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Transcript of Improved Tablet Focus on stability Focus on reasonable production Focus on packaging material...
Improved TabletImproved Tablet Focus on stability Focus on stability Focus on reasonable Focus on reasonable
productionproduction Focus on packaging Focus on packaging
materialmaterial
High-End TabletHigh-End Tablet Vision?! Vision?!
Study Medication Study Medication Focus on time line Focus on time line Focus on GCP Focus on GCP
compliancecompliance
G&H Meeting 18-20 February, 2003G&H Meeting 18-20 February, 2003Liverpool, UKLiverpool, UK
WP 7 Pharmaceutics (Lichtwer Pharma)WP 7 Pharmaceutics (Lichtwer Pharma)
Objectives…Objectives…
Improved TabletImproved Tablet
ComparingComparing…
Dragee Dragee (Market Standard)(Market Standard)
300 mg Garlic powder300 mg Garlic powder Higher amounts of excipientsHigher amounts of excipients Coating time: up to 15 hCoating time: up to 15 h Total process time: up to 24 hTotal process time: up to 24 h
Novel film coated tablet Novel film coated tablet
300 mg Garlic powder300 mg Garlic powder Less amounts of excipients Less amounts of excipients
(pre dried)(pre dried) Coating time: Coating time: up to 5 h up to 5 h Total process time: up to 14 hTotal process time: up to 14 h
Advantages of a film tablet…Advantages of a film tablet… Size (Compliance)Size (Compliance) Costs for ExcipientsCosts for Excipients Costs for Production (time)Costs for Production (time)
Improved stabile TabletImproved stabile Tablet
Details on Stability StudyDetails on Stability Study
Full ICH-guideline complianceFull ICH-guideline compliance- Tests under GMP conditions with validated methodsTests under GMP conditions with validated methods- Three production batches providing a minimum of 100.000 Three production batches providing a minimum of 100.000
tablets per batchtablets per batch- Three different controlled climatic zonesThree different controlled climatic zones
Up to seven different packaging materialsUp to seven different packaging materials- PVC-, PVDC, COC-Aluminium blisterPVC-, PVDC, COC-Aluminium blister- Two different kinds of Alu-Alu blistersTwo different kinds of Alu-Alu blisters- PE-, and glass bottlesPE-, and glass bottles
Two different dosage formsTwo different dosage forms- 100 mg and 300 mg Tablets100 mg and 300 mg Tablets
Estimated full costs for the study: Estimated full costs for the study: 160 k€160 k€
Improved TabletImproved Tablet
Dragees (Commercial Products)
25°C/60% and 40°C/75%
Commercial products
are insufficient !!!
Improved TabletImproved Tablet
Comparison Powder/Dragees
25 °C / 60% r.h.
Proof that commercial
tablet formulations are
sub optimal
Comparing… Comparing… Commercial Dragee vs. Novel Film TabletCommercial Dragee vs. Novel Film Tablet
DrageeDragee 300 mg 300 mg Garlic powderGarlic powder 117 mg117 mg Lactose Lactose
monohydratemonohydrate 9 mg9 mg CelluloseCellulose 5 mg5 mg Silicium dioxideSilicium dioxide 3 mg3 mg Mg StearateMg Stearate
224 mg224 mg SaccharoseSaccharose 46 mg46 mg TalcumTalcum 22 mg22 mg HPMC (mod. HPMC (mod.
Cellulose)Cellulose) 9 mg9 mg Castor oil, nativeCastor oil, native 5 mg5 mg PolyethylenglycolPolyethylenglycol 5 mg5 mg PolyvinylpyrrolidonPolyvinylpyrrolidon 2 mg2 mg Silicium dioxideSilicium dioxide 2 mg 2 mg GelatineGelatine 1 mg1 mg Montan glycol waxMontan glycol wax
750 mg750 mg Total WeightTotal Weight
Novel film coated tablet Novel film coated tablet
300 mg 300 mg Garlic powderGarlic powder 117 mg117 mg microcristalline microcristalline
CelluloseCellulose 24 mg24 mg Lactose, anhydrousLactose, anhydrous 10 mg10 mg CelluloseCellulose 5 mg5 mg Silicium dioxideSilicium dioxide 6 mg 6 mg Soy polysaccharidesSoy polysaccharides 3 mg3 mg TriglyceridesTriglycerides
25 mg25 mg HPMC (mod. Cellulose)HPMC (mod. Cellulose) 5 mg5 mg TalcumTalcum 4 mg 4 mg Titan dioxideTitan dioxide 1 mg 1 mg Carnauba waxCarnauba wax
500 mg500 mg Total WeightTotal Weight
Improved TabletImproved Tablet
Improved TabletImproved TabletComparison Tablets with lyophilisised/non lyophilisised Powder/Dragees
25 °C / 60% r.h.
Improvement of
Stability
of at least >100%
Influence of Packaging Material - 100 mg Tablets
50
60
70
80
90
100
0 6 12 18 24 30 36Months
rel.
Act
ivit
y (%
)
PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister
PE Bottles Glass Bottles
Improved TabletImproved Tablet
Comparison Packaging Material
25 °C / 60% r.h.
Influence of Packaging Material - 100 mg Tablets
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Months
rel.
Ac
tiv
ity
(%
)
PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister PE Bottles Glass Bottles
Improved TabletImproved Tablet
Comparison Packaging Material
30 °C / 70% r.h.
Improved TabletImproved Tablet
Comparison Packaging Material
40 °C / 75% r.h.
Conclusion
- at least 24 months stability
available
- countries with difficult
climatic conditions
included!
Comparison Packaging Material - 300 mg Tablets
30
40
50
60
70
80
90
100
110
0 6 12 18 24Months
rel.
Ac
tiv
ity
(%
)
PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister PE Bottles Glass Bottles
Improved TabletImproved Tablet
Comparison Packaging Material
25 °C / 75% r.h. – 300 mg Tablets
Influence of Packaging Material - 300 mg Tablets
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24Months
rel.
Ac
tiv
ity
(%
)
PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister
PE Bottles Glass Bottles
Improved TabletImproved Tablet
Comparison Packaging Material
30 °C / 70% r.h. – 300 mg Tablets
Comparing Packaging Material - 300 mg Tablets
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15Months
rel.
Act
ivit
y (%
)
PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister PE Bottles Glass Bottles
Improved TabletImproved Tablet
Comparison Packaging Material
40 °C / 75% r.h. – 300 mg Tablets
Comparison Polymer Blister Material
20
30
40
50
60
70
80
90
100
110
0 3 6 9 12 15 18 21 24Months
rel.
Ac
tiv
ity
(%
)
PVC/Alu Blister - DRAGEES
PVDC/Alu Blister - DRAGEES
PVDC/Alu Blister - Film Tablet
COC190/Alu Blister - Film Tablet
Alu/Alu Polymer Composite Blister - Film Tablet
Improved TabletImproved Tablet
Comparison Blister Material
25 °C / 60% r.h. – 300 mg Tablets
Improved TabletImproved Tablet
Sugar coated tablets are not suitable to meet the high Sugar coated tablets are not suitable to meet the high international standards of pharmaceutical stability international standards of pharmaceutical stability
No kind of transparent polymer blister quality provide No kind of transparent polymer blister quality provide sufficient protection sufficient protection
A strict dry formulation (ingredients and process) A strict dry formulation (ingredients and process) combined with…combined with…
a 100% water vapour resistant packaging a 100% water vapour resistant packaging …are indispensable…are indispensable
ConclusionConclusion
High-End TabletHigh-End Tablet
Laboratory experiments to gain a alliin enriched Laboratory experiments to gain a alliin enriched extract were successful extract were successful
4-5 fold enrichment of alliin (up to 7%in total) 4-5 fold enrichment of alliin (up to 7%in total) without transformation to allicin by an economic without transformation to allicin by an economic single-step extraction proceduresingle-step extraction procedure
Extract seems to be suitable for direct use for Extract seems to be suitable for direct use for production (“crystalline like” – not sticky)production (“crystalline like” – not sticky)
Scale up experiments – still openScale up experiments – still open
Garlic powder combined with a alliin Garlic powder combined with a alliin rich extractrich extract
High-End TabletHigh-End Tablet
Development of a slow release matrix tablet – open Development of a slow release matrix tablet – open
Additional development time of 9-15 months is Additional development time of 9-15 months is necessary (only with orientating stability data) necessary (only with orientating stability data)
Realisation: not really realistic – see end of the Realisation: not really realistic – see end of the project in Jan 2004!project in Jan 2004!
Garlic powder combined with Garlic powder combined with an alliin rich extractan alliin rich extract
Study medicationStudy medicationHuman Intervention StudyHuman Intervention Study
Three arm study – double blind performing Three arm study – double blind performing a double dummy designa double dummy design
Verum: Verum: Garlic powder tabletsGarlic powder tabletsReference: Reference: Statin medication (Cholesterol-Statin medication (Cholesterol-Synthesis-InhibitorSynthesis-InhibitorPlacebo:Placebo: for Garlic tablets and for statin for Garlic tablets and for statin medicationmedication
30 Volunteers in each group; 2100 mg garlic 30 Volunteers in each group; 2100 mg garlic powder a day; Treatment over 100 dayspowder a day; Treatment over 100 days
Medication produced and packed under GMPMedication produced and packed under GMP
Formulation – Study medicationFormulation – Study medication
Improved TabletImproved Tablet
““Film-Dragee”Film-Dragee” 300 mg 300 mg Garlic powderGarlic powder 187 mg187 mg Lactose anhydrousLactose anhydrous 25 mg25 mg CelluloseCellulose 4 mg4 mg Silicium dioxideSilicium dioxide 4 mg4 mg Mg StearateMg Stearate
ca. 40 mgca. 40 mg Methacrylic acid copolymerMethacrylic acid copolymer ca. 10 mgca. 10 mg Citric acidCitric acid ca. 5 mg ca. 5 mg TalcumTalcum
224 mg224 mg SaccharoseSaccharose 46 mg46 mg TalcumTalcum 5 mg5 mg PolyethylenglycolPolyethylenglycol 5 mg5 mg PolyvinylpyrrolidonPolyvinylpyrrolidon 2 mg2 mg Silicium dioxideSilicium dioxide 2 mg 2 mg GelatineGelatine 1 mg1 mg Montan glycol waxMontan glycol wax
Ca. 800 mgCa. 800 mg Total weightTotal weight
Tablet core
Gastric resistant film
Sugar coating
Study medicationStudy medicationHuman Intervention StudyHuman Intervention Study
Verum: Tablet designVerum: Tablet design
Tablet CoreGastric Fluid Resistant Coating
Sugar Coating„Dragee“
Study medicationStudy medicationTime scheduleTime schedule
77thth-8-8thth Week Week Production Verum & PlaceboProduction Verum & Placebo
77thth-8-8thth Week Week Writing & Authorisation production Writing & Authorisation production protocolprotocol
99thth-10-10thth Week Week Writing Randomisation PlanWriting Randomisation Plan
99thth-10-10thth Week Week Quality Control Verum & PlaceboQuality Control Verum & Placebo
1010thth-11-11thth Week Week Writing & Authorisation packaging/ Writing & Authorisation packaging/ labellinglabelling
1212th th WeekWeek Packaging & LabellingPackaging & Labelling
1313thth-14-14thth Week Week Final Release & DeliveryFinal Release & Delivery
Thanks for listening!!!Thanks for listening!!!
Anybody who fell asleep?
Fine!