RESP - D. AEROSOLS-COVERED

Question 1

why are the lungs good at adsorbing drugs into systemic circulation

Answer 1

• massive SA but
• air velocity decreases as air goes deeper into lung

Question 2

why drug delivery via the lungs

Answer 2

1. rapid onset of action
2. smaller doses than oral formulations as avoid first-pass metabolism (10-40% reaches lungs and hence sys circulation)
3. less systemic and GI adverse effects
4. relatively comfortable

Question 3

advantages for local action in upper resp tract

Answer 3

1. direct access
2. rapid onset of action
3. avoid GIT and first-pass hepatic metabolism
4. lower doses
5. fewer side effects

Question 4

advantages for systemic action

Answer 4

1. avoids GIT (acidic pH, enzymes)
2. avoids first-pass hepatic metabolism
3. non-invasive
4. high bioavailability
5. rapid absorption, rapid onset of action (insulin - not degraded by proteases in stomach)

Question 5

what is the purpose of the airways

Answer 5

• heat and humidify inhaled air ‘conditioning’
• remove particles from inhaled air by deposition (filter) - KEY FUNCTION
• clear away deposited particles efficiently into GIT (via mucociliary escalator)
• particles shouldn’t reach alveoli where gas exchange takes place
• particles >10microns don’t reach alveoli
• 0.5-5microns deposit by impaction and sedimentation in lower regions
• <3microns can reach alveoli

Question 6

clearance of deposited particles

Answer 6

1. upper airway regions (trachea, top of lung)
   - epithelium covered with mucus which traps particles
   - mucociliary escalator: cilia move mucus with particles towards pharynx, swallowed into GIT
   - clearance in hours
2. alveolar region
   - no mucus or cilia
   - insoluble particles cleared very slowly (months/years)
   - clearance of soluble: dissolve, enter blood stream
   - clearance of insoluble by macrophages (phagocytosis) or surface tension effects (up to mucociliary escalator)

Question 7

how do we deliver pulmonary drugs

Answer 7

• aerosol: suspension of liquid/solid particles or droplets in a gas, sufficiently small to remain airborne for a considerable time

Question 8

properties to be an effective resp medicine

Answer 8

• deposit drug in appropriate lung position
• right dose
• overcome physiological barrier and resp defence mechanism

Question 9

Powder flow

Answer 9

10microns = stick together due to LSA and won’t flow so we granulate (form balls of particles which flow)

particle 70-100 microns = good flow
<70 microns = poor flow

Question 10

Inertial impaction

Answer 10

• most important in large airways
• air flows easily around bends
• particles in air leave flow due to inertia
• may impact on airway walls
• heavier the particle = more inertia (straight line)
  *proportional to diameter^2
• bigger particles deposit quickly in upper airways ie - back of throat and swallowed

Question 11

Sedimentation (settling)

Answer 11

• most important in smaller airways and alveoli and horizontally orientated airways
• particles settle by gravitation on airway walls
• settling velocity proportional to diameter^2 - Stoke’s law

Question 12

what is the aerodynamic diameter

Answer 12

• diameter related to how particles behave in air
  ‘diameter of a ‘pretend’ sphere with a density of 1g/cm^3 that has the same settling velocity in air as particle of interest’
• governs deposition by sedimentation and inertial impaction
• different sized particles can have same aerodynamic diameter as can have different overall densities

Question 13

Brownian diffusion

Answer 13

• most important is smaller airways and mechanism for particles <0.5microns
• small particles leave original flow lines by diffusion and deposit onto airway walls
• displacement from flow line proportional to 1/diameter
• smaller particles therefore show more diffusion

Question 14

Interception

Answer 14

• not for spherical particles
• for fibre-like particles
• particles contact airway surface due to their physical size/shape
• long fibres easily intercepted
• not due to aerodynamic diameter
• not used for medicines

Question 15

electrostatic deposition

Answer 15

• charged particles attracted towards airway walls by electrostatic charges
• aerosols with high charge and conc can repel each other and drive particles towards airway walls
• only for freshly generated (and charged) aerosols ie: from nebulisers

Question 16

what is the respirable fraction

Answer 16

• % of drug present in aerosol particles less that 5 microns in size (aerodynamic diameter) and hence likely to be deposited

Question 17

what devices stimulate inhalation process to figure out respirable fraction

Answer 17

1. Anderson cascade impacter
2. next generation impinger (more modern)

Question 18

particle sizing techniques to determine respirable fraction

Answer 18

1. microscopy
2. laser diffusion
3. aerosizer

Question 19

1. microscopy

Answer 19

1. optical - 0.5-1000microns
2. electron - 1nm - 5microns (higher resolution)

• several equivalent diameters: feret’s, martin’s

methods of size measurement:
1. manual measurements: expert visual judgement
2. automatic image analysis: can quantify shape data, impact of AI in processing

Question 20

2. laser diffusion (most common)

Answer 20

• the way particles scatter as light passes through it
• aerosols passes laser beam, light diffracted
• small particles diffract light through a large angle (big defraction)
• large particles diffract light through a small angle (straight through)
• detector measures refraction pattern produced
• computer calculator particle size distribution
• assumes spherical particle
• inhaler - aerosol blown into machine

Question 21

3. aerosizer

Answer 21

• time of flight of particles (0.2-700microns) between 2 laser beams
• detect light scattered by particles
• dry powder/sprayed from liquid suspension
• blown and accelerated by a constant known force due to airflow
• measurement of aerodynamic diameter
• smaller particles accelerated at greater rate

Question 22

Impaction methods

Answer 22

• recommended by pharmacopeias
• use of artificial lungs
• measurement of the aerodynamic diameter of particles
• prediction of site of deposition in lungs
• principle of inertial impaction

Question 23

principle of operation of impaction methods

Answer 23

• impactors: stages arranged in stack
• connected to a vacuum pump
• large particles impact on upper stages
• smaller particles remain in airstream and progress to next stage
• jets/nozzles decrease in diameter: increases air velocity
• particles separated according to their aerodynamic diameter

Question 24

Twin and multi-stage liquid impingers

Answer 24

• powder pulled from inhaler by vacuum pump
• large particles impact in upper chamber
• small particles carried to lower chamber
• cut-off diameter: 6.4 microns
• powder collected in solvent, minimal powder bounce and re-entrainment
• cheap, easy to use
• no size distribution
• BP method, not accepted by USP

Question 25

Andersen cascade impactor

Answer 25

- 8 stages - calibrated for a flow rate of 28.3L/min - cut-offs calculated according to flow rate - powder collected on dry stages - risk of particle bounce and re-entrainment (stages coated with oil to reduce this) - size distribution info - labour intensive - largely accepted

Question 26

Next generation acceptor

Answer 26

- easier to use - 7 stages - calibrated to flow rate required - powder collected in cups - minimal powder bounce - size distribution info - combines adv. of cascade impactor and multi-stage liquid impinger - BP accepted