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WO2016121892A1 - Infertility ameliorating agent compound - Google Patents

Infertility ameliorating agent compound Download PDF

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Publication number
WO2016121892A1
WO2016121892A1 PCT/JP2016/052548 JP2016052548W WO2016121892A1 WO 2016121892 A1 WO2016121892 A1 WO 2016121892A1 JP 2016052548 W JP2016052548 W JP 2016052548W WO 2016121892 A1 WO2016121892 A1 WO 2016121892A1
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WIPO (PCT)
Prior art keywords
infertility
activity
extract
fruit
administration
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PCT/JP2016/052548
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French (fr)
Japanese (ja)
Inventor
正雄 神野
道生 山田
祥子 竹下
知広 上村
Original Assignee
正雄 神野
林兼産業株式会社
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Priority claimed from JP2015088110A external-priority patent/JP6077045B2/en
Application filed by 正雄 神野, 林兼産業株式会社 filed Critical 正雄 神野
Priority to EP16743495.0A priority Critical patent/EP3251681B1/en
Priority to AU2016213061A priority patent/AU2016213061B2/en
Priority to US15/126,331 priority patent/US20170165313A1/en
Publication of WO2016121892A1 publication Critical patent/WO2016121892A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a composition for improving infertility that is safe and highly active and applicable to a wide range of symptoms related to infertility.
  • infertility refers to “a state in which pregnancy is not achieved for more than 12 months even though there is sufficient sex without contraception.” Infertility has both a cause on the male side and a cause on the female side. The former is called male infertility and the latter is called female infertility. As a cause of male infertility, for example, the following factors can be considered. (1) Impaired spermatogenic function: azoospermia, oligospermia, asthenozoospermia, etc., and is said to account for about 90% of male infertility.
  • Ovulation disorder Central ovulation disorder (endocrine failure), ovarian dysfunction, ovarian cyst, luteal unruptured follicle, hyperprolactinemia, etc.
  • Fallopian tube failure fallopian tube adhesion, fallopian tube stenosis, fallopian tube Obstruction, fallopian tube edema, etc.
  • Cervical disorders Cervical mucus failure, anti-sperm antibody formation, cervical stenosis, etc.
  • Endometriosis Chocolate cyst, uterine adenomyosis, etc.
  • Implantation disorder Uterus Myoma, uterine malformation, luteal dysfunction, endometrial polyp, etc.
  • Treatment methods for male infertility include sperm collection from semen, vas deferens, and testis and drug therapy such as artificial insemination, microinsemination, and hormone replacement therapy.
  • examples of treatment methods for female infertility include administration of an ovulation inducer, ovulation disorders, cervical mucus insufficiency, hyperprolactinemia, etc., advanced reproductive medicine such as artificial insemination and in vitro fertilization.
  • an ovulation inducer clomiphene (for example, refer to Patent Document 1), an internal medicine such as cyclophenyl, and an injection such as gonatotropin are widely used.
  • Dopaminergic drugs such as bromocriptine, terguride and cabergoline are used for pharmacotherapy for hyperprolactinemia. Moreover, it has been reported that the pregnancy rate of polycystic ovary syndrome and non-polycystic ovary syndrome improves by administering the insulin sensitizer metformin (see Non-Patent Document 1).
  • infertility may involve multiple factors in addition to the above factors, such as glycation stress due to lifestyle-related diseases and allergic diseases (for example, Shinji Komori, “Clinical Conference”). (Reproductive endocrine region): 1.
  • the present invention has been made in view of such circumstances, and an object thereof is to provide a composition for improving infertility that is safe and has high activity and can be applied to a wide range of symptoms related to infertility.
  • the present invention that meets the above-described object provides a composition for improving infertility, which comprises, as an active ingredient, one or more compounds contained in one or both of the skin and the fruit of a plant belonging to the family Chinaceae.
  • the present invention solves the above problems.
  • the active ingredient contains one or a plurality of compounds separated from the extract of one or both of the fruit skin and the fruit or the extract.
  • the infertility improving composition of the present invention preferably has an activity to inhibit one or more reactions related to the production of a terminal glycation product from protein and sugar.
  • the infertility improving composition of the present invention preferably has an activity of promoting one or more reactions related to the degradation of the terminal glycation product.
  • the infertility improving composition of the present invention preferably has an activity of reducing allergic symptoms.
  • the active ingredient of the composition for improving fertility of the present invention is one or a plurality of compounds contained in one or both of the skin and the fruit of a plant belonging to the family Chinaceae with dietary experience. Therefore, safety has been confirmed, and it has a high infertility improving activity.
  • a safe and highly active fertility improving composition is provided.
  • 3 is a graph showing measurement results of ⁇ -dicarbonyl bond cleavage activity. It is a graph which shows the measurement result of AGE bridge
  • infertility improving composition according to an embodiment of the present invention (hereinafter, also referred to as “infertility improving composition” or simply “composition”) may be used for the pericarp and fruit of the Chinaceae plants.
  • infertility improving composition may be used for the pericarp and fruit of the Chinaceae plants.
  • One or more compounds contained in one or both are included as active ingredients.
  • pericarp and fruit of the Chinaceae plant which is an active ingredient
  • pulverized or finely divided pericarp and fruit In the case of production of a composition used as an injection, for example, fruit juice and one or both of fruit and fruit peel extracts are preferably used.
  • the one or more compounds contained in one or both of the pericarp and fruit of the Chestnut plant are preferably one or both of the pericarp and fruit extract or one or more compounds separated from the extract.
  • the preparation method of the extract of one or both of a fruit skin and a fruit is explained in full detail.
  • the fruits and pericarps of the Chinaceae plants may be raw fruits or those collected from raw fruits, dried after collection, dried fruits or those collected from dried fruits.
  • pretreatment such as crushing or pulverization may be performed using any method before solvent extraction.
  • Chrysanthemum plant used for extraction there are no particular restrictions on the Chrysanthemum plant used for extraction, but specific examples include horsetail (Trapa japonica), sea bream (Trapa natans L. ver. It is done.
  • water, an aqueous solution, a mixed solvent (aqueous solvent) obtained by mixing water in an arbitrary ratio with any one or more solvents miscible with water can be used.
  • Water, methanol, ethanol, and an aqueous solvent in which any two or more of these are mixed in an arbitrary ratio, and particularly preferable extraction solvents are water, ethanol and water which are organic solvents recognized as food additives, and water. It is the aqueous solvent mixed in the ratio.
  • the temperature of the extraction solvent may be any temperature that exceeds room temperature and is not higher than the boiling point of the extraction solvent, but is preferably determined in consideration of extraction efficiency, heat resistance and volatility of the extraction target, and the like.
  • an acid, a base, a salt, and the like may be appropriately included as necessary in order to improve extraction efficiency.
  • the temperature and pH of water used for extraction are not particularly limited, but the pH is preferably near neutral, more specifically pH 4-9, more preferably 6-8, considering use in living organisms. More preferably. If necessary, a heated extraction solvent may be used in order to improve the extraction efficiency.
  • Hot water extraction can be performed by any known method. For example, after mixing one or both of pericarp and fruit of a Chinaceae plant in a solvent for a predetermined time, it is separated from a solid content by filtration, centrifugation, decantation, or the like. Or a continuous extraction method such as a Soxhlet extraction method can be used.
  • Pre-treatment by dialysis, ultrafiltration, filtration, column chromatography, etc. to remove high molecular weight components and insolubles before separating one or more compounds from the solvent extract of persimmon skin May be performed.
  • an adsorbent such as activated carbon, bentonite, or celite or a filter aid may be added as necessary to remove impurities.
  • an adsorbent such as activated carbon, bentonite, or celite or a filter aid
  • Separation of the hot water extract subjected to the pretreatment as described above as necessary can be performed using any known method such as column chromatography, reverse phase chromatography, ion chromatography, and the like, which will be described later. It can be carried out by fractionating various highly active fractions that seem to be related to the improvement of infertility.
  • AGEs Advanced glycation end products
  • Maillard reaction products are protein derivatives with various structures that are generated by non-enzymatic reactions between reducing sugars such as glucose and amino groups of proteins. It is.
  • AGEs can be produced in various ways as a result of cellular functions caused by glycation modification of extracellular matrix proteins, membrane proteins, and intracellular proteins, as well as the breakdown of the functions of these proteins and their dependent cellular functions, or by receptors using AGEs as ligands. Involved in the onset and exacerbation of lesions.
  • AGEs are recognized by RAGE, one of the AGEs receptors, the production of intracellular oxidative stress substances by intracellular NADPH oxidase is enhanced, and this changes the gene expression in epithelial cells, thereby causing various diabetic properties. Vascular disorders are thought to develop.
  • AGEs have been developed in addition to diabetic vascular disorders, cardiovascular disorders such as myocardial infarction and arteriosclerosis, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and brains caused by alcoholism.
  • diabetic nephropathy, diabetic retinopathy, diabetic complications such as diabetic neuropathy, bone metabolism abnormalities such as osteoporosis, aging phenomenon, insulin resistance, tumor growth and metastasis It is suggested that
  • Diabetes is known to be one of the causes of infertility and irregular menstruation. Although the mechanism is not always clear, insulin resistance plays an important role in the mechanism of ovulation due to insulin resistance, and damage to the ovaries, fallopian tubes, cervix, endometrium by AGEs, etc. Conceivable. Gestational diabetes is a risk factor such as premature detachment of the placenta, premature birth and stillbirth, abnormal growth of the fetus due to excessive carbohydrate supply, and hypoglycemia after birth.
  • the reactions to be inhibited by the infertility improver composition are the generation of Schiff bases by the reaction of protein amino groups and reducing sugars, 1,2-enaminol by 2, Amadori rearrangement, or 2, It may be any one or more reactions such as the production of 3-enediol, degradation of the Amadori transfer product and the polymerization product of the degradation product with amino acids, peptides or proteins.
  • the activity of inhibiting one or more reactions related to the generation of AGEs from proteins and sugars is, for example, AGEs produced by reacting serum proteins such as human serum albumin with glucose (for example, 60 ° C., 40 hours).
  • activities that may be related to the improvement of infertility include activities that promote one or more reactions related to the degradation of advanced glycation end products (AGEs).
  • Reactions related to the degradation of AGEs include the production of Schiff bases by the reaction of protein amino groups with reducing sugars, the production of 1,2-enaminol or 2,3-enediol by Amadori rearrangement, and the degradation of Amadori transfer products. And a reaction that cleaves a bond formed by the formation of a polymerization product of the degradation product and an amino acid, peptide, or protein.
  • reaction used for evaluating the activity that promotes the reaction related to the degradation of AGEs include And a reaction that cleaves an ⁇ -dicarbonyl bond peculiar to AGEs, a reaction that cleaves a crosslink formed by a reaction between a protein such as collagen and AGEs, and the like.
  • Allergic diseases such as atopic dermatitis, allergic rhinitis, and hay fever have been pointed out to be associated with endometriosis and are also said to cause infertility due to the immune system.
  • the mechanism by which one or more compounds contained in one or both of the pericarp and the fruit of the Chinaceae plant alleviate allergic symptoms and its relationship with improvement of infertility are not necessarily clear, but contain such compounds as active ingredients It has been confirmed that an infertility improving composition can reduce allergic symptoms and improve infertility.
  • the composition for improving infertility By mixing the composition for improving infertility with a carrier or the like, it can be used as a pharmaceutical composition having one or both of a therapeutic effect and a preventive effect for diabetes and related diseases and symptoms.
  • the dosage form of the pharmaceutical composition for humans or animals include oral, rectal, parenteral (for example, intravenous administration, intramuscular administration, subcutaneous administration, etc.), and the dosage is the formulation of the pharmaceutical composition.
  • the active ingredient generally contained in the formulation is difficult to determine and uniquely determined depending on the administration method, purpose of use, and age, weight, and symptoms of the subject to be applied.
  • the amount is preferably 0.1 to 2000 mg / day per day for an adult.
  • an amount smaller than the above dosage may be sufficient or may be necessary beyond the above range.
  • the above-mentioned desired dosage form can be prepared by blending an infertility improving composition with a pharmaceutically acceptable carrier or diluent, a stabilizer, and other desired additives.
  • the food containing the infertility improving agent composition can take any form commonly used for foods or supplements, such as those obtained by blending the infertility improving composition with food, or capsules, tablets, and the like.
  • the type of food to be blended for example, liquid (fluid) foods such as coffee, fruit juice, soft drinks, beer, milk, miso soup, soup, tea, tea, nutrients, syrup, margarine, jam, etc.
  • it may be formed into a powder, granule, tablet or the like.
  • an improving agent composition can also be added and administered to feed. That is, a food containing an infertility improving composition as an active ingredient can be safely added to livestock such as pigs, cows, horses, sheep, and feed such as pets (dogs, cats). It can be used as a functional feed having activity to improve infertility.
  • the present invention relates to a method for improving human infertility by administering a composition for improving infertility containing one or more compounds contained in one or both of the pericarp and fruits of Chinaceae as an active ingredient and non-human It also provides a method for improving infertility in other mammals.
  • Example 1 Preparation of an extract of persimmon pericarp and oral administration containing the same
  • a hot water extract of a Coriaceae plant hereinafter abbreviated as "Hoshi pericarp extract” bispinosa
  • the extract was concentrated at a predetermined concentration rate that was determined in advance so as to be 25% by weight or more.
  • Example 2 Effect of continuous administration of Hoshi peel extract on blood glucose level, blood AGEs concentration, blood cholesterol concentration 50 female subjects were divided into Hishi peel extract administration group and placebo administration group (25 each), For 12 weeks, the former contains an extract of persimmon peel (referred to as “Hishi extract” in Tables 1 to 6 and FIGS. 1 and 2), a placebo for the latter, The dose described in Example 1 (2) above was administered in a double-blind manner. Every 4 weeks, blood tests (blood HbA1c concentration, blood neutral lipid concentration, blood cholesterol concentration (total cholesterol concentration, HDL-cholesterol concentration and LDL-cholesterol concentration), blood pentosidine concentration measurement) are measured. went. The respective measurement results are shown in Tables 1 to 6.
  • 0W”, “4W”, “8W” and “12W” represent the results of the 0th, 4th, 8th and 12th weeks, respectively, and “Mean” is the average value. “SD” represents standard deviation, “SE” represents standard error, and “Wilcoxon” represents the result of Wilcoxon's sign rank test.
  • Example 3 Effect of administration of an extract of persimmon peel on postprandial blood glucose level For 4 subjects (average age 28.7 years old, 1 male, 3 females) whose fasting blood glucose level was 70 to 110 mg / dL The test was conducted according to the following protocol.
  • fasting blood glucose was measured at 8:00 on the day of the study, and then an oral preparation containing placenta extract or placebo was administered (double blind) The test method was used.) After 5 minutes, eat 200g of cooked rice + 2.5g of sprinkles (total calorie 308kcal, carbohydrate amount 70.2g) as a loaded meal, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes and 120 minutes after eating The blood glucose level was measured.
  • Example 4 Measurement of ⁇ -Dicarbonyl Bond Cleavage Activity
  • the dicarbonyl bond cleavage activity was determined by measuring the benzoic acid concentration obtained by decomposing 1-phenyl-1,2-propanedione (PPD), which is a dicarbonyl compound, by HPLC. It calculated by measuring by. Dissolve 4.2 ⁇ L of 98% PPD solution in 25 mL of 50 mM phosphate buffer (pH 7.4) / 50% methanol (methanol buffer), and prepare the PPD solution so that the concentration in the final reaction solution is 1.0 mM. did.
  • PPD 1-phenyl-1,2-propanedione
  • the analysis column used was TSKgel ODS-80T, 150 ⁇ 6.0 mm (ID) (Tosoh).
  • the eluent was 50 mM phosphate buffer (pH 2.2), the flow rate was 1.0 mL / min, and the detection wavelength was 230 nm.
  • benzoic acid concentration in each measurement sample is calculated from a calibration curve using benzoic acid at each concentration (manufactured by Wako Pure Chemical Industries, Ltd.), and 1.0 mM benzoic acid is obtained from 1.0 mM PPD. From this, the dicarbonyl bond cleavage activity in the PPD structure was determined using the following formula.
  • Dicarbonyl bond cleavage activity 100 ⁇ benzoic acid concentration (mM) / 1 mM
  • Example 5 Measurement of AGE cross-linking cleavage activity
  • the AGE cross-linking cleaving activity is obtained by measuring the cross-linking formed between type I collagen and AGE-BSA by the ELISA method, and calculating the cross-linking cleaving rate by adding the pericarp extract. It was evaluated by.
  • AGE-BSA 10 ⁇ g / mL solution (100 ⁇ L) was added to BD BioCoat Collagen I 96 well micro test plate and incubated at 37 ° C. for 4 hours. The plate was washed 5 times with 0.05% Tween20 / PBS ( ⁇ ), 100 ⁇ L of each concentration sample dissolved in PBS ( ⁇ ) was added, and reacted at 37 ° C. for 20 hours. Each well after the reaction was washed three times with 0.05% Tween 20 / PBS ( ⁇ ), and 1 ⁇ g / mL anti-bovine serum albumin (BSA) rabbit polyclonal antibody solution (ROCKLAND) was added to each well as a primary antibody.
  • BSA anti-bovine serum albumin
  • the AGE-BSA crosslinking residual ratio was calculated from the following formula.
  • Example 6 Test administration to refractory infertile patients (1) Five female patients with refractory infertility with repeated ART (Advanced Reproductive Assistance Medicine) were administered as subjects for oral administration containing Hishi peel extract over 3 months. After administration for 3 months, the blood HbA1c concentration decreased by 0.1 to 0.4 points for all of them. In addition, there was one subject who had a symptom of atopic dermatitis, one subject who had a symptom of allergic rhinitis (hay fever), and one subject who had improved makeup riding. Among the subjects, one woman in her 40s who had suffered from atopic dermatitis and diabetes and had previously failed 13 in vitro fertilizations succeeded in pregnancy by in vitro fertilization during the test period.
  • ART Advanced Reproductive Assistance Medicine
  • Example 7 Test administration to refractory infertile patients (2) From July 2014 to March 2015, 32 cases of refractory infertility (including 5 cases of Example 6) with unsuccessful repetitive ART (advanced assisted reproductive medicine) ART was performed while administering persimmon peel extract every day from 1 to 2 months in advance (once daily, taking 100 mg immediately before the start of breakfast).
  • ART advanced assisted reproductive medicine

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Abstract

The present invention pertains to an infertility ameliorating agent compound that is safe and has high activity. This infertility ameliorating agent compound contains, as an active ingredient, one or a plurality of compounds that are contained in either or both of the peel and the fruit of a plant of Trapaceae, and preferably contains an extract of either or both of the peel and the fruit of a plant of Trapaceae or one or a plurality of compounds separated from the extract. The one or the plurality of compounds preferably have one or a plurality of: activity for inhibiting one or a plurality of reactions relating to production of an advanced glycation end product from a protein and a sugar; activity for accelerating one or a plurality of reactions relating to degradation of the advanced glycation end product; and activity for reducing allergic symptoms.

Description

不妊の改善剤組成物Infertility improver composition
 本発明は、安全で高い活性を有し、不妊に関連する幅広い症状に適用可能な不妊の改善剤組成物に関する。 The present invention relates to a composition for improving infertility that is safe and highly active and applicable to a wide range of symptoms related to infertility.
 世界保健機関の定義によると、「不妊」とは、「避妊なしで十分な頻度の性交渉があるのに12ヶ月以上にわたって妊娠に至れない状態」をいう。不妊には、男性側に原因がある場合及び女性側に原因がある場合の双方があり、前者を男性不妊、後者を女性不妊という。男性不妊の原因としては、例えば、下記のような要因が考えられる。
(1)造精機能障害:無精子症、乏精子症、精子無力症等で、男性不妊の約90%を占めると言われている。
(2)その他の要因:精索静脈瘤、閉塞性無精子症、先天性精管欠損、膿精液症、無精液症、逆行性射精、勃起不全(ED)、膣内射精障害等
According to the definition of the World Health Organization, “infertility” refers to “a state in which pregnancy is not achieved for more than 12 months even though there is sufficient sex without contraception.” Infertility has both a cause on the male side and a cause on the female side. The former is called male infertility and the latter is called female infertility. As a cause of male infertility, for example, the following factors can be considered.
(1) Impaired spermatogenic function: azoospermia, oligospermia, asthenozoospermia, etc., and is said to account for about 90% of male infertility.
(2) Other factors: varicocele, obstructive azoospermia, congenital vaginal defect, pyospermia, azoospermia, retrograde ejaculation, erectile dysfunction (ED), intravaginal ejaculation disorder, etc.
 また、女性不妊の原因としては、例えば、下記のような要因が考えられる。
(1)排卵障害:中枢性の排卵障害(内分泌不全)、卵巣機能不全、卵巣嚢腫、黄体未破裂卵胞、高プロラクチン血症等
(2)卵管障害:卵管癒着、卵管狭窄、卵管閉塞、卵管水腫等
(3)子宮頸管障害:頸管粘液不全、抗精子抗体の形成、頸管狭窄等
(4)子宮内膜症:チョコレート嚢腫、子宮腺筋症等
(5)着床障害:子宮筋腫、子宮奇形、黄体機能不全、子宮内膜ポリープ等
Moreover, as a cause of female infertility, the following factors can be considered, for example.
(1) Ovulation disorder: Central ovulation disorder (endocrine failure), ovarian dysfunction, ovarian cyst, luteal unruptured follicle, hyperprolactinemia, etc. (2) Fallopian tube failure: fallopian tube adhesion, fallopian tube stenosis, fallopian tube Obstruction, fallopian tube edema, etc. (3) Cervical disorders: Cervical mucus failure, anti-sperm antibody formation, cervical stenosis, etc. (4) Endometriosis: Chocolate cyst, uterine adenomyosis, etc. (5) Implantation disorder: Uterus Myoma, uterine malformation, luteal dysfunction, endometrial polyp, etc.
 男性不妊の治療法としては、精液、精管、精巣からの精子の採取と人工授精や顕微授精、ホルモン補充療法等の薬物療法等が挙げられる。また、女性不妊の治療法としては、排卵誘発剤の投与、排卵障害、頸管粘液不全、高プロラクチン血症等に対する薬物療法、人工授精、体外受精等の高度生殖医療等が挙げられる。排卵誘発剤としては、クロミフェン(例えば、特許文献1参照)、シクロフェニル等の内服薬、ゴナトトロピン等の注射剤が広く用いられている。高プロラクチン血症に対する薬物療法には、ブロモクリプチン、テルグリド、カベルゴリン等のドーパミン作動薬が用いられている。また、インスリン増感薬のメトホルミンを投与することで多嚢胞性卵巣症候群及び非多嚢胞性卵巣症候群の妊娠率が改善することが報告されている(非特許文献1参照)。 Treatment methods for male infertility include sperm collection from semen, vas deferens, and testis and drug therapy such as artificial insemination, microinsemination, and hormone replacement therapy. In addition, examples of treatment methods for female infertility include administration of an ovulation inducer, ovulation disorders, cervical mucus insufficiency, hyperprolactinemia, etc., advanced reproductive medicine such as artificial insemination and in vitro fertilization. As an ovulation inducer, clomiphene (for example, refer to Patent Document 1), an internal medicine such as cyclophenyl, and an injection such as gonatotropin are widely used. Dopaminergic drugs such as bromocriptine, terguride and cabergoline are used for pharmacotherapy for hyperprolactinemia. Moreover, it has been reported that the pregnancy rate of polycystic ovary syndrome and non-polycystic ovary syndrome improves by administering the insulin sensitizer metformin (see Non-Patent Document 1).
特表2009-503096号公報Special table 2009-503096 gazette
 しかしながら、不妊の薬物療法に用いられている医薬品には、多胎妊娠や、卵巣過剰刺激症候群等の、生命に危険を及ぼしかねないものを含む様々な副作用が存在する(例えば、矢内原巧著、「生殖医療と生命倫理 多胎妊娠とその問題点」、学術の動向(日本学術会議) 1999年4月 p. 31-37参照)。不妊には、上記の諸要因に加え、生活習慣病等に起因する糖化ストレス、アレルギー性疾患等の症状が複合的に関与している場合も考えられるが(例えば、小森 慎二著、「クリニカルカンファレンス(生殖内分泌領域);1.不妊診療の問題点と対策 3)免疫性不妊、日産婦誌(日本産婦人科学会)59巻9号参照)、そのような場合における有効な治療法は、未だ確立されているとは言えないのが現状である。複数の医薬品を同時に投与する場合、その組み合わせによっては、予期せぬ重篤な副作用の発生等のリスクが存在する。そのため、様々な要因が複合的に関与している不妊について、安全で効果の高い治療薬及び治療法の確立が望まれている。 However, pharmaceuticals used for infertility pharmacotherapy have various side effects including those that may be life-threatening, such as multiple pregnancy and ovarian hyperstimulation syndrome (for example, Takumi Yanaihara, “ Reproductive medicine and bioethics "Multiple pregnancy and its problems", academic trends (Japan Science Council), April 1999, p. 31-37). Infertility may involve multiple factors in addition to the above factors, such as glycation stress due to lifestyle-related diseases and allergic diseases (for example, Shinji Komori, “Clinical Conference”). (Reproductive endocrine region): 1. Problems and countermeasures for infertility treatment 3) Immune infertility, see the Journal of Japan Women's Gynecology (Japanese Society of Obstetrics and Gynecology) No. 59, No. 9), effective treatment in such cases is still In the current situation, when multiple drugs are administered at the same time, depending on the combination, there are risks such as the occurrence of unexpected serious side effects. It is desired to establish a safe and highly effective therapeutic agent and treatment method for infertility that is involved in multiple ways.
 本発明はかかる事情に鑑みてなされたもので、安全で高い活性を有し、不妊に関連する幅広い症状に適用可能な不妊の改善剤組成物を提供することを目的とする。 The present invention has been made in view of such circumstances, and an object thereof is to provide a composition for improving infertility that is safe and has high activity and can be applied to a wide range of symptoms related to infertility.
 前記目的に沿う本発明は、ヒシ科に属する植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物を有効成分として含むことを特徴とする不妊の改善剤組成物を提供することにより上記課題を解決するものである。 The present invention that meets the above-described object provides a composition for improving infertility, which comprises, as an active ingredient, one or more compounds contained in one or both of the skin and the fruit of a plant belonging to the family Chinaceae. The present invention solves the above problems.
 本発明の不妊の改善剤組成物において、前記有効成分として、果皮及び果実の一方又は双方の抽出物又は該抽出物より分離される1又は複数の化合物を含むことが好ましい。 In the infertility improving composition of the present invention, it is preferable that the active ingredient contains one or a plurality of compounds separated from the extract of one or both of the fruit skin and the fruit or the extract.
 本発明の不妊の改善剤組成物において、タンパク質と糖からの終末糖化産物の生成に関連する1又は複数の反応を阻害する活性を有していることが好ましい。 The infertility improving composition of the present invention preferably has an activity to inhibit one or more reactions related to the production of a terminal glycation product from protein and sugar.
 本発明の不妊の改善剤組成物において、終末糖化産物の分解に関連する1又は複数の反応を促進する活性を有していることが好ましい。 The infertility improving composition of the present invention preferably has an activity of promoting one or more reactions related to the degradation of the terminal glycation product.
 本発明の不妊の改善剤組成物において、アレルギー症状を軽減する活性を有していることが好ましい。 The infertility improving composition of the present invention preferably has an activity of reducing allergic symptoms.
 本発明の不妊の改善剤組成物の有効成分は、食経験のあるヒシ科に属する植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物である。したがって、安全性が確認されたものであると共に、高い不妊の改善活性を有する。このように、本発明によると、安全で活性の高い不妊の改善剤組成物が提供される。 The active ingredient of the composition for improving fertility of the present invention is one or a plurality of compounds contained in one or both of the skin and the fruit of a plant belonging to the family Chinaceae with dietary experience. Therefore, safety has been confirmed, and it has a high infertility improving activity. Thus, according to the present invention, a safe and highly active fertility improving composition is provided.
α-ジカルボニル結合切断活性の測定結果を示すグラフである。3 is a graph showing measurement results of α-dicarbonyl bond cleavage activity. AGE架橋切断活性の測定結果を示すグラフである。It is a graph which shows the measurement result of AGE bridge | crosslinking cutting | disconnection activity.
 続いて、添付した図面を参照しつつ、本発明を具体化した実施の形態につき説明し、本発明の理解に供する。
 本発明の一実施の形態に係る不妊の改善剤組成物(以下、「不妊の改善剤組成物」又は単に「組成物」と略称する場合がある。)は、ヒシ科植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物を有効成分として含んでいる。
Next, embodiments of the present invention will be described with reference to the accompanying drawings for understanding of the present invention.
An infertility improving composition according to an embodiment of the present invention (hereinafter, also referred to as “infertility improving composition” or simply “composition”) may be used for the pericarp and fruit of the Chinaceae plants. One or more compounds contained in one or both are included as active ingredients.
 有効成分であるヒシ科植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物としては、例えば、経口投与用の組成物の場合には、果皮や果実の粉砕物又は微粉化したものを含んでいてもよいが、例えば、注射剤として用いられる組成物等の製造の場合には、果実の搾汁や、果実及び果皮の一方又は双方の抽出物が好ましく用いられる。 As one or a plurality of compounds contained in one or both of the pericarp and fruit of the Chinaceae plant which is an active ingredient, for example, in the case of a composition for oral administration, pulverized or finely divided pericarp and fruit In the case of production of a composition used as an injection, for example, fruit juice and one or both of fruit and fruit peel extracts are preferably used.
 ヒシ科植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物は、好ましくは、果皮及び果実の一方又は双方の抽出物又は該抽出物より分離される1又は複数の化合物である。以下、果皮及び果実の一方又は双方の抽出物の調製方法について詳述する。 The one or more compounds contained in one or both of the pericarp and fruit of the Chestnut plant are preferably one or both of the pericarp and fruit extract or one or more compounds separated from the extract. Hereinafter, the preparation method of the extract of one or both of a fruit skin and a fruit is explained in full detail.
 ヒシ科植物の果実及び果皮は、生の実又は生の実から採取したもの、採取後乾燥したもの、乾燥した実又は乾燥した実から採取したもののいずれであってもよい。抽出効率を向上させるために、溶媒抽出の前に任意の方法を用いて破砕又は粉砕等の前処理を行ってもよい。 The fruits and pericarps of the Chinaceae plants may be raw fruits or those collected from raw fruits, dried after collection, dried fruits or those collected from dried fruits. In order to improve the extraction efficiency, pretreatment such as crushing or pulverization may be performed using any method before solvent extraction.
 抽出に用いられるヒシ科植物は特に制限されないが、具体例としては、ヒシ(Trapa japonica)、オニビシ(Trapa natans L. ver. japonica)、ヒメビシ(Trapa incisa)及びトウビシ(Trapa bispinosa Roxb.)が挙げられる。 There are no particular restrictions on the Chrysanthemum plant used for extraction, but specific examples include horsetail (Trapa japonica), sea bream (Trapa natans L. ver. It is done.
 抽出に用いる溶媒としては、水、水溶液、水と混和する任意の1種以上の溶媒と水とを任意の割合で混合した混合溶媒(水性溶媒)を用いることができるが、好ましい抽出溶媒は、水、メタノール、エタノール及びこれらの任意の2以上を任意の割合で混合した水性溶媒であり、特に好ましい抽出溶媒は、水、食品添加物として認められている有機溶媒であるエタノールと水とを任意の割合で混合した水性溶媒である。抽出溶媒の温度は、室温を超え抽出溶媒の沸点以下の任意の温度であってよいが、抽出効率、被抽出物の耐熱性及び揮発性等を考慮して決定されることが好ましい。 As the solvent used for extraction, water, an aqueous solution, a mixed solvent (aqueous solvent) obtained by mixing water in an arbitrary ratio with any one or more solvents miscible with water can be used. Water, methanol, ethanol, and an aqueous solvent in which any two or more of these are mixed in an arbitrary ratio, and particularly preferable extraction solvents are water, ethanol and water which are organic solvents recognized as food additives, and water. It is the aqueous solvent mixed in the ratio. The temperature of the extraction solvent may be any temperature that exceeds room temperature and is not higher than the boiling point of the extraction solvent, but is preferably determined in consideration of extraction efficiency, heat resistance and volatility of the extraction target, and the like.
 抽出溶媒として水及び水性溶媒を用いる場合には、抽出効率を向上させるために、必要に応じて、酸、塩基、塩等を適宜含んでいてもよい。抽出に用いる水の温度及びpHについては特に制限はないが、pHについては、生体への使用を考慮して中性付近、より具体的にはpH4~9であることが好ましく、6~8であることがより好ましい。必要に応じて、抽出効率を向上させるために、加熱した抽出溶媒を用いてもよい。 In the case of using water and an aqueous solvent as the extraction solvent, an acid, a base, a salt, and the like may be appropriately included as necessary in order to improve extraction efficiency. The temperature and pH of water used for extraction are not particularly limited, but the pH is preferably near neutral, more specifically pH 4-9, more preferably 6-8, considering use in living organisms. More preferably. If necessary, a heated extraction solvent may be used in order to improve the extraction efficiency.
 熱水抽出は任意の公知の方法により行うことができ、例えば、ヒシ科植物の果皮及び果実の一方又は双方を溶媒中で所定時間混合後、ろ過、遠心分離、デカンテーション等により固形分と分離する方法、ソックスレー抽出法等の連続抽出法等の方法を用いることができる。 Hot water extraction can be performed by any known method. For example, after mixing one or both of pericarp and fruit of a Chinaceae plant in a solvent for a predetermined time, it is separated from a solid content by filtration, centrifugation, decantation, or the like. Or a continuous extraction method such as a Soxhlet extraction method can be used.
 ヒシ科植物の果皮の溶媒抽出物から、1又は複数の化合物を分離する前に、高分子量成分や不溶分等を除去するために、透析、限外ろ過、ろ過、カラムクロマトグラフィー等による前処理を行ってもよい。 Pre-treatment by dialysis, ultrafiltration, filtration, column chromatography, etc. to remove high molecular weight components and insolubles before separating one or more compounds from the solvent extract of persimmon skin May be performed.
 ろ過により不溶分等を除去する場合には、必要に応じて、不純物を除去するために活性炭、ベントナイト、セライト等の吸着剤やろ過助剤を添加してもよい。特に抽出液の状態で用いる場合には、メンブレンフィルター等による除菌ろ過を併せて行うことが好ましい。 When removing insolubles by filtration, an adsorbent such as activated carbon, bentonite, or celite or a filter aid may be added as necessary to remove impurities. In particular, when used in the state of an extract, it is preferable to perform sterilization filtration using a membrane filter or the like.
 必要に応じて上述のような前処理を行った熱水抽出物の分離は、カラムクロマトグラフィー、逆相クロマトグラフィー、イオンクロマトグラフィー等の任意の公知の方法を用いて行うことができ、後述する、不妊の改善に関連すると思われる各種の活性の高い画分を分画することにより行うことができる。 Separation of the hot water extract subjected to the pretreatment as described above as necessary can be performed using any known method such as column chromatography, reverse phase chromatography, ion chromatography, and the like, which will be described later. It can be carried out by fractionating various highly active fractions that seem to be related to the improvement of infertility.
 不妊の改善に関連すると思われる活性の一例として、タンパク質と糖からの終末糖化産物の生成に関連する1又は複数の反応を阻害する活性が挙げられる。終末糖化産物(Advanced Glycation Endproduct、AGEs)は、糖化タンパク質、メイラード反応産物等とも呼ばれ、グルコース等の還元糖とタンパク質のアミノ基との非酵素的な反応により生成する種々の構造を有するタンパク質誘導体である。AGEsは、細胞外マトリックスタンパク質、膜タンパク質及び細胞内タンパク質の糖化修飾に起因するこれらのタンパク質の機能及びそれに依存する細胞機能の破綻、或いはAGEsをリガンドとするレセプターが引き起こす細胞応答の結果として、種々の病変の発症及び増悪に関与している。 As an example of the activity that seems to be related to improvement of infertility, there is an activity that inhibits one or more reactions related to the production of a terminal glycation product from protein and sugar. Advanced glycation end products (AGEs), also called glycated proteins and Maillard reaction products, are protein derivatives with various structures that are generated by non-enzymatic reactions between reducing sugars such as glucose and amino groups of proteins. It is. AGEs can be produced in various ways as a result of cellular functions caused by glycation modification of extracellular matrix proteins, membrane proteins, and intracellular proteins, as well as the breakdown of the functions of these proteins and their dependent cellular functions, or by receptors using AGEs as ligands. Involved in the onset and exacerbation of lesions.
 例えば、AGEsレセプターの1つであるRAGEによってAGEsが認識されると、細胞内NADPHオキシダーゼによる細胞内酸化ストレス物質の産生が亢進し、これが上皮細胞における遺伝子発現を変化させることにより、種々の糖尿病性血管障害が発症すると考えられている。 For example, when AGEs are recognized by RAGE, one of the AGEs receptors, the production of intracellular oxidative stress substances by intracellular NADPH oxidase is enhanced, and this changes the gene expression in epithelial cells, thereby causing various diabetic properties. Vascular disorders are thought to develop.
 また、近年、AGEsは、糖尿病性血管障害に加え、心筋梗塞、動脈硬化症等の心血管障害、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症等の神経変性疾患、アルコール依存症による脳障害及び肝障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性神経症等の糖尿病合併症、骨粗鬆症等の骨代謝異常、老化現象、インスリン抵抗性、腫瘍の増殖及び転移等にも関与していることが示唆されている。 In recent years, AGEs have been developed in addition to diabetic vascular disorders, cardiovascular disorders such as myocardial infarction and arteriosclerosis, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and brains caused by alcoholism. Involved in disorders and liver disorders, diabetic nephropathy, diabetic retinopathy, diabetic complications such as diabetic neuropathy, bone metabolism abnormalities such as osteoporosis, aging phenomenon, insulin resistance, tumor growth and metastasis It is suggested that
 糖尿病は、不妊や月経不順の原因の一つであることが知られている。その機序は必ずしも明らかではないものの、インスリン抵抗性により排卵機構にも重要な役割を果たすインスリンの機能が阻害されることや、AGEsによる卵巣、卵管、子宮頸管、子宮内膜の損傷等が考えられる。また、妊娠糖尿病は、胎盤早期剥離、早産や死産、糖質の過剰供給による胎児の成長異常や出生後の低血糖等の様々なリスク要因となっている。 Diabetes is known to be one of the causes of infertility and irregular menstruation. Although the mechanism is not always clear, insulin resistance plays an important role in the mechanism of ovulation due to insulin resistance, and damage to the ovaries, fallopian tubes, cervix, endometrium by AGEs, etc. Conceivable. Gestational diabetes is a risk factor such as premature detachment of the placenta, premature birth and stillbirth, abnormal growth of the fetus due to excessive carbohydrate supply, and hypoglycemia after birth.
 AGEs生成時の各反応のうち、不妊の改善剤組成物による阻害対象となる反応は、タンパク質のアミノ基と還元糖との反応によるシッフ塩基の生成、アマドリ転位による1,2-エナミノール又は2,3-エンジオールの生成、アマドリ転移生成物の分解及び分解産物とアミノ酸、ペプチド又はタンパク質との重合生成物の生成等の任意の1又は複数の反応であってよい。 Among the reactions at the time of AGEs generation, the reactions to be inhibited by the infertility improver composition are the generation of Schiff bases by the reaction of protein amino groups and reducing sugars, 1,2-enaminol by 2, Amadori rearrangement, or 2, It may be any one or more reactions such as the production of 3-enediol, degradation of the Amadori transfer product and the polymerization product of the degradation product with amino acids, peptides or proteins.
 タンパク質と糖からのAGEsの生成に関連する1又は複数の反応を阻害する活性は、例えば、ヒト血清アルブミン等の血清タンパク質とグルコースを反応(例えば、60℃、40時間)させて生成したAGEsを蛍光法で測定し、不妊の改善剤組成物を加えた時の生成阻害率(%)を算出する方法や、不妊の改善剤組成物の投与が、血中のAGEs(HbA1cやペントシジン等)の濃度に及ぼす影響を評価する方法等により評価できる。ヒシ科植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物がAGEsの生成に関連する1又は複数の反応を阻害する機序及びそれと不妊の改善との関連については必ずしも明らかではないが、かかる化合物を有効成分として含む不妊の改善剤組成物は、AGEsの生成を抑制し又はAGEsを分解できると共に、不妊を改善できることが確認されている。 The activity of inhibiting one or more reactions related to the generation of AGEs from proteins and sugars is, for example, AGEs produced by reacting serum proteins such as human serum albumin with glucose (for example, 60 ° C., 40 hours). The method of calculating the production inhibition rate (%) when the infertility improving agent composition is added, measured by the fluorescence method, and the administration of the infertility improving agent composition is effective for the blood AGEs (HbA1c, pentosidine, etc.) It can be evaluated by a method for evaluating the influence on the concentration. It is not always clear about the mechanism by which one or more compounds contained in one or both persimmon skins and fruits inhibit one or more reactions associated with the production of AGEs and its association with improved infertility. However, it has been confirmed that a composition for improving infertility containing such a compound as an active ingredient can suppress the generation of AGEs or decompose AGEs and improve infertility.
 不妊の改善に関連すると思われる活性の他の例として、終末糖化産物(AGEs)の分解に関連する1又は複数の反応を促進する活性が挙げられる。AGEsの分解に関連する反応としては、タンパク質のアミノ基と還元糖との反応によるシッフ塩基の生成、アマドリ転位による1,2-エナミノール又は2,3-エンジオールの生成、アマドリ転移生成物の分解及び分解産物とアミノ酸、ペプチド又はタンパク質との重合生成物の生成により生成した結合を切断する反応が挙げられ、AGEsの分解に関連する反応を促進する活性の評価に用いられる反応の具体例としては、AGEsに特有なα-ジカルボニル結合を切断する反応や、コラーゲン等のタンパク質とAGEsとの間の反応により形成される架橋を切断する反応等が挙げられる。 Other examples of activities that may be related to the improvement of infertility include activities that promote one or more reactions related to the degradation of advanced glycation end products (AGEs). Reactions related to the degradation of AGEs include the production of Schiff bases by the reaction of protein amino groups with reducing sugars, the production of 1,2-enaminol or 2,3-enediol by Amadori rearrangement, and the degradation of Amadori transfer products. And a reaction that cleaves a bond formed by the formation of a polymerization product of the degradation product and an amino acid, peptide, or protein. Specific examples of the reaction used for evaluating the activity that promotes the reaction related to the degradation of AGEs include And a reaction that cleaves an α-dicarbonyl bond peculiar to AGEs, a reaction that cleaves a crosslink formed by a reaction between a protein such as collagen and AGEs, and the like.
 不妊の改善に関連すると思われる活性の他の例として、アレルギー症状を軽減させる活性が挙げられる。アトピー性皮膚炎、アレルギー性鼻炎、花粉症等のアレルギー性疾患は、子宮内膜症との関連が指摘されていると共に、免疫系に起因する不妊の原因であるとも言われている。ヒシ科植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物がアレルギー症状を軽減させる機序及びそれと不妊の改善との関連については必ずしも明らかではないが、かかる化合物を有効成分として含む不妊の改善剤組成物は、アレルギー症状を軽減できると共に、不妊を改善できることが確認されている。 ∙ Another example of activity that seems to be related to improvement of infertility is activity that reduces allergic symptoms. Allergic diseases such as atopic dermatitis, allergic rhinitis, and hay fever have been pointed out to be associated with endometriosis and are also said to cause infertility due to the immune system. The mechanism by which one or more compounds contained in one or both of the pericarp and the fruit of the Chinaceae plant alleviate allergic symptoms and its relationship with improvement of infertility are not necessarily clear, but contain such compounds as active ingredients It has been confirmed that an infertility improving composition can reduce allergic symptoms and improve infertility.
 不妊の改善剤組成物を担体等と混合することにより、糖尿病及びそれに関連する疾患及び症状に対する治療効果及び予防効果の一方又は双方を有する医薬組成物として用いることができる。医薬組成物のヒト或いは動物に対する投与形態としては、経口、経直腸、非経口(例えば、静脈内投与、筋肉内投与、皮下投与など)等が挙げられ、投与量は、医薬組成物の製剤形態、投与方法、使用目的及びこれに適用される投与対象の年齢、体重、症状によって適宜設定され一義的に決定することは困難であるが、ヒトの場合、一般には製剤中に含有される有効成分の量で、好ましくは成人1日当り0.1~2000mg/日である。もちろん投与量は、種々の条件によって変動するので、上記投与量より少ない量で十分な場合もあるし、或いは上記範囲を超えて必要な場合もある。 By mixing the composition for improving infertility with a carrier or the like, it can be used as a pharmaceutical composition having one or both of a therapeutic effect and a preventive effect for diabetes and related diseases and symptoms. Examples of the dosage form of the pharmaceutical composition for humans or animals include oral, rectal, parenteral (for example, intravenous administration, intramuscular administration, subcutaneous administration, etc.), and the dosage is the formulation of the pharmaceutical composition. However, in the case of humans, the active ingredient generally contained in the formulation is difficult to determine and uniquely determined depending on the administration method, purpose of use, and age, weight, and symptoms of the subject to be applied. The amount is preferably 0.1 to 2000 mg / day per day for an adult. Of course, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient or may be necessary beyond the above range.
 経口投与製剤として調製する場合は、錠剤、顆粒剤、散剤、カプセル剤、コーティング剤、液剤、懸濁剤等の形態に調製でき、非経口投与製剤にする場合には、注射剤、点滴剤、座薬等の形態に調製することができる。製剤化には、任意の公知の方法を用いることができる。例えば、不妊の改善剤組成物と、製薬学的に許容し得る担体又は希釈剤、安定剤、及びその他の所望の添加剤を配合して、上記の所望の剤形とすることができる。 When it is prepared as an oral preparation, it can be prepared in the form of tablets, granules, powders, capsules, coatings, liquids, suspensions, etc. When it is made into a parenteral preparation, injections, drops, It can be prepared in the form of a suppository or the like. Any known method can be used for formulation. For example, the above-mentioned desired dosage form can be prepared by blending an infertility improving composition with a pharmaceutically acceptable carrier or diluent, a stabilizer, and other desired additives.
 不妊の改善剤組成物を含む食品としては、不妊の改善剤組成物を食品に配合したもの、或いは、カプセル、錠剤等、食品又はサプリメントに通常用いられる任意の形態をとることができる。配合される食品の種類に特に制限はなく、例えば、コーヒー、果汁、清涼飲料水、ビール、牛乳、味噌汁、スープ、紅茶、茶、栄養剤、シロップ、マーガリン、ジャム等の液状(流動状)食品、米飯、パン、じゃがいも製品、もち、飴、チョコレート、ふりかけ、ハム、ソーセージ、キャンディーなどの固形形状食品等の主食、副食、菓子類ならびに調味料に配合することも可能である。用途に応じて、粉末、顆粒、錠剤等の形に成形してもよい。また、必要に応じて、賦形剤、増量剤、結合剤、増粘剤、乳化剤、着色料、香料、食品添加物、調味料等と適宜混合してもよい。 The food containing the infertility improving agent composition can take any form commonly used for foods or supplements, such as those obtained by blending the infertility improving composition with food, or capsules, tablets, and the like. There are no particular restrictions on the type of food to be blended, for example, liquid (fluid) foods such as coffee, fruit juice, soft drinks, beer, milk, miso soup, soup, tea, tea, nutrients, syrup, margarine, jam, etc. , Rice, bread, potato products, rice cake, rice cake, chocolate, sprinkle, ham, sausage, candy, and other staple foods, side dishes, confectionery, and seasonings. Depending on the application, it may be formed into a powder, granule, tablet or the like. Moreover, you may mix suitably with an excipient | filler, a filler, a binder, a thickener, an emulsifier, a coloring agent, a fragrance | flavor, a food additive, a seasoning etc. as needed.
 また、ヒトの消費に供する食品及びサプリメント以外にも、改善剤組成物を飼料中に混合して、家畜、ペット等のほ乳動物の雌に投与する場合には、予め飼料の原料中に混合して、機能性を付与した飼料として調製することができる。また、改善剤組成物を飼料に添加して投与することもできる。すなわち、不妊の改善剤組成物を有効成分として含む食品は、ブタ、ウシ、ウマ、ヒツジ等の家畜や、ペット(イヌ、ネコ)等の飼料に添加することにより、安全で、これらの動物における不妊を改善する活性を有する機能性飼料として用いることができる。 In addition to foods and supplements for human consumption, when the improver composition is mixed in feed and administered to mammal females such as livestock and pets, it is mixed with feed ingredients in advance. And can be prepared as a feed with added functionality. Moreover, an improving agent composition can also be added and administered to feed. That is, a food containing an infertility improving composition as an active ingredient can be safely added to livestock such as pigs, cows, horses, sheep, and feed such as pets (dogs, cats). It can be used as a functional feed having activity to improve infertility.
 本発明は、ヒシ科植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物を有効成分として含む不妊の改善剤組成物を投与することにより、ヒトの不妊を改善する方法及びヒト以外の哺乳動物における不妊を改善する方法を提供するものでもある。 The present invention relates to a method for improving human infertility by administering a composition for improving infertility containing one or more compounds contained in one or both of the pericarp and fruits of Chinaceae as an active ingredient and non-human It also provides a method for improving infertility in other mammals.
 次に、本発明の作用効果を確認するために行った実施例について説明する。
実施例1:ヒシ果皮抽出物及びそれを含む経口投与剤の調製
(1)ヒシ科植物の熱水抽出物(以下、「ヒシ果皮抽出物」と略称する。)の調製
 収穫後のトウビシ(Trapa bispinosa)の果実を乾燥させ、乾燥果皮を回収した。フードプロセッサーを使用して乾燥果皮を粉末化し、熱水抽出(乾燥果皮の1重量部に対し6重量部の90℃の熱水を使用)し、最終的に得られるヒシ果皮抽出物のポリフェノール含量が25重量%以上となるよう予め定めた所定の濃縮率で抽出液を濃縮した。濃縮液67重量%に対し33重量%のデキストリンを添加し、スプレードライヤーで噴霧乾燥した。このようにして得られた粉末(ポリフェノール含量25重量%以上)を、ヒシ果皮抽出物として、以下の試験に使用した。
Next, examples carried out for confirming the effects of the present invention will be described.
Example 1: Preparation of an extract of persimmon pericarp and oral administration containing the same (1) Preparation of a hot water extract of a Coriaceae plant (hereinafter abbreviated as "Hoshi pericarp extract") bispinosa) fruit was dried and the dried pericarp was recovered. Powdered dry skin using a food processor, hot water extraction (6 parts by weight of 90 ° C hot water is used for 1 part by weight of dry skin), and finally the polyphenol content of the castor peel extract obtained The extract was concentrated at a predetermined concentration rate that was determined in advance so as to be 25% by weight or more. 33% by weight of dextrin was added to 67% by weight of the concentrated liquid, and spray-dried with a spray dryer. The powder thus obtained (polyphenol content of 25% by weight or more) was used in the following tests as a persimmon peel extract.
(2)ヒシ果皮抽出物を含む経口投与剤の調製
 上記(1)で調製したヒシ果皮抽出物100mgに、賦型剤としてコーンスターチ187mg及びステアリン酸カルシウム3mgを加え、これをゼラチンハードカプセルに封入した。後述する実施例2~4において、被験者には、上記ハードカプセルを一日一カプセル、食前に水又はぬるま湯で服用していただいた。また、ヒシ果皮抽出物の代わりにデキストリンを用いて調製したものをプラセボ(ヒシ果皮抽出物を含む経口投与剤と外観上区別できない。)として用いた。
(2) Preparation of orally-administered agent containing castor peel extract To 100 mg of castor peel extract prepared in (1) above, 187 mg of corn starch and 3 mg of calcium stearate were added as excipients, and this was enclosed in a gelatin hard capsule. In Examples 2 to 4, which will be described later, the subjects took the above-mentioned hard capsules once a day with water or lukewarm water before meals. Moreover, what was prepared using dextrin instead of a persimmon peel extract was used as a placebo (it is indistinguishable externally from the oral administration agent containing a persimmon peel extract).
実施例2:ヒシ果皮抽出物の継続投与が血糖値、血中AGEs濃度、血中コレステロール濃度に及ぼす影響
 女性被験者50名をヒシ果皮抽出物投与群及びプラセボ投与群(各25名)に分け、12週間にわたり、前者にはヒシ果皮抽出物(表1~表6、図1及び図2には、「ヒシエキス」と記載されている。)を含む経口投与剤を、後者にはプラセボを、二重盲検法により、上述の実施例1(2)に記載の用量で投与した。4週間ごとに、血液検査(血中HbA1c濃度、血中中性脂質濃度、血中コレステロール濃度(総コレステロール濃度、HDL-コレステロール濃度及びLDL-コレステロール濃度)、血中ペントシジン濃度の測定)の測定を行った。それぞれの測定結果を、表1~表6に示す。なお、表中、「0W」、「4W」、「8W」及び「12W」は、それぞれ、0週目、4週目、8週目及び12週目の結果を表し、「Mean」は平均値を、「SD」は標準偏差を、「SE」は標準誤差を、「Wilcoxon」は、ウィルコクソンの符号順位検定の結果をそれぞれ表す。
Example 2: Effect of continuous administration of Hoshi peel extract on blood glucose level, blood AGEs concentration, blood cholesterol concentration 50 female subjects were divided into Hishi peel extract administration group and placebo administration group (25 each), For 12 weeks, the former contains an extract of persimmon peel (referred to as “Hishi extract” in Tables 1 to 6 and FIGS. 1 and 2), a placebo for the latter, The dose described in Example 1 (2) above was administered in a double-blind manner. Every 4 weeks, blood tests (blood HbA1c concentration, blood neutral lipid concentration, blood cholesterol concentration (total cholesterol concentration, HDL-cholesterol concentration and LDL-cholesterol concentration), blood pentosidine concentration measurement) are measured. went. The respective measurement results are shown in Tables 1 to 6. In the table, “0W”, “4W”, “8W” and “12W” represent the results of the 0th, 4th, 8th and 12th weeks, respectively, and “Mean” is the average value. “SD” represents standard deviation, “SE” represents standard error, and “Wilcoxon” represents the result of Wilcoxon's sign rank test.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
 表1~6の結果より、ヒシ果皮抽出物を含む経口投与剤の投与により、血中HbA1c濃度、血中総コレステロール濃度、血中LDL-コレステロール濃度及び血中ペントシジン濃度については、有意な低下が認められた。 From the results of Tables 1 to 6, the administration of the oral preparation containing the persimmon peel extract significantly decreased blood HbA1c concentration, blood total cholesterol concentration, blood LDL-cholesterol concentration and blood pentosidine concentration. Admitted.
実施例3:ヒシ果皮抽出物の投与が食後血糖値に及ぼす影響
 空腹時血糖値が70~110mg/dLの被験者4名(平均年齢28.7歳、男性1名、女性3名)を対象に下記のプロトコールに従って試験を行った。
Example 3: Effect of administration of an extract of persimmon peel on postprandial blood glucose level For 4 subjects (average age 28.7 years old, 1 male, 3 females) whose fasting blood glucose level was 70 to 110 mg / dL The test was conducted according to the following protocol.
 試験前日の21時以降に絶食(水以外の飲食を禁止)した被験者について、試験当日の8時に空腹時血糖を測定後、ヒシ果皮抽出物を含む経口投与剤又はプラセボを投与した(二重盲検法を用いた。)。5分後に、負荷食として、米飯200g+ふりかけ2.5g(総熱量308kcal、炭水化物量70.2g)を喫食させ、喫食後15分、30分、45分、60分、90分及び120分経過時の血糖値を測定した。1週間のウォッシュアウト期間後、初回の試験時にヒシ果皮抽出物を含む経口投与剤を投与した者にはプラセボを、プラセボを投与した者にはヒシ果皮抽出物を含む経口投与剤を投与する以外は、初回の試験と同様のプロトコールにより、2度目の試験を行った。試験結果を表7に示す。 For subjects who fasted after 21:00 on the day before the study (prohibition of eating and drinking other than water), fasting blood glucose was measured at 8:00 on the day of the study, and then an oral preparation containing placenta extract or placebo was administered (double blind) The test method was used.) After 5 minutes, eat 200g of cooked rice + 2.5g of sprinkles (total calorie 308kcal, carbohydrate amount 70.2g) as a loaded meal, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes and 120 minutes after eating The blood glucose level was measured. After a 1-week washout period, except for those who received an oral preparation containing a persimmon peel extract at the first test, except those who received a placebo and those who received a placebo received an oral preparation containing a persimmon peel extract Conducted a second test according to the same protocol as the first test. The test results are shown in Table 7.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
 表7の結果から明らかなように、ヒシ果皮抽出物を含む経口投与剤の投与により、食後15分経過時の血糖値の上昇がプラセボ投与時に比べ有意に抑制されていることが確認された。 As is apparent from the results in Table 7, it was confirmed that the increase in blood glucose level after 15 minutes after meal was significantly suppressed by administration of an orally-administered agent containing a persimmon peel extract compared to the placebo administration.
実施例4:α-ジカルボニル結合切断活性の測定
 ジカルボニル結合の切断活性は、ジカルボニル化合物である1-フェニル-1,2-プロパンジオン(PPD)を分解し得られる安息香酸濃度をHPLC法にて測定することで算出した。
 98%PPD溶液4.2μLを50mMリン酸緩衝液(pH7.4)/50%メタノール(メタノール緩衝液)25mLへ溶解し、最終反応液中の濃度が1.0mMとなるようにPPD溶液を調製した。調製したPPD溶液900μLへ任意濃度のヒシ果皮抽出物溶液100μLを添加し、混和後、37℃にて振とうさせながら4時間反応させた。反応液へ2NHClを200μL添加し反応を停止させ、0.45μmフィルターにてろ過を施しHPLC用サンプルとした。
Example 4 Measurement of α-Dicarbonyl Bond Cleavage Activity The dicarbonyl bond cleavage activity was determined by measuring the benzoic acid concentration obtained by decomposing 1-phenyl-1,2-propanedione (PPD), which is a dicarbonyl compound, by HPLC. It calculated by measuring by.
Dissolve 4.2 μL of 98% PPD solution in 25 mL of 50 mM phosphate buffer (pH 7.4) / 50% methanol (methanol buffer), and prepare the PPD solution so that the concentration in the final reaction solution is 1.0 mM. did. To 900 μL of the prepared PPD solution, 100 μL of a persimmon peel extract solution having an arbitrary concentration was added, and after mixing, the mixture was reacted for 4 hours while shaking at 37 ° C. The reaction was stopped by adding 200 μL of 2N HCl to the reaction solution, and filtered through a 0.45 μm filter to obtain a sample for HPLC.
 分析カラムはTSKgel ODS-80T、150×6.0mm(I.D)(東ソー)を使用した。溶離液は50mMリン酸緩衝液(pH2.2)を用い、流速1.0mL/min、検出波長230nmとした。 The analysis column used was TSKgel ODS-80T, 150 × 6.0 mm (ID) (Tosoh). The eluent was 50 mM phosphate buffer (pH 2.2), the flow rate was 1.0 mL / min, and the detection wavelength was 230 nm.
 各濃度の安息香酸(和光純薬工業製)を用いた検量線から各測定サンプル中の安息香酸濃度を算出し、1.0mMのPPDから1.0mMの安息香酸が得られると仮定されることから次式を用いてPPD構造中のジカルボニル結合切断活性を求めた。 It is assumed that the benzoic acid concentration in each measurement sample is calculated from a calibration curve using benzoic acid at each concentration (manufactured by Wako Pure Chemical Industries, Ltd.), and 1.0 mM benzoic acid is obtained from 1.0 mM PPD. From this, the dicarbonyl bond cleavage activity in the PPD structure was determined using the following formula.
 ジカルボニル結合切断活性=100×安息香酸濃度(mM)/1mM Dicarbonyl bond cleavage activity = 100 × benzoic acid concentration (mM) / 1 mM
 結果を図1に示す。図1中、「Con」は対照群を示し、「PTB」は、陽性対照として、臭化N-フェナシルチアゾリウム(PTB)を用いて同様の条件で測定した結果を示す。図1から明らかなように、ヒシ果皮抽出物は、PTBよりも高いα-ジカルボニル結合切断活性を示すことが確認された。 The results are shown in FIG. In FIG. 1, “Con” indicates a control group, and “PTB” indicates the results of measurement under the same conditions using N-phenacylthiazolium bromide (PTB) as a positive control. As is clear from FIG. 1, it was confirmed that the persimmon peel extract showed higher α-dicarbonyl bond cleavage activity than PTB.
実施例5:AGE架橋切断活性の測定
 AGE架橋切断活性は、タイプIコラーゲンとAGE-BSA間に形成された架橋をELISA法にて測定し、ヒシ果皮抽出物添加による架橋切断率を算出することにより評価した。
Example 5: Measurement of AGE cross-linking cleavage activity The AGE cross-linking cleaving activity is obtained by measuring the cross-linking formed between type I collagen and AGE-BSA by the ELISA method, and calculating the cross-linking cleaving rate by adding the pericarp extract. It was evaluated by.
 BD BioCoat Collagen I 96 well micro test plateに、AGE-BSA(MBL)10μg/mL溶液(100μL)を添加し、37℃にて4時間インキュベートした。0.05%Tween20/PBS(-)にて5回洗浄し、PBS(-)に溶解した各濃度の試料100μLを加え、37℃で20時間反応させた。反応後の各ウェルを0.05%Tween20/PBS(-)にて3回洗浄し、第一次抗体として1μg/mL抗ウシ血清アルブミン(BSA)ウサギポリクローナル抗体溶液(ROCKLAND)を各ウェルに100μL加え、室温にて30分間インキュベートした。インキュベート後の各ウェルを0.05%Tween20/PBS(-)にて5回洗浄し、第二次抗体として1μg/mL HRP標識抗ウサギIgG抗体(フナコシ)溶液を各ウェルに100μL加え、室温で30分間インキュベートした。0.05%Tween20/PBS(-)にて3回洗浄し、洗浄後の各ウェルにTMB Microwell Peroxidase Substrate(KPL)を100μL添加し、室温にて15分反応させた。1N HSOを各ウェルに100μL添加し反応を停止させ、マイクロプレートリーダーを用いて450nmにおける吸光度を測定した。試料添加群と試料を無添加群(コントロール)の測定値を用い、下式よりAGE-BSA架橋残存率を算出した。 AGE-BSA (MBL) 10 μg / mL solution (100 μL) was added to BD BioCoat Collagen I 96 well micro test plate and incubated at 37 ° C. for 4 hours. The plate was washed 5 times with 0.05% Tween20 / PBS (−), 100 μL of each concentration sample dissolved in PBS (−) was added, and reacted at 37 ° C. for 20 hours. Each well after the reaction was washed three times with 0.05% Tween 20 / PBS (−), and 1 μg / mL anti-bovine serum albumin (BSA) rabbit polyclonal antibody solution (ROCKLAND) was added to each well as a primary antibody. In addition, it was incubated at room temperature for 30 minutes. Each well after incubation was washed 5 times with 0.05% Tween 20 / PBS (−), and 100 μL of 1 μg / mL HRP-labeled anti-rabbit IgG antibody (Funakoshi) solution was added to each well as a secondary antibody at room temperature. Incubated for 30 minutes. The plate was washed 3 times with 0.05% Tween 20 / PBS (−), 100 μL of TMB Microwell Peroxidase Substrate (KPL) was added to each well after washing, and the mixture was reacted at room temperature for 15 minutes. 100 μL of 1N H 2 SO 4 was added to each well to stop the reaction, and the absorbance at 450 nm was measured using a microplate reader. Using the measured values of the sample addition group and the sample non-addition group (control), the AGE-BSA crosslinking residual ratio was calculated from the following formula.
 AGE-BSA残存率(% of CTR)=100×試料添加群の吸光度/コントロールの吸光度 AGE-BSA residual rate (% of CTR) = 100 × absorbance of sample addition group / absorbance of control
 結果を図2に示す。図2中、「Con」は対照群を示し、「PTB」は、陽性対照として、臭化N-フェナシルチアゾリウム(PTB)を用いて同様の条件で測定した結果を示す。図2から明らかなように、ヒシ果皮抽出物は、PTBよりも高いAGE架橋切断活性を示すことが確認された。 The results are shown in FIG. In FIG. 2, “Con” indicates a control group, and “PTB” indicates the results of measurement under the same conditions using N-phenacylthiazolium bromide (PTB) as a positive control. As is clear from FIG. 2, it was confirmed that the persimmon peel extract showed higher AGE cross-linking activity than PTB.
実施例6:難治性不妊患者への試験投与(1)
 反復ART(高度生殖補助医療)不成功の難治性不妊の女性患者5名を被験者として、3ヶ月間にわたり、ヒシ果皮抽出物を含む経口投与剤を投与した。3ヶ月間の投与後、全員について血中HbA1c濃度が0.1~0.4ポイント低下した。その他、アトピー性皮膚炎の症状が軽快した被験者が1名、アレルギー性鼻炎(花粉症)の症状が軽快した被験者が1名、化粧乗りが改善した被験者が1名いた。被験者のうち、アトピー性皮膚炎及び糖尿病に罹患しており、これまで13回の体外受精が不成功に終わっていた40代女性1名が、試験期間中に体外受精による妊娠に成功した。
Example 6: Test administration to refractory infertile patients (1)
Five female patients with refractory infertility with repeated ART (Advanced Reproductive Assistance Medicine) were administered as subjects for oral administration containing Hishi peel extract over 3 months. After administration for 3 months, the blood HbA1c concentration decreased by 0.1 to 0.4 points for all of them. In addition, there was one subject who had a symptom of atopic dermatitis, one subject who had a symptom of allergic rhinitis (hay fever), and one subject who had improved makeup riding. Among the subjects, one woman in her 40s who had suffered from atopic dermatitis and diabetes and had previously failed 13 in vitro fertilizations succeeded in pregnancy by in vitro fertilization during the test period.
実施例7:難治性不妊患者への試験投与(2)
 2014年7月~2015年3月に、反復ART(高度生殖補助医療)不成功の難治性不妊症32例(実施例6の5例を含む)に対し、説明と同意のもと、ARTの1~2ヶ月前よりヒシ果皮抽出物を連日投与(1日1回、朝食開始直前に100mgを内服)しながら、ARTを施行した。
Example 7: Test administration to refractory infertile patients (2)
From July 2014 to March 2015, 32 cases of refractory infertility (including 5 cases of Example 6) with unsuccessful repetitive ART (advanced assisted reproductive medicine) ART was performed while administering persimmon peel extract every day from 1 to 2 months in advance (once daily, taking 100 mg immediately before the start of breakfast).
 全32例のうち、24例(75%)で以前のARTに比し胚発育が改善し、5例(16%)で不変、3例(9%)で不良だった。その結果、7例が臨床妊娠となり、4例が化学的妊娠となった(総妊娠率34%、臨床妊娠率22%)。 Of the 32 cases, embryo development improved in 24 cases (75%) compared to the previous ART, unchanged in 5 cases (16%) and poor in 3 cases (9%). As a result, 7 cases became clinical pregnancy and 4 cases became chemical pregnancy (total pregnancy rate 34%, clinical pregnancy rate 22%).
 ヒシ果皮抽出物投与が、血中のCML(カルボキシメチルリジン:AGEsの一種)値に及ぼす影響については、低下傾向があるも、有意ではなかった(1.3±0.2μg/mLから1.0±0.2への低下;p=0.30、n=15、対応のあるt-検定)。しかし、ヒシ果皮抽出物投与前のCML値が高い(>1.0μg/mL)群と、CML値が低い(≦1.0)群の2群に分けて解析すると、高CML群(7例)では、CML値は、投与前の2.0±0.2から、投与後の1.1±0.3へと、有意に低下している(p<0.01)のに対し、低CML群(8例)では、投与前の0.6±0.05から、投与後の1.0±0.2へと、増加傾向を示した(p=0.09)。 The effect of the persimmon peel extract administration on CML (carboxymethyllysine: a kind of AGEs) value in the blood was declining but not significant (from 1.3 ± 0.2 μg / mL to 1. Reduction to 0 ± 0.2; p = 0.30, n = 15, paired t-test). However, when the analysis was divided into two groups, a CML value before administration of the persimmon peel extract (> 1.0 μg / mL) and a CML value (≦ 1.0) group, the high CML group (7 cases) ), The CML value decreased significantly from 2.0 ± 0.2 before administration to 1.1 ± 0.3 after administration (p <0.01), while low The CML group (8 cases) showed an increasing tendency from 0.6 ± 0.05 before administration to 1.0 ± 0.2 after administration (p = 0.09).
 臨床妊娠率は、高CML群で43%(3/7例)、低CML群で0%(0/8例)と、高CML群でより高い傾向が示された(p=0.08、Fisher直接検定)。これらの結果より、ヒシ果皮抽出物の投与は、血中AGEs値が高い症例に有効で、血中AGEsの低下作用により妊娠率が向上することが推察された。 The clinical pregnancy rate was 43% (3/7 cases) in the high CML group and 0% (0/8 cases) in the low CML group, indicating a higher tendency in the high CML group (p = 0.08, Fisher direct test). From these results, it was presumed that administration of an extract of persimmon peel was effective in cases with high blood AGEs, and the pregnancy rate was improved due to the action of reducing blood AGEs.
 なお、本発明は、本発明の広義の精神と範囲を逸脱することなく、様々な実施形態及び変形が可能とされるものである。また、上述した実施形態は、本発明を説明するためのものであり、本発明の範囲を限定するものではない。つまり、本発明の範囲は、実施形態ではなく、請求の範囲によって示される。そして、請求の範囲内及びそれと同等の発明の意義の範囲内で施される様々な変形が、本発明の範囲内とみなされる。本出願は、2015年1月29日に出願された日本国特許出願2015-14907号及び2015年4月23日に出願された日本国特許出願2015-88110号に基づくものであり、その明細書、特許請求の範囲、図面および要約書を含むものである。上記日本国特許出願における開示は、その全体が本明細書中に参照として含まれる。 The present invention is capable of various embodiments and modifications without departing from the broad spirit and scope of the present invention. Further, the above-described embodiment is for explaining the present invention, and does not limit the scope of the present invention. That is, the scope of the present invention is shown not by the embodiments but by the claims. Various modifications within the scope of the claims and within the scope of the equivalent invention are considered to be within the scope of the present invention. This application is based on Japanese Patent Application No. 2015-14907 filed on January 29, 2015 and Japanese Patent Application No. 2015-88110 filed on April 23, 2015. Including the claims, drawings and abstract. The entire disclosure in the above Japanese patent application is incorporated herein by reference.

Claims (5)

  1.  ヒシ科に属する植物の果皮及び果実の一方又は双方に含まれる1又は複数の化合物を有効成分として含むことを特徴とする不妊の改善剤組成物。 An infertility improving composition comprising one or a plurality of compounds contained in one or both of the skin and fruits of a plant belonging to the family Chinaceae as an active ingredient.
  2.  前記有効成分として、果皮及び果実の一方又は双方の抽出物又は該抽出物より分離される1又は複数の化合物を含むことを特徴とする請求項1記載の不妊の改善剤組成物。 2. The infertility improving composition according to claim 1, wherein the active ingredient contains one or a plurality of compounds separated from the extract of one or both of the skin and the fruit, or the extract.
  3.  タンパク質と糖からの終末糖化産物の生成に関連する1又は複数の反応を阻害する活性を有することを特徴とする請求項1又は2記載の不妊の改善剤組成物。 3. The infertility improving composition according to claim 1 or 2, which has an activity of inhibiting one or more reactions related to the production of a terminal glycation product from protein and sugar.
  4.  終末糖化産物の分解に関連する1又は複数の反応を促進する活性を有することを特徴とする請求項1から3のいずれか1項記載の不妊の改善剤組成物。 4. The infertility improving composition according to any one of claims 1 to 3, which has an activity of promoting one or a plurality of reactions related to the degradation of a terminal glycation product.
  5.  アレルギー症状を軽減する活性を有することを特徴とする請求項1から4のいずれか1項記載の不妊の改善剤組成物。 5. The infertility improving composition according to any one of claims 1 to 4, which has an activity of reducing allergic symptoms.
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