wpc-2014 hu_final
TRANSCRIPT
The Shape of Cures to Come™Cubist Pharmaceuticals
Nano-Suspension Technology Why, How & the Impact on Drug Performance
Lieyu (Richard) HuMay 21st, 2014
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Why go Nano?
How does Nanosizing Impact Performance
Nano-suspension Injectable
Outline
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Poorly Water Soluble API
High SolubilityHigh Permeability
35%
Low SolubilityHigh Permeability
30%
High SolubilityLow Permeability
25%
Low SolubilityLow Permeability
10%
Class 1 Class 2
Class 3 Class 4
Solubility
Perm
eabi
lity
High SolubilityHigh Permeability
5%
Low SolubilityHigh Permeability
70%
High SolubilityLow Permeability
5%
Low SolubilityLow Permeability
20%
Class 1 Class 2
Class 3 Class 4
Solubility
Perm
eabi
lity
Marketed Drugs Small Molecule Candidates
Leslie Z. Benet, Ph.D. 2008 ASCPT Annual Meeting Orlando April 4, 2008
Drug Discovery Trend
90% of Candidatesare poorly soluble!
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•Improving the performance of such compounds could lead to great return in discovery. •Growing list:
Prodrugs, Solubilizer, Solid Dispersions, Micelle formation, Emulsions, SEDDS/Lipids, Co-Crystals, Nanosizing
Surface area:
Effective thickness of diffusion layer*:− >30μ: ~30μ− <30μ: ~Diameter
Size and Dissolution Rate: Noyes-Whitney Equation
*C. Galli, 2006, Int. J. Pharm. 313,114-122; D. Junemann, 2012,J. Pharm. Pharmco. 64, 931-943
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~500 nm particles
dM/dt = D*S(CS-C)/h
Nano-sized pure drug particles (albeit tiny) are still in crystalline form, which is generally the most thermodynamically stable form of an API.
Preparing nano particles Stabilizing nano particles
– Size: Brownian motion– Stabilizer: prevent aggregation
Nano applications:– Oral– Parenteral– Inhalation– Topical
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Nano Suspension
Ref: E, Merisko-Liversidge, G. Liversidge, Toxicologic Pathology, 36:43-48, 2008
Top Down
<1umBottom Up
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Why go Nano?
How does Nanosizing Impact Performance
Nano-suspension Injectable
Outline
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World of Potential Benefits
Nano Suspension
Fed/Fasted Variation
Accelerate PK Onset
Dose Reduction
Reduced PK Variability
Extended Duration
Increase Bioavailability
Improved Safety Profile
Dose Proportionality
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Marketed Nano Products and Basis of Filing
Ref: Liversidge E&G, ADDR, 2011, pg427
2001 Wyeth 23% improvement in bioavailabilityReplace a solutionNo refrigeration required
2003 Merck Elimination of food requirement 600% improvement in bioavailability
2004 Fournier & Abbott Minimized food effect
2004 Celgene
Protein bound suspensionEliminates cremophor toxicity
IV
2005 Par 28% improvement in bioavailabilityEasier administration
2009 JanssenLong acting (1 month) Ease of administration High patient compliance
IM
TriCor® 145 Decreased Fed / Fasted Variability
Nanonizing
Before
After
Ref: www.tricortablets.com
160 mg Fed & Fasted
FED
145 mg Fed & Fasted
FEDFasted
Fasted
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dM/dt = D*S(CS-C)/hNanosizing, particle size engineering, can do more.
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How does Nanosizing Impact Performance
Why go Nano?
Nano-suspension Injectable
Outline
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Dream Injectable for a Formulation Scientist
Fast + Long = Holy Grail
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Dosing of an Injectable Suspension
Perfuse1& dissolve Aggregate with tissue
Injection of a Suspension
A Computer Simulated PSD of a compound
1: Nano Lett., 2011, 11 (2), pp 694–700
Brownian motion of larger particles Light diffraction from small particles
No Brownian motion
Seeing is Believing(Optical Microscopy of A Model Compound)
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Micro ParticlesNano Particles
Perfusion + Dissolution Dissolution
Road to “Holy Grail” 1. Compound of interest (highly potent and low solubility)2. Prepare suspensions at different sizes (nano and micro)
Tight controlled of PSD
3. Correlate PK with Size and DoseRelease phases
4. Understand Size and population5. Design the ideal formulation intelligently
A Computer Simulated PSD of a compound
Invega Sustenna
Long acting treatment of schizophrenia– Once monthly– 1st Long acting nano suspension injectable
API: Paliperidone Palmitate– Practically insoluble (<0.001%) in water (pH 1.1-12.9)
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Ref: Formulary Monograph: Paliperidone Palmitate Extended-Release Injectable Suspension (Invega® Sustenna™) http://www.dshs.state.tx.us/
Invega Sustenna in Rats
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Ref: Australian Public Assessment Report for Paliperidone Palmitate, september 2010
Invega Sustenna in Human
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Ref: Formulary Monograph: Paliperidone Palmitate Extended-Release Injectable Suspension (Invega® Sustenna™) http://www.dshs.state.tx.us/
InitiationDose 1
InitiationDose 2
MaintenanceDose
You be the judge!
1. API: Low solubility and high potency √2. PK with dose (TBV) √3. PK with size (Size and Population) ?4. Room for improvement ?
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Summary
Particle size engineering can really impact performance
Nano suspension and the “Holy Grail” injectable– Excellent Syringeability and Injectability
30% Solid Load of a Model Compound
Acknowledgement
Pharmaceutical Science at Cubist
Thank You & ?