Bioavailability solubility conference 2011
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Transcript of 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
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 3Confidential
Pharmacokinetics
ToxicologyPharmacology
Discovery Formulation Support
Formulations in Drug Discovery
© 2012 Lexicon Pharmaceuticals, Inc.
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
© 2012 Lexicon Pharmaceuticals, Inc.
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
Discovery Formulation
Support
Discovery Formulations: Pharmacology Studies
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 6Confidential
Toxicology Studies Early studies in rodents
Oral route
Typically very high doses
Repeat dose studies
Consider impact on toxicology readouts
Toxicology Studies
Discovery Formulation
Support
Discovery Formulations: Toxicology Studies
© 2012 Lexicon Pharmaceuticals, Inc.
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
© 2012 Lexicon Pharmaceuticals, Inc.
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
© 2012 Lexicon Pharmaceuticals, Inc.
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
© 2012 Lexicon Pharmaceuticals, Inc.
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
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 11Confidential
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.
Slide 12Confidential
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
• Solutions• Suspensions
• Solutions• Suspensions
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 13Confidential
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
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 14Confidential
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.
Slide 15Confidential
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
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 16Confidential
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;
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 17Confidential
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)
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 18Confidential
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
Suma Gopinathan, Amr Nouraldeen and Alan GE Wilson, Future M ed. Chem. (2010) 2(9) 1394
Key Y: Yes N: NoNS: Not SolubleAS: Adequate solubility at target concentrationPS: Partially soluble
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 19Confidential
Formulation Screening in Drug Discovery
3hr, 6mg
* Formulations are incubated in Simulated Intestinal Fluid (SIF), Simulated Gastric Fluid (SGF) and/or PBS
Suma Gopinathan, Amr Nouraldeen and Alan GE Wilson, Future M ed. Chem. (2010) 2(9) 1394
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 20Confidential
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%
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 21Confidential
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
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 22Confidential
Compound B:
VehicleSalt Form
% Soluble in SIF
Captisol HCl 42%
PEG 400 HCl 10%
Methyl cellulose HCl 9%
Tween 80 HCl 9%
Molecular Weight 449.5AlogP 1.68
Molecular Polar Surface Area 126.65Apparent Solubility (mg/mL) < 0.01mg/mL
Target Conc. (mg/mL) 2
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 23Confidential
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
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 24Confidential
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 Weight 282.7AlogP 4.7
Molecular Polar Surface Area 65.5Apparent Solubility (mg/mL) < 0.1mg/mL
Target Conc. (mg/mL) 20
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 25Confidential
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)
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 26Confidential
Impact of Early Formulation Screening
2005
2007
2009
Sol
utio
ns
# of Discovery Formulations
54% solutions
84% solutions
88% solutions
© 2012 Lexicon Pharmaceuticals, Inc.
Slide 27Confidential
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
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