Ulizaon)of)Technology)Guidance)Mapsto) AddressCompound...
Transcript of Ulizaon)of)Technology)Guidance)Mapsto) AddressCompound...
U"liza"on of Technology Guidance Maps to Address Compound’s Delivery Challenges
Ravi Shanker Senior Research Fellow
Pharmaceu5cal Science, Worldwide R&D [email protected]
June 2nd 2013 Drug Formula5on & Bioavailability West, San Diego, California
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Acknowledgements
• Pfizer scien5sts and management for their tremendous intellectual partnership, hard work and belief in the advancement of solubiliza5on & drug delivery “systems”
• Mul5disciplinary effort – Medicinal Chemistry/Biology – Pharmacokine5cs & Drug Metabolism – Drug Safety – Clinical Research – Pharmaceu5cal Sciences (API, Analy5cal, Drug Product Design, Regulatory, Quality etc)
• External partners – academic, industry (vendors, CRO’s, technology) and regulators • Literature – extensive use of non-‐pharmaceu5cal & pharmaceu5cal; incessant exchange
of scien5fic thinking and debate • Organizers of this symposium
Poignant Reminder v Contents of presentation – personal views & I take full responsibility v Perspectives from a novice – there is still so much to learn
Outline of Presentation
• Historical perspective: The foundations
• Opportunities for bioavailability and modified release technology enabled drug products: Basic considerations
– Dose – Solubility – Dissolution – Crystallization – Permeation
• Development of guidance maps for selection of appropriate technology – Thermodynamic and kinetic considerations – Illustrative guidance maps – Limitations of guidance maps
• Future directions ---- cross industry collaboration?
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Thermodynamics: A tribute to two of the greatest whose contributions continue to influence development & understanding of solubilization and drug delivery technologies
J. Willard Gibbs
– Theore7cal physicist /physical chemist at Yale
– Developed unique graphical display of phase equilibria
• Van der Waals during his Nobel prize acceptance speech acknowledged Gibbs
• Max Planck declared “not only in America but in the whole world will ever be reckoned among the most renowned theore7cal physicists of all 7mes”
• Albert Einstein stated "the greatest mind in American history“.
• created sta7s7cal mechanics (a term that he coined), explaining the laws of thermodynamics as consequences of the sta7s7cal proper7es of large ensembles of par7cles
Arnold Sommerfeld
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– Theore7cal physicist in Germany
– One of the greatest mentors of physicists
• 7 PhD/ post doc students won Nobel Prize
– Werner Heisenberg, Wolfgang Pauli, Peter Debye, and Hans Bethe
– Linus Pauling, Isidor I. Rabi and Max von Laue
• Nominated 81 7mes for the Nobel Prize!
“Thermodynamics is a funny subject.
– The first 7me you go through it, you don't understand it at all.
– The second 7me you go through it, you think you understand it, except for one or two small points.
– The third 7me you go through it, you know you don't understand it, but by that 7me you are so used to it, so it doesn't bother you any more.”
Kinetics: A tribute to two of the greatest whose contributions continue to influence development & understanding of solubilization and drug delivery technologies
Jacob Henricus van’t Hoff – First Nobel Prize in Chemistry (1901) – Discovery of the laws of chemical
kinetics and osmotic pressure of solutions
•
Wilhelm Ostwald
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– Nobel Prize in Chemistry (1909) Catalysis – Coined the term 'Mole'
Ostwald dilution law Ostwald ripening Ostwald's rule Ostwald viscometer Ostwald–Freundlich equation
founded an influential scientific magazine named Zeitschrift für physikalische Chemie ("Journal of Physical Chemistry")
Ostwald, van 't Hoff and Svante Arrhenius are credited with being the modern founders of the field of physical chemistry
Insolubility & the Formulation “Tool Kit”
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H.D. Williams et al: Strategies to Address Low Drug Solubility in Discovery & Development. Pharmacol. Rev. 65: 315- 499 (2013)
Which tool? Which size? What to fix?
What are the biopharmaceutics considerations in evaluating solubilization & MR technologies?
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Dosage Form
Drug in Solu7on
Drug in Systemic circula7on
Therapeu7c & Adverse Effects
Transit of compound through GI
tract
Compound Permeability (and “flux”)
Drug release and dissolu7on
Absorp7on
Elimina7on
Excre7on and Metabolism
In the ever expanding world of insoluble drugs: how much improvement in solubility and/or dissolu7on is needed for a specific drug to achieve op7mal (maximal?) frac7on of dose absorbed? Which is the preferred enabling technology & why? How is it linked to achieving desired PK characteris7cs – enhancement of oral BA and CR Is it possible to “dial-‐a-‐PK” to achieve desired balance of efficacy & safety? What is the role of drug product design?
Selecting Enabling Technology for Enhancing Oral Bioavailability of Insoluble Compounds – Basis?
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BA Enhancing Delivery Desired Dose(s): FIH to Commercial
Technology (excluding MR)
< 50 mg 50 to 150 mg 150 to 300 mg > 300 mg
Crystalline (conventional)
Salt/Co-‐crystal Particle size reduction Soft gel (aqueous miscible or non aqueous)
SEEDS/ SMEDDS etc Solid Dispersion Complexation Nanoparticle Nanoadsorbates (mesoporous silica etc)
§ Differentiate dose at which absorption is dissolution or solubility limited § How much solubilization or dissolution enhancement is really necessary? § Which is the preferred enabling technology for a particular compound of interest? § Does the selection of preferred enabling technology have to be an iterative process? § How to increase efficiency of optimal drug product design by balancing absorption, safety
& efficacy? §
Progressing Low Solubility Drug Through Better Understanding of Factors Influencing Oral Absorption – Balancing Exposure with Safety & Efficacy : Estimating dissolution & solubility limiting regions
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Solution Fasted
Suspension Fasted
Suspension Fed
2nd Gen.Susp. Fasted
Susp. Standard Fed
Phase Diagrams/thermodynamic considerations for development of guidance maps
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Murdande, S.; Pikal, M.; Shanker, R.; Bogner, R. J Pharm Sci (2010), 99(3), 1254-‐1264 Murdande, S.; Pikal, M.; Shanker, R.; Bogner, R.. Pharm Research (2010) 27, 2704-‐2714
Enthalpy & Free Energy of Amorphous Solid is always greater than crystalline form: Could this be the universal solubiliza7on technology if the amorphous form is kine7cally stable?
[ ] ( )( )a
xax
s aIRTTG
Rαα
−
−⋅−⋅⎥
⎦
⎤⎢⎣
⎡ Δ=
11)(exp
)((exp 2
,
Favvas EP, Mitraplous AC: J. Engg. Scii. Technol. Rev. 1: 25-‐27 (2008)
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• What physicochemical proper7es of organic molecules lead to insolubility? • Are these parameters universally relevant for solubility and solubiliza7on? • Insolubility of a solute is an outcome of a solvent’s insufficient free energy to disrupt lahce energy and/or its
inability to solvate solute molecules
log P
Tm
• Polar • Solva5on energy
• High lahce energy
• Non-‐polar • Solva5on energy
• High lahce energy Tg
• Polar • Solva5on energy
• Low lahce energy
• Non-‐Polar • Solva5on energy
• Low lahce energy
“Brick Du
st”
“Grease Ball”
Fundamental Reasons for Insolubility of Organic Molecules
Lahce energy of a crystal represents the summa5on of all intermolecular forces in a crystalline solid that is necessary to be overcome to release the molecules into gaseous state. A par5al measure of lajce energy is Tm and Hfusion
Par77on coefficient of a solute between two immiscible solvents represents the free energy necessary to cross the solvent interface . In the case of drugs the octanol-‐water par55on coefficient (log P) represents its lipophilicity. Higher log P reflects reduced ability of the drug to be solvated by water.
140 years ago Berthelot and Jungfleisch published a predic5ve theory of distribu5on of solutes between two immiscible liquids In 1891 Nernst published that par55on coefficient would be constant only if a single molecular species was considered to distribute between the two phases Berthelot & Jungfleisch: Ann. Chim. Phys. 4, 26 (1872) W. Nernst: Z. Phys. Chem. 8, 110 (1891)
120 Years ago I. Schroder published the rela5onship for the “solubility curve of a non-‐electrolyte” by considering fusion, dissolu5on and recrystalliza5on
I. Schroder: Z.Physik. Chem. Stoichiom. Verwandscharl. 11, 449 (1893)
⎟⎠
⎞⎜⎝
⎛−
Δ−=
m
11ln
TTRH
X f
Development of technology guidance maps
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Calcula7on of Maximum Absorbable Dose (MAD) for development of guidance maps MAD(mg) = ka(min-‐1) * 7me(min) * solubility(mg/ml) * volume(ml)
MAD Solubility
(ml) = 0.2 * 250 * 200 = 10,000 ml For high ka
MAD Solubility
(ml) = 0.001 * 250 * 200 = 50 ml For low ka
• Posi7ve slope of lines/curves in the guidance maps are due to following considera7ons/assump7ons: 1) Increase in ka with increasing Log P
2) Increase in micelle/aqueous par55on coefficient with Log P 3) In-‐vivo observa5ons with a large number of proprietary compounds and published literature
• Guidance maps for each solubiliza5on technology addresses the probability that sufficient absorp5on (>50% frac5on absorbed) can be achieved for the drug to be efficacious
• Other aspects of applicability(processing, stability) are not addressed – separate maps developed (not shown) • Probability that acceptable exposure is obtained is plowed as a func5on of the following
• The dose(mg) to solubility(mg/ml) ra5o • Log P • Permeability is considered as an important factor in the development of guidance maps
• Guidance maps developed for • Crystalline Drug (non-‐ionizable form) • Dispersions (HME and SDDs) • Liquid-‐Filled Capsules (water miscible and immiscible components) -‐ not shown • Submicron crystals(~200 nm)-‐ not shown
Guidance map for delivery of crystalline (non-ionizable drugs)
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Guidance map for delivery of solid dispersions (spray dried or hot melt extrusion)
Thermodynamics and solubilization technology: Overall Technology Guidance Map
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1 = Nanocrystals 2 = Liquid Fill Capsules/ solvents 3 =Solid Dispersions(Spray Dried
Dispersions or Hot Melt Extrusions)
Solubilization Technology Guidance Maps
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• Equilibrium solubility: Na salt >> arginine salt • Dissolu7on rate: Na salt >> arginine salt • Forma7on and permeability of ion-‐pairs: only with arginine salt
Bioa
vailability
in Dogs (%)
0
20
40
60
80
100
FreeAcid
Sodiumsalt
Argininesalt
S
N
Cl
ON
O
OH
O
Example of Impact of Salt Form on Oral Bioavailability: Significant challenges for developing maps
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N
N N
O
O
F
N
O
O
• Equilibrium solubility is not always an indicator of bio-‐performance of polymorphs
• Polymorphism can significantly affect bioavailability
0
100
200
300
400
500
Aq. Solubility(mcg/mL)
Bioavailabilityin Dogs (%)
Form BForm A
Bioa
vailability
Aque
ous S
olub
ility
Mol Wt.: 482.6 Solubility (A and B): 396, 402 mg/mL (water, 25oC) (pH 6.34) Melting Point: 134,139oC (DSC)
Heat of Fusion: 5.4,6.0 Kcal/mol
Only non-‐sink dissolu7on tes7ng revealed forma7on of supersaturated solu7on by Polymorph B
40
20
60
80 100
0
Example of Impact of Polymorphic Form on Oral Bioavailability: Significant challenges for developing maps
CR Technology Applicability Map
1
10
100
1000
0.001 0.01 0.1 1 10 100 1000
Solubility (mg/mL)
Daily Dose (m
g)
Solubiliza7on Needed for CR (SDD, etc.)
Matrix Tablets
Asymmetric Membrane Tablet -‐ Osmo7c
Mul7par7culates
Swellable Core Tablets -‐Osmo7c
GITS -‐ Osmo7c
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• Short half-‐life • Reduce dosing frequency • Reduce Cmax
Increase efficiency in utilization of scientific advances in individual disciplines for inter-disciplinary applications
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Enhanced understanding of the mechanisms of supersaturation & nucleation kinetics in the GI tract
ten Wolde & P.R. Frenkel: Science 277, 1975-‐1978 (1997)
Cryo-‐SEM of solu7ons of citric acid at 5, 20 & 40 wt% in water K. Ohgaki et al Chem Engg Sci 47, 1819-‐1823 (1992)
Future Directions: Systems based Pharmaceutics (SbP) – A 2014 Cross-industry Partnership
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Objec7ve: Create a modeling and simula7on framework that would provide unprecedented capability of considering the complete train of effects from synthe7c crystalliza7on to oral absorp7on in the design of medicines to assess the impact of local perturba7on of arributes on performance arributes of final drug product
API Manufacturing
Drug Product Manufacturing
In-‐vivo pharmacokine5cs
Polymorph, Morphology, Par5cle Size Distribu5on, Purity, etc
Solvent /Seed, Unit opera5ons – crystalliza5on,
filtra5on, drying, etc
Manufacturing Process Control: Feedback/Feed-‐
forward: Content uniformity, Hardness, Disintegra5on etc
Dosage Form – tablet, capsule etc Excipient: Quality Awributes Unit Opera5ons -‐ wet/dry
granula5on/ direct compression, film coa5ng etc.
BE: Cmax, AUC
Dosage Strengths
In-‐Vitro Characteriza5on e.g. Dissolu7on
Stability
Analy5cal Method
Development
Conclusions
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• Company specific strategies of the past – non sustainable (cost, 5me and resources) v Guidance maps based on fundamental considera7ons can be extremely useful v Need more collabora7ve and integrated and mul7-‐disciplinary approaches to address solubility and other drug delivery challenges; impera5ve to be abreast with advances in fundamental science and allied disciplines
v Advances in biology and chemistry will require efficiency in inden5fica5on of effec5ve drug delivery technologies in the future – organ, 5ssue, cell specific delivery & intra-‐cellular delivery
v System based Pharmaceu7cs a necessity for risk management – advanced computa5onal tools to link local perturba5on in awributes to ul5mate quality & performance of product
• Emerging Efforts: innova5on should be driven through science & collabora5on via global v Industrial consor5a for pre-‐compe55ve partnerships v Enhanced partnerships with academic ins5tu5ons v Partnerships across Excipient, CRO, Biotech & Drug Delivery companies v Strong partnership with Regulatory Agencies
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Nature Thermodynamics
(independent of pathway)
Ini7al State Final State
Kine7cs (it is the pathway!)
Metastable states
• Thermodynamics is fundamental • Kinetics influences outcomes
Knowledge of both is essential for optimizing the biopharmaceutics properties of a drug product through all stages of discovery & development
Biopharmaceu7cs: A Conundrum Between Thermodynamics & Kine7cs ?
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Comments, suggestions, questions, disagreements?
THANK YOU!
ravi.m.shanker@ pfizer.com