1. The Shape of Cures to Come™
Cubist Pharmaceuticals
Nano-Suspension Technology
Why, How & the Impact on Drug Performance
Lieyu (Richard) Hu
May 21st, 2014
2. 1
2
3
Why go Nano?
How does Nanosizing Impact Performance
Nano-suspension Injectable
Outline
2
3. Poorly Water Soluble API
High Solubility
High Permeability
35%
Low Solubility
High Permeability
30%
High Solubility
Low Permeability
25%
Low Solubility
Low Permeability
10%
Class 1 Class 2
Class 3 Class 4
Solubility
Permeability
High Solubility
High Permeability
5%
Low Solubility
High Permeability
70%
High Solubility
Low Permeability
5%
Low Solubility
Low Permeability
20%
Class 1 Class 2
Class 3 Class 4
Solubility
Permeability
Marketed Drugs Small Molecule Candidates
Leslie Z. Benet, Ph.D. 2008 ASCPT
Annual Meeting Orlando April 4, 2008
Drug Discovery Trend
90% of Candidates
are poorly soluble!
3
•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
5. 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
5
Nano Suspension
Ref: E, Merisko-Liversidge, G. Liversidge, Toxicologic Pathology, 36:43-48, 2008
<1um
6. 1
2
3
Why go Nano?
How does Nanosizing Impact Performance
Nano-suspension Injectable
Outline
6
8. Marketed Nano Products and Basis of Filing
Ref: Liversidge E&G, ADDR, 2011, pg427
2001 Wyeth
23% improvement in bioavailability
Replace a solution
No refrigeration required
2003 Merck Elimination of food requirement
600% improvement in bioavailability
2004
Fournier &
Abbott
Minimized food effect
2004 Celgene
Protein bound suspension
Eliminates cremophor toxicity
IV
2005 Par
28% improvement in bioavailability
Easier administration
2009 Janssen
Long acting (1 month)
Ease of administration
High patient compliance
IM
9. TriCor® 145 Decreased Fed / Fasted Variability
Nanonizing
Before
After
Ref: www.tricortablets.com
160 mg Fed & Fasted
FED
145 mg Fed & Fasted
FED
Fasted
Fasted
9
dM/dt = D*S(CS-C)/hNanosizing, particle size engineering, can do more.
12. 12
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
13. Brownian motion of larger particles
Light diffraction from small particles
No Brownian motion
Seeing is Believing
(Optical Microscopy of A Model Compound)
13
Micro ParticlesNano Particles
Perfusion + Dissolution Dissolution
14. 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 Dose
Release phases
4. Understand Size and population
5. Design the ideal formulation intelligently
A Computer Simulated PSD of a compound
15. 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)
15
Ref: Formulary Monograph: Paliperidone Palmitate Extended-Release Injectable Suspension (Invega® Sustenna™)
http://www.dshs.state.tx.us/
16. Invega Sustenna in Rats
16
Ref: Australian Public Assessment Report for Paliperidone Palmitate, september 2010
18. 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 ?
19. 19
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
Opening punch line: Thank you for your introduction and thank you for staying to almost the end of the day. My name is Indiana Jones and I’m here to talk about nano suspension and Holy Grail. Sorry, My name is Richard and I am here to talk about Nano Suspension and their impact on drug performance
PK and Safety.
Immunosuppressant,
Emend: anti-emetic,
Tricor: cholesterol control,
Abraxane: breast cancer
Megace ES: Anorexia, cachexia, or unexplained significant weight loss i
I will give you one example. In a simplified way, surface area increase and decrease of effective diffusion layer thickness Making the effect of PH insignificant.
Or Holy Grail of Injectable. And the question is how to get it. Fast onset of therapeutic plasma levels
Maintain long acting component
Let’s go back to our PK data and dig a little more
Critical Size and Population
I am not from Janssen, which is part of J&J. My understanding of their public data
Why there are different Cmax? Based on the aforementioned theoryh, With higher dose, the 1st phase became more prominent with more and more nano particle <CS. If I have to guess. I would guess the high Cmax are from high doses are at 1-5 hours, the low Cmax are from low does are at day 7.
As I predicted, we are seeing plausible Bi-phasic release to be confirmed by folks at J&J.
Having said all that, Let’s look at the performance of current Invega sustenna in human.
Hit Therapeutic Windows within a Week
Fairy complicated: Initiate dosing: 234mg day 1 and 156mg one week later, both deltoid. Monthly maintenance dose:117mg in deltoid or gluteal.
Has room for improvement.
Can engineer better formulation with better understanding: finer control or cocktail formulation
Does it proves my theory? You be the judge. I think it being partially.
Dose dependent: Although it is TBV, I am pretty confident that it support the theory.
Size dependent (critical size and population): I did not do this work and I can’t and it is not hard to do. However, the slight burst in human profile can not simply explained by “inadvertent IV administration”
Recommend to do, make a serial of formulation at different sizes, dose to animal and understand the critical size and population.
Great nano formulation and have the opportunity to be better.
