Download Quality control & standardization of herbal drugs

Biodiversity Wealth and Opportunities for
Asia Pacific Countries in Biotechnology &
Herbal Technology
P. Pushpangadan
National Botanical Research Institute
(Council of Scientific &Industrial Research),
Rana Pratap Marg, Lucknow-226001
(September 2003)
WORLD TRADE AND ECONOMIES:
THE PARADIGM SHIFT
 “Resource – based economies’ to
‘Knowledge –based economies’
 21
Century will be the Century
of Knowledge”……
“A
st
nation’s ability to convert
knowledge in to wealth and social
good through the process of
innovation will determine its
future” ( R A Mashelkar, 2001)
st
21
Century
21st century is the century of Biology powered and
propelled by scientific knowledge and technological
expertise
Three technologies namely
 Biotechnology
 Herbal technology
 Information technology (Bioinformatics)
are going to be the most powerful elements
that are crucial for prosperity and welfare
for the people of nations.
Herbal technology
All technologies for the manufacture of value
added plant products can be called as herbal
technology
 Herbal drugs and pharmaceuticals,
 Nutraceuticals,
 Functional foods, designer foods or health foods
and health drinks
 Cosmaceuticals
 Biocontrol agents
 Biopesticides
WORLD TRADE AND ECONOMIES:
THE PARADIGM SHIFT
 “Resource – based economies’ to
‘Knowledge –based economies’
 21
Century will be the Century
of Knowledge”……
“A
st
nation’s ability to convert
knowledge in to wealth and social
good through the process of
innovation will determine its
future” ( R A Mashelkar, 2001)
Genesis of the Global Concern on
Biodiversity Conservation
• UNEP constituted an ad-hoc Working Group of
Technological and Legal experts to prepare
an
international
legal
instrument
for
conservation
and
sustainable
use
of
Biodiversity which resulted in ‘CONVENTION
ON BIOLOGICAL DIVERSITY’ (CBD).
–171 countries signed CBD in June 1992
during the Earth summit at Rio de Janeiro.
• CBD came - into force as an International Law
on 29th Dec. 1993.
• 186 countries are now parties to CBD (as on
Feb. 2003)
Conservation of Biodiversity
Strategies & Priorities
IUCN, UNEP & WWF 1980 came out with the
first Global Strategy for Conservation.
This Strategy defined conservation as:
“Management of human use of biodiversity so that
it may yield the greatest sustainable benefit to
present generation while maintaining its potential
to meet the needs and aspirations of future
generation”
This definition involves two complementary
components ‘Conservation’ and ‘sustainability’
Biodiversity & TK: Capital Assets
of Asia-Pacific Countries
Biodiversity and TK are two invaluable
capital assets of South countries for:
 Building up IPR- covered bio-industrial
enterprises
Herbal Drugs
Pharmaceuticals
Natural product development sectors
 Generating economic wealth and
improving quality of life and well- being of
people
Contd…….
Biodiversity & TK: Capital Assets
of Asia-Pacific Countries
(Contd.)
 Building up S&T capability in advanced
technologies of bioprospecting
 Human resource development in
Biotechnology, Bioinformatics and
Bioprospecting
 Empowering local and indigenous
communities for conservation,
sustainable use and building up location –
specific biodiversity enterprises through
S&T intervention
Biodiversity & TK: Bridging the
North-South Gap
Asia-Pacific countries SHOULD:
 Develop capability in biotechnology,
bioinformatics and bioprospecting through
national, regional and global
‘biopartnership’ programmes
 Address and resolve the issues of access
to and transfer of genetic resources and
technologies between North- South
countries
Contd……..
Biodiversity & TK: Bridging the
North- South Gap
Asia-Pacific Countries should:
 Prevent bio-piracy and
misappropriation of genetic
resources and TK
 Develop an international system for
protection of TK
 Develop effective mechanisms for
fair and equitable benefit sharing
and technology transfers
Convention of Biodiversity (CBD)
Relevant Provisions of CBD
• Article 3 recognizes the sovereign rights of States
over their biological resources.
• Article 15 states that when access to genetic
resources is granted, it shall be on mutually agreed
upon terms and subject to Prior Informed Consent.
• Incentives to biodiversity-rich countries to conserve
and sustainably use their genetic resources,
including joint research, access to & transfer of
technology (Articles 15,16).
Relevant Provisions of CBD
(Contd...)
• Article 16.2 addresses issues surrounding the
access to and transfer of technology, governed by
patents.
• Article 16.5 anticipates the difference in
objectives between IPR regimes and the CBD and
seeks to ensure that IPRs don't run counter to the
CBD.
• Article 8(j) underlines the need to protect TK and
points to the potential benefits to be realized from
such knowledge through involvement of its
holders and equitable benefit-sharing.
Relevant Provisions of TRIPs on
Biological Resources
• Under Article 27, virtually all inventions are to be
patented if they are new, involve an
innovative/inventive step and are capable of
industrial application.
• Exceptions to patentability include plants, animals
( other than microbes) and biological processes for
the production of the above. However plant
varieties must be protected either by sui generis or
by patenting (27.3(b)).
Relevant Provisions of TRIPs on
Biological Resources
(Contd….)
• Article 30 confers limited exceptions to the rights
conferred on patent holders, taking into account
the legitimate interests of third parties.
• Article 29 imposes two conditions on patent
applicants; that they disclose the invention clearly
and completely enough for a person skilled in the
art to reproduce it and it 'may' require an applicant
to provide information concerning the applicant's
corresponding foreign applications and grants.
TRIPS-CBD Relationship
• Absence
of
explicit
compatibility,
Difference of approach and priority given to
issues which are ultimately related. This has
led to violation of the CBD (Articles 8,15
&16).
• TRIPs ignores a vast range of valuable,
traditional knowledge (TK) because it
doesn't meet the standards of patentability.
TRIPS-CBD Relationship
(Contd..)
• TRIPs undermines CBD in cases of biopiracy, by
putting the burden of proof on the source country
rather than patentee. Identification of unique source
material as required in Art.29 of TRIPs is
insufficient. Lack of transparency in the patent
application procedure.
• TRIPs doesn't require the recognition of domestic
laws protecting access to genetic resources and TK
and subsequent benefit sharing.
The Need to Amend the TRIPs
Agreement
• Absence of a clear reference to CBD and the
relationship with CBD could hinder the
implementation of the latter by violating the
primary principle of sovereignty over genetic
resources.
• TRIPs should provide international recognition of
relevant domestic legislation of its member
countries, especially as far as access and benefit
sharing issues are concerned.
The Need to Amend the TRIPs
Agreement (Contd...)
• It is far more cost effective in the long run to
establish an internationally accepted solution
through TRIPs for the prevention of biopiracy.
• TK associated patents have fetched large profits
and it makes ethical and economic sense for
TRIPs Agreement to recognize a need for benefit
sharing.
The Need to Amend the TRIPs
Agreement (Contd...)
• It is far more cost effective in the long run to
establish an internationally accepted solution
through TRIPs for the prevention of biopiracy.
• TK associated patents have fetched large profits
and it makes ethical and economic sense for
TRIPs Agreement to recognize a need for benefit
sharing.
Bioprospecting and the new IPR regime
Given the global trends in capturing
the
intellectual property markets, the Third World
nations in the Asia pacific now needs to look
ahead for the best possible ways and means by
which they can generate IPR and build up IPR
covered bioindustrial regimes.
Biotechnology (BT), Information Technology (IT)
and Herbal Technology (HT) are the three fast
emerging and powerful areas of R&D in current
century. The rich biodiversity, associated
knowledge systems and human resources etc. are
the strength of Asia-pacific countries, and
therefore have the best opportunity.
Bioprospecting
Chemical Prospecting
Drugs and pharmaceuticals
Pesticides
Cosmetics
Food additives
Other industrially valuable
Chemical products
Gene Prospecting
Genetic engineering
Crop development
Fermentation
Cell culture
Bionic Prospecting
Designs
Sensor technologies
Architecture
Bioengineering
Biomodeling
Bioprospecting: Linkages and leads
Biodiversity
& IK/TK
Biotechnology
Information
technology
Herbal
technology
Bioprospecting
Drug development
Pharmaceuticals
Agrochemistry
Cosmetics
Proteins
Conservation
Sustainable
use
Benefit
sharing
Bioinformatics
Enzymes
New crop varieties
GMOs
GM foods
IPR
Designs etc.
IPR Issues / Benefit Sharing
Strategies
 Appropriate
Procedures
for
IPR
Protection/Benefit sharing
 Documentation & Registration of TK – Medicinal
plant use & Conservation at local , state and
national level.
 Contribution to TKDL & TKRC
 Value addition to TK & Indigenous Medicinal
Plants – Scaling up IPRs
 Herbal drugs, Pharmaceuticals, Natural
products & byproducts, Nutraceuticals,
Functional foods, etc.
Some features of international health care
 Health care policies largely market driven by the
pharmaceutical industry diverting attention from health
preservation to illness cure
 Prevention and eradication of diseases undermines the
economic basis of this industry
 No satisfactory drugs available for most of the
degenerative disorders characteristic of graying population
and for re-emerging resistant infections
 Many currently used modern drugs do not have valid
proven clinical utility.
 USA has among the highest per capita annual expenditure
on health care ($3600) but still about 15% population is
denied even basic care facilities (the best Indian state like
Kerala have an annual per capita expenditure ~ $15)
Herbal drugs in international health care
 Economic aspects:
Global market of herbal drugs, Nutraceuticals ~$60 billion
with 6% annual growth rate. Major share of Chinese and
Koreans. Indian share variously estimated at 0.35-3.0%.
Chinese production increased 200% between 1995-1999.
 Local acceptance:
Developed
USA: 42% use CAM spending over 29 billion US$ and 629
million visits in 1998.
UK: 28% use, spent 1.6 billion pounds and 127 million visits in
1998.
Australia: 60% use, A$ 620 billion in 1999.
Developing
Malaysia: Per capita consumption of traditional drugs, more than
double of modern pharmaceuticals.
S.Korea: Per capita consumption of traditional drugs 36% more
than modern drugs.
African countries: 9 to 10 patients attending hospital OPD have
first consulted a traditional healer.
Advantages of herbal drugs
 Modern drugs can produce serious side
effects
Latrogenic diseases fourth leading cause of
death in USA and other developed nations
(JAMA, April 1998).
Side effects of drugs kill more Americans
annually than the world war II and Vietnam war
combined (M. Rath N. Y. Times 28.2.2003).
Around 2600 persons died in the Twin Tower
tragedy on 11th September 2001 causing global
repercussions. It is, however, not recognized that
about the same number die in USA from side
effects of prescription drugs every 10 days
(JAMA, April 1998).
Herbal drugs are best suited for:
 PRIMARY HEALTH CARE
 INFECTIOUS DISEASES
AIDS and other viral infections
Opportunistic infections
MDR infections (e.g. T.B., Malaria)
 DEGENERATIVE & GERONTOLOGICAL
CONDITIONS
Osteoporosis
Chronic arthritis like osteoarthritis and rheumatoid arthritis
Neurological like Alzheimer, Parkinsonism
Anti-aging
 Metabolic disorders
Diabetes
Dyslipidemias
 Other conditions
Microcirculatory disorders
Liver diseases
Immunostimulants
Anti-cancer
Drugs affecting male libido
Standardization of Herbal drugs
Raw Drugs
 Passport data of Raw Plant Drugs (Crude drugs)
 Correct taxonomic identification & authentication
 Study on the medicinal part: root, stem, bark, leaves,
flowers, fruits,nuts, gum, resins etc.
 Collection details: Location, stage & development/
growth of the plants, time, pre-processing storage etc.
 Organoleptic examination of raw drug:
Evaluation by means of sensory organs: touch, odour taste
 Microscopic & molecular examination
 Chemical composition (TLC, GLC, HPLC, DNA
fingerprinting)
 Biological activity of the whole plant
 Shelf life of raw drugs
Standardization of Herbal drugsHerbal Formulation
 Follow defined Good Manufacturing Practices
(GMP)
 Scientific Verification
Toxicity evaluation
Chemical profiling
Pharmacodynamics – effect of drug in the body
Pharmacokinetics – absorption, distribution,
metabolism, mechanism of action and execution
Dosage
Stability and shelf life
Presentation and Packing
Therapeutic merits – Compared with other drugs
Good Practices/Techniques in Herbal
Products
 Good Survey of literature (Ancient & Modern)
 Develop and Observe Norms of:
Good Agricultural Practices (GAP)
Good Collection/Harvesting and Post Harvest Handling
Practices (GCP/ GHP & GPHP)
Good Laboratory Practices (GLP)
Good Clinical Practices (GCP)
Good Manufacturing Practices (GMP)
Good Marketing Techniques (GMT)
Physico-chemical
value
Parameters required for quality evaluation of herbal drugs
Standardization & Quality Evaluation of Herbal drugs
QUALITY EVALUATION OF
HERBAL DRUGS
‘DARU HARIDRA’ - A Controversial drug of
Ayurveda
Three plants used as ‘Daruharidra’
• In Northern India Berberis aristata DC. (FamilyBerberidaceae),
• In Southern part Coscinium fenestratum (Gaertn.) Colebr
(Family- Menispermaceae),
• In Easter part Coptis teeta Wall. (Family- Ranunculaceae)
Berberine is the active constituent present in all the three species
thus on the basis of berberine all of these can be used as substitutes
of ‘Daruharidra’. However, scientific investigation also suggest that
different Berberis species viz. B. asiatica, B. chitra and B. lycium
can also be used as substitute of ‘Daruharidra’ as all the species
have almost similar chemical profile.
Different vernacular Names of Berberis spp.
Arabic
- Ambarbaris
Bhutia
- Tsema
Bengali
- Darvi
Canarese
- Bagisutra
English
- Indian Barbery, Tree turmeric
Greek
- Lykion indikon
Garhwal Himalayas - Kingora, Kilmora, Kashmal
Hindi
- Daruhaldi, Darhald, Chitra
Jaunsar
- Kashmoi
Japanese
- Indo-ohbaku
Latin
- Berberis
Malayalam
- Maradarisina, Maramanjal
Nepal
- Chitra, Chotra
Persian
- Bedana, Chitra, Zirishk
Punjab
- Chachar
Himanchal Pradesh - Kammul, Kashmal, Kaumul
Sanskrit
- Daruharidra, Darvi
Tamil
- Maramanjal, Mullukala
Telugu
- Kasturipaspu
Urdu
- Ambar
Medicinal uses of Berberis spp.
Ayurveda:
It is bitter and at the same time hot and pungent useful in boils, diabetes, affections of ear,
eye and mouth. The decoction is very useful preperation for opthalmic infection, cough, poison
and boils.
Local health traditions (folk remedies) of Berberis spp. in Northern India:
B. aristata DC. and B. asiatica Roxb. :
In Garhwal region (U. P.) :
In Dhanulti and Raithal locality near to Uttarkashi of U.P. :Rasaut a root extracts is used for: Eye
conjuctivitiis, Malarial fever, Skin diseases.
In Kumaun region (U. P.) :
In Ranikhet locality of Nainital (U.P.) :Decoction of root bark is used in eye troubles. local people
they use root extract for treating fever and skin diseases. Roots are also used for snake and
scorpion bite.
B. Chitria Lindl.
In Kangra valley (Himanchal Pradesh): The filtered decoction of root is used for treating
conjunctivitis and other ophthalmic diseases.
B. Lycium Royle
In Kangra vally(Himanchal Pradesh):The decoction of root is given orally as blood purifier. Raw
fruits are also eaten for digestive disorders. Leaves are used as fodder. It is taken with the juice of
radish for jaundice.
Market Survey of Berberis Spp.
Roots of Berberis spp. are collected in fairly large quantities in Chamba District Of Himanchal Pradesh and in
Tehri-Garhwal of Uttar Pradesh during Aug., Sept. and are being sold in the nearby markets or to the traders
which finally reach the drug markets of India.
Different market samples are identified as –
Trichur samples - Stem of Coscinium fenestratum.
Banglore samples - Root of Coscinium fenestratum.
Amritsar, Aligarh, Dehradun, Hyderabad, Jammu, Lucknow, and Varanasi samples- the different
Berberis species.
Major constituent of Berberis spp.
O
O
+
N
H3CO
OCH3
Berberine
Quantitative Estimation of Berberine in different Berberis species
B. aristata
Root
Stem
B. asiatica
Root
Stem
B. chitria
Root
Stem
B. lycium
Root
Stem
0
) %( en irebreB
1
2
1.4
2.005
2.25
3
4
1.024
1.417
3.55
3.99
5
5.2
6
B. chitria Root
B. chitria Stem
B. lycium Root
B. lycium Stem
B. aristata Root
B. aristata Stem
B. asiatica Root
B. asiatica Stem
Quantitave estimation of berberine in different market
samples of Berberis spp.
Locations
0
0.5
)%( en ir ebr eB
1
1.5
1.45
2
2.5
1.927
3
2.18
2.27
2.272
2.81
3.5
2.73
3.01
3.36
3.71
4
Jammu
Aligarh
Hyderabad
Amritsar
Lucknow
Bangalore 1
Trichur
Bangalore 2
Varanasi
Delhi
Comparative HPTLC profile of Berberine in different
market samples
Densitometric scan of different samples of Berberis
spp. at UV 266 nm
Berberis aristata D.C.
Brief Taxonomic description
B. aristata DC., Syst. Nat. 2:8.1821; Hook f. &
Thomson in Fl. Brit. India 1:110. 1872 pp.: Naithani, Fl.
Chamoli 1:46.1984; Sharad, LWG 221239, 1998.
Berberis aristata DC. is a large deciduous shrub
usually 1.8-3.6 m high; twigs whitish or pale yellowish
brown, erect cylindrical, smooth and strongly striate; blaze 57.5 mm, bright yellow with coarse reticulate fibres; leaves
3.8-10 x 1.5-3.3 cm, obovate or elliptic, entire or spinoustoothed, base gradually narrowed, with prominent reticulate
nerves, glossy dark green above and glossy pale green
beneath; flowers numerous, stalked; inflorescence a simple
drooping raceme, bracts small, linear, acuminate; sepals 8 or
9, imbricate, oval, petaloid, yellow; petals 6, in two whorls,
strongly imbricate, concave, bright yellow veined with two
oval linear glands at the base of the lateral veins; stamens 6
equal, hypogynous, opposite and slightly shorter than the
petals; ovary simple, 1-celled, with a few erect ovules; style
short, stigma peltate; fruit a small berry about 7-10 mm,
ovoid or oblong ovoid, blue black with a whitish bloom
tipped along with the persistent style and stigma.
Flowering and Fruiting: August – October
Berberis aristata DC. – Macroscopic & Microscopic
T.S. cellular structure of stem (x 100)
Dried Root
T.S. of the root (x 100)
Fruits and Seeds
TLS of the root (x100)
Powder study (x400)
Botanical Analysis of root of Berberis aristata DC
Macroscopic
Woody, yellowish brown, cylindrical, knotty with thin brittle bark.
Cut surface bright yellow
Fracture hard, texture short, odourless and bitter in taste.
Outline
Circular
Cork cells
Brown, 10-20 Layered, rectangular
Cortical
zone
30-35 layered, parenchymatous, filled with tannin, starch grains and
rhomboidal crystals of Ca-oxlate.
Sclereids
Solitary or in group of 2 to 10
Pericyclic
fibres
Mostly solitary but sometimes in groups of 2 to 10.
Alkaloidal
contents
Present
Vessels
Solitary or in group of 2 or 3
Medullary
Rays
Heterogenous, 2 to 4 cells broad, pitted, filled with starch and alkaloidal
content
HPTLC profile and densitometric
chromatogram of B. aristata root
Berberine
THE AYURVEDIC THERAPEUTIC
STRATEGY
1.
2.
3.
4.
5.
6.
7.
Determine PRAKRUTI (Constitution) by -history taking
-observations
NIDANA (Diagnosis)
Nature, degree and extent of imbalance of Tridoshas. Library
of 5800 clinical signs and symptoms in Ayurvedic texts
CHRONOBIOLOGY: Impact of season, time and
environment on Tridoshas.
SWASTHAVRUTA: Life style modification
AHARA: Dietary modifications
PANCHAKARMA: Purification of the body
AUSHADHI: "Designer Medicine" unique for the particular
patient prepared from a Pharmacopoeia utilising 1200 plants,
100 minerals and 100 animal products in numerous
formulations.
OBJECTIVES OF RESEARCH ON
AYURVEDIC DRUGS
 Improved formulations and reduced number of
Ayurvedic drugs
Use of GMP procedures and QC
Certified shelf life and improved dosage form
Validated indications and contraindications
Deletion of obsolete or toxic formulations
 Use of Ayurvedic drugs in modern clinical practice
Inclusion in essential list of drugs
Adjunct to existing drugs
Treatment of diseases where modern drugs not available
or unsatisfactory
Development of suitable formulations, standardized
extracts or active constituents
IPR protection wherever feasible
Inclusion in Pharmacopoeias.
OBJECTIVES OF RESEARCH ON
AYURVEDIC DRUGS
New indications for Ayurvedic drugs
Development of new drugs for
Ayurvedic practice
Utilizing leads from other countries
Study of unscreened flora, specially
endemic or threatened species
Studies on Ayurvedic drugs for
veterinary use
Development of new drug/ novel uses
for Ayurvedic drugs
Utilization of new leads on natural products
from other countries. Several of these plants
or related species are found in India
The vast unscreened flora of the country
and published activity data on some of these
Study of further accessions from families
yielding active plants
Vision of Herbal Drug Industry
“To provide intellectual capital to make
available safe, cost effective, affordable
therapeutics to the people of Indo-Pacific region
– to help to reduce the percentage of mortality,
morbidity and to emerge as significant players in
the global market place.”
BIOPARTNERSHIP: RELEVANCE
OF APCTT
APCTT can bring the Asia-Pacific Countries
should come together to develop Strategies for:
Easy and regulated access to genetic
resources & TK and biotechnologies
Exchange of information pertaining to
conservation and sustainable use of
biogenetic resources and associated TK
 Mutually Agreed Terms
 Prior Informed Consent
 Equitable Benefit Sharing Agreement
BIOPARTNERSHIP: RELEVANCE
OF APCTT
APCTT can help Asia Pacific Countries:
Build up S&T Capabilities
Capitalize biodiversity and TK for
bioindustrial development
Insulate from Biopiracy
Ensure national sovereign rights over
biodiversity and TK
Empower local and indigenous communities,
including women
Build up location –specific biodiversity
enterprises using local bio-resources and TK
through S&T applications
BIOPARTNERSHIP: RELEVANCE
OF APCTT
APCTT can help in Capacity building and
Training for Asia-Pacific countries
AREAS: Biodiversity & TK
Biotechnology
Bioinformatics
Bioprospecting
APCTT can help in in Capacity Building and
Training for Asia-Pacific countries
STRATEGIES:
1. Development of Transparent Policies and
Mechanisms to ensure:
Access to and transfer of genetic
resources and technologies among
participating countries
Evolving equitable benefit sharing
models based on sustainable use and S
& T based value addition to bioresources
and associated TK
Contd...
STRATEGIES (Contd.):
2. Promotion of multi-country collaborative
R&D projects on various facets of
Bioprospecting, particularly herbal drug
and pharmaceutical prospecting and
other natural product development
sectors
3. Generation of IPR- covered products,
processes, technologies and services,
and thereby converting the bio-resources
and associated TK in to economic wealth
of the country and its people.
Action Programme
Important points that the biodiversity rich
third world nations should undertake:
Complete inventory & documentation of all
Biological resources including the microorganisms
Check list/database of the floristic wealth of the
nation along with the associated knowledge system
Ground check to know the actual situation and
identify the gaps:
Study - genetic diversity, distribution pattern,
association pattern and gradients
Identify- rare, endemic and endangered status of
spp. , if any.
Action Programme
Prepare -passport data of all important
and endemic biodiversity. Passport data
should
cover
morphological,
cytological, chemical and molecular
level (DNA/gene level) information so as
to prevent bio/gene piracy.
Identification of problems and solutions
in conservation, threatened status of
species, ecosystems -with causes of
threats.
Identification of problems and solutions
in conservation.