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

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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