WP7 - Haffner
Download
Report
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
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…
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
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”
300 mg
187 mg
25 mg
4 mg
4 mg
Garlic powder
Lactose anhydrous
Cellulose
Silicium dioxide
Mg Stearate
Tablet core
ca. 40 mg
ca. 10 mg
ca. 5 mg
Methacrylic acid copolymer
Citric acid
Talcum
Gastric resistant film
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?