WO2007043796A1 - Composition comprising the fraction of salviae miltiorrhizae radix for treating or preventing cognitive dysfunction and use thereof - Google Patents
Composition comprising the fraction of salviae miltiorrhizae radix for treating or preventing cognitive dysfunction and use thereof Download PDFInfo
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- WO2007043796A1 WO2007043796A1 PCT/KR2006/004078 KR2006004078W WO2007043796A1 WO 2007043796 A1 WO2007043796 A1 WO 2007043796A1 KR 2006004078 W KR2006004078 W KR 2006004078W WO 2007043796 A1 WO2007043796 A1 WO 2007043796A1
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- WIPO (PCT)
- Prior art keywords
- salviae miltiorrhizae
- bge
- diethyl ether
- cognitive function
- function disorder
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
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- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
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- 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
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Definitions
- compositions containing present composition may be prepared in any form, such as oral dosage form (powder, tablet, capsule, soft capsule, aqueous medicine, syrup, elixirs pill, powder, sachet, granule), or topical preparation (cream, ointment, lotion, gel, balm, patch, paste, spray solution, aerosol and the like), or injectable preparation (solution, suspension, emulsion).
- oral dosage form prowder, tablet, capsule, soft capsule, aqueous medicine, syrup, elixirs pill, powder, sachet, granule
- topical preparation cream, ointment, lotion, gel, balm, patch, paste, spray solution, aerosol and the like
- injectable preparation solution, suspension, emulsion
- the inventive composition may additionally comprise one or more than one of organic acid, such as citric acid, fumaric acid, adipic acid, lactic acid, malic acid; phosphate, such as phosphate, sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate; natural anti-oxidants, such as polyphenol, catechin, ⁇ - tocopherol, rosemary extract, vitamin C, green tea extract, licorice root extract, chitosan, tannic acid, phytic acid etc.
- organic acid such as citric acid, fumaric acid, adipic acid, lactic acid, malic acid
- phosphate such as phosphate, sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate
- natural anti-oxidants such as polyphenol, catechin, ⁇ - tocopherol, rosemary extract, vitamin C, green tea extract, licorice root extract, chitosan, tannic acid, phytic acid etc.
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Abstract
The present invention relates to a composition comprising diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE showing potent treating and preventing activity of cognitive function disorder by the mechanism of inhibiting beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid. Therefore it can be used as the therapeutics or health food for treating and preventing cognitive function disorder with safe.
Description
Description
COMPOSITION COMPRISING THE FRACTION OF SALVIAE
MILTIORRHIZAE RADIX FOR TREATING OR PREVENTING
COGNITIVE DYSFUNCTION AND USE THEREOF
Technical Field
[1] The present invention relates to a composition comprising the fraction of Salviae miltiorrhizae showing preventive and treating activity of cognitive dysfunction disease and the use thereof. Background Art
[2] CNS (Central Nervous System) consisting of brain and spinal cord which plays a main role in regulating life phenomenon is a essential organ governing all the human function through from sensory and (in)voluntary movement to thinking, memory, motion, language etc. Accordingly, a rapidly progressed apoptosis of neuronal cell caused by stroke, trauma etc as well as slowly progressed apoptosis such as degenerative disease occurring in CNS caused by senile dementia for example, Alzheimer disease or Parkinson disease etc result in irreversible functional disorder of neuronal network, which give rise to immortal failure of human function in the end. Among them, the patients suffering from Alzheimer disease, a representative senile dementia have been increased in proportion to both of extended life-span and modernized welfare facility. According to the public survey of Korea Institute for Health and Social Affair, the ratio of older people among Korean people exceeds 7% in 2000, reaches to 8.3% (3,970,000) and shall approach to 14.4% in 2019. Especially, the ratio of more than 65 years old patient suffering with senile dementia is presumed to 8.2% in Korea. In Western countries, about 10% among more than 65 years old and about 40-50% among 80 years old patient suffers with senile dementia. Since more than five million patients suffer with the disease, the medical expense caused thereby is presumed to hundred billion dollars in a year. There have been found that more than about two hundred thousand people are suffering from dementia in Korea. In America, it has been presumed the number of the patients be increased to two fold than the number of present patients in 2030 and fourteen million (more than 350%) in 2050.
[3] Since Alzheimer's disease initiated with cognitive function disorder is one of long- term degenerative diseases resulting in the breakdown of human nature, there have been tried to develop effective and preventive drugs till now, for example, acetylcholi- neesterase inhibitor such as Aricept® (Pfizer Co.), Exelon ®(Novartis Co.), Reiminyl ®(Yanssen Co.) or NMDA receptor antagonist such as Ebixa ®(Lundbeck Co.). However, the acetylcholineesterase inhibitor could just alleviate reduced cognitive
ability and could not satisfactorily treat etiological cause of the disease. Although the drug shows temporarily alleviated effect on only some of patients (about 40-50%), it could not maintain it's potency for a long time moreover it shows various adverse response such as hepato-toxicity, vomiting, anorexia in case of long-term treatment. Accordingly, there has been urgently needed to develop new therapeutic agent to prevent and treat the disease nowadays. Many multi-national pharmaceutical companies have been invested on the development in a large scale and in particular, focused in the development for beta- or gamma secretase inhibitor reducing the reproduced amount of beta-amyloid consisting of about 40 amino acids which has been presumed to be an etiological factor of Alzheimer disease. The basic study on the Alzheimer disease has been actively attempted in Korea however the development of Alzheimer treating agent has been merely progressed till now. Since there have been found in animal model test as well as clinical trial that the development of gamma secretase inhibitor is associated with considerable toxicity, it has been proved to be not recommendable whereas the development of beta secretase inhibitor is recommendable as proven by gene deficiency transformed animal model test. It is also regarded as a safe tool to focus on targeting the factors involved in beta amyloid aggregation. There has been reported that 'phenserine' developed by Axonyx Co. in USA has been progressed in Clinical trial 2 phase and it shows dual activities of inhibiting cholinesterase as well as beta amyloid aggregation (Greig et al., J. Med. Chem. 44 pp4062-4071, 2001; www,medicalnewstoday.com; www.alzforum.org/drg/drc)
[4] The development of vaccine using beta amyloid has been known as another possible method. There has been reported that the serial study on the vaccine progressed by Elan Co. failed because of its un-predictable adverse response such as encephalitis during clinical trial. However, it has been reported that beta amyloid vaccine could alleviate cognitive function in animal model test and improve the activity of brain cell as well as damaged brain neuronal cells, resulting in alleviating Alzheimer syndrome (Janus et al., Nature 408. pp979-982, 2000; Morgan et al., Nature 408. pp982-985, 2000)
[5]
[6] There have been reported that the extract of Salviae miltiorrhizae Bunge (Labiatae) can treat various disease, for example, abdominal pain, trauma, insomnia, skin rash etc and contains several diterpene quinine pigments belong to abietanoid compound, for example, tanshinone I, dihydrotanshinone I, tanshinone HA, tanshinone HB, methylene tanshinone etc. (Il-Moo Chang et al, Oriental Medicine and Medical Science Encyclopedia, Seoul National University, 2003).
[7] There have been also reported on the pharmacological activity of Salviae miltiorrhizae Bunge (Labiatae), for example, anti-oxidative activity (Yun-Hwa Kim,
Korean J. Soc. Food Cookery ScL, 19 p4, 2003), anti-cancer activity (Ok-Hee Kim, The Journal of Applied Pharmacology, 7, pp29-34, 1999), lowering effect on blood pressure (Korean Patent No. 10-0327894) etc. However, there has been not reported or disclosed about therapeutic effect on cognitive function disorder of the fraction of Salviae miltiorrhizae Bunge (Labiatae) in any of above cited literatures, the disclosures of which are incorporated herein by reference.
[8]
[9] To investigate an inhibiting effect of Salviae miltiorrhizae Bunge (Labiatae) on cognitive function disorder through already well-known screening tests, the inventors of the present invention have intensively screened various plants showing potent inhibiting activity of beta-amyloid aggregation and the toxicity caused by beta amyloid etc, and finally completed present invention by confirming that the specific fraction of Salviae miltiorrhizae Bunge (Labiatae) inhibits beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid resulting in stimulating the proliferation of neuronal cells.
[10] These and other objects of the present invention will become apparent from the detailed disclosure of the present invention provided hereinafter.
[H]
Disclosure of Invention
Technical Problem
[12] Accordingly, it is an object of the present invention to provide a pharmaceutical composition comprising diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE as an active ingredient in an effective amount to treat and prevent cognitive function disorder by the mechanism of inhibiting beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid. Technical Solution
[13] In accordance with the present invention to provide a pharmaceutical composition comprising diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE as an active ingredient and pharmaceutically acceptable carrier, diluents or adjuvants to treat and prevent cognitive function disorder.
[14] It is an object of the present invention to provide a method of treating or preventing cognitive function disorder in a mammal comprising administering to said mammal an effective amount of diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE, together with a pharmaceutically acceptable carrier thereof.
[15] It is an object of the present invention to provide a use of diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE for the manufacture of therapeutic agent for the treatment and prevention of cognitive function disorder by the mechanism of
inhibiting beta- amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid.
[16] The term "cognitive function disorder" disclosed herein includes Alzheimer type dementia, cerebrovascular type dementia, pick's disease, Creutzfeldt-jakob's disease, dementia caused by cephalic damage, Parkinson's disease, and so on, preferably, Parkinson's disease.
[17] The term "diethyl ether soluble extract of Salviae miltiorrhizae BGE" disclosed herein can be prepared by the steps consisting of: adding 0.1 to 0.2-fold volume of methanol to dried rhizoma of Salviae miltiorrhizae BGE; extracting with extraction method by the reflux extraction, or ultra-sonication extraction; subjecting the solution with filtering to obtain the supernatant to be concentrated with rotary evaporator, at the temperature ranging from 35 to 45 0C; drying to obtain dried crude extract powder of Salviae miltiorrhizae BGE at 1st step; Suspending said crude extract in distilled water and adding diethylether thereto; mixing and subjecting to fractionation with 3 to 6 times to obtain diethylether soluble fraction of Salviae miltiorrhizae BGE.
[18]
[19] In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising diethyl ether soluble fraction of Salviae miltiorrhizae prepared by above described preparation method as an active ingredient in an effective amount to treat and prevent cognitive function disorder by the mechanism of inhibiting beta- amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid.
[20] It is an object of the present invention to provide a method of treating or preventing cognitive function disorder in a mammal comprising administering to said mammal an effective amount of diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE prepared by above described preparation method, together with a pharmaceutically acceptable carrier thereof.
[21] It is an object of the present invention to provide a use of diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE prepared by above described preparation method for the manufacture of therapeutic agent for the treatment and prevention of cognitive function disorder by the mechanism of inhibiting beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid.
[22]
[23] The pharmaceutical composition of the present invention can contain about 0.01 ~
50 % by weight of the above extract based on the total weight of the composition.
[24]
[25] Through various screening test to determine inhibiting effect of diethyl ether fraction of Salviae miltiorrhizae Bunge (Labiatae) on cognitive function disorder, it
has confirmed that the diethyl ether fraction of Salviae miltiorrhizae Bunge (Labiatae) inhibits beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid resulting in stimulating the proliferation of neuronal cells.
[26]
[27] The inventive composition for treating and preventing cognitive function disorder may comprises above extracts as 0.01 ~ 50 % by weight based on the total weight of the composition.
[28]
[29] The inventive composition may additionally comprise conventional carrier, adjuvants or diluents in accordance with a using method well known in the art. It is preferable that said carrier is used as appropriate substance according to the usage and application method, but it is not limited. Appropriate diluents are listed in the written text of Remington's Pharmaceutical Science (Mack Publishing co, Easton PA).
[30]
[31] Hereinafter, the following formulation methods and excipients are merely exemplary and in no way limit the invention.
[32]
[33] The composition according to the present invention can be provided as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants or diluents, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starches, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. The formulations may additionally include fillers, anti-agglutinating agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a patient by employing any of the procedures well known in the art.
[34]
[35] For example, the compositions of the present invention can be dissolved in oils, propylene glycol or other solvents that are commonly used to produce an injection. Suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited to them. For topical administration, the extract of the present invention can be formulated in the form of ointments and creams.
[36]
[37] Pharmaceutical formulations containing present composition may be prepared in any form, such as oral dosage form (powder, tablet, capsule, soft capsule, aqueous
medicine, syrup, elixirs pill, powder, sachet, granule), or topical preparation (cream, ointment, lotion, gel, balm, patch, paste, spray solution, aerosol and the like), or injectable preparation (solution, suspension, emulsion).
[38]
[39] The composition of the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
[40]
[41] The desirable dose of the inventive extract or composition varies depending on the condition and the weight of the subject, severity, drug form, route and period of administration, and may be chosen by those skilled in the art. However, in order to obtain desirable effects, it is generally recommended to administer at the amount ranging 10 g/kg, preferably, 1 to 3 g/kg by weight/day of the inventive extract or compounds of the present invention. The dose may be administered in single or divided into several times per day. In terms of composition, the amount of inventive extract should be present between 0.01 to 50% by weight, preferably 0.5 to 40% by weight based on the total weight of the composition.
[42]
[43] The pharmaceutical composition of present invention can be administered to a subject animal such as mammals (rat, mouse, domestic animals or human) via various routes. All modes of administration are contemplated, for example, administration can be made orally, rectally or by intravenous, intramuscular, subcutaneous, intracutaneous, intrathecal, epidural or intracerebroventricular injection.
[44]
[45] It is another object of the present invention to provide a health food or food additives comprising a diethyl ether fraction of Salviae miltiorrhizae BGE, together with a sitologically acceptable additive for the prevention and improvement of cognitive function disorder.
[46] The health food of the present invention comprises above extracts as 0.01 to 80 %, preferably 1 to 50 % by weight based on the total weight of the composition.
[47]
[48] Above health food can be contained in health food, health beverage etc, and may be used as powder, granule, tablet, chewing tablet, capsule, beverage etc.
[49]
[50] Also, the present invention provide a composition of the health food beverage for the prevention and improvement of cognitive function disorder adding above described extract 0.01 to 80 % by weight, amino acids 0.001 to 5 % by weight, vitamins 0.001 to
2 % by weight, sugars 0.001 to 20 % by weight, organic acids 0.001 to 10 % by weight, sweetener and flavors of proper amount.
[51]
[52] To develop for health food, examples of addable food comprising above extracts of the present invention are various food, beverage, gum, vitamin complex, health improving food and the like, and can be used as power, granule, tablet, chewing tablet, capsule or beverage etc.
[53]
[54] Also, the extract of the present invention will be able to prevent and improve blood circulatory disease by way of adding to child and infant food, such as modified milk powder, modified milk powder for growth period, modified food for growth period.
[55]
[56] Above described composition therein can be added to food, additive or beverage, wherein, the amount of above described extract in food or beverage may generally range from about 0.1 to 80w/w %, preferably 1 to 50 w/w % of total weight of food for the health food composition and 1 to 30 g, preferably 3 to 10 g on the ratio of IOOD of the health beverage composition.
[57]
[58] Providing that the health beverage composition of present invention contains above described extract as an essential component in the indicated ratio, there is no particular limitation on the other liquid component, wherein the other component can be various deodorant or natural carbohydrate etc such as conventional beverage. Examples of aforementioned natural carbohydrate are monosaccharide such as glucose, fructose etc; disaccharide such as maltose, sucrose etc; conventional sugar such as dextrin, cy- clodextrin; and sugar alcohol such as xylitol, and erythritol etc. As the other deodorant than aforementioned ones, natural deodorant such as taumatin, stevia extract such as levaudioside A, glycyrrhizin et al., and synthetic deodorant such as saccharin, aspartam et al., may be useful favorably. The amount of above described natural carbohydrate is generally ranges from about 1 to 20 g, preferably 5 to 12 g in the ratio of 100 D of present beverage composition.
[59]
[60] The other components than aforementioned composition are various nutrients, a vitamin, a mineral or an electrolyte, synthetic flavoring agent, a coloring agent and improving agent in case of cheese chocolate et al., pectic acid and the salt thereof, alginic acid and the salt thereof, organic acid, protective colloidal adhesive, pH controlling agent, stabilizer, a preservative, glycerin, alcohol, carbonizing agent used in carbonate beverage et al. The other component than aforementioned ones may be fruit juice for preparing natural fruit juice, fruit juice beverage and vegetable beverage,
wherein the component can be used independently or in combination. The ratio of the components is not so important but is generally range from about 0 to 20 w/w % per 100 w/w % present composition. Examples of addable food comprising aforementioned extract therein are various food, beverage, gum, vitamin complex, health improving food and the like.
[61]
[62] The inventive composition may additionally comprise one or more than one of organic acid, such as citric acid, fumaric acid, adipic acid, lactic acid, malic acid; phosphate, such as phosphate, sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate; natural anti-oxidants, such as polyphenol, catechin, α- tocopherol, rosemary extract, vitamin C, green tea extract, licorice root extract, chitosan, tannic acid, phytic acid etc.
[63]
[64] The above fraction of Salviae miltiorrhizae BGE may be 20 to 90 % high concentrated liquid, power, or granule type.
[65]
[66] Similarly, the above extract of Salviae miltiorrhizae BGE can comprise additionally one or more than one of lactose, casein, dextrose, glucose, sucrose and sorbitol.
[67]
[68] Inventive extract of the present invention have no toxicity and adverse effect therefore; they can be used with safe.
[69]
[70] It will be apparent to those skilled in the art that various modifications and variations can be made in the compositions, use and preparations of the present invention without departing from the spirit or scope of the invention.
[71]
Advantageous Effects
[72] As described in the present invention, the diethyl ether soluble extract of Salviae miltiorrhizae Bunge (Labiatae) inhibits beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid resulting in stimulating the proliferation of neuronal cells, Therefore, it can be used as the therapeutics or health food for treating and preventing cognitive function disorder without adverse action.
[73]
Brief Description of the Drawings
[74] The above and other objects, features and other advantages of the present invention will more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which;
[75]
[76] Fig. 1 shows the inhibition effect of the extract of Salviae miltiorrhizae BGE on beta amyloid aggregation and the cyotoxicity caused by beta amyloid.
Best Mode for Carrying Out the Invention
[77] The present invention is more specifically explained by the following examples.
However, it should be understood that the present invention is not limited to these examples in any manner.
[78] The following Reference Example, Examples and Experimental Examples are intended to further illustrate the present invention without limiting its scope.
[79]
[80] Example 1. Preparation of the diethyl ether soluble extract of Salviae miltiorrhizae
[81]
[82] 1-1. Preparation of methanol soluble extract
[83] 15kg of dried of Sαlviαe miltiorrhizae BGE purchased from Kyung-dong Market located in Seoul was cut into small pieces, mixed with 2.5 L of methanol and subjected to reflux-extraction for 3 hours at three times. The residue is filtered to obtain the supernatant and the filtrate was dried with vaccum evaporator at 4O0C to obtain 3.4kg of methanol soluble extract.
[84]
[85] 1-2. Preparation of diethyl ether soluble extract
[86] 3.4 kg of methanol soluble extract was suspended in distilled water and diethylether solvent was added thereto. The suspension was subject to fractionation at 3 to 4 times to obtain water soluble extract and diethyl ether soluble extract. The diethylether soluble extract was concentrated and dried to obtain 300g of diethyl ether soluble extract of Salviae miltiorrhizae BGE
[87]
[88] Experimental Example 1. Effect on beta amyloid
[89] 1-1. Inhibition of beta amyloid aggregation
[90] Synthetic beta amyloid 1-42 (BACHEM) was dissolved in DMSO in order to 250 μM solution and diluted with PBS into 1/10 on fluorescent black plate to induce aggregation. By comparing with inhibition activity of the diethyl ether extract prepared in Example 1 on beta amyloid aggregation, the test sample showing more than 50% inhibition activity was chosen to use and added to react for 1 hour at room temperature. ThT(Thioflavin T) was diluted with 5OmM glycine buffer solution and the diluted solution was added to each well by 150 μl. The absorbance was determined by microplate reader (SAFIRE, TECAN) at 450 nm excitation wavelength/480 nm
emission wavelength and the inhibition activity of the test sample on beta amyloid aggregation was transformed into IC .
[91] It has confirmed that the diethyl ether soluble extract of Salviae miltiorrhizae BGE showed potent inhibitory effect on beta amyloid aggregation (IC = 0.8 μl/ml).
[92] 1-2. Inhibition of beta amyloid toxicity
[93] HT 22 mouse neuronal cell line was incubated in DMEM (Dulbecco's Modified
Eagle's Medium, Gibco-BRL) medium supplemented with 10% FBS (Fetal Bovine Serum, Hy clone) and 1% penicillin/streptomycin (Sigma Co.) Prior to test, HT22 cell was incubated on 96 well plates with a density of 5x10 cell/well and further incubated in serum free DMEM medium for 1 hour before the treatment of test sample. Various concentration of diethyl ether extract prepared in Example 1 used as a test sample was added thereto and incubated for 1 hour. Aggregated beta amyloid (US peptide) was treated thereto to the concentration of 25mM and incubated for 18 hours to induce cell necrosis. 5mg/ml of MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) solution was added each well with 15 μl/well and the well was incubated for 4 hours. Dissolving buffer solution (10% SDS, 50%dimethyl formamide, pH 4.7) was added to each well with 100 μl/well and reacted for overnight. 18 hours after the reaction, the absorbance of solution was determined by microplate reader (SAFIRE, TECAN) at 570 nm/630 nm wavelength (Gillardon, F. et al., Brain Research, 706(D ppl69-172, 1996).
[94] As can be shown in Fig. 1, the diethyl ether soluble extract of Salviae miltiorrhizae
BGE showed potent inhibitory effect on beta amyloid toxicity at 100 D/D.
[95]
[96] 1-3. Determination of cytotoxicity
[97] To determine the toxicity of test sample, HT22 cell was incubated in accordance with similar method disclosed in 1-2 and various concentration of the test sample prepared in Example 1 was added to the cell to incubate for 18 hours. MTT solution and Dissolving buffer solution was added to cell serially and the absorbance was determined by microplate reader (SAFIRE, TECAN) at 570 nm.
[98] As can be shown in Fig. 1, it has been confirmed that the diethyl ether soluble extract of Salviae miltiorrhizae BGE showed no cytotoxicity comparing with the survival rate of control group (100%).
[99]
[100] Hereinafter, the formulating methods and kinds of excipients will be described, but the present invention is not limited to them. The representative preparation examples were described as follows.
[101]
[102] Preparation of powder
[103] Dried powder of Example 1 50mg
[104] Lactose lOOmg
[105] Talc lOmg
[106] Powder preparation was prepared by mixing above components and filling sealed package.
[107]
[108] Preparation of tablet
[109] Dried powder of Example 1 50mg
[110] Corn Starch lOOmg
[111] Lactose lOOmg
[112] Magnesium Stearate 2mg
[113] Tablet preparation was prepared by mixing above components and entabletting.
[114] Preparation of capsule
[115] Dried powder of Example 1 50mg
[116] Corn starch lOOmg
[117] Lactose lOOmg
[118] Magnesium Stearate 2mg
[119] Tablet preparation was prepared by mixing above components and filling gelatin capsule by conventional gelatin preparation method.
[120]
[121] Preparation of injection
[122] Dried powder of Example 1 50mg
[123] Distilled water for injection optimum amount
[124] PH controller optimum amount
[125] Injection preparation was prepared by dissolving active component, controlling pH to about 7.5 and then filling all the components in 2ml ample and sterilizing by conventional injection preparation method.
[126]
[127] Preparation of liquid
[128] Dried powder of Example 1 0.1~80g
[129] Sugar 5~ 1Og
[130] Citric acid 0.05-0.3%
[131] Caramel 0.005-0.02%
[132] Vitamin C 0.1-1%
[133] Distilled water 79-94%
[134] CO2 gas 0.5-0.82%
[135] Liquid preparation was prepared by dissolving active component, filling all the components and sterilizing by conventional liquid preparation method.
[136]
[137] Preparation of health food
[138] Extract of Example 1 lOOOmg
[139] Vitamin mixture optimum amount
[140] Vitamin A acetate 70mg
[141] Vitamin E l.Omg
[142] Vitamin B 0.13mg
[143] Vitamin B 0.15mg
[144] Vitamin B6 0.5mg
[145] Vitamin B 12 0.2mg
[146] Vitamin C lOmg
[147] Biotin lOmg
[148] Amide nicotinic acid 1.7mg
[149] Folic acid 50mg
[150] Calcium pantothenic acid 0.5mg
[151] Mineral mixture optimum amount
[152] Ferrous sulfate 1.75mg
[153] Zinc oxide 0.82mg
[154] Magnesium carbonate 25.3mg
[155] Monopotassium phosphate 15mg
[156] Dicalcium phosphate 55mg
[157] Potassium citrate 90mg
[158] Calcium carbonate lOOmg
[159] Magnesium chloride 24.8mg
[160] The above-mentioned vitamin and mineral mixture may be varied in may ways.
Such variations are not to be regarded as a departure from the spirit and scope of the present invention. [161]
[162] Preparation of health beverage
[163] Extract of Example 1 lOOOmg
[164] Citric acid lOOOmg
[165] Oligosaccharide lOOg
[166] Apricot concentration 2g
[167] Taurine Ig
[168] Distilled water 900D [169]
[170] Health beverage preparation was prepared by dissolving active component, mixing, stirred at 850C for 1 hour, filtered and then filling all the components in IOOOD ample
and sterilizing by conventional health beverage preparation method.
[171]
[172] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. Industrial Applicability
[173] As described in the present invention, the diethyl ether soluble extract of Salviae miltiorrhizae Bunge (Labiatae) inhibits beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid resulting in stimulating the proliferation of neuronal cells, Therefore, it can be used as the therapeutics or health food for treating and preventing cognitive function disorder without adverse action.
[174]
Claims
[1] A pharmaceutical composition comprising diethyl ether soluble fraction of
Salviae miltiorrhizae Bunge BGE as an active ingredient in an effective amount to treat and prevent cognitive function disorder by the mechanism of inhibiting beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid.
[2] The pharmaceutical composition according to claim 1 wherein said cognitive function disorder is selected from Alzheimer type dementia, cerebrovascular type dementia, pick's disease, Creutzfeldt-jakob's disease, dementia caused by cephalic damage or Parkinson's disease.
[3] The pharmaceutical composition according to claim 2 wherein said diethyl ether soluble extract of Salviae miltiorrhizae BGE is prepared by the steps consisting of: adding 0.1 to 0.2-fold volume of methanol to dried rhizoma of Salviae miltiorrhizae BGE; extracting with extraction method by the reflux extraction, or ultra- sonication extraction; subjecting the solution with filtering to obtain the supernatant to be concentrated with rotary evaporator, at the temperature ranging from 35 to 45 0C; drying to obtain dried crude extract powder of Salviae miltiorrhizae BGE at 1st step; Suspending said crude extract in distilled water and adding diethylether thereto; mixing and subjecting to fractionation with 3 to 6 times to obtain diethylether soluble fraction of Salviae miltiorrhizae BGE.
[4] A method of treating or preventing cognitive function disorder in a mammal comprising administering to said mammal an effective amount of diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE, together with a pharmaceutically acceptable carrier thereof.
[5] A use of diethyl ether soluble fraction of Salviae miltiorrhizae Bunge BGE for the manufacture of therapeutic agent for the treatment and prevention of cognitive function disorder by the mechanism of inhibiting beta-amyloid aggregation as well as the toxicity and cell apoptosis caused by beta amyloid.
[6] A health food comprising diethyl ether soluble fraction of Salviae miltiorrhizae
Bunge BGE, together with a sitologically acceptable additive for the prevention and improvement of cognitive function disorder.
[7] The health food according to claim 6 wherein said health food is provided as powder, granule, tablet, chewing tablet, capsule or beverage type.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2005-0095657 | 2005-10-11 | ||
| KR1020050095657A KR20070040209A (en) | 2005-10-11 | 2005-10-11 | Composition comprising the fraction of salviae miltiorrhizae radix for treating or preventing cognitive dysfunction |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007043796A1 true WO2007043796A1 (en) | 2007-04-19 |
Family
ID=37942993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2006/004078 WO2007043796A1 (en) | 2005-10-11 | 2006-10-11 | Composition comprising the fraction of salviae miltiorrhizae radix for treating or preventing cognitive dysfunction and use thereof |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20070040209A (en) |
| WO (1) | WO2007043796A1 (en) |
Cited By (6)
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| US8017168B2 (en) | 2006-11-02 | 2011-09-13 | The Coca-Cola Company | High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith |
| CN101658601B (en) * | 2008-08-25 | 2012-09-05 | 上海中医药大学 | Chinese medicinal preparation for treatment or adjuvant treatment of Parkinson's diseases |
| EP2411028A4 (en) * | 2009-03-27 | 2013-03-06 | Moleac Pte Ltd | Therapy for promoting cell growth |
| WO2012134194A3 (en) * | 2011-03-29 | 2013-03-21 | Viromed Co., Ltd. | Herbal compositions for treating neurological diseases and improving memory impairment |
| US9101160B2 (en) | 2005-11-23 | 2015-08-11 | The Coca-Cola Company | Condiments with high-potency sweetener |
| WO2021121528A1 (en) * | 2019-12-20 | 2021-06-24 | Clutch Cognition Aps | Nutraceutical composition for mental activity |
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| KR101729716B1 (en) | 2015-06-03 | 2017-04-24 | 원광대학교산학협력단 | A composition for prevent or treatmen of neurodegerative diseases |
| KR102371285B1 (en) * | 2018-05-10 | 2022-03-08 | 주식회사 헬릭스미스 | Herbal Composition For Treating Attention Deficit Hyperactivity Disorder |
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| US9101160B2 (en) | 2005-11-23 | 2015-08-11 | The Coca-Cola Company | Condiments with high-potency sweetener |
| US8017168B2 (en) | 2006-11-02 | 2011-09-13 | The Coca-Cola Company | High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith |
| CN101658601B (en) * | 2008-08-25 | 2012-09-05 | 上海中医药大学 | Chinese medicinal preparation for treatment or adjuvant treatment of Parkinson's diseases |
| EP2411028A4 (en) * | 2009-03-27 | 2013-03-06 | Moleac Pte Ltd | Therapy for promoting cell growth |
| US9289459B2 (en) | 2009-03-27 | 2016-03-22 | Moleac Pte. Ltd. | Therapy for promoting cell growth |
| US10188688B2 (en) | 2009-03-27 | 2019-01-29 | Moleac Pte. Ltd. | Therapy for promoting cell growth |
| WO2012134194A3 (en) * | 2011-03-29 | 2013-03-21 | Viromed Co., Ltd. | Herbal compositions for treating neurological diseases and improving memory impairment |
| KR20130130069A (en) * | 2011-03-29 | 2013-11-29 | 주식회사 바이로메드 | Herbal compositions for treating neurological diseases and improving memory impairment |
| JP2014510752A (en) * | 2011-03-29 | 2014-05-01 | バイロメッド カンパニー リミテッド | Herbal medicine composition for treatment of neurological disorders and improvement of memory loss |
| KR101601860B1 (en) * | 2011-03-29 | 2016-03-09 | 주식회사 바이로메드 | Herbal Compositions for Treating Neurological Diseases and Improving Memory Impairment |
| US10058583B2 (en) | 2011-03-29 | 2018-08-28 | Viromed Co., Ltd. | Herbal compositions for treating neurological diseases and improving memory impairment |
| WO2021121528A1 (en) * | 2019-12-20 | 2021-06-24 | Clutch Cognition Aps | Nutraceutical composition for mental activity |
Also Published As
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|---|---|
| KR20070040209A (en) | 2007-04-16 |
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