechanism of sedimentation must be promoted

How do nebulisers work?

Drug formulated as an aqueous solution or suspension
▪ Compressed air or ultrasound aerosolises the formulation into liquid droplets
▪ Patient slowly inhales mist through a mouthpiece or face mask

Types of nebuliser;

• jet, ultrasonic

What is a jet nebuliser ?

Compressed air is forced through a narrow hole (venturi)
▪ High-velocity air breaks drug solution/suspension up into droplets
▪ Large droplets are forced back into the liquid formulation by baffles
▪ Compatible with most drugs/formulations
▪ Heavy and noisy!
▪ Long delivery time

What are the advantages and limitations of nebulisers?

Advantages
▪ Very easy to use by anyone
▪ Aqueous formulation
▪ Can deliver large doses (antibiotics)
▪ Visible mist (patient reassured)

Limitations
▪ Bulky, not portable
▪ Lengthy nebulisation time
▪ Low efficiency
▪ 50% of the dose wasted
▪ < 10% reach the lungs
▪ Susceptible to microbiological contamination (sterility required, high maintenance)

How do pressurised metered dose inhalers (pMDIs) work?

Drug formulated in a liquefied gas (‘propellant’) under pressure inside an aluminium canister
▪ One dose is released when the pMDI is actuated
▪ Aerosol formed by evaporation of the gas at atmospheric pressure
▪ Patient inhales cloud through the mouthpiece

What is the role of the metering valve?

Ensures an accurate and reproducible VOLUME of drug formulation is delivered
▪ Different from continuous spray valves (household aerosols, medicinal aerosols for skin applications)
▪ Volume: 25-100 μL

How it works (3 steps)

1. At rest: The upper valve is open, and the lower valve is closed, allowing the metering chamber to fill with the drug formulation.

2. Firing (pressing the inhaler): The upper valve closes, and the lower valve opens, releasing the measured dose of medicine as an aerosol.

3. Refilling (releasing the inhaler): The lower valve closes, and the upper valve opens again, allowing the metering chamber to refill for the next dose

What are the requirements for propellants in pMDI?

• Liquid under pressure (3-5 atmosphere)
  ▪ Gas at atmospheric pressure and ambient temperature
  (low boiling point)
  ▪ Vapour pressure must remain constant (dose uniformity)
  ▪ Non-flammable, non-toxic
  ▪ Chemically inert and compatible with drug formulations
  ▪ Available in pharmaceutical grade

Which gases are used as ?propellants

Previously: Chlorofluorocarbons (CFC, Freon)
▪ Ozone-depleting gases
▪ Have been phased out

▪ Currently: Hydrofluoroalkanes (HFA-134a, HFA-227),High global warming potential

▪ New propellant: Hydrofluoroalkane HFA-152a:
▪ 90% reduction in global warming potential
▪ First approved by MHRA in July 2026 (beclometasone
dipropionate)
▪ Slightly flammable
▪ Has been linked to addiction (euphoria)

How are drugs formulated in propellants?

Most commonly as a suspension:
▪ Most drugs are insoluble in the propellant
▪ Better control of drug particle size

▪ Main concern: to deliver a correct dose
▪ Each volume of suspension must be homogeneous

▪ Surfactants added to the formulation to:
▪ Improve stability/homogeneity of the suspension
▪ Aid in the formation of a flocculated suspension (easily redispersible)
▪ Very few surfactants are approved in inhaled products (ex:oleic acid, lecithin, sorbitan trioleate)

Which other excipients are added?

Flavours – to mask bitter drugs
▪ Sweeteners – to mask bitter drugs
▪ Lubricants – to improve valve operation
▪ Density modifiers – to decrease sedimentation rate
▪ Antioxidants – to prevent chemical degradation
▪ Ethanol − to help solubilisation

Issues: They must be soluble in the propellant and approved
for inhalation

How to use a pMDI correctly?

pMDI first needs to be:
▪ shaken
▪ primed (fired to waste) if not used daily

The patient needs to:
▪ synchronise actuation with inhalation
▪ inhale slowly, smoothly and deeply
▪ hold their breath for 5-10 sec

What are the drug delivery
issues with pMDI?

A large proportion of patients are unable to co-ordinate
actuation with inhalation
▪ Particles leave the pMDI at a high velocity
▪ Patients’ inhalation rate is too high
▪ Young children are unable to hold their breath

Consequences:
▪ High deposition in the oropharynx
▪ low deposition in the lungs (± 20% of emitted dose)
▪ Side effects (cough, dysphonia, candidiasis, systemic effects)

What are possible solutions? 1- spacer devices

Patient fires pMDI inside spacer and inhales through a face mask or mouthpiece
Advantages:
▪ Delay between actuation and inhalation
▪ Decreased velocity of the spray
▪ More time for the propellant to evaporate
▪ Allows the ‘tidal breathing’ technique

BUT are cumbersome
▪ Decreases the dose inhaled by the patient (deposition in the device, electrostatic charges)
▪ Need to be cleaned regularly

What are possible solutions? 2- Breath-actuated pMDI

Inhaler fired by the patient’s inhalation:
▪ No coordination needed
▪ Inhalation flow rate must be high enough to trigger the device (30 ml/min for Autohaler, 20 ml/min for Easibreathe) → may not be an option for young children, frail elderly

▪ Particles still leave the inhaler at a high velocity
▪ Expensive!

What are the advantages and limitations of pMDIs?

Advantages
▪ Compact, portable, robust
▪ Multi-dose
▪ Rapid delivery
▪ Consistent format and operation
▪ Good dose content uniformity
▪ Good protection against moisture and pathogens
▪ Inexpensive

Limitations
▪ Usually no breath-actuation
▪ Low lung deposition
▪ No dose counter on most!
▪ Only low doses can be delivered (< 1mg)
▪ Need priming
▪ Drug formulation is challenging
▪ High carbon footprint