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transcript
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.