WO2008060112A1 - Composition comprising araliae cordatae radix extract or compounds isolated from the same for preventing or treating periodontitis - Google Patents
Composition comprising araliae cordatae radix extract or compounds isolated from the same for preventing or treating periodontitis Download PDFInfo
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- WO2008060112A1 WO2008060112A1 PCT/KR2007/005741 KR2007005741W WO2008060112A1 WO 2008060112 A1 WO2008060112 A1 WO 2008060112A1 KR 2007005741 W KR2007005741 W KR 2007005741W WO 2008060112 A1 WO2008060112 A1 WO 2008060112A1
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- araliae cordatae
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- cordatae radix
- radix extract
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- NIKHGUQULKYIGE-MHHCCDILSA-N C[C@](CCC1)([C@H](CCC(C2)C(C3)=C)[C@@]23CC2)[C@H]2[C@]1(C)C(O)=O Chemical compound C[C@](CCC1)([C@H](CCC(C2)C(C3)=C)[C@@]23CC2)[C@H]2[C@]1(C)C(O)=O NIKHGUQULKYIGE-MHHCCDILSA-N 0.000 description 1
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)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
- A61K36/237—Notopterygium
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- 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)
- A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to a composition comprising an Araliae Cordatae
- Periodontal disease refers to a bacterial infection that results in the destruction of tissues that support the teeth and alveolar bone.
- a periodontal tissue is composed of alveolar bone, gingiva (gum), and periodontal ligament.
- Gingiva is a part of the tooth-supporting tissues of the mouth, in which gingivitis primarily occurs. If gingivitis may progress and spread to the supporting tissues, the periodontal ligament that is attached to bone tissue surrounding the tooth root and tooth is destroyed, and the alveolar bone is also destroyed, which leads to periodontal disease.
- Periodontal disease is the most common oral disease, in addition to dental caries.
- Periodontal disease has various clinical symptoms such as gingival bleeding and swelling, periodontal pocket formation, loss of fixed gingiva, alveolar bone destruction, and halitosis, and is the main cause of tooth loss (AIi, R. W. et al., J. Clin. Periodontal. 1997, 24, 830-835; Socransky, S. S. et al., J. Clin. Periodontal. 1998, 15, 440-444).
- Periodontal disease is one of the most common chronic diseases of infectious origin known in humans, and the prevalence varies between 10-60% of adults, depending on diagnostic criteria (Xiong, X. et al., BJOG. 2006, 113, 135-143; Papapanou, P. N., Ann.
- Periodontal disease There are two major types of periodontal disease, gingivitis and periodontitis.
- Gingivitis is an infection of the soft tissue surrounding the teeth or gingiva, and periodontitis involves destruction of the underlying supporting tissues such as periodontal ligament, alveolar bone, cementum, or soft tissue (Kinane D. F., Periodontol. 2000, 2001, 25, 8-20).
- Periodontitis is one of bacterial infectious diseases that may cause tooth loss, and a specific inflammatory condition that arises as the result of the interaction of microorganisms and their products causing inflammation in dental plaque (biofilm) (Feng, Z., and A. Weinberg, Periodontol. 2000, 2006, 40, 50-76). It has been estimated that 500-600 species of bacteria inhabit the human oral cavity, and among them about 400 species of bacteria inhabit the subgingival plaque (Kazor, C.
- Periodontal disease is initiated by excessive growth of gram-negative anaerobic bacterial species that inhabit the periodontal tissue and adjacent subgingival plaque. Severe inflammation and destruction are generated in the periodontal tissue supporting teeth by periodontal pathogens (Kinane D. F., Pe- riodontol. 2000. 2001, 25, 8-20; Kornman, K. S. et al., Periodontol. 2000, 1997, 14, 33-53).
- periodontal disease can be divided into non-surgical and surgical procedures.
- a physical method scaling and root planing
- removing plaque and calculus around teeth affected by periodontal disease is generally performed.
- the physical method can treat periodontal disease in the early stages, and more advanced cases may require surgical treatment (open flap curettage).
- advanced periodontal disease defined by the destruction of the alveolar bone to one third of root apex is hardly treated, and thus the tooth has to be removed.
- scaling, root planing, open flap curettage or the like is generally performed to remove causes such as plaque and calculus and to block the activities of inflammatory factors induced by the causes, thereby preventing the progress of periodontal disease and promoting complete regeneration of injured or defective periodontal tissue.
- gingivitis can be easily treated only with scaling and oral hygiene care (brushing).
- brushing advance and subsidence of clinical symptoms are repeated, and thus in its early stage, a patient does not visit a dental clinic for treatment.
- a patient visits a dental clinic, which generates a lot of economic and social loss. Therefore, it is the best way to prevent any further progress of periodontal disease.
- the way to prevent periodontal disease is brushing with toothpaste, and a method using an oral rinse solution.
- Many researchers have recently studied on the development of antimicrobial agents or active formulations having antimicrobial effect against periodontal pathogens or increasing the activity of periodontal tissue in respect to toothpaste and oral rinse solution.
- antibiotics with bactericidal or bacteriostatic effect against periodontal pathogens have been developed for inhibiting and treating dental caries, periodontal disease, and pulpal and periapical infection.
- the antibiotics may induce the emergence of resistant bacteria in oral cavity and superinfection, in addition to systemic side effects in the body, and thus the antibiotics is problematic for long-term use, but used as a therapeutic agent.
- Listerine that is one of the most popular antimicrobial agents worldwide, excluding antibiotics is an oral rinse solution containing phenol compounds such as thymol, eucalyptol, methyl salicylate, benzoic acid, and boric acid, and alcohol as a main ingredient. Listerine has Dental Association approval in the USA because of its effect of reducing plaque and gingivitis, and sold under various brand names. However, it has been reported that listerine does not effectively remove plaque, has not prominent antimicrobial effect, and has side effects such as burning sensation and staining of teeth. Further, chlorhexidine has been known as the most excellent therapeutic agent for preventing and treating periodontal disease and for inhibiting plaque formation.
- chlorhexidine has side effects such as tissue irritation, staining and discoloration of tissue, and a strong taste and smell, and may also induce superinfection. Further, chlorhexidine is carcinogenic, thereby not being used for pregnant women. Therefore, for the purpose of treating and preventing periodontal disease, chlorhexidine can not be used for long-term due to such limitations (Contemporary periodontics [ed. RJ. Genco et al.], pl61 ⁇ 169, p368 ⁇ 369, p433, CV. Mosby Company, St. Louis, 1990).
- Araliae Cordatae Radix is a medicinal plant, and its roots (Aralia cordata Thumberg, Araliaceae) are frequently used for muscle soreness, spastic paraplegia, headache, hemiplegia due to paralysis or the like.
- the root of Araliae Cordatae Radix contains a large amount of pimaric acid derivative, which is diterpene, as a fat-soluble ingredient, and a large amount of araloside, which is oleanolic acid or hederagenin saponin, as a water-soluble ingredient.
- Araliae Cordatae Radix has a unique aromatic smell, and a muddy and slightly bitter taste.
- Araliae Cordatae Radix contains chemical ingredients including chlorogenic acid, alanine, glutamic acid, tyrosine, aspartic acid, asparagine (S-form, L- form), terpinen-4-ol, ⁇ -pinene, ⁇ -pinene, ⁇ -cadinene, oleanolic acid, (-)- ⁇ -copaene, myrcene, p-cymene, 3(15),6-caryophylladiene, ⁇ -ocimene, (-)-limonen, 16- ⁇ -17-dihydroxy-kauran-19-oic acid, 3-0- ⁇ -D-glucuronopyranosyloleanolic acid, sabinene, camphene, kaurenoic acid, ⁇ -caryophyllene, 3-carene, trans-Sabinene hydrate (IR, 4R, 5R), udosaponin F methylester, ud
- 10-0513490 discloses a pharmaceutical composition for treating or preventing diseases caused by deficiency of growth hormone, in which an Araliae Cordatae Radix extract functions to promote release of growth hormone to increase the production of growth hormone.
- Korean Patent Registration No. 10-0224633 discloses a combustional composite for moxibustion in a mixed form of a variety of other herbal medicines including Araliae Cordatae Radix.
- Japanese Patent Publication No. 1996-099993 discloses a method for extracting saponin from Araliae Cordatae Radix and use thereof
- Japanese Patent Publication No. 1996-283169 discloses a sugar absorption suppressing agent containing saponin mixture extracted from Araliae Cordatae Radix as an active ingredient.
- CN 1276222A discloses that Araliae Cordatae Radix is used as an anti-inflammatory agent or used for treating cardiovascular and cerebrovascular diseases
- Chinese Patent Publication No. CN 1273857A discloses that Araliae Cordatae Radix is used for fracture diseases as a composite
- Chinese Patent Publication No. CN 1236627A discloses that Araliae Cordatae Radix is used for diabetes, antitumor, and hyperos- teoblastic activity.
- the present invention provides a composition comprising an Araliae Cordatae
- FIG. 1 is a drawing showing growth inhibitory effect on Porphyromonas en- dodontalis (ATCC 35406), Porphyromonas gingivalis (ATCC 53978) and Prevotella intermedia (ATCC 25611) according to concentrations of the ethanol extract of Araliae Cordatae Radix of the present invention;
- FIG. 2 is a drawing showing growth inhibitory effect on Porphyromonas en- dodontalis, Porphyromonas gingivalis and Prevotella intermedia according to concentrations of the hexane fraction of Araliae Cordatae Radix extract of the present invention.
- FIG. 3 is a drawing showing growth inhibitory effect on Porphyromonas en- dodontalis, Porphyromonas gingivalis and Prevotella intermedia according to concentrations of (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 of the present invention. Best Mode for Carrying Out the Invention
- the present invention provides a composition comprising an Araliae Cordatae
- Radix extract for preventing or treating periodontitis.
- the present invention provides a composition comprising a compound represented by the following Formula 1 for preventing or treating periodontitis.
- the present invention provides a composition comprising a compound represented by the following Formula 2 for preventing or treating periodontitis.
- Formula 2 a compound represented by the following Formula 2 for preventing or treating periodontitis.
- the compounds of Formulae 1 and 2 include compounds extracted and isolated from the Araliae Cordatae Radix.
- composition according to the present invention includes a pharmaceutical composition, oral rinse composition and food composition.
- An Araliae Cordatae Radix is added to water, alcohol, or a mixed solvent thereof, and stirred at 5 to 4O 0 C to be filtered. Then, the resultant is concentrated under reduced pressure, and freeze-dried to give an Araliae Cordatae Radix extract according to the present invention as a powder.
- the mixed solvent of water and alcohol can be selected from 10 to 100% methanol and 10 to 100% ethanol, preferably 10 to 100% ethanol.
- hexane is added to the suspended extract, stirred at room temperature to separate a hexane layer, and concentrated under reduced pressure to remove the hexane layer.
- the resultant is freeze-dried to give a hexane fraction of Araliae Cordatae Radix extract as a powder.
- the Araliae Cordatae Radix extract according to the present invention or compound isolated from the same shows excellent antimicrobial and bactericidal activities against Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia, which are periodontal pathogens, thereby being used as a medicine, dental care product and health food to prevent or treat periodontal disease.
- composition of the present invention may include at least one known active ingredient having the effects of preventing or treating periodontal disease in addition to the Araliae Cordatae Radix extract or compounds isolated from the same.
- the composition of the present invention can be prepared including at least one pharmaceutically acceptable carrier, in addition to the active in- gredients as described above.
- the pharmaceutically acceptable carrier include a saline solution, sterile water, a Ringer's solution, a buffered saline solution, a dextrose solution, a maltodextrin solution, glycerol, ethanol and a mixture of two or more thereof.
- the composition may also contain other conventional additives, such as antioxidants, buffers, and bacteriostatic agents.
- the composition may additionally contain diluents, dispersants, surfactants, binders, and lubricants in order to formulate it into injectable formulations, such as aqueous solution, suspension, and emulsion, pills, capsules, granules and tablets.
- injectable formulations such as aqueous solution, suspension, and emulsion, pills, capsules, granules and tablets.
- the composition may preferably be formulated depending on particular diseases and its components, using the method described in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, which is a suitable method in the relevant field of art.
- composition of the present invention may be administered orally or parenterally
- the dosage of the composition can vary depending on various factors, including patient's weight, age, sex, health condition, and diet, and administration time, administration route, secretion rate, disease severity, etc., and the Araliae Cordatae Radix extract or compounds isolated from the extract can be administered at a daily dosage of about 0.1-100 mg/kg, preferably 0.1-10 D/D, more preferably one time or several times.
- composition of the present invention may be used alone or in combination with surgical operations, hormone therapies, chemical therapies, and other methods using biological reaction regulators in order to prevent or treat periodontitis.
- composition of the present invention may be formulated to a toothpaste, an oral rinse solution, an ointment, a spray, a dressing solution, a topical agent, a dental floss or a periodontal pack in order to prevent or treat periodontitis.
- suitable ingredients have to be used depending on the formulation or desirable efficacy in addition to the active ingredients as described above, and the composition may further contain additives such as abrasives, wetting agents, foaming agents, solubilizing agents, binders, sweeteners, pH regulators, preservatives, fluoride compounds, other active ingredients, flavors, brightening agents, coloring agents, astringents, solvents or the like.
- additives such as abrasives, wetting agents, foaming agents, solubilizing agents, binders, sweeteners, pH regulators, preservatives, fluoride compounds, other active ingredients, flavors, brightening agents, coloring agents, astringents, solvents or the like.
- Examples of the abrasive include calcium carbonate, precipitated silica, aluminum hydroxide, calcium monohydrogen phosphate, and insoluble sodium metaphosphate.
- the abrasive is used alone or in combination of two or more thereof, and in an amount of 1-60% by weight, preferably 10-50% by weight.
- wetting agent examples include glycerine, a sorbitol solution, polyethylene glycol, and propylene glycol.
- the wetting agent is used alone or in combination of two or more thereof, and in an amount of 10-60% by weight, preferably 20-50% by weight.
- foaming agent examples include anionic and non-ionic surfactant such as sodium lauryl sulfate, sodium lauryl sarcosinate, sucrose fatty-acid ester, poly- oxyethylene hardened castor oil, and polyoxyethylene-polyoxypropylene copolymer.
- anionic and non-ionic surfactant such as sodium lauryl sulfate, sodium lauryl sarcosinate, sucrose fatty-acid ester, poly- oxyethylene hardened castor oil, and polyoxyethylene-polyoxypropylene copolymer.
- the foaming agent is used alone or in combination of two or more thereof, and in an amount of 0.5-5% by weight, preferably 0.5-3% by weight.
- binder examples include sodium carboxymethyl cellulose, hydroxymethyl cellulose, carrageenan, xanthan gum, and sodium alginate.
- the binder is used alone or in combination of two or more thereof, and in an amount of 0.1-5% by weight, preferably 0.1-2% by weight.
- sweetener examples include saccharine sodium, aspartame, stevioside, xylitol, and glycyrrhetinic acid.
- the sweetener is used alone or in combination of two or more thereof, and preferably in an amount of 0.05-5% by weight.
- Examples of the pH-control agent include sodium phosphate, disodium phosphate, trisodium phosphate, sodium pyrophosphate, citric acid, sodium citrate, and tartaric acid.
- Examples of the preservative include paraoxybenzoic acid methyl, paraoxybenzoic acid propyl, and sodium benzoate, and the preservative is used alone or in combination of two or more thereof.
- Examples of the active ingredient include sodium fluoride, sodium monofluo- rophosphate, stannous fluoride, chlorohexidine, allantoinchlorohydroxyaluminate, aminocaproic acid, tranexamic acid, triclosan, cetylpyridinium chloride, zinc chloride, pyridoxine hydrochloride, and tocopherol acetate, and the active ingredient is used alone or in combination of two or more thereof.
- Examples of the flavor include peppermint oil, spearmint oil, menthol, and anethole, and suitable amounts of the flavors are blended to be used. Titanium oxide is blended as the brightening agent, and a food color is blended as the coloring agent. Purified water or ethanol is blended as the solvent.
- the composition of the present invention may be added to health foods for the purpose of improving diseases caused by periodontal disease. If the Araliae Cordatae Radix extract or compounds isolated from the same of the present invention is/are used as a food additive, the Araliae Cordatae Radix extract or compounds isolated from the same may be added as it is, or after being mixed with other food or ingredients, and may be suitably used according to a conventional method.
- the mixing ratio of active ingredients can be determined by the purpose of use (prevention, health or therapeutic treatment).
- the Araliae Cordatae Radix extract or compounds isolated from the same of the present invention is/are generally added by 15% by weight or less, preferably 10% by weight or less, to the raw material.
- the content of the active ingredient may be less than the above when it is administered for long-term to improve health and hygiene or to control health.
- the active ingredient can be used more than the above amount because the extract of the invention is very safe.
- Health beverages containing the composition of the present invention may additionally include various flavors or natural carbohydrates, like conventional beverages.
- the natural carbohydrates described above may include one of monosaccharide such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitole, sorbitol and erythritol.
- the sweetener either natural sweetener such as thaumatin and stevia extract or artificial sweetener such as saccharin and aspartame can be used.
- the ratio of natural carbohydrate per 100 ml of the composition of the present invention is generally about 0.01-0.04 g, preferably about 0.02-0.03 g.
- the composition of the present invention may include a variety of nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, arginic acid and its salts, organic acid, protective colloidal viscosifiers, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonators which used to be added to soda or the like.
- the composition of the present invention may also include natural fruit juice, fruit beverages and fruit flesh addable to vegetable beverages. All the mentioned ingredients can be added singly or in any combination thereof. The mixing ratio of those ingredients does not matter in fact, but is generally selected in the range of 0.01-0.1 part by weight per 100 parts by weights of the composition of the present invention. Mode for the Invention
- Liquid media consisting of 3% Trypticase Soy Broth (TSB), 0.5% yeast extract, 0.05% L-cysteine, 5 D/ml of Hemin, and 0.2 D/ml of vitamin K was used for the experiment. Each pathogen was cultured under anaerobic conditions (5% CO , 5% H , 90% N ) for 1-2 days.
- Each periodontal pathogen was cultured in 10 ml of the liquid media until reaching the late log phase, and each culture medium was diluted with the fresh media at a ratio of 1:50, and 200 D of each diluted medium was put in a microplate. Then, the ethanol extract of Araliae Cordatae Radix and hexane fraction of Araliae Cordatae Radix extract prepared in Example 1, and (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 and (-)-kaur-16-en-19-oic acid of Formula 2 prepared in Example 2 were added thereto at a predetermined concentration. Distilled water was added thereto as a control group.
- the liquid media containing cultured pathogens were completely resuspended with a pipette, and then optical density of each pathogen was measured using a microplate r eader at 590 nm, and culture degree in the liquid media was compared.
- FIG. 1 shows growth inhibitory effect on Porphyromonas endodontalis, Por- phyromonas gingivalis and Prevotella intermedia according to concentrations of the ethanol extract of Araliae Cordatae Radix of the present invention
- Fig. 2 shows growth inhibitory effect on Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia according to concentrations of the hexane fraction of Araliae Cordatae Radix extract of the present invention
- Fig. 1 shows growth inhibitory effect on Porphyromonas endodontalis, Por- phyromonas gingivalis and Prevotella intermedia according to concentrations of the hexane fraction of Araliae Cordatae Radix extract of the present invention
- Fig. 1 shows growth inhibitory effect on Porphyromonas endodontalis, Por- phyromonas gingivalis and Prevotella intermedia according to concentrations of the hexane fraction of
- Radix and hexane fraction of Araliae Cordatae Radix extract prepared in Example 1, and (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 and (-)-kaur-16-en-19-oic acid of Formula 2 prepared in Example 2 were cultured in the liquid media. 5 D of each culture medium was added dropwise to plate media, which were prepared by adding 1.5% agar to the culture media, for inoculation and cultured under anaerobic conditions for 1-2 days. Colony formation by the growth of each pathogen was observed to examine the minimum bactericidal concentration.
- Radix extract (or compound of Formula 1 or compound of Formula 2) of 20 - 95% by weight.
- Formula 2 of 0.5 ⁇ 5.0 % by weight was added to wheat flour, and foods for health improvement including bread, cake, cookies, cracker, and noodles were prepared using the mixture.
- Formula 2 of 10 % by weight was added to ground beef to prepare ground beef for health improvement.
- Formula 2 of 5 ⁇ 10 % by weight was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.
- Formula 2 was added to 1,000 ml of apple or grape juice to produce fruit juice for health improvement.
- the Araliae Cordatae Radix extract or compounds isolated from the extract according to the present invention has/have excellent antimicrobial and bactericidal activities against Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia, which are periodontal pathogens, thereby being used to prevent or treat periodontitis.
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Abstract
The present invention relates to a composition comprising an Araliae Cordatae Radix extract or compounds isolated from the same for preventing or treating periodontitis. The Araliae Cordatae Radix extract or compounds isolated from the extract according to the present invention has/have excellent antimicrobial and bactericidal activities against Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia, which are periodontal pathogens, thereby being used to prevent or treat periodontitis.
Description
Description
COMPOSITION COMPRISING ARALIAE CORDATAE RADIX
EXTRACT OR COMPOUNDS ISOLATED FROM THE SAME
FOR PREVENTING OR TREATING PERIODONTITIS
Technical Field
[1] The present invention relates to a composition comprising an Araliae Cordatae
Radix extract or compounds isolated from the same for preventing or treating periodontitis. Background Art
[2] Periodontal disease (gum disease) refers to a bacterial infection that results in the destruction of tissues that support the teeth and alveolar bone. A periodontal tissue is composed of alveolar bone, gingiva (gum), and periodontal ligament. Gingiva is a part of the tooth-supporting tissues of the mouth, in which gingivitis primarily occurs. If gingivitis may progress and spread to the supporting tissues, the periodontal ligament that is attached to bone tissue surrounding the tooth root and tooth is destroyed, and the alveolar bone is also destroyed, which leads to periodontal disease.
[3] Periodontal disease is the most common oral disease, in addition to dental caries.
Periodontal disease has various clinical symptoms such as gingival bleeding and swelling, periodontal pocket formation, loss of fixed gingiva, alveolar bone destruction, and halitosis, and is the main cause of tooth loss (AIi, R. W. et al., J. Clin. Periodontal. 1997, 24, 830-835; Socransky, S. S. et al., J. Clin. Periodontal. 1998, 15, 440-444). Periodontal disease is one of the most common chronic diseases of infectious origin known in humans, and the prevalence varies between 10-60% of adults, depending on diagnostic criteria (Xiong, X. et al., BJOG. 2006, 113, 135-143; Papapanou, P. N., Ann. Periodontal, 1996, 1, 1-36; Albandar, J. M. and T. E. Rams, Periodontal. 2000, 2002, 29, 7-10; Albandar, J. M., Periodontal. 2000, 2002, 29, 31-69; Offenbacher, S. et al, Ann. Periodontal, 2001, 6, 164-174).
[4] There are two major types of periodontal disease, gingivitis and periodontitis.
Gingivitis is an infection of the soft tissue surrounding the teeth or gingiva, and periodontitis involves destruction of the underlying supporting tissues such as periodontal ligament, alveolar bone, cementum, or soft tissue (Kinane D. F., Periodontol. 2000, 2001, 25, 8-20). Periodontitis is one of bacterial infectious diseases that may cause tooth loss, and a specific inflammatory condition that arises as the result of the interaction of microorganisms and their products causing inflammation in dental plaque (biofilm) (Feng, Z., and A. Weinberg, Periodontol. 2000, 2006, 40, 50-76). It has been estimated that 500-600 species of bacteria inhabit the human oral cavity, and among
them about 400 species of bacteria inhabit the subgingival plaque (Kazor, C. E. et al. J. Clin. Microbiol. 2003, 41, 558-563). Periodontal disease is initiated by excessive growth of gram-negative anaerobic bacterial species that inhabit the periodontal tissue and adjacent subgingival plaque. Severe inflammation and destruction are generated in the periodontal tissue supporting teeth by periodontal pathogens (Kinane D. F., Pe- riodontol. 2000. 2001, 25, 8-20; Kornman, K. S. et al., Periodontol. 2000, 1997, 14, 33-53).
[5] It has been reported that high correlation is found between periodontal disease and the risk of systemic diseases such as arteriosclerosis, myocardial infarction, cerebral apoplexy, diabetes, and pregnancy complications, and the reports have been increased for the past 10 years (Desvarieux, M. et al., Circulation, 2005, 111, 576-582; Of- fenbacher, S. et al., J. Periodontol., 1996, 67, 1103-1113; Garcia, R. I. et al., Periodontol. 2000, 2001, 25, 21-36; Champagne, C. M. et al., J. Int. Acad. Periodontol., 2000, 2, 9-13; Paquette, D. W., J. Int. Acad. Periodontol., 2002, 4, 101-119). It has been reported that pregnancy complications associated with periodontal disease is preterm birth, low birth weight, miscarriage, and preeclampsia (McCormick, M. C, N. Engl. J. Med., 1985, 312, 82-90; Shennan, A. H., BMJ, 2003, 327, 604-618). Periodontal disease is a high-risk factor for human health. Therefore, it can be said that development of its prevention method is more important than that of its treatment method.
[6] The treatment of periodontal disease can be divided into non-surgical and surgical procedures. In the early stages of periodontal disease, a physical method (scaling and root planing) removing plaque and calculus around teeth affected by periodontal disease is generally performed. However, the physical method can treat periodontal disease in the early stages, and more advanced cases may require surgical treatment (open flap curettage). Further, advanced periodontal disease defined by the destruction of the alveolar bone to one third of root apex is hardly treated, and thus the tooth has to be removed. That is, for treatment of periodontal disease, scaling, root planing, open flap curettage or the like is generally performed to remove causes such as plaque and calculus and to block the activities of inflammatory factors induced by the causes, thereby preventing the progress of periodontal disease and promoting complete regeneration of injured or defective periodontal tissue.
[7] In the early stage of periodontal disease, gingivitis can be easily treated only with scaling and oral hygiene care (brushing). However, in periodontal disease, advance and subsidence of clinical symptoms are repeated, and thus in its early stage, a patient does not visit a dental clinic for treatment. As the disease progresses to the middle stage, a patient visits a dental clinic, which generates a lot of economic and social loss. Therefore, it is the best way to prevent any further progress of periodontal disease. The
way to prevent periodontal disease is brushing with toothpaste, and a method using an oral rinse solution. Many researchers have recently studied on the development of antimicrobial agents or active formulations having antimicrobial effect against periodontal pathogens or increasing the activity of periodontal tissue in respect to toothpaste and oral rinse solution.
[8] A variety of antimicrobial agents including antibiotics with bactericidal or bacteriostatic effect against periodontal pathogens have been developed for inhibiting and treating dental caries, periodontal disease, and pulpal and periapical infection. However, the antibiotics may induce the emergence of resistant bacteria in oral cavity and superinfection, in addition to systemic side effects in the body, and thus the antibiotics is problematic for long-term use, but used as a therapeutic agent.
[9] Listerine that is one of the most popular antimicrobial agents worldwide, excluding antibiotics is an oral rinse solution containing phenol compounds such as thymol, eucalyptol, methyl salicylate, benzoic acid, and boric acid, and alcohol as a main ingredient. Listerine has Dental Association approval in the USA because of its effect of reducing plaque and gingivitis, and sold under various brand names. However, it has been reported that listerine does not effectively remove plaque, has not prominent antimicrobial effect, and has side effects such as burning sensation and staining of teeth. Further, chlorhexidine has been known as the most excellent therapeutic agent for preventing and treating periodontal disease and for inhibiting plaque formation. However, there are problems in that chlorhexidine has side effects such as tissue irritation, staining and discoloration of tissue, and a strong taste and smell, and may also induce superinfection. Further, chlorhexidine is carcinogenic, thereby not being used for pregnant women. Therefore, for the purpose of treating and preventing periodontal disease, chlorhexidine can not be used for long-term due to such limitations (Contemporary periodontics [ed. RJ. Genco et al.], pl61~169, p368~369, p433, CV. Mosby Company, St. Louis, 1990).
[10] In order to solve such problems in the treatment or prevention of periodontal disease using known antibiotics and chemical therapy, as increasingly interest has focused on antimicrobial materials extracted from herbal medicines, the development of a therapeutic agent for preventing or treating periodontal disease using the herbal materials has been needed.
[11] Meanwhile, Araliae Cordatae Radix is a medicinal plant, and its roots (Aralia cordata Thumberg, Araliaceae) are frequently used for muscle soreness, spastic paraplegia, headache, hemiplegia due to paralysis or the like. The root of Araliae Cordatae Radix contains a large amount of pimaric acid derivative, which is diterpene, as a fat-soluble ingredient, and a large amount of araloside, which is oleanolic acid or hederagenin saponin, as a water-soluble ingredient. Araliae Cordatae Radix has a
unique aromatic smell, and a muddy and slightly bitter taste. Araliae Cordatae Radix contains chemical ingredients including chlorogenic acid, alanine, glutamic acid, tyrosine, aspartic acid, asparagine (S-form, L- form), terpinen-4-ol, α-pinene, β-pinene, δ-cadinene, oleanolic acid, (-)-α-copaene, myrcene, p-cymene, 3(15),6-caryophylladiene, α-ocimene, (-)-limonen, 16-β-17-dihydroxy-kauran-19-oic acid, 3-0-β-D-glucuronopyranosyloleanolic acid, sabinene, camphene, kaurenoic acid, α-caryophyllene, 3-carene, trans-Sabinene hydrate (IR, 4R, 5R), udosaponin F methylester, udosaponine E methylester, udosaponine B methylester, udosaponine C methylester, udosaponine D methylester, udosaponine A methylester, β- D-glucopyranosylcolumbianetin, osthenol, osthol, bergapten, isoimperatorin, xanthotoxin, columbianadin, columbianetin, columbianetin acetate, angelol B.
[12] It has been recently reported that as the studies on Araliae Cordatae Radix, a flavonoid ingredient among active ingredients has antioxidant activity (Kor. J. Pharmacogn. 1998, 29(1), 13-17), and a poly acetylene ingredient has cytotoxicity against various cancer cell lines (Yakhak Hoeji, 1995, 39(2), 405-7). Further, an ingredient having analgesic and hypothermic effects has been isolated from Araliae Cordatae Radix (Chem. Pharm. Bull., 1991, 39(2), 405-7). Further, Korean Patent Registration No. 10-0513490 discloses a pharmaceutical composition for treating or preventing diseases caused by deficiency of growth hormone, in which an Araliae Cordatae Radix extract functions to promote release of growth hormone to increase the production of growth hormone. Korean Patent Registration No. 10-0224633 discloses a combustional composite for moxibustion in a mixed form of a variety of other herbal medicines including Araliae Cordatae Radix. Further, Japanese Patent Publication No. 1996-099993 discloses a method for extracting saponin from Araliae Cordatae Radix and use thereof, and Japanese Patent Publication No. 1996-283169 discloses a sugar absorption suppressing agent containing saponin mixture extracted from Araliae Cordatae Radix as an active ingredient. Further, Chinese Patent Publication No. CN 1276222A discloses that Araliae Cordatae Radix is used as an anti-inflammatory agent or used for treating cardiovascular and cerebrovascular diseases, Chinese Patent Publication No. CN 1273857A discloses that Araliae Cordatae Radix is used for fracture diseases as a composite, and Chinese Patent Publication No. CN 1236627A discloses that Araliae Cordatae Radix is used for diabetes, antitumor, and hyperos- teoblastic activity.
[13] Accordingly, various pharmacological activities of an Araliae Cordatae Radix extract or compounds isolated from the same have been reported, however there is no report of its pharmacological activities on periodontal disease. Disclosure of Invention
Technical Problem
[14] The present inventors have conducted studies on herbal medicines which has no toxicity to human and excellent antimicrobial activity against periodontal pathogens. They found that an Araliae Cordatae Radix extract and compounds isolated from the extract show very excellent antimicrobial activity against periodontal pathogens, thereby completing the present invention. Technical Solution
[15] The present invention provides a composition comprising an Araliae Cordatae
Radix extract or compounds isolated from the same for preventing or treating periodontitis. Brief Description of the Drawings
[16] Fig. 1 is a drawing showing growth inhibitory effect on Porphyromonas en- dodontalis (ATCC 35406), Porphyromonas gingivalis (ATCC 53978) and Prevotella intermedia (ATCC 25611) according to concentrations of the ethanol extract of Araliae Cordatae Radix of the present invention;
[17] Fig. 2 is a drawing showing growth inhibitory effect on Porphyromonas en- dodontalis, Porphyromonas gingivalis and Prevotella intermedia according to concentrations of the hexane fraction of Araliae Cordatae Radix extract of the present invention; and
[18] Fig. 3 is a drawing showing growth inhibitory effect on Porphyromonas en- dodontalis, Porphyromonas gingivalis and Prevotella intermedia according to concentrations of (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 of the present invention. Best Mode for Carrying Out the Invention
[19] The present invention provides a composition comprising an Araliae Cordatae
Radix extract for preventing or treating periodontitis.
[20] Further, the present invention provides a composition comprising a compound represented by the following Formula 1 for preventing or treating periodontitis.
[21] [Formula 1]
[22]
[23] Further, the present invention provides a composition comprising a compound
represented by the following Formula 2 for preventing or treating periodontitis. [24] [Formula 2]
[25]
[26] The compounds of Formulae 1 and 2 include compounds extracted and isolated from the Araliae Cordatae Radix.
[27] The composition according to the present invention includes a pharmaceutical composition, oral rinse composition and food composition.
[28] Hereinafter, the present invention will be described in detail.
[29] An Araliae Cordatae Radix is added to water, alcohol, or a mixed solvent thereof, and stirred at 5 to 4O0C to be filtered. Then, the resultant is concentrated under reduced pressure, and freeze-dried to give an Araliae Cordatae Radix extract according to the present invention as a powder. The mixed solvent of water and alcohol can be selected from 10 to 100% methanol and 10 to 100% ethanol, preferably 10 to 100% ethanol.
[30] The Araliae Cordatae Radix extract is added to distilled water, and suspended.
Then, hexane is added to the suspended extract, stirred at room temperature to separate a hexane layer, and concentrated under reduced pressure to remove the hexane layer. The resultant is freeze-dried to give a hexane fraction of Araliae Cordatae Radix extract as a powder.
[31] The hexane fraction of Araliae Cordatae Radix extract is subjected to a silica gel column chromatography with hexane-ethyl acetate gradient to separate and purify [(-)-pimara-8(14),15-diene-19-oic acid] as a compound of Formula 1 and [(-)-kaur-16-en-19-oic acid] as a compound of Formula 2.
[32] The Araliae Cordatae Radix extract according to the present invention or compound isolated from the same shows excellent antimicrobial and bactericidal activities against Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia, which are periodontal pathogens, thereby being used as a medicine, dental care product and health food to prevent or treat periodontal disease.
[33] The composition of the present invention may include at least one known active ingredient having the effects of preventing or treating periodontal disease in addition to the Araliae Cordatae Radix extract or compounds isolated from the same.
[34] For administration, the composition of the present invention can be prepared including at least one pharmaceutically acceptable carrier, in addition to the active in-
gredients as described above. Examples of the pharmaceutically acceptable carrier include a saline solution, sterile water, a Ringer's solution, a buffered saline solution, a dextrose solution, a maltodextrin solution, glycerol, ethanol and a mixture of two or more thereof. If necessary, the composition may also contain other conventional additives, such as antioxidants, buffers, and bacteriostatic agents. Moreover, the composition may additionally contain diluents, dispersants, surfactants, binders, and lubricants in order to formulate it into injectable formulations, such as aqueous solution, suspension, and emulsion, pills, capsules, granules and tablets. Furthermore, the composition may preferably be formulated depending on particular diseases and its components, using the method described in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, which is a suitable method in the relevant field of art.
[35] The composition of the present invention may be administered orally or parenterally
(for example, intravenous, subcutaneous, intraperitoneal, or topical application) depending on its purpose. The dosage of the composition can vary depending on various factors, including patient's weight, age, sex, health condition, and diet, and administration time, administration route, secretion rate, disease severity, etc., and the Araliae Cordatae Radix extract or compounds isolated from the extract can be administered at a daily dosage of about 0.1-100 mg/kg, preferably 0.1-10 D/D, more preferably one time or several times.
[36] The composition of the present invention may be used alone or in combination with surgical operations, hormone therapies, chemical therapies, and other methods using biological reaction regulators in order to prevent or treat periodontitis..
[37] The composition of the present invention may be formulated to a toothpaste, an oral rinse solution, an ointment, a spray, a dressing solution, a topical agent, a dental floss or a periodontal pack in order to prevent or treat periodontitis.
[38] For the formulation of the oral rinse composition, suitable ingredients have to be used depending on the formulation or desirable efficacy in addition to the active ingredients as described above, and the composition may further contain additives such as abrasives, wetting agents, foaming agents, solubilizing agents, binders, sweeteners, pH regulators, preservatives, fluoride compounds, other active ingredients, flavors, brightening agents, coloring agents, astringents, solvents or the like.
[39] Examples of the abrasive include calcium carbonate, precipitated silica, aluminum hydroxide, calcium monohydrogen phosphate, and insoluble sodium metaphosphate. The abrasive is used alone or in combination of two or more thereof, and in an amount of 1-60% by weight, preferably 10-50% by weight.
[40] Examples of the wetting agent include glycerine, a sorbitol solution, polyethylene glycol, and propylene glycol. The wetting agent is used alone or in combination of two
or more thereof, and in an amount of 10-60% by weight, preferably 20-50% by weight.
[41] Examples of the foaming agent include anionic and non-ionic surfactant such as sodium lauryl sulfate, sodium lauryl sarcosinate, sucrose fatty-acid ester, poly- oxyethylene hardened castor oil, and polyoxyethylene-polyoxypropylene copolymer. The foaming agent is used alone or in combination of two or more thereof, and in an amount of 0.5-5% by weight, preferably 0.5-3% by weight.
[42] Examples of the binder include sodium carboxymethyl cellulose, hydroxymethyl cellulose, carrageenan, xanthan gum, and sodium alginate. The binder is used alone or in combination of two or more thereof, and in an amount of 0.1-5% by weight, preferably 0.1-2% by weight.
[43] Examples of the sweetener include saccharine sodium, aspartame, stevioside, xylitol, and glycyrrhetinic acid. The sweetener is used alone or in combination of two or more thereof, and preferably in an amount of 0.05-5% by weight.
[44] Examples of the pH-control agent include sodium phosphate, disodium phosphate, trisodium phosphate, sodium pyrophosphate, citric acid, sodium citrate, and tartaric acid. Examples of the preservative include paraoxybenzoic acid methyl, paraoxybenzoic acid propyl, and sodium benzoate, and the preservative is used alone or in combination of two or more thereof.
[45] Examples of the active ingredient include sodium fluoride, sodium monofluo- rophosphate, stannous fluoride, chlorohexidine, allantoinchlorohydroxyaluminate, aminocaproic acid, tranexamic acid, triclosan, cetylpyridinium chloride, zinc chloride, pyridoxine hydrochloride, and tocopherol acetate, and the active ingredient is used alone or in combination of two or more thereof. Examples of the flavor include peppermint oil, spearmint oil, menthol, and anethole, and suitable amounts of the flavors are blended to be used. Titanium oxide is blended as the brightening agent, and a food color is blended as the coloring agent. Purified water or ethanol is blended as the solvent.
[46] Further, if the Araliae Cordatae Radix extract or compounds isolated from the same of the present invention is/are mixed with a conventional antibiotic, and then formulated as described above to be used, periodontal disease, pulpal and periapical diseases, and other oral diseases can be prevented or treated.
[47] The composition of the present invention may be added to health foods for the purpose of improving diseases caused by periodontal disease. If the Araliae Cordatae Radix extract or compounds isolated from the same of the present invention is/are used as a food additive, the Araliae Cordatae Radix extract or compounds isolated from the same may be added as it is, or after being mixed with other food or ingredients, and may be suitably used according to a conventional method. The mixing ratio of active
ingredients can be determined by the purpose of use (prevention, health or therapeutic treatment). In the case of producing food or beverages, the Araliae Cordatae Radix extract or compounds isolated from the same of the present invention is/are generally added by 15% by weight or less, preferably 10% by weight or less, to the raw material. However, the content of the active ingredient may be less than the above when it is administered for long-term to improve health and hygiene or to control health. However, the active ingredient can be used more than the above amount because the extract of the invention is very safe.
[48] There is no limit in applicable food, which is exemplified by meats, sausages, bread, chocolate, candies, snacks, cookies, pizza, ramyun, other noodles, chewing gums, dairy products including ice cream, soups, beverages, tea, drinks, alcoholic drinks and vitamin complex or the like, and in fact every health food generally produced are all included.
[49] Health beverages containing the composition of the present invention may additionally include various flavors or natural carbohydrates, like conventional beverages. Examples of the natural carbohydrates described above may include one of monosaccharide such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitole, sorbitol and erythritol. As the sweetener, either natural sweetener such as thaumatin and stevia extract or artificial sweetener such as saccharin and aspartame can be used. The ratio of natural carbohydrate per 100 ml of the composition of the present invention is generally about 0.01-0.04 g, preferably about 0.02-0.03 g.
[50] In addition to the ingredients mentioned above, the composition of the present invention may include a variety of nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, arginic acid and its salts, organic acid, protective colloidal viscosifiers, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonators which used to be added to soda or the like. The composition of the present invention may also include natural fruit juice, fruit beverages and fruit flesh addable to vegetable beverages. All the mentioned ingredients can be added singly or in any combination thereof. The mixing ratio of those ingredients does not matter in fact, but is generally selected in the range of 0.01-0.1 part by weight per 100 parts by weights of the composition of the present invention. Mode for the Invention
[51] Hereinafter, the preferred Examples are provided for better understanding.
However, these Examples are for the illustrative purpose only, and the invention is not intended to be limited by these Examples.
[52] Example 1 : Preparation of Araliae Cordatae Radix extract
[53] 1. Preparation of ethanol extract of Araliae Cordatae Radix
[54] 300 g of powder of dried Araliae Cordatae Radix were added to 200 ml of 80% ethanol aqueous solution, and stirred at room temperature for 3 days (this procedure was repeated three times). The resulting solution obtained after stirring was filtered with a filter paper, and then concentrated under reduced pressure to remove the solvent. The resultant was freeze-dried and moisture was completely removed to give 50 g of ethanol extract of Araliae Cordatae Radix as a powder.
[55] 2. Preparation of hexane fraction of Araliae Cordatae Radix extract
[56] 200 ml of distilled water was added to 50 g of ethanol extract of Araliae Cordatae
Radix prepared in the above process, and suspended well. Then, 200 ml of hexane was added thereto. After stirring, the resulting solution was stayed in place. Then, a hexane layer was separated, and concentrated under reduced pressure. Hexane was removed, and then freeze-dried to give 25 g of hexane fraction of Araliae Cordatae Radix extract as a powder.
[57]
[58] Example 2 : Separation of compound from hexane fraction of Araliae
Cordatae Radix extract
[59] 200 ml of hexane was added to 25 g of hexane fraction of Araliae Cordatae Radix extract prepared in Example 1, and evenly dissolved. Then, a silica gel column chromatography was performed with hexane-ethyl acetate gradient to separate and purify 150 mg of the compound of Formula 1 and 10 mg of the compound of Formula 2.
[60] Physical/chemical properties of the compounds represented by Formulae 1 and 2 are as follows (Dang, N. H. et al., Arch. Pharm. Res., 2005, 28, 28-33).
[61] <Compound of Formula 1>
[62] : (-)-pimara-8(14),15-diene-19-oic acid [C H O ]
[63]
[64] - Feature: Colorless needle (hexane);
[65] - Melting point: 165-1660C;
[66] - [α]D-120° (c=0.75, CHCl3);
[67] - UV λ MeOH nm (log ε: 213 (3.34); max
[68] - IR v max cm"1: 1690 (C=O); I1
[69] - H-NMR (300 MHz, CDCl ) δ: 5.69 (IH, dd, J = 10.5, 17.1 Hz, H-15), 5.17 (IH,
s, H-14), 4.96 (IH, dd, J= 2.1, 5.1 Hz, H- 16b), 4.90 (IH, dd, J= 2.1, 10.5 Hz, H- 16a),
1.32 (3H, s, H-18), 1.02 (3H, s, H-17), 0.68 (3H, s, H-20); [70] - 13C-NMR (75 MHz, CDCl ) δ: 39.6 (C-I), 20.0 (C-2), 38.4 (C-3), 44.4 (C-4), 56.5
(C-5), 24.5 (C-6), 36.2 (C-7), 138.3 (C-8), 50.9 (C-9), 38.9 (C-IO), 19.6 (C-I l), 36.8
(C-12), 39.6 (C-13), 128.4 (C- 14), 147.6 (C-15), 113.2 (C-16), 29.7 (C-17), 14.1
(C-18), 183.9 (C-19), 29.5 (C-20). [71 ] <Compound of Formula 2>
[72] : (-)-kaur-16-en-19-oic acid [C H O ]
20 30 2
[73]
[74] - Feature: Cubic crystal (hexane- acetone);
[75] - Melting point: 178~180°C;
[76] - [α] -110°(c=1.00, CHCl );
[77] - UV λ max MeOH nm (log ε: 211 (3.23);
[78] - IR v max cm"1: 3450 (OH), 1690 (C=O), 1470 (C=C);
[79] - 1H-NMRQOO MHz, CDCl ) δ: 4.76-4.82 (IH each, br s, H-17), 2.66(1H, br s, H-
13), 2.07 (2H, d, J= 3.0 Hz, H-6), 1.61-1.63(2H, m, H-I l), 1.4-1.6 (4H, m, H-7, 12), 1.26 (3H, s, H-18), 1.0-2.2 (4H, m, H-2, 3), 1.07-1.09 (IH, m, H-5), 0.98(3H, s, H-20), 0.83 (2H, dd, J = 4.2, 13.2 Hz, H-I);
[80] - 13C-NMR(75 MHz, CDCl3) δ: 41.1 (C-I), 19.5 (C-2), 38.2 (C-3), 44.3 (C-4), 57.5
(C-5), 22.2 (C-6), 41.7 (C-7), 44.6 (C-8), 55.5 (C-9), 40.7 (C-10), 18.8 (C-I l), 33.5 (C-12), 44.1(C- 13), 40.1 (C-14), 49.4 (C-15), 156.3 (C-16), 103.4 (C-17), 29.4 (C-18), 184.7 (C-19), 16.0 (C-20).
[81]
[82] Experimental Example 1 : Antimicrobial activity test (Determination of minimum inhibitory concentration)
[83] In order to confirm antimicrobial activity of the Araliae Cordatae Radix extract or compounds isolated from the same according to the present invention against periodontal pathogens, the following experiment was performed.
[84] Periodontal pathogens used in the experiment were Porphyromonas endodontalis
(ATCC 35406), Porphyromonas gingivalis (ATCC 53978) and Prevotella intermedia (ATCC 25611). Liquid media consisting of 3% Trypticase Soy Broth (TSB), 0.5% yeast extract, 0.05% L-cysteine, 5 D/ml of Hemin, and 0.2 D/ml of vitamin K was used
for the experiment. Each pathogen was cultured under anaerobic conditions (5% CO , 5% H , 90% N ) for 1-2 days.
[85] Each periodontal pathogen was cultured in 10 ml of the liquid media until reaching the late log phase, and each culture medium was diluted with the fresh media at a ratio of 1:50, and 200 D of each diluted medium was put in a microplate. Then, the ethanol extract of Araliae Cordatae Radix and hexane fraction of Araliae Cordatae Radix extract prepared in Example 1, and (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 and (-)-kaur-16-en-19-oic acid of Formula 2 prepared in Example 2 were added thereto at a predetermined concentration. Distilled water was added thereto as a control group. The liquid media containing cultured pathogens were completely resuspended with a pipette, and then optical density of each pathogen was measured using a microplate r eader at 590 nm, and culture degree in the liquid media was compared.
[86] Fig. 1 shows growth inhibitory effect on Porphyromonas endodontalis, Por- phyromonas gingivalis and Prevotella intermedia according to concentrations of the ethanol extract of Araliae Cordatae Radix of the present invention, Fig. 2 shows growth inhibitory effect on Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia according to concentrations of the hexane fraction of Araliae Cordatae Radix extract of the present invention, and Fig. 3 shows growth inhibitory effect on Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia according to concentrations of (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 of the present invention.
[87] As shown in Fig. 1, when the ethanol extract of Araliae Cordatae Radix of the present invention was added to media at the concentration of 15 D/ml, the growth of Porphyromonas endodontalis was inhibited by 90% or more. The growth of Porphyromonas gingivalis was inhibited by 90% or more at the concentration of 40 D/ml, and the growth of Prevotella intermedia was inhibited by 90% or more at the concentration of 12 D/ml.
[88] Further, as shown in Fig. 2, when the hexane fraction of Araliae Cordatae Radix extract of the present invention was added to media at the concentration of 6 D/ml, the growth of Porphyromonas endodontalis was inhibited by 90% or more. The growth of Porphyromonas gingivalis was inhibited by 90% or more at the concentration of 3.5 D/ml, and the growth oΨrevotella intermedia was inhibited by 90% or more at the concentration of 5 D/ml.
[89] Further, as shown in Fig. 3, when the compound of Formula 1 of the present invention was added to media at the concentration of 3 D/ml, the growth of Porphyromonas endodontalis was inhibited by 90% or more. The growth of Porphyromonas gingivalis was inhibited by 90% or more at the concentration of 2.5 D/ml, and the growth of Prevotella intermedia was inhibited by 90% or more at the con-
centration of 3 D/ml. In the case of adding the compound of Formula 2 of the present invention, the result was similar to that of the compound of Formula 1.
[90]
[91] Experimental Example 2 : Bactericidal activity test (Determination of minimum bactericidal concentration)
[92] In order to confirm bactericidal activity of the Araliae Cordatae Radix extract or compounds isolated from the same according to the present invention against periodontal pathogens, the following experiment was performed.
[93] As described in Experimental Example 1, the ethanol extract of Araliae Cordatae
Radix and hexane fraction of Araliae Cordatae Radix extract prepared in Example 1, and (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 and (-)-kaur-16-en-19-oic acid of Formula 2 prepared in Example 2 were cultured in the liquid media. 5 D of each culture medium was added dropwise to plate media, which were prepared by adding 1.5% agar to the culture media, for inoculation and cultured under anaerobic conditions for 1-2 days. Colony formation by the growth of each pathogen was observed to examine the minimum bactericidal concentration.
[94] If colony formation by the growth of pathogen in the liquid media was observed on the plate media, it means that the cultured pathogen was not completely killed. If colony formation was not observed on the plate media, it means that the cultured pathogen was completely killed.
[95] As a result, colonies of Porphyromonas endodontalis were not formed on the plate media, when the ethanol extract of Araliae Cordatae Radix of the present invention was added to the culture media at a concentration of 25 D/ml. Colonies of Porphyromonas gingivalis were not formed on the plate media at the concentration of 50 D/ml, and colonies oΨrevotella intermedia were not formed on the plate media at the concentration of 25 D/ml.
[96] Further, colonies of Porphyromonas endodontalis were not formed on the plate media, when the hexane fraction of Araliae Cordatae Radix extract of the present invention was added to the culture media at a concentration of 8 D/ml. Colonies of Porphyromonas gingivalis were not formed on the plate media at the concentration of 8 D/ml, and colonies oΨrevotella intermedia were not formed on the plate media at the concentration of 8 D/ml.
[97] Further, colonies of Porphyromonas endodontalis were not formed on the plate media, when (-)-pimara-8(14),15-diene-19-oic acid of Formula 1 of the present invention was added to the culture media at a concentration of 4 D/ml. Colonies of Porphyromonas gingivalis were not formed on the plate media at the concentration of 3 D/ml, and colonies oΨrevotella intermedia were not formed on the plate media at the concentration of 3.5 D/ml.
[98] Further, colonies of Porphyromonas endodontalis were not formed on the plate media, when (-)-kaur-16-en-19-oic acid of Formula 2 of the present invention was added to the culture media at a concentration of 8 D/ml. Colonies oΨorphyromonas gingivalis were not formed on the plate media at the concentration of 4 D/ml, and colonies of Prevotella intermedia were not formed on the plate media at the concentration of 4 D/ml.
[99] Accordingly, it was found that the Araliae Cordatae Radix extract or compounds isolated from the same according to the present invention has/have excellent antimicrobial and bactericidal activities against periodontal pathogens.
[100]
[101] Hereinbelow, Formulation Examples for the composition of the present invention will be illustrated.
[102] Formulation Example 1 : Preparation of pharmaceutical formulation
[103] 1. Preparation of powder formulation
[104] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) 2 g
[105] Lactose 1 g
[106] The above ingredients were mixed, and charged in an air-tight package to prepare a powder formulation.
[107] 2. Preparation of tablet formulation
[108] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) 100 mg
[ 109] Corn starch 100 mg
[110] Lactose 100 mg
[111] Magnesium stearate 2 mg
[112] The above ingredients were mixed, and then table tted according to a conventional preparation method to prepare a tablet formulation.
[113] 3. Preparation of capsule formulation
[114] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) 100 mg
[115] Corn starch 100 mg
[116] Lactose 100 mg
[117] Magnesium stearate 2 mg
[118] The above ingredients were mixed, and then sealed in a gelatin capsule according to a conventional preparation method to prepare a capsule formulation.
[119]
[120] Formulation Example 2 : Preparation of food
[121] Foodstuffs containing the Araliae Cordatae Radix extract,
(-)-pimara-8(14),15-diene-19-oic acid of Formula 1, or (-)-kaur-16-en-19-oic acid of
Formula 2 of the present invention were prepared as follows. [122] 1. Preparation of cooking seasoning
[123] A cooking seasoning for health improvement was prepared using Araliae Cordatae
Radix extract (or compound of Formula 1 or compound of Formula 2) of 20 - 95% by weight.
[124] 2. Preparation of tomato ketchup and sauce
[125] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) of 0.2 ~ 1.0 % by weight was added to tomato ketchup or sauce to prepare tomato ketchup or sauce for health improvement. [126] 3. Preparation of flour food
[127] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) of 0.5 ~ 5.0 % by weight was added to wheat flour, and foods for health improvement including bread, cake, cookies, cracker, and noodles were prepared using the mixture.
[128] 4. Preparation of soup and gravies
[129] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) of 0.1 ~ 5.0 % by weight was added to soup and gravies to prepare soup and gravies of processed meat products and noodles for health improvement. [130] 5. Preparation of ground beef
[131] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) of 10 % by weight was added to ground beef to prepare ground beef for health improvement.
[132] 6. Preparation of dairy products
[133] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) of 5 ~ 10 % by weight was added to milk, and various dairy products such as butter and ice cream were prepared using the milk. [134]
[135] Formulation Example 3 : Preparation of beverage
[136] 1. Preparation of carbonated beverage
[137] Additives including 5-10% sugar, 0.05-0.3% citric acid, 0.005-0.02% caramel, and 0.1-1% vitamin C were mixed with each other, and 79-94% of purified water was mixed therewith to prepare syrup. The syrup was sterilized at 85-980C for 20-180 seconds, and then mixed with cooling water at the ratio of 1:4. Then, carbon dioxide gas (0.5-0.82%) was given to the mixture to prepare carbonated beverages containing the Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) of the present invention. [138] 2. Preparation of health beverage
[139] Additive materials including liquid fructose (0.5%), oligosaccharide (2%), sugar
(2%), salt (0.5%) and water (75%) were all mixed with the Araliae Cordatae Radix extract (or compound of Formula 1 or compound of Formula 2) evenly, followed by sterilization. The mixture was put in a small container such as a glass bottle or pat bottle, resulting in beverages for health improvement. [ 140] 3. Preparation of vegetable juice
[141] 5 g of Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) was added to 1,000 ml of tomato or carrot juice to prepare vegetable juice for health improvement. [ 142] 4. Preparation of fruit juice
[143] 1 g of Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) was added to 1,000 ml of apple or grape juice to produce fruit juice for health improvement. [144]
[145] Formulation Example 4 : Preparation of dental care product
[146] 1. Toothpaste
[147] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) 1 mg
[148] Aluminum hydroxide 47 mg
[149] Sodium monofluorophosphate 0.76 mg
[150] Glycerine 5 mg
[151] Sorbitol solution 40 mg
[152] Sodium carboxymethylcellulose 0.7 mg
[153] Silicon dioxide 4 mg
[154] Sodium laurylsulfate 2 mg
[155] Methyl paraben 0.15 mg
[156] Flavor 1 mg
[157] Titanium dioxide 0.4 mg
[158] Sodium saccharin 0.2 mg
[159] Purified water Residual amount
[160] 2. Oral rinse solution
[161] Araliae Cordatae Radix extract (or compound of Formula 1 or compound of
Formula 2) 0.1 mg [ 162] Sodium fluoride 0.22 mg
[163] Triclosan 0.03 mg
[164] Glycerine 3.0 mg
[165] Sorbitol solution 10.0 mg
[166] Prophylene glycol 5.0 mg
[167] Xylitol 2.0 mg
[168] Ethanol (edible) 5.0 mg
[169] Sodium saccharin 0.10 mg
[170] Polyoxyethylene hardened castor oil 2.50 mg
[171] Sodium lauryl sulfate 0.20 mg
[172] Flavor 0.20 mg
[173] L-Menthol 0.20 mg
[174] Purified water Residual amount
Industrial Applicability
[175] The Araliae Cordatae Radix extract or compounds isolated from the extract according to the present invention has/have excellent antimicrobial and bactericidal activities against Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia, which are periodontal pathogens, thereby being used to prevent or treat periodontitis.
Claims
[9] An oral rinse composition comprising a compound represented by the following Formula 2. [Formula 2]
[10] The oral rinse composition according to any one of claims 7 to 9, wherein the composition is formulated to a toothpaste, an oral rinse solution, an ointment, a spray, a dressing solution, a topical agent, a dental floss or a periodontal pack.
[H] A food composition comprising an Araliae Cordatae Radix extract for improving periodontitis. [12] A food composition comprising a compound represented by the following Formula 1 for improving periodontitis. [Formula 1]
[13] A food composition comprising a compound represented by the following Formula 2 for improving periodontitis. [Formula 2]
Applications Claiming Priority (2)
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KR10-2006-0113000 | 2006-11-15 | ||
KR1020060113000A KR100829045B1 (en) | 2006-11-15 | 2006-11-15 | Composition comprising araliae cordatae radix extract or compounds isolated from the same for preventing or treating periodontitis |
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PCT/KR2007/005741 WO2008060112A1 (en) | 2006-11-15 | 2007-11-15 | Composition comprising araliae cordatae radix extract or compounds isolated from the same for preventing or treating periodontitis |
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WO (1) | WO2008060112A1 (en) |
Cited By (5)
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WO2013035333A1 (en) * | 2011-09-08 | 2013-03-14 | 株式会社ロッテ | Oral composition |
CN103432309A (en) * | 2013-08-18 | 2013-12-11 | 董翠兰 | Preparation method of traditional Chinese medicine for treating liver depression forming fire-type periapical periodontitis |
CN103432398A (en) * | 2013-08-18 | 2013-12-11 | 刘长河 | Preparation method of traditional Chinese medicine for treating fever-type periapical periodontitis |
CN103432446A (en) * | 2013-08-18 | 2013-12-11 | 李红 | Method for preparing traditional Chinese medicine for treating dark urine type periapical periodontitis |
CN103463383A (en) * | 2013-08-18 | 2013-12-25 | 董翠兰 | Preparation method of traditional Chinese medicine for treatment of constipation type periapical periodontitis |
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KR101245582B1 (en) | 2012-09-24 | 2013-03-20 | 김창호 | Composition for controlling of rice blast containing aralia continentalis extract and a method of controlling rice blast using the composition |
KR102496013B1 (en) | 2015-11-30 | 2023-02-06 | (주)아모레퍼시픽 | Skin external composition containing aralosides |
KR102500957B1 (en) * | 2021-06-04 | 2023-02-17 | 김철한 | Herbal medicine extract composition for gargle and its manufacturing method |
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JP2004123630A (en) * | 2002-10-03 | 2004-04-22 | Chisso Corp | Cariostatic and antiperiodontic composition |
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JP2004123630A (en) * | 2002-10-03 | 2004-04-22 | Chisso Corp | Cariostatic and antiperiodontic composition |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013035333A1 (en) * | 2011-09-08 | 2013-03-14 | 株式会社ロッテ | Oral composition |
JP2013056855A (en) * | 2011-09-08 | 2013-03-28 | Lotte Co Ltd | Oral composition |
CN103781466A (en) * | 2011-09-08 | 2014-05-07 | 罗蒂株式会社 | Oral composition |
US10201493B2 (en) | 2011-09-08 | 2019-02-12 | Lotte Co., Ltd. | Method of reducing oral biofilm |
CN103432309A (en) * | 2013-08-18 | 2013-12-11 | 董翠兰 | Preparation method of traditional Chinese medicine for treating liver depression forming fire-type periapical periodontitis |
CN103432398A (en) * | 2013-08-18 | 2013-12-11 | 刘长河 | Preparation method of traditional Chinese medicine for treating fever-type periapical periodontitis |
CN103432446A (en) * | 2013-08-18 | 2013-12-11 | 李红 | Method for preparing traditional Chinese medicine for treating dark urine type periapical periodontitis |
CN103463383A (en) * | 2013-08-18 | 2013-12-25 | 董翠兰 | Preparation method of traditional Chinese medicine for treatment of constipation type periapical periodontitis |
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