Title: Product Development and Clinical Studies of Traditional Medicines
1Product Development and Clinical Studies of
Traditional Medicines
- N. L. Phang
- Nova Laboratories Sdn. Bhd.
- Malaysia
- (www.nova.com.my)
2Objectives
- To discuss the main issues and regulatory
guidelines on product development. - 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.
3Successful herbal productDevelopment of
bromhexine
- Ethnobotany approach in drug development
- Bromhexine (Trade name Bisolvon)
- Is a popular mucolytic agent for cough.
- It is derived from Indian Adhatoda vasica (the
malabar nut tree) which is traditionally used in
cough therapy.
4Definition of herbal products
- Three categories of herbal products
- A. Drugs (NCE, new chemical entities)
- Single active ingredient pharmaceuticals
originating from plants. - E.g. vinblastine, digoxin.
5Definition of herbal products (Contd)
- B. Botanical drugs (Multi-component botanical
drugs) - Botanical drugs are manufactured medicines
obtained exclusively from plants to relieve,
prevent or cure a disease or to alter
physiological and pathological process. - E.g. None in USA, several in clinical trials.
-
- Dietary supplements / herbal supplements
- Plant components with health benefits.
- E.g. Garlic or Echinacea
6Why do we develop botanical drugs?
- Diverge chemical range
- Enormous propensity to synthesize diverse
bioactive compounds. - (Multiple and mutually potentiating therapeutic
effects) - Complex molecules with unique
properties. - Biomanufacturing factories
- Relatively low-cost, highly effective and
complex. - 3. Higher investment cost on chemical synthesis.
- 4. Perception that phytochemicals provide a safer
and more holistic approach to disease treatment
and prevention.
7Development process of botanical drugs
- Development of botanical drugs is a hard and
expensive task. - Each new drug requires a big investment and a
minimum of 5 - 10 years of work. - Therefore, we have to adopt a very carefully
planned strategy. - The development of botanical drug emphasizes on
three important aspects of the product - Quality
- Efficacy
- Safety
- Inter-related as efficacy and safety largely
depend on the quality.
8Herbal product developmentThe 6S Process
- Selection
- Herb informatics
- Unmet health need
- Sourcing
- Chemotaxonomy
- Raw material analysis
- Structure
- Identification of active constituents
- Method validation
- Standardization
- Chemical profile
- Pharmacological profile
- Safety
- Historical / traditional use
- Toxin analysis
- Safety studies in animals
- Substantiation
- . Review of pre-existing data
- Prospective clinical study
Joseph Chang, Biochemical Pharmacology, Vol.
59, pp 211-219, 2000.
9Study the guidelines for botanical drugs
- The final products are strictly controlled by the
regulatory authorities. - It is important to study the requirements of
several important regulatory guidelines.
10USA FDA CDER Guidelines for botanical drugs
- The Guidance for Industry Botanical Drug
Products quality standards for standardized
plant extracts (botanical drugs). - Guidelines for the development of drug products
from botanicals. - It is now possible to market these products under
the New Drug Application (NDA) approval process.
11Abbreviated preclinical and clinical testing
protocols
For plants with safe history of human use USA
FDA proposed abbreviated preclinical and clinical
testing protocols for botanical drugs derived
from plants.
12Companies in North America and the UK currently
involved in development of botanical drugs for
clinical trials
Company Areas of clinical testing
Ancile pharmaceuticals. San Diego, CA Sleep, anxiety disorders
CV Technologies. Edmonton, Canada Respiratory infection
GW Pharmaceuticals. Salisbury, UK Cannabis-based prescription medicines
Oxford Natural Products. Oxford, UK Dysmenorrhoea, hepatitis-C symptoms, cognitive decline
PhytoCeutica. New Haven, CT Cancer, neurovascular disease
Phytomedics. Dayton, NJ Autoimmune diseases, cancer
Phytopharm. Godmanchester, UK Appetite suppressant, inflammatory bowel disease, Alzheimers disease, cancer
13WHO EMEA guidelines
- The WHO Guidelines for the Assessment of Herbal
Remedies, adopted by the International Conference
of Drug Regulatory Authorities (Ottawa, October
1991). - EMEA Guidelines.
14Pharmacopoeial monographs Quality specification
- Define the quality standards of herbal products.
- E.g USP NF (USA), Indian Pharmacopoeia, Chinese
Pharmacopoeia.
15USP NF
- 21 monographs for medicinal plants and medicinal
extracts.
16Structure of USP botanical monograph
Monograph for Gingko (USP26 NF21) Monograph for Gingko (USP26 NF21)
Definition of herbal product Microbial limits
Identification tests Limit tests For soil and sand contamination
Content tests Quantitative determination of marker compounds Content of flavonol glycosides by HPLC Content of terpene lactones by HPLC Heavy metals vii.. Pesticide residues
17Indian Herbal Pharmacopoeia Volume 2 Monograph
for Phyllanthus
- Describes analytical methods (HPLC) of marker
compounds - Phyllanthin and Hypophyllanthin
phyllanthin
hypophyllanthin
phyllanthin
hypophyllanthin
(a) Reference standards
(b) Sample preparation
18Chinese Pharmacopoeia Volume 1Monograph for
Ginkgo
- -- Describes assay method (HPLC) for flavonol
glycosides.
19Main specification requirement of botanical
drugs
- Chemical standardization
- i. quality identification of the product.
- ii. quantitative determination of the marker
- compound(s) of the product.
20Chemical standardization
Chemical standardization emphasizes the
importance of determination of the content of the
herbal products.
21Importance 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
22Malaysian 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.
23HEPAR-P capsuleApproved for clinical trial
- HEPAR-P Capsule contains standardized Phyllanthus
niruri extract. - 1st local product approved by Medical Research
Ethics Committee, Ministry of Health Malaysia. - For clinical testing to evaluate antiviral
activities in patients with chronic hepatitis B.
24Two phases of development process Pre-clinical
and clinical studies
- Pre-clinical studies (Animal studies)
- Evaluate the pharmacological activities.
- Evaluate the toxicity.
-
- Clinical studies (Human studies)
- Evaluate the efficacy.
- Evaluate the toxicity.
25Flow chart of development of HEPAR-P Capsule (1)
Medical plant
Extract
Fractions
Toxicology
Bioassays
Chemical characterization
26Flow chart of development of HEPAR-P Capsule (2
- Contd)
Chemical standardization Qualitative
quantitative analytical methods
Standardized extract EPN 797
Pure compound
Drug Delivery Technology
New chemical entity
Manufacturing technology for Finished product
Stability studies
27Flow chart of development of HEPAR-P Capsule (3 -
Contd)
- Quality control protocol
- Chemical standardization
- Biological standardization
Complete monograph (of herbal product)
Approved herbal supplement
Animal toxicology studies (on the finished
product) -- Rodents Non-rodents -- According
to FDA / WHO / Malaysian guidelines
28Flow chart of development of HEPAR-P Capsule (4 -
Contd)
- LD 50
- Acute toxicology studies
- Sub-acute toxicology studies
- Chronic toxicology studies
Completion of pre-clinical 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
29Specification of a botanical drug
- Chemical standardization
- Identification of chemical constituents
- Measurement of marker compounds
- Biological standardization
- In vitro anti-HBsAg activity (ELISA method)
- In vivo liver protective activity in rats
- Stability of the finished product
- Accelerated stability study
- Real time stability study
30Chemical structureCorilagin Phyllanthus
flavonoids
Corilagin Polyphenol (Anti-viral liver
protective)
Phyllanthus flavonoids (Liver protective)
Chemical structure of rutin, one of the
Phyllanthus total flavonoids.
Chemical structure of corilagin.
31TLC fingerprint
TLC identification of Phyllanthin and
fingerprints of HEPAR-P capsule
Niranthin
Hypophyllanthin
Phyllanthin
32TLC fingerprints (Contd)
TLC identification of rutin in HEPAR-P capsule
TLC identification of corilagin in HEPAR-P capsule
Corilagin
Rutin
33Chemical standardizationHEPAR-P Capsule
- Content of one HEPAR-P Capsule
- 250 mg of Phyllanthus niruri extract EPN
797 standardized to contain - Corilagin 10 mg
- Total flavonoids 45 mg
34HPLC analysis of corilagin
Chromatogram of Phyllanthus niruri extract EPN 797
35Biological 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.
36HEPAR-P CapsuleQuality control
- Chemical standardization
- Ensures batch-to-batch consistency in chemical
composition. - Biological standardization
- Ensures batch-to-batch reproducible biological
activities.
37Biological standardization
- Liver protective In vivo (animal study)
- Anti-viral In vitro (ELISA test)
38Result of liver protective study
Effect of Phyllanthus on CCL4 induced Liver
injury in rats.
Effect of Phyllanthus on CCL4 induced Liver
injury in rats.
AST (U/L)
ALT (U/L)
39Result of Inactivation of HBsAg study
In vitro inhibitory activity against Hepatitis B
surface antigen (HBsAg) by HEPAR-P
40HEPAR-P CapsuleMonograph
- Quality specification (as compared to USP , IHP ,
CP) - Definition of product
- Chemical identification
- Chemical assays for characteristic marker
compounds - Assays for biological activity (or biological
assay) - Heavy metals
- Microbial limits
41Specification of HEPAR-P Capsule
Specification
Appearance description
Identity
Impurities
Potency
Contaminants
Quality
Heavy metals Microbial Pesticide residues
Color Smell
Product related
Process related
42Safety of HEPAR-P CapsuleAnimal toxicology
studies
- Toxicology evaluation on the finished product
- Acute studies (14 days, rodents and non-rodents)
- Sub-acute studies (90 days , rodents and
non-rodents) - Chronic study Rodents (180 days)
- Chronic study Non-rodents (270 days)
43Pre-clinical studies for HEPAR-P Capsule (Animal
studies)
- 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.
44Completion of pre-clinical studiesApproval for
clinical trial
-- Approval by National Committee For
Research And Development In Herbal Medicine
(NRDHM). -- Clinical trial at Selayang General
Hospital on Jan / Feb., 2005.
45Clinical studies (Human studies)
- Clinical evaluation of safety and efficacy in
human subjects by appointed clinical
investigators. - Report of the clinical evaluation by the
investigators. - Recommendation by National Committee for Research
and Development in Herbal Medicine. - Submission to DCA for registration of product as
botanical drugs with approved therapeutic claim.
46Conclusion
- 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. - 3. 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).
47Thank you