Exam 3- Lecture 5: Pulmonary Drug Delivery I

What is the mean regional diameter & volume for mouth?

• 5 cm

• 30 cm³

What is the mean regional diameter & volume for tracheobronchial (TB)?

• 0.2 cm

• 170 cm³

What is the mean regional diameter & volume for alveolar?

• 0.073 cm

• 2800 cm³

What are alveoli?

Tiny air sacs at end of bronchioles, where crucial exchange of oxygen & carbon dioxide b/w blood in capillaries & inhaled air takes place

What is the alveolar membrane?

Quite thin, allowing efficient diffusion of gases across

What does the vast number of alveoli create?

A huge surface area for gas exchange

What are the advantages for pulmonary delivery?

• Large surface area for delivery ~100m² in adults

• Close proximity to blood flow

• Avoids first-pass hepatic metabolism

• Small doses are enough to achieve equivalent therapeutic effects as compared to oral administration

What are the disadvantages of pulmonary delivery?

• Anatomical, aerodynamic (deposition) filter is difficult to overcome during administration

• Drug particles may become entrapped in mucus lining airways & cleared during normal mucociliary movement

• Only ~10-40% of drug particles from conventional inhalation devices are absorbed

What is local pulmonary delivery?

• Minimally invasive

• High concentration of drug delivery immediately to site of action

• Minimized risk of side effects

• Rapid clinical response

• Bypasses barrier to therapeutic efficacy

• Achieves a similar or superior therapeutic effects as a fraction of systemic dose

What is systemic pulmonary delivery?

• Noninvasive

• Potentially suitable for a wide range of substances, ranging from small molecules to peptides

• Prolonged residence time will increase absorption

• Reproducible absorption kinetics w/o worry of dietary complications

• Afrezza → inhaled insulin

What is the key to pulmonary drug delivery?

• Deliver the correct mass to correct location

  • Too large a mass en route to target may prevent particles from marking it to target

  • Particles that are too small run the risk of being exhaled

What typically happens once a drug particle contacts surface of lungs?

It will “stick” whether that is an airway tract or alveolar sac

What is deposition?

Process by which inhaled drug particles settle onto or adhere to surfaces w/in respiratory tract & involved inertial impact, sedimentation, & Brownian motion (diffusion)

What is inertial impaction?

Deposition mechanism in which high-momentum aerosol particles (generally aerodynamic diameter >5micrometers) deviate from changing airstream trajectories & impact airway walls, predominately occurring in oropharynx, trachea, & large conducting bronchi where airflow velocity & directional changes are greatest

What is gravitational sedimentation?

Deposition process by which particles in approximate 1-5 micrometer aerodynamic diameter range settle out of airstream under gravitational forces during low-velocity airflow & inspiratory pause, occurring primarily in small conducting airways, terminal bronchioles, & alveoli

What is Braumian diffusion (motion)?

Random thermally driven motion of submicron particles (<1 micrometer aerodynamic diameter) leading to deposition by molecular collision & concentration gradients, occurring predominately in alveolar region where airflow is minimal & residence time is prolonged

What can clearance of inhaled particles be impacted at?

Multiple levels that include mucus barrier, mucociliary clearance, alveolar clearance (primarily trough lympathic drainage), immune response (primarily by alveolar/airway macrophages, ~dendritic cells)

What must drugs be?

• Large enough to avoid diffusion-based deposition

• Small enough to not get stuck on way to where drug is intended to be delivered

• Ideal size 1-5 micrometers → 0.5-5

What is a metered dose inhaler (MDI)?

Primary dosage form used for local pulmonary drug delivery (albuterol)

What are key components of MDI?

• Pressurized container

• Metered dose chamber & valves

• Nozzle

• Mouthpiece

What does each dose (press of the actuator) produce?

Particles having an appropriate size & size distribution to achieve maximum absorption deep w/in the lungs

What do propellants function as?

Pressurized vehicle systems that, upon valve actuation, undergo rapid phase transition & expansion to generate a fine aerosolized plume w/ controlled droplet size distribution for deposition in lower respiratory tract

What are the most common propellants?

• C2H2F4

• C3HF7