Improved Tablet Focus on stability Focus on reasonable production Focus on packaging material High-End Tablet Vision?! Study Medication Focus

Improved TabletImproved Tablet Focus on stability Focus on stability Focus on reasonable Focus on reasonable

productionproduction Focus on packaging Focus on packaging

materialmaterial

High-End TabletHigh-End Tablet Vision?! Vision?!

Study Medication Study Medication Focus on time line Focus on time line Focus on GCP Focus on GCP

compliancecompliance

G&H Meeting 18-20 February, 2003G&H Meeting 18-20 February, 2003Liverpool, UKLiverpool, UK

WP 7 Pharmaceutics (Lichtwer Pharma)WP 7 Pharmaceutics (Lichtwer Pharma)

Objectives…Objectives…

Improved TabletImproved Tablet

ComparingComparing…

Dragee Dragee (Market Standard)(Market Standard)

300 mg Garlic powder300 mg Garlic powder Higher amounts of excipientsHigher amounts of excipients Coating time: up to 15 hCoating time: up to 15 h Total process time: up to 24 hTotal process time: up to 24 h

Novel film coated tablet Novel film coated tablet

300 mg Garlic powder300 mg Garlic powder Less amounts of excipients Less amounts of excipients

(pre dried)(pre dried) Coating time: Coating time: up to 5 h up to 5 h Total process time: up to 14 hTotal process time: up to 14 h

Advantages of a film tablet…Advantages of a film tablet… Size (Compliance)Size (Compliance) Costs for ExcipientsCosts for Excipients Costs for Production (time)Costs for Production (time)

Improved stabile TabletImproved stabile Tablet

Details on Stability StudyDetails on Stability Study

Full ICH-guideline complianceFull ICH-guideline compliance- Tests under GMP conditions with validated methodsTests under GMP conditions with validated methods- Three production batches providing a minimum of 100.000 Three production batches providing a minimum of 100.000

tablets per batchtablets per batch- Three different controlled climatic zonesThree different controlled climatic zones

Up to seven different packaging materialsUp to seven different packaging materials- PVC-, PVDC, COC-Aluminium blisterPVC-, PVDC, COC-Aluminium blister- Two different kinds of Alu-Alu blistersTwo different kinds of Alu-Alu blisters- PE-, and glass bottlesPE-, and glass bottles

Two different dosage formsTwo different dosage forms- 100 mg and 300 mg Tablets100 mg and 300 mg Tablets

Estimated full costs for the study: Estimated full costs for the study: 160 k€160 k€


Dragees (Commercial Products)

25°C/60% and 40°C/75%

Commercial products

are insufficient !!!


Comparison Powder/Dragees

25 °C / 60% r.h.

Proof that commercial

tablet formulations are

sub optimal

Comparing… Comparing… Commercial Dragee vs. Novel Film TabletCommercial Dragee vs. Novel Film Tablet

DrageeDragee 300 mg 300 mg Garlic powderGarlic powder 117 mg117 mg Lactose Lactose

monohydratemonohydrate 9 mg9 mg CelluloseCellulose 5 mg5 mg Silicium dioxideSilicium dioxide 3 mg3 mg Mg StearateMg Stearate

224 mg224 mg SaccharoseSaccharose 46 mg46 mg TalcumTalcum 22 mg22 mg HPMC (mod. HPMC (mod.

Cellulose)Cellulose) 9 mg9 mg Castor oil, nativeCastor oil, native 5 mg5 mg PolyethylenglycolPolyethylenglycol 5 mg5 mg PolyvinylpyrrolidonPolyvinylpyrrolidon 2 mg2 mg Silicium dioxideSilicium dioxide 2 mg 2 mg GelatineGelatine 1 mg1 mg Montan glycol waxMontan glycol wax

750 mg750 mg Total WeightTotal Weight

Novel film coated tablet Novel film coated tablet

300 mg 300 mg Garlic powderGarlic powder 117 mg117 mg microcristalline microcristalline

CelluloseCellulose 24 mg24 mg Lactose, anhydrousLactose, anhydrous 10 mg10 mg CelluloseCellulose 5 mg5 mg Silicium dioxideSilicium dioxide 6 mg 6 mg Soy polysaccharidesSoy polysaccharides 3 mg3 mg TriglyceridesTriglycerides

25 mg25 mg HPMC (mod. Cellulose)HPMC (mod. Cellulose) 5 mg5 mg TalcumTalcum 4 mg 4 mg Titan dioxideTitan dioxide 1 mg 1 mg Carnauba waxCarnauba wax

500 mg500 mg Total WeightTotal Weight


Improved TabletImproved TabletComparison Tablets with lyophilisised/non lyophilisised Powder/Dragees

25 °C / 60% r.h.

Improvement of

Stability

of at least >100%

Influence of Packaging Material - 100 mg Tablets

50

60

70

80

90

100

0 6 12 18 24 30 36Months

rel.

Act

ivit

y (%

)

PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister

PE Bottles Glass Bottles


Comparison Packaging Material

25 °C / 60% r.h.


30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Months

rel.

Ac

tiv

ity

(%

)

PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister PE Bottles Glass Bottles



30 °C / 70% r.h.



40 °C / 75% r.h.

Conclusion

- at least 24 months stability

available

- countries with difficult

climatic conditions

included!

Comparison Packaging Material - 300 mg Tablets

30

40

50

60

70

80

90

100

110

0 6 12 18 24Months

rel.

Ac

tiv

ity

(%

)




25 °C / 75% r.h. – 300 mg Tablets


0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24Months

rel.

Ac

tiv

ity

(%

)

PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister

PE Bottles Glass Bottles



30 °C / 70% r.h. – 300 mg Tablets

Comparing Packaging Material - 300 mg Tablets

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15Months

rel.

Act

ivit

y (%

)




40 °C / 75% r.h. – 300 mg Tablets

Comparison Polymer Blister Material

20

30

40

50

60

70

80

90

100

110

0 3 6 9 12 15 18 21 24Months

rel.

Ac

tiv

ity

(%

)

PVC/Alu Blister - DRAGEES

PVDC/Alu Blister - DRAGEES

PVDC/Alu Blister - Film Tablet

COC190/Alu Blister - Film Tablet

Alu/Alu Polymer Composite Blister - Film Tablet


Comparison Blister Material

25 °C / 60% r.h. – 300 mg Tablets


Sugar coated tablets are not suitable to meet the high Sugar coated tablets are not suitable to meet the high international standards of pharmaceutical stability international standards of pharmaceutical stability

No kind of transparent polymer blister quality provide No kind of transparent polymer blister quality provide sufficient protection sufficient protection

A strict dry formulation (ingredients and process) A strict dry formulation (ingredients and process) combined with…combined with…

a 100% water vapour resistant packaging a 100% water vapour resistant packaging …are indispensable…are indispensable

ConclusionConclusion

High-End TabletHigh-End Tablet

Laboratory experiments to gain a alliin enriched Laboratory experiments to gain a alliin enriched extract were successful extract were successful

4-5 fold enrichment of alliin (up to 7%in total) 4-5 fold enrichment of alliin (up to 7%in total) without transformation to allicin by an economic without transformation to allicin by an economic single-step extraction proceduresingle-step extraction procedure

Extract seems to be suitable for direct use for Extract seems to be suitable for direct use for production (“crystalline like” – not sticky)production (“crystalline like” – not sticky)

Scale up experiments – still openScale up experiments – still open

Garlic powder combined with a alliin Garlic powder combined with a alliin rich extractrich extract

High-End TabletHigh-End Tablet

Development of a slow release matrix tablet – open Development of a slow release matrix tablet – open

Additional development time of 9-15 months is Additional development time of 9-15 months is necessary (only with orientating stability data) necessary (only with orientating stability data)

Realisation: not really realistic – see end of the Realisation: not really realistic – see end of the project in Jan 2004!project in Jan 2004!

Garlic powder combined with Garlic powder combined with an alliin rich extractan alliin rich extract

Study medicationStudy medicationHuman Intervention StudyHuman Intervention Study

Three arm study – double blind performing Three arm study – double blind performing a double dummy designa double dummy design

Verum: Verum: Garlic powder tabletsGarlic powder tabletsReference: Reference: Statin medication (Cholesterol-Statin medication (Cholesterol-Synthesis-InhibitorSynthesis-InhibitorPlacebo:Placebo: for Garlic tablets and for statin for Garlic tablets and for statin medicationmedication

30 Volunteers in each group; 2100 mg garlic 30 Volunteers in each group; 2100 mg garlic powder a day; Treatment over 100 dayspowder a day; Treatment over 100 days

Medication produced and packed under GMPMedication produced and packed under GMP

Formulation – Study medicationFormulation – Study medication


““Film-Dragee”Film-Dragee” 300 mg 300 mg Garlic powderGarlic powder 187 mg187 mg Lactose anhydrousLactose anhydrous 25 mg25 mg CelluloseCellulose 4 mg4 mg Silicium dioxideSilicium dioxide 4 mg4 mg Mg StearateMg Stearate

ca. 40 mgca. 40 mg Methacrylic acid copolymerMethacrylic acid copolymer ca. 10 mgca. 10 mg Citric acidCitric acid ca. 5 mg ca. 5 mg TalcumTalcum

224 mg224 mg SaccharoseSaccharose 46 mg46 mg TalcumTalcum 5 mg5 mg PolyethylenglycolPolyethylenglycol 5 mg5 mg PolyvinylpyrrolidonPolyvinylpyrrolidon 2 mg2 mg Silicium dioxideSilicium dioxide 2 mg 2 mg GelatineGelatine 1 mg1 mg Montan glycol waxMontan glycol wax

Ca. 800 mgCa. 800 mg Total weightTotal weight

Tablet core

Gastric resistant film

Sugar coating

Study medicationStudy medicationHuman Intervention StudyHuman Intervention Study

Verum: Tablet designVerum: Tablet design

Tablet CoreGastric Fluid Resistant Coating

Sugar Coating„Dragee“

Study medicationStudy medicationTime scheduleTime schedule

77thth-8-8thth Week Week Production Verum & PlaceboProduction Verum & Placebo

77thth-8-8thth Week Week Writing & Authorisation production Writing & Authorisation production protocolprotocol

99thth-10-10thth Week Week Writing Randomisation PlanWriting Randomisation Plan

99thth-10-10thth Week Week Quality Control Verum & PlaceboQuality Control Verum & Placebo

1010thth-11-11thth Week Week Writing & Authorisation packaging/ Writing & Authorisation packaging/ labellinglabelling

1212th th WeekWeek Packaging & LabellingPackaging & Labelling

1313thth-14-14thth Week Week Final Release & DeliveryFinal Release & Delivery

Thanks for listening!!!Thanks for listening!!!

Anybody who fell asleep?

Fine!

Documents

Improved Tablet Focus on stability Focus on reasonable production Focus on packaging material High-End Tablet Vision?! Study Medication Focus