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Drug Discovery and Development Process of Anti-diabetic Plants

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Drug Discovery and Development Process of Anti-diabetic Plants Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Professor of Pharmaceutics KLE University College of Pharmacy – PowerPoint PPT presentation

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Title: Drug Discovery and Development Process of Anti-diabetic Plants


1
Drug Discovery and Development Process of
Anti-diabetic Plants
  • Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
  • Professor of Pharmaceutics
  • KLE University College of Pharmacy
  • BELGAUM- 590010, Karnatka, India.
  • Cell No 0091 974243100
  • E-mail bknanjwade_at_yahoo.co.in

28/12/2010
2
Sources of drugs
Animal Insulin (Pig, cow)
Growth hormone (Man) (Creutzfeldt-Jakob) Plant
Metformin (Gallega officinalis )
Morphine (Papaver somniferum) Inorganic Arsenic,
Mercury, Lithium
Synthetic Chemical (Propranolol)
Biological (Penicillin)
Biotechnology (Human insulin)
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3
Drug Discovery
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4
Drug Discovery
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5
The Regulatory process
  • Differs from country to country
  • Demands safety and quality of product
  • Encourages efficacy and need for product
  • Grants clinical trials certificate if volunteer
    and animal data OK
  • Approves protocols and examines data
  • 50-400 volumes (30,000-150,000 pages)
  • Original data available
  • Two way process authority and company trying to
    produce a safe effective product
  • Release for a specific purpose and use

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6
Marketing
  • Getting the product right (packaging
    formulation)
  • Right therapeutic slot
  • Information on new drug
  • Information for honest comparison
  • Reporting problems
  • Reporting new indications
  • Therapeutic trends

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7
Schema diagram representing anti diabetic plants
data
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8
A screen shot of the database Database on
anti-diabetic plants home page with links and
dropdown search window.
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9
Annona squamosa (SugarApple)
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10
Nigella sativa
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11
Polyherbal formulation of Annona squamosa and
Nigella sativa
  • This study was undertaken to investigate the
    effect of Polyherbal formulation of Annona
    squamosa and Nigella sativa on blood glucose,
    plasma insulin, tissue lipid profile, and
    lipidperoxidation in streptozotocin induced
    diabetic rats. Aqueous extract of Polyherbal
    formulation of Annona squamosa and Nigella sativa
    was administered orally (200 mg/kg body weight)
    for 30 days. The different doses of Polyherbal
    formulation on blood glucose and plasma insulin
    in diabetic rats were studied and the levels of
    lipid peroxides and tissue lipids were also
    estimated in streptozotocin induced diabetic
    rats. The effects were compared with tolbutamide.
    Treatment with Polyherbal formulation and
    tolbutamide resulted in a significant reduction
    of blood glucose and increase in plasma insulin.
    Polyherbal formulation also resulted in a
    significant decrease in tissue lipids and lipid
    peroxide formation. The decreased lipid peroxides
    and tissue lipids clearly showed the
    antihyperlipidemic and antiperoxidative effect of
    Polyherbal formulation apart from its
    antidiabetic effect.

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INTRODUCTION
  • Diabetes mellitus is syndrome, initially
    characterized by a loss of glucose homeostasis
    resulting from defects in insulin secretion,
    insulin action both resulting impaired metabolism
    of glucose and other energy yields fuels such as
    lipids and protein. Experimental diabetes in
    animals has provided considerable insight into
    the physiologic and biochemical derangement of
    the diabetic state. Many of the derangement have
    been characterized in hyperglycemic animals.
    Significant changes in lipid metabolism and
    structure also occur in diabetes. In these cases
    the structural changes are clearly oxidative in
    nature and are associated with development of
    vascular disease in diabetes. In diabetic rats,
    increased lipidperoxidation was also associated
    with hyperlipidemia. Liver, an insulin dependent
    tissue that plays a pivotal role in glucose and
    lipid homeostasis and it is severely affected
    during diabetes.

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13
Animals
  • Male Wistar albino rats (weighing 160200 g) were
    procured from Venkateshwara Enterprise, Bangalore
    and they kept in under standard environmental
    conditions (12 h light/dark cycles at 2528 0C,
    6080 relative humidity) in clean and dry cages
    and maintained in well-ventilated animal house.
    Animals were divided into 8 groups of five each
    and were fed with standard diet and water ad
    libitum. The study was approved by the
    Institutional Animal Ethics Committee.

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14
Preparation of drug
  • The seeds of Nigella sativa obtained from Prgati
    Ayurvedic Drug store Belgaum and matured fruit of
    Annona squamosa from local market of Belgaum and
    they were authenticated from Botanical Survey of
    India, Pune (Maharastra).
  • The extracts of the both antidiabetic plants were
    mixed and polyherbal formuation was prepared
    (Table 1). Five hundred grams of each plant
    (chopped into small pieces) was extracted
    individually and were soaked overnight in 1l of
    water. This suspension was filtered and the
    filtrates were pooled and the solvents were
    evaporated in a rotavapor at 4050 0C under
    reduced pressure and lyophilized.

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15
Chemicals
  • Streptozotocin and other biochemicals used in
    this experiment were purchased from Sigma
    Chemical Company Inc., St. Louis, Mo, and USA.
    Enzyme linked immunosorbant assay (ELISA) kit for
    insulin assay was purchased from Boehringer
    Mannheim, Germany.
  • Tolbutamide was a generous gift sample from Sun
    Pharmaceuticals Limited, Baroda, India. All other
    chemicals used were of analytical grade.

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Drug administration
  • Polyherbal formulation of Annona squamosa and
    Nigella sativa was suspended in distilled water
    and administered orally through intragastric tube
    at the following doses of 50, 100 and 200 mg/kg
    body weight.

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17
Streptozotocin-induced diabetes
  • Rats were made diabetic by single administration
    of streptozotocin (60 mg/kg/i.p) dissolved in 0.1
    M-citrate buffer, pH 4.5. Forty-eight hours
    later, blood samples were collected and glucose
    levels were determined to confirm the development
    of diabetes.
  • Only those animals which showed hyperglycemia
    (blood glucose levels gt 250 mg/dl) were used in
    the experiment.

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Experimental design
  • In the experiment, a total of 42 rats (30
    diabetic surviving rats, 12 normal rats) were
    used. The rats were divided into seven groups of
    six rats each after the induction of
    streptozotocin diabetes.

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Experimental design
  • Group1 Normal treated rats.
  • 2. Group2 Normal rats given aqueous solution of
    Polyherbal formulation (200 mg/kg body weight)
    daily using an intragastric tube for 30 days.
  • 3. Group 3 Diabetic control rats.
  • 4. Group 4 Diabetic rats given aqueous solution
    of Polyherbal formulation (50 mg/kg body weight)
    daily using an intragastric tube for 30 days.

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Experimental design
  • 5. Group 5 Diabetic rats given aqueous solution
    of Polyherbal formulation (100 mg/kg body weight)
    daily using an intragastric tube for 30 days.
  • 6. Group 6 Diabetic rats given aqueous solution
    of Polyherbal formulation (200 mg /kg body
    weight) daily using an intragastric tube for 30
    days.
  • 7. Group 7 Diabetic rats given aqueous solution
    of Tolbutamide (250 µg/kg bodyweight) daily use
    an intragastric tube for 30 days.

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Experimental design
  • At the end of 30 days, all the rats were killed
    by decapitation under pentobarbitone sodium (60
    mg/kg) anesthesia. Blood was collected in tubes
    containing potassium oxalate and sodium fluoride
    solution for the estimation of blood glucose and
    plasma was separated for the assay of insulin.

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Table 1 Polyherbal Formulation of Annona
Squamosa and Nigella Sativa (Composition and
Concentration).
Sl. No. Botanical Name Common Name Family Part used Conc. ()
1 Annona squamosa Sharifa Annonnaceae Matured fruits 50
2 Nigella sativa Kalonji Ranunculaceae Seeds 50
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Table 2 Changes in blood glucose and plasma
insulin levels of control and experimental animals
Group Fasting blood glucose (mg/dl) Plasma insulin (IU/ml)
Normal 81.04 2.29 11.26 0.96
Diabetic control 262.24 22.23 3.48 0.69
Diabetic Polyherbal formulation (50 mg/kg) 209.58 12.46 5.59 0.34
Diabetic Polyherbal formulation (100 mg/kg) 155.58 11.69 6.03 0.45
Diabetic Polyherbal formulation (200 mg/kg) 104.16 6.56 7.15 0.45
Diabetic Tolbutamide (250 mg/kg) 110.65 9.35 6.32 0.48
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Pharmaceutical Product Quality Cannot Be Tested
in - It Is Built in
  • Pharmaceutical product quality is assured by
  • comprehensive development program
  • extensive manufacturing and environmental
    controls
  • rigorous validation procedures and requirements
  • The high quality thus built into the final
    product is ensured through in-process controls
    and verified in a series of confirmatory tests
    before each manufactured batch is released to the
    market

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25
Building-in of Quality Starts Early.Development
Builds-in Quality
  • The chemistry, manufacturing and controls (CMC)
    aspect of drug development is focused on
    producing medicines suitable for human use with
    specified quality, safety and efficacy
    characteristics
  • The drug development program is geared towards
  • thorough understanding of the drug products
    performance
  • identification of drug products critical
    characteristics (which would be monitored on a
    batch-by-batch basis)
  • demonstration of drugs safety and efficacy
  • ultimately leads to the review and approval of
    the drug

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26
Relationship between Safety, Efficacy and Quality
  • Every drug product (with its specifications) has
    been thoroughly tested in clinical trials for
    safety and efficacy
  • Specifications for release and stability testing
    may be equal to or tighter than the
    specifications for clinical trial batches
  • Therapeutic indication and QC are considerations
    in establishing specifications

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27
Drug Development Process
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28
Drug Development Process
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29
Quality is Always Part of the Picture - Built-In
and Built-Up
Quality Control and Quality Assurance
Less established
Fully established
Commercial Manufacturing
Pre-IND
Phase I
Phase II
Phase III
Specification/Manufacturing Development for the
Product
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30
Drug Development Cycle
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31
Examples of QA QC Considerations During Drug
Development
  • Evolution of documentation systems
  • SOP
  • change control
  • trend analysis
  • Evolution of QA and QC systems
  • internal audits
  • supplier audits
  • document review (e.g., SOP, batch records,
    specifications, data)

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32
Chemistry Manufacturing Controls Evolve During
Drug Development
  • The goal is to have process and product
    performance determined by the time of validation,
    although some level of validation occurs along
    the continuum and eventually leads to the
    full-scale validation.

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Examples of CMC Considerations During Drug
Development
  • Selection of appropriate technology and raw
    materials
  • Optimization
  • of formulation and device
  • of manufacturing process
  • of specifications and analytical methods
  • Careful selection and control of container
    closure systems
  • Identification and control of critical
    manufacturing process parameters
  • Process capability established
  • Technical transfer to larger scale, i.e.,
    scale-up
  • Process validation

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Process Registration Requirements
  • Sponsor is required to describe how the product
    was developed
  • Companies need to optimize, justify and register
    the entire recipe
  • ranges
  • temperatures
  • mixing times
  • hold times
  • etc.
  • quantities
  • active ingredient
  • excipients
  • raw material specifications
  • in-process limits
  • in-process methods
  • product specifications
  • etc.

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Validation
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What is Validation?
  • Documented evidence that the manufacturing
    process consistently produces product that meets
    predetermined specifications
  • Defines product quality
  • Developed and validated based on a thorough
    understanding of the critical process parameters
  • Parameters are carefully controlled within the
    validated ranges to ensure a consistent
    manufacturing process.
  • Manufacturing process validation consists of
    successfully manufacturing at least three
    full-scale batches in succession, which pass all
    in-process and product quality attributes

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Validation is Always Part of the Picture
Commercial Manufacturing
Pre-IND
Phase I
Phase II
Phase III
Final process validation
Specification Development
Re-validation
Ongoing Validation (DOE, IQ, OQ, PQ, PV)
DOE Design of Experiment IQ Installation
Qualification OQ Operational Qualification
PQ Performance Qualification PV Process
Validation
  • The extent of IQ, OQ, PQ, validation, etc.
    depends on complexity of product

28/12/2010
38
Role of QC Tests
  • Each batch of orally inhaled and nasal drug
    products (OINDP), manufactured by the validated
    process, is tested to the critical QC attributes
    as defined during development
  • Confirms consistent performance
  • The Delivered Dose Uniformity test for OINDP is
    one of several confirmatory QC tests of the
    finished product
  • a result of a long and careful development and
    characterization process
  • QC tests confirm the quality built-in through a
    well-understood and well-controlled manufacturing
    process

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Pre-Approval Inspection
  • Confirms Facility is Ready
  • Sponsor can do what they submit in the NDA
  • Process is validated or validation protocols are
    in place
  • Validation required prior to launch
  • Thorough documentation review
  • Quality systems are established and capable
  • Confirms specifications are met
  • Compliance versus Review Division
  • Specifications may change based on NDA review

28/12/2010
40
Foreign Marketing Data
  • Several Ayurvedic, Siddha and Unani drugs have
    been marketed for centuries in India. The drugs
    are also dispensed to the patients by recognized
    and qualified physicians of the complimentary
    systems.
  • Most of these drugs have been found to be safe,
    It may be worthwhile for the, FDA to accord
    adequate weightage to the data already available
    in these countries in determining whether a drug
    has been used under particular conditions to a
    material extent and for a material time to
    qualify for inclusion in an OTC drug monograph.

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Foreign Market Data
  • Since the FDA is proposing to make it available
    the facility for OTC marketing agencies in the
    United States, who are already marketing their
    products, the same exemptions can be made
    available to overseas marketing firms who have
    safely-marketed their products in their
    respective countries.

28/12/2010
42
Chemistry Manufacturing Controls (CMC)
information for the botanical drug products
  • Botanical, drugs. are derived from vegetable
    matter and are usually complex mixtures. The
    chemical constituents of such a mixture are not,
    always defined and in most cases even the active
    constituent in a botanical drug is not defined
    nor its biological activity well characterized.

28/12/2010
43
Chemistry Manufacturing Controls (CMC)
information for the botanical drug products
  • Therefore the CMC documentation would have to be
    substantially liberal in comparison to that of
    synthetic or highly purified drugs. Simple or
    combination tests like spectroscopic,
    chromatographic, fingerprints,, chemical and or
    biological assays can be the main reliability
    criteria to understand the product.
  • While these tests may not generate the necessary
    specifics that are desirable, it can atleast
    bring about a rational approach to Quality
    Control.

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44
Applicability of Combination Drug Regulations
  • It would be practical not to confine the
    botanical drug products that are derived from a
    single part of a plant such as leaves, stems,
    roots seeds under the fixed combination drug
    category.
  • The current requirement of Botanical drugs
    composed of multiple parts of a single plant
    species under the combination requirement should
    also be revised and exemption accorded.

28/12/2010
45
Studies on bioavailability and drug interactions
  • Bioavailability and Pharmacokinetic studies are
    cumbersome and extremely difficult to generate in
    complex formulations, where a number of herbs are
    involved. It would be desirable to have a very
    practical view in this area.
  • Well-controlled clinical trials can substitute
    the bioavailability and Pharmacokinetic studies.

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46
Studies on bioavailability and drug interactions
  • Ayurvedic and Siddha pharmacopoeia are full of
    formulations which have a. combination of several
    herbs and most of them can never be launched in
    the next decade or two if requirements are not
    simplified by the FDA.

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Natural Vs Cultivable source of Plants
  • In a Country like India where the source of raw
    materials for Drug preparations is predominantly
    from the forests (80) a practical solution has
    to be found in connection with the source of the
    raw material for quality enforcements.
  • When a medicinal plant is cultivated a lot of the
    Quality aspects are directly under the control of
    the grower.

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Natural Vs Cultivable source of Plants
  • However, when the plant material is collected
    from the forests, it would be reasonable to
    presume that the origin of the source is, from
    nature and variations if any would be natural.
  • The document should highlight separate guidelines
    for natural and cultivable sources for
    manufacturers using plants from the above two
    sources

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Conclusions
  • Pharmaceutical quality is built-in through the
    entire drug development process
  • validation is key element of ensuring quality
  • in-process controls assure quality during
    manufacturing
  • Specifications established based on thorough
    understanding of process

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49
BIRDEM ANRAP, Dhaka, Bangladesh
50
  • THANK YOU

Cell No 0091 974243100 E-mail
bknanjwade_at_yahoo.co.in
28/12/2010
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