1. Improved Tablet  Focus on stability  Focus on reasonable production  Focus on packaging material High-End Tablet  Vision?! Study Medication  Focus on time line  Focus on GCP compliance G&H Meeting 18-20 February, 2003 Liverpool, UK WP 7 Pharmaceutics (Lichtwer Pharma)  Objectives…

2. Improved Tablet Improved Tablet  Comparing  Comparing…  Dragee (Market Standard)  300 mg Garlic powder  Higher amounts of excipients  Coating time: up to 15 h  Total process time: up to 24 h  Novel film coated tablet  300 mg Garlic powder  Less amounts of excipients (pre dried)  Coating time:  up to 5 h  Total process time: up to 14 h  Advantages of a film tablet…  Size (Compliance)  Costs for Excipients  Costs for Production (time)

3. Improved stabile Tablet Improved stabile Tablet  Details on Stability Study  Full ICH-guideline compliance -Tests under GMP conditions with validated methods -Three production batches providing a minimum of 100.000 tablets per batch -Three different controlled climatic zones  Up to seven different packaging materials -PVC-, PVDC, COC-Aluminium blister -Two different kinds of Alu-Alu blisters -PE-, and glass bottles  Two different dosage forms -100 mg and 300 mg Tablets  Estimated full costs for the study: 160 k€

4. Dragees (Commercial Products) 25°C/60% and 40°C/75% Commercial products are insufficient !!!

5. Comparison Powder/Dragees 25 °C / 60% r.h. Proof that commercial tablet formulations are sub optimal

6.  Comparing… Commercial Dragee vs. Novel Film Tablet  Dragee  300 mg Garlic powder  117 mgLactose monohydrate  9 mgCellulose  5 mgSilicium dioxide  3 mgMg Stearate  224 mgSaccharose  46 mgTalcum  22 mgHPMC (mod. Cellulose)  9 mgCastor oil, native  5 mgPolyethylenglycol  5 mgPolyvinylpyrrolidon  2 mgSilicium dioxide  2 mg Gelatine  1 mgMontan glycol wax  750 mgTotal Weight  Novel film coated tablet  300 mg Garlic powder  117 mgmicrocristalline Cellulose  24 mgLactose, anhydrous  10 mgCellulose  5 mgSilicium dioxide  6 mg Soy polysaccharides  3 mgTriglycerides  25 mgHPMC (mod. Cellulose)  5 mgTalcum  4 mg Titan dioxide  1 mg Carnauba wax  500 mgTotal Weight

7. Comparison Tablets with lyophilisised/non lyophilisised Powder/Dragees 25 °C / 60% r.h. Improvement of Stability of at least >100%

8. Comparison Packaging Material 25 °C / 60% r.h.

9. Comparison Packaging Material 30 °C / 70% r.h.

10. Comparison Packaging Material 40 °C / 75% r.h. Conclusion -at least 24 months stability available -countries with difficult climatic conditions included!

11. Comparison Packaging Material 25 °C / 75% r.h. – 300 mg Tablets

12. Comparison Packaging Material 30 °C / 70% r.h. – 300 mg Tablets

13. Comparison Packaging Material 40 °C / 75% r.h. – 300 mg Tablets

14. Comparison Blister Material 25 °C / 60% r.h. – 300 mg Tablets

15. Improved Tablet Improved Tablet  Sugar coated tablets are not suitable to meet the high international standards of pharmaceutical stability  No kind of transparent polymer blister quality provide sufficient protection  A strict dry formulation (ingredients and process) combined with…  a 100% water vapour resistant packaging …are indispensable  Conclusion

16. High-End Tablet High-End Tablet  Laboratory experiments to gain a alliin enriched extract were successful  4-5 fold enrichment of alliin (up to 7%in total) without transformation to allicin by an economic single-step extraction procedure  Extract seems to be suitable for direct use for production (“crystalline like” – not sticky)  Scale up experiments – still open  Garlic powder combined with a alliin rich extract

17. High-End Tablet High-End Tablet  Development of a slow release matrix tablet – open  Additional development time of 9-15 months is necessary (only with orientating stability data)  Realisation: not really realistic – see end of the project in Jan 2004!  Garlic powder combined with an alliin rich extract

18. Study medication Human Intervention Study Study medication Human Intervention Study  Three arm study – double blind performing a double dummy design  Verum: Garlic powder tablets Reference: Statin medication (Cholesterol- Synthesis-Inhibitor Placebo:for Garlic tablets and for statin medication  30 Volunteers in each group; 2100 mg garlic powder a day; Treatment over 100 days  Medication produced and packed under GMP

19.  Formulation – Study medication  “Film-Dragee”  300 mg Garlic powder  187 mgLactose anhydrous  25 mgCellulose  4 mgSilicium dioxide  4 mgMg Stearate  ca. 40 mgMethacrylic acid copolymer  ca. 10 mgCitric acid  ca. 5 mg Talcum  224 mgSaccharose  46 mgTalcum  5 mgPolyethylenglycol  5 mgPolyvinylpyrrolidon  2 mgSilicium dioxide  2 mg Gelatine  1 mgMontan glycol wax  Ca. 800 mgTotal weight Tablet core Gastric resistant film Sugar coating

20. Study medication Human Intervention Study Study medication Human Intervention Study  Verum: Tablet design Tablet Core Gastric Fluid Resistant Coating Sugar Coating „Dragee“

21. Study medication Time schedule Study medication Time schedule  7 th -8 th WeekProduction Verum & Placebo  7 th -8 th WeekWriting & Authorisation production protocol  9 th -10 th WeekWriting Randomisation Plan  9 th -10 th WeekQuality Control Verum & Placebo  10 th -11 th WeekWriting & Authorisation packaging/ labelling  12 th WeekPackaging & Labelling  13 th -14 th WeekFinal Release & Delivery

22. Thanks for listening!!! Thanks for listening!!! Anybody who fell asleep? Fine!