Agent for promoting urinary excretion of sugar

Abstract

To provide a novel agent having an action of promoting urinary excretion of sugar.SOLUTION: Provided is an agent for promoting urinary excretion of sugar, the agent containing Dai-saiko-to or Bofu-tsusho-san. Also provided is an agent for promoting urinary excretion of sugar, the agent containing Dai-saiko-to and being used so as to be taken before meals. Also provided is an agent for promoting urinary excretion of sugar, the agent containing Bofu-tsusho-san and being used so as to be taken before meals. Further provided is an SGLT2 inhibitor that contains Dai-saiko-to or Bofu-tsusho-san.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to an agent, composition and food composition for promoting urinary excretion of sugar. [Background technology]

[0002] After blood glucose is filtered into the renal tubules in the glomerulus of the kidney, approximately 90% of the glucose is reabsorbed by SGLT2 (sodium / glucose cotransporter 2). The remaining glucose (approximately 10%) is reabsorbed by SGLT1, and the glucose that is not reabsorbed is excreted in the urine. SGLT is a transporter that actively transports glucose into cells using the difference in sodium ion concentration inside and outside the cells.

[0003] Thus, SGLT2 is one of the major transporters involved in glucose reabsorption in the renal tubules. Inhibition of SGLT2 activity suppresses glucose reabsorption, increasing urinary glucose excretion and lowering blood glucose levels.

[0004] SGLT2 inhibitors are primarily used to treat type 2 diabetes. They inhibit the activity of SGLT2 and promote the excretion of excess glucose in the urine. As a result, they have been reported to have effects such as improved blood sugar control, weight loss, lowered blood pressure, and protection of the heart and kidneys. These effects make SGLT2 inhibitors useful not only for the treatment, improvement, and prevention of diabetes, but also for hypertension, heart disease, and kidney disease.

[0005] As an SGLT2 inhibitor, for example, Patent Document 1 discloses dapagliflozin. Dapagliflozin inhibits sodium-glucose reabsorption in the kidney through SGLT2 inhibition, thereby enhancing urinary glucose excretion. This action reduces plasma glucose levels in an insulin-independent manner. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 6,515,117 Summary of the Invention [Problem to be solved by the invention]

[0007] As mentioned above, SGLT2 inhibitors are expected to improve blood sugar control, reduce weight, lower blood pressure, and protect the heart and kidneys by promoting urinary glucose excretion. However, existing SGLT2 inhibitors lower blood sugar levels, which can cause side effects such as hypoglycemia and dizziness. Furthermore, SGLT2 inhibitors increase urinary glucose excretion from the kidney, which can lead to water loss in the urine and dehydration and dry mouth. Furthermore, known side effects of SGLT2 include frequent urination, polyuria, urinary tract infections, rashes, and eczema. Therefore, the development of new drugs with fewer side effects is needed.

[0008] Therefore, an object of the present invention is to provide a novel drug that has the effect of promoting the excretion of glucose into urine. [Means for solving the problem]

[0009] In order to solve the above problems, the present inventors focused on Bofutsushosan and Daisaikoto among various herbal medicines. First, when a high concentration of Daisaikoto extract was administered to mice using an evaluation system for urinary glucose excretion, a significant increase in urinary glucose levels was observed.

[0010] Furthermore, it was found that daisaikoto extract significantly increased urinary glucose levels when administered 60 or 30 minutes before glucose administration. On the other hand, bofutsushosan extract effectively increased urinary glucose levels when administered 0 minutes (immediately before) glucose administration. These results demonstrated that the timing of administration (taking the medicine) is important for the promotion of urinary glucose excretion by bofutsushosan extract and daisaikoto extract.

[0011] Furthermore, when tested using starch, which contains slowly absorbed polysaccharides, daisaikoto extract caused a large increase in urinary glucose levels both when administered 30 minutes before starch administration and when administered 0 minutes (immediately before) starch administration. Furthermore, urinary glucose levels were higher when daisaikoto extract was administered 30 minutes before starch administration than when administered 0 minutes (immediately before) starch administration. Meanwhile, bofutsushosan extract caused a slight increase in urinary glucose levels when administered 30 minutes before starch administration, but caused a greater increase in urinary glucose levels when administered 0 minutes (immediately before) starch administration.

[0012] These results suggest that administering (taking) Bofutsushosan extract before ingesting sugar, especially just before (0 to 5 minutes before) ingesting sugar, can more effectively promote the excretion of sugar into urine. It also suggests that administering (taking) Daisaikoto extract before ingesting sugar, especially 30 minutes to 1 hour before ingesting sugar, can more effectively promote the excretion of sugar into urine. The present invention was made based on these findings.

[0013] The present invention provides an agent for promoting urinary excretion of glucose, which contains Daisaikoto or Bofutsushosan.

[0014] The present invention also provides a urinary glucose excretion promoter containing Daisaikoto, which is taken before meals.

[0015] The present invention also provides an agent for promoting urinary excretion of glucose, which is the above-mentioned agent containing Daisaikoto and is taken 30 minutes to 1 hour before a meal.

[0016] The present invention also provides a urinary glucose excretion promoter containing Bofu-tsusho-san, which is taken before meals.

[0017] The present invention also provides an agent for promoting urinary excretion of sugar, which is the above-mentioned agent containing Bofu-tsusho-san and is taken 0 to 5 minutes before a meal.

[0018] The present invention also provides the above-mentioned urinary sugar excretion promoter, wherein Daisaikoto is taken in a daily amount of 22 g to 24.5 g as a crude drug or in a single dose of 2.7 g to 5.4 g as an extract, and Bofutsushosan is taken in a daily amount of 26.3 g to 27.2 g as a crude drug or in a single dose of 2.85 g to 5.7 g as an extract.

[0019] The present invention also provides an SGLT2 inhibitor containing Daisaikoto or Bofutsushosan. [Effects of the Invention]

[0020] By using the present invention, it is possible to promote the excretion of sugar into urine with almost no side effects such as hypoglycemia, dizziness, dehydration, dry mouth, etc. [Brief explanation of the drawings]

[0021] [Figure 1] Graph showing urinary glucose levels one hour after oral administration of glucose and an SGLT2 inhibitor. [Figure 2] Graph showing urinary glucose levels 2 hours after oral administration of glucose and an SGLT2 inhibitor. [Figure 3] Graph showing urinary glucose levels after oral administration of glucose and Daisaikoto extract in the untreated group and the Daisaikoto group. [Figure 4] Graph showing urine glucose levels when Bofutsushosan or Daisaikoto was administered at each timing. [Figure 5] Graph showing urinary glucose levels when Bofutsushosan or Daisaikoto was administered at various times during starch loading. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention provides an agent for promoting urinary excretion of glucose, which contains Daisaikoto or Bofutsushosan.

[0023] As used herein, "urinary glucose excretion" means that glucose (glucose) is excreted in the urine without being reabsorbed by the kidney. After blood glucose is filtered into the renal tubules at the glomerulus of the kidney, approximately 90% is reabsorbed by SGLT2 (sodium / glucose cotransporter 2). The remaining glucose (approximately 10%) is reabsorbed by SGLT1, and the glucose that is not reabsorbed is excreted in the urine. SGLT is a transporter that actively transports glucose into cells using the difference in sodium ion concentration between the inside and outside of the cells. Due to the action of SGLT, healthy people usually excrete very little glucose in the urine.

[0024] As used herein, "promoting" urinary sugar excretion means increasing the amount of sugar excreted in urine (urinary sugar) outside the body, i.e., increasing the level of sugar in urine (urinary sugar level). For example, "promoting" urinary sugar excretion means increasing the level of sugar excreted in urine (urinary sugar level) by about 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 2-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 8-fold or more, or 10-fold or more when a subject is administered Daisaikoto or Bofutsushosan, compared to when the subject is not administered Daisaikoto or Bofutsushosan. "Promoting urinary sugar excretion" in the present invention can refer to the promotion of urinary sugar excretion caused by inhibition of sugar reabsorption in the kidney, for example, SGLT2 inhibition.

[0025] Daisaikoto is a powdered mixture of herbs consisting of Bupleurum Root, Pinellia Root, Scutellaria Root, Peony Root, Jujube Root, Zhishi Root, Ginger Root, and Rhubarb. The amounts of each herb can be as specified in the Japanese Pharmacopoeia, for example, the usual weight ratio can be 6.0 parts Bupleurum Root, 4.0 parts Pinellia Root, 3.0 parts Scutellaria Root, Peony Root, and Jujube Root, 2.0 parts Zhishi Root, 1.0 parts Ginger, and 1.0 parts Rhubarb (Kinkui Yaolue).

[0026] Bofutsushosan is a powdered herbal mixture consisting of Angelica sinensis, Peony root, Szechuan ginger, Gardenia fruit, Forsythia fruit, Mint, Jingjiang, Bofu, Ephedra, White Atractylodes macrocarpa, Platycodon grandiflorum, Scutellaria root, Licorice root, Gypsum, Talc, Ginger, Rhubarb, and Glauber's salt. The amounts of each herb can be as specified in the Japanese Pharmacopoeia, for example, by weight, typically: Angelica sinensis, Peony root, Szechuan ginger, Gardenia fruit, Forsythia fruit, Mint, Jingjiang, Bofu, Ephedra, White Atractylodes macrocarpa, Platycodon grandiflorum, Scutellaria root, Licorice root, Gypsum, Talc, Ginger, Rhubarb, and Glauber's salt. Anhydrous Glauber's salt or dried sodium sulfate can be used instead of Glauber's salt.

[0027] The herbal medicines used in the present invention may be extracts obtained from the raw plant material. Furthermore, Daisaikoto and Bofutsushosan may be extracts obtained by extracting the respective herbal powder mixtures. The "extract" in the present invention includes extracts obtained by adding a solvent to the raw plant material or the herbal powder mixture to extract it, the squeezed liquid obtained after squeezing the raw material, extracts obtained by adding a solvent to the residue after squeezing the raw material to extract it, concentrates obtained by concentrating these, and extract powders obtained by drying these.

[0028] The extract used in the present invention can be produced by known methods. For example, the extract used in the present invention can be produced by room temperature extraction or heated extraction using an extraction solvent. Extraction may be performed under reduced pressure or pressure, if necessary. The obtained extract may be used as is as the extract in the present invention, or may be subjected to any treatment before or after extraction before use as the extract in the present invention. For example, the extract may be used after concentration or after being dried by freeze-drying.

[0029] The extract may be subjected to hydrolysis after extraction with an extraction solvent. Hydrolysis can be carried out using any conventionally known method. Alternatively, the extract may be subjected to enzymatic hydrolysis before extraction with an extraction solvent. Enzymatic hydrolysis can be carried out using any conventionally known method.

[0030] The extract can be obtained by extracting with an extraction solvent and then removing solid matter by filtration, centrifugation, and / or decantation, etc. Filtration, centrifugation, and decantation can be carried out using any conventionally known method.

[0031] Examples of extracting solvents that can be used include water, physiological saline, alcohols (e.g., lower alcohols such as methanol, absolute ethanol, and ethanol, and polyhydric alcohols such as propylene glycol and 1,3-butylene glycol), ketones such as acetone, esters such as ethyl ether, dioxane, acetonitrile, and ethyl acetate, xylene, benzene, and chloroform. Among these, it is preferable to use water, alcohols such as methanol and ethanol, or mixed solvents of these as the extracting solvent. The above-mentioned extracting solvents may be used alone or in combination of two or more.

[0032] The extract can be pH adjusted as necessary and subjected to gel filtration and / or ultrafiltration to remove macromolecules without losing its activity. The extract or its fractions may be concentrated by methods such as vacuum concentration, ultrafiltration and / or freeze concentration. The extract may also be dried by methods such as freeze drying, spray drying and / or plate drying, resulting in a dried product, such as a powder.

[0033] The route of administration of the agent for promoting urinary excretion of sugar of the present invention is not particularly limited and may be either oral or parenteral. Parenteral administration includes administration via transdermal, nasal, and intravenous injection. The route of administration of the agent of the present invention is preferably oral administration. In this specification, "administration" can be replaced with "ingestion."

[0034] The agent for enhancing urinary sugar excretion of the present invention can be a preparation in any form. As an oral administration preparation, the agent for enhancing urinary sugar excretion of the present invention can be, for example, tablets such as sugar-coated tablets, buccal tablets, coated tablets, and chewable tablets; troches; pills; powders; capsules including hard capsules and soft capsules; granules; and liquid preparations such as suspensions, emulsions, syrups, and elixirs.

[0035] Furthermore, the urinary sugar excretion enhancer of the present invention can be a parenteral administration preparation such as intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, nasal administration, pulmonary administration, enteral administration, oral administration, and transmucosal administration. The urinary sugar excretion enhancer of the present invention can be, for example, an injection, a transdermal absorption tape, an aerosol, or a suppository.

[0036] Furthermore, the agent for promoting urinary sugar excretion of the present invention may be in a form suitable for consumption, such as a solid, liquid, granular, particulate, powder, capsule, cream, or paste form.

[0037] The agent for enhancing urinary sugar excretion of the present invention may further contain any component commonly used in pharmaceuticals, quasi-drugs, and foods, for example, a pharmaceutically acceptable base, carrier, excipient, binder, disintegrant, lubricant, colorant, etc.

[0038] Examples of carriers and excipients used in the agent for promoting urinary sugar excretion of the present invention include lactose, glucose, sucrose, mannitol, dextrin, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, and crystalline cellulose.

[0039] Examples of binders include starch, gelatin, syrup, tragacanth gum, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, and the like.

[0040] Examples of disintegrants include starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, sodium carboxymethylcellulose and calcium carboxymethylcellulose.

[0041] Examples of lubricants include magnesium stearate, hydrogenated vegetable oil, talc, macrogol, etc. As the coloring agent, any coloring agent permitted to be added to pharmaceuticals, quasi-drugs, and foods can be used.

[0042] Furthermore, the urinary sugar excretion promoter of the present invention may be coated with one or more layers of sucrose, gelatin, purified shellac, gelatin, glycerin, sorbitol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl methacrylate, methacrylic acid polymers, or the like, if necessary.

[0043] Furthermore, the agent for promoting urinary excretion of sugar of the present invention may contain, as necessary, a pH adjusting agent, a buffering agent, a stabilizer, a preservative, an antiseptic, a diluent, a coating agent, a sweetener, a flavoring agent, a solubilizing agent, and the like.

[0044] The agent for promoting urinary excretion of glucose of the present invention can contain either Daisaikoto or Bofutsushosan, or both.

[0045] The content of Daisaikoto in the agent for promoting urinary glucose excretion of the present invention may be any amount sufficient to fully exert the effects of the present invention, and can be appropriately determined depending on the subject, purpose, and administration method (intake method). For example, when orally ingested by humans, the content of Daisaikoto can be set so that the daily amount of herbal medicine is 10 g to 50 g, preferably 20 g to 25 g, and more preferably 22 g to 24.5 g. Furthermore, the content of Daisaikoto can be set so that the daily intake amount of Daisaikoto extract is 0.5 g to 10 g, preferably 2 g to 6 g, and more preferably 2.7 g (half amount) to 5.4 g (full amount).

[0046] The content of bofutsushosan in the urinary glucose excretion promoter of the present invention may be any amount sufficient to fully exert the effects of the present invention, and can be appropriately determined depending on the subject, purpose, and administration method (intake method). For example, when orally ingested by humans, the content of bofutsushosan can be set so that the daily intake of the herbal medicine is, for example, 10 g to 50 g, preferably 20 g to 30 g, and more preferably 26.3 g to 27.2 g. Furthermore, the content of bofutsushosan can be, for example, 0.5 g to 10 g, preferably 2 g to 6.5 g, and more preferably 2.85 g (half amount) to 5.7 g (full amount) per day as bofutsushosan extract.

[0047] When the urinary glucose excretion promoter of the present invention contains both Daisaikoto and Bofutsushosan, the contents of Daisaikoto and Bofutsushosan may be in amounts sufficient to fully exert the effects of the present invention, and can be appropriately set depending on the target, purpose, and administration method (intake method). For example, when administered orally to humans, the contents of Daisaikoto and Bofutsushosan may be within the appropriate intake ranges described above. Furthermore, the contents of Daisaikoto and Bofutsushosan can be ingested in a daily amount of, for example, 1 g to 20 g, preferably 4 g to 12.5 g, and more preferably 5.55 g to 11.1 g, as the total amount of Daisaikoto extract and Bofutsushosan extract.

[0048] The timing of administration of the urinary sugar excretion enhancer of the present invention is not particularly limited, and may be before, between, or after a meal. "Before a meal" means 0 minutes to about 1 hour before a meal. "Between meals" means between meals, for example, about 2 to about 3 hours after consuming a meal. "After a meal" means about 30 minutes after consuming a meal. Meals may be breakfast, lunch, dinner, or snacks. The number of times the urinary sugar excretion enhancer of the present invention is administered per day is not particularly limited, and may be once, twice, or three or more times.

[0049] When the agent for promoting urinary sugar excretion of the present invention contains Daisaikoto as an active ingredient, it may be administered (ingested) preferably before meals, more preferably about 30 minutes to about 1 hour before a meal. By administering (ingesting) Daisaikoto before meals, particularly about 30 minutes to about 1 hour before a meal, it is possible to more effectively promote urinary sugar excretion.

[0050] When the agent for promoting urinary sugar excretion of the present invention contains bofutsushosan as an active ingredient, it may be administered (ingested) preferably before meals, more preferably 0 to about 30 minutes before meals, and even more preferably 0 to about 5 minutes before meals. 0 to about 5 minutes before meals can also be referred to as "immediately before meals." By administering (ingesting) bofutsushosan before meals, particularly 0 to about 5 minutes before meals, it is possible to more effectively promote urinary sugar excretion.

[0051] The urinary glucose excretion promoter of the present invention can be a combination drug that combines Daisaikoto and Bofutsushosan as active ingredients. Daisaikoto and Bofutsushosan may be administered (ingested) simultaneously before meals, or may be administered (ingested) separately at appropriate times.

[0052] The present invention also provides an SGLT2 inhibitor containing Daisaikoto and / or Bofutsushosan as an active ingredient. The SGLT2 inhibitor of the present invention can be configured in the same manner as the above-mentioned urinary glucose excretion enhancer.

[0053] As used herein, "SGLT2" is not particularly limited, but may refer to SGLT2 (sodium / glucose cotransporter 2) located in the S1 segment of the proximal tubule of the kidney.

[0054] As used herein, "inhibiting" SGLT2 means reducing SGLT2 activity. "SGLT2 inhibition" in the present invention includes, for example, reducing SGLT2 activity by about 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99% or more compared to when the agent of the present invention is not administered or before administration. "Reducing SGLT2 activity" includes reducing glucose reabsorption in the kidney and increasing glucose excretion in the urine. A reduction in SGLT2 activity can be detected, for example, by an increase in urinary glucose levels.

[0055] The SGLT2 inhibitors of the present invention may be used in combination with existing SGLT2 inhibitors. By using them in combination with existing SGLT2 inhibitors, the dose of the existing SGLT2 inhibitor can be reduced, thereby alleviating side effects. Existing SGLT2 inhibitors include, for example, canagliflozin, ipragliflozin, luseogliflozin, dapagliflozin, tofogliflozin, and empagliflozin. Known side effects of SGLT2 inhibitors include hypoglycemia, dizziness, dehydration, dry mouth, frequent urination, polyuria, urinary tract infection, rash, and eczema. These side effects were not observed with the SGLT2 inhibitors of the present invention. This is thought to be because, unlike existing SGLT2 inhibitors, the active ingredient of the present invention promotes urinary excretion of glucose for only a limited period of time. Therefore, by using the SGLT2 inhibitors of the present invention in combination with existing SGLT2 inhibitors, the dose of the existing SGLT2 inhibitor can be reduced, thereby alleviating any or all of the above-mentioned side effects.

[0056] As used herein, the term "treatment" includes inhibiting, alleviating or alleviating a disease or symptom, inhibiting, suppressing, slowing or eliminating the progression of a disease or symptom, achieving remission, and achieving an improved prognosis.

[0057] As used herein, the term "amelioration" includes alleviating or alleviating a disease or symptom, as well as inhibiting, slowing or eliminating the progression of a disease or symptom.

[0058] As used herein, the term "prevention" includes inhibiting, suppressing or delaying the occurrence (development) of a disease or condition, and inhibiting, suppressing or delaying the recurrence of a disease or condition.

[0059] The present invention also provides a food composition for promoting urinary excretion of sugar, which contains Daisaikoto or Bofutsushosan as an active ingredient. The food composition of the present invention can be configured in the same manner as the above-mentioned agents and compositions.

[0060] As used herein, "food compositions" include not only general foods and beverages, but also foods for the sick, health foods, functional foods, foods for specified health uses, nutritional supplements, and supplements. General foods and beverages include, for example, various beverages, various foods, confectioneries, seasonings, liquid foods (such as soups), nutritional drinks, and processed foods. Supplements include, for example, tablet-type supplements.

[0061] Examples of beverages include water, tea, coffee, fruit juice drinks, carbonated drinks, cocoa, dairy drinks, alcoholic beverages, jelly drinks, sports drinks, and energy drinks. The beverage may be in the form of powder, granules, or tablets that are dissolved before consumption. The beverage may also be a teabag-type beverage that is extracted and consumed. The beverage may be a packaged beverage. The containers used for the packaged beverage may be those typically used for beverages, such as plastic bottles, metal cans, paper cartons, and bottles.

[0062] The various foods include, for example, bread, noodles, rice, tofu, oily foods, and dairy products.

[0063] Examples of confectioneries include candy, chewing gum, candy, gummy candies, tablets, chocolates, tablet sweets, cookies, biscuits, snacks, baked goods, cakes, rice crackers, yokan, puddings, jellies, jams, creams, ice creams, popsicles, sherbets, crackers, and chips.

[0064] The seasonings include, for example, miso, soy sauce, dressing, mayonnaise, sweeteners, and food additives.

[0065] As used herein, the term "processed food" refers to natural ingredients (such as animals and plants) that have been processed or cooked, and includes, for example, processed meat products, processed vegetables, processed fruit products, frozen foods, retort foods, canned foods, bottled foods, and instant foods.

[0066] The food composition of the present invention may be a food product labeled with a claim that it promotes urinary excretion of sugar. The food composition of the present invention may also be provided in a sealed form, such as a bag or container. The bag or container used in the present invention may be any bag or container commonly used for food products.

[0067] The food composition may contain any of the following ingredients, if necessary, as long as the object of the present invention is not impaired: for example, carbohydrate sweeteners (monosaccharides such as fructose, glucose, tagatose, and arabinose, oligosaccharides such as lactose, oligosaccharides, maltose, and trehalose, powdered starch syrup, dextrin, and sugar alcohols), high-intensity sweeteners (sucralose, acesulfame K, and stevia), polysaccharides such as starch, oils and fats, dairy products, stabilizers, emulsifiers, flavors (vanillin, linalool, and natural flavors), pigments, coloring agents, acidulants, flavoring ingredients (eggs, coffee, tea, cocoa, fruit juice and pulp, yogurt, and alcoholic beverages), flavorings (raspberry flavor, apple flavor, and the like), and the like. flavors and coffee flavors, etc.), anti-humectants, electrolytes, preservatives, humectants, proteins, amino acids, peptides, dietary fiber, organic acids (citric acid, malic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, lactic acid, etc.), vitamins (L-ascorbic acid, dl-α-tocopherol, vitamin B1, vitamin B2, niacin, pantothenic acid, vitamin B6, vitamin B12, folic acid, biotin, inositol, etc.), gold, silver, platinum, minerals (zinc, iron, calcium, magnesium, chromium, selenium, potassium, sodium, etc.). ), marine collagen, hydrolyzed collagen, hyaluronic acid, fermented yeast extract, glucosamine, yeast, eggshell membrane, lycopene, astaxanthin, other carotenoids, silk, chondroitin, ceramide, placenta extract, shark fin extract, deep sea shark extract, squalene, gamma-aminobutyric acid, casein dodecapeptide, raw chestnut skin extract, chestnut leaf extract, chestnut bur extract, chestnut pulp extract, chestnut bark extract, fermented cabbage extract, rose petal extract, grape leaf extract, grape seed extract, apple polyphenols, chamomile extract, lychee seed Extract, gotu kola extract, shell ginger leaf extract, lotus germ extract, star fruit leaf extract, mulberry leaf extract, guava tea extract, red wine, green tea, black tea, oolong tea, coffee, cocoa, chocolate, black sesame, beans, soy milk, nuts, mushrooms, green and yellow vegetables, egg-derived ingredients such as iodine eggs, catechins, other polyphenols, raspberry ketone, low molecular weight alginic acid, psyllium seed coat, ginkgo leaf extract, pine bark extract, nattokinase, plant sterols, diacylglycerol, chitosan, hyaluronic acid, methylsulfonylmethane,These include kojic acid, ellagic acid, arbutin, rucinol, magnolignan, magnesium L-ascorbate phosphate, CoQ10, and α-lipoic acid.

[0068] The present invention also provides a method for promoting urinary excretion of glucose in a subject, comprising administering Daisaikoto or Bofutsushosan to the subject. The present invention also provides a method for inhibiting SGLT2 in a subject, comprising administering Daisaikoto or Bofutsushosan to the subject. In the methods of the present invention, Daisaikoto or Bofutsushosan can be administered in the form of the agent or composition described above.

[0069] In the method of the present invention, the dosage of Daisaikoto may be any amount that can exert its effect, and can be appropriately determined depending on the subject, purpose, and administration method (intake method). For example, when orally ingested by humans, the daily dose of the herbal medicine can be, for example, 10 g to 50 g, preferably 20 g to 25 g, and more preferably 22 g to 24.5 g. Furthermore, the daily intake of Daisaikoto extract can be, for example, 0.5 g to 10 g, preferably 2 g to 6 g, and more preferably 2.7 g (half amount) to 5.4 g (full amount).

[0070] In the method of the present invention, the dosage of bofutsushosan may be any amount sufficient to exert its effect, and can be appropriately determined depending on the subject, purpose, and administration method (intake method). For example, when orally ingested by humans, the daily dose of the herbal medicine can be, for example, 10 g to 50 g, preferably 20 g to 30 g, and more preferably 26.3 g to 27.2 g. Furthermore, the daily intake of bofutsushosan extract can be, for example, 0.5 g to 10 g, preferably 2 g to 6.5 g, and more preferably 2.85 g (half amount) to 5.7 g (full amount).

[0071] The present invention is applicable to humans and non-human mammals. Non-human mammals include, for example, mice, rats, rabbits, cats, dogs, cows, horses, and monkeys. When targeting non-humans, the intake (dosage) can be determined by appropriately modifying the above-mentioned intake (dosage) for humans based on the body weight of the target animal. For example, the above-mentioned intake (dosage) for humans can be used as the amount per 50 kg of body weight, and an appropriate intake (dosage) for each target animal can be calculated.

[0072] The present invention is applicable to a wide variety of subjects, including those who require enhanced urinary glucose excretion. Examples of such subjects include not only diabetic patients but also those diagnosed with borderline diabetes (prediabetes), those experiencing symptoms of blood glucose spikes, and those suffering from symptoms associated with postprandial blood glucose spikes. Borderline diabetes may be diagnosed, for example, when HbA1c is less than 6.5% and fasting blood glucose is 110-125 mg / dL, or when blood glucose levels two hours after a 75-g oral glucose load are 140-199 mg / dL. A blood glucose spike is a condition in which blood glucose levels rise rapidly and remain elevated for a short period of time after a meal. Symptoms of a blood glucose spike are not particularly limited, but include, for example, a blood glucose level of 140 mg / dL or higher two hours after a meal. A blood glucose spike can be detected, for example, by an oral glucose tolerance test (OGTT). Known symptoms associated with postprandial blood glucose spikes include drowsiness, fatigue, decreased concentration, headache, thirst, and anxiety.

[0073] The present invention also provides Daisaikoto or Bofutsushosan for use in promoting urinary excretion of glucose.The present invention also provides Daisaikoto or Bofutsushosan for inhibiting SGLT2.

[0074] The present invention also provides use of Daisaikoto or Bofutsushosan for promoting urinary excretion of glucose.The present invention also provides use of Daisaikoto or Bofutsushosan for inhibiting SGLT2.

[0075] The present invention also provides use of Daisaikoto or Bofutsushosan for producing an agent for promoting urinary glucose excretion, a composition for promoting urinary glucose excretion, a food composition for promoting urinary glucose excretion, or an SGLT2 inhibitor. [Example]

[0076] Example 1: Daisaikoto Extract Daisaikoto extract was prepared in-house by extracting, concentrating, sterilizing, and spray-drying each herbal medicine using standard manufacturing methods.

[0077] Example 2: Bofutsushosan Extract The Bofutsushosan extract was prepared in-house by extracting, concentrating, sterilizing, and spray-drying each herbal medicine using a common manufacturing method.

[0078] [Test 1: Evaluation of urinary sugar excretion] We investigated an evaluation system for urinary glucose excretion using tofogliflozin hydrate (generic name: Deberza; manufactured by Kowa Co., Ltd.), a selective SGLT2 inhibitor.

[0079] C57BL / 6J mice (13 months old, male) were orally administered sterilized water or glucose diluted in sterilized water (2 g / kg). The SGLT2 inhibitor tofogliflozin hydrate was then diluted in sterilized water and orally administered at 100 μg / mouse. Urine was collected from each mouse 1 and 2 hours after glucose and SGLT2 inhibitor administration, and urinary glucose (urinary glucose) was measured using the Autocera S GLU urine glucose measurement kit (Sekisui Medical Co., Ltd.).

[0080] Figure 1 shows the urinary glucose levels one hour after oral administration of glucose and SGLT2 inhibitors, and Figure 2 shows the urinary glucose levels two hours after. In the group that did not receive an SGLT2 inhibitor (SGLT2 inhibitor (-)), no increase in urinary glucose levels was observed even when glucose was administered orally. On the other hand, in the group that did receive an SGLT2 inhibitor (SGLT2 inhibitor (+)), an increase in urinary glucose levels was confirmed even without administration of glucose, and a more stable increase in urinary glucose levels was observed when glucose was administered. These results suggest that the glucose excretion effect of SGLT2 inhibition can be more easily evaluated by administering glucose beforehand.

[0081] [Test 2: Oral administration of Daisaikoto extract] The effect of oral administration of high-concentration Daisaikoto extract on urinary glucose excretion was examined.

[0082] C57BL / 6J mice (13 months old, male) were divided into two groups: an untreated group and a daisaikoto group. Each group received oral administration of glucose (2 g / kg) diluted in sterile water three times, every hour. The daisaikoto treatment group received 1 g / kg of daisaikoto extract (Example 1) at the time of the second glucose administration, and 2 g / kg of daisaikoto extract at the time of the third glucose administration. Urine samples were collected immediately before the second glucose administration (urine 1), 1 hour after the second glucose administration (urine 2), and 1.5 hours after the third glucose administration (urine 3). Urinary sugar levels (urine glucose levels) were measured using a urine glucose measurement kit, Autocera S GLU (Sekisui Medical Co., Ltd.).

[0083] Figure 3 shows the urinary glucose levels after oral administration of glucose and daisaikoto extract in the untreated and daisaikoto groups. In the daisaikoto group, a significant increase in urinary glucose levels was observed in a dose-dependent manner. These results demonstrate that oral administration of high-concentration daisaikoto extract promotes urinary glucose excretion. This suggests that daisaikoto has an SGLT2 inhibitory effect.

[0084] [Test 3: Examination of dosage timing] Glucose (2 g / kg) diluted in sterilized water was orally administered to C57BL / 6J mice (6-week-old, male). The timing of glucose administration was designated as time 0, and 2 g / kg of Bofutsushosan extract (Example 2) or Daisaikoto extract (Example 1) was orally administered 60 minutes, 30 minutes, or time 0 minutes (just before glucose administration) before glucose administration (n=5). Urine was collected 40 minutes after glucose administration, and the glucose content in the urine was measured using Autocera S GLU (Sekisui Medical Co., Ltd.), a urine glucose measurement reagent kit.

[0085] It is known that in glucose tolerance tests, blood glucose levels peak 15 to 30 minutes after glucose administration and then decline. Therefore, it was assumed that glucose is excreted in the urine 30 minutes after glucose administration, and urine collection was set for 40 minutes after glucose administration. The SGLT2 inhibitor Debelza was used as a positive control. Debelza was administered 0 minutes (immediately before) glucose administration, and urine was collected 40 minutes after glucose administration.

[0086] Figure 4 and Table 1 show the urinary glucose levels when Bofutsushosan or Daisaikoto was administered at each timing.

[0087] When Bofutsushosan was administered 60 minutes or 30 minutes before glucose administration, almost no significant increase in urinary glucose levels was observed. On the other hand, when Bofutsushosan was administered 0 minutes (immediately before) glucose administration, an increase in urinary glucose levels, that is, promotion of sugar excretion in urine, was confirmed. These results show that Bofutsushosan can effectively promote sugar excretion in urine by administering it before meals, preferably 0 to 5 minutes before a meal.

[0088] When Daisaikoto was administered 0 minutes (immediately before) after glucose administration, there was almost no increase in urinary glucose levels. On the other hand, when Daisaikoto was administered 60 minutes or 30 minutes before glucose administration, there was a significant increase in urinary glucose levels, which indicated that urinary glucose excretion was promoted. These results indicate that administrating Daisaikoto before meals, preferably about 30 minutes to about 1 hour before a meal, can effectively promote urinary glucose excretion.

[0089] These results indicate that the timing of administration is important for the urinary glucose excretion-promoting effects of Bofutsushosan and Daisaikoto. They also suggest that the appropriate administration timing differs between Bofutsushosan and Daisaikoto.

[0090] When Bofu-tsusho-san was orally administered 15 minutes after glucose administration, almost no increase in urinary glucose levels was observed (not shown).

[0091] [Table 1]

[0092] [Test 4] While glucose is rapidly absorbed by the body, starch, which is found in rice and bread, which are commonly consumed as staple foods, contains polysaccharides that are absorbed slowly. Therefore, we investigated the appropriate administration timing of Bofutsushosan and Daisaikoto when ingesting starch, in relation to their effect of promoting urinary glucose excretion.

[0093] C57BL / 6J mice (6-week-old, male) were orally administered 3 g / kg of starch diluted with sterilized water. The timing of starch administration was set as time 0, and 2 g / kg of Bofutsushosan extract (Example 2) or Daisaikoto extract (Example 1) was orally administered 30 minutes or time 0 minutes (just before) before starch administration (n=5).

[0094] Urine was collected 90 and 120 minutes after starch administration, and the sugar content in the urine was measured using Autocera S GLU (Sekisui Medical Co., Ltd.), a urine sugar measurement reagent kit, or New Uriace Ga (Terumo Corporation), which allows for simple measurement of urine sugar levels.

[0095] Figure 5 and Table 2 show the urinary glucose levels when Bofutsushosan or Daisaikoto was administered at each timing.

[0096] When Bofutsushosan was administered 30 minutes before starch administration, urine glucose levels increased slightly, but when it was administered 0 minutes (immediately before) starch administration, urine glucose levels increased more significantly.

[0097] Regarding Daisaikoto, urine glucose levels increased significantly both when it was administered 30 minutes before starch administration and when it was administered 0 minutes (immediately before) starch administration. When Daisaikoto was administered 30 minutes before starch administration, urine glucose levels were higher than when it was administered 0 minutes (immediately before) starch administration.

[0098] It was confirmed using New Uriace Ga that the urinary glucose level did not increase in urine collected 120 minutes after starch administration (not shown).

[0099] Considering the results of glucose loading together, it was shown that Bofutsushosan can more effectively promote the excretion of sugar into the urine when administered 0 to 30 minutes, preferably 0 to 5 minutes (just before) before ingesting sugar. It was shown that Daisaikoto can more effectively promote the excretion of sugar into the urine when administered 30 minutes to 1 hour before ingesting sugar.

[0100] Furthermore, unlike existing SGLT2 inhibitors, when blood glucose levels were not elevated, administration of Bofutsushosan or Daisaikoto hardly promoted glucose excretion. Therefore, Bofutsushosan and Daisaikoto are thought to have an extremely low risk of developing side effects such as hypoglycemia.

[0101] [Table 2] [Industrial Applicability]

[0102] The present invention can be suitably used in medicines, foods, etc. for promoting urinary excretion of sugar.

Claims

1. A drug that promotes the excretion of sugar in urine, containing Daisaikoto or Bofutsushosan.

2. 2. The urinary sugar excretion promoter according to claim 1, which contains Daisaikoto and is taken before meals.

3. 3. The urinary sugar excretion promoter according to claim 2, which is taken 30 minutes to 1 hour before a meal.

4. 2. The urinary sugar excretion promoter according to claim 1, which contains Bofutsushosan and is taken before meals.

5. 5. The urinary sugar excretion promoter according to claim 4, which is taken 0 to 5 minutes before a meal.

6. The Daisaikoto is taken at a daily dose of 22g to 24.5g as herbal medicine or 2.7g to 5.4g as an extract, The urinary sugar excretion promoter according to any one of claims 1 to 5, wherein the Bofutsushosan is taken in an amount of 26.3 g to 27.2 g per day as a herbal medicine, or 2.85 g to 5.7 g per dose as an extract.

7. SGLT2 inhibitors containing daisaikoto or bofutsushosan.

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