platform approach for inhaled drug delivery products · 2020. 6. 26. · source: pharmacircle,...

Platform approach for inhaled

drug delivery products

RDD 2017

Now a part of Lonza Pharma & Biotech

Presentation Overview

2

• Overview of inhalation drug delivery options

• Introduction to platform concept

✓Customized formulation and process definition

✓ Formulation and process considerations

✓ Encapsulation and drug product options

✓Capsule understanding and fundamentals

✓ Analytical considerations

• Translation of pre-clinical to clinical models

Pulmonary Drug Delivery

3

• Multiple platforms for drug delivery with different

advantages

• Preferred delivery technology may shift during

development✓ Pre-clinical versus clinical

✓ Demographics of product

✓ Dose

• Nebulizers

• pMDI✓ Suspension

✓ Solution

• DPI✓ Carriers based

✓ Particle Engineering

• With the complexity of pulmonary drug delivery

add complexity only when neededLRRI Translational Research Model

Delivery Modes

Particle Engineering (Spray Dry Technology)

Industry Trends in Inhalation

4

• What trends do we see?

• Emerging therapies require innovation that conventional

inhalation delivery technologies doesn’t deliver

✓ Things we can’t mill

✓ Incompatibility with lactose/excipient flexibility

✓ Solubility or stability with water/HFA

✓ High doses

• Drug sparing during feasibility and scale up

✓ Expensive API’s; don’t have kg

✓ Low delivery efficiency

✓ Reproducible delivery

✓ Dose range flexibility for toxicology and clinical (ug to 10’s of mg)

• Compatible with wide range of devices (reservoir, blister or

capsule based)

• Tuneability of PK and/or stability needs based on amorphous

or crystalline format

/wikipedia/commons/a/a9/Antibody_IgG2.png

5

Global Inhalation Projects by DDT and Molecule TypeSmall Molecules Dominate Pipeline Across all Inhalation Platforms

Source: PharmaCircle, Capsugel Analysis

N=664

0

50

100

150

200

250

Dry Powder Inhalers Liquid Inhalers/Nebulizers Other Inhalation/Unknown Metered Dose Inhalers

Inhalation Projects by Molecule TypeGlobal Market, November 2016

antibody carbohydrate cell therapy gene oligonucleotide peptide polymeric protein siRNA small molecule undisclosed

N=215 (32%)

N=194 (29%)

N=143 (22%)

N=112 (17%)

Global Inhalation Drug Delivery Market, Top Products with Multiple TechnologiesIn most cases, the top products identified have multiple technology formulations.

6Excluded products having only one technology type:Anoro Ellipta/Laventair; Breo Ellipta; Brovana; Eklira Genuair; Flutiform; Incruse Ellipta; Laventair; Performist; Pulmozyme; Reventy Ellipta; Ultibro; Ulunar Breezhaler; Xoterna Breehaler

Global Brand

NameMolecule Indication DPI MDI Nebulizer ASP 2016 (DPI)

ASP 2016

(MDI)

ASP 2016

(Nebulizer)

AsmanexUMECLIDINIUM

BROMIDE/VILANTEROLAsthma X X 3.38 1.38 N/A

Beclazone BECLOMETASONE Asthma X X Not Sold in US 1.28 N/A

Clenil BECLOMETASONE Asthma X X X Not Sold in US Not Sold in US Not Sold in US

Dulera FORMOTEROL/MOMETASONE Asthma X X Not Sold in US 2.08 N/A

Flixotde FLUTICASONE Asthma X X X 2.68 1.58 Not Sold in US

Foradil FORMOTEROL Asthma X X 3.72 Not Sold in US N/A

Formodual BECLOMETASONE/FORMOTEROL Asthma X X Not Sold in US Not Sold in US N/A

Foster BECLOMETASONE/FORMOTEROL Asthma X X Not Sold in US Not Sold in US N/A

Inuvair BECLOMETASONE/FORMOTEROL Asthma X X Not Sold in US Not Sold in US N/A

Pulmicort BUDESONIDE Asthma X X X 1.67 Not Sold in US 9.40

Salamol SALBUTAMOL Asthma X X X 0.24 0.23 Not Sold in US

Seretide FLUTICASONE/SALMETEROL Asthma X X 5.06 2.63 N/A

Serevent SALMETEROL Asthma X X 4.53 Not Sold in US N/A

Symbicort BUDESONIDE/FORMOTEROL Asthma X X Not Sold in US 2.13 N/A

Ventolin SALBUTAMOL Asthma X X X Not Sold in US 0.23 Not Sold in US

Atrovent IPRATROPIUM BROMIDE Asthma/COPD X X X Not Sold in US 1.24 Not Sold in US

CombiventIPRATROPIUM

BROMIDE/SALBUTAMOLCOPD X X N/A Not Sold in US 2.36

Spiriva TIOTROPIUM BROMIDE COPD X X 9.66 N/A 4.40

Proventil SALBUTAMOL Bronchospasms X X N/A 0.27 Not Sold in US

Xopenex LEVOSALBUTAMOL Bronchospasms X X N/A 0.28 4.77

TOBI TOBRAMYCINInfections

Pseudomonas aeruginosaX X 35.75 N/A 109.97

Source: IMS Global Midas, Capsugel Analysis

How have these issues been addressed?

7

PulmoSphere™ (Novartis)TOBI®

iSPERSE (Pulmatrix)

Emulsion free nanoporous/nanoparticulate microaprticles (NPMP’s)

TechnoSpheres (MannKind)

AFREZZA®

• Multiple approaches (Both Spray Drying and Others)

PRINT® (Liquidia) Capsugel Approaches

7

Engineered Dry Powder ParticlesNeat API

Amorphous API/Excipient

Crystalline API/Excipient

Mixed Approaches

Single Solvent Solution

Single Co-Solvent Solution

Single, Dual, or Variable Process Settings – Solution or Suspension


Design, Development, and Manufacture – Inhalation Platform

8

Capsule/Device

Product CharacterizationMaterials

Formulation/Process Guidance

0.1

1

10

100

1000

10000

1.0E-06 1.0E-05 1.0E-04 1.0E-03 1.0E-02 1.0E-01 1.0E+00 1.0E+01

Permeability Limited Solubility Limited

High Solubility, High Pepi

Solution, amorphous, crystalline - all fast

Low Solubility , High Permeability

Solution, amorphous – fast

Crystalline - slow

High Solubility, Low Pepi

Solution, amorphous,

crystalline - all fast

Low Solubility, Low Pepi


crystalline - all slow

Aq

ue

ou

s S

olu

bilit

y (

µg

/mL

)

Epithelial Permeability (ƒ of LogP, MW, …) (cm/s)

• Compound physical properties

• Biomodel guidance for formulation impact on PK/PD

• 300mg to >1kg scale• Development + cGMP

• Precedented and GRAS• Materials science

Particle Engineering Encapsulation

• Xcelodose 600 Filling• Harro ModUC MS with 100k CPH

• Performance• Stability• Release

Target Product Profile

ActiveProduct Concept

Robust formulation & process for clinical trials

• Delivery Profile• Specialized capsules• FTO device

http://www.google.com/url?sa=i&rct=j&q=lactose&source=images&cd=&cad=rja&docid=GrrIA7kLtSLfkM&tbnid=DutjdF_v7PHfgM:&ved=0CAUQjRw&url=http://en.wikipedia.org/wiki/Lactose_intolerance&ei=iL8BUoWDGMjxiQLajoHQCg&bvm=bv.50310824,d.cGE&psig=AFQjCNE0KgkWEr2gQ2TBYp5DiHvYgED_7A&ust=1375932678909549

Class II

Solubility/Dissolution

Perm

eabi

lity

Class ILow Retention

Class IIIDose limited

Class IVBiologics

BSC Classifications

Product Concept Definition – Inhalable Molecules

9

• Product concept starts with knowing the molecules attributes and target profile✓ Inhalation delivery has evolved to include a variety of molecular profiles/properties which requires

flexible formulation technologies

Product Design

Location

Dose/TechnologySolubility/Dose in Lung Fluid

Mechanism of action

Amorphous - FastCrystalline - Slow

Amorphous - FastCrystalline - Fast

Amorphous - SlowCrystalline - Slow


Permeability/Dissolution/Form

BCS Classifications

CONFIDENTIAL

• Modulating particle properties through formulation and or process design

• Understand impacts for PK, physical stability etc.

• Key Properties to Consider

✓ Aqueous and organic solvent solubility (Or lack thereof for anti-solvent concepts)

✓ Preferred physical form

✓ Hydrophobicity

✓ Tm, Tg, and pkA

✓ Dose

Formulation Considerations Based on Compound Properties and PK

10

Formulation Approach Based on Compound Properties Formulation Approach Based on PK


11

Capsule/Device



0.1

1

10

100

1000

10000

1.0E-06 1.0E-05 1.0E-04 1.0E-03 1.0E-02 1.0E-01 1.0E+00 1.0E+01






Crystalline - slow







Aq

ue

ou

s S

olu

bilit

y (

µg

/mL

)














Simplified Spray Dryer Process Overview

12

CycloneDrying

Chamber

Drying nitrogenAtomizationDefine target particle sizeƒ (geometry, pressure)

Drying ConditionsProduct morphologyWater contentPhysical stateƒ (TIn Tout Msoln Mgas)

Atomizer

Droplet

Collection EfficiencyHigh Value Productƒ (geometry, product properties)

Dro

plet Su

rface

Spray Solution

Surface-active excipients

Engineered Dry Powder Particles

Spray SolutionStability versus process timeShear, pH, concentration, interactions

Hot drying gas contacts droplet

Neat API


Crystalline API/Excipient

Mixed Approaches

Single Solvent Solution

Single Co-Solvent Solution



Rationale for Pulmonary Excipient Selection

• Ideally nothing – Safety paramount in selection; keep it simple

Rationale for Excipients (If Needed) Key Properties

Bulking agent – dilution for dose/fill Nonhygroscopic

API stabilization Competes at air/liquid interfaces,H-bonding to stabilize from heat, shear or water displacementBuffer salts to chemically stabilize product

Physical Stability Nonhygroscopic, high Tg to limit mobility

Particle dispersability* Hydrophobic component at surface of particle

Lactose Trehalose L-Leucine

*Lechuga-Ballasteros et al. J. Pharm. Sci. 2008, 97(1), 287-302

Bulking or Stabilizing High Tg Sugar Surface ModificationSurface Modification1,2-Distearoyl-sn-glycero-3-

phosphocholine (DSPC)

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=nbyh-rgBOFO9FM&tbnid=6J05FMlA41_6lM:&ved=0CAUQjRw&url=http://www.chemicalbook.com/ChemicalProductProperty_EN_CB0177832.htm&ei=onqgU5f-DJakqAaPhIDICw&bvm=bv.68911936,d.b2k&psig=AFQjCNHWr19AJeTiz4TPmArqeVeO8NdEmQ&ust=1403112462824411

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=jPCd22mURGk91M&tbnid=Yl6X3qHLC21eJM:&ved=0CAUQjRw&url=http://www.viacheminc.com/ausvita/l-leucine/&ei=ynqgU4rLI5CGqgbflYGgBg&bvm=bv.68911936,d.b2k&psig=AFQjCNGnq1prJFHesUp5d4wzTy4rsD10Lw&ust=1403112509727671

http://upload.wikimedia.org/wikipedia/commons/9/9f/Trehalose.svg

CONFIDENTIAL

Formulation Selection – Pulmonary Excipients with Precedence

14

Use of Leucine for Surface Modification and Improved Dispersability

S. Mangal et al./ European Journal of Pharmaceutics and Biopharmaceutics 94 (2015 160-169

Effect of increasing Leucine in PVP/Leucine

Formulations

0% 2.5% 5.0%

7.5% 10%

12.5% 15%

• Concentrates on Surface• Higher Loads Enable Crystalline Shell

• Minimize hygroscopicity of a formulation• Impacted morphology improves aersolization

10µm

0%

25%

50%

Effect of Increasing Leucine in Trehalose/LeucineFormulations

CONFIDENTIAL

0

2

4

6

8

10

12

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Wat

er

Co

nte

nt

(wt%

)

Gla

ss T

ran

siti

on

Te

mp

era

ture

(°C

)

Relative Humidity (%)

Trehalose

Lactose

Water Uptake During Development –An Ongoing Discussion

• Amorphous spray dried formulations and excipients used for inhalation generally are very

hydroscopic

• Control of water content during entire process train is critical to maintain physical stability

and key aerosol properties.

13

Dynamic Vapor Sorption Profile and Glass Transition Temperature Relationship of Amorphous Trehalose and Lactose

Crystallization Events

CONFIDENTIAL

Spray-Drying Process Background

17

Spray Drying Tools – Processing Keys and bulk sparing methods

CycloneDrying Chamber

Drying nitrogen

Atomizer

Nozzle Characterization on Nozzle Test Stand (NTS)

Desired Product• Particle Size• Purity specification• Water content• High product recovery0

12345678

0 10 20 30 40

Wat

er

Up

take

(%

)


Cyclone CFD Models

Hot-Bench Experiment (Thermal Constraints)

Water Uptake via Dynamic Vapor Sorption

Thermodynamic Operating Space

Dobry et al. “A Model Based-Methodology for Spray Drying Process Development” 2009 Sep;4(3):133-142. Epub 2009 Jul 25

Spray Drying: Scalable and Bulk SparingSimilar aerosol properties achieved across batch sizes and scales with high yields

Bend Lab Dryer 35 kg/Hr Drying Gas Capacity

Pilot Scale (PSD-1) Spray Dryer with 100

kg/Hr Drying Gas Capacity

NGI distribution of hand-filled capsules

0%

5%

10%

15%

20%

25%

30%

Capsule Device Throat (USP) Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6 Stage 7 Stage 8(MOC)

BLD-35 0.3g

BLD-35 5g

PSD-1

MA

SS %

* 10 mg of powder was filled into Capsugel Vcaps DPI Size 3 HPMC actuated through a NGI set to 60l/min,, 4 seconds (4L). All results collected based on chemical analysis and CITDAS evaluation

Formulation 10%A Albuterol Sulfate Formulation

Dryer Scale BLD-35 BLD-35 Pilot (PSD-1)

Drying Gas Capacity [kg/hr] 35 35 80

Batch Size (g-solids) 0.30 5 100

Process Yield (%) 80 88 89

Water Content (wt%) 2.4 + 0.3 2.0 ± 0.2 2.1 ± 0.1

MMAD (µm) 2.4 ± 0.2 2.6 ± 0.1 2.5 ± 0.2

GSD 1.9 ± 0.1 1.8 ± 0.1 2.0 ± 0.1

Emitted Fraction * (%) 89.3 ± 1.7 89.8 ± 1.2 85.5 ± 5.4

Fine Particle Fraction <5µm (%) 82.1 ± 3.7 81.5 ± 2.7 79.6 ± 0.4

NGI Results: Batch Sizes and Spray Dryer Scales

Spray Drying is Tunable to Meet Product Profile

Albuterol Sulfate Active Loading

10 40

Spray Dryer Scale BLD-35 PSD-1 BLD-35 PSD-1

Batch Size (g-solids) 5 100 5 100

Process Yield (%) 88 89 88 83

Water Content 2.0 ± 0.2 2.1 ± 0.1 2.2 ± 0.1 2.7 ± 0.1

MMAD (µm) 2.6 ± 0.1 2.5 ± 0.2 2.8 ± 0.1 2.9 ± 0.1

GSD 1.8 ± 0.1 2.0 ± 0.1 1.7 ± 0.0 1.8 ± 0.1

Emitted Fraction * 89.8 ± 1.2% 85.5 ± 5.4% 86.9 ± 2.3% 87.6 ± 0.8

FPF (<5µm) 81.5 ± 2.7% 79.6 ± 0.4% 76.6 ± 1.2% 77.1 ± 1.5

BLD-35 (Lab Scale Spray Dryer)

PSD-1

(Pilot Scale Spray Dryer)0%

5%

10%

15%

20%

25%

30%

Capsule Device Throat (USP) Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6 Stage 7 Stage 8(MOC)

10%A BLD-35

10%A PSD-1

40%A BLD-35

40%A PSD-1

MA

SS %

* 10 mg of powder was filled into Capsugel Vcaps DPI Size 3 HPMC actuated through a NGI set to 60l/min,, 4 seconds (4L). All results collected based on chemical analysis and CITDAS evaluation

NGI Results: Active Loading and Spray Dryer Scales

Similar aerosol properties achieved across active loadings and spray dryer scales

CONFIDENTIAL

Geometric Particle Size Summary Across Scales

• Similar Morphology and Geometric Particle Size Distributions Achievable Across

Active Loadings and Scales

Active Loading Spray Dryer Scale D(v 0.1) µm D(v 0.5) µm D(v 0.9) µm D[3,2] µm D[4,3] µm Span

10 BLD-35 0.7 2.0 4.0 1.4 2.2 1.7

10 PSD-1 0.8 2.2 4.4 1.5 2.4 1.7

40 BLD-35 0.8 1.9 3.7 1.5 2.1 1.5

40 PSD-1 0.7 2.2 4.5 1.5 2.5 1.7

Particle Size Method with Malvern Mastersizer 2000: 4.0 Bar Dispersive Air Pressure with 60% Vibratory Feed

0

1

2

3

4

5

6

7

8

9

0.01 0.1 1 10 100 1000

Vo

lum

e %

Diameter (µm)

10% Albuterol (BLD-35)

10% Albuterol (PSD-1)

40% Albuterol (BLD-35)

40% Albuterol (PSD-1)

10% AS

40% AS

BLD-35 (200mg-100g) PSD-1 (10g->1kg)

CONFIDENTIAL

0

2

4

6

8

10

12

0

20

40

60

80

100

120

0 20 40 60

Wat

er

Co

nte

nt

(wt%

)

Gla

ss T

ran

siti

on

Te

mp

era

ture

(°C

)


Trehalose

Water Uptake During Development – An Ongoing Discussion….



• Local control (e.g. open powder handling) or complete suite control of humidity is used

during development and clinical manufacturing for process equipment

13

CONFIDENTIAL

One size fits all?

23

Inhalation Platform – Breadth of Approaches

24

Large Molecules

Aqueous Spray DryingAmorphous Product

Aqueous Spray Drying Crystalline Product

Organic Solvent for active – use water as anti solvent to drive crystallization

Aqueous/Organic Co- SolventAmorphous product

Heated solvents to drive crystallization and process

Heated Solvents To Drive Process

Efficiency

Suspension Sprays

In-line Mixing or Organic Only

• Enabling process to stabilize API in a preferred solvent or create an

improved product by adding excipients or an anti-solvent

25

Spray Dried In-Line Mixing Approach

APIORGANIC SOLVENT

LeucineWATER

CYCLONE

Pumps

Product Condition D(v 0.5) um D(v 0.9) um

API Alone Initial 2.3 5.0

4 wk 30°C 3.1 6.5

API + Leucine Initial 2.1 4.2

4 wk 40°C 2.0 4.2

6 mo 40°C 2.0 4.1

APIGrowth Axis Growth Axis

API

Distance Controlled

DRYING CHAMBER

OR

0

1

2

3

4

5

6

7

Initial 1mo 6mo

D(v

0.9

) u

m

//

API Alone

w/ Leu.

vPSD Analysis

26

“Hot Process” Spray Drying Overview

PRESSURE PUMP

APISOLVENT

EXCIPIENTS(Suspension)

IN LINE HEAT EXCHANGER

(Tunable)

FLASH NOZZLE

DRYING CHAMBER

NOZZLE SHROUD GAS

CYCLONE

API Solubility vs. Temp

Patents: US 20120015924A1, EP2411137B1, EP3130396A1

• Enabling process to increase throughput or setup C/S ratios for In-situ crystallization

Crystalline Spray Dried Product

Crystalline API/Excipient Mixed Approaches

Materials Solublized


27

Spray-Drying Equipment Scales at Capsugel - Bend

Late Stage Clinical/Commercial

Process DevelopmentToxicology and Early-Phase Clinical Supplies

FormulationIdentification

Mini Spray Dryer

25 mg → 1 g

Lab Spray Dryer

(BLD-35)

0.2 g → 100 g

Lab to Pilot Scale

(Niro PSD-1)

5 g → 5 kg

Pilot to Commercial

Scale (Niro PSD-2)

kgs → tons

Patents: US9084944, US9084876

• Modular Facility Design• Modular spray dryer • Minimize footprint and construction

times• 0.2g to tons (e.g no scale-up pre-clin

through commercial)• High on time – Run longer• Niche high value product and/or

Variable commercial volumes/estimates• Stockpiling/rapid production for

vaccines• Designed for inhalation spray drying

Intranasal Delivery - Equipment Design To Enable Droplet Drying

Lab Dryer with 6-Foot Extension

PSD-1 Dryer with 6-Foot Extension

What about intranasal delivery where large particle sizes are required (>30µm)?

0

2

4

6

8

10

0.1 1 10 100 1000

Vo

lum

e F

req

uen

cy (

%)

Particle Diameter (µm)

Pulmonary Distribution

Nasal Distribution

Dv(0.1) [µm]

Dv(

0.5

) [µ

m]

Minimize inhalable

fraction for intranasal delivery

• Formulation Considerations

• What is your target/end point

• How does it translate to clinical setting

• Selection of fit for purpose model

• Understanding the data the study gives you

Merging Formulations with Animal Models

Product Concept Definition – Inhalable Molecules

30

• Product concept starts with knowing the molecules attributes and target profile✓ Inhalation delivery has evolved to include a variety of molecular profiles/properties which requires

flexible formulation technologies

Product Design

Class II

Solubility/Dissolution

Perm

eabi

lity

Class ILow Retention

Class IIIDose limited

Class IVBiologics

BSC Classifications

Location

Dose/TechnologySolubility/Dose in Lung Fluid

Mechanism of action

Amorphous - FastCrystalline - Slow


Amorphous - SlowCrystalline - Slow


Permeability/Dissolution/Form

All Models are wrong, some models are useful

A lung is a lung… well, not really……….

• Each System is set up as fit for purpose

✓ What animal model to use?

• Compound typically available in limited quantities

• Often utilize small animal models to determine / screen

PK/PD

• Formulation as simple as possible for pulmonary delivery

✓Need not represent potential clinical formulation

• Typically utilize off-the-shelf delivery devices as much as

possible

• Key is to understand what question/hypothesis is being

testing first

Non-Clinical Inhalation Drug Delivery

• Nose only, whole body, oral

aspiration, intratracheal

installation, intubated,

anesthetized/awake

• Mice, rats, ferrets, rabbits, guinea

pigs, rabbits, dogs, primates and

humans

• Aerosol generation of aqueous,

non-aqueous, dry powder and

novel formulations

✓Nebulizer, dry powder, pMDI,

etc.

Aerosol Delivery

Inhalation Exposures – Nose Only

• pMDI Generation • Dry Powder – Rotating Brush

Generator

• Injection of material into the lungs

• Light anesthesia – often

isoflurane

• Trained technical staff insert

‘catheter into trachea to near the

bifurcation

• Utilize a syringe to deliver material

directly to the lungs

Intratracheal Installation

• Specialized devices

✓Marketed to deliver ‘aerosol’ via intratracheal means

Intratracheal Installation

Tepper, Kuehl, et. al., Int J. Tox, 2016

• Trained technician (15+ years)

✓Material is delivered to the lung

Intratracheal Installation – What can you expect

Rodent PK/PD Case Study with PYY• Peptide tyrosine tyrosine (PYY) is an endogenous

peptide

• Early data suggest it has efficacy to suppress appetite

• Preclinical data generated via conventional delivery

routes (SC/IP injections)

• Does this compound have the potential for inhalation

delivery?

Rodent PK / PD Case study

SubQ PK Data

• Initial pharmacodynamic studies

included pharmacokinetic

sampling

• Build the relationship between

efficacy (PD) and exposure (PK)

• Develop an inhalation delivery

‘method’ that enables similar PK

profile

– Hypothesis: with similar PK,

PD will be similarTime (Hr)

Pla

sm

a C

on

c (

ng

/mL

)

0 2 4 60.1

1

10

100

1000SC 0.03 mg/kg

SC 0.1 mg/kg

SC 0.3 mg/kg

Inhalation Delivery to Rodents

• Nose only inhalation

• Delivers aerosol of the

formulation to free

breathing rodents

• Determine the PK as a

function of pulmonary

dose

• Utilize ‘matching’ dose to

conduct PD studiesOxygen Sensor

House Vacuum

(chamber exhaust)

Sample Port Adaptor

Sample Flow

Flow-past Nose-only

Rodent Exposure System

Main Exhaust Filter

Rodent Nose-Only

Exposure Tube

Rotating Brush Generator

Inhalation PK Data

• Normal, healthy mice

• Systemic plasma

concentration shown as

average (n = 3) with standard

deviation

Time (Hr)

Pla

sm

a C

on

c (

ng

/mL

)

0.0 0.5 1.0 1.5 2.0 2.50.1

1

10

100

1000 0.006 mg/kg

0.02 mg/kg

0.21 mg/kg

PYY PharmacokineticsMean PYY(3-36) Pharmacokinetic Parameters in Mice Following SC, IP and inhalation dosing

PK ParameterIP – 0.1 mg/kg

SC – 0.1 mg/kg

SC 0.3 mg/kgIH - 0.006

mg/kgIH - 0.02 mg/kg

IH - 0.21 mg/kg

Plasma Plasma Plasma Plasma Plasma Plasma

Cmax (ng/mL) 126.0 103.8 237.7 2.83 15.0 237

Tmax (hr) 0.25 0.25 0.50 0.08 0.08 0.08

AUC0-t (ng*hr/mL) 73.53 96.2 234.4 1.05 9.62 86.0

T1/2 (hr) 0.38 0.49 0.40 NA 1.65 1.10

Inhalation PK Data

PYY Case Study PD• Inhalation, SC and IP dosing of

mice

• Quantify food consumption at

defined intervals out to four hours

• Inhalation doses that resulted in

similar PK profiles result in

similar PD

• Peptide in systemic appetite

suppression PD/PK model

• Entire study – 10 grams of

material, 30% active0.

5 hr

1 hr

2 hr

4 hr

0

2

4

6

8Control

Inhalation - 0.22 mg/kg

Inhalation - 0.65 mg/kg

Avera

ge

Fo

od

C

on

su

med

(g

)

IP - 0.1 mg/kg

SC - 0.1 mg/kg

Kuehl, et al., Drug Dev Ind Pharm

Inhalation PD Data

• Typically dogs or non-human primates

✓ Dogs – small molecules

✓ NHPs – biologicals

• Often Non-terminal

• Free breathing or anesthetized

• Ability to deliver pMDI and dry powders by oral

inhalation via ‘clinically relevant’ maneuver

• PD model of local inflammation via challenge with

LPS

• Previously established in a repeated dose model

• Preliminary data to support acute response

Inhalation Exposures – Large Animals

Clinical / Preclinical Inhalation Dose Delivery

• Patient trained to use device

• Dry powder devices typically

include a controlled

inhalation over 1-3 seconds

• Breath held up to 10 seconds

• Calm exhalation

• Patient training/controlled

inhalation/breath hold

• Really?

Clinical Drug Delivery Preclinical Drug Delivery

• Anesthetized with Isoflurane, intubated animals, induced apnea, forced aerosol delivery,

with breath hold

• Aerosols generated into expansion chamber from pMDI or dry powder

• Minimizes/eliminates oral deposition

• Characterize pulmonary dose at terminus of endotracheal tube

Aerosol Delivery

Canine PK/PD Study Design

• Compare / contrast PK/PD from IV, pMDI, and dry powder formulations

✓ Modulation of PK based on physical chemical properties

• PK assessment after each dose

• BAL for inflammatory markers 24 hr post

BaselineBAL+Diff

Days -3 or -4 0 1

Hours 0 1 + 7 + 24 +27

PK bloodpre, 5, 15, 30, 45 and 60 min

post treatment 1

Test Article

Inhalation #1

Day1BAL+Diff

Test Article

Inhalation #2

LPS challenge

PK bloodpre, 5, 15, 30, 45, 60, 90, 120, 240 min

post treatment 2

PK blood

1200 min

post treatment 2

• All doses well tolerated by all animals

• Final Dose(s) within 10% of target for all formulations

• Particle size within 2 – 3 μm MMAD for all FP formulations

• BUD formulation PSD larger as the formulation was not as optimized

• FP dry powder required ~ 0.5 gram active for entire study

Formulation Percent FP (%) Excipient MMAD (µm) GSD Dose (µg/kg)

Flovent pMDI NA HFA134a 2.9 1.4 47

Flovent pMDI NA HFA134a 2.9 1.4 25

Crystalline FP 65 Leucine/Lactose 2.2 1.6 50

Amorphous FP 80 Lactose 2.1 1.4 50

Crystalline

BUD65 Leucine 4.5 2.3 93

FP IV NA Plasma NA NA 45

Aerosol Delivery - Results

Pharmacokinetic Results

• Repeated dose for all formulations show solid repeatability (shown

with SEM)

• Marketed difference between systemic absorption of dry powder

formulations (regardless of crystallinity) compared to Flovent HFA

Time (hours)

Pla

sm

a le

ve

ls (

ng

/mL

)

0.0 0.5 1.0 1.51

10

100Flovent HFA - 50 ug/kg

Amorphous FP

Crystalline FP

Flovent HFA - 25 ug/kg


• Non-compartmental analysis

• Tmax and Cmax show delayed and potentially less complete

absorption of Flovent HFA

• Not specifically designed to analyze by standard BE methods

– Crystalline and Amorphous Cmax outside of 90% CI

Tm

ax

(hr)

0.0

0.2

0.4

0.6

0.8

1.0

IV

Flovent - 50 ug/kg

Crystalline

Flovent - 25 ug/kg

Amorphous

Cm

ax

(ng

/mL

)

0

10

20

30

40

150

200

250

IV

Flovent - 50 ug/kg

Crystalline

Flovent - 25 ug/kg

Amorphous

*

*


• Dose normalized AUC indicate decreased exposure from Flovent

HFA

• Amorphous outside of 90% CI

MR

T (

hr)

0

2

4

6

IV

Flovent - 50 ug/kg

Crystalline

Flovent - 25 ug/kg

Amorphous

AU

C/D

(n

g*h

r/m

L)/

(ug

/kg

)

0.0

0.2

0.4

0.6

0.8

1.03

4

5

6

IV

Flovent - 50 ug/kg

Crystalline

Flovent - 25 ug/kg

Amorphous

*

Pharmacodynamic Results

• Total cell number within BAL

• All formulations resulted in significant reduction compared to

vehicle

• No different (95% CI) between any formulation

Day 1 after LPS

To

tal cell n

um

ber

(% o

f veh

icle

)

0

50

100

150

MDI FP 25g/kg

MDI FP 50g/kg

Amorphous FP 50g/kg

Crystalline FP 50g/kg

FP IV 45g/kg

Budesonide 100g/kg

Day 1 after LPS

To

tal cell n

um

ber

(% o

f veh

icle

)

0

50

100

150

MDI FP 25g/kg

MDI FP 50g/kg

Amorphous FP 50g/kg

Crystalline FP 50g/kg

FP IV 45g/kg

Budesonide 100g/kg

• Bolus delivery system characterized with both Exubera and

BRI Dextran 10-insulin

• System characterized over a range of loadings for ejection

efficiency and delivery efficiency

• Ejection efficiency – percent of loaded material ejected from

reservoir

• Delivery efficiency – percent of ejected material collected at

terminus of endotracheal tube

Formulation Ejection Efficiency Delivery Efficiency

BRI D10-Insulin 81% 67%

Exubera 73% 49%

Biological PK/PD study

C-Peptide

• Measurement of endogenous insulin

secretion

• Both groups show similar rapid drops in

C-Peptide indicating suppression of

endogenous insulin

0 50 100

150

200

250

0.0

0.1

0.2

0.3

0.4Exubera

D10 - Insulin

Time (min)

Art

eri

al P

lasm

a C

-Pep

tid

e (

ng

/mL

)


• Arterial plasma insulin

concentration versus time

• Both formulations follow

apparent 1st order

elimination

• Rapid absorption of both

formulations into systemic

plasma

• No significant difference in

insulin levels, although

tendency for increase from

Dextran 10-insulin between

35 and 95 minutes

0 50 100

150

200

250

0

50

100

150Exubera

D10 - Insulin

Time (min)

Art

eri

al P

lasm

a In

su

lin

(

U/m

l)


• Arterial blood glucose

levels similar for all dogs

over the duration of the

study

• Glucose infusion rate

needed to achieve

euglycemia tended to be

greater in Dextran

10-insulin group✓ Not significant

0 50 100

150

200

250

0

30

60

90

120

150Exubera

D10 - Insulin

Time (min)

Art

eri

al B

loo

d G

luco

se (

mg

/dL

)

0 50 100

150

200

250

0

5

10

15

20Exubera

D10 - Insulin

Time (min)

Glu

co

se

Infu

sio

n

Rate

(m

g/k

g/m

in)


• Insulin pharmacokinetics indicate rapid absorption

with Tmax values of 14 (Exubera) and 20 (Dextran

10-Insulin) minutes

• Dose normalized exposure (AUC) revealed a

non-statistical increase for the Dextran 10-Insulin

formulation

Dextran 10 – Insulin Exubera

Tmax (min) 20 (10) 14 (8)

Cmax (µU/mL) 126 (24) 121 (21)

AUC0-245 Dose normalized 7728 (1516) 6237 (2621)


Insulin Case Study Summary

• The utility of LRRI dog PK/PD model melted with BRI dry

powder for inhalation enabled the assessment of PK/PD

between Exubera and Dextran 10-Insulin formulation

• In vivo PK and PD assessment established the equivalence

of the BRI Dextran 10-Insulin formulation with Exubera

• This proof of concept study establishes the synergies of

formulation expertise at BRI and translational research

capabilities at LRRI to address complex problem

statements

Kuehl, et al., AAPS PharmSciTech, 15(6), 2014


Clinical Delivery


60

Capsule/Device



0.1

1

10

100

1000

10000

1.0E-06 1.0E-05 1.0E-04 1.0E-03 1.0E-02 1.0E-01 1.0E+00 1.0E+01






Crystalline - slow







Aq

ue

ou

s S

olu

bilit

y (

µg

/mL

)














CONFIDENTIAL

Encapsulation Development and Scale-up

• Xcelodose 600s

✓ Suitable for early clinical development (Phase 1 to 2a)

✓ 200-300CPH for engineered particles

✓ Gravimetric filling mechanism such that 100% weight check

✓ Bulk sparing during development and clinical production

✓ Early phase dose range flexibility (e.g. same

process/equipment can fill multiple doses)

✓ ~1mg to 10’s of mgs

✓ RSD <3%

61

Late Stage Clinical/CommercialProcess Development

and Early-Phase Clinical SuppliesPre-Clinical

• Harro Hofliger ModUC MS with drum fill station

✓ Suitable for late stage through commercial

✓ 72,000 CPH

✓ Volumetric drum microdosing (~5mg to 10s of mgs)

✓ Ideally suited for cohesive engineered particles with difficult

handling properties

✓ In-line capacitance weight monitoring, with individual lane

diagnostics

✓ RSD <3%

✓ Suite with <10%RH control

Late Stage Clinical/Commercial

4

4.5

5

5.5

6

6.5

0 100 200 300

Fill

we

igh

t (m

g)

Capsule Number

8

9

10

11

12

13

14

0 100 200 300

Fill

we

igh

t (m

g)

Capsule Number

Encapsulation Case Studies

62

• Repeatable fill weights achieved across target weights

Process Developmentand Early-Phase Clinical Supplies

Pre Clinical

0

5

10

15

0.01 0.1 1 10 100

Vo

lum

e %

Diameter (µm)

80/20Trehalose/LeucineSpray Dried

vPSD of 10 mg Fills

Average Fill Wt. = 4.97 mg

RSD = 2.2, Yield 78%

Average Fill Wt. = 10.00 mg

RSD = 2.3, Yield 84%

15

17

19

21

23

25

0 100 200

Fill

we

igh

t (m

g)

Capsule Number

Average Fill Wt. = 20.03mg

RSD = 1.7, Yield 95%Machine Speed (CPH) 72,000

Fed Capsules 35043

Dosed Capsules 99.5%

Rejected Capsules (%) 0.4%

Rejected Capsules (dosed) 0.4%

Accepted Capsules (%) 99.1%

Mean Dose (mg) 12.74

Dose RSD 1.4%

CONFIDENTIAL

0

2

4

6

8

10

12

0

20

40

60

80

100

120

0 20 40 60

Wat

er

Co

nte

nt

(wt%

)

Gla

ss T

ran

siti

on

Te

mp

era

ture

(°C

)


Trehalose






13


64

Capsule/Device



0.1

1

10

100

1000

10000

1.0E-06 1.0E-05 1.0E-04 1.0E-03 1.0E-02 1.0E-01 1.0E+00 1.0E+01






Crystalline - slow







Aq

ue

ou

s S

olu

bilit

y (

µg

/mL

)














CONFIDENTIAL

Deliverable Dose of Powder

• Wide range of fine particle doses achievable by varying active loading and fill

weight within a capsule (or blister

65

Spray Dried Bulk Density Ranges = 0.2 - 0.5 g/cc

* Total Fill Mass is based on a 90% total capsule volume – Limit of Aerosolization

Capsule Volumes

Size 3 Capsule with Representative Powder

Emit

ted

Mas

s (m

g)

0

10

20

30

40

60 15 5

Pote

nti

al F

PD

(m

g)

Fill Mass (mg)

Assumptions - >85% EF, 70%FPF → 60% FPD

Delivery Space

4.4

13.9

57.6

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60 70

Fill mass (mg)

Cough Limit? (e.g. Aridol high dose)

CONFIDENTIAL






13

Hard Gelatin Capsules

HPMC capsules

Capsules with low mositure content after puncturing

Capsules with standard mositure content after

puncturing

Low %RH Conditions


67

Capsule/Device



0.1

1

10

100

1000

10000

1.0E-06 1.0E-05 1.0E-04 1.0E-03 1.0E-02 1.0E-01 1.0E+00 1.0E+01






Crystalline - slow







Aq

ue

ou

s S

olu

bilit

y (

µg

/mL

)












• Specialized capsules• FTO device


Morphology• Lack of agglomeration• Surface morphology

Particle Size • Geometric Particle Size – 1.5 to 3.5µm• Aerosol Performance – Product

dependent deposition profile

Water Analysis• Water Uptake Equilibrium• Water Content ~ 2-6%

Physical stability• Amorphous versus Crystalline• Crystal size• Predictive Stability

TPP/Analytical Focused DPI analysis

Spray dried formulations – Specific considerations of crystalline and

amorphous content coupled with water uptake

Imaging• Optical microscopy• Scanning electron microscopy (SEM)

Particle Size/Aerosol Performance• Laser diffraction (GPSD)• Impaction (NGI)• Dose Content Uniformity

Hygroscopicity• Dynamic vapor sorption (DVS)• Karl Fischer (KF)

Thermal• Modulated Differential Scanning

Calorimetry mDSC• pXRD• Iso-calorimetry (TAM)

Analytical Tool Kit Product Profile

Aerosol Testing

Chemical Stability

CONFIDENTIAL

0

2

4

6

8

10

12

0

20

40

60

80

100

120

0 20 40 60

Wat

er

Co

nte

nt

(wt%

)

Gla

ss T

ran

siti

on

Te

mp

era

ture

(°C

)


Trehalose

Lactose




• Aerosol analytical characterization can require precise RH control during testing to ensure

consistent analysis

36

Next-Generation ImpactorDDU Testing

Questions

Thanks:

LovelaceRamesh ChandTed BarrettKarin RudolphMany others

Capsugel:David VodakDavid LyonDevon DuBoseMichael Burke

Now a part of Lonza Pharma & Biotech

Want to learn more?https://pharma.lonza.com/contact

https://pharma.lonza.com/contact

platform approach for inhaled drug delivery products · 2020. 6. 26. · source: pharmacircle,...

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