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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 & ?