Drug Delivery and Formulation

Conference, Boston

Understanding Developability Assessment of Small Molecules

Sudhakar Garad, Ph.D.

Novartis Cambridge, MA

Sudhakar.Garad@Novartis.com

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

2

Developability: Design a Molecule with Delivery in Mind

3

OralTopical/Transdermal

InhalationBrain Targeting

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Ophthalmic

Developability “Broad Terminology”

• Technical

– Physchem properties

– Synthesis

– Formulations

– Device

• DMPK

– Permeability

– Transporter

– Enzyme degradation

– PK/PD

• Commercial opportunities

– Block buster (> $1B per year)

– Orphan indication

– Targeted Product Profile

Compounds/Scaffolds

In-Vivo Testing- PK

In-Vivo/In-Vitro

Correlation (IVIVC)

In-Vitro Data

Generation- ADME

Developable Molecule

Risks for Absorption

and PD

Mitigation or

Termination

4

Biopharmaceutical Classification

SystemCurrent Industry Trends

⚫ BCS I and III: 10% - Soluble

⚫ BCS II: 70% - Insoluble

⚫ BCS IV: 20% - Insoluble

and poorly permeable

Class I

5-10%

Class II

60-70%

Class III

5-10%

Class IV

10-20%

Biopharmaceutical Classification System

High Solubility Low Solubility

Hig

h

Pe

rme

ab

ility

Low

Pe

rme

ab

ility

5

Marketed Drug Molecules According to the BCS Classification System. Available online: http://www. capsugel.com/knowledge-

center/webinars/archived-webinars/paginate/P15

Traditional Drug Development Process

6

Time: 9-13Years

Cost of Development: High

Developability

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

Funding can be very tight

Lead Opt. Phase I Phase IIa Phase IIb MarketPhase IIICD

(1)

Evaluation of first-in-

human (FIH)

formulation

Development

CS

(1-4)

Drug Development Process

9-13 years

Research

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

Class II--------Require technology, significant time

Class III and IV-------- Potent

7

Phase IIa Phase IIb Phase IVPhase IIICD

Development

CS

Drug Development Process6-10 years

Research

Why Development associates are involved in Research

⚫ Majority of NCE are BCS Class II, and IV

⚫ Non-developable candidate selection

⚫ 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

Lead Opt. Phase I

Developability

Assessment

8

Pre-clinical in-vitro data

▪ Solubility (pH 4.5 and 6.8)

▪ Permeability

▪PAMPA (Parallel Artificial Membrane Permeability Assay)

▪Caco-2

▪ Microsomal stability

▪ Drug-drug interactions

▪ hERG assay (cardiac safety)

▪ Ames test (carcinogenicity)

Compounds/Scaffolds

~ 500

~5

9

Roadmap to Address Biopharmaceutic Liabilities in Discovery/Optimization

• In-vitro permeability

• In-vitro FaSSIF solubility

• Dose

Developability Classification

System

• Target > 0.1 mg/mL FaSSIFSolvent-Shift

Solubility

• GastroPlus modeling in pre-clinical species to understand absorption limitations

• Confidence formulation principle will achieve sufficient exposure in toxicology studies

Absorption Modeling

Poor PK cannot always be fixed with formulation!

10

11

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)

12

Identify and prioritize compounds that can maintain good

supersaturation solubility in FaSSIF over time

Step 2: Evaluate Maintenance of Supersaturation in FaSSIF

Maintain high supersaturation

Step 2: Evaluate Maintenance of Supersaturation in FaSSIF

13

• 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)

Compound X Compound Y

Discovery

Pre-clinical

Clinical

Step 3: Absorption Modelling

Accurate estimates of the gap we face:

What is limiting exposure?

• In-silico tools

• Predict

physicochemical/

pharmacokinetic

properties

• Identify metabolism risks

• Determine absorption

limitations

• Tox formulation selection

• Suitable formulation

principle selection

• FIH Prediction

• Dose-exposure relationship

• Formulation bridging

• IVIVC

• Special populations, food

effect

14

GastroPlus Influence on Candidate Selection

2. Understand critical parameters for

absorption (next slide)• Can formulation improve exposure?

3. Risk Management

1. Validate preclinical models with PK

data, predict human %Fa

Low Risk

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

High Risk

Formulation cannot improve exposure,

terminate compound.• e.g. high clearance or poor solubility and/or low

supersaturation

15

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

16

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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• 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

Pre-formulation Studies

18

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)

19

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

20

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

21

Formulation Scenario 1 Scenario 2 Scenario 3 Scenario 4

Solution High High High Low

Suspension High Low Medium Low

Conclusions Easy to develop

Exposure limited by solubility

Exposure limited by dissolution rate /solubility

Permeability, efflux, metabolism

% NCE/pBCS 5 (I/III) 90 (II) <5 (IV)

Solubility vs. Dissolution ApproachTechnology Selection GLP Tox and Clinical Formulation

Tablet/Capsule - Portal Vein

- Rat intestine

permeability

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

- Dose (MAD)

- Food Effect

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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

23

Pro-drug Approach

Name of the API Solubility

mg/ml

Clindamycin

Clindamycin-2-PO4

0.2

150

Chloramphenicol

Succinate sodium

2.5

500

Metronidazole

N,N-dimethylglycinate

10

200

Phenytoin

Glycerides of SA

0.03

2.26

Garad, American Pharmaceutical Review, Feb 2004 24

Salt Solubility

Name of the API Solubility mg/ml

( water)

Codeine

– Sulfate

– Phosphate

8.3

33

445

Atropine

–Sulfate

1.1

2600

Pseudoephedrine

– Hydrochloride

0.02

2000

Cetrizine

– Dihydrochloride

0.03

300

Garad, American Pharmaceutical Review, Feb 2004 25

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

Dissolution Rate of a Poorly Soluble Drug

0

20

40

60

80

100

120

0 15 30 45 60 75 90 105 120 135

Time in Minutes

Me

an

Pe

rce

nt

Dis

so

lve

d

0.1µ

0.2µ

0.5µ

1.0µ

5.0µ

25µ

Mean Plasma Concentration Profile For Reduced

Particle Size Formulations

0

1

2

3

4

5

0 4 8 12 16 20 24

Time in Hours

Me

an

Pla

sm

a

Co

nce

ntr

ati

on

(m

cg

/mL

)

Formulation A (0.1µ)

Formulation B (0.5µ)

Formulation C (25µ)

Garad, American Pharmaceutical Review, Feb 2004 26

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

27

Methods to prepare solid dispersions:

• Fusion (melting/hot melt extrusion)

• Co-precipitation

• Spray drying

• Lyophilization

• Milling

Physical Form Change

28

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)

29

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

30

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)

31

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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