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
Jan 05, 2016
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
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Drug Delivery
““The Promise”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)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Transformation of a Molecule to a Medicinevia Creation of a Dosage Form
Drug ProductMolecule / Compound
Delivery Technology
ExcipientManufacturing
Process
Drug Delivery makes the difference between a great molecule and a great medicine
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Advancements in Drug Delivery SystemsBreakthrough Research in Industry and Academia
Past Present Future
Dru
g D
elivery
S
op
his
ticati
on
1st Technology
Emerging New Technology
3rd Technology
2nd Technology
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Modern Medicines “ Wide Variety of Molecules”Diversity of disease targets lead to diversity of molecular formats
Different Molecular Formats Present Unique Delivery Challenges
Small Molecules
Solubility
Oral Bioavailability
Peptides
Solubility
Stability
Proteins
Stability
Aggregation
MAb
Solubility / Viscosity
Aggregation
Oligonucleotides
Targeting
Stability
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Modern Drug MoleculesDesired Attributes of New Molecules
Drug Delivery
Contribution
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
“Druggable”•Desirable PK/PD characteristics•Desirable physiochemical properties•Transformation to dosage form
achievable
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Desired Attributes of a Dosage FormEnable development of efficacious, safe, and quality
products
Manufacturable
•Robust Process
•Cost effective
•Differentiated Product
•Patient Compliance
Efficacious
Stable•Shelf-life•Transport
Drivers
• Molecule Specific Delivery Needs
• Clinical Advantage
• Patient Compliance
• Novel Technology
• Intellectual Property
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Interdisciplinary Approach is Critical to Successful Drug Delivery
A flexible interdisciplinary approach is critical to the future drug delivery innovation
PharmaceuticalSciences
MaterialSciences
Biology
Bioinformatics
Chemistry
SafetyBiochemistry
Pharmaco-kinetics
Engineering
ClinicalSciences
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Key Challenges and Opportunities in Drug DeliveryTransformation of Molecules into Medicines
Delivery of emerging modalities• siRNA, stem cells
Targeted delivery systems• Site specific delivery, tumor targeting
Alternate delivery routes for proteins and peptides
• Pulmonary, nasal, oral, buccal
Parenteral sustained delivery of Protein/Peptides
• Conjugation• Formulation/Depot
Injectable delivery of high dose proteins, MAb, peptides• Viscosity, Aggregation
Oral delivery of solubility limited molecules• BCS Class II and IV
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Oral delivery of poorly soluble molecules
•BCS Class II and IV
• Solubility
• Permeability
• StabilityPrecipitationDissolution solution necessary for absorption
Absorption
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Journey of Molecules from Tablet to Target TissueIn-Vitro In-Vivo Performance Impacting PK/PD
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
DosageForm
Drug inSolution
Blood Site of Action
Therapeutic Effect
PharmacokineticMeasurement
Clinical / PDMeasurement
Gu
t Wall
In-VivoDissolution
Solubility Permeability
In-VitroDissolution
Elevated Gastric pH (4.5):FaSSIF
0.0
20.0
40.0
60.0
80.0
100.0
120.0
140.0
160.0
180.0
200.0
0 30 60 90 120 150 180 210 240
Time (minutes)
mg
Dis
solv
ed
F4_Lot 134884 F1_Lot 97302 F2_Lot 119463
Crystalline Tab
Amorphous Tab 35% - 60% SDP
Amorphous Solubility
Form III Solubility
pH 4.5FaSSIF
Am
t D
issolv
ed
(m
g)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Biopharmaceutical Classification System (BCS)Formulation intervention required to increase bioavailability of poorly soluble compounds
1 10 100 1000 10000 100000 1000000
1
10
100
1 10 100 1000 10000 100000 1000000
1
10
100
BCS class III
BCS class II
BCS class IV
BCS class I
volume needed to dissolve anticipated dose (ml)
perm
eabi
lity
in C
aco-
2 (x
10
-6cm
/sec
)
Increased risk, resources, development time and COGs
Solubility: high
Permeability: high Solubility: low
Permeability: high
Solubility: high
Permeability: low
Solubility: low
Permeability: low
Increased risk, resources, development tim
e and CO
Gs1 10 100 1000 10000 100000 1000000
1
10
100
1 10 100 1000 10000 100000 1000000
1
10
100
BCS class III
BCS class II
BCS class IV
BCS class I
volume needed to dissolve anticipated dose (ml)
perm
eabi
lity
in C
aco-
2 (x
10
-6cm
/sec
)
Increased risk, resources, development time and COGsIncreased risk, resources, development time and COGs
Solubility: high
Permeability: high Solubility: low
Permeability: high
Solubility: high
Permeability: low
Solubility: low
Permeability: low
Solubility: high
Permeability: high Solubility: low
Permeability: high
Solubility: high
Permeability: low
Solubility: low
Permeability: low
Increased risk, resources, development tim
e and CO
Gs
Increased risk, resources, development tim
e and CO
Gs
•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 effectIndustry average for BCS2/4 compounds is 40-
60%
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Oral Formulations Approaches for Poorly Water Soluble Compounds Conventional to Innovative Technologies to enable Enhanced Bioavailability
Need for novel formulations has increased significantly
Conventional Non-Conventional : Risk and complexity
Crystalline Solid Dispersion
Complexes Particle size
reduction
NanoparticlesSEDDS/SMEDDS Salts
Amorphous
(high dissolution rate and super saturation)
NO
FF
F
F
Cl
Cl
NO
FF
F
F
Cl
Cl
NO
FF
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl
NO
F F
F
F
Cl
Cl ~ 100 nm
~ 10 µm
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Design of Amorphous FormulationsPolymer selection critical to stablization and improving solubility
•Higher chemical potential results in higher dissolution rate and solubility but also makes them thermodynamically unstable
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
Crystalline API
Amorphous (Glass) API
/////////////////////////////////
StabilizedAmorphous Formulation
//////////////////////////////////////////// API
+
Polymer
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Amorphous Solid DispersionsStabilized amorphous form of the drug
Amorphous drug uniformly embedded in a polymer matrix
Amorphous Drug
Stabilizing Polymer
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Processing Technologies for Amorphous FormulationsChoice of technology depends on physico-chemical properties of molecule
API + Polymer +Solvent
Filter
Acidified Cold Water
WashingWith water
Filter
Drying
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
…. Transformation of a highly efficacious but challenging molecule to a medicine using an innovative bioavailable formulation
Story of Compound “X”
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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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
Form II characteristic signal
Phase 1 Capsule
Form II
Lin
(C
oun
ts)
0
1000
2000
2-Theta - Scale1 10 20 30 40
07-0029, 300 mg, 5/2007
07-0020, 100 mg, stability 3/2007
07-0020, 100 mg, clinical 3/2007
07-0045, 100 mg, 7/2007
07-0046, 300 mg, 7/2007
Form II
Capsules Lot 07 -0029 and 07 -0045 show unmistakable level of Form II in them
Capsules with Metastable Form I – Converted to Form II ( as seen by precipitation/ loss of solubility during dissolution
Capsule DissolutionUSP App-2, 75 rpm, FASSIF(500 mL)
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
0 50 100 150 200
% Time (minutes)
Mg
dis
solv
ed
07-0020 100 mg 3 capsules 07-0020 100 mg 1 capsule
07-0029 300 mg capsule
Formulation Challenges of Compound “X”Bioavailable formulation was critical for the success of the efficacious molecule
MBP based amorphous formulation was invented based on physico-chemical properties of the molecule
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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MBP based high dose tablet formulation inventedSuitable downstream process developed ensuring amorphous form stability
Micropreciptated Bulk Powder (MBP)Roche invented and patented technology
Polymer
SDD & HME technologies unsuitable Very high melting point Poor solubility in organic solvents
Advantages of MBP High Bioavailability Unique stabilizing polymer offers
innovative approach
Crystalline
drug
Polymer + Drugdissolved in organic
solvent
Cold Acidified Water Controlled
precipitation
Filtration
DryingWashing MBP
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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MBP Formulation delivered desired exposure in the ClinicCompound “X”
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
Dose Escalation in clinic
Crystalline API Formulation
MBP formulation
3 patients
4 pts4 pts
3 pts
4 pts4 pts
4 pts
100 200 400 800 1600Daily Dose (mg) BID
160 240 360Daily Dose (mg)
BID
All Comersn = 18Max Dose: 1600 (Bid)
720
100
600
500
400
300
200
shrinkage
stasis
700
PK Bridging Study
1200
1000
900
1400
1600
1800
2000
2200
2400
2600
2800
AU
C
( μM*h
r)
900
1000
800
1100
1200
1300
1400
1500
1600
1700
1800
1900
1120
100
500
400
300
200
600
700 5 pts
7 pts
4 pts
2000
2100
2200
2300
2400
2500
2600
2700
2800
2900
3000
AU
C
( μM*h
r)
900
1000
800
1100
1200
1300
1400
1500
1600
1700
1800
1900
500
600
700
2000
2100
2200
2300
2400
2500
2600
2700
2800
2900
3000
960
4 pts
720 BID
960 BID
1120 BID
Target AUC for regression
PK Bridging
1000
2000
3000
AU
C 0
-24
hr
(uM
*hr)
1000
2000
3000
AU
C 0
-24
hr
(uM
*hr)
Daily BID Dose (mg)
100 200 400 800 1600
Daily BID Dose (mg)
160 240 360 720 1120 960
Target AUC for stasis
…………………..............................…………………..............................
…………………..............................…………………..............................
AUC
AUC0-24h
0
500
1000
1500
2000
2500
3000
3500
4000
0 200 400 600 800 1000 1200
Dose (mg BID)
Mea
n D
rug
Exp
osu
re (
uM
*hr)
MBP formulation
N. Engl. J. Med. 363: 809 (2010)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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MBP Formulation Enabled Efficacy in the Clinic for Compound “X”Highly bioavailable formulation with reduced pill burden
Day 15Day 0
Melanoma patient PET scan at baseline and day +15; 720 mg BID
Reference: New England J. Medicine 2010
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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MBP Formulation Enabled Efficacy in the Clinic for Compound “X”Highly bioavailable formulation with reduced pill burdenMelanoma patient PET scan at baseline and day +15;
720 mg BID
Reference: Nature 467, 596-599 (7 September
2010)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Injectable delivery of high dose proteins, MAb, peptides• Viscosity, Aggregation
• Subcutaneous parental delivery limited to ~ 1.0 mL
• High viscosity of concentrated solutions (Syringability)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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IV Infusion versus Subcutaneous AdministrationPatient Convenience is a key driver in design of delivery systems
Subcutaneous Injection
Subcutaneous parenteral delivery limited to ~ 1.0 mL
Intravenous Infusion
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Injectable Delivery of High Dose Monoclonal Antibody (MAb) Challenges – SC Delivery
Challenges
• Risk of aggregation– Physical stability
• High viscosity– Processing /manufacturing challenges– Administration challenges
High Dose Requiring high concentration (50 -200 mg/mL)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
26S. Kanai et al., J Pharm Sci 97 (2008) 4219-4227
1mg/mL
150 mg/mL
125 mg/mL
100 mg/mL
50 mg/mL
1 mg/mL
sc lyosc liquidim lyoiv lyoiv liquid
„Landscape“ of marketed MAb formulations
Kanai, Del Terzo, Wurth, Roche 2008
IgG
MAb / Peptides viscosity increases with concentrationViscosity and Aggregation mitigation is critical
Novel Technology to Enable Subcutaneous Injection of > 1 mL
Injection
Enzyme based Technology
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Subcutaneous Administration of volumes >1 mLAllowing administration of larger volumes – paradigm shift
Challenges of SC Delivery without EnhanzeTM
• Low BA after SC injection (50%-70%)
• Strong hyaluronan network hinders injection and tissue distribution of administered drugs
• Limitation of small volume administration to avoid pain and patient discomfort
– Tissue backpressure
– Injection pain
– Blebs after injection
Hyaluronidase temporarily opens SC tissue
-20
0
20
40
60
80
100
120
140
0 50 100 150 200
Time (h)
Se
rum
co
nc
(µ
g/m
L)
IgG SC
IgG SC + PH20
15 mg/kg MAb SC in Göttingen minipigs (mean ± SD)
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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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
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• Technology being applied to several Medicines
• Well tolerated
• Clinical programs ongoing
Administration of larger volumes (>1 mL) Halozyme EnhanzeTM Technology
Technology allows subcutaneous delivery of intravenous medicines
Halozyme Therapeutics Website
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Interferon Alfa-2a to PEG Interferon
Parenteral sustained delivery of Protein/Peptides
• Conjugation• Formulation/Depot
“Conjugation Approach”
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Advances in Formulation Development
Improved safety, efficacy and compliance
“Evolution” of Interferon Dosage Forms
Albumin free
solution
Specialized delivery devices
(PFS, pen, NFI)
Chemically Modified Interferons(Pegylation)
Albumin containi
ng solution
Albumin containinglyophilizate
20041986
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Synthesis of Pegylated InterferonSelection of suitable size of peg moiety was critical to achieve sustained exposure
Interferon alfa-2a
• 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
Branched 40 kD PEG
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Pegasys vs. Interferon Human PK StudiesAchieved 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
Ref. S. Zeuzem et. al. EASL, Rotterdam 2000Pegylation enabled once-a week dosing
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Conclusions
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Drug Delivery/Formulation Innovation
Enhance OralAbsorption
• Increase BA• Reduce Food
Effect
Optimized Protein & Peptide Formul.• Solubilization• Stabilization• High conc. SC Form. Improve Tolera-
bility/Efficacy• Parenteral Form. (Including SR)
Enhanced PatientCompliance• Oral Modified Release• Pediatric / Geriatric• Needle-Free Inj.
Alternate Delivery for Proteins and Peptides
Nasal, Pulmonary, Buccal, Oral
Brain Delivery• BBB Transport
Targeted Delivery• Parenteral Delivery (Micelles)• Bioadhesion•Tumor targetting• Colon Targeting
ImprovedImprovedTherapeuticTherapeutic OutcomeOutcome
Delivery of Oligonucleotides
For Gene Silencing
“Drug Delivery System can make or break a drug”
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Drug Delivery ImpactSubstantial Market Value for innovative drug delivery products
Prescription Drug Sales ($Bn)
US Ethical Drug Market - Strategies for Sustained Growth - BCC Res
Drug delivery intervention accounts for
> 2/3 of FDA product approvals
US Drug Approvals from 2002–‘06
Information from www.fda.gov
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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Emerging Drug Delivery Landscape
On-demand Release
Nanomachines
Intracelluar Delivery
Tumor targetting
BBB Delivery Biomateria
ls
Multifunct. Nanopartic
les
Nanochips
Bio MEMs
NanoshellsOligonucleo. Delivery
Oral Protein/ Peptide Delivery
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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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
ISPE Annual Meeting & Student Poster Competition, April 21, 2011
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