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sudhkar-garad

The document outlines the key aspects of drug delivery and formulation, focusing on the developability assessment of small molecules. It discusses the biopharmaceutical classification system, the drug development process, and various pre-clinical studies necessary for evaluating drug efficacy and safety. Emphasis is placed on the importance of selecting appropriate formulations and understanding the physicochemical properties of new chemical entities (NCEs) to ensure successful clinical outcomes.

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0% found this document useful (0 votes)
3 views33 pages

sudhkar-garad

The document outlines the key aspects of drug delivery and formulation, focusing on the developability assessment of small molecules. It discusses the biopharmaceutical classification system, the drug development process, and various pre-clinical studies necessary for evaluating drug efficacy and safety. Emphasis is placed on the importance of selecting appropriate formulations and understanding the physicochemical properties of new chemical entities (NCEs) to ensure successful clinical outcomes.

Uploaded by

pioneersgastro
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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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

2
Developability: Design a Molecule
with Delivery in Mind

Topical/Transdermal
Oral

Brain Targeting Ophthalmic Inhalation


3

Image Sources: PaylessImages, vupulepe, alexraths, olegdudko, woodoo007, sheeler, and iarada ©123RF.com
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

4
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

5
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

7
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

8
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)

9
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!

10
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)
11
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

12
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)

13
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

14
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

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)

17
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

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
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

22
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 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

27
Physical Form Change

Methods to prepare solid dispersions:

• Fusion (melting/hot melt extrusion)


• Co-precipitation
• Spray drying
• Lyophilization
• Milling

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

32
Thank you

33

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