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

edic

ted

P effin

Hum

ans c

m/s

ec x

10-4

I

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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120

0 10 20 30

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

azol

e C

onte

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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