Routes of delivery Flashcards
why are drugs delivered to the lungs
- local administration- targets large and small bronchial airways
- bronchodilators, steroids - systemic- target alveolar region
- insulin (macromolecule)
what occurs in the nasopharyngeal and tracheobronchial
air conduction/conditioning
what occurs in the alveolar
gas exchange
what does the pulmonary epithelium in the alveolar region consist of
- type I pneumocytes
- type II pneumocytes
- alveolar macrophages
what are the properties of type I pneumocytes
- thin
- 93% surface area
- half number of type II
what are the properties of type II pneumocytes
- cuboidal
- store and secrete surfactant
what are the properties of alveolar macrophages
- 3% of cells
- phagocytic cells which scavenge and transport particulate matter to lymph nodes and mucociliary escalator
- antigen presenting cells and recruit lymphocytes to lung
what are the barriers in delivering to the lung
- reaching site of absorption
- being absorbed
what factors affect reaching the site of absorption
- aerodynamic particle size of aerosol
- stability of formulation in aerosol generation process
- sufficient and reproducible deposition
- filters- mucociliary clearance
what factors affect the drug being absorbed at the site of absorption
- alveolar lining fluid
- macrophages
- absorptive epithelium
- basement membranes
- enzymes
- disease
what are the major clinical issues affecting treatment via lungs
- drug formulation and stability
- drug safety
- dosing issues- reaching site of absorption
- absorbed proportion of deposited drug- getting into bloodstream
- safety and efficacy of additives
- pharmacokinetics
what are the parameters affecting particle deposition in the lungs
- aerodynamic particle behaviour- size, density, shape
- breathing pattern- inhaled volume, flow rate of inhalation, breathe holding
- time of aerosol pulse injection into breathing cycle
- airway anatomy and morphometry of patient
what is meant by aerodynamic particle diameter
the diameter of a sphere with a density of 1gcm-3 that has the same aerodynamic behaviour as the particle which shall be characterised
describe the relationship between aerodynamic diameter and geometric diameter in a water droplet vs in large porous particles
water droplet, aerodynamic diameter= geometric diameter
large porous particles, aerodynamic diameter< geometric diameter
what are the 3 types of aerodynamic particle behaviour
- brownian diffusion- particles <0.5 microns
- not significant for inhaled drugs - gravitational sedimentation- particles >0.5 microns
- inertial impaction- particles >3 micron
- prevents aerosol particles entering the lungs
what does residence time depend on
- air flow rate
- inhaled and exhaled volume
- end inspiratory breathe hold of the patient
what are the 2 types of breathing patterns
- fast inhalation- enhanced deposition by impaction in nose and trachea
- poor penetration into deep lung - slow inhalation- particles up to 10um can enter lung but variable
- decreased variability if particles 1-3um
- if too small then exhaled
what is meant by aerosol bolus
- pulse of aerosol sandwiched in clean air
- time of injection into inhalation manouvre can influence site of deposition
- early in cycle, deeper lung penetration
- exploited in breath actuated MDIs and dry powder inhalers
- used by AERx device
what occurs after deposition
- mucus barrier- dissolution, diffusion
- mucociliary clearance- ends at terminal bronchioles
- alveolar clearance- uptake by alveolar macrophages
what are the advantages of lung delivery over oral route
- less harsh environment
- avoids first pass intestinal and hepatic metabolism
what are the disadvantages of pulmonary route for systemic delivery
- poor access
- devices difficult to use
- poor reproducibility
- mucociliary clearance
- alveolar macrophages
what are the factors affecting systemic pulmonary delivery of insulin
- drug factors- peptide hormone, large molecule molecular weight
- biopharmaceutical factors- not absorbed after oral administration
- therapeutic factors- aim to mimic insulin secretion by normal pancreas
name examples of inhaled insulin devices
Exubera, afrezza, AERx
what are the requirements for inhaled insulin
- particle size range 1-3 um- to aid alveolar deposition
- good inhalation technique and device- release of insulin in early part of slow inhalation
- reproducible dose- to avoid hyper/hypoglycaemia
what is afrezza and how is it used
- lyophilised rapid acting inhaled insulin
- technosphere particles
- taken at beginning of each meal and used in combination with a long acting injected insulin
- not recommended for treatment of diabetic ketoacidosis or patients who smoke
- no propellant or power source
- 1 chamber
what are the properties of technosphere particles
- FDKP
- high internal porosity
- high surface area
- high adsorption of insulin
what are the requirements of an inhaled insulin device
- portable
- convenient to use
- give reproducible delivery to lower airways where absorption is good
- avoid delivering insulin too fast
describe the properties of Exubera
- lyophilised regular insulin in blister packets
- no propellant or power source
- 2 chambers
- release unit to be changed biweekly
- upper chamber and mouthpiece to be washed weekly
What is the AERx insulin diabetes management system
- phase III trials
- microprocessor controlled
- liquid insulin delivered under pressure
- breath check system
- chaser volume of fresh air
- 1-10 units can be delivered
- 1 AERx unit= 1 IU insulin sc
- electronic download capability- monitors dosing, frequency of use and breathing pattern
what is the main difference between Exubera and Afrezza
exubera is inhaled regular insulin, whereas afrezza is a monomer
