Lecture 8 - formulation of medicines for respiratory system Flashcards
what are pulmonary delivery devices used to generate an aerosol?
pressurised meter dose inhalers pMDI
dry powder inhalers DPIs
nebulisers
the most common type of APIs delivered by these device types are
- beta2 agonist
- anticholinergics
- corticosteroids
what is an aerosol
colloidal systems constituting of a very finely subdivided liquid or solid particles in and surrounded by gases
what is mass median aerodynamic diameter MMAD?
diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller than the median diameter
what is fine particle fraction?
fraction of particles < 5 micron diameter that can achieve deposition in the lower respiratory tract
what is labelled dose?
dose that is metered and stated on device packaging eg flixotide 125 (125mcg fluticasone per actuation of inhaler)
what is emitted dose?
the mass of drug emitted per actuation that is a actually available for inhalation at the mouth
what are advantages of local treatment of respiratory disease?
non-invasive and painless
delivers high drug concentrations directly to the disease sites
rapid clinical response
bypasses barriers to therapeutic efficacy eg poor GI absorption, first pass metabolism
achieves similar or superior clinical affects with a fraction of a systemic dose eg 2-4mg salbutamol PO is equivalent to 100 - 200mcg by pMDI
what are disadvantages of local treatment of respiratory disease?
administration techniques differ between and within device categories
less than optimal administration technique of device can compromise therapeutic effect
more patient training and time is required for effective drug administration
what are the 5 components of pressurised meter dosed inhalers ?
container, propellants, actuator, metering valve and formulation
describe the container in PMIs
must be capable to withstand the high pressures by the propellant
- vapour pressure of a typical hydrofluroalkane propellant in container is 275kPa to 550kPa (2.5 - 5.5 atmosphere)
commonly made form aluminium
- light, inexpensive and compact material
- prevents ingress of daylight - good for photostability
internal surfaces may be coated with an inert polymer to prevent interaction of the formulation with the container surface eg adhesion of drug particles in a suspension formulation
- nothing should be leachable from the inner lining
describe propellants
all formulations contain one of 2 hydrofluoroalkanes which replaced chlorofluorocarbons in 1990s due to Montreal protocol (ozone depletion treaty)
descrie the actuator
manufactured using pasltic injection moulding technique
the actuator houses the pMDI canister and has an inbuilt nozzle
the actuator polymer and the nozzle design can impact upon aerosol particle size distribution and subsequent lung distribution:
- expansion chamber
-orifice jet length
- orifice nozzle diameter
usually results in the generation of a poly disperse aerosol
describe the metering valve
The metering valve is crimped onto the container
Typically it delivers a 25 - 100 mL volume of the formulation
Many design variants but all operate on the same basic principle:
- Prior to activation a channel between the container body and the metering chamber is open to allow formulation entry into dosing chamber
- As the pMDI is activated, this channel closes, and another channel connecting the metering chamber to the atmosphere opens
- The pressurized formulation is expelled rapidly into the valve stem, which, together with the actuator expansion chamber allows the propellant to start to boil resulting in the production of an aerosol plume
The canister is used in the inverted position, with the valve below the container to allow valve filling under gravity
Some valves are surrounded by a retaining cup that contains a few doses of drug
describe a pMDI solution type
a solution formulation where drug is dissolved in the propellant
- Homogeneous phase so patients do not need to shake the inhaler immediately prior to use
- Opportunities for a finer residual aerosol and potentially larger fine particle fraction with each dose
describe what is used when drug solubility in hfa is limited
Drug solubility in HFA may be limited so commonly a co-solvent and/or surfactant may be used
- Surfactants e.g. sorbitan trioleate, oleic acid, or soya lecithin, typically at 0.1% to 2% w/w
- Co-solvents most commonly ethanol but sometimes glycerol or propylene glycol
what effects can ethanol exert?
Changing the formulation density and thus changing the total mass of formulation atomized during device actuation
Changing atomization of the formulation and the size of the atomized droplets
Changing the evaporation rate of the droplets towards their residual particle sizes
is clonal or Qvar potent?
Qvar is approximately 2.5 times more potents than clonal modulite
how are pMDI suspension formaultiosn used?
Large crystalline drug particles, broad particle size distribution –> particle size reduction/ milling micronising –> Small crystalline/amorphous drug particles, narrow particle size distribution
what does the spiral jet mill do?
Spiral jet mill:
Particle size reduction due to high velocity drug particle – particle collisions.
Larger particles subjected to greater centrifugal forces and forced to the outer perimeter of the chamber. Smaller particles exit the mill through the central discharge stream
what is a principle consideration for a suspension formulation
the drug must be practically insoluble in the formulation vehicle
This can be facilitated by the use of an insoluble salt form e.g. salbutamol sulfate, fluticasone propionate
Particles in formulation may sediment or cream (rise) upon standing
Need to shake to uniformly re-suspend particles before use and ensure uniform dosing
what are formulation issues with pMDI suspensions?
Particle – particle interactions changing particle size distribution
- Mechanical interlocking due to surface asperities
- Capillary forces from the presence of water
- Electrostatic interactions
- van der Waals forces
Can be minimised by use of suspending agent stabilisers e.g.
PEG 0.05 - 0.5% (w/w) with 0.001% (w/w) PVP to reduce inter-particle cohesiveness
Surfactants (minimise electrostatic interactions)
MMAD from suspension pMDI is dependent on aerosol droplet size and particle concentration
Larger droplets have increased propensity to contain multiple drug particles
- Greater chance of particle interactions which result in larger residual particle size distributions with reduced FPF
Suspension pMDI formulations with very fine micronized drug present at a low concentration have best opportunity for MMAD approximating to micronised drug dimensions and having a relatively high FPF
describe why dPIs are used
They are simpler to use and are breath activated
They are propellant-free and environmentally friendly
DPIs preferred for their stability and processing since they are formulated as one phase, solid-particle blends
what are 4 basic features of DPIs
a dose-metering mechanism
an aerosolisation mechanism
a de-aggregation mechanism
an adaptor to direct the aerosol into the mouth.
DPIs can be either single- or multi-unit devices
what do DPIs consist of
DPIs normally consist of micronised API (0.5 - 5 mm) supported on a coarse carrier e.g. lactose particles (~ 50–200 mm).
at happens upon inhalation of dpi by the patient ?
Upon inhalation by the patient using device mouthpiece turbulent flow is created within the reservoir
- causes de-agglomeration of the micronized API from the lactose carrier, creating an aerosol dispersion of the API for inhalation
what are DPI dose dependant on ?
The properties of the drug formulation
powder flow
particle size
shape and surface properties
drug - carrier interactions
The performance of the inhaler device
aerosol generation and delivery
Correct inhalation technique for deposition in the lungs by patient
Breathe in quickly and deeply for all DPI devices
Patient inspiratory flow rates
hat are formulation issues for DPI?
Good API aerosolisation requires adhesive forces between API particle and the coarse carrier particle to be overcome
Lactose particles have surface asperities which can prevent API not being fully exposed to flow stream preventing detachment
Fine lactose (<32 μm) is blended with larger lactose particles to enhance re-dispersion of API
This is the ‘active site theory’
Fine lactose particles occupy the high energy surface areas of the larger lactose carrier particle
This leaves only lower energy binding sites (less adhesion) on the surface for the API to occupy.
DPI are blended formulations of small API particles and large excipient carrier particles
Mixing powders with different properties, particle sizes and ratios is technically challenging and if inadequate can cause poor dose uniformity
Blending is therefore a critical step in the manufacture of a DPI
- Process optimisation:
- Mixer selection
- Rotation speed
- Capacity and fill level
what are nebulisers and common types of nebulisers design in use?
nebulisers were the first devices developed for inhalation therapy
two common types of nebuliser design in use
- air jet nebulisers- vibration mesh nebulisers
describe air jet nebulisers
Traditional nebulizer type
Uses compressed air to generate a fine mist
Offers a range of particle sizes
Can be loud
No medication restrictions
Durable
Available in table top models and handheld models
describe vibrating mesh nebuliser
Newer nebuliser technology
Uses ultrasonic vibrations passed through water to generate a fine mist
Offers a very consistent particle size
Virtually Silent
Medication restrictions
- suspensions
- heat is transferred to the medication e.g. dornase alpha
Available in handheld models only
what inhalation methods are used in patients with inspiratory flow >30L per minute or inspiratory flow <30L per minute
inspiratory flow >30L per minute:
pMDI
BA - pMDI
nebuliser
inspiratory flow <30L per minute:
