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
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
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
Solution, amorphous,
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
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
Amorphous - FastCrystalline - Fast
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
Design, Development, and Manufacture – Inhalation Platform
11
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
Solution, amorphous,
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
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
Amorphous API/Excipient
Crystalline API/Excipient
Mixed Approaches
Single Solvent Solution
Single Co-Solvent Solution
Single, Dual, or Variable Process Settings – Solution or Suspension
Single, Dual, or Variable Process Settings – Solution or Suspension
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)
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
(%
)
Relative Humidity (%)
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
)
Relative Humidity (%)
Trehalose
Water Uptake During Development – An Ongoing Discussion….
• Control of water content during entire process train is critical to maintain physical stability
and key aerosol properties.
• 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
Amorphous API/Excipient
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 - FastCrystalline - Fast
Amorphous - SlowCrystalline - Slow
Amorphous - FastCrystalline - Fast
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
Pharmacokinetic Results
• 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
*
*
Pharmacokinetic Results
• 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
)
Biological PK/PD study
• 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)
Biological PK/PD study
• 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)
Biological PK/PD study
• 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)
Biological PK/PD study
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
Biological PK/PD study
Clinical Delivery
Design, Development, and Manufacture – Inhalation Platform
60
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
Solution, amorphous,
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
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
)
Relative Humidity (%)
Trehalose
Water Uptake During Development – An Ongoing Discussion….
• Control of water content during entire process train is critical to maintain physical stability
and key aerosol properties.
• Local control (e.g. open powder handling) or complete suite control of humidity is used
during development and clinical manufacturing for process equipment
13
Design, Development, and Manufacture – Inhalation Platform
64
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
Solution, amorphous,
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
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
Water Uptake During Development – An Ongoing Discussion….
• Control of water content during entire process train is critical to maintain physical stability
and key aerosol properties.
• Local control (e.g. open powder handling) or complete suite control of humidity is used
during development and clinical manufacturing for process equipment
13
Hard Gelatin Capsules
HPMC capsules
Capsules with low mositure content after puncturing
Capsules with standard mositure content after
puncturing
Low %RH Conditions
Design, Development, and Manufacture – Inhalation Platform
67
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
Solution, amorphous,
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
• 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
)
Relative Humidity (%)
Trehalose
Lactose
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
• 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
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