Lecture 8 - formulation of medicines for respiratory system

Question 1

what are pulmonary delivery devices used to generate an aerosol?

Answer 1

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

Question 2

what is an aerosol

Answer 2

colloidal systems constituting of a very finely subdivided liquid or solid particles in and surrounded by gases

Question 3

what is mass median aerodynamic diameter MMAD?

Answer 3

diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller than the median diameter

Question 4

what is fine particle fraction?

Answer 4

fraction of particles < 5 micron diameter that can achieve deposition in the lower respiratory tract

Question 5

what is labelled dose?

Answer 5

dose that is metered and stated on device packaging eg flixotide 125 (125mcg fluticasone per actuation of inhaler)

Question 6

what is emitted dose?

Answer 6

the mass of drug emitted per actuation that is a actually available for inhalation at the mouth

Question 7

what are advantages of local treatment of respiratory disease?

Answer 7

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

Question 8

what are disadvantages of local treatment of respiratory disease?

Answer 8

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

Question 9

what are the 5 components of pressurised meter dosed inhalers ?

Answer 9

container, propellants, actuator, metering valve and formulation

Question 10

describe the container in PMIs

Answer 10

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

Question 11

describe propellants

Answer 11

all formulations contain one of 2 hydrofluoroalkanes which replaced chlorofluorocarbons in 1990s due to Montreal protocol (ozone depletion treaty)

Question 12

descrie the actuator

Answer 12

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

Question 13

describe the metering valve

Answer 13

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

Question 14

describe a pMDI solution type

Answer 14

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

Question 15

describe what is used when drug solubility in hfa is limited

Answer 15

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

Question 16

what effects can ethanol exert?

Answer 16

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

Question 17

is clonal or Qvar potent?

Answer 17

Qvar is approximately 2.5 times more potents than clonal modulite

Question 18

how are pMDI suspension formaultiosn used?

Answer 18

Large crystalline drug particles, broad particle size distribution –> particle size reduction/ milling micronising –> Small crystalline/amorphous drug particles, narrow particle size distribution

Question 19

what does the spiral jet mill do?

Answer 19

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

Question 20

what is a principle consideration for a suspension formulation

Answer 20

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

Question 21

what are formulation issues with pMDI suspensions?

Answer 21

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

Question 22

describe why dPIs are used

Answer 22

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

Question 23

what are 4 basic features of DPIs

Answer 23

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

Question 24

what do DPIs consist of

Answer 24

DPIs normally consist of micronised API (0.5 - 5 mm) supported on a coarse carrier e.g. lactose particles (~ 50–200 mm).

Question 25

at happens upon inhalation of dpi by the patient ?

Answer 25

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

Question 26

what are DPI dose dependant on ?

Answer 26

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

Question 27

hat are formulation issues for DPI?

Answer 27

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

Question 28

what are nebulisers and common types of nebulisers design in use?

Answer 28

nebulisers were the first devices developed for inhalation therapy

two common types of nebuliser design in use
- air jet nebulisers- vibration mesh nebulisers

Question 29

describe air jet nebulisers

Answer 29

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

Question 30

describe vibrating mesh nebuliser

Answer 30

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

Question 31

what inhalation methods are used in patients with inspiratory flow >30L per minute or inspiratory flow <30L per minute

Answer 31

inspiratory flow >30L per minute:
pMDI
BA - pMDI
nebuliser

inspiratory flow <30L per minute: