WO2023068778A1 - Composition for prevention and treatment of female menopausal diseases comprising phytogen as active ingredient - Google Patents

Abstract

The present invention relates to a composition for the prevention and treatment of female menopausal diseases, comprising phytogen as an active ingredient, and may contribute to the prevention and treatment of female menopausal diseases such as fat gain, weight gain, body temperature increase, hormone decrease, bone density decrease, and the like.

Description

Composition for preventing and treating female menopausal diseases containing phytogen as an active ingredient

The present invention relates to a composition for preventing and treating female menopausal diseases, comprising phytogen as an active ingredient.

A woman's ovaries are actively functioning for approximately 35 years. After puberty, women secrete the female hormones estrogen and progesterone. Under the direction of the hypothalamus, which regulates the secretion of hormones, the pituitary gland secretes related hormones. When the gonadotropin secreted at this time transmits a signal, follicle stimulating hormone (FSH) and luteinizing hormone (LH), hormones that regulate the menstrual cycle and enable pregnancy, are secreted. , which in turn acts on the ovaries to secrete estrogen and progesterone. However, with age, the function of the ovaries deteriorates, resulting in a significant decrease in estrogen secretion, resulting in a reduced response to follicle stimulating hormone (FSH) and luteinizing hormone (LH). In addition, the early follicular phase is shortened, so the menstrual cycle is further shortened, the ovulation phase is further shortened, and progesterone production is reduced. Eventually, the follicle becomes unable to respond and thus cannot produce estrogen. As such, ovulation is stopped and menstruation disappears, which is called menopause, and symptoms of menopause appear due to a decrease in hormones during or before menopause. Decreased secretion of estrogen has a great effect on women's urinary and reproductive systems as well as throughout the body.

Postmenopausal women experience symptoms such as hot flushes, heart palpitations due to sudden changes in heart rate, sweating, insomnia, anxiety and sleep disorders due to a rapid decrease in estrogen. This lack of estrogen can lead to neurosis, irritability, difficulty concentrating, depressed mood, anxiety, loss of self-confidence and sexual desire. In addition, due to the decrease in estrogen, the blood supply is not smooth, so the elasticity and moisture of the skin and vaginal mucosa are lost. For example, if the mucous membranes of the eyes, nose, or mouth are dry, you may experience discomfort in your eyes or a burning sensation in your throat. Sometimes, the urinary tract or vagina is dry, and some complain of pain due to vaginal dryness and repeated urinary tract infections. In addition, osteoporosis, atherosclerosis, etc. may occur due to a lack of estrogen, and since these diseases cause chronic diseases, the need for treatment for postmenopausal women is gradually emerging. Hormone replacement therapy (HRT), which artificially administers estrogen, is widely used as a method for symptomatic treatment of postmenopausal women, but there have been concerns that hormone therapy increases the risk of breast cancer.

On the other hand, flax (亞麻, Linum usitatissimum , English: flax, common flax, linseed) is an annual plant native to Central Asia, and fibers such as linen are woven into fibers of the shell, and flaxseed is 'linseed' (亞麻仁). ), and is also used as a medicine by making oil. Flax seed's 'Flax' is derived from the Latin word for 'useful'. Phytogen, which is abundant in flaxseed, promotes insulin secretion and regulates sugar to an appropriate level, which is effective in preventing and improving diabetes. It is known to prevent cancer cell formation and help cancer cells metastasize. In addition, flaxseed is rich in fiber, so it facilitates bowel movements, relieves skin diseases such as atopy, blemishes, acne, and melasma, and maintains elasticity.

The present inventors confirmed the effect of flaxseed-derived phytogen on female menopausal diseases and completed the present invention.

Korean Patent Registration No. 10-1810421, which is a prior art, describes a method for preparing a pill for improving female menopausal symptoms containing horseback riding extract powder, angelica extract powder, linseed powder, pomegranate concentrate, and L-arginine in a certain ratio. In addition, Korean Patent Registration No. 10-2153369 discloses a composition for preventing and improving female menopausal symptoms containing gamma-linolenic acid, including (A) borage seed oil, blackcurrant seed oil, evening primrose seed oil, or a mixture of two or more of them; (B) linseed oil, walnut oil, or mixtures thereof; And (C) it is described that various diseases that may appear before and after female menopause can be prevented and improved by including pine bark extract, cranberry extract, or a mixture thereof as an active ingredient. In addition, Korean Patent Registration No. 1693573 describes a pharmaceutical composition for preventing or treating menopausal symptoms, including red root, brown flower, temple, golden, yellow lotus, yellow white, gardenia, hairy hair, and white hazelnut. and effects are different.

An object of the present invention is to provide a composition for preventing and treating female menopausal diseases comprising phytogen as an active ingredient.

The present invention provides a composition for preventing and treating female menopausal diseases comprising phytogen as an active ingredient.

The composition provides a composition for preventing and treating female menopausal diseases, including the phytogen and a pharmaceutically acceptable excipient.

The phytogen may be added in an amount of preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight, and most preferably 0.001 to 30% by weight based on the total weight of the total pharmaceutical composition.

The pharmaceutical composition is formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, liquids, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. can Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants, sweeteners, and acidulants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, in addition to the phytogen of the present invention. It is prepared by mixing Tod's and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, preservatives, and acidulants are used. can be included Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. As a base for the suppository, witepsol, macrogol, tween-61, cacao butter, laurin paper, glycerogeratin, and the like may be used.

The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the prescriber's judgment. Determination of dosage based on these factors is within the level of those skilled in the art, and generally dosages range from 0.01 mg/kg/day to approximately 500 mg/kg/day. A preferred dose is 0.1 mg/kg/day to 200 mg/kg/day, and a more preferred dose is 1 mg/kg/day to 200 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, eg oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection and dermal application. Since the phytogen of the present invention has almost no toxicity and side effects, it is a drug that can be safely used even when taken for a long period of time for preventive purposes.

In addition, the present invention provides a health functional food for preventing and improving symptoms of women's menopausal diseases containing phytogen as an active ingredient.

In the health functional food, phytogen may be added in an amount of preferably 0.001 to 50% by weight, more preferably 0.001 to 30% by weight, and most preferably 0.001 to 10% by weight based on the total weight of the total food.

The health functional food includes the form of tablets, capsules, pills or liquids, and foods to which the extract of the present invention can be added include, for example, various foods, beverages, gum, tea, vitamin complexes, health functional foods, etc.

The present invention relates to a composition for preventing and treating female menopausal diseases containing phytogen as an active ingredient, and can contribute to the prevention and treatment of female menopausal diseases such as fat gain, weight gain, body temperature decrease, hormone decrease and bone density decrease. .

1 is a graph showing the effect of phytogen according to the present invention on body weight change in menopausal animal models.

Figure 2 is a graph showing the effect of phytogen according to the present invention on body temperature change in menopausal animal models.

Figure 3 is a photograph showing the effect of phytogen according to the present invention on fat formation in menopausal animal models.

4 is a photograph showing the effect of phytogen according to the present invention on the size of fat in skin tissue of a menopausal animal model.

Figure 5 shows the ABTS assay (A) and FRAP assay (B) results showing the antioxidant ability of the phytogen according to the present invention in the liver tissue of the menopausal animal model.

Figure 6 is a graph showing the hormonal changes (A. Serotonin, B. 17β-Estradiol) of the menopausal animal model of the extract according to the present invention.

Figure 7 shows the effect of the extract according to the present invention on bone density in menopausal animal models.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<Example 1. Preparation of Phytogen>

Phytogen is made from flaxseed extract. Flaxseed is produced by CanMar Foods Ltd., located in Saskatchewan, Canada. was purchased and used. Phytogen was extracted from linseed by a supercritical extraction method, and was extracted using Vitalis' F-Series. The extraction process was performed at a temperature of 55 °C, a pressure of 30 MPa, a co-solvent rate of 5%, a CO ₂ flow rate of 3.0 ml/minute, and a particle size range of 425 μm. The extraction time was 180 minutes in total, and the purity of phytogen was more than 90% using HPLC analysis method (maximum absorbance of 280 nm).

<Example 2. Production of menopausal animal models>

In order to confirm the effect of the phytogen of the present invention on female menopausal diseases, a menopausal animal model was prepared.

A 10-week-old ovariectomized ddY female mouse (ovariectomized-mouse, OVX mouse) was used. After the ovariectomy was performed at the age of 8 weeks, the mice were additionally bred for 2 weeks for recovery from surgery. As a control group, Sham mouse group (normal control group) without ovarian excision and OVX mouse group (negative control group) administered only with physiological saline to ovariectomized mice were used. 8-week-old sham-operated mice and ovariectomized ddY female mice were purchased from Orient Bio, and after a 2-week acclimatization period in the laboratory animal center quarantine room at Sungkyunkwan University, they were moved to a clean animal breeding area and raised.

<Example 3. Confirmation of the effect of phytogen on weight change in menopausal animal models>

In a menopausal animal model, the effect of phytogen on body weight change was confirmed. As shown in Table 1 below, phytogen and red ginseng (Korean Red Genseng, KRG) were administered at 50 mg/kg/day to the control group and the experimental group, respectively, and the change in body weight was observed for 8 weeks, as shown in FIG.

Group kill diet drug Normal Sham-kun normal diet - Control Hysterectomy animal model normal diet - FL Hysterectomy animal model normal diet + Phytogen 50 mg/kg/day KRG Hysterectomy animal model normal diet + Red ginseng extract 50 mg/kg/day

As shown in Figure 1, the menopausal animal model (Control, C) significantly increased the body weight compared to the Normal group (Nor). However, in the phytogen (FL) and red ginseng (KRG)-administered groups, the body weight decreased significantly, and the FL-administered group showed a slightly larger weight loss than the red ginseng (KRG)-administered group.

<Example 4. Confirmation of the effect of phytogen on body temperature change in menopausal animal models>

The effect of phytogen on body temperature changes was confirmed in a menopausal animal model. After 8 weeks, the body temperature of the rats in each group of Example 3 was measured from the abdomen and is shown in FIG. 2 . As shown in Figure 2, the menopausal animal model (Control, C) showed a significant increase in body temperature compared to the Normal group (N), and a significant decrease in average body temperature in the phytogen (FL) and red ginseng (KRG) administered groups. Confirmed.

<Example 5. Confirmation of effect of phytogen on abdominal adipogenesis in menopausal animal models>

The effect of phytogen on adipogenesis was confirmed in a menopausal animal model. The animals of each group treated as shown in Table 1 were sacrificed after 5 weeks, and the state of visceral fat formation was confirmed and shown in FIG. 3 .

As shown in FIG. 3, it was confirmed that the menopausal animal model (Control, C) had excess fat formed on the outer wall of the abdominal intestine compared to the Normal group (Normal). At this time, the increased fat was significantly reduced by the administration of phytogen (FL) and red ginseng (KRG).

<Example 6. Confirmation of the effect of phytogen on subcutaneous fat formation in menopausal animal models>

The effect of phytogen on subcutaneous fat formation was confirmed in a menopausal animal model. The abdominal skin of the rat sacrificed in Example 3 was stained with Eosin to confirm whether or not the epidermal thickness was increased, as shown in FIG. 4 .

As shown in FIG. 4, it was confirmed that fat was excessively formed under the skin in the menopausal animal model (Control, C) compared to the Normal group (Normal). At this time, the increased fat was significantly reduced by the administration of phytogen (FL) and red ginseng (KRG).

<Example 7. Confirmation of antioxidant activity effect in liver tissue of phytogen in menopausal animal model>

In a menopausal animal model, the antioxidant activity of phytogen in liver tissue was confirmed.

7.1 Measurement of ABTS radical scavenging activity

ABTS [2,2'-azin0-bis(3-ethylbenzthiazoline-6-sulfonate)] radical scavenging ability is that the ABTS free radical generated by the reaction with potassium persulfate is removed by the antioxidant of the sample, It was measured by a method using the decolorization of the characteristic blue-green color. After obtaining liver tissues from each group of animals sacrificed in Example 3, physiological saline in an amount equal to the volume of each liver was added, ground using a grinder, precipitated using a centrifuge, and supernatants were obtained. . A 7.4 mM ABTS solution was mixed with 2.4 mM potassium persulfate and reacted for about 15 hours in a dark room. Take 100 μl of the diluted solution so that the absorbance at 730 nm is 0.9, mix with 100 μl of the obtained supernatant, react for 30 minutes in the dark, measure the absorbance at 730 nm, and measure the absorbance difference between the sample-added group and the non-added group as a percentage and shown in Figure 5A.

7.2 Measurement of FRAP radical scavenging activity

The FRAP method directly evaluates the total antioxidant activity. The ferric tripyridyltriazine (Fe ³⁺ -TPTZ) complex is reduced to blue-colored ferrous tripyridyltriazine (Fe ²⁺ -TPTZ) by a reducing agent (antioxidant) at a low concentration of pH. use the principle of After preparing a TPTZ solution by making 10 mM TPTZ dissolved in 40 mM HCl, 20 mM ferric chloride, and acetate buffer (pH 3.6) at a ratio of 1: 1: 10, respectively, 10 mg of liver tissue suspension from each group of animals sacrificed in Example 3 After vortexing 3ml of TPTZ solution at 0.1ml /ml, absorbance was measured at 593nm in the 0th minute. Thereafter, the absorbance was measured again after 4 minutes after being placed in a constant temperature water bath at 37° C., and the difference in absorbance between the sample-added group and the sample-free group was expressed as a percentage and is shown in FIG. 5B.

As shown in Figures 5A and 5B, the menopausal animal model (Control, C) had a significant decrease in antioxidant activity compared to the Normal group (Normal), and in the case of the phytogen (FL) and red ginseng (KRG) administration groups, the antioxidant activity increased. , In particular, it was confirmed that it significantly increased compared to the Normal group.

<Example 8. Confirmation of the effect of phytogen on hormone concentration in menopausal animal models>

The effect of phytogen on hormone concentration was confirmed in a menopausal animal model.

8.1 Measurement of Serotonin Concentration

Before sacrificing the animals of each group of Example 3, whole blood was collected from the abdominal aorta, and the collected whole blood was transferred to an SST tube, and when blood coagulation by fibrin proceeded sufficiently, centrifuged at 4,000 rpm for 10 minutes, The serum, the supernatant, was collected with attention to hemolysis of red blood cells, and each collected blood serum was applied to a serotonin measurement kit (Abcam's Serotonin ELISA Kit; ab133053) to measure the content of serotonin contained in each serum according to the manufacturer's manual. This is shown in Figure 6A.

As shown in Figure 6A, the menopausal animal model (Control, C) showed a significant decrease in blood serotonin concentration compared to the Normal group. This reduced serotonin concentration was significantly increased in the phytogen (FL) administration group. However, in the case of the red ginseng (KRG) administration group, the decreased serotonin concentration was not recovered.

8.2 17β - Estradiol ( 17β - Estradiol ) concentration measurement

The blood concentration of 17β-estradiol was measured according to the manufacturer's manual using an ELISA kit (Enzo Life Sciences, U.S.A.) for measuring 17β-estradiol in blood in the serum of each group of experimental animals of Example 8.1, shown in Figure 6B.

As shown in FIG. 6B, the blood concentration of 17β-estradiol in the menopausal animal model (Control, C) was significantly decreased compared to the Normal group. This reduced serotonin concentration was significantly increased in the phytogen and red ginseng (KRG) administration groups. The increase in 17β-estradiol concentration of the Ewha Womans University Phytogen (FL)-administered group was superior to that of the red ginseng (KRG)-administered group, and the 17β-estradiol concentrations of the two groups showed a significant difference.

<Example 9. Confirmation of the effect of phytogen on bone density in menopausal animal models>

The effect of phytogen on bone mineral density was confirmed in a menopausal animal model. After excising the femur of each group of experimental animals in Example 3, it was fixed using a 4% formaldehyde solution for 5 days. For the fixed tissues, 3D X-ray pictures are taken using the SKYSCAN 1076 device, and Bone Mineral Density (BMD) is measured using the pictures in the part exactly in the middle of the length of each bone among the pictures taken. Measurements were taken, and the BMD values were converted into percentages in FIGS. 7A and 7B and shown in FIGS. 7C and 7D.

As shown in Figures 7A to 7D, the menopausal animal model (Control, C) had a significant decrease in bone mineral density (BMD) compared to the Normal group (N), and this reduced bone density was due to phytogen (FL) and red ginseng (KRG). ) significantly increased in the administration group.

<Formulation Example 1. Pharmaceutical formulation>

Formulation Example 1-1. manufacture of tablets

200 mg of the phytogen of the present invention was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. After adding 10% gelatin solution to this mixture, it was pulverized and passed through a 14 mesh sieve. It was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of active agent, and 5 g of magnesium stearate was made into tablets.

Formulation Example 1-2. Preparation of injection solution

100 mg of the phytogen of the present invention, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was bottled and sterilized by heating at 20° C. for 30 minutes.

<Formulation Example 2. Manufacture of health functional food>

Formulation Example 2-1. Manufacture of health functional food

Phytogen of the present invention 2g, appropriate amount of vitamin mixture, vitamin A acetate 70μg, vitamin E 1.0mg, vitamin B1 0.13mg, vitamin B2 0.15mg, vitamin B6 0.5mg, vitamin B12 0.2μg, vitamin C 10mg, biotin 10μg . 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride were mixed to form granules, but it can be prepared by transforming into various formulations depending on the use. In addition, the composition ratio of the vitamin and mineral mixture may be arbitrarily modified, and it may be prepared by mixing the above components according to a conventional health functional food manufacturing method.

Formulation example 2-2. Manufacture of health functional beverages

1 g of the phytogen of the present invention, 0.1 g of citric acid, 100 g of fructooligosaccharide, and 900 g of purified water were mixed and stirred, heated, filtered, sterilized, and refrigerated according to a conventional beverage manufacturing method to prepare a beverage.

Claims (6)

A composition for preventing and treating female menopausal diseases comprising phytogen as an active ingredient. According to claim 1, The phytogen is a composition for preventing and treating female menopausal diseases, characterized in that extracted from flaxseed. According to claim 1, The female menopausal disease is a composition for preventing and treating female menopausal disease, characterized in that at least one selected from the group consisting of weight gain, abdominal fat increase, subcutaneous fat increase, facial flushing, insomnia, serotonin decrease, estrogen decrease, bone density decrease and osteoporosis . Health functional food for preventing and improving women's menopausal diseases, containing phytogen as an active ingredient. According to claim 4, The phytogen is a health functional food for preventing and improving female menopausal diseases, characterized in that extracted from flaxseed. According to claim 4, The female menopausal disease is characterized in that at least one selected from the group consisting of weight gain, abdominal fat increase, subcutaneous fat increase, facial flushing, insomnia, serotonin decrease, estrogen decrease, bone density decrease and osteoporosis Female menopausal disease prevention and improvement for health functional food.

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