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Thai Herbal Medicine Development to the World Market
Dr. Krisana Kraisintu
Industrial Uses of Medicinal Plants PHYTOPHARMACEUTICALS TRADITIONAL M EDICINES
GALENICALS M EDICINAL HEALTH FOODS
PLANTS
INTERM EDIATES FOR DRUG MANUFACTURE NEW DRUGS
HERBAL TEAS
INDUSTRIAL/ PHARMACEUTICAL ANCILLIARY PRODUCTS
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Global use of herbal medicinal products
It is estimated that eighty percent of the world's population depends on botanical resources for their primary health care needs
Asia is the largest continent and has 60 % of the world’s population It has abundant medicinal and aromatic plant species, well documented traditional knowledge, a long-standing practice of traditional medicine, and the potential for social and economic development of medicinal and aromatic plants
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The countries of the region have large flora Species of higher plants: China 30,000 Indonesia 20,000 India 17,000 Myanmar 14,000 Malaysia 12,000 Thailand 12,000
Production of Phytomedicines and Cosmetics from Indigenous Resources:From Lab to Market Scientists in developing countries must accept the added role of being the intermediary player between technological development and market needs
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In this new role the scientist should posses the following qualities • Ability to translate technology into products • Include both marketing and scientific orientations in key decision • Technical and/or product development experience in the target market(s) • Ability to build teams and facilitate brainstorming sessions • Excellent communication skills
WHO has outlined three basic strategies for the use of medicinal plants with standardised pharmacoligically active constitutents • Application of known and effective technologies to the cultivation, processing and manufacture of herbal medicines in order to meet health needs a a culturally acceptable manner and to promote self reliance
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• The distribution of seeds or plants to individuals and communities to be cultivated in home gardens and consumed as infusions • The quality control of drugs derived from traditional plant remedies by using modern techniques and applying suitable standards and good manufacturing practices
Current Trends in Cosmetics and Personal Care Products
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Traditional Uses of Plant Extracts in Personal Care include • • • • • • • •
Wound Healing Antiseptic Anti-irritant Anti-inflammatory Anti-infective Body decoratives Toning (mud packs) Mouth and Teeth Cleaning
Global Resurgence in the Use of Phytopharmaceuticals
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The current increase in the use of plant based drugs may be associated with the following factors • High cost and long time invested in the development of a new drug • Relatively high incidence of toxicity side effects of synthetic drug • Non-renewed source of basic raw materials • Environmental pollution by the chemical industry
• Cost of orthodox medicines • Non-availability in developing countries • Clinical limitations, especially in the management of some chronic diseases
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Phytopharmaceuticals have the following advantages • Long history of use • Renewed source of raw materials • Both cultivation and processing are environmentally friendly • Locally available in developing countries • Plants are generally depository of new sources of new chemical moieties
Natural personal care products
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Major classes of natural products • • • • • • • •
Bio-saponins; steroids and triterpenoids Flavonoids: bioflavonoids and biflavonoids Amino acids: non-protein, biocomplexes Proteins and phytoamines Anti-oxidants Alpha hydroxy acids Formulation aids Vitamins (esp. Vit. A and E)
The following factors must be borne in mind when considering ingredients for the formulation of natural products
• • • • •
Safety/efficacy Quality of raw materials Reliable source of materials Regulatory requirements Claims development
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The steps that are important in commercial success of herbal medicinal products are (in order of importance) : 1. Research and clinical trials supporting health benefits 2. Consumer awareness of the health benefits 3. Media attention 4. An FDA-approved health claim 5. A proprietary marketing position 6. Proprietary technologies such as processes or ingredients
What’s in the Name? Herbal medicines Botanicals Phytopharmaceuticals Traditional Chinese medicines (TCM)
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What’s in the Name? Ayurvedics Complementary Alternative Medicine (CAM)
Commercialization of Medicinal Plants Phase 1: Design, Research and development Phase 2: Design, Production and Marketing Phase 3: Design, Sales and Distribution
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Approach to Raw Materials Selection and Development • Conduct Ethnobiological Evaluation and Inventory • Determine Activity of Interest • Establish a Selection and Replication Criteria • Identify Active Plant Extract or Compound • Fractionate/Purify
The design concept is retained to ensure that the original idea is not lost in the complexity of product development The ingredients selected must satisfy both technical specifications and marketing concerns Integration of commercial considerations as early as possible is vital for a successful development of new herbal products
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A product makes an elegant research topic does not necessarily mean that it will be a marketable product
Disadvantage of Traditional Methods: • Authenticity and purity of raw material not known • Variability of raw material quality • Post-harvest deterioration of raw material • Seasonal nature of plants • Non uniformity of dosage • Poor stability of the preparation • User difficulties owing to bulkiness and transport
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Advantages of Introducing Modern Technology: Verification of authenticity and purity Control of quality of raw material Proper post-harvest treatment Controlled and efficient processing methods which are reproducible Standardized product and therefore uniformity of dosage Conversion into conveniently handled dosage forms Significant increase in stability
Research and product development •
Proven safe
• Effective • Absorbed, distributed, metabolized
and excreted • Effective on targeted cells, organs,
tissues or physiological systems
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Product concept The traditional herbs and herbal formulations may be derived from historical texts or from the vast experience base of the practice of traditional systems, including current methods used in the art
Technology levels in processing of medicinal plants
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MEDICINAL PLANTS LEVEL I
LEVEL II
LEVEL III
LEVEL IV
1. Collection/Drying 1. Collection/Drying 1. Collection/Drying 1. Collection/Drying 2. Pulverization
2. Crushing
2. Crushing
2. Crushing
3. Extraction
3. Extraction
3. Extraction
4. (Concentration)
4. (Concentration) 4. (Concentration) 5. Purification
5. Purification 6. Chemical Conversion
ORAL & TOPICAL DOSAGE FORMS
PARENTERAL DOSAGE FORMS
Technologies involved in development of plant based medicinal and aromatic plants
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Botanical Screening the flora for plants of therapeutic or aromatic value
Study of distribution pattern, biological diversity assessment of natural stock, regeneration
Biotechnological Plant breeding; tissue culture, genetic and biochemical engineering
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Chemical Extraction, chemical analysis, physico-chemical evaluation, isolation and identification of useful compound
Pharmacological and olfactory evaluation Pharmacology, pharmacodynamics, clinical studies, olfactory evaluation (in the case of aromatic products)
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Agrotechnology Introduction and domestication, agronomy, harvest and post harvest handling
Processing Laboratory scale, bench scale, pilot scale, standardization
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Chemical engineering Instrumentation, large scale processing
Multidisciplinary approach to drug development from medicinal plants Selection and authentication of plant species
- pure compound - crude extract - crude drug - Pharmacological studies - Bioscreening
Toxicological studies
- Chemical studies on plant constituents - Standardisation of extracts
Selection of specific pharmacological action
- Preformulation - Stability studies
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Multidisciplinary approach to drug development from medicinal plants Cultivation of plant candidate
- Formulation studies on extracts into dosage form - Stability studies of the dosage form
- Clinical studies Phase I - Pharmacokinetics studies
Final formulation
Analytical studies on quantitative assessment of major Constituents
Multidisciplinary approach to drug development from medicinal plants Final formulation
Clinical studies Phase II and III
Packaging design
Pilot scale production
Transferring technology to industry
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STRAIN IMPROVEMENT
SURVEY & COLLECTION
BOTANIST
TAXONOMY
CULTIVATION PACKET
CHEMIST SEMI-SYNTHETIC DERIVATIVES
ISOLATION AND CHARACTERIZATION OF ACTIVE PRINCIPLES
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DETAILED PHARMACOLOGY
ACTIVITY PROFILE
PHARMACOLOGIST
TOXICOLOGY PHARMACOKINETICS
GMP NORMS
DOSAGE FORM
LABELLING
PHARMACIST
STANDARDIZATION AND SHELF LIFE PACKAGING
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POST MARKETING SURVEILLANCE
CLINICIAN
CLINICAL TRIAL OF TRADITIONAL REMEDIES
PHASE I & II NEW PRODUCTS
Chemical Standardization Methods Challenges • Complex and variable mixtures • Choice of compounds to quantitate • Difficult sample preparation • Lack of pure reference standards • Lack of methods with adequate tolerances by analytical chemistry standards
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Chemical Markers • Specifications for raw materials • Quality assurance in process control • Standardization of product • Obtain stability profiles • Single marker vs. “fingerprint”
Stability test The stability of the medicinal product should be determined by appropriate fingerprint chromatograms It must be shown that interactions between the active ingredients and the excipients in the finished product are unlikely to occur
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Phytopharmaceuticals should always contain the active principles together with coexisting materials from the source plant, these additional materials having a greater or lesser beneficial influence upon the activity of the drug.
Requirement for Any Phytopharmaceutical when for Human Use
Purity Constancy Stability Residual solvent Pesticides
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Parameters Influencing Quality of Plant Material and Quality of the Extracts
• Botany • Harvesting period • Area of origin • Storage of the plant material • Microbial counting
Parameters Influencing Quality of Plant Material and Quality of the Extracts
• Chemistry • Content of active principles • Qualitative composition of the plant • Extractive content • Ratio among the various compounds • Content of heavy metals • Solvents used for extraction
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Scheme of Preparation of any Standardized Extract • • • • •
Selection of the biomass Grinding process Extraction Concentration Drying process
Good Manufacturing Practice
GMP
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Agricultural production GAP
• selection of seeds • conditions of cultivation • harvesting generating reproducible quality herbal drugs
Quality of herbal medicines
GLP
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Active substance
• Herbal
drugs
• Herbal
drug preparations
Other constituents
• solvents • diluents • preservatives
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GHP
• site of collection • time of harvesting • stage of growth • treatment during growth with pesticides • drying • storage conditions
Herbal drugs with constituents of known therapeutic activity
Assays of their contents
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Herbal drugs without constituents of known therapeutic activity
Assays of marker substances
Markers are chemically defined constituents of a herbal drug which are of interest for control purposes
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Other tested
microbiological quality residues of pesticides and fumigation agents radioactivity toxic metals likely contaminants and adulterants
Analytical procedures not given in a pharmacopoeia should be validated
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Description and validation of the manufacturing process for the herbal drug preparation Quantitative determination of markers or of substances with known therapeutic activity is required
Control tests on the finished product
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Qualitative and quantitative determination of the composition of
• markers • constituents
of known therapeutic
activity
If a herbal medicinal product contains several herbal drugs or preparations of several herbal drugs Determination may be carried out jointly for several active substances.
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Stability tests
Herbal drug or herbal drug preparation is the active substance
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• Appropriate
fingerprint chromatograms • Other substances are stable • Proportional content remains constant
Herbal medicinal product contains several herbal drugs or preparations Stability is determined by appropriate fingerprint , chromatograms
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Efficacy of herbal medicines
GCP
Post-marketing experience for individual products and for all related products originating from the same herbal drug
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Quality assessment of phytopharmaceuticals • Assessment of crude plant material
• General description of the plant • Part used • Production of crude drugs • Cultivation • Harvesting • Post-harvest handling • Packaging and storage
Quality assessment of phytopharmaceuticals • Assessment of crude plant material
• Quality specification • Quality specification • Chemical/chromatographic identification • Foreign organic matter limit
• Ash content • Acid-insoluble ash content • Water-soluble extractive • Alcohol-soluble extractive
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Quality assessment of phytopharmaceuticals • Assessment of crude plant material
• Quality specification • Moisture content • Main/active constituent content • Microbial limit • Pesticide residue limit • Heavy metal limit • Likely contaminants • Adulterants
Quality assessment of phytopharmaceuticals
• Assessment of finished product at intermediate stage of the manufacturing process Same as described for finished products
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Quality assessment of phytopharmaceuticals • Assessment of finished product
• For tablets • Weight variation • Disintegration time (not more than 30 minutes) • Identification of preservatives and active ingredients
Quality assessment of phytopharmaceuticals • Assessment of finished product
• For tablets • Determination of extractives in various solvents • Microbial limit • Heavy metals
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Quality assessment of phytopharmaceuticals • Assessment of finished product
• For solutions • pH
• Identification of preservatives and active ingredients • Alcohol content (not more than 15 percent) • Microbial limit • Sodium saccharin content (not more than allowable limit)
Quality assessment of phytopharmaceuticals • Assessment of finished product
• For infusion • Weight variation • Identification of preservatives and active ingredients
• Determination of extractives in various solvents • Microbial limit • Heavy metals • Borax
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Quality assessment of phytopharmaceuticals • Assessment of finished product
• For sugar coated tablets Similar to tablets except for disintegration time which is not more than 1 hour
Chemical Standardization Methods - Challenges Complex and variable mixtures Choice of compounds to quantitate Difficult sample preparation Lack of pure reference standards Lack of methods with adequate tolerances by analytical chemistry standards
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TENGCHONG
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Herbal Medicinal Products •Future
of evidence •Future of traditional medicine •Future of public utilization •Future of future
Thank you
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