WO2007024108A1 - A composition containing timosaponin a-iii for prevention and treatment of type 2 diabetes mellitus - Google Patents
A composition containing timosaponin a-iii for prevention and treatment of type 2 diabetes mellitus Download PDFInfo
- Publication number
- WO2007024108A1 WO2007024108A1 PCT/KR2006/003332 KR2006003332W WO2007024108A1 WO 2007024108 A1 WO2007024108 A1 WO 2007024108A1 KR 2006003332 W KR2006003332 W KR 2006003332W WO 2007024108 A1 WO2007024108 A1 WO 2007024108A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diabetes mellitus
- iii
- type
- timosaponin
- blood glucose
- Prior art date
Links
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 28
- 239000000203 mixture Substances 0.000 title claims abstract description 25
- MMTWXUQMLQGAPC-YXOKLLKRSA-N Timosaponin A-III Chemical compound O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1C[C@H]2CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(OC[C@@H](C)CC1)O5)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O MMTWXUQMLQGAPC-YXOKLLKRSA-N 0.000 title abstract description 38
- MMTWXUQMLQGAPC-XWIAVXRASA-N timosaponin A-III Natural products C[C@@H]1CC[C@@]2(OC1)O[C@@H]3C[C@H]4[C@H]5CC[C@@H]6C[C@H](CC[C@]6(C)[C@H]5CC[C@]4(C)[C@@H]3[C@@H]2C)O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O)[C@H]7O[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O MMTWXUQMLQGAPC-XWIAVXRASA-N 0.000 title abstract description 38
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 241000700605 Viruses Species 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
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- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
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- 235000012241 calcium silicate Nutrition 0.000 description 1
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- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
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- 239000007903 gelatin capsule Substances 0.000 description 1
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- 235000020688 green tea extract Nutrition 0.000 description 1
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- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
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- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
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- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
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- 229950004994 meglitinide Drugs 0.000 description 1
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- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
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- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
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- 229960001110 miglitol Drugs 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
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- 229960005323 phenoxyethanol Drugs 0.000 description 1
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- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
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- 229960004586 rosiglitazone Drugs 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 238000011664 type 2 diabetes animal model Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960001296 zinc oxide Drugs 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to a composition for the prevention or
- type 2 diabetes mellitus which comprises timosaponin A-III, and
- diabetes mellitus comprising timosaponin A-III as an active ingredient, which is
- diabetes mellitus where insulin lacks the function of controlling the blood glucose
- Diabetes mellitus is a disease related to the metabolism of hydrocarbons
- type 1 diabetes mellitus insulin-dependent diabetes mellitus; about 10% of total
- type 2 diabetes mellitus insulin-independent diabetes mellitus
- Type 1 diabetes mellitus patients have little or no
- Type 1 diabetes mellitus arises mainly in childhood, and
- type 2 diabetes mellitus is usually discovered in adults and originates from
- the patients may secret insulin but in a very lower level or may be off their balance
- mellitus is reported to originate from obstruction to appropriate secretion of insulin
- ketoasidosis like type 1 diabetes mellitus patients.
- type 1 diabetes ketoasidosis like type 1 diabetes mellitus patients.
- type 1 diabetes ketoasidosis like type 1 diabetes mellitus patients.
- the blood glucose level may be lowered by meal control, exercise and
- the blood glucose level lowering medicine may be divided into three
- the second group is insulin sensitizer such as biguanide or
- Acarbose or miglitol is included in the third
- type 1 diabetes mellitus animal model there are a medicine-induced model using alloxan or streptozotocin and a naturally induced
- animal model and the representative examples are db/db mouse (diabetes mellitus
- KK ovalbuproliferative diabetic mellitus model
- KK-Ay obese diabetes mellitus
- model type 1, type 2 and choose the most appropriate model.
- rats where diabetes mellitus was induced by alloxan and streptozotocin, which are the representative drugs used in experimental diabetes mellitus model [N.
- Alloxan (5,5-dihydroxy-2,4,6(lH,3H,5H)-pyrimidinetrione) is an oxidized
- glucose derivative moves into beta cells based on strong alkylating action
- XOD xanthine oxidase
- XOD xanthine oxidase
- mellitus e.g. administration of additional medicines such as dexamethasone [S. J.
- animal model should be differentiated from neonatal streptozotocin (referred to as
- N-streptozotocin-induced diabetic rat model is widely explored.
- streptozotocin-induced diabetic model in adult rats is type 1 model while
- n-streptozotocin-induced diabetic model in newborn rats is type 2 model [B. M.
- the present invention aims to provide a novel use of timosaponin
- the present invention relates to a composition for the prevention or
- the present invention relates to a health food comprising
- timosaponin A-III as an active ingredient, which is effective for type 2 diabetes
- Bunge rhizome (Zhi Mu) comprises:
- the present inventors ascertained that timosaponin A-III is far superior in
- the present invention relates to a composition for the prevention or
- composition herein when subject to clinical test, may be administered
- administration and may be used in the form of medicine or health food.
- composition herein may be formulated into tablets, pills, an emulsion
- liquid dosage form or a liquid dosage form, aerosols, troches, logenge, aqueous or oily suspension,
- Tablet or capsule formulation may comprise binding agents such as lactose,
- disintegrants such as corn starch or sweet potato
- Capsule formulation may further include lubricants such as magnesium stearate, calcium stearate, sodium stearylfumarate or polyethylene glycol wax.
- lubricants such as magnesium stearate, calcium stearate, sodium stearylfumarate or polyethylene glycol wax.
- composition herein may be administered
- parenterally such as by subcutaneous, intravenous, intramuscular or pectoral
- Pareteral preparation may be manufactured by mixing the composition
- Suitable examples of carriers, excipients and diluents are aluminum salt,
- phenoxyethyl alcohol water, physiological saline solution, lactose, dextrose, sorbitol,
- mannitol calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose,
- magnesium stearate and mineral oil magnesium stearate and mineral oil.
- any formulation of the composition herein may further comprise
- fillers anti-aggregants, lubricant, wetting agent, spice, suspending agent or
- the dosage level for an adult is 0.1-15
- composition herein may be prepared into food or medicine, and be
- 'a health food' refers to a food in the form capsule, powder
- Figure 1 shows a destruction process of beta cells by alloxan
- Figure 2 is a graph showing an effect of lowering blood glucose level of Zhi
- Figure 3 is a graph showing an effect of the lowering blood glucose level of
- Figure 4 is a graph showing an effect of the lowering blood glucose level of
- Figure 5 is a graph showing an effect of the lowering blood glucose level of
- white needle-shaped material is referred to as compound I (Rf 0.38, 90% MeOH,
- Example 1 Effect of lowering the blood glucose level in db/db mouse
- mice 8-9 week old db/db male mice (C57BL/Ks-db/db) were used in the
- CMC carboxymethyl cellulose
- CMC carboxymethyl cellulose
- mice and feed were weighed right before the
- biochemical parameters were measured for analyzing the lipids and the function of
- Figure 2 shows the effect of lowering the blood glucose level after the
- Figure 3 shows an effect of lowering the blood glucose level after the
- timosaponin A-III is a major active ingredient in EA-V fraction.
- Example 2 Effect of timosaponin A-III in lowering the blood glucose level in
- KK-Ay mouse is prepared by introducing obesity genes into KK mouse, which was
- CMC carboxymethyl cellulose
- CMC carboxymethyl cellulose
- mice and feed were weighed right before the administration
- Figure 4 shows an effect of lowering the blood glucose level after the
- glucose level was ascertained at a dosage of 200 mg/kg.
- Example 3 Effect of timosaponin A-III in lowering the blood glucose level in
- mice streptozotocin-induced diabetic rat 7-weeek-old wistar male mice (weight: 180-200 g) were intraperitoneal
- CMC carboxymethyl cellulose
- CMC carboxymethyl cellulose
- mice and feed were weighed right before the administration
- Figure 5 shows an effect of lowering the blood glucose level in the
- streptozotocin-induced diabetic rats i.e. type 1 diabetes model of timosaponin A-III
- mice 16-hour-fasted 4-5 week old ICR mice (5 mice each group) were selected as test
- timosaponin A-III 100 mg was admixed with 14.8 mg of lactose, 3 mg of
- Ointment was prepared as set forth below by using timosaponin A-III: Active ingredient 5 g, cetyl palmitate 20 g, cetanol 40 g, stearyl alcohol 40 g,
- Active ingredient 100 mg, mannitol 180 mg, dibasic sodium phosphate 25
- health food was prepared by using 0.3 g of timosaponin
- A-III 0.3 g, powdered vitamin E, ferrous lactate, zinc oxide, nicotinamide, vitamin A,
- vitamin Bl and vitamin B2 based on a daily dosage.
- Vitamin C 100 mg Powdered vitamin E 120 mg
- the present invention is very useful in medicine or
- A-III is superior in preventing or treating type 2 diabetes mellitus while is poor in
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Nutrition Science (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Botany (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a composition for the prevention or treatment of type 2 diabetes mellitus, which comprises timosaponin A-III, and in particular, it relates to a composition for the prevention or treatment of type 2 diabetes mellitus comprising timosaponin A-III as an active ingredient, which is completed by finding that timosaponin A-III is superior in preventing or treating type 2 diabetes mellitus while is poor in preventing or treating type 1 diabetes mellitus, in contrary to what has been known.
Description
A COMPOSITION CONTAINING TIMOSAPONIN A-III FOR PREVENTION
AND TREATMENT OF TYPE 2 DIABETES MELLITUS
TECHNICAL FIELD
The present invention relates to a composition for the prevention or
treatment of type 2 diabetes mellitus, which comprises timosaponin A-III, and
particularly it relates to a composition for the prevention or treatment of type 2
diabetes mellitus comprising timosaponin A-III as an active ingredient, which is
supported by the findings that timosaponin A-III is superior in preventing or
treating type 2 diabetes mellitus while is poor in preventing or treating type 1
diabetes mellitus contrary to what has been known.
According to the National Institutes of Health (NIH), there are about 1,570
patients suffering from type 2 diabetes mellitus, one of obesity related diseases [The
evidence report: clinical guideline on the identification, evaluation, and treatment of
overweight and obesity in adults, 1999, NIH].
Further, WHO expected that the number of diabetes mellitus patients will
reach about 300 million in 2025. Particularly, the patients suffering from type 2
diabetes mellitus, where insulin lacks the function of controlling the blood glucose
level, amount to about 5.9% of the U.S. population [A. S. Wagman et al., Current
Pharmaceutical Design, 7, 417, 2001].
Diabetes mellitus is a disease related to the metabolism of hydrocarbons
and shows a symptom of high blood glucose level. This disease is divided into
type 1 diabetes mellitus (insulin-dependent diabetes mellitus; about 10% of total
patients) and type 2 diabetes mellitus (insulin-independent diabetes mellitus; about
90% of total patients) [B. Set, Clin Therapeu., 25, 1895, 2003; S. N. Davis, J Diabetes
Complications., 18, 367, 2004]. Type 1 diabetes mellitus patients have little or no
ability to secrete insulin because of damages in pancreas due to heredity or virus
invasion and resulting destruction of beta cells in pancreas. Further, these patients
show intense high blood glucose level, which are likely to proceed into symptoms of
ketosis and ketoasidosis. Type 1 diabetes mellitus arises mainly in childhood, and
the control of blood glucose level is necessary through insulin administration. In
contrast, type 2 diabetes mellitus is usually discovered in adults and originates from
inheritance, obesity, stress, abnormality in hormone secretion, and medicine use.
The patients may secret insulin but in a very lower level or may be off their balance
because of increased secretion of adversely active hormones. Type 2 diabetes
mellitus is reported to originate from obstruction to appropriate secretion of insulin,
increased production of endogenic glucose in the liver or insulin resistance due to
lowered glucose utilization in peripheral tissue. Although this disease may also
develop into high blood glucose level, the patients are not so sensitive ketosis or
ketoasidosis like type 1 diabetes mellitus patients. In case of type 1 diabetes
mellitus, the blood glucose level may be lowered by meal control, exercise and
insulin medication. However, type 2 diabetes mellitus requires additional
administration of blood glucose level lowering medicine.
The blood glucose level lowering medicine may be divided into three
groups according to the mechanism of action. Sulfonylurea or meglitinide based
medicine is the first group, and stimulates beta cells in pancreas to promote the
insulin secretion. The second group is insulin sensitizer such as biguanide or
thiazolidinedion based medicines. Acarbose or miglitol is included in the third
group, and it inhibits the degradation of saccharides and lowers saccharide
absorption in intestines. Preferable blood glucose level lowering medicine should
quickly inhibit excessive rise in blood glucose level after meal and also lose the
activity not to cause low blood glucose level. Further, it should improve the
abnormal metabolism accompanied by diabetes mellitus. In that respect, the
aforementioned drugs are not perfectly preferable, and it is necessary to develop a
stable blood glucose level lowering medicine for oral administration in order to
appropriately treat diabetes mellitus, which is in a rise all over the world.
Among type 1 diabetes mellitus animal model, there are a
medicine-induced model using alloxan or streptozotocin and a naturally induced
model prepared by breeding diabetes-induced animals for generations such as NOD
(non-obese diabetic) mouse and BB (bio breeding) rat. On the contrary, a
generically manufactured model is very widely used for type 2 diabetes mellitus
animal model, and the representative examples are db/db mouse (diabetes mellitus
model due to deficiency in leptin receptor), ob/ob mouse (obese model due to
deficiency in leptin), zucker (obese diabetes mellitus model) rat, OLETF (The Otsuka
Long-Evans Tokushima fatty; obese and glucose resistant diabetes mellitus model)
rat, KK (obese diabetes mellitus model) mouse, KK-Ay (obese diabetes mellitus,
hyperinsulinism model) mouse [S. Makino et al., Exp Anim., 29, 1, 1980; A. F.
Nakhooda et al., Diabetes, 26, 100, 1977; M. Nakamura et al., DiabetoL, 3, 121, 1967;
K. Kawano et al., Diabetes, 41, 1422, 1992; D. A. Rees et al., Diabetic Medicine, 22,
359, 2005]. Therefore, it is important to understand the nature of each animal
model (type 1, type 2) and choose the most appropriate model.
RELATED PRIOR ART
N. Nakashima et al. reported the effect of pseudotimosaponin A-III,
prototimosaponin A-III, timosaponin A-III in lowering the blood glucose level in the
rats, where diabetes mellitus was induced by alloxan and streptozotocin, which are
the representative drugs used in experimental diabetes mellitus model [N.
Nakashima et al., J. Nat. Prod. Vol. 56, 345, 1994]. Besides, timosaponin A-III is
reported to have an activity of inhibit platelet aggregation [A. Niwa et al., Yakugaku
Zasshi 108 (6), 555, 1988] and the relaxation of blood vessel [G. Wang et al., Life Sci.
71, 1081, 2002].
Alloxan and streptozotocin are used as representative medicine for
inducing type 1 diabetes mellitus because they move into beta cells in pancreas
through expression of glucose transfer protein (GLUT-2), induce DNA destruction
or NAD+ exhaustion, and cause apoptosis of beta cells in pancreas. [K. Bloch et al.,
Diabetes Metab Res Rev 21, 253, 2005; D. A. Rees et al., Diabetic Medicine, 22, 359,
2005; J. Kawada et al., Yakugaku Zasshi, 112, 773, 1992; V. M. F. Rastelli et
al., Inflamm Res., 54, 173, 2005; R. K. Cuman et al., Inflamm Res. 50, 460, 2001; refer
to Figure I].
Alloxan (5,5-dihydroxy-2,4,6(lH,3H,5H)-pyrimidinetrione) is an oxidized
product of ureic acid or pyrimedine derivatives. Alloxan anion destroys beta cells
in pancreas by cytochrome P-450 mediated radical reaction [K. Bloch et al., Diabetes
Metab Res Rev 21, 253, 2005; Yakugaku Zasshi, 112, 773, 1992]. However, it has
been reported that alloxan has toxicity and results in high death rate of animals. I.
F. Federiuk et al. tried to find an optimal way to minimize the death rate in
alloxan-induced diabetes mellitus model by changing alloxan administration route
or the dosage. As a result, intraperitoneal administration of high dosage alloxan
(200 mg/kg) decreased the death rate by 10%, and type 1 diabetes mellitus was
induced more than 70% [I. F. Federiuk, Compara Med, 54, 252, 2004].
Streptozotocin (2-deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose), a
glucose derivative, moves into beta cells based on strong alkylating action and
generates superoxide radicals, thus causing an oxidizing damage to the beta cells.
The generation of superoxide radicals was induced either by indirect activation of
XOD (xanthine oxidase) due to high concentration of ADP in cells as mitochondria
are inhibited from producing ATP or by direct activation of XOD (xanthine oxidase)
[D. A. Rees et al., Diabetic Medicine, 22, 359, 2005; Yakugaku Zasshi, 112, 773, 1992].
Although it was reported that type 2 diabetes mellitus was induced by
using streptozotocin, most of these reports disclosed additional measurements were
required in combination with the drugs administration to induce the type 2 diabetes
mellitus, e.g. administration of additional medicines such as dexamethasone [S. J.
Giddings et al., Diabetes, 34, 235, 1985], nicotinamide [S. Ozyazgan et al.,
Pharmacol., 74, 119, 2005] or high fat diet at least 1-2 weeks [R. de Souza Santos et
al., Clin Chim Acta., 2005, Epub ahead of print; M. J. Reed et al., Metabolism., 49,
1390, 2000; F. Zhang et al., Exp Anim., 52, 401, 2003]. That is, what is induced by
streptozotocin alone irrespective of dosage or administration route is type 1 diabetes
mellitus, which appears to be irrefutable. This streptozotocin-induced diabetic
animal model should be differentiated from neonatal streptozotocin (referred to as
'n-streptozotocin' hereinafter) induced diabetic model in two-day-old rat [I.
Degirmenci et al., J EthnopharmacoL, 97, 555, 2005; D. N. Umrani et al., Clin Exp
Hypertens., 25, 221, 2003]. N-streptozotocin-induced diabetic rat model is widely
used type 2 diabetic model, and in fact, the reports also expressly described that
streptozotocin-induced diabetic model in adult rats is type 1 model while
n-streptozotocin-induced diabetic model in newborn rats is type 2 model [B. M.
Kim., Diabetol., 44, 2192, 2001; V. M. F. Rastelli et al., Inflamm Res., 54, 173, 2005; R.
K. Cuman et al., Inflamm Res. 50, 460, 2001; U. A. Shinde et al., J Cell MoI Med., 7,
322, 2003; U. A. Shindea et al., J Trace Elem Med Biol., 18, 23, 2004].
In conclusion, the effect of timosaponin A-III in lowering the blood glucose
level, which N. Nakashima et al. reported [N. Nakashima et al., J. Nat. Prod, vol 56,
345, 1994], is applicable only to type 1 diabetes mellitus model, which is not related
to the activity of lowering the blood glucose level in type 2 diabetes mellitus as
claimed herein. Moreover, N. Nakashima et al. only disclosed the comparative
activity in lowering the blood glucose level, and did not describe the absolute effect
in lowering the blood glucose level at all. Hence, N. Nakachima et al. failed to
suggest that timosaponin A-III is superior in lowering the blood glucose level in
type 2 diabetes mellitus model, based on the fact that timosaponin A-III has weaker
activity than prototimosaponin A-III or pseudotimosaponin A-III7 which is claimed
herein.
Thus, the present invention aims to provide a novel use of timosaponin
A-III in preventing or treating type 2 diabetes mellitus.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to a composition for the prevention or
treatment of type 2 diabetes mellitus, which comprises timosaponin A-III as an
active ingredient.
Moreover, the present invention relates to a health food comprising
timosaponin A-III as an active ingredient, which is effective for type 2 diabetes
mellitus.
Hereunder is provided a detailed description of the present invention.
The present invention is supported by the findings that timosaponin A-III is
superior in preventing or treating type 2 diabetes mellitus while is poor in
preventing or treating type 1 diabetes mellitus, in contrary to what has been known.
In the present invention, timosaponin A-III
(3-O-β-D-glucopyranosyl-(l→2)-β~D-galactopyranosyl sarsasapogenin) of formula
(1) was separated from Anemarrhena asphodeloides.
The process for separating timosaponin A-III from Anemarrhena asphodeloides
Bunge rhizome (Zhi Mu) comprises:
(a) obtaining an extract of Anemarrhena asphodeloides Bunge rhizome (referred to as
'Zhi Mu' hereinafter) in alcoholic aqueous solution and recovering the extract
with third distilled water;
(b) causing a layer separation of the recovered extract with the same amount of
hexane and removing the upper layer;
(c) washing the lower aqueous layer with the same amount of methylene chloride,
causing a layer separation with the same amount of ethyl acetate, and separating
ethyl acetate layer; and
(d) performing fractionation of the separated ethyl acetate layer with silica gel
column chromatography, and separating and obtaining timosaponin by means of
recrystallization with dioxane aqueous solution.
The present inventors ascertained that timosaponin A-III is far superior in
preventing or treating type 2 diabetes mellitus while is poor in preventing or
treating type 1 diabetes mellitus, in contrary to what has been known.
Thus, the present invention relates to a composition for the prevention or
treatment of type 2 diabetes mellitus comprising timosaponin A-III as an active
ingredient.
The composition herein, when subject to clinical test, may be administered
orally or parenterally, e.g. by intravenous, subcutaneous, peritoneal and local
administration, and may be used in the form of medicine or health food.
The composition herein may be formulated into tablets, pills, an emulsion
or a liquid dosage form, aerosols, troches, logenge, aqueous or oily suspension,
preparation, powders, granules, emulsion, hard or soft capsule, syrup or exixirs.
Tablet or capsule formulation may comprise binding agents such as lactose,
saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients
such as dicalcium phosphate; disintegrants such as corn starch or sweet potato
starch; lubricants such as magnesium stearate, calcium stearate, sodium
stearylfumarate or polyethylene glycol wax. Capsule formulation may further
comprise liquid carrier. Moreover, the composition herein may be administered
parenterally such as by subcutaneous, intravenous, intramuscular or pectoral
injection. Pareteral preparation may be manufactured by mixing the composition
herein with stabilizing agent or buffering agent in water, followed by formulation
into a single dosage form of ampule or vial.
Suitable examples of carriers, excipients and diluents are aluminum salt,
phenoxyethyl alcohol, water, physiological saline solution, lactose, dextrose, sorbitol,
mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose,
polyvinyl pyrollidone, methyl hydroxybenzoate, propyl hydroxybenzoate, talc,
magnesium stearate and mineral oil.
Moreover, any formulation of the composition herein may further comprise
fillers, anti-aggregants, lubricant, wetting agent, spice, suspending agent or
antiseptic.
Meanwhile, appropriate dosage level of the active ingredient herein may be
determined by considering various informations such as absorption level of the
active ingredient, inactivation rate, excretion rate or age, sex, physical conditions,
etc., of a patient. In a preferred embodiment, the dosage level for an adult is 0.1-15
g per day.
The composition herein may be prepared into food or medicine, and be
taken once or twice a day, according to the aforementioned daily dosage
As used herein, 'a health food' refers to a food in the form capsule, powder
or suspension, which is prepared by adding the active ingredient herein in various
food such as drinks, tea, spice, gums, snacks, thus providing a desired effect without
any side effect even after taking for a long period of time, unlike medicine.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 shows a destruction process of beta cells by alloxan and
streptozotocin.
Figure 2 is a graph showing an effect of lowering blood glucose level of Zhi
Mu ethyl acetate fraction (AA-EA) and its sub-fractions (EA-I-EA-V) in db/db
mouse model.
Figure 3 is a graph showing an effect of the lowering blood glucose level of
timosaponin A-III in db/db mouse model.
Figure 4 is a graph showing an effect of the lowering blood glucose level of
timosaponin A-III in KK-Ay mouse model.
Figure 5 is a graph showing an effect of the lowering blood glucose level of
timosaponin A-III in streptozotocin-induced diabetic rat model.
EXAMPLES
The present invention is described more specifically by the following
Examples. Examples herein are meant only to illustrate the present invention, but
in no way to limit the claimed invention.
Preparatory Example 1: Preparation of active EA fraction from Zhi Mu
3 kg of Zhi Mu was immersed in 20 L of 50% ethanol for 4 hours two times.
This was performed at 80 0C with stirring for effective extraction. After 4 hours,
solids were allowed to precipitate, and the final floating material was removed with
a funnel and absorbent cotton. Filtrates were distilled with a rotating evaporator,
and the extracts obtained therefrom were weighed. 100 g of extracts were
recovered in 500 mL of third distilled water, which was repeated. The obtained
extracts were admixed with the same amount of n-hexane (Jin chemicals
pharmaceutical Co. Ltd., Korea), and stirred in a separation funnel. After 24 hours,
the upper hexane layer was removed, and this process was repeated two or three
times.
The remaining aqueous layer was washed with the same amount of
methylene chloride (Jin chemicals pharmaceutical Co. Ltd., Korea, referred to as
"MC" hereinafter) three or four times in the same process as above. The remaining
aqueous layer was admixed with the same amount of ethyl acetate (Jin chemicals
pharmaceutical Co. Ltd., Korea, referred to as "EA" hereinafter), and was placed in a
separation funnel. After 24 hours, the upper EA layer was removed. The desired
Zhi Mu EA fraction (AA-EA) was obtained by fractionation two or three times with
EA and the concentration at reduced pressure. It was pulverized and stored at
-20 0C for use.
Preparatory Example 2: Subfractionation of Zhi Mu EA fraction
290 g of Zhi Mu EA fraction (AA-EA) was subject to consecutive
fractionation with silica gel column chromatography (170-230 mesh, 3 kg). Five
different fractions were obtained by using 15 L of the following solvents, EA (15 L),
EA:MeOH=20:l (20 L), EA:MeOH:Water = 20:2:0.1 (20 L), EA:MeOH:Water =
10:2:0.2 (20 L), respectively. The fractions are referred to as EA-I, EA- II , EA-III,
EA-IV and EA-V in this order. Each fraction was concentrated at reduced pressure,
pulverized and stored at -20 0C for use.
Preparatory Example 3: Separation of active ingredients and structure
characterization
40 mL of 70% dioxane aqueous solution was added in 1 g of Zhi Mu EA
sub-fraction (EA-V), and totally dissolved by using water bath and sonication. The
dissolved EA-V fraction was placed at room temperature for 24 hours, thus
providing white needle-shaped material. The material prepared by filtering the
white needle-shaped material is referred to as compound I (Rf 0.38, 90% MeOH,
charring after 5% ethanolic H2SO4 spray, RP-18 F254s, MERCK ).
The separated compound I was subject to the structure characterization
with HL-NMR, C13-NMR and ESI-MS, and was ascertained to be timosaponin A-III [S.
Saito et al, Chem. Pharm. Bull. 2342. 1994] as previously reported. Furthermore,
standardized products were commercially purchased (SKF 7862, WAKO pure
chemical industries. LTD.), and ascertained to be the same material with the
obtained material by using HPLC.
Example 1: Effect of lowering the blood glucose level in db/db mouse
8-9 week old db/db male mice (C57BL/Ks-db/db) were used in the
experiments. C57BL/Ks-db/db mouse, which was developed by Jackson
Laboratory in the U.S., begins to be obese from 4-5 weeks after birth and is subject to
rise in the blood glucose level as the deficiency of leptin receptor in hypothalamus
induces obesity-related diabetes through abnormal signal transferring system.
Because of this nature, it is used as a representative type 2 diabetes animal model for
analyzing and finding the mechanism of obesity, diabetes and their complications or
for screening medicines for lowering the blood glucose level [D. A. Rees et al.,
Diabetic Medicine, 22, 359, 2005; G. H. Lee et al., Nature, 379, 632, 1996; S. C. Chua et
al., Science, 271, 994, 1996; J. K. Naggert et al., Mamm Genome., 6, 131, 1995].
An experimental group was administered with test medicine, and a
negative control group and a positive control group were subject to the
intraperitoneal or oral administration of 0.5% carboxymethyl cellulose (CMC)
solution and rosiglitazone dissolved in 0.5% carboxymethyl cellulose (CMC)
solution, respectively, every afternoon. The blood glucose level was measured
right before the administration at a scheduled time in the afternoon at an interval
of 3-4 days by incising tail vein. The mice and feed were weighed right before the
administration at an interval of 2 days. After administration, weighing and
measurement for 10 days, serum was separated from the blood taken and various
biochemical parameters were measured for analyzing the lipids and the function of
liver or kidney.
Figure 2 shows the effect of lowering the blood glucose level after the
administration of 300 mg/kg of Zhi Mu EA fraction(AA-EA) prepared in
Preparatory Example 1 and 300 mg/kg of sub-fraction(EA-I, EA- II , EA-III, EA-IV,
EA-V) prepared in Preparatory Example 2.
As a result, EA-V was ascertained to show superior activity compared to
Zhi Mu EA fraction(AA-EA). Moreover, as the activity was equivalent to the
positive control, this fraction was subject to the screening of active ingredient.
Figure 3 shows an effect of lowering the blood glucose level after the
administration of timosaponin A-III prepared in Preparatory Example 3 in a dosage
of 100 mg/kg, 200 mg/kg and 3000 mg/kg, respectively. This showed an effect
equivalent to the positive control at a dosage of 200 mg/kg, and even superior effect
of lowering the blood glucose level at a dosage of 300 mg/kg, which ascertained that
timosaponin A-III is a major active ingredient in EA-V fraction.
Example 2: Effect of timosaponin A-III in lowering the blood glucose level in
KK-Ay mouse
9-10 weeek old KK-Ay male mice (C57BL/Ks) were used in the experiments.
KK-Ay mouse is prepared by introducing obesity genes into KK mouse, which was
originated from Kaskabe Saitamihyun Iapan and developed by Takeda
Pharmaceutical Industry Corporation for research on genetics. It is used as type 2
diabetes mellitus model showing obesity at early stage and hyperinsulinemia due to
high blood glucose level [M. Okazaki et al., Exp Anim., 51, 191, 2002; J. Suto et al.,
Eur J Endocrinol., 139, 654, 1998].
A negative control group and an experimental group were subject to the
oral administration of 0.5% carboxymethyl cellulose (CMC) solution and test
medicine dissolved in 0.5% carboxymethyl cellulose (CMC) solution, respectively,
every afternoon. The blood glucose level was measured right before the
administration at a scheduled time in the afternoon at an interval of 3-4 days by
incising tail vein. The mice and feed were weighed right before the administration
at an interval of 2 days. After administration, weighing and measurement for 8
days, serum was separated from the blood taken and various biochemical
parameters were measured for analyzing the lipids and the function of liver or
kidney.
Figure 4 shows an effect of lowering the blood glucose level after the
administration of timosaponin A-III prepared in Preparatory Example 3 in a dosage
of 100 mg/kg and 200 mg/kg, respectively. Strong effect in lowering the blood
glucose level was ascertained at a dosage of 200 mg/kg.
Example 3: Effect of timosaponin A-III in lowering the blood glucose level in
streptozotocin-induced diabetic rat
7-weeek-old wistar male mice (weight: 180-200 g) were intraperitoneal
administered once with streptozotocin (STZ: 40 mg/kg) dissolved in 50 mM citrate
buffer (pH 4.5) to induce diabetes. 5 days after the STZ administration, rats that
showed stable blood glucose level of above 400 mg/dl were selected and used in
experiments.
An experimental group was administered with test medicine, and a
negative control group and a positive control group were subject to the oral
administration of 0.5% carboxymethyl cellulose (CMC) solution and glibeclamide
dissolved in 0.5% carboxymethyl cellulose (CMC) solution, respectively, every
afternoon for 8 days. The blood glucose level was measured right before the
administration at a scheduled time in the afternoon at an interval of 3-4 days by
incising tail vein. The mice and feed were weighed right before the administration
at an interval of 2 days.
Figure 5 shows an effect of lowering the blood glucose level in the
streptozotocin-induced diabetic rats, i.e. type 1 diabetes model of timosaponin A-III,
prepared in Preparatory Example 3. Contrary to the report of N. Nakashima et al.
[N. Nakashima et al., J. Nat. Prod, vol 56, 345, 1994], timosaponin A-III (150 mg/kg)
was not ascertained to have statistically meaningful effect of lowering the blood
glucose level.
Based on the aforementioned results in Examples 1-3, the present inventors
ascertained that timosaponin A-III has a strong and selective effect of lowering the
blood glucose level in type 2 diabetes mellitus.
Example 4: Toxicity test of timosaponin A-III in ICR mouse
For toxicity study in case of repeatd dosage of timosaponin A-III (1 g),
16-hour-fasted 4-5 week old ICR mice (5 mice each group) were selected as test
subjects. 1 g of timosaponin A-III dissolved in 0.5% carboxymethyl cellulose
(CMC) was orally administered for 5 days. There was neither dead subject nor
abnormal findings such as damages to internal organs.
Formulation Example 1: Preparation of powders and capsules
100 mg of timosaponin A-III was admixed with 14.8 mg of lactose, 3 mg of
crystalline cellulose and 0.2 mg of magnesium stearate. The mixture was filled in
No. 5 gelatin capsule by using an appropriate device.
Formulation Example 2: Preparation of ointment
Ointment was prepared as set forth below by using timosaponin A-III:
Active ingredient 5 g, cetyl palmitate 20 g, cetanol 40 g, stearyl alcohol 40 g,
isopropyl myristate 80 g, sorbitan monostearate 20 g, polysorbate 60 g, propyl
p-hydroxybenzoate 1 g, methyl p-hydroxybenzoate 1 g and appropriate amount of
distilled water and phosphoric acid
Formulation Example 3: Preparation of injection
Injection was prepared as set forth below by using timosaponin A-III:
Active ingredient 100 mg, mannitol 180 mg, dibasic sodium phosphate 25
mg, distilled water for injection 2974 mg
Formulation Example 4: Preparation of health food
As set forth below, health food was prepared by using 0.3 g of timosaponin
A-III 0.3 g, powdered vitamin E, ferrous lactate, zinc oxide, nicotinamide, vitamin A,
vitamin Bl and vitamin B2 based on a daily dosage. The contents of the health food
are as follows (based on a daily dosage):
Active ingredient 300 mg
Ginseng extracts 100 mg
Green tea extracts 100 mg
Vitamin C 100 mg
Powdered vitamin E 120 mg
Ferrous lactate 2 mg
Zinc oxide 2 mg
Nicotinamide 20 mg
Vitamin A 5 mg
Vitamin Bl 2 mg
Vitamin B2 2 mg
Corn starch 200 mg
Magnesium stearate 20 mg
As described above, the present invention is very useful in medicine or
health food for preventing or treating type 2 diabetes mellitus in that timosaponin
A-III is superior in preventing or treating type 2 diabetes mellitus while is poor in
preventing or treating type 1 diabetes mellitus, in contrary to what has been known.
Claims
1. A composition for preventing or treating type 2 diabetes mellitus, the
composition comprising a compound of formula (1) as an active ingredient.
2. The composition of claim 1 in an oral or parenteral formulation.
3. A health food comprising a compound of formula (1) as an active ingredient,
which is effective for type 2 diabetes mellitus.
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| KR10-2005-0077988 | 2005-08-24 | ||
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| CN110025717B (en) * | 2019-05-20 | 2022-02-08 | 上海中医药大学 | Application of timosaponin enzymatic hydrolysate in preparation of medicines for inhibiting skin superficial fungi |
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| KR20040063290A (en) * | 2003-01-06 | 2004-07-14 | 에스케이케미칼주식회사 | Preparation method of Anemarrhena asphodeloides Bunge extracts and pharmaceutical composition for diabetes therapeutics using thereof |
| KR20050071789A (en) * | 2004-01-02 | 2005-07-08 | 한국 한의학 연구원 | Composition comprising timosaponin A-Ⅲ for promoting release of growth hormone |
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| KR20050071789A (en) * | 2004-01-02 | 2005-07-08 | 한국 한의학 연구원 | Composition comprising timosaponin A-Ⅲ for promoting release of growth hormone |
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