Inhalation Drug Delivery Flashcards
(43 cards)
Benefits of 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:
• 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
Upper respiratory tract =
- 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
Lower respiratory tract =
trachea – branching to primary and then secondary bronchi
• 2o bronchi branching to bronchioles
• Bronchioles terminating in alveoli
Diameter of human trachea?
1.5-2cm, bronchioles 1mm diameter or less, terminal bronchioles = 0.5mm
• 300 million alveoli per lung (70 m2 surface area
Extent & loci of particle deposition are affected by:
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
Inertial impaction is?
momentum of particle renders it unable to follow the airflow in a curved airway so that it impacts onthe wall
Gravitational sedimentation is?
related to the residence time in an airway & terminal settling velocity, increased by holding breath
Brownian diffusion is?
random collision of particle with airway wall; significant only for particles < 0.1 mm. Smaller.
Electrostatic attraction is?
charge on particle induces opposite charge on airway wall and accelerates particle into wall. Occurs in last stages in narrow airways.
Interception:
particle size approaches airway diameter – not significant for spherical particles, only for those that are asymmetrical and needle like
Deposition by impaction & sedimentation are directly
proportional to:
particle size; most significant for particles > 1mm
Deposition by diffusion is inversely related to:
particle size; significant only for sub-micron sized particles
In traditional delivery devices, deposition achieved primarily through:
impaction and sedimentation; particles < 10 mm (typically, 2 – 8 mm); 80-90% of dose not deposited; large losses to GI absorption (& side effects)
Inhalation Devices e.g.
- 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
What is vianase?
- 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
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
- Device inserted in mouth and nostrils
What are pMDI’s?
- 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
Excipients for pMDI’s?
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
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?
- 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.
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?
- 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
• 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?
- 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.
• 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?
- 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.
• Which particle size … for systemic delivery of drug & why?
- 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.
Superfine Particle Inhalers are for:
• 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
