JP2021042152A - Phosphodiesterase 5a1 activity inhibitor, muscle relaxation or contraction inhibitor, and dysuria preventive or improver - Google Patents

Abstract

To provide a phosphodiesterase 5A1 activity inhibitor, a muscle relaxation or contraction inhibitor, and a dysuria preventive or improver that effectively inhibit phosphodiesterase 5A1 activity.SOLUTION: The present disclosure provides a phosphodiesterase 5A1 activity inhibitor, a muscle relaxation or contraction inhibitor, and a dysuria preventive or improver containing at least one plant material selected from Mangifera indica, Rhodiola Rosea, Bacopa monnieri, and Hibiscus sabdariffa.SELECTED DRAWING: None

Description

The present invention relates to a composition capable of inhibiting the activity of phosphodiesterase 5A1 (PDE5A1), suppressing muscle relaxation or contraction, and preventing or ameliorating dysuria.

Phosphodiesterase 5A1 is abundant in the bladder, urethra, and prostate, and has a function of constricting blood vessels and muscles. In order to prevent the adverse effects caused by the contraction of blood vessels and muscles, for example, black ginger (Kaempferia parviflora) has been proposed as a material for inhibiting the activity of phosphodiesterase 5A1 (Patent Document 1).
However, the inhibitory effect of this black ginger on the phosphodiesterase 5A1 activity was not sufficient.

Japanese Unexamined Patent Publication No. 2013-224326

An object of the present invention is to provide a novel muscle relaxant or contraction inhibitor and a urinary disorder preventive or ameliorating agent that effectively inhibits the activity of phosphodiesterase 5A1.

While exploring the functions of various plant materials, the present inventors have an effect of effectively inhibiting the activity of phosphodiesterase 5A1, and are effective in preventing or ameliorating dysuria by suppressing muscle relaxation or contraction. It was found that the present invention was completed.

That is, the present invention is as follows.
[1] A phosphodiesterase 5A1 activity inhibitor comprising at least one plant material selected from mango, Rhodiola rosea, waterhyssop, and hibiscus.
[2] The phosphodiesterase 5A1 activity inhibitor according to [1], which is for oral use.
[3] A muscle relaxant or contraction inhibitor comprising at least one plant material selected from mango, Rhodiola rosea, waterhyssop, and hibiscus.
[4] The muscle relaxant or contraction inhibitor according to [3], which is for oral use.
[5] An agent for preventing or improving dysuria, which comprises at least one plant material selected from mango, Rhodiola rosea, waterhyssop, and hibiscus.
[6] The agent for preventing or improving dysuria according to [5], which is for oral use.

The composition of the present invention can effectively inhibit the activity of phosphodiesterase 5 to suppress muscle relaxation or contraction, and prevent or improve dysuria.

The phosphodiesterase 5A1 activity inhibitor, muscle relaxant or contractile inhibitor, dysuria preventive or ameliorating agent of the present invention contains at least one plant material selected from mango, Rhodiola rosea, waterhyssop, and hibiscus. In the phosphodiesterase 5A1 activity inhibitor and the like of the present invention, one type of plant material may be contained, two types may be contained, or three or more types may be contained. When two or more kinds are contained, it is preferable to combine those having a high single effect.

The phosphodiesterase 5A1 activity inhibitor and the like of the present invention effectively inhibit the activity of phosphodiesterase 5. Phosphodiesterase 5A1 is abundant mainly in the bladder, urethra, etc. and has a function of constricting blood vessels and muscles. Therefore, by inhibiting this phosphodiesterase 5A1 with the composition of the present invention, muscles in the bladder, urethra, etc. are relaxed. Frequent urination and urinary leakage can be improved by facilitating urination and reducing the number of urine by suppressing abnormal urinary intention. That is, it can be used for suppressing muscle relaxation or contraction, and for preventing or ameliorating dysuria.

The composition of the present invention is a phosphodiesterase 5A1 activity inhibitor, a muscle (smooth muscle) relaxation or contraction inhibitor in the bladder, a muscle relaxation or contraction inhibitor in the urethra or urinary tract, a preventive or ameliorating agent for pollakiuria, a urinary leak prevention or It can be used as an ameliorating agent, a preventive or ameliorating agent for dysuria, and a preventive or ameliorating agent for urinary urgency.

Hereinafter, each plant material contained in the phosphodiesterase 5A1 activity inhibitor of the present invention (hereinafter, may be referred to as the plant material of the present invention) will be described.
[mango]
Mango is a plant of the genus Mango of the family Rhus family, and its scientific name is Mangifera indica. In the present invention, various parts such as flowers, leaves, bark, roots and seeds can be used, but it is preferable to use leaves because the activity of phosphodiesterase 5A1 can be more effectively inhibited.

In the present invention, the harvested mango can be processed and used, and examples of the processed mango product include chips, crushed products, squeezed products, extracts, and dry powders thereof. The mango used in the present invention is a pulverized product because it is easy to apply in consideration of the medicinal properties when used as a tablet, a capsule, a round, or a chewable tablet, which are preferred forms of use of the present invention described later. , A squeezed product, an extract or a dry powder thereof, and more preferably an extract or a dry powder thereof from the viewpoint of effect. The processed mango product may be produced by a method generally known to those skilled in the art or may be commercially available.

Examples of the mango extract include an extract obtained by extracting the components contained in mango with a solvent according to a conventional method, a diluted solution or a concentrated solution thereof, or a dried product thereof or a powder thereof. ..

Examples of the solvent used for extraction include water; lower alcohols such as methanol, ethanol, isopropanol and butanol; lower esters such as ethyl acetate and methyl acetate; acetone; and a mixed solvent of these and water. In the present invention, a mixed solvent of an organic solvent and water can be used, and as the mixed solvent, for example, a mixed solvent of methanol, ethanol, isopropanol, butanol, ethyl acetate, methyl acetate, acetone and water is used. Acetone / water (2/8 to 8/2, volume ratio) mixture, ethanol / water (2/9 to 9/2, volume ratio) mixture and the like can be mentioned. The temperature of the extraction solvent can be appropriately set from room temperature to below the boiling point depending on the solvent used.

[Rhodiola rosea]
Rhodiola rosea is a plant belonging to the genus Rhodiola in the family Rhodiola rosea, and its scientific name is Rhodiola Rosea. In the present invention, various parts such as flowers, leaves, bark, roots and seeds can be used, but it is preferable to use roots because the activity of phosphodiesterase 5A1 can be more effectively inhibited.

In the present invention, the harvested Rhodiola rosea can be processed and used, and examples of the processed Rhodiola rosea include chips, crushed products, squeezed products, extracts, and dry powders thereof. The Rhodiola rosea used in the present invention is a pulverized product because it is easy to apply in consideration of the medicinal properties when used as a tablet, a capsule, a round, or a chewable tablet, which are preferred forms of use of the present invention, which will be described later. , A squeezed product, an extract or a dry powder thereof, and more preferably an extract or a dry powder thereof from the viewpoint of effect. The Rhodiola rosea processed product may be produced by a method generally known to those skilled in the art, or may be commercially available. The extraction method and the like are the same as those for mango.

[Waterhyssop]
Waterhyssop is a plant of the genus Waterhyssop in the family Plantain, and its scientific name is Bacopa monnieri. In the present invention, various parts such as flowers, leaves, bark, roots and seeds can be used, but it is preferable to use leaves because the activity of phosphodiesterase 5A1 can be more effectively inhibited.

In the present invention, the harvested waterhyssop can be processed and used, and examples of the processed waterhyssop product include chips, crushed products, squeezed products, extracts, and dry powders thereof. The waterhyssop used in the present invention is a pulverized product because it is easy to apply in consideration of the medicinal properties when used as a tablet, a capsule, a round, or a chewable tablet, which are preferred forms of use of the present invention, which will be described later. , A squeezed product, an extract or a dry powder thereof, and more preferably an extract or a dry powder thereof from the viewpoint of effect. The processed waterhyssop product may be produced by a method generally known to those skilled in the art or may be commercially available. The extraction method and the like are the same as those for mango.

[hibiscus]
Hibiscus is a plant belonging to the genus Confederate rose in the Malvaceae family, and its scientific name is Hibiscus sabdarifa, also called roselle. In the present invention, various parts such as flowers, leaves, bark, roots and seeds can be used, but it is preferable to use flowers because the activity of phosphodiesterase 5A1 can be more effectively inhibited. The flowers may include calyxes and the like in addition to petals.

In the present invention, the harvested hibiscus can be processed and used, and examples of the processed hibiscus product include chips, crushed products, squeezed products, extracts, and dry powders thereof. The hibiscus used in the present invention is a pulverized product because it is easy to apply in consideration of the medicinal properties when used as a tablet, a capsule, a round, or a chewable tablet, which are preferred forms of use of the present invention, which will be described later. , A squeezed product, an extract or a dry powder thereof, and more preferably an extract or a dry powder thereof from the viewpoint of effect. The hibiscus processed product may be produced by a method generally known to those skilled in the art or may be commercially available. The extraction method and the like are the same as those for mango.

The phosphodiesterase 5A1 activity inhibitor, muscle relaxation or contraction inhibitor, urinary disorder preventive or ameliorating agent of the present invention are, for example, pharmaceutical products (including non-pharmaceutical products), foods for specified health use, foods with nutritional function, foods with functional claims. It can be used as a so-called health food such as a functional food whose efficacy has been approved by a predetermined organization such as.

The phosphodiesterase 5A1 activity inhibitor, muscle relaxant or contractile inhibitor, dysuria preventive or ameliorating agent of the present invention contains the plant material of the present invention and contains phosphodiesterase 5A1 activity inhibitor, muscle relaxant or contractile inhibitory, dysuria prevention or In terms of being used for improvement, the product is not particularly limited as long as it can be distinguished from other products. For example, the main body of the product according to the present invention, packaging, instructions, advertising material (advertising medium). ), Which indicates that it has a phosphodiesterase 5A1 activity inhibitory function, a muscle relaxant or contractile inhibitory function, and a function of preventing or ameliorating dysuria, is included in the scope of the present invention. The phosphodiesterase 5A1 activity inhibitor and the like of the present invention are not limited to those in which the plant material of the present invention is displayed as an active ingredient on the packaging of the product or the like. For example, the active ingredient may not be specified. Further, even general foods that are manufactured and sold by suggesting their uses are included in the scope of the present invention.

Specifically, in so-called health foods, "inhibits the activity of phosphodiesterase 5", "inhibits the activity of phosphodiesterase 5A1", "improves pollakiuria", "suppresses pollakiuria", and "improves urine leakage". "Do", "Suppress urine leakage", "Trouble with toilet", "For those who say many times at night", "For those who are uneasy at night", "For peace of mind at night", "(When traveling) It is possible to exemplify a display such as "to feel fidgety". The target for ingesting the dysuria preventive or ameliorating agent of the present invention is not particularly limited as long as it is a person who needs improvement of each of the above symptoms, but an elderly person can be preferably exemplified.

Examples of the form of the phosphodiesterase 5A1 activity inhibitor of the present invention include tablets, capsules, powders, granules, liquids, granules, rods, plates, blocks, solids, rounds, pastes, and creams. Examples include a shape, a capsule shape, a gel shape, a chewable tablet shape, and a stick shape. Among these, the tablet-shaped, capsule-shaped, powder-shaped, granular-shaped, round-shaped, and chewable tablet-shaped forms are preferable, and the tablet-shaped, capsule-shaped, round-shaped, and chewable tablet-shaped are more preferable.

When the composition of the present invention is in the form of tablets, pills, or chewable tablets, it was obtained by adding one or more of excipients, pills, and fluidizing agents to improve moldability. It is preferable because it improves the storage stability of tablets, pills or chewable tablets. In particular, storage stability can be further enhanced by using excipients and lubricants.

Excipients are added to improve the handling or molding of the composition and to make it more convenient to take. The excipient that can be used in the present invention is not particularly limited, and is, for example, starch, pregelatinized starch, partially pregelatinized starch, starch such as starch decomposition product or a derivative thereof, crystalline cellulose, sugar alcohol, lactose, beer yeast, low. Substitution degree Hydroxypropyl cellulose, hydroxypropyl cellulose, purified sucrose, light anhydrous silicic acid, calcium silicate, titanium oxide, precipitated calcium carbonate and the like can be mentioned. These may be used alone or in combination of two or more.

The lubricant is used to alleviate the friction between the tableting machine pestle and the tablet when compressing the powder for tablets, and to prevent tableting obstacles such as sticking. The lubricant that can be used in the present invention is not particularly limited as long as it is a component capable of achieving the above object. For example, stearic acid such as stearic acid, calcium stearate, magnesium stearate or a salt thereof, fumaric acid. Examples thereof include stearyl sodium, sucrose fatty acid ester, talc, polyethylene glycol, vegetable oil and fat, and hydrogenated oil. These may be used alone or in combination of two or more.

The fluidizing agent is used to improve the fluidity of mixed powders and granules. The fluidizing agent that can be used in the present invention is not particularly limited, and examples thereof include silicon dioxide, aluminum silicate, magnesium silicate aluminate, calcium phosphate, magnesium carbonate, and magnesium oxide. These may be used alone or in combination of two or more. In the present invention, commercially available products can be used as the excipient, the lubricant, and the fluidizing agent.

The content of the plant material of the present invention in the phosphodiesterase 5A1 activity inhibitor of the present invention may be appropriately contained within the range in which the effect is exhibited.

Specifically, when the phosphodiesterase 5A1 activity inhibitor of the present invention is in the form of tablets, rounds, capsules, or chewable tablets, the plant material of the present invention is converted into dry mass from the viewpoint of further enhancing its action. It is preferably contained in an amount of 5 to 100% by mass, more preferably 10 to 80% by mass, and particularly preferably 20 to 60% by mass. In the case of powder or granules, it is preferably contained in an amount of 0.1 to 100% by mass, more preferably 1 to 75% by mass in terms of dry mass, from the viewpoint of further enhancing the action. , 10 to 50% by mass is particularly preferable. In the case of a liquid, it is preferably contained in an amount of 0.01 to 100% by mass, more preferably 0.1 to 70% by mass, in terms of dry mass, from the viewpoint of further enhancing its action. It is particularly preferable that the content is ~ 40% by mass.

The intake of the phosphodiesterase 5A1 activity inhibitor of the present invention is not particularly limited, but from the viewpoint of further enhancing its action, the intake of the plant material of the present invention should be 5 mg or more per day for adults. It is more preferable to take it so as to be 10 mg or more, and it is more preferable to take it so as to be 20 mg or more. The upper limit is, for example, 2000 mg, preferably 1500 mg, and more preferably 1000 mg.

The phosphodiesterase 5A1 activity inhibitor and the like of the present invention may be appropriately designed so that the daily intake is the above-mentioned intake amount, and may be taken once or divided into a plurality of times. .. For example, in the case of tablets, capsules, pills or chewable tablets, the number of intakes should be 1 to 4 times a day, and the total amount should be the intake, and in the case of beverages, the intake should be the daily intake. It suffices if the amount is mixed. The phosphodiesterase 5A1 activity inhibitor and the like of the present invention shall be contained in one container or, for example, divided into a plurality of containers of 2 to 3 so as to have the daily intake as the above-mentioned intake. Can be done.

The phosphodiesterase 5A1 activity inhibitor and the like of the present invention can be produced by a known method by adding components other than the plant material of the present invention, if necessary. Other components include, for example, water-soluble vitamins (vitamins B1, B2, B3, B5, B6, B12, B13, B15, B17, biotin, choline, folic acid, inositol, PABA, vitamin C, vitamin P), oil-soluble. Vitamins such as vitamins (vitamins A, D, E, K); minerals such as magnesium, phosphorus, zinc, iron; sulfur-containing compounds contained in taurine, garlic, etc .; flavanoids or flavonoids such as hesperidin, quercetin; collagen Proteins such as; peptides; amino acids; animal fats and oils; vegetable fats and oils; crushed products or extracts of animals and plants.

1. 1. Sample preparation 1-1 Test substance (Example 1)
As mango, a water extract (dry powder) of mango (Mangifera Indica) leaves was used. Specifically, the crushed and ground mango leaves were extracted with water, and the obtained extract was purified, distilled, and then dried, and then dried powder was used.
(Example 2)
As Rhodiola rosea, a hydrous ethanol extract (dry powder) of the root of Rhodiola Rosea PE was used. Specifically, a powder obtained by extracting dried roots of Rhodiola rosea with hydrous ethanol (ethanol content 85%), concentrating the extract and drying it was used.
(Example 3)
As the waterhyssop, an ethanol extract (dry powder) of the leaves of the waterhyssop (Bacopa monnieri) was used. Specifically, the leaves of Waterhyssop were extracted with ethanol, and the obtained extract was concentrated and then dried to use a powder.
(Example 4)
As the hibiscus, a water extract (dry powder) of the flowers of hibiscus (Hibiscus sabdariffe L.) was used. Specifically, a powder obtained by extracting hibiscus flowers with water, concentrating the obtained extract, and then drying it was used.
(Example 5)
As the hibiscus, a hydrous ethanol (30% ethanol) extract (dry powder) of hibiscus (Hibiscus sabdariffe L.) flowers was used. Specifically, a hibiscus flower was crushed, extracted with hydrous ethanol (30% ethanol), the obtained extract was concentrated, and then dried powder was used.
(Example 6)
As the hibiscus, a hydrous ethanol (50% ethanol) extract (dry powder) of hibiscus (Hibiscus sabdariffe L.) flowers was used. Specifically, hibiscus flowers were crushed, extracted with hydrous ethanol (50% ethanol), the obtained extract was concentrated, and then dried powder was used.
(Reference example 1)
As a positive control, a hydrous ethanol extract (dry powder) of the rhizome of commercially available black ginger (Kaempferia parviflora), which is known to have an inhibitory effect on phosphodiesterase 5A1, was used.
1-2 Preparation of sample solution (1) The test substance was prepared by DMSO so as to be 100 mg / mL.
(2) Vortexed with a tube mixer for 30 minutes.
(3) Centrifugation (15,000 g × 5 minutes, room temperature) was performed, and the supernatant was collected in a new 1.5 mL tube.
(4) A sample solution was prepared by appropriately diluting with DMSO.

2. Measurement of phosphodiesterase 5A1 (PDE5A1) inhibitory activity 1. The inhibitory activity against PDE5A1 of each sample prepared in the above was measured by PDE5A1 Assay Kit (# 60350) (manufactured by BPS Bioscience). The measurement was performed according to the procedure manual of the kit.

(1) 25 μL of FAM-Cyclic-3'and 5'-GMP diluted and prepared were added to the wells other than "Blank".
(2) 45 μL of PDE buffer was added to “Blank” and 20 μL of PDE buffer was added to “Substrate control”.
(3) 5 μL of DMSO was added to “Blank”, “Substrate control”, and “Positive control”.
(4) 5 μL of the prepared sample solution was added to the “Test” well.
(5) 20 μL of diluted and prepared PDE5A1 was added to the wells of “Test” and “Positive control” (200 pg / reaction well).
(6) The reaction was carried out at 25 ° C. for 1 hour in the dark. 100 μL of the diluted binding agent was added to each well, and the reaction was carried out at 25 ° C. for 30 minutes with shaking.
_{(7) IC 50} was calculated based on the inhibitory activity of each sample obtained by measuring the fluorescence polarization degree with a plate reader (Excitation: 485 nm, Emission: 535 nm).

The results are shown in Table 1. Table 1 shows the IC50 values.

It was found that each material according to the example showed an effect at a lower concentration as compared with black ginger, which is known to have a phosphodiesterase 5A1 inhibitory effect. Therefore, the composition of the present invention can be expected to relax muscles in the bladder, urethra and the like to improve urinary disorders such as pollakiuria and urine leakage.

[Formulation Example 1]
A tablet (250 mg per tablet) consisting of the following components was produced. By ingesting 4 tablets per day, an excellent effect of preventing or improving dysuria can be obtained.

[Formulation Example 2]
A capsule consisting of the following components (300 mg of content per capsule) was produced. By ingesting 6 tablets per day, an excellent effect of preventing or improving dysuria can be obtained.

[Formulation Example 3]
Granules (3 g of contents per packet) consisting of the following components were produced. By ingesting the obtained granules by dissolving 2 packets per day in water or the like, an excellent effect of preventing or improving dysuria can be obtained.

[Formulation Example 4]
A liquid preparation (50 ml of contents per bottle) composed of the following components was produced. By ingesting one of the obtained liquid preparations per day, an excellent effect of preventing or improving dysuria can be obtained.

Since the phosphodiesterase 5A1 activity inhibitor, muscle relaxant or contractile inhibitor, dysuria preventive or ameliorating agent of the present invention can be used as health foods and the like, they are highly industrially useful.

Claims (3)

A phosphodiesterase 5A1 activity inhibitor characterized by containing at least one plant material selected from mango, Rhodiola rosea, waterhyssop, and hibiscus. A muscle relaxant or contractile inhibitor characterized by containing at least one plant material selected from mango, Rhodiola rosea, waterhyssop, and hibiscus. A dysuria preventive or ameliorating agent comprising at least one plant material selected from mango, Rhodiola rosea, waterhyssop, and hibiscus.