dh 29 development of analytical methods dh 30 analysis of eu market products dh 33 development of...

DH 29 DH 29 Development of analytical methods Development of analytical methods

DH 30 DH 30 Analysis of EU market products Analysis of EU market products

DH 33 DH 33 Development of a novel tablet Development of a novel tablet

DH 36 DH 36 Preparation of study medication Preparation of study medication

DH 31,32,34,35 DH 31,32,34,35 Publication/Patents (Dissemination) Publication/Patents (Dissemination)

G&H Meeting Jan 20 - 21, 2003G&H Meeting Jan 20 - 21, 2003Leiden, The NetherlandsLeiden, The Netherlands

WP 7 Pharmaceutics (Lichtwer Pharma)WP 7 Pharmaceutics (Lichtwer Pharma)

Objectives…Objectives…

G&H Meeting,G&H Meeting, Leiden 2004Leiden 2004

Overall analytical method for garlicOverall analytical method for garlic

0 10 20 30 40 50 60min

1 234

5

6

7

1 Alliin2 g-Glutamyl-S-allylcysteine3 g-Glutamyl-S-trans-1-propenylcysteine4 g-Glutamyl phenylalanine5 Allicin6 Dithiines7 Sulfides

Garlic under enzyme inhibiting conditionsGarlic under enzyme inhibiting conditions

0.1

0.3

0.5

0.7

0.9

0 2 4 6 8 10 12 14 16 18 20 22 24

Retention time [min]

Ab

sorp

tio

n (

AU

)

1 Alliin2 unknown (Allylcysteine)3 g-Glutamyl-S-allylcysteine4 g-Glutamyl-S-trans-1-propenylcysteine5 g-Glutamyl phenylalanine

1

2

34

5


Garlic under aqueous conditionsGarlic under aqueous conditions


0.1

0.3

0.5

0.7

0.9

0 2 4 6 8 10 12 14 16 18 20 22 24

Retention time [min]

Ab

sorp

tio

n (

AU

)

1

2

3 4

51 unknown (Allylcysteine)2 g-Glutamyl-S-allylcysteine3 g-Glutamyl-S-trans-1-propenylcysteine4 g-Glutamyl phenylalanine5 Allicin

0

0,5

1

1,5

2

2,5

3

Alliin Allicin Peptides

Co

nte

nt

[%]

AUT 1

AUT 2

GER 1

ITA 1

ITA 2

NL 1

NL 2

SWE 1

SWE 2

SWE 3

UK 1

Quality of EU garlic productsQuality of EU garlic products


Stability of EU garlic productsStability of EU garlic products


0

20

40

60

80

100

Re

fere

nc

e

AU

T 1

AU

T 2

GE

R 1

ITA

1

ITA

2

NL

1

NL

2

SW

E 1

SW

E 2

SW

E 3

UK

1

AlliinAllicinPeptides

% o

f s

tart

ing

va

lue


Garlic of the future!

Jungleof the market

Details on Stability StudiesDetails on Stability Studies

Organic film basedOrganic film based Full compliance to ICH-guidelinesFull compliance to ICH-guidelines Up to seven different packaging materialsUp to seven different packaging materials Two different dosage formsTwo different dosage forms

Aqueous film basedAqueous film based Reformulation of tablet coreReformulation of tablet core Formulation of coatingFormulation of coating Establishing aqueous coating procedureEstablishing aqueous coating procedure


Commercial Products (Dragees)100mg and 300mg

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36Months

rel.

Act

ivit

y (%

)

100mg Tablets; Standard Polymer Blister; 25°/60%




Tolerance

100 mg Tablets - 25°C / 60% Long Term Condition; Climatic Zone IV

40

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

Tolerance

OrganicOrganic Film Tablets (100 mg) Film Tablets (100 mg)


300 mg Tablets 25°C / 60%Long Term Condition; Climatic Zone II

30

40

50

60

70

80

90

100

110

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

Tolerance

OrganicOrganic Film Tablets (300 mg) Film Tablets (300 mg)


For the organic coated tablets real time stability according EU guidelines are available for 30 – 36 months (4 time improvement!)

For aqueous coated tablets real time stability according EU guidelines are available for 1 – 5 months (ongoing studies!)

Conclusion Novel Tablet (Stability)Conclusion Novel Tablet (Stability)


A EU drug application procedure will be done when 6 months of real time stability data for the 300 mg tablets are available (3rd quarter of 2004)

A 100 mg tablet will be developed within the next 6 months according to the 300 mg one

Outlook Dissemination Novel Tablet Outlook Dissemination Novel Tablet (Aqueous Coating)(Aqueous Coating)


Tabletting Minor difficulties with the flowability and compressibility of the EU garlic powder

Coating Everything went fine…

Sugar Coating Everything went fine…

Release Full compliance with specifications!

GCP Minor deviations

Study Medication for the Study Medication for the Human Intervention Study - Human Intervention Study - RésuméRésumé ……


Publication (Dissemination)Publication (Dissemination)


Auger J and Haffner T et al. Congress for Hyphenated Technologies in Chromatography, February 6-8 2002, Bruges, Belgium)

Keiss H-P, Dirsch V, Hartung T, Haffner T, Truemann L, Auger J, Kahane R. and Vollmar A M. J. Nutrition 133(7), 2171-5 (2003)

Arnault, I, Christidès, J P, Mandon, N, Haffner, T, Kahane, R and AugerJournal of Chromatography A, 2003 Mar 28;991(1):69-75

Siess M-H, Haffner T et al.. J Agric Food Chem 51, 7617-23 (2003)

Le Bon A-M, Vernevaut M.-F., Vernevaut L G., Kahane R., Auger, J., Haffner T., Siess, M.-H.. SSubmitted for publication

Auger J and Haffner T et al. Congress for Hyphenated Technologies in Chromatography, February 6-8 2002, Bruges, Belgium)

Keiss H-P, Dirsch V, Hartung T, Haffner T, Truemann L, Auger J, Kahane R. and Vollmar A M. J. Nutrition 133(7), 2171-5 (2003)

Arnault, I, Christidès, J P, Mandon, N, Haffner, T, Kahane, R and AugerJournal of Chromatography A, 2003 Mar 28;991(1):69-75

Siess M-H, Haffner T et al.. J Agric Food Chem 51, 7617-23 (2003)

Le Bon A-M, Vernevaut M.-F., Vernevaut L G., Kahane R., Auger, J., Haffner T., Siess, M.-H.. SSubmitted for publication


Many thanks toMany thanks to

Marie-Hélène, Verena, Angelika, Marie-Hélène, Verena, Angelika,

Ingrid, Anne-Marie, Jacques, and Ingrid, Anne-Marie, Jacques, and

Hans-PeterHans-Peter… …

……for covering my for covering my Achilles heelAchilles heel – –

the publication work!the publication work!

Who is a Who is a Cesar Cesar without his… without his…

A A NobodyNobody ! !

Wolfgang LüdekeWolfgang Lüdeke José Galan-SousaJosé Galan-SousaSilvia StrieglSilvia StrieglAnke Wermann

& Anja Müller

Anke Wermann &

Anja Müller


Bianca BeutkeStability

Coordination

Bianca BeutkeStability

Coordination

Cleopatra?!

Cleopatra?!


Thank you Thank you very much!very much!

I will miss you!I will miss you!


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