Recent Advances in Oral Granules and Bi-Layer Tablet Technologies
Transcript of 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
February 2012 OSDrC® OPTIDOSETM Technology 1
OSDrC® OPTIDOSETM Tablet Press
February 2012 OSDrC® OPTIDOSETM Technology 2
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
February 2012 OSDrC® OPTIDOSETM Technology 4
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
February 2012 OSDrC® OPTIDOSETM Technology 6
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
OSDrC® OPTIDOSETM 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
OSDrC® OPTIDOSETM 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
February 2012 OSDrC® OPTIDOSETM Technology 12
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
An effective solution – delivers drug precisely, reproducibly & safely
Fully integrated solution –equipment, materials, human
resource from End-to-End
Fully integrated solution –equipment, materials, human
resource from End-to-End
Exclusive solution / Freedom to Operate –IP or technical barriers to competition,
Exclusive solution / Freedom to Operate –IP or technical barriers to competition,
Operational solution – acceptable unit dose cost
Operational solution – acceptable unit dose cost
Compliant solution – equipment, controls, scientific knowledge are
current & approvable
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
30% itraconazole in Soluplus
45% itraconazole in Soluplus
60% 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
SOURCE: BASF Pharma Ingredients & Services
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
SOURCE: BASF Pharma Ingredients & Services
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
An effective solution – delivers drug precisely, reproducibly & safely
An effective solution – delivers drug precisely, reproducibly & safely
Fully integrated solution –equipment, materials, human
resource from End-to-End
Fully integrated solution –equipment, materials, human
resource from End-to-End
Exclusive solution / Freedom to Operate –IP or technical barriers to competition,
Exclusive solution / Freedom to Operate –IP or technical barriers to competition,
Operational solution – acceptable unit dose cost
Operational solution – acceptable unit dose cost
Compliant solution – equipment, controls, scientific knowledge are
current & approvable
Compliant solution – equipment, controls, scientific knowledge are
current & approvable
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
11July 2011 OSDrC® OPTIDOSETM Technology
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® OPTIDOSETM Tableting Process
12July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® Technology
Pre-compression by the upper and lower center punches
OSDrC® OPTIDOSETM Tableting Process
13July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® TechnologyOSDrC® OPTIDOSETM Tableting Process
14July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® Technology
Space is filled with powder for the API layer
OSDrC® OPTIDOSETM Tableting Process
15July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® Technology
Pre-compression by the upper and lower center punches
OSDrC® OPTIDOSETM Tableting Process
16July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® TechnologyOSDrC® OPTIDOSETM Tableting Process
17July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® Technology
Die is filled with remaining powder for the coating
OSDrC® OPTIDOSETM Tableting Process
18July 2011 OSDrC® OPTIDOSETM Technology
Pre-shaped API layer is pushed up inside the die; the API layer is now completely surrounded by the coating
OSDrC® OPTIDOSETM Tableting Process
19July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® Technology
Compression is completed by the upper and lower punches in flush alignment
OSDrC® OPTIDOSETM Tableting Process
20July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® Technology
Finished tablet is released
OSDrC® OPTIDOSETM Tableting Process
21July 2011 OSDrC® OPTIDOSETM Technology
OSDrC®
OPTIDOSETM
Tablets
22July 2011 OSDrC® OPTIDOSETM Technology
• 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
23July 2011 OSDrC® OPTIDOSETM Technology
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
• Low manufacturing cost
• Simplified process control
Controlled Release Based on Thickness of Outer Coating
24July 2011 OSDrC® OPTIDOSETM Technology
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
• Low manufacturing cost
• Simplified process control
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)
25July 2011 OSDrC® OPTIDOSETM Technology
• 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
• 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
27July 2011 OSDrC® OPTIDOSETM Technology
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
30July 2011 OSDrC® OPTIDOSETM Technology
• Tests have obtained same release characteristics ascapsules
OSDrC® Tablets
Possible to encase pellets as a replacement for capsules
Replacing Capsules with Tablets
31July 2011 OSDrC® OPTIDOSETM Technology
• 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)
Replacing Capsules with Tablets
32July 2011 OSDrC® OPTIDOSETM Technology
OSDrC® Tablets
Accurate placement of multiple cores makes it possible to manufacture pulsatile release formulations
Pulsatile Release Tablets
33July 2011 OSDrC® OPTIDOSETM Technology
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)
34July 2011 OSDrC® OPTIDOSETM Technology
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
35July 2011 OSDrC® OPTIDOSETM Technology
Various tablet configurations can be produced simply by changing double punches
OSDrC® Tablets
• Various core configurations
Potential for a Host of New Formulations
36July 2011 OSDrC® OPTIDOSETM Technology
OSDrC®
OPTIDOSETM
Data
37July 2011 OSDrC® OPTIDOSETM Technology
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
40July 2011 OSDrC® OPTIDOSETM Technology
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
OSDrC® OPTIDOSETM Technology
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
OSDrC® OPTIDOSETM Technology
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
SOURCE: BASF Pharma Ingredients & Services
• 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