1. Objectives… G&H Meeting 18-20 February, 2003 Liverpool, UK
WP 7 Pharmaceutics (Lichtwer Pharma)
Objectives…
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

2. Advantages of a film tablet…
Improved Tablet
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. Details on Stability Study
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 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. Commercial products are insufficient !!!
Improved Tablet
Dragees (Commercial Products)
25°C/60% and 40°C/75%
Commercial products are insufficient !!!

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

6. Comparing… Commercial Dragee vs. Novel Film Tablet
Improved Tablet
Comparing… Commercial Dragee vs. Novel Film Tablet
Dragee
300 mg Garlic powder
117 mg Lactose monohydrate
9 mg Cellulose
5 mg Silicium dioxide
3 mg Mg Stearate
224 mg Saccharose
46 mg Talcum
22 mg HPMC (mod. Cellulose)
9 mg Castor oil, native
5 mg Polyethylenglycol
5 mg Polyvinylpyrrolidon
2 mg Silicium dioxide
2 mg Gelatine
1 mg Montan glycol wax
750 mg Total Weight
Novel film coated tablet
300 mg Garlic powder
117 mg microcristalline Cellulose
24 mg Lactose, anhydrous
10 mg Cellulose
5 mg Silicium dioxide
6 mg Soy polysaccharides
3 mg Triglycerides
25 mg HPMC (mod. Cellulose)
5 mg Talcum
4 mg Titan dioxide
1 mg Carnauba wax
500 mg Total Weight

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

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

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

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

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

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

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

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

15. Conclusion 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

16. Garlic powder combined with a alliin rich extract
High-End Tablet
Garlic powder combined with a alliin rich extract
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

17. Garlic powder combined with an alliin rich extract
High-End Tablet
Garlic powder combined with an alliin rich extract
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!

18. 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. Gastric resistant film
Improved Tablet
Formulation – Study medication
“Film-Dragee”
300 mg Garlic powder
187 mg Lactose anhydrous
25 mg Cellulose
4 mg Silicium dioxide
4 mg Mg Stearate
ca. 40 mg Methacrylic acid copolymer
ca. 10 mg Citric acid
ca. 5 mg Talcum
224 mg Saccharose
46 mg Talcum
5 mg Polyethylenglycol
5 mg Polyvinylpyrrolidon
2 mg Silicium dioxide
2 mg Gelatine
1 mg Montan glycol wax
Ca. 800 mg Total weight
Tablet core
Gastric resistant film
Sugar coating

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

21. Study medication Time schedule
7th-8th Week Production Verum & Placebo
7th-8th Week Writing & Authorisation production protocol
9th-10th Week Writing Randomisation Plan
9th-10th Week Quality Control Verum & Placebo
10th-11th Week Writing & Authorisation packaging/ labelling
12th Week Packaging & Labelling
13th-14th Week Final Release & Delivery

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