WO2014126269A1 - Composition pharmaceutique pour améliorer la fonction sexuelle masculine et pour traiter l'infertilité - Google Patents

Composition pharmaceutique pour améliorer la fonction sexuelle masculine et pour traiter l'infertilité Download PDF

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WO2014126269A1
WO2014126269A1 PCT/KR2013/001080 KR2013001080W WO2014126269A1 WO 2014126269 A1 WO2014126269 A1 WO 2014126269A1 KR 2013001080 W KR2013001080 W KR 2013001080W WO 2014126269 A1 WO2014126269 A1 WO 2014126269A1
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extract
ethanol
infertility
pharmaceutical composition
sexual function
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PCT/KR2013/001080
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English (en)
Korean (ko)
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황성연
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주식회사 한국전통의학연구소
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Priority to PCT/KR2013/001080 priority Critical patent/WO2014126269A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/40—Cornaceae (Dogwood family)
    • 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)
    • A61K36/43—Cuscutaceae (Dodder family), e.g. Cuscuta epithymum or greater dodder
    • 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)
    • A61K36/68—Plantaginaceae (Plantain Family)
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A61K36/815—Lycium (desert-thorn)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the present invention relates to a pharmaceutical composition for improving male sexual function and infertility, and more particularly, comprising at least one extract selected from Cornus extract, Goji extract, Bokbunja extract, Tosa extract, Schisandra extract and Cha-cha extract as active ingredients. It relates to a pharmaceutical composition for improving male sexual function and infertility, and to a food composition for improving male sexual function and infertility.
  • the composition improves male sexual function through NO concentration, angiotensin converting enzyme (ACE) inhibitory effect, PDE (Phosphodiesterase) -5 inhibitory effect, CREM expression, sperm count, sperm activity, and testosterone content in HUVEC. It is effective against infertility.
  • ACE angiotensin converting enzyme
  • PDE Phosphodiesterase
  • infertility is a major social problem. It is also important to solve the problem of erectile dysfunction through improved blood flow, but more fundamentally, it is more important to resolve infertility by improving sex hormones, improving sperm count and activity.
  • Infertility refers to the fact that a couple cannot live in pregnancy for more than a year without contraception. Infertile couples account for 10 to 20% of the total couple. The incidence of infertility is infertility in 15% of normal women in the United States and 8% of outpatients of obstetrics and gynecology in Korea. The cause of infertility is about 40% in women only, about 40% in men only, about 10% in both men and women, and about 10% in case of unknown causes. Half of them are male factors (Korean society for Sexual Medicine and Andrology.Namseonggwahak.Seoul, Gunjachulpansa. 5-54, 161-163. (2003); The Korean Urological Association.Textbook of Urology.3rd.Seoul Goryeouihak.507 -22. (2001)).
  • Sperm formation is not normal due to the cause, or a high rate of malformed sperm production (The Korean Urological Association.Textbook of Urology.3rd.Seoul Goryeouihak.507-22. (2001)).
  • Sperm motility is essential in the process of fertilization in combination with eggs (Tienthai P. Anim Reprod Sci. 80, 131-46. (2004)).
  • Sperm motility begins to acquire fertility as it passes through the woman's womb and induces hyperactivation motility and acrosome reactions (Guzick DS et. Al., N Engl J Med. 345, 1388-93. (2001).
  • sperm disorders As a cause of male infertility, there are major causes of infertility, sperm disorders, spermatogenesis disorders and sperm motility (The Korean Urological Association.Textbook of Urology. 3rd. Seoul Goryeouihak. 507-22. (2001)).
  • Spermatogenic disorders include oligozoospermia, which are produced in the testicles, and then produce less sperm (asalnozoospermia). (Saleh RA and Agarwal A. J Androl. 23, 737-52. 2002)).
  • the condition of sperm that can be conceived includes 60 million to 100 million sperm in 1 ml of semen, the number of abnormal sperm should be 20-30% or less, and 50% or more activity for 4-8 hours after ejaculation.
  • the amount of semen should be 2 to 5 ml, but sperm deficiency is a symptom that causes infertility because the number of sperm in 1 ml of semen is less than 30 million.
  • compositions for preventing or treating male hypogonadism Various studies have been patented or registered for compositions for preventing or treating male hypogonadism.
  • oral administration of cadmium chloride to experimental animals to induce sperm damage artificially to induce male reproductive function JP-A-2002-0085401
  • tetrachlorodibenzo-pi-dioxin to experimental animals
  • efficacy screening studies for the prevention or treatment of all male reproductive dysfunctions were not reasonable, not considering the actual duration of sperm production.
  • the three hundred seconds fermentation stock solution (Korean Patent 10-0508539) that enhances the reproductive function of men has not been described in detail the experimental method in the efficacy screening method using experimental animals, preventing or treating male reproductive function or hematopoiesis
  • testis were extracted one or two weeks after oral administration of a liquid solution to an experimental animal, and sperm count and sperm activity were observed.
  • composition for the prevention and treatment of male reproductive function (Publication Patent Publication No. 10-2005-0028475) intraperitoneally administered the composition to the experimental animals twice a day for l8 days 1 day after the end of the autopsy, sperm count, sperm Activity and sperm activity persistence were measured.
  • the present inventors are trying to develop a male infertility treatment, one or more extracts selected from cornus extract, goji berry extract, bokbunja extract, earthworm extract, Schizandra extract and chaja extract is cytotoxic in TM3 cells, NO in HUVEC
  • ACE Angiotensin converting enzyme
  • PDE Phosphodiesterase
  • CREM expression serum cGMP changes
  • serum testosterone changes
  • organ weight testis, spermatozoa, seminal vesicles
  • An object of the present invention is to provide a pharmaceutical composition for improving male sexual function and infertility using a cornus extract, goji berry extract, bokbunja extract, earthenware extract, Schizandra extract and chacha extract.
  • Another object of the present invention to provide a food composition for improving male sexual function and infertility using a cornus extract, goji berry extract, bokbunja extract, tosa extract, Schizandra extract and chacha extract.
  • male sexual function improvement and infertility treatment pharmaceutical composition comprising at least one extract selected from Cornus extract, Goji berry extract, Bokbunja extract, Tosa extract, Schisandra extract and cha-cha extract as an active ingredient
  • at least one extract selected from Cornus extract, Goji berry extract, Bokbunja extract, Tosa extract, Schisandra extract and cha-cha extract as an active ingredient
  • the present invention improves male sexual function comprising at least one extract selected from cornus extract, goji berry extract, bokbunja extract, earthenza extract, schisandra extract and chaja extract including a food supplement acceptable as a active ingredient It provides a food composition for preventing infertility.
  • the present invention provides a pharmaceutical composition for improving male sexual function and infertility, comprising at least one extract selected from Cornus extract, Goji berry extract, Bokbunja extract, Tosa extract, Schizandra extract and chacha extract as an active ingredient.
  • the extract further comprises a pharmaceutically acceptable carrier, wherein the cornus extract, wolfberry extract, bokbunja extract, earthworm extract and Schizandra extract Extract consisting of (preferably named the five extracts KH-204 in the present invention) is preferred, based on 100 parts by weight of cornus extract 50-150 parts by weight, bokbunja 20-100 parts by weight, earthenware 20-100 weight It is more preferable that it is 10-50 weight part of parts and Schizandra chinensis. Or the composition is preferably containing the chajeon extract as an active ingredient.
  • the extract is i) adding water or ethanol to the medicine and extracting for 1 to 4 hours at 80 to 150 °C; ii) removing the precipitated impurities by centrifugation at 1000-5000 rpm and filtering the extract solution with a 0.3-0.6 ⁇ m filter; And iii) concentrating the filtrate with a rotary vacuum concentrator.
  • 1 to 20 times of water is added to the cornus, goji berry, bokbunja, earth and sand, schisandra and chacha, and at 1 to 24 hours at 80 to 150 ° C. It is preferably obtained by filtration after extraction, or by adding 1 to 20 times of 10 to 50% ethanol, extracting at 40 to 100 ° C. for 1 to 24 hours, and then filtering.
  • composition consisting of Cornus, Wolfberry, Bokbunja, Tosa and Schisandra chinensis extract was named as KH-204, and their ethanol extract and hot water extract were measured.
  • the extract may be obtained by extracting each medicinal herb with water or an organic solvent
  • the organic solvent may include lower alcohol, acetone, chloroform, methylene chloride, ether, ethyl acetate, hexane and the like.
  • Lower alcohols include methanol, ethanol, propanol and butanol, with ethanol being most preferred.
  • ethanol extract of each medicinal herb may be prepared by extracting the mixture at 100, preferably 50 to 60 hours for 1 to 24 hours, preferably for 3 to 5 hours, more preferably for 4 hours, and then filtering the same.
  • the filtrate can be prepared by concentration under reduced pressure.
  • the extraction process may be repeated two or more times as necessary, and the extract obtained after filtration may be freeze-dried or reduced-pressure drying to form a powder.
  • the pharmaceutical composition of the present invention may further include other pharmaceutically acceptable herbal medicines or extracts thereof to enhance the pharmacological effect.
  • other pharmaceutically acceptable herbal medicines or extracts thereof to enhance the pharmacological effect.
  • pharmaceutically acceptable means a physiologically acceptable and, when administered to a human, usually does not cause an allergic reaction or the like.
  • compositions according to the invention may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration.
  • Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like.
  • carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives.
  • Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • Other pharmaceutically acceptable carriers may be referred to those described in the following documents (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).
  • the pharmaceutical composition for improving male sexual function and infertility of the present invention may be administered to any mammal, including humans.
  • it can be administered orally or parenterally.
  • Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration.
  • the pharmaceutical composition of the present invention may be administered transdermally.
  • transdermal administration 'means that the active ingredient contained in the pharmaceutical composition for improving male sexual function and infertility is administered into the skin by administering the pharmaceutical composition of the present invention to cells or skin.
  • the pharmaceutical composition of the present invention may be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin injection needle, or directly applying to the skin.
  • composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.
  • compositions of the present invention may be formulated using methods known in the art as powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like.
  • oral formulations can be obtained by tablets or dragees by combining the active ingredients with solid excipients, milling them, adding suitable auxiliaries and then processing them into granule mixtures.
  • excipients examples include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, including starch, corn starch, wheat starch, rice starch and potato starch, etc. Fillers such as celluloses, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.
  • Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a prescription generally known in all pharmaceutical chemistries.
  • the total effective amount of one or more extracts selected from cornus extract, goji berry extract, bokbunja extract, earthworm extract, schizandra extract, and chacha extract, which are the active ingredients of the composition of the present invention may be administered to a patient in a single dose. It may be administered by a fractionated treatment protocol which is administered for a long time in multiple doses.
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease.
  • the preferred total dose of one or more extracts selected from Cornus extract, Goji berry extract, Bokbunja extract, Tosa extract, Schizandra extract and Chacha extract of the present invention is about 100 ⁇ g to 5 mg per kg of patient body weight per day, most preferably Preferably from 500 ⁇ g to 1 mg.
  • the dosage of the extract is determined in consideration of various factors such as the age, weight, health status, sex, severity of the disease, diet and excretion rate, as well as the route and frequency of treatment of the pharmaceutical composition. In view of this, one of ordinary skill in the art will be able to determine the appropriate effective dosage for the particular use of the extract as an agent for improving male sexual function and infertility.
  • the pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.
  • 'male sexual improvement and infertility treatment generally means normalization or enhancement of sperm count, sperm activity, testosterone hormone, sexual behavior, and sexual function that can cause infertility.
  • the present invention improves male sexual function comprising at least one extract selected from cornus extract, goji berry extract, bokbunja extract, earthenza extract, schisandra extract and chaja extract including a food supplement acceptable as a active ingredient It provides a food composition for preventing infertility.
  • the food composition of the present invention includes all forms such as functional foods, nutritional supplements, health foods and food additives.
  • Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
  • the cornus extract, Goji berry extract, Bokbunja extract, Tosa extract, Schisandra chinensis extract and chasen extract themselves are prepared in the form of tea, juice and drink, or granulated, encapsulated and Can be ingested powdered.
  • the cornus extract, goji berry extract, Bokbunja extract, Tosa fruit extract, Schisandra chinensis extract and chacha extract and mixed with a known substance or active ingredient known to improve male sexual function and infertility effect to be prepared in the form of a composition Can be.
  • functional foods include beverages (including alcoholic beverages), fruits and processed foods (e.g. canned fruit, canned foods, jams, marmalade, etc.), fish, meat and processed foods (e.g. ham, sausage cornebipe) Etc.), breads and noodles (e.g. udon, soba noodles, ramen, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, syrups, dairy products (e.g.
  • the retort food, frozen food, various seasonings may be prepared by adding the cornus extract, wolfberry extract, bokbunja extract, earthworm extract, schisandra extract and chasen extract of the present invention.
  • Goji berry extract, Bokbunja extract, Tosa extract, Schisandra chinensis extract and chacha extract of the present invention in the form of food additives can be prepared in powder or concentrate form.
  • Cornus is a deciduous arborescent belonging to the dogwood family. According to “Agreement Gagam” and “Hyangjakbangbang”, etc., it is effective in strengthening sound tone, Shinjeong and Shingi, and converging. Headache, tinnitus, seawater disease, fever, excessive menstruation, etc. It is said that it can also be used for cold weather. It is the most widely known Chinese medicine for the general public such as Jayang Yangjiang. ⁇ ⁇ ⁇ ), cornus oil is used as the most important medicine in this prescription.
  • the wolfberry is a deciduous shrub reaching 2.5 m in height, the tip of the branch hangs downward, the short branch is thorny, and the leaves are 2 to 3 single-footed under the long branch. From the old days, the agreement was written as "Homan ( ⁇ ), beautiful”, “non-toxic” Great oar ) And breath ( Reigns, strengthens the musculature, strengthens yin, and ono ) And Seven Statues ), And to maintain regular, change the complexion to whiten, nominal, anxin and longevity. ”Also, in the herbal wood, it is not toxic, cools, accumulates in the body, and inflammation of the chest. It is good for diabetes, joints, rheumatism, neuralgia, etc. It is said that if you take a long time to keep the muscles healthy and refresh the young, do not know the heat and cold youth, it has been used for a long time in various ways such as tea and alcohol.
  • Bokbunja is a dry, deciduous shrub belonging to the fruit of the ripe Bokbunja strawberry dried and tastes warm and has the effect of protecting the liver and kidneys.
  • the bokbunja are flat, taste sweet, sour, and have no poison.
  • ⁇ and the woman's ignorance, to strengthen and lengthen the man's tone, to help the liver, to clear the eyes, to fill the energy of the kidneys, to lighten the body and not to whiten the hair.
  • " In addition, recent studies have demonstrated the effects of clearing the kidneys, infertility, vulgaris, well-being dreams, tonics, blood, and protecting the liver and clearing the eyes, as a hydrolyzable tannin of the unripe fruit of bokbunja strawberry.
  • Tosa is a sweet, sweet and plain nature, and is effective in protecting cancer, heart, blood pressure and blood sugar, kidney and spleen.
  • Dongbobogam "enhancing energy and invigorating, low back pain and knee ache symptomatic effect is good if you drink from time to time, it is effective for diabetes.” Longer doses can make your eyes brighter and longer.
  • Schisandra chinensis is a dried fruit of Schisandra chinensis, belonging to the Magnolia family, and has five flavors, and is effective in protecting liver function, anti-aging, antibacterial action, metabolism and immune function. In Dongbogam, protect lungs and kidneys ), It is said that it corrects the mouth, the heat, the dissolution.
  • These schizandra are used in various ways such as tea, liquor, and flower.
  • Chason refers to the seed of Plantago asiatica L., a plant belonging to the Plantaginaceae, which is a Korean medicine Efficacy in water, clear heat, nominal, expectorant, and is effective in treating urinary irritation, lobster, hematuria, seawater, and the purpose.
  • Cha is mainly for treating weakness of urine due to weak energy, controlling five kinds of gonorrhea, clogging and urinating urine, draining water well, brightening eyes and congestion Eliminates, and is said to rule the soy sauce. Therefore, the tea can improve the symptoms of swelling due to toxic edema.
  • the present inventors measured the cytotoxicity of TM3 cells, which are testicular cells of male mice, by MTT assay, using hydrothermal and 30% ethanol extracts and mixed extracts of Cornus, Goji, Bokbunja, Tosa, Schisandra chinensis and Cha-chan. (See Table 1 and FIGS. 1-8). As a result, it was confirmed that there is no toxicity in KH-204 ethanol, KH-204 hydrothermal water, cornus oil, Schisandra chinensis, and wolfberry, and the samples of earth and sand, tea and bokbunja were found to be slightly toxic.
  • HUVEC cells were used to measure the NO production efficacy involved in eNOS and closely involved in erection (see Table 3 and FIGS. 9 and 10). As a result, it was confirmed that KH-204 30% ethanol extract and hot water extract group increased the concentration of nitrate. In other words, the samples improve the function of the penis by increasing the production of vasodilator NO.
  • ACE Angiotensin converting enzyme
  • PDE Phosphodiesterase
  • mice Malem water tended to increase as the concentration of KH-204 (ethanol extract) increased, and more sperm counts were found in all groups treated with KH-204 (ethanol extract) than the red ginseng 400 group used as a positive control (Table 14). And FIG. 19).
  • the sperm motility of the mice tended to increase as the concentration of KH-204 (ethanol extract) increased, and higher sperm motility was observed in all groups treated with KH-204 (ethanol extract) than the red ginseng 400 group used as a positive control. (See Table 15 and FIGS. 20-26).
  • the present invention constituted as described above is a pharmaceutical composition for improving male sexual function and infertility, and has the effect of increasing sperm count, sperm motility, testosterone hormone content, sexual behavior, sexual function, etc. It can help improve male reproductive and sexual function, as well as patients suffering from sexual dysfunction and male infertility, without the side effects and ethical and social problems.
  • 1 is a graph showing the cytotoxicity test of KH-204 ethanol extract.
  • Figure 2 is a graph showing the cytotoxicity test of KH-204 hydrothermal extract.
  • Figure 3 is a graph showing the cytotoxicity test of cornus extract.
  • Figure 4 is a graph showing the cytotoxicity test of the Schizandra chinensis extract.
  • 5 is a graph showing the cytotoxicity test of the bokbunja extract.
  • Figure 6 is a graph showing the cytotoxicity test of the soil extract.
  • Figure 7 is a graph showing the cytotoxicity test of the tea extract.
  • FIG. 9 is a graph showing the change of nitrate in HUVEC of KH-204 ethanol extract.
  • 10 is a graph showing the change of nitrate in HUVEC of KH-204 hydrothermal extract.
  • 11 is a graph showing the results of measuring the ACE inhibition rate of each sample (%), it shows the inhibition rate of angiotensin-converting enzyme by each sample (concentration: 500 ppm).
  • FIG. 12 is a view illustrating the principle of measuring the PDE (Phosphodiesterase) -5 inhibitory effect used in the present invention.
  • FIG. 13 and 14 are graphs showing measurement results of standard curve (FIG. 13) and phosphodiesterase-5 inhibition rate for each sample (500 ppm) for obtaining PDE-5 inhibition rate (%), respectively (FIG. 14).
  • Figure 15 is a graph showing the final weight of the mouse after oral administration of KH-204 30% ethanol extract samples by concentration for 8 days.
  • Figure 16 is a graph showing the left mouse vesicle weight after oral administration of KH-204 30% ethanol extract samples by concentration for 8 days.
  • Figure 17 is a graph showing the left testis weight of the mouse after oral administration of KH-204 30% ethanol extract samples by concentration for 8 days.
  • FIG. 18 is a graph showing left mouse anaerobic weights after oral administration of KH-204 30% ethanol extract samples by concentration for 8 days.
  • 19 is a graph showing the number of mouse sperm after oral administration of KH-204 30% ethanol extract sample for 8 days by concentration.
  • 20 is a graph showing mouse sperm motility (%) after oral administration of KH-204 30% ethanol extract sample for 8 days at different concentrations.
  • 21 to 26 are micrographs showing the motility of sperm, the sperm photograph of the control group (optical microscope 200x magnification) (Fig. 21), the sperm photograph of the group administered with 50 mg / kg of KH-204 30% ethanol extract (Optical microscope 200x magnification) (FIG. 22), KH-204 30% ethanol extract 100 mg / kg sperm photograph (Optical microscope 200x magnification) (FIG. 23), KH-204 30% ethanol extract 200mg / kg Sperm picture (optical microscope 200x) (FIG. 24), group sperm picture (optical microscope 200x) (FIG. 25) administered with KH-204 30% ethanol extract 400 mg / kg, and positive control group This is a sperm photograph (optical microscope 200x magnification) of the group administered red ginseng 400 mg / kg.
  • the supernatant was collected and filtered using a 0.45 ⁇ m filter, followed by a rotary vacuum concentrator (Eyela A-1000S). , Tokyo Rikakikai Co., Tokyo, Japan), the sample was recovered and lyophilized (ILSHIN, Korea) to recover 23.5 g and stored at -20 °C was used in the experiment.
  • TM3 Mouse testicular cell TM3 was analyzed for cytotoxicity of the sample by MTT analysis.
  • TM3 cells (KCLB21714) were distributed by the Korea Cell Line Bank. Fetal bovine serum (FBS), Dulbecco's Modified Eagle Medium (DMEM), 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (MTT), Sigma (Sigma Chem. Co., USA) ). ELISA microplate reader was used VersaMax (Molecular Device, USA).
  • TM3 cells using the method of Sladowski et al. (Sladowski D, et. Al. J Immunol Methods 157, 203-207. (1993)) Analysis was performed. 180 ⁇ l of TM3 cells (2 X 10 5 cells) in 96 well plates were treated by 20 concentrations of each sample, and then treated to 62.5 ppm, 125 ppm, 250 ppm, 500 ppm, 1000 ppm, 2000 ppm, and 4000 ppm, respectively. After incubation at 37 for 24 hours, 20 ⁇ l of MTT solution (5 mg / ml) was added and incubated at 37 ° C. for 3 hours.
  • MTT solution 5 mg / ml
  • the supernatant was removed, and 200 ⁇ l of DMSO was added per well, followed by reaction for 20 minutes, and the survival rate was calculated by measuring absorbance at an ELISA reader 570 nm.
  • the value of the normal group (group treated with PBS instead of sample treatment) was used as a control, and the OD (Optical density) value at this time was defined as 100% of cell viability, and the measured OD value of the remaining group was converted to relative value. Is as follows.
  • Cell viability was measured by treating the samples with concentrations of TM3 cells, and the cell viability of the control group without the sample was compared to 100%. When the cell count of 20% or more decreased, it was determined to be cytotoxic.
  • the KH-204 ethanol extract sample had a survival rate of 73.58% at 4000 ppm concentration, and the KH-204 hydrothermal extract sample had a slight toxicity from 4000 ppm with a survival rate of 78.25% at 4000 ppm concentration.
  • Cornus, Schisandra chinensis, and Goji were viable at 2000 ppm, with viability of 68.2%, 79.49%, and 79.22%, respectively.
  • Tosa and char were found to be 65.58% and 75.35% at 500 ppm, respectively.
  • Bokbunja was cytotoxic at 69.98% at 125 ppm.
  • NO is biosynthesized by the biochemical action of nitric oxide synthase (NOS) in the body. Immunohistochemistry revealed NOS-containing neurons and their organs, and their distributions were similar in neuroanatomy in rats and humans. NO, a factor that promotes vascular smooth muscle relaxation in penile corpus cavernosum tissue and improves erectile function, is an incomplete and instable substance and cannot be directly quantified because its half-life is very short. By measuring, the content of NO can be expected. HUVEC cells were used to measure the NO production efficacy involved in eNOS and closely involved in erection.
  • HUVEC 900 110 4 cells per well was added to a 12 well plate and incubated in a 37, 5% CO 2 incubator for 24 hours, then the medium was discarded and the cultured cell surface was washed with 1 ⁇ PBS. Samples dissolved in 1X PBS were mixed with EGM-2 so that the final concentration was 0, 50, 100, 200, 400 ppm and incubated in 37, 5% CO 2 incubator for 48 hours. After incubation, NADH 25 and nitrate reductase 25 were mixed in the culture medium 50, and then reacted for 37 to 30 minutes.
  • the concentration of nitrate was about 3.877, 6.038, 7.508, 16.369 ⁇ mol / ml as the KH-204 30% ethanol extract sample was treated with 50, 100, 200, and 400 ppm.
  • the negative control resulted in 0.002 ⁇ mol / ml, and compared with this, the concentration of nitrate was increased in the KH-204 30% ethanol extract group (FIG. 9).
  • the concentration of nitrate was about 0.031, 0.454, 2.438, 7.438 ⁇ mol / ml when the KH-204 hydrothermal extract sample was treated with 50, 100, 200, 400 ppm, compared with the negative control treated with the medium instead of the sample.
  • KH-204 was shown to increase as 30% ethanol extract (Fig. 10).
  • the concentration of 400 ppm of KH-204 30% ethanol extract was 16.369 ⁇ mol / ml, and the concentration of nitrate was increased more than the value of 8.362 ⁇ mol / ml of 400 ppm of red ginseng used as a positive control.
  • the KH-204 hydrothermal extract samples showed higher concentrations of nitrate than the negative control, but were lower than the nitrate concentration of the 400 ppm group of red ginseng, the positive control, so that the KH-204 30% ethanol extract was higher than the KH-204 hydrothermal extract. In comparison, it was found that nitrate was produced more effectively.
  • the test results suggest that the sample improves penile function by increasing the production of vasodilator NO.
  • Angiotensin-converting enzyme (ACE; peptodyldipeptide hydrolase EC 3.4.15.1) is an enzyme that plays an important role in controlling blood pressure. The enzyme increases blood pressure by hydrolyzing angiotensin, which consists of 10 amino acids, to angiotensin. Angiotensin, a potent vasoconstrictor, stimulates the release of aldosterone.
  • aldosterone increases the retention of Na + and water in the kidney and increases arterial blood pressure.
  • Inhibiting the production of angiotensin by inhibiting ACE can lower blood pressure. Relaxing the blood vessels also increases the blood flow in the penis, which is significant in that penile erection is induced.
  • N-Hippuryl-His-Leu was used in place of ACE substrate
  • Angiotensin and ACE was extracted from rabbit lung tissue powder and used as enzyme solution. Inhibition rate was confirmed by measuring hippuric acid produced through enzymatic reaction at 228 nm (I., M., Y., Shon and S., H., Na., J Korean Soc Food Sci Nutr. 36, 1511-1516. (2007); E., K., Cho et. Al, J. Life Sci. 21, 811-818. (2011); C. Liang et. Al., Natural product sciences, 17 ( 4), 363-366. (2011).
  • Table 4 summarizes the samples, extraction conditions and concentrations used in this test.
  • the substrate was used after dissolving HHL (hippuryl-histidyl-leucine) in 0.1 M Sodium borate buffer (pH 8.3) containing 0.3 M NaCl at a concentration of 5 mg / ml (w / v).
  • HHL hippuryl-histidyl-leucine
  • the ACE inhibitory activity was added to 50 ⁇ l of ACE coenzyme solution, followed by preliminary reaction at 37 ° C. for 5 minutes, followed by the addition of a substrate solution, followed by reaction at 37 ° C. for 30 minutes.
  • 150 ⁇ l of 0.1 M HCl was added to stop the reaction.
  • After adding 750 ⁇ l of ethyl acetate the mixture was stirred for 15 seconds and centrifuged at 4, 3000 rpm for 5 minutes. The supernatant was completely dried and dissolved in 3 ml of distilled water, and the absorbance was measured at 228 nm.
  • ACE inhibition rate was calculated using the following formula.
  • the inhibition rate was 5 mg / ml HHL (hippuryl-histidyl-leucine) was used as a substrate and the absorbance was measured at 228 nm by reacting 0.1 g / ml ACE coenzyme solution at 37 °C for 30 minutes.
  • Gojija 49.1%
  • KH-204 hydrothermal extraction 47.0%)
  • Schisandra chinensis 45.9%
  • Cha-chan 36.3%
  • KH-204 30% ethanol extract 34.2%)
  • Bokbunja 29.9%
  • cGMP cyclic GMP
  • 5-GMP is produced by PDE-5 using 3,5-cGMP as a substrate
  • phosphoric acid is produced by 5-Nucleotidase.
  • the amount of phosphate produced was measured to determine how much PDE-5 activity was inhibited, and based on this, it was intended to be used as a data for improving male infertility (FIG. 12).
  • the Cyclic nucleotide phosphodiesterase assay kit (BML-AK800, Enzo life science) was purchased and used for measuring the absorbance.
  • the UV-VIS spectrophotometer is a Spectronic Genesys 5 (Milton Roy Co., Ivyland, USA) model and an ELISA microplate reader VersaMax (Molecular Device, Sunnyvale, USA) was used.
  • Table 6 summarizes the medicinal samples, extraction conditions and concentrations, including KH-204 ethanol and hot water extract used in this test.
  • Treatment with -nucleotidase and treatment with BIOMOL GREEN reagent measured absorbance at 620 nm, and the amount of 5-GMP produced was compared with the control group to calculate PDE inhibition rate.
  • the negative control group excluded substrate only and the positive control group used 3-isobutyl-1-methylxanthine (IBMX) as a positive control group.
  • the IC 50 value of IBMX was 5.5 ppm.
  • the IC 50 value of Sildenafil is 3.5 nM
  • the IC 50 value of Vardenafil is 6.6 nM
  • the IC 50 value of Tadalafil is 0.2 nM.
  • the inhibitory effects of PDE-5 were favorable in the order of Bokbunja (34.5%), Schisandra chinensis (35.6%), Goji (32.8%), and KH-204 (30% ethanol extract, 25.6%).
  • ICR-based mice (Woongseong, 8 weeks old) were purchased from Orient Bio Co., Ltd. (Gapyeong, Gyeonggi-do), and were used for 1 week after the experiment. During the experiment, water and feed were freely ingested. The room temperature was 22 ⁇ 2 °C, the humidity was 55 ⁇ 5%, and the contrast was automatically adjusted in 12 hour cycles.
  • the samples were orally administered to the negative control group administered sterile water, the sample treatment group administered KH-204 (30% ethanol extract), and the red ginseng administered group to the positive control group once daily for 8 days.
  • the male mice were divided into the control group and the sample administration group, and the sample administration group was divided into 50, 100, 200, and 400 mg / kg concentration groups, and 6 mice were used in each group.
  • Oral administration was performed once a day for 8 days.
  • the mice were weighed, and then sacrificed to separate left testes, left testes, and left testes. The mL was dispensed into 24 wells and 10 minutes later sperm count was measured on a microscope at 200 magnification.
  • Control 50 (mg / kg) 100 (mg / kg) 200 (mg / kg) 400 (mg / kg) Red Ginseng 400 (mg / kg) Weight (g) 37.01 ⁇ 1.63 36.53 ⁇ 1.09 36.73 ⁇ 1.13 34.61 ⁇ 1.85 29.29 ⁇ 1.58 36.09 ⁇ 1.08
  • Control 50 (mg / kg) 100 (mg / kg) 200 (mg / kg) 400 (mg / kg) Red Ginseng 400 (mg / kg) Seminal vesicles (g) 0.075 ⁇ 0.02 0.078 ⁇ 0.01 0.084 ⁇ 0.02 0.089 ⁇ 0.02 0.091 ⁇ 0.01 0.094 ⁇ 0.01
  • the weight of the seminal vesicles of the mice tended to increase as the KH-204 (ethanol extract) concentration was higher.
  • testis weight of the mouse is shown in Table 12 and FIG.
  • mice had the highest weight in the group administered KH-204 (ethanol extract) 200 (mg / kg), and the same results as the group administered red ginseng 400 (mg / kg).
  • mice tended to increase as the concentration of KH-204 (ethanol extract) increased, and all KH-204 (ethanol extract) were administered to the red ginseng 400 (mg / kg) group as a positive control. Many sperm counts were identified in the group.
  • the sperm motility of the mice tended to increase as the concentration of KH-204 (ethanol extract) increased, and all the KH-204 (ethanol extract) were administered to the red ginseng 400 (mg / kg) group as a positive control. High sperm motility was identified in the group.
  • the present inventors confirmed that the KH-204 ethanol extract of the male infertility treatment effect is excellent through the above embodiment to prepare a male infertility treatment containing KH-204 ethanol extract as an active ingredient as follows.
  • the preparation of the following therapeutic agent can be used for the application of the health food as well as the therapeutic agent.
  • KH-204 Ethanol Extract 35%, Vitamin C 15%, Vitamin D 3 0.001%, Manganese Sulfate 0.1%, Crystalline Cellulose 25.0%, Lactose 21.999%, Magnesium Stearate 2.9%
  • KH-204 ethanol extract is excellent in the male infertility treatment activity through the above embodiment to prepare a functional food containing it as an active ingredient as follows.
  • Chewing gum was prepared using conventional methods using 40% gum base, 56.36% sugar, 0.64% KH-204 ethanol extract, 1% fruit flavor, 2% water, and the composition and content.

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Abstract

La présente invention concerne une composition pharmaceutique qui permet d'améliorer la fonction sexuelle masculine et d'améliorer l'infertilité, laquelle invention concerne plus particulièrement une composition pharmaceutique destinée à améliorer la fonction sexuelle masculine et à traiter l'infertilité qui comprend comme ingrédient actif au moins un extrait choisi parmi un extrait de corni, un extrait de buis épineux, un extrait de framboise, un extrait de graine de cuscute, un extrait de Omija et un extrait de graines de plantain ainsi qu'une composition alimentaire destinée à améliorer la fonction sexuelle masculine et à prévenir l'infertilité. La composition a un effet d'amélioration de la fonction sexuelle masculine ou de l'infertilité, par le biais de la concentration de NO dans des cellules HUVEC, d'un effet de réduction de ACE (enzyme de conversion de l'angiotensine), d'un effet de diminution de PDE (phosphodiestérase)-5, d'une expression de protéine CREM, d'une augmentation du nombre et de l'activité des spermatozoïdes, d'une augmentation dans la teneur en testostérone et analogues.
PCT/KR2013/001080 2013-02-12 2013-02-12 Composition pharmaceutique pour améliorer la fonction sexuelle masculine et pour traiter l'infertilité WO2014126269A1 (fr)

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CN106902306A (zh) * 2017-03-14 2017-06-30 孙自学 一种治疗肾虚血瘀型良性前列腺增生症膀胱逼尿肌功能障碍的中药及其制备方法
JP2018108946A (ja) * 2016-12-28 2018-07-12 小林製薬株式会社 ホスホジエステラーゼ５活性阻害用組成物

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JP7058939B2 (ja) 2016-12-28 2022-04-25 小林製薬株式会社 ホスホジエステラーゼ５活性阻害用組成物
CN106902306A (zh) * 2017-03-14 2017-06-30 孙自学 一种治疗肾虚血瘀型良性前列腺增生症膀胱逼尿肌功能障碍的中药及其制备方法

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