P2

How is the aerosol formed by the propellant?

Formed as a gas is compressed

Pressure coverts the gas to a liquid

Then converted to a gas when the pressure is released, and liquid boils quickly to gas.

In the propellant; what converts the gas to a liquid and then to a gas

Pressure

And then the release of this pressure.

In a pmdi, the drug is in the device starts as what and what does it turn into?

Gas to liquid by pressure

Drug formulated in the liquid

When pressure is release, the liquid propellant rapidly boils to form a gas.

Gas→liquid→gas.

The gas leaves behind an aerosol of drug particles.

What are HFA pMDI’s?

Why are CFC’s no longer used?

Current pMDI propellants are hydrofluroalkanes

CFC’s = chlorofluoroalkanes we’re once used. Are now banned as they deplete the ozone layer.

How is the spray formed?

Drug formulations for pMDIs?

For most drugs, what formulations are generally preferred?

Suspensions

Why are suspensions generally preferred?

Capable of delivering high powder loads

What are the requirements for having suspensions as formulation, for pmdi?

Needs drugs to be milled/ micronised

Needs drug to be practically insoluble in propellant

Drug needs to be freely dispersed in the propellant.

So need to shake to ensure re-dispersion and formulation is homogenous.

Physical instability:

Rapid Flocculation

Loose Agglomerates  (Interparticulate Forces)

Physical instability:

Bulk separation

Creaming or sedimentation (density, particle size)

Physical instability:

Irreversible aggregation

Crystal growth and caking (solubility)

Physical instability:

Crystal structure instability

Polymorphic inter conversion.

Flocculated system vs deflocculated system

What does creaming and sedimentation look like?

What is the role of excipients?

Ensure physical stability of suspension

Capable of dispersing and re-dispersing drug in suspension

Allows homogenous distribution of drug within suspension.

Minimal segregation during period prior to administration.

What are commonly used surfactants in HFA propellants

Oldie acid, PEG, PVP, magnesium stearate

What are typical suspension formulations?

Micronised drug

Surfactant - like oleic acid

Propellant - HFA 134a (e.g).

Testing the pMDI formulation:

Testing for:

• sedimentation rates

• Particle size changes

• Dose uniformity measurements

• Ultimate test - uniformity in the aerosol dose (Consistent dose and particle size distribution needs to be consistent also)

Solution based formulations:

What are the requirements and when can they be used?

Can only be used if solubility and stability of drug in propellant with co-solvent are adequate.

Need to check the chemical stability of drug in the solution.

The amount of dose emitted is directly related to solubility

Usually needs a co-solvent (like ethanol)

Name a co solvent that is usually used with solution based formulations for inhalers?

Ethanol.

Do solution based formulations have the potential to crystallise out during their shelf-life?

Yes.

Solution based formulations with cosolvents have potential to crystallise out.

What is the typical solution based formulation?

• Drug (not micronised)

• Ethanol (co-solvent)

• Saccharine (for taste)

• Menthol (for flavour)

• Ascorbic acid (antioxidant)

• Propellant (vapour pressure)

What are the problems associated with solution based formulations?

Co solvents can erode aluminium canisters

Drugs can be relatively unstable

There needs to be modification of drug chemical structure.

What are the advantages of pMDI’s?

+ many doses

+ Compact

+ Consistent delivery

+ Relatively cheap

+ Sealed container protects the drug

+ Lower capital costs for market entry.

What are the disadvantages of pMDI’s?

- Patient co-ordination and force is needed to actuate the drug

- Cold freon effect

- Tail off at the end of a can

- Force of aerosol spray

- Varying deposition pattern in airways

What devices can you use to train a patient to use their inhaler?

Vitalograph AIM

In-Check Dial

Spacers

pMDI actuated into a chamber with a valve to prevent aerosol escaping

Patient can then inhale aerosol from spacer

Gives space for particles to slow down

Propellant evaporates  smaller particles

No “cold Freon effect”

No need to coordinate

actuation & inhalation

Washing spacers

Electrostatic charge can cause drug to adhere to spacer

Regularly clean spacer with water with a drop of washing up liquid

Allow to air dry – do not rub with a cloth

Summary

pMDIs are a convenient dosage form

Requires a pressurised propellant

Both solutions and suspensions possible

Many patients have difficulties using them, which can lead to poor disease control

Patients need your support with pMDIs

Important to reduce pMDIs where clinically appropriate