Recent advances in dissolution/in-vitro release methodology
supporting product development and IV-IVC
James ButlerExploratory Development Sciences
GlaxoSmithKline, Harlow, UK
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Outline
• Six reasons why conventional (single medium, paddle/ basket) dissolution may not correlate with in-vivo dissolution/absorption
• Filling the knowledge gap: Emerging technologies to improve in-vivo prediction
• Innovative Medicines Initiative (IMI) collaboration: Oral Biopharmaceutics Tools (OrBiTo)
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Reason 1: in-vitro sensitivity > in-vivo sensitivity
• Most likely when solubility in-vivo is adequate and formulation is designed for immediate release
• A good scenario?
In-vitro (typically 0-1hr for IR) In-vivo (typically 0-24hr)
Examples: Ranitidine, BCS class 3 (Polli J. Adv Exp Med Biol. 1997 423:191-8), Metoprolol, BCS class 1 (Rekhi et al. Pharm Dev Tech. 1997 2: 11-24) 4
250 500 1000 10000 100000Dose/solubility ratio
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1
0.1
5000Pr
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ted
P effin
Hum
ans c
m/s
ec x
10-4
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Good solubility and permeability
II
Good permeability, poor solubility
III
Good solubility, poor permeability
IV
Poor solubility and permeability
BCS – conservative, regulatory driven - when is there a risk of bio-inequivalence?
DCS – developability classification system - what is most likely to happen?
Solubility: measured on a few mgs of API, permeability: estimated from cell line or in-silico model
IIa (dissolution rate limited)
IIb (solubility limited)
Using jejunal solubility, typically FaSSIF@37°C
Butler, Dressman. The developability classification system: application of biopharmaceutics concepts to formulation development.(2010) J. Pharm. Sci. 99: 4940–4954
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DCS and probability of in-vitro/in-vivo relationships (Immediate Release)
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Reason 2: media/ environment
• Significant progress with the use of “bio-relevant media” in the last 15 years– Fasted/fed state simulated intestinal/gastric fluids
• FaSSIF, FeSSIF, FaSSGF...etc– E. Galia et al. Evaluation of various dissolution media for predicting in-vivo performance of class I and
II drugs. Pharm Res (1998) 15: 698-705– E. Jantratid et al. Dissolution media simulating conditions in the proximal human gastrointestinal
tract: an update. Pharm Res (2008) 25: 1663-1676
• In-vivo, the environment experienced by the dosage form is constantly changing
• Bio-relevant media therefore represent a snapshot (related to time after dosing and location) of the in-vivo environment for dissolution
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Example: Biorelevant media plus multiple media change for prediction of extended release
formulations
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Time (hours)
Con
cent
ratio
n % PK Data-FAST
PK Data-MED
PK Data-SLOW
USP3-FAST
USP3-MED
USP3-SLOW
Padles-FAST
Paddles-MED
Paddles-SLOW
Flow through (USPIV) and reciprocating cylinder (USPIII -shown) methods offer the possibility of multi-condition bio-relevant dissolution to better mimic GI transit
For literature examples see: N. Fotaki et al. Eur J Pharm Biopharm (2009) 73: 115–120, E. Jantratid et al. Eur J Pharm Sci (2009) 37: 434–441 and S. Klein et al. J Pharm Pharmacol (2005) 57: 709-719 8
Reasons 2&3: supersaturation & precipitation
Dissolution
Supersaturation/ Solubilisation
Precipitation
CS
time
A simple “sink condition” test will only characterise the initial dissolution phase
Precipitation will be influenced by the dynamics of media change
Also see: J Brouwers et al. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci (2009) 98: 2549–2572
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When is in-vivo supersaturation likely?
• Salts of poorly soluble weak acids– in the stomach
• Poorly soluble weak bases– in the intestine
• Psachoulias et al. Precipitation in and supersaturation of contents of the upper small intestine after administration of two weak bases to fasted adults. Pharm Res (2011) 28:3145–3158
• Psachoulias et al. An in vitro methodology for forecasting luminal concentrations & precipitation of highly permeable lipophilic weak bases in the fasted upper small intestine. Pharm Res (2012) in press
• Other drug forms for improved solubility– Amorphous, co-crystal, prodrug, etc.
• Bioenhanced /solubilising formulations– Liquids, semi-solids, solid dispersions, etc
• Bevernage et al. Supersaturation in human gastric fluids. Eur J Pharm Biopharm (2012) 81: 184-189
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What technologies may help?
• “Non-sink” methods with dynamic media transfer– Vary in complexity
– Simple “stirred beaker” based models:
– More complex:
E. Kostewicz et al. J Pharm Pharmacol (2004) 56: 43–51
SystemicIntestinalGastric
For more, see M. McAllister, Dynamic dissolution: A step closer to predictive dissolution testing? Mol Pharm (2010) 7: 1374–1387 11
Reason 4: Solubility/permeability interplay
Undissolved drug
Free drug in solution
“Bound drug” in solution
Epithelial cell layer
Aqueous boundary layer
Based on concepts in papers by Dahan & Miller, e.g. Mol. Pharmaceutics 2011, 8, 1848–1856 12
What technologies may help?• Combine “permeability” and “dissolution” in a single test
– Dissolution in apical compartment of a cell line measurement– E.g. Kataoka et al. Application of dissolution/permeation system for evaluation
of formulation effect on oral absorption of poorly water-soluble drugs in drug development. Pharm Res (2011) 29:1485–1494
– Dialysis to remove drug in solution• TNO-TIM uses this approach
– Organic layer– E.g. D Phillips et al. Overcoming sink limitations in dissolution testing: a review
of traditional methods and the potential utility of biphasic systems. J Pharm Pharmacol (2012) in press
• Estimate permeability separately, then modify the dissolution test or the dissolution data to account for it
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Reason 5: complex agitation/ mechanical stress
In vitro• Constant agitation• Low to moderate agitation
– typically via media movement over a static dosage form in a stirred vessel
• Low viscosity
In-vivo• Variable agitation
– From virtually nil to very high• Fundus/antrum/intestine
– Depends on prandial state, motility cycle and dosage form location
– churning, grinding, peristaltic propulsion
• Viscosity may be increased by food components
The lack of in-vivo relevance in standard in-vitro methods is a particular problem for slowly eroding dosage forms 14
What technologies may help?
See Garbacz et al. A biorelevant dissolution stress test device - background and experiencesExpert Opin Drug Deliv (2010) 7: 1251-1261
Burke et al. Patent application US20100126287
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Reason 6: individual in-vivo variability
• Food– Fed v fasted, food type
• Age– Elderly, paediatric
• Patient population v healthy volunteers– Disease state– Co-medication
• Etc.......
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In-vivo studies on the effect of gastric pH
• Various in-vivo studies with poorly soluble weak bases show significant PK sensitivity to gastric pH:– With/without drugs (e.g. PPIs) that raise gastric pH/suppress gastric
secretion– Pre-selected individuals with/without achlorhydria
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Example:25mg Cinnarizine capsules in Japanese volunteers with low or high gastric acidity.
Solubility: >1mg/ml in SGF, but ~1-3µg/ml in HIF
Capsule A & B were the fastest and slowest dissolving in-vitro of 32 marketed. Adapted from data in: H Otaga et al. 1986. Int J Pharm 29 113-120.
Graph is for Cmax in ng/ml. Similar trend for AUC.
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Normal
Achlorhydic
Red – slowest dissolving marketed capsuleBlue – fastest dissolving marketed capsule
What technologies may help?
• TNO-TIM-1 (TNO Intestinal model -1)– Dynamic, multicompartmental, peristaltic forces – Stomach & 3 small intestine compartments
• Model Gut• Dynamic Gastric Model (DGM)
– Dynamic, multicompartmental– Principal focus on mimicking gastric dynamics
– Fundus and antrum compartments 18
Chart To Show Comparison Of Dialysis Samples for Ketoconazole under normal and simulated PPI conditions
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Time (Mins)
Ket
ocon
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nt (u
g/m
l)
normal pH total high pH total
A – Ketoconazle + glass of waterB – Ketoconazole with omeprazole induced achlorhydriaC – Ketoconazole woth Omeprazole induced achlorhydria + glass of cokeRef: Antimicrobial agents and chemotherapy, Aug 1995, p1671 - 1675
TNO TIM1 profiles with low and high stomach pH
Example: Ketoconazole – impact of gastric pH e.g. via the co-administration of PPI’s
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Summary and future challenges
• Many novel in-vitro models now available, but:
– When to use which?• Case by case: what degree of complexity is required?
– Validation: how well do these models actually work on a wider set of examples?
– Is it possible to convert predictive, but complex tools into anything of use in a QC and/or regulatory environment?
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IMI: OrBiTo collaboration• What is it?
• 5 year, part EU funded European industry/academia collaboration• Aim:
• Developing and validating better models for predicting oral human absorption and pharmacokinetics.
• Work-packages:• phys-chem. properties (API focussed)• In-vitro tools (dissolution, supersaturation, precipitation, permeability…), • In-vivo tools• PBPK models
• Eleven industry partners, and a similar no. of academic partners• Industry partners: GSK, AZ, MSD, Pfizer, J&J (Janssen), Novartis, Bayer, Boehringer
Ingelheim, Lundbeck, Aventis, Orion.
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