The Impact of Drug Delivery on Modern Medicines
Waseem Malick Ph.D.
Roche, Nutley, New Jersey
ISPE Meeting & Annual Student Poster Competition, Roche, Nutley, April 21, 2011
Drug Delivery
“The Promise”
Drug Delivery Technologies can increase the likelihood of
getting the right medicine for the right patient at the right
place and at the right time
A. D. Roses, Lancet (2000)
2
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Transformation of a Molecule to a Medicine
via Creation of a Dosage Form
Delivery
Technology
Excipient
Manufacturing Process
Drug Product
Molecule / Compound
Drug Delivery makes the difference between a great molecule and a great medicine
3
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Advancements in Drug Delivery Systems
Drug Delivery Sophistication
Breakthrough Research in Industry and Academia
Emerging New Technology
3rd Technology
2nd Technology
1st Technology
Past
Present
Future
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
4
Modern Medicines “ Wide Variety of Molecules”
Diversity of disease targets lead to diversity of molecular formats
Small Molecules
Peptides
Proteins
MAb
Oligonucleotides
Solubility
Solubility
Stability
Solubility / Viscosity
Targeting
Oral Bioavailability
Stability
Aggregation
Aggregation
Stability
Different Molecular Formats Present Unique Delivery Challenges
5
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Modern Drug Molecules
Desired Attributes of New Molecules
Mechanism Based
• Novel biological targets (Discovery)
• Thorough biological understanding
• Known disease markers
• Personalized health care
Highly Potent
• Specific for the disease target
• Wide therapeutic index
• Well tolerated
Drug Delivery
“Druggable”
• Desirable PK/PD characteristics
• Desirable physiochemical properties
• Transformation to dosage form achievable
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Contribution
6
Desired Attributes of a Dosage Form
Enable development of efficacious, safe, and quality products
Efficacious
Drivers
• Molecule Specific Delivery Needs
• Clinical Advantage
• Patient Compliance
• Differentiated Product
• Patient Compliance
• Novel Technology
• Intellectual Property
Stable
• Shelf-life
• Transport
Manufacturable
• Robust Process
• Cost effective
7
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Interdisciplinary Approach is Critical to Successful Drug Delivery
Material
Sciences
Clinical
Sciences
Biology
Bioinformatics
Engineering
Pharmaceutical
Sciences
Chemistry
Pharmacokinetics
Safety
Biochemistry
A flexible interdisciplinary approach is critical to the future drug delivery innovation
8
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Key Challenges and Opportunities in Drug Delivery
Transformation of Molecules into Medicines
Oral delivery of solubility limited molecules

• BCS Class II and IV
Injectable delivery of high dose proteins, MAb, peptides

• Viscosity, Aggregation

Parenteral sustained delivery of Protein/Peptides
•
•
Conjugation
Formulation/Depot
Alternate delivery routes for proteins and peptides
• Pulmonary, nasal, oral, buccal
Targeted delivery systems
• Site specific delivery, tumor targeting
Delivery of emerging modalities
• siRNA, stem cells
9
ISPE Annual Meeting & Student Poster Competition, April 21, 2011

Oral delivery of poorly soluble molecules
• BCS Class II and IV
• Solubility
• Permeability
• Stability
Precipitation
Absorption
Dissolution
solution
necessary for
absorption
10
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Journey of Molecules from Tablet to Target Tissue
In-Vitro In-Vivo Performance Impacting PK/PD
In-Vivo
Dissolution
Pharmacokinetic
Measurement
Clinical / PD
Measurement
Solubility Permeability
Gut Wall
Dosage
Form
Drug in
Solution
Blood
Site of
Action
Therapeutic
Effect
In-Vitro
Dissolution
pH 4.5
Elevated Gastric pH (4.5):FaSSIF
FaSSIF
200.0
Amorphous Solubility
180.0
160.0
mg Dissolved
Amt Dissolved (mg)
140.0
120.0
Amorphous Tab 35% - 60% SDP
100.0
80.0
60.0
40.0
Crystalline Tab
20.0
Form III Solubility
0.0
0
30
60
90
120
150
180
210
240
Time (minutes)
F4_Lot 134884
F1_Lot 97302
F2_Lot 119463
Adapted From : 2007 AAPS-FDA BCS, BE, and Beyond Workshop Presentation, entitled General BA/BE Issues, Dale Conner, Division of
Bioequivalence, Office of Generic Drugs, CDER, FDA
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
11
Biopharmaceutical Classification System (BCS)
Formulation intervention required to increase bioavailability of poorly soluble
compounds
-6
cm/sec)
1
100
1000
BCS class I
100
permeability in Caco-2 (x 10
10
10000
100000 1000000
BCS class II
100
Solubility: high
Solubility: low
Permeability: high
Permeability: high
10
10
1
Solubility: high
Solubility: low
Permeability: low
Permeability: low
BCS class III
1
10
100
1
BCS class IV
1000
10000
100000 1000000
Increased risk, resources, development time and COGs
volume needed to dissolve anticipated dose (ml)
• Root causes for poor bioavailability
– Low aqueous solubility
– Poor permeability
• Challenges with poor bioavailability
– Insufficient exposure
– Lack of dose proportional absorption
– High inter- and intra-subject variability
– Potential side effects for narrow TI drugs
– Food effect
Increased risk, resources, development time and COGs
Industry average for BCS2/4 compounds is 40-60%
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
12
Oral Formulations Approaches for Poorly Water Soluble Compounds
Conventional to Innovative Technologies to enable Enhanced Bioavailability
Conventional  Non-Conventional : Risk and complexity
SEDDS/SMEDDS
Nanoparticles
Amorphous
Salts
O
(high dissolution rate
and super saturation)
N
F
Cl
F
F
Cl
F
O
N
F
Cl
F
O
N
F
F
Cl
F
Cl
F
Cl
F
F
O
N
F
Cl
O
Cl
F
N
O
F
F
N
F
F
O
N
F
Cl
Cl
F
Cl
F
F
F
Cl
Cl
F
F
F
O
N
Cl
F
F
F
Cl
F
F
N
O
Cl
O
F
N
F
F
O
N
F
Cl
Cl
F
Cl
F
F
F
Cl
Cl
F
F
F
O
N
F
F
Cl
F
Cl
F
F
O
Cl
F
N
O
O
F
F
F
O
F
Cl
F
F
O
O
F
O
F
F
F
Cl
N
F
Cl
F
Cl
F
F
Cl
F
Cl
F
F
Cl
F
F
Complexes
O
~ 100 nm
Cl
Cl
F
N
N
Cl
Cl
F
N
F
Cl
F
F
N
F
Particle size
reduction
O
Cl
F
Cl
F
Cl
F
F
N
N
F
Cl
F
F
Crystalline Solid
Dispersion
N
O
N
F
F
Cl
F
F
Cl
Cl
F
F
~ 10 µm
F
Cl
O
Cl
F
F
Cl
F
Need for novel formulations has increased significantly
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
N
F
F
13
Design of Amorphous Formulations
Polymer selection critical to stablization and improving solubility
///////////
///////////
///////////
Crystalline API
• Higher chemical potential results in higher
dissolution rate and solubility but also makes
them thermodynamically unstable
Amorphous (Glass) API
///////////
///////////
///////////
///////////
API
o API, without protection from matrix, may
revert back to crystalline state
o Polymer matrix can make amorphous system
more stable, if properly selected
• Selection of polymer and process are crucial
+
Polymer
Stabilized
Amorphous Formulation
14
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Amorphous Solid Dispersions
Stabilized amorphous form of the drug
Amorphous drug uniformly embedded in a polymer matrix
Amorphous Drug
Stabilizing Polymer
15
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Processing Technologies for Amorphous Formulations
Choice of technology depends on physico-chemical properties of molecule
API +
Polymer +
Solvent
Acidified
Cold Water
Washing
With water
Filter
Drying
Filter
Spray Drying (SDD)
• Solvent evaporation
• Acceptable solubility of drug
in low boiling solvent
required
Hot Melt Extrusion (HME)
• Temp. and shear
• Non-solvent
• MP < 200 °C required
Microprecipitation (MBP)
• Antisolvent process
• Allows use of high BP solvent
• Stability in antisolvent critical
16
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
…. Transformation of a highly efficacious but challenging
molecule to a medicine using an innovative bioavailable
formulation
Story of Compound “X”
Formulation Challenges of Compound “X”
Bioavailable formulation was critical for the success of the efficacious molecule
 Poor Solubility (crystalline API) >>>>> Poor Bioavailability
 Prone to polymorphic transformation (metastable Form I to stable Form II) >>>> Loss of systemic exposure
 High Dose >>>> Patient Dosing Convenience (Number of tablets per dose)
Polymorphic conversion detected by Dissolution and pXRD
Capsule Dissolution
USP App-2, 75 rpm, FASSIF(500 mL)
Capsules with Metastable Form I – Converted to Form II (
as seen by precipitation/ loss of solubility during
dissolution
40.0
35.0
Form II
Form II
25.0
20.0
07-0029, 300 mg, 5/2007
Phase 1 Capsule
15.0
07-0045, 100 mg, 7/2007
10.0
5.0
07-0020, 100 mg, clinical
3/2007
2000
0.0
0
50
07-0020 100 mg 3 capsules
07-0029 300 mg capsule
100
150
% Time (minutes)
07-0020 100 mg 1 capsule
200
Lin (Counts)
Mg dissolved
30.0
Form II characteristic signal
Capsules Lot 07 -0029 and 07 -0045 show
unmistakable level of Form II in them
07-0020, 100 mg, stability
3/2007
1000
07-0046, 300 mg, 7/2007
0
1
10
20
40
30
2-Theta - Scale
MBP based amorphous formulation was invented based on physico-chemical properties of the
molecule
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
18
MBP based high dose tablet formulation invented
Suitable downstream process developed ensuring amorphous form stability
Crystalline
drug
Polymer
SDD & HME technologies unsuitable
 Very high melting point
 Poor solubility in organic solvents
Polymer + Drug
dissolved in organic solvent
Advantages of MBP
 High Bioavailability
 Unique stabilizing polymer offers innovative approach
Cold Acidified Water Controlled
precipitation
Filtration
Washing
Drying
MBP
Micropreciptated Bulk Powder (MBP)
Roche invented and patented technology
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
19
MBP Formulation delivered desired exposure in the Clinic
Compound “X”
Crystalline API Formulation
MBP formulation
MBP formulation
AUC0-24h
3000
3000
3000
3000
2900
2900
2800
2200
2100
2000
1900
2800
1800
2600
1700
2400
1600
2200
1500
1400
2000
1800
1300
1600
1200
1400
1100
1000
1200
1000
3500
2500
2300
3000
2200
2100
960 BID
2000
2000
1900
1800
4 pts
1700
720 BID
1600
1500
7 pts
1400
1300
1200
1100
1000
1000
900
1000
900
900
800
800
700
5 pts
700
Target AUC for regression
…………………..............................
Target AUC for stasis
PK Bridging
…………………..............................
160
240
360
720
1120
960
100
200
400
800
1600
600
500
4 pts
400
300
200
AUC
2400
shrinkage
400
Mean Drug Exposure (uM*hr)
2300
500
500
4000
2600
AUC ( μM*hr)
AUC 0-24 hr (uM*hr)
2400
AUC ( μM*hr)
AUC 0-24 hr (uM*hr)
2500
600
600
1120 BID
2700
2600
2000
4 pts
2800
2700
2500
2000
1500
1000
500
300
All Comers
n = 18
Max Dose: 1600 (Bid)
4 pts
4 pts
PK Bridging
Study
200
4 pts
4 pts
100
100
stasis
3 pts
3 patients
100
200
400
800
Daily Dose (mg) BID
1600
160
Daily BID Dose (mg)
240
360
720
Daily Dose (mg)
BID
1120
960
0
0
200
800
1000
1200
Dose-Proportionality of Plasma AUC
MBP formulation provided 8-10x higher exposure than crystalline formulation
• The MBP formulation was dose proportional
• Target exposures were achieved
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
600
Dose (mg BID)
Daily BID Dose (mg)
Dose Escalation in clinic
400
N. Engl. J. Med. 363: 809 (2010)
20
MBP Formulation Enabled Efficacy in the Clinic for Compound “X”
Highly bioavailable formulation with reduced pill burden
Melanoma patient PET scan at baseline and day +15; 720 mg BID
Day 0
Day 15
Reference: New England J. Medicine 2010
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
21
MBP Formulation Enabled Efficacy in the Clinic for Compound “X”
Highly bioavailable formulation with reduced pill burden
Melanoma patient PET scan at baseline and day +15; 720 mg BID
Reference: Nature 467, 596-599 (7
September 2010)
22
ISPE Annual Meeting & Student Poster Competition, April 21, 2011

Injectable delivery of high dose proteins, MAb, peptides
• Viscosity, Aggregation
• Subcutaneous parental delivery limited to ~ 1.0 mL
• High viscosity of concentrated solutions (Syringability)
23
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
IV Infusion versus Subcutaneous Administration
Patient Convenience is a key driver in design of delivery systems
Subcutaneous Injection
Intravenous Infusion
Subcutaneous parenteral delivery limited to ~ 1.0 mL
24
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Injectable Delivery of High Dose Monoclonal Antibody (MAb) Challenges – SC Delivery
High Dose Requiring high concentration (50 -200 mg/mL)
Challenges
• Risk of aggregation
– Physical stability
• High viscosity
– Processing /manufacturing challenges
– Administration challenges
25
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
MAb / Peptides viscosity increases with concentration
Viscosity and Aggregation mitigation is critical
„Landscape“ of marketed MAb formulations
IgG
150 mg/mL
125 mg/mL
sc lyo
sc liquid
im lyo
iv lyo
iv liquid
100 mg/mL
50 mg/mL
1 mg/mL
1mg/mL
Kanai, Del Terzo, Wurth, Roche 2008
S. Kanai et al., J Pharm Sci 97 (2008) 4219-4227
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
26
Novel Technology to Enable Subcutaneous Injection of > 1 mL
Injection
Enzyme based Technology
Subcutaneous Administration of volumes >1 mL
Allowing administration of larger volumes – paradigm shift

Challenges of SC Delivery without EnhanzeTM
• Low BA after SC injection (50%-70%)
Hyaluronidase temporarily opens SC tissue
• Limitation of small volume administration to avoid pain and
patient discomfort
140
120
– Tissue backpressure
100
Serum conc (µg/mL)
• Strong hyaluronan network hinders injection and tissue
distribution of administered drugs
80
– Injection pain
60
40
– Blebs after injection
IgG SC
IgG SC + PH20
20
15 mg/kg MAb SC in Göttingen minipigs
(mean ± SD)
0
-20
0
50
100
150
200
Time (h)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
28
Administration of larger volumes (>1 mL)
Halozyme EnhanzeTM Technology
• Temporary breakdown of hyaluronan fibers by use of rHuPH20,
a human soluble hyaluronidase
(pores in subcutis)
• Decreases tissue back-pressure and injection pain
• Faster drug distribution, larger administration volumes, higher BA for biologics
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
29
Administration of larger volumes (>1 mL)
Halozyme EnhanzeTM Technology
• Technology being applied to several Medicines
• Well tolerated
• Clinical programs ongoing
Technology allows subcutaneous delivery of intravenous medicines
Halozyme Therapeutics Website
30
ISPE Annual Meeting & Student Poster Competition, April 21, 2011

Parenteral sustained delivery of Protein/Peptides
• Conjugation
• Formulation/Depot
Interferon Alfa-2a to PEG Interferon
“Conjugation Approach”
31
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Advances in Formulation Development
“Evolution” of Interferon Dosage Forms
1986
Albumin
containing
lyophilizate
2004
Albumin
containing
solution
Albumin
free
solution
Specialized delivery
devices
(PFS, pen, NFI)
Chemically Modified
Interferons
(Pegylation)
Improved safety, efficacy and compliance
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
32
Synthesis of Pegylated Interferon
Selection of suitable size of peg moiety was critical to achieve sustained exposure
Interferon alfa-2a
Branched 40 kD PEG
• PEGASYS created with a 40-kDa polyethylene glycol (PEG) strand (Lys linkage)
• Allows stable therapeutic serum levels up to a full week with a single dose
33
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Pegasys vs. Interferon Human PK Studies
Achieved sustained exposure
Interferon
• Short half-life
• Rapid absorption
• Sharp rise and decline
• High peak of systemic IFN
• Deep troughs
Pegasys
• Sustained exposure - 72-96 h
• Reduced clearance
• Longer half-life - 168 h
• Steady state drug levels 5-8 wks
Pegylation enabled once-a week dosing
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Ref. S. Zeuzem et. al. EASL, Rotterdam 2000
34
Conclusions
35
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Drug Delivery/Formulation Innovation
Enhance Oral
Absorption
• Increase BA
• Reduce Food
Effect
Optimized Protein &
Peptide Formul.
• Solubilization
• Stabilization
• High conc. SC Form.
Improved
Therapeutic
Outcome
Delivery of
Oligonucleotides
For Gene
Silencing
Enhanced Patient
Compliance
• Oral Modified Release
• Pediatric / Geriatric
• Needle-Free Inj.
Improve Tolerability/Efficacy
• Parenteral Form.
(Including SR)
Alternate Delivery
for Proteins
and Peptides
Nasal, Pulmonary,
Buccal, Oral
Brain Delivery
• BBB Transport
Targeted Delivery
• Parenteral Delivery
(Micelles)
• Bioadhesion
•Tumor targetting
• Colon Targeting
“Drug Delivery System can make or break a drug”
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
36
Drug Delivery Impact
Substantial Market Value for innovative drug delivery products
Prescription Drug Sales ($Bn)
US Drug Approvals from 2002–‘06
Information from www.fda.gov
Drug delivery intervention accounts for
> 2/3 of FDA product approvals
US Ethical Drug Market - Strategies for Sustained Growth - BCC Res
37
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
Emerging Drug Delivery Landscape
Intracelluar
Delivery
Oligonucleo.
Delivery
On-demand
Release
BBB Delivery
Nanomachines
Nanoshells
Nanochips
Multifunct.
Nanoparticles
Bio MEMs
Tumor targetting
Biomaterials
Oral Protein/
Peptide Delivery
38
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
My Belief
• Drug Delivery is becoming more interdisciplinary
• Innovation is happening at interfaces of diverse disciplines
• Cross training in multiple areas is emerging as a key success factor in delivery research
• Universities providing multidisciplinary education are making an invaluable contribution
to future drug delivery science
• Pharmaceutical Researchers must reach out to other industries for finding innovative
solutions to complex delivery challenges
39
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
We Innovate Healthcare
40
ISPE Annual Meeting & Student Poster Competition, April 21, 2011