The Impact of Drug Delivery on Modern Medicines Waseem Malick Ph.D. Roche, Nutley, New Jersey ISPE Meeting & Annual Student Poster Competition, Roche,

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

2

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)


3

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


4

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


5

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


6

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


7

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


8

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


9

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


10

Oral delivery of poorly soluble molecules

•BCS Class II and IV

• Solubility

• Permeability

• StabilityPrecipitationDissolution solution necessary for absorption

Absorption


11

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)


12

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: high

Permeability: low

Solubility: low

Permeability: low

Solubility: high


Permeability: high

Solubility: high

Permeability: low

Solubility: low

Permeability: low


e and CO

Gs


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%


13

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


14

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


15

Amorphous Solid DispersionsStabilized amorphous form of the drug

Amorphous drug uniformly embedded in a polymer matrix

Amorphous Drug

Stabilizing Polymer


16

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”


18

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


19

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


20

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)


21

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


22

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)


23

Injectable delivery of high dose proteins, MAb, peptides• Viscosity, Aggregation

• Subcutaneous parental delivery limited to ~ 1.0 mL

• High viscosity of concentrated solutions (Syringability)


24

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


25

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)


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


28

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)


29

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


30

• 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


31

Interferon Alfa-2a to PEG Interferon

Parenteral sustained delivery of Protein/Peptides

• Conjugation• Formulation/Depot

“Conjugation Approach”


32

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


33

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


34

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


35

Conclusions


36

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”


37

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


38

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


39

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


40

We Innovate Healthcare

Documents

The Impact of Drug Delivery on Modern Medicines Waseem Malick Ph.D. Roche, Nutley, New Jersey ISPE Meeting & Annual Student Poster Competition, Roche,