pMDIs

Describe the device used (before pMDIs were used) to treat asthma?

Bulky devices made up glass (fragile). Difficult to co-ordinate pressing device and inhaling the drug

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Which gases were previously used in the formulation for an inhaler?

CFCs (gas under pressure as liquid phase, mixed with drug, put in canister with crimp to ensure solidity). Used to solubilise drug molecules. Drug becomes gas when exposed to air (rapid)

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Why were CFCs removed from the market?

Due to being ozone-depleting gases

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Outline features of the prototype of pMDI (1)

Press canister to release metered dose and inhale the drug. High pressure in container (solution inside is a liquid). When release to atmospheric pressure (evaporation occurs). Solution becomes small droplets of particles of drug

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Outline features of the prototype of pMDI (2)

Use of propellant properties. From high pressure in canister to lower/normal pressure in atmospheric air, droplets expand/evaporate, single particles of drug formed

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Give examples of pMDIs

Airomir, Ventolin, Atrovent, Becloforte, QVAR etc. Devices look the same, principle is the same

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What are the requirements for all inhalers?

All inhalers must - generate an aerosol of reproducible aerodynamic size and size distribution, deliver a therapeutically relevant dose of drug, be easy to use for patients (patient education about inhaler technique). Inhalers need to be tested

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How does an inhaler work? (1)

Solution/suspension in canister. Crimp (canister seal). Materials in inhaler needs to be compatible (need to make sure it is stable/no interaction with solution or suspension)

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How does an inhaler work? (2)

Al canisters are used (solution under high pressure, prevent expansion/explosion when dropped). Ensure no oxygen/moisture entering (could lead to instability/hydrolysis of drug/contamination/change in properties)

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How does an inhaler work? (3)

Drug shouldn't be at the bottom (uneven distribution, dose not measured properly by metering valve, not mixed properly - doses used up with first use). Aerosol spray cone

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How does an inhaler work? (4)

Press canister, drug released, solution left in canister, drug particles enter into the lungs. Spacer can be used to slow down the movement of particles (no co-ordination needed) and small drug particles enter lungs (large particles on spacer wall)

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How does an inhaler work? (5)

Use of excipients used to solubilise drugs but don't want to add extra concentrations of excipients into the lungs (don't want damage the lungs) - restrictions/stability testing/storage testing e.g. temperature

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How does the metering valve work? (1)

At rest (storage of particles). Actuation (shake inhaler, ensure drug concentration is equal throughout solution, metering valve measures amount of drug to be delivered/closes valve). Firing (valve opens to release droplets)

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How does the metering valve work? (2)

Release (both valves closed). Chamber refilling. Important to shake inhaler and prime inhaler

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How does the principle of atomisation work?

Two hypotheses for atomisation - internal flash evaporation (from one droplet, evaporation and drug particles released) or aerodynamic breakup (one droplet, evaporation, droplet expands, smaller droplets, drug particles released)

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Which propellants are used for pMDIs? (1)

HFA 134a and HFA 227 (not ozone depleting gases but contribute to global warming, restricted use). Non-flammable, non-toxic but very low aqueous/lipid solubility (difficult to formulate). Small amount exposed to atmosphere

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Which propellants are used for pMDIs? (2)

More H bonding for HFA 134a (H more exposed) compared to HFA 227 (H hidden). More Cs and Fs in HFA 227. Negative b.p. (liquid in canister at high pressure, gas in atmosphere/lower pressure, from 4 bar to 1 bar)

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Is a solution or suspension a better formulation for an inhaler?

Both should be the same (given good inhaler techniques and other factors are equal). Solution - could get crystallisation during evaporation/smaller particles (less then 1-5 microns)

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What are the environmental problems of HFAs?

Contribute to global warming (highly controlled, ensure for only essential use)

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What are the technical problems associated with HFAs?

Suspension stability (use of co-solvents/alcohol, taste). Valve material incompatibility (metal, rubber, plastic, co-solvent). Moisture (co-solvent used, chemical stability/storage, bioavailability)

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What properties must the drug particles have in a pMDI formulation?

Drug particles must be micronised. Use of high energy. Fluid energy mill. Target size of 1-5 microns. Careful monitoring of solid state properties

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Describe features of drug suspensions

Drugs with low solubility in HFA propellant. Some spray droplets will be drug free. High chemical stability. Suspension could clog spray exit orifice. Could lead to caking/flocculation/dose variations

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Describe features of drug solutions

Drugs with high solubility in HFA propellant. All spray droplets will contain drug. Chemical stability issue. No clogging. No caking/flocculation problems

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How does particle size relate to lung deposition?

Smaller mass medium aerodynamic diameter leads to higher percentage of lung deposition

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Which components are involved in formulation suspensions for inhalers?

Drug, propellants (HFA 134a, HFA 227), co-solvent (ethanol, glycerin - low concentrations), surfactant (oleic acid, sorbitan mono-oleate, lecithin, cetylpyridium bromide)

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Which are the issues with exit velocity?

Rapid exit of drug (may need to use spacer) - goes into one space, no time for dispersion of particles, may not have time to get into airstream/enter lungs

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Describe features of spacers

Slows down the movement of particles, gives time for dispersion, particles can enter the airstream/into the lungs. Large particles deposit on walls of spacer and smaller particles enter the drugs (higher percentage of lung deposition/deeper)

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What do spacers achieve? (1)

Provide extra time for propellant droplet to evaporate (reduce cold shock). Reduce droplet velocity (reduce drug impact on mouth/throat). Capture larger droplets/particles in spacer reducing deposition in mouth/throat

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What do spacers achieve? (2)

No need to coordinate actuation/inhalation. Multiple inhalations can be taken from a spacer

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What are breath-actuated pMDIs?

Aerosol is generated and released automatically with inhalation (more expensive device)

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What should the patient be advised when using pMDIs?

HFA inhalers must be shaken before use (except QVAR). HFA inhalers require priming (wasting first few pumps) before first use. Exhale deeply before inhalation. Slow/deep inhalation. Hold breath after inhalation. Use spacer

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pMDIs

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