Patricia KP BurnellInhalation Product Development

• Inhaled products: types, development• The critical parameters• In-vitro testing• Ex-vivo testing

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Product Development: drug ���� medicine

What dose?

Lung site to target?

Particles? Drops? Safe

ty a

nd E

ffica

cy

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‘Safe’ dose

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FTIM Is the drug safe?

Proof of concept

Does the drug workas intended in (a few)patients?

Phase III Does the medicinework as intended withmany patients?

ClinicalPharmaceutical

Estimate formulation anddelivery device

Optimise formulation andchose inhaler

Consistency of manufactureStabilityRegistration of product

Phase IV Life-cyclemanagement

Line extensions

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• Rescue therapy : Bronchodilators– β2 adrenergic (e.g. salbutamol (albuterol),

salmeterol, formoterol, terbutaline)– M3 anticholinergics (e.g. ipratropium, tiotropium)

• Prophylaxis– inhaled corticosteroids (ICS, e.g. fluticasone,

beclomethasone, dexamethasone, budesonide)– NSAIDs (cromoglycates, xanthines)

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-5

0

5

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0 10 20 30 40Dose (µµµµg)

∆∆ ∆∆ FE

V 1 (%

)

Placebo 1.5 um 2.8 um 5 um

Zanen et al., Int J Pharmaceut 107 (1994) 211-17

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0

200

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0 30 60 90 120 150 Time (mins)

FEF

25-7

5 (m

ls) I

mpr

ovem

ent

6.0 um

3.0 um

1.5 um

Placebo

10 20 40 100 Cumulative Dose (ug)

Brompton Study: Improvement in FEF vs. particlesize

Inhalation of monosizedalbuterol (salbutamol)sulphate.

Screening FEV1 with 200µg albuterol MDI was978 mls

FEF25-75= Forced ExpiratoryFlowrate between 25 - 75%lung deflation

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00.10.20.30.40.50.60.70.80.9

1

Trachea Bronchi Bronchioles Alveoli

Rece

ptor

Rel

ativ

e de

nsit

y

Carstairs et al, Am Rev Respir Dis 132: 541-7 (1985); Mak & Barnes, Am Rev Respir Dis 141:1559-1568(1990); Jeffrey, p 80-108 in Asthma and Rhinitis, Blackwell Scientific (1995)

Airway smoothmuscle

M3 receptors

ββββ2 receptors

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Distribution of inflammation in the airwaysIn

flam

mat

ory

inde

xIn

flam

mat

ory

inde

x(a

ctiv

ated

(act

ivat

ed e

osin

ophi

ls e

osin

ophi

ls/m

m)

/mm

)

00

1010

2020

3030

4040

5050

6060

7070

Large airwaysLarge airways Central airwaysCentral airways Small airwaysSmall airwaysHamid et al 1997

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Comparison of morning PEFR after treatment withfluticasone 250 µµµµg from Diskus and budesonide400 µµµµg from Turbuhaler

200

210

220

230

240

250

260

270

280

Baseline Week 20

FP 250µg bd (n=166)BUD 400µg bd (n=167)

am P

EFR

(L/m

in)

ns

P=0.002

(Ferguson et al, J Pediatr 1999)

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0.0

10.0

20.0

30.0

40.0

50.0

60.0

0 2 4 6 8 10

Particle size (µµµµm)

% o

f cha

ract

eris

ed d

ose

FPBud

NOT ALL DEVICES DELIVER THE SAME DOSE SIZE DISTRIBUTION

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• Pressurised (propellant based) metered doseinhalers

• Dry powder inhalers• Liquid inhalers

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Inhaled air entry

Metering valve

Mouthpiece

Formulation

CrimpGasket

Valve stem

Atomising nozzle

Actuator body

Aluminiumcan

Headspace

Propellant = Built in energy source���� GlaxoSmithKline

Unit dose(Spinhaler, Rotahaler)

Energy assist

Reservoir Multi unit dose

Turbuhaler, UltrahalerDiskhaler

Diskus

Dryhaler

Inhale Device

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Lactose + Salmeterol xinafoate= Serevent50 µ µ µ µg

Fluticasone propionate = Flixotide/Flovent50, 100, 250 and 500 µµµµg

Salbutamol sulphate= Ventolin200 µµµµg

Salmeterol xinafoate + Fluticasone propionate = Seretide50 µ µ µ µg 100, 250 and 500 µµµµg

12.5 or 25 mg

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• Nebulizers (Sidestream, Ventstream, Pari, Halolite)– Dosing over minutes (5 to 15 mins)– Soft flume of fine droplets– High capability for targeting lung regions– Aqueous stability issues

• Respimat (Boehringer Ingelheim)– Soft flume of fine droplets– High capability for targeting lung regions

Air compressors, piezoelectric nozzles andothers provide the energy

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• Dosing constraints• Physiochemical stability of drug substance• Commercial strategy

Particle size characteristics of the emitted dosefrom each type of inhaler may be vastly different

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• Inertial impaction• Turbulent effects• Sedimentation• Diffusion• Electrostatic forces (?)

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Big particle,high inertia

Small particle,low inertia

Stk= d2ρV/(9 ηL)where ρ = density of particleV= velocityη= air viscosityD= characteristic dimension

Impaction =f (d2.Q)where d= particle diameterand Q is flowrate

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LIPS

Turbulence deposition ∝ d2, v

Turbulence depends on Re and StwhereRe, Reynold’s Number = ρv/µ andSt, Strouhal Number = τv/D

ρ = density of airµ = dynamic viscosity τ = time scale for unsteady flowsv = velocityD= characteristic dimension

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Sedimentation velocity= d2ρg/18η

µm Vts (cms-1) T (s)

1 3.5e-03 57

3 2.9e-02 7

5 7.8e-02 3

8 2.0e-01 1

T = time take to settle 2 mm

Breath-hold during inhalation

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Alveoli

Diffusion for particles < 0.5 µmBrownian motion, concentration gradient

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Space charge forcesparticles of same polarityrepel each other

+++

++ +

As charged particles approachwalls, equal and opposite imagecharges are induced, resulting inenhanced deposition

+ +

+

+

+

+ -

--

-

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For inhaled bronchodilators and corticosteroids

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• Pharmaceutical development• Regulatory submissions• Benchmarking

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Patient:•Age•Ability to use inhaler•Disease

Inhaler:•Formulation

Lung dose

Nominal dose > emitted dose

Regional lung dose

Blood levels

Safety Efficacy

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In-vitro Ex-vivo In-vivo

• Content uniformity• Particle size

distribution• Degradation

products• Potency

• Pharmacokinetics• Pharmacodynamics

• Lung dose• Particle size

How does the emitted dose affect the lung dose andsubsequent clinical response?

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Emitted dose

How much leaves the inhaler

Particle sizeof emitted

doseRegional lung deposition

Uni

form

ity

Lung dose

Dose to the target organ

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• Pumps to ‘inhale’ dose• Standard flowrates (or pharmacopoeial methods)• Standard instruments• Determination of emitted dose by chemical assay• Determination of particle size distribution by

cascade impaction and chemical assay.

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Pump

Filter

Inhaler

Replace filter witha cascade impactor to measure particle size distribution

time

Flowrate

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AndersenCascade Impactor

Multi StageLiquid Impinger

Marple-MillerImpactor

Slide: Courtesy B Olsson, AstraZeneca

Andersen Cascade ImpactorThroat

Preseparator

Baseplate

Collectionstage

Jet(s)

01234567Filter

Stages

Stk= d2ρV/(9 ηL)

Air

Jet

Collection plate

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Andersen Cascade Impactor

Cutoffs shown correspond to 28 L/min.Adjusted for other flow rates.

Andersen samplers simulatedeposition in the humanrespiratory tract

Throat

Preseparator

Baseplate

Collectionstage

Jet(s)

01234567Filter

Stages

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In-vivo• γ scintigraphy, PET• Gives estimation of regional

deposition• PET enables tracking of

both deposition anddisposition of label

• Labelling may affect particlesize distribution comparedto standard product.

Ex-vivo• Recording of patients’

inhalation (and doseactuation) profiles

• Use of breathing simulatorsto assess dose in-vitro

• Product used is thestandard product

• Assessment of particle sizeis realistic of patient use

• ‘Finger print’ of the product• Relatively cheap���� GlaxoSmithKline

Pd time

Pressure

0 t

Electronic Lung

Q

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The Electronic LungTM

Throat

Inhaler

Sample chamber(11 litres)

Cascade Impactorrun at 28 l/min

Piston

time

Pressuredrop

pressure feedback

Particle Cloud Detector

Filter

Pump

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ice

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sure

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p (k

Pa)

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rate

(L/m

in)

Pressure drop

Flowrate

Time (s) Time (s)

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ice

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sure

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p (k

Pa)

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Flow

rate

(L/m

in)

Pressure drop

Flowrate

Good inhalation Poor inhalation

Peak ≈≈≈≈ 7.5 kPa (95 L/min)

Peak ≈≈≈≈ 1.3 kPa (40 L/min)

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TM TM µµµµ

0

20

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0 50 100 150Peak inspiratory flowrate

mg

of d

rug

Total Emitted Dose of Inhaledß - Agonist (µg)Fine Particle Mass of Inhaledß - Agonist (µg)Total Emitted Dose of InhaledCorticosteroid (µg)Fine Particle Mass of InhaledCorticosteroid (µg)

Study DEV40026: GSK data on fileSeretide and Diskus are registered trademarks of GlaxoSmithKline

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0

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0 50 100 150

Peak inspiratory flowrate (L/min)

µµ µµg o

f dru

g

Total Emitted Dose of Inhaled Corticosteroid (µg)Fine Particle Mass of Inhaled Corticosteroid (µg)

Peak inspiratory flowrate (L/min)

0

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7

0 20 40 60 80 100 120

µµ µµg o

f dru

gTotal Emitted Dose of Inhaled ß - Agonist (µg)

Fine Particle Mass of Inhaled ß - Agonist (µg)

Study DEV40026: GSK data on file

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• Consortium (GSK, AstraZeneca and AventisPharma)

• Magnetic Resonance Imaging (D McRobbie,Charing Cross Hospital)

• 4 way randomised crossover study (n= 20) usingtidal breathing.

• Data-set has been reduced to 11 variables• Testing has been carried out (and on-going) to

determine filtration efficiencies• Intent is to develop an ‘average’, ‘large’ and ‘small’

throat���� GlaxoSmithKline

a b

c d

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a c

Device Diameter Ratio Area Ratioa 2.5 4.9c 1.4 1.5

MRI Scans Mouth vol Total vola 34252.9 53622.6c 22552.4 40798.2

1.8 3.2

1.5 1.3

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a b

Device Diameter Ratio Resistivity Ratioa 2.5 0.0044b 2.5 0.0489MRI Scan Mouth vol Total vola 34252.9 53622.6b 32052.7 51558.3

1.0 0.1

1.07 1.04

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In-vitro throat is not too different from twointra-subject anatomical models

(Data: GlaxoSmithKline)

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Particle diameter ( µµµµ m)

Cum

ulat

ive

per

cent

und

ersi

ze (%

)

GSK

Narrow mouth

Normal mouth

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Data: AstraZenecaFlowrate= 30 L/min

0

5

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25

Swift cadaver Narrow Normal

Dos

e ex

cas

t (%

of L

C)

Data: AstraZeneca

(VentolinTM AccuhalerTM, n=6, 4 kPa, 76 L/min)

0

5

10

15

20

25

30Pe

rcen

tage

of T

otal

Dos

e

Normal Narrow

Data: Aventis Pharma

Ventolin and Accuhaler are both trademarks of GlaxoSmithKline

• In-vitro tests: standardised conditions to give anindication of emitted dose and its attributes, usedfor QA.

• In-vivo tests: Human conditions to determineclinical safety and efficacy

• Ex-vivo tests: potential to link the above

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• In-vitro tests fulfil the requirements for regulatorypurposes to demonstrate uniformity of the product.

• In-vivo tests fulfil the requirements to demonstratesafety and efficacy of the formulation and deliverydevice

• Ex-vivo tests are novel, may yet be proven to linkthe two but are primarily aimed in understandingthe effect of the molecule/formulation/deliverysystem on the patient.

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