With globalization trends and product patent regime in place, drug discovery has become the new mantra particularly for the big and cash rich Indian pharma companies. Development of NCEs from plant sources typically involves the following steps:
- Screening of large number of plant extracts in in vitro assays and identification of 'hits'
- Bioassay guided fractionations of 'hits'
- Isolation and identification of bioactive chemical entities.
- Medicinal chemistry to modify the chemical structure towards optimization of parameters related to oral absorption, metabolic stability, desired physiological response and toxicity.
- Systematic pharmacological and clinical trials to establish efficacy, safety and dose.
Last mentioned points -medicinal chemistry and pharamacological/clinical studies, however, are common to all drug discovery programmes, synthetic or natural. It has been recognized that natural product structures have the characteristic of high chemical diversity, biochemical specificity and other molecular properties that make them favourable as lead structures for drug discovery and which serve to differentiate them from libraries of synthetic and combinational compounds.
Screening involves automated testing of large collections (libraries) of samples for activity as inhibitors or activators of a specific biological target such as a cellular surface receptor or enzyme. The natural product library (NPL) will typically have mixtures such as crude extracts (10-100s of compounds), semi pure mixtures (5-10 compounds) or alternatively single purified / isolated phytocompounds. Building NPL with plant extracts / fractions is quite difficult and time consuming as it involves manual collection of plants, identification, preparation of extracts and fractions. Once built, the NPL could become a precious asset of the organization / company. For small to medium R&D based companies in India who can not afford full fledged drug discovery programmes, building NPLs and offering to big pharma companies could become a source of revenue.
Isolation and identification of bioactive chemical constituents from extracts typically involve bioassay (in vitro) guided fractionations. This once again is very tedious and generally considered as the rate limiting step as it involves searching for the active principle(s) constituting less than 1%w/w of an exceptionally complex matrix. One of the fundamental concerns in natural product drug discovery is what is commonly known as "supply issue". Unlike simpler synthetic compounds, natural products can be limited in supply owing to sourcing limitations or the impracticality of synthesis. A classic example here is that of paclitaxel from Taxus species.
This limitation could open up new areas of R&D driven business for small to medium size companies in India as the chromatographic options are becoming more affordable and flexible (in terms of different stationary phases, approaches, techniques, instruments etc.) in India.
Elucidation of complex structures of natural compounds has been greatly benefited by significant advances seen in the last decade in spectroscopic techniques particularly in high resolution Nuclear Magnetic Resonance (NMR) and hence is no longer a major impasse in the drug discovery process.
DEVELOPMENT OF HERBAL PRODUCTS AND STANDARDIZATION (DHPS)
The major R&D programmes of Indian herbal industry have been in the area of development of herbal products and standardization. During the last decade there has been a huge increase demand in the western world for herbal products classified in different countries under categories such as phytomedicines, dietary supplements, food and beverage ingredients and traditional medicines.
One of the major differences between herbal product and chemical drug is that the former is a complex mixture of primary and secondary metabolites of the herb while the latter is typically a single or a combination of 2-3 chemical entities.
Obviously, the chemical drugs have distinct advantages in terms of controlling the quality, dose, efficacy, safety and stability. In the case of herbal products the issues are far complex mainly due to the following reasons.
1. Complex chemistry of herbs which is often inconsistent due to geographical and seasonal variations, age of plant etc
2. Lack of understanding of bioactive constituents of the herb
3. 100% chemical analysis is not possible / practical from routine quality control point of view
4. Problems related to botanical identification of herbs, adulteration, use of pesticides etc
5. Herbal products do not undergo the rigorous protocols of chemical drug development and hence potential problems, particularly related to toxicity may remain unaddressed
6. Herbal products, particularly aqueous extracts are highly prone to microbial contamination and the associated problems like presence of aflatoxins etc
7. Stability assessment of herbal products is difficult mainly due to the complex chemistry of herbs and lack of understanding of bioactive constituents.
An in-depth analysis of the problems clearly indicates that R&D activities in the areas of concerns mentioned above can throw up new business opportunities particularly in the export front.
Traditional DHPS for a given medical indication typically involves the following steps:
- Selection of plants based on traditional knowledge and available scientific literature.
- Preparation of extracts
- Combination of extracts and formulation development
- Development of quality control parameters, isolation of marker constituents etc
- Efficacy and safety studies in animals
- Investigations on mechanisms of actions (not always done)
- Clinical trials (not always done)
However, vibes of modern drug discovery approaches have started influencing the process of DHPS, mainly on how the plants are selected, on identification of bioactive constituents, mechanism of actions and during selection of the best / synergistic combination of herbs. In the present day DHPS, we can see examples of selection of plants based on screening programmes on plant extracts using in vitro bioassays, analogous to the high throughput screening programs during development of NCEs. Bioassay guided fractionations (BAGF) are then carried out on the interesting extracts to identify the active principles.
Conceptualization of formulations based on the levels of bioactive constituents and synergy studies is being heard these days in the herbal sector. In fact, BAGF reports form a major chunk of articles being published in indexed international journals like Planta Medica, Journal of Natural Products etc. Stability studies and shelf life determinations are being attempted based on the knowledge of bioactive constituents.
R&D programs of herbal sector in India are on the verge of moving to new and dynamic directions dictated by the needs of international requirements related to safety, efficacy, quality and scientific understandings.
- (The author is with R&D centre, Natural Remedies Pvt. Ltd., Bangalore)