“Optimizing High Dose ODTsODTsUsing DOE DesignsUsing DOE Designs”

(OOrally rally DDisintegratingisintegrating TTabletsablets)

Feb 3, 2008

Cecil W. Propst PhDcpropst@spipharma.com

Presentation Outline

• What is an ODT? Who requires it?• How is it designed?• Therapeutic benefits?• How is it tested?• Regulatory Requirements• Basis for Design for High Dose Actives• SPI Pharma – Formulation Wizard

What is an ODT?The Center for Drug Evaluation and Research (CDER) states an ODT to be (1998):

"A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue.”

Alias: Quick DissolveQuick Dissolve Fast MeltFast MeltRapid DisintegratingRapid Disintegrating Flash MeltFlash MeltMouth DispersingMouth Dispersing

Market a standard or a trademark!

Who requires (prefers) ODT?• Patients who have difficulty in swallowing tablets especially

children and elderly (approx. 1/3 of the patients have difficulty swallowing)– Parkinson, Migraine, Epilepsy, Schizophrenia

• Convenience “on-the-move”, requires no water intake • Compliance• Quicker onset of action (Migraine, ED, Insomnia)• “Preference for the wafer drug delivery system [Zydis] over

tablets was noted by 75% of the sample population. The findings were consistent for younger (<60 years) and older (>60 years) subjects”

Ref: Schwartz et al. J Clin Pharmacol 1995; 35: 362-367

• Four out of five patients would prefer ODTs vs swallow tablets. (Market Survey)

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Little water

Limited Insolubles

Fast to disintegrate

Fast to dissolve

Smooth mouth feel

5

Therapeutic benefits of ODTs

• Buccal, Mucosal, Sublingual Absorption (Pre –GI)– Avoid first pass effects

• Might be able to lower API dosing with same AUC – therapeutic effect – (Migrane, ED)

• Less side effects due to potential lower dosing– Increase permeability /bioavailability (insomnia drug) – Faster adsorption

• Faster onset of action? (Lower tmax)– Proven with API’s (due to API adsorption in mouth)

• Consumers perception of “quicker relief”

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Bioequivalence - Selegiline ODTFirst-pass metabolism greatly reduced!

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1.2

0 2 4 6 8 10 12 14

Time (hours)

Plas

ma

Con

c. (n

g/m

l)

Immediate Release Tab (10 mg)

Lyophilized ODT (1.25 mg)

Slide courtesy of Cardinal Health 7

How are ODTs tested?

• FDA recommends the USP/EP Disintegration Method

30 seconds is fast for the test!

Less than 12 up and down motions inUSP/EP unit..

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USP/EP Compliant Units (Automatic Endpoint)

1) Time lift2) Proximity

sensor3) Conductivity

100 um spaceErweka, Distech

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What types of products are in ODT form?What types of products are in ODT form?

• Products that disintegrate in a few seconds (Lyophilized)

• Majority disintegrate in less than 30 seconds (Direct Compression)

• Some are intentionally made to disintegrate in 1 - 2 minutes (Buccal adsorption longer oral residence sought)

• Analgesics/Pain/Migraine (Ibuprofen - APAP)• Cough/Cold/Antihistamine• Psychiatric/Neural medications (ED therapy)• Anti-emetic, Other

ODT Brands • Alavert™ ODT (Loratidine)• Aricept® ODT (Donepazil)• Benadryl® FastMelt™

• Claritin® RediTabs®

• Dimetapp® Quick Dissolve• Excederin® Quicktabs™

• Feldene® Melt• Maxalt® MLT (Rizatriptan)• NuLev®

• Paracetamol ODT• Parcopa® (Carbadopa/Levodopa)• Pepcid® RPD

• Prevacid® SoluTab(Lansoprazole)

• Risperdal® M-tab (Risperidone)• Remeron® SolTab™

(Mirtazapine)• Tempra® FirsTabs• Tramadol® ODT (Tramadol)• Triaminic® Softchews®

• Zofran ODT® (Ondansetron)• Zolpidem ODT®

• Zomig-ZMT® Rapimelt(Zolmitriptan)

• Zoton FasTab®

• Zyprexa® Zydis™(Olanzapine)

Products above are registered trademarks of Cima, Novartis, BMS, Pfizer, GSK, Schwarz, Schering Plough, Tap, Janssen, Eli Lilly, Merck. Pharmaburst is used with APIs in RED.

Harmonization

Legal definition!

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Regulatory Guidance Summary/Targets

1. USP/EP Disintegration Test is recommended2. Test media: Must pass disintegration time in saliva

or water without chewing or drinking liquids3. Disintegration time: ODTs must disintegrate in less

than 30 seconds4. Tablet weight recommended: Not to exceed 500 mg.

Larger tablets may have an effect on patient safety and compliance, regulators say.– The extent of component solubility can influence the acceptability

of a larger tablet being labeled an ODT.

To fit within the Orally Disintegrating Tablet Classification

Deadline to submit comments to US FDA is June 8, 2007 13

Consumer PreferencesAPI should be…………..• Effective• Easy to Take• Quick Acting• Convenient to carry• Pleasant Tasting• Robust• Cost effective

“It is estimated that more than 50% of patients do not comply with dosing recommendations primarily due to: poor taste, difficulty in administration, or inconvenience”. www.eurand.com

MysteriesMysteriesCan Can ODTODT’’’’ss Deliver:Deliver:

Convenient to carryConvenient to carryEasy to take/ Fast MeltingEasy to take/ Fast MeltingQuick onset/less side effectsQuick onset/less side effectsPleasant TastePleasant TasteGreater StabilityGreater StabilityRobust TabletsRobust TabletsCost EffectiveCost Effective

Taste Masking• Taste vs Speed in ODTs

– If the product tastes bad, the consumer could care less about speed and may prefer the swallow tablet

– If a product tastes great the consumer may prefer the ODT over aconventional tablet solely based upon taste

• Poor taste can negate benefits of convenient dosing– Difficulty in administration (Pediatric and Geriatric patients)– General inconvenience (Need to find something to drink)

Taste Masking Systems

Particles small enough. Non-gritty. Not broken in compression.

Meet dissolution criteria.

• Approaches to reduce drug dissolution on unit dispersion in the mouth• pH modification• pH of minimum solubility

– Complexation/Partitioning• Ion-exchange Resins• Emulsions

– Coating/Microencapsulation• Coating must withstand tablet forming process

– Fracture of coatings– Provide control release profile– Conventional addition of flavours and masking agents

Pharmacaps

Pharmacaps

Pleasant Taste

Non Gritty – smooth!!

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Tablet Requirements

– USP Disintegration <30s – Robust units of good appearance and can be

removed intact from blister pocket without significant residue

– Survive packaging into bottles < 1% friability– Acceptable physical and chemical stability

• ICH stability conditions • Requirements as for immediate release solid

oral dosage forms

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Pharmaburst ®• Pharmaburst™ is a specially engineered excipient

system• Free flowing white powder• Made with pharmaceutical

monographed excipients• Smooth mouth feel• Rapid disintegration properties• Cost effective• In-house development on standard equipment• Can be manufactured at standard temperature and

humidity conditions

Optimization of Tablet Design!

Optimize tablet diameter to height for force distribution (4:1)(Tool Diameter Selection)

Same compressed tablet density for porosity (Targeted final tablet density)Same compression force per unit surface area

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In Pharmaburst Design Space!

Chose Matrix of High Dose Actives for Design Challenge!

Tool Selection Guide

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8

10

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100 300 500 700 900 1100

Tab Wt., mg

Tool

Siz

e, m

m

Optimized around true density of Pharmaburst

And final tablet density targets..

Pharmaburst Design SpaceActives:• Pharmaburst

Evaluated:HardnessThicknessFriabilityODT disintegrationUSP disintegrationEjection Force

Challenge:< 30 sec USP disintegration<1% Friability> 5 kP hardness

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Tablet Weight600, 900, 1200, 1500 mgForce/Area40, 60, 80 N/mm2

60 N / mm2 centers the compressed density

N/mm2mgUnits601050Center20450Scale Units00.512-0.511+-0.510--0.59+-8+0.57--60+50-4++30-0.52-+1

Force (KN)Weight (mg)Row

<0.000114.870.14472.1515Interaction (a x b)

<0.000143.780.09414.1193Force/Area (b)

<0.000128.850.12553.6197Tablet Weight (a)

<0.000199.570.07977.9348Intercept

Prob > tt RatioStd. ErrorEstimateTerm

Parameter Estimates

<.0001240.9014812C. Total

Prob > F0.07240.652019Error

1105.4280.0832240.249463Model

F-RatioMean SquareSum of SquaresDFSource

Analysis of Variance

13Observations

y = 3.6197 (a) + 4.1193 (b) + 2.1515 (a x b)^0.5 + 7.93488.643077Mean of Response

0.269158Root Mean Square Error

0.996391Rsquare Adj

0.997293Rsquare Placebo Fity = Hardness in kPa = Tab Weightb = F/A

Pharmaburst ®

5

10

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25

30

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Hardness (kp)

USP

/EP

Dis

inte

grat

ion

(sec

)

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Pharmaburst ®

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Hardness (kp)

Fria

bilit

y (%

)

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Pharmaburst ®

• Lloyds LR 30K– Measures compressed

density– BFI (Brittle Fracture

Index)– SI (Strain Index)– BI (Bond Index)

Active Classification:

Actives for Matrix Challenge!• Aspirin

(Plastic with a low energy high strain distance displacement)

• Acetominophen(Elastic with higher energy recovery strength)

• Ibuprofen (Ductile with a high strain distance displacement)

Design with Actives!Actives:• Placebo• Ibuprofen • Paracetamol• Aspirin

Evaluated:HardnessThicknessFriabilityODT disintegrationUSP disintegrationEjection Force

Challenge:< 30 sec USP disintegration<1% Friability> 5 kP hardness

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Amounts %: Tablet Weight100% : 600, 900, 1200, 1500 mg10, 25, 40 %: 500, 750, 1000 mg10, 25, 40 %: 600, 900, 1200 mg20, 30, 40 %: 300, 600, 900 mg

Experimental Design- Aspirin

Design for Wizard

2x2x2 Factrol2 level of API

10% and 40%2 level - tab. wt.

600 and 1200 mg2 levels for force per area

40 & 80 N/mm2

2 center points 25%, 900 mg, 40 N/mm2

2 center points around face area25%, 900 mg, 40 N/mm2 & 80 M/mm2

Active %

Tabl

et W

t, m

g

F/A, N/mm2

1200

600

80

40

10 %

40 %

+ -0

Design Prediction

Active Ingredient AspirinDesired Dose (mg) 250

Desired Tablet Weight (mg) 500Desired Tooling Diameter (mm) 11

Compression Force (KN) 7PositiveOutliers

Oral Disintgration Time 25.0 SecondsBP/USP (sec) 16.4 Seconds < 30 13.6Hardness (kp) 6.7 kP > 5 1.7Friability (%) 0.3 % < 0.5 0.2

Thickness (mm) 3.8 mmEjection (N) 115.2 Newtons < 100 -15.2

INPUT VARIABLES

OUTPUT RESULTS Targets

Not Stated

Tablet Wizard

Click Here To Launch

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Experimental Design- ApAp

Active %

Tabl

et W

t, m

g

F/A, N/mm2

1200

600

80

40

10 %

40 %

+ -0

Design for Wizard

2x2x2 Factrol2 level of API

10% and 40%2 level - tab. wt.

600 and 1200 mg2 levels for force per area

40 & 80 N/mm2

2 center points 25%, 900 mg, 40 N/mm2

2 center points around face area25%, 900 mg, 40 N/mm2 & 80 M/mm2

6090025%Center2030015%Scale Units+0012-0011++-100009--+8-++7+++6-+-5+--4---3+-+20001

Force/AreaWeight (mg)[APAP], %Row

187-343.06.5605.117.013.51493500/65 mg Pharmaburst

plus Caffeine

19434541.05.9508.817211500500 mg Pharmaburst using APAP-E

18329550.95.1919.716201200325 mg Pharmaburst using APAP-E

9820300.74.5874.31410750160 mg Pharmaburst using APAP-E

8214290.73.5824.411737580 mg Pharmaburst using APAP-E

Acetaminophen

Tablet Wt. (m

g)

Diam

eter mm

Hardness (kP)

Thickness (mm

).

Friability (%).

OD

T (Sec)

USP/EP D

isint. (Sec).

Ejection Force (N).

Force (KN

).

Paracetamol Examples

Ibuprofen Examples

15823440.35.2678.21715.51400400 mg Pharmaburst Iubprofen

8816291.04.5334.1149700200 mg Pharmaburst Iubprofen

8517300.74.1885.11312500100 mg Pharmaburst Iubprofen

Ibuprofen

Tablet Wt. (m

g)

Diam

eter mm

Hardness (kP)

Thickness (mm

).

Friability (%).

OD

T (Sec)

USP/EP D

isint. (Sec).

Ejection Force (N).

Force (KN

).

ODTs Summary

• Can improve bioavailability for selected compounds• Can deliver topical activity• Can improve onset of therapeutic action• Can improve product stability through freeze-drying• Can improve compliance• Easy to swallow• Convenient to use • Unique dosage form• Preferred by patients to tablets• Provides patent-protected line extensions

PatentsCompany: SPI Pharma, Patent Application #: US 2003/0118642 A1, Technology:

“Pharmaburst”, Title: Co-processed carbohydrate system as a quick-dissolve matrix for solid dosage forms.

Company: Akina, Inc., Patent #: WO 2004/100857, Technology: “Frosta” Title: Highly Plastic Granules for Making Fast Melting Tablets

Company: Cima Labs, Inc., Patent: US 6,024,981 also WO/98/46215, plus continuation US 6,221,392 B1, Technology: DuraSolv and/or OraSolv, Title: Rapidly Dissolving Robust Dosage Form

Company: Therics, Inc., Patent #: US 6,471,992 B1, Technology: “Flash Dose”, Title: Dosage form exhibiting rapid Disperse properties, methods of use and process for the manufacture of same.

Company: Yamanouchi Pharmaceutical Co., Patent #: US 5,576,014, Technology: “Wowtabs”, Title: Intrabuccally dissolving moldings and production process thereof

Van Scoik KG. Solid Pharmaceutical Dosage in Tablet Triturate Form and Method of Producing the Same. US Patent No. 5,082,667 1992.

Masaki K. Intrabuccally-Disintegrating Preparation and Production Thereof. US Patent No. 5,466,464 1995.

Blank RG et al. Fast-Dissolving Dosage Forms. US Patent No. 4,946,684. 1990Hienemann H, Rothe W. Preparation of Porous Tablets. US Patent No. 3,885,026. 1975Roses BJ, Blair J. Rapidly Soluble Oral Dosage Forms, Methods of Masking the Same and

Compositions. US Patent No. 5,762,961. 1998Eurand International S.p.A. Fast-Disintegrating Tablets. US Patent No. 6,596,311. 2003Others