Enteric Capsule Technologies to Help Fast-Track Pharmaceutical Drug Development

Eduardo Jule, PhD

Director Pharmaceutical Business Development

Our Global Footprint

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Capsugel Technology Platforms

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Pro

duct

Range

Liquid-filled

Hard Capsules

Soft Gelatin

CapsulesSachetHard Capsules

Powder / Multi-particulate

Filled CapsulesOsmotic, Matrix, Orally

Dissolving Tablets

Key

Serv

ices API Characterization /

Pre-formulation Studies

API-in-Capsule / Micro-dosing

Evaluations

Commercial

Manufacturing

Technology Selection

Models / Methodologies

Clinical Trial Material (CTM)

Manufacture

CTM Primary / Secondary

Packaging & Distribution

Drug Product

Intermediate

Specialized Handling

(highly potent API, controlled

substances, cold chain,

hormones, probiotics, other)

Bioavailability

EnhancementTargeted Release

Capsule Technologies /

Encapsulation

Specialized

Applications

Salt Screening / Selection

Micronization

Spray-Dried Dispersions

Hot-Melt Extrusion

Lipid-Based Formulations

Liquid / Solvent-Based Formulations

Nanotechnologies

• Nano-milling

• Nano-crystals

Enteric / Delayed Release Capsule

Technologies

Multi-particulate Technologies

• Fluid-bed layering

• Extrusion/Spheronization

• Lipid Multiparticulates (LMP)

• Mini-tabs

Fixed Dose Combinations

• Bi/Tri Layer Matrix

• Capsule-in-Capsule

• Multiparticulates

Extended / Controlled Release

• Osmotic / zero order release

• Matrix and MP / 1st order release

Colonic Delivery / Liquid Fill Tech

Gelatin Capsules (Coni-Snap)

Specialty Polymer Capsules

• Vcaps Plus (HPMC)

• PlantCaps and OceanCaps

Enteric Capsules

• DRcaps

• Vcaps Enteric

• enTRinsic DDT

DPI Capsules (inhalation)

Sprinkle Capsules

Encapsulation Technologies

Specialized Clinical Trial Capsules

Taste-Masking Approaches

Pediatric Applications

• MP formulations

• Sprinkle Capsules

Biotherapeutics

• Bio-processing

• Bio-formulations

Inhalation

• SD-based formulations

• Particle Engineering

• DPI capsules

Abuse Deterrent Forms

Enteric Delivery and Limitations of Current Approaches

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Why enteric

properties?

APIs Stomach Intestine

Sensitivity to Acid

Sensitivity to Enzymes

Local Toxicity

Fast Intestinal Absorption

Small Molecules

Biomolecules (peptides, proteins)

Live organisms (bacteria, virus)

Capsugel

Research

Enteric protection / upper gastro-intestinal drug delivery targeting

has historically been achieved primarily through functional coating.

Why the need for enteric protection?

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• Though enteric coating is routine and well understood, it still poses a few

challenges:

Functional coating is a complex process, adding 12-30% weight

– up to a 7-step preparation for enteric coating

There are a number of key additional considerations:

– substrate (tablet) condition

• too soft = erosion

• too hard = poor adhesion

– proper balance in coat spray application

– coating distribution and drying

– sufficient protection of edges

Coating defect potentials:

Capping Chipping Picking Logo Bridging

Considerations for applying enteric coating

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Reliance on functional coating may slow down product development

Can we provide faster screening of NCE’s with capsule technology?

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Integrated enteric functionality in dosage form enables rapid development

of prototypes for formulation screening

Permits rapid testing of in vivo performance

Removes need for process development and scale-up of enteric coat

Minimizes scope of overall process development and validation program

Obviates dependency between enteric functionality and coating process

parameters and variability

Minimizes risk of enteric performance changes on scale-up and stability

“Each day a drug is delayed from market, sponsors lose up to $8 million”

Beasely, "Recruiting". 2008

9 months potential savings through phase I and up to 14 months potential

savings through phase III by eliminating enteric coating

H2 Pharma Study 2015

Benefits throughout the development

Intrinsically enteric capsule technologies

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A history of capsule development

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Gelatin

ConisnapVcaps Plus DRcaps Enteric HPMC

Composition Gelatin HPMCHPMC + gelling

agentEnteric HPMC

Dissolution pH

dependanceNo No Yes Yes

Immediate Release Immediate Release

Delayed release

(1-hour resistance

in acid medium)

Enteric release

(USP, EP

compliant)

Water content 13-16%<9%

Can be customized

<9%

Can be customized2-7%

Oxygen

permeability+ ++ ++ ++

Compatible with

liquid or semi-

solid formulation

Yes Yes Yes Yes

Potential cross-

linking issuesYes No No No

Target segment Pharma, H&N Pharma, H&N H&N Pharma

Vcaps® Enteric capsule

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Product description

Two-piece enteric hard capsule

Manufactured with pharmaceutical grade of cellulosic

enteric derivatives

Immediate and full disintegration at pH 6.8

Sizes: Size #0 and #00 off-white available

Regulatory Status

Contains fully approved polymers (HPMCAS, HPMC)

Complies with relevant European, Japanese and US

Pharmacopeia monographs

Water content: 2-7%

Storage recommendations: 15 – 25°C & 35 – 65% RH, in

aluminium tight packaging

Vcaps® Enteric: disintegration test performance

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Disintegration testing according to

USP method

Integrity of the Vcaps® Enteric confirmed

after 2 hours in gastric conditions pH 1.2

Capsules were not sealed (nor banded) to

obtain such performance

Vcaps® Enteric capsules

following 2-hours in gastric pH 1.2

Vcaps® Enteric: in vitro dissolution test performance

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0

10

20

30

40

50

60

70

80

90

100

0 30 60 90 120 150 180 210 240 270 300

% R

efe

ren

ce

AP

I d

issolv

ed

Time (minutes)

T = 0

3 months 40°C/75%RHopen

3 months 40°C/75%RHclosed

Acetaminophen API

dissolution test data

Fully compliant

and robust enteric

release properties

Method: spiral sinkers used for capsules (float w/o sinkers), 2-stage test with 2-

hours gastric (750mL, HCl 0,1N) pH 1,2 then medium added at 2 hours to final:

1000mL phosphate buffer USP, pH 6.8; Acetaminophen UV detection l = 300nm;

n=6.

In-vitro performance study: reducing gastric side effects

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Dimethyl Fumarate (TECFIDERA®,

Biogen)

Treatment of adult patients with

relapsing remitting multiple sclerosis

Gelatin capsule containing enterically

coated micro-tablets (anionic

copolymers based on methacrylic

acid and methyl methacrylate)

DMF associated with flushing and

stomach aches

Formulation has been designed to

allow to bypass the stomach and

release DMF in the intestine

DMF is rapidly metabolized at the

level of the gastrointestinal tract to its

primary, active metabolite

Test conditions (USP): Conditions: n=6 ; spiral sinkers

2-stage test with 2-hours gastric (750mL, HCl, 0,1N)

then medium added at 2 hours to final: 1000mL 0.20M

tribasic sodium phosphate , pH 6.8 , 100 rpm, HPLC-

UV

• DMF 240mg directly filled in Vcaps Enteric

• Grinded micro-tablets filled in Vcaps Enteric

Vcaps® Enteric as potential

alternative to enteric coated

micro-tablets in capsule

In vitro performance study: delaying release to maximize absorption

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Budesonide

(ENTOCORT®, AstraZeneca)

Corticosteroids used to treat the

inflammation of the small bowel

and the first part of the large

bowel, known as Crohn’s disease

Gelatin capsule containing

enterically coated saccharose

based microgranules (anionic

copolymers based on methacrylic

acid and methyl methacrylate)

Release in the ileum and

ascending colon where the API is

more favorably absorbedTest Budesonide: Conditions: 9µgA/mL (9mg into 1L); n=6 ;

spiral sinkers used for capsules (float w/o sinkers), 2-stage

test with 2 hours gastric (500mL, 100mM HCl) then medium

added at 2 hours to final: 1000mL 95mM phosphate buffer

w/0.5% Kolliphor HS15, pH 6.8; 100 rpm, Test Ref: IRD384-

068 (HPLC-UV)

Budesonide pure API directly filled in Vcaps Enteric

Vcaps® Enteric as potential

alternative to enteric coated

microgranules in capsule

In vitro performance study: allowing release on site of action

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Bisacodyl

(DULCOLAX®, Boehringer)

Laxative used for relief of

constipation (OTC)

Enterically coated tablet

(anionic copolymers based on

methacrylic acid and methyl

methacrylate)

Local action stimulating colonic

motility

Test Bisacodyl: Conditions: 5µgA/mL (5mg into 1L); n=6 ; spiral

sinkers used for capsules (float w/o sinkers), 2-stage test with 2-

hours gastric (500mL, 100mM HCl) then medium added at 2

hours to final: 1000mL 95mM phosphate buffer w/0.5% SLS, pH

6.8; 100 rpm, Test Ref: 092 (HPLC-UV)

Amorphous bisacodyl pure API directly filled in Vcaps Enteric

Vcaps® Enteric as simple

alternative to enteric coated

tablet

In vivo behavior of Vcaps® Enteric

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Study synopsis (Center of Drug Absorption

& Transport, University of Greifswald, DE)

MR imaging study with 8 healthy volunteers

in fasted state

Vcaps Enteric capsules formulated with dry

pineapple (opaque to MRI, used as tracer)

Primary evaluation : Disintegration time and

location

In-vivo behavior of Vcaps®Enteric

Demonstration of gastro-resistance

Disintegration occurs in ileum

No evidence for influence of gastric residence

time on intestinal disintegration time

Variability of time to disintegration similar to

coated enteric tablet

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enTRinsic™ Drug Delivery Technology

Product description

Two-piece enteric hard capsule

Manufactured with 100% pharmaceutical grade of cellulosic

enteric derivatives

Size #0 & #3 standard (additional sizes upon request)

White opaque standard for capsules (specific colors upon request)

Regulatory Status

Contains fully approved enteric polymers

Complies with relevant European, Japanese and US

Pharmacopeia monographs

Water content: 2-7%

Stability: After storage in HDPE bottles and blisters no change in

dimensions and enteric properties:

@ 40°C/75%RH for 6 months

@ 30°C/65%RH 12 months

@ 5°C 9 months

@ 20°C 9months

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enTRinsic™ enteric protection using highly acid sensitive drug

Nexium® (gelatin capsules with enteric coated pellets)

Rationale

Esomeprazole Magnesium Trihydrate selected as an acid labile model compound which can act as a model for peptides, nucleotides, vaccines, live biotherapeutics for which gastric stability is limited (acid and enzymes)

Very fast degradation in acid medium with a solution becoming yellow/brown

OBSERVATIONS

1. Acid stage

• Quick dissolution of the gelatin capsules

• No dissolution of the pellets

• % EMT dissolved after 120 min (mean) = 0%

2. Buffer stage

• Complete dissolution of pellets

• % EMT dissolved after 30 min (mean) = 94%

No unit more than 10%

Degradation

of EMT

Acid stage HCl 0.1N No unit less

than 80%

(Q+5%)

pH 6.8

Buffer stage

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enTRinsic™ enteric protection using highly acid sensitive drug

enTRinsic™ filled with EMT layered uncoated pellets

In acid stage, the amount of Esomeprazole released is below the limit of quantification of the analytical

method.

enTRinsic™ provides an effective protection of Esomeprazole content from acid degradation and

therefore meets requirements of USP monograph for Esomeprazole delayed-release capsules.

0

20

40

60

80

100

0 50 100 150

% d

isso

lved

Sampling time (min)

Average dissolution profile of enTRinsicTM

(N = 6 capsules, with SD interval)

pH 6.8

Buffer stage

Specification: No unit

more than 10%

No unit less than

80% (Q+5%)

Acid stage HCl 0.1N

Rationale

Esomeprazole Magnesium Trihydrate selected as an acid labile model compound which can act as a model for peptides, nucleotides, vaccines, live biotherapeutics for which gastric stability is limited (acid and enzymes)

Very fast degradation in acid medium with a solution becoming yellow/brown

enTRinsic™ Technology Human Biostudy – Protocol

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• Randomized, open-label, single dose and crossover pharmacokinetic and gamma

pharmacoscintigraphy study conducted using healthy volunteers under fasted state

• Radiolabeled pellets added to both enTRinsic™ capsules and Nexium RLD capsules

in order to detect location of capsule opening in the GI tract

• Study treatments

• Scintigraphy imaging (SI)

• Anterior & posterior images acquired at dosing + regular time points

• Pharmacokinetic study (PK)

• Blood sampling at pre-dose + regular time points post-dose

enTRinsic™One radiolabelled enteric capsule filled with layered

uncoated pellets containing 40mg EMT given in fasted state

(i.e. an overnight fast of at least 10 h)

RLD

Nexium®

One radiolabelled Nexium® gelatin capsule containing 40mg

enteric-coated pellets of EMT given in fasted state

(i.e. an overnight fast of at least 10 h)

NEXIUM and the color purple as applied to the capsule are registered trademarks of the AstraZeneca group of

companies

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Scintigraphy studies on enTRinsic™ capsule drug delivery technology

Scintigraphy images

Site of onset releaseenTRinsic™

(n = 12)

Esophagus 0

Stomach 0

Small intestine 11

Ileocaecal junction 1

No release and remain in

stomach after 12h0

No release and remain in

small intestine after 12h0

Anterior scintigraphy images confirmed that, in

fasted conditions, enTRinsic™ capsules

integrity in the stomach, with gastric

emptying occurring within 60 min and

followed by rapid opening of capsules and

pellets release in duodenum

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enTRinsic™ Immediate Release for intestinal delivery: Esomeprazole Pharmacokinetic profile

The high Esomeprazole plasma

concentration confirmed that the

drug was not degraded in stomach

and achieved intact its absorption

site in intestine

The fast enTRinsic™ capsule

opening and pellets release in

duodenum is also demonstrated by

the fast onset of Esomeprazole in

plasma, followed by a quick and

complete Esomeprazole absorption

Despite different dosage forms

(monolithic enTRinsic™ versus

Nexium® enteric coated pellets)

human PK profiles of enTRinsic™

and Nexium showed similar extent

of drug absorption and Tmax in

fasted state

Conclusions

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Selecting the appropriate enteric solution for your product

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Protecting the

stomach from

aggressive APIs

Delaying the release

to achieve maximum

absorptionProtecting a sensitive

molecule from acidic

environment

Vcaps® Enteric

EP/USP compliant

enteric capsule

Easy to implement solution for

gastric-irritating actives or

delayed release

Ready to use capsule

enTRinsic™ Drug Delivery

EP/USP compliant

Full gastro protection

and enteric release

Enabling technology for oral

delivery of heat and acid

sensitive molecules

DDT available under license

Addressing needs of small molecules and biopharmaceuticals

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Rapid Advancement Tool for NCEs & Biopharmaceuticals

Easy to implement solution in early stages of development

Eliminate coating process complexity

Potential nine months cumulative savings in development

Product Differentiation for Generic / 505b2 / CHC

Efficient solution for tailored delayed or modified release profile (alone or in

combination with multiparticulate approach)

Powerful brand differentiation for CHC

Potential IP circumventing tool

Manufacturing efficiency through reduced process complexity

QbD approach

Compatible with high speed filling machine and continuous manufacturing

Six Sigma Quality

Competitive Advantages

Thank You!

Questions?

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