Inhalation & Nasal Drug Delivery

Inhalation and nasal drug delivery routes exploit the large mucosal surface areas of the respiratory tract for local and systemic drug delivery. The lungs offer approximately 100 m² of alveolar surface area, thin epithelium, and rich blood supply — properties ideal for rapid drug absorption and avoidance of first-pass hepatic metabolism. This lesson covers respiratory anatomy, particle deposition, inhaler device types, metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulisers, nasal drug delivery, and spacer devices.

Respiratory Tract Anatomy and Drug Deposition

Upper Respiratory Tract (URT)

The nasal cavity, nasopharynx, and oropharynx filter large particles (>10 μm) through impaction and mucociliary clearance. The nasal turbinates create turbulent flow that deposits particles >5 μm by inertial impaction.

Lower Respiratory Tract (LRT)

• *Trachea and main bronchi*: Large-diameter airways; deposition of 5–10 μm particles by impaction.
• *Bronchi and bronchioles (generations 3–16)*: Intermediate airways; particles 2–5 μm deposit by sedimentation (gravity) in the upper bronchial tree and are cleared by mucociliary escalator.
• *Respiratory bronchioles and alveolar ducts (generations 17–23)*: Fine airways; particles 1–3 μm deposit by sedimentation and diffusion. This is the target zone for bronchodilator and corticosteroid delivery.
• *Alveoli (generations 24–)*: Particles <1 μm are exhaled; nanoparticles (< 0.5 μm) may deposit via diffusion (Brownian motion).

Mechanisms of Deposition

1. *Inertial impaction*: Particles with high momentum cannot follow airstream curves → deposit at bifurcations; dominant for large particles (>5 μm) and high flow rates.
2. *Gravitational sedimentation*: Larger particles fall under gravity in slow-moving air of small airways; dominant for 2–5 μm at slow inhalation.
3. *Brownian diffusion*: Random motion of very small particles (<0.5 μm) causes deposition; significant only in alveoli.

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Mass Median Aerodynamic Diameter (MMAD)

The aerodynamic diameter determines where a particle deposits in the respiratory tract, regardless of its physical shape or density. MMAD is the diameter at which 50% of particles (by mass) are above and 50% below.

Target MMADs for Drug Delivery

• Nose/URT: > 5–10 μm (deliberate for nasal sprays acting locally)
• Bronchial tree (larger airways): 3–5 μm
• Peripheral lung/alveoli: 1–3 μm (inhaled corticosteroids, bronchodilators — target for maximum lung deposition)
• Alveolar gas exchange: <1 μm (largely exhaled; not useful)

Fine Particle Fraction (FPF)

The proportion of the emitted dose with MMAD ≤ 5 μm. FPF is a critical quality parameter for inhalers; regulatory specifications typically require FPF > 20–30% to ensure adequate lung delivery.

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Metered Dose Inhalers (MDIs)

MDIs are pressurised aerosol devices that deliver a metered dose of drug in a propellant upon actuation. Originally using CFC propellants (now phased out globally under the Montreal Protocol), modern MDIs use hydrofluoroalkane (HFA) propellants (HFA 134a, HFA 227ea), which are ozone-benign.

Components

• Canister: Pressurised drug-propellant formulation (solution or suspension) under 200–500 kPa.
• Metering valve: Delivers a precise volume (25–100 μL) per actuation.
• Actuator (mouthpiece): Shapes the aerosol plume.

How MDIs Work

1. Shaking (suspension MDIs) ensures homogeneous drug distribution.
2. Patient actuates canister by pressing down — propellant and drug are released.
3. Flash evaporation of propellant generates aerosol with initial droplet velocity >100 km/h.
4. Droplets evaporate as they travel through actuator; final MMAD 1–5 μm.
5. Patient inhales slowly and deeply, followed by a 10-second breath hold.

MDI Technique Errors

Poor MDI technique is common: studies show 50–90% of patients make at least one critical error. Key errors:

• Not shaking (suspension) → dose inconsistency
• Actuation before/after inhalation → oropharyngeal deposition rather than lung deposition
• Too fast inhalation (>60 L/min) → increased impaction; spacers reduce this
• Not breath-holding → premature exhalation of fine particles
• Cold MDI → reduced propellant pressure → spray too slow

Priming

New MDIs and those unused for >7–14 days must be primed (1–4 actuations to waste) to ensure accurate dose delivery from initial use.

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Dry Powder Inhalers (DPIs)

DPIs deliver drug as a dry powder, without propellant. The patient's own inspiratory effort de-aggregates (disperses) the powder into fine particles suitable for lung deposition. This patient-driven de-aggregation means that adequate inspiratory flow is essential.

Types of DPI

• *Single-dose*: Each dose is loaded manually (e.g., Handihaler, Aerolizer). Requires patient dexterity and cognitive function.
• *Multi-dose reservoir*: Drug stored in bulk reservoir; device meters individual doses on actuation (e.g., Turbuhaler, Clickhaler). Desiccant included; protection from moisture essential.
• *Multi-dose blister*: Pre-metered doses in blister strips (e.g., Diskus/Accuhaler, Ellipta). Dose counter visible; moisture protection from individual blisters.

Inspiratory Flow Requirement

Minimum inspiratory flow: typically 30–60 L/min (device-specific). Turbuhaler requires ≥60 L/min; Diskus requires ~30–60 L/min; Handihaler requires ~20–30 L/min. Patients with severe airflow obstruction (FEV1 < 30% predicted) may be unable to generate adequate flow.

DPI Advantages vs MDIs

• No propellant; lower carbon footprint (HFA MDIs have significant global warming potential)
• No coordination required
• Dose counter provides feedback
• Breath-actuated → automatically triggered by inhalation

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Nebulisers

Nebulisers convert a drug solution or suspension into a fine aerosol mist suitable for inhalation without requiring patient coordination or high inspiratory flow. They are used in:

• Acute severe asthma and COPD exacerbations (hospital and home)
• Patients unable to use MDI/DPI (infants, severely debilitated, intubated patients)
• Drug delivery of certain agents not available in MDI/DPI format (e.g., dornase alfa, tobramycin, amphotericin B for nebulisation)

Types of Nebuliser

1. *Jet (pneumatic) nebulisers*: Compressed air or oxygen passes through a narrow orifice (Venturi effect), atomising the drug solution. Most common; cheap; efficient.
2. *Ultrasonic nebulisers*: Piezoelectric crystal vibrates at ultrasonic frequency, creating standing waves that generate aerosol from the liquid surface. Not suitable for proteins (denaturalisation by heat/ultrasonic energy) or suspension formulations.
3. *Mesh nebulisers*: Drug solution is forced through a vibrating mesh plate with precision micro-holes. Efficient; quiet; suitable for proteins; used in hospital-grade and portable devices (Aerogen Solo).

Clinical Considerations

• Fill volume: Minimum 2 mL; 4–5 mL optimal (residual dead volume ~0.5–1 mL).
• Nebulisation time: 10–15 minutes for jet nebulisers; 5–7 minutes for mesh.
• Drug stability: Drug must be stable at room temperature throughout nebulisation; mixing of drugs in nebuliser must be validated (not all combinations are compatible).
• Infection control: Nebuliser components must be cleaned and dried after every use; replace every 3 months (community) or per single use (hospital).

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Nasal Drug Delivery

The nasal route is used for both local (rhinitis, sinusitis) and systemic (migraine, osteoporosis, nausea) drug delivery.

Anatomy Relevant to Nasal Delivery

• Total nasal mucosal surface area: ~150 cm²
• Nasal epithelium: Pseudostratified ciliated columnar epithelium; mucociliary clearance (MCC) removes particles to nasopharynx within 15–20 minutes
• Rich submucosal vascular supply → rapid systemic absorption
• Olfactory epithelium at roof of nasal cavity: Potential route for CNS delivery (nose-to-brain pathway)

Advantages of Nasal Route for Systemic Drugs

• Rapid absorption (avoids GI degradation and first-pass metabolism)
• Suitable for peptides and proteins (though MCC limits contact time; formulation strategies — bioadhesives, absorption enhancers — extend residence time)
• Non-invasive; patient-friendly compared to injection

Nasal Sprays — Clinical Examples in NZ

• Intranasal corticosteroids: Fluticasone furoate (Avamys), budesonide (Rhinocort), mometasone (Nasonex) — local anti-inflammatory for allergic rhinitis; minimal systemic absorption
• Intranasal DDAVP (desmopressin): For nocturnal enuresis, diabetes insipidus; absorbed rapidly
• Zolmitriptan nasal spray: 5 mg intranasal for acute migraine; faster onset than oral
• Naloxone nasal spray: 1.8 mg/0.1 mL for opioid overdose reversal; used by NZ police, first responders
• Calcitonin salmon intranasal spray: For Paget's disease; convenient alternative to injection

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First-Pass Avoidance

Pulmonary inhalation is one of the most effective routes for first-pass avoidance. Drugs absorbed from the alveolar surface enter the pulmonary capillaries and drain directly into the pulmonary veins → left atrium → systemic circulation, bypassing hepatic portal circulation entirely.

This is of particular clinical importance for:

• Short-acting beta-2 agonists (SABAs): Oral salbutamol undergoes significant first-pass metabolism (bioavailability ~50%); inhaled salbutamol achieves therapeutic concentrations in the bronchial tree with minimal systemic absorption.
• Inhaled corticosteroids (ICS): Beclomethasone, fluticasone, budesonide — inhaled doses are 100-fold lower than would be required orally.
• However: Drug deposited in the oropharynx IS swallowed, absorbed from GI tract, and subjected to first-pass metabolism. For high-potency ICS (fluticasone), oropharyngeal deposition can cause oral candidiasis (thrush); rinsing the mouth after ICS use is recommended to reduce this.

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Spacer Devices

A spacer (or valved holding chamber, VHC) is an add-on device for MDIs that holds the aerosol cloud in an intermediate chamber, allowing the patient to inhale at their own pace.

Functions of a Spacer

1. Eliminates the need for patient hand-breath coordination (the actuate-then-inhale coordination error is the most common MDI error).
2. Slows aerosol velocity and allows propellant evaporation → smaller particle size → greater fine particle fraction → better lung deposition.
3. Removes large oropharyngeal droplets that cause local side effects (oropharyngeal candidiasis with ICS; dysphonia with ICS).

NZ Recommendations

BPAC NZ and the Asthma Foundation recommend spacers for:

• All children using MDIs (mandatory in under-5s; strongly recommended under-12s)
• Adults with poor MDI coordination
• All patients using ICS via MDI

Spacer Maintenance

• Wash weekly with warm soapy water; do not dry with cloth (electrostatic charge reduces drug delivery) — leave to air dry.
• Replace annually or when visibly damaged.
• One MDI actuation at a time into spacer; multiple actuations reduce dose per actuation (fine particles collide and aggregate).