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

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)

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 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€

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

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

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

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%

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

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

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!

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

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

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

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

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

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

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!

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

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

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

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

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