WP7 - Haffner

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Transcript WP7 - Haffner

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
Improved Tablet
 Comparing…
 Dragee (Market Standard)
 Novel film coated tablet
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
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
 300 mg Garlic powder
 Less amounts of excipients
(pre dried)
 Coating time:  up to 5 h
 Total process time: up to 14 h
300 mg Garlic powder
Higher amounts of excipients
Coating time: up to 15 h
Total process time: up to 24 h
 Advantages of a film tablet…
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

Size (Compliance)
Costs for Excipients
Costs for Production (time)
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€
Improved Tablet
Dragees (Commercial Products)
25°C/60% and 40°C/75%
100mg / 300mg Commercial Products (Dragees)
100
rel. Activity (%)
90
80
70
60
50
40
30
100mg Tablets; Standard Polymer Blister; 25°/60%
20
100mg Tablets; Standard Polymer Blister; 40°/75%
300mg Tablets; Standard Polymer Blister; 25°/60%
10
300mg Tablets; Standard Polymer Blister; 40°/75%
0
0
3
6
9
12
15
18
Months
21
24
27
30
33
36
Improved Tablet
Comparison Powder/Dragees
25 °C / 60% r.h.
Powder vs 100mg and 300mg Dragees
100
rel. Activity (%)
90
80
70
60
50
100mg Tablets; Standard Polymer Blister; 25°/60%
300mg Tablets; Standard Polymer Blister; 25°/60%
40
Powder in PE Bottles
30
0
3
6
9
12
15
18
Months
21
24
27
30
33
36
Improved Tablet
 Comparing…
Commercial Dragee vs. Novel Film Tablet
 Novel film coated tablet
 Dragee











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


300 mg
117 mg
9 mg
5 mg
3 mg
224 mg
46 mg
22 mg
9 mg
5 mg
5 mg
2 mg
2 mg
1 mg
750 mg
Garlic powder
Lactose monohydrate
Cellulose
Silicium dioxide
Mg Stearate
Saccharose
Talcum
HPMC (mod. Cellulose)
Castor oil, native
Polyethylenglycol
Polyvinylpyrrolidon
Silicium dioxide
Gelatine
Montan glycol wax
Total Weight







300 mg
117 mg
24 mg
10 mg
5 mg
6 mg
3 mg




25 mg
5 mg
4 mg
1 mg

500 mg
Garlic powder
microcristalline Cellulose
Lactose, anhydrous
Cellulose
Silicium dioxide
Soy polysaccharides
Triglycerides
HPMC (mod. Cellulose)
Talcum
Titan dioxide
Carnauba wax
Total Weight
Improved Tablet
Comparison Tablets with
lyophilisised/non lyophilisised Powder/Dragees
25 °C / 60% r.h.
100mg and 300mg Novel Film Coated Tablets
rel. Activity (%)
100
95
90
85
80
300 mg Tablets; Alu/Alu Blister 25°/60%
300 mg Tablets; Alu/Alu Blister 30°/70%
75
300 mg Tablets; Alu/Alu Blister 25°/60% lyoph. Garlic
300 mg Tablets; Alu/Alu Blister 30°/70% lyoph. Garlic
70
0
3
6
9
12
15
18
Months
21
24
27
30
33
36
Improved Tablet
Comparison Packaging Material
25 °C / 60% r.h.
Influence of Packaging Material - 100 mg Tablets
rel. Activity (%)
100
90
80
70
PVDC 60 Polymer/Alu Blister
pure Alu/Alu Blister
Alu/Alu Polymer Composite Blister
PE Bottles
Glass Bottles
60
50
0
6
12
18
Months
24
30
36
Improved Tablet
Comparison Packaging Material
30 °C / 70% r.h.
Influence of Packaging Material - 100 mg Tablets
100
rel. Activity (%)
90
80
70
60
PVDC 60 Polymer/Alu Blister
pure Alu/Alu Blister
Alu/Alu Polymer Composite Blister
PE Bottles
Glass Bottles
50
40
30
0
6
12
18
Months
24
30
36
Improved Tablet
Comparison Packaging Material
40 °C / 75% r.h.
Comparision Packaging Material - 100 mg Tablet
100
90
rel. Activity (%)
80
70
60
50
40
PVDC 60 Polymer/Alu Blister
pure Alu/Alu Blister
Alu/Alu Polymer Composite Blister
PE Bottles
Glass Bottles
30
20
10
0
0
3
6
Months
9
12
15
Improved Tablet
Comparison Packaging Material
25 °C / 75% r.h. – 300 mg Tablets
Comparison Packaging Material - 300 mg Tablets
110
rel. Activity (%)
100
90
80
70
60
PVDC 60 Polymer/Alu Blister
pure Alu/Alu Blister
Alu/Alu Polymer Composite Blister
PE Bottles
Glass Bottles
50
40
30
0
6
12
Months
18
24
Improved Tablet
Comparison Packaging Material
30 °C / 70% r.h. – 300 mg Tablets
Influence of Packaging Material - 300 mg Tablets
100
rel. Activity (%)
90
80
70
60
50
40
PVDC 60 Polymer/Alu Blister
pure Alu/Alu Blister
Alu/Alu Polymer Composite Blister
PE Bottles
Glass Bottles
30
20
10
0
0
3
6
9
12
Months
15
18
21
24
Improved Tablet
Comparison Packaging Material
40 °C / 75% r.h. – 300 mg Tablets
Comparing Packaging Material - 300 mg Tablets
100
90
rel. Activity (%)
80
70
60
50
40
PVDC 60 Polymer/Alu Blister
pure Alu/Alu Blister
Alu/Alu Polymer Composite Blister
PE Bottles
Glass Bottles
30
20
10
0
0
3
6
Months
9
12
15
Improved Tablet
Comparison Blister Material
25 °C / 60% r.h. – 300 mg Tablets
Comparison Polymer Blister Material
110
100
rel. Activity (%)
90
80
70
60
PVC/Alu Blister - DRAGEES
50
PVDC/Alu Blister - DRAGEES
PVDC/Alu Blister - Film Tablet
40
COC190/Alu Blister - Film Tablet
30
Alu/Alu Polymer Composite Blister - Film Tablet
20
0
3
6
9
12
Months
15
18
21
24
Improved Tablet
 Conclusion
 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
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
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:
Reference:
Placebo:
Garlic powder tablets
Statin medication (CholesterolSynthesis-Inhibitor
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
Improved Tablet
 Formulation – Study medication
 “Film-Dragee”
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300 mg
187 mg
25 mg
4 mg
4 mg
Garlic powder
Lactose anhydrous
Cellulose
Silicium dioxide
Mg Stearate
Tablet core
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ca. 40 mg
ca. 10 mg
ca. 5 mg
Methacrylic acid copolymer
Citric acid
Talcum
Gastric resistant film
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224 mg
46 mg
5 mg
5 mg
2 mg
2 mg
1 mg
Saccharose
Talcum
Polyethylenglycol
Polyvinylpyrrolidon
Silicium dioxide
Gelatine
Montan glycol wax
Sugar coating

Ca. 800 mg Total weight
Study medication
Human Intervention Study
 Verum: Tablet design
Gastric Fluid
Resistant
Sugar
Tablet
Coating
Core Coating
„Dragee“
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
Thanks for listening!!!
Fine!
Anybody who fell asleep?