Pulmonary Delivery and Aerosols

What is local or topical drug administration?

Directing aerosol particles to the surface of the lung e.g asthma, COPD, CF (use of antibiotics), pulmonary hypertension, lung infections

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What is systemic application via the lung?

Directly enters into blood. Avoids first pass metabolism and to ensure fast action (due to thin barrier used for gas exchange, drug passes through barrier). E.g. CNS stimulation, anaesthetics, diabetes (insulin), pain/migraine, appetite suppression

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Outline features of insulin formulation (1)

Formulating insulin as inhaler instead of injections (type 2 diabetes). Not successful in the market (people unsure about effectiveness, clinicians not aware of formulation, cheaper to use injections rather than inhalers)

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Outline features of insulin formulation (2)

Improvements made - still not successful due to clinicians not being taught how to use product

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Which are the factors considered when designing formulations/devices?

Pathophysiology. Pharmacology of drugs. Chemistry of drugs. Formulation and drug delivery of medications. Therapeutics - for asthma/COPD/CF

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How do we delivery drugs to or via the lungs?

Gases (exchange in alveolar regions, fast acting into systemic absorption). Aerosol (smokes - solid particles suspended in air, mists - liquid droplets suspended in air)

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What are the barriers for drug formulations for inhalation? (1)

Mouth, throat and lung (trachea, bronchioles etc). Bronchioles can be inflamed and contain mucus (resistant airway). Lungs (alveoli may not function properly/elastic recoil). Also, children (lungs are growing, size of lungs affects air flow, CF)

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What are the barriers for drug formulations for inhalation? (2)

Change in diameter affects airflow, changes in resistance. Airflow in lung decreases with increasing branching (graph). Airflow in lung affects by disease

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How do inhaled medicines really get to where we want them to go? (1)

Impaction (larger particles caught up, don't have time to turn around, impact on wall, >5 micron sizes, too large to be caught up in airstream). Sedimentation (particles 1-5 microns, in airstream slowly become heavier in deeper regions, sediment)

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How do inhaled medicines really get to where we want them to go? (2)

Diffusion (smaller particles, go around, impact on walls as well). Electrostatic deposition (charged particles)

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Which size of particles are required in the drug formulation for inhalation?

1-5 microns (want particles to reach bronchioles). <1 microns (can reach alveoli but can also be removed by mucus)

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Describe features of intertial impaction (1)

Impaction depends on particles momentum (size), position of particle in airstream on parent branch, angle of bifurication). Impaction is of significance for largest particles moving at highest speed in respiratory tract

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Describe features of intertial impaction (2)

10 microns (50% impaction). 5 microns (20% impaction), 3 microns (10% impaction), 1 micron (1% impaction)

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Describe features of sedimentation

Particles (0.5-5 microns) suspended in gas are subject to vertical gravitational force. Dominant mechanism for particles depositing in lower airways. 2 microns (55%), 1 micron (29%), 0.5 microns (10%)

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Describe features of diffusion

Dominant mechanism for particles <0.5 microns. Smaller particles, more deposit via diffusion in peripheral lung/alveolar space. Minor mechanisms for deposition - interception for elongated particles, charge reflection for charged particles

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Describe features of the aerodynamic diameter

da = dg (p^0.5). Two particles, same diameter, different densities, particle with lower density will move at a faster speed. Decrease density, increase size of particle, faster movement of particle

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What are the factors influencing lung deposition?

Particle size (airways 3-5 microns, alveoli 1-3 microns). Particle size distribution. Particle density. Particle shape. Particle hygroscopicity (solubility of drug)

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What happens to the drug once it deposits in the lung?

Depends on location in the lungs e.g. airways, alveoli (different properties/functions). Mucus layer, airway surface layer, epithelium, lamina propria, submucosa (removal of dust)

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What happens to the drug once it deposits in the upper airways?

Insoluble (drug removed via mucociliary escalator, lower local drug concentration). Drug dissolution (soluble drug - decrease local drug concentration, removal from lungs)

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What happens to the drug once it deposits in the alveolar region?

Macrophage clearance (local drug concentration decreases). Translocation (local drug concentration decreases, some drug passes through)

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What are the advantages of local delivery of drugs to the lung?

Drug delivered directly to target organ. Lower doses required for optimal effect. Rapid onset of action. Fewer systemic side effects. Non-invasive delivery

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What are the disadvantages of local delivery of drugs to the lung?

Low efficiency of delivery. Difficulty in breath coordination, manual handling of device or breathing through device. Corticosteroid use can suppress immune response. Throat irritation is possible

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What are the advantages of systemic delivery of drugs to the lung?

Very rapid onset of action. Circumvents first pass effect. Non-invasive delivery route. Good for biopharmaceuticals

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What are the disadvantages of systemic delivery of drugs to the lung?

Low efficiency of delivery. Some patients may have difficulty using some devices (handling/coordination). May need very low or very exact doses or special devices. Expensive compared with oral therapies

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Pulmonary Delivery and Aerosols

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