Drug Delivery to the Lung

Question 1

– Advantages of pulmonary drug delivery

Answer 1

• Avoids hepatic first-pass metabolism
• Non-invasive
• Rapid onset of therapeutic effect
• Potential for local and systemic delivery: – Asthma – bronchioles – Systemic – alveoli – Recent attempts to use this route for systemic therapies
• Minimises side effects

Question 2

“Recent” research in systemic therapy via

the lungs?

Answer 2

• Diabetes
– Insulin (Exubra®)
• Pain Management
– Morphine
• Multiple Sclerosis
– Interferon β1a
• Osteoporosis
– Parathyroid hormone

Question 3

Disadvantages of pulmonary drug delivery

Answer 3

• Co-ordination in use, of activation of an inhaler and
actuation – May lead to deposition in the upper airway – Systems not requiring actuation (i.e. nebulisers) are bulky and often not convenient
• Mucus, i.e. from an infection, can reduce deposition
• Physical stability of aerosols (i.e. suspensions)
• Inefficiency of delivery (% uptake of administered dose,
c.f. Corcoran et al., slide 72)

Question 4

Cellular Uptake

Answer 4

• Particles must be hydrophilic enough to dissolve in the lung fluid lining and be lipophilic enough to cross epithelia
• They should be small enough to undergo endocytosis / to navigate the intercellular route through tight junctions
• log P, MW and charge of the drug / particle / droplet

Question 5

Particle / Droplet Size

Answer 5

• Airway size decreases into the lung
• Deposition of particles / droplets depends on particle size
• Particle distribution is usually non-normal, described by the aerodynamic diameter:
– The diameter of a spherical particle of a defined density – 1gcm-3
– Particle distribution is also non-normal in the lung

Question 6

• Aerodynamic diameter:

Answer 6

ds = (square root) p/po . d

• ds is the aerodynamic diameter
• p – density of the particle being investigated
• p0 – the spherical “reference” particle (1gcm-3)
• d – diameter of the particle
• ds is proportional to settling velocity in the lung
• Also expressed as mass median aerodynamic diameter (MMAD) which divides particle distribution equally in terms of particle weight

Question 7

Inertial impaction

Answer 7

• Inertia: the property of a particle that allows it to remain at rest or in uniform motion until exposed to an external force.
• After a particle is inhaled, it often changes direction, due to i.e. flow of air
• Inertia resists this movement
– Particles with sufficient momentum will try to maintain their original trajectory / path of flow
– Particles therefore impact at parts of the respiratory tract prior to the target sites (bronchioles and alveoli)
• As airflow velocity decreases within the lower sections of the respiratory tract, due to factors such as branching or resistance to air flow, the contribution of inertial impaction on particle deposition is lower
– Efficiency of delivery; drug not reaching its intended target

Question 8

Brownian diffusion

Answer 8

• The random movement of particles within a fluid (liquid or air)
• In the respiratory tract, this enables small particles (usually <0.5µm) to move towards and be deposited on the walls of the various sections of the tract
• Not very significant from medicinal / therapeutic aerosols

Question 9

Electrostatic precipitation

Answer 9

• Where the surface change may affect deposition
– i.e. if a charged particle interacts with an oppositely charged site in the respiratory tract
• Not usually important if particle size is > 4µm
• Surface charge may also affect the storage of the product (containers, spacers, inhalers) so it is usually avoided where possible

Question 10

Devices for pulmonary delivery

Answer 10

• pMDI
• DPI
• Nebuliser

Question 11

How can the device, and its use, affect dosing?

Answer 11

• pMDI, DPI, nebulisers
• pMDI coordination
• High tidal capacity required (i.e. 60 L/min DPI)
• Side effects of oropharangeal impaction: pMDI > DPI
• Inter-nebuliser variation

Question 12

pMDI - stability

Answer 12

• Leaching of drugs from polymeric systems by fluorinated propellants (HFA)
– Packaging and product – leaching / extraction
• Ingress of water through valve actuation
– Oleic acid surfactant can counter water (capillary Hbonding adhesive action)
• Possibility of drug adherence to metal canister requires that the can be lacquered

Question 13

pMDI

Answer 13

• Propellant must:
Have low viscosity
Have low surface tension
Be stable on storage
Disperse freely
Evaporate quickly
• Use double diaphragm pump1 with non-return valve to minimalise water ingress
• Use stainless steel tubing with temperature resistant SwagelockTM valves

Question 14

Propellants

Answer 14

• Provides the driving pressure to force the drug from the
device into the patient’s upper respiratory tract
• Evaporates at a rate that allows effective particle delivery to the required site within the respiratory tract
• Both relate to the partial vapour pressure of the propellants in the device.
• Mixtures of propellants are often used to allow the exact
properties required to be obtained.
• Propellants used included CFCs: dichlorofluoromethane , dichlorothtrefluoroethane and trichloromonofluoromethane.

Question 15

Vapour Pressure

Answer 15

ptotal = p1 + p2

Where ptotal is the total vapour pressure in the device chamber and p1 and p2 are the vapour pressures of the individual components (the two propellants)

Also, pn (where, in this case n is 1 or 2) is the partial vapour pressure for each component, represented by p1 = χ1 x p1o

where χ1 is the mole fraction of that propellant and its partial vapour pressure

Question 16

Propellants

Answer 16

• Widespread use of CFCs has been shown to affect the ozone layer – Can only be used in MDIs if no suitable alternative is available
• Propellants now used include hydrofluorocarbons, HFCs: – They do not damage the ozone layer to the same degree as CFCs do
– Include: heptafluoropropane and tetrafluoroethane
– Very hydrophobic materials that affect the solubility of
commonly used surfactants (i.e. oleic acid, sorbitan trioleate), meaning that their solubility is often reduced and may not be able to stabilise a formulation suitably.
– Hence, the use of blends of propellants.

Question 17

Vapour Pressure

Answer 17

• Too high (i.e. from very hydrophobic propellants):
– Excessive impaction on the surfaces in the upper respiratory tract
– Reduces effectiveness of drug delivery and clinical performance
• Too low:
– May resolve the limitations mentioned above if lowered,
but if too low then the propellant is less volatile which may reduce the percentage of actuated dose reaching the
lower airways.

Question 18

Breath-actuation in MDIs

Answer 18

• Aims to eliminate co-ordination difficulties by firing in response to the patient’s inspiratory effect.
• For example, in patients with poor inhaler technique, the
breath-actuated pressurized inhaler, Autohaler™ (3M),
increased lung deposition from 7.2% (conventional MDI) to 20.8% of the dose.
– However, breath-actuated MDIs do not help patients who stop inhaling at the moment of actuation,
– Also, they do not improve lung deposition in patients with good MDI technique.
– The oropharyngeal dose was the same as for the MDI device.
– Patients preferred using the Autohaler™ to the MDI even though clinical outcomes were the same.

Question 19

Aerosol particle size

Answer 19

• Aerosol particle size defines the dose deposited and the distribution of drug aerosol in the lung.
• Fine aerosols are distributed on peripheral airways but they deposit less drug per unit surface area than larger particle aerosols, which tend to
deposit more drug per unit surface area, but on the larger, more central airways
– i.e. it is important to consider where something is delivered / deposited, as well as how much, and particle size w.r.t. drug content
• Most pharmaceutical aerosols are heterodispersed, consisting of a wide range of particle sizes, non-normally distributed.
• As the delivered dose is important for pharmaceutical aerosols, particle number may be misleading, as smaller particles contain less drug than larger ones.

Question 20

Humidity and particle size

Answer 20

• Natural humidity in the airways
• Lipophilic particles
– Little effect on MMAD, as adsorption is minimal
• Hydrophilic particles
– Potentially significant effect on MMAD, as adsorption may cause dissolution of the particle

Question 21

Deposition and Distribution

Answer 21

• Therapeutic effect of aerosolised medicines / therapies depends on the dose deposited and its distribution within the lung.
• The influence of distribution on the effectiveness of inhaled therapies is less clear, i.e.:
– A small dose of histamine aerosol deposited predominantly in the large conducting (central) airways was as effective in decreasing airway obstruction as an 11-fold greater dose of histamine aerosol deposited diffusely
– This suggests that the receptors for histamine reside mainly in the large airways and that surface concentration of a drug affects response.

Question 22

Deposition and Distribution 2

Answer 22

• If a drug aerosol is delivered at a lower than ideal dose (i.e. sub-therapeutic) or to a part of the lung devoid of the targeted disease or receptor, then efficacy / quality of
therapy may be affected, i.e.:
– The receptors for the β2 agonist, salbutamol, and the muscarinic-3 (M3) antagonist, ipratropium bromide are not uniformly distributed throughout the lung.
–β2 adrenergic receptors are present in high density in the airway epithelium from the large bronchi to the terminal bronchioles. Airway smooth muscle has a lower β-receptor density, greater in the bronchioles than bronchi.
– β-receptors are located mostly found in the alveolar wall, a region where no smooth muscle exists

Question 23

Deposition and Distribution 3

Answer 23

– Another study has shown a high density of M3 receptors in submucosal glands and airway ganglia, as well as a moderate density in smooth muscles throughout the airways, nerves in intrapulmonary bronchi and in alveolar walls.
– The location of these receptors in the lung suggests that ipratropium bromide needs to be delivered to the conducting airways, while salbutamol requires a more peripheral delivery to the medium and small airways to produce a therapeutic effect.
– i.e. delivery to a certain part of the lung, not “just” to the lung generally

Question 24

Deposition and Distribution

• Summary:

Answer 24

– Local delivery is not the same for all drugs
– Two different therapies, two different required distributions:
– Inhaled anti-inflammatory therapy is probably most
beneficial when evenly distributed throughout the lung
– Different targets – different particle size / distribution –
different propellants, different formulations andexcipients?

Question 25

Particle size and efficacy

Answer 25

• Particle size affects the lung deposition of an aerosol,
and as such it also can influence the clinical efficacy of a
drug:
– bronchodilation response to cumulative doses of ipratropium bromide delivered either as a 3.3-µm or 7.7-µm aerosol was identical
– the response to salbutamol was significantly greater with the finer (3.3 µm) aerosol
– These results suggest targeting a pharmaceutical aerosol to the location of their receptors in the lung does significantly influence its effectiveness

Question 26

Particle size and efficacy 2

Answer 26

• The varying clinical effect of 250 µg of inhaled terbutaline (via MDI) in asthmatics – given as three different particle sizes: <5 µm, 5–10 µm and 10–15 µm – was reported.
• The greatest increase in forced expiratory volume, specific airway conductance and flow at 50% of vital capacity was found with the smallest particle size (<5 µm).
• This suggests that the smaller particle aerosol was more effective than larger particle size aerosols in producing bronchodilation, as it had the best penetration and retention in the lungs in the presence of airway narrowing.

Question 27

Particle size and efficacy 3

Answer 27

• Using three salbutamol aerosols (with MMADs of 1.5 µm, 2.8 µm and 5 µm), it was shown in mild to moderate asthma therapy that the 2.8 µm particle size aerosol resulted in the best bronchodilation.
• This suggests that small particles penetrate more deeply into the lung and more effectively dilate the small airways than larger particles, which are filtered out in the upper airways. The 1.5µm aerosol induced significantly
less bronchodilation than the 2.8µm aerosol, suggesting this fine aerosol may be deposited too peripherally to be effective since smooth muscle is not present in the alveolar region.
– Particle size and efficacy are not necessarily linearly
correlated

Question 28

Particle inhalation - fundamentals

Answer 28

• An inspiration rate where the upward flow of air exceeds gravitational pull is required – the minimum fluid velocity (MFV)
• The large drug particle (<10 µm) will mostly deposit in the trachea
• The drug particle (if <5 µm) must then liberate from cohesive (drug particle) and adhesive (carrier particles – which aid powder flow) via:
– Impact based detachment
– Fluid based detachment
– Particle must then navigate the oropharngeal bend and bronchial network
• If the particle is <1.0µm then it may deposit deep in the lungs, but is that (i.e. previous slide) always the right target?

Question 29

Deposition and efficacy

Answer 29

• The optimal site of deposition in the respiratory tract for
aerosolized antibiotics depends on the condition being
treated.
– Many pneumonias represent a mixture of purulent tracheobronchitis and alveolar infection.
– Successful therapy would, in theory, require the antibiotic to be evenly distributed throughout the lungs (or similar site of administration).
– However, those confined to the alveoli would probably benefit from greater peripheral deposition.
– Pneumocystis carinii pneumonia (common in HIV patients), is found predominately within the alveolar spaces.
– Treated with inhaled pentamidine given as a 1-µm MMAD aerosol.

Question 30

Mechanism?

Answer 30

• An atypical release / distribution profile?
• Poor apical deposition of the aerosol (i.e. at the apex of the airway).
• Regional changes in intrapleural pressure result in the lower lung regions receiving relatively more of the inspired volume than the upper lung when sitting in an upright position or standing. – This has been shown experimentally to be a 2:1 ratio in overall deposition for a 4 µm aerodynamic diameter aerosol
• This gradient can theoretically be reduced by administering aerosolized pentamidine to patients in the supine position.

Question 31

Bronchoconstriction, inflammation and airway

narrowing alter lung deposition.

Answer 31

• Respiratory diseases, such as CF and bronchiectasis, change the nature of the lung through:
– alterations in bifurcation angles
– obstruction of the airways due to mucus accumulation
• …these factors may modify deposition and distribution
patterns of aerosols.
– Obstruction of the lung decreases cross-sectional area and results in an increase in air velocities and turbulence (in regions where the airflow is normally laminar).
– Obstructions divert air to unobstructed airways and very little drug gets deposited in obstructed areas, and these are often the areas that need to be reached by the drugs being inhaled.

Question 32

Airway restriction and deposition

Answer 32

In an obstructed lung, drug is deposited more centrally
in the lungs (caused usually by inertial impaction), compared with the uniform distribution achieved in the normal lung. Is testing an aerosol on a “healthy” lung a reasonable thing to do?

Question 33

COPD

Answer 33

• Patients with COPD have a significantly lower aerosol penetration than healthy volunteers.
• However, if their forced expiratory volume (FEV1) is increased through bronchodilation, an increase in
peripheral penetration of drug particles can occur.
• Wide variation in deposition (CoV = 60.2%). Control of breathing patterns led to a reduction in variance (CoV =
19%) showing the importance of breathing pattern (and advice / counselling) on the deposition and effectiveness of aerosols.
• According to this study, gender may be an issue?

Question 34

Spacer devices for MDIs

Answer 34

Spacers have been developed to:
• eliminate or substantially reduce coordination requirements
• reduce the ‘cold Freon®’ effect (when the below-freezing spray temperature may cause some patients to stop inhaling)
• reduce the amount of drug deposited in the oropharynx by decreasing the particle size distribution and slowing
the aerosol’s velocity.

Question 35

Spacer devices

Answer 35

• Improve deposition from pMDI
• Coordinate breath with actuation
• Clinically efficacious dose after two breaths
– Particles reside within the device following actuation
– Larger particle may impact on device walls
– Allows propellant to evaporate
• Drug is inhaled from the spacer device
– No need for co-ordination with the use of the inhaler
• Size is a disadvantage – reduces portability
• Non-conducting and anti static devices available
• Pharmaceutical advice is to wash in non-ionic/mildly
ionic detergent and drip dry

Question 36

Spacer devices for MDIs

Answer 36

• The aerosol from a MDI and holding chamber is finer than that with the MDI alone
– There is usually a 25% decrease in the MMAD compared with the original aerosol.
– Big particles stick to the walls of the spacer…
• This aerosol produced in the spacer is more
uniformly distributed in the normal lung, with increased delivery to the peripheral airway.
• However, in patients with airway obstructions, the addition of a holding chamber to the MDI does not significantly change the distribution of the aerosol (why?
technique?).

Question 37

Dry powder inhalers

Answer 37

• Inhalation of a powder by the patient into the respiratory
tract
– Developed to reduce co-ordination difficulties with MDIs
– No propellant required; aerosol is created by directing air through a loose powder of drug and excipients
– Literature often reports DPIs to be less efficient than pMDIs
• Traditionally use carriers of lactose 30 – 60µm in size
• Drug particles ca. 3-5 µm adhere to surface
FPF (F< 5 µm) increased using smoother carriers
• Lactose spheres or Mg Stearate have been used to increase fine particle fraction (cohesion / adhesion)

Question 38

Deposition from DPIs

Answer 38

• Lung deposition varies among different types of DPIs
available.
• Approximately 12–40% of the emitted dose is delivered to the lungs with 20–25% of the drug being retained within the device.
– Poor drug deposition with DPIs is usually the result of inefficient disaggregation of the fine drug particles from coarser carrier lactose particles or drug pellets.
– Slow aerosolisation, high humidity and rapid, large changes in temperature are known to effect drug dis-aggregation (and therefore efficiency) of drug delivery with DPIs.
• With most DPIs, drug delivery to the lungs is augmented by fast inhalation.
– Increasing the inspiratory flow rate (IFR) from 35 L.min−1 to 60L.min−1 using the Turbuhaler™ device increased the total lung dose delivered of terbutaline from 14.8% to 27.7%.
– This is very different to MDIs, which require slow inhalation (and for the patient to hold his or her breath) to increase or enhance lung deposition of the drug.
– The Spiros DPI, however, deposits significantly more in the lung when lower IFRs (i.e. <30 L.min−1) are used.
• Device selection and its dependence on efficacy
• How does a healthcare professional select the correct device for a patient and disease?

Question 39

DPIs – formulation considerations

Answer 39

• Therapeutic agent
– mass-median aerodynamic diameter (MMAD) < 5µm
• Excipients used to facilitate production:
– As the DPI usually has a low dose an inert excipient is used as filler
• Excipients used to improve flow properties during inhalation
– excipients used to facilitate flow and the cohesive / adhesive balance
• Polymorphism
• Example of systemic delivery from a DPI:
– Exubera® (Pfizer) device for the delivery of insulin
– Acquired by Aerogen / Dance in 2011

Question 40

Nebulisers

Answer 40

• Solutions – Sterile – Acidic solutions (pH < 5) may cause bronchoconstriction – Therefore, pH > 5 is required (requires buffers) – May use co-solvents
• Should consider toxicity to the respiratory epithelia – Osmolality-modifying agents (i.e. salts) – Other ingredients (preservatives, antioxidants (sulphites
may cause bronchospasm)
• Portability and convenience of devices

Question 41

Correlation Between Particle Size and

Thoracic Deposition

Answer 41

Correlation suggests that greater particle diameter correlates with reduced lung deposition

Question 42

Types of Nebulizers

Answer 42

• Jet nebulizer / compressor systems
– Most common type of nebulizer use
• Ultrasonic nebulizers
– Not suitable for viscous solutions
– May damage certain drugs / particles

Question 43

Inhalation Velocity Affects Lung Deposition With Nebulizer

Answer 43

• The effect of inspiratory flow rate on the distribution of radiolabeled aerosol in the lungs of patients with asthma.
• 9 patients (aged 23 to 36 years) with a history of allergic or exercise-induced asthma inhaled radiolabeled (99mTc sulfur) 0.9% buffered saline aerosol administered by a No. 42 De Vilbiss hand-held jet nebulizer at a rapid ( ≈60 L/min) or slow ( ≈12 L/min) inspiratory flow rate on 2 study days.
• Aerosol distribution in the airways was quantified by gamma-camera scan.
• Methacholine challenge was performed after gamma scan; albuterol was administered to reverse airway obstruction after each challenge.
• The amount of radiolabeled aerosol deposited in the trachea and lungs was reduced in 6 of 9 patients
during rapid versus slow inhalation, but mean values were similar (5.1 ± 3.0µL versus 5.2 ± 2.3 µL).
• As shown in the scans, rapid inspiration resulted in greater heterogeneity in lung deposition and regions of higher-density labeling compared with slow inspiration.
• Rapid inhalation resulted in greater aerosol deposition in the inner lung and less penetration to the lung
periphery. The ratio of inner zone (large, central airways) to outer zone (peripheral airways and alveoli) deposition was 2.91 ± 0.51 during rapid inhalation, compared with 1.84 ± 0.30 during slow inspiration (P

Question 44

Advantages of Nebulizers

Answer 44

• Any age
– requires less co-ordination than inhalers
• Easy to teach and use
• Patient coordination not required
• High drug doses possible due to continuous nebulisation
• No propellant
– E.g. they do not contain CFCs or HFAs
• Can be used with supplemental oxygen

Question 45

Disadvantages of Nebulizers

Answer 45

• Less portable than inhalers
– Also requires power source, maintenance, and cleaning
• Output is device dependent
• Delivery may take 5 to 10 minutes or longer
• Formulation limitations

Question 46

Reasons for poor asthma control

Answer 46

• Wrong diagnosis or confounding illness
• Incorrect choice of inhaler or poor technique
• Concurrent smoking
• Concomitant rhinitis
• Unintentional or intentional non-adherence
• Individual variation in treatment response
• Undertreatment
•“asthma guidelines, which are based on results of these trials, often do not provide the answers we need for patient care, particularly in the primary care setting”
• Comorbidities can worsen asthma symptoms (and make
asthma products less effective?): – allergic rhinitis – COPD – gastro-oesophageal reflux disease (GERD) – respiratory infection – cardiac disorders – anaemia – vocal cord dysfunction
• Therefore, these conditions can be treated to successfully help in controlling asthma

Question 47

Incorrect inhaler choice or poor technique

Answer 47

• There is little or no clinical difference between inhaler devices when used correctly, but each type requires a different pattern of inhalation for optimal drug delivery to the lungs.
– This may be due to the physical needs of particular drugs and how that may limit or influence device selection.
• Problems with inhaler technique are common in clinical practice and can lead to poor asthma control.
– Asthma control worsens as the number of mistakes in inhaler technique increases, or poor technique becomes accepted as the norm.
• All patients should be trained in inhaler technique, and trainers should be competent with the inhalation technique required for a wide range of devices
(all of them…). They are not all the same.

Question 48

Inhaler choice and technique

Key recommendations:

Answer 48

• Take patient preference, or ability to use a particular device, into account when choosing the inhaler device
• Keep treatment regimen simple
– do not mix inhaler device types
• Choice of steroid inhaler is particularly important due to the narrower therapeutic window (compared to other drugs)
• Invest the time to train each patient in proper inhaler technique:
• Observe technique & let patient observe self
• Devices to check technique & maintain trained technique are available (eg, 2Tone Trainer & Aerochamber Plus spacer for metered dose inhalers; In-Check Dial, Turbuhaler whistle, Novolizer for dry powder inhalers)
• Re-check inhaler technique on each revisit

Question 49

Inhibition of ILC cells

Answer 49

Innate lymphoid cells (ILCs) produce cytokines that

drive allergic responses in asthma and can be inhibited by lipoxin A4

Question 50

Gravitational sedimentation

Answer 50

• The downward movement of particles under gravity
• Important for particles with a small mass-median aerodynamic diameter (MMAD)
– i.e. around 1.0 – 5.0µm
– Usually because larger particles will have been deposited by impaction
• Impaction by gravitational sedimentation is increased by a steady rate of breathing or holding the breath (turbulence)
– More pronounced for particles ca. 1.0µm

Question 51

So why use aerosols?

Answer 51

• Limited number of trained personnel in some countries
• Inadequate safe injection practices
– Re-use of equipment
– Unsafe collection
– Unsafe disposal
• Usually more of an issue during large campaigns when more doses are administered
• Problems:
– Bioavailability and consistent dosing
– Costs
– Not yet tested in humans / regulatory approval
• Formulation: DPI