Inhalation drug delivery Flashcards
What are the benefits or inhalation medication?
• 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:
o For acute and breakthrough pain treatment
o Where physical and/or chemical interactions with other medications must be avoided
o When the drug exhibits variable or erratic pharmacokinetics when given orally
o When critical to avoid GI degradation of the therapeutic agent e.g. biologics
What makes up the upper respiratory tract?
Buccal, sub-lingual, and nasal cavities, pharynx, upper larynx (above the vocal cards)
What size particles do the nasal cavity filter out?
Large particles (>15 micrometres), go to mouth to swallow or cough/sneeze (expel)
What covers the entrance to airways when swallowing?
Epiglottis
What makes up the lower respiratory tract?
Trachea - branching to primary and then secondary bronchi, then branching to bronchioles and terminating in alveoli
How many alveoli are there per lung?
300 million (70 m^2 surface area)
What is the extent of particle deposition affected by?
o Product characteristics:
Dry powder: particle diameter, shape, density,
charge, and surface chemistry
Liquid aerosol: droplet size distribution,
velocity, nature of propellant
o Anatomical and physiological characteristics:
Geometry of the respiratory tract
Lung capacity
Breathing patterns (frequency, tidal volume)
Pathology
What is inertial impaction?
Momentum of particle renders it unable to follow the airflow in a curved airway so that it impacts on the wall – finds it hard to deviate round the corner (larger particles)
What is gravitational sedimentation?
related to the Residence time in an airway & terminal settling velocity, increased by holding breath – heavier particles settle first
What is Brownian diffusion?
Random collision of particle with airway wall; significant only for particles < 0.1 mm (small)
What is electrostatic attraction?
Charge on particle induces opposite charge on airway wall and accelerates particle into wall – narrow airways
What is interception?
Particle size approaches airway diameter
What is the relationship between deposition by impaction and sedimentation and particle size?
Deposition by impaction and sedimentation are directly proportional to particle size; most significant for particles > 1micrometres
What is the relationship between deposition by diffusion and particle size?
Deposition by diffusion is inversely related to particle size; significant only for sub-micron sized particles
How is deposition achieved in traditional delivery services?
Through impaction and sedimentation; particles < 10 mm (typically, 2 – 8 mm); 80-90% of dose not deposited; large losses to GI absorption (& side effects)
How is improved deposition achieved in inhalers?
Improved deposition achieved in inhalers emitting smaller particles at lower velocities (only 50% - 70% losses) with > 30% deposition achieved in peripheral airways
What inhalation devices are useful for upper respiratory tract?
Sprays
What inhalation device uses solvent propellant and was banned because of this?
Pressurised metered dose inhalers (pMDIs)
What inhalation device is useful for small airways diseases?
Superfine particle inhalers
What are nebulisers?
drug dispersed in polar solvent (usually H2O); cumbersome; mainly used in hospitals and in ambulatory care; recent smaller aerosolisation developments
What are Dry Powder Inhalers?
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
What are nasal sprays used for?
Used for hay fever medications (antihistamines), treatment of sinusitis (steroids), and in decongestants
What is ViaNase?
From Kurve Technology; uses electronic atomiser to give controlled particle dispersion (with narrow size range: 10 – 30 mm); minimises pulmonary and GI deposition
What is Optinose?
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
What do pMDIs do?
- 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;
- Dose counters incorporated
- Excipients: co-solvent (ethanol), 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
Why would 20 micrometres 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?
o Large particle – sediments in the first place it comes across, - 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
o A relatively small fraction of the 20micrometre particles will penetrate to the lower respiratory tract, and those that do will deposit there through gravitational sedimentation
o Only a very low proportion of the 20um particles will thus escape deposition and remain in the exhaled
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?
o Upper (ciliated) airways (particles get stuck in mucus), mouth or throat – could get swallowed and then end up in the stomach (GI tract) o Drug will be enzymatically degraded in the stomach
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?
o Small particles have less momentum and inertia and will impact to a lesser extent in the larger and less branched upper airways, less likely to sediment and bump into the walls of upper airways. The impaction of the 6 and 2um particles is more likely to take place in the more highly branched lower airways
o Particles have less inertia
o More of the 2-micron particles will be exhaled
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?
o Sub-micron 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 significant
o 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.
Which particle size is most favourable for systemic delivery of drug & why?
o 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.
o The lower airways are non-ciliated, present a high surface area for absorption, and have a rich blood supply
Where do most particles generated in traditional pMDIs and DPIs deposit?
In the wider upper airways by sedimentation and impaction
What diseases are inadequately treated using traditional inhalers?
Small airways diseases conditions (e.g. COPD, chronic asthma)
What size are small airways?
<2mm diameter - major sire of airflow limitation
What happens to particles 0.5-1mm?
Deposited poorly, with most exhaled
What size are extra-fine particles?
<1mm**?
What size are ultra-fine particles?
<100nm
What are the extra-thoracic regions?
Neck upwards
What are the differences in deposition between thoracic (TH) and extra-thoracic (ET) regions for particles 1-9 (2.8) micron?
1 – 9 (2.8) micron size gives high ET (throat) (high throat deposition means particles may end up in the stomach - swallowed) 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
What are the differences in deposition between thoracic (TH) and extra-thoracic (ET) regions for particles 0.25-1 micron?
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
What are the differences in deposition between thoracic (TH) and extra-thoracic (ET) regions for particles 0.15-0.5 micron?
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 –> better deposition in the thoracic region as they are small enough to reach that area and deposit via Brownian diffusion
What increases with particle size?
Deposition
What happens to deposition with a lower breathing rate and higher tidal volume?
Higher deposition due to greater contribution of sedimentation between breaths
What is the deposition through gravitational sedimentation and inertial impaction for small particles (0.5-1 micron)?
LOWER and diffusional deposition is not yet significant, resulting in the loss of particles on exhalation
What contributes far less with nanoparticles (0.01-0.5 micron)?
Inertial impaction and gravitational sedimentation
Where are nanoparticels more likely to travel to?
Ultrafine particles are unlikely to impact or sediment in the upper airways and more likely to be inhaled into the lower, smaller airways
Why is there a high deposition of nanoparticles in the lower, smaller airways?
Diffusion dominates the deposition of very small particles and is inversely related to particle size, and so there will be a high deposition of these NPs in the lower, smaller airways
When are nebulisers used?
Used - in the home and in hospitals – to treat patients with conditions that render them unable to use other types of inhaler devices
What are traditional (air jet) nebulisers?
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
What are ultrasonic nebulisers?
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
What are vibrating mesh ultrasonic nebulisers?
Vibrating mesh ultrasonic nebulisers: 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)
What are passive breath-dispersing DPIs?
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
What are active DPIs?
in development, use an internal power source to aerosolize the powder; SpirosTM, uses a battery-powered motor, Oriel, uses a piezoelectric polymer
What is included in the formulation of DPIs?
carriers (e.g., lactose) not always used; drug crystals may be used (e.g., Pulmicort (budenoside), Turbuhaler (AZ)
How are the APIs for DPIs micronized?
micronized by jet, pin or ball milling, or else by spray drying or use of supercritical fluid
What particle size shows efficient alveolar delivery?
particles with aerodynamic diameters of 1 – 5 microns
What is aerodynamic diameter?
describes dynamic behaviour of a particle, relating gravitational settling and inertial impaction
What can aerodynamic diameter be decreased by?
o decreasing (geometric) size
o decreasing density
o increasing shape factor
What formulation would be LEAST likely to be considered to treat a fungal lung infection?
Dry powder inhaler with drug particles micronized to a few microns in aerodynamic diameter
–> Drug particles that are microns in size with NOT get into the lower airways, and if they are dry, they will not dissolve well
What affect would increasing the geometric size and density, and reducing the shape factor of particles have on systemic bioavailability?
Increasing the geometric size and density and reducing the shape factor of the aerosol particles will all serve to increase the particle aerodynamic diameter and this will result in even more deposition in the upper airways (NOT improving bioavailability)
Can the shape of dry powder particles be elongated by different production conditions to decrease their aerodynamic diameter?
YES
