Lung, Inhaler devices & Formulations

Question 1

Advantages of inhaling drugs into lungs -4

Answer 1

1. Direct to site of action - has a rapid onset due to blood supply & large SA
2. Lower doses than PO or IV - fewer S/Es & less chance of toxicity.
3. Avoids first pass metabolism, so greater BA
4. alternative to injection

Question 2

Requirements of Aerosol - 2

Answer 2

1. Stable suspension of solid particles or liquid droplets in a gas.
2. < 100micrometers, low mass so particle collisions suspend particles in air

Question 3

5 Deposition mecdhanisms

Answer 3

Inertial impaction(90%)
Gravitational Sedimentation(9%)
Diffusion(1%)
Interception(too long to go past some junctions)
Electrostatic Deposition(increases migration to airway walls)

Question 4

Inertial impaction - 2

Answer 4

1. Force of airstream causing particles tendency to move in a straight line.
2. Proportional to aerodynamic diameter & typically occurs for larger particles.

Question 5

Gravitational Sedimentation - 2

Answer 5

1. Dependant on terminal settling velocity - typically happens lower down in the respiratory tract due to lower air velocity, causing higher residence time.
2. Proportional to aerodynamic diameter^2 x residence time.

Question 6

Diffusion deposition - 2

Answer 6

1. Important for small particles - want deposition in terminal bronchioles & alveoli.
2. Higher residence time increases deposition.

Question 7

Factors controlling rate of aerosol deposition - 8

Answer 7

1. Aerodynamic diameter
2. Particle size distribution (ideally mono-dispersed)
3. Speed of release - if too fast will be deposited too high up in the airways
4. Flow rate
5. Inhaled volume
6. Breath holding pause
7. Anatomical & physiology variations
8. Obstructive airway diseases

Question 8

Factors controlling delivery to lung - 5

Answer 8

1. Formulation - Drug + excipients & blending
2. Device - Design, efficiency & performance
3. Patient Activation - Deagglomeration & inhaled dose
4. Lung deposition - Particle size, impaction & sedimentation
5. Physicochemical properties

Question 9

What role do propellants have in pMDIs - 3

Answer 9

1. Gas compressed & pressure turns gas into a liquid where drug is formulated.
2. Releasing pressure boils propellant into gas, leaving behind aerosol of drug particles.
3. pMDI propellants currently hydrofluoroalkanes (HFAs)

Question 10

3 main drug formulations for pMDIs

Answer 10

Suspension - drug crystal + propellant, small drugs

Solution - soluble drug in liquified propellant, particle size determined by solubility of drug in propellant.

Non-volatile solution - aerosol droplet, such as glycerine that will not evaporate, particle size is determined by the additive

Question 11

Requirements for suspension based formulations - 2

Answer 11

1. Drug to be milled/micronized & relatively insoluble in the propellant.
2. Drug must be freely dispersed in the propellant - required vigorous shaking before drug release to ensure re-dispersion.

Question 12

What is the main problem of suspension based formulations?

Answer 12

Physical instability.

Question 13

5 causes of physical instability in suspension based formulations?

Answer 13

Flocculation - Loss agglomerates clumping particles together

Bulk Sedimentation - Creaming or sedimentation

Irreversible Aggregation - Crystal growth and caking

Crystal Structure Instability - Polymorphic Interconversion

Adhesion to Cannister - Inside surface is often coated for this reason, e.g. PTFE

Question 14

What may be used to avoid physical instability in suspension based formulations?

Answer 14

Surfactants or dispersing agents.

Question 15

Other solution based problems - 4

Answer 15

1. Co-solvent can cause corrosion of aluminium canister
2. Drugs can be relatively unstable.
3. Co-solvent lowers the internal propellant pressure, thus, atomisation is less effective.
4. Modification of drug chemical structure

Question 16

What tests are done on a pMDI formulation - 2

Answer 16

1. Check sedimentation rates, particle size changes & microscopy.
2. Dose uniformity

Question 17

How is an aerosol dose check done

Answer 17

Using an impactor: particles filtered through 8 increasingly smaller compartments - collecting the smaller particles in pans, indicates where particles reach in the lung.

Question 18

Differences between suspensions & solution-based formulations - 2

Answer 18

1. Solution is a soluble drug while suspensions are typically insoluble.
2. Suspensions are more chemically stable but less physically stable.

Question 19

5 Adv of pMDIs

Answer 19

1. Many doses
2. Compact
3. Consistent delivery
4. Relatively cheap
5. Sealed cannister protects drug

Question 20

4 Dis of pMDIs

Answer 20

1. Patient co-ordination & force requires to actuate
2. Uncomfortable (cold & forceful)
3. Tail off at the end of a can
4. Varying deposition pattern in airways

Question 21

Inhaler technique for pMDI - 3

Answer 21

1. Shake before usage & breath out as far as comfortably possible away from the inhaler.
2. Place inhaler in the mouth & inhale slowly while simultaneously pressing the canister. Continue to inhale slowly until lungs are full.
3. Hold breath for 10 seconds to allow drug to settle in target region

Question 22

What are breath actuated inhalers?

Answer 22

The mechanism automatically activates the pMDI when the patient inhales at a fast enough rate.

Question 23

Outline what a dry powder inhaler - 2

Answer 23

1. Inspirational flow driven inhalers - the drug is formulated as a dry powder, which the patient sucks into their lungs.
2. It is automatically breath-actuated and relatively easy to use.

Question 24

Aerosolization - 5

Answer 24

1. Conversion of a powder to an aerosol: Air separates powder bed & creates a flow between to pick up particles allowing them to travel.
2. The particles further disaggregated by physically pulling them apart.
3. Prior to inhalation, DPI formulation has no potential for lung deposition
4. Patient’s forced inspiration provides energy for fluidisation & entrainment of the formulation & de-aggregation of the drug for delivery to the lungs
5. Patients need to generate a minimum inhalation flow (Qmin) → Variation of inhalation flow rate a variation of drug delivery

Question 25

What key factors determine DPI respirable dose delivery?

Answer 25

Inhaler device, patient inspiratory flow & powder formulation.

Question 26

What importance does DPI device design hold - 4

Answer 26

1. DPI designed to create turbulence in airflow to increases de-aggregation allowing for more drug to be delivered to the lungs. 2. These features also create a resistance - which helps in turbulence 3. However, the higher the resistance the lower the flow rate for the same amount of patient effort. 4. This can cause asthma to be uncontrolled.

Question 27

3 Adhesive forces

Answer 27

1. Van der Waals forces Finite attractive force between all atoms, the sum of attractions between molecules that are temporary dipoles. Short range & dominant at low humidifies. 2. Electrostatic forces Caused by frictional contact between dissimilar materials - is a long range force that can be attractive or repulsive. 3. Capillary forces Condensation of water vapour between contiguous bodies forms a liquid bridge. Strength of the force is directly related to relative humidity & hydrophobicity.

Question 28

What factors influence interparticulate adhesion forces - 3

Answer 28

1. Particle size & shape 2. Surface roughness & chemistry (especially micronized particles) 3. Humidity

Question 29

Outline carrier based systems in DPIs - 2

Answer 29

1. Adv: accurate dose measurement, improved handling & processing & carrier properties can be altered to control fine particle fraction. 2. Properties that control drug delivery: size, shape, roughness, physical form, salt form, carrier material & Drug:Carrier ratio.

Question 30

Outline agglomerated systems in DPIs - 4

Answer 30

1. For high dose drugs where carrier based systems are not feasible. 2. Free flowing macroscopic agglomerates can be produced via cohesive bond formation. 3. Efficient de-aggregation required so drug presented to lungs as particles. 4. Roughness of particles results in less adhesion so deaggregation is easier.

Question 31

DPI Adv - 5

Answer 31

1. Propellant free – more climate friendly 2. Some have no excipients 3. Breath-actuated 4. Can deliver relatively large doses 5. Drug is in dry, solid form

Question 32

DPI Dis - 5

Answer 32

1. Powder de-aggregation dependant upon patient’s ability to inhale 2. ↑ inhaled air velocity, ↑ de-aggregation of particles, but ↑ potential for inertial impaction 3. Exposure to ambient conditions may ↓ stability 4. Generally less efficient at delivery vs. pMDI 5. Some devices difficult for some patients to activate

Question 33

DPI inhaler tech - 6

Answer 33

1. Prepare the inhaler device & load the dose. 2. Breath out as far as comfortably possible away from the inhaler. 3. Place inhaler in mouth & seal lips around the mouthpiece. 4. Breathe in quick and deep until lungs full. 5. Initial flow rate most important, so breath must accelerate quickly 6. Hold breath for around 10 seconds

Question 34

What limitations do pMDIs & DPIs have - 4

Answer 34

1. Require a specific technique – not all patients are able to do this: 2. 10 second breath hold, may need to stop for oxygen 3. Can’t be used for very large doses 4. Can’t use DPIs for ventilated patients

Question 35

Nebulisers - 3

Answer 35

1. Drug contained in sterile aqueous solution 2. Uses external energy supply (e.g. electricity) to aerosolise drug solution 3. Aerosol then inhaled via mask or mouthpiece using tidal breathing - no special techniques or coordination.

Question 36

What are the pros and cons of pneumatic nebulisers?

Answer 36

Pros - Chest, small particle sizes Cons - Variable performance, dead volume, lower output, low portability.

Question 37

How do pneumatic nebulisers produce aerosols - 5

Answer 37

1. Drug solution in reservoir. 2. Drawn up capillary tube by capillary action. 3. High velocity air jet passes end of capillary tube, creating interface between drug solution & air jet. 4. The shear force of air causes droplets to form. 5. A baffle traps oversize drops by inertial impaction.

Question 38

What are the pros and cons of ultrasonic nebulisers?

Answer 38

Pros - reproducible, small particle size, high output, & low aerosol inertia. Cons - particle size depends on fill volume so dose increases towards end, expensive, heats solution (stability issues), poor for suspensions.

Question 39

What are static mesh nebulisers?

Answer 39

The mesh is a perforated plastic grid that forces the drug solution through these holes forcing the drug to become an aerosol.

Question 40

Outline vibrating nesh nebulisers (pros & cons included)

Answer 40

Vibrates mesh to force drug down into smaller drugs, solution forced through the holes into a respirable aerosol. Pros - reproducible, high output, smaller dead volume, portable, quiet, low aerosol inertia Cons - expensive

Question 41

Outline soft mist inhalers - 6

Answer 41

1. Emerging class of portable inhalers based off the drug dissolved in a non-volatile liquid (usually water) 2. Aerosolised in a single breath actuation 3. Requires tight control of droplet size via a mechanism within device. 4. Requires an external energy source, e.g. battery or spring 5. Aerosol is emitted as a slow-moving cloud 6. Combines adv ease of access wi/ nebulisers slow moving aerosol delivery.