Drug Delivery and Formulation

Conference, Boston

Understanding Developability
Assessment of Small Molecules
Sudhakar Garad, Ph.D.
Novartis Cambridge, MA
[email protected]
Sep 9th 2019
 Outline

▪ Biopharmaceutical classification system

▪ Drug development process
▪ Developability Classification System (DCS)
▪ Pre-clinical in-vitro data
▪ Pre-clinical formulations
▪ Pre-formulation studies
▪ Pharmacokinetic data
▪ Clinical formulations

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 Developability: Design a Molecule
with Delivery in Mind

Topical/Transdermal
Oral

Brain Targeting Ophthalmic Inhalation

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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

• Commercial opportunities Mitigation or

Termination
– Block buster (> $1B per year)
– Orphan indication Developable Molecule
– Targeted Product Profile

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Biopharmaceutical Classification
System
Current Industry Trends

Biopharmaceutical Classification System

High Solubility Low Solubility

⚫ BCS I and III: 10% - Soluble

Permeability

Class I Class II ⚫ BCS II: 70% - Insoluble

High

⚫ BCS IV: 20% - Insoluble

5-10% 60-70% and poorly permeable
Permeability

Class III Class IV

Low

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

Time: 9-13Years Funding can be very tight

Cost of Development: High

6 Source: World Federation of Science Journalists http://wfsj.org

 Drug Development Process
9-13 years
CS CD
Lead Opt. Phase I Phase IIa Phase IIb Phase III Market
(1-4) (1)

Research Development

Evaluation of first-in-
human (FIH)
formulation

Class I--------- Easy to Develop

Class II--------Require technology, significant time
Class III and IV-------- Potent

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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

Why Development associates are involved in Research

⚫ Majority of NCE are BCS Class II, and IV
⚫ Non-developable candidate selection
Research
⚫ Recommendation of a physical form, i.e.
physically and chemically stable
⚫ Right formulation for efficacy and toxicological
studies
⚫ Feasibility of formulations in humans
⚫ Immediate feedback to research team

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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

Developability • In-vitro permeability

Classification • In-vitro FaSSIF solubility
System • Dose

Solvent-Shift
Solubility • Target > 0.1 mg/mL FaSSIF

• GastroPlus modeling in pre-clinical

species to understand absorption
Absorption limitations
Modeling • Confidence formulation principle will
achieve sufficient exposure in
toxicology studies

Poor PK cannot always be fixed with formulation!

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 Step 1: Dev. Classification System:
DCS Risk Assessment

Compounds considered “solubility-limited” in absorption (pink region) will

likely require enabling formulations for adequate exposure (e.g. solid
dispersion, microemulsion)
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 Step 2: Evaluate Maintenance of
Supersaturation in FaSSIF

Maintain high supersaturation

Identify and prioritize compounds that can maintain good

supersaturation solubility in FaSSIF over time

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 Step 2: Evaluate Maintenance of
Supersaturation in FaSSIF

Compound X Compound Y

• In-vitro tool: Supersaturation assay

– Generate in-vitro “spring” via solvent (DMSO), quantify

• In-vivo “spring” must be generated by rapid dissolution (stomach pH or

salt) or by an enabling formulation (e.g. solid dispersion)

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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

2. Understand critical parameters for

High Risk
absorption (next slide)
• Can formulation improve exposure? Formulation cannot improve exposure,
terminate compound.
• e.g. high clearance or poor solubility and/or low
3. Risk Management supersaturation

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 Pre-clinical Formulations
• Prerequisite: route of administration, animal model, dosing
volume/kg, doses/kg and type and duration of study

• Tolerability of vehicles in animal models (LD50)

• Solubility: pH, co-solvents, surfactants, CD’s, lipids, alone
and in combinations

• Formulations selection based on solubility

• Physical and chemical stability
• Poor solubility: formulate as a suspension
• Compare solution vs. suspension in animal models

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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

• Physico-chemical properties of NCE

• pKa
• Log P
• Solubility
• Crystalline physical form with melting point

• pH solubility and stability profile

• Solid state and light stability
• Excipients compatibility

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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

• For topical NCE, it helps to select stabilizer in the formulation

• Solid state stability: physical (polymorphism) and chemical

stability
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 Pre-formulation
• It is very important to know the route of administration prior to
initiation of solubility studies

• Depending on route of administration determine:

• Solubility
• In suitable excipients
• Stability profile in those excipients
• Combinations of excipients for solubility screening

• 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

• Single excipient or combination of excipients are subjected for stability studies

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 Solubility vs. Dissolution Approach
Technology Selection GLP Tox and Clinical Formulation

Formulation Scenario 1 Scenario 2 Scenario 3 Scenario 4

Solution High High High Low
Suspension High Low Medium Low
Conclusions Easy to Exposure limited Exposure limited Permeability, efflux,
develop by solubility by dissolution metabolism
rate /solubility
% NCE/pBCS 5 (I/III) 90 (II) <5 (IV)
- Dose (MAD)
Tablet/Capsule - Food Effect - Portal Vein
- Rat intestine
permeability

Salts/ Nano/HMG/ SD Solutions/ SD / Emulsions

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 Scenario 2
• Most of the NCE’s follow Scenario 2 because of poor
solubility

• Scenario 3: very little or no improvement by formulations

• Following techniques can help convert Scenario 2 to 1
• Pro-drug approach
• Particle size reduction
• Salt synthesis
• Complexation
• Physical form change (co-evaporation/melting)
• Lipid-based drug delivery

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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

24 Garad, American Pharmaceutical Review, Feb 2004

 Salt Solubility
Name of the API Solubility mg/ml
( water)
Codeine 8.3
– Sulfate 33
– Phosphate
445
Atropine 1.1
–Sulfate 2600
Pseudoephedrine 0.02
– Hydrochloride 2000
Cetrizine 0.03
– Dihydrochloride 300

25 Garad, American Pharmaceutical Review, Feb 2004

 Particle Size Reduction
• Particle size reduction increases the bioavailability of
poorly soluble drugs by increasing surface area, thereby
increasing the dissolution rate
• Graph represents the increase in the dissolution rate
and bioavailability

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

26 Garad, American Pharmaceutical Review, Feb 2004

 Complexation

•Cyclodextrins are most commonly used as

complexing agent to improve solubility
▪ HP--CD (hydroxypropyl -cyclodextrin)
▪ SBE--CD (sulfobutyl ether -cyclodextrin)

• Examples of drugs which form a complex with

cyclodextrins:
▪ Itraconazole (Sporonax®) -Oral
▪ Chlordiazepoxide (Trinxillium®) -Oral
▪ Voriconazole (Vfend®) -Parenteral
▪ Ziprasidone mesylate (Geodon®) -Oral/Parenteral

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 Physical Form Change

Methods to prepare solid dispersions:

• Fusion (melting/hot melt extrusion)

• Co-precipitation
• Spray drying
• Lyophilization
• Milling

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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

• Use same formulation principle across all pre-clinical studies

• Either suspension/solutions of a free form or a salt form

• Select a final physical form for GLP tox and clinical studies to
avoid variable exposure due to physical form change

• Select the right formulation principle for the clinical studies

which helps to avoid bridging BA/BE studies as much as
possible, faster to market (patients)

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 Acknowledgement

▪ Solubility/Permeability working group at Novartis

▪ GDC/PKS: Suzanne Skolnik, Bing Wang, Muneto Mogi, Bernard Faller,
Joerg Berghausen, Barnard Faller, Olivier Kretz and Karin Briner
▪ CPP-TRD: Stephanie Dodd, Chris Towler, Manuel Sanchez-Felix, Paulo
Santos, Xuan Dai, Andrea Decker, and Kat Vulic

▪ Chemical and Pharmaceutical Profiling group

▪ Cambridge, Basel and China
▪ Technical R and D colleagues (PHAD, ARD and
CHAD)
▪ NIBR colleagues

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 Thank you

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