0. modified release technologies
Orodispersible Tablets:
A Review & Opportunities
September, 2011

1. Fast Dissolve Dosage Form
What are ODTs?
Solid dosage form
Rapid
disintegration
on the tongue
Oral route of
administration
Fast Dissolve
Dosage Form
So what are oral dispersing tablets?
Essentially an oral dosage form which can disintegrate rapidly on the tongue and allow the patient to swallow as if it were a liquid formulation.
Has the advantages of a tablet formulation- Dose uniormity, no need for patient to shake or dose accurately.
Has the advatages of a liquid formulation – Ease of swallowing- particularly where this is difficult – children, elderly many of general population….
A stable, oral dosage form
with the dosing ease of a liquid

2. Regulatory Definitions
US Definition
Orally Disintegrating Tablet
A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue.
Tablet weight <500mg. In-vitro USP disintegration test <30 seconds.
FDA Guidance for Industry -Orally Disintegrating Tablets (Dec 2008)
EU Definition
Orodispersible tablets
Orodispersible tablets are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed
Disintegration Test: Orodispersible tablets disintegrate within 3 mins when examined by the test for disintegration…….
European Pharmacopoeia (Ph.Eur.)
There are 2 regulatory definitions : -
Read from slides…
The US definition is preferred as it is felt that many conventional tablets or chewable tablets would comply with the EU definition though they aren’t truly fast melt in the same way as Zydis or many of the other true fast dispersion technologies.
< 5 seconds melt in the mouth is typical for some dosage forms. Patients could become adverse to the technology if the take a tablet that disperses over 3 minutes…

3. ODT Why use ODT? Clinical Formulation Marketing Pregastric delivery
Faster onset
Better S&E
Bioequivalence
Local delivery
Compliance
Convenience
Stability
Ease of use
New presentation
Extend exclusivity
Broader application
USP

4. ODT Technologies
Can be broadly categorised according to method of manufacture:
Lyophilised
Loosely Compressed
Other
Moulded tablets
Spray dried powders
Sugar Floss
Mass Extrusion

5. Example ODT Technologies
Technology Platform
Technology
Company
Example Products
Lyophilised
Zydis ®
Catalent
15 commercial products
Grazax
Claritin
Lyoc
Cephalon
7 commercial products
Proxalyoc
Loperamide Lyoc
Pharmafreeze
SPI Pharmaceuticals
Unknown
Janssen
Quicksolv
Risperdal
Compressed Tablets
AdvaTab
Eurand
Cetirizine
Lactimal
Orasolve / Durasolv
CIMA
Remeron Soltab
Zomig-ZMT
Niravam
FazaClo
Orapred
Flashtab
Ethypharm
Prevacid Solutab
Ibuprofen
Pharmaburst
Not known
Sugar floss
Flashdose
Biovail
Molded tablet
Wowtab
Yamanouchi / Astellas
Hamal D

6. ODT Technologies Loosely Compressed Spray Dried Rely on the use of:
Super-disintegrants
Effervescent agents
Highly aqueous soluble excipients
Combinations of the above
Uses standard tabletting process with low compression forces
Can incorporate encapsulated API for taste masking or modified release
Compression forces need to be minimised to prevent damage to API coating
Effervescent systems can be moisture sensitive
May be friable
Typically comprises:
Superdisntegrants e.g. Na Glycolate
Bulking agent e.g. mannitol
Supporting matrix e.g. gelatin
Spray drying produces porous powder

7. ODT Technologies Sugar Floss Moulded Tablets
Spun fibres of sacharrides (sucrose, dextrose) or polysacharrides
Floss fibres blended with API + other excipients
Blend is loosely compressed
Requires conditioning step at elevated temperature and humidity to convert amorphous sugar fibres to crystalline
Disintegration dependant on soluble sugars and porosity
Use water soluble ingredients e.g. sugars
Powder blend is wetted
Wetted mass moulded into tablet under loose compression
Moulded mass is then dried

8. Thin Film Strips Comprise hydrophilic polymers e.g. pullulan
Process is based on liquid casting of polymer solution to form the film
Dosage controlled by concentration of API in bulk solution and film thickness (50 to 200mm)
Once dried film is cut into single unit doses prior to packaging
During manufacture dried film must be protected from heat & humidity
Final pack must protect from moisture
Use of encapsulated API challenging due to particle size

9. Examples, Thin Film Strips
Supplier
Product
Dose Strength
Novartis
Various under Theraflu and Triaminic brands
Phenylephrine HCl 2.5 to 10mg
Dextromethorphan HBr 5 to 20mg
Diphenhydramine HCl 12.5 to 25mg
Pfizer
Benadryl
Diphenhydramine HCl 12.5mg and 25mg
Sudafed
Phenylephrine HCl 10mg
Prestige
Chloraseptic
Benzocaine 3mg
Menthol 2mg

10. ODTs – How do they compare?

11. ODTs – How do they compare?
Technology Platform
Lyophilized
Compressed Tablet
Sugar Floss
Manufacturing requirements
Process
Specific
Common equipment
Facility
Some dedication
Product Characteristic
FDA Guidance
Zydis / QuickSolve
Lyoc
AdvaTab
OraSolv
DuraSolv
FlashDose
Max Tablet weight
< 500mg
400mg
750mg
500mg
600mg
Taste Masking
Not specified
Flavors, sweeteners, pH adjustment, ion
exchange resin
Taste Masked particles (Lyopan)
Flavours, sweeteners, taste masked particles
Flavours, sweeteners
Mouthfeel
Smooth
Variable (some gritty)
Clinical Applications
Not Specified BE
Buccal
Oral Vaccines
MR (Lyopan) MR
BE*
*CIMA / Cephalon have also developed Oravescent, on ODT designed to facilitate oral transmucosal delivery.

12. Freeze Dried ODT - Zydis®
I will now focus the rest of the presentation on Freeze dried orally disintegrating tabelets using Zydis as an example.
I have some placebo marketing samples to give away if any one wishes to take a closer look.

13. Zydis® Product Characteristics
Disintegrates in less than 10s, typically less than 5s
Robust, can withstand transport & handling
Typical shelf-life of up to years (physical & chemical)
Improved stability for some compounds due to freeze drying
Packaging integral part of product design, robustness, stability & child resistance
Applications:
Bioequivalence to conventional tablet
Pre-gastric absorption
Improved onset of action
Topical oral delivery

14. Rapid Disintegration What does rapid mean?
1 second
2 seconds
3 seconds
What does rapid mean?
Zydis products typically less than 5 seconds to disintegrate. Some products claim rapid disintegration with times greater than 50 seconds. Ok still fast compared to a standard tablet or capsule but the perceived difference is important (hence the preference for the US FDA definition)

15. Product Embossing and packaging
Zydis – delicate formulation not meant to be stable outside of pack for more that minutes (will shrink / softent)
Aluminium pack – moisture resistance

16. Zydis® Technical Review
Basic Formulation Composition

17. The Zydis® Process - Schematic
blister
freeze
freeze dry
pores
matrix
filling nozzle
rapid water permeation
and dispersion
drug in minimum
volume of liquid
Solution or
Suspension
Talk through slide

18. Zydis® Manufacturing process
Mix
Form Blister
Dose
Freeze
Talk through process, highlighting packaging as integral to product
at low temperature
Freeze Dry
Seal
Pack

19. Zydis® Formulation & Process - Key considerations
Dose and Solubility
Insoluble API ~ 400mg
Soluble API ~ 60mg
Lyopan will increase dose capability
Drug particle size
Zydis d90 ~ 30um
Lyopan no limits
Stability / Compatibility
Physical & chemical stability considerations
Taste Masking Strategies

20. Formulation - Taste Masking
Flavors
Appropriate selection to mask bitterness and match marketing requirements
Sweeteners
High intensity sweeteners routinely used
Aspartame
Acesulfame K
Sucralose
Ion Exchange Resins
Coated APIs - Lyopan
Unlike standard tablets or capsules orally disintegrating tablets release the drug in the mouth. If the drug tastes bad as many of them do a flavour and sweetener is often required to ensure palatability / patient complience. Particularly important for OTC as patient not likely to return to a formulation that is unpalatable
Japanese market has interest in other natural sweeteners (Stevia /Thaumatin).
Flavours and sweeteners are usually used in combination.

21. Zydis® – Taste Masking Example of Ion-Exchange Taste Masking
% Drug in Solution vs pH for Cationic Drug : IRP64 Complex (1:3)
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH

22. Zydis® – Taste Masking Example of Drug Encapsulation for Taste Masking
Integrity of Reverse Enteric Coating at pH 8 over 48 hours Aqueous Processing
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH

23. Zydis® Stability Considerations
Must be chemically stable for up to 48 hours in aqueous matrix
Potential for hydrate / polymorphic transitions
Employ pH optimisation to stabilise
Employ low temperature processing conditions ~ 10˚C
Matrix has stabilising affect
Matrix can be optimised to minimize crystal changes

24. Zydis® Evaluation SEM XRD DSC DVS
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH
DSC
DVS

25. Scanning Electron Microscopy
Rapid dissolution due to high porosity (also soluble nature of stucture formers).
Aero bar – sometimes sell 90% air – but expensive process to replace the ice with air!

26. Zydis® Process -Technical Considerations
Frozen hold (Mannitol Crystallisation) on Cracking
Anneal for 0.25hr
Cracking noted
Anneal for 30 hr
< 0. 4% Cracking
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH
Anneal for 8 hr
Cracking noted

27. Zydis® Process -Technical Considerations
Moisture, Tg and Storage Conditions
Product stored at or close to the Tg, matrix loses its strength and product will shrink
Recommend to stored at least 25oC below the Tg
Use Tg to justify moisture content specification with respect to storage temperature
Product X
At 7.5% moisture content, Tg = 61oC
Store at 40oC, propensity for shrinkage
Store at ambient, product physically stable
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH

28. Zydis® Process –Freeze Drying
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH

29. Zydis® Process –Eutectic Freezing Curve
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH
5% Mannitol °C
5% Potassium chloride °C
5% Sodium chloride °C
1% Trehalose °C
1% Glucose °C
1% Fructose °C

30. Zydis® Process –Sublimation
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH
Water: triple point 0.04°C, mbar
Menthol: melting point 42-44°C, vapor pressure 1.1 mbar
Ammonium bicarbonate: triple point ~50-60°C, ~500 mbar

31. Zydis® Process –Freezing Rate
Develop freezing process to optimize crystal structure
Large crystal  rapid disintegration, short freeze-drying cycle
Small crystals  product strength and robustness
Annealing of crystal structure after freezing
Amorphous structure (soluble actives)  crystalline structure
Hold above Tg, glass transition temperature
Small crystal structure
Hold near Te, eutectic melting point
Homogenous suspension – not like bottle suspension formulations only needs to be physically stable for few minutes. Constantly kept homogenous during process by stirring / recirculation.
Unlike traditional freeze drying technology this is performed in a liquid nitrogen freeze tunnel (not on shelf).
Mannitol (and sometimes other components) needs to crystallize to ensure product strength / robustness. Annealing time / Frozen storage sometimes required.
Manufaturing facility controlled to low RH

32. Examples of Technical Opportunities

33. Clinical Considerations
Bio equivalence
Pregastric Delivery
Faster Onset
Better S & E
Nano particle delivery system
Proteins / Peptides / Vaccines

34. Bioavailability - Bioequivalence
Plasma concentration ng/ml

35. Disintegration vs Water Volume
Agenda for this presentation.
What’s happening at Cardinal Health, at PTS, and our business unit.

36. Zydis® Pre-Gastric Absorption
Pre-Gastric Absorption - Efficacy & Safety of Selegiline

37. Metabolites of Selegiline Mean AUC (Nm.h)
Zydis Selegiline (1.25mg)
Selegiline Tablets (10mg)

38. Nanoparticle Formulation using Zydis®
Goals:
1. Nanoparticle stabilization during wet milling AND freeze drying
2. Use low conc. of stabilizers that do not have adverse taste
3. Rapid dispersion of nanoparticle solid dosage form

39. Nanoparticle Stability in Zydis®

40. In vitro dissolution of nanoparticulate Zydis®

41. Zydis® for Peptides & Proteins
Solid, unit doses presented in protective pack
Freeze drying – proven technology for stable protein formulations
Low temperature processing minimises potential for manufacturing losses
Solution / suspension dosing achieves good content uniformity
Solid dosage form aids long term stability
Liquid processing facilitates containment of potent drugs in production

42. Grazax® ODT Case Study: Oral Allergy Vaccine
Product: Oral vaccine alternative to injection
Active: Grass Pollen Extract from Phleum pratense (timothy grass)
Dose: 75,000 SQ-T (Equiv. ~15 mg Phl p5)
Dosing: Zydis® once-daily dosing, start >2 month before allergy season

43. Grazax® ODT Case Study: Oral Allergy Vaccine
Clinical Data2:
30% reduction in rhinoconjunctivitis symptoms score &
38% reduction in medication score compared with placebo. (P<0.0001).
2 Dahl et al J Allergy Clin. Immunol. 2006, 1118, p434

44. Activity Retained in Zydis® for 36 Months
Allergen Activity (Phl p5) in Zydis® vs. Time

45. What is Lyopan® Fast - Dissolve Technology?
Patented technology covering the manufacture of fast dissolve lyophilized dosage forms
Designed by University Basel and Pantec, a Swiss company linked to Rohrer, the equipment supplier in 2008
The process involves dosing powder into blisters and then adding a small amount of water, prior to freezing to bind the unit together
It is then frozen and dried like Zydis® Fast Dissolve Tablets
July 2011
Lyopan® Fast Dissolve Technology 44

46. The Zydis® and Lyopan® Fast-Dissolve Technology Process
Zydis ® Technology : Pre-mix
liquid & solids
Dose
Freeze
Lyopan ® Technology :Dispense the aqueous mixture and API separately
Seal
Dry
July 2011
Lyopan® Fast Dissolve Technology

47. Better Treatments with the combined Lyopan® and Zydis® Fast-Dissolve Technologies
Catalent has exclusive rights to Lyopan technology
Patent protected technology
Catalent will be both a development and manufacturing partner
Partnership complements the current Zydis technology
A wider group of molecules can now be formulated as a fast-dissolve lyophilized ODT
more molecules
Lyopan adds innovation to proven fast dissolve technology
Both processes produce a fast dissolve which disperses in as little as 10 seconds
Increased options for taste masking
Options for enteric coating or controlled release
Enables formulation of molecules at a higher dose ( >200 mg )
Potential to improve manufacturing efficiency by reducing cycle times
better treatments
Catalent will introduce Lyopan technology in the upcoming months
Pantec will continue to collaborate with Catalent
Non-GMP POC will be available
First GMP line anticipated to be established at the Zydis Swindon UK manufacturing site over next year
reliably supplied
July 2011
Lyopan® Fast Dissolve Technology 47

48. ODTs – A Review & Opportunities
Questions ?

49. discover more. THANK YOU
CATALENT PHARMA SOLUTIONS 14 SCHOOLHOUSE ROAD SOMERSET, NJ 08873
OSDrC® is a registered trademark of Sanwa Kagaku Kenkyusho Co., Ltd
Lyopan® is a registered trademark of Pantec AG