Drivers from Indian perspective

GOLDEN TRIANGLE APPROACH

Traditional KnowledgeModern Science

Modern Medicine

Drug Discovery and Development Process

Expensive, time consuming, numerous bottlenecks

CLINICALTRIALS

DRUG TOMARKET

LEADOPTMIZATION

LEAD IDENTIFICATION

PRECLINICALSTUDIES

TARGET IDENTIFICATION

Economical, time sparing, least bottlenecks

CLINICALTRIALS

PHASE III & I

AnimalPharmacology

DRUGDEVELOPMENTRELEVANT

SCIENCEPhase IV

DRUG TO GLOBAL MARKET

Reverse Pharmacology

Traditional Traditional

wisdom

wisdom

DRUG TO MARKET

Safety studySafety study

New Botanicals under Clinical trials using Reverse Pharmacology approach

Drug Clinical Indication•M-97 (live 1) Hepato-protective•NMHPT Viral Hepatitis-curative•RRLJCD-SFE Anti-Psoriasis •NMITLI-DM-FN Type II Diabetes•NMITLI-OA-JP Osteo-arthritis•RRLJ0125-F09 Anti-Hepatocellular

carcinoma•AP9CD Breast Cancer•RJMActeo Anti-oxidant

NMITLI ProgrammeNMITLI ProgrammeDeliverables: 3New BotanicalsDeliverables: 3New Botanicals TargetsTargets

• Q.O.L.• Antiviral • New leads

• Sarcopenia • N.A.S.H.• Oxidant damage

• TNF - ∝• Immunomodulation• P.C.O.S.

• Chondroprotective• Antifibrotic • Complications

• Anti-inflammatory • Hydrocholeretic • Dyslipidemia

• Pain relief • Cytoprotective • Insulin sensitisation

Arthritis Hepatitis Diabetes mellitus

Ayurveda

• The traditional approach is to prescribe formulations with frequent and consistentrepetition of certain herbals individually or as a group for a variety of diseases

•The rationality of this kind of therapy was investigated scientifically and systematically by team of scientists at RRL, Jammu

The ancient wisdom of Ayurveda which is embedded in the art of multi-

component therapy has beenscientifically revealed.

It could be the ability of specific plants(s) to synergise each other

for enhanced action profile. (Biological Response Modifiers)

• One of the foremost of such group of herbals which has been documented very frequently as an essential part of about 70% prescriptions is `Trikatu’ which contains three herbs in equal proportions:

Piper longumPiper nigrumZingiber officinalis

• Studies conducted at RRl, Jammu, have revealed the important role of `Trikatu’as a drug bioavailability/ bioefficacy enhancer.

• During the last 20 years a new approach of enhancement of drug bioavailability using drugs in combination with plant based substances as an adjunct was conceptualized and developed at RRL, Jammu

BIOENHANCERAN AGENT CAPABLE OF ENHANCING

- BIOAVAILABILITY

- BIOEFFICACYOF SPECIFIC DRUG WITH WHICH IT IS COMBINED WITHOUT ANY TYPICAL PHARMACOLOGICAL ACTIVITY OF ITS OWN AT THE DOSE USED

0

2

4

6

8Lo

g 10

CFU

Lungs

Spleen

Effect of PIP + Rif against Mtb infection (mice)[in vivo]

E.C L.C

.

Rif

10

Rif

10+

PIP

Rif

20

4.5

6.5

3.52.0 2.2

Comparison of plasma levels of rifampicin in volunteers dosed with 200 & 450 mg of the drug with and

without pip

0

5

10

15

20

0 4 8 12 16 20 24

Time in hrs

Rif

pla

sma

leve

ls (u

g/m

l)

Rif 200mg Rif 450mg

Rif 200 mg+ Pip Rif 450 + Pip

New conceptbased on TK

(Ayurveda

New Drugformulations

Transformed into a Product(Anti TB drug formulation)Final approval

of DCG (I) for marketing permission

Reduction in:• Dose related toxicity• Cost

Anti-infectiveAnti-cancerAnti-hypertensives

Dose ReductionDose Reductionby 50 by 50 –– 80 %80 %

Drug Activity ModifiersDrug Activity Modifiers

Herbal TherapeuticsHerbal Therapeutics

Expected Deliverable:

Antigastric ulcer IND (Botanical)Ap76p (Batch 31)v Six constituentsv All the constituents are necessary

Active against different modelsØ Cold restraint induced ulcer testØ Asprin induced ulcerØ Histamine induced ulcerØ Pyloric ligationØ Ethanol induced ulcerØ Active against H. pylori (in vitro)

ü Equal or better than Omeprazoleü Acts by multiple mechanismsü Only one drug is requiredü Presently combination of three drugs are used in Allopathicü Nontoxic (LD50 = >2200 mg/kg)

Anticancer (Colon, Cervix, Breast)AVS AP9a AP9cd

(Mix 3 Compounds)

Ø Active in vitro

Ø Active in vivo

Ø Non-toxic

Ø US Patent ( 6649650 dt. 18.11.03)

Ø PCT & Indian patent filedØ Agreement with a Company for development

• • ••• Human cancer cell

lines

RJM 0125 P04 A003 F009(K001 & K002)Model: Hepatitis B Virus

Disease causing gene

Liver Cancer

(Hepatocellular carcinoma)

HCC HCC NO HCC

Breeding

BIO RESOURCES

PLANTS HERBAL BACTERIA PREPs & FUNGI

TRADITIONAL WISDOM

AYURVEDA UNANI SIDDHA (AVS) (CCRUM) (INCOPS)

MODERN SCIENCE & TECHNIQUES

CHEMISTRY BIOLOGY STATISTICS

ANTICIPATEDOUTPUTS

NEW BIOENHANCERS

INVESTIGATIVE NEW DRUGS (IND)

ENTIRELY NEW HERBALS

SERVICES TO ISM

Resource Management

Standardization

Agrotechnologies

Automation

Product Safety

PLANTS

(RRL, J)

NBRICSMCRI RRL, JtIICB

CIMAP IHBT NCL

IHBT RRL, JmCIMAP

NIO

BH

GNDGOA JAMMUBARODA

ANNAMALAI

DELHI

SELECTION OF NICHE AREAS

CODINGBIOASSAY

LEADIDENTIFICATION

ISOLATION &EXTRACTION

DISTRIBUTION

RRL(Bh)

FUNGI & MICROBES

(IMTECH)

RRL(Bl)

RRL, Tvm

DEGENE-RATIVES

METABOLICDISORDERS

CNS

TROPICAL INFECTIVES

OTHERS

NBRI CDRI CIMAP

IICBIICT ITRC

RRL,J

+ALZHEIMER

+ATHEROSCLEROSIS

+BACTERIAL

+CANCER

+DEPRESSION

+DIABETICS

+ FILARIASIS

+ FUNGAL

+GASTRIC ULCER

+HEPATITIS

+HYPERTENSION

+ IMMUNOMO-DEFICIENCIES

+ INFLAMMATION

+ LEISCHMANIA

+MALARIA

+MEMORY REDUCTION

+NEURO DISORDERS (3)

+PARKINSONIAN

IN VITRO SCREENING

SELECTION

CSIR - ISMIDENTIFIED

ISM DESIGNED

CSIR -ISM DESIGNED

CCRUM

AVS

IICT

Activity evaluationAt 12 centers

Lead optimisation

IND Processing

TRADITIONAL WISDOM WITH SCIENCE

COUPLING

RRL,J

SIDDHA

CLRI

OBJECTIVESuDEVELOP NEW

FORMULATIONS OR NCEs

uSTRUCTURE OPTIMIZATION

uFAST TRACK SCREENS

uMULTIDISCIPLINARY

u PHYTOCHEMISTRY

u SYN.ORG. CHEMISTRY

u MODELLING

u PHARMACOLOGY

Anti-MALARIA

Anti-HYPER

TENSION

MEMORYENHANCERS

Anti-Parkinson’s

HEPATO-PROTECTIVE

Anti-Inflammation

2 3 7

6 7

5

TB2

Anti-GASTRIC

ULCER6

Immunostimulatory

Anti-FILARIA

36

Anti-Leishmania

2

Anti-CANCER

10

59 Discovery Groups in 13 Institutes59 Discovery Groups in 13 Institutes

CSIR Agenda

• New Drug discovery

• Cost effective generic drugs

• New 6 bioenhancer based formulations

• New standardized botanicals

• New standardized traditional knowledge based

drugs

Thanks for your patiencePlease visit us at

www.rrljammu.orgwww.herbalnet.org

www.csir.res.in