bioavailability solubility conference 2011

Working to Improve Patients’ Lives

Enabling Drug Discovery with the Strategic

Application of Early Formulation Screening

Suma Gopinathan, Alan G. E. Wilson

© 2012 Lexicon Pharmaceuticals, Inc.

Slide 2Confidential

Outline of Presentation

– Formulations in drug discovery

– Changing the formulation paradigm in early drug discovery

– Critical role of solubility and formulation screening

– Innovative formulation screening with low amounts of test compound

– Impact of early formulation screening on Pharmacokinetic studies


Slide 3Confidential

Pharmacokinetics

ToxicologyPharmacology

Discovery Formulation Support

Formulations in Drug Discovery


Slide 4Confidential

Pharmacokinetic Studies Rodents

Intravenous route

Other routes and species to match pharmacology studies

Typically lower doses

Single dose studies

Pharmacokinetic Studies

Discovery Formulation

Support

Discovery Formulations: Pharmacokinetic Studies


Slide 5Confidential

Pharmacology Studies Early studies in rodents

Oral route, other routes

Typically low doses

Consider pharmacology model limitations

Short to long term studies

Pharmacology Studies


Support

Discovery Formulations: Pharmacology Studies


Slide 6Confidential

Toxicology Studies Early studies in rodents

Oral route

Typically very high doses

Repeat dose studies

Consider impact on toxicology readouts

Toxicology Studies


Support

Discovery Formulations: Toxicology Studies


Slide 7Confidential

Changing Paradigm of Formulation in Drug Discovery

Alan GE Wilson, Amr Nouraldeen and Suma Gopinathan, Future Medicinal Chemistry, January 2010, Vol. 2, No. 1, Pages 1-5


Slide 8Confidential

Formulation Screening in Drug Discovery

Challenges

• Limited compound availability

• Need for rapid turnaround time

• Limited physicochemical profiling

• Limited or no salt forms available

• Negligible solubility information

• Multiple routes of administration, species and disease models

• Predominantly liquid dosage forms

What we have

• Calculated values – cLogP, pKa

• Apparent solubility data (in presence of 1% DMSO), pH 7.4


Slide 9Confidential

Why Optimizing Formulation in Discovery is Critical

Drug in Gut• Dissolution,

Disintegration

Intestinal Wall• Permeability

Liver• Metabolism• Elimination

(bile)

Circulation• Plasma

Protein Binding

Target Organ• Pharmacology

Response

Kidney• Elimination

ADME Processes for Orally Administered Drug

FORMULATION: Enabling Solubility to

Maximize exposure, affecting PD result

Reduce study variability


Slide 10Confidential

Ideal Characteristics of Discovery Formulations

– Enable exposure

– Suitable over a wide range of doses

– Reproducible

– Easily administered

– Stable

– Minimal interaction with disease model

– Easy transition to FIH formulation



Excipients & Solubilizing Strategies in Discovery Formulations

– FDA approved excipients

– pH 4-8

– Organic phase in aqueous formulations < 30% of total volume

– Avoid excessive heat in formulation preparation

Suma Gopinathan, Amr Nouraldeen and Alan GE Wilson, Future M ed. Chem. (2010) 2(9) 1394



Routes of Administration & Applicable Formulations

I.P

Ophthalmic

Dermal I.C.V

S.C.

I.V.

Oral

Routes

• Solutions• Suspensions• Emulsions• Capsules

• Solutions

• Solutions• Suspensions

• Solutions

• Patches• Solutions• Emulsions• Ointments





Choice of Excipients

Route

Physico- Chemical

Disease Model

Animal Species

Selecting Excipients in Drug Discovery

Route:• Oral• Intravenous• Subcutaneous• Intraperitoneal• Ophthalmic• Dermal

Animal Species:• Mouse• Rat• Dog• Primate• Others

Disease Model:• Minimal impact on PD parameters• Well tolerated for duration of study

Physicochemical:• pKa• Clog P



Effect of Excipients on Preclinical Species

Extensive in house data on impact of excipients and combinations of excipients

– Route of administration

– Dose Volume

– Duration of dosing

– Species difference on tolerability

– Maximum dose tolerated

– Impact on gross morphology, hematology



Dose volume in different species

Karl-Heinz Diehl et. al., J. Appl. Toxicol. 21, 15–23 (2001)

Mouse – 5mL/kg, up to 10mL/kgRats – 5mL/kg, up to 20mL/kgIn house



Oral dose volume has minimal impact repeat administration

Body Wt gain (g)Ratio of Heart Wt

to Body WtRatio of Liver Wt

to Body Wt

RBC (x106/µL) Hgb (g/dL) ALT (U/L) AST (U/L)

Male Sprague-Dawley rats, QD p.o., 5 days:

Group B: Saline at 5 mL/kg; Group C: Saline at 10 mL/kg; Saline at 20 mL/kg;



Oral excipients can influence gross morphology, blood chemistry and hematology

Male Sprague-Dawley rats, QD; p.o., 5 days:

Group A: Control (Water, 5mL/kg); Group B: Corn oil at 5 mL/kg;

Group C: Corn oil at 10 mL/kg; Group D: Corn oil at 20 mL/kg

Corn Oil: Triglyceride(mg/dL)

*P < 0.05**P < 0.01

Corn Oil: BUN (mg/dL)

*

Corn Oil: BIL (mg/dL)



Discovery Formulations – Choice of Excipients

AS

SolubilitypH based

formulation +/- salt form

Solubility

Co-solvent formulation +/- salt form, pH,

surfactant

Lipid formulation +/-

salt form, surfactant, co-

solvent

Solubility

Y

Y

Suspension based

formulations

API

Salt form available?

SolubilityAqueous

formulation of salt form

SolubilitySurfactant

formulation +/- salt form, pH

Solubility

Cyclodextrin based

formulation +/- salt form, pH,

co-solvent

pH based solubility

In situ salt formation?

Surfactants

Co-solvents

Cyclodextrins

Lipids

Y

Y

Y

Y

Y

N

N

N, NS

PS

Aqueous or lipid based

suspensions

SolubilityAqueous

formulationY

AS

AS

PS

PS

PS

PS

AS

N, NS

N, NS

N, NS

N, NS

PS

AS

AS

AS

PS


Key Y: Yes N: NoNS: Not SolubleAS: Adequate solubility at target concentrationPS: Partially soluble



Formulation Screening in Drug Discovery

3hr, 6mg

* Formulations are incubated in Simulated Intestinal Fluid (SIF), Simulated Gastric Fluid (SGF) and/or PBS




Compound A:

Molecular Weight 434.51AlogP 2.192

Molecular Polar Surface Area 122.56Apparent Solubility (mg/mL) 0.016

Target Conc. (mg/mL) 3 to 10

VehicleSalt

FormConc.

(mg/mL)% Soluble

in SIF

Captisol - 3 97%

PEG 400, Solutol - 3 38%

Kollidon - 3 24%

Vitamin E TPGS - 3 11%

Cremophor, Tween 80 - 3 9%

Captisol - 10 9%

Captisol HCl 10 65%



Compound A: In Vitro – In Vivo Correlation

Form Dose (mg/mL)

In Vitro In Vivo

% Soluble in SIF Cmax (nM) AUC (nM*hr)

Free Base 3 97% 557 ± 100 1319 ± 425

Free Base 10 9% 29 ± 8.9 94, 79

HCl salt 10 65% 2963 ± 530 3815 ± 977



Compound B:

VehicleSalt Form

% Soluble in SIF

Captisol HCl 42%

PEG 400 HCl 10%

Methyl cellulose HCl 9%

Tween 80 HCl 9%


Molecular Polar Surface Area 126.65Apparent Solubility (mg/mL) < 0.01mg/mL

Target Conc. (mg/mL) 2



Compound B: Improving Oral Bioavailability

Vehicle

In Vitro In Vivo

% SIF solubility CMAX (nM) AUC (nM*hr) %BACaptisol 42% 2153 2066 28

Tween 80 9% 306 501 7

1

10

100

1000

10000

0 1 2 3 4 5 6

Cp (n

M)

Time (hr)

Captisol

Tween 80



Compound C:

Vehicle

Highest Soluble

Conc (mg/mL)

% Soluble in SIF

Notes

Tween 80 < 1 mg/mL 52 ±20Suspension formulation, variable dissolution data

Cremophor 10 mg/mL 65 ±12 Precipitation visible in 3hrs

Cremophor with Kollidon

> 20 mg/mL 81 ±2 Stable solution formulation


Molecular Polar Surface Area 65.5Apparent Solubility (mg/mL) < 0.1mg/mL

Target Conc. (mg/mL) 20



Compound C: Improving exposure and minimizing variability

Vehicle

In Vitro In Vivo

% SIF solubility CMAX (µM) AUC (µM*hr)Tween 80 52 ±20 220 ± 147 1426 ± 556

Cremophor with Kollidon 81 ±2 317 ± 51 1217 ± 100

0 4 8 12 16 20 240

50000

100000

150000

200000

250000

Tween 80

Time (hr)

Cp (n

M)

0 4 8 12 16 20 24

0

50000

100000

150000

200000

250000

300000

350000

Cremophor Kollidon

Time (hr)

Cp (n

M)



Impact of Early Formulation Screening

2005

2007

2009

Sol

utio

ns

# of Discovery Formulations

54% solutions

84% solutions

88% solutions



A Case for Early Formulation Screening

Effort Reward

Early read, enabling FIH formulations

Reliable, consistent dosing

Improved Exposure

Enabled formulations

Minimal Compound Requirements

Quick Turnaround

Working to Improve Patients’ Lives

Breakthrough Treatments

for Human Disease

NASDAQ: LXRX

www.lexpharma.com

bioavailability solubility conference 2011

Documents

lexicon pharmaceuticals

studies pharmacology

confidential slide

drug discovery challengeswhat

impact of excipients

formulation paradigm

paradigm of formulation

low doses studies