DR. ETIK MARDLIYATI, M.ENG

1) Centre for Pharmaceutical and Medical Technology

Agency for the Assessment and Application of Technology (BPPT)

2) Head Division of Pharmaceutics and Health, Indonesia Society for Nano (MNI)

Commercialization of Nanotechnologies

generated by R&D Institutes in Indonesia

Presented at National Workshop on Strengthening R&D Management Capacity of Researchers and Research Managers of R&D Institutes in the Area of Nanotechnology, Jakarta, 27 Juni 2013

1. Bioresources Significance of Indonesia

INDONESIA

Indonesia is blessed with abundance of natural resources

including its biodiversities (the 2nd greatest after Brazil)

Country Diversity value

Endemic value

Total value

Brazil 3.0 1.8 4.8

Indonesia 1.8 2.2 4.0

Columbia 2.6 1.0 3.6

Australia 0.5 1.6 2.1

Mexico 0.8 0.7 1.5

Madagaskar 0.2 1.2 1.4

Peru 0.9 0.3 1.2

China 0.7 0.2 0.9

Philippine 0 0.8 0.8

India 0.4 0.4 0.8

Ecuador 0.5 0 0.5

Venezuela 0.3 0 0.3

Source: Mittermaler et al., 1997

Indonesia is home to

11% of the world's flowering plants

12% of the world's mammals

15% of all amphibians and reptiles

17% of all birds, and

37% of the world's fish.

PLANT DIVERSITY In term of plant diversity, Indonesia ranks fifth in the world

There are about 40,000 species of plant

grow in Indonesia (55% endemic)

1,845 species are inventoried

940 species are identified

There are many medicinal plants, but still

only 283 species (0.7% of species

population) are registered at BPOM

(Indonesia’s Food & Drug Administration)

as recognizable ingredients for healthcare

In Indonesia there are also many

fruits and vegetables has been used

for ancient as active ingredients of

cosmetic products

Source: Mustika Ratu ppt, 2011

PLANTS FOR HEALTH CARE (Herbal Medicine)

Temulawak (Curcuma xanthorrhiza ROXB.)

Source: from many literatures

Sambiloto (Andrographis paniculata Ness)

Pegagan (Centella asiatica)

Brotowali (Tinospora crispa L.)

Jahe (Zingiber officinale)

Laban Abang (Aglaia odorata)

Kina (Chinchona spp)

Keji Beling (Strobilanthes crispus)

Source: Medicinal Plants, Joy et al, 1998

PLANTS FOR HEALTH CARE (Herbal Medicine)

PLANTS FOR BODYCARE & COSMETIC

Aloe vera (Aloe barbadensis Milleer)

Source: from many literatures

Papaya (Carica Papaya L)

Cananga (Canangium odoratum)

Jasmine (Jasminum sambac Air)

Seaweed (Zingiber officinale)

Mangosteen (Garcinia mangostana)

Kemuning (Murraya paniculata)

Langsat (Lansium domesticum)

In recent year, there is a global interest to “back to nature” relating to safety issue.

Research on medicinal plants has attracted a lot of attention globally. A number of evidence has been demonstrate promising potential of medicinal plants used in the maintenance of personal health and well-being

WHO estimated 80% of world population uses herbal preparation and noted that 119 plants are with efficacy and used in making modern medicines

74% of those plants are used in the modern medicines the same way they use in the traditional medications

GLOBAL TREND IN THE HERBAL USE

medicinal plants will, seemingly, continue to play an important role as an health aid.

Advantages of nanotechnology:

enhance the solubility and bioavailability of active compounds

remove plant cellulose barriers, thus making the active constituents more

easily digestible, and thus, more easily assimilated into the bloodstream

enhance the pharmacological activity of active compound

easier to further dosage formulation, transport and storage

SIGNIFICANCE ROLE OF NANOTECHNOLOGY in the utilization of Indonesia Bioreseouces

Problem status in the utilization of medicinal plants:

Active compound content is very small, so it needs to large dosage form to

achieve the effective therapy

Sustainable ability of raw plant materials (large cultivation and harvesting

problems) when turn in industrialization stage

application of nanotechnology might play a significance role in

the improving the medicinal effect of natural sources

2. Global Status of Nanotechnology Development

- Learning from China and India -

Generally, there are 2 main ways of nanotech applications:

1. Particle reduction for the improvement the bioactivity and

bioavailability pharmacological effect of natural medicine is not only due to the special chemical components, but also closely connected with the physical state

2. Green synthesis (utilization of biological system to produce

nanomaterials) recently it was found that highly evolved organisms like plants, algae, diatoms, human cell and other components of eukaryotes possess the capability not only to sorb and reduce insoluble toxic metal ions, but also to convert the inorganic metal ions to metal nanoparticles

CURRENT PUBLICATIONS

Phytomedicine 15: 23–30 (2008)

Enhanced antioxidant bioactivity of Salvia miltiorrhiza (Danshen)

products prepared using nanotechnology

Liu et al, National Taiwan University, Taiwan

Goal: to compare the antioxidant activities of medicinal plant materials prepared using nanotechnology or traditional grinding methods.

Results: Stronger antioxidant bioactivities were observed for the extracts prepared using nanotechnology. It suggested that the release of the constituents will be more rapid and more complete in nanotechnology preparations compared to those prepared using the traditional methods.

Example 1.

DPPH radical scavenging activity Concentration differences of salvianolic acid

Journal of Nanobiotechnology 2007, 5:3 Polymeric nanoparticle-encapsulated curcumin ("nanocurcumin"):

a novel strategy for human cancer therapy Bisht et al, University of Delhi, India

Goal: to improve the solubilty of hydrophobic curcumin by nanoparticle-based drug delivery approaches

Results: Nanocurcumin, unlike free curcumin, is readily dispersed in aqueous media. Nanocurcumin demonstrates comparable in vitro therapeutic efficacy to free curcumin against a panel of human pancreatic cancer cell lines. Further, nanocurcumin's mechanisms of action on pancreatic cancer cells mirror that of free curcumin.

Example 2.

Solubility difference Nanocurcumin inhibits the clonogenic potential of

pancreatic cancer cell lines

Advances in Colloid and Interface Science (2011)

Green synthesis of biogenic metal nanoparticles by terrestrial and aquatic phototrophic and heterotrophic eukaryotes and biocompatible agents Narayanan et al, Pondicherry University, India

Goal: to review the recent advancements in the green synthesis of metal nanoparticles by plants, aquatic autotrophs, human cell lines, biocompatible agents and biomolecules

Highlights

► Nanoparticles synthesized using biological processes are gaining merit. ► Biological synthesis is inexpensive and uses non-hazardous chemicals. ► Use of phototrophic eukaryotes and biocompatible agents is eco-friendly. ► Greener nanoparticles are used in biomedical applications.

Example 3.

Nanoparticles: cobalt, copper, silver, gold, bimetallic

alloys, silica, palladium, platinum, iridium, magnetite

and quantum dots

3. Several Bioresources-Based

Nanotechnology R,D&C in Indonesia

Research Projects Institution

Bioprospecting Indonesian medicinal plants BPPT

(Joint research with

KRIBB Korea)

Application of nanotechnology for improving

herbal medicines efficacy in diabetes therapy

BPPT

Development of nanoparticulate herbs and their

formulation for cosmetic application (antiacne)

BPPT

(joint research with

national cosmetic industry)

Development of nanoemulsion system of herbs and

its application in healthcare application

(anticellulite)

LIPI

(joint research with

national cosmetic industry)

Development of nanoseparation system to improve

the purity of catechin from Gambier

RISTEK

(joint research with

province goverment)

Note: BPPT : Indonesia Agency for the Assessment and Application of Technology LIPI : Indonesia Institute of Sciences RISTEK: Ministry of Research and Technology, Republic of Indonesia

Ex 1: Bioprospecting Indonesian medicinal plants (Joint Research Collaboration: BPPT-Indonesia and KRIBB-Korea, Since 2009)

ACTIVITIES:

a) Collection of Indonesian plant materials

b) Extraction of the Indonesian plant materials

c) Screening of biological activities of the Indonesian plant materials:

cytotoxic, anti-inflammation, and anti-insecticidal activity

Location of

Sample Collection

Ujung Kulon

Halimun

Gunung Gede Pangrango Baluran

Meru Betiri

Pangandaran

Bodogol

Serpong (Puspiptek)

Research Members: Tarwadi, Fifit J, Doddy ISU, and Bambang S.

Sample Collected: 800 samples of plants

18

0

50

100

150

200

250

PuspiptekSerpong

GunungHalimun SalakNational Park

Ujung KulonNational Park

Gunung GedePangrango

National Park

PangandaranNatureReserve

BaluranNational Park

Meru BetiriNational Park

BodogolConservation

EducationCenter

4

125

220

54

99

125

69

106

Nu

mb

er

of

Sp

eci

men

Location

Sample Classification: based on family

19

23

5

1 4

8

25

13

7 7

1

6

2

29

2 1 3 4

1 2 3 3 1 2 1

7

3

10

2 1

10

1 1 2 3 1

5 7

2

10

5 2

49

64

6 5

1

7

1 1 1 1 2 2 1

9

16

7

2 5

1 1 4

1

25

3 1

13

26

6

1

38

1 2

6 8

17

2 2 2 1 4

7

1 3

1

16

1

8

1 1 1 1 2

7 4

52

1

18

1

11

3 1

3 3 5

1 3

12

2 5

1

9 7 10

12

17

0

10

20

30

40

50

60

70

Aca

nth

ace

ae

Am

aryl

lidac

eae

Ap

ocy

nac

eae

Ara

uca

riac

eae

Ast

erac

eae

Be

gon

iace

ae

Bo

ragi

nac

eae

Car

yop

hyl

lace

ae

Clu

siac

eae

Co

nn

arac

eae

Co

rdia

ceae

Cu

curb

itac

eae

Dill

enia

cae

Elae

oca

rpac

eae

Fab

ace

ae

Frag

ilari

acea

e

Go

od

en

iace

ae

Hip

po

crat

eace

ae

Lam

iace

ae

Lilia

ceae

Lyco

po

dia

ceae

Mal

vace

ae

Me

last

om

atac

eae

Mir

tace

ae

Mu

sace

ae

Myr

tace

ae

Ole

acea

e

Pan

dan

ace

ae

Ph

yto

lacc

ace

ae

Po

ace

ae

Po

lygo

nac

eae

Rh

izo

ph

ora

ceae

Ru

scac

eae

Sap

ind

acea

e

Sim

aru

bac

eae

Son

ner

atti

ace

ae

Teh

reac

eae

Un

ide

nti

fied

Vit

acea

e

Nu

mb

er

of

Spe

cie

s

Family

Potential USE of samples: Based on Literature Review/ Ethnopharmacology

20

FAMILY Number of

Specimen

collected

MEDICINAL USE

Fabaceae 64 Anti diabetic, Anti inflammatory, Anti cancer, Heart disease,

Rubiaceae 52 Anti diabetic, Anti inflammatory, Anti cancer, Heart disease

Euphorbiaceae 49 Anti diabetic, Anti inflammatory, Anti cancer, Heart disease

Moraceae 38 Anti diabetic, Anti inflammatory, Anti cancer, Heart disease

Asteraceae 29 Anti diabetic, Anti inflammatory, Anti cancer, Heart disease

Meliaceae 26 Anti diabetic, Anti inflammatory

Annonaceae 25 Anti inflammatory, Anti cancer

Malvaceae 25 Anti inflammatory, Anti cancer, Heart disease

Acanthaceae 23 Anti diabetic, Anti inflammatory

http://www.ars-grin.gov/duke/ethnobotuse.html

Bio Screening RESULTS

21

41 57

191

91

0

50

100

150

200

250

< 20% 20 - 50 % 50 - 100 % > 100 %

Nu

mb

er

of

Spe

cim

en

% Viability

28

68

101

49

0

20

40

60

80

100

120

< 0% 0 - 20 % 20 - 50 % 50 - 100 %

Nu

mb

er

of

Spe

cim

en

% Inhibition on NO Production

18

36

15

62

0

10

20

30

40

50

60

70

> 80 % 80 - 50 % 20 - 50 % < 20 %

Nu

mb

er

of

Spe

cim

en

Insecticidal Activity

Further Direction

Sample collection: Java Island samples from West, East Java and Banten provinces

have been collected

Outside Java samples from Kalimantan have been collected

Biological screening: other assays needed? Medical : + anti viral? , + anti diabetic?, ???

Cosmetics : whitening?, ???

Others???

Product development: what kind of products to be developed??

Anti cancer? Anti inflammation? Immune modulation? Anti diabetics? Others? refer to original location and collect more samples?

22

50 National Parks in Indonesia

www.dephut.go.id

Ex. 2: Application of nanotechnology for improving the efficacy of medicinal plants in diabetes therapy

Rationale

Rapid increasing global incidence of diabetes mellitus is becoming a serious

threat to mankind health in all parts of the world

It is the fact that diabetes can’t be cured and it has never been reported that

someone had recovered totally from diabetes.

Nowadays, there are increasing attention in the use of natural medicines for

the therapy of diabetes, since it has both effects to delay the development of

diabetic complications and correct the metabolic abnormalities.

During the past few years some of the new bioactive drugs isolated from plants

showed antidiabetic activity with more efficacy than oral hypoglycemic agents

Recent research has excitingly indicated that antihyperglycemic effects of medicinal

plants are attributed to their ability to restore the function of pancreatic tissues by

causing an increase in insulin output or inhibit the intestinal absorption of glucose

or to the facilitation of metabolites in insulin dependent processes.

WHO has pointed out this prevention of diabetes and its complications is not

only a major challenge for the future, but essential if health for all is to attain.

Year 2011 2012 2013 2014

Market

Product

Design Engineering

R&D

Resources

Funding: 100 million IDR Human: 9 persons Infrastucture: LAPTIAB Partner: -

Funding: 500 million IDR Human: 9 persons Infrastucture: LAPTIAB Partner: Klinik Herbal Hortus Medikus

Funding: 500 million IDR Human: 9 persons Infrastucture: LAPTIAB Partner: Klinik Herbal Hortus Medikus

Funding: 500 million IDR Human: 9 persons Infrastucture: LAPTIAB Partner : Klinik Herbal Hortus Medikus

TRM KEGIATAN 2011-2014

Roadmap of Nanoherbal Development for Diabetes Therapy

Nanoparticulation Technique

(bottom-up approach

Nanoparticulation Technique (top-down approach)

Characterization and Evaluation

Nanoparticle Design

Formuation Technique

(Single Dosage)

Nanoparticle Design

Internal Clinical Trial

Herbal medicine drug dosage formulation

Formulation Technique (Mixture Dosage)

Prototype I nanoparticulated

antidiabetes herbs

Drug dosage formulation in single herbs

Prototype II nanoparticulated

antidiabetes herbs

Drug dosage formulation in mixture herbs

PLANTS EXPLORED: Sambiloto (Andrographis paniculata Ness)

It is an herbaceous plant, commonly known as ‘King of Bitters”, in the family

Acanthaceae. It is widely cultivated in sourthern Asia. It has been traditionally used over

the centuries for many medicinal pusposes, particularly for diabetes therapy

A. paniculata Nano-extracts

In this study, we are trying to prepare the plant material in nanoscale system and investigate

the influence of the size on its pharmacological activity by in vitro analysis (enzyme

inhibition and insulin secretion analysis).

Size distribution analysis by PSA

Mean diameter: 150 nm

Ex. 3: Nanoencapsulation of herbal extracts and formulation in cosmetic product

(Joint Research Collaboration: BPPT and National Cosmetic Industry)

GOAL:

a) Development of method for preparing nanoherbal extracts

b) Evaluation of the improvement activity

c) Application study in cosmetic products

PLANTS EXPLORED:

1. Pegagan (Centella asiatica) herbs:

2. Mangosteen (Garcinia mangostana L.) shell:

Research Members: Eriawan R, Susi K., and Idah R.

Mangosteen

Pegagan

Cosmetic formulation Nano-extracts

Bacteria inhibition activity

Ex. 4: Nanoencapsulation of vitamin and formulation in cosmetic product

(Joint Research Collaboration: BPPT and National Cosmetic Industry)

GOAL: a) Development of method for preparing vitamin A ester with high efficacy

as antiageing agent by encapsulation in chitosan nanoparticles b) Evaluation of the improvement activity c) Application study in cosmetic products (antiageing topical cream)

BIORESOURCES EXPLORES:

Chitosan (deacetilated chitin; from shrimp shell)

Research Members: Etik M, Sjaikhurrizal EM., and Damai RS

Nanoencapsulated Vit A (size ± 130 nm)

In vitro diffusion profile (using mouse skin)

0

3

6

9

12

15

1 2 3 4 5 6 7 8 9

Waktu (jam)

% R

ele

ase

Sample 1

Sample 2

Cream formulation

Chitosan

Nanorice, nanocarbon black, nanotongkat ali, nanocurcumin, etc.

Ex. 5: Several products developed by Nanotech Indonesia

(based on industry demand)

NANOHERBAL PARTICLES FOR COSMETICS Day cream

Night crean

Soap etc

Coffee Product with Herbal Nanoparticle (Eurycoma longifolia: Tongkat Ali) for increasing stamina

Coffee Product with Herbal Nanoparticle ginger and gojiberry for increasing stamina

Technology Transfer for NanoHerbal Indonesia Collaboration with PT Gizi Indonesia, SCI-Kalbe Farma, PT

QueenBee, PT Tirta Buana Kemindo, PT Qolbi, PT Awmit, etc

http://nanoherbal-technology.com

CONCLUDING REMARKS

Indonesia has abundant bioresources that very potential to use

in healthcare and cosmetic products. Application of

nanotechnology in this field provide many benefits to improve

the quality of natural-based products.

Nowadays, particularly in Asia countries, there is research trend

in application of nanotechnology for bioresources-based

materials, in the aims of improvement of efficacy or for green

synthesis (production of nanomaterials using biological system).

In Indonesia, bioresources-based research, development, and

commercialization of nanotechnology has been started. There

are still many problems should be solved together, particulary

in term of scientific evidences and regulations.

Laboratoria for Agroindustry and Biomedical Technology Development, Indonesia Agency for the Assessment and Application of Technology (BPPT)