NATTOKINASE SLIDES

Japan Bio Science Laboratory- 1 -
Nattokinase NSK-SD®
The pioneer of Nattokinase
Established in 1974

Osaka Head Office
Kyushu
Factory
Beppu Onsen
Kyushu
Factory
Kyushu Factory (Oita pref.)
Yufuin Onsen
Tokyo Office
Kyoto
Factory

• Japanese traditional fermented
food
• Has been eaten for more than
1000 years
• Prepared by fermenting boiled
soy beans in the presence of
Bacillus natto
What is Natto?

Production Flow of Natto
Fermentation
Inoculation of
Natto bacteria
Boil the soybean
Soak the soybean
in water

Active Ingredients of Natto
Nattokinase
(by Bacillus natto)
Vitamin K2
Polyamine
Polyglutamic AcidVitamin E
Protein
Lecithin
Isoflavone
Calcium
Active Ingredients contained in the sticky part produced by BacillusNatto
Active Ingredients from Soybeans
(From Soybeans)
Vitamin B

What is Nattokinase?
• Found in Natto in 1980
• Serine protease
• Composed of 275 amino
acids
• Molecular weight is 27,728
• Specifically degrades fibrin
(thrombi): dissolving blood
clots without inhibiting
wound healing
• Activity is indicated as
FU （Fibrin Degradation Unit）

• 1907: Dr. S. Sawamura Natto bacteria is product of Protease
• 1925: Dr. K. Oshima Characterization report of Protease
(Protease degrades fibrin and gelatin)
• 1953: Dr. S. Miyake et al Crystalization of Protease
• 1956: Dr. S. Miyake et al First amino acid composition defined
• 1987: Dr. H. Sumi et al Named “Nattokinase”
• 1989: Dr. M. Fujita et al Identification of amino acid sequence
• 1992: Dr. E. Ichishima et al Identification of DNA sequence
• 1995: Dr. M. Fujita et al Transport of nattokinase across rat
intestinal tract.
Study History

History of nattokinase for supplement
1998: The first Nattokinase supplement in the world was launched
by JBSL (NSK-FD)
2001: Nattokinase supplement without the odor was launched
by JBSL (NSK-SD)
2003: Japan NattoKinase Association (JNKA) was established
JNKA mark was set up
2003: The standard of specification of fermented soybean extract
was established through Japan Health and
Nutrition Food Association (JHFA mark)
2006: JBSL obtained the process patent (JP3834048)
2006: JBSL obtained the substance & process patent (JP3881494)

JBSL’s Nattokinase Raw Material: NSK-SD
• Nattokinase Activity: >20,000FU/g
• No VK2 contained (<0.1ppm)
• No smell of natto
• Recommended daily intake:
2,000FU (100mg of NSK-SD)
• Product application:
Capsules, tablets, powdery supplement etc.

1. Fibrinolytic Effect
2. Reduction of Hypertension
 Kim, J. et al. Effects of NSK-SD (nattokinase) on blood pressure: A randomized controlled trial. ISSN 0916-9636. Vol. 31, No. 8, August
2008, Hypertension Research.
3. Decrease of Blood Viscosity
 Pais, E., Alexy, T., Holsworth, R.E., and Meislman, H.J., 2006. Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell
aggregation and whole blood viscosity. Clin. Hemorheol. Microcirc. 35: 139-142.
4. Antiplatelet aggregating activity
 Takaoka, S., Murata, Y., Moriyama, H. and Hoshi, K. The 123rd Annual Meeting of the Pharmaceutical Society of Japan, Tokyo, Japan.
Nagasaki, Antiplatelet effects of nattokinase (NSK-SD), p.134.
5. Effect on blood flow improvement
 Iuchi, S., Dokai, H. and Shionoya, K. Improvement of blood flow increase by ingestion of NSK II. FOOD Style 21, Vol. 10, No. 8, 78-90
(2006).
6. Reduction of Plasminogen Activator Inhibitor type 1 (PAI-1)
Urano, T., Ihara, H., Suzuki, Y., Oike, M., Akita, S., Tsukamoto. Y., Suzuki, I., and Takada, A., 2001. The pro-fibrinolytic enzyme
Subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor. J. Bio. Chem. 276: 24690-24696.
Functions of Nattokinase

Plasmin
Attack
Increase
Nattokinase
Fibrin
Degradation
Products
（FDP)
Degradation
➊AttackFibrin
Thrombus
Fibrinogen
Thrombin
Tissue
Plasminogen
Activator
（t-PA)
➋Activation(in vitro)➌Degradation
Plasminogen
Activator
Inhibitor
Type1(PAI-1)
Urokinase
Pro-Urokinase
Plasminogen
Direct & Indirect Effects of NK on the Fibrinolytic System
Mechanism of Nattokinase

Degradation of Artificial Thrombus by Nattokinase
As time goes by, nattokinase degrades the artificial
thrombus and it becomes clear liquid.
Mechanism of Nattokinase
0 hour 1 hour 3 hours

Safety of NSK-SD
• Single Oral Toxicity Study
Max. Dose : 1,000 mg/kg・day
Result : No Influence
• 13-Weeks Oral Toxicity Study
Max. Dose : 1,000 mg/kg・day
• Reverse-Mutation Assay (Ames Test)
Result : Negative
• Chromosomal Aberration Test
Result : Negative
• Pathogenicity Study of Nattokinase Producing Bacteria
Safety Tests: Animal & Microorganism

Safety of NSK-SD
1) An Oral Safety study of NK containing food, NSK II
 Randomized, Double-blinded Study
 31 participants (22=NSKII 3 capsule/day, 9=placebo)
 4 wks + 2-wk observation
 Result : Safe
2) Clinical Study of Effect and Safety of NK Administration on CV
Patients with Warfarin
 Double-blinded, Placebo Controlled Study
 60 participants with cardiovascular disease (taking warfarin)
Low dose: 15=1,700FU/ day, 15=placebo
High dose: 15=3,400FU/ day, 15=placebo
 26 wks
 Result : Safe
Safety Tests: Human Clinical Studies

3) An Open Clinical Pilot Study Study to Evaluate the Safety &
Efficacy of NK as an Add-on Oral Fibrinolytic Agent Tolow
Molecular weight Heparin & Anti-platelet in Acute Ischeamic
Stroke
Prospective Multicenter Proof-of-concent Open Pilot Study
12 participants in hospital after a stroke (taking heparin & antiplatelet drugs)
6,000FU/ day for 7 days + 90-day monitoring
Result : Safe
Safety of NSK-SD

Natto vs. Nattokinase
NK Amount
Calorie
Odor
Purines
Vitamin K2
VSNatto
Nattokinase
Supplement
Unstable
(Varies among products too)
Approx. 100kcal/50g
Has unique odor
Contained
Contained
Stable
A few kcal/g
Odorless
Not contained
Not contained

Preservation Stability of Nattokinase
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14
Day
Relativeactivity（％）
Preservation stability of commercially Natto （preserved at 5℃）
Preservation stability of NSK-SD (preserved at RT)
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40 45
Time (months)
Residualactivity(%)

Comparison of NK activities of commercially
available natto per pack
FU

The growth of nattokinase market in Japan
JBSL occupies more than 70% of
nattokinase market in Japan.

Areas JBSL is directly exporting NSK-SD
• USA
• EU
• China
• Korea
• Taiwan
• Vietnam
• Indonesia
• Malaysia
• Singapore
(As of Dec 2012)
Occupies about 80% of the world market
= Approx. US$300M as the end products
NSK-SD in Other Countries

NSK-SD in Korea Latest News! 

Korea Food & Drug Administration （KFDA）
Health Functional Food, Certification of Functional Raw Material
Raw material: Fermented soybean extract powder
Indicator component: Fibrin degrading enzyme activity
1) Characteristics: White to milk-white color powder
2) Fibrin degrading enzyme activity (FU/g) : 18,000~28,000
3) Lead (mg/kg): <1.0
4) Total arsenic (mg/kg): <1.0
5) Cadmium (mg/kg): <0.5
6) Total mercury (mg/kg): <0.5
7) Total coliforms: Negative
8) Total aflatoxin (㎍/kg): <10.0
Functions claimed: Effective for the hypertensive
(Physiological activation function 2nd grade)
Daily intake: 100mg as fermented soybean extract powder
Test Method: Assay Method of Nattokinase (Fibrin
degradation method)
The key points of Health Functional Food in Korea

NSK-SD in USA
• Raw Material & Bulk Softgels
→ Brand/Contract Manufacturer
- No.1 direct marketer of doctor-formulated
nutritional product, etc
• Started in 2003
• Channel
- Clinics (Doctors)
- Direct Marketing (Internet, Mail Order)
- Retail Shops (DS, Health Food)

More than 50
products are on the
U.S. market
NSK-SD in USA Picture taken in a supplement shop

Case: Direct Marketing
• Premium Brand by Clinical Doctor
- Formulated & Recommended by Doctor
- Dr’s Expert Knowledge & Experience
→ ↑Customer’s trust on the product
• Clinical Data → Doctors
- Doctors highly value clinical studies/data
- Communication with doctors
NSK-SD in USA

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50
Coenzyme Q10
Collagen
Natokinase
Soy Isoflavones
Soy Peptide
DHA
Ginkgo extract
Turmeric extract
Soy lecithin
Instant Green Juice
Catechin
Soy saponin
Maca
Lycopene
Glucosamine
Ceramide
Hyaluronic acid
Heme iron
Chondroitin
Chinese blackberry extract
Chitosan
Taurine
Sesamin
Gaba(γ-aminobutyric acid)
Citric acid
BCAA（Branched chain amino acid）
Rutin
Capsaicin
β-carotene
Squalene （The ocean shark extract）
Indigestible dextrin（Dietary fiber）
Gymnema
EPA(Eicosapentaenoic acid)
CCP（Casein calcium peptide）
Garcinia
Fucoidan
Lactoferrin
Flavangenol
Sardine peptide
Fructo-oligosaccharide
Melilot
Plant sterol
L-carnitine
AnhydrideⅢ
Creatine
CPP（Casein phosphopeptide）
β-glucan
Wheat albumin
Diacylglycerol
Globin protein resolutions
24.2
14.1
13.6
13.4
12.0
12.0
11.3
11.3
11.3
11.1
10.2
9.7
9.4
9.0
8.8
8.7
8.1
8.1
7.6
7.6
7.6
7.6
7.1
7.1
6.9
6.5
6.4
6.2
6.2
6.2
5.8
5.8
5.5
5.3
5.3
5.1
4.9
4.4
4.4
4.4
4.4
4.1
3.9
3.9
3.7
3.7
3.5
3.2
3.0
3.8
Ranking of most expected functional nutrients (%)
Note: The figure shows the percentage of people answered they wish to buy products with the nutritional component.
(Ref: Nikkei new product review Vol.78)
Survey 

63.4
59.0
55.4
53.9
48.9
46.3
45.6
40.7
39.6
34.5
32.2
31.1
29.0
28.7
24.9
0 10 20 30 40 50 60 70％
Make blood flow smooth and
improve the blood circulation
Heal the eyestrain
Enhance the brain work such as memorization
Abstain the obesity
Heal the stiff shoulders
Abstain and control stress
Activate the skin cells
Abstain the activities of negative Active Oxygen
Providing the good sleep
Providing hair with nutrition
Enhance the foot muscle’s abilities
Improve the food and hand’s bone abilities
Enhance the duration and muscle abilities for sports
Improving the good circulation
Abstain the side effects of drinking alcohol
Functional nutrients expected to be developed in the future
(Multiple answer up to 3)Survey 

What is thrombus?
A scab made with hemocyte and platelet tangled with
fibrin to repair injured vessel.
Injury
Platelet Aggregation
Coagulation
Reparation
Fibrinolysis
Thrombus will not be removed if
fibrinolytic activity is decreased
due to various reasons.
Process: Injury to Repair

What is thrombosis?
Arteriosclerosis make the brain vessel narrow and thrombus can
get stuck there. This will make the blood flow stop all of sudden.
Arteriosclerosis Thrombus
Cholesterol precipitated and
accumulated in a blood
vessel
How cerebral
infarction occurs

Approx. 100,000km in total
= 2.5 x earth
circumference!!
The length of vessels in our body
is…
In this length of vessel, thrombus
are produced every time vessels get
injured in our daily life.
Blood Vessels of Whole Body

Others
17%
Cerebrovasucu
lar Diseases
14%
Heart
Diseases
15%
Cancer
31%
Chronic
Obstructive
Lung Diseases
1%
Lung Diseases
2%
Renal Failure
2%
Senile Decay
2%
Suicide
3%
Accidents
4%
Pneumonia
9%
28.8%
Ref. 2002 Vital Statistics
The rate of the cause of death
Thrombosis in data

Dementia
10%
Heart Diseases
5%
Fracture&Fall
13%
Colds&Pneumon
ia
3%
Decay
15%
Others
10%
Rheumatic&Arth
ritis
6%
Patients with cerebrovascular diseases (e.g. cerebral Infarction,
hemorrhage) will need nursing and rehabilitation. This brings a big
effect on the society and now is a social problem.
Causes of Bedridden: Age Over 65
Thrombosis in data
Cerebrovascular
Diseases
38%
Comprehensive
Survey of Living
Condition 2004

・Genetic diabetes
・Obesity
・Smoking
・Lack of exercise
・Stress
・Excess intake of alcohol
・Excess intake of salt
・Aging etc.
Obesity
High-blood
Pressure
Hyperlipidaemia
Diabetes
Lifestyle diseasesCauses of lifestyle disease
Cardiac infarction, cerebral
Infarction, angina
cerebral hemorrhage,
cerebral embolism
renal sclerosis, renal
insufficiency
fundal hemorrhage
Metabolic
Syndrome
How thrombosis occurs?
Onset of complications

Nattokinase and Prevention of Thrombosis
To prevent thrombosis…
 Prevent arteriosclerosis by reconsidering
your lifestyle habit
Proper diet, proper amount of exercise
 Don’t forget thrombus are produced inside
our body all the time for vessel recovery
Prevention: Intake of Nattokinase
TOO LATE TO TAKE ACTIONS
AFTER THROMBOSIS HIT YOU!

It is widely known that the crisis rate of thrombosis is higher in a
cold season. HOWEVER the mortality rate of thrombosis
DRAMATICALLY INCREASES OVER 32 deg C.
The graphs above show the results of the study on the relationship between the
temperature and thrombosis. A significant increase in the mortality rate was seen at 32 deg
C. especially in cerebral infarction (1.66 times more compared to 31 deg C.).
(Source：Pan WH et al., Lancet 345: 353-5, 1995)
Appendix: Thrombosis vs. Temperature
Mortalityrate
(per100,000ppl)
Temperature (Ave.)
1.66 times higher
Increase by 3%
Cardiac Infarction Cerebral Infarction
Age: Over 65
Age: 25-44 Age: 45-64

NATTOKINASE SLIDES

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