Advanced Drug Delivery to the Lungs
description
Transcript of Advanced Drug Delivery to the Lungs
Advanced drug delivery to
the lungs
Dr.Cynthia Bosquillon
Drug inhalation -applications
Local delivery
(bronchodilators, corticosteroids,
antibiotics, mucolytics, rhDNAse, alpha-
1 antitrypsin)
Systemicdelivery
(insulin, otherpeptides and proteins,
opioids, antimigrainedrugs)
(Under development)
Drug inhalation -recent
developments
�Local delivery
�Improvement of current therapies
�Delivery of macromolecules for local action
�Systemic delivery
�Insulin
�Peptides and proteins (pulmonary route = most effective
non invasive route)
�Conventional drugs with poor oral bioavailability
�Vaccines
The lungs–tw
oregions
�Airways
�Main targetsite for
local action
�Alveolarregion
�Target site for
systemicdelivery
Alveoli –target site for systemic
delivery
�Huge surface area(140 m
2)
�Thin barrierto the bloodstream
�alveolar epithelium < 0.5 µm thick
�thin interstitiumbetween epithelium and capillaries
�High blood flow
(entire cardiac output; i.e., 5L/min)
�No mucus/mucocilliaryclearance (but macrophages)
�Low enzymatic activity (some peptidases though)
�Neutral pH
�Avoidance of first-pass hepatic metabolism
(worth for bronchial region as well)
Delivery
to the alveoli-
challenges
�Only particles with an aerodynamic diameter
1-3 µm reach the alveoli
Nasopharynx
Oropharynx > 10 µm
Tracheobronchial
region, 3-10 µm
Alveolar
region, 3-1 µm
Particles< 1 µm are exhaled
Aerodynamicdiameter-
definition
g
(Stoke’s law)
gd
η181
2 aer
=
ρg
dη
181
V2
=
ρρd
d1
aer=
withρ 1
=1 g
/cm
3
Conventional inhalers –
three classes
�Nebulisers
�Aqueous drug solution/suspension aerosolised into
droplets
�Energy provided by compressed air or ultrasounds
�pMDI
�Drug formulated in a liquifiedgas under pressure
�Aerosol formed by gas evaporation at atmospheric
pressure
�DPI �
Drug +/-excipientsin a dry powder state
�Aerosolisationby patient’s inhalation
Conventional inhalers –
main advantages/drawbacks
•Breath-actuated
(patient-dependent)
•Affected by humidity
•Portable, multi-dose
•Breath-actuated
(no coordination)
•Dry state (stability)
DPI
•Not breath-actuated
(coordination)
•Propellants
•Portable, Multi-dose
•Cheap
pMDI
•Not portable
•Aqueous environment
(drug stability, pathogens)
•Easy to use
•Aqueous environment
(peptides, proteins)
nebulisers
Drawbacks
Advantages
Conventional inhalers –
limitations
�Poorly effective(< 20% of the emitted dose reach the lung)
�Poorly reproducible
(dose delivered to the lung depends
on patient’s inhalation technique)
�Consequences:
�Not suitable for delivery of expensive drugs or those
with a narrow therapeutic window
�New high performance delivery systems are required
High perform
ance delivery
systems –tw
o approaches
�Design of high-tech inhalers
�Portable nebulisers
�Breath-synchronised pMDIs
�Second-generation DPI
�Particle engineering
�Spray-drying
�Large and porous particles
�Technospheres®
New inhalers -requirements
�Compact, portable, multi-dose
�Easy to usecorrectly (children, disease severity)
�Lower mouth deposition/higher lung deposition
�Emitted dose and dose delivered to the lungs
reproducible; therefore, independent of
patient’s inhalation technique
�Cost effective
Portable liquid spray systems –
Respimat®
Soft MistTMinhaler
�Sterile drug solution in an
aluminium cartridge
�Pre-metered volume
transferred into a capillary
tube by compression of a
spring
�Liquid forced through a
nozzle by depression of the
spring
�Generation of a slow moving
Soft MistTM
�40-50% lung deposition
�Reproducibility ±
�Used in asthma/COPD
Res
pim
at®
(Boeh
ringer
Ingel
hei
m)
�Sterile drug solution in a
blister
�Piston punctures blister and
forces
solution
through
laser drilled nozzles
�Electronic system delivers
the dose only if patient’s
inspiratoryflow rate is OK
�> 50% lung deposition
�Phase III clinical trials with
insulin, morphine, fentanyl
Portable liquid spray systems –
AERx®
AER
x®
(Ara
dig
mC
orp
ora
tion)
Breath-synchronisedpMDIs–
TempoTMinhaler
�pMDIequipped with
�Synchronous trigger
→automatically
discharges a dose independently of
patient’s inhalation flow rate
�Flow control chamber
→decreases
the velocity of emitted droplets
�Lung deposition > 40%
�Phase II clinical trials with β 2-
agonist/glucocorticoid (asthma/COPD)
�Phase
III
clinical
trials
with
dihydroergotamine(migraine)
TempoTMinhaler, MAP Pharm
aceuticals
Second generation DPI -
Exubera
®
�Spray-dried insulin
powder
with stabilisers in blister
�Blister loaded at the base of
the inhaler and punctured by
actuation
�Fluidization/deaggregationin
aerosolisationchamber by
compressed air
�Patient inhales the particle
cloud through a slow deep
breath
�On the marketin 2006 but
withdrawn a few months later
Exuber
a®
(Pfize
r? a
nd N
ekta
r
Ther
apeu
tics
)
Particle engineering –
spray-drying
�Particles in conventional inhalers micronised
by milling
�Irregular shapes with planar surfaces
�No control on particle characteristics
�Peptides and proteins denaturatedby heat
produced
�Particles in new generation inhalers produced
by spray-drying
Spray-drying -principle
�Drug solution atomised
by spinning disk or gas
under pressure
�Solvent evaporated by
heated gas in the main
chamber
�Dry particles collected
by impaction on the
walls of a cyclone
Spray-drying –advantages
�One-step process
�Scalable
�Particles in the respirablesize range
�Sphericaland usually hollow particles
�Control on size, size distribution, density,
morphology, moisture content…
�Heat conditions favourable to proteins(cooling effect of
evaporation)
�Amorphous particles (protein stability)
spray-drying -drawbacks
�Recovery can be low
�Final moisture content can be high (↑cohesiveness)
�Creation of an air-interfaceduring atomisation
�Denaturationof proteins
�Incorporation of stabilisers
(sugars, amino acids, phospholipids)
Particle engineering –
large porous particles
�Particles < 5 µm are cohesive
�Spray-dried large porous particles
�Geometric diameter > 5 µm with
wrinkled surfaces (↓cohesiveness)
�Density < 0.4 g/cm3
�Aerodynamic diameter < 3 µm
�Endogenous and non-toxic excipients
�High deposition in the alveolar region
�Can be delivered using a simple DPI
�Scope for sustained-release (escape
phagocytosisby alveolar macrophages)
�In phase III clinical trials with insulin
AIR
TM
tech
nolo
gy
(Alk
erm
es)
Particle engineering -
Technospheres®
(MannkindCorporation)
�Insulin dry powder formulation based on a pH-
sensitive excipientwhich self-assembles to form
inhalable particles at low pH
�The excipientrapidlyforms a liquid in the alveolar fluid
at neutral pH releasing insulin
in a monomericform
�Can be delivered using a simple DPI
�In phase III clinical trials with insulin
High perform
ance delivery
systems -summary
�Compact, portable, multi-dose? DEPENDS on
the system
�Easy to use? DEPENDS on the system
�Higher lung deposition? YES
�Reproducible? YES
�Cost effective? NO
Nanoparticlesfor pulmonary
delivery
-advantages
�Sustained release
�Retentionin the lungs
�Slow release of the encapsulated drug from the
particles
�Avoidance of phagocytosisby alveolar macrophages
(if < 200 nm)
�Targeting of specific cells
(e.g. macrophages if > 200 nm)
�Nanoparticlesare too small to deposit in the
lungsand are exhaled
�Strategies:
�Administration as a suspension using nebulisers
(BUT inconvenient, propensity to form aggregates)
�Administration as dry powders in the micron range
�Use of a carrier
�«Trojan»particles
Nanoparticlesfor pulmonary
delivery
–delivery
issues
�Use of a carrier
�Nanoparticlesare incorporatedintoporouslactose microparticles
by spray-drying(→
highdepositionin the lungs)
�Lactose dissolves in the lungfluidreleasing the nanoparticles
Nanoparticlesfor pulmonary
delivery
–delivery
issues
Shamet al, Int.J.Pharm269 (2004) 457-467
�Trojan particles
�Large
hollow
microparticles
whose walls are made of
nanoparticles
held
together
using lactose and surfactants
�Disassemble in the lung fluid
releasing the nanoparticles
Nanoparticlesfor pulmonary
delivery
–delivery
issues
Tsapiset al, Proc.Natl.Acad.Sci.99 (2002) 12001-5
�Large surface area →
more reactive than
larger particles
�Can accumulate in lung cells
�Can bypass clearance mechanisms in the lungs
�Can be absorbed into the systemic circulation
�Further investigation needed
Nanoparticlesfor pulmonary
delivery
–toxicityissues?
Advanced drug delivery to the
lung -applications
�insulin
�other peptides and proteins
�conventional molecules
�vaccines
Diabetes mellitus
�~ 400 millions people affected worldwide
�Two categories
�Type 1 (10%): insulin deficiency
�Type 2 (90%): resistance to insulin and inadequate secretion
�Conventional treatment
�Type 1: 3-6 insulin SC injections per day
�Type 2: diet →
oral antidiabeticdrugs →
insulin SC
Diabetes mellitus –
poor glycaemiccontrol
�Insulin SC fails to mimic endogenous insulin
secretion
�Lack of acceptance of multiple daily injections by
patients
�Complications: retinopathy, nephropathy, neuropathy
Inhaled insulin
�Was shown to induce a hypoglycaemic effect
in 1925
�No inhalers could reproducibly deliver insulin
to the deep lung until recently
�First inhaled dry powder insulin
commercialisedin 2006 for the treatment of
type 1 and type 2 diabetes (Exubera®)
Inhaled insulin –
pharm
acokinetics/dynamics
�Serum concentrations peak earlier and decay more
rapidly than after SC injection of regular insulin →
mimic endogenous secretion
�Onset of action quicker and duration of action
prolonged as compared to rapid-acting insulin
analogues →more efficient control of post-prandial
glucose
�Patients can inhale insulin just 10 min before meal
but they still need a bedtime SC injection
Inhaled insulin –adverse effects
�Nonrespiratory
�Hypoglycaemia (frequency and severity similar to SC
injections)
�Increase in insulin antibodies (no clinical effects so far
but long-term?)
�Respiratory
�Cough, increased sputum
�Decrease in lung function in some patients
(recommended patients undergo lung tests before and
periodically thereafter)
Inhaled insulin –
contraindications
�Asthma
�No asthma exacerbations
�Lower absorption with higher variability
�Smoking
�Higher and quicker absorption (hypoglycaemia)
�OK if smoking cessation for more than 6 months
�Patients < 18 years
�No studies in children so far
Inhaled insulin -Bioavailability
�10-15%vsSC injection with Exubera®,
AERx®, AIR
TMtechnology
�~ 25% with Technospheres®
�A high dose of insulin needs to be inhaled →
high costs
Inhaled insulin –
why a low bioavailability?
�50% of the dose reach the lungs
�50% lost in the inhaler or patient’s oro-pharynx
�50% of the lung dose deposit in the alveoli
�50% deposit in the upper airways and is cleared by mucociliary
clearance
�30% of the alveolar dose is absorbed intact
�relatively large hydrophilic molecule (5.6 kDa)
�transported by passive paracellulardiffusion through tight
junctions
Inhaled insulin –
fate of the non-absorbed dose
�Not yet well known
�A fraction is degraded by enzymes in the lung
fluid
�A fraction might be cleared by alveolar
macrophages
�A fraction might bind to components of the
lung fluid (albumin, surfactant)
Inhaled insulin -summary
�Most efficientnon invasive deliveryroute
�Mimicendogeneouspost-prandialinsulin
secretion
�Welltoleratedand wellacceptedby patients
�Lowbioavailability
�Veryexpensive
�Long-term
safety?
Other inhaled peptides and
proteins in development
prostate cancer, infertility, endometriosis
osteoporosis, Paget’s disease
osteoporosis
pituitary dwarfism
multiple sclerosis
thrombosis
emphysema (local action)
leuprolideacetate (LHRH)
calcitonin
parathyroid hormone
human growth hormone
interferon β
(Heparin)
α1-antitrypsin
Indication
Peptide/protein
Inhaled opioids
�Severe pain management
�Treatment by IV injection
�Slow onset of action via oral, transdermal, nasal routes
�Morphine, fentanylrapidly, completely and
reproducibly absorbed with the AERxinhaler
�IV-like pharmacokinetic profile
�bioavailability~100% (if corrected for device efficiency)
�Main issues
�Local side effects (bronchospasm)
�Drug abuse (patient’s identification keys on the device)
Inhaleddihydroergotamine
�Antimigrainedrugs
→tablets, auto-injector, nasal
spray, suppositories
�Slow onset of action (> 30 min)
�Inhaled dihydroergotamine
�Pain relief as fast as 10 min after delivery
�Lung inflammation?
Inhaled cyclosporinA
�Immunosuppressive drugs
to prevent lung transplant
rejection
�Only 50% of lung transplant recipients survive after 3 years
�Oral cyclosporin
�Neurotoxicity
�Kidney failure
�Vulnerability to opportunistic infections
�Inhaled cyclosporin
�Administration of high doses locally
�Decrease of systemic side effects
�Improvement of survival rate
�Highly hydrophobic drug
�Currently administered three times
a week by
nebulisation using propylene glycol (PG) as a vehicle
�PG safe by oral, dermal routes BUT limited info on lung toxicity
(might cause inflammation)
�Highly viscous
→30 min per nebulisation
�Pre-treatmentwith nebulised lidocaine/albuterolto make the
treatment tolerable
�Only 10% of the dose reach the lungs(300 mg delivered while 5 mg
is the effective dose in the lungs)
�Ongoing clinical trials with sugar-based dry powders
Inhaled cyclosporinA -
delivery issues
Inhaled vaccines
�Advantages
�Needle-free
�Induction of a local immunity
�Candidate diseases:
�influenza, measles, rubella/measles
�Large program of immunisation against measles using
adapted nebulisers conducted by WHO in developing
countries
�Dry powdersunderdevelopment
Advanced drugdelivery
to the
lungs-summary
�New delivery systems
�Improvement of local treatment
�Development of the lungs as a portal of entry to the
bloodstream
�Pulmonary route effective for systemic delivery of
peptides and proteins
�Pulmonary route offers advantageous pharmacokinetic
profiles for some molecules
�Many challenges still need to be overcome