workshop - inhalation drug delivery

Question 1

Why would 20 mm sized particles deposit largely in the upper airways with little deposition in the lower airways, and why would less than 10% of these particles escape from the airways?

Answer 1

• 20um particles are more likely to impact and deposit on the walls of the upper airways, and if the flow rate of the air is low and/or if the residence time is longer (with the inhaling individual holding their breath), some will also be deposited on these walls as a result of gravitational sedimentation.
• A relatively small fraction of the 20um particles will penetrate to the lower respiratory tract, and this which do will deposit through gravitational sedimental
• Only a very low proportion of the 20um particles will thus escape deposition and remain in the exhaled.

Question 2

what would be the fate if a significant proportion of the 20mm sized particles and where would their drug payload be likely to be absorbed?

Answer 2

The high proportion of 20um particles depositing in the upper ciliated airways will mean that these particles are carried up the airways to the throat and will then be swallowed, and this will result in drug absorption from the GI tract.

Question 3

why would particles of 6mm and 2mm in size be deposited largerly in lower airwaysm with little in the upper airways. and why would 50% of 2mm sized particles but less than 20% of the 6mm sized partciles be lost from the airways?

Answer 3

The smaller 6um and 2um particles will have less inertia and will impact to a lesser extent in the larger and less branched upper airways, where sedimenation would also be likely be less significant. The impaction of the 6um and 2um particles is more likely to take place in the more highly branches lower airways.
By comparison with the 2um particles more of the larger 6um particles will be less likely yo impact and sediment in the lower airways. There will this be more of the 2um particles that are exhaled.

Question 4

Why does no significant deposition of 0.6 mm sized particles occur in upper airways & why little deposition also in the lower airways, such that over 80% of the particles would be lost from the airways? .

Answer 4

Sub-micron sized particles will have very low momentum and so will be unlikely to impact in the upper or lower airways and since they have very low mass their deposition through gravitational sedimentation will also be insignificant.
The particles may deposit through Brownian diffusion to a limited extent but this mechanism of deposition is only really significant for particles <0.5um and so most of the 6um particles will not deposit anywhere in the airways and will instead be exhaled.

Question 5

which particle size if best for systemic delivery of drug and why?

Answer 5

Given the greater level of deposition and the higher retention of 6um particles in the lower airways, particles of this size will be more effective in providing drug absorption into blood circulation for systemic delivery. The lower airways are non-ciliated, present a high surface area for absorption and have a rich blood supply.

Question 6

what are the benefits of inhalation medication?

Answer 6

• Rapid onset of drug action
• Avoids gi degradation-straight into blood
• Avoids first pass metabolism in liver
• Use of lower doses reduces adrs due to above
• Accurate dose adjustment & titration to individual needs and ideal for prn (as needed) medication
• Use of small volumes (25 – 100 ml)
• Tamperproof containers-prevents abuse and helps child safety
• Protect from instabilities due to air, moisture

Question 7

what does the nasal cavity do?

Answer 7

warm and moiten inhaled air passes through, it filters out larger particles >15mm via the cillia

Question 8

what are the epiglottis for?

Answer 8

covers entrance to airways when swallowing and prevents things going down the wrong way

Question 9

how many alveoli per lung?

Answer 9

300 million 70m2 surface area

Question 10

what affects the depostition of dry powders?

Answer 10

particle diameter
shape
denisty
charge
suface chemistry

Question 11

what affects deposition of liquid aerosol?

Answer 11

droplet size distrubition
velocity
nature of propellant

Question 12

what is inertial impaction?

Answer 12

momentum of particle renders it unable, to follow the airflow in a curved airway so that it impacts on the wall-travels too fast so just hit the walls. Significant forward momentum.

Question 13

what is gravitational sedimentation?

Answer 13

related to the residence time in an airway and terminal settling velocity, increased by holding breath.
brief moment when the air in airways is still which is when the particle tends to drop towards to wall but may not hit the wall

Question 14

what is brownian diffusion?e

Answer 14

random collision of a particle with airway wall; significant only for particles <0.1mm

Question 15

what is electrostatic attraction?

Answer 15

charge on particle induces opposite charge on airway wall and accelerates into wall by attraction. needs to be travelling quite slow

Question 16

what is interception?

Answer 16

particle size approaches airway diameter. only for asymmetric and needle like particles.

Question 17

what are directly proportional to particle size?

Answer 17

impact and sedimentaion

Question 18

qwhat is inversley related to particle size?

Answer 18

deposition

Question 19

what are different types of inhalation devices?

Answer 19

sprays
PMDIS
superfine particle inhaler
nebuliser
dry powder inhaler

Question 20

what is a nasal spray?

Answer 20

used for hayfever medication

actuator is pressed to release drug, when it returns to normal position, more drug is drawn up to replenish stores

Question 21

what is a pMDIS?

Answer 21

uses liquid propellant
generates fast moving micro-fine suspensions
slow and deep inhalation down into lungs
patients inhales and valve opens, manually operates
dose counter is included

Question 22

what are super fine particles inhalers?

Answer 22

• Small airways disease conditions (e.g., copd, chronic asthma) are inadequately treated using traditional inhalers; small airways (< 2 mm dia.) Present the major site of airflow limitation
• Most particles generated in traditional pmdis and dpis deposit in the wider upper airways (by sedimentation and impaction)
• The smaller (0.5 – 1 mm) particles delivered by the traditional inhalers are believed to deposit poorly, with most reckoned to be exhaled
• Small particle aerosols afford a reduction in the daily dose of inhaled corticosteroids
• Small particle aerosols afford better management and quality of life for asthma sufferers
• Clinical evidence indicates that the superfine particles generated in hfa pmdis (extra-fine, < 1 mm; ultra-fine, < 100 nm) lead to improved treatment. Different properties, particles that are produced are smaller as well as better for the planet.

Question 23

when are nebulisers used?

Answer 23

in home or in a hospital

to treat pateitns with conditions that render them unable to use other types of inhaler devices

Question 24

what is a traditonal neubuliser?

Answer 24

compressed air or oxygen exits a narrow orifice at high velocity, creating negative pressure which draws liquid to top of tube, where it is aerosolised, giving droplets > 40 mm; very large droplets removed through impaction on bends in the equipment

Question 25

what is a ultrasonic nebuliser?

Answer 25

piezoelectric transducers used to focus (1- 3 mhz) ultrasound waves in liquid, with intense agitation at the focus to disperse the liquid and form aerosol

Question 26

what is a vibrating mesh ultrasonic nebuliser?

Answer 26

alternating current causes piezo crystal to expand and contract rapidly, pulling mesh into liquid and then thrusting forward to create a monodisperse aerosol of superfine droplets (virtually all of which is appropriate for inhalation) these are much smaller and better for use

Question 27

what is a dry powder inhaler?

Answer 27

• Passive breath-dispersing devices: commercially-available devices require quick, strong and deep inhalation; small drug particles adhered to larger carrier particles – separated by sheer with large particles then being deposited in the oropharynx, and the smaller (drug) particles going down to the lower airways

Question 28

what is aerodynamic diameter?

Answer 28

describes the behaviour of the particles as it is moving through the air. determines where the particles deposit

Question 29

what can decrease aerodynamic diameter?

Answer 29

• Decreasing (geometric) size
• - decreasing density eg more porous or more asymmetric/ needle like
- increasing shape factor

Question 30

what does inhalation method provide?

Answer 30

alternative route of drug admin for

• acute and breakthrough pain relief
• if interactions need to be avoided
• if the drug has erratic pharmacokinetics if given orally
• when critical to avoid GI degradation