modified release technologies orodispersible tablets: a review & opportunities september, 2011
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modified release technologiesOrodispersible Tablets:
A Review & Opportunities
September, 2011
Oral route ofadministration
Oral route ofadministration
Solid dosage formSolid dosage form
Rapiddisintegrationon the tongue
Rapiddisintegrationon the tongue
Fast DissolveDosage Form
A stable, oral dosage formwith the dosing ease of a liquid
A stable, oral dosage formwith the dosing ease of a liquid
What are ODTs?
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?
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
ODT
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
Lyophilised Zydis ® Catalent 15 commercial productsGrazaxClaritin
Lyoc Cephalon 7 commercial productsProxalyocLoperamide Lyoc
Pharmafreeze SPI Pharmaceuticals Unknown
Janssen Quicksolv Risperdal
Compressed Tablets AdvaTab Eurand CetirizineLactimal
Orasolve / Durasolv CIMA Remeron SoltabZomig-ZMTNiravamFazaCloOrapred
Flashtab Ethypharm Prevacid SolutabIbuprofen
Pharmaburst SPI Pharmaceuticals Not known
Sugar floss Flashdose Biovail
Molded tablet Wowtab Yamanouchi / Astellas
Hamal D
ODT Technologies
Loosely Compressed Spray DriedRely on the use of:
oSuper-disintegrantsoEffervescent agentsoHighly aqueous soluble excipientsoCombinations of the above
Uses standard tabletting process with low compression forcesCan incorporate encapsulated API for taste masking or modified releaseCompression forces need to be minimised to prevent damage to API coatingEffervescent systems can be moisture sensitiveMay 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 10mgDextromethorphan HBr 5 to 20mgDiphenhydramine HCl 12.5 to 25mg
Pfizer Benadryl Diphenhydramine HCl 12.5mg and 25mg
Pfizer Sudafed Phenylephrine HCl 10mg
Prestige Chloraseptic Benzocaine 3mgMenthol 2mg
ODTs – How do they compare?
Group 1Direct
Compression
Group 2Moulding /
FlossGroup 3
LyophilisedGroup 4
Film - WafersEasyTec OrasolvDurasolv FlashdoseOraVescent Flashtab Biovail / Fuisz
ZydisLyocQuicksolv LTS - Wafers
ProcessStandard Specific Specific Specific
FacilitySome dedication Specific Specific Specific
ProcessStandard Standard
DedicatedComplex
DedicatedComplex
TransportSome can be fragile<10N
Moderate Friability<30N
Little strengthbut low friability N/A
DT's 20-30 S <20S <10S <15SDrug Load 500mg 250mg 40-300mg 1-15mg
Manufacturing
Pack
Performance
Technology
ODTs – How do they compare?
Technology Platform Lyophilized Compressed Tablet Sugar Floss
Manufacturing requirements
Process Specific Common equipment Specific
Facility Specific Some dedication Specific
Product Characteristic
FDA Guidance
Zydis / QuickSolve
Lyoc AdvaTab OraSolv DuraSolv FlashDose
Max Tablet weight
< 500mg 400mg 750mg 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 Not specified
Smooth Variable (some gritty) Smooth
Clinical Applications
Not Specified
BEBuccal
Oral VaccinesMR (Lyopan)
BE BEMR
BE* BE* 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
1 second 2 seconds 3 seconds
Rapid Disintegration
Product Embossing and packagingProduct Embossing and packaging
Zydis® Technical Review
Basic Formulation CompositionBasic Formulation Composition
Formulation Function
Typical Component
Matrix Former Gelatin (Bovine, Fish) Non – gelatin polymers
Structure Former Mannitol
Structure Promotor Glycine
Sweeteners Aspartame, Acesulfame K
Other Flavours pH modifiers Colours
The Zydis® Process - Schematic
blister
freeze
freeze drypores
matrixfilling nozzle
rapid water permeationand dispersion
drug in minimum volume of liquid
Solution orSuspension
Zydis® Manufacturing process
at low temperature
Mix
Form Blister
Dose
Freeze
Freeze Dry
SealPack
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
ZydisZydis® Formulation & Process - Key considerations Formulation & Process - Key considerations
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
55.1
40.1
34.631.1
11.4
0.5 1.0 0.1
0
10
20
30
40
50
60
Dru
g f
ree
in
so
luti
on
(%
)
3.0 4.0 5.0 6.0 7.0 8.0 8.6 10.6 pH of solution (prior to addition of resin)
Example of Ion-Exchange Taste MaskingExample of Ion-Exchange Taste Masking% Drug in Solution vs pH for Cationic Drug : IRP64 Complex (1:3)
Zydis® – Taste Masking
-1
1
3
5
7
9
11
13
15
10 20 30 40 50 60
time (min)
% d
iss
olu
tio
n
7:3 BD
7:3 48D
Example of Drug Encapsulation for Taste MaskingIntegrity of Reverse Enteric Coating at pH 8 over 48 hours Aqueous Processing
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
0
20
40
60
80
100
0 10 20 30 40
2 Theta Angle
-15
-10
-5
0
5
10
-50 -30 -10 10 30 50
Temperature (C)
He
at
Fo
w (
W/g
)
-1
0
1
2
3
4
5
6
7
0 10 20 30 40 50 60
target RH (%RH)
wa
ter
up
tak
e (
% w
eig
ht
ga
in)
sorption
desorption
SEM XRD
DSC DVS
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
Product X •At 7.5% moisture content, Tg = 61oC•Store at 40oC, propensity for shrinkage•Store at ambient, product physically stable
Moisture Content & Onset Tg Profile HDM Placebo & HDM/Grazax Active Samples
y = -4.4148x + 94.327
R2 = 0.9272
40.00
45.00
50.00
55.00
60.00
65.00
70.00
75.00
80.00
85.00
90.00
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00
Moisture Content (%w/w)
Ons
et T
g (°
C)
HDM/Grazax active samples HDM Placebo Linear (HDM Placebo)
Zydis® Process –Freeze Drying
Zydis® Process –Eutectic Freezing CurveT
em
peratu
re [°C
]
arbitrary time scale
20
0
t1 t2 t3 t4 t5
-50
-21eutectic temperature
10
°C
10
°C
— 5% Mannitol -3.2°C— 5% Potassium chloride -11.0°C— 5% Sodium chloride -21.1°C— 1% Trehalose -28.4°C— 1% Glucose -41.4°C— 1% Fructose -48°C
Zydis® Process –Sublimation
Pressure at eutectic teperature
Pres
sure
[mba
r]
Temp [*C]
vapour
solid
liquid
1013
TEu
Freezing pointSolution
pEuSublimation
3-5 °CpP
TP
A
B 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
low cooling ratelow number of big ice crystals
high cooling rate
high number of small ice crystals
Heatremoval
• 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
0
500
1000
1500
2000
2500
0 1 4 9 15 36 72 120 168
Capsules
Zydis with water
Zydis without water
Pla
sma
con
cen
trat
ion
ng
/ml
Bioavailability - Bioequivalence
Disintegration vs Water Volume
Disintegration Time as a Function of Water Volume (Alavert vs Zydis)
05
1015202530
500
mL
400
mL
300
mL
200
mL
100
mL
50 m
L
25 m
L
10m
L
5mL
2.5m
L
Volume (mls)
Dis
inte
gra
tio
n T
ime
(sec
)
Alavert Claritin Reditabs Difference in Time (sec)
Zydis® Pre-Gastric Absorption
Pre-Gastric Absorption - Efficacy & Safety of Selegiline
0
2
4
6
8
10
12
0 2 4 6 8 10 12
Time (h)
Pla
sm
a c
on
cen
trati
on
(n
g/m
l)
Zydis 10mg
Eldepryl 10mg
Zydis 1.25mg
Metabolites of Selegiline Mean AUC (Nm.h)
2.09.5
203.3114.2
1521.0
56.4
698.7
2.8
Selegiline
N-desmethylselegiline
Methamphetamine
Amphetamine
Zydis Selegiline (1.25mg) 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®
0
100
200
300
400
500
600
0 1 2 3 6
Time (months)
Par
ticl
e S
ize
(n
m)
D50 - 25°C D50 - 40°C/75% RHD90 - 25°C D90 - 40°C/75% RH
In vitro dissolution of nanoparticulate Zydis®
Fenofibrate 48 mg Dissolution in 0.4%SLS - With Pre-filter
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25 30Time (minutes)
Per
cent
Rel
ease
Tricor ZydisNano
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 g Phl p5)
Dosing: Zydis® once-daily dosing,start >2 month before allergy season
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
Grazax® ODT Case Study: Oral Allergy Vaccine
Activity Retained in Zydis® for 36 Months
Allergen Activity (Phl p5) in Zydis® vs. Time
0
25
50
75
100
125
150
0 6 12 18 24 30 36
Time (months)
% L
abel
cla
im
Grazax Batch1, 25°C
Grazax Batch2, 25°C
Grazax Batch3, 25°C
Grazax Batch4, 40°C
Grazax Batch5, 40°C
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
44July 2011 Lyopan® Fast Dissolve Technology
46
DrySeal
Freeze
Zydis ® Technology : Pre-mix liquid & solids
Dose
The Zydis® and Lyopan® Fast-Dissolve Technology Process
Lyopan ® Technology :Dispense the aqueous mixture and API separately
July 2011 Lyopan® Fast Dissolve Technology
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
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
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
47July 2011 Lyopan® Fast Dissolve Technology
ODTs – A Review & Opportunities
Questions ?
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., LtdLyopan® is a registered trademark of Pantec AG
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