session3track6b

Quality of Dietary Supplements

Session III, Thursday, September 25, 2008 10 00 12 30

Quality of Dietary Supplements

10:00 a.m.12:30 p.m.Werner Busse, Ph.D., Schwabe PharmaceuticalsPhytoequivalence and Flexible Monograph Approach for Botanical Preparationsp

Development of USP DS Monographs

USP develops quality monographs for p q y g pselected DS after a sound review of the

dietary ingredients safetydietary ingredients safety

Criteria for USP DS Monograph Articles

Sources of information1. Human data (safety and clinical studies, PMS, AEs,

interactions)2 Ph l i l d t ( t i t l i l2. Pharmacological data (reprotox, experimental animal

studies, pharmacokinetics, presence of toxic constituents)3 Extend of use globally and in the U S3. Extend of use globally and in the U.S.4. Historical use5. Regulatory status in the U.S. and other countries6. Existence of (pharmacopeial) monographs

incl. WHO, ESCOP, Com. E, Health Canada

total turnover in mio - MAT Sept 2007 vs previous year

Success of Herbal Medicinal Products in Germany

1. history / culture: decision in drug law (1968) herbal products decision in drug law (1968) herbal products

should be regulated as drugs herbal medicine remained mainstream2. need for up to date regulatory data package high quality (drug GMP, surveillance) proof of safety and efficacy

(Comm. E monographs/ own scientific data)t t d b ti t d h lth idtrusted by patients and health care providers

3 incentives for research into HMPs3. incentives for research into HMPs

Herbal Medicinal Productsdossier for marketing authorisation CTD

EU FDA MHLW EFPIA JPMA and PhRMA

Module 1regional and

administrative information

EU, FDA, MHLW, EFPIA, JPMA and PhRMA

li i l

CTD introduction2.2

CTD table of contents2.1

nonclinical overview

2.4

clinicaloverview

2.5nonclinical written

and tabulatedsummaries

2 6

clinicalsummaries

2 7

qualityoverall

summary2.3

2.6 2.7

Module 3Quality

3.0

Module 5clinical

study reports5 0

Module 4nonclinical

study reports4 03.0 5.04.0

Herbal Medicinal Products (HMP)

New productMajor claims,

disevere diseases

Medium claimsB

AHerbal Medicinal

Products

Minor claims

Products (Well established

medical use)C

TMinor conditionsSelf-medication

Traditional Herbal Medicinal Products

XFraudulent or misleading claims

(adapted from Keller, 2003)

UK: Traditional Herbal Medicinal Product

European Pharmacopoeia

Monographs on herbal drugs and herbal drug preparations

233 244200220240260

p

h

s

194

120140160180200

f

m

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n

o

g

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p

67

125

406080

100

N

u

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o

020

2nd 3th 4th 5th *6th-1996Year: 1997-2001 2002-2004 2005-2007 2008-

*) Including supplements 6.1 and 6.2


Monographs on herbal drugs and herbal drug preparationsg p p

6th Edition* (2008) 244 monographs

Essential oils10% (26)

Plant parts59% (127)

Fatty oils9% (22)

( )

Exudates, starchs, gums and mucilages

Extracts10% (26)

8% (20)( )

*) Including supplements 6.1 and 6.2

Committee on Human Medicinal Products

the herbal drug or herbal drug preparation in its entirety is regarded aspreparation in its entirety is regarded as the active substance.

Constituents of Herbal Drugs I

1 ith k th ti ti it ( ti i i l )1. with known therapeutic activity (active principles)

2. with pharmacological activity (active markers)

3. otherwise contributing to efficacy (active markers)

4. markers relevant for QC (analytical markers)

Constituents of Herbal Drugs II

5. accompanying substances p y g(e.g. traces of inorganic salts, sugars or amino acids) (inactive principles)

6. constituents with negativeimpact like allergens or toxins (negative markers)

7 matrix substances usually not soluble7. matrix-substances, usually not soluble(cellulose, lignins )

Constituents with known therapeutic activity

senna (Cassia angustifolia / - acutifolia, folium, ( gfructus)sennosidesb ll d (A b ll d di f li ) belladonna extract (Atropa bella-donna, radix, folium)l-hyoscyamine

milk thistle extract (Silybum marianum fructus) milk thistle extract (Silybum marianum, fructus)silymarin

horse chestnut (Aesculus hippocastanum, semen)horse chestnut (Aesculus hippocastanum, semen)escin(s)

Constituents with pharmacological activity contributing to efficacy

ginkgo extract (Ginkgo biloba, folium)g g ( g )ginkgo flavone glycosides, terpene lactones

hypericum extract (Hypericum perforatum, herba)hypericin, hyperforin, flavonoids (e.g. rutine)

German Chamomile (Matricaria chamomilla, flos)h l bi b l l fl id ( i i )chamazulene, bisabolol, flavonoids (e.g. apigenin)

hawthorn extract (Crataegus oxyacantha, folium, flos )oligomeric procyanidin(s) flavonoids (e g hyperosid)oligomeric procyanidin(s), flavonoids (e.g. hyperosid)

Constituents which serve as analytical marker(s)

valerian extract (Valeriana officinalis, radix)( )valerenic acids

echinacea extract (Echinacea angustifolia, radix)caffeic acid derivatives

balm extract (Melissa officinalis, folium)i i idrosmarinic acids

nettle extract (Urtica dioica, radix)scopoletinscopoletin

Constituents considered as negative marker(s)

valerian extract (Valeriana officinalis, radix)( )valepotriates

ginkgo extract (Ginkgo biloba, folium)alkylphenols (ginkgolic acids, urushiols)

comfrey herb/leaf (Symphytum officinale, herba / folium) li idipyrrolizidins

coltsfoot leaf (Tussilago farfara, folium)pyrrolizidinspyrrolizidins

Biopharmaceutical characterisation

HMPs often used for a long period of timeHMPs often used for a long period of time

use often not based on systematic preclinical and clinical studies

bibli hi d t ti h t bibliographic documentations may show great differences in the extracts used, the dosage form and strengthg

clinical relevance of existing differences


The knowledge of chemical constituents gmay be used to investigate

the phytoequivalence among commercialthe phytoequivalence among commercialproducts and their traditional analogs.

6. Reference to other products

6.1 Active substances complex biological mixtures, e.g. herbal extracts co p e b o og ca tu es, e g e ba e t acts

produced by different manufacturers, are never identical

Influence of various parameters on composition and yield of a herbal extract

PLANT MATERIAL SOLVENTnature ofplant materialnature of solvent

part of plant material

concentration of solvent

cultivation of plant material

degree of processing

amount of solvent

filling height

extract degree of processing

water contents method of extraction

filling height

velocity of flow

statical pressure

MANUFACTURINGMETHOD

MANUFACTURINGEQUIPMENT

time of extraction

extraction pressure

Batch size statical pressure

extraction temperatureMETHOD EQUIPMENT extraction pressure

(adapted from Gaedcke, 1998)

Plant material

0,6 4

Hypericin, Hyperforin content in SJW flowers

in different developmental stages

0,5

3

3,5

m

a

t

e

r

i

a

l

)

(mg/100m

0,3

0,4

2

2,5

Total hypericin

H

y

p

e

r

i

c

i

n

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d

p

l

a

n

t

m Hyperfor

mg dried p

0,2

,

1

1,5

2ypHyperforin

T

o

t

a

l

H

/

1

0

0

m

g

d

r

i

e

rinlant mater

0

0,1

0

0,5

1

(

m

g

/

ial)

0flower buds flowers with open

petalsgreen capsules brown capsules

0

Solvent concentration

35

Influence on markers of Ginkgo biloba

25

30

15

20

5

10

00% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

AcetoneAcetone

Yield Terpenes x 2 Flavones Ginkgolic acids

Type of solvent

inhibition of p s

influence on the pharmacological activity

solventinhibition of

prostate growth (%)

p vs.control

cyclohexane -23.5 0.040

ethyl acetate 5.0 1.000

n-butanol 1.3 0.916

th l 20% 51 3 0 003methanol 20% 51.3 0.003

water 26.5 0.267

suramine 25.7 0.156

effect of nettle root extracts (U. dioica) on experimentally induced prostatehyperplasia in miceyp p

(adapted from Lichius and Muth, 1997)

Manufacturing method

manufacturing parameters

influence on composition (chamomile liquid extract)

manufacturing parameterspharmacopoeia quality

parameterssingle

macerationpercolation percolation

with concentration

essential oil (V/w) [%] 0.33 0.56 0.64

dry residue [%] 7 15 26DER native 15 : 1 6.5 : 1 4 : 1

ethanol content (V/V) [%] 52 47 39

supplementary testsalpha-Bisabolol (ppm) 17 15 40apigenin-7-glucoside [%] 0.08 0.15 0.27

Drug-extract ratio

40influence on composition of saw palmetto extracts

25303540

batch 160 (ratio* = 14.1 : 1)

batch 227 (ratio* = 8.5 : 1)

oleic acidlauric/myristic acid

152025

%

( )

palmitic/stearic acid

caproiccaprylic glycerides

05

10 capryliccapric acidlinolic acid

wax alcoholsglycerides

phyto sterols

a b c d e f g h

* DER = drug/extract ratio

Reference to other products assessment of comparability for the API has to include

botanical starting material preferably complies with a pharmacopeial monograph

solvent used for extraction type and concentration

manufacturing process maceration, percolation, liquid-liquid extraction

d h ifi i f h i data on the specification of the preparation

drug-extract-ratio


6th Edition

Type of extracts

A standardisedcontain constituents that are solely responsibley pfor the therapeutic activity; standardization andadjustment to a defined content acceptable

B1 quantifiedcontain constituents with relevant pharmacological

ti t d di ti b bl di t blproperties; standardization by blending acceptable;adjustment using excipients not acceptable

Type of extracts

B2 otherno constituents documented as being determinant or relevant for efficacy or as havingdeterminant or relevant for efficacy, or as having pharmacological or clinical relevance

Biopharmaceutical Characterisation of HMPs considerations

A differences in solvents, manufacturer, extraction method may be considered to be pharmaceutical

related to active substance(s)

method may be considered to be pharmaceutical alternatives if the quantity of the active principles is identical as well as the DER

B1 if the specification related to the active markers, the extraction solvent and the DER are the same, a preparation may be considered as a pharmaceutical alternative

B2 if the extraction solvent and the DER are the same, a preparation may be considered as a pharmaceutical alternativealternative

Biopharmaceutical Characterisation of HMPs considerations

A pharmaceutical equivalence may be accepted if in both products the in vitro release of the active principles exceeds

related to finished HMPs

products the in vitro release of the active principles exceeds90 %; otherwise BE studies may be necessary

B1 in vitro release of the active markers and solubility of the extract should be compared with the reference product(> 90 % release); otherwise clinical safety studies or BE(> 90 % release); otherwise clinical safety studies or BE studies may be necessary

B2 l bili h ld b d h f d ifB2 solubility should be compared to the reference product or if not possible release of (an) appropriate marker(s) (>90 %);a comparison of the disintegration profile may be acceptable; p g p y potherwise clinical safety studies or BE studies are necessary

The reality of herbal extracts

Aactive principles known t d di dAactive principles known standardised

B1active markers known quantified

analytical markers otherB2

analytical markers other

computerized control extraction vessels

evaporation belt dryer

Composition of Ginkgo extract (EGb 761)

Unknown13% Various

Flavonglycosides24%Water, solvent

3%

13% Various3%

High molecular4%

Inorganic5%

Terpenelactones6%

4%

Carboxylic acidsNonflavonglyco-

id

Proanthocyani-dines

7%Catechines

2%

Carboxylic acids13%

sides20%

HPLC fingerprint gradient of EGb 761

DM 1430 DM 1986

DM 2067 DM 2068

ES-MS (electrospray mass spectometry) of EGb 761

The more the better?

500

comparison of antioxidative properties of 24/6 and 48/12 ginkgo extracts (alloxane induced hyperglycemia)

350

400

450

250

300

350

e

(

m

g

%

)

EGb 761 (24/6 extract)

150

200

250

g

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( )CP 401 (48/12 extract)

50

100

150

0

50

control alloxan 10 mg 20 mg 40 mg

Human pharmacology studyHuman pharmacology study with different U.S. ginkgo products

HZI Research Center, Tarrytown, NY

product flavone glycosides* terpene lactones*

A 10 18 mg 2 40 mgA 10.18 mg 2.40 mg

B 15.65 mg 3.25 mg

C 8 36 2 12C 8.36 mg 2.12 mg

*content per single dose

Itil and Martorano, Psychopharmacology Bulletin 1995; 31(1): 147-158

Time related changes in pharmaco-EEG (n = 14)

Product A

3,353

4Product A

Product B

Product C

1,82,2

1,82

3 Product C

0

,

00 -0,2-0,30

1

0

-1

00 Hrs 1 Hr pre 3 Hr pre

Itil and Martorano, Psychopharmacology Bulletin 1995; 31(1): 147-158.

German Pharmacopoeia

Ginkgo Dry Extract, quantified

processingmanufactured from dried leaves with acetone/water and subsequent purification w.o. addition of q pconcentrates or isolated compounds

drug-extract ratio 35 - 67 : 1 flavone-glycosides 22 - 27 % ginkgolides A,B and C 2.8 - 3.4 % bilobalide 2 6 3 2 % bilobalide 2.6 - 3.2 % alkylphenols < 5 ppm

(ginkgolic acids urushiols)(ginkgolic acids, urushiols)

Comparison of two St. John's Wort preparations

Population: 147 patients with mild to moderate depression according to DSM IV

(randomized, double blind, placebo-controlled study)

depression according to DSM-IV

Duration: 6 weeks

Dose: 300 mg SJW 0.5, SJW 5.0 or matching placebo t.i.d.

Criteria for evaluation Hamilton depression scale (HAMD, 17 items)( , )v. Zerssens depression scale (D-S)clinical global impressionglobal self ratingglobal self rating

Laakmann, 1998

Reduction of depressive symptoms

after treatment with two St. John's Wort (SJW) preparations

change in patients general condition (CGI, item 2)

SJW 0.5% hyperforin SJW 5.0% hyperforinPLACEBO

Laakmann, 1998


St. Johns Wort Dry Extract, quantified

processingsuitable procedure using ethanol (50 - 80 % V/V) or

th l (50 80 % V/V)methanol (50 80 % V/V)

total hypericins 0.1 - 0.3 %total hypericins 0.1 0.3 %

hyperforin not more than 6.0 %

flavone glycosides minimum 6%

Rutin is essential for antidepressant activity of SJW

y

200controlmethanol-extract 1 (M1)rutin

n

t

a

c

t

i

v

i

t

y

150

methanol-extract 1 + rutinimipramine

y

[

s

]

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p

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s

a

n

100***

o

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-

d

50

***

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a

s

0Control 300 9 300 + 9 20

mg/kg b.w.

Specification of clinical tested St. Johns Wort dry extract

processing

Lecrubier et al, Am J Psychiatry. 2002 Aug; 159 (8):1361-6. Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial.Unit Institut National de la Sant et de la Recherche Mdicale 302, Hpital Piti Salptrire, Paris, France.

processingthe extract is produced by using methanol 80 % (V/V)

total hypericins 0.12 - 0.28 %

h f i 4 0 6 0 % hyperforin 4,0 - 6.0 %

flavone glycosides 6 - 12 %g ythereof rutine not less than 1.5 %


Powdered Echinacea purpurea Extract, NFPowdered Echinacea purpurea Extract, NF

extraction with hydroalcoholic mixtures or other suitable solvents

drug-extract ratio: 2-8:1

not less than 4% total phenolsnot less than 4% total phenols calculated as sum of caftaric, chicoric and chlorogenic acids andechinacoside

not less than 0.025% of alkamides(dodecatetraenoic acid isobutylamides)

Conclusion herbal extracts are complex biological mixtures

based on whether active principles or active markers are known,

extracts are classified as type A B1 or B2extracts are classified as type A, B1 or B2

main parameters in equivalence considerations of extracts are

- the botanical starting material

- type and concentration of extraction solvent

- manufacturing process

- drug-extract ratio- drug-extract ratio

additional parameters for finished dosage forms apply

criteria for biopharmaceutical equivalence also depend on

- regulatory status of the product

- safety / therapeutic range

- intended use/ indicationintended use/ indication

Q ti ?Questions?

Th k !Thank you!

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