NUTRACEUTICALS

Bambang Prajogo E.W.

Departemen Farmakognosi dan Fitokimia

Fakultas Farmasi Universitas Airlangga
2011
 bahan yg tidak perlu proses shingga bisa dikonsumsi dalam keadaan
segar
• Foods = Conventional Foods (CF)
• Functional Foods (FF) are CF
• Nutritive Value (NV): supplies one or
more essential nutrients and/or energy
from CHO, protein, fat, and limited DF
• Foods, CF and FF have NV
• Functional Foods (FF): “food or food
ingredients that may provide a health
benefit beyond the traditional nutrients it
contains”
suplemen untuk melengkapi nutrisi dalam tubuh
produk bahan alam —> nutraceutical —> sumber dari hewan, tanaman,
biota laut, mineral
Functional Food vs. Bioactive Ingredient
Must differentiate!

• Functional Food may be beneficial by

itself
• Functional food may contain beneficial
bioactive (BIOA) substance(s)
• Whole grain Dietary fiber
• Distinguish between FF and BIOA
• Avoid term “ingredients”; suggest
“nutraceutical(s)”
 Two FDA Approved Options to
Highlight Functional Foods on Label

• Quantitative statements
– contains 108 cfu Lactobacillus per
serving
– contains 500 mcg of Lutein per serving
• Structure/function claims
– promotes eye health
– promotes a healthy intestine
 NUTRACEUTICAL
• A nutraceutical(s) is not an essential nutrient
until proven to be essential through scientific
study
Special Case
• Isolated-Concentrated Nutraceutical(s) added
to a conventional food (CF) to increase
compound’s level in CF, use word “added” or
similar notation with quantitative statement,
such as “added Lutein, 1000 mcg per
serving”
Must prepare GRAS notification for FDA
 digunakan sebagai pencegahan

DEFINITION
The term "nutraceutical" was coined from
"nutrition" and "pharmaceutical" in 1989 by Dr.
Stephen DeFelice, chairman of the Foundation for
Innovation in Medicine (FIM), Cranford, NJ.

NUTRACEUTICAL any substance that may be

considered a food or part of a food that provides
medical and health benefits, including the
prevention and treatment of disease. Under this
broad definition, nutraceutical might be isolated
nutrients, dietary supplements or diets,, herbal
products or genetically engineered ‘designer foods’,
and processed foods such as cereals, soups and
beverages.
 untuk membantu treatment pengobatan, proteksi penyakit kronik

Health Canada
A nutraceutical is a product isolated
or purified from foods, and generally
sold in medicinal forms not usually
associated with food and
demonstrated to have a
physiological benefit or provide
protection against chronic disease.
orang diabet butuh mineral (kromium) —> banyak terkandung
dalam kubis
NUTRACEUTICAL Vs FUNCTIONAL FOODS
• When food is being cooked or prepared using
"scientific intelligence" with or without
knowledge of how or why it is being used, the
food is called "functional food." Thus,
functional food provides the body with the
required amount of vitamins, fats, proteins,
carbohydrates, etc, needed for its healthy
survival.
• When functional food aids in the prevention
and/or treatment of disease(s) and/or
disorder(s) other than anemia, it is called a
nutraceutical.
• Thus, a functional food for one consumer can
act as a nutraceutical for another consumer.
Nutraceuticals differ from dietary
supplements in the following aspects:
– Nutraceuticals must not only
supplement the diet but should also aid
in the prevention and/or treatment of
disease and/or disorder.
– Nutraceuticals are represented for use
as a conventional food or as the sole
item of meal or diet.
The use of nutraceuticals :
– As an attempt to accomplish desirable
therapeutic outcomes with reduced
side effects.
– As compared with other therapeutic
agents has 4,5 met with great
monetary success.
 Pharmaceutical and Biotechnology
Companies
Some of the pharmaceutical and biotechnology
companies, which commit major resources to the
discovery of nutraceuticals include
– Monsanto (St Louis, MO)
– American Home Products (Madison, NJ)
– DuPont (Wilmington, DE)
– Abbott Laboratories (Abbott Park, IL)
– Warner-Lambert (Morris Plains, NJ)
– Johnson & Johnson (New Brunswick, NJ)
– Novartis (Basel, Switzerland)
– Metabolex (Hayward, CA)
– Genzyme Transgenic, PPL Therapeutics,
Interneuron (Lexington, KY).
 Employ - Interact
• Generally Recognized as Safe (GRAS)
notification
– suggest Tolerable Upper Limit
• Generally Recognized as Efficacious
– (GRAE) panels for structure/function claims
• Better communication with FDA
ORGANOSULFUR COMPOUNDS
FROM GARLIC
GARLIC / Allium sativum (Liliaceae)
Garlic has been used throughout recorded
history for both culinary and medicinal
purposes. It has a characteristic pungent, spicy
flavor that mellows and sweetens considerably
with cooking.

HISTORY :
• 3000 BC. Summarian of Mesopotamia
& people of Ancient India
• 1550 BC. Egyptians : more than 22
therapeutic garlic formula
CHEMICAL COMPOSITION
• 33 sulfur compounds organosulfur
containing compounds medicinally
significant components
• 17 amino acids
• Germanium, Calcium, Copper, Iron,
Magnesium, Selenium, Zinc
• Vitamins A, B, C, and E
CHEMISTRY
• -Glutamyl-Cysteines ( -glutamyl-S-trans-1-
propenyl-cysteine, -glutamyl-S-allylcysteine, -
glutamyl-S-methylcysteine)
• Cysteine Sulfoxides (alliin, methiin, asoaliin)
• Alliinase (alliin lyase)
• Thiosulfinates (allicin (allyl 2-propene
thiosulfinates), allyl methyl thiosulfinates)
volatile and reactive physiologically and
medicinally active compound in garlic, formed
when garlic is cut, crushed, or chewed

Alliinase
Cysteine Sulfoxides Thiosulfinates
COMMERCIALLY AVAILABLE GARLIC
SUPPLEMENTS
PRODUCTS PROCESSING POTENTIAL ACTIVE PRINCIPLE
Fresh garlic Raw Cysteines ( -glutamylcysteine and S-allylcysteine)

Thiosulfinates (allicin and allicin-derived sulfur

compound)
Boiled Mainly diallyl trisulfide, diallyl disulfide, allyl methyl
trisulfide
Fry/microvawe Mainly diallyl disulfide, allyl methyl disulfide, vinyl
dithiins
Garlic Spray dried Varying amounts of cysteines and thiosulfinates
powder Freeze dried Varying amounts of cysteines and thiosulfinates
Oven dried Varying amounts of cysteines and thiosulfinates
Garlic oil Steam-distilled Mainly diallyl disulfide, diallyl triisulfide, allyl methyl
trisulfide
Macerate in oil Thiosulfinates transformation compounds (vinyl
dithiins, ajoenes, diallyl sulfide)
Ether extraction Thiosulfinates transformation compounds (vinyl
dithiins, ajoenes, diallyl sulfide)
Aged garlic S-allylcysteine and S-allylmercaptocysteine
extract
HEALTH BENEFITS
• Cholesterol-lowering properties
• Plaque regression properties
• Anti-thrombotic activity
• Blood pressure- lowering properties
• Antioxidant effects
• Anti-cancer properties
• Antimicrobial effects
 ISOFLAVONE FROM SOYBEAN

CONSUMPTION
OF SOY FOOD

ISOFLAVONE

HEALTH BENEFITS

• Potential cancer prevention breast, prostate, colon

• Heart disease prevention
• Increase bone density osteoporosis prevention
• Reduction of postmenopausal syndromes
CHEMICAL STUCTURES
The structural variation of isoflavones are
numerous, depending upon their substituents,
oxidation levels, and extra heterocyclic rings
attached on the basic skeleton.
The most commonly of the 12 forms in soy are
genistein, daidzein, and glycitein, and their
glucosides, 6”-O-acetyl and 6”-O-malonyl-
glucosides.
 Effect of Conventional Protein
Concentration, Isolation, and Traditional
Food Processing
Production of protein concentrate
• Alcohol wash removed most of the
isoflavones. Aqueous washing had little
effect on isoflavones.
• ± 50 % of the isoflavones were lost
during the manufacturing of soy isolate
• Alcohol treated protein concentrate had
low isoflavones
Extraction at alkaline pH, acid precipitation,
and aqueous washing on soy protein isolate
production 19%, 14%, 22% of total
isoflavones were lost, respectively.
Isoflavones profile : the isolate had more
aglycones than the soy flour, therefore :
Alkaline hydrolysis of glucosides may
have occurred during the process
Aglycones may bind to the protein more
firmly than the glucosides
Production of fermented soy foods
Soaking and heating caused losses of 12% and 49% of
total isoflavones.
Fermentation of tempeh greatly increase the level of
aglycones, daidzein and genistein, through β-
glucosidase hydrolysis.
Murakami et al (1984) found that tempeh, a fermented
soy food obtained by fermenting cooked soybeans for
40 h with Rhizopus oligosporus, has only aglycones
and no glucosides.
Fungal fermentation produced β-glucosidases to
hydrolyze the glucosides to aglycones. The high level
of aglycone contributed to antioxidant activity to
increase the self life of tempeh.
Effect of Cooking/Heating
(Hot Water extraction, Frying, Toasting and Baking)
on Isoflavone Stucture
Most of the malonyl isoflavones were converted to respective glucosides
after extraction at 80 °C for 15 h.
Hot aqueous extraction as well as hot extraction in the making of tofu
and soy milk converted some malonyl glucosidase to β-glucoside.
Toasting (dry heat) of soy beans convert malonyl forms to acetyl
glucosides.
Production of low-fat soy milk and low-fat tofu reduced total isoflavones
by 57% and 88%.
Frying converted some malonyl glucosidases to glucosides, acetyl
glucoside and aglycones.
Cookies baking for 7,5 min doubled the amount of glucosides, and 15
min produced more glucosides, acetyl glucosides, and aglycones.
As food was burnt, total isoflavone decreased with an increase in
aglycones.
 Effect of Acid and Base Treatment
Glucosides (malonyl and acetyl form) of isoflavones
can de hydrolized by acid treatment. Conversion of
glucosides to aglycones by acid treatment was the
best at 1 N of HCl for 2 h. A higher concentration of
acid that 1 N will decrease the aglycone content.
Alkaline treatments at a high temperatures cause the
breakdown of the malonyl or acetyl ester linkages.
A summary of the food processing on chemical structures of
isoflavones is ilustrated on the figure bellow
Summary of the chemical reactions of isoflavones that may occur during
food processing as affected by acid, heat, enzymes, and fermentation.
Genistein and their glucosides are used for illustration.
Nutritional and Pharmaceutical Product from Soy

1. ISOFLAVONE OR AGLYCONE-ENRICHED
PROTEIN CONCENTRATE
Contains 1-2 mg/g genistein and 0.7-1.5 mg
daidzein on a dry-weight basis
Process to obtain:
• pH 4,5 washing to remove soluble
carbohydrates then suspending in water
• Reacted with β-glucosidases or esterases
(pH 4-8) at 40-60 ºC
• Drying
2. ISOFLAVONE ENRICHED PROTEIN MOLASSES
Process to obtain the isoflavone enriched molasses
cake :
• Heating the soy molasses at pH 6-13 to
hydrolize malonyl or acetyl glucosides to
isoflavone glucosides.
• Reacting with enzyme to produce aglycones
• Adjusting to pH 4,5
• Cooling and centrifugation or filtration
3. SOY FIBER
Process to obtain:
• Treating protein extract slurry with β-
glucosidase, pH 6-8 to produce aglycones
• Separating the soluble protein extract with
the insoluble spent flakes, wich was an
aglycone-enriched soy fiber
• Drying the fiber fraction
The dried fiber fraction contains 1-2 mg/g
genistein and 0.7-1.7 soy fiber/g
4. PROTEIN EXTRACT AND ISOLATE
a)Isoflavones-rich protein isolate
1. The soy flakes were extracted at an alkaline pH and
were precipitated at pH 4,5
2. The precipitates were washed minimally, cooled at
40-80 ºF and held 1 hour before separation
b)Isoflavones-rich protein extract
1. A low-stacyose soybean variety was dehulled, flaked
(0,25-0,6 mm), defatted by hexane and desolventized
by vacum
2. A water extraction at 80 ºC was carried out for 6-10
min, and it was then cooled to 40-45 ºC by adding
more water
3. The extract after centrifugation was neutralized and
spray-dried. The product contained 2,5 mg/g
isoflavones.
 ECHINACEA imunostimulan

• Echinacea is a perennial plant. In general, the flower can be

characterized by hues of purple ray florets that surround an
orange-brown colored head containing numerous achenes,
i.e., fruiting bodies that contain seeds.
Echinacea is a dietary supplements promoted as an
immunostimulatory agent. It is one of the best-selling
herbal product in U.S.
The most widely used Echinacea species for medicinal
purposes :
Echinacea purpurea (L) Moench.,
E. angustifolia DC.,
E. pallida Nutt.

E. purpurea
Echinacea Phytochemicals
• Caffeic Acid Derivatives (CADs)
• Alkamides
• Essential Oil
• Glycoproteins and Polysacharides
 CADs and Phenolic Compounds
• CADs make up the largest precentage of the phenolic
compounds.
• CADs can be classified as:
– Quinyl esters of caffeic acid
– Tartaric acid derivatives
– Phenylpropanoid glycosides
• Tartaric acid derivatives are believed to be
responsible for some immune-enhancing activity
• Clorogenic acid, verbacoside, and echinacoside have
no immune-enhancing activity, but possess
antioxidant activity
Caffeic acid derivatives of Echinacea
Alkamides

• Alkamides have immune enhancing

activity as well as antiinflamatory activity
• Alkamide level of 0.62% and 0.10% were
shown on E. purpurea roots and aerial
parts, respectively. Further study showed
average alkamide levels of 0.89, 0.26,
0.01 and 0.08% in the root, flower, leaf,
and stem segments, respectively.
• 19 alkamides have been identified.
Alkamides found in E. purpurea
Alkamides Part of plant Alkamide
Level
Dodec-2E,4E,8Z-tetraenioc acid Roots 45 %
isobutylamide
Aerial parts 76 %

Undeca-2Z,4E-diene-8,10- Roots 18 %
diyonic acid isobutylamide
Dodeca-2E,4Z-diene-8,10- Roots 15 %
diyonic acid isobutylamide
Undeca-2E,4Z-diene-8,10- Roots 20 %
diyonic acid isobutylamide
Aerial parts 6%
ALKILAMIDES ISOLATED FROM ECHINACEA
Essential Oil
• The alkamide component of liphophilic
fraction partially responsible for the
immune-enhancing response
• Essential oil can act as antioxidant
• The essential oil content ranges from 0.1
% to 2.0 %
 Essential oil components of
Echinacea Species
Plant Species Essential oil compounents
E. angustifolia Dodeca-2,4-diene-1-yl-isovalerate
Pentadeca-1,8Z-diene
E. Pallida Pentadeca-1,8Z-diene
Pentadeca-8Z-en-2-one
E-10-hydroxy-4,10-dimethyl-4,11-
dodecadien-2-one (Echinolon)
E. purpurea Predominantly ß-myrcene
STABILITY
• Enzymatic, i.e. polyphenol oxidase, reactions
responsible for degradation of cichoric acid
the enzyme activity can be decreased by the
addition of ascorbic acid or ethanol during the
extraction process and storage in a low
moisture.
• Oxidation may lead the reduction of alkamide
levels storage under solvent (i.e. acetonitril,
ethanol) or the plant parts remain whole to
prevent oxidative degradation.
HEALTH BENEFITS
• Improving immune response by
enhancing phagocytosis of erythrocyte,
the rate of Immunoglobulin G (IgG)
production and cytokine production.
• Glycoprotein-polysaccharide complex
stimulated the release of interleukin 1,
tumor necrosis factor, and interferon in
macrophages, in vitro
Antimicrobial and Antiviral Activities
• Promoting cell resistance to viruses such as
influenza, herpes an vesicular stomatitis.
• Inhibiting two strains of Escherecia coli, Bacillus
cereus, Salmonella thyphymurium and
Staphylococcus aureus.
• CADs may be responsible for the microbial
inhibition. Cichoric and caftaric acid inhibited the
hyalurinidase enzyme, an enzyme produced by
microorganisms to penetrate tissue and cause
infection.
Antioxidant and Antiinflamatory
Activities
• Cichoric and other CADs such as
achinacoside, cynarine, and chlorogenic
acid were found to act as radical
scavenger.
• Alkamides and polysaccharides have been
found to have antiinflamatory activity.
Application of alkamides has shown to
inhibit 5-lipooxygenase.
LYCOPENE FROM TOMATOES
• Lycopene is a bright red carotenoid
pigment, a phytochemical found in
tomatoes (Solanum lycopersicum) and
other red fruits.
• Lycopene is a liphophilic carotenoid
pigment, a pigment distributed widely in
fruits and vegetables.
• Carotenoid pigments consists of two major
classes :
1. the hydrocarbon carotenes
(including lycopene)
2. the oxygenated xanthophylls
PHYTOCHEMICAL
• All chemical structures of of carotenoids
may be formally derived from the acyclic
C40H50 structure of lycopene.
• A polyisoprenoid backbone and a series of
centrally located conjugated double bonds
characterize the carotenoids.
• Lycopene and the other carotenes (e.g. -,
-, -, and -carotene) do not contain
oxygen.
• Structurally, lycopene is a highly unsaturated
aliphatic hydrocarbon.
• The chain contains 13 carbon-carbon double
bonds, 11 of which are conjugated and arranged
in linear array.
• The extensively conjugated polyene system is
the key to lycopene biological activity, which
includes its susceptibility to oxidative
degradation.
• There are cis- and trans- isomers of lycopene
structure. The trans-isomeres are about 35-90%,
while cis-isomeres makes 27% of the total
lycopenes in tomato.
• Unlike many other carotenes, lycopene has no
vitamin A activity because it lacks a -ionone ring
structure.
 Lycopene and -carotene molecular structure

Lycopene -carotene
Molecular C40H56 C40H56
formula
IUPAC (6E,8E,10E,12E,14E,16E,18E,20E, 1,3,3-trimethyl-2-[(1E,3E,5E,7E,9E,11E,
name 22E,24E,26E)-2,6,10,14,19,23,27,31- 13E,15E,17E)-3,7,12,16-tetramethyl-18-(2,
Octamethyldotriaconta-2,6,8,10,12,14, 6,6-trimethyl-1-cyclohexenyl)-octadeca-
16,18,20,22,24,26,30-tridecaene 1,3,5,7,9,11,13,15,17-
nonaenyl]cyclohexene
Physical Properties of Lycopene
• Molecular formula : C40H56
• Molecular weight : 536.85 Da
• Melting point : 172 -175 ºC
• Crystal form : long red needles separate from a
mixture of carbon disulfide & ethanol
• Powder form : Dark reddish-brown
• Solubility : Soluble in chloroform, hexane,
benzene, carbon disulfide, acetone,
petroleum ether & oil
• Stability : Sensitive to light, oxygen, high
temperatures, acids, catalyst &
metal ions
Lycopene content of Some Commonly
Consumed Fruits and Vegetable
Material Lycopene Content
mg/100 g Wet Basis
Tomato 0.72 - 20
Watermelon 2.3 - 7.2
Guava (pink) 5.23 - 5.50
Grapefruit (pink) 0.35 - 3.36
Papaya 0.11 - 5.30
Rose hip 0.68 - 0.71
Carrot 0.65 - 0.78
Pumpkin 0.38 - 0.46
Sweet potato ubi jalar 0.02 - 0.11
Apple pulp 0.11 - 0.18
Apricot 0.01 - 0.05
BIOLOGICAL ACTIVITY
ANTIOXIDANT PROPERTIES
The large array of conjugated double bonds system
lead the lycopene molecules to have antioxidant effect.
Antioxidant activity:
• Quenching singlet oxygen (O2√ )
• Trapping peroxyl radicals (ROO•)
The antioxidants properties of lycopene are associated
with in vitro lowering of oxidative damage to the DNA,
slowing down of the transformation to malignant state,
and lowering biological oxidative damage of proteins,
lipids and other cells.
ARTHEROSCLEROSIS PREVENTION
• Protecting plasma lipids from oxidation
Comparison of the antioxidant activities
(Quenching of singlet oxygen) of Different Carotenoids
Carotenoid Rate Constant for
Quenching of Singlet Oxygen
Kq x 10 9 (mol -1 s -1 )
Lycopene 31
-Carotene 25
-Carotene 19
-Carotene 14
Lutein 8
Astaxanthin 24
Bixin 14
Canthaxanthin 21
Zeaxanthin 10
Lycopene Preparation for
Nutraceutical Product
Purification and separation process
including:
• extraction with organic solvent
• supercritical CO2 fluid extraction (SFE-
CO2) still at laboratory scale
• distillation
• membrane separation
• chromatography
• crystallization
STABILITY
• As a highly conjugated polyene, lycopene
can undergo 2 types of change :
isomerization and oxidation
• The factors contributing the degradation of
carotenoid including lycopene are:
Elevated temperatures
Exposure to light, oxygen, metalic ions
(Cu2+ and Fe2+), extreme pH and
active surface
Other Nutraceutical That Are Widely Used :
• Flavonoids from berries and grapes with its
antioxidant activity
• Tocopherol and tocotrienols from oil and cereal
grains that are widely used as antioxidant and
preventing coronary heart disease.
• Pectin from fruits with potential effect in
increasing carbohydrates and lipids metabolisms
• Limonene from citrus
TERIMA KASIH