Pulmonary Drug Delivery: Mechanisms, Devices, and Factors Affecting Deposition

Pulmonary Drug Delivery

Introduction

Pulmonary drug delivery refers to the administration of medications directly into the lungs, primarily for the treatment of respiratory diseases such as asthma and COPD. This route offers rapid onset of action, minimizes systemic side effects, and avoids hepatic first-pass metabolism.

• Direct delivery to the site of action in the lungs.

• Lower doses required due to targeted delivery.

• Rapid onset for certain medications (e.g., bronchodilators).

• Minimizes GI upset and systemic absorption.

Advantages and Disadvantages of Pulmonary Drug Delivery

Advantages

• Delivery to site of action (local effect).

• Lower doses required.

• Reduction of systemic side effects.

• Large surface area for absorption.

• Rapid onset of action.

• Avoids GI upset and first-pass metabolism.

• Lung environment can be less hostile for certain drugs.

Disadvantages

• Dose estimation and reproducibility can be difficult due to many variables.

• Proper technique and guidance are required for effective use.

• Mucus and infection may impede drug deposition in lower airways.

• Physical stability of pharmaceutical aerosols may be problematic.

• If systemic effect is intended: absorption limited by mucous layer and mucociliary clearance reduces retention of drugs in the lungs.

Respiratory Tract Anatomy

Lower Respiratory Tract

• Trachea divides into bronchi.

• Bronchi divide into bronchioles.

• Bronchioles end in alveoli, where gas exchange occurs with the blood.

Factors Affecting Drug Deposition in the Lung

Overview

• Physicochemical properties of aerosolized droplets and/or active pharmaceutical ingredient (API).

• Physiological and anatomical considerations (e.g., lung structure, breathing patterns).

• Delivery device characteristics.

Physicochemical Factors

• Particles must settle on lung tissues for effective delivery.

• Mean Aerodynamic Diameter (MAD): Diameter of a unit density sphere with the same settling velocity as the particle.

• Stokes Diameter: Diameter of a sphere with the same density and settling velocity as the particle.

Aerosol Size and Work Region

Aerosol Size	Work Region
> 10 μm	Nasopharyngeal or oropharyngeal regions (e.g., nasal spray for perennial rhinitis, corticosteroids)
5 to 10 μm	Central airway (e.g., mucokinetic drugs)
2 to 5 μm	Oropharynx and large airways to overall respiratory tract (e.g., bronchoactive aerosols)
0.8 to 3 μm	Terminal airways and alveolar region (e.g., anti-infective drug pentamidine)

Settling Velocity

Settling velocity describes the motion of particles in a viscous fluid, adapted from Stokes' law:

• $D_{ae}$ = aerodynamic diameter

• $D_v$ = volume equivalent diameter

• $P_p$ = density of the particle

For spherical particles between 2 to 5 μm, slip factors can be eliminated. For particles <1 μm, slip factors must be considered.

Additional Formulation Factors

• Humidity: Respiratory tract humidity is 99.5% at 37°C. Hydrophilic particles increase in MAD due to hygroscopicity.

• Temperature

• Stability: Drug should not decompose before reaching target.

• Penetration

• Electrostatic charge

• Inertial impact: Velocity of airstream affects deposition, especially in upper airways.

Particle Size Considerations

• Very small particles (<1 μm) may remain airborne and be exhaled, reducing efficacy.

• Aerosols with a large proportion of sub-micron particles have poor lung deposition.

Dispersed Liquid Phase

• For drugs dissolved or dispersed in a liquid phase, solvent evaporation can occur, reducing droplet size over time.

Patient Factors Affecting Deposition

• Lung anatomy and breathing patterns.

• Age: Lung function declines with age.

• Disease state (e.g., bronchitis, asthma).

• Food and amount of food do not play a significant role.

Types of Pulmonary Drug Delivery Systems

Aerosols

• Pressurized dosage forms emitting fine dispersions of liquid/solid drug in a gaseous medium.

• Dependent on container, valve assembly, and propellant.

• Can dispense dry powders.

Metered-Dose Inhalers (MDIs)

Advantages

• Reliable, consistent dose delivery.

• Quick onset of action.

• Fewer side effects compared to oral route.

• Most medications available in this form.

• Portable and low cost.

Disadvantages

• Requires good coordination of actuation and inhalation.

• Not very efficient as a delivery device.

• Most have no built-in counter; uncertainty when cartridge is empty.

MDI Components

• Container

• Metering valve (releases fixed volume per actuation)

• Elastomer seal (controls propellant leakage)

• Actuator (discharges spray)

• Drug (suspension in liquefied propellant or solution in cosolvent + propellant)

• Propellant/excipient mixture

MDI Operation

1. Pressing canister releases drug-propellant mixture under pressure.

2. Propellant expansion and vaporization create aerosol.

3. Propellant (usually HFA) is required for function.

MDI System Types

• Two-phase system: Active ingredient in liquid propellant and vapor phase.

• Three-phase system: Water-immiscible liquid propellant, propellant-immiscible liquid (usually water), and vapor phase.

Additional MDI Details

• Contains surfactants for suspension and valve lubrication.

• Metering chamber volume: 30–100 μL.

• Produces MAD of about 3–6 μm (depends on technique and velocity).

Dry Powdered Inhalers (DPIs)

Advantages

• Automatic coordination between dose delivery and inhalation.

• No propellants needed.

• Potential drug stability advantages.

• High dose carrying capacity.

Disadvantages

• Requires high inspiratory flow rate from patient.

• Procedural errors possible.

DPI Operation

• Micronized medication particle size: ~1–5 μm.

• Aerosol generated by drawing air through drug powder dose.

• Contains carrier (bulking agent) to enhance dose metering and reproducibility; drug dissociates from carrier upon inhalation.

• Carrier also improves flow properties and protects powder from humidity.

DPI Devices

• Diskus: Examples include Advair Diskus and Flovent Diskus.

• Ellipta: Smaller, easier to use; contains two reels of strips for combination products (e.g., Arnuity, Breo).

Nebulizers

Mechanism

• Transform liquid medication into fine mist using piezoelectric crystal vibration.

• Allows deep airway inhalation.

• Droplet size and deposition depend on orifice diameter, pressure, density, concentration, viscosity, surface tension, and flow rate.

• Surfactants lower surface tension for fine droplet formation.

• Delivered via compressed air, oxygen, or ultrasonic power.

Advantages

• Passive breathing; minimal coordination needed.

• Good for pediatric patients and those with low inspiratory flows/volumes.

• Drug concentration can be adjusted.

• Anything in solution can be nebulized.

Disadvantages

• Time consuming.

• Requires external power source.

• Requires cleaning.

• Inefficient (delivers as little as 10% of dose); cumbersome.

Nebulizer Components

• Air compressor (Jet Nebulizer only)

• Nebulizer cup

• Mask or mouthpiece

• Medication (unit dose vials or bottles with measuring devices)

• Compressor tubing

• Baffle (ultrasonic nebulizer only; decreases MAD)

Concerns with Nebulizers

• Risk of contamination with multi-use vials.

• Older nebulizers may cause drug solution evaporation and heating, increasing drug concentration over time.

• API can crystallize if machine is not cleaned after use.

Spacers/Holding Chambers

• Help ensure medication is delivered to lung.

• Decrease particle size for improved delivery.

• Less/no coordination required; good for pediatric patients.

• Faster and cheaper than nebulizer.

• Reduce medication settled in oropharynx.

• Bulkier device; requires cleaning.

Summary Table: Pulmonary Drug Delivery Devices

Device	Advantages	Disadvantages
MDI	Reliable dose, rapid onset, portable	Requires coordination, no dose counter
DPI	No propellant, automatic coordination	High inspiratory flow required
Nebulizer	Passive breathing, adjustable dose	Time consuming, inefficient
Spacer	Less coordination, improved delivery	Bulkier, cleaning required

Key Terms and Concepts

• Aerosol: Suspension of fine solid or liquid particles in a gas.

• Mean Aerodynamic Diameter (MAD): Diameter of a unit density sphere with same settling velocity as particle.

• Stokes Diameter: Diameter of sphere with same density and settling velocity as particle.

• Brownian Motion: Random movement of particles <1 μm.

• Inertial Impact: Effect of particle velocity on deposition, especially in upper airways.

Example

Albuterol (Proventil HFA®, Ventolin HFA®) is a common bronchodilator delivered via MDI for rapid relief of asthma symptoms. Advair Diskus is a DPI used for maintenance therapy in asthma and COPD.

Additional info: These notes cover the core principles of pulmonary drug delivery, including device mechanisms, physicochemical and patient factors, and comparative advantages/disadvantages, suitable for Anatomy & Physiology students studying respiratory physiology and pharmacology.