Japan Bio Science Laboratory- 1 -
Nattokinase NSK-SD®
The pioneer of Nattokinase
Established in 1974
Japan Bio Science Laboratory- 2 -
Osaka Head Office
Kyushu
Factory
Beppu Onsen
Kyushu
Factory
Kyushu Factory (Oita pref.)
Yufuin Onsen
Tokyo Office
Kyoto
Factory
Japan Bio Science Laboratory- 3 -
• 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?
Japan Bio Science Laboratory- 4 -
Production Flow of Natto
Fermentation
Inoculation of Natto bacteria
Boil the soybean
Soak the soybean in water
Japan Bio Science Laboratory- 5 -
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
Japan Bio Science Laboratory- 6 -
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)
Japan Bio Science Laboratory- 7 -
• 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
What is Nattokinase?
Japan Bio Science Laboratory- 8 -
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)
What is Nattokinase?
Japan Bio Science Laboratory- 9 -
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.
Japan Bio Science Laboratory- 10 -
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
Japan Bio Science Laboratory- 11 -
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
Japan Bio Science Laboratory- 12 -
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
Japan Bio Science Laboratory- 13 -
Safety of NSK-SD
• Single Oral Toxicity Study
Max. Dose : 1,000 mg/kg・day
Result : No Influence
• 13-Weeks Oral Toxicity StudyMax. Dose : 1,000 mg/kg・day
Result : No Influence
• Reverse-Mutation Assay (Ames Test)Result : Negative
• Chromosomal Aberration TestResult : Negative
• Pathogenicity Study of Nattokinase Producing BacteriaResult : No Influence
Safety Tests: Animal & Microorganism
Japan Bio Science Laboratory- 14 -
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
Japan Bio Science Laboratory- 15 -
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
Japan Bio Science Laboratory- 16 -
Natto vs. Nattokinase
NK Amount
Calorie
Odor
Purines
Vitamin K2
VSNatto
NattokinaseSupplement
Unstable(Varies among products too)
Approx. 100kcal/50g
Has unique odor
Contained
Contained
Stable
A few kcal/g
Odorless
Not contained
Not contained
Japan Bio Science Laboratory- 17 -
Preservation Stability of Nattokinase
0102030405060708090
100
0 2 4 6 8 10 12 14
Day
Rel
ativ
e ac
tivi
ty (%)
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)
Res
idua
l act
ivit
y (%
)
Japan Bio Science Laboratory- 18 -
Comparison of NK activities of commercially available natto per pack
FU
Japan Bio Science Laboratory- 19 -
The growth of nattokinase market in Japan
JBSL occupies more than 70% of
nattokinase market in Japan.
Japan Bio Science Laboratory- 20 -
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
Japan Bio Science Laboratory- 22 -
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) : 18,000~28,0003) Lead (mg/kg): <1.04) Total arsenic (mg/kg): <1.05) Cadmium (mg/kg): <0.56) Total mercury (mg/kg): <0.57) Total coliforms: Negative8) 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
Japan Bio Science Laboratory- 23 -
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)
Japan Bio Science Laboratory- 24 -
More than 50 products are on the U.S. market
NSK-SD in USAPicture taken in a supplement shop
Japan Bio Science Laboratory- 25 -
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
Japan Bio Science Laboratory- 26 -
123456789
10111213141516171819202122232425
26 272829303132333435363738394041424344454647484950
Coenzyme Q10CollagenNatokinaseSoy IsoflavonesSoy Peptide DHAGinkgo extractTurmeric extractSoy lecithinInstant Green JuiceCatechinSoy saponinMaca LycopeneGlucosamineCeramideHyaluronic acidHeme ironChondroitinChinese blackberry extractChitosanTaurineSesaminGaba(γ-aminobutyric acid)Citric acid
BCAA(Branched chain amino acid)RutinCapsaicinβ-caroteneSqualene (The ocean shark extract)Indigestible dextrin(Dietary fiber)Gymnema EPA(Eicosapentaenoic acid)CCP(Casein calcium peptide)GarciniaFucoidanLactoferrinFlavangenolSardine peptideFructo-oligosaccharideMelilotPlant sterolL-carnitineAnhydrideⅢCreatineCPP(Casein phosphopeptide)β-glucanWheat albuminDiacylglycerolGlobin protein resolutions
24.214.113.613.412.012.011.311.311.311.110.29.79.49.08.88.78.18.17.67.67.67.67.17.16.9
6.56.46.26.26.25.85.85.55.35.35.14.94.44.44.44.44.13.93.93.73.73.53.23.03.8
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
Japan Bio Science Laboratory- 27 -
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
Japan Bio Science Laboratory- 28 -
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
Japan Bio Science Laboratory- 29 -
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
Japan Bio Science Laboratory- 30 -
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
Japan Bio Science Laboratory- 31 -
Others17%
Cerebrovasucular Diseases
14%
HeartDiseases
15%
Cancer31%
ChronicObstructive
Lung Diseases1%
Lung Diseases2%
Renal Failure2%
Senile Decay2%
Suic ide3%
Accidents4%
Pneumonia9%
28.8%Ref. 2002 Vital Statistics
The rate of the cause of death
Thrombosis in data
Japan Bio Science Laboratory- 32 -
Dementia10%
Heart Diseases5%
Fracture&Fall13%
Colds&Pneumonia3%
Decay15%
Others10%
Rheumatic&Arthritis6%
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
Japan Bio Science Laboratory- 33 -
・Genetic diabetes・Obesity・Smoking・Lack of exercise・Stress・Excess intake of alcohol
・Excess intake of salt・Aging etc.
Obesity
High-bloodPressure
Hyperlipidaemia
Diabetes
Lifestyle diseasesCauses of lifestyle disease
Cardiac infarction, cerebral Infarction, anginacerebral hemorrhage, cerebral embolismrenal sclerosis, renal insufficiencyfundal hemorrhage
Metabolic
Syndrome
How thrombosis occurs?
Onset of complications
Japan Bio Science Laboratory- 34 -
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 recoveryPrevention: Intake of Nattokinase
TOO LATE TO TAKE ACTIONS
AFTER THROMBOSIS HIT YOU!
Japan Bio Science Laboratory- 35 -
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. TemperatureM
ort
alit
y ra
te
(per 100,0
00 p
pl)
Temperature (Ave.)
1.66 times higher
Increase by 3%
Cardiac Infarction Cerebral Infarction
Age: Over 65
Age: 25-44 Age: 45-64
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