herbal medicine quality and safety issues · herbal medicine quality and safety issues – a primer...
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Herbal Medicine quality and safety issues – a primer for health professionals
Dr Hans Wohlmuth PhD BSc
Southern Cross University Lismore NSW
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EFFECTIVE
QUALITY
SAFE
Expectations of all medicines
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Medicine
Plant Species
Chemotype
Plant part
Age
Environment Stability
Post-harvest
Harvest
Extraction
Formulation
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After Booker A et al, J Ethnopharmacology 2012;140:624-33
The industry chain
Grower / Collector
Primary processor / Regional middlemen / Cooperative
Middlemen
Exporter
Consumer country importer / Secondary processor
Retailer / Practitioner
Patient / Consumer
Secondary processor / National retailer
Consumer / Patient
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The challenge of herbal quality control
Chemical complexity Natural variability
CONSISTENT MEDICINE
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vs
Analytical Chemistry 101 Advanced Analytical Chemistry
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Aspects of quality of medicines
• Authenticity
– they are what they purport to be
• Consistency
– they have a consistent composition
• Purity
– they contain ONLY what they’re supposed to contain
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Authenticity
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Herbal authentication
Authentication
Taxonomy
Chemistry
Macroscopic morphology
Microscopic morphology
DNA analysis
TLC HPLC LC-MS GC-MS Reaction tests
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Thyme from Morocco
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Comparative chemistry
Fluid extract
Authentic reference
HPTLC HPLC
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There is something about Marigold…
Authentic reference
Extract
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Calendula officinalis
Tagetes erecta
Don’t rely on common names!
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Skullcap (Scutellaria lateriflora)
• Native to N America
– cultivated US, Chile, Mexico, Costa Rica, Australia
• Leaf rich in flavonoid glycosides
– baicalin (~5%), dihydrobaicalin, lateriflorin
• King’s Dispensatory 1898:
– ‘larger part of the drug sold… is derived from two other species…’
• AHP Monograph 2009:
– substituted with S. galericulata, S. alpina, S. incana, S. baicalensis, Teucrium spp.
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HPTLC on silica gel 60 F254 plates Mobile phase: tetrahydrofuran:toluene: formic acid:water (16:8:2:1 v/v) Visualisation: Natural Products Reagent followed by polyethylene glycol 4000 Photographed under UV 366 nm
S. lateriflora (6 samples) S. lateriflora (left) Scutellaria sp. (4 samples)
Left to right: Scutellaria sp. S. baicalensis root S. galericulata Scutellaria ‘Bluebird’ S. baicalensis aerial
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iflora S3
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ird' S3
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alensi
s root S
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S. baic
alensi
s leaf
S33
Scute
llaria
sp. S
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S. altis
sima S3
4
S. barb
ata S4
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Conc
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Scutellarin Baicalin Baicalein Chrysin
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Looking for Teucrium spp.
• No Teucrium found in Scutellaria samples
• T. chamaedrys contained teucrioside – no verbascoside
– no flavonoids typical of Scutellaria
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S. lateriflora T. chamaedrys
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Saffron – the world’s most precious botanical commodity
• Styles and stigmas from Crocus sativus
• Retails for $10-30 per gram
• 100-150 flowers needed for 1 g
• Spice
• Anti-cancer, anti-depressant activity
O
R1OOR2
O
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70% EtOH extracts from (l-r): Iran, Tasmania, Kashmir
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Safranal
Crocetin HOOC
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Fake saffron
Authentic saffron
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Variability
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Natural variability
Sirvent et al. Economic Botany 2002
8 wild SJW population in Montana and N California
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Passiflora incarnata
• Some material grown in Australia have atypical C-glycosyl flavone profiles
Six Australian samples (1-6) and two typical samples. (C=chlorogenic acid, H=hyperoside, R=rutin.) Wohlmuth et al. Biol Pharm Bull 2010
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Passiflora incarnata chemotypes
• Much (but not all) material grown in Australia is of swertisin chemotype
• Typical material is of shaftoside/isovitexin chemotype
HPLC trace of four samples with the typical flavonoid profile.
Isovitexin
Vitexin
Schaftoside/isoschaftoside Isovitexin-2-O- β-glucopyranose
Wohlmuth et al. Biol Pharm Bull 2010
Vitexin
Isovitexin Swertisin
Isovitexin-2-O- β-glucopyranose
HPLC trace of six samples of swertisin chemotype
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Rosmarinic acid from Melissa - extraction efficiency of different solvents
Extraction solvent matters!
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Non-alcoholic liquid extract
60% EtOH
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Sorbate: E200 Sorbic acid E201 Sodium sorbate E202 Potassium sorbate
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Alkylamides in Echinacea preparations
min13 13.5 14 14.5 15 15.5 1616.517
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60% EtOH 0% EtOH
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Purity
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Assay aglycones before and after hydrolysis:
A(glycosides) = A(post) — A(pre)
Ginkgo biloba adulteration
• USP, EP/BP – 22-27% flavonoids, expressed as flavonol glycosides, but
quantified after hydrolysis
– specified aglycone ratios:
• kaempferol : quercetin 0.8-1.2
• isorhamnetin : quercetin ≥0.1
• Does not allow for detection of adulteration with aglycones!
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• Ginkgo leaf (5) contained no free aglycones
• 8 ginkgo products tested
Ginkgo biloba adulteration
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Ginkgo biloba adulteration
• Current USP method overestimated flavonoid glycoside content by 29-41%.
Genistein
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Ginkgo biloba adulterant?
• Styphnolobium japonicum
– genistein
– quercetin and kaempferol glycosides
– previously reported as a suspected adulterant of ginkgo extracts
He K, Roller M (2011) In Formulating, Packaging and Marketing of Natural Cosmetic Products, ed. N Dayan & L Kromidas, Wiley, pp. 361-85. Qi Y et al. (2007) J Chromatogr A 1140:219-24.
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Heavy metal contamination
• Heavy metals may be intentionally added to Indian and Chinese remedies
• Some plants accumulate heavy metals from the soil (e.g. Hypericum, Salix – cadmium)
(Wenzig & Bauer, in Houghton & Mukherjee, Evaluation of Herbal Medicinal Products 2009)
• 3.5% of 317 batches of dried herbs delivered to German TCM hospital had heavy metal content exceeding legal limits
(Melchart, Alt Ther Health Med 2001)
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Pharmaceuticals in traditional Chinese medicines
In Taiwan, 24% of 2600 TCM preparations contained at least one drug compound
(Huang, J Clin Pharmacol 1997)
In the US, 10% of 500+ Chinese patent
medicines contained undeclared drugs and/or toxic levels of heavy metals
(Au, Bull Env Contam Toxicol 2000)
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Herbal Viagra products…
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Herbal Viagra – indeed!
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Tea tree oil Oil of Melaleuca, terpinen-4-ol type
ISO 4730 , Australian Standard 2782: α-pinene 1-6%
sabinene tr-3.5% α-terpinene 5-13% limonene 0.5-1.5% p-cymene 0.5-8% 1,8-cineole tr-15% γ-terpinene 10-28% terpinolene 1.5-5% terpinen-4-ol 30-48% α-terpineol 1.5-8% + 4 others
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Tea tree oil – adulteration issues
• Terpinen-4-ol content >40% attracts premium
• Adulteration with t-4-ol from other sources: – pine bark – marjoram – synthetic
• T-4-ol chiral ratio (+/-) should be ~2.1 • Synthetic oil
– lacks sesquiterpenes – short-chain hydrocarbons
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Tea tree oil – safety concerns
• Methyl eugenol – <0.01-0.06% (mean 0.02%)
– 106 times lower than carcinogenic dose in rats
• Contact allergy
• Sensitising potential linked to oxidation products – increased p-cymene – peroxides, endoperoxides
and epoxides – protect from oxygen,
light, heat
Southwell et al. Flavour & Fragrance 2011
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Conclusions
• Quality assurance of natural products presents unique challenges
• Rigorous quality assurance must be maintained to ensure the quality, safety and effectiveness of herbal medicines
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Acknowledgments
Ashley Dowell, SCU
Peter Mouatt, SCU
Roy Upton, American Herbal Pharmacopoeia
Dr Reg Lehmann, Integria Healthcare
Rose Cornelissen, Integria Healthcare
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