[go: up one dir, main page]

WO2019039810A1 - Composition comprenant un extrait de lonicera coerulea pour la prévention ou le traitement de la douleur - Google Patents

Composition comprenant un extrait de lonicera coerulea pour la prévention ou le traitement de la douleur Download PDF

Info

Publication number
WO2019039810A1
WO2019039810A1 PCT/KR2018/009517 KR2018009517W WO2019039810A1 WO 2019039810 A1 WO2019039810 A1 WO 2019039810A1 KR 2018009517 W KR2018009517 W KR 2018009517W WO 2019039810 A1 WO2019039810 A1 WO 2019039810A1
Authority
WO
WIPO (PCT)
Prior art keywords
pain
group
control group
extract
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2018/009517
Other languages
English (en)
Korean (ko)
Inventor
엄주환
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H&K BIOSCIENCE CO Ltd
Original Assignee
H&K BIOSCIENCE CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by H&K BIOSCIENCE CO Ltd filed Critical H&K BIOSCIENCE CO Ltd
Publication of WO2019039810A1 publication Critical patent/WO2019039810A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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)
    • A61K36/35—Caprifoliaceae (Honeysuckle family)
    • A61K36/355—Lonicera (honeysuckle)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health

Definitions

  • the present invention relates to a composition for prevention or treatment of pain comprising a farinacea tree extract, and more particularly to a pharmaceutical composition for preventing or treating pain, including a farinacea tree extract or a fraction thereof, a food composition, a quasi-drug composition, .
  • Pain is caused by a variety of causes. If the pain persists for a long period of time or if the stimulus is too severe, it may interfere with daily life and cause anxiety and fear. Therefore, people with chronic pain often have depression. In particular, it is known that 7-8% of the population is suffering from neuropathic pain caused by injury or disease. Primary dysmenorrhea, or menses, has a prevalence of 45- 95%, it is urgent to develop materials and methods for treating such diseases.
  • acetylsalicylic acid, ibuprofen, acetaminophen, and indomethacin are widely used to treat pain.
  • the above-mentioned painkillers are effective when they are administered in a high dose, and when they are effective in the early stage, they are resistant to long-term use and often have no effect.
  • amitriptyline is widely used as an analgesic and antidepressant in chronic pain patients, and is known to exhibit relatively strong anti-inflammatory and antioxidative effects.
  • cardiac toxicity Goodnick PJ, Expert Opin Pharmacother. 2002, 3: 479-98 .; Thanacoody HK, Toxicol Rev. 2005, 24: 205-14.
  • a new analgesic agent having excellent analgesic effect even at a low dose is urgently required.
  • an analgesic agent including gold silver is developed (Korean Patent Registration No. 10-0554079). It is well known that Lonicera japonica Thunb. Has excellent thermoregulation, antipyretic, detoxification and antiinflammatory effects, and in particular, it has antiseptic and analgesic effects. Earthen flower buds or flowers that start to bloom are widely used as traditional medicines as medicines.
  • Lonicera caerulea var. Edulis is a plant in Korea, China and Japan. Its fruit has been used as a traditional medicine.
  • the fruit of the japanese tree is rich in ascorbic acid, phenolic compounds such as anthocyanins and flavonoids having excellent antioxidative effects, and has excellent lipid and glucose metabolism improving effect, liver protecting effect, anti-inflammatory effect and promoting wound healing It is known.
  • its analgesic effect was not known.
  • the herbal extract according to the present invention exhibits analgesic effects such as suppression of weight loss, cold allodynia, mechanical allodynia, menstrual pain and the like, and thus can be effectively used for preventing, improving or treating analgesia.
  • FIG. 1 is an image showing a step-by-step process of CCI (Chronic Constriction Injury) surgery according to an embodiment of the present invention.
  • FIG. 2 is a schematic diagram of an experiment for confirming the analgesic effect on neuropathic pain of a farina tree extract (hereinafter referred to as 'BH') according to an embodiment of the present invention.
  • FIG. 3 is a schematic view of an experiment for confirming the analgesic effect on the menstrual cramp of the Butterfly tree extract according to an embodiment of the present invention.
  • FIG. 4 is a graph showing the effect of weight gain of the above-described Swine Extract on the neuropathic pain rat model.
  • Fig. 5 is a graph showing writhing, i.e., abdominal pain-reducing effect, of the abdomen in the model of the rats.
  • 500 mg / kg body weight 500 mg / kg BH 500 mg / kg body weight, and 500 mg / kg BH 500 mg / kg body weight, respectively, for intact control, / kg, 250 BH for 250 mg / kg BH, and 125 BH for 125 mg / kg BH.
  • a indicates that p ⁇ 0.01 as compared with the normal control as a result of LSD test
  • b indicates that p ⁇ 0.01 as compared with the pseudorabies control group as a result of LSD test.
  • Fig. 6 is an image showing the effect of reducing the uterine congestion and enlargement of the above-described Swallow's tree extract in a ricket-cell rat model. Scale bars represent 11 mm, A is a normal control group, B is a menstrual control group, C is an indomethacin 5 mg / kg, D is a 500 mg / kg LF group, and E is 500 mg / kg BH , F means 250 mg / kg BH, and G means 125 mg / kg BH.
  • FIG. 7 is a graph showing the effect of uterus weights reduction on the uterine weight of the above-described Swallow's tree extract in a menses-based rat model.
  • a and b indicate that p ⁇ 0.01 and p ⁇ 0.05, respectively, as compared with the normal control group, and c indicates that p ⁇ 0.01 as compared with the control group, and d indicates the MW test as compared with the normal control group p < 0.01, and e indicates that p < 0.01 as compared to the dumbbell control group as a result of MW test.
  • FIG. 8 is an image showing the effect of reducing the inflammation in the uterine tissue of the above-described Swine Extract in the model of the rats in the rats.
  • FIG. 8 shows the thickness of the entire uterus.
  • B is a 500 mg / kg BH group
  • F is a BH group
  • B is a normal control group.
  • B is a control group
  • C is an indomethacin 5 mg / kg group
  • D is LF 500 mg / kg group, 250 mg / kg administration group
  • G means 125 mg / kg BH administration group.
  • a and b indicate that p ⁇ 0.01 and p ⁇ 0.05, respectively, as compared with the normal control group, and c indicates that p ⁇ 0.01 as compared with the control group, and d indicates the MW test as compared with the normal control group p ⁇ 0.01, and e indicates that p ⁇ 0.01 as compared to the dumbbell control group as a result of MW test.
  • FIG. 9 shows immunoreactive cells against TNF-.alpha. And iNOS-2 as an image showing the effect of reducing the inflammation in the uterine tissue of the above-described Butterfly tree extract in a menses-rat model.
  • B is a 500 mg / kg BH group
  • F is a BH group
  • B is a normal control group.
  • B is a control group
  • C is an indomethacin 5 mg / kg group
  • D is LF 500 mg / kg group, 250 mg / kg administration group
  • G means 125 mg / kg BH administration group.
  • one aspect of the present invention provides a pharmaceutical composition for preventing or treating pain, comprising a farina tree extract or a fraction thereof.
  • the present inventors have confirmed that the extract of Staphylococcus aureus reduces weight loss, cold / mechanical allodynia and abdominal pain by relieving pain in rats induced pain, and the pain relieving effect is inhibited by peroxidation, microglial cell / Inhibition of expression of proinflammatory cytokines, promotion of antioxidative activity, and inhibition of inflammation.
  • the above-described Butterfly tree extract can be effectively used for preventing, ameliorating or treating pain.
  • buttock tree refers to Lonicera caerulea var. means a deciduous broad-leaved shrub and has a scientific name of edulis L, honeysuckle, and more Blueberry (var. emphyllocalyx), broad leaf daengdaengyi (var. longibracteata), round leaves daengdaengyi include various sub-species, called the like (var. venulosa) one , But is not limited thereto.
  • the fruit of the buttock tree is elliptical berry, which is blackened in autumn and eaten raw. It is known that the fruit of the buttock tree is effective for dementia, wrinkle improvement, whitening, etc. However, the therapeutic effect on the pain has not been known and it was firstly described by the present inventors.
  • roots, stems, leaves, fruits, flowers and the like of the buttock tree may be used for preventing or treating pain, and more specifically, fruits may be used.
  • fruits may be used.
  • it is not limited.
  • the butt-knot can be purchased commercially, sold in the nature, or cultivated.
  • extract refers to an extract obtained by extracting the buttock tree, a diluted solution or concentrate of the extract, a dried product obtained by drying the extract, a controlled preparation or a purified product of the extracted solution, Itself and extracts of all formulations which can be formed using extracts.
  • the method of extracting the buttock wood is not particularly limited, and may be extracted according to a method commonly used in the art.
  • Non-limiting examples of the extraction method include hydrothermal extraction, ultrasonic extraction, filtration, and reflux extraction. These may be performed alone or in combination with two or more methods.
  • the type of the extraction solvent used for extracting the butte wood is not particularly limited, and any solvent known in the art can be used.
  • Nonlimiting examples of the extraction solvent include water, alcohols having 1 to 4 carbon atoms, and mixed solvents thereof. These solvents may be used alone or in combination.
  • fraction of the present invention means a product obtained by performing fractionation to separate a specific component or a specific component group from a mixture containing various components.
  • the fractionation method for obtaining the fraction is not particularly limited and may be carried out according to a method commonly used in the art.
  • Non-limiting examples of the fractionation method include a solvent fractionation method performed by treating various solvents, an ultrafiltration fractionation method performed through an ultrafiltration membrane having a constant molecular weight cut-off value, various chromatography (size, charge, hydrophobicity Or affinity-based separation), and a combination thereof, and the like.
  • the kind of the fraction solvent used for obtaining the fraction in the present invention is not particularly limited, and any solvent known in the art can be used.
  • Non-limiting examples of the fraction solvent include polar solvents such as water and alcohols having 1 to 4 carbon atoms; Non-polar solvents such as hexane (Hexan) and ethyl acetate (Ethyl acetate); Or a mixed solvent thereof. These may be used alone or in combination of one or more, but the present invention is not limited thereto.
  • extract or fraction may be prepared and used in the form of a dry powder after extraction, but is not limited thereto.
  • pain refers to an unpleasant sensation caused by stimulation of a specific nerve having a pain receptor, and includes all symptoms that the sensation is alleviated, prevented or cured by the leaves of the Japanese persimmon tree or its fractions . It is commonly referred to as headache, chest pain, abdominal pain, back pain, etc., depending on the area of the pain. Somatic pain, visceral pain, and neuropathic pain are classified according to the generation of the pain.
  • the pain may include anatomically distinct pain, such as neck pain, back pain, back pain, chest pain, head pain, and the like.
  • the pain is caused by nociceptive pain due to cell damage, psychogenic pain caused by psychological conditions, inflammatory pain associated with tissue damage and immune cell infiltration, Or neuropathic pain caused by its abnormal function, and the like.
  • the painful water-soluble pain may include a somatic tube and a visceral tube.
  • the pain may be at least one selected from the group consisting of achromatic pain, cardiogenic pain, inflammatory pain and neuropathic pain, and more particularly, it may be at least one selected from the group consisting of painful pain, inflammatory pain, cancer pain and postoperative pain; Trigeminal neuralgia pain corresponding to neuropathic pain, idiopathic pain and diabetic neuropathic pain; And a migraine head and a menstrual cramp corresponding to a visceral tube, but the present invention is not limited thereto.
  • prophylactic of the present invention refers to any act that inhibits or delays pain by administration of a composition comprising the Swallow's tree extract or its fractions.
  • treatment refers to any action in which the pain is alleviated, improved or beneficially altered by the administration of a composition comprising the farinacea tree extract.
  • composition of the present invention can also treat or prevent secondary symptoms such as appetite suppression and weight gain caused by pain.
  • the extract of Staphylococcus aureus exhibits analgesic effects such as inhibition of weight loss, cold allodynia and mechanical allodynia in rats induced by chronic constriction injury (CCI) surgery 4, and Tables 3 to 5), the analgesic effect was due to a decrease in spinal lipid peroxidation, an increase in antioxidant activity of the spinal cord, a decrease in the expression of microglia / astrocytic cell activation factor in spinal cord tissues, and a decrease in expression of proinflammatory cytokines (Tables 6, 7, 9 and 11).
  • estradiol benzoate and oxytocin induced weight loss inhibition and abdominal analgesia (Table 12 and Fig.
  • the herb extract or its fractions exhibit therapeutic effects of pain caused by various causes, and exhibit effects such as suppression / reduction / alleviation / improvement of pain. Therefore, the pharmaceutical composition of the present invention Suggesting that the composition can be usefully used for preventing or treating pain. Moreover, such an effect is higher or similar to existing drugs such as amitriptyline, indomethacin or gingival extract, and provides a possibility as a therapeutic agent derived from safe natural products.
  • the pharmaceutical composition of the present invention may include, but is not limited to, 0.001 to 80, specifically 0.001 to 70, more specifically 0.001 to 60% by weight of the above-described farinacea extract or fraction thereof, based on the total weight of the composition.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent conventionally used in the manufacture of a pharmaceutical composition, which carrier may comprise a non-naturally occuring carrier have.
  • carrier examples include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, But are not limited to, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
  • the pharmaceutical composition may be formulated into tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze- And the formulations may be of various forms, such as oral or parenteral. In the case of formulation, it may be prepared by using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like which are usually used, but the present invention is not limited thereto.
  • solid formulations for oral administration tablets, pills, powders, granules, capsules and the like may be used.
  • These solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like may be used.
  • excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like may be used.
  • lubricants such as magnesium stearate, talc, and the like may be used, but the present invention is not limited thereto.
  • liquid preparation for oral administration suspensions, solutions, emulsions, syrups and the like may be used.
  • various excipients such as wetting agents, sweeteners, Etc. may be used.
  • sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations or suppositories may be used.
  • non-aqueous solvent and suspension agent include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
  • suppository base examples include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like, but the present invention is not limited thereto.
  • Another embodiment provides a method for treating pain, comprising administering the pharmaceutical composition to a subject in which pain is caused or suspected of being caused.
  • administering means introducing a composition comprising said Swine Extract or fraction thereof to a subject in an appropriate manner.
  • individual of the present invention means all animals such as rats, mice, livestock, etc., including humans, in which pain can be induced or induced. As a specific example, it may be a mammal and may be an individual other than a human.
  • the pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the species and severity, age, sex, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts.
  • the pharmaceutical composition may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. In addition, it can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by a person skilled in the art.
  • the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be determined depending on the condition and weight of the patient, , The type of drug, the route of administration, and the time, but may be suitably selected by those skilled in the art.
  • the pharmaceutical composition may be administered in an amount of generally 0.001 to 1000 mg / kg, more particularly 0.05 to 200 mg / kg, most specifically 0.1 to 100 mg / kg, once / ,
  • the preferred dosage may be appropriately selected by those skilled in the art depending on the condition and the weight of the individual, the degree of disease, the type of drug, the route of administration and the period of time.
  • Another embodiment provides a food composition for preventing or ameliorating pain comprising a farinacea tree extract or a fraction thereof.
  • the food composition of the present invention can be ingested routinely, it can be expected to have an excellent effect of improving pain and unlike general drugs, there is no side effect that may occur when a natural product is used as a raw material, It can be very useful for preventing or improving pain.
  • improvement of the present invention means any action that reduces the degree of the parameter associated with the condition being treated, such as the severity of symptoms, by administration of the food composition.
  • food of the present invention includes dairy products such as meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, various soups, drinks, tea, , A vitamin complex, a health functional food, and a health food, all of which include foods in a conventional sense.
  • the health functional food is the same term as food for special health use (FoSHU).
  • the health functional food has a high medical effect, It means food.
  • 'function (sex)' refers to the structure and function of the human body to obtain nutritional effects or obtain a beneficial effect for health use such as physiological action.
  • the health food refers to a food having an active health promotion or promotion effect compared with a general food, and a health supplement food refers to a food for health assistance.
  • the terms health functional foods, health foods, and health supplements may be used interchangeably.
  • the health functional food is a food prepared by adding the Swine Extract or its fraction of the present invention to a food material such as a beverage, a tea, a spice, a gum, or a confection, or encapsulating, pulverizing, , But it has the advantage that there is no side effect that can occur when a drug is taken for a long time using a food as a raw material unlike a general medicine.
  • the food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and components which are conventionally added in the art.
  • the food composition can be produced in various forms without limitations as long as it is a food-acceptable formulation.
  • the food composition may further comprise a physiologically acceptable carrier.
  • the carrier is not particularly limited and any carrier conventionally used in the art can be used.
  • the food composition may contain additional components that are commonly used in food compositions and can improve odor, taste, visual appearance, and the like.
  • Minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu) and chromium (Cr); And amino acids such as lysine, tryptophan, cysteine, valine, and the like.
  • the food composition may contain at least one kind selected from the group consisting of preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate), disinfectants (such as bleaching powder and highly bleached white powder, sodium hypochlorite), antioxidants (butylhydroxyanisole (BHA) (Sodium nitrite), bleach (sodium sulfite), seasoning (sodium MSG glutamate, etc.), sweeteners (dicin, cyclamate, saccharin, etc.), coloring agents , Sodium, etc.), perfume (vanillin, lactones, etc.), swelling agents (alum, potassium hydrogen D-tartrate), emulsifiers, thickeners (foams), encapsulating agents, gum bases, foam inhibitors, solvents, And may include food additives.
  • the additives can be selected according to the type of food and used in an appropriate amount.
  • the extract of Staphylococcus aureus exhibits analgesic effects such as inhibition of weight loss, cold allodynia and mechanical allodynia in rats induced by chronic constriction injury (CCI) surgery 4, and Tables 3 to 5), the analgesic effect was due to a decrease in spinal lipid peroxidation, an increase in antioxidant activity of the spinal cord, a decrease in the expression of microglia / astrocytic cell activation factor in spinal cord tissues, and a decrease in expression of proinflammatory cytokines (Tables 6, 7, 9 and 11).
  • estradiol benzoate and oxytocin induced weight loss inhibition and abdominal analgesia (Table 12 and Fig.
  • the herb extract or its fractions exhibit the effect of treating or improving the pain caused by various causes, and exhibit the effects of inhibiting / reducing / alleviating / improving the pain.
  • the present invention Suggesting that the food composition of the present invention can be usefully used for prevention or improvement of pain.
  • Another embodiment provides a quasi-drug composition for preventing or ameliorating pain comprising a farina tree extract or a fraction thereof.
  • quasi-drug product of the present invention refers to products which are used for diagnosis, treatment, improvement, alleviation, treatment or prevention of diseases of human beings or animals, and whose action is less than that of drugs.
  • Quasi-drugs are products that are used for the treatment or prevention of diseases of humans / animals, products which are mild to the human body or which do not act directly.
  • the quasi-drug composition of the present invention may be manufactured by, but not limited to, a body cleanser, a foam, a soap, a mask, an ointment, a cream, a lotion, an essence and a spray.
  • the composition may be manufactured in the form of bands, sanitary napkins, etc., but is not limited thereto.
  • the composition may be added as it is or may be used together with other quasi-drugs or quasi-drugs, and may be suitably used according to a conventional method.
  • the amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use.
  • the extract of Staphylococcus aureus exhibits analgesic effects such as inhibition of weight loss, cold allodynia and mechanical allodynia in rats induced by chronic constriction injury (CCI) surgery 4, and Tables 3 to 5), the analgesic effect was due to a decrease in spinal lipid peroxidation, an increase in antioxidant activity of the spinal cord, a decrease in the expression of microglia / astrocytic cell activation factor in spinal cord tissues, and a decrease in expression of proinflammatory cytokines (Tables 6, 7, 9 and 11).
  • estradiol benzoate and oxytocin induced weight loss inhibition and abdominal analgesia (Table 12 and Fig.
  • the herb extract or its fractions exhibit the effect of treating or improving the pain caused by various causes, and exhibit the effects of inhibiting / reducing / alleviating / improving the pain.
  • the present invention Of quasi-drug compositions may be useful for preventing or improving pain.
  • the BH contained 4.54 ⁇ 0.09% of betaine, 210.63 ⁇ 23.65 mg of GAE / g of total phenols, 159.30 ⁇ 12.51 mg of CE / g of total flavonoids, 133.5 of total antocyanins ⁇ 4.06 mg M3GE / g was included.
  • Example 1-1 1 liter of 25% ethyl alcohol was added to 100 g of pulverized royal jelly as in Example 1-1, and the mixture was thoroughly stirred. Then, the mixture was heat-refluxed for 3 hours at an extraction temperature of 80 to 90 ° C., The herbal medicine extract was concentrated under reduced pressure at 55 to 65 ° C and then lyophilized to obtain 19.5 g of herbal composition powdery extract.
  • BH contained 4.54 ⁇ 0.09% of betaine, 210.63 ⁇ 23.65 mg of GAE / g of total phenol, 159.30 ⁇ 12.51 mg of CE / g of total flavonoid and 133.57 ⁇ 4.06 mg of M3GE / g of total anthocyanin.
  • Experimental Example 1-1 An experimental animal in which neuropathic pain was induced
  • a total of 70 male rats (SPF / VAF Outbred Crl: CD) were obtained (OrientBio, Seungnam, Korea) for 7 days and then subjected to sham-surgery or CCI constriction injury) surgery. After 24 hours of operation, eight experimental animals of similar weight were selected for each group. At this time, the control group and the experimental group are shown in Table 1 below, and classified according to the type of surgery and the drug to be administered.
  • a total of 73 female SD (SPF / VAF Outbred Crl: CD) rats were obtained (OrientBio, Seungnam, Korea) and purified for 28 days, and menstrual cramps were induced by administering a damping inducer according to the method described in Experimental Example 3 below. Then, 10 animals with similar body weights were selected for each group. At this time, the control group and the experimental group are as shown in Table 2 below, and classified according to the type of surgery and the drug to be administered.
  • CCI chronic constriction injury
  • the sham control was not closed after confirming the left sciatic nerve by the same method, and the muscle and the skin were closed in the same manner.
  • rats were administered estradiol benzoate and oxytocin.
  • estradiol benzoate was subcutaneously administered once a day for 10 days (2.5 mg / kg at the initiation and final administration and 1 mg / kg when administered 2 to 9 times), and then the estradiol One hour after administration of benzoate, 1 U / kg of oxytocin was administered in a single dose.
  • estradiol benzoate and oxytocin were suspended or dissolved in physiological saline and administered subcutaneously or intraperitoneally with a 26 G needle attached to a 5 ml syringe.
  • physiological saline was subcutaneously or intraperitoneally injected at the same dose and frequency.
  • FIG. 2 The method of administering the drug to the control group, the comparative group and the experimental group according to the present invention is shown in detail in FIG. 2 and FIG.
  • the test drug, BH was dissolved in sterile distilled water at concentrations of 100, 50, and 25 mg / ml, and adhered to a 5 ml syringe for 14 days at a dose of 5 ml / kg (500, 250 and 125 mg / Orally administered with zonde.
  • the highest dose of BH 500 mg / kg was set based on the results of previous studies on the evaluation of pharmacological effect and mouse toxicity in hypothyroidism rat models of the present inventors (Kim HS, Toxicol Res. 2015, 31 : 61-8.).
  • intermediate doses (250 mg / kg) and low doses (125 mg / kg) were set for half the doses.
  • the comparative drug, LF was dissolved in sterilized distilled water at a concentration of 100 mg / ml and orally administered at the dose of 5 ml / kg (500 mg / kg) for the same period and method as the BH administration.
  • Amitriptyline another comparative drug, was dissolved in saline at a concentration of 2 mg / ml and was injected with a dose of 5 ml / kg (10 mg / kg) from 24 hours after CCI surgery, Were intraperitoneally administered using a 26 G needle attached to the mouse.
  • the administration dose and administration method of amitriptyline were set as known in the art (Berrocoso E, Eur J Pharmacol. 2011, 655: 46-51).
  • Indomethacin another comparative drug, was suspended in sterile distilled water at a concentration of 1 mg / ml and dosed with 5 ml / kg (5 mg / kg) once daily for 10 days with estradiol benzoate Min, orally administered with sonde attached to a syringe.
  • the dosage and administration method of the indomethacin were set as known in the art (Kim et al., J Periodontal Res. 2012, 47: 800-10).
  • distilled water was orally administered by the same period and in the same manner as the BH administration in order to apply the same correction and stress to the administration.
  • Example 1-1 Check changes in weight and weight gain
  • body weight was measured once a day on the 1st, 3rd, 7th, 10th, and 14th days after the administration of the drug (day 0) and 24 hours after the CCI surgery, respectively.
  • the weight gain after 14 days of administration was calculated as shown in Equation 1 below. The results are shown in FIG. 4 and Table 3 below.
  • the body weight was increased 3 days after the start of administration compared with the CCI control.
  • the body weight gain was increased by 2200.00 and 1291.67%, respectively, as compared with the CCI control group
  • the 500 mg / kg BH group showed similar or better weight gain and reduced body weight gain than the amitriptyline 10 mg / kg group and LF 500 mg / kg group.
  • CCI causes a variety of allodynia, such as cold allodynia, very similar to the clinical symptoms of human neuropathic pain (Jasmin L, KPain 1998, 75: 367-82.).
  • the rats were placed on a metal plate at a low temperature (4 ⁇ 1 ° C), and a transparent plastic box (280 ⁇ 250 ⁇ ) was prepared using a hot / cold plate test system (Model 35150, Ugo Basile SRL) 210 mm 3 , Varese, Italy). The number of times the rats lifted the left hind paw for 2 minutes was then calculated as a painful response. At this time, this experiment was performed at 24 hours after CCI surgery, before (0 day) and 1, 3, 7, 10 and 14 days after administration of the drug, respectively.
  • a hot / cold plate test system Model 35150, Ugo Basile SRL
  • cold allodynia decreased from 3 days after administration of BH 500, 250 and 125 mg / kg, respectively, as compared with CCI control.
  • the three BH-treated groups showed a dose-dependent reduction of cold allodynia, and it was confirmed that the cold allodynia was reduced by -55.93, -41.81 and -31.07% on the 14th day of the drug administration .
  • the BH 500 mg / kg group showed a similar cold aldosterol reduction effect as the amitriptyline 10 mg / kg group and the LF 500 mg / kg group, and the low dose BH 125 mg / kg group also showed lower LF 500 mg / It was confirmed that it exhibits excellent cold allodynia reduction effect.
  • CCI causes a variety of allodynia, including mechanical allodynia, which is very similar to the clinical symptoms of human neuropathic pain (Jasmin L, KPain 1998, 75: 367-82.).
  • the rat subjected to the low-temperature plate test according to Example 1-2 was put on a wire net in the air and was confined in Perspex boxes (185 x 210 x 135 mm 3 ). The pain was then measured using a dynamic plantar aesthesiometer system (Model 37450, Ugo Basile SRL, Varese, Italy) and von Frey filament (Bio-VF -M, Bioseb, Chaville, France) in grams (g). 50 g was set as the cutoff limit, and the force inducing the retraction reaction was set as a threshold. At this time, this experiment was performed at 24 hours after CCI surgery, at 1, 3, 7, 10, and 14 days after administration of the drug (0 day), and the results are shown in Table 5 below.
  • the threshold value was increased 3 days after the start of administration compared with the CCI control group. Also, at the 14th day of drug administration, the threshold value was increased by 126.13 and 43.24%, respectively, as compared with the CCI control group.
  • the threshold values of BH 500, 250 and 125 mg / kg administration groups were significantly increased after 3 days of administration compared to the CCI control group.
  • the dose-dependent threshold increase was observed in the three BH-treated groups, and that the threshold values were increased by 121.62, 81.08 and 48.65%, respectively, on the 14th day of the administration of the drug compared to the CCI control group.
  • the 500 mg / kg BH group exhibited a similar or better threshold increase effect than the amitriptyline 10 mg / kg group and the LF 500 mg / kg group.
  • Example 2-1 Decreased effect of spinal lipid peroxidation
  • oxidative stress is one of the causes of chronic neuropathic pain
  • MDA is the final product of lipid peroxidation, which is useful as a measure of lipid peroxidation (Messarah M, Exp. Toxicol Pathol. 2010, 62: 301-10 .).
  • the lumbosacral spinal cord of the L4-L6 portion was separated from the rats in which the von Frey hair filament test according to Example 1-3 was completed, and the weight thereof was measured. Thereafter, a bead beater (Model TacoTMPre, GeneResearch Biotechnology Corp., Taichung, Taiwan) and an ultrasonic cell crusher (manufactured by Takara Shuzo) in a buffer solution composed of 10 mM sucrose, 10 mM Tris-HCl and 0.1 M MEDTA (Model KS-750, Madell Technology Corp., Ontario, CA) and centrifuged at 12,000 g for 15 minutes. The homogenate of the obtained spinal cord tissues was stored at -150 ° C until use with a cryocooler (MDF-1156, Sanyo, Tokyo, Japan).
  • a cryocooler MDF-1156, Sanyo, Tokyo, Japan
  • the degree of peroxidation of the spinal cord lipid was confirmed by measuring the absorbance at 525 nm using a thiobarbituric acid test and a UV / Vis spectrophotometer (OPTIZEN POP, Mecasys, Daejeon, Korea) Concentration (nM). Total protein content was calculated using bovine serum albumin as the internal standard. The results are shown in Table 6 below.
  • d shown in Table 6 indicates that p ⁇ 0.01 as compared with the surgical control group as a result of MW test, and e indicates that p ⁇ 0.01 as compared with the CCI control as a result of MW test.
  • the MDA content that is, the peroxidation of the spinal cord lipid was significantly increased and the peroxidation was increased by 264.60% as compared with the gastric surgery control group.
  • the spinal lipid peroxidation was decreased in comparison with the CCI control group.
  • the degree of peroxidation was -55.27, -51.26 and -41.99% Respectively.
  • the BH 500 mg / kg group showed a similar decrease in peroxidation compared with the 10 mg / kg group of amitriptyline and the 500 mg / kg group of LF, and the lower dose of 125 mg / kg of BH was also superior to the LF 500 mg / kg group And it was confirmed that it showed the effect of reducing the degree of peroxidation.
  • the extract of P. japonica reduces the MDA content of the rat, i.e., the lipid peroxidation of the spinal cord lipid, and exhibits a similar or better spinal lipid peroxidation effect as that of amitriptyline or gingival extract, Therefore, it can be used as a preventive or therapeutic agent for neuropathic pain.
  • Example 2-2 Identification of function improvement of spinal cord antioxidant defense system
  • GSH glutathione
  • SOD superoxide dismutase
  • CAT catecholamines
  • GSH is a typical endogenous antioxidant, which controls tissue injury by removing ROS at a relatively low concentration in cells (Odabasoglu F, J Ethnopharmacol. 2006, 103: 59-65).
  • SOD and CAT are also endogenous antioxidant enzymes and act as part of the enzyme defense system of cells (Cheeseman KH, Br Med Bull. 1993, 49: 481-93).
  • the prepared homogenate was mixed with 0.1 ml of 25% trichloroacetic acid (Merck, San Francisco, Calif., USA) and centrifuged at 4,200 rpm for 40 minutes at 4,200 rpm.
  • GSH content was measured using a spectrophotometer at 412 nm using 2-nitrobenzoic acid (Sigma-Aldrich, St. Louis, Mo., USA) and expressed as concentration per gram of protein (nM).
  • CAT activity is defined as the amount of enzyme required to degrade 1 nM H 2 O 2 per minute at 25 ° C and pH 7.8, the amount of H 2 O 2 remaining measured using a spectrophotometer at an absorbance of 240 nm, Concentration (U).
  • SOD activity can be confirmed by the degree of formation of superoxide radicals.
  • SOD reacts with NBT (nitroblue tetrazolium) xanthine is produced, and xanthine oxidase ), Superoxide radicals are produced.
  • the supercoxide radical was measured at 560 nm using a spectrophotometer and expressed as a concentration (U) per mg of protein.
  • 1U means the amount of enzyme which reduces the initial absorbance of NBT by 50% for 1 minute. The results are shown in Table 7 below.
  • GSH content, SOD activity and CAT activity that is, antioxidative activity were significantly decreased in the CCI control group compared to the gastric surgery control group, and the degree of decrease was -59.62%, -63.41 % And -86.51%, respectively.
  • the antioxidant activity of spinal cord was increased in the case of 10 mg / kg of amitriptyline and 500 mg / kg of LF compared to the CCI control.
  • GSH content, SOD activity and CAT activity were increased by 76.43, 95.39 and 388.56%, respectively, in the amitriptyline-treated group.
  • GSH content, SOD activity and CAT activity were increased by 56.02, 48.39 and 160.70%, respectively, in the LF administration group.
  • the antioxidative activity of spinal cord was increased and the antioxidative activity was increased dose-dependently in comparison with the CCI control group in the BH 500, 250 and 125 mg / kg administration groups.
  • GSH content, SOD activity and CAT activity were 95.23, 100.46 and 402.49% for the 500 mg / kg BH group, respectively; 70.14, 87.10 and 317.41% for the BH 250 mg / kg administration group, respectively; , And 57.79, 48.39 and 157.21%, respectively, for the 125 mg / kg BH group.
  • BH 500 mg / kg administration group showed better antioxidant activity than amitriptyline 10 mg / kg and LF 500 mg / kg administration group.
  • the extract of Thymus nuts increases the GSH content, SOD activity and CAT activity of the rat, that is, the antioxidant activity of the spinal cord, and particularly the antioxidant activity of the amitriptyline or gallium arsenide extract As a result, it could be used as a preventive or therapeutic agent for neuropathic pain.
  • microglia and astrocytic activation factors in the spinal cord namely Iba-1 (Ionized calcium-binding adapter molecule-1) and GFAP fibrillary acidic protein expression was confirmed by RT-PCR analysis.
  • microglial cells and astrocytes are activated in response to nerve injury and are known to cause various neuropathies such as neurotoxicity, chronic inflammation and hyperpolarization, and chronic neuropathic pain (Milligan ED, Nat Rev Neurosci. 2009 , 10: 23-36).
  • Target factor 5 'to 3' order NCBI accession No. Iba-1 Forward CAGACTGCCAGCCTAAGACA (SEQ ID NO: 1) NM_017196 Reverse AGGAATTGCTTGTTGATCCC (SEQ ID NO: 2) GFAP Forward AGAAAACCGCATCACCATTCC (SEQ ID NO: 3) NM_017009 Reverse CAGGGCTCCATTTTCAATCTG (SEQ ID NO: 4) GAPDH Forward GCTAGGACTGGATAAGCAGGG (SEQ ID NO: 5) NM_017008 Reverse GCCAAATCCGTTCACACCG (SEQ ID NO: 6)
  • the expression of the activating factor was decreased in the 10 mg / kg group of amitriptyline and the 500 mg / kg of LF group compared to the CCI control group. Specifically, the amount of mRNA expression of Iba-1 and GFAP was decreased by -42.87 and -30.31%, respectively, in the group treated with amitriptyline. In addition, in the LF-treated group, mRNA expression levels of Iba-1 and GFAP were decreased by -30.18 and -17.53%, respectively.
  • the expression of the activating factor in the spinal cord was decreased and the expression level was decreased dose-dependently in the BH 500, 250 and 125 mg / kg administration group, as compared with the CCI control group.
  • the mRNA expression levels of Iba-1 and GFAP were -40.91 and -26.90%, respectively, in the group administered with BH 500 mg / kg; -37.07 and -23.56% for BH 250 mg / kg treated group, respectively; And decreased by -31.44 and -17.18%, respectively, in the 125 mg / kg BH group.
  • the BH 500 mg / kg group showed a decrease in the expression of microglial cells and astrocytic cell activation factors similar or superior to those of the amitriptyline 10 mg / kg group and LF 500 mg / kg group, and the low dose BH 125 mg / kg was also superior to the LF 500 mg / kg group.
  • the extract of Thymus nuts decreases the expression level of mRNA of Iba-1 and GFAP in the rat spinal cord, that is, the expression of microglial cells and astrocytic cell activating factor, and particularly amitriptyline And exhibit similar or better expression reduction effects as the Euglena extract, it can be used as a preventive or therapeutic agent for neuropathic pain.
  • Examples 2-4 Decreased expression of proinflammatory cytokines in spinal cord tissues
  • proinflammatory cytokines in the spinal cord namely TNF (Tumor Necrosis Factor) - ⁇ and iNOS (Inducible Nitric Oxide Synthase ) MRNA expression was confirmed by RT-PCR analysis.
  • proinflammatory cytokines are also involved in neuropathic pain, and the expression of proinflammatory cytokines such as TNF- ⁇ and iNOS following neuronal injury triggers an inflammatory reaction, resulting in pain (Liang F, Saudi Pharm J. 2017 , 25: 649-54.).
  • RT-PCR was carried out using primers as shown in Table 10 by the method according to Example 2-3, and the results are shown in Table 11 below.
  • Target factor 5 'to 3' order NCBI accession No. TNF-a Forward CTACTGAACTTCGGGGTGAT (SEQ ID NO: 7) NM_012675 Reverse CTTGGTGGTTTGTGAGTGTG (SEQ ID NO: 8) iNOS Forward AGCCTAGTCAACTGCAAGAG (SEQ ID NO: 9) NM_012611 Reverse TCTTGTATTGTTGGGCTGAGA (SEQ ID NO: 10)
  • c shown in Table 11 shows that p ⁇ 0.01 compared to the surgical control group as a result of MW test, and d indicates that p ⁇ 0.01 as compared with CCI control.
  • the expression level of TNF- ⁇ and iNOS mRNA was significantly increased in the CCI control group compared to the gastric surgery control group and increased by 291.01 and 538.28% Respectively.
  • the expression of the cytokine was decreased in the case of 10 mg / kg of amitriptyline and 500 mg / kg of LF compared to the CCI control.
  • the amount of mRNA expression of TNF- ⁇ and iNOS in the group treated with amitriptyline was -52.11 and -62.13%, respectively.
  • the amount of TNF- ⁇ and iNOS mRNA expression was decreased by -30.87 and -41.48%, respectively, in the LF-treated group.
  • the expression of the cytokine in the spinal cord was decreased in the BH 500, 250 and 125 mg / kg administration group as compared to the CCI control group.
  • the expression levels of TNF- ⁇ and iNOS mRNA were -53.58 and -62.11%, respectively, in the group administered with BH 500 mg / kg; -45.75 and -50.44% for the BH 250 mg / kg administration group, respectively; And -31.35 and -41.30%, respectively, for the 125 mg / kg BH group.
  • the BH 500 mg / kg group showed a similar or better effect to the activation factor than the amitriptyline 10 mg / kg group and the LF 500 mg / kg group, and the low dose BH 125 mg / kg group also showed LF And 500 mg / kg, respectively.
  • the extract of Staphylococcus aureus decreases the expression level of TNF- ⁇ and iNOS mRNA in rat spinal cord, that is, the expression of proinflammatory cytokine, and is similar to that of amitriptyline or gingkoff extract Or exhibit a more excellent proinflammatory cytokine expression reduction effect, it can be used as a preventive or therapeutic agent for neuropathic pain.
  • Example 3-1 Check changes in weight and weight gain
  • estradiol benzoate promotes the secretion of endogenous and exogenous cholecystokinin hormones, and thus feels fullness. Therefore, the menstrual cramps caused by estradiol benzoate are directly linked to poor appetite, resulting in significant weight loss. Thus, inhibition of weight loss is an important indicator of analgesic effects on menstrual cramps (Asarian L et al., Endocrinology 2007, 148: 5656-66.).
  • body weight was measured once a day for 10 days before the treatment with estradiol benzoate (0 day) and last administration (9 days).
  • the weight gain after 10 days of administration was calculated as shown in Equation 2 below. The results are shown in Table 12 below.
  • the BH 500, 250, and 125 mg / kg administration groups showed significant weight gain compared to the menstrual control group.
  • dose-dependent weight gain was observed in the three BH-treated groups, and the body weight gain was increased by 141.98, 104.26, and 82.97% on the 10th day of drug administration, respectively.
  • the low dose of 125 mg / kg of BH showed similar or better inhibitory effects on body weight gain and body weight gain than the 5 mg / kg of indomethacin and 500 mg / kg of LF.
  • the degree of menstrual pain is measured through abdominal stiffness, and an increase in abdominal stiffness response generally means an increase in abdominal pain (Yang et al., J Agr Food Chem. 2004, 52: 6787-93).
  • the rats were placed in a separate polycarbonate box (280 x 420 x 180 mm) and the stump of the abdomen was recorded for 30 minutes. Two authors were recorded in a double-blind manner for the accuracy of the results.
  • the degree of strangulation was decreased in the BH 500, 250, and 125 mg / kg administration groups as compared with the menstrual control group.
  • the three BH-treated groups showed dose-dependent wrinkle reduction, and the degree of writhing was -42.78, -33.08, and -23.88%, respectively, as compared to the control group.
  • the 500 mg / kg BH group exhibited a similar or better abdominal weight reduction effect to the indomethacin 5 mg / kg group and the LF 500 mg / kg group.
  • Example 4-1 Confirming the effect of suppressing uterine congestion and enlargement
  • Oxidative stress or inflammation is one of the major pathogenesis of menstrual cramps, causing uterine congestion and edema resulting in increased uterine weight (Chen L et al., J Sci Food Agric., 2014, 94: 180- 8.).
  • the rats were sacrificed and uterine weights were measured at g level (absolute wet weight). To reduce individual differences, the weight of the relative uterus (% of body weight) was calculated using Equation 3 using the weight at sacrifice.
  • the BH 500, 250 and 125 mg / kg administration group also showed a decrease in uterine congestion and edema symptoms compared to the control group.
  • the three BH-treated groups showed a dose-dependent reduction in uterine conization and edema symptoms, and the relative weight of the uterus was decreased by -38.58, -34.55 and -25.01%, respectively, as compared with the control group.
  • the 500 mg / kg BH group had similar or better uterine weight reduction effects than the 5 mg / kg indomethacin group and 500 mg / kg LF group.
  • the extract of Staphylococcus aureus decreases the uterine weight by reducing the symptoms of uterine congestion and edema in rats induced by menstrual cramps, and in particular, a uterus similar or superior to the indomethacin or gingival extracts Weight reduction effect, it can be used as a preventive or therapeutic substance for menstrual cramps.
  • Oxidative stress is one of the causes of menstrual cramps, and MDA is the final product of lipid peroxidation, which is useful as a measure of lipid peroxidation (Chen L et al., J Sci Food Agric., 2014, 94: 180 -8.).
  • the left uterine horn tissues were separated from the uterus weight-measured rats according to Example 4-1, and their weights were measured. Thereafter, a homogeneous liquid of the uterine tissue was obtained by the method according to Example 2-1, and MDA was measured therefrom. The results are shown in Table 13 below.
  • the peritoneal lipid peroxidation was decreased in comparison with the control group, and the degree of peroxidation was -70.07, -56.90 and -46.46% Respectively.
  • the BH 500 mg / kg group showed a better reduction of peroxidation compared with the 10 mg / kg group of amitriptyline and the 500 mg / kg group of LF, and the LH 500 mg / kg group It was confirmed that it exhibited a superior degree of peroxidation reduction.
  • the extract of Thymus nuts decreases the MDA content of rats, i.e., the lipid peroxidation of uterine lipids, and exhibits a similar or better cervical lipid peroxidation effect than the indomethacin or gingkofumhara extracts, , And as a preventive or therapeutic agent for menstrual cramps.
  • Example 4-3 Improvement of function of antioxidant defense system in uterine tissues
  • Example 14 the activity of GSH content, SOD, and CAT was determined by the method according to Example 2-2 with respect to the homogeneous liquid of uterine tissue prepared in Example 4-2. The results are shown in Table 14 below.
  • GSH content, SOD activity, and CAT activity i.e., antioxidative activity, were significantly decreased in the case of the menstrual pain control group compared to the normal control group, which was -67.47%, -51.63%, and -66.55% Respectively.
  • the antioxidant activity of spinal cord was increased and the dose - dependent antioxidative activity was also increased in the BH 500, 250 and 125 mg / kg group, compared to the control group.
  • GSH content, SOD activity, and CAT activity were 105.82, 64.05, and 101.67% for the 500 mg / kg BH group, respectively; 83.32, 41.43 and 72.21% for the BH 250 mg / kg administration group, respectively; And BH 125 mg / kg, respectively, which were increased by 57.03, 29.43 and 49.36%, respectively.
  • the BH 500 mg / kg group showed a better antioxidant activity than the 5 mg / kg indomethacin group and the LF 500 mg / kg group, and the low dose BH 125 mg / kg group was also superior to the LF 500 mg / kg group Antioxidant activity was increased.
  • the extract of Staphylococcus aureus increases the GSH content, SOD activity and CAT activity of the rat, that is, the antioxidant activity of the uterus, and particularly the antioxidative activity increasing effect It can be used as a preventive or therapeutic agent for menstrual cramps.
  • Example 4-4 Decreased expression of inflammatory and proinflammatory factors in uterine tissues
  • Example 4-2 the homogenate of the cervical tissues prepared in Example 4-2 was subjected to RT-PCR in the same manner as in Example 2-3, and primers as shown in Table 15 were used. RT-PCR results are shown in Table 16 below.
  • Target factor 5 'to 3' order NCBI accession No. NF- ⁇ B Forward GCGCATCCAGACCAACAATAA (SEQ ID NO: 11) NM_001276711 Reverse GCCGAAGCTGCATGGAC ACT (SEQ ID NO: 12) COX-2 Forward CTGCATGTGGCTGATGTCATC (SEQ ID NO: 13) S67722 Reverse AGGACCCGTCATCTCCAG GGTAATC (SEQ ID NO: 14)
  • the expression of the factor was decreased as compared with the control group. Specifically, in the indomethacin-treated group, the amounts of mRNA expression of NF- ⁇ B and COX-2 were decreased by -53.49 and -44.93%, respectively. In addition, the amount of mRNA expression of NF- ⁇ B and COX-2 in the LF-treated group was decreased by -31.37 and -24.55%, respectively.
  • the expression of the above-mentioned factors in the uterus was decreased in the BH 500, 250 and 125 mg / kg administration group as compared to the control group.
  • the expression levels of NF- ⁇ B and COX-2 mRNA were -51.57 and -46.35%, respectively, in the 500 mg / kg BH group; -38.58 and -34.91% for BH 250 mg / kg treated group, respectively; And -31.51 and -25.62%, respectively, for the 125 mg / kg BH group.
  • the BH 500 mg / kg administration group exhibited a similar or better effect of the activation factor than the 5 mg / kg indomethacin group and the LF 500 mg / kg administration group, and the low dose BH 125 mg / mg / kg administration group, respectively.
  • Example 4-5 Identification of inflammation reduction in uterine tissues
  • the right uterine corpuscle was cut and fixed with 10% formalin, inserted into paraffin, cut into 3-4 ⁇ m sections, and HE stained with hematoxylin and eosin. Histopathological morphology of each sample was then observed with an optical microscope (Model 80i, Nikon, Tokyo, Japan).
  • the total thickness ( ⁇ m) and mucosal thickness ( ⁇ m) of uterine cornea and the number of inflammatory cells (cell / mucous membrane 2 ) penetrating into the mucosa were measured using a computer-based automatic image analyzer ( i Solution FL ver 9.1, IMT i -solution Inc ., Vancouver, Quebec, Canada), and the results are shown in Table 17 below.
  • a and b shown in Table 17 indicate that p ⁇ 0.01 and p ⁇ 0.05, respectively, as compared with the normal control group, and c indicates Will result indicating that the LSD test p ⁇ 0.01 compared with the control group cramps, d will result indicating that the MW black p ⁇ 0.01 compared with the control group, e is indicating that the test result MW p ⁇ 0.01 compared with the control group cramps.
  • the degree of inflammation was decreased compared to the control group.
  • the total thickness of the uterus, the thickness of uterine mucosa, and the number of inflammatory cells infiltrating into the mucosa were decreased by -26.55, -34.57 and -76.78%, respectively.
  • the LF administration group it was also found to decrease by -12.63, -18.61 and -42.38%, respectively.
  • the degree of inflammation was decreased and the dose of inflammation was decreased dose-dependently compared to the control group.
  • the changes in uterine total thickness, uterine mucosal thickness, and number of inflammatory cells infiltrated into the mucosa were -24.92, -34.65, and -76.65%, respectively, in the BH 500 mg / kg group; -17.06, -23.15 and -68.00%, respectively, for the BH 250 mg / kg administration group; And -14.26, -19.70 and -44.65%, respectively, for the 125 mg / kg BH group.
  • the BH 500 mg / kg group showed a better inflammation reduction effect than the 5 mg / kg indomethacin group and the LF 500 mg / kg group, and the low dose BH 125 mg / And it is confirmed that it shows a reduction effect.
  • reactive inflammatory cells for proinflammatory cytokines TNF-a and iNOS present in the right uterine mucosa were purified with ABC and peroxidase substrate kit (Vector Labs, Burlingame, Calif., USA) Primary antibodies were used to confirm.
  • the number of cells labeled with TNF- ⁇ and iNOS was calculated using a computer-based automatic image analyzer and the results are shown in Table 18 below. At this time, the cells that occupied more than 20% of the reactivity, that is, the density, of TNF- ⁇ and iNOS were regarded as reactive (positive) cells.
  • a and b shown in Table 18 indicate that p ⁇ 0.01 and p ⁇ 0.05, respectively, as compared with the normal control group, and c indicates Will result indicating that the LSD test p ⁇ 0.01 compared with the control group cramps, d will result indicating that the MW black p ⁇ 0.01 compared with the control group, e is indicating that the test result MW p ⁇ 0.01 compared with the control group cramps.
  • the numbers of TNF- ⁇ and iNOS-immunoreactive cells were decreased in the 5 mg / kg indomethacin group and the 500 mg / kg LF group compared to the control group.
  • the changes in the numbers of TNF- ⁇ and iNOS-immunoreactive cells were -82.01 and -79.06%, respectively.
  • the decrease was -35.70 and -41.22%, respectively.
  • the numbers of TNF- ⁇ and iNOS-immunoreactive cells were decreased in the BH 500, 250, and 125 mg / kg groups compared to the control group, and the number of immune response cells was decreased in a dose-dependent manner.
  • the degree of changes in the number of TNF- ⁇ and iNOS-immunoreactive cells was -79.61 and -76.85%, respectively, in the group administered with BH 500 mg / kg; -67.52 and -64.35% for the BH 250 mg / kg administration group, respectively; And -38.63 and -43.10%, respectively, for the 125 mg / kg BH group.
  • the BH 500 mg / kg group showed a similar effect to that of the indomethacin 5 mg / kg group and the LF 500 mg / kg group.
  • BH 125 mg / kg group LF 500 mg / kg of the control group.
  • the extract of Staphylococcus aureus decreases the number of immunoreactive cells present in the rat uterine mucosa, that is, the degree of inflammation, and exhibits a more excellent inflammation-reducing effect than the indomethacin or gingkofumara extract, Therefore, it can be used as a preventive or therapeutic agent for menstrual cramps.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Epidemiology (AREA)
  • Food Science & Technology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Nutrition Science (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Polymers & Plastics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition comprenant un extrait de Lonicera coerulea pour la prévention ou le traitement de la douleur et, spécifiquement, une composition pharmaceutique, une composition alimentaire, et une composition de produit quasi-pharmaceutique, pour la prévention ou le traitement de la douleur, chacune des compositions comprenant un extrait de Lonicera coerulea ou une fraction de celui-ci, et un procédé de traitement de la douleur. L'extrait de Lonicera coerulea selon la présente invention inhibe la perte de poids et présente des effets d'élimination de la douleur, tels que l'inhibition de l'allodynie au froid et de l'allodynie mécanique, de la douleur menstruelle, et similaire, et peut ainsi être favorablement utilisé dans la prévention, le soulagement ou le traitement de la douleur.
PCT/KR2018/009517 2017-08-21 2018-08-20 Composition comprenant un extrait de lonicera coerulea pour la prévention ou le traitement de la douleur Ceased WO2019039810A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020170105478A KR102020371B1 (ko) 2017-08-21 2017-08-21 댕댕이나무 추출물을 포함하는 통증의 예방 또는 치료용 조성물
KR10-2017-0105478 2017-08-21

Publications (1)

Publication Number Publication Date
WO2019039810A1 true WO2019039810A1 (fr) 2019-02-28

Family

ID=65440114

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/009517 Ceased WO2019039810A1 (fr) 2017-08-21 2018-08-20 Composition comprenant un extrait de lonicera coerulea pour la prévention ou le traitement de la douleur

Country Status (2)

Country Link
KR (1) KR102020371B1 (fr)
WO (1) WO2019039810A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220039197A (ko) 2020-09-22 2022-03-29 강원대학교산학협력단 향청란 추출물을 유효성분으로 포함하는 패혈증 및 통증의 예방 또는 치료용 조성물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013116889A (ja) * 2011-10-31 2013-06-13 Kowa Co 防已含有組成物
KR20150032511A (ko) * 2014-11-19 2015-03-26 (주)제주사랑농수산 댕댕이덩굴 추출물을 이용한 항산화용 조성물 및 항염증용 조성물
KR20150033504A (ko) * 2013-09-24 2015-04-01 주식회사 에이치앤케이바이오사이언스 댕댕이나무 열매 추출물을 유효성분으로 포함하는 갑상선 질환의 예방 또는 치료용 약학적 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013116889A (ja) * 2011-10-31 2013-06-13 Kowa Co 防已含有組成物
KR20150033504A (ko) * 2013-09-24 2015-04-01 주식회사 에이치앤케이바이오사이언스 댕댕이나무 열매 추출물을 유효성분으로 포함하는 갑상선 질환의 예방 또는 치료용 약학적 조성물
KR20150032511A (ko) * 2014-11-19 2015-03-26 (주)제주사랑농수산 댕댕이덩굴 추출물을 이용한 항산화용 조성물 및 항염증용 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIM, JEONG HWA ET AL.: "Anti-inflammatory Activity of the Fruits of Blue Honeysuckle", YAKHAK HOEJI, vol. 60, no. 5, 2016, pages 235 - 242 *
RYU, K. H. ET AL.: "Anti-Inflammatory and Analgesic Activities of SKLJI, a Highly Purified and Injectable Herbal Extract of Lonicera Japonica", BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY, vol. 74, no. 10, 2010, pages 2022 - 2028, XP055224458 *

Also Published As

Publication number Publication date
KR102020371B1 (ko) 2019-09-11
KR20190020469A (ko) 2019-03-04

Similar Documents

Publication Publication Date Title
WO2017095138A1 (fr) Complexe de nanoparticules lipidiques contenant de la curcumine comprenant des ginsénosides
WO2012124888A2 (fr) Composition contenant un extrait d'une combinaison d'herbes utilisable en vue de la prévention ou du traitement de la neuropathie diabétique périphérique
WO2010087577A2 (fr) Utilisation d'extrait de thymus capitatus, d'extrait de satureja hortensis, ou de carvacrol pour traiter des maladies métaboliques
WO2015111832A1 (fr) Composition de prévention ou de traitement de maladies liées à la prostate, contenant un extrait de poncirus trifoliata
WO2019059634A1 (fr) Composition de blanchiment de la peau comprenant de la d-tyrosine ou un peptide comprenant celle-ci
WO2020085826A1 (fr) Composition pour soulager une irritation de la peau induite par des facteurs de pollution environnementaux ou pour la protection de la peau, contenant comme principe actif un extrait de noix de muscade ou du macelignane
WO2019039810A1 (fr) Composition comprenant un extrait de lonicera coerulea pour la prévention ou le traitement de la douleur
WO2018070707A1 (fr) Composition pour la prévention ou le traitement de maladie musculaire, contenant comme principe actif decanal ou un sel pharmaceutiquement acceptable de celui-ci
WO2017183924A1 (fr) Composition pour prévenir ou traiter le syndrome de l'oeil sec comprenant un extrait de feuilles d'érable
WO2020218720A1 (fr) Composition pour la prévention ou le traitement de troubles musculaires ou l'amélioration de la fonction musculaire, contenant un extrait de leonurus japonicus ou de la léonurine
WO2021201502A1 (fr) Composition pharmaceutique orale comprenant un extrait d'herbes combinées comprenant du longanae arillus pour le traitement ou le soulagement d'une maladie inflammatoire et son utilisation
WO2015160226A1 (fr) Soulagement de la ménopause chez la femme, utilisation d'une composition contenant un extrait composite de trèfle rouge et de grenade en tant que principe actif
WO2019017677A2 (fr) Composition comprenant du citral utilisé comme principe actif pour présenter un effet de raffermissement musculaire, de renforcement musculaire, de différenciation musculaire, de régénération musculaire ou de suppression de sarcopénie
WO2022050601A1 (fr) Composition destinée à prévenir ou à traiter l'obésité ou le diabète, comprenant un extrait d'acanthopanax senticosus et un extrait de garcinia cambogia ou un composé isolé à partir de ces derniers
WO2012081831A2 (fr) Composition comprenant un extrait de loranthus yadoriki sieb. ayant une activité inhibitrice sur la monoamine oxydase
WO2020145619A1 (fr) Composition pour la prévention des allergies, le soulagement de la dermatite atopique ou la régénération de la peau, contenant, en tant que principe actif, un undécane ou un undécanal
WO2015046743A1 (fr) Composition pharmaceutique pour prévenir ou traiter des maladies thyroïdiennes, contenant de l'extrait de fruit de lonicera caerulea l. var. edulis comme principe actif
WO2017146486A1 (fr) Composition destinée à prévenir ou traiter l'hyperplasie bénigne de la prostate contenant de l'extrait de morus alba linnaeus
WO2019139365A1 (fr) Nouveau dérivé d'oxazole phénylsulfonyle et son utilisation
WO2022092461A1 (fr) Composition pharmaceutique pour prévenir ou traiter l'obésité ou le diabète et procédé de préparation s'y rapportant
WO2019045467A2 (fr) Pâte de poisson plat ayant un effet antioxydant et antihypertenseur et procédé de fabrication associé
WO2023153861A1 (fr) Composition pharmaceutique comprenant de la curcumine et du ginsénoside, et formulation de cette dernière
WO2021206455A1 (fr) Extrait de fraction de feuilles de mélisse-citronnelle et nouvelle composition pharmaceutique le comprenant
WO2021060927A1 (fr) Composition permettant de soulager, de prévenir ou de traiter la sarcopénie, contenant un hydrolysat de protéines de lactosérum en tant que principe actif
WO2020130478A1 (fr) Composition antiallergique, de soulagement de dermatite atopique ou de régénération de la peau contenant de la jasmone en tant que principe actif

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18847650

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18847650

Country of ref document: EP

Kind code of ref document: A1