Routes of delivery

Question 1

why are drugs delivered to the lungs

Answer 1

1. local administration- targets large and small bronchial airways
   - bronchodilators, steroids
2. systemic- target alveolar region
   - insulin (macromolecule)

Question 2

what occurs in the nasopharyngeal and tracheobronchial

Answer 2

air conduction/conditioning

Question 3

what occurs in the alveolar

Answer 3

gas exchange

Question 4

what does the pulmonary epithelium in the alveolar region consist of

Answer 4

1. type I pneumocytes
2. type II pneumocytes
3. alveolar macrophages

Question 5

what are the properties of type I pneumocytes

Answer 5

• thin
• 93% surface area
• half number of type II

Question 6

what are the properties of type II pneumocytes

Answer 6

• cuboidal
• store and secrete surfactant

Question 7

what are the properties of alveolar macrophages

Answer 7

• 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

Question 8

what are the barriers in delivering to the lung

Answer 8

1. reaching site of absorption
2. being absorbed

Question 9

what factors affect reaching the site of absorption

Answer 9

1. aerodynamic particle size of aerosol
2. stability of formulation in aerosol generation process
3. sufficient and reproducible deposition
4. filters- mucociliary clearance

Question 10

what factors affect the drug being absorbed at the site of absorption

Answer 10

1. alveolar lining fluid
2. macrophages
3. absorptive epithelium
4. basement membranes
5. enzymes
6. disease

Question 11

what are the major clinical issues affecting treatment via lungs

Answer 11

1. drug formulation and stability
2. drug safety
3. dosing issues- reaching site of absorption
4. absorbed proportion of deposited drug- getting into bloodstream
5. safety and efficacy of additives
6. pharmacokinetics

Question 12

what are the parameters affecting particle deposition in the lungs

Answer 12

1. aerodynamic particle behaviour- size, density, shape
2. breathing pattern- inhaled volume, flow rate of inhalation, breathe holding
3. time of aerosol pulse injection into breathing cycle
4. airway anatomy and morphometry of patient

Question 13

what is meant by aerodynamic particle diameter

Answer 13

the diameter of a sphere with a density of 1gcm-3 that has the same aerodynamic behaviour as the particle which shall be characterised

Question 14

describe the relationship between aerodynamic diameter and geometric diameter in a water droplet vs in large porous particles

Answer 14

water droplet, aerodynamic diameter= geometric diameter
large porous particles, aerodynamic diameter< geometric diameter

Question 15

what are the 3 types of aerodynamic particle behaviour

Answer 15

1. brownian diffusion- particles <0.5 microns
   - not significant for inhaled drugs
2. gravitational sedimentation- particles >0.5 microns
3. inertial impaction- particles >3 micron
   - prevents aerosol particles entering the lungs

Question 16

what does residence time depend on

Answer 16

• air flow rate
• inhaled and exhaled volume
• end inspiratory breathe hold of the patient

Question 17

what are the 2 types of breathing patterns

Answer 17

1. fast inhalation- enhanced deposition by impaction in nose and trachea
   - poor penetration into deep lung
2. slow inhalation- particles up to 10um can enter lung but variable
   - decreased variability if particles 1-3um
   - if too small then exhaled

Question 18

what is meant by aerosol bolus

Answer 18

• 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

Question 19

what occurs after deposition

Answer 19

1. mucus barrier- dissolution, diffusion
2. mucociliary clearance- ends at terminal bronchioles
3. alveolar clearance- uptake by alveolar macrophages

Question 20

what are the advantages of lung delivery over oral route

Answer 20

1. less harsh environment
2. avoids first pass intestinal and hepatic metabolism

Question 21

what are the disadvantages of pulmonary route for systemic delivery

Answer 21

1. poor access
2. devices difficult to use
3. poor reproducibility
4. mucociliary clearance
5. alveolar macrophages

Question 22

what are the factors affecting systemic pulmonary delivery of insulin

Answer 22

1. drug factors- peptide hormone, large molecule molecular weight
2. biopharmaceutical factors- not absorbed after oral administration
3. therapeutic factors- aim to mimic insulin secretion by normal pancreas

Question 23

name examples of inhaled insulin devices

Answer 23

Exubera, afrezza, AERx

Question 24

what are the requirements for inhaled insulin

Answer 24

1. particle size range 1-3 um- to aid alveolar deposition
2. good inhalation technique and device- release of insulin in early part of slow inhalation
3. reproducible dose- to avoid hyper/hypoglycaemia

Question 25

what is afrezza and how is it used

Answer 25

1. lyophilised rapid acting inhaled insulin 2. technosphere particles 3. taken at beginning of each meal and used in combination with a long acting injected insulin 4. not recommended for treatment of diabetic ketoacidosis or patients who smoke 5. no propellant or power source 6. 1 chamber

Question 26

what are the properties of technosphere particles

Answer 26

- FDKP - high internal porosity - high surface area - high adsorption of insulin

Question 27

what are the requirements of an inhaled insulin device

Answer 27

1. portable 2. convenient to use 3. give reproducible delivery to lower airways where absorption is good 4. avoid delivering insulin too fast

Question 28

describe the properties of Exubera

Answer 28

1. lyophilised regular insulin in blister packets 2. no propellant or power source 3. 2 chambers 4. release unit to be changed biweekly 5. upper chamber and mouthpiece to be washed weekly

Question 29

What is the AERx insulin diabetes management system

Answer 29

1. phase III trials 2. microprocessor controlled 3. liquid insulin delivered under pressure 4. breath check system 5. chaser volume of fresh air 6. 1-10 units can be delivered 7. 1 AERx unit= 1 IU insulin sc 8. electronic download capability- monitors dosing, frequency of use and breathing pattern

Question 30

what is the main difference between Exubera and Afrezza

Answer 30

exubera is inhaled regular insulin, whereas afrezza is a monomer