Patricia KP Burnell Inhalation Product Development

Patricia KP Burnell Inhalation Product Development

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

What dose? Product Development: drug medicine Safety and Efficacy Lung site to target? Particles? Drops?

Safe dose

Pharmaceutical Estimate formulation and delivery device Optimise formulation and chose inhaler Consistency of manufacture Stability Registration of product Line extensions FTIM Proof of concept Phase III Phase IV Clinical Is the drug safe? Does the drug work as intended in (a few) patients? Does the medicine work as intended with many patients? Life-cycle management

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)

25 20 FEV1 (%) 15 10 5 0-5 0 10 20 30 40 Dose (µg) Placebo 1.5 um 2.8 um 5 um Zanen et al., Int J Pharmaceut 107 (1994) 211-17

Brompton Study: Improvement in FEF vs. particle size FEF25-75 (mls) Improvement 1200 1000 800 600 400 200 0 Placebo 6.0 um 3.0 um 1.5 um 0 30 60 90 120 150 Time (mins) 10 20 40 100 Cumulative Dose (ug) Inhalation of monosized albuterol (salbutamol) sulphate. Screening FEV 1 with 200 µg albuterol MDI was 978 mls FEF 25-75 = Forced Expiratory Flowrate between 25-75% lung deflation

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Receptor Relative density Airway smooth muscle M3 receptors β 2 receptors Trachea Bronchi Bronchioles Alveoli 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)

Distribution of inflammation in the airways 70 Inflammatory index (activated eosinophils/mm) 60 50 40 30 20 10 0 Hamid et al 1997 Large airways Central airways Small airways

Comparison of morning PEFR after treatment with fluticasone 250 µg from Diskus and budesonide 400 µg from Turbuhaler 280 270 P=0.002 am PEFR (L/min) 260 250 240 230 220 ns FP 250µg bd (n=166) BUD 400µg bd (n=167) 210 200 Baseline Week 20 (Ferguson et al, J Pediatr 1999)

% of characterised dose 60.0 50.0 40.0 30.0 20.0 10.0 FP Bud 0.0 0 2 4 6 8 10 Particle size (µm) NOT ALL DEVICES DELIVER THE SAME DOSE SIZE DISTRIBUTION

Pressurised (propellant based) metered dose inhalers Dry powder inhalers Liquid inhalers

Inhaled air entry Headspace Formulation Aluminium can Crimp Gasket Metering valve Valve stem Atomising nozzle Actuator body Mouthpiece Propellant = Built in energy source

Dryhaler Energy assist Inhale Device Unit dose (Spinhaler, Rotahaler) Reservoir Multi unit dose Turbuhaler, Ultrahaler Diskhaler Diskus

Lactose + 12.5 or 25 mg Salmeterol xinafoate= Serevent 50 µg Fluticasone propionate = Flixotide/Flovent 50, 100, 250 and 500 µg Salbutamol sulphate= Ventolin 200 µg Salmeterol xinafoate + Fluticasone propionate = Seretide 50 µg 100, 250 and 500 µg

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 and others provide the energy

Dosing constraints Physiochemical stability of drug substance Commercial strategy Particle size characteristics of the emitted dose from each type of inhaler may be vastly different

Inertial impaction Turbulent effects Sedimentation Diffusion Electrostatic forces (?)

Big particle, high inertia Small particle, low inertia Impaction =f (d 2.Q) where d= particle diameter and Q is flowrate Stk= d 2 ρv/(9 ηl) where ρ = density of particle V= velocity η= air viscosity D= characteristic dimension

LIPS Turbulence deposition d 2, v Turbulence depends on Re and St where Re, Reynold s Number = ρv/µ and St, Strouhal Number = τv/d ρ = density of air µ = dynamic viscosity τ = time scale for unsteady flows v = velocity D= characteristic dimension

Breath-hold during inhalation Sedimentation velocity = d 2 ρg/18η µm V ts (cms -1 ) T (s) 1 3.5e-03 57 3 2.9e-02 7 T = time take to settle 2 mm 5 7.8e-02 3 8 2.0e-01 1

Alveoli Diffusion for particles < 0.5 µm Brownian motion, concentration gradient

+ + ++ + + Space charge forces particles of same polarity repel each other - - + + + + + + - - As charged particles approach walls, equal and opposite image charges are induced, resulting in enhanced deposition

For inhaled bronchodilators and corticosteroids

Pharmaceutical development Regulatory submissions Benchmarking

Patient: Age Ability to use inhaler Disease Lung dose Regional lung dose Inhaler: Formulation Nominal dose > emitted dose Blood levels Safety Efficacy

In-vitro Ex-vivo In-vivo Content uniformity Particle size distribution Degradation products Potency Lung dose Particle size Pharmacokinetics Pharmacodynamics How does the emitted dose affect the lung dose and subsequent clinical response?

Uniformity Emitted dose Particle size of emitted dose How much leaves the inhaler Regional lung deposition Lung dose Dose to the target organ

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.

Inhaler Flowrate Pump Filter time Replace filter with a cascade impactor to measure particle size distribution

Andersen Cascade Impactor Multi Stage Liquid Impinger Marple-Miller Impactor Slide: Courtesy B Olsson, AstraZeneca

Andersen Cascade Impactor Air Jet Collection plate Stk= d 2 ρv/(9 ηl) Throat Preseparator Jet(s) Collection stage Base plate Stages 0 1 2 3 4 5 6 7 Filter

Andersen Cascade Impactor Throat Preseparator Jet(s) Collection stage Base plate Stages 0 1 2 3 4 5 6 7 Filter Andersen samplers simulate deposition in the human respiratory tract Cutoffs shown correspond to 28 L/min. Adjusted for other flow rates.

In-vivo γ scintigraphy, PET Gives estimation of regional deposition PET enables tracking of both deposition and disposition of label Labelling may affect particle size distribution compared to standard product. Ex-vivo Recording of patients inhalation (and dose actuation) profiles Use of breathing simulators to assess dose in-vitro Product used is the standard product Assessment of particle size is realistic of patient use Finger print of the product Relatively cheap

Pressure Q Pd 0 t time Electronic Lung

Particle Cloud Detector Inhaler Throat The Electronic Lung TM Filter Sample chamber (11 litres) Pressure drop time Piston Cascade Impactor run at 28 l/min Pump pressure feedback

Good inhalation Poor inhalation Peak 1.3 kpa (40 L/min) 1.4 45 6 5 Peak 7.5 kpa (95 L/min) 90 80 1.2 40 35 4 Pressure drop 70 60 1.0 0.8 Pressure drop 30 25 Device Pressure Drop (kpa) 3 2 1 Flowrate 50 40 30 20 10 Flowrate (L/min) Device Pressure Drop (kpa) 0.6 0.4 0.2 Flowrate 20 15 10 5 Flowrate (L/min) 0 0 1 2 3 4 5 6 7 8 9 10 0 0 0 1 2 3 4 5 6 7 8 9 0 10 Time (s) Time (s)

TM TM µ 120 mg of drug 100 80 60 40 20 Total Emitted Dose of Inhaled ß - Agonist (µg) Fine Particle Mass of Inhaled ß - Agonist (µg) Total Emitted Dose of Inhaled Corticosteroid (µg) Fine Particle Mass of Inhaled Corticosteroid (µg) 0 0 50 100 150 Peak inspiratory flowrate Study DEV40026: GSK data on file Seretide and Diskus are registered trademarks of GlaxoSmithKline

µg of drug 160 140 120 100 80 60 40 20 µg of drug 7 6 5 4 3 2 1 0 0 50 100 150 Peak inspiratory flowrate (L/min) 0 0 20 40 60 80 100 120 Peak inspiratory flowrate (L/min) Total Emitted Dose of Inhaled Corticosteroid (µg) Fine Particle Mass of Inhaled Corticosteroid (µg) Total Emitted Dose of Inhaled ß - Agonist (µg) Fine Particle Mass of Inhaled ß - Agonist (µg) Study DEV40026: GSK data on file

Consortium (GSK, AstraZeneca and Aventis Pharma) Magnetic Resonance Imaging (D McRobbie, Charing Cross Hospital) 4 way randomised crossover study (n= 20) using tidal 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

a b c d

a c Device Diameter Ratio Area Ratio a 2.5 4.9 c 1.4 1.8 1.5 3.2 MRI Scans Mouth vol Total vol a 34252.9 53622.6 c 22552.4 1.5 40798.2 1.3

a b Device Diameter Ratio Resistivity Ratio a 2.5 0.0044 b 2.5 1.0 0.0489 0.1 MRI Scan Mouth vol Total vol a 34252.9 53622.6 b 32052.7 1.07 51558.3 1.04

In-vitro throat is not too different from two intra-subject anatomical models 100.0 80.0 Cumulative percent undersize (%) 60.0 40.0 20.0 0.0 GSK Narrow mouth Normal mouth 0.0 2.0 4.0 6.0 8.0 10.0 12.0 Particle diameter ( µ m) (Data: GlaxoSmithKline)

Data: AstraZeneca Flowrate= 30 L/min

25 Dose ex cast (% of LC) 20 15 10 5 0 Swift cadaver Narrow Normal Data: AstraZeneca

(Ventolin TM Accuhaler TM, n=6, 4 kpa, 76 L/min) Percentage of Total Dose 30 25 20 15 10 5 0 Normal Narrow Data: Aventis Pharma Ventolin and Accuhaler are both trademarks of GlaxoSmithKline

In-vitro tests: standardised conditions to give an indication of emitted dose and its attributes, used for QA. In-vivo tests: Human conditions to determine clinical safety and efficacy Ex-vivo tests: potential to link the above

In-vitro tests fulfil the requirements for regulatory purposes to demonstrate uniformity of the product. In-vivo tests fulfil the requirements to demonstrate safety and efficacy of the formulation and delivery device Ex-vivo tests are novel, may yet be proven to link the two but are primarily aimed in understanding the effect of the molecule/formulation/delivery system on the patient.