Inhalation Drug Delivery

Question 1

Benefits of Inhalation Medication:

Answer 1

• Rapid onset of drug action
• Avoids GI degradation
• Avoids first pass metabolism
• Use of lower doses reduces ADRs
• Accurate dose adjustment & titration to individual needs and ideal for PRN (as needed) medication
• Use of small volumes (25 – 100 mL)
• Tamperproof containers
Protect from instabilities due to air, moisture

Provides a useful alternative route of drug administration:
• For acute and breakthrough pain treatment
• Where physical and/or chemical interactions with other medications must be avoided
• When the drug exhibits variable or erratic pharmacokinetics when given orally
• When critical to avoid GI degradation of the therapeutic agent, e.g., biologics

Question 2

Upper respiratory tract =

Answer 2

• buccal, sub-lingual, and nasal cavities, pharynx, upper larynx (above the vocal cords)
  • Nasal cavity, warm & moisten inhaled air, filter out large particles (> 15 mm), traffic to mouth to swallow or cough/sneeze to expel
  • Epiglottis covers entrance to airways when swallowing

Question 3

Lower respiratory tract =

Answer 3

trachea – branching to primary and then secondary bronchi
• 2o bronchi branching to bronchioles
• Bronchioles terminating in alveoli

Question 4

Diameter of human trachea?

Answer 4

1.5-2cm, bronchioles 1mm diameter or less, terminal bronchioles = 0.5mm
• 300 million alveoli per lung (70 m2 surface area

Question 5

Extent & loci of particle deposition are affected by:

Answer 5

Product characteristics:
• Dry powder: particle diameter, shape, density, charge,
–> and surface chemistry
• Liquid aerosol: droplet size distribution, velocity, nature of propellant

Anatomical & Physiological characteristics:
• Geometry of the respiratory tract
• Lung capacity
• Breathing patterns (frequency, tidal volume)
• Pathology

Question 6

Inertial impaction is?

Answer 6

momentum of particle renders it unable to follow the airflow in a curved airway so that it impacts onthe wall

Question 7

Gravitational sedimentation is?

Answer 7

related to the residence time in an airway & terminal settling velocity, increased by holding breath

Question 8

Brownian diffusion is?

Answer 8

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

Question 9

Electrostatic attraction is?

Answer 9

charge on particle induces opposite charge on airway wall and accelerates particle into wall. Occurs in last stages in narrow airways.

Question 10

Interception:

Answer 10

particle size approaches airway diameter – not significant for spherical particles, only for those that are asymmetrical and needle like

Question 11

Deposition by impaction & sedimentation are directly

proportional to:

Answer 11

particle size; most significant for particles > 1mm

Question 12

Deposition by diffusion is inversely related to:

Answer 12

particle size; significant only for sub-micron sized particles

Question 13

In traditional delivery devices, deposition achieved primarily through:

Answer 13

impaction and sedimentation; particles < 10 mm (typically, 2 – 8 mm); 80-90% of dose not deposited; large losses to GI absorption (& side effects)

Question 14

Inhalation Devices e.g.

Answer 14

• Sprays – useful for upper respiratory tract
• Pressurised metered dose inhalers (pMDIs) – use solvent propellants; CFCs banned 1994 with exceptions; 1997 further restricted; alternative propellants developed
• Superfine particle inhalers – for small airways disease; developed post-CFC ban; use hydrofluoroalkanes (HFAs); produce very small aerosol particles
• Nebulisers – drug dispersed in polar solvent (usually H2O); cumbersome; mainly used in hospitals and in ambulatory care; recent smaller aerosolisation developments
• Dry powder inhalers (DPIs) – replacing pMDIs; no solvent propellant (thus, no environmental issues); dry powder fluidises when patient inhales; drug shears from larger particles and so penetrates deeper into the lungs

Question 15

What is vianase?

Answer 15

• Nasal spray from Kurve Technology; uses electronic atomiser to give controlled particle dispersion (with narrow size range: 10 – 30 mm); minimises pulmonary and GI deposition

Question 16

What is optinose?

Answer 16

• Uses bidirectional flow – exploiting the blow reflex (exhalation delivery system) – to ensure large particles go to the nasal mucosa and prevent smaller particles going down into the lungs
• Device inserted in mouth and nostrils

Question 17

What are pMDI’s?

Answer 17

• Use liquid propellant (HFAs now, not CFCs);
• Generate fast moving micro-fine suspensions;
• Slow and deep inhalation down into lungs;
• Patient inhales and valve operates simultaneously; manually operated valves, breath-actuated valves, battery-activated valves;
• Syncronisation is very important
• Dose counters incorporated

Question 18

Excipients for pMDI’s?

Answer 18

co-solvent (ethanol) -enhances propellant solubility , inverse micelles, or liposomes to enhance solubility of surfactant propellants; surfactants (e.g., lecithin, oleic acid),to adsorb to particles & prevent agglomeration (shake before use);
menthol, flavouring; ascorbic acid, antioxidant; phenylethanol, preservative

Question 19

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 19

• 20 mm 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 the result of gravitational sedimentation.
• A relatively small fraction of the 20 mm particles will penetrate to the lower respiratory tract, and those that do will deposit there through gravitational sedimentation.
• Only a very low proportion of the 20 mm particles will thus escape deposition and remain in the exhaled air.

Question 20

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

Answer 20

• As a large proportion is deposited on the mouth/throat, a lot of it will be swallowed.
• Even on trachea can still be swallowed as it sticks to the mucous layer and is moved by the cilia into the stomach
• The high proportion of 20 mm 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 21

• Why would particles of 6 mm & 2 mm in size be deposited largely in the lower airways, with little deposition in the upper airways, and why would more than 50% of the 2 mm sized particles but less than 20% of the 6 mm sized particles be lost from the airways?

Answer 21

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

Question 22

• 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 22

• A lot smaller molecules, so have less inertia.
• 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 < 0.5 mm and so most of the 6 mm particles will not deposit anywhere in the airways and will instead be exhaled.

Question 23

• Which particle size … for systemic delivery of drug & why?

Answer 23

• 6um – given the greater level of deposition and the higher retention of 6u particles in the lower airways.
• Given the greater level of deposition and the higher retention of 6mm particles in the lower airways, particles
  of this size will be the more effective in providing for drug absorption into the 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 24

Superfine Particle Inhalers are for:

Answer 24

• 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

Question 25

Superfine Particle Inhalers benefits:

Answer 25

• 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  

Question 26

Images of a child respiratory model (baboon), indicating the relative deposition of particles in three different (Activity Median) Aerodynamic Diameter (AMAD) size ranges of drug in the thoracic (TH) and extra-thoracic regions (ET), with the brighter/yellow areas indicating high deposition, and the darker/red-brown areas indicating low deposition.

Explain the differences in deposition in the thoracic (TH) &
extra-thoracic (ET) regions in respect of possible benefits in
the treatment of small airways disease

Answer 26

1 – 9 (2.8) micron size gives high ET (throat) deposition, with < 30% deposited in TH region, largely due to inertial impaction. Particles that escape impaction are well-dispersed in TH region, but there are no regions of high deposition to benefit small airways disease
• Half of the mid-size (0.25 – 1 micron) particles deposit in ET region, as airways smaller in the child / baboon model and more would be impacted, so serving little benefit in treatment of small airways disease
• Ultrafine 0.15 – 0.5 micron (230 nm) size much less ET deposition, as low impaction, with diffusional deposition contributing to strong well-dispersed TH deposition.

Question 27

Explain the physical factors governing the deposition
of particles in the size range delivered from a
traditional pMDI (0.5 – 10 mm) and their relative
deposition in the upper & lower airways:

Answer 27

• Unit density spheres – no shape or density effects
• Inertial impaction of larger particles in upper airways, with less effect of flow rate
• As particle size reduced toward 1 mm, deposition falls, since it is proportional to size for impaction and gravitational sedimentation
• Where the breathing rate is lower and the tidal volume is higher, higher deposition due to greater contribution of sedimentation in between breaths
• For small particles (0.5 - 1 mm), deposition through
gravitational sedimentation and inertial impaction is lower, and diffusional deposition is not yet significant, resulting in the loss of particles on exhalation

Question 28

Tidal volume=

Answer 28

how much your breathing in

Question 29

Breathing frequency =

Answer 29

how many times you breathe per min

Question 30

Volumetric flow rate =

Answer 30

how fast

Question 31

Nebulisers are used:

Answer 31

– in the home and in hospitals – to treat patients with conditions that render them unable to use other types of inhaler devices
Cumbersome and inefficient (delivering only ~13% of nebulised drug) but allow for the administration of higher doses

Question 32

What are traditional (air jet) nebulisers:

Answer 32

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 bend

Question 33

What are ultrasonic nebulisers?

Answer 33

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 34

What are vibrating mesh ultrasonic nebulisers?

Answer 34

AC 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)

Question 35

Dry Powder Inhalers:

Passive breath-dispersing devices –>

Answer 35

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 36

Dry Powder Inhalers:

Active DPIs –>

Answer 36

in development, use an internal power source to aerosolize the powder; SpirosTM, uses a battery-powered motor, Oriel, uses a piezoelectric polymer

Question 37

Efficient alveolar delivery of particles with aerodynamic diameters of:

Answer 37

1 – 5 mm

Question 38

Formulation of dry powder inhalers?

Answer 38

• Formulation: carriers (e.g., lactose) not always used; drug crystals may be used (e.g., Pulmicort (budenoside), Turbuhaler (AZ) );
• APIs micronized by jet, pin or ball milling, or else by spray drying or use of supercritical fluid

Question 39

Aerodynamic diameter describes:

Answer 39

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

Question 40

Aerodynamic diameter can be decreased by:

Answer 40

• decreasing (geometric) size
• decreasing density
• increasing shape factor

Question 41

Itraconazole is a poorly-soluble, weakly basic, anti-fungal drug with a cLogP of 6.2 and poor or erratic oral absorption. Its aqueous solubility is estimated at ca. 1 ng.mL-1 at neutral pH and needs to reach a 500x higher concentration to prevent germination of fungal spores in the lung.

Given the poor water solubility of the active at neutral pH as the principal issue, which one of the following would you expect to be most considered in the development of an inhaled itraconazole formulation to treat fungal lung infections?

A) Liquid aerosol nanosuspension of submicron drug particles (incorrect as liquid aerosol and drug is poorly soluble In water)
B) Nebulisation of a larger volume of liquid aerosol of a cyclodextrin (increase solubility) formulation
C) Lipid nanoparticle liquid aerosol formulation (incorrect again due to poor water soluble)
D) Dry powder inhaler with drug particles micronized to a few microns in aerodynamic diameter
E) Dry powder inhaler with nanoparticulate drug which agglomerates into a few microns in aerodynamic diameter

Answer 41

D) Dry powder inhaler with drug particles micronized to a few microns in aerodynamic diameter

Explanation: Options A and C refer to nano-sized particles and so are viable development strategies. The use of lipid nanoparticles and cyclodextrin will help to improve the drug’s apparent water solubility

Question 42

MCQ: DPI Particle Size & Density
Which one of the following is least likely to improve the systemic bioavailability of a drug administered from a dry powder inhaler with a high proportion of deposition in the upper airways?

A) Reduction in the density and geometric size of the particles and an increase in their shape factor
B) Reduction in the density, geometric size and shape factor of the particles
C) Reduction in the geometric size and shape factor and an increase in the density of the particles
D) Increase in the density and shape factor of the particles and a reduction in their geometric size
E) Increase in the geometric size and density and a reduction in the shape factor of the particles

Answer 42

A) Reduction in the density and geometric size of the particles and an increase in their shape factor

Question 43

In pulmonary drug delivery, the shape of particles should be considered when optimising their deposition in the alveolar region and drug bioavailability.
Which ONE of the following statements is consistent with using particle shape to alter the aerodynamic properties of particles and increasing deposition in the alveolar region of the lung?

A) The shape of the particles used in dry powder inhalers may be elongated to increase their aerodynamic diameter
B) The elongated shape of drug particles used in a dry powder inhaler may be reduced to decrease their aerodynamic diameter
C) The shape of dry powder particles may be elongated by different production conditions to decrease their aerodynamic diameter
D) The shape of liquid aerosol particles from a metered dose inhaler may be elongated to reduce their aerodynamic diameter
E) Elongating the shape of liquid aerosol particles from a metered dose inhaler increases deposition by interception

Answer 43

C) The shape of dry powder particles may be elongated by different production conditions to decrease their aerodynamic diameter