WPC-2014 Hu_Final
- 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
- 4. 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 4 ~500 nm particles dM/dt = D*S(CS-C)/h
- 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
- 7. 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 7
- 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.
- 10. 1 2 3 How does Nanosizing Impact Performance Why go Nano? Nano-suspension Injectable Outline 10
- 11. Dream Injectable for a Formulation Scientist Fast + Long = Holy Grail
- 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
- 17. Invega Sustenna in Human 17 Ref: Formulary Monograph: Paliperidone Palmitate Extended-Release Injectable Suspension (Invega® Sustenna™) http://www.dshs.state.tx.us/ Initiation Dose 1 Initiation Dose 2 Maintenance Dose
- 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
- 20. Acknowledgement Pharmaceutical Science at Cubist Thank You & ?
Editor's Notes
- #2: 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
- #9: PK and Safety. Immunosuppressant, Emend: anti-emetic, Tricor: cholesterol control, Abraxane: breast cancer Megace ES: Anorexia, cachexia, or unexplained significant weight loss i
- #10: 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.
- #12: Or Holy Grail of Injectable. And the question is how to get it. Fast onset of therapeutic plasma levels Maintain long acting component
- #14: Let’s go back to our PK data and dig a little more
- #15: Critical Size and Population
- #16: I am not from Janssen, which is part of J&J. My understanding of their public data
- #17: 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.
- #18: 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
- #19: 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.
- #20: Great nano formulation and have the opportunity to be better.