WO2019009354A1 - Composition for amelioration of dysuria - Google Patents

Abstract

The purpose of the present invention is to provide a composition for amelioration of dysuria, containing, in addition to a natural substance such as nobiletin which is a prior art, a component derived from a natural substance that is similarly effective against dysuria, is safe, and can be produced from starting materials that are readily available in large quantities. The foregoing is achieved by a composition for amelioration of dysuria containing a Rumex japonicus extract as an active ingredient.

Description

Composition for improving urination disorder Cross-reference to related applications

This application claims the priority of Japanese Patent Application No. 2017-132109 filed on July 5, 2017, the entire disclosure of which is incorporated herein by reference.

The present invention relates to a composition for improving urination disorder.

The bladder of a healthy person can store up to 300-500 ml of urine. In adults, when about 200 ml of urine accumulates in the bladder, a signal related to urination is sent to the brain and the first urination is felt. When such a signal is received by the brain, the parasympathetic nerve is excited and as a result, the muscarinic receptors of the bladder are stimulated and the smooth muscle (detrusor muscle) contracts. On the other hand, in the urine storage stage, the sympathetic nerve is dominant and the detrusor muscle is in a relaxed state.

Healthy people can urinate properly when they feel their urgency, but if urinating disorders such as frequent urination and urinary incontinence occur due to various causes, the quality of life (QOL) significantly decreases. At present, many people are left with such urination disorder. The reason is that besides being embarrassing to go to the hospital, it can not be recognized that it is a urination disorder.

At the International Continence Society, which was held in 2002, "Urinary urgency" was the main symptom, and symptoms accompanied by "Utauria" and "notauria" were "Overactive Bladder" (Overactive Bladder: It was proposed as a disease called OAB. Based on this proposal, efforts to diagnose, treat and prevent urination disorders have become popular.

OAB is a disease in which the bladder in the storage stage responds excessively, resulting in sudden and strong urination, and it has been reported that its prevalence increases with age. In patients with OAB, sympathetic and parasympathetic nerves break down, and urination and frequent urination occur due to involuntary contraction of the detrusor muscle regardless of urine storage. In men, OAB has been reported to be associated with prostatic hyperplasia. The prostate is located just below the bladder and surrounding the urethra. When the prostate enlarges with age, the urethra at the outlet of the bladder is compressed, causing "reduction of urine" and "feeling of residual urine". Female patients with OAB suffer from "stress incontinence" (loose leaks during transient movements such as sneezing, coughing, exercise, etc.) due to relaxation of the pelvic floor muscles due to aging or childbirth. It has been reported that they frequently occur at the same time. This is because the female urethra is shorter than the male urethra. Urination disorder can be said to be an age-related disease that develops due to various factors in the range from the bladder to the urethra. Therefore, preventing urination disorder is extremely important to live a comfortable elderly person's life.

Anticholinergics have been reported to be effective for the treatment of OAB (eg, Non-patent Document 1, the entire description of the document is incorporated herein by reference). However, long-term use of commercially available anticholinergic drugs has a risk of side effects.

Since OAB treatment may last for a long time, recently, nobiletin, tangeretin, as a medicine for preventing and / or ameliorating urination disorder using food materials that are highly safe for long-term use A composition for improving dysuria comprising 3 ', 4', 5, 7, 7-tetramethyl quercetin and sinensetin as active ingredients is described in Patent Document 1 (the entire description of the document is incorporated herein by reference). ing.

WO 2016/075960 Brochure

Chapple et al. , Eur Urol. 2005 Sep; 48 (3): 464-70

The composition containing nobiletin, tangeretin, 3 ', 4', 5,7-tetramethyl quercetin and sinensetin described in Patent Document 1 is mainly obtained from extracts using the peel of Shikuwasa in citrus fruits. However, production areas such as Shikuwasa are limited, and there is a need for raw materials that can be obtained more easily.

Therefore, the present invention is effective in preventing urination as compared with the natural product containing nobiletin etc. described in Patent Document 1, but it is possible that the urination disorder includes a component derived from a natural product which can be obtained easily and in large quantities. It is an object of the present invention to provide a composition for improvement.

MEANS TO SOLVE THE PROBLEM The present inventors advanced research and development earnestly in order to solve the said subject, and when various natural products considered to contain a physiologically active ingredient were examined, they came to look at a gourd, which is a plant of the family Tadeidae. Furthermore, as a result of repeated trial and error, surprisingly, it has been found that the extract of berry extract has the effect of improving dysuria, and creates a composition for improving dysuria comprising the extract of moth extract as an active ingredient. Succeeded.

Raspberry ( Rumex ) is a perennial herb of the family Rade ( Rumex ), and R. japonicus , R. crispus , R. obtusifolius, R. maritimus etc. are known. . Gishigishi is a perennial plant distributed all over Japan, and is a natural product that can secure a sufficient supply.

In addition, the anchovy extract contains various components, among which nepogin and its analogues are mainly contained in a large amount. For example, nepogin (CAS registration number: 3785-24-8) is also referred to as mucidin or dianeridin, and has a structure represented by the following formula (1).

（１）

(1)

This nepogin has a pharmacological action to improve various symptoms by activating 5 'adenosine monophosphate activated protein kinase (AMPK) such as glucose tolerance improving action, blood lipid concentration improving action and metabolic syndrome improving action. It is known to have (see Patent No. 5727481).

However, the extract of Musk has urination disorder, eg, urge incontinence from overactive bladder, urination frequency during the daytime, urination frequency during the night, urgency frequency and urination frequency from the prostate hypertrophy during the day, urination frequency during the night, urgency feeling It is not known at all that it is extremely effective in improvement such as residual urine, poor appearance, and bladder outlet obstruction and reduction in urethral closure pressure, which is a new finding of the present inventors. . The present invention is an invention that has been completed based on these findings and successful examples.

Therefore, according to one aspect of the present invention, the following compositions [1] to [7] are provided.
[1] A composition for ameliorating urination disorder, which comprises an extract of moth extract as an active ingredient.
[2] The composition according to [1], wherein the logbook extract contains nepogin, nepogin analogue and / or anthraquinones as an active ingredient.
[3] The above urination disorder is at least one selected from the group consisting of pollakiuria, nocturia, urinary incontinence, residual urine, decreased urinary retention, reduced bladder contraction, bladder outlet obstruction and reduced urethral closure pressure. The composition according to [1] or [2], which is a voiding disorder of
[4] The composition according to any one of [1] to [3], which is a composition for ameliorating urination disorder for oral use.
[5] The composition according to any one of [1] to [4], wherein the composition is a food or drink composition or a pharmaceutical composition.
[6] The composition according to any one of [1] to [5], wherein the composition is a composition administered at 0.001 to 600 mg / kg per day as a berry extract.
[7] A method for ameliorating urination disorder, comprising the step of ameliorating urination disorder in the individual by administering the composition according to any one of [1] to [6] to the individual.

According to the composition of one aspect of the present invention, it is possible to produce a whole country from the whole country and process as an active ingredient an extract obtained by processing a large amount of easy to obtain an extract as compared with the prior art. It is possible to produce products for improving urination disorders of industrial scale and economically superior.

In addition, since the berry is originally used in herbal medicines and its safety has been demonstrated, the berry extract used as an active ingredient in the present invention is taken when taking a long time characteristic of the treatment for urination disorder Even if it is possible to use it with reduced side effects. The composition according to one aspect of the present invention may be effective against a pelvic congestion model, which is one of the causes of frequent urination in women due to lower urinary tract disorders among urination disorders, and thus the potential demand is extremely high. It has the convenience that it can be taken easily at the time of treatment.

FIG. 1 is a view showing the effect of intravenous administration of a extract of Gishigiri on continuous intravesical pressure measurement (bladder contraction interval) of pelvic congestion frequent urination rats in an example described later. FIG. 2 is a view showing the frequency of nocturnal urination at night in a patient with pelvic congestion frequent in the examples described later.

Hereinafter, although the composition and method which are one aspect of the present invention are explained in detail, the technical scope of the present invention is not limited only by the matter of this item, as long as the present invention achieves the purpose. Can take various aspects.

The composition which is one aspect of the present invention is a composition for ameliorating urination disorder containing an extract derived from berry as an active ingredient.

[Gishigishi]
"Gishigishi" is a kind of generally known family Tadeaceae plant, and is, for example, a perennial plant distributed all over Japan, and it is known as a weed often found in roadsides and ridges of paddy fields. Gishigishi is also known as a plant that spreads a stem about 1 m in early summer and gives a flower resembling buckwheat to a bell. No particular limitation is imposed on the resin, such as, for example, Rumex japonicus, R. crispus, R. obtusifolius, R. gmelini, R. nepalensis, R. hastatus, R. alpinus, sorrel (R. acetosa), R. a. cripus, R. stenophyllus, R.S. patientia, R .; chalepensis, R. Orientalis etc. are mentioned.

Gigirs include plants closely related to Gishi. Examples of plants that are closely related to Gishigishi include Dianella ensifolia, which is a plant that is closely related to a plant of the family Tadeidae. revoluta, D. callicarpa D. nigra; Hemerocallis minor; Simethis bicolor Kunth, which is a family of Rhizophoraceae; Limonium myrianthum, which is an isomatsuaceae isopus genus plant; Rhamnus prinoides, which is a family of Euphorbiaceae; wightii, R. procumbens; Myrsine africana, which is a genus of Ruminaceae, and other plants such as Maesopsis eminii, but not limited thereto.

It is sufficient if it is 1 type or 2 types or more of a plant related to the above-mentioned Tadeaceae plant or Tadeaceae plant as described above, and it may be a hybrid species of the plants mentioned as the specific examples.

There are no particular limitations on the site of the hook, but it is preferably a root. In addition to roots, it may be mixed with other parts such as stems, leaves and flowers.

Specific examples of gussula sieboldii are as follows: gussula sieboldii, scutellaria vulgaris, scutellaria s. hastatus, D. ensifolia, D. callicarpa (Liliaceae), D. R. nigra, H. vulgaris and Myrsine africana roots; leaves of Prinoides; such as bark of wightii. Among them, the root of berry root is preferred because it has been used as a herbal medicine in the name of ovine. In addition to the nepogin contained a lot, chrysophanol, emodin, chrysophanoanthrone, oxalic acid, etc. are contained in the roots of snail, and it is known that they have an antibacterial action and a coagulant action.

[Gishigishi extract]
There is no particular limitation on the extract of spinach as long as it exhibits an action to improve urination disorder. Although the technical scope of the present invention is not limited by any theory or speculation, the extract of the abalone, which is obtained by the process of extracting a high content of nepogin, nepogin analogue and / or anthraquinones, causes urination as described below. Since it exerts the effect of improving the disorder, it can be assumed that nepogin and its analogues and anthraquinones, among them, a high content of nepogin exerts the effect of improving urination disorder. Therefore, it is preferable that the anchovy extract is an anchovy extract containing nepogin, nepogin analogues and / or anthraquinones, and more preferably an anchovy extract containing nepogin.

Examples of the nepogin analogues include nakahalene etc. shown in the following formula (2). Examples of anthraquinones include emodin, chrysophanol, physcion and the like.

（２）

(2)

It is preferable that the extract of Neemaria japonicum contains a high concentration of nepogin. The nepogin concentration (content) in the extract is not particularly limited. For example, nepogin is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, based on the dry weight of the extract. In addition to nepogin in the snail extract, the nepogin analogue nakahalene may be contained in an amount of about 1 to 15 wt%, preferably 10 wt% or less, and anthraquinones emodin, chrysophanol, physcion, etc. in an amount of about 1 to 10 wt%, Preferably, it may be contained at 8 wt% or less.

Although it does not specifically limit about the manufacturing method of a berry extract, For example, the method as described in the specification of international application number PCT / JP2017 / 006435 etc. can be mentioned. Specifically, a method for producing a nepogin-containing anchovy extract and the like comprising the following steps (1) to (5) can be mentioned:
(1) a step of obtaining a crude extract of a moth by subjecting the moth to an extraction treatment using a nepogin soluble solvent;
(2) a step of obtaining a crude extract of the crude extract of Gishigishi by subjecting the crude extract of the Gishigishi extract to a hydrolysis treatment and / or a concentration treatment;
(3) a step of obtaining a weakly alkaline insoluble matter by subjecting the above crude extract of crude extract to a weakly alkaline treatment;
(4) a step of obtaining a strong alkali solution by subjecting the weak alkali insoluble matter to a strong alkali treatment; and (5) a nepogin-containing glutinous extraction by subjecting the strong alkali solution to a neutralization treatment A process of obtaining an object.

Hereinafter, as a representative example of the method for producing the extract of sage extract, a method for producing the extract of sage extract containing a high concentration of nepogin etc. using the roots of sage root as a raw material will be described. It is not limited to things.

The fine roots are removed from the roots of the moss which was dug up when the flower stems die (July-September), dried in sun, and dried thoroughly. 2 to 10 times by mass of ethanol is added to the roots of the dried graminea to which a predetermined amount was weighed, and extraction treatment is carried out by allowing the mixture to stand at room temperature for 5 to 15 hours. The crude extract is obtained by removing the residual residue by means of solid-liquid separation.

Next, 0.2 to 0.5 times the amount of water is added to the obtained fresh shigishi crude extract with respect to the shigishi crude extract, and then subjected to concentration under reduced pressure to carry out a hydrolysis treatment and concentration treatment, and solid-liquid The crude extract crude extract solid content is obtained by removing the crude extract crude liquid component by separation means. At this time, instead of the hydrolysis treatment and the concentration treatment, only the hydrolysis treatment or the concentration treatment may be performed.

Next, a weak alkali treatment is carried out using 0.05 to 1% (w / v) a weakly alkaline aqueous solution (pH 8 to 10) on the solid content of the crude extract of the hardwood which has been obtained By removing the lysate, a weakly alkaline insoluble is obtained.

Next, the obtained weakly alkaline insoluble matter is subjected to a strongly alkaline treatment using a 0.05-1% (w / v) strongly alkaline aqueous solution (pH 12 to 14), and the strongly alkaline By removing the lysate, a strong alkaline lysate is obtained.

Next, the obtained strong alkaline solution is neutralized using an acid (pH 1 to 3) such that the pH of the solution becomes 7 to 8, and the solution for neutralized solution is dissolved by solid-liquid separation means By removing the extract to give a fresh extract.

As described above, it is possible to obtain, from the extract of the roots of the berry root, an extract of the berry root which is rich in nepogin etc. of the present invention. The structure can be determined by subjecting the obtained mass spectrometry (MS), nuclear magnetic resonance analysis (NMR) and the like to obtain various spectrum data and comparing them with literature values.

[Urinary dysfunction]
The composition of one embodiment of the present invention has a urination disorder ameliorating effect. As used herein, the term "voiding disorder" means that difficulty in urination is recognized as a subjective symptom or as a result of a suitable test in a subject, where the difficulty in urinating is symptoms of excretion and urine collection. It includes any condition in which any inconvenience associated with urination has occurred, including symptoms. Urination disorder can be said to be lower urinary tract dysfunction. Here, discharge symptoms mainly refer to urine discharge disorders, and are states in which urine decline, urinary line disruption, urination delay, urinary retention, residual urine feeling and the like occur. The term “storage symptoms” refers to a state in which urine is not stored in the bladder, resulting in, for example, frequent daytime urination, frequent nighttime urination, urinary urgency, urinary incontinence, and the like. The compositions of the present invention are directed to at least any one of these types of dysuria. As described below, these symptoms can occur concomitantly with various diseases.

As used herein, the term "improvement" refers to the prevention and delay of occurrence of a disease or condition, etc .; reduction of risk of occurrence of a disease or condition, etc .; improvement of a disease, condition or condition; deterioration of a disease, condition or condition Prevention and delay; maintenance of function, prevention of deterioration and delay etc. Therefore, the composition of one aspect of the present invention can be expected to prevent, suppress, alleviate, treat, etc. urination disorder in the individual using it by having a urination disorder improving action.

The drainage or storage symptoms as exemplified above may be associated with a disease or condition such as, for example, overactive bladder, prostatic hypertrophy, reduced bladder contraction, bladder outlet obstruction, and reduced urethral closure pressure. . The urination disorder ameliorated by the composition of one embodiment of the present invention is, for example, excretory symptoms and urine accumulation symptoms as described above, and overactive bladder, prostate hypertrophy, bladder contraction reduction, bladder outlet obstruction, and urethral closure pressure reduction. And the like may be associated with a disease or condition such as

Overactive bladder is accompanied by a sense of urgency, which is a symptom of sudden, unbearable urgency. Overactive bladder may also be associated with one or more symptoms selected from the group consisting of pollakiuria, nocturia and urinary incontinence. In the treatment of overactive bladder, anticholine is used as the first choice drug. Prostatic hyperplasia may be associated with increased flow resistance and / or impaired bladder blood flow due to lower urinary tract obstruction. In prostatic hyperplasia, an alpha 1 blocker is used as the first-line drug. Bladder contraction, bladder outlet obstruction, and urethral closure pressure reduction are urinary discharge disorders and are accompanied by symptoms such as urinary loss, urination loss, delayed urination, urinary retention, and residual urine.

In the present specification, urination disorder is one or more symptoms selected from the group consisting of pollakiuria, nocturia, urinary incontinence, residual urine feeling, urinary decline, urinary retention, urination delay, urinary retention. May be Frequent urination is a condition in which the frequency of urination from getting up to bedtime increases. Usually, when the number of times of urination per day is 8 or more, it is diagnosed as frequent urination, but it is not limited to this. Nocturia is a symptom of temporary rising for urination from bedtime to waking up, and usually it is diagnosed as nocturia if there is more than one urination, but it is not limited thereto. Urinary incontinence refers to a condition in which urine leaks involuntarily or unconsciously. Urinary incontinence includes stress incontinence, urge incontinence, overflow incontinence, reflex incontinence, true incontinence. The feeling of residual urine is a symptom accompanied by the sensation that urine remains in the bladder (residual urine) even after urination, and such sensation occurs regardless of the presence or absence of residual urine. Attenuation is a symptom in which the momentum of urination decreases and the urination time becomes long, and it is a symptom said to be poor in appearance.

Urinary line disruption is an abnormal urinary tract when there is an abnormality in the external urethral opening, which is the outlet of urine, and urination is interrupted during urination, and urinary line interruption is referred to as urinary line disruption. Bladder calculus and clot Happens to block the outlet of the bladder. Delayed urination is a time-consuming task until urine begins to come out, and is seen when a foreign body is created below the bladder or inflammation occurs and the urethra narrows. Urinary retention is a condition in which urine does not come out despite the accumulation of urine in the bladder, and it can be caused by hypertrophy of the prostate if the bladder becomes tight with intense urination. When the contraction force of the bladder decreases, the ability to urinate decreases and the urinary line narrows. In addition, there are cases of overactive bladder with a sense of urgency as frequent urination and urinary incontinence, and cases of frequent urination without a sense of urgency. When urinary urgency is present, bladder contractions that can not usually be suppressed by one's own will appear, that is, non-suppressed bladder contractions.

Overactive bladder may be due to detrusor overactivity due to the lower urinary tract itself or to detrusor hyperreflexia due to the central nervous system. The cause of frequent urination without urgency also includes congestion of the bladder, which is said to be one of the causes of chronic prostatitis. The above symptoms may be urinalysis, prostate specific antigen (PSA) measurement, urine flow measurement, ultrasonography, computed tomography (CT) examination, magnetic resonance imaging (MRI) examination, urination cystography, urodynamic examination or these It can be judged by the combination of For example, the urination disorder improved by the composition of one embodiment of the present invention includes urge incontinence from overactive bladder, urination frequency during the day, urination frequency during the night, urgency, urination frequency from the prostatic hyperplasia, during the night It may be the frequency of urination, a sense of urgency, a feeling of residual urine, poor appearance, or a bladder contraction, bladder outlet obstruction, and a feeling of urinary retention or residual urine due to a reduction in urethral closure pressure.

Evaluation of the urination disorder ameliorating action is to perform continuous intravesical pressure measurement when predetermined doses of these extracts are intravenously administered for a predetermined period to lower urinary tract disorder model animals, and differences in bladder activity are continuously determined. It can do by measuring. In addition, it can be carried out by measuring the frequency of nocturia and the like when a predetermined amount of the composition of one embodiment of the present invention is orally administered to a used individual.

[Composition for improving urination disorder]
One specific embodiment of the composition of the present invention is a composition for ameliorating urination disorder, which comprises an extract of the abalone extract as an active ingredient. Substances having a urination disorder ameliorating action are said to be able to improve the neurotransmission environment by improving the binding between the neurotransmitter and the receptor, which is generally related to the urination of the used individual applied. ing. Thus, the composition for improving urination disorder may be for improving the above-mentioned neurotransmission environment, but is not limited thereto.

There is no particular limitation on the application target and application method of the composition for improving urination disorder. For example, the used individual includes animals, particularly mammals, and mammals include humans, dogs, cats, cattle, horses, etc. Among them, human is preferred.

The composition for ameliorating urination disorder can take the form of a composition for food or drink, a composition for medicine, etc. in which it is used alone or in itself. Therefore, one specific embodiment of the composition of the present invention is an oral or non-oral composition containing a composition for improving urination disorder which contains a berry extract as an active ingredient or containing a berry extract as an active ingredient. The composition is an oral food / drink composition, a pharmaceutical composition, a quasi drug composition, a cosmetic composition, an animal feed composition, and the like.

The composition for improving urination disorder may be orally or parenterally administered as described above, but in view of daily intake, The composition for oral use is preferable, and the composition for food and drink or the composition for oral medicine is more preferable.

One specific aspect of the composition for food and drink is, for example, a functional food and drink which is a food and drink having certain functionality to a living body. Functional food and drink include, for example, food and drink for specified health, functional indication food and drink, nutrition function food and drink, health function food and drink, special purpose food and drink, nutrition supplement food and drink, health support food and drink, supplement, beauty food, etc. In addition to the so-called health food and drink, the food and drink for specific persons such as food and drink for infants, food and drink for pregnant women, food and drink for elderly people, and the like are included. Furthermore, functional food and drink include health food and drink to which health claim (Health claim) based on the food standards of Codex (FAO / WHO Joint Food Standards Committee) is applied.

The oral pharmaceutical composition may take any oral pharmaceutical form as long as it can at least ameliorate urination disorder after application. In addition, the composition for oral pharmaceutical use may contain a physiologically active substance having an action to improve urination disorder other than the extract only, as long as the object of the present invention can be achieved. In combination with other agents containing as an active ingredient a physiologically active substance having the Such agents include anticholinergics, α1 inhibitors, adrenoceptor agonists (mirabegron, TAK259 etc.) which have been used as conventional vomiting disorder symptomatic treatments, pentosan polysulfate, sodium hyaluronate hydrochloride, flavoxate, sernitine porene Although an extract, a beta 3 receptor stimulant, etc. are mentioned, it is not limited to these.

The intake amount of the composition for improving urination disorder is not particularly limited, and may be appropriately set according to the degree of the urination improvement effect required for the individual used, the intake mode, etc. For example, as a single dose orally ingested And based on the weight of the individual used, it is 0.0001 to 1,000 mg / kg, preferably 0.001 to 600 mg / kg, and more preferably 0.1 to 60 mg / kg, per day as an extract of Gishigishi It is. For example, when the nepozin content of the anchovy extract is 10 to 30 wt%, 0.001 to 600 mg / kg of the anchovy extract corresponds to a nepogin dose of 0.0001 to 180 mg / kg, and the anchovy extract 0.1 ~ 60 mg / kg corresponds to a dose of 0.01 to 18 mg / kg of nepogin.

The frequency of intake of the composition for improving urination disorder is not particularly limited, but is, for example, 1 to 3 times a day, and can be increased or decreased appropriately according to the degree of urination disorder and the intake amount of the used individual. The intake period of the composition for improving urination disorder is continuously for a fixed period, that is, 3 days or more, preferably 1 week or more, more preferably 2 weeks or more, still more preferably 1 month or more, for example 6 months or 1 year or more It is preferred to administer. Although administration of the composition for improving urination disorder is preferably performed daily, it may not be administered daily as long as it is continuously administered for a period.

The daily intake of the composition according to one aspect of the present invention is not particularly limited, and is, for example, 0.1 to 60,000 mg, preferably 10 to 6,000 mg, based on the total amount of the sage extract.

The form of the composition for ameliorating urination disorder for oral use is not particularly limited, and can be any form. The composition for ameliorating urination disorder for oral use may take the form of, for example, tablets, powders, granules, powders, capsules, pills, troches, solutions and the like. Here, tablets include sugar-coated tablets, coated tablets, and buccal agents, and capsules include both hard capsules and soft capsules. Granules also include coated granules. In addition, solutions include suspensions, emulsions, syrups, elixirs and the like, and syrups also include dry syrup.

When it is set as a composition for food and drink, for example, a berry extract or a composition for improving urination disorder, bread, cookies, biscuits, barley for rice addition, cereals, udon, soba, pasta and other noodles, cheese, yogurt and the like Dairy products, jams, mayonnaise, miso, soy sauce and other soy products, tea, coffee, cocoa, soft drinks, fruit drinks and other non-alcoholic beverages, medicinal liquor, other alcoholic beverages, candies, chocolate and other snacks, It can be added to chewing gum, rice crackers, gluten, and other confections using soybeans as a raw material in the form of a general food and drink.

The composition for improving urination disorder may at least contain a berry extract, but it may be a combination of a berry extract and other components. The other components are not particularly limited, but, for example, additives for food and drink or oral medicine can be used as other components. For example, various excipients, binders, lubricants, stabilizers, diluents, extenders, emulsifiers, colorants, perfumes, perfume oils, thickeners, brighteners and the like can be used as other components. The content of the other components can be appropriately selected according to the form of the composition of one embodiment of the present invention, and the like, as long as the solution to the problems of the present invention is not hindered.

As an excipient, for example, lactose, glucose, sucrose, mannitol, potato starch, dextrin, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, gentian powder and the like can be mentioned. As the binder, for example, starch, gum tragacanth, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like can be mentioned. Examples of disintegrants include starch, agar, gelatin powder, sodium carboxymethylcellulose, calcium carboxymethylcellulose, microcrystalline cellulose, calcium carbonate, methylcellulose, ethylcellulose, carboxymethylcellulose and the like. As the lubricant, for example, talc, magnesium stearate and the like can be mentioned. As a coloring agent, what is permitted to be added to food-drinks, a pharmaceutical for oral use, etc. can be used, It does not specifically limit.

In the case of tablets and granules, if desired, sucrose, gelatin, refined shellac, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methyl methacrylate, It may be coated with a methacrylic acid polymer or the like, or may be coated with a plurality of layers. Furthermore, granules and powders can be packed in capsules such as ethyl cellulose and gelatin to make capsules.

The method of using the composition for ameliorating urination disorder for oral use is not particularly limited. For example, the composition for ameliorating urination disorder may be taken orally by eating or drinking as it is, diluted with water or the like or diluted with water or the like. be able to. The composition for improving urination disorder and another solid or liquid may be mixed and taken orally, depending on the preference of the individual used. When the composition for improving urination disorder is an orally disintegrating dosage form, it can be taken orally without water.

The composition for ameliorating urination for parenteral use can be produced by adding a pH adjuster, a buffer, a stabilizer, a solubilizer, and the like. The composition for ameliorating urination disorder for parenteral use can be used, for example, in a form suitable for a pharmaceutical composition for parenteral use and a cosmetic composition, that is, as a pharmaceutical composition for parenteral use and a cosmetic composition. For example, a composition for improvement of dysuria for parenteral use may be used as it is or mixed with additives usually used for processing of pharmaceutical compositions for parenteral use and cosmetic compositions, lotions, emulsions, gels, It can be processed into various forms such as creams and ointments.

The parenteral pharmaceutical composition can be present in the form of a pharmaceutically acceptable salt form, wherein the extract of the abalone extract is dissolved in a water-soluble solvent. Such pharmaceutically acceptable salt forms include those that are buffered at physiological pH in the form of physiologically acceptable water-soluble salts, such as sodium, potassium, magnesium, calcium and the like salts. Be In addition to water-soluble solvents, non-water-soluble solvents can be used, and examples of such non-water-soluble solvents include alcohols, ethanol, propylene glycol and the like.

Pharmaceutical compositions for parenteral use may contain preservatives, buffers, and the like as other components other than the extract of shiitake mushroom. As preservatives, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methyl paraben, polyvinyl alcohol, phenylethyl alcohol, ammonia, dithiothreitol, Beta mercaptoethanol etc. are mentioned. In addition, as the buffer, sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate and the like can be mentioned. The dosage form of the pharmaceutical composition for parenteral use is not particularly limited, and examples thereof include injections (muscle, subcutaneous and intradermal), oral preparations, nasal preparations and the like.

The composition for improving urination disorder can be packed in a container to make a container-packed composition sealed. The container is not particularly limited. For example, metal such as aluminum, paper, plastic such as PET or PTP, single layer or laminated film bag, retort pouch, vacuum pack, aluminum container, plastic container, bottle, can, etc. Packaging containers. In order to avoid deterioration over time, the composition for improving urination disorder is preferably packed and sealed in a container and then sterilized by pressurization and / or heating or the like.

[Method to improve urination disorder]
The method of one aspect of the present invention is a method of ameliorating urination disorder, comprising the step of ameliorating the urination disorder of the individual by administering the composition of one aspect of the present invention to the individual. The above items can be appropriately referred to for the administration method and the confirmation method for the improvement effect of the urination disorder of an individual. In addition, in the method according to one aspect of the present invention, various steps and operations can be added before, during, or after the above steps as long as the problems of the present invention can be solved.

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples, and the present invention can take various aspects as long as the problems of the present invention can be solved. .

[Example 1. Method of measuring the components of the extract of moth extract]
The extractables content (mg) of the berry extract was measured using a COSMOSIL 5C18-AR-2 column as a column and MeOH: H ₂ O = 70: 30 0.1% TFA as a mobile phase at a flow rate of 1 ml / min, The measurement wavelength was set to 225.0 nm, and it was measured by the calibration curve method as a peak having a retention time of about 11 to 12 minutes.

[Example 2. Method of producing an extract of moth extract]
500 g of Gishigishi root was cut with a garden shredder ("GS-2010", RYOBI), followed by hot-air drying at 40 ° C for 24 hours to obtain 100 g of dried Gishigiri root. Subsequently, the dried anchovy root was added in 1 L of ethanol, and it left still at room temperature for 8 hours, and the anchovy root crude extract was obtained. The obtained fresh root extract of spinach was suction filtered using a diaphragm pump and a filtration bottle to obtain a rough root extract of spinach.

Water (500 mL) was added to the rough root extract of moth root, and the solution was concentrated under reduced pressure to about 300 mL, whereby a solid content was precipitated. The precipitated solid content was separated and collected by centrifugation (7,500 rpm, 10 minutes).

The resulting solid was added to 100 ml of a 0.1% (w / v) aqueous sodium hydrogen carbonate solution and stirred to obtain a suspension. The resulting suspension was separated by centrifugation (7,500 rpm, 10 minutes) to obtain a supernatant and a precipitate. The resulting precipitate is added to 200 ml of a 0.1% (w / v) aqueous solution of sodium hydroxide, stirred, and then separated by centrifugation (7,500 rpm, 10 minutes) to obtain a supernatant and a precipitate. I got An appropriate amount of acetic acid was added to the obtained supernatant liquid for neutralization to precipitate a solid content, and then separated by centrifugation (7,500 rpm, 10 minutes) to obtain a supernatant liquid and a precipitate. The resulting precipitate was dried, and the amount of dried precipitate was 52 mg. Moreover, when the active ingredient of the dry matter of the precipitate was identified using the above-mentioned measuring method, the concentration of nepogin was 39.6 wt%.

In addition, analogues of nepogin (8%; nakahalene) and anthraquinones (5%; emodin, chrysophanol, physcion) were included. Thus, it was possible to obtain a berry root extract containing 39.6 wt% of nepogin as the final product.

As described above, the extract of ethanol crude root extract extracted with ethanol is further treated with water, weak alkali, strong alkali and acid to obtain an extract of root extract containing nepogin etc. at high concentration. I got Thus, the extract of the present invention was obtained.

[Example 3. An action to improve urination disorder by a berry extract (1)]
1. Preparation of pelvic congestion and urination disorder rat model Sixteen Sprague-Dawley (SD) female rats (about 200 g) are undercut in the middle of the lower abdomen under 2% isoflurane inhalation anesthesia, and ligatures of both common iliac vein and uterine vein to pelvis He was congested and closed, and he was treated as a pelvic congestion group (disability treatment). In addition, eight SD female rats (about 200 g) which were subjected to only an operation of removing both common iliac veins and uterine veins from surrounding tissues were used as a control group (sham treatment). It was used for the following experiment 3 weeks after the operation.

2. Intravenous administration experiment of gishigishi In 8 animals of pelvic congestion group and 8 animals of control group, insert a catheter for measuring intravesical pressure about 1 mm in diameter transurethrally into the bladder under 2% isoflurane inhalation anesthesia and insert a 3-way stopcock It was used as a saline injection passage into the bladder and an internal pressure measurement passage. A venous indwelling needle was inserted into the femoral vein on one side, and it was used for administration of the extract of moth. With continuous isoflurane inhalation anesthesia stopped, continuous intravesical pressure measurement was performed while instilling saline (3 ml / h) into the bladder under urethane (0.6 mg / kg) light anesthesia restraint, and where bladder contraction appeared at regular intervals , 39.6 wt% nepogin content of the sage extract (0.1, 0.3, 1, 3 mg / kg) prepared in Example 2 as groups 2-5, and pelvic congestion group at intervals of 15-25 minutes The mice were intravenously administered to the control group and the control group, respectively, and the effect on bladder activity was examined in comparison with that before the administration of the extract (group 1). Continuous bladder pressure measurement refers to a test that measures the pressure in the bladder while injecting a certain amount of physiological saline from the urethra to confirm bladder function. Here, bladder contraction interval (minutes), baseline Pressure (cm H ₂ O), maximum bladder contraction pressure (cm H ₂ O) were examined.

The results are expressed as mean ± standard error, and p <0.05 was made significant as compared with each control group of Groups 1 to 5 using paired t-test or non-paired test. The results are shown in Tables 1 to 3 below and in FIG.

3. As a result of the intravenous administration of the berry extract in the first group before administration of the berry extract, the pelvic congestion group had a significantly shorter bladder contraction interval (voiding interval) and a frequent urination than the control group (Table 1, Figure 1, before administration). In the pelvic congestion group, when 0.3 to 3 mg / kg ivy extract is intravenously administered, the bladder contraction interval is extended in a concentration dependent manner, and for the 4 th group extract 1 mg / kg, the bladder contraction interval is It was prolonged to approximately twice compared to the pelvic congestion group in the first group before administration (Table 1, FIG. 1). In addition, when 3 mg / kg of the extract of snail extract of Group 5 is intravenously administered, the frequency of contraction intervals in the pelvic congestion group is smaller than that in the control group, even if the pelvic congestion group has a frequent urination level Was improved to near normal levels (Table 1, Figure 1).

It should be noted that intravenous administration of the extract of Aspergillus had no effect on the baseline pressure or maximal contraction pressure of the bladder in any of the control group and the pelvic congestion group (Table 2, Table 3). Here, since the baseline pressure of the bladder (pressure when accumulating urine) (Table 2) and the maximum contraction pressure (pressure when urine was exhausted) (Table 3) had no effect, It was found that the effect was not due to other physical pressure or other factors, but due to the action of the extract extract.

[Example 4. An action to improve urination disorder by the extract of moth extract (2)]
The following tests were conducted on subjects in order to prove that the extract of Muskworm has an effect of improving symptoms and phenomena due to dysuria.

1. Test substance 30 mg (low dose group) and 60 mg (high dose group) of the anchovy extract (powder containing 39.6 wt% nepogin) obtained in Example 2 above, and dextrin as a pharmaceutically acceptable excipient thereto In addition, hard capsules were prepared (hereinafter referred to as "Gishigishi extract tablets").

2. The subjects were obese adult male and female volunteers who were over 40 years old with metabolic syndrome, locomotive syndrome, or their risk, and 60 males and females over 20 years old with a waist width of 85 cm or more and women 90 cm or more.

3. Test method The above subjects receive dextrin alone without administration of the extract extract tablet and receive the extract without extract intake group (n = 20), and the extract extract powder of the extract extract tablet 30 mg / person / day. The low dose group (n = 20), and the berry extract powder was divided into three groups, a high dose group (n = 20) which was administered 60 mg / person of the berry extract tablets per day. In addition, a drug containing a capsule containing only dextrin without the berry extract powder was orally administered to the group without the berry extract intake under the same conditions as described above. The same diet was given to both groups.

The administration was once a day in the morning, and was administered daily (orally). At the start of administration, the first three weeks and the second six weeks later, the frequency of nocturia was checked by a questionnaire, and hematological examination and blood biochemistry examination were performed.

4. Test results There are no differences in glycoalbumin concentration, TG value and blood sugar level as hematological examination and blood biochemistry examination in any group, and blood glucose level by administration of berry extract and neutral fat concentration in serum Was shown to have no effect (not shown). The frequency of nighttime urination is shown in Table 4 and FIG. 2 below. In the high dose group, 1.1 ± 0.7 times at the start is 0.7 ± 0.9 three weeks after the start of administration (first time) and 0.7 ± at six weeks (second time) It was suppressed significantly with 0.7 times. In Table 4 and FIG. 2, the results are expressed as mean ± standard deviation, and significant difference from the start of administration of each group *: p <0.05.

From the above results, it has been shown that the extract of Gishigishi extract does not affect its blood glucose level or neutral fat, and has the effect of improving dysuria of metabolic syndrome and locomotive syndrome.

From the results shown in the above examples, it has been shown that the composition containing Nepogin etc.-containing moth extract has the effect of treating urination disorder, since it suppresses the number of urination at night.

The composition according to one aspect of the present invention is a useful extract of moth extract, which is capable of improving dysuria on a used individual.

Claims (7)

A composition for ameliorating urination disorder, which comprises an extract of moth extract as an active ingredient. The composition according to claim 1, wherein the anchovy extract comprises nepogin, nepogin analogues and / or anthraquinones as an active ingredient. The above urination disorder is at least one type of urination disorder selected from the group consisting of frequent urination, nocturia, urinary incontinence, residual urine feeling, decreased urination, reduced bladder contraction, bladder outlet obstruction and urethral closure pressure reduction The composition according to claim 1 or 2, which is The composition according to any one of claims 1 to 3, wherein the composition is a composition for ameliorating urination disorder for oral use. The composition according to any one of claims 1 to 4, wherein the composition is a food or drink composition or a pharmaceutical composition. The composition according to any one of claims 1 to 5, wherein the composition is a composition administered at 0.001 to 600 mg / kg per day as a berry extract. A method for ameliorating urination disorder, comprising the step of ameliorating urination disorder in the individual by administering the composition according to any one of claims 1 to 6 to the individual.

Images