WO2010090423A2 - Composition comprising combined crude drug extract for preventing and treating hyperlipidemia and diabetic hyperlipidemia - Google Patents
Composition comprising combined crude drug extract for preventing and treating hyperlipidemia and diabetic hyperlipidemia Download PDFInfo
- Publication number
- WO2010090423A2 WO2010090423A2 PCT/KR2010/000613 KR2010000613W WO2010090423A2 WO 2010090423 A2 WO2010090423 A2 WO 2010090423A2 KR 2010000613 W KR2010000613 W KR 2010000613W WO 2010090423 A2 WO2010090423 A2 WO 2010090423A2
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- WIPO (PCT)
- Prior art keywords
- extract
- hyperlipidemia
- radicis
- cortex
- crude drug
- Prior art date
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- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 1
- 229950004514 torcetrapib Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
- A61K36/605—Morus (mulberry)
-
- 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
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
- A61K36/815—Lycium (desert-thorn)
-
- 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
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/894—Dioscoreaceae (Yam family)
- A61K36/8945—Dioscorea, e.g. yam, Chinese yam or water yam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- the present invention is related to a crude drug composition
- a crude drug composition comprising combined crude drug extract of Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma, and Lonocerae Flos for the prevention and treatment of hyperlipidemia and diabetic hyperlipidemia and the use thereof.
- Diabetes mellitus is a mammalian condition in which the amount of glucose in the blood plasma is abnormally high. Elevated glucose levels in some instances can lead to higher than normal amounts of particular hemoglobin, HbAIc. This condition can be life-threatening and high glucose levels in the blood plasma, hyperglycemia, can lead to a number of chronic diabetes syndromes, for example, atherosclerosis, microangiopathy, kidney disorders or failure, cardiac disease, diabetic retinopathy and other ocular disorders, including blindness.
- HbAIc hemoglobin
- Diabetes mellitus is known for two forms of the disease.
- Type II non-insulin dependent diabetes (NIDDM) or adult-onset, as opposed to juvenile diabetes or Type I
- NIDDM non-insulin dependent diabetes
- the pancreas often continues to secrete normal amounts of insulin.
- this insulin is ineffective in preventing the symptoms of diabetes which include cardiovascular risk factors such as hyperglycemia, impaired carbohydrate mechanism, particularly glucose metabolism, glycosuria, decreased insulin sensitivity, centralized obesity hypertriglyceridemia, low HDL levels, elevated blood pressure and various cardiovascular effects attending these risk factors.
- cardiovascular risk factors such as hyperglycemia, impaired carbohydrate mechanism, particularly glucose metabolism, glycosuria, decreased insulin sensitivity, centralized obesity hypertriglyceridemia, low HDL levels, elevated blood pressure and various cardiovascular effects attending these risk factors.
- Many of these cardiovascular risk factors are known to precede the onset of diabetes by as much as a decade.
- diabetic hyperlipemia increases the ratio of death by 2 or 3 folds comparing with the other diabetic complications, which forms 75% among the etiology of dead patients suffering from diabetes (malmberg K. et al., circulation, 102, pp.1014- 1019, 2000).
- the treatment of diabetic disease shall be performed to prevent and treat not only hyperglycemia but also diabetic complication, especially, hyerlipidemia.
- cholesterol synthesis inhibitors for example, HMG Co-A reductase inhibitor such as simvastatin, atrovastatin etc and lipoprotein lipase activator such as clofibrate, fenofibrate etc; sequestrant such as cholestyramine, colesevelam, PPAR agonist etc; and cholesterol absorption inhibitor such as ACAT inhibitor (Ezetimbe, avasimibe) or CEPT inhibitor (torcetrapib, JTT705).
- HMG Co-A reductase inhibitor such as simvastatin, atrovastatin etc and lipoprotein lipase activator such as clofibrate, fenofibrate etc
- sequestrant such as cholestyramine, colesevelam, PPAR agonist etc
- cholesterol absorption inhibitor such as ACAT inhibitor (Ezetimbe, avasimibe) or CEPT inhibitor (torcetrapib, JTT705).
- statin drug most frequently prescribed drug, shows several adverse response such as myalgia, hypotonia, gait disturbance, parethesia, muscle contracture etc (statin-related muscle toxicity, Clinical Pharmacology, 3(10), pp554-560, 2003).
- Mori Cortex Radicis a cortex radix of Morus alba, Morus lactifolia, Moras bombycis, Morus mongolica and the like belonged to Moraceae family has been reported to comprise adenine, betaine etc and to show anti-bacterial activity, antioxidant activity and anti-allergic activity (http ://hebmed.kfda. go.krffor. J. Pharmacogn., 29(D. ppl-7, 1998).
- Solanaceae family has been reported to comprise betaine, linoleic acid etc ( http ://hebmed.kfda. go.kr)
- Dioscoreae Rhizoma a rhizoma of Dioscorea batatas D, Dioscorea japonica Thunb and the like belonged to Juncaceae family, has been reported to comprise saponin, mucin, arginine, allantoin, amylase, choline etc and to treat diarrhea, fatigue, osteoporosis etc (http ://hebmed.kfda. go.kr.Kor. J. Oriental Preventive Medical Society, 1(1). pp55-66, 2003).
- Caprifoliaceae family has been reported to comprise acetylcholine, bata-carotene, alpha-terpineol, apigenin etc and to show anti-cancer activity, anti-bacterial activity and anti-allergic activity (http ://hebmed.kfda. go.kr.Kor. J. Pharmacogn., 29(1). pp22-27, 1998).
- the present inventors have endeavored to find the effective crude drag for- mulation for treating and preventing hyperlipidemia and diabetic hyperlipidemia and to study the pharmacological effect of the above mentioned combined crude drug extract and finally, the present inventors have found that the above-described combined crude drug extract is effective in treating and preventing hyperlipidemia and diabetic hyperlipidemia.
- the present invention provides a pharmaceutical composition comprising the extract of combined crude drug with Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma, and Lonocerae Flos for preventing and treating hyperlipidemia and diabetic hyperlipidemia.
- the present invention also provides pharmaceutical compositions comprising the above-mentioned extract as an active ingredient in an amount effective to preventing and treating hyperlipidemia and diabetic hyperlipidemia, together with a pharmaceutically acceptable carrier.
- the present invention also provides a method for treating hyperlipidemia and diabetic hyperlipidemia in a mammal comprising administering to said mammal an effective amount of above-mentioned extract, together with a pharmaceutically acceptable carrier thereof.
- the present invention also provides a use of above described extract for the preparation of for manufacture of medicament employed for treating or preventing hyperlipidemia and diabetic hyperlipidemia in human or mammal.
- the present invention also provides a health functional food comprising above extract for the prevention or improvement of hyperlipidemia and diabetic hyperlipidemia as an active ingredient in an amount effective to prevent or improve the disease, together with a sitologically acceptable additive.
- a pharmaceutical composition comprising an extract of combined crude drug consisting of Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma, as an active ingredient in an amount effective to prevent and treat hyperlipidemia and diabetic hyperlipidemia, together with a pharmaceutically acceptable carrier.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising an extract of combined crude drug additionally comprising the extract of Lonicerae Flos, beside the above-mentioned combined herbs for preventing and treating hyper- lipidemia and diabetic hyperlipidemia.
- extract comprise the extract of combined crude drug, i.e., Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma with the mixed ratio based on the dried weight of each herb (w/w) ranging from 1: 0.1-10: 0.1-10, preferably, 1: 0.1-5: 0.1-5, more preferably, 1: 1-2: 1-2 in the present invention.
- the extract disclosed herein comprise the extract of combined crude drug i.e., Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma and Lonicerae Flos with the mixed ratio based on the dried weight of each herb (w/w) ranging from 1: 0.1-10: 0.1-10: 0.1-10, preferably, 1: 0.1-5: 0.1-5: 0.1-5, more preferably, 1: 1-2: 1-2: 1-2, in the present invention.
- combined crude drug i.e., Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma and Lonicerae Flos with the mixed ratio based on the dried weight of each herb (w/w) ranging from 1: 0.1-10: 0.1-10: 0.1-10, preferably, 1: 0.1-5: 0.1-5: 0.1-5, more preferably, 1: 1-2: 1-2: 1-2, in the present invention.
- the herbs which can be used in the present invention, include the same genus plants which would be apparent to those skilled in the art to be used for identical or similar purpose and can be substituted for the prevention and treatment of the diseases.
- the term “Mori Cortex Radicis” disclosed herein comprises the cortex radix of Morus alba, Morus lactifolia, Morus bombycis, Morus mongolica and the like belongs to Moraceae family;
- the term “Licii radicis Cortex” disclosed herein comprises the cortex radix of Lycium chinensis and the like belonged to Solanaceae family;
- the term “Dioscoreae Rhizoma, " disclosed herein comprises the rhizoma of Dioscorea batatas D, Dioscorea japonica Thunb and the like belonged to Juncaceae family;
- composition of the present invention is used in the form of pulverized form thereof, extracted form therefrom or dried extract form thereof.
- the above extract from the above-described mentioned crude drug can be obtained by extracting the combined herb with distilled water, lower alcohols such as methanol, ethanol and the like, or the mixtures thereof, preferably, water, ethanol and the mixture thereof.
- the pharmaceutical composition for treating the purposed diseases could contain about 0.01 to 95 w/w%, preferably 0.5 to 80 w/w% of the above herb composition of present invention based on the total weight of the composition.
- An inventive herb composition may be prepared in accordance with the following preferred embodiment.
- the inventive extract can be prepared by following procedure;
- the present invention also provide a method for preparing the inventive extract comprising the steps of; mixing dried Licii Radicis Cortex, or Dioscoreae Rhizoma with 1 to 20-fold, preferably, 10 to 15-fold volume of distilled water, alcohols such as methanol, ethanol and the like, or the mixtures thereof, preferably, distilled water, ethanol or the mixture thereof, more preferably, 60-90% ethanol respectively at 1 st step; extracting each solution with the extraction method by the extraction with hot water, cold water, reflux extraction, or ultra- sonication extraction, preferably, reflux extraction at the temperature ranging from 5O 0 C-IOO 0 C, preferably, 85°C ⁇ 95°C, for the period ranging from 1 to 24 hours, preferably, 2 to 5 hours at 2 nd step; repeating the above-described extraction process to collect each filtrate with filtration, concentrating at the temperature ranging from 90°C ⁇ l 1O 0 C, and drying to obtain respective dried extract of Lici
- It is still another object of the present invention to provide a pharmaceutical composition comprising the crude drug extract of the above-mentioned crude drug obtained by the above described process as an active ingredient for preventing and treating hy- perlipidemia and diabetic hyperlipidemia.
- the inventive composition of the present invention prepared by above-described process significantly decreases blood glucose, cholesterol, and triglyceride in strep- tozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat as well as type-II diabetic hyperlipidemia animal model using by high fat feeding KK/ Ay rat.
- the extract had no apparent effect on mortality, clinical signs, body weight changes, and gross findings at necropsy.
- composition for treating purposed diseases could contain about
- the inventive composition may additionally comprise conventional carrier, adjuvants or diluents in accordance with a using method. 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).
- the crude drug 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.
- pharmaceutically acceptable carriers e.g., lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starches, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, poly
- 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.
- compositions of the present invention can be dissolved in oils, propylene glycol or other solvents which 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.
- the compounds of the present invention can be formulated in the form of ointments and creams.
- compositions containing crude drug 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), suppository, or sterile injectable preparation (solution, suspension, emulsion).
- the crude drug 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.
- the desirable dose of the inventive 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 0.01-lOg/kg, preferably, 1 to 5g/kg by weight/day of the inventive composition of the present invention.
- the dose may be administered in a single or multiple doses per day.
- the crude drug composition should be present between 0.01 to 80% by weight, preferably 0.5 to 50% by weight based on the total weight of the composition.
- 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.
- a health functional food comprising the above extract for the prevention or improvement of hy- perlipidemia and diabetic hyperlipidemia as an active ingredient in an amount effective to prevent or improve the disease, together with a sitologically acceptable additive.
- inventive health functional food is used in the form of pulverized form thereof, extracted form therefrom or dried extract form thereof.
- the health functional food composition for preventing and improving purposed diseases could contain about 0.01 to 95 w/w%, preferably 0.5 to 80 w/w% of the above extract of present invention based on the total weight of the composition.
- the above-described crude drug composition therein can be added to food, additive or beverage for the prevention and improvement of purposed diseases.
- the amount of above described crude drug composition in food or beverage may generally range from about 0.1 to 15 w/w %, preferably 1 to 10 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 10Om ⁇ of the health beverage composition.
- the health beverage composition of present invention contains above described crude drug composition as an essential component in the indicated ratio
- the other component can be various deodorant or natural carbohydrate etc such as conventional beverage.
- natural carbohydrate are monosaccharide such as glucose, fructose etc; disaccharide such as maltose, sucrose etc; conventional sugar such as dextrin, cyclodextrin; and sugar alcohol such as xylitol, and erythritol etc.
- natural deodorant such as taumatin, stevia extract such as levaudioside A, glycyrrhizin et al., and synthetic deodorant such as saccharin, aspartam et al.
- 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 10Om ⁇ of present beverage composition.
- 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 % in the present composition.
- the combined herb composition shows potent reducing effect on the blood glucose, cholesterol, and triglyceride in type-II diabetic hyperlipidemia animal model.
- the inventive compositions according to the present invention are useful in the prevention and treatment of hyperlipidemia and diabetic hyperlipidemia.
- FIG. 1 shows the effect of each extract of MC, LR, DR or LF on blood cholesterol level in streptozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat
- Fig. 2 shows the effect of each extract of MC, LR, DR or LF on blood glucose level in streptozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat
- Fig. 1 shows the effect of each extract of MC, LR, DR or LF on blood glucose level in streptozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat
- Fig. 2 shows the effect of each extract of MC, LR, DR or LF on blood glucose level in streptozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat
- Fig. 1 shows the effect of each extract of MC, LR, DR or LF on blood glucose level in streptozotocin-induced
- FIG. 3 shows the effect of the inventive extracts (PAI-Nl and PAI-N2) on blood cholesterol level in streptozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat;
- Fig. 4 represents the effect of the inventive extracts (PAI-Nl and PAI-N2) on blood glucose level in streptozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat;
- Fig. 5 represents the effect of the inventive extracts (PAI-Nl and PAI-N2) on blood triglyceride level in streptozotocin-induced type-II diabetic — hyperlipidemia animal model using by SD rat.
- the SD rats prepared in 1-1 were divided into four groups which consists of 10 rats/group, i.e., normal group, negative control group, test sample group and positive control group treated with atrovastatin.
- the negative control group, test sample group and positive control group were allowed to freely access to high-fat feed (AIN-76A, Feedlab Co. Table 1) for 3 weeks and then streptozotocin was orally administrated into the rats in an amount of 20mg/kg, once a day for 3 days to induce type II diabetes.
- the diabetes -induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 350mg/dL ⁇ 10) and blood cholesterol (more than 550mg/dL ⁇ 10) are regarded as diabetes-induced rats.
- the group of test sample group was treated with the extract of MC, LR, DR or LF in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks.
- the negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day.
- the blood of rats was collected from rat caudal vena cava and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL- cholesterol and triglyceride was determined using by determining apparatus (BT2000+, SEAC Co.).
- the diabetes -induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 350mg/dL ⁇ 10) and blood cholesterol (more than 550mg/dL ⁇ 10) are regarded as diabetes-induced rats.
- the group of test sample group was treated with the inventive extract (PAI-Nl) in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks.
- the negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day. 4 weeks after the drug treatment, the blood of rats was collected from rat caudal vena cava and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL-cholesterol and triglyceride were determined using by determining apparatus (BT2000+, SEAC Co.).
- the diabetes -induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 350mg/dL+10) and blood cholesterol (more than 550mg/dL+10) are regarded as diabetes-induced rats.
- the group of test sample group was treated with the inventive extract (PAI-N2) in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks.
- the negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day. 4 weeks after the drug treatment, the blood of rats was collected from rat caudal vena cava and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL-cholesterol and triglyceride was determined using by determining apparatus (BT2000+, SEAC Co.).
- the KK/Ay rat rats prepared in 1-1 were divided into four groups which consists of 6 rats/group, i.e., normal group, negative control group, test sample group and positive control group treated with atrovastatin.
- the negative control group, test sample group and positive control group were allowed to freely access to high-fat feed (AIN-76A, Feedlab Co. Table 1) for 3 weeks and the diabetes-induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 381.2+5.7 mg/dL) determined by glucometer (Accu-chek. Roche) are regarded as diabetes-induced rats.
- the group of test sample group was treated with the inventive extracts (PAI-Nl and PAI-N2) in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks.
- the negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day.
- the blood of rats was collected from rat caudal vena cava through autopsy and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL-cholesterol and triglyceride was determined using by apparatus (BT2000+, SEAC Co.).
- inventive extract To examine the toxicity of the inventive extract, acute toxicity tests were performed on rats. [171] The 15 male and female SD rats were divided with 3 groups and three dosages of inventive extract, i.e., lg/kg, 2g/kg and 5g/kg were administered to each 5 rats for 14 days and water was treated to the control group. The symptom of toxicity was observed for 4 weeks such as the change of weight, the hematological analysis and histological test.
- Injection preparation was prepared by dissolving active component, controlling pH to about 7.5 and then filling all the components in 2m# ample and sterilizing by conventional injection preparation method.
- Powder preparation was prepared by mixing above components and filling sealed package.
- Tablet preparation was prepared by mixing above components and filling gelatin capsule by conventional gelatin preparation method. [205]
- Liquid preparation was prepared by dissolving active component, and then filling all the components in 100Om ⁇ ample and sterilizing by conventional liquid preparation method. [212]
- the combined herb composition shows potent reducing effect on the level of blood glucose, cholesterol, and triglyceride in type-II diabetic hyperlipidemia animal model.
- inventive compositions according to the present invention are useful in the prevention and treatment of hyperlipidemia and diabetic hyperlipidemia.
Abstract
The present invention is related to combined crude drug extract of Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma, and Lonocerae Flos for the prevention and treatment of hyperlipidemia and diabetic hyperlipidemia, the use thereof and the preparation method thereof.
Description
The present invention is related to a crude drug composition comprising combined crude drug extract of Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma, and Lonocerae Flos for the prevention and treatment of hyperlipidemia and diabetic hyperlipidemia and the use thereof.
Diabetes mellitus is a mammalian condition in which the amount of glucose in the blood plasma is abnormally high. Elevated glucose levels in some instances can lead to higher than normal amounts of particular hemoglobin, HbA1c. This condition can be life-threatening and high glucose levels in the blood plasma, hyperglycemia, can lead to a number of chronic diabetes syndromes, for example, atherosclerosis, microangiopathy, kidney disorders or failure, cardiac disease, diabetic retinopathy and other ocular disorders, including blindness.
Diabetes mellitus is known for two forms of the disease. In the form of this disease known as Type II, non-insulin dependent diabetes (NIDDM) or adult-onset, as opposed to juvenile diabetes or Type I, the pancreas often continues to secrete normal amounts of insulin. However, this insulin is ineffective in preventing the symptoms of diabetes which include cardiovascular risk factors such as hyperglycemia, impaired carbohydrate mechanism, particularly glucose metabolism, glycosuria, decreased insulin sensitivity, centralized obesity hypertriglyceridemia, low HDL levels, elevated blood pressure and various cardiovascular effects attending these risk factors. Many of these cardiovascular risk factors are known to precede the onset of diabetes by as much as a decade. These symptoms, if left untreated, often lead to severe diabetic complications, including premature atherosclerosis, retinopathy, nephropathy, and neuropathy. Especially, the cardiovascular diseases caused by diabetic hyperlipemia increase the ratio of death by 2 or 3 folds comparing with the other diabetic complications, which forms 75% among the etiology of dead patients suffering from diabetes (malmberg K. et al., circulation, 102, pp.1014-1019, 2000).
Accordingly, the treatment of diabetic disease shall be performed to prevent and treat not only hyperglycemia but also diabetic complication, especially, hyerlipidemia.
Current treating agents for hyperlipemia can be classified into three categories,i.e., cholesterol synthesis inhibitors, for example, HMG Co-A reductase inhibitor such as simvastatin, atrovastatin etc and lipoprotein lipase activator such as clofibrate, fenofibrate etc; sequestrant such as cholestyramine, colesevelam, PPAR agonist etc; and cholesterol absorption inhibitor such as ACAT inhibitor (Ezetimbe, avasimibe) or CEPT inhibitor (torcetrapib, JTT705). However, statin drug, most frequently prescribed drug, shows several adverse response such as myalgia, hypotonia, gait disturbance, parethesia, muscle contracture etc (statin-related muscle toxicity, Clinical Pharmacology, 3(10), pp554-560, 2003).
However, there has been still needed for developing effective and safe drugs showing less adverse action to treat and prevent lipidemia and diabetic hyperlipidemia till now.
Mori Cortex Radicis, a cortex radix of Morus alba, Morus lactifolia, Morus bombycis, Morus mongolica and the like belonged to Moraceae family has been reported to comprise adenine, betaine etc and to show anti-bacterial activity, anti-oxidant activity and anti-allergic activity (http://hebmed.kfda.go.kr Kor. J. Pharmacogn., 29(1), pp1-7, 1998).
Licii radicis Cortex, a cortex radix of Lycium chinensis and the like belonged to Solanaceae family has been reported to comprise betaine, linoleic acid etc (http://hebmed.kfda.go.kr)
Dioscoreae Rhizoma, a rhizoma of Dioscorea batatas D, Dioscorea japonica Thunb and the like belonged to Juncaceae family, has been reported to comprise saponin, mucin, arginine, allantoin, amylase, choline etc and to treat diarrhea, fatigue, osteoporosis etc (http://hebmed.kfda.go.kr Kor. J. Oriental Preventive Medical Society, 7(1), pp55-66, 2003).
Lonicerae Flos, a flower bud of Lonicera japonica Thunb and the like belonged to Caprifoliaceae family, has been reported to comprise acetylcholine, bata-carotene, alpha-terpineol, apigenin etc and to show anti-cancer activity, anti-bacterial activity and anti-allergic activity (http://hebmed.kfda.go.kr Kor. J. Pharmacogn., 29(1), pp22-27, 1998).
However, there has been not reported or disclosed about the therapeutic effect of the crude drug extract described above on hyperlipidemia and diabetic hyperlipidemia disease in any of above cited literatures, the disclosures of which are incorporated herein by reference.
Therefore, the present inventors have endeavored to find the effective crude drug formulation for treating and preventing hyperlipidemia and diabetic hyperlipidemia and to study the pharmacological effect of the above mentioned combined crude drug extract and finally, the present inventors have found that the above-described combined crude drug extract is effective in treating and preventing hyperlipidemia and diabetic hyperlipidemia.
According to one aspect, the present invention provides a pharmaceutical composition comprising the extract of combined crude drug with Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma, and Lonocerae Flos for preventing and treating hyperlipidemia and diabetic hyperlipidemia.
The present invention also provides pharmaceutical compositions comprising the above-mentioned extract as an active ingredient in an amount effective to preventing and treating hyperlipidemia and diabetic hyperlipidemia, together with a pharmaceutically acceptable carrier.
The present invention also provides a method for treating hyperlipidemia and diabetic hyperlipidemia in a mammal comprising administering to said mammal an effective amount of above-mentioned extract, together with a pharmaceutically acceptable carrier thereof.
The present invention also provides a use of above described extract for the preparation of for manufacture of medicament employed for treating or preventing hyperlipidemia and diabetic hyperlipidemia in human or mammal.
The present invention also provides a health functional food comprising above extract for the prevention or improvement of hyperlipidemia and diabetic hyperlipidemia as an active ingredient in an amount effective to prevent or improve the disease, together with a sitologically acceptable additive.
Accordingly, it is an object of the present invention to provide a pharmaceutical composition comprising an extract of combined crude drug consisting of Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma, as an active ingredient in an amount effective to prevent and treat hyperlipidemia and diabetic hyperlipidemia, together with a pharmaceutically acceptable carrier.
The present invention also provides a pharmaceutical composition comprising an extract of combined crude drug additionally comprising the extract of Lonicerae Flos, beside the above-mentioned combined herbs for preventing and treating hyperlipidemia and diabetic hyperlipidemia.
It is another object of the present invention to provide a use of the above described extract for the manufacture of medicament employed for treating or preventing hyperlipidemia and diabetic hyperlipidemia in human or mammal.
It is the other object of the present invention to provide a method for treating hyperlipidemia and diabetic hyperlipidemia in a mammal comprising administering to said mammal an effective amount of the above-mentioned extract, together with a pharmaceutically acceptable carrier thereof.
The term "extract" disclosed herein comprise the extract of combined crude drug, i.e., Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma with the mixed ratio based on the dried weight of each herb (w/w) ranging from 1: 0.1-10: 0.1-10, preferably, 1: 0.1-5: 0.1-5, more preferably, 1: 1-2: 1-2 in the present invention.
Additionally, the extract disclosed herein comprise the extract of combined crude drug i.e., Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma and Lonicerae Flos with the mixed ratio based on the dried weight of each herb (w/w) ranging from 1: 0.1-10: 0.1-10: 0.1-10, preferably, 1: 0.1-5: 0.1-5: 0.1-5, more preferably, 1: 1-2: 1-2: 1-2, in the present invention.
The herbs, which can be used in the present invention, include the same genus plants which would be apparent to those skilled in the art to be used for identical or similar purpose and can be substituted for the prevention and treatment of the diseases.
Specifically, the term "Mori Cortex Radicis" disclosed herein comprises the cortex radix of Morus alba, Morus lactifolia, Morus bombycis, Morus mongolica and the like belongs to Moraceae family; the term "Licii radicis Cortex" disclosed herein comprises the cortex radix of Lycium chinensis and the like belonged to Solanaceae family; the term "Dioscoreae Rhizoma," disclosed herein comprises the rhizoma of Dioscorea batatas D, Dioscorea japonica Thunb and the like belonged to Juncaceae family; the term "Lonicerae Flos," disclosed herein the flower bud of Lonicera japonica Thunb and the like belonged to Caprifoliaceae family in the present invention.
Inventive composition of the present invention is used in the form of pulverized form thereof, extracted form therefrom or dried extract form thereof.
The above extract from the above-described mentioned crude drug can be obtained by extracting the combined herb with distilled water, lower alcohols such as methanol, ethanol and the like, or the mixtures thereof, preferably, water, ethanol and the mixture thereof.
The pharmaceutical composition for treating the purposed diseases could contain about 0.01 to 95 w/w%, preferably 0.5 to 80 w/w% of the above herb composition of present invention based on the total weight of the composition.
An inventive herb composition may be prepared in accordance with the following preferred embodiment.
For the present invention, the inventive extract can be prepared by following procedure;
For example, the present invention also provide a method for preparing the inventive extract comprising the steps of; mixing dried Licii Radicis Cortex, or Dioscoreae Rhizoma with 1 to 20-fold, preferably, 10 to 15-fold volume of distilled water, alcohols such as methanol, ethanol and the like, or the mixtures thereof, preferably, distilled water, ethanol or the mixture thereof, more preferably, 60-90% ethanol respectively at 1st step; extracting each solution with the extraction method by the extraction with hot water, cold water, reflux extraction, or ultra-sonication extraction, preferably, reflux extraction at the temperature ranging from 50℃∼100℃, preferably, 85℃∼95℃, for the period ranging from 1 to 24 hours, preferably, 2 to 5 hours at 2nd step; repeating the above-described extraction process to collect each filtrate with filtration, concentrating at the temperature ranging from 90℃∼110℃, and drying to obtain respective dried extract of Licii Radicis Cortex and Dioscoreae Rhizoma as the 1st and 2nd components; performing dried Mori Cortex and Lonicerae Flos with the extraction process as mentioned above respectively at 3rd step; collecting the resulting each filtrate with filtration, concentrating at the temperature ranging from 90℃∼110℃, extracting each concentrate with enflurage extraction by adding appropriates amount of 70-80% ethanol and leaving alone the solution for more than 12 hours to afford the supernatant and drying each supernatant to obtain a dried extract of Mori Cortex and Lonicerae Flos as the 3rd and 4th components at 4th step; mixing the 1st to 3rd components, if necessary, the 4th component with the mixed ratio as defined herein to prepare inventive extract of the present invention.
It is another object of the present invention to provide a process for preparing the extract of the present invention as described above for the preparation of composition effective in treating or preventing the purposed diseases.
It is still another object of the present invention to provide a pharmaceutical composition comprising the crude drug extract of the above-mentioned crude drug obtained by the above described process as an active ingredient for preventing and treating hyperlipidemia and diabetic hyperlipidemia.
The inventive composition of the present invention prepared by above-described process significantly decreases blood glucose, cholesterol, and triglyceride in streptozotocin-induced type-II diabetic―hyperlipidemia animal model using by SD rat as well as type-II diabetic hyperlipidemia animal model using by high fat feeding KK/Ay rat. When the oral acute toxicity of the extract was tested, the extract had no apparent effect on mortality, clinical signs, body weight changes, and gross findings at necropsy.
The pharmaceutical composition for treating purposed diseases could contain about 0.01 to 95 w/w%, preferably 0.5 to 80 w/w% of the above crude drug composition of present invention based on the total weight of the composition.
The inventive composition may additionally comprise conventional carrier, adjuvants or diluents in accordance with a using method. 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).
Hereinafter, the following formulation methods and excipients are merely exemplary and in no way limit the invention.
The crude drug 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.
For example, the compositions of the present invention can be dissolved in oils, propylene glycol or other solvents which 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 compounds of the present invention can be formulated in the form of ointments and creams.
Pharmaceutical formulations containing crude drug 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), suppository, or sterile injectable preparation (solution, suspension, emulsion).
The crude drug 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.
The desirable dose of the inventive 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 0.01-10g/kg, preferably, 1 to 5g/kg by weight/day of the inventive composition of the present invention. The dose may be administered in a single or multiple doses per day. In terms of composition, the crude drug composition should be present between 0.01 to 80% by weight, preferably 0.5 to 50% by weight based on the total weight of the composition.
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.
In accordance with one aspect of the present invention, there provided a health functional food comprising the above extract for the prevention or improvement of hyperlipidemia and diabetic hyperlipidemia as an active ingredient in an amount effective to prevent or improve the disease, together with a sitologically acceptable additive.
The crude drug composition of inventive health functional food is used in the form of pulverized form thereof, extracted form therefrom or dried extract form thereof.
The health functional food composition for preventing and improving purposed diseases could contain about 0.01 to 95 w/w%, preferably 0.5 to 80 w/w% of the above extract of present invention based on the total weight of the composition.
The above-described crude drug composition therein can be added to food, additive or beverage for the prevention and improvement of purposed diseases. For the purpose of preventing and improving purposed diseases, wherein, the amount of above described crude drug composition in food or beverage may generally range from about 0.1 to 15 w/w %, preferably 1 to 10 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 100㎖ of the health beverage composition.
Providing that the health beverage composition of present invention contains above described crude drug composition 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, cyclodextrin; 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㎖ of present beverage composition.
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 % in the present composition.
Examples of addable food comprising aforementioned crude drug composition therein are various food, beverage, gum, vitamin complex, health improving food and the like.
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.
As described in the present invention, the combined herb composition shows potent reducing effect on the blood glucose, cholesterol, and triglyceride in type-II diabetic hyperlipidemia animal model.
The inventive compositions according to the present invention are useful in the prevention and treatment of hyperlipidemia and diabetic hyperlipidemia.
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;
Fig. 1 shows the effect of each extract of MC, LR, DR or LF on blood cholesterol level in streptozotocin-induced type-II diabetic―hyperlipidemia animal model using by SD rat,;
Fig. 2 shows the effect of each extract of MC, LR, DR or LF on blood glucose level in streptozotocin-induced type-II diabetic―hyperlipidemia animal model using by SD rat;
Fig. 3 shows the effect of the inventive extracts (PAI-N1 and PAI-N2) on blood cholesterol level in streptozotocin-induced type-II diabetic―hyperlipidemia animal model using by SD rat;
Fig. 4 represents the effect of the inventive extracts (PAI-N1 and PAI-N2) on blood glucose level in streptozotocin-induced type-II diabetic―hyperlipidemia animal model using by SD rat;
Fig. 5 represents the effect of the inventive extracts (PAI-N1 and PAI-N2) on blood triglyceride level in streptozotocin-induced type-II diabetic―hyperlipidemia animal model using by SD rat.
The following Examples and Experimental Examples are intended to further illustrate the present invention without limiting its scope.
Comparative Example 1. Preparation of each component
1-1. The extract of
Mori Cortex Radicis
500g of Mori Cortex Radicis purchased from Kyung-dong market located in Seoul was washed and added to 7L of 70% ethanol to perform the 1st extraction with reflux extraction for 3 hours at 90℃. The filtrated extract was performed to the 2ndextraction method with reflux extraction using by 7L of 80% ethanol for 3 hours at 90℃ and the extract was concentrated under vaccuo at 105℃ to the extent that the final volume of the extract reached to 1L. The concentrate was added with 4.5L of 95% ethanol to make 75% ethanol solution and left alone for more than 12 hours to collect supernatant. The collected supernatant was concentrated , dried at 60℃ and pulverized to afford 59.10g of the dried extract of Mori Cortex Radicis (yield: 11.82%, designated as MC hereinafter), which is used as a comparative test sample in following experiment.
1-2. The extract of
Licii Radicis Cortex
1,000g of Licii Radicis Cortex purchased from Kyung-dong market located in Seoul was washed and added to 10L of 70% ethanol to perform the 1st extraction with reflux extraction for 2 hours at 95℃. The filtrated extract was performed to the 2nd extraction method with reflux extraction using by 7L of 80% ethanol for 2 hours at 95℃ and the extract was concentrated under vaccuo at 105℃ to the extent that the final volume of the extract reached to 1L. The concentrate was dried at 60℃ and pulverized to afford 71.1g of the dried extract of Licii Radicis Cortex (yield: 15.25%, designated as LR hereinafter), which is used as a comparative test sample in following experiment.
1-3. The extract of
Dioscoreae Rhizoma
500g of Dioscoreae Rhizoma purchased from Kyung-dong market located in Seoul was washed and added to 7L of distilled water to perform the 1st extraction with reflux extraction for 2 hours at 105℃. The filtrated extract was performed to repeated extraction according the similar method to the above-extraction method and the extract was concentrated under vaccuo at 105℃ to the extent that the final volume of the extract reached to 1L. The concentrate was dried at 60℃ and pulverized to afford 10.2g of the dried extract of Dioscoreae Rhizoma (yield: 20.40%, designated as DR hereinafter), which is used as a comparative test sample in following experiment.
1-4. The extract of
Lonicerae Flos
1,000g of Lonicerae Flos purchased from Kyung-dong market located in Seoul was washed and added to 10L of distilled water to perform the 1st extraction with reflux extraction for 2 hours at 105℃. The extract was concentrated under vaccuo at 105℃ to the extent that the final volume of the extract reached to 1L. The concentrate was added with 4.5L of 95% ethanol to make 75% ethanol solution and left alone for more than 12 hours to collect supernatant. The collected supernatant was concentrated , dried at 60℃ and pulverized to afford 170.72g of the dried extract of Lonicerae Flos (yield: 18.26%, designated as LF hereinafter), which is used as a comparative test sample in following experiment.
Example 1. Preparation of combined formulation
1-1. Preparation of combined formulation (PAI-N1)
Each extract of Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma prepared in Comparative Example 1 was mixed with the ratio of 1:1:1 (w/w) to obtain invention formulation (PAI-N1), which is used as a comparative test sample in following experiment.
1-2. Preparation of combined formulation (PAI-N2)
Each extract of Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma and Lonicerae Flos
prepared in Comparative Example 1 was mixed with the ratio of 1:1:1:1 (w/w) to obtain invention formulation (PAI-N2), which is used as a comparative test sample in following experiment.
Experimental Example 1. Effect on streptozotocin-induced type II-diabetic animal model
In order to investigate the inhibitory effect of the inventive extract obtained in Examples on the blood glucose, cholesterol, and triglyceride in streptozotocin-induced type-II diabetic―hyperlipidemia animal model using by SD rat, following experiment was performed in the procedure.
1-1. Reagent and experimental animals
Sterptozotocin (Sigma Aldrich Co. USA), glucose (Glu, Stanbio Co.), cholesterol (CHO, Stanbio Co.), LDL-cholesterol (LDLc, Stanbio Co.), triglyceride (TG, Stanbio Co.), and atrovastatin (Pfizer Co., Germany) were purchased from commercial company to use in the experiment.
Male Sprague-Dawley rats weighing about 200g (Daehanbiolink Co. Ltd., Korea) were used in the experiment and were allowed to access to normal feed (Harlan, teklan, USA), high-fat feed (AIN-76A, Feedlab Co. Table 1) and drinking water. All animals were bred in a controlled environment maintained with temperatures at 21℃ - 24℃ and humidity at 60%-80% with 12 hours of light and dark cycles for at least one week prior to use.
Table 1
component | Content (kg) | component | Content (kg) |
casein | 20 | Mineral mix | 3.5 |
DL-methionine | 0.3 | Vitamin mix | 1.0 |
Corn starch | 15 | Choline bitrate | 0.2 |
| 50 | cholesterol | 1.0 |
Cellulose | 5.0 | Cholic acid | 0.5 |
Corn oil | 5.0 | sum | 101.5 |
1-2. The effect of comparative extract on blood on glucose, cholesterol, and triglyceride
For determining the effect of the comparative extract prepared in Comparative Example on the level of blood glucose, cholesterol, and triglyceride in streptozotocin-induced type-II diabetic―hyperlipidemia animal model, the SD rats prepared in 1-1 were divided into four groups which consists of 10 rats/group, i.e., normal group, negative control group, test sample group and positive control group treated with atrovastatin. The negative control group, test sample group and positive control group were allowed to freely access to high-fat feed (AIN-76A, Feedlab Co. Table 1) for 3 weeks and then streptozotocin was orally administrated into the rats in an amount of 20mg/kg, once a day for 3 days to induce type II diabetes.
The diabetes-induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 350mg/dL±10) and blood cholesterol (more than 550mg/dL±10) are regarded as diabetes-induced rats.
The group of test sample group was treated with the extract of MC, LR, DR or LF in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks. The negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day. 4 weeks after the drug treatment, the blood of rats was collected from rat caudal vena cava and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL-cholesterol and triglyceride was determined using by determining apparatus (BT2000+, SEAC Co.).
At the result, the level of blood cholesterol in normal group and negative control group treated with streptozotocin showed 134±10.0 mg/dl and 1,222.2±59.4 mg/dl whereas the blood cholesterol level in test sample group treated with the extract of MC, LR, DR or LF for 4 weeks showed significantly reduced, i.e., 930±61.5 mg/dl (MC), 620±56.4 mg/dl (LR), 605±72.0 mg/dl (DR) and 861±31.5 mg/dl (LF), respectively.
The blood cholesterol level in positive control group treated with atrovastatin was sharply reduced to 517.6±65.4 mg/dl. Accordingly, it has been confirmed that the extract of MC, LR, DR and LF test showed decreasing effect on the level of blood cholesterol as can be seen in Table 2 and Fig.1.
Additionally, the blood glucose level in normal group and negative control group treated with streptozotocin showed 88±4.0 mg/dl and 639.6±59.4 mg/dl whereas the blood glucose level in test sample group treated with the extract of MC, LR, DR or LF for 4 weeks was significantly reduced, i.e., 430±63.8 mg/dl (MC), 465±51.2 mg/dl (LR), 487±45.9 mg/dl (DR) and 501±58.6 mg/dl (LF), respectively ( See Table 2 and Fig. 2).
Table 2
mg/dl | cholesterol | LDL-cholesterol | triglyceride | Glucose |
Normal | 134±10.0 | 51.3±1.4 | 60.3±2.1 | 88±4.0 |
Negative control | 1,222.2±59.4 | 347.5±18.5 | 241±17.6 | 639.6±59.4 |
MC | 930±61.5 | 322±20.6 | 210±12.6 | 430±63.8 |
LR | 620±56.4 | 253±32.4 | 195±24.7 | 465±51.2 |
DR | 605±72.0 | 301±28.6 | 188±11.3 | 487±45.9 |
LF | 861±31.5 | 264±38.4 | 170±17.4 | 501±58.6 |
Positive control | 517.6±65.4 | 220.6±42.7 | 163.6±22.9 | 613.6±62.4 |
1-3. The effect of inventive extract (PAI-N1) on blood on glucose, cholesterol, and triglyceride
For determining the effect of the inventive extract (PAI-N1) prepared in Example 1-1 on the level of blood glucose, cholesterol, and triglyceride in streptozotocin-induced type-II diabetic―hyperlipidemia animal model, the SD rats prepared in 1-1 were divided into four groups which consists of 10 rats/group, i.e., normal group, negative control group, test sample group and positive control group treated with atrovastatin. The negative control group, test sample group and positive control group were allowed to freely access to high-fat feed (AIN-76A, Feedlab Co. Table 1) for 3 weeks and then streptozotocin was orally administrated into the rats in an amount of 20mg/kg, once a day for 3 days to induce type II diabetes.
The diabetes-induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 350mg/dL±10) and blood cholesterol (more than 550mg/dL±10) are regarded as diabetes-induced rats.
The group of test sample group was treated with the inventive extract (PAI-N1) in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks. The negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day. 4 weeks after the drug treatment, the blood of rats was collected from rat caudal vena cava and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL-cholesterol and triglyceride were determined using by determining apparatus (BT2000+, SEAC Co.).
At the result, the level of blood cholesterol in normal group and negative control group treated with streptozotocin showed 134±10.0 mg/dl and 1,222.2±59.4 mg/dl whereas the blood cholesterol level in test sample group treated with the inventive extract (PAI-N1) and positive control group treated with atrovastatin for 4 weeks was significantly reduced, i.e., 463.5±29.5 mg/dl and 517.6±65.4 mg/dl, which result confirms that the inventive extract (PAI-N1) has more potent reducing activity of the level of blood cholesterol than the positive control group treated with atrovastatin known as a representative drug for treating hyperlipidemia ( See Table 3 and Fig. 3).
Additionally, the blood glucose level in normal group and negative control group treated with streptozotocin showed 88±4.0 mg/dl and 639.6±59.4 mg/dl whereas the blood glucose level in test sample group treated with the inventive extract (PAI-N1) for 4 weeks was significantly reduced to 423.8±58.2 mg/dl ( See Table 3 and Fig. 4).
1-4. The effect of inventive extract (PAI-N2) on blood on glucose, cholesterol, and triglyceride
For determining the effect of the inventive extract (PAI-N2) prepared in Example 1-2 on the level of blood glucose, cholesterol, and triglyceride in streptozotocin-induced type-II diabetic―hyperlipidemia animal model,the SD rats prepared in 1-1 were divided into four groups which consists of 10 rats/group, i.e., normal group, negative control group, test sample group and positive control group treated with atrovastatin. The negative control group, test sample group and positive control group were allowed to freely access to high-fat feed (AIN-76A, Feedlab Co. Table 1) for 3 weeks and then streptozotocin was orally administrated into the rats in an amount of 20mg/kg, once a day for 3 days to induce type II diabetes.
The diabetes-induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 350mg/dL±10) and blood cholesterol (more than 550mg/dL±10) are regarded as diabetes-induced rats.
The group of test sample group was treated with the inventive extract (PAI-N2) in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks. The negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day. 4 weeks after the drug treatment, the blood of rats was collected from rat caudal vena cava and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL-cholesterol and triglyceride was determined using by determining apparatus (BT2000+, SEAC Co.).
At the result, the level of blood cholesterol in normal group and negative control group treated with streptozotocin showed 134±10.0 mg/dl and 1,222.2±59.4 mg/dl whereas the blood cholesterol level in test sample group treated with the inventive extract (PAI-N2) and positive control group treated with atrovastatin for 4 weeks was significantly reduced, i.e., 439.5±63.8 mg/dl and 517.6±65.4 mg/dl, which result confirms that the inventive extract (PAI-N2) has more potent reducing activity of the level of blood cholesterol than the positive control group treated with atrovastatin known as a representative drug for treating hyperlipidemia ( See Table 3 and Fig. 3).
Additionally, the blood triglyceride level in test sample group treated with the inventive extract (PAI-N2) also was significantly reduced ( See Fig. 5) and the blood glucose level in normal group and negative control group treated with streptozotocin showed 88±4.0 mg/dl and 639.6±59.4 mg/dl whereas the blood glucose level in test sample group treated with the inventive extract (PAI-N2) for 4 weeks was significantly reduced to 310.5±60.4 mg/dl ( See Table 3 and Fig. 4).
Table 3
mg/dl | cholesterol | LDL-cholesterol | triglyceride | Glucose |
Normal | 134±10.0 | 51.3±1.4 | 60.3±2.1 | 88±4.0 |
Negative control | 1,222.2±59.4 | 347.5±18.5 | 241±17.6 | 639.6±59.4 |
PAI-N1 | 463.5±29.5 | 225±29.7 | 163.5±13.6 | 423.8±58.2 |
PAI-N2 | 439.5±63.8 | 205.8±43.9 | 94.3±14.5 | 310.5±60.4 |
Positive control | 517.6±65.4 | 220.6±42.7 | 163.6±22.9 | 613.6±62.4 |
Experimental Example 2. Effect on type II-diabetic animal model (KK/Ay)
In order to investigating the inhibitory effect of the inventive extract obtained in Examples on the level of blood glucose, cholesterol, and triglyceride in type-II diabetic―hyperlipidemia animal model using by KK/Ay rat, following experiment was performed in the procedure.
1-1. Reagent and experimental animals
Sterptozotocin (Sigma Aldrich Co. USA), glucose (Glu, Stanbio Co.), cholesterol (CHO, Stanbio Co.), LDL-cholesterol (LDLc, Stanbio Co.), triglyceride (TG, Stanbio Co.), and atrovastatin (Pfizer Co., Germany) were purchased from commercial company to use in experimental.
Male KK-Ay/TaJcl rats weighing about 30±10g (Clea Japan Inc., Japan) were used in the experiment and were allowed to access to normal feed (Harlan, teklan, USA), high-fat feed (AIN-76A, Feedlab Co. Table 1) and drinking water. All animals were bred in a controlled environment maintained with temperatures at 21℃ - 24℃ and humidity at 60% with 12 hours of light and dark cycles for at least one week prior to use.
1-2. The effect of inventive extracts (PAI-N1 and PAI-N2) on blood on glucose, cholesterol, and triglyceride
For determining the effect of the inventive extracts (PAI-N1 and PAI-N2) prepared in Example 1 on the level of blood glucose, cholesterol, and triglyceride in type-II diabetic―hyperlipidemia animal model, the KK/Ay rat rats prepared in 1-1 were divided into four groups which consists of 6 rats/group, i.e., normal group, negative control group, test sample group and positive control group treated with atrovastatin. The negative control group, test sample group and positive control group were allowed to freely access to high-fat feed (AIN-76A, Feedlab Co. Table 1) for 3 weeks and the diabetes-induced rats were discriminated according to the criteria that the rats showing blood glucose level (more than 381.2±5.7 mg/dL) determined by glucometer (Accu-chek. Roche) are regarded as diabetes-induced rats.
The group of test sample group was treated with the inventive extracts (PAI-N1 and PAI-N2) in a dose of 50mg/kg suspended in 2ml/rat of physiological saline solution, and the positive control group was orally-administrated with atrovastatin in a dose of 0.3mg/kg/day for 4 weeks. The negative control group and normal group were treated with physiological saline solution in a dose of 2ml/rat/day. 4 weeks after the drug treatment, the blood of rats was collected from rat caudal vena cava through autopsy and centrifuged for 20 mins at the speed of 3000 rpm and the level of blood glucose, cholesterol, LDL-cholesterol and triglyceride was determined using by apparatus (BT2000+, SEAC Co.).
At the result, the level of blood cholesterol in normal group and negative control group treated with streptozotocin showed 98±3.9 mg/dl and 250±12.5mg/dl whereas the blood cholesterol level in test sample groups treated with the inventive extracts (PAI-N1 and PAI-N2) and positive control group treated with atrovastatin for 4 weeks was significantly reduced, i.e., 200±23.1 mg/dl (PAI-N1), 157±16.3 mg/dl and 148±15.4 mg/dl, which result confirms that the inventive extract (PAI-N2) has the similar reducing activity of blood cholesterol to the positive control group treated with atrovastatin known as a representative drug for treating hyperlipidemia ( See Table 4).
Table 4
mg/dl | cholesterol | LDL-cholesterol | triglyceride | Glucose |
Normal | 98±3.9 | 50.15±3.1 | 66±1.2 | 88.4±4.0 |
| 250±12.5 | 230.2±17.6 | 98.5±18.5 | 650.3±15.1 |
PAI- | 200±23.1 | 163.5±13.6 | 75±9.7 | 419.5±26.3 |
PAI-N2 | 157±16.3 | 94.3±14.5 | 60.8±13.9 | 483.0±17.6 |
Positive control | 148±15.4 | 98.5±22.9 | 63.0±22.7 | 621.0±10.5 |
Experimental Example 3. Evaluation of acute toxicity
To examine the toxicity of the inventive extract, acute toxicity tests were performed on rats.
The 15 male and female SD rats were divided with 3 groups and three dosages of inventive extract, i.e., 1g/kg, 2g/kg and 5g/kg were administered to each 5 rats for 14 days and water was treated to the control group. The symptom of toxicity was observed for 4 weeks such as the change of weight, the hematological analysis and histological test.
As a result of experiment, there was no death example of the rats administered with inventive extract and there was no significant abnormality in the gain of weight, and the histological test etc. In accordance with above results, it was confirmed that the inventive extract, i.e., PAI-N1 and PAI-N2 were safe.
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.
Preparation of injection
PAI-N1 _ 100mg
Sodium metabisulfite _ 3.0mg
Methyl paraben _ 0.8mg
Propyl paraben _ 0.1mg
Distilled water for injection _ optimum amount
Injection preparation was prepared by dissolving active component, controlling pH to about 7.5 and then filling all the components in 2㎖ ample and sterilizing by conventional injection preparation method.
Preparation of powder
PAI-N2 _ 500mg
Corn Starch _ 100mg
Lactose _ 100mg
Talc _ 10mg
Powder preparation was prepared by mixing above components and filling sealed package.
Preparation of tablet
PAI-N2 _ 200mg
Corn Starch _ 100mg
Lactose _ 100mg
Magnesium stearate _ optimum amount
Tablet preparation was prepared by mixing above components and entabletting.
Preparation of capsule
PAI-N1 _ 100mg
Lactose _ 50mg
Corn starch _ 50mg
Talc _ 2mg
Magnesium stearate _ optimum amount
Tablet preparation was prepared by mixing above components and filling gelatin capsule by conventional gelatin preparation method.
Preparation of liquid
PAI-N2 _ 1000mg
Sugar _ 20g
Polysaccharide _ 20g
Lemon flavor _ 20g
Liquid preparation was prepared by dissolving active component, and then filling all the components in 1000㎖ ample and sterilizing by conventional liquid preparation method.
Preparation of health food
PAI-N2 _ 1000mg
Vitamin mixture _ optimum amount
Vitamin A acetate _ 70㎍
Vitamin E _ 1.0mg
Vitamin B1 _ 0.13mg
Vitamin B2 _ 0.15mg
Vitamin B6 _ 0.5mg
Vitamin B12 _ 0.2㎍
Vitamin C _ 10mg
Biotin _ 10㎍
Amide nicotinic acid _ 1.7mg
Folic acid _ 50㎍
Calcium pantothenic acid _ 0.5mg
Mineral mixture _ optimum amount
Ferrous sulfate _ 1.75mg
Zinc oxide _ 0.82mg
Magnesium carbonate _ 25.3mg
Monopotassium phosphate _ 15mg
Dicalcium phosphate _ 55mg
Potassium citrate _ 90mg
Calcium carbonate _ 100mg
Magnesium chloride _ 24.8mg
The above mentioned vitamin and mineral mixture 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.
Preparation of health beverage
PAI-N1 _ 1000mg
Citric acid _ 1000mg
Oligosaccharide _ 100g
Apricot concentration _ 2g
Taurine _ 1g
Distilled water _ 900㎖
Health beverage preparation was prepared by dissolving active component, mixing, stirred at 85℃ for 1 hour, filtered and then filling all the components in 1000㎖ ample and sterilizing by conventional health beverage preparation method.
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.
As described in the present invention, the combined herb composition shows potent reducing effect on the level of blood glucose, cholesterol, and triglyceride in type-II diabetic hyperlipidemia animal model.
The inventive compositions according to the present invention are useful in the prevention and treatment of hyperlipidemia and diabetic hyperlipidemia.
Claims (12)
- A pharmaceutical composition comprising an extract of combined crude drug consisting of Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma, as an active ingredient in an amount effective to prevent and treat hyperlipidemia and diabetic hyperlipidemia, together with a pharmaceutically acceptable carrier.
- The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises the dried extract of Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma, with the mixed ratio based on the dried weight of each herb (w/w) of 1: 0.1-10: 0.1-10.
- The pharmaceutical composition according to claim 1, wherein said crude drug further comprise the extract of Lonicerae Flos, beside above-mentioned combined herbs for preventing and treating hyperlipidemia and diabetic hyperlipidemia.
- The pharmaceutical composition according to claim 3, wherein said pharmaceutical composition comprises the dried extract of Mori Cortex Radicis, Licii Radicis Cortex, Dioscoreae Rhizoma and Lonicerae Flos with the mixed ratio based on the dried weight of each herb (w/w) of 1: 0.1-10: 0.1-10: 0.1-10.
- The pharmaceutical composition of claims 1, wherein said extract solvent is selected from the group consisting of distilled water, lower alcohol and the mixture thereof.
- The pharmaceutical composition of claim 1 or 3, wherein said extract is contained about 0.01 to 95 w/w% based on the total weight of the composition.
- A use of the extract of combined crude drug as set forth in claim 1 or 3 for the manufacture of medicament employed for treating or preventing hyperlipidemia and diabetic hyperlipidemia in human or mammal.
- A method for treating hyperlipidemia and diabetic hyperlipidemia in human or mammal comprising administering an effective amount of an extract of combined crude drug as set forth in claim 1 or 3 to said mammal, together with a pharmaceutically acceptable carrier thereof.
- A method for preparing the inventive extract as set forth in claim 1 or 3 comprising the steps of; mixing dried Licii Radicis Cortex, and Dioscoreae Rhizoma with 1 to 20-fold volume of distilled water, alcohols such as methanol, ethanol and the like, or the mixtures thereof at the 1st step; extracting each solution with the extraction method by the extraction with hot water, cold water, reflux extraction, or ultra-sonication extraction, at the temperature ranging from 50℃∼100℃, for the period ranging from 1 to 24 hours, at the 2nd step; repeating the above-described extraction process to collect each filtrate with filtration, concentrating at the temperature ranging from 90℃∼110℃, and drying to obtain respective dried extract of Licii Radicis Cortex and Dioscoreae Rhizoma as the 1st and 2nd components; performing dried Mori Cortex and Lonicerae Flos with the extraction process as mentioned above respectively at 3rd step; collecting the resulting each filtrate with filtration, concentrating at the temperature ranging from 90℃∼110℃, extracting each concentrate with enflurage extraction by adding appropriate amount of 70-80% ethanol and leaving alone the solution for more than 12 hours to afford the supernatant and drying each supernatant to obtain a dried extract of Mori Cortex and Lonicerae Flos as the 3rd and 4th components at 4th step; and mixing the 1st to 3rd components, if necessary, with the 4th component to prepare inventive extract as set forth in claim 1 or 3.
- A health functional food comprising an extract of combined crude drug consisting of Mori Cortex Radicis, Licii Radicis Cortex, and Dioscoreae Rhizoma for the prevention or improvement of hyperlipidemia and diabetic hyperlipidemia as an active ingredient in an amount effective to prevent and improve the disease, together with a sitologically acceptable additive.
- The health functional food according to claim 10 said crude drug further comprise the extract of Lonicerae Flos, beside the combined herbs as set forth in claim 10.
- The health functional food according to claim 10, wherein said health functional food is provided as powder, granule, tablet, capsule or beverage type.
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KR101646757B1 (en) | 2014-08-29 | 2016-08-09 | 주식회사 하원제약 | Composition for prevention or treatment of hyperlipidemia |
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KR20030055127A (en) * | 2001-12-24 | 2003-07-02 | 주식회사 닥터즈메디코아 | Composition for anti-hyperlipidemia |
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Non-Patent Citations (4)
Title |
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JEONG RYAE JEON ET AL.: 'Effect of Ethanol Extract of Dried Chinese Yam (Dio scorea batatas) Flour Containing Dioscin on Gastrointestinal Function in Rat Model' ARCH. PHARM. RES. vol. 29, no. 5, 2006, pages 348 - 353 * |
NAM JAE KIM ET AL.: 'Pharmacological Effects of Lycium chinensis' KOR. J. PHARMACOGN. vol. 25, no. 3, 1994, pages 264 - 274 * |
SEONG HEE HONG ET AL.: 'Thereapeutic Effects of Mulberry Root-Bark(Mori radi cis Cortex) Ethanol Extract on Atherosclerosis in Hypercholesterolemic Rabbits' LAB. ANIM. RES. vol. 21, no. 3, 2005, pages 273 - 279 * |
WU LAN ET AL.: 'Effect of chlorogenic acid on antioxidant activity of Flos Lonicerae extracts' J. OF ZHEJIANG UNIVERSITY SCIENCE B vol. 8, no. 9, 2007, pages 673 - 679 * |
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