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Objectives
1. To discuss the main issues and regulatory guidelines on product development. 2. To describe develop process of a traditional medicine with therapeutic claim.
To illustrate with a case study The development of a botanical drug containing standardized Phyllanthus niruri extract EPN 797.
2.
3. 4.
iv.
Companies in North America and the UK currently involved in development of botanical drugs for clinical trials
Company Ancile pharmaceuticals. San Diego, CA CV Technologies. Edmonton, Canada GW Pharmaceuticals. Salisbury, UK Oxford Natural Products. Oxford, UK PhytoCeutica. New Haven, CT Phytomedics. Dayton, NJ Phytopharm. Godmanchester, UK Areas of clinical testing Sleep, anxiety disorders Respiratory infection Cannabis-based prescription medicines
USP NF
21 monographs for medicinal plants and medicinal extracts.
ii.
Identification tests
v.
iii.
vi.
hypophyllanthin
Chemical standardization
Chemical standardization emphasizes the importance of determination of the content of the herbal products.
Importance of measurement
A quotation from Lord Kelvin:
When you can measure what you are speaking about, and express it in numbers, you know something about it
Malaysian guidelines
Guidelines for Standardization of Herbal products Guidelines for Levels and Kinds of Evidence to Support Claims for Therapeutic Products
-- Published by National Committee For Research And Development In Herbal Medicine (NRDHM) -- Similar to FDA guidelines, they allow the development of botanical drugs with therapeutic claim.
Extract
Bioassays
Fractions
Toxicology
Chemical characterization
Standardized extract EPN 797 Drug Delivery Technology Manufacturing technology for Finished product Stability studies
Submission to National Committee for Research and Development In Herbal Medicine (NRDHM)
Approval to conduct clinical trial at appointed hospitals Report of clinical trial by clinical investigators Recommendation by NRDHM Application to DCA for registration with therapeutic claim
Phyllanthus flavonoids
(Liver protective)
TLC fingerprint
TLC identification of Phyllanthin and fingerprints of HEPAR-P capsule
Corilagin
Rutin
Biological standardization
Chemical standardization is inadequate. Botanical drug contains a complex mixture of chemical compounds. Chemical standardization does not give a complete picture of a herbal product. We have combined biological assays with chemical fingerprints to provide assurance of efficacy and consistency.
Chemical standardization
Ensures batch-to-batch consistency in
chemical composition.
Biological standardization
Ensures batch-to-batch reproducible biological activities.
Biological standardization
Liver protective In vivo (animal study)
150
150
100
100
50
50
0
Control CCL4 control Treatment with Phyllanthus
0
Control CCL4 control Treatment with Phyllanthus
Appearance description
Color Smell
Identity
Impurities
Potency
Contaminants
Quality
Product related
Process related
i.
ii. iii. iv.
Identification The active fraction. Characterization The marker compound(s). Establishment Chemical standardization methods. (Optional Biological standardization methods) Animal toxicology studies. Stability studies. Formulation development. To establish a complete monograph of the product. Medical Research & Ethnics Committee approval to conduct clinical trial.
Medicine (NRDHM).
-- Clinical trial at Selayang General
Conclusion
1. The development of botanical drugs is likely to be a major area of plant biotechnology expansion in the 21st century. The future of botanical drugs will depend on consumer and regulatory acceptance. The important challenge is to provide science-based evidence to consumers and regulatory authority on: i. Efficacy (By clinical evaluation in human), ii. Quality (Establish monograph of the standardized extract), and iii. Safety (By toxicological evaluations in animals and in human).
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3.
Thank you