Stephen B. Ruddy, Ph.D.Elan Corporation, plc

Advisory Committee for Pharmaceutical Science and Clinical Pharmacology

Rockville, MD

22 July 2008

Nanoparticle Technology:Leveraging Rapid Dissolution to Improve

Performance of Poorly Water-Soluble Drugs

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 2 –

Nanoscale particles of API:

• characterized by an extremely high surface-area to mass ratio and stabilized against agglomeration using surface modifiers

• not naturally occurring; prepared by:

- molecular deposition/complexation (“bottom up”)

- attrition of larger non-nanoscale materials (“top down”)

• range in size from ca. 80 to 1000 nm for many pharmaceutical applications

What are Engineered Nanoparticles?

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 3 –

aqueousphase

drug particle

80 - 1000 nm

primary stabilizer

adsorbed stabilizer

secondary stabilizer(optional)

Schematic of an Aqueous Nanoparticle Dispersion

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 4 –

)( CCVhDS

dtdC

S −=

kSdtdC

=

(1)

(3)

(2)

x = 0 x = h

Undissolved

Solid

Cs

C

Bulk

Solution

Aqueous Diffusion Layer

Con

cent

ratio

n

Rationale for Engineered Nanoparticles in Drug Delivery

• For a freely soluble drug, S is not critical: large Cs large k large dC/dt

• For a poorly soluble drug, k is small dC/dt is highly responsive to S

)( SCVhDS

dtdC

=

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 5 –

x ½

x ½

x ½

perform 24 times…

To What Extent Can We Increase Surface Area?

2.0 cm3 of material - single cube with side length of ca. 1.25 cm - divided 24 times will produce enough 1 nm-sized cubes to completely cover a rugby field in a single layer

Source: Adapted from work of Clayton Teague, National Nanotechnology Initiative (www.nano.gov)

Source: http://flickr.com/photos/learza/114576761/. This image is licensed under Creative Commons Attribution ShareAlike 2.0 License.

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 6 –

• It is estimated that approximately 40% of all new drugs are insoluble, many of which suffer from poor oral bioavailability*

• For readily permeable compounds (BCS Class 2), a reduction in particle size can translate to substantial improvement in the rate and extent of oral absorption

*Source: Merisko-Liversidge et al., “Nanosizing: A Formulation Approach for Poorly-Water-Soluble Compounds”, Eur. J. Pharm. Sci., Vol. 18, 2003 (113-120).

PERMEABILITY

High Low

High Class 1 Class 3SOLUBILITY

Low Class 2 Class 4

Applicability of Engineered Nanoparticles for Oral Delivery

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 7 –

• Increased bioavailability

• Increased rate of absorption

• Reduced fed/fasted variable absorption

• Improved dose proportionality

• Avoidance of uncontrolled precipitation

after dosing

Benefits of Engineered Nanoparticles in Oral Drug Delivery

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 8 –

Large API Particlesdissolution time >> GI transit time

Window ofAbsorption

API Nanoparticlesdissolution time < GI transit time

Overcoming the Gastrointestinal “Window of Absorption”

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 9 –

Redrawn from: Y. Wu et al., “The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in humans.”, Int. J. Pharm, Vol. 285 Number 1-2, 2004 (135-146).

Time

Plas

ma

Con

cent

ratio

n Wet milled, 0.12 μm Wet milled, 0.5 μmJet milled, 1.9 μmMicronized 5.5 μm

Example: Particle-Size Dependence of MK-0869

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 10 –

See, for example: J.P. Donnelly, J.W. Mouton, N.M.A. Blijlevens, A. Smiets, P.E. Verweij, B.E. DePauw, Dept of Hematology, Dept of Med Microbiology, Univ. Med. Ctr Nijmegen, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands, “Pharmacokinetics of a 14 day course of itraconazole NanoCrystal®s given intravenously to allogeneic haematopoietic stem cell transplant recipients” Paper presented at the Interscience Conference on Anti-microbials and Chemotherapy, 2001

• High drug loading in aqueous formulations (up to 45% w/w)

• Avoidance of harsh vehicles (e.g., cosolvents, solubilizers, pH extremes)

• Readily syringable formulations facilitate use of traditional small-bore needles

• Safety established for IV*, IM and SC routes of administration

Benefits of Engineered Nanoparticles in Parenteral Delivery

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 11 –

Example: Preclinical Pharmacokinetics of Compound X Following Intravenous and Intramuscular Administration

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

0 6 12 18 24C (hr)

IM NCD

IV NCD

Metacam

Commercial product (solution), IV

Nanoparticle dispersion, IV

Nanoparticle dispersion, IM

Time (h)

Mea

n P

lasm

a Conc.

(ng/m

L)

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 12 –

• Precision delivery to target site

• Increased uniformity of surface coverage

• Shorter nebulization times

Benefits of Engineered Nanoparticles in Pulmonary Delivery

A much greater portion of the emitted dose can be deposited in the lung

NanoparticleFormulation

MicronizedFormulation

Therapeutic quantities of drug can be delivered rapidly using ultrasonic nebulizers

Formulation Concentration (mg/mL)

Source: www.elan.com

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 13 –

• Spray freezing into liquid (SFL)

• Emulsification

• Precipitation with a compressed fluid antisolvent (PCA)

• Rapid expansion from a liquefied-gas solution (RESS)

• Evaporative precipitation into aqueous solution (EPAS)

• High-pressure homogenization

• Microfluidization

• High-energy wet milling

Source: V. Kharb, “Nanoparticle Technology for the Delivery of Poorly Water-Soluble Drugs”, Pharmaceutical Technology, Vol. 30 Number 2, February, 2006.

How are Engineered Nanoparticles Produced?

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 14 –

NCDRecirculation

Vessel APIStabilizer

WFI

CWI

CWO

CWI

CWO

CWI

CWO

RecirculationPump

Motor

Mechanical Seal

WFISeal Coolant

Reservoir

PolyMill-500Polystyrene Milling Media

Dynamic Media Separator

Screen

Agitator

MillingChamber

Preparation of Engineered Nanoparticles by Wet Milling

PolyMill® is a registered trademark of Elan Pharma International Limited.

®

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 15 –

NanoMill®–2 Manufacturing Platform

NanoMill® is a registered trademark of Elan Pharma International Limited.

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 16 –

before milling after milling

Morphology of Unmilled and Milled Drug Particles

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Broad Range Required in Our Application

0

5

10

15

20

25

30

0.01 0.1 1 10 100 1000

Size (μm)

f (%

)

76543210

Time (h)

pre-milled

Particle Size Determination by Laser Diffraction

Time Dependence of Particle Size Reduction by Wet Milling

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 18 –

Scalability of Wet Milling Process

0

2

4

6

8

10

12

14

16

18

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5

Particle Size (microns)

% F

requ

ency

NanoMill-10 (33 kg)NanoMill-2 (4 kg)

NanoMill-60 (299 Kg)NanoMill-10 (131 Kg)

0

2

4

6

8

10

12

14

16

18

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5

Particle Size (microns)

% F

requ

ency

NanoMill-10 (33 kg)NanoMill-2 (4 kg)

NanoMill-60 (299 Kg)NanoMill-10 (131 Kg)NanoMill-10 (33 kg)NanoMill-10 (33 kg)NanoMill-2 (4 kg)NanoMill-2 (4 kg)

NanoMill-60 (299 Kg)NanoMill-60 (299 Kg)NanoMill-10 (131 Kg)NanoMill-10 (131 Kg)

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 19 –

Reproducibility of Wet Milling Process

Batch ID Batch ID

Ass

ay

Part

icle

Siz

e

Batch IDBatch ID Batch ID

Ass

ayAss

ay

Part

icle

Siz

ePa

rtic

le S

ize

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 20 –

Commercial Example:Megace® ES (megestrol acetate oral suspension)

• 16-fold reduction in viscosity• 75% reduction in dose volume• elimination of fed/fasted variability

Megace® is a registered trademark of Bristol-Myers Squibb Company licensed to Par Pharmaceutical, Inc.

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 21 –

Source: www.tricortablets.com The information, documents, and related graphics published in this Internet Web site (the "Information") are the sole property of Abbott Laboratories, except for information provided by third-party providers under contract to Abbott, its subsidiaries or affiliates. Tricor® is a registered trademark of Abbott Laboratories.

Mean plasma concentration of fenofibric acid after administration of one 160-mg fenofibrate tablet in low-fat fed (n=36) and fasting (n=36) conditions.

Mean plasma concentration of fenofibric acid after a single administration of one 145-mg fenofibrate tablet in low-fat fed and fasting conditions (n=44).

*The two regimens high-fat fed and fasting were found to be bioequivalent, as were the two regimens low-fat fed and fasting2

Commercial Example:Tricor® 145 (fenofibrate tablets)

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 22 –

Potential Challenges in Developing Nanoparticle Products

• Particle agglomeration

• Particle size growth (Ostwald ripening)

• Changes in particle morphology

• Changes in polymorphic form

• Process-related impurities (e.g., residual solvents, media attrition)

• Process scalability and reproducibility

• Lack of a universal particle sizing method

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 23 –

Key Characterization Needs for Nanoparticle Applications

• Particle size distribution

• Solid-state properties

• Dissolution behavior

• Microbial limits testing (for aqueous products or product intermediates)

• Application specific methods (e.g., route of administration)

• Technology specific methods (i.e., novel, unique to formulation/process)

FDA Advisory Committee Meeting_22Jul08_Elan_SBR ©2008 – 24 –

Concluding Remarks

• Nanoparticle engineering offers significant potential to improve the delivery

performance of poorly water-soluble drugs, and hence the treatment outcomes

of patients who will benefit from these novel drug products.

• A number of commercial drug products employing nanoparticle technology

have already been approved by FDA.

• FDA’s current requirements for assessing drug product safety, efficacy and

quality appear adequate for evaluation of nanoparticle-based drug products.

• Future evolution of more complex nanotechnologies (e.g., drug targeting,

intracellular delivery, etc.) will likely drive the need for periodic evaluation of

FDA policy and procedures for regulating nanotechnology based drug products.