Salmon ovary outer membrane hydrolysate Salmon Ovary-based Peptides (SOP) KYOWA PHARMA CO. LTD. History of Placenta ① Ancient Greece (BC 400): Hippocrates (Father of Medicine) confirmed natural healing power of Placenta Ancient China (Tang period – 4000 years ago): Placenta presented in a ancient Chinese medical book China (Ming period): A Chinese herbalism book presented Human Placenta curative properties such as tonicity, menstrual regulation effect, postpartum disorder improvement and lactogenic action USSR in 1933 Dr. Filatov developed tissue therapy with Placenta History of Placenta ② Japan (Kaga region) Placenta was deemed as drug conferring immortality Medical application of Placenta in Japan: Dr. K. MITSUBAYASHI (Gynecology professor of Kyoto University): Development of Placenta formulation “Vita-X” (drug improving forcing, galactopoiesis, hematopoietic function, etc.) Dr. K. HIEDA (Pathology professor of Kurume University): Development of Placenta injectable solution “Laennec”: For neuralgia, rheumatism, sirrhosis, chloasma, frozen shoulder, menopausal syndrome and tonicity Medical application of Placenta covered by insurance in Japan: For hepatic dysfunction, menopausal syndrome, agalactorrhea, etc. Background of development ① Beneficial effects of Placenta - Concentrated source of nutrition - Human growth factor - Cellular stimulant activity - Improvement of menopausal syndrome Example of human placenta: After BSE problems, placenta derived from pigs is used for cosmetic and medicinal products. Concentrated source of nutrition Provides nutrition to the baby & the mother itself. The child’s brain, eyes, muscles, bones, organs, glands, nerves, skin, tissues and fluids are entirely make from the nutrients taken from its mother’s bloodstream via the placenta. Human growth factor The hormone can promotes tissue repair. Create cell regeneration in the bones. Re-generate tissue for muscle & vital organs. Can support immune system in combating infection and disease. Cellular stimulant activity placenta also has metabolic and endocrine activity. produces, among other hormones, progesterone's which is important in maintaining the pregnancy. maintain the uterine lining as well as inhibit the production Improvement of menopausal syndrome With concentrated source of nutrition's, it can improved the menopausal syndrome. Make looks younger. Background of development ② - Avoidance of animal ingredient’s use (quadruped) for health and cosmetic products in Europe - Safety issue (diseases characteristic of animal) - Shifting to marine-derived ingredients for the safety - Use of biomass in a positive manner (for environmental care) ↓ Focus on salmon ovary outer membrane (disposal part of salmon) for its “baby protective action” similar to placenta action ↓ Development of Salmon ovary outer membrane hydrolysate = Salmon Ovary Peptides (SOP) SOP Safety data Residual pesticides Heavy metals Hormones BHC Not detected DDT Not detected Aldrin & Dieldrin Not detected Endrin Not detected Arsenic Not detected Cadomium Not detected Total mercury Not detected Tin Not detected Total chromes Not detected Cyanogens Not detected Progesterone Not detected Estragiol Not detected Physical aspect of SOP Origin and production: SOP is freeze-dried salmon (Salmonidae) ovary-based peptides, obtained by enzymatic decomposition Aspect: Slightly yellow-brown powder having a characteristic odor Molecular weight distribution: 600~1500 Mean molecular weight: 600~800 Very special ingredient! Patented product! Extraction of amino-acid constituents from fish ovary outer membrane by enzymatic decomposition. Patent in Japan No. 3691497 International patents In China ZC 03148699.1 In Hong-Kong 04105531.1 In Korea 92899/2003 In USA 10/733.627 Physical aspect SOP Analysis data (in 100g) < Nutritional data> <Minerals> <Vitamins> Other amino acids Analysis Item Result Water 5。2g Total nitrogen 14。9g Lipid 0。1g Ash 5。5g Sodium 1。7g Dietary fiber 0。5g Fe 3。37mg Ca 497mg Mg 39。4mg Cu 127mg Zn 0。09mg Mn 0。51mg Se 172μg B2 0。61mg B6 0。31mg B12 2。4mg Biotin 26。4μg Niacin equivalent 11。2mg Niacin (nicotine acid equivalent) 0。16mg Triptophan 660mg Amino acids Pig Placenta Human Placenta Salmon Collagen Asparagine acid 7.25 7.29 4.91 5.25 Threonine 4.00 4.74 3.39 2.13 Serine 5.96 7.32 4.09 4.86 Glutamine acid 10.11 14.01 5.84 8.27 Proline 7.49 4.42 4.58 9.27 Glycine 21.38 11.52 9.34 36.52 Alanine 10.58 13.38 5.18 11.35 Cysteine 0.55 Valine 3.59 6.53 3.00 1.73 Methionine 2.06 1.97 1.16 1.58 Isoleucine 2.79 1.91 Leucine 5.13 3.88 4.23 1.95 Tyrosine 1.81 0.71 1.19 0.28 Phenylalanine 1.90 1.52 1.29 Histidine 1.32 1.91 1.30 0.98 Lysine 5.34 7.71 3.61 2.62 Arginine 5.44 3.89 2.88 5.22 Hydroxyproline 3.08 0.45 Tryptophan 0.32 Carnosine 0.33 0.43 Ornithine 0.39 0.65 1.8 Phosphoserine 0.25 0.66 5.00 0.45 Taurine Hydroxyrysine 1.05 Amino acids profile comparative chart between SOP and Pig Placenta extract SOP (Unit: mol%) Amino acids profile comparison between SOP and Animal origin Placenta extract SOPのアミノ酸組成 SOP profile Lys Pse Orn His Phe Arg Hyp Trp Hyl Asp Thr Tyr Ser Glu Leu Ile Pro Met Val Ala Gly Cyt His Orn Pse Trp Phe Tyr Leu ヒトプラセンタエキスのアミノ酸組成 Human Placenta profile 豚プラセンタエキスのアミノ酸組成 Pig Placenta profile Hyp Lys Arg Hyl Asp Phe Thr Ser Hyp Lys Arg Orn Hyl Pse Asp Tyr Thr Ser Leu Ile Met Glu Val Cyt Trp His Ala Gly Pro Ile Glu Met Val Cyt Ala Pro Gly Safety of SOP LD50 > 2,500mg/kg Nothing abnormal detected on Performance status, Weight and Necropcy Nothing abnormal detected on Biochemical examination of blood Clinical trial results on the drink containing SOP menopausal symptomsimproving effect Various effects of Placenta - Activation of cell division - Activation of metabolism - Hormonal adjustment - Improvement of immunity/resistance - Improvement of metabolism/blood circulation - Suppression of inflammation - Regulation of autonomic nerves (ataractic effect) - Improvement of menopausal syndrome - Elimination of radical oxygen Activation and regulation of physical function and detoxification Placenta-like function of SOP Composition: Similar to human or pig placenta Function: Similar to Animal Placenta - Inhibition of functional decline for liver and pancreas (antitoxic effect) - SOD-like function - Inhibition of tyrosinase activation - Inhibition of visceral fat accumulation On the base of this function, we realized a clinical trial. Summary of trial ① Object: Validation of SOP efficacy on improvement of Skin condition, anti-fatigue action and improvement of menopausal syndrome Subjects: - 17 women aged between 35 and 55 (just before or after menopause), having symptoms of menopause such as rough dry skin, insomnia, fatigable, stiff shoulder, etc. - Menopausal Index between 25 and 55 (They have some symptoms of menopause, but not so serious. Medical treatment is not required.) Exclusion criteria: Subjects hormonally treated Summary of trial ② Methods Taking a drink containing SOP 500mg per day ・For 17 subjects: during 4 consecutive weeks ・For 4 subjects of them: during 4 consecutive weeks + 1 week of time-out +1 week for retaking SOP drink ・For 4 subjects of them: during 4 consecutive weeks + 1 week of time-out +1 week for retaking Placebo drink Summary of trial ③ Measurement Measurement timing: Before trial – After 1 week – After 4 weeks – (1 week of time-out) – After 5 weeks (just after time-out) – After 6 weeks Summary of measurement: ・Skin condition was measured in 15 minutes after face-washing by Robo Skin Analyzer ・Menopausal index ・Skin condition questionnaire Robo Skin Analyzer Evaluation: - on facial pigmentation - on facial pores Skin condition analysis by Robo Skin Small pigments on face (observed value and rank) 平均 色素沈着数(小)(実測値) 2007C01 平均 色素沈着総面積( 小) ( ランク) 2007C 01 6 2007C02 2007C 02 2007C03 40 0.05<P<0.1 0 0.05<P<0.1 0 35 2007C04 2007C 03 5 2007C 04 2007C05 2007C06 2007C 05 2007C 06 4 2007C07 30 2007C 07 2007C08 2007C09 25 2007C 08 3 2007C 09 2007C 10 2007C10 2007C11 2007C 11 2 2007C 12 2007C12 20 2007D 01 2007D01 2007D03 15 2007D 03 1 2007D 05 2007D05 2007D 06 2007D06 10 0 試飲前 1週間後 1ヵ月後 2007D09 試飲前 1週間後 1ヵ月後 2007D 09 We observed significative diminution of small pigments number and its surface after 1 week and at 4th week. This result shows improvement effect of Ocean Placenta on small pigments. Dr. Y. NOMURA: Director of Nomura Dermatological Clinic Dr. S. HIRASAWA: Director of My City Clinic Large pigments on face (observed value and rank) ⇒ so-called “pigmented spot” 平均 色素沈着数(大)(実測値) 2007C01 2007C02 90 2007C03 P>0.10 2007C04 P>0.10 80 2007C05 2007C06 70 2007C07 2007C08 60 2007C09 2007C10 50 2007C11 2007C12 40 2007D01 2007D03 30 2007D05 2007D06 20 試飲前 1週間後 1ヵ月後 2007D09 We observed slight diminution of large pigments after 1 week and at 4th week, but not significant. According to these results, SOP should have diminution effect of facial pigments in small and large cases. Dr. Y. NOMURA: Director of Nomura Dermatological Clinic Dr. S. HIRASAWA: Director of My City Clinic Facial pores (observed value) Visible pores number 平均 毛穴数(実測値) 2007C01 2007C02 0.02<P<0.05 1700 2007C03 0.02<P<0.05 2007C04 1500 2007C05 2007C06 1300 2007C07 2007C08 1100 2007C09 2007C10 900 2007C11 2007C12 700 2007D01 2007D03 500 2007D05 2007D06 300 試飲前 1週間後 1ヵ月後 2007D09 We observed slight diminution of visible pores number after 1 week and at 4th week. This result shows tighten effect of Ocean Placenta on visible pores. Dr. Y. NOMURA: Director of Nomura Dermatological Clinic Dr. S. HIRASAWA: Director of My City Clinic Self-evaluation: Change in Menopausal Index and Skin & Physical conditions ① Menopausal Index Self-evaluation by scoring Trial I: 17 subjects Trial II: 8 subjects from them (4 subjects for Placebo group) ② Change in skin and physical conditions <Skin condition> Inscribing subjective symptom <Physical condition> Inscribing subjective symptom Change in Menopausal Index Trial I Improvement of Menopausal Index on 16 of 17 subjects after 1 week, on 17 of 17 after 2 weeks, on 15 on 17 after 3 weeks and on 17 of 17 after 4 weeks Trial II During 1 week of time-out: Aggravation of Menopausal Index on 8 of 8 1 week after the resumption: Improvement on 4 of 4 for SOP group (for Placebo group: improvement on 2 of 4, aggravation or no change on 2 of 4) This result shows menopausal index improvement effect of SOP after 1 week of use. Change in Menopausal Index 0 -5 -10 -15 ■Trial I 試験Ⅰ -20 -25 -30 After 1 Week After2週間後 2 Weeks 1週間後 After 3 Weeks After 4 Weeks 4週間後 3週間後 17 subjects Change in Menopausal Index (M.I.) Test period 試飲期間 Before week After 2 weeks After3週間後 3 weeks After 4 weeks 試飲前After 1 1週間後 2週間後 4週間後 Change in M.I. 更年期指数変化 0 -5 Trial I 試験Ⅰ 被験者17名 Subjects: 17 -10 -15 -20 -25 -30 -35 -19.4 -20.5 -22.2 -29.0 Change in Skin and physical conditions <Skin condition ①> Trial I (during 4 weeks) (Remarks from the subjects) Skin dryness was improved after 1 week of use. During face-washing, skin became smooth at 2nd week. Skin became velvety at 4th week. Good blood circulation of face in the morning and clear facial skin at 4th week. One subject got a cold during the test and took a drug, but she didn’t have any skin problem, such as skin roughness or drug eruption. Improvement of skin roughness during menstruation Skin condition within 4 weeks NO. OF WEEK REMARK WEEK 1 Skin dryness improved WEEK 2 Skin became smooth WEEK 3 Skin became smoother WEEK 4 - Good blood circulation - Improvement of skin roughness Change in Skin and physical conditions <Skin condition ②> Trial II (Remarks from the subjects) At 5th week ‘time-off period”: Sensation of itching and skin dryness Not easy to make-up At 6th week: Ocean Placenta group Improvement of skin brilliance Improvement of dullness skin color At 6th week: Placebo group Skin still dried But skin remains satiny from 4th week Change in Skin and physical conditions <Physical condition ①> Trial I (during 4 weeks) Easy to sleep from 3rd day Fatigue reduced after 1 week Intolerance to cold reduced after 1 week Improvement of impatience at 4th week Augmentation of menstrual bleeding Physical condition within 4 weeks NO. OF WEEK REMARK WEEK 1 Easy to sleep WEEK 2 Fatigue reduced after 1st week WEEK 3 Intolerance to cold reduced WEEK 4 - Improvement of impatience - Augmentation of menstrual bleeding Change in Skin and physical conditions <Physical condition ②> Trial II At 5th week ‘time-off period”: Feeling bleu due to time-off period Easily-fatigued with shoulder hurt Difficulty of falling sleep Sensation of impatience Intolerance to cold At 6th week: Ocean Placenta group Good view and shoulder hurt reduced from 3rd day. Sensation of fatigue reduced Keeping good mental condition during ill health At 6th week: Placebo group Sensation of impatience (same as 5th week) Intolerance to cold Difficulty of falling sleep Physical condition 5th week time of period Oceanta Placenta Group at 6th week Placebo Group at 6th week Difficulty of falling sleep Improved to a good sleep Difficulty of falling sleep Sensation of impatience Sensation of fatigue reduced Sensation of impatience (same as 5th week) Intolerance to cold Keeping good mental condition during ill health Intolerance to cold Resume These results show SOP effects on symptoms of menopause and skin condition of women of menopausal age. Nearly all of the subjects had a gut feeling of SOP effects on their skin and physical condition from first week. Nearly all of and physical condition from only first week. So, we observed immediate action of SOP and its continuous effect during the dosing. Thanks to SOP’s efficacy, we can hope a wide variety of SOP application, such as beauty supplement or drink, anti-fatigue supplement or drink for women of menopausal age.