Selecting the Right Enabling Technology for Poorly Soluble Compounds

Irena McGuffyManager, R&D Formulations

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NCE Outlook For The Future –Lots of Potential for Poor Bioavailability

BCS Class I

~5%

BCS Class III

~5%

BCS Class II

~70%

BCS Class IV

~20%

Solubility

Low

High

High

LowPermeability

New Chemical Entities

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Optiform™ Technologies

• High-throughput platform for salt, crystal-form, and cocrystal screening

• Developed and refined over the past ten years within GlaxoSmithKline

• Applied to more than 500 compounds, spanning from early stage lead compounds through launched products

• Team of scientists with diverse backgrounds

— Analytical Chemistry

— Synthetic Chemistry

— Physical Chemistry

— Materials Science

— Crystal Engineering

— Pharmaceutical Sciences

— Automation and Software Development

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Hot Melt Extrusion (HME) - Introduction

HME is used in Pharma to develop Solid Dispersion dosage forms that enhance bioavailability of poorly soluble drugs.

HME is a fast-growing technology, due to recent commercialization of Solid Dispersion HME products

Reasons for HME success:

• Well-understood technology outside of Pharma

• Continuous processing allows good process control & scalability

• Solvent-free (unlike competing Solid Dispersion approaches)

• Extrudate is versatile in its end use, including potential incorporation in controlled release delivery formulations

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4

Solid Dispersion Products – Melt Approach Common

Product Company Matrix Excipient

Afeditab (nifedipine) Elan Poloxamer/PVP

HPMC

Cesamet (nabilone) Valeant PVP

Rezulin (troglitazone)* Pfizer PVP

PEG

Gris-Peg (griseofulvin) Pedinol PEG

Various

HPMC

Various

PEG-glyceride

PVP/PVA

HPMC

HPMC

Certican (everolimus) Novartis

Fenoglide (fenofibrate) LifeCycle Ph.

Ibuprofen Soliqs

Intelence (etravirine) Tibotec

Isoptin SRE-240 (verapamil) Soliqs

Norvir (ritonavir) Abbott

Kaletra (lopinavir/ritonavir) Abbott-Soliqs

LCP-Tacro (tacrolimus) LifeCycle Ph.

Sporanox (itraconazole) Janssen

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Hot Melt Extrusion – The Basics

• Twin-screw extruders with varying screw design / rotation achieve intimate mixing of drug and excipient

• Shear forces and heat drive melting of excipient, dissolution of API

• Cooled mixture is a Solid Dispersion preferably containing amorphous (non-crystalline) drug

• Process opportunities— Liquid drugs

— Potent drugs— Labile drugs (solvent or moisture sensitive)— Generation of “emulsifying systems”

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66.8.11 6

OSDrC® OPTIDOSETM Technology: Flexibility to Improve Your Treatments

• OSDrC® OPTIDOSETM Technology

— The broadest range: controlled release, combination products (tablet-within-a-tablet and pellets-within-a-tablet) and direct compression orally disintegrating tablets

— Optimized dosing, therapeutic, and plasma release profiles to meet patient needs in a high quality, one step manufacturing process.

• Broad Range of Tablet Options:

— Pulsatile Release Tablets

— Bi-Layer Tablets

— Combination Products (multiple API in single tablets)

— Dividable Tablets

— IR/ER Combination Tablets

— Direct Compression Orally Disintegrating Tablets (ODT)

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OSDrC® OPTIDOSETM makes it possible to control API release by altering the thickness of the outer coating.

Advantages over film-coated tablets include:

OSDrC® Tablets

• Simplified manufacturingprocess

• No solvents required

• Simplified process control

Controlled Release Based on Thickness of Outer Coating

24July 2011 OSDrC® OPTIDOSETM Technology

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• With conventional technology, enteric tablets could not be divided

OSDrC® Tablets

Target drug release profiles can be maintained, whether thetablets are divided or not

Dividable Core Tablets

26July 2011 OSDrC® OPTIDOSETM Technology

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OSDrC® TabletsReplacing Capsules with Tablets

Capsule Issues

• Cannot be divided

• Difficult to swallow

• Difficult to prevent tampering

July 2011 30OSDrC® OPTIDOSETM Technology

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• Tests have obtained same release characteristics ascapsules

Possible to encase pellets as a replacement for capsules

OSDrC® TabletsReplacing Capsules with Tablets

31July 2011 OSDrC® OPTIDOSETM Technology

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OSDrC® Tablets

Accurate placement of multiple cores makes it possible to manufacture pulsatile release formulations

Pulsatile Release Tablets

33July 2011 OSDrC® OPTIDOSETM Technology

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Nanoparticulate Oral Drug Delivery

Neat API Size-Reduced High-Energy Solid

Liquid API

Disintegrants, Surfactants

Micronized Amorphous,

Solid Dispersion

Softgels, SEDDS, liq.fill caps, etc.

Stability

DissolutionNanosized

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Spraying

• 4 commercial products: Tricor®, Triglide®, Emend®, Rapamune®

• Processed into variety of dosage forms (capsules, tablets) using established technologies

• High excipient:API ratio

• Redispersant excipients required

Freeze Drying

• No commercial products

• Requires specialized equipment

• Low excipient:API ratio

• Highly porous structure favorable for redispersing nano-particles

Nanoparticulate Oral Drug Delivery

146.8.11 14

Patient Preferred Zydis® Fast-Dissolve Helps Improve Therapeutic Profile and Patient Adherence

• Zydis® Fast-Dissolve is a unique, freeze-dried oral solid dosage:

— Disperses instantly in the mouth - usually in about 3 seconds

— Taken without water, meeting the needs of patients who cannot or will not swallow oral medications

• Zydis® Fast-Dissolve provides valuable product differentiation for Branded OTC and Rx products: — Fastest dispersion dosage form on the market today combines with an

elegant and smooth mouth-feel to create product and brand loyalty for OTC products

— Immediate dispersion of API in the oral cavity supports buccal delivery for an improved therapeutic profile

— Shown to help drive market share and brand growth gains— Improved compliance in multiple therapeutic areas

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Zydis® Nanoparticulate Formulation Development Goals

1. Nanoparticle stabilization during wet milling AND freeze drying

2. Use of low concentrations of stabilizers with little to no adverse taste

3. Rapid dispersion of nanoparticle solid dosage form

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NAPROXEN Neat API Post milling 24hr hold

Gelatin #1

Gelatin #2

22 micron 164 nm 166 nm

22 micron 177 nm 175 nm

d50 Particle Size measured using Malvern Mastersizer

INDOMETHACIN Neat API Post milling 24hr hold

Gelatin #1

Gelatin #2

37 micron 151 nm 145 nm

37 micron 159 nm 150 nm

Wet Milling with Gelatin as stabilizer

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API concentration 15%w/w

Gelatin concentration 5%w/w

Optional excipients e.g. bulking agent, sweetener, flavor

Dose into blister Freeze

Freeze Dry

pores

ice matrix

Nano-susp.

Nanostabilization in Freeze-Dried Process

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NAPROXEN Neat API Post milling Freeze-Dried

Gelatin #1

Gelatin #2

22 micron 164 nm 167 nm

22 micron 177 nm 21 micron

INDOMETHACIN Neat API Post milling Freeze-Dried

Gelatin #1

Gelatin #2

37 micron 151 nm 142 nm

37 micron 159 nm 30 micron

In-process Particle Size During Milling & Freeze Drying

Similar results for phenacetin and fenofibrate

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0

100

200

300

400

500

600

0 1 2 3 6Time (months)

Part

icle

Siz

e (n

m)

D50 - 25°C D50 - 40°C/75% RHD90 - 25°C D90 - 40°C/75% RH

Nanoparticle Stability in Freeze-Dried Tablets

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Properties of Zydis® NanoparticulateFormulation

Drug Disintegration Time

Naproxen 2 seconds

8 seconds

2 seconds

Fenofibrate (48mg) 4 seconds

5 seconds

Indomethacin

Phenacetin

Fenofibrate (148mg)

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Fenofibrate 48 mg Dissolution in 0.4%SLS - With Pre-filter

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25 30Time (minutes)

Per

cent

Rel

ease

Tricor ZydisNano

In-Vitro Dissolution of Zydis® NanoparticulateFormulation

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Animals – 10Kg Beagle Dogs (n=6), fasted.

Dose – 48mg fenofibrate (human dose)

Test Articles:#1 Nanoparticulate API in tablet

#2 Micron-sized API In tablet

0500

10001500

200025003000

35004000

45005000

0 2 4 6 8

Time (hours)

Plas

ma

conc

(ng/

mL) Zydis-Nano

Zydis As-is

In-Vivo PK of Zydis® Nanoparticulate Formulation

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Softgel Technology

Good NCE Candidates• Poorly water soluble• Poorly permeable• Highly potent, low dose• Oxygen sensitive• Light sensitive• Liquid or low melting pointAdvantages of the Dosage Form• Proven technology• Robust dosage form (no brittleness or leaking)

• Appropriate for low to high viscosity formulations (up to ~15,000 cps)• Fill formulation temperatures up to ~40°C for gelatin-based softgels

and up to ~70°C for Vegicaps® Capsules• Minimal to no scale-up issues

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Colors,

Opacifiers,

Flavors

Composition of a Softgel Capsule

Lipophilic,Hydrophilic,

or Mixed Vehicle

Solution, Suspensionor highly viscous formula of Drug

GELATIN +

Plasticizerwater

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Polyethylene glycolsurfactants

Hydrophilic”water-loving"

Partial glyceridesSurfactantsFatty acids

Microemulsion"self-emulsifing systems"

OilsFatty acidsGlycerides

Partial glycerides

Lipophilic"oil-loving"

Solution, suspensionor semi-solid

The fill material can be a…

Softgel Fills

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Solubility Screening

• Solubility prediction

• Visual and quantitative solubility determination

• Use of robotics

Identification of SMEDDS/SNEDDS regions

• Pseudo-Ternary Phase Diagrams

SMEDDS Droplet Size Assessment

• Photon Correlation Spectroscopy @37°C

Digestibility

• In vitro lipolysis

Key Elements of a Softgel Formulation Development Program

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Dispersion Properties • 0.01N HCl• Neutral buffered solution

Challenge Studies • Temperature

— Cycling studies— Holding studies

• Water • Plasticizer• Characterization of precipitate

Compatibility Studies

• API:excipient mixes @ 40°C/75%RH, 50°C/Dry, 60°C/Dry

• Fill stability

Key Elements of a Fill Formulation Development Program

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Formulation of Lipid-based Fills…The Choice of Excipients Can Impact Performance

Nature of Lipid

• Lipids that can dissolve the drug

• Lipids (or their digestion products) have good solvent capacity to maintain drug solubility through the G.I.T.

Type of Surfactant

• Surfactants that can dissolve the drug

• Surfactants that maximize dispersion of the lipid phase

• Surfactants that can impact digestion negatively or positively

• Susceptibility of surfactant to digestion and its impact on solubilization capacity of formulations

Relative Proportion of Lipid to Surfactant

• Solubilization capacity of formulations before and after digestion

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Addressing Formulation Challenges Beyond Solubility Improvement

• Lipid-based formulations affect membrane permeability

— Passive transport through enterocytes

— Passive transport around enterocytes (tight junctions)

• Lipid-based formulations interact with intestinal-based drug transporter and metabolic processes

— P-gp efflux

— CYP3A4 metabolism

• Lipid-based formulations influence absorption pathways

— Lymphatic transport

Softgels for Permeation Enhancement

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Plasma Concentration Versus Time Curves for 3 Formulations of Cinnarizine in the Dog (n=6)

Time (hours)

Plas

ma

Cin

nariz

ine

(ng/

ml) 150

00 2 4 6 8 10 12 14 16 18

100

50

20 22 24

Formulations:Softgel: LCT Lipolysing AUC(0-24hr) 665 ng.h/mlSoftgel: Non-Lipolysing AUC(0-24hr) 451 ng.h/mlTablet: AUC(0-24hr) 406 ng.h/ml

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LBDS for Solubility and Permeability EnhancementExample: Amprenavir With Vitamin E TPGS

Ref: L.Yu, et al., Pharm. Res., 16: 1812 (1999)

Amprenavir absorption flux as a function of Vitamin E-TPGS concentration.

Amprenavir solubility as a function of Vitamin E-TPGS concentration in pH 7 phosphate buffer, ionic strength 0.15M.

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Softgels for Altering the Route of Absorption

Lipid in SMEDDSLymphatic transport

Plasma availability

Total bioavailability

% of total bioavailability due

to lymphatic transport

MLM 17.9±1.3 56.9±5.5 74.9±6.0 24.4±1.9

LML 27.4±1.3 37.2±6.2 64.6±7.1 43.3±3.1

Halofantrine bioavailability (mean % dose ± s.e., n=4-5) in lymph-cannulated canines after oral administration of SMEDDS formulation containing structured triglycerides

SMEDDS Formulation (%w/w)Halofantrine 5%Triglyceride 29%Maisine-35-1 29%Cremophor EL 20%Ethanol 7%

TriglycerideMLM (C8:0-C18:2-C8:0)LML (C18:2-C8:0-C18:2)

Ref: R.Holm, et al., Eur. J. Pharm. Sci., 20: 91 (2003)

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• Post-gastric (targeted) drug delivery

• Protection of acid-labile drugs from gastric fluids

• Reduced local gastric side effects

• Potential for enhanced drug absorption— Rapid release of fill contents at targeted site of delivery following

dissolution of film coat— High local concentrations of API and permeation enhancers

Film-coated Softgels for Targeted Delivery

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Film-coated Softgels for Targeted Delivery

USP <701>

T=0 T=3 mon T=6 mon T=9 mon T=12 mon

SGF, n=6

No evidence of disintegration

No evidence of disintegration

No evidence of disintegration

No evidence of disintegration

No evidence of disintegration

SIF, n=6

26 – 28 22 – 26 25 – 30 25 – 29 23 – 25

In-vitro Disintegration(min)

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Softgels for Targeted Delivery of Large Molecules

BCS Class III NCE

– MW > 2,500 Da

– Over 10 ionic groups

– Poorly permeable

– Freely soluble

Drug is not subject to enzymatic degradation

SC injection show complete absorption

36Catalent Pharma Solutions data

EC softgel passing the pylorus to deliver proper absorption (78 % bioavailability)

time

Softgels for Targeted Delivery of Large Molecules

Vegicaps® Capsules –The Only True Non-gelatin Softgel Option

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Non-gelatin based shell using plant-derived polysaccharides

Supports encapsulation of liquid fills, including lipid-based and hydrophilic formulations

Vegicaps® capsules expand the capabilities of softgel technology by enabling:

Vegicaps® Technology: Expands the Range of Fill Formulations Encapsulated into Softgels

• High melting point and sealing temperature of semi-solid fills for modified release (up to 70°C), improved stability, and conversion from hard-shell capsules

• Fill formulations prone to cross-linking hard or soft gelatin-derived capsules

• Compatibility with high pH fill formulations, and a broader range of fill excipients

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Differences in the properties of the Vegicaps® shell expands the capabilities of softgel technology

• Self-emulsifying formulations can be formulated with higher concentrations of “low” m.w. ingredients

• Co-solvents (propylene glycol)

• Solubilizers

• Penetration enhancers (Na caprate, lauric acid and its salts)

• Example: Octanoic acid (caprylic acid, C8)

Vegicaps® Technology: Expands the Range of Fill Formulations Encapsulated into Softgels

Softgels filled with ‘neat’caprylic acid

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