modified
release
technologies
Orodispersible Tablets:
A Review & Opportunities
September, 2011
What are ODTs?
Solid dosage form
Rapid
disintegration
on the tongue
Oral route of
administration
Fast Dissolve
Dosage Form
A stable, oral dosage form
with the dosing ease of a liquid
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.)
Why use ODT?
ODT
Clinical
Formulation
• Pregastric
delivery
• Compliance
• Faster onset
• Stability
• Better S&E
• Bioequivalence
• Local delivery
• Convenience
• Ease of use
Marketing
• New
presentation
• Extend
exclusivity
• Broader
application
• USP
ODT Technologies
Can be broadly categorised according to method of manufacture:
•Lyophilised
•Loosely Compressed
•Other
•Moulded tablets
•Spray dried powders
•Sugar Floss
•Mass Extrusion
Example ODT Technologies
Technology
Platform
Technology
Company
Example Products
Zydis ®
Catalent
15 commercial products
Grazax
Claritin
Lyoc
Cephalon
7 commercial products
Proxalyoc
Loperamide Lyoc
Pharmafreeze
SPI Pharmaceuticals
Unknown
Janssen
Quicksolv
Risperdal
AdvaTab
Eurand
Cetirizine
Lactimal
Orasolve /
Durasolv
CIMA
Remeron Soltab
Zomig-ZMT
Niravam
FazaClo
Orapred
Flashtab
Ethypharm
Prevacid Solutab
Ibuprofen
Pharmaburst
SPI Pharmaceuticals
Not known
Sugar floss
Flashdose
Biovail
Molded tablet
Wowtab
Yamanouchi /
Astellas
Lyophilised
Compressed Tablets
Hamal D
ODT Technologies
Loosely Compressed
Spray Dried
Rely on the use of:
oSuper-disintegrants
oEffervescent agents
oHighly aqueous soluble
excipients
oCombinations 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
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
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
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
Pfizer
Sudafed
Phenylephrine HCl 10mg
Prestige
Chloraseptic
Benzocaine 3mg
Menthol 2mg
ODTs – How do they compare?
Technology
Process
Manufacturing
Facility
Process
Pack
Group 1
Direct
Compression
EasyTec
Orasolv
Durasolv
Flashdose
OraVescent
Flashtab
Zydis
Lyoc
Biovail / Fuisz Quicksolv
LTS - Wafers
Standard
Specific
Specific
Specific
Some dedication Specific
Specific
Specific
Dedicated
Complex
Little
strength
but low
friability
<10S
40-300mg
Dedicated
Complex
Standard
Group 2
Moulding /
Floss
Standard
Transport
Some can be
fragile
<10N
DT's
20-30 S
Performance
Drug Load 500mg
Moderate
Friability
<30N
<20S
250mg
Group 3
Lyophilised
Group 4
Film - Wafers
N/A
<15S
1-15mg
ODTs – How do they compare?
Technology Platform
Manufacturing
requirements
Product
Characteristic
Lyophilized
Compressed Tablet
Sugar Floss
Process
Specific
Common equipment
Specific
Facility
Specific
Some dedication
Specific
Lyoc
AdvaTab
OraSolv
DuraSolv
FlashDose
750mg
750mg
500mg
600mg
FDA
Guidance
Zydis /
QuickSolve
Max Tablet
weight
< 500mg
400mg
Taste Masking
Not
specified
Flavors, sweeteners, pH
adjustment, ion
exchange resin
Taste Masked particles
(Lyopan)
Flavours, sweeteners, taste
masked particles
Flavours,
sweeteners
Mouthfeel
Not
specified
Smooth
Variable (some gritty)
Smooth
Clinical
Applications
Not
Specified
BE*
BE
BE
Buccal
Oral Vaccines
MR (Lyopan)
BE
BE
MR
BE*
*CIMA / Cephalon have also developed Oravescent, on ODT designed to facilitate oral transmucosal delivery.
Freeze Dried ODT - Zydis®
Zydis® Product Characteristics
Disintegrates in less than 10s, typically less than 5s
Robust, can withstand transport & handling
Typical shelf-life of up to 2 - 3 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
Rapid Disintegration
1 second
2 seconds
3 seconds
Product Embossing and packaging
Zydis® Technical Review
Basic Formulation Composition
Formulation Function
Typical Component
Matrix Former
Structure Former
Gelatin (Bovine, Fish)
Non – gelatin polymers
Mannitol
Structure Promotor
Sweeteners
Glycine
Aspartame, Acesulfame K
Other
Flavours
pH modifiers
Colours
The Zydis® Process - Schematic
Solution or
Suspension
filling nozzle
matrix
freeze
freeze dry
blister
drug in minimum
volume of liquid
rapid water permeation
and dispersion
pores
Zydis® Manufacturing process
Mix
Form Blister
Dose
at low temperature
Freeze Dry
Pack
Seal
Freeze
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
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
Zydis® – Taste Masking
Example of Ion-Exchange Taste Masking
% Drug in Solution vs pH for Cationic Drug : IRP64 Complex (1:3)
60
5 5 .1
Drug free in solution (% )
50
4 0 .1
40
3 4 .6
3 1 .1
30
20
1 1 .4
10
0 .5
1 .0
0 .1
0
3 .0
4 .0
5 .0
6 .0
7 .0
8 .0
p H o f s o lu tio n (p r io r to a d d itio n o f r e s in )
8 .6
1 0 .6
Zydis® – Taste Masking
Example of Drug Encapsulation for Taste Masking
Integrity of Reverse Enteric Coating at pH 8 over 48 hours Aqueous Processing
15
13
% dissolution
11
9
7:3 BD
7
7:3 48D
5
3
1
-1
10
20
30
40
time (min)
50
60
Zydis® Stability Considerations
Zydis Stability
•
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
Zydis® Evaluation
SEM
XRD
100
80
60
40
20
0
0
10
20
30
40
2 Theta Angle
7
6
water uptake (% weight gain)
Heat Fow (W/g)
10
5
0
-5
-10
-15
sorption
5
desorption
4
3
2
1
0
-50
-30
-10
10
30
50
-1
Temperature (C)
0
10
20
30
target RH (%RH)
DSC
DVS
40
50
60
Scanning Electron Microscopy
Zydis® Process -Technical Considerations
Frozen hold (Mannitol Crystallisation) on Cracking
Anneal for 0.25hr
Cracking noted
Anneal for 8 hr
Cracking noted
Anneal for 30 hr
< 0. 4% Cracking
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
M oisture C ontent & O nset Tg P rofile
H D M P laceb o & H D M /G razax Active S am p les
90.00
85.00
y = -4.4148x + 94.327
2
R = 0.9272
80.00
75.00
O n se t T g ( ° C )
Product X
•At 7.5% moisture content, Tg =
61oC
•Store at 40oC, propensity for
shrinkage
•Store at ambient, product
physically stable
70.00
65.00
60.00
55.00
50.00
45.00
40.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
M o istu re C o n ten t (% w /w )
H D M /G razax active sam ples
H D M P lacebo
Linear (H D M P lacebo)
8.00
9.00
Zydis® Process –Freeze Drying
Temperature [°C]
Zydis® Process –Eutectic Freezing Curve
20
t1
t2
t4
t3
t5
0
10°C
a rb itra ry tim e s c a le
e u te c tic te m p e r a tu re
10°C
-2 1
-5 0
—
5% Mannitol
-3.2°C
—
5% Potassium chloride
-11.0°C
—
5% Sodium chloride
-21.1°C
—
—
1% Trehalose
1% Glucose
—
1% Fructose
-28.4°C
-41.4°C
-48°C
Zydis® Process –Sublimation
A
P re ssu re [m b a r]
1013
Pressure at
eutectic teperature
liquid
solid
Sublim ation
p Eu
pP
B
C
vapour
3-5 °C
TP
T Eu
Freezing point
Solution
T em p [*C ]
• Water: triple point 0.04°C, 6.11 mbar
• Menthol: melting point 42-44°C, vapor pressure 1.1 mbar
• Ammonium bicarbonate: triple point ~50-60°C, ~500 mbar
Zydis® Process –Freezing Rate
H eat
re m o v a l
h ig h c o o lin g ra te
h ig h n u m b e r o f sm a ll ic e c ry s ta ls
lo w c o o lin g ra te
lo w n u m b e r o f b ig ic e c ry s ta ls
• 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
Examples of Technical
Opportunities
Clinical Considerations
• Bio equivalence
• Pregastric Delivery
• Faster Onset
• Better S & E
• Nano particle delivery system
• Proteins / Peptides / Vaccines
Bioavailability - Bioequivalence
2500
Plasma concentration ng/ml
Capsules
2000
Zydis with water
Zydis without water
1500
1000
500
0
0
1
4
9
15
36
72
120
168
Disintegration vs Water Volume
2.5mL
5mL
10mL
25 mL
50 mL
100
mL
200
mL
300
mL
400
mL
30
25
20
15
10
5
0
500
mL
Disintegration Time
(sec)
Disintegration Tim e as a Function of Water Volum e (Alavert vs Zydis)
Volum e (m ls)
Alavert
Claritin Reditabs
Difference in Time (sec)
Zydis® Pre-Gastric Absorption
Pre-Gastric Absorption - Efficacy & Safety of Selegiline
12
Zydis 10mg
Plasma concentration (ng/ml)
Eldepryl 10mg
10
Zydis 1.25mg
8
6
4
2
0
0
2
4
6
Time (h)
8
10
12
Metabolites of Selegiline
Mean AUC (Nm.h)
1521.0
Selegiline
N-desmethylselegiline
Methamphetamine
698.7
Amphetamine
2.8
114.2 56.4
9.5
Zydis Selegiline (1.25mg)
203.3
2.0
Selegiline Tablets (10mg)
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
Nanoparticle Stability in Zydis®
600
Particle Size (nm)
500
400
300
200
100
0
0
1
D50 - 25°C
D90 - 25°C
2
3
Time (months)
D50 - 40°C/75% RH
D90 - 40°C/75% RH
6
In vitro dissolution of nanoparticulate Zydis®
Fenofibrate 48 mg Dissolution in 0.4%SLS - With Pre-filter
Percent Release
100%
80%
60%
40%
Tricor
ZydisNano
20%
0%
0
5
10
15
20
Time (minutes)
25
30
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
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
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
Activity Retained in Zydis® for 36 Months
Allergen Activity (Phl p5) in Zydis® vs. Time
150
% Label claim
125
Grazax Batch
1, 25°C
100
Grazax Batch
2, 25°C
75
Grazax Batch
3, 25°C
50
Grazax Batch
4, 40°C
Grazax Batch
5, 40°C
25
0
0
6
12
18
Time (months)
24
30
36
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
—
July 2011
It is then frozen and dried like Zydis® Fast Dissolve Tablets
Lyopan® Fast Dissolve Technology
44
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
July 2011
Dry
Lyopan® Fast Dissolve Technology
46
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
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
more molecules
July 2011
better treatments
Lyopan® Fast Dissolve Technology
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
47
ODTs – A Review & Opportunities
Questions ?
THANK YOU
discover more.
CATALENT PHARMA SOLUTIONS
14 SCHOOLHOUSE ROAD
SOMERSET, NJ 08873
+ 1 866 720 3148
www.catalent.com
OSDrC® is a registered trademark of Sanwa Kagaku Kenkyusho Co., Ltd
Lyopan® is a registered trademark of Pantec AG