Redefining Phytopharmaceuticals

Sukhdev Swami Handa

Affiliation to Institute

Phytopharmaceutical

• Phyto…………………Plant

• Pharmaceutical….Medication/Medicament

• Medicine/drug

• Phytopharmaceutical….Phytomedication/Phy-tomedicament/Phytomedicine/Phytotherapy/

JOURNEY OF”PHYTO”IN THERAPEUTICS -WHEEL HAS TURNED FULL CIRCLE

1800

1950

PLANTS USED IN TRADITIONAL MEDICINES

(TM)

ADOPTION IN ALLOPATHIC

MEDICINE

ISOLATION OF ACTIVE

CONSTITUENTS -DRUGS - LEADS

IMPACT OF CHEMICAL

INDUSTRIES/ TECHNOLOGY

CONTINUED USE TO MODERN TIMES AS

TRADITIONAL SYSTEMS’ MEDICINE

SCREENING OF: -PLANT EXTRACTS

-MICROBIAL BROTHS

MOLECULAR MODIFICATIONS TO DESIGNED

DRUGS

BEGINNING OF MODERN ERA

GOLDEN PERIOD OF

MODERN DRUG RESEARCH

1951

1975

BETTER APPRECIATION

OF PLANT DRUGS

RESURGENCE OF HERBAL DRUGS

PROBLEMS ENCOUNTERED WITH

MODERN DRUG THERAPY

THERAPEUTIC GAPS WITH MODERN DRUGS

BACK TO NATURE MOVEMENT

PROPER ASSESSMENT

OF MODERN

DRUG THERAPY

IMPACT OF MOLECULAR

BIOLOGY AND

BIOTECHNOLOGY

1976

HERBAL DRUGS IN – MODERN MEDICINE

– TRADITIONAL SYSTEMS OF MEDICINE

•SYNTHETIC DRUGS •MICROBIAL PRODUCTS

•ENDOGENOUS REGULATORY PROTEINS •AB.IN THERAPEUTICS •DNA BASED THERAPEUTICS

MAPs AS A

BIORESOURCE

FOR

HERBAL DRUGS

HERBAL DRUG PREP.

HERBAL MED. PROD.

PHYTOMEDICINES

BOTANICAL DRUGS

ASU DRUGS

TRADITIONAL MED.

DIETARY SUPPLE.

ESSENTIAL OILS

TERPENOIDS

AROMA CHEMICALS

FLAVOURS

FRAGANCES

PERFUMES

MODERN DRUGS

DRUG INTERMEDIATES

NOVEL STRUCTURES (NCEs)

NEW GRUG LEADS

PHYTOPHARMACEUTICALS

PHARMACEUTICAL AIDS

GUMS

MUCILAGES

SWEETNERS

EDIBLE DYES

INSECT REPELLANTS

INSECTICIDES

PESTICIDES

RATIONALE FOR USE OF EXTRACS IN ASU DRUGS/ PHYTOPHARMACEUTICALS

Rt, Rtbk, St, Stbk, Lf, Fl, Fr, Frp, Frd, Sd, Wp

CELLULAR

MATERIAL

NON CELLULAR

MATERIAL

PRIMARY

METABOLITES

SECONDARY

METABOLITES

STARCH

CARBOHYDRATES

POLYSACCHARIDES

AMINO ACIDS

ENZYMESS

HOT EXTRACTION COLD EXTRACTION

• DECOCTION • MACERATION

• SOXHELT • PERCOLATION

50% AQ. ALC ALCOHOLIC AQUEOUS

MEDIUM

POLAR

NON

POLAR POLAR

GLYCOSIDES

ANTHRAQUINONE

SAPONIN

CYANOPHORE

ISOTHIOCYANATE

FLAVONOL

ALCOHOL

ALDEHYDE

LACTONE

PHENOL

PHENOLICS/TANNINS

FLAVANOIDS

ANTHOCYANIDINS

ELLAGITANNINS

GALLITANNINS

ALKALOIDS

PYRIDINE –

PIPERIDINE

TROPANE

QUINOLINE

INDOLE

IMIDAZOLE

STEROIDAL

AMINES

PURINES

HYDRO/STEAM

DISTILLATE

VOLATILE OIL /TERPENES RESINS LIPIDS STEROIDS

HYDROCARBON MONO- OLEORESIN FIXED OILS DIOSGENIN

ALCOHOL SESQUI- OLEO-GUM-RESIN FATS SOLASODINE

ALDEHYDE DI- BALSAM WAXES CARDENOLIDES

KETONE TRI- FATTY ACIDS STROPHANTHIN

ESTER TERPENE SCILLAREN

?

6 6

AYURVEDA

YOGA & NATUROPATHY

UNANI

SIDDHA

HOMOEOPATHY

DEPARTMENT OF AYUSH

A

Y

U

S

H

Min. of Health & Family Welfare

Govt. of India

Established in 1995 as ISM (Indian Systems of Medicine)

Renamed AYUSH in

2003.

REGULATING ASU MEDICINES

i) Drug & Cosmetic Act, Chapter IV A, Rule 161, Schedule

T & Schedule 1 (D&C Act).

ii) Drugs & Magic Remedies Objectionable Advertisement

Act (DMROA Act).

iii) Biodiversity Bill.

iv) Environment & Forest Act (Director General Foreign

Trade).

v) Indian Patents Act.

vi) Central & State Excise Act.

REGULATORY CONTROLS

ASU Drug defined in D & C Act clause 3 (a) & 3(h)

D & C rules 1945 Rule 161 prescribes

labeling requirements for

Ayurvedic Medicines No sale license is required

Mfg. License required for premises & items

Mfg. License issued by Licensing Authority of state govts. (LA). In some states Drugs controller is LA, while in others Director of Ayurveda or ISM’s are designated as LA

*Rational combination of herbs based on experience of qualified Ayurvedic Physician (Anubhuta Yoga) *Each of the ingredients in the Proposed composition must be mentioned in one of the books of Schedule I of the D & C Act.

Recipe & Method of manufacturing as per Schedule I Books

Proprietary D & C Act clause 3(h) Classical preparations D & C Act Clause 3 (a)

Quality & Standardization of ASU Drugs

IV. Efficacy Studies

V. Safety Studies

II. Multiple Ingredient Formulations (600)

Plants

I. Single Drugs (1250)

Minerals

Extracts

Metals

Plant Based drugs 95%

Herbo-mineral / Animal by products 2%

Herbo-mineral / Metal / Calcined metals / Metal Ashes 2-3%

SOP of manufacturing process, testing

procedures for various

Dosage forms

III. Various Pharmaceutical Dosage forms (25)

Herbo-mineral / metallic

Rasayogas

Pragmmatic approach

Ayurvedic Pharmacopoeia of India

Part I (Monographs on Single Drugs):

Publication of Ayurvedic Pharmacopeia Year Monographs

1. Ayurvedic Pharmacopoeia of India Vol. I 1986 80

2. Ayurvedic Pharmacopoeia of India Vol. II 1999 78

3. Ayurvedic Pharmacopoeia of India Vol. III 2001 100

4. Ayurvedic Pharmacopoeia of India Vol. IV 2004 68

5. Ayurvedic Pharmacopoeia of India Vol. V 2006 92

6. Ayurvedic Pharmacopoeia of India Vol. VI 2008 101

7. Ayurvedic Pharmacopoeia of India Vol. VII 2008 21

(Minerals and Metals)

8. Ayurvedic Pharmacopoeia of India Vol. VIII

( Aqueous and Hydro-alcoholic extracts ) 2011 60

Total (Monograph) = 600

Ayurvedic Pharmacopoeia of India (API-Part II): (Multiple ingredient Formulations)

Publication of Ayurvedic Pharmacopeia Year No. of Monographs

1. Ayurvedic Pharmacopoeia of India Part II - Vol. I 2008 50

2. Ayurvedic Pharmacopoeia of India Part II - Vol. II 2009 51 3. Ayurvedic Pharmacopoeia of India Part II - Vol. III 2010 50 4. Ayurvedic Pharmacopoeia of India Part II - Vol. IV 2014 60

(under publication )

5. Ayurvedic Formulary of India (AFI) Vol. 1 1978 444

6. Ayurvedic Formulary of India (AFI) Vol. 2 1992 192

7. Ayurvedic Formulary of India (AFI) Vol. 3 2011 350

Why Phytopharmaceuticals as Drugs?

• Chapter IV of the D&C Act deals with drugs of Allopathic system. Chapter IV A deals with ASU drugs (restricted to drugs of texts of Schedule1of D&C Act)

• Under the definition, the D&C Act does not include the words like TM, herbal drugs, herbal medicines, phytomedicines, MCBT.

• Phytopharmaceuticals can be from any medicinal plant of the globe ( not restricted to plants mentioned in the texts of Schedule 1 of D&C Act.

• It does not entirely depend upon traditional knowledge , rather encourages innovative approach for new drug discovery for unmet needs.

• NCE pipeline with Pharma MNCs shrinking drastically, introduction of phytopharmaceutical category of drugs will open new vista of drug discovery

• Leads for phytopharmaceuticals may have their origin not only in ASU but also in TCM, Kampo, ethanobotanicals, tribal plant drugs or any plant of the globe.

Phytopharmaceutical Initiative (August 2008) • Several eminent leaders of the Pharmaceutical Industry & Pharmaceutical

Scientists who delivered their presidential addresses at the Indian Pharmaceutical Congress, which is held annually since the last six decades, talked about need to develop Botanical drugs from leads developed by a number of institutes engaged in Pharmacological investigations on medicinal plants, but no translational approach to the level of developing drug because of paucity of regulations on Phytomedicines/phytopharmaceticals.

• In June 2004, US FDA published a document on “Guidance to Industry for Botanical Drugs”.

• In August 2008, Govt. of India appointed a Committee Chaired by Dr.Nitya Anand & Dr. DBA Narayana as Covener. Prof. S.S. Handa, Dr.G.N.Singh, Dr. C.K.Katiyar and Dr.Amit Agarwal (Members).

Draft Rules Published for Comments vide Gazette notification GSR 702 (24.10.13):Phytopharmaceuticals

• Rule 2 “(eb)”: “Phytopharmaceutical drug” includes processed or unprocessed standardised material derived from plants or parts thereof or combination of parts of plants, extracts or fractions thereof in a dosage form for internal or external use of human beings or animals and intended to be used for diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings or animals, but does not include administration by parenteral route.”

Comments by the Dept. of AYUSH, GoI, MHFW • The draft notification dated 24th Oct. 2013 to amend the D&C

Rules,1945 defines: “Phytopharmaceutical drug” includes processed or unprocessed standardised material derived from plants or parts thereof or combination of plants, extracts or fractions thereof for internal & external use of…………….. As per the definition, simple powders (Churna) of raw herbs or their combinations and extracts which are drugs of ISM would also be termed as phytopharmaceutical drug. Thus the notification is subsuming the drugs of ISM&H and encroaching upon the mandate of the Deptt. of AYUSH which cannot be agreed to.

Chapter 1 Section – 3 “Definitions” Drugs & Cosmetics Act

3 (a) ASU Drug

• “Ayurvedic, Sidha or Unani drug” include all medicines intended for internal or external use for or in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, and manufactured exclusively in accordance with the formulae described in, the authoritative books of Ayurveda, Sidha or Unani Tibb systems of medicine, specified in the First Schedule of D&C Act.

3(h) “ Patent or Proprietary Medicine” • (i) In relation to Ayurvedic, Sidha or Unani Tibb systems of

medicine all formulations containing only such ingredients mentioned in the formulae described in the authoritative books of Ayurveda, Sidha or Unani Tibb systems of medicine specified in the First Schedule, but does not include a medicine which is administered by parenteral route and also a formulation included in the authoritative books as specified in Clause 3(a);

• (ii) in relation to any other system of medicine, a drug which is a remedy or prescription presented in a form ready for internal or external administration of human beings or animals and which is not included in the edition of the Indian Pharmacopeia for the time being or any other pharmacopeia authorised in this behalf by the Central Govt. after consultation with the Drugs Technical Advisory Board constituted under section 5:1.

Licensing Requirements for ASU drugs under D & C Act (G.notification Aug 2010)

Category Ingredients Indications Safety study Experience / evidence of effectiveness

3 (a) Published lit. Proof of

effectiveness

A. Classical As per text As per text Not required Required Not Required

B. Classical change in dosage form

As per text As per text Not Required

Required

Not Required

C. Classical with new indications

As per text New Not Required

Required

Required

3 ( h ) As per text

Textual rationale

Not Required

Required

Required

A. P & P. ASU drugs

B. P & P ASU drugs with schedule E (1) ingredient

As per text As per text Required

Required

Required

Licensing Requirements for “Aushadh Ghana” Extracts (dry or wet) of medicinal plants: Gazette Notification Aug 2010

Category Ingredients Indications Safety Study Experience/evidence of effectiveness

Published Lit. Proof of effectiveness

(A) aqueous ext.

As per text As per text NR Required NR

(A1)

aqueous ext.

As per text New indication

NR Required Required

(B) Hydro alcoholic ext.

As per text As per text NR Required NR

(B1) hydro alcoholic ext.

As per text New indication

Required Required Required

(C ) other than hydro alcoholic ext.

As per text As per text Required

Required Required

Comments by the Dept. of AYUSH …….continue • The Deptt. of AYUSH is of the view that the definition & the

draft notification dated 24th Oct 2013GSR 702(E) to amend the D&C Rules are grossly defective and inconsistent with the mandate given to both the departments and their respective Pharmacopeia Commission. Therefore,the notification needs to be withdrawn and the matter needs to be resolved through detailed discussion between both the departments & their respective Pharmacopeia commission to delineate their respective boundries and evolve suitable definition and terminology consistent there with. In view of the above, the department of Health may consider withdrawing its draft notification as the content of the draft fall within the jurisdiction of the deptt. of AYUSH and Pharmacopeia Commission of Indian Medicine.

My comments on Opinion sought by DCGI • There exists now separate Pharmacopeia Commission of Indian Medicines

under the deptt. of AYUSH to look after development & publication of standards of plant drugs as whole or parts thereof, plant drug preparation (processed as powder or extract) and multi-component classical formulations as is evident from the already published Pharmacopeias (part I) for ASU single ingredient plant drugs; and Pharmacopeias (part II) devoted to classical multiingredient formulations. Plant extract monographs have been published in volume VIII of API (Part I).

• Phytopharmaceutical drugs including whole medicinal plants or parts thereof, in powder (Churna) and extract (Ghan & Kwath) form fall absolutely under the domain of AYUSH. These represent wholistic profile of Phytopharmaceuticals. The Rules pertaining to various aspects of these drugs have been already covered under Chapter IV A of the D&C Act.

• Upto this I endorse the comments of the Deptt. of AYUSH w.r.t. “allocation of business Rules” the Deptt. of AYUSH mandated to.

Joint Meeting of Dept of Health & AYUSH 24 March 2014 *Eleven Members’ Committee: Secretary , Deptt.of Health&FW; Secretary, AYUSH;

Additional Secretary &DG-CGHS; Joint Secretary AYUSH; Prof.S.S.Handa; Joint Secretary H & FW; DCGI (India); Joint Drugs Controller(I); Deputy Drugs Controller (I); Director PLIM; Joint Advisor(Ay) AYUSH.

*After deliberations, it was decided that the proposed notification may be examined by a Technical Committee in the light of the issues raised by the deptt. of AYUSH and ensure that there is no overlapping of the domain of the respective systems of medicines. The Technical Committee cosists of:

*Prof.S.S. Handa;Dr.R.A.Vishwakarma; Dr.Rajeev K. Sharma; Dr.Manoj Nesari; Drugs Controller General (India) or his representative CDSCO,HQ.

The revised draft will then be considered by the Regulatory committee of both the deptts of AYUSH & Deptt. of Health for finalisation of the proposed amendment.

*The Committee will consist of: Joint Secretary (Drugs) Deptt.of Health; Joint Secretary (Shri RP Singh) Deptt.of AYUSH; Dr.GN Singh (DCGI)

Way Forward to Phytopharmaceuticals:

• When an extract is fractionated either through solvent fractionation or other suitable means to separate a fraction or phytoconstituents with a view to get more potent entity may be considered under the proposed category of Phytopharmaceuticals.

• The definition of Phytopharmaceutical drug has to be changed accordingly leading to restructuring the entire draft notification.

Redefining Phytopharmaceutical Drug

• “Phytopharmaceutical drug comprises of purified standardised fraction (with most of the phytoconstituents determined qualitatively & quantitatively) of an extract of medicinal plant or its part/(s), formulated as stable dosage form as new drug for internal or external use of human beings or animals for diagnosis, treatment, mitigation or prevention of any disease or disorder but does not include administration by parenteral route.”

Some Examples for way to Phytopharmaceuticals

• CDRI- Gugulip (Commiphora wightii) Antihyperlipidaemic; ; Memory Plus/Bacomind (Bacopa monnieri) Nootropic/Neurodegenerative disorders (Worked by Natural Remedies through project fromTIFAC); Picroliv: (Picrorhiza kurroa) hepatoprotective.

• IIIM-Sallaki: & Polysal fraction( Boswellia serrata)Antiinflammatory/ Anti-arthritic; Tinospora cordifolia polysachharide fraction immunomodulator Trichopus zeylanicus fraction: Adaptogen; Adhatoda vesica fraction for respiratory health; Withanolide+Withaferin fraction of Ashwagandha (Withania somnifera) Anti stress;

• ICMR- Vijaysar (Pterocarpus marsupium) flavonoid glycoside fr. &( Salacia prinoides) anthocyanin fr. :Diabetes; Shirish (Albizia lebbeck) triterpenoid fraction Bronchial Asthma ; Shakotak (Sterblus asper) :sterbloside/asperoside fraction in Filaria

• DBT- Cissampelos pareira ext. fraction: All four sero-types of Dengue; Oxalis corniculata fraction in Amoebic dysentary; Peptide fraction of Momordica chirantia in Diabetes.

More examples for way to Phytopharmaceuticals

• Fraction of defatted seed extract of Fenugreek (Trigonella foenum-graecum) standardised for contents of saponins, 4-hydroxyisolucine and trigonelline (Diabetes).

• Fraction of Cinnamomum Cassia leaf containing Cinnamaldehyde, 2-hydroxy-cinnamylacetate is PTP-1B inhibitor stimulating autophosphorelation of truncated insulin receptors.

• Purified methylhydroxy chalcone (MHCP) fraction of Cinnamomum cassia as a mimetic for insulin in 3T3-L1 adipocytes stimulating glucose uptake and glycogen synthesis.

• Purified fraction of Tagetes erecta flower extract standardised for zeaxanthin & lutein as dietary supplement in USP ( Retinopathy).

• Deglycyrrhizinated fraction of aqueous extract of Licorice (Glycyrrhiza glabra) in Gut health (Peptic ulcer).

• Andrographolide+Neoandrogapholide+Aandrographoside rich fraction of the extract of Andrographis paniculata (cough-cold & as hepatoprotective).

Liver protecting

Phytopharmaceuticals

REGIONAL HEPATOPROTECTANTS

SILYMARIN

CATECHIN

GLYCYRRIZIN;SNMC

BUPLEURUM

SCHIZANDRA

ANDROGRAPHIS

PICRORHIZA

PHYLLANTHUS

S.S. Handa (2008)

EUROPE

JAPAN

CHINA

INDIA

Renewed Interest in Phytopharmaceuticals

• Certain major pharmaceutical companies have demonstrated renewed interest in investigating MAPs as sources for new lead structures and also for development of highly standardised phytopharmaceutical agents with proven safety, efficacy & quality through relevant pharmacological, toxicological, phytochemical, chromatographic, pharmacokinetic and clinical studies.

• Phytopharmaceuticals have been employed as both therapeutically active agents for treating chronic diseases especially metabolic disorders such as diabetes, bronchial asthma, arthritis because of multicomponent ingredients affecting multitargets and also as pharmaceutical excepients used as suspending , emulsifying, flavouring agents, viscosifiers and as formulation bases,

Some broad expectations from this Workshop

• Regulations on Phytopharmaceuticals should avoid any overlapping of the domain areas of the respective systems of medicines.

• Remove apprehensions that the proposed definition may be misused by the industry as backdoor entry of ASU drugs in the modern system of medicine.

• Definition as proposed beyond extract needs consideration. Qualitative & Quantitative estimation of at least 80% constituents of the fraction need discussion.

• Draft rules for Quality (including stability), Safety and Efficacy need to be as per ‘New Drug’ may be discussed.

• Pharmacokinetic/bioavailability studies need inclusion.

• Any interaction with other drugs need consideration.

• Can the ISM practitioners be authorized to use phytopharmaceuticals.

• Economically Sustainable availability of the authentic resource material.

• Can final recommendations be made available for TCM on19.6.14

g

T H A N K YOU

Let noble thoughts come to us from every side -Rigveda 1-89-i

Thank you