sudhkar-garad
sudhkar-garad
Conference, Boston
Understanding Developability
Assessment of Small Molecules
Sudhakar Garad, Ph.D.
Novartis Cambridge, MA
[email protected]
Sep 9th 2019
Outline
2
Developability: Design a Molecule
with Delivery in Mind
Topical/Transdermal
Oral
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Developability “Broad Terminology”
• Technical Compounds/Scaffolds
– Physchem properties
– Synthesis
– Formulations
– Device
In-Vitro Data
• DMPK Generation- ADME
In-Vivo Testing- PK
– Permeability
In-Vivo/In-Vitro
– Transporter Correlation (IVIVC)
– Enzyme degradation Risks for Absorption
– PK/PD and PD
4
Biopharmaceutical Classification
System
Current Industry Trends
5-10% 10-20%
Marketed Drug Molecules According to the BCS Classification System. Available online: http://www. capsugel.com/knowledge-
center/webinars/archived-webinars/paginate/P15
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Traditional Drug Development Process
Developability
Research Development
Evaluation of first-in-
human (FIH)
formulation
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Drug Development Process
6-10 years
Lead Opt. CS CD Phase I Phase IIa Phase IIb Phase III Phase IV
Developability Development
Assessment
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Pre-clinical in-vitro data
▪ Solubility (pH 4.5 and 6.8)
Compounds/Scaffolds
▪ Permeability
▪ PAMPA (Parallel Artificial Membrane Permeability Assay) ~ 500
▪ Caco-2
▪ Microsomal stability
▪ Drug-drug interactions
▪ hERG assay (cardiac safety)
~5
▪ Ames test (carcinogenicity)
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Roadmap to Address Biopharmaceutic
Liabilities in Discovery/Optimization
Solvent-Shift
Solubility • Target > 0.1 mg/mL FaSSIF
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Step 1: Dev. Classification System:
DCS Risk Assessment
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Step 2: Evaluate Maintenance of
Supersaturation in FaSSIF
Compound X Compound Y
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Step 3: Absorption Modelling
Accurate estimates of the gap we face:
What is limiting exposure?
Clinical
Pre-clinical
• FIH Prediction
• Dose-exposure relationship
• Formulation bridging
• Determine absorption • IVIVC
limitations • Special populations, food
• Tox formulation selection effect
Discovery • Suitable formulation
principle selection
• In-silico tools
• Predict
physicochemical/
pharmacokinetic
properties
• Identify metabolism risks
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GastroPlus Influence on Candidate
Selection
Low Risk
1. Validate preclinical models with PK
data, predict human %Fa Modeling predicts good exposure across tox
and anticipated human dose range from
conventional formulation
Medium Risk
Special formulations may provide adequate
exposure, invest in formulation evaluation
• e.g. poor exposure from suspension, but
compound can maintain supersaturation →
candidate for enabled formulation evaluation
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Pre-clinical Formulations
• Prerequisite: route of administration, animal model, dosing
volume/kg, doses/kg and type and duration of study
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Pre-clinical Formulations (cont.)
• Solutions
– Single dose (up to 70% organic vehicle)
– Multiple doses (no greater than 30% of organic vehicle)
• Suspensions
– 200 mg/mL – No limit as long as it is easy to manufacture and dose
i.e. syringe flowability
– Choice of surfactant (good wetting agent)
– Choice of suspending agent (no physical form change)
– Uniform average particle size (no change in particle size as a
function of time)
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Pre-formulation Studies
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Physico-chemical Properties
• pKa
• Possibility of salt synthesis
• Selection of counter ions for salt synthesis
• Log P
• Permeability of the molecule
• Solubility in lipophilic vehicles
• Physical form
• Crystalline; high or low melting point
• Amorphous; high or low Tg (glass transition)
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Physico-chemical Properties (cont.)
• pH solubility and stability profile
• Use of optimal pH to improve the solubility
• Understand the optimal pH for stability of the NCE in solution or solid
dosage form
• Light stability
• Determines manufacturing and storage conditions
• NCE deposits/excretes in skin, light unstable compound may lead to skin
toxicity
• Excipient compatibility
• Depending on final dosage form strategy, excipient compatibility must be performed
• Generate stability data using (1-1), (1-3), and (1-10) ratio of NCE to excipients at
accelerated conditions as per ICH guidelines
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Solubility vs. Dissolution Approach
Technology Selection GLP Tox and Clinical Formulation
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Scenario 2
• Most of the NCE’s follow Scenario 2 because of poor
solubility
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Pro-drug Approach
Name of the API Solubility
mg/ml
Clindamycin 0.2
Clindamycin-2-PO4 150
Chloramphenicol 2.5
Succinate sodium 500
Metronidazole 10
N,N-dimethylglycinate 200
Phenytoin 0.03
Glycerides of SA 2.26
Reduction in Particle Size Increased the Mean Plasma Concentration Profile For Reduced
Dissolution Rate of a Poorly Soluble Drug Particle Size Formulations
Mean Percent Dissolved
Concentration (m cg/m L)
120
0.1µ
100 4 Formulation A (0.1µ)
Mean Plasm a
0.2µ
80 Formulation B (0.5µ)
0.5µ 3
60 Formulation C (25µ)
1.0µ 2
40
20 5.0µ 1
0 25µ
0
0 15 30 45 60 75 90 105 120 135 0 4 8 12 16 20 24
Time in Minutes Tim e in Hours
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Physical Form Change
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Lipid-Based Drug Delivery
Solubility in oils, surfactant and hydrophilic solvents
• Emulsions
•Micro emulsions
•Nano emulsions
• Challenges
• Solubility limitations
• Physico-chemical instability
• Dose (has to be low)
• Very few marketed formulations
• Neoral (Novartis)
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Clinical Formulation
(Capsules or Tablets)
• Physical form: chemically stable, soluble, reproducible, no
polymorphism
• Drug/excipient compatibility
• Effect of drug load on dissolution/exposure
• Physico-chemical stability as per ICH guidelines
• Manufacturing of prototype batches
• One month stability data
• Manufacturing of clinical batches
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Summary
• It is very important to understand developability of molecules
with risk mitigation plan. If non-developable, terminate
molecule as soon as possible
• Select a final physical form for GLP tox and clinical studies to
avoid variable exposure due to physical form change
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Acknowledgement
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Thank you
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