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 and the impact of early formulation screening on pharmacokinetic studies from Suma Gopinathan at Lexicon Pharmaceuticals.

1. Enabling Drug Discovery with
the Strategic Application of
Early Formulation Screening
Suma Gopinathan, Alan G. E. Wilson
Working to Improve Patients’ Lives

2. 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
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 2

3. Formulations in Drug Discovery
Pharmacokinetics
Discovery Formulation
Support
Pharmacology Toxicology
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 3

4. Discovery Formulations: Pharmacokinetic Studies
Discovery Pharmacokinetic Studies
Formulation
Support  Rodents
 Intravenous route
Pharmacokinetic  Other routes and species to match
Studies pharmacology studies
 Typically lower doses
 Single dose studies
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 4

5. Discovery Formulations: Pharmacology Studies
Discovery Pharmacology Studies
Formulation
Support  Early studies in rodents
 Oral route, other routes
Pharmacology  Typically low doses
Studies
 Consider pharmacology model limitations
 Short to long term studies
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 5

6. Discovery Formulations: Toxicology Studies
Discovery Toxicology Studies
Formulation
Support  Early studies in rodents
 Oral route
Toxicology  Typically very high doses
Studies  Repeat dose studies
 Consider impact on toxicology readouts
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 6

7. 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
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 7

8. Formulation Screening in Drug Discovery
Challenges What we have
• Limited compound availability • Calculated values – cLogP, pKa
• Need for rapid turnaround time • Apparent solubility data (in presence of
1% DMSO), pH 7.4
• Limited physicochemical profiling
• Limited or no salt forms available
• Negligible solubility information
• Multiple routes of administration, species and
disease models
• Predominantly liquid dosage forms
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 8

9. Why Optimizing Formulation in Discovery is Critical
ADME Processes for Orally Administered Drug
FORMULATION: Enabling Solubility to
 Maximize exposure, affecting PD result
 Reduce study variability
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 9

10. 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
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 10

11. 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
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 11

12. Routes of Administration & Applicable Formulations
• Solutions
• Suspensions
• Emulsions
• Capsules
•Solutions
•Suspensions •Solutions
Oral
I.P I.V.
Routes
•Solutions Ophthalmic S.C.
•Suspensions
•Solutions
•Suspensions
Dermal I.C.V
• Patches
• Solutions •Solutions
• Emulsions
• Ointments
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 12

13. Selecting Excipients in Drug Discovery
Route:
• Oral
• Intravenous
• Subcutaneous Route Physicochemical:
• Intraperitoneal
• pKa
• Ophthalmic
• Clog P
• Dermal
Animal Choice of Physico-
Species Excipients Chemical
Animal Species:
• Mouse
• Rat Disease
Model
Disease Model:
• Dog
• Minimal impact on PD parameters
• Primate
• Well tolerated for duration of study
• Others
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 13

14. 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
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 14

15. Dose volume in different species
Karl-Heinz Diehl et. al., J. Appl. Toxicol. 21, 15–23 (2001)
Mouse – 5mL/kg, up to 10mL/kg
In house Rats – 5mL/kg, up to 20mL/kg
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 15

16. Oral dose volume has minimal impact repeat
administration
Ratio of Heart Ratio of Liver Wt
Body Wt gain (g) Wt to Body 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;
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 16

17. Oral excipients can influence gross morphology,
blood chemistry and hematology
Corn Oil: Triglyceride(mg/dL) Corn Oil: BUN (mg/dL) Corn Oil: BIL (mg/dL)
*
*P < 0.05
**P < 0.01
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
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 17

18. Discovery Formulations – Choice of Excipients
Y AS Aqueous
API Solubility
formulation
Y Salt form PS
available?
N
Aqueous
AS Y In situ salt
formulation of Solubility
formation?
salt form
N
pH based
PS pH based Y AS
Solubility formulation +/-
solubility
salt form
N, NS
Surfactant PS
AS Y
formulation +/- Solubility Surfactants
salt form, pH Co-solvent
N, NS
formulation +/-
PS Y AS
Co-solvents Solubility salt
Cyclodextrin form, pH, surfa
based N, NS
ctant
formulation AS Y PS
Solubility Cyclodextrins
+/- salt
form, pH, co- N, NS Lipid
solvent formulation +/-
PS Y AS
Lipids Solubility salt
form, surfactan
N, NS
t, co-solvent
Aqueous or Suspension PS
lipid based based
suspensions formulations
Key
Y: Yes
N: No
NS: Not Soluble
Suma Gopinathan, Amr Nouraldeen and Alan GE Wilson, Future M ed. Chem. (2010) 2(9) 1394 AS: Adequate solubility at target concentration
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 18 Partially soluble
PS:

19. Formulation Screening in Drug Discovery
Suma Gopinathan, Amr Nouraldeen and Alan GE Wilson, Future M ed. Chem. (2010) 2(9) 1394
3hr, 6mg
* Formulations are incubated in Simulated Intestinal Fluid (SIF), Simulated Gastric Fluid
(SGF) and/or PBS
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 19

20. Compound A:
Molecular Weight 434.51
AlogP 2.192
Molecular Polar Surface Area 122.56
Apparent Solubility (mg/mL) 0.016
Target Conc. (mg/mL) 3 to 10
Salt Conc. % Soluble
Vehicle
Form (mg/mL) 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%
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 20

21. Compound A: In Vitro – In Vivo Correlation
In Vitro In Vivo
Form Dose % Soluble in
(mg/mL) 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
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 21

22. Compound B:
Molecular Weight 449.5
AlogP 1.68
Molecular Polar Surface Area 126.65
Apparent Solubility (mg/mL) < 0.01mg/mL
Target Conc. (mg/mL) 2
% Soluble in
Salt Form
SIF
Vehicle
Captisol HCl 42%
PEG 400 HCl 10%
Methyl cellulose HCl 9%
Tween 80 HCl 9%
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 22

23. Compound B: Improving Oral Bioavailability
In Vitro In Vivo
Vehicle % SIF solubility CMAX (nM) AUC (nM*hr) %BA
Captisol 42% 2153 2066 28
Tween 80 9% 306 501 7
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 23

24. Compound C:
Molecular Weight 282.7
AlogP 4.7
Molecular Polar Surface Area 65.5
Apparent Solubility (mg/mL) < 0.1mg/mL
Target Conc. (mg/mL) 20
Highest
Soluble % Soluble
Vehicle Notes
Conc in SIF
(mg/mL)
Suspension formulation, variable
Tween 80 < 1 mg/mL 52 ±20
dissolution data
Cremophor 10 mg/mL 65 ±12 Precipitation visible in 3hrs
Cremophor with
> 20 mg/mL 81 ±2 Stable solution formulation
Kollidon
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 24

25. Compound C: Improving exposure and minimizing
variability
400000 400000
350000 350000 Cremophor Kollidon
Tween 80
300000 300000
250000 250000
Cp (nM)
Cp (nM)
200000 200000
150000 150000
100000 100000
50000 50000
0 0
0 4 8 12 16 20 24
0 4 8 12 16 20 24
Time (hr) Time (hr)
In Vitro In Vivo
Vehicle % SIF solubility CMAX (µM) AUC (µM*hr)
Tween 80 52 ±20 220 147 1426 556
Cremophor with Kollidon 81 ±2 317 51 1217 100
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 25

26. Impact of Early Formulation Screening
88%
solutions
84%
solutions 2009
Solutions
2007
54%
solutions
2005
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 26

27. A Case for Early Formulation Screening
Effort Reward
© 2012 Lexicon Pharmaceuticals, Inc. Confidential Slide 27

28. Breakthrough Treatments
for Human Disease
NASDAQ: LXRX
www.lexpharma.com
Working to Improve Patients’ Lives