Pulmonary Drug Delivery [Vitaliy] Flashcards
What is pulmonary drug delivery?
Drug is delivered to the lungs to be absorbed into the blood circuulation
What occurs in the lungs?
The lung is an organ of external respiration
Oxygen and carbon dioxide are exchanged between blood and inhaled air
Why are the lungs an attractive drug target?
Large surface area
Good blood supply
What is the aerodynamic particle diameter (da)
The diameter of a sphere with a density of 1 g/cm3 that has the same aerodynamic behaviour as the particle which shall be characterised
List the 3 processes responsible for particulate deposition in the lungs
- Impaction
- Gravitational sedimentation
- Diffusion
Different particles will deposit differently in the lungs
What is gravitational sedimentation?
Particles settling under gravity will attain a constant terminal settling velocity, Vt
Gravitational sedimentation of an inhaled particle is dependent on its size, density and residence time in the airways
What is inertial impaction?
This is the dominant deposition mechanism for particles > 1um in the upper tracheobronchial regions
A particle with a large momentum may be unable to follow the changing direction of the inspired air as it passes the bifurcations - so it will collide with the airway walls
What is brownian diffusion?
Of little significance for particles > 1um
Particles below this size are displaced by a random bombardment of gas molecules = particle collision in the airways
The probability of particle deposition by diffusion increases as the particle size decreases
How are larger particles (greater then 10um) deposited in the airways?
The particles will impact in the upper airways
They are rapidly removed by coughing, swallowing and mucociliary processes
How are smaller particles (0.5-5um) deposited in the airways?
The particles may escape impaction in the upper airways and will deposit by impaction and sedimentation in the lower airways
Describe the structure of the airways
Trachea > Mainstream bronchus > Lobar bronchus > (Segmental bronchus) > Bronchiole > Aveolar duct > Aveolus
List the 4 physical factors which affect particle deposition in the airways
- Lung morphology = drug particles must pass down a successive series of branching tubes of constantly decreasing size
- Oral vs nasal breathing = for pulmonary, aerosols are inhaled via the mouth
- Inspiratory rate flow = increasing inspiratory rate flow will enhance deposition by impaction in the larger airways
- Breath holding = enhances the deposition of particles by sedimentation and diffusion
How does optimal aerosol deposition occur?
With slow, deep inhalations to total lung capacity
Followed by breath-holding prior to exhalation
List 5 pharmaceutical factors affecting aerosol deposition
- Aerosol velocity
- Size and size distribution
- Shape
- Density
- Physical stability
Describe the journey of the drug particles through the mucus barrier
The drug needs to dissolve in the mucus layer
Once in solution, the drug will then diffuse through the mucus layer and enter the aqueous environment of the epithelial lining liquid
What will the rate of diffusion through the mucus layer depend on?
Mucus viscosity
Molecular size of drug
Interactions between drug and mucus
What is mucociliary clearance?
The mucus layer does not exist as a stagnant layer - constantly propelled along the airways by rhythmic beating of the cilia on epithelial cells
List 3 advantages of pulmonary drugs delivery for locally-acting drugs
- Reduced dose compared to oral dosing
- rapid onset of action
- Reduced side effects as reduced dose
List 2 advantages of pulmonary drug delivery for systemically acting drugs
- Large surface area for drug absorption
2. Highly vascular surface promotes rapid absorption and onset of action
List 2 disadvantages of delivery of systematically-acting drugs via the pulmonary route
- Complex delivery delivery devices are required to target drugs to the airways - may be inefficient
- Drug absorption may be limited because of mucus
What are the 3 current devices use to delivery drugs to the lungs?
- Pressurised metered-dose (pMDI)
- Dry powder inhalers (DPI)
- Nebulisers
Explain how a pressurised metered-dose inhaler (pMDI) works
The most commonly used inhalation drug delivery system
- Drug is either dissolved or suspended in a liquid propellant with other excipients
- It is preserved in a pressurised canister and fitted with a metering valve
- A predetermined dose is released as a spray on actuation on the metering valve
- When released from the canister, it undergoes volume expansion and forms a mixture of gas and liquid
- The high speed gas flow helps to break up the liquid into a fine spray of droplets
What components make up a pMDI?
Container - chemically inert
Metering valve - designed to release fixed volume
An elastomeric seal
The actuator
What are propellants?
Usually liquefied gases
Traditionally these are CFCs and increasingly hydrofluoroalkanes (HFAs)
List 3 criteria of propellants used in pMDIs
- Low pulmonary toxicity
- High chemical stability
- Compatibility with packaging
Most of the drugs are insoluble in the propellants, they are usually presented in suspensions
How does a dry powder inhaler work (DPI)?
- The drug is inhaled as a cloud of fine particles
- The drug is either preloaded in the device or filled into hard gelatin capsules/foil blister discs which are loaded into the device prior to use
How do multi-dose DPIs work?
The drug is mixed with a coarse lactose carrier and filled into an aluminium foil blister disk
The patient loads this into the device on a support wheel
Each disc contains 4 or 8 doses of drug
How do nebulisers work?
- Nebulisers convert aqueous solutions or micronised suspensions of drug into an aerosol for inhalation
- They deliver relatively large volumes of drug solutions/suspensions
- Frequently used where the therapeutic dose is too large for delivery with the inhalers
How can the regional distribution of aerosols in the airways be measured?
Using radiopharmaceuticals
How can the aerosol size by analysed?
- Microscopy
- Laser diffraction
- Cascade impaction
