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Medicine Year 3, Sem 1 - Drug Development Process > Inhalation Drug Delivery > Flashcards

Inhalation Drug Delivery Flashcards

1
Q

What are some of the benefits of inhalation medication? (8)

A 
Rapid onset 
Accurate dose adjustment and titration
Ideal for PRN
Tamperproof containers
Avoids degradation and first pass 
Use of lower doses reduces ADR's
Protected from instabilities (from air/moisture)
Useful alternative RoA
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2
Q

When does inhalation medication provide a useful alternative RoA? (4)

A

Acute and breakthrough pain treatment
Where physical/chemical interactions with other meds must be avoided
When critical to avoid GI degradation e.g. biologics
When the drug exhibits variable/erratic PK when given orally

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3
Q

Inhaled medications can be for what effect?

A

Local e.g. small airways diseases

Systemic e.g. anaesthetics

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4
Q

What does the URT include?

A

Buccal, SL and nasal cavities
Pharynx
Upper larynx (above vocal cords)

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5
Q

What is the role of the nasal cavity?

A

Warms and moistens inhaled air
Filters out large particles (>15μm)
Traffics to mouth to be swallowed, coughed or sneezed out

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6
Q

What is the role of the epiglottis?

A

Covers the entrance to the airways when swallowing or eating

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7
Q

What does the LRT include?

A

Trachea, primary and secondary bronchi, bronchioles and alveoli

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8
Q

What is the size of the trachea? How is it structured?

A

12cm in length, 1.5-2cm in diameter

Supported by loops of cartilage

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9
Q

What is the diameter of the bronchioles?

A

0.5-1mm

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10
Q

What is the structure of the alveoli?

A

‘Air sacs’
300 million/lung
70m² s.a. for drug absorption

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11
Q

A typical adult human breathes how many times a minute?

A

20 times

Each breath is a coupled inhalation and exhalation thus lasting around 3 seconds

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12
Q

What is happening during inhalation?

A

Diaphragm muscles contract to flatten the diaphragm in the direct of the abdomen
Intercostal muscles contract to expand and raise the ribcage
Volume of the thoracic cavity therefore increases, and air pressure within the airways drops
Air is drawn in through the nose/mouth
These processes reverse for exhalation

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13
Q

How does the speed of air travel vary in the airways?

A

On inhalation, the speed of air is high in the upper airways and then decreases as the air moves through the bifurcations and lower/narrower airways
Air travels more quickly in the central region of the lumen and more slowly near the airway walls

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14
Q

How can we visualise loci and extent of deposition of aerosol particles? How does this method work?

A

Radio-scintigraphy
Technetium 99m can be used to radiolabel the inhaled aerosol particles
This isotope has a half-life of around 6 hours and emits gamma rays which can be detected on the outside of the body using a gamma camera

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15
Q

Where do we often see heavy deposition of aerosol on imaging photos?

A

Central regions of lungs
Throat
Stomach (accumulation at the back of the throat and then swallowed)

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16
Q

What affects the extent and loci of particle deposition?

A

Product characteristics

Anatomical and physiological characteristics

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17
Q

What product characteristics affect the extent and loci of particle deposition?

A

Dry powder - particle diameter, shape, density, charge and surface chemistry
Liquid aerosol - droplet size distribution, velocity and nature of propellant

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18
Q

What anatomical and physiological characteristics affect the extent and loci of particle deposition?

A

Geometry of the respiratory tract
Lung capacity
Breathing patterns (frequency, tidal volume)
Pathology (the above are compromised in some pathological states)

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19
Q

Define ‘inertial impaction’.

A

Momentum (large particles = significant momentum) of particle renders it unable to follow the airflow in a curved way so that it impacts on the wall

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20
Q

Define ‘gravitational sedimentation’.

A

Related to the residence time in the airway and terminal settling velocity, increased by holding breath

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21
Q

Define ‘brownian diffusion’.

A

Random collision of particle with airway wall, only significant for particles <0.1μm

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22
Q

Define ‘electrostatic attraction’.

A

Charge on particles induces opposite charge on airway wall and accelerates particle into wall

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23
Q

Define ‘interception’.

A

Particle size approaches airway diameter, refers to long fibre-like particles where the long part is a similar length to the airway diameter

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24
Q

Deposition by impaction and sedimentation are directly proportional to…

A

Particle size

Most significant for particles >1μm

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25
Q

Deposition by diffusion is…

A

Inversely related to particle size

Significant only for sub-micron sized particles

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26
Q

How is deposition achieved in traditional delivery devices?

A

Primarily through impaction and sedimentation
Particles <10μm (typically 2-8μm)
80-90% of dose not absorbed
Large losses to GI absorption and side effects

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27
Q

How is improved deposition achieved in newer devices?

A

Smaller particles at lower velocities

Only 50-70% losses with >30% deposition in peripheral airways

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28
Q

The pattern of aerosol deposition within the respiratory tract will vary depending on…

A

Whether it enters by oral or nasal inhalation

29
Q

What is the pattern of deposition following oral inhalation?

A

Particles >3μm will deposit in the ET region via inertial impaction
Particles 0.1-1μm are too big to deposit by diffusion but too small to deposit by impaction/sedimentation, so they’re breathed back out
Particles <0.1μm will deposit in the P region as a result of diffusion

30
Q

What is the pattern of deposition following nasal inhalation?

A

Extensive deposition of particles >1μm in the ET region (nasal cavity, back of the mouth and down into the throat), primarily as a result of inertial impaction
There is also high deposition of the smallest particles in the ET region through diffusion
Some of the inhaled material deposited ET will be swallowed and pass into the GIT

31
Q

Is high deposition in the ET favourable with nasal inhalation?

A

Yes, nasal inhalation is most often employed when the inhaled drug is required to act locally

32
Q

What are the 5 types of inhalation devices?

A 
Sprays 
pMDI's
Superfine particle inhalers 
Nebulisers
DPI's
33
Q

What are sprays useful for delivery to? What sort of medications are they used for?

A

URT

Used for hayfever medications, treatment of sinusitis and decongestion

34
Q

Nebulisers contain a drug dispersed in what?

A

A polar solvent, usually H₂O

35
Q

How do traditional, metered dose pump, nasal spray devices work?

A

Patient uses 2 fingers to depress the actuator and a fine spray of aerosol is ejected from the delivery chamber and into the nasal cavity
When the patient releases the actuator, it returns to the resting position and at the same time causes more of the liquid aerosol formulation to pass up into the dip tube, to replenish the delivery chamber so the device is primed and ready for its next use

36
Q

Give 2 examples of nasal spray devices and a brief description of how they work.

A

Vianase - uses an electronic atomiser to give controlled particle dispersion
Optinose - uses bidirectional flow, exploiting the blow reflex (exhalation delivery system)

37
Q

pMDI’s are useful for delivery to the what?

A

LRT

38
Q

How do pMDI’s deliver drug?

A

Use liquid propellant (HFA’s, no longer CFC’s), to generate a fast moving micro-fine suspension

39
Q

How should the patient inhale when using a pMDI?

A

Slow and deep

40
Q

How is a pMDI operated?

A

Patient inhales and valve operates simultaneously

Can be manually operated, breath actuated or battery activated valve (coordination may be necessary)

41
Q

What excipients can be found in pMDI’s? Give examples.

A 
Co-solvents e.g. ethanol 
Surfactants e.g lecithin, oleic acid 
Menthol 
Ascorbic acid 
Phenylethanol
42
Q

Why are co-solvents added to pMDI’s?

A

Form inverse micelles or liposomes to enhance the solubility of the propellant

43
Q

Why are surfactants added to pMDI’s?

A

To adsorb particles and prevent agglomeration (shake before use)

44
Q

Why is menthol added to pMDI’s?

A

Flavouring

45
Q

Why is ascorbic acid added to pMDI’s?

A

Antioxidant

46
Q

Why is phenylethanol added to pMDI’s?

A

Preservative

47
Q

Is the treatment of small airways diseases (e.g. asthma, COPD) adequate?

A 
Inadequate using traditional inhalers 
Small airways (<2mm) present the major site of airflow limitation and most particles generated in traditional pMDI's and DPI's deposit in the wider upper airways (by sedimentation and impaction)
The smallest (0.5-1μm) particles in traditional inhalers are believed to be poorly deposited, with the majority exhaled
48
Q

Why are superfine particle inhalers needed?

A

Evidence indicates that superfine particles generated by HFA pMDI’s (extra fine <1μm, ultra fine <100nm) lead to improved treatment due to increased deposition by diffusion

49
Q

Small particle aerosols afford a reduction in…

A

TDD of inhaled corticosteroids, allowing for better management and QoL for small airways disease sufferers

50
Q

Are nebulisers efficient?

A

Generally very inefficient, delivering only 10-15% of nebulised drug

51
Q

What are some of the benefits of nebulisers?

A

Allow administration of higher does, mg rather than μg quantities
Require no coordination or specific inhalation technique
Can be used at home or in hospital to treat infants or patients who are too ill or incapable of using other, more convenient types of inhaler device

52
Q

What are some of the downsides to nebulisers?

A

Large, heavy and relatively expensive

53
Q

What are the 3 different types of nebuliser device?

A

Traditional (air jet) nebuliser
Ultrasonic nebuliser
Vibrating mesh ultrasonic nebuliser

54
Q

How do traditional (air jet) nebulisers work?

A

Compressed air or O₂ exits a narrow orifice at high velocity, creating negative pressure which draws liquid to the top of the tube, where it is aerosolised giving droplets >40μm, very large droplets are removed through impaction on bend

55
Q

Traditional (air jet) nebulisers are now superseded by…

A

Ultrasonic devices, which are smaller and more portable

56
Q

How does an ultrasonic nebuliser work?

A

Piezoelectric transducers are used to focus (1-3 mHz) ultrasound waves in liquid, with intense agitation at the focus used to dispense the liquid and form aerosol

57
Q

How does a vibrating mesh ultrasonic nebuliser work?

A

Alternating current causes piezo crystal to expand and contract rapidly, pulling mesh into liquid and then thrusting it forward to create a monodisperse aerosol of superfine droplets (virtually all of which are appropriate for inhalation)

58
Q

Most commercially available DPI’s are…

A

Passive breath-dispensing devices that require quick, strong and deep inhalation

59
Q

What type of DPI’s are in development?

A

Active DPI’s, use an internal power source to aerosolise the powder e.g. spiros device, which uses a battery powered motor or oriel, which uses a piezoelectric polymer

60
Q

How are DPI’s formulated?

A

Microionised drug particles (around 5 microns) are adsorbed onto larger, coarse-grained carrier particles e.g. lactose (around 50-200 microns)

61
Q

How are DPI’s metered?

A

When the patient inhales from the DPI, the drug formulation passes through some sort of metering device, varies according to product, to ensure delivery of the required dose
Metering devices include powder reservoirs, blister disks, blister strips and capsules

62
Q

How does deposition occur from DPI’s?

A

When the aerosol enters the patient, the small drug particles are sheared from the larger, carrier particles, the latter depositing in the oropharynx and the former passing down into the airways

63
Q

Why are the carrier particles needed in DPI’s?

A

They improve powder flow characteristics, allowing the filling of the device in manufacture and more accurate dosing, particularly in low dose therapeutics

64
Q

Do all DPI’s use carrier molecules?

A

No, can instead use crystals e.g. Pulmicort and Turbohaler
The API is microionized by jet, pin or ball milling, or else by spray or use of supercritical fluid to give particles of 1-2μm

65
Q

What can aerodynamic diameter be used to determine?

A

Location and extent of deposition of particles

66
Q

Efficient alveolar delivery of particles with aerodynamic diameters…

A

1-5μm

67
Q

Aerodynamic diameter describes…

A

Dynamic behaviour of a particle, relating gravitational settling and inertial impaction

68
Q

Aerodynamic diameter can be reduced by…

A 
Decreasing geometric size
Decreasing density (more porous)
Increasing shaper factor (longer and thinner)

Medicine Year 3, Sem 1 - Drug Development Process (8 decks)

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