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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”

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the impact of drug delivery on modern medicines

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
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)

transformation of a molecule to a medicine via creation of a dosage form
Transformation of a Molecule to a Medicinevia 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

advancements in drug delivery systems breakthrough research in industry and academia

Drug Delivery Sophistication

Emerging New Technology

3rd Technology

2nd Technology

1st Technology

Past Present Future

Advancements in Drug Delivery SystemsBreakthrough Research in Industry and Academia
slide5

Small Molecules

Solubility

Oral Bioavailability

Peptides

Solubility

Stability

Proteins

Stability

Aggregation

MAb

Solubility / Viscosity

Aggregation

Oligonucleotides

Targeting

Stability

Modern Medicines “ Wide Variety of Molecules”Diversity of disease targets lead to diversity of molecular formats

Different Molecular Formats Present Unique Delivery Challenges

modern drug molecules desired attributes of new molecules
Modern Drug MoleculesDesired 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

Contribution

  • “Druggable”
  • Desirable PK/PD characteristics
  • Desirable physiochemical properties
  • Transformation to dosage form achievable
desired attributes of a dosage form enable development of efficacious safe and quality products
Desired Attributes of a Dosage FormEnable development of efficacious, safe, and quality products

Efficacious

  • Differentiated Product
  • Patient Compliance
  • Drivers
  • Molecule Specific Delivery Needs
  • Clinical Advantage
  • Patient Compliance
  • Novel Technology
  • Intellectual Property
  • Stable
  • Shelf-life
  • Transport
  • Manufacturable
  • Robust Process
  • Cost effective
interdisciplinary approach is critical to successful drug delivery

Material

Sciences

Biology

Clinical

Sciences

Pharmaceutical

Sciences

Bioinformatics

Engineering

Chemistry

Pharmaco-kinetics

Safety

Biochemistry

Interdisciplinary Approach is Critical to Successful Drug Delivery

A flexible interdisciplinary approach is critical to the future drug delivery innovation

key challenges and opportunities in drug delivery transformation of molecules into medicines

Delivery of emerging modalities

  • siRNA, stem cells
  • Oral delivery of solubility limited molecules
  • BCS Class II and IV
  • Alternate delivery routes for proteins and peptides
  • Pulmonary, nasal, oral, buccal
Key Challenges and Opportunities in Drug DeliveryTransformation of Molecules into Medicines

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

  • Parenteral sustained delivery of Protein/Peptides
  • Conjugation
  • Formulation/Depot

  • Targeted delivery systems
  • Site specific delivery, tumor targeting
slide10

Oral delivery of poorly soluble molecules

  • BCS Class II and IV

Dissolution solution

necessary for absorption

Precipitation

Absorption

  • Solubility
  • Permeability
  • Stability
journey of molecules from tablet to target tissue in vitro in vivo performance impacting pk pd

PharmacokineticMeasurement

Clinical / PDMeasurement

In-VivoDissolution

Permeability

Solubility

Gut Wall

DosageForm

Drug inSolution

Blood

Site of Action

Therapeutic Effect

In-VitroDissolution

pH 4.5

FaSSIF

Amt Dissolved (mg)

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

slide12
Biopharmaceutical Classification System (BCS)Formulation intervention required to increase bioavailability of poorly soluble compounds
  • 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

Industry average for BCS2/4 compounds is 40-60%

slide13
Oral Formulations Approaches for Poorly Water Soluble CompoundsConventional to Innovative Technologies to enable Enhanced Bioavailability

Conventional  Non-Conventional : Risk and complexity

Salts

SEDDS/SMEDDS

Nanoparticles

Amorphous

(high dissolution rate and super saturation)

~ 100 nm

Particle size reduction

Complexes

Crystalline Solid Dispersion

~ 10 µm

Need for novel formulations has increased significantly

slide14

///////////

///////////

///////////

Crystalline API

Amorphous (Glass) API

///////////

///////////

///////////

///////////

API

+

Stabilized

Amorphous Formulation

Polymer

Design of Amorphous FormulationsPolymer selection critical to stablization and improving solubility
  • Higher chemical potential results in higher dissolution rate and solubilitybut also makes them thermodynamically unstable
    • API, without protection from matrix, may revert back to crystalline state
    • Polymer matrix can make amorphous system more stable, if properly selected
  • Selection of polymer and process are crucial
amorphous solid dispersions stabilized amorphous form of the drug
Amorphous Solid DispersionsStabilized amorphous form of the drug

Amorphous drug uniformly embedded in a polymer matrix

Amorphous Drug

Stabilizing Polymer

slide16

API +

Polymer +

Solvent

Washing

With water

Filter

Acidified

Cold Water

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
Processing Technologies for Amorphous FormulationsChoice of technology depends on physico-chemical properties of molecule
slide17

…. Transformation of a highly efficacious but challenging molecule to a medicine using an innovative bioavailable formulation

Story of Compound “X”

slide18

Form II characteristic signal

Capsules Lot 07

-

0029 and 07

-

0045 show

unmistakable level of Form II in them

Form II

Form II

Phase 1 Capsule

07

-

0029, 300 mg, 5/2007

07

-

0045, 100 mg, 7/2007

07

-

0020, 100 mg, clinical

2000

3/2007

Lin (Counts)

07

-

0020, 100 mg, stability

1000

3/2007

Capsule Dissolution

07

-

0046, 300 mg, 7/2007

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

0

40.0

1

10

20

40

30

2-Theta - Scale

35.0

30.0

25.0

20.0

Mg dissolved

15.0

10.0

5.0

0.0

0

50

100

150

200

% Time (minutes)

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
  • 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

MBP based amorphous formulation was invented based on physico-chemical properties of the molecule

slide19

Crystalline drug

Polymer

SDD & HME technologies unsuitable

  • Very high melting point
  • Poor solubility in organic solvents

Polymer + Drugdissolved in organic solvent

Cold Acidified Water Controlled precipitation

Advantages of MBP

  • High Bioavailability
  • Unique stabilizing polymer offers innovative approach

Filtration

MBP

Drying

Washing

MBP based high dose tablet formulation invented

Suitable downstream process developed ensuring amorphous form stability

Micropreciptated Bulk Powder (MBP)

Roche invented and patented technology

mbp formulation delivered desired exposure in the clinic compound x

Crystalline API Formulation

MBP formulation

MBP formulation

AUC

0-24h

3000

1120 BID

3000

4000

3500

AUC

3000

960 BID

2000

2000

AUC 0-24 hr (uM*hr)

AUC 0-24 hr (uM*hr)

2500

720 BID

2000

Mean Drug Exposure (uM*hr)

1500

1000

1000

1000

…………………..............................

Target AUC for regression

500

…………………..............................

PK Bridging

Target AUC for stasis

0

0

200

400

600

800

1000

1200

160 240 360 720 1120 960

100 200 400 800 1600

Dose (mg BID)

Daily BID Dose (mg)

Daily BID Dose (mg)

MBP Formulation delivered desired exposure in the ClinicCompound “X”

Dose-Proportionality of Plasma AUC

Dose Escalation in clinic

  • MBP formulation provided 8-10x higher exposure than crystalline formulation
  • The MBP formulation was dose proportional
  • Target exposures were achieved

N. Engl. J. Med. 363: 809 (2010)

slide21

Day 0

Day15

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: New England J. Medicine 2010

slide22
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)

slide23

Injectable delivery of high dose proteins, MAb, peptides

  • Viscosity, Aggregation

  • Subcutaneous parental delivery limited to ~ 1.0 mL
  • High viscosity of concentrated solutions (Syringability)
slide24
IV Infusion versus Subcutaneous AdministrationPatient Convenience is a key driver in design of delivery systems

Subcutaneous Injection

Intravenous Infusion

Subcutaneous parenteral delivery limited to ~ 1.0 mL

injectable delivery of high dose monoclonal antibody mab challenges sc delivery
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
slide26

sc lyo

sc liquid

im lyo

iv lyo

iv liquid

150 mg/mL

125 mg/mL

100 mg/mL

50 mg/mL

1mg/mL

1 mg/mL

MAb / Peptides viscosity increases with concentrationViscosity and Aggregation mitigation is critical

„Landscape“ of marketed MAb formulations

IgG

Kanai, Del Terzo, Wurth, Roche 2008

S. Kanai et al., J Pharm Sci 97 (2008) 4219-4227

slide28

Hyaluronidase temporarily opens SC tissue

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

15 mg/kg MAb SC in Göttingen minipigs

(mean ± SD)

administration of larger volumes 1 ml halozyme enhanze tm technology
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
administration of larger volumes 1 ml halozyme enhanze tm technology1
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

slide31

Parenteral sustained delivery of Protein/Peptides

  • Conjugation
  • Formulation/Depot

Interferon Alfa-2a to PEG Interferon

“Conjugation Approach”

advances in formulation development
Advances in Formulation Development

“Evolution” of Interferon Dosage Forms

1986

2004

Albumin containing

lyophilizate

Albumin containing solution

Albumin free solution

Specialized delivery

devices

(PFS, pen, NFI)

Chemically Modified Interferons

(Pegylation)

Improved safety, efficacy and compliance

slide33
Synthesis of Pegylated InterferonSelection 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
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

Pegasys vs. Interferon Human PK StudiesAchieved sustained exposure

Pegylation enabled once-a week dosing

Ref. S. Zeuzem et. al. EASL, Rotterdam 2000

drug delivery formulation innovation

Optimized Protein & Peptide Formul.

  • Solubilization
  • Stabilization
  • High conc. SC Form.
  • Improve Tolera-bility/Efficacy
  • Parenteral Form.
  • (Including SR)
  • Enhance Oral
  • Absorption
  • Increase BA
  • Reduce Food Effect

Improved

Therapeutic

Outcome

Alternate Delivery

for Proteins

and Peptides

Nasal, Pulmonary,

Buccal, Oral

Delivery of

Oligonucleotides

For Gene

Silencing

  • Enhanced PatientCompliance
  • Oral Modified Release
  • Pediatric / Geriatric
  • Needle-Free Inj.
  • Brain Delivery
  • BBB Transport
  • Targeted Delivery
  • Parenteral Delivery (Micelles)
  • Bioadhesion
  • Tumor targetting
  • Colon Targeting
Drug Delivery/Formulation Innovation

“Drug Delivery System can make or break a drug”

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

Drug Delivery ImpactSubstantial Market Value for innovative drug delivery products
emerging drug delivery landscape
Emerging Drug Delivery Landscape

Intracelluar Delivery

Nanomachines

Nanochips

Nanoshells

Oligonucleo. Delivery

Multifunct. Nanoparticles

On-demand Release

Bio MEMs

Tumor targetting

BBB Delivery

Biomaterials

Oral Protein/ Peptide Delivery

my belief
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
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