RESP - D. DELIVERY SYSTEMS-COVERED

Question 1

what is an aerosol

Answer 1

dispersion of solid particles of liquid droplets in a gas
need energy to form an aerosol

Question 2

what are the 3 types of inhalers

Answer 2

1. nebulisers
2. pMDI - stored in pressure off solid (most common)
3. DPI - no pressure. energy source is the the force of inhalation

Question 3

Nebulisers

Answer 3

• aq drug solution/suspension aerosolised into droplets
• energy provided by compressed air or ultrasound
• not portable
• can deliver a large dose but it’s not a unit dose

Question 4

pMDI

Answer 4

• drug formulated in a liquefied gas under pressure
• aerosol formed by evaporation of gas at atm
• produces a unit dose on each actuation

Question 5

DPI

Answer 5

• drug with solid excipients in a dry powder state
• aerosolisation by patient’s inhalation
• produces a unit dose on each actuation

Question 6

Jet nebuliser (or atomizer)

Answer 6

• air from compressor forced through a narrow hole to give a high velocity air stream
• air stream breaks drug solution/suspension into droplets for inhalation
• baffles removes larger particles
• mask/mouthpiece used
• energy source = compressed air
• involves a pump and power source

Question 7

Ultrasonic nebuliser

Answer 7

• piezoelectric crystal emits a high frequency ultrasound that breaks a drug solution/suspension into droplets for inhalation (electric charge which creates sound waves - vaporises liquid)
• particles in suspension may be degraded by ultrasound as lots of energy put in
• suspension: inhale undissolved particles (≤5 microns)
• solution: droplets (≤5 microns)
• lighter and quieter than jet nebuliser
• no pump

Question 8

how to use nebulisers

Answer 8

• patient breathes normally into facemask/mouthpiece
• good for children and elderly

Question 9

advantages of nebulisers

Answer 9

• aq drug solutions used (easy or soluble drugs)
• no hand-lung co-ordination needed
• no controlled inhalation manoeuvre
• large doses can be given
• low cost
• visible mist - patient reassured

Question 10

disadvantages of nebulisers

Answer 10

• not fully portable
• equipment not yet fully regulated
• lengthy nebulisation time (1 hour)
• low efficacy: 10% drug reaches lungs
• solution concentrates as water evaporates
• insoluble drugs require surfactants or use suspension
• suspension can be difficult to nebulise
• microbiological contamination: chance of infection

Question 11

pMDI canister

Answer 11

• withstand high pressure
• robust (resistant to damage)
• light in weight (steel/aluminium)
• inert and non-stick (internal surface coated to prevent drug adhesion/degradation)
• aluminium/stainless steel

Question 12

pMDI metering valve

Answer 12

• ensures accurate and reproducible volume of drug
• 25-100 microlitres
• if want more drug: DPI

Question 13

pMDI propellant

Answer 13

• liquid under pressure (3-5 atmospheres)
• gas at atmospheric pressure and ambient temperature - low bpt (liquid boils to form gas)
• vapour pressure must stay constant (dose uniformity)
• non-flammable and non-toxic
• chemically inert and compatible with drug formulation
• chlorofluorocarbons were used
  ozone depleting gases
  banned
  responsible for cold-freon effect
• hydrofluoroalkanes
  drugs needed to be reformulated due to different properties of HFA vs CFC
  new valve materials
  reduce carbon footprint of MDI by 90% to a level similar to a DPI
  HFA-152a

Question 14

pMDI drug aspects

Answer 14

• dose per actuation = 5micrograms - 5mg
• particle (droplet) size of drug: <5microns needed
• drug substances usually large solid particles when manufactured (100microns - allow good flow) and poly disperse so size reduction required:

milling
micronisation
can change physical form of drug - can lead to polymorph change (different solubility and stability and hence bioavailability), degradation due to heat and formation of amorphous material

Question 15

pMDI drug formulation

Answer 15

• soluble in propellent
• insoluble in propellent:
  micronised drug particles suspended in propellent
  surfactants added to increase suspension stability
  (most common)

Question 16

pMDI suspension formulation

Answer 16

• each volume of suspension must be homogenous
• surfactants aded to improve stability/homogeneity of suspension and aid in formation of a flocculated suspension (easily redispersible)
  oleic acid, lecithin
  if insoluble in HFA - ethanol as co-solvent to solubilise them

Question 17

problems with suspensions

Answer 17

1. sedimentation
   - non-homogeneity
2. flocculation
   - reversible aggregation (good if controlled)
3. caking
   - clumping in layer
   - hard to redisperse
4. particle size growth by Ostwald ripening
   - large particles grow at expense of smaller ones
   - small crystals dissolve, and redeposit onto larger crystals

Question 18

how to minimise caking

Answer 18

controlled flocculation:
- slow flocculation (patient shakes, doesn’t immediately sediment out, time to use device)
- slow sedimentation
- easy redispersion

always shake before use to redisperse settled flocculates

Question 19

excipients that can be included in a pMDI

Answer 19

• flavours: mask bitter drugs
• sweeteners: mask bitter drugs
• lubricants: improves valve operation (surfactants?)
• density modifiers: decrease sedimentation rate
• anti-oxidants: prevent chemical degradation (esp liquids)

Question 20

why is co-ordinating activation with inhalation so difficult for patients

Answer 20

• due to the speed of drug release (0.1 seconds)
• particles leave at high velocity
• therefore get high deposition in oro-phayrnx and low deposition in lung

Question 21

how does a spacer help with improving inhalation with pMDI

Answer 21

• doesn’t suspend med for an extended period
• so still need to co-ordinate to an extent their breath to begin slightly before actuating pMDI

Question 22

how does a valve holding chamber device help with improving inhalation with pMDI

Answer 22

• added-one way valve which prevents medication loss if patients exhales into device
• traps and suspends particles long enough to be inhaled over a few seconds

Question 23

advantages of spacer and VHC devices

Answer 23

increased lung deposition
- delay actuation and inhalation
- decrease velocity of spray (less back of throat)
- more time for propellant to evaporate (get rid of taste)

Question 24

disadvantages of spacer and VHC devices

Answer 24

• cumbersome
• decreases dose inhaled due to deposition in device

Question 25

breath-actuated pMDI

Answer 25

- inhaler fired patients inhalation - no co-ordinated needed - aerosol still leaves inhaler at high velocity so some loss Easibreathe (some include a dose counter)

Question 26

advantages of pMDIs

Answer 26

- compact, portable, robust, convenient - multi-dose - short treatment time - consistent format and operation for all pMDIs - dose uniformity - good protection against moisture and pathogens - inexpensive - simpler formulation than DPI

Question 27

disadvantages of pMDIs

Answer 27

- no breath-actuation so need coordination - low lung deposition - no dose counter - only low doses (5micrograms - 5mg) - need priming before use - not environmental friendly

Question 28

DPIs

Answer 28

- no solvent involved - can deliver larger dose (20mg) - breath-actuated so no co-ordination required - more stable as no water to promote chemical reactions - store <30 degrees Celsius

Question 29

main components of a DPI

Answer 29

- drug powder/ bend with excipients - drug reservoir or pre-metered doses (cartridge, blister, capsule) - body - cap to protect from dust and moisture

Question 30

what does the patients inspiratory flow do in DPIs

Answer 30

- fluidises the static powder blend - deaggregate particle agglomerates into inhalable particle (drug deposited depends on inspiratory flow)

Question 31

DPI powder de-aggregation

Answer 31

- particles <5 microns are very cohesive due to large SA:mass ratio - moisture increases agglomeration so 1. drug blended with a carrier powder (50-100mm) with large particle size (lactose) = ORDERED MIX - flows well as large - drug must be separated from this carrier particle to be inhaled - large carrier particles deposit in oro-pharynx and swallowed - drug deposits in lungs *particles can't segregate due to size differences as they are adhered to each other. Only if a force is applied - turbulent flow on inhalation 2. spherical particles (spray-dried powders) can reduce particle contact area and hence aggregation 3. protection from moisture (blister pack)

Question 32

what are the 3 types of DPI

Answer 32

1. unit dose devices 2. multiple unit dose devices 3. reservoir devices

Question 33

Unit-dose DPI

Answer 33

- drug and excipient in capsule - capsule inserted into device - capsule pierced by pins as closed - patient inhales blend (SLOW AND DEEP) - have to refill - good dose uniformity Aerolizer Handihaler

Question 34

Multi-unit dose DPIs

Answer 34

- drug and excipient in blisters - 4-8 unit doses on a disk - Discinhaler (rotates) - Diskus has a coiled strip of 60 double foil-wrapped individual doses (1 month supply) and a dose counter - blisters pierced by moving lid/ratchet mechanism - disk/strip discarded when empty - not refillable - dispose

Question 35

multi dose reservoir DPIs

Answer 35

- drug/blend only in a compartment within device - drug dispensed into dosing chamber by patients action: twist shaves material off a pellet of the powdered drug - disposable one use only - powder equivalent to a pMDI - dose uniformity not as good and drug exposed to humidity (1 reservoir) - need a stronger inhalation than multi-unit dose DPI Turbohaler Easyhaler

Question 36

advantages of DPIs

Answer 36

- compact, portable, convenient - breath-actuated - no coordination - higher doses than pMDI - dose counter - dry state so better stability - environmentally friendly - no propellants

Question 37

disadvantages of DPIs

Answer 37

- breath-actuated - need sufficient force - can't be used by young children - different designs - affected by ambient humidity - need to get balance of particle carrier and drug particle adhesion and seperation - expensive