MEDICINAL PLANTS: Screening and development of Active Pharmaceutical

Ingredients (API)

Gundu HR Rao, Professor, Laboratory Medicine and Pathology, University

of Minnesota, Minneapolis, Minnesota 55455

The modern pharmacopoeia is estimated to contain at least 25% drugs derived

from or their synthetic analogues built on prototype compounds isolated from
plants. The World Health Organization (WHO) estimates that 80% of the
population of developing countries may be relying on traditional medicines,
mostly plant-derived drugs, for their primary health care needs.

Demand for medicinal plant is increasing in both developing and developed

countries which offer the following advantages:
1. They are natural products
2. Non-narcotic
3. Having no side-effects, or less side effects
4. Easily available at affordable prices
5. Provide opportunity to genetically engineer them for better use

Medicinal plant sector has traditionally occupied an important position in the

socio-cultural, spiritual and medicinal arena of rural and tribal lives of India. There
are roughly around 25000 effective plant based formulations used in folk
medicine and known to rural communities all over India and around 10000
designed formulations are described in the indigenous medical texts.

Medicinal plants as a group comprise approximately 8000 species and account

for around 50% of all the higher flowering plant species of India. It is estimated
that there are over 7800 drug-manufacturing units in India. An estimate of the
EXIM Bank puts the international market of medicinal plants related trade at US$
60 billion per year growing at the rate of 7%.

Around 70% of India’s medicinal plants are found in tropical areas mostly in the
various forests spread across the Western and Eastern ghats, the Vindhyas,
Chotta Nagpur plateau, Aravalis & Himalayas. Of the 386 families and 2200
genera in which medicinal plants are recorded, the families Asteraceae.
Euphorbiacae. Laminaceae, Fabaceae, Rubiaceae., Poaceae, Acanthaceae,
Rosaceae and Apiaceae share the larger proportion of medicinal plant species
with the highest number of species (419) falling under Asteraceae. About 90% of
medicinal plants used by the industries are collected from the wild. While over
800 species are used in production by industry, less than 20 species of plants
are under commercial cultivation. Therefore, there is a renewed interest in
several States of India to develop medicinal plant nurseries for commercial use.
Plant collections for medicinal uses involve destructive harvesting because of the
use of parts like roots, bark, wood, stem and the whole plant in case of herbs.
This obviates the need for a mechanism for a continuous cultivation. Crude drugs
are usually the dried parts of medicinal plants (roots, stem wood, bark, leaves,
flowers seeds, fruits, and whole plants etc.) that form the essential raw materials
for the production of traditional remedies of Ayurveda, Siddha, Unani,
Homeopathy etc.

Medicinal plants arena is not without its own set of problems. Current practices of
harvesting are unsustainable and many studies have highlighted depletion of
resource base. Consequently, the raw-material supply situation is shaky,
unsustainable and exploitative. Confusion also exists in the identification of plant
materials where the origin of a particular drug is assigned to more than one plant,
sometimes having vastly different morphological and taxonomical characters.
In most cases, where the identity of plant sources is doubtful or still unknown;
adulteration is a common sequel. The quality of medicinal plants depends on the
geographical origin, time and stage of growth when collection has been done and
post harvest handling. Experienced botanists, pharmacologists, biochemists
combined with locals with the expertise from traditional knowledge could resolve
all such confusion and emerge with protocols for better use of the treasure.

On glancing at the regulatory aspects, trade in medicinal plants at all levels in

India is marked by secrecy and lack of transparency. There has been little
attempt at external regulation by Government and self-regulation by traders and
herbal medicine company. The government has no negotiations or relations with
the collectors or growers & buyers. Indian Council of Medical Research (ICMR)
has set up a separate cell to oversee research on medicinal plants. Research in
India, except for a few dedicated groups are mostly short-term and do not
contribute to knowledge of any particular species in detail. Also, efforts for
looking into newer species are mostly dictated by ancient texts albeit translated
to its nearest best. This essentially leads to ambiguity in identification and
consequently the related problems.

A UNDP Country Cooperation Program assisted Sub-program on “Medicinal

Plants Conservation and Sustainable Utilization” has been approved and initiated
in December 1999. Foundation for Revitalization of Local Health Traditions
(FRLHT), Bangalore, has been designated as the co-coordinating agency. This
is a demonstration project to replicate the activities being carried out in the three
Southern States of Karnataka, Kerala and Tamil Nadu and in the States of
Andhra Pradesh and Maharashtra. The executing agencies in Andhra Pradesh
are Environmental Protection Training Research Institute (EPTRI), Hyderabad
and Rural Communes (RC), Mumbai in Maharashtra. The State Forest
Departments are the key players in the activities and would be responsible for
providing the forest land for the in-situ conservation activities envisaged in the
program.
Indigenous Drug Development in India:

Central Drug Research Institute (CDRI) in Lucknow has been researching in this
area for over 50 years and has screened over 60,000 plant products for
medicinal properties. In spite of this massive effort in one of the State-of-the-art
Institute, India has not produced a single FDA approve drug for commercial use.
Apart from this Institute, Himalayan Drugs and Hamdard are two independently
operated institutions, which develop drug supplements and unani products for
therapeutic purposes. These two organizations have not paid too much emphasis
on development of drugs using state-of-the-art methodology or testing by
classical clinical trials. On the other hand they may be happy selling their
products in countries, which does not require EMEA or FDA regulations.
However looking at the success of the Indian and Chinese Pharma companies I
for one feel strongly the aim of the future policy makers is to insist that we
develop medicinal products form herbal, microbial or marine sources under
cGMP conditions so that we can compete proudly in the Global Market

The appropriate steps towards utilization of these natural resources into a profit
oriented effort could be done by taking following steps:

 Isolate pure active compounds for formulation into drugs.

 Develop in vitro assays for testing the active ingredients
 Develop small animal facility for evaluating toxicity and efficacy
 Isolate intermediates for the production of semi-synthetic drugs
 Prepare standardized galenicals (abstracts, powders, tinctures etc.) If one
is to produce known pure phyto-pharmaceutical used in modern medicine,
more processing stages and more sophisticated machinery are required.
 Plans to be laid down for hosting gene banks to store germplasm for
propagation.

Safety, efficacy, effects of pollution on the raw materials have to be considered.

Protocols taking into account detailed biochemical, pharmacological, toxicological
studies need to be laid down. Animal experiments need to be facilitated. The
quality requirements for medicinal plant preparations are to be made stringent in
terms of content of active principles and toxic materials. Quality has to be built
into the whole process beginning from the selection of propagation material to
the final product reaching the consumer. The requirements for ISO 9000
certification and Good Manufacturing Practices (cGMP) have to be complied
with.

WHO has published guidelines for the assessment of herbal medicines taking
into account long and extensive usage of them (WHO, 1999). Wherever
possible, patents may be obtained or IP rights established for the process and
preparation of products from medicinal plants.
For convenience of initiating efforts, one may categorize medicinal species into :
(a) those which are of proven medicinal value as per scientific parameters, (b)
those on which sufficient leads are available, and (c) those on which much work
is required to be done. This shall help in choice of agenda in a phase wise
manner for an entrepreneur. Research & Development, other than studies
related to pharmacokinetics, bioavailability, toxicity etc must also concentrate in
modalities for bulk production, quality assurance and in identifying multiple
properties of a species.

LIST OF MEDICINAL PLANTS IN SHORT SUPPLY IN INDIA

(Source: Task Force on Medicinal Plants, Government of India)

Sl. Common Name Botanical Name Quantity From when the

No. required supply got
Tonnes/ reduced
Annum

1. Ashtavarga - 0.095 Last 23 year

2. Ativisha Aconitum heterophyllum 0.550 “ 15 “
3. Ashok sal Saraca asoca 6.800 “ 4 “
4. Indrajava Wrighatia tinctoria 0.418 “ 5 “
5. Kamalphool Nelumbo nucifera 0.310 “ 8 “
6. Kapila Mallotus philippiensis 0.155 “ 12 “
7. Kankol Piper cubeba 0.335 “ 5 “
8. Kapurkachari Curcuma zedoaria 0.225 “ 5 “
9. Kakadshingi Pistacia chinesis 0.450 “ 10 “
10. Kaiphal Myrica esculenta 0.225 “ 5 “
11. Kalimusali Curculigo orchioides 2.250 “ 4 “
12. Krishnageru Aquilaria agallocha 0.170 “ 12 “
13. Kirata Swertia chirata 2.500 “ 7 “
14. Kirmani ova Artemisia maritima 0.330 “ 5 “
15. Kutaki Picrorhiza kurrooa 1.550 “ 5 “
16. Koshtha Saussurea lappa 0.430 “ 5 “
17. Kosthakolinjan Alpinia galanga 0.220 “ 4 “
18. Khair sal Acacia catechu 2.400+ “ 5 “
19. Guggul Commiphora wightii 2.300 “ 5 “
20. Chavak Hemidesmus indicus 1.200 “ 3 “
21. Chopchini Smilex china 0.550 “ 5 “
22. Jatamansi Nardostachys jatamansi 0.660 “ 5 “
23. Jaiphal Myristica fragrans 0.330 “ 3 “
24. Tagar Valeriana wallichii 0.275 “ 5 “

Sl. Common Name Botanical Name Quantity From when the

No. required supply got
 Tonnes/ reduced
Annum

25. Triman Gentiana kurroo 0.220 “ 4 “

26. Dantimool Baliospermum montanum 0.320 “ 3 “
27. Daruhalad Berberis aristata 2.700 “ 6 “
28. Devdar Cedrus deodara 2.200 “ 10 “
29. Nagkesar kala Mesua ferrea 0.650 “ 6 “
30. Dukkarkand Dioscorea bulbifera 0.175 “ 7 “
31. Pippali Piper longum 1.250 “ 5 “
32. Pippalmool Piper longum 0.850 “ 5 “
33. Pokharmool Inula racemosa 0.650 “ 6 “
34. Phanas ambe Artocarpus heterophyllus 0.055 “ 5 “
(fleshy fungus)
35. Manjistha Rubia cordifolia 1.150 “ 4 “
36. Motiringani Solanum indicum 1.150 “ 5 “
37. Raktaroda Tecoma undulata 0.300 “ 6 “
38. Raktachandan Pterocarpus santalinum 1.025 “ 18 “
39. Chitrak lal Plumbago zeylanica 3.500 “ 5 “
40. Vakeri bhate Wagatia spicata 0.120 “ 4 “
41. Vavading Embelia ribes 3.400 “ 3 “
42. Vala Vetiveria zinzanioides 1.150 “ 4 “
43. Shvet miri Piper nigrum 0.090 “ 13 “
44. Harenvel Convolvulus arvensis 0.156 “ 6 “

CONCLUSIONS

The demand on plant based therapeutics is increasing in both developing and

developed countries due to the growing recognition that they are natural
products, being non-narcotic, having no side-effects, easily available at
affordable prices and sometimes the only source of health care available to the
poor. The global thrust areas for drugs from medicinal plants include disease
conditions, whose incidence is increasing and where the modern drugs are either
unavailable or unsatisfactory.

Conservation and sustainable use of medicinal plants are issues on which

immediate focus is required in the context of conserving biodiversity and
promoting and maintaining the health of local communities, besides generating
productive employment for the poor with the objective of poverty alleviation in
tribal and rural areas.

International market of medicinal plants is over US $ 60 billion per year, which is

growing at the rate of 7%. There is an enormous scope for India also to emerge
as a major player in the global herbal product based medicines (Alternate
Medicine). Estimated Global Market by 2050 is several trillion dollars.
There is also considerable interest in the area of drug discovery, which is
neglected (orphan drugs). For instance, development of drugs for disease of the
resource poor countries is totally neglected by the big Pharma companies. In
view of this Council of Industrial Research (CSIR) has developed a scheme
called “Open Source Drug Discovery (OSDD)”, to hasten discovery for orphan
drugs like TB and Malaria.

Setting up of Mini- and a Pilot Extraction, Concentration and

Characterization Facility for APIs:

Mini- Extraction Facility:

For extraction, concentration and characterization of small quantities

of API, we need a standard extraction facility with laboratory
equipment for extractions of the active ingredients from raw materials,
analysis and characterization;

General Laboratory:

1. Raw material receiving, cleaning and processing unit

2. Aqueous extraction set up
3. Solvent extraction set up
4. Concentration capability
5. Lyophilizers
6. Storage of active ingredients for analysis

Analytical Laboratory:

1. Balances
2. UV-Visible-Infra red spectrophotometers
3. Microscopes
4. Gas Chromatography-Mass Spectrometers
5. High Pressure Liquid Chromatography-Mass Spectrometry
6. Thin layer chromatography and Densitometry set up
7. Industrial HPLC
8. Column Chromatography set up
Pilot Extractions Facility:

We need five acres of land and 2000 sq.ft. of laboratory space to

establish a pilot level facility to scale up the extraction, concentration
and characterization of active ingredients
Eg: Avigna Pharmaceuticals, Jigni, Bangalore

Disease Specific Drug Development:

India is the capital of Type-2 diabetes. We have more than 50 million

people with diabetes and this will increase to 80 million by 2025. Yet
we do not have any indigenous drug commercially available for
management of this disease.

Polypill of blood sugar control:

Betaine, a natural product from sugar beets has several medicinal

properties. The active ingredient is tri-methyl glycine a simple amino
acid. Studies from our group have demonstrated that the green tea
made from mulberry leaves also reduces the post-prandial blood
glucose. The active component is DNJ. Furthermore, there are active
ingredients in fenugreek and karela that could be also extracted and
used for making the polypill for managing blood glucose.

Special equipment needed for this study is blood glucometer and

strips for monitoring blood glucose.

Lipid Lowering Drugs:

Billions of dollars are spent on development of lipid lowering drugs.

The commonly used lipid lowering drugs, Statins are expensive and
long term use may result in undesirable side effects. Therefore there
is a need for plant-derived lipid lowering drugs for the management of
blood lipids such as Cholesterol, LDL and Triglycerides.

Common sacred basil thulasi leaves are supposed to have active

ingredients capable of lowering lipids. There are more than 50
species of Ocimum. There is a need to screen them select the
species with high content of the active ingredient of interest.
Special equipment needed:

Hand-held lipid monitoring devices

Blood Pressure lowering Drugs:

Over 600 million individuals world-wide suffer from elevated blood

pressure (BP). There are many synthetic compounds that are in use
for the management of BP. There is a great need to develop
indigenous plat-derived drugs for the management of BP.

Special equipment needed:

Standard Blood pressure monitors as well as ambulatory blood
pressure monitors.

Immuno-modulators:

There are very few drugs to mange this aspect of human physiology.
In recent years there are more and more situations that lead oen to a
immune compromised state. This state will lead to predisposal of
individuals to variety of opportunistic diseases as well as complicated
disorders. There is a great need to develop this class of drugs for the
management of immune compromised patients.

Special equipment needed:

Flow Cytometers

Special Purpose Drugs:

Tuberculosis and Malaria are typical diseases of the resource poor

countries. Since these diseases have been well controlled in the
western world, there is very little attention paid for the development of
drugs to manage these diseases. There is a great opportunity to
develop this class of drugs from plant sources.

Special equipments needed:

Special Microscopes or Hand-held device, for monitoring TB bacillus
in sputum of patients and malaria parasites in RBC of patients.

Screening for activity at the cellular level:

Inhibitory drugs of medical importance can be identified, by using

assays at cellular level. In vitro assays could used to monitor the
inhibitory effect of APIs on important cell signaling pathways. For
instance for anticancer drug screening, one can use assays for
caspace, tumor necrosis factor or heat shock proteins. These
processes play an important role in tumor cell death. Similarly assay
models can be developed for angiogenesis to screen drugs that
prevent this process.

Screening for Toxicity and safety at the animal level:

Once we have identified drugs of importance, we need to test the

safety availability and efficacy in animal models (mouse, rabbit).

Small scale clinical studies using human subjects:

Those found effective in animal models can be evaluated using

human volunteers or patients. For these studies we need the
permission of the ethical committee as well as regulator bodies.
It is possible to contract this phase out to standard clinical facilities.

Budget:

Recurring expenditures

Senior staff: Botanist, Pharmacologists, Biochemists, Scientists –

Mid-level: Research Associates with a minimum experience of 4-5
years in ethno-botany and/or phyto-extraction procedures –
Biochemists, analysts, molecular biologists, bioinformatists
Junior level: Research Assistants, Helpers
Administrative staff:
Non-recurring expenditure
Equipment:

Spectrophotometer: UV, Visible and Infra red

GC Mass Spec
HPLC Mass Spec
Maldi/MS
Flow Cytometers
Distillation setup:
Basic equipment:
Deep freezers:
Refrigerators:
Glassware:
Computers & analysis software:

Molecular biology setup when required:

Infrastructural costs not included

sumanchatterjee02@gmail.com, ic@yahoo.com, ic@yahoo.co.inAPIs can

also be used for making Ayurvedic or Unani formulations.

This unique plant-to-clinic set-up could also be a teaching and

research facility in an advanced center of excellence for AYUSH
Research.