Delivery Systems & Formulation For Inhalation Flashcards
How do we deliver drugs to the lungs?
Aerosol
Dispersion of solid particles or liquid droplets in a gas
(Needs a source of energy required to form an aerosol)
Types of inhalers
1) Nebulisers
2) Pressurised metered dose inhalers (pMDI) - widely used + most convienient
3) Dry powder Inhalers (DPI)
Nebulisers
Aqueous drug solution/suspension aerolised onto droplets
- energy provided by compressed air or ultrasound
pMDI
Drug formulated in a liquefied gas under pressure
- Aerosol formed by evaporation of the gas at atmospheric pressure
DPI
Drug normally with other solid excipients in a dry powder state
- Aerosolisation by patient’s inhalation
2 types of Nebulisers
Jet Nebuliser
Ultrasonic Nebuliser
Jet Nebuliser
Air from a compressor forced through a narrow hole to give high velocity air stream
- High velocity air breaks drug solution/suspension into droplets for inhalation
- baffles used to remove larger particles
Ultrasonic Nebuliser
- Piezoelectric (vibrating) crystal emits high frequency signal
- breaks drug solution/suspension into droplets for inhalation
- lighter + quieter than a jet nebuliser
How to use nebulisers
Patient breaths normally into face mask/mouthpiece
Patient needs to wash it every time
Advantages of Nebulisers
- aqueous drug solutions
- no hand-lung coordination
- good for elderly + children
- no controlled inhalation manoeuvre required
- useful in severe, acute asthma attacks
- large doses of drugs not normally available can be given
- low cost
- visible mist (patient reassured)
Disadvantages of nebulisers
- not fully portable
- equipment not fully regulated
- lengthy nebulisation time
- low efficiency
- as low as 10% of drug reaches lungs
- solution concentrates as water evaporates
- insoluble drugs require solubilisation
- some suspensions can be difficult to nebulise
- susceptible to microbiological contamination
Name the different parts of a MDI
Metered dose inhaler (Canister) container requirements
Must:
- withstand high pressure
- Robust
- Light in weight
- Inert
- Made of aluminium/stainless steel
pMDI metering valve
Ensures accurate + reproducible volume of drug formulation is delivered
Different from continuous spray valves
volume = 25-100 microlitres
pMDI propellant requirements
Must be:
- liquid under pressure
- gas at atmospheric pressure + ambient temperature
- that its vapour pressure must stay constant
- non-flammable, non-toxic
- chemically inert + compatible with drug formulation
Types of propellants in pMDIs
Chlorofluorocarbons
Hydrofluoroalkanes
CFCs
Ozone depleting gases
Banned
Responsible for ‘cold-freon effect’
Hydrofluoroalkanes
Drugs need to be re-formulated due to different properties of HFA vs CFC
New valve materials had to be developed
What is the dose range for each actuation in a pMDI?
Dose per actuation from 5 microgram to 5 milligram
Drug formulation types for pMDIs
Drug is soluble in propellant
- drug solubilised in propellant
- ethanol might be added as a co-solvent
Drug is insoluble in propellant (most common)
- micronised drug particles suspended in propellant
- surfactants added to increase suspension stability
Suspension formulation of a pMDI
- each volume of suspension must be homogenous
- surfactants added to formulation to
- improve stability
- aid in the formulation of a flocculated suspension
- surfactants approved in inhaled products: oleic acid, sorbitan trioleate, lechitin
Problems with suspensions
Sedimentation
Flocculation (reversible aggregation by shaking)
Caking (difficult to redisperse)
Particle size growth by Ostwald ripening (deposition in lungs reduce)
How can we minimise caking
Controlled flocculation
what is the ideal suspension stability
Slow flocculation (>30 secs)
Slow sedimentation (>30 secs)
Easy redispersion
(still need to shake device before use to redisperse settled flocculates)
Excipients included in pMDI drug formulation
Flavours - to mask bitter drugs
Sweeteners - to mask bitter drugs
Lubricant - to improve valve operation
Density modifiers - to decrease sedimentation rate
Antioxidants - to prevent chemical degradation
Why use spacer devices with pMDI
Increase lung deposition
- delay between actuation + inhalation
- decrease velocity of the spray
- more time for the propellant to evaporate
However, it is cumbersome (have to carry around bulky device) + decreases dose inhaled by patient (deposition in the device as electrostatic charges cause droplets to stick to chamber)
How to improve inhalation of pMDI
Spacer devices
Breath-actuated pMDI
Why does a Breath-actuated pMDI improve inhalation for the patient?
Inhaler is fired by the patients inhalation
No coordination needed
Particles still leave inhaler at a high velocity
Advantages of pMDI
Compact, portable, robust, convenient
Multi-dose
Short treatment time
Consistent format
Good dose content uniformity
Inexpensive
Good protection against moisture + pathogen
Inexpensive
Disadvantages of pMDI
Usually no breath-actuation
Low lung depostion
No dose counter
Only low doses can be delivered (<1mg)
Need priming before use
Performance depends on temperature
Drug formulation is challenging
Not environmentally friendly - HFAs are still greenhouse gases
What are Dry Powder Inhalers?
Delivers dry powder, no solvent
Developed for delivery of sodium cromoglicate as large dose could not be delivered by pMDI
Breath actuated (no coordination required)
As a drug + excipients in a dry form tend to be more stable than drug dispersed in a solvent as in pMDI
Components of DPI
Drug powder or blend of drug with excipients
Drug reservoirs or pre-metered doses
Body of device
Cap to protect powder from dust, moisture
Principles of DPI operation
Patient’s inspiration flow is used to:
- fluidise the static powder blend
- de-aggregate particle agglomerates into inhalable particles
Dose delivered + deposited into the lungs depends on the patient’s inspiratory flow rate
DPI - particle de-aggregation
Particles less than 5 micrometers are extremely cohesive
Types of DPI
Unit dose device
Multiple unit dose
Reservoir devices
DPI: Single uni dose device
Drug excipients In capsule
DPI: multi-unit dose
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DPI- multidose reservoir devices
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