Drug Delivery To The Lung Flashcards
Lung Flow
- Lung has areas of turbulent flow
* Particulates/droplets collect at apex/areas of turbulence and dispersed by cilia
Airway structure
• Airway Anatomy
– The cellular composition of the airway epithelia differs significantly
• In the upper airways, the ciliated cells are interspersed with secretory cells,
• At lower levels they are interspersed with Clara cells (bronchiolar exocrine cells)
• Squamous cell (Types I &II) are found in the alveolar regions
Cellular Uptake
• 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
Advantages of pulmonary drug delivery
• Avoids hepatic first-pass metabolism • Non-invasive • Rapid onset of therapeutic effect • Local and systemic delivery: –Asthma – bronchioles –Systemic – alveoli • Minimises side effects
– Disadvantages of pulmonary drug delivery
• 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
• Efficiency of delivery
• Physical stability of aerosols (i.e. suspensions)
Particle / Droplet Size
• 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
Particle / Droplet Size
• Aerodynamic diameter:
- 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 proportional to settling in the lung
- Also expressed as mass median aerodynamic diameter (MMAD) which divides particle distribution equally in terms of particle weight
Particle inhalation – fundamentals
• An inspiration rate where the upward flow of air exceeds gravitational pull is required – this is called
minimum fluid velocity (MFV)
• The drug particle (<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
Mechanisms of particle deposition
- Inertial impaction
- Gravitational sedimentation
- Brownian diffusion
- Electrostatic precipitation
Inertial impaction
• 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)
• Probability of inertial impaction happening increases as the angle and velocity of airflow increases
• Probability of inertial impaction reduces in airways of larger radius
• Primpaction = UtUsinθ / rg
• 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
Ut
Ut is the terminal settling velocity – the velocity of motion when the force of the particle downwards is equal to the drag force acting in the opposite direction; U is the velocity of the airstream following inhalation sinq is the angle of airflow change; G is gravity; R is the radius of the
airway
Gravitational sedimentation
• 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
Brownian diffusion
- 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
Electrostatic precipitation
• 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 of particle size is > 4µm
• Surface charge may also affect the storage of the product (containers, spacers, inhalers) so it is usually
avoided where possible
Devices for pulmonary delivery
- pMDI
- DPI
- Nebuliser
How can the device, and its use,
affect dosing?
• pMDI coordination
• High tidal capacity required (i.e. 60 L/min DPI)
• Side effects of oropharangeal impaction: pMDI
> DPI
• Inter-nebuliser variation
Tidal volume:
Tidal volume: that volume of air moved into or out of the lungs during quiet breathing
(VT indicates a subdivision of the lung; when tidal volume is precisely measured, as
In the gas exchange calculation, the symbol VT or VT is used).
Formulation
- Propellant
- Therapeutic agent – Solution or suspension (depends on the drug properties?) – Excipients?
- Actuation mixes drug and propellant, which is released – Controlled by the metering value of the canister, allows the release of a defined volume – Droplet size ca. 40 µm MMAD
Formulation – Particle Size
• Target areas in the lung and required particle size
• Particles / droplets must have the right particle size and
polydispersity (an inconsistent size, shape and mass
distribution) for the target site
– Reduction of particle sizing is achieved by milling
– Achieving polydispersity is difficult
• Shaking of the pMDI should ensure ready redispersion of the drug in suspension
– Aggregation / caking leads to variations in particle size and inconsistent dosing
• Propellant ensures delivery of the drug particle but must
evaporate rapidly
Propellant
• Provides driving force to expel drug / formulation
from the device to the upper respiratory tract
• To evaporate quickly enough to facilitate delivery to
the required region of the lung
• Depends on the partial vapour pressure within the
canister of the device – Appropriate blends can be used to give the required clinical properties
Vapour Pressure
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
- whereχ1 is the mole fraction of that propellant and p1o its partial vapour pressure
Vapour Pressure
• Too high:
– Excessive impaction on the surfaces in the upper respiratory tract
– Reduces effectiveness of drug delivery and clincial performance
Vapour Pressure
• 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.
pMDI devices
- Over 500,000,000 units
- Currently use HFA propellants
- CFCs as a propellant in a pressurized aluminium canister. CFCs are inert, stable, and safe
- 1970s: concerns regarding the adverse effects of CFCs on the levels of stratospheric ozone were raised.
- CFCs are resistant to degradation by the environment and/or biological systems
- CFCs are broken down by solar radiation, releasing chlorine radicals that actively destroy ozone. It is estimated that 1 chlorine radical can destroy up to 100 000 molecules of ozone
- High packaging interaction – oral route
HFA MDIs
Aerosol mist:
- Softer Warm spray
- Requires slower inhalation
Maintenance and cleaning of device:
-More frequent cleaning
necessary, at least weekly
Efficacy of salbutamol MDI:
-Equal to CFC MDI
Efficacy of steroid MDI:
-Improved (greater amount deposited in small airways)
Cost:
-More expensive
Environmentally safe:
-Yes
Loss of dose from inhaler
when stored in cold climate:
-No
Less dose variability at end of canister’s life:
-Yes
CFC MDIs
Aerosol mist:
-More forceful
-Cold spray (“cold Freon
effect”)
Maintenance and cleaning of device:
-Less frequent cleaning
needed
Efficacy of salbutamol MDI:
-Equal to HFA MDI
Efficacy of steroid MDI: -Less efficacious than HFA MDIs
Cost:
-Less expensive
Environmentally safe:
-No
Loss of dose from inhaler
when stored in cold climate:
-Yes
Less dose variability at end of canister’s life:
-No
pMDI
• Propellant must:
- Have low viscosity
- Have low surface tension
- Be stable on storage
- Disperse freely
- Evaporate quickly
- Use double diaphragm pump with non-return valve to minimalise water ingress
- Use stainless steel tubing with temperature resistant Swagelock valves
MDI Formulation
• Solubility in propellant
– Reduced solubility may lead to fluctuations in solubility due to e.g. re-crystallisation
– May lead to larger particles
• MMAD / polydispersibility of dispersed particles
– Must remain within the desired range for inhalation / inspiration to the target site(s) of action
pMDI – Stability
• 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 H-bonding adhesive action)
• Drug adherence to metal canister requires can to be lacquered
• Caking of suspended particles
– Can use various materials, including sorbitan trioleate or oleic acid
• No real need to enhance stability by viscosity modification
Spacers
- 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
Dry powder inhalers
• Inhalation of a powder by the patient into the
respiratory tract
– No propellant required
– However, 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)
Dry powder inhalers
• Different types:
– Inhalers in which the formulation (the drug and excipients) are present within a hard gelatin capsule
• Capsule is held within the delivery device
• Prior to use, it is pierced in two places to allow flow of air
• Patient inhales and a rotator activates resulting in turbulent air flow ( 35 l/min), carrying the powder to the patient
– Inhalers in which the drug and excipients are present
within a blister pack
• Assembled (loaded) into the device and actuation sees the pack pierced and the drug delivered
– Inhalers in which the drug and excipients are presented in the inhaler device
• May be loaded in the form of cartridges
• Drug and excipients may be added together or individually
• Actuation is by twisting the base, resulting in the drug being drawn into a chamber and then delivered
Carrier particle considerations in DPI’s
- Baffles in a DPI allow particle detachment
- Seen in the high resistance Turbohaler device
- Over 20% higher FPF compared to conventional DPI device e.g. Fison Spinhaler
DPIs – formulation considerations
• 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
inhilation
– excipients used to facilitate flow and the cohesive / adhesive balance
• Polymorphism
Controlled Release
Polylactide co-glycolide (PLGA) – Higher % glycolide = faster dissolution
Nebulisers
- 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
BP Testing
• Implication on Impactor testing
NGI
ACI
MSLI
Growth expansion of particles in the lung
• Increase in humidity of air from RH (75%) to 99%
• As a hydrophilic particle enters the lung it becomes a saturated droplet
• Droplet increases in size
• Refrigeration and humidification of impactors used to mirror this increase
– In vivo/Impactor correlation r2= 0.67
Pre-clinical Testing
- May assess adverse effects locally and systemically
- Unique delivery route but universal considerations: – condition of animals – environmental conditions
- Rodent - snout only
- Non-rodent – oro-nasal mask
- Oropharangeal tube when the resource is in short supply
- Delivery is “estimated”
Clinical example:
Colistin
• Colistimethate sodium (CMS) is a polymyxin antibiotic - a
cyclic heptapeptide
• CMS forms the active base Colistin in water
• Colistin will degrade over time in saline so must be used
immediately after preparation
• CMS is efficacious in the treatment of recurrent lower
respiratory infections in CF patients
• Active against pseudomonas aeruginosa – most prevalent bacterial infection in >18 years CF patients.
• P. aeruginosa thrives on mucus (an ideal substrate
for the strain) and can become a chronic infection
• Bacteria attacks pulmonary epithelia, increasing
goblet cell secretion and inflammation – this can
eventually can result in pulmonary failure due to
irreversible damage, and death
• Daily nebulised CMS reduces hospitalisation and slows respiratory function decline
• Colistin exhibits low bacterial resistance
• Colistin powder formulation requires dilution with isotonic saline and gentle shaking until dissolved and should then be allowed to stand for 15 minutes to dissipate foam
• Nebulised dose is erratic and nebuliser dependent
Diabetes
• Lung volume is 6.0 L with 1.2 L residual volume
• Alveolar volume 2.1 L (35%)
• Only 0.9 L of the alveolar air is refreshed
• Exubera (inhaled insulin) withdrawn in 2007 due to patient compatability issues – Bulky device, inconsistent dosing – PEG was included to significantly reduced the elimination of insulin, increasing its systemic residence time and duration of action – Polyethylene glycol (PEG) accumulation caused pulmonary
distress in sensitive patients
Exubera
- Exubera inhaled insulin bioavailability varied between 10-20%
- 2.45 x in vitro dose (2.04 x in vivo) from Twincer
