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