JP7713295B2 - 5α-reductase inhibitors and prostatic hyperplasia inhibitors - Google Patents

Description

The present invention relates to a 5α-reductase inhibitor and a prostate hyperplasia suppressant.

It is known that dihydrotestosterone (DHT) is involved in prostatic hyperplasia. It is believed that testosterone is reduced to dihydrotestosterone (DHT) by 5α-reductase (3-oxo-5α-steroid-4-dehydrogenase), and that the action of the reduced dihydrotestosterone causes prostatic hyperplasia. For this reason, it is known that inhibiting the reduction of testosterone to dihydrotestosterone, i.e. inhibiting 5α-reductase, is effective in treating prostatic hyperplasia.

On the other hand, it has been reported that extracts from plants belonging to the Trachyspermum genus have excellent Maillard reaction inhibitory effects (Patent Document 1).

It has also been reported that compounds isolated from hot water extracts of either or both of the pericarp and fruit of plants belonging to the family Trachycarpa, and having molecular weights in the ranges of 70 to 130 and 290 to 380 as measured by gel filtration chromatography, have a high ability to inhibit the formation of advanced glycation end products (Patent Document 2).

Furthermore, it has been reported that one or more compounds contained in either or both of the pericarp and fruit of plants belonging to the family Trachycarpa have the activity of improving infertility (Patent Document 3).

It has also been reported that one or more compounds contained in either or both of the pericarp and fruit of plants belonging to the family Trachycarpa have high adiponectin secretion promoting activity and adipose precursor cell differentiation promoting activity (Patent Document 4).

It has been reported that one or more compounds contained in either or both of the pericarp and fruit of plants belonging to the family Trachycarpa have high amyloid β aggregation inhibitory activity and BACE1 inhibitory activity, and can be used as a component of an anti-Alzheimer's composition (Patent Document 5).

JP 2014-94964 A JP 2015-209420 A JP 2016-145182 A JP 2019-52122 A JP 2020-83815 A

As described above, it is known that extracts of plants belonging to the Trachyspermum genus have various effects, but it is not known that extracts of plants belonging to the Trachyspermum genus have 5α-reductase inhibitory effects or prostate hyperplasia suppressive effects.

The present invention aims to provide a 5α-reductase inhibitor that exhibits excellent 5α-reductase inhibitory activity, and a prostate hyperplasia inhibitor that exhibits excellent prostate hyperplasia inhibitory activity.

As a result of intensive research conducted by the inventors to achieve the above-mentioned object, they discovered that a hot water extract of Trapa bisporus peel exhibits a significantly excellent 5α-reductase inhibitory effect. They also discovered that a hot water extract of Trapa bisporus peel exhibits a significantly excellent prostate hyperplasia inhibitory effect.

The present invention was completed based on these findings and through further investigation, and provides the following 5α-reductase inhibitor and prostate hyperplasia suppressant.

Item 1. A 5α-reductase inhibitor containing an extract of a plant belonging to the genus Trapa.
Item 2. The 5α-reductase inhibitor according to Item 1, which contains an extract from the pericarp of a plant belonging to the genus Trapa.
Item 3. The 5α-reductase inhibitor according to Item 1 or 2, wherein the plant belonging to the genus Trapa is Trapa.
Item 4. A 5α-reductase inhibitor comprising one or more compounds contained in the pericarp and/or fruit of a plant belonging to the family Trachycarpa.
Item 5. A prostate hyperplasia inhibitor containing an extract of a plant belonging to the genus Trapa.
Item 6. The prostatic hyperplasia inhibitor according to Item 5, which contains an extract of the pericarp of a plant belonging to the genus Trapa.
Item 7. The prostatic hyperplasia inhibitor according to Item 5 or 6, wherein the plant belonging to the genus Trapa is Trapa.
Item 8. A prostatic hyperplasia inhibitor comprising one or more compounds contained in the pericarp and/or fruit of a plant belonging to the family Trachycarpa.

Extracts of plants belonging to the Trachyspermum genus have a significantly superior 5α-reductase inhibitory effect, and are therefore useful as an active ingredient in 5α-reductase inhibitors. Furthermore, extracts of plants belonging to the Trachyspermum genus have a significantly superior prostate hyperplasia inhibitory effect, and are therefore useful as an active ingredient in prostate hyperplasia inhibitors.

In addition, extracts from plants belonging to the Trachyspermum genus are highly safe because they are naturally derived ingredients.

1 is a graph showing the results of the 5α-reductase inhibition test in Test Example 1. FIG. 1 is a diagram showing the schedule of Test Example 2. 1 is a graph showing the results of the prostate hyperplasia inhibition test in Test Example 2. Left: seminal vesicle weight (g), center: prostate width (mm), right: prostate length (mm). Data are mean values ± standard error values. One-way ANOVA,^*: P<0.05,^***: P<0.005 vs TP

The following describes in detail the embodiments of the present invention.

In this specification, "contain" includes the meanings "essentially consist of" and "consist of only."

The 5α-reductase inhibitor and prostate hyperplasia suppressant of the present invention are characterized by containing an extract of a plant belonging to the Trapa genus.

Extracts of Plants Belonging to the Genus Trapa Plants belonging to the genus Trapa are not particularly limited, and examples thereof include Trapa japonica, Trapa natans L. ver. Japonica, Trapa incisa, Trapa bispinosa Roxb., Trapa acornis, Trapa natans, etc. Among them, Trapa bispinosa is preferred.

A part or the whole of a plant belonging to the genus Trapa can be used to produce an extract of a plant belonging to the genus Trapa. Examples of parts of a plant include flowers, inflorescences, pericarp, fruit, flesh, stems, leaves, branches, foliage, trunks, bark, rhizomes, root bark, roots, seeds, galls, heartwood, above-ground parts, and underground parts, and these can be used alone or in combination of multiple parts. The parts of a plant used to produce an extract are preferably fruits and pericarp, and particularly preferably pericarp. In addition, any state of the plant, such as raw, dried, cut, or crushed, can be used to produce an extract.

The method for producing an extract of a plant belonging to the genus Trachyspermum is not particularly limited, and can be carried out by a commonly used method. For example, each part of a plant belonging to the genus Trachyspermum is cut into pieces of appropriate size or as is, and then squeezed or extracted with a solvent. Hot water extraction is particularly preferred as an extraction method. As such an extraction solvent, water, an organic solvent, or a water-containing organic solvent can be used. Examples of the organic solvent include lower alcohols having 1 to 5 carbon atoms such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, and 3-pentanol, ethers such as diethyl ether, esters such as methyl acetate and ethyl acetate, ketones such as acetone, and organic acids such as acetic acid, glacial acetic acid, and propionic acid. The extraction solvent is preferably water, methanol, ethanol, or an aqueous solvent obtained by mixing any two or more of these in any ratio, and the particularly preferred extraction solvent is water, or an aqueous solvent obtained by mixing ethanol, an organic solvent approved as a food additive, and water in any ratio.

The temperature of the extraction solvent can be any temperature above room temperature and below the boiling point of the extraction solvent, and is desirably determined taking into consideration the extraction efficiency, heat resistance, volatility, etc. of the substance to be extracted. If necessary, a heated extraction solvent can be used to improve the extraction efficiency. The extraction time can be within the range of 1 hour to 15 days. When water or an aqueous solvent is used as the extraction solvent, an acid, a base, a salt, etc. can be appropriately contained as necessary to improve the extraction efficiency. There are no particular limitations on the pH of the water used for extraction, and it is preferably near neutral in consideration of use in living organisms, more preferably pH 4 to 9, and even more preferably pH 6 to 8.

Hot water extraction can be carried out by any known method, for example, a method in which a plant belonging to the genus Trapa is mixed in an extraction solvent for a predetermined time and then separated from the solid matter by filtration, centrifugation, decantation, etc., or a continuous extraction method such as the Soxhlet extraction method can be used.

When removing insoluble matter by filtration, adsorbents and filter aids such as activated carbon, bentonite, celite, etc. can be added to remove impurities as necessary. In particular, when using the extract in the form of a liquid, it is preferable to also perform sterilization filtration using a membrane filter, etc.

Solvent extracts of plants belonging to the genus Trapa can be used as is, or, if necessary, can be purified by ultrafiltration, molecular sieve chromatography (gel filtration), adsorption chromatography, ion exchange chromatography, affinity chromatography, high performance liquid chromatography (HPLC), dialysis, or a combination of these.

Solvent extracts of plants belonging to the genus Trapa include the recovered extract (including those further purified as necessary), concentrates obtained by concentrating the extract, and solids obtained by removing the solvent from the extract by freeze-drying, spray-drying, etc. Here, the concentration, freeze-drying, and spray-drying of the extract can be carried out according to conventional methods.

5α-reductase inhibitor and prostate hyperplasia inhibitor The proportion of the extract of a plant belonging to the genus Trachysus contained in the 5α-reductase inhibitor and prostate hyperplasia inhibitor of the present invention is not particularly limited, and can be, for example, a concentration of 0.01 to 99% by mass.

5α-reductase inhibitors are substances that inhibit the enzyme activity of 5α-reductase (EC 1.3.1.22) (the conversion of testosterone to dihydrotestosterone).

The 5α-reductase inhibitor and prostate hyperplasia suppressant of the present invention may be appropriately blended with known ingredients other than the extract of a plant belonging to the genus Trapa, as long as the effects of the present invention are not impaired.

The 5α-reductase inhibitor and prostate hyperplasia suppressant of the present invention can be used as food and beverages (particularly food and beverages intended for health, maintaining or improving health, etc. (e.g., health foods, functional foods, nutritional supplements, supplements, foods for specified health uses, foods with nutrient functions, or foods with functional claims)), medicines (including quasi-drugs), etc. Furthermore, the 5α-reductase inhibitor and prostate hyperplasia suppressant of the present invention also include the meaning of additives that impart a 5α-reductase inhibitory effect and a prostate hyperplasia suppressing effect, respectively.

In the above-mentioned foods and beverages, extracts of plants belonging to the genus Trapa can be used as is, but if necessary, vitamins, flavonoids, minerals, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, colorants, flavorings, stabilizers, preservatives, disintegrants, lubricants, sustained-release regulators, surfactants, solubilizers, wetting agents, etc. can also be added.

Food and drink includes all foods and drinks that animals (including humans) can ingest. The types of foods and drinks are not particularly limited, and examples include dairy products; fermented foods (yogurt, cheese, etc.); beverages (soft drinks such as coffee, juice, and tea drinks, dairy drinks, lactic acid bacteria drinks, drinks containing lactic acid bacteria, yogurt drinks, carbonated drinks, sake, Western liquor, and alcohol such as fruit wine); spreads (custard cream, etc.); pastes (fruit paste, etc.); Western sweets (chocolate, donuts, pies, cream puffs, gum, candy, jelly, cookies, cakes, puddings, etc.); Japanese sweets (daifuku, mochi, manju, castella, anmitsu, yokan, etc.); frozen desserts (ice cream, popsicles, sorbet, etc.); foods (curry, beef bowl, porridge, miso soup, soup, meat sauce, pasta, pickles, jam, etc.); and seasonings (dressing, furikake, umami seasonings, soup bases, etc.).

The method for producing the food or beverage is not particularly limited, and any known method can be used as appropriate.

When using foods and beverages as supplements, the dosage unit form is not particularly limited and can be selected appropriately, and examples include tablets, capsules, granules, liquids, powders, etc.

The amount of food and beverage intake can be set appropriately depending on various conditions such as the weight, age, sex, and symptoms of the person taking the food and beverage.

The above medicines can contain only extracts of plants belonging to the genus Trachyspermum, or they can be mixed with other medicinal ingredients listed in the Japanese Pharmacopoeia, such as vitamins and herbal medicines.

When prepared as a medicine, the extract of a plant belonging to the genus Trapa can be used as it is, or can be prepared together with pharmaceutical acceptable ingredients into a pharmaceutical preparation in the form of tablets (including plain tablets, sugar-coated tablets, film-coated tablets, effervescent tablets, chewable tablets, troches, etc.), capsules, pills, powders (dispersed medicines), fine granules, granules, liquids, suspensions, emulsions, syrups, pastes, injections (including cases where the extract is mixed with distilled water or infusions such as amino acid infusions or electrolyte infusions at the time of use to prepare a liquid), etc.

In addition to extracts of plants belonging to the genus Trachyspermum, pharmaceuticals can contain, as necessary, pharma- ceutical acceptable ingredients such as excipients, binders, disintegrants, lubricants, suspending agents, thickeners, antioxidants, absorption promoters, pH regulators, colorants, preservatives, surfactants, stabilizers, sweeteners, flavorings, and fragrances.

The method of administration of the pharmaceutical is not particularly limited, and can be, for example, oral administration, intra-arterial administration, intravenous administration, buccal administration, rectal administration, enteral administration, transdermal administration, etc.

The dosage of a pharmaceutical product can be determined appropriately depending on various conditions such as the patient's weight, age, sex, symptoms, administration method, and type of dosage form.

The dosage and intake of foods, beverages, and medicines for humans is generally the amount of active ingredient contained in the formulation, and is preferably 0.1 to 2000 mg/day per adult. Of course, the dosage and intake will vary depending on various conditions, so in some cases a smaller dosage and intake than the above will be sufficient, and in other cases a dosage exceeding the above range will be necessary.

The 5α-reductase inhibitor and prostate hyperplasia suppressant of the present invention described above are applicable to mammals, including humans.

As shown in the examples below, the present inventors have found that extracts of plants belonging to the genus Trachysus exhibit excellent 5α-reductase inhibitory activity and prostate hyperplasia suppression activity. Therefore, since extracts of plants belonging to the genus Trachysus have excellent 5α-reductase inhibitory activity and prostate hyperplasia suppression activity, they can be suitably used as active ingredients of 5α-reductase inhibitors and prostate hyperplasia suppressors.

In addition, extracts from plants belonging to the Trachyspermum genus are highly safe because they are naturally derived ingredients.

The following examples are provided to further explain the present invention. However, the present invention is not limited to these examples.

<Measurement sample>
Preparation of hot water extract of water chestnut plant (hereinafter referred to as "water chestnut extract") After harvest, the fruits of Trapa bispinosa were dried and the dried skin was collected. The dried skin was powdered using a food processor and extracted with hot water (using 6 parts by weight of 90°C hot water per 1 part by weight of dried skin), and the extract was concentrated at a predetermined concentration rate so that the polyphenol content of the finally obtained water chestnut skin extract was 25% by weight or more. 33% by weight of dextrin was added to 67% by weight of the concentrated liquid, and spray-dried with a spray dryer. The powder obtained in this way (polyphenol content of 25% by weight or more) was used as water chestnut extract in the following tests.

Test Example 1
<Test Method>
10 μl of enzyme solution (rat liver extract fraction 20 μg/ml), 1 μl of measurement sample, and 80 μl of 40 mM potassium phosphate buffer (pH 6.5, containing 50 μM NADPH and 1 mM DTT) were mixed and pre-incubated at 37° C. for 15 minutes. Then, 10 μl of 0.9 μM testosterone solution was added, and the mixture was incubated at 37° C. for 30 minutes, and 20 μl of reaction stop solution (1N hydrochloric acid) was added. Then, 20 μl of neutralizing solution (1N NaOH) was added, and centrifuged for 10 minutes. The supernatant was collected, and the amount of remaining testosterone contained in the supernatant was measured using an ELISA kit, and the 5α-reductase inhibition rate was calculated.

<Results>
The results are shown in Figure 1. The water chestnut extract showed concentration-dependent 5α-reductase inhibitory activity. The _IC50 of the water chestnut extract was 32.4μg/ml, demonstrating its 5α-reductase inhibitory activity.

Test Example 2
<Test Method>
As shown in Figure 2, 7-week-old C57BL6/N mice were castrated, and after a recovery period until the wound healed, testosterone propionate was administered intraperitoneally at a concentration of 2.0 mg/kg body weight on the 6th day of the study. From the day of testosterone propionate administration, finasteride or water chestnut extract was administered by automatic drinking water (water chestnut extract was dissolved in tap water, and finasteride was suspended in 0.1% carboxymethylcellulose water). On the 16th day of the study, the mice were euthanized by cervical dislocation and tissues were removed. The weight of the seminal vesicles and the length and width of the prostate were then measured. The study was conducted in the following 4 groups (n=5).
CRL: Control group
TP: Testosterone propionate (TP) group 2.0 mg/kg ip
TP+F: TP+finasteride group 0.08% po
TP+WC: TP+water chestnut extract 2% po

<Results>
The results are shown in Figure 3. Water chestnut extract significantly reduced seminal vesicle weight and prostate size, and the effect was equal to or greater than that of finasteride, a 5α-reductase type II inhibitor. Thus, water chestnut extract showed a significant prostate hyperplasia suppression effect when administered in drinking water.

Claims (2)

A 5α-reductase inhibitor containing an extract from the pericarp of Trapa bisporus , wherein the extraction solvent for the extract is at least one selected from the group consisting of water, methanol, ethanol, 1-propanol, and 2-propanol . A prostate hyperplasia inhibitor containing an extract of the pericarp of Trapa bispinosa , wherein the extraction solvent for the extract is at least one selected from the group consisting of water, methanol, ethanol, 1-propanol, and 2-propanol .