Recent Advances in Oral Granules and Bi-Layer Tablet Technologies

Michael J. Valazza, R.Ph.

Vice President

Global Modified Release TechnologiesEmail: [email protected]

Recent Advances in Oral Granules and Bi-Layer Tablet Technologies, Solubility Enhancement Solutions, and Oral Disintegrating Tablet Applications

01 FEB 2012 1

Catalyst + Talent.

Our name combines these ideas.

From drug and biologic development

to delivery technologies and supply

solutions, we are the catalyst

for your success.

01 FEB 2012 2

As the #1 drug development and delivery partner in the world, we

provide leading development solutions, advanced delivery technologies

and innovative supply solutions to the global pharmaceutical, biotech

and consumer health industries.

Whether you are looking for a single, tailored solution or multiple

answers throughout your product’s lifecycle, we can improve the total

value of your treatments—from discovery to market and beyond.

Catalent. More products. Better treatments. Reliably supplied.™

01 FEB 2012 3

WHY CATALENT? Unrivaled experience, deepest expertise and a track record of market success on a global scale.

We are the #1 industry partner in the development andformulation of drugs, biologics and consumer healthproducts and a world leader in drug delivery technology

We partner with 90 of the top 100 pharmaceutical and 44 of the top 50 biotech companies, as well as hundreds of smaller innovators

We operate 20+ global sites serving 1,000+ customers in over 100+ countries

We support 40% of recent new U.S. drug approvals and are now working on 500+ new development programs

We use a multi-faceted approach to improve bioavailability,therapeutic profiles and patient adherence

We are fully dedicated to high standards of quality, cGMP leadership and LEAN operational excellence

* source: United Nations World Investment Report, 2011

Presentation Overview

1. OSDrC® OptiDoseTM Concept – an advancement in tab-in-tab

and bi-layer tablet technology

2. Developing Better Treatments for Poorly Soluble Compounds

with OptiMeltTM HME

3. Oral Disintegrating Tablets – case studies of Zydis fast-

dissolve applications.

4. Appendix

The OSDrC®

OPTIDOSETM

ConceptAn advancement in tab-in-tab and bi-layer tablet technology

One-Step Dry-CoatingOne-Step Dry-CoatingSingle-step manufacturing opens the door to a host of new formulations

About OSDrC® OPTIDOSETM

February 2012 OSDrC® OPTIDOSETM Technology 1

One-Step Dry-CoatingOne-Step Dry-CoatingSingle-step manufacturing opens the door to a host of new formulations

• An innovative first-of-its-kind manufacturing process

• Newly developed rotary punch tableting machine

• Research and technical collaboration between pharmaceutical

manufacturer and tableting machine manufacture

About OSDrC® OPTIDOSETM


OSDrC® OPTIDOSETM Tablet Press


OSDrC® Technology

Die

Upper center punch

Lower center punch

Upper outer punch

Lower outer punch

Cam

Cam

The Key to OSDrC® OPTIDOSETM Manufacturing Technology: Variable Double-Punch Configuration

3OSDrC® OPTIDOSETM TechnologyFebruary 2012

Process Flow for an OSDrC® OPTIDOSETM Tablet

• Three individual hoppers containing bulk powders

• Excess powder is removed between each layer

• First two layers receive a light compression

• Thieving mechanisms at each stage to continuously monitor process


OSDrC® Technology

Active pharmaceutical ingredients form core

Outer layer forms sides and top

Outer layer forms base

Basic Structure of an OSDrC® OPTIDOSETM Tablet

5OSDrC® OPTIDOSETM TechnologyFebruary 2012

Representative Punches for OSDrC® OPTIDOSETM

Various tablet configurations can be produced simply by changing punches


7

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 dividable 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:

● Bi-Layer Tablets

● Dividable Tablets

● IR/ER Combination Tablets

● Combination Products (multiple API in single tablets)

● Direct Compression Orally Disintegrating Tablets (ODT)

● Pulsatile Release Tablets

OSDrC® OPTIDOSETM TechnologyFebruary 2012

One-Step Dry-Coating TechnologySupports single-step manufacturing of pharmaceutical

products

Accurate & Flexible ControlTechnology allows

accurate and flexiblepositioning of cores

Poor-Compressibility EncasingTechnology allows

incorporation of core ingredients with poor compressibility

Three Enabling Technologies comprise OSDrC® OPTIDOSETM

OSDrC® OPTIDOSETM TechnologyFebruary 2012 8

One-Step Dry-Coating Technology

OSDrC® OPTIDOSETM Technology

• Supports single-step manufacturing

of pharmaceutical products

• Ultimate one-step compression system

• Permits commercial scale production of conventional

cored tablets

• Requires no separate core preparation or supply

• Permits production of a broad spectrum of high-quality

formulations at low cost

• Potential replacement for sugar- or film-coated tablets

February 2012 9

Accurate & Flexible Control Technology


• Allows accurate and flexible positioning

of cores

• Allows positioning of any number of cores

• Allows positioning in various configurations

• Permits release control by varying either the positioning

of core or thickness of coating

• Permits commercial-scale production of cored tablets

without misaligned cores

February 2012 10

Poor-Compressibility Encasing Technology


• Allows incorporation of core ingredients

with poor compressibility

• Allows incorporation of pharmacological agents with

poor compressibility (e.g. pure API with a flow aid)

• Incorporation of pellets in the core permits use as a

replacement for capsules

• Permits development of oral rapid disintegration tablets

(ODT) and various other innovative formulations

February 2012 11

Delivery Capabilities of OSDrC® OPTIDOSETM


Controlled Release● Positioning technology enables control over the release of the

API by the altering thickness of the outer coating.

Divided Core● Since the core remains fully encased in the coating even

when the tablet is divided, the intended release profileremains unaffected by dividing the tablet.

Pellet Core● By using pellets in the core instead of powders, drugs that

normally must be formulated as capsules can be produced astablets.

Thin Coated● Able to produce cored tablets with extremely thin coats

in a one-step process and can replace sugarand film-coated tablets, substantially reducing manufacturing stages and production costs.

Variable Core● Tablets do not have to be round. The shape of the core, coating

thickness, and tablet configuration can be varied simply bychanging the punches.

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

Advantages over film-coated tablets include:

OSDrC® Tablets

• Simplified manufacturingprocess

• No solvents required

• Low manufacturing cost

• Simplified process control

Controlled Release Based on Thickness of Outer Coating Layer

OSDrC® OPTIDOSETM TechnologyFebruary 2012 13

Developing Better Treatments for Poorly Soluble Compounds withOptiMeltTM HMEA solubility enhancement solution

Bioavailability enhancement represents the biggest challenge in oral drug delivery

SOURCE: Mckinsey & Company Customer interviews

What is your biggest challenge in oral drug delivery/formulation development?

N=12

Bioavailability

enhancement

Other

10

2

“We are seeing more poorly soluble drugs in early phase development. Most of the compounds I have right now are poorly soluble”

– VP, Pharmaceutical Development

“We are seeing more poorly soluble drugs in early phase development. Most of the compounds I have right now are poorly soluble”

– VP, Pharmaceutical Development

“It can be quite resource intensive to develop formulations for poorly-soluble drugs. The problem is most severe when the molecule has both low solubility and high-dose”

– Exe. Director, Pharmaceutical R&D

“It can be quite resource intensive to develop formulations for poorly-soluble drugs. The problem is most severe when the molecule has both low solubility and high-dose”

– Exe. Director, Pharmaceutical R&D

“Historically, our infrastructure is based on conventional technologies. We don’t have enough capacity and capability in new technologies that address bioavailability issues”

– Director, Formulation Development

“Historically, our infrastructure is based on conventional technologies. We don’t have enough capacity and capability in new technologies that address bioavailability issues”

– Director, Formulation Development

Drug Delivery Technology Platform -What attributes are needed to capture full value?

An effective solution – delivers drug precisely, reproducibly & safely


Fully integrated solution –equipment, materials, human

resource from End-to-End



Exclusive solution / Freedom to Operate –IP or technical barriers to competition,


Operational solution – acceptable unit dose cost


Compliant solution – equipment, controls, scientific knowledge are

current & approvable



Technology Platform Attributes – Hot Melt Extrusion

• An effective solution

• Fully integrated solution

• Compliant solution

• Exclusive solution

• Operational solution

Critical Attributes

• HME dispersions achieve a specific solubility increase in vivo & utilize GRAS excipients

• HME is a continuous process suited for scale-up, and finished dosage forms may be made using conventional equipment

• Numerous oral products and devices have been filed with regulatory agencies

• HME technology requires significant know-how to commercialize. The drug delivery profile may be patentable

• Proven in pharma & other industries as a robust process readily integrated into a manufacturing operation

OptiMeltTM

• GMP Bench to Pilot to Commercial scale, with global capabilities— Schorndorf, Germany and Somerset, New Jersey

• Broadest selection of downstream processing technologies, co-located with OptiMeltTM hot melt extrusion

• Integrated solutions provider, with over 75 years of industry experience— Development, formulation, scale-up, manufacturing, packaging

• Formulation acceleration and optimization with open Catalent-BASF bioavailability alliance— Broad range of excipients designed specifically to enhance solubility,

particularly with hot melt extrusion— Non-exclusive arrangement to increase development efficiency and deliver

better treatments for your molecules

24

OptiMeltTM HME Technology Platform

The Amorphous State &

Solid Dispersions

• The Amorphous State of a Poorly Soluble API can generate enhanced dissolution and bioavailability due to increased apparent solubility

• The Amorphous State is a thermodynamically unstable relative to the crystalline state, which must be considered when developing a viable drug product

• The Amorphous State is formed by quenching from a melt (e.g. extrusion, granulation, capsule filling) or by controlled precipitation (rotary evaporation, spray drying, freeze drying)

Amorphous State Properties

Amorphous State Stabilization

• Amorphous State Stabilization is directed at preventing the initiation and/or reducing the rate of crystal nucleation and growth

• Regulatory Agencies will demand to see good control and understanding of this property

• Available strategies:

— Avoid Tg reduction (e.g. moisture protection)

— Elevate Tg significantly above room temperature

— Chemical interactions (H-bonding, complexation)

— Anti-nucleation methods (additives, surface modification)

Principles of Solid Dispersions

28

HME

Precipitatemethods

Crystalline active + polymer Solid Dispersion Tablets

• Solid Dispersions are intimate mixtures of two (or more) components that typically have a high degree of miscibility.

• Poorly Soluble Drug Dispersions can achieve enhanced solubility by creating a physically stable and processable non-crystalline form.

GRAPHIC SOURCE: Modified from BASF Pharma Ingredients & Services

OptiMeltTM Hot Melt

Extrusion (HME)

Catalent’s OptiMeltTM hot melt extrusion addresses many needs

Approximately 40% of compounds on the market and >80% in development are poorly soluble (BCS class 2/4)

OptiMeltTM hot melt extrusion enhances solubility to bring more products and better treatments to market:

• Achieve desired efficacy, progressing more molecules to approval

• Differentiate product profiles; enhanced solubility

• Enhance patient compliance; reduced pill size/pill burden

• Optimize product performance; controlled release dosage forms

Catalent’s OptiMeltTM hot melt extrusion offers multiple benefits

OptiMeltTM hot melt extrusion provides many benefits beyond solubility enhancement:

• polymeric formulation matrix eliminates hydrolysis associated with wet agglomeration

• suitability for sustained/controlled release or enteric coating

• ability to form capsules, tablets, and multi-particulate dosage forms

• control dose over a wide range of solubilities or dispersion concentrations

• film capability for buccal dosage forms

• very high drug loading up to 90%, decreases tablet size

• robust, compact, high-throughput manufacturing with little waste

• solvent-free processing, eliminating need for explosion-proof equipment

• potential for patient abuse deterance formulations for certain compounds

• potential for improved safety and side effect profile with lower dosing

• taste-masking

• Twin-screw design delivers excellent co-mixing of components

• Solvent free

• Process is well-controlled and scalable

• Good materials handling/ containment

• Extrudate downstream processing is flexible

• Feasibility trials are easy to design and predictive

OptiMeltTM HME Process Advantages

OptiMeltTM Hot Melt Extrusion – The Basics

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

• Shear forces drive co-melting of drug and excipient

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

• Process opportunities— Liquid drugs— Potent drugs— Labile drugs (solvent or moisture

sensitive)

Hot Melt Extrusion

Formulation Case

Studies

SolubilityITRACONAZOLE + KOLLIDON VA 64

0,00

25,00

50,00

75,00

100,00

125,00

0 25 50 75 100

Time [minutes]

So

lub

ilit

y [

mg

/l]

extrudate Itraconazole+Kollidon VA 64 10+90extrudate Itraconazole+Kollidon VA 64 30+70powder mix Itraconazole+Kollidon VA 64

suspension - tested at pH ~ 1

solubility enhancement [mg/L]

Itraconazole < 1 ./.physical mixture 8.1 > 810+90 extrudate 114 >11430+70 extrudate 124 >124

Itraconazole – Kollidon® Solubility Enhancement

SOURCE: Catalent Pharma Solutions – Schornforf site

Drug Release from Soluplus® Extrudates

0102030405060708090

100

0 30 60 90 120

t [min]

drug

rele

ase

[%]

15% itraconazole in Soluplus




Very high drug loads (~50%) are possible without affecting therelease profiles in a negative way

USP II, 50 rpm, 700 mL 0.1 N HCl, cut extrudates, 100 mg API (n=3)

SOURCE: BASF Pharma Ingredients & Services

In vivo Performance of Solid Dispersion

0

50

100

150

200

250

300

350

400

450

0 5 10 15 20t [h]

bloo

d co

ncen

tratio

n [n

g/m

L]

solid solutionphysical mixturecrystalline itraconazole

Itraconazole 10 mg / kg bw, beagle dogs (n=5) fasted state

Massively increased bioavailability of itraconazole from Soluplus®

extrudates compared to physical mixture and crystalline API


Stability of Solid Dispersion (3 month 40oC/75%RH)

0

20

40

60

80

100

0 20 40 60 80 100 120

Drug release [%]

Time [min]

- after production- after storage

USP II, 50 rpm, 700 mL 0.1 N HCl, granulated extrudates with 100 mg itraconazole, (n=3)

After accelerated storage conditions dissolution rates arestill comparable


HME: Capturing Value in the future

Relative to crystalline references, Amorphous Solid Dispersions improve bioavailability in 82%

Source: Newman et al. Journal of Pharmaceutical Sciences, Vol. 101, No. 4, April 2012

HME provides the platform to realize this potential and capture the full value of your API

Future of OptiMeltTM Platform Technology

• An effective solution

• Fully integrated solution

• Compliant solution

• Exclusive solution

• Operational solution

Critical Attributes

• Expertise in selecting formulations that maximize solubility enhancement potential of Solid Dispersions

• Parallel R&D effort on downstream processing (e.g. milling, compression, calendering)

• Leverages Catalent’s strong audit record. Working with reliable equipment and raw materials suppliers

• Optimized HME formulations may yield IP for customers. Opportunities to combine with Catalent proprietary platforms

• Fully integrated with other manufacturing, analytical and packaging services

OptiMeltTM

In Summary –OptiMeltTM: A Viable Platform Technology















Oral Disintegrating TabletsCase studies of Zydis® fast-dissolve applications

Selegiline Zydis®

fast dissolve:anti-parkinsons market

43

Selegiline vs. Zelapar® fast-dissolve tablets

Tablet/Capsule Selegiline Zelapar formulated withZydis fast-dissolve

(traditional formulation) (innovative formulation)

Lower Dose and Less Frequent Dosing

5-mg doses, taken twice a day (BID). Pill or capsule that must be swallowed.

1.25-mg or 2.5-mg doses, taken once a day (QD). Tablet that dissolves in mouth within seconds,

without water.

Increased Bioavailability/Faster Onset

of Action

Tmax=1 hour. Digested in the gut, absorbed through

the small intestine, processed by the liver.

Tmax=15 minutes. Innovative transmucosal drug delivery absorbed

rapidly through the lining of the mouth directly into the

blood.

Lower Side Effect Potential Processed through the liver, producing undesired

metabolites.

Significantly by-passes the liver, producing lower undesired metabolites.

Zydis Fast Dissolve buccal reformulation of Selegiline: Impact on Product Profile

44

Patients benefited from less frequent dosing, reduced side effects and shorter off-periods

Zydis re-formulation improved patient compliance

Zelapar has highest Patient Compliance for Medicare patients, based on 12 month longitudinal patient records analysis.

Zelapar, Age: Total, Gender: Total, Pay Type: MedicareData Source: SDI Health Patient Data, 2011

Additional Cohort Compliance Improvements: Zelapar SelegilineAll Ages, Female, All Payers 91.6% 83.7%Age 19-65, All genders, All Payers 87.3% 83.8%

Com

plia

nce

60

65

70

75

80

85

90

95

100

ZELAPAR ZYDIS ELDEPRYL SELEGILINE HCL

98.5%

87.9%

81.0%

%

®

45

$0

$5,000,000

$10,000,000

$15,000,000

$20,000,000

$25,000,000

2005 2006 2007 2008 2009 2010

Sales

Year

US Sales ‐ Selegiline Class: Anti‐Parkinson Market

Zelapar (Zydis)

Eldepryl

Selegiline GenericsZydis

Data Source: IMS Health, 2010

2005 2006 2007 2008 2009 2010Year

Zelapar was launched as a branded generic and experienced substantial sales growth

US Sales – Selegiline Class: Anti-Parkinson Market

$25,000,000

$20,000,000

$15,000,000

$10,000,000

$5,000,000

$0

Sale

s

Zelapar(Zydis)

Eldepryl

Selegiline Generics

46

Zelapar 2010 $ market share: 39.3%Zelapar 2010 Unit market share: 10.1%

Allergy Market:Ebastine antihistamine

47

0

50,000

100,000

150,000

200,000

250,000

300,000

Tota

l Uni

ts S

old

G5

(1,0

00's

)

2009 2010 2011

Ebastine Units Sold G5 (1,000's)

Other SalesZydis Sales

Zydis formulation of Ebastine for allergic rhinitis has delivered substantial market impact

482011 IMS data

Launch of a new bioequivalent line extension increased overall sales for the marketer of this product

Zydis Product has maintained 50% overall unit market share for the entire ebastine class

83% of patients stated they preferred Zydis fast dissolve tablets vs. standard tablets

Allergy Market:Grazax® oral immunotherapy

49

50

GRAZAX oral immunotherapy: An innovative application of Zydis fast dissolve technology

Positive Phase 3 results recently released for US approval

Value enhancement for patients, physicians and payers in management of this chronic condition

First once-daily, oral allergy immunotherapy tablet (AIT) approved as a disease altering agent for grass allergy

Efficacy and compliance benefits shown in multiple studies.

Benefits over sub-cutaneous delivery:

● Patient preference for oral treatment (needle phobia)

● Improved patient adherence and compliance, supported by studies

● Prevents accidental needle sticks for patients and providers

● Eliminates needle (sharps) disposal

Catalent drug delivery technologies enhance product value by differentiating product profiles

51

Efficacy Safety / Tolerability Payer Value Dosage / Admin. Indications/

Populations

• Increased bioavailability

• Faster onset of action

• Targeted drug delivery

• Sustained drug plasma profile (pK)

• Controlled drug plasma profile (pK) to match specific treatment needs

Targeted drug delivery

Controlled drug plasma profile (pK)

Reduction in first pass metabolism through the liver

Increased patient compliance

Reduction in patient pill burden

Extended and flexible dosing –lower cost to treat with increased convenience

Poly-therapy with a single dose

• Less frequent dose regimen (eg. Once daily vs. BID)

• Orally Disintegrating tablets –disperses in mouth without water in usually <3 seconds

• Tablets, Pills, Capsules

• Orally Dissolving Powder –loose free flowing powder granules

• Entire labeled patient population

• Elderly patient segment

• Pediatric patient segment

• “On the go” life style patient segment

Catalent delivers Better Treatments:Broadest range of Drug Delivery Technologies and deep Expertise

52

Catalent’s full range of value added services:

DEVELOPMENT

BIOLOGICSGPEX® CELL LINE ENGINEERING BIOMANUFACTURING

PRE-FORMULATION & FORMULATIONORAL DOSE FORMS: SOFTGEL, CONTROLLED RELEASE, IMMEDIATE RELEASE, ORALLY-DISINTEGRATING TABLETS

INHALATION

PARENTERAL

OPTIFORM™ TECHNOLOGY & SOLID STATE SERVICES

PHARMACEUTICAL & BIOPHARMACEUTICAL LAB SERVICESCOMPENDIAL, RELEASE, POTENCY & MICROBIOLOGY TESTING METHOD DEVELOPMENT & VALIDATION PHYSICAL, MATERIAL & BIOPHYSICAL CHARACTERIZATION STABILITY TESTING & STORAGE IMPURITY & STRUCTURAL CHARACTERIZATION FACILITY & PROCESS VALIDATION VIRAL CLEARANCE & VIRAL SAFETY

PK & IMMUNOGENICITY

REGULATORY CONSULTINGEARLY STAGE DEVELOPMENT SERVICES LATE STAGE DEVELOPMENT SERVICES COMPLETE LIFE-CYCLE MANAGEMENT CUSTOMIZED EDUCATION PROGRAMS

DELIVERY

SOFTGEL TECHNOLOGIESSOFTGEL CAPSULES

VEGICAPS® CAPSULES

ZYDIS® & LYOPAN® FAST-DISSOLVE TECHNOLOGIES

CONTROLLED RELEASE TECHNOLOGIESOSDrC® OPTIDOSETM

COMPLEX TABLETS

COATED PELLETS & BEADS

ADVANCED CAPSULES

INNOVATIVE API SOLUTIONS

COMBINATION SOLID PHARMACEUTICALS

FIXED DOSE COMBINATIONS

INHALATIONPRESSURIZED METERED-DOSE INHALERS

DRY POWDER INHALERS

NASAL SPRAYS

NEBULIZED SOLUTIONS/SUSPENSIONS

INJECTABLESFORMULATION DEVELOPMENT

PREFILLED SYRINGES

CLICK-IN SAFETY DEVICE

PROTECTOR SAFETY SHIELD SYSTEM™

ASI™ AUTOINJECTOR

PHASE I/II VIALS

CONSUMER HEALTH

SUPPLY

CLINICAL SUPPLYGLOBAL COMPARATOR SOURCING

MANUFACTURING & BLINDING

PACKAGING & LABELING

ANALYTICAL SERVICES

DISTRIBUTION & WAREHOUSING

MANUFACTURINGSOFTGEL & VEGICAPS® CAPSULES

CONTROLLED RELEASE TABLETS

ZYDIS® & LYOPAN® FAST-DISSOLVE TABLETS

STERILE: BLOW/FILL/SEAL, IV BAGS, INJECTABLES

COMMERCIAL PACKAGINGBOTTLING

BLISTER PACKAGING

CUSTOMIZED BLISTERS/WALLETING

INJECTABLE PACKAGING & KITTING

SPECIALTY PRODUCT HANDLING

PACKAGING DELIVERY SOLUTIONSINTEGRATED SUPPLY CHAIN

LATE-STAGE CUSTOMIZATION

PRODUCT LIFECYCLE MANAGEMENT

ANTI-COUNTERFEITING

DESIGN SOLUTIONS

PATIENT ADHERENCE SOLUTIONS

DELPOUCH® UNIT DOSE DELIVERY SYSTEM

MEDIA ENHANCED PACKAGING™ TECHNOLOGY

discover more.CATALENT PHARMA SOLUTIONS14 SCHOOLHOUSE ROADSOMERSET, NJ 08873

+ 1 866 720 3148

www.catalent.com

OSDrC® is a registered trademark of Sanwa Kagaku Kenkyusho Co., Ltd

THANK YOU

To discover more, please continue on

to the Appendix slides which follow.

APPENDIX

OSDrC®

OPTIDOSETM

Technology

8July 2011 OSDrC® OPTIDOSETM Technology

OSDrC® Technology

Only the lower center punch slides down

OSDrC® OPTIDOSETM Tableting Process


OSDrC® Technology

Space is filled with powder for the coating, which becomes the base layer of the tablet; at this time, the lower outer punch acts as a die



OSDrC® Technology

Pre-compression by the upper and lower center punches



OSDrC® TechnologyOSDrC® OPTIDOSETM Tableting Process


OSDrC® Technology

Space is filled with powder for the API layer



OSDrC® Technology

Pre-compression by the upper and lower center punches



OSDrC® TechnologyOSDrC® OPTIDOSETM Tableting Process


OSDrC® Technology

Die is filled with remaining powder for the coating



Pre-shaped API layer is pushed up inside the die; the API layer is now completely surrounded by the coating



OSDrC® Technology

Compression is completed by the upper and lower punches in flush alignment



OSDrC® Technology

Finished tablet is released



OSDrC®

OPTIDOSETM

Tablets


• Permits controlled interaction of APIs

• Permits controlled release of API

• Can mask bitter taste of API

• Permits more visually appealing

formulations

OSDrC® Tablets

OSDrC® OPTIDOSETM permits creation of various value-added

tablet formulations

Merits of Cored Tablet


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


OSDrC® Tablets





Controlled Release Based on Thickness of Outer Coating


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


OSDrC® Tablets





0

20

40

60

80

100

120

0 2 4 6 8 10Time (h)

Perc

ent d

isso

lved

0.5 mm

1.0 mm2.0 mm

Yuichi Ozeki, Masaki Ando, Yukinao Watanabe, Kazumi Danjo,Evaluation of novel one-step dry-coated tablets (OSDRC®) as a platform for delayed-release tablets,Journal of Controlled Release, vol 95/1 pp. 51-60 (2004)

Controlled Release Based on Thickness of Outer Coating

Yuichi Ozeki, Masaki Ando, Yukinao Watanabe, Kazumi Danjo,Evaluation of novel one-step dry-coated tablets (OSDRC® OPTIDOSETM) as aplatform for delayed-release tablets,Journal of Controlled Release, vol 95/1 pp. 51-60 (2004)


• 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


• With conventional technology, enteric tablets could not be divided

OSDrC® Tablets

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

0

25

50

75

100

0 2 4 6 8 10 12 14Time (h)

Perc

ent d

isso

lved

pH1.2 pH 6.8

divided two-half

whole

divided one-half

core only

Yuichi Ozeki, Yukinao Watanabe, Hirokazu Okamoto, Kazumi Danjo,Development of Dividable One-Step DRy-Coated Tablets (Dividable-OSDRC®) and Their Evaluation as a New Platform for Controlled Drug Release,Pharmaceutical Research, vol 21(7) pp. 1177-1183 (2004)

Dividable Core Tablets


Yuichi Ozeki, Yukinao Watanabe, Hirokazu Okamoto, Kazumi Danjo,Development of Dividable One-Step DRy-Coated Tablets (OSDRC® OPTIDOSETM – Dividable) and Their Evaluation as a New Platformfor Controlled Drug Release,Pharmaceutical Research, vol 21(7) pp. 1177-1183 (2004)

OSDrC® Tablets

Capsule Issues

• Do not facilitate dosage control (cannot be divided)

• Difficult to swallow

• Difficult to prevent tampering

• Relatively high

manufacturing cost

Replacing Capsules with Tablets


• Tests have obtained same release characteristics ascapsules

OSDrC® Tablets

Possible to encase pellets as a replacement for capsules



• Tests have obtained same release characteristics ascapsules

OSDrC® Tablets

Possible to encase pellets as a replacement for capsules

0

20

40

60

80

100

120

0 1 2 3 4 5 6Time (h)

Perc

ent d

isso

lved

Capsule

whole

divided one-half

divided two-half

Yuichi OzekiSKK company data (2004)



OSDrC® Tablets

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

Pulsatile Release Tablets


OSDrC® Tablets

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

ex.

Time (h)

0

25

50

75

100

0 6 12

Perc

en

t d

isso

lved

1st core

2nd core

Yuichi Ozeki,"The Nakai Award winner's article" Development of one-step dry-coated tablets (OSDRC) and the study for its physical characteristics.Journal of Japan Society of Pharmaceutical Machinery and Engineering, Japan. vol 14/4 pp. 12-21 (2005)

Pulsatile Release Tablets

Yuichi Ozeki,"The Nakai Award winner's article" Development of one-step dry-coatedtablets (OSDRC) and the study for its physical characteristics.Journal of Japan Society of Pharmaceutical Machinery and Engineering, Japan. vol 14/4 pp. 12-21 (2005)


Yuichi Ozeki,"The Nakai Award winner's article" Development of one-step dry-coatedtablets (OSDRC® OPTIDOSETM) and the study for its physical characteristics.Journal of Japan Society of Pharmaceutical Machinery and Engineering, Japan. vol 14/4 pp. 12-21 (2005)

Made possible by technology that permits encasement of core pharmaceutical powders in powder form

OSDrC® Tablets

• Oral rapid disintegration (OD) tablets

Potential for a Host of New Formulations


Various tablet configurations can be produced simply by changing double punches

OSDrC® Tablets

• Various core configurations

Potential for a Host of New Formulations


OSDrC®

OPTIDOSETM

Data


OSDrC® Data

Core

OSDrC® rotary tableting machines showed core alignment of less

than 0.1mm, a level that is not considered significant to performance

0.0

0.2

0.4

0.6

0.8

30000 50000 70000 90000 110000

Tabletting speed (tab hr.-1)

△r (

mm

)

OSDrC

DC

Yuichi Ozeki“The Nakai Award winner’s article” Development of one-step dry-coated tablets (OSDRC®) and the study for its physical characteristics,Journal of Japan Society of Pharmaceutical Machinery and Engineering, Japan. vol 14/4 pp. 12-21 (2005)

Core Misalignment

Yuichi Ozeki“The Nakai Award winner’s article” Development of one-step dry-coatedtablets (OSDRC® OPTIDOSETM) and the study for its physical characteristics,Journal of Japan Society of Pharmaceutical Machinery and Engineering, Japan. vol 14/4 pp. 12-21 (2005)

OSDrC® OPTISODETM rotary tableting machines showed core alignment of less than 0.1mm, a level that is not considered significant to performance


Individual

OSDrC® rotary tableting machines showed the ability to produce individual coatings comparable to film coating

0.00

0.25

0.50

0.75

1.00

0 10 20 30

Tabletting time in minute

Perc

ent

coef

ficie

nt o

f var

iatio

n1.5 mm

0.5 mm

0.75 mm

Yuichi OzekiAdvanced dry-coated tablets as a solid coating technology (2)“Evaluation of novel one-step dry-coated tablets (OSDRC®) as the delayed-release tablets and its machine performance”,PHARM TECH JAPAN, vol 21/9 pp. 1407-1413 (2005)

Individual Coatings

Yuichi OzekiAdvanced dry-coated tablets as a solid coating technology (2)“Evaluation of novel one-step dry-coated tablets (OSDRC® OPTIDOSETM) asthe delayed- release tablets and its machine performance”,PHARM TECH JAPAN, vol 21/9 pp. 1407-1413 (2005

41July 2011

OSDrC® OPTIDOSETM rotary tableting machines showed the ability to produce individual coatings comparable to film coating


Cross-contamination was an extremely low 0.03%OSDrC® can effectively control the interaction between the API and the coating excipient

Cross0.00

0.03

0.05

0.08

0.10

0 40 80 120Time (min)

Ace

tam

inop

hen

cont

ent (

%)

side surface bottom surface upper surface

Yuichi Ozeki“The Nakai Award winner’s article” Development of one-step dry-coated tablets (OSDRC®) and the study for its physical characteristics,Journal of Japan Society of Pharmaceutical Machinery and Engineering, Japan. vol 14/4 pp. 12-21 (2005)

Cross-Contamination

Yuichi Ozeki“The Nakai Award winner’s article” Development of one-step dry-coated tablets (OSDRC® OPTIDOSETM) and the study for its physical characteristics,Journal of Japan Society of Pharmaceutical Machinery and Engineering, Japan. vol 14/4 pp. 12-21 (2005)

42July 2011

Cross-contamination was an extremely low 0.03%OSDrC® OPTIDOSETM can effectively control the interactionbetween the API and the coating excipient


The Amorphous State

& Solid Dispersions

Amorphous State Structure

Hexagonal Close Packing Random Close Packing

fraction of voids = 0.26 fraction of voids > 0.36

DATA SOURCES: Jalali, J. Chem. Phys. 120 (2004) 1138; Bates, et al. Pharm.Res. 23 (2006) 2333

Amorphous State Thermodynamics

Temp.

Enthalpy

Crystal

Amorphous (glass)

SupercooledLiquid

Liquid

TmTg

Higher Energy State of Amorphous phase is shown relative to Crystalline phase

Amorphous State Thermal Analysis

-20000

-15000

-10000

-5000

0

5000

10000

20 40 60 80 100 120 140 160 180

Temperature (oC)

Pow

er (u

W)

Endothermic

Tg Tc Tm

Differential Scanning Calorimetry of Amorphous Indomethacin API

• The Amorphous State of a Poorly Soluble API can generate enhanced dissolution and bioavailability due to increased apparent solubility

• The Amorphous State is a thermodynamically unstable relative to the crystalline state, which must be considered when developing a viable drug product

• The Amorphous State is formed by quenching from a melt (e.g. extrusion, granulation, capsule filling) or by controlled precipitation (rotary evaporation, spray drying, freeze drying)

Amorphous State Properties

Amorphous State Materials Characterization

Spectroscopy (Raman, SSNMR)

Relaxation times (SSNMR, rheology)

Molecular conformation / mobility

X-ray Diffraction (XRD)

Differential Scanning Calorimetry (DSC)

Polarized Light Microscopy

Absence of crystal lattice (no 3D structure)

Kinetic solubility studies

(e.g. dissolution, supersaturation)

Increased apparent solubility

Dynamic Vapor Sorption (DVS)Moisture absorption

Analytical ToolsCritical Properties

Amorphous State Stability

Model glass-former:

Indomethacin (IMC)

Tg ~ 45oC

• Critical relationship between Glass Transition Temp (Tg) and storage temperature

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 100 200 300

Time (days)

Wei

ght F

ract

ion

Cry

stal

lized

40 C30 C20 C

SOURCE: Andronis and Zografi, J. Non-Cryst. Solids 271 (2000) p236

Crystallization kinetics for different particle sizes of amorphous IMC at 30 oC

♦ 0-40 μm

■ 75-150 μm

▲ 250-425 μm

●● 600600--710 710 μμmm

0

20

40

60

80

100

0 20 40 60 80 100

Time (days)

Perc

ent c

ryst

allin

ityAmorphous State Stability

SOURCE: Crowley and Zografi, Pharm. Res. 20 (2003) p1417

Amorphous State Stabilization

• Amorphous State Stabilization is directed at preventing the initiation and/or reducing the rate of crystal nucleation and growth

• Regulatory Agencies will demand to see good control and understanding of this property

• Available strategies:

— Avoid Tg reduction (e.g. moisture protection)

— Elevate Tg significantly above room temperature

— Chemical interactions (H-bonding, complexation)

— Anti-nucleation methods (additives, surface modification)

Principles of Solid Dispersions

96

HME

Precipitatemethods

Crystalline active + polymer Solid Dispersion Tablets

• Solid Dispersions are intimate mixtures of two (or more) components that typically have a high degree of miscibility.

• Poorly Soluble Drug Dispersions can achieve enhanced solubility by creating a physically stable and processable non-crystalline form.

GRAPHIC SOURCE: Modified from BASF Pharma Ingredients & Services

0

20

40

60

80

100

120

140

160

180

200

0 20 40 60 80 100

PVP content (%w/w)

T g (o C

)

Stabilization of Amorphous IMC using poly(vinylpyrrolidone) by increasing Tg in a molecular dispersion

CH3O

N

CH2COOH

CH3

Cl

O

Indomethacin

N O

CH

CH2

n

PVPSOURCE: Yoshioka et al. J. Pharm. Sci. 84 (1995) p983

Solid Dispersions – Control of Tg

0

20

40

60

80

100

0 50 100

Time (days)

Perc

ent c

ryst

alliz

edpure IMC5%PVP

SOURCE: Matsumoto and Zografi, Pharm. Res. 16 (1999) p1722

Amorphous IMC containing 5% PVP has greatly increased physical stability stored at 30 oC storage for 100 days

Solid Dispersions – Drug-Polymer Interactions

IMC-PVP H-bonding reduces crystal nucleation and growth

OptiMeltTM Hot Melt

Extrusion (HME)

Catalent’s OptiMeltTM hot melt extrusion addresses many needs

Approximately 40% of compounds on the market and >80% in development are poorly soluble (BCS class 2/4)

OptiMeltTM hot melt extrusion enhances solubility to bring more products and better treatments to market:

• Achieve desired efficacy, progressing more molecules to approval

• Differentiate product profiles; enhanced solubility

• Enhance patient compliance; reduced pill size/pill burden

• Optimize product performance; controlled release dosage forms

Catalent’s OptiMeltTM hot melt extrusion offers multiple benefits

OptiMeltTM hot melt extrusion provides many benefits beyond solubility enhancement:

• polymeric formulation matrix eliminates hydrolysis associated with wet agglomeration

• suitability for sustained/controlled release or enteric coating

• ability to form capsules, tablets, and multi-particulate dosage forms

• control dose over a wide range of solubilities or dispersion concentrations

• film capability for buccal dosage forms

• very high drug loading up to 90%, decreases tablet size

• robust, compact, high-throughput manufacturing with little waste

• solvent-free processing, eliminating need for explosion-proof equipment

• potential for patient abuse deterrence formulations for certain compounds

• potential for improved safety and side effect profile with lower dosing

• taste-masking

• Twin-screw design delivers excellent co-mixing of components

• Solvent free

• Process is well-controlled and scalable

• Good materials handling/ containment

• Extrudate downstream processing is flexible

• Feasibility trials are easy to design and predictive

OptiMeltTM HME Process Advantages

OptiMeltTM Hot Melt Extrusion – The Basics

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

• Shear forces drive co-melting of drug and excipient

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

• Process opportunities— Liquid drugs— Potent drugs— Labile drugs (solvent or moisture

sensitive)

OptiMeltTM HME Twin Screw Extruder Equipment Variables

Feeder configuration Processing zone configurationDie size / number

Hot-Melt Extrusion

Drive motorand

gearboxSide stuffer

Liquid injection

Liquid injectionVent

Main feed

Feedmotor

polymer API

Die

DistributiveMixing

DispersiveMixing

Conveying

Forward Elements

30 degree

90 degree

Zoning Feeding/ CompressingDistributiveMixing

DispersiveMixing

Conveying

Forward Elements

30 degree

90 degree

Zoning Feeding/ Compressing

OptiMeltTM HME - Process Variables and Outputs

Drive motorand

gearbox

Main feed

Feedmotor

polymer API

Die

Feed rate input

Screw speed input

Barrel temperature inputs

TorqueBarrel temperature outputs

Screw speed

Material temp,Pressure, PAT

ExtruderExtruder

Feeder IFeeder I Feeder IIFeeder II

GranulatorGranulator

1. Upstream

2. Compounding Extrusion

3. Downstream Pellets, Granules, Calendering, Inj molding

OptiMeltTM HME – Downstream ExtrudateProcessing


• A wide range of finished dosage forms can be generated

OptiMeltTM HME Development – Feasibility Plan

107

Request for Proposal

Miscibility study HME process simulationFormulation concept

Accelerated stability study

HME small scale trials

Stability prediction

Scale-up

Technical analysis / IP

Downstream dosage form trials

GLP / GMP batches

OptiMeltTM HME – Feasibility Assessments

• Miscibility may be assessed by predictive or small-scale experimental techniques

• DSC of binary mixtures to identify single Tg

• Hot stage microscopy to observe phase melting/dissolution at different temperatures

• Film casting of binary mixtures from common solvent – visual examination for crystal formation

A significant benefit of HME is that proof-of-concept evaluations may be performed at small-scale, quickly and with minimal API

OptiMeltTM HME – Feasibility Assessments

The following API information directs formulation strategy:

• API Tg if available or otherwise estimate

(Tg / Tm [Kelvin] Ratio ~0.7 based on fragility theory )

• API chemical stability at increased temperature

• API availability for H-bonding

• Poorly Soluble Model Drugs:

5

45 / 155

Indomethacin

Solubility at pH7 (µg/mL)

Tg / Tm (oC)

~1~1

59 / 166-20 / 80

ItraconazoleFenofibrate

discover more.CATALENT PHARMA SOLUTIONS14 SCHOOLHOUSE ROADSOMERSET, NJ 08873

+ 1 866 720 3148

www.catalent.com

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