JP4585201B2 - Androgen receptor binding inhibitor, hair nourishing agent, sebum secretion inhibitor and prostate hypertrophy inhibitor - Google Patents

Description

  The present invention relates to an androgen receptor binding inhibitor capable of inhibiting the expression of testosterone activity through an androgen receptor binding inhibitory action, and a hair nourishing agent, a sebum secretion inhibitor and a prostatic hypertrophy inhibitor containing the androgen receptor binding inhibitor. About.

  Many steroid hormones are expressed in the form of molecules secreted from the production organ and bind to receptors to express their action. In the case of male hormones collectively called androgens, for example, testosterone enters the cells of the target organ and enters testosterone 5α. -It is reduced to 5α-dihydrotestosterone (hereinafter referred to as “5α-DHT”) by reductase, and then binds to a receptor to express an action as an androgen.

  The above androgen is an important hormone, but its excessive action induces various unfavorable symptoms such as male pattern baldness, hirsutism, seborrhea, acne, benign prostatic hyperplasia, prostate tumor, premature boyhood To do.

  Therefore, a technique for improving these undesirable symptoms by suppressing the action of excess androgen has been studied. Specifically, a method that does not express androgenic activity by inhibiting binding of 5α-DHT generated from testosterone to a receptor has been proposed.

For this purpose, various proposals have been made for androgen receptor binding inhibitors. For example, an extract of the leaves of the genus Ranunculaceae (see Patent Document 1), an extract from the leaves of a pentagon (see Patent Document 2), an extract of Majito and / or cuta (see Patent Document 3) ), Extracts from branches and leaves of Fuji tea (see Patent Document 4), and the like.
JP 2001-226278 A JP 2002-241296 A JP 2002-241297 A JP 2002-308790 A

  However, a specific compound that inhibits androgen receptor binding in the above extract has not yet been identified, and a natural androgen receptor binding inhibitor having further androgen receptor binding inhibitory effect is strongly desired. However, there is an extremely strong demand for androgen receptor binding inhibitors that have high androgen receptor binding inhibitory activity while being excellent in safety and productivity, and are inexpensive, and those that are still satisfactory can be provided. The current situation is not.

  Therefore, the present invention provides a novel androgen receptor binding inhibitor containing an androgen receptor binding inhibitor as an active ingredient, and a hair nourishing agent, sebum secretion inhibitor and prostate hypertrophy inhibitor containing the androgen receptor binding inhibitor. The purpose is to do.

  In order to solve the above-mentioned problems, the present inventors have conducted extensive research on many safe plants that have an androgen receptor binding inhibitory effect, and as a result, extracts from specific citrus fruits, Nobiletin contained therein has a high androgen receptor binding inhibitory action, and by using them as active ingredients, male and male dependent baldness, hirsutism, seborrhea, acne, The present inventors have found that androgen receptor binding inhibitors, hair nourishing agents, sebum secretion inhibitors and prostate hypertrophy inhibitors that are effective in preventing or improving prostatic hypertrophy, prostate tumors, male premature ripening, etc. have been obtained. .

That is, the androgen receptor binding inhibitor of the present invention contains an extract from Ponkan as an active ingredient, and the sebum secretion inhibitor or prostate hypertrophy inhibitor of the present invention purifies the Ponkan extract. It is characterized by blending the obtained nobiletin purified product (hereinafter sometimes simply referred to as “nobiletin purified product”) or Ponkan extract .

The Ponkan extract, which is an active ingredient of the androgen receptor binding inhibitor of the present invention, has an androgen receptor binding inhibitory action, and is a male hormone-dependent disease such as hirsutism, seborrhea, acne, prostate It is not known at all to be effective in preventing or improving hypertrophy, prostate tumor, male premature ripening, etc., which is a new finding of the present invention.

  The androgen receptor binding inhibitor of the present invention is extremely effective in suppressing the expression of androgen action due to the androgen receptor binding inhibitory action possessed by nobiletin, a specific citrus extract or a purified nobiletin product.

  Further, the hair nourishing agent, sebum secretion inhibitor and prostate hypertrophy inhibitor of the present invention containing the androgen receptor binding inhibitor are male-type baldness, hirsutism, seborrhea, acne, It is extremely effective for the prevention or treatment of benign prostatic hyperplasia, prostate tumor, premature boyhood.

Hereinafter, the present invention will be described in detail.
[Androgen receptor binding inhibitor]
The androgen receptor binding inhibitor of the present invention includes nobiletin; an extract from Yawata, an extract from Wenzhou mandarin orange, an extract from grapefruit, an extract from Valencia orange, an extract from Seaquars, and an extract from Ponkan 1 or 2 or more citrus extracts selected from the group of products, extracts from lemons, extracts from marcots and extracts from Shiranui; or purified nobiletin obtained by purifying the citrus extracts Is contained as an active ingredient.

Here, “androgen receptor binding inhibition” means inhibition of binding between 5α-DHT and androgen receptor, and the mode of inhibition is not particularly limited. For example, competitive antagonists, non-competitors Inhibition as an antagonist such as a selective antagonist is conceivable.
The “nobiletin purified product” also includes a crude product of nobiletin.

  Nobiletin is a kind of polymethoxyflavonoid and can be produced by synthesis. However, it is preferable to use a product obtained by extraction and purification from the following citrus fruits (including a crude product). In addition, the synthesis | combining method of nobiletin is not specifically limited, A conventionally well-known method can be utilized.

  As the citrus fruits used as the raw material for nobiletin, it is preferable to use one or more of Hachiman, Wenzhou mandarin orange, grapefruit, Valencia orange, Siquarcer, Ponkan, lemon, Marcot and Shiranui. In this case, nobiletin may be obtained by mixing two or more kinds of extraction raw materials, extracting the mixed extraction raw materials by an extraction process, and purifying the extract by the extraction process. Each extract extracted from the seed extraction raw material by the extraction process may be mixed and the mixture purified.

  The specific citrus extract containing the androgen receptor binding inhibitor of the present invention as an active ingredient is obtained using the citrus as an extraction raw material, and the extraction method is not particularly limited.

  In the present specification, “citrus extract” refers to an extract obtained from citrus fruits as an extraction raw material, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, or these Either a crude product or a purified product is included.

Each citrus fruit used in the present invention will be described below.
<Yawata>
Yawata (scientific name: Citrus hassaku Hort.) Is an evergreen tree of the mandarin orange family that is cultivated in Wakayama Prefecture. The pericarp is used as an aromatic stomachic medicine for the treatment or prevention of abdominal pain, bloating, constipation and the like, and also used to calm cough or sputum.

<Wenzhou mandarin orange>
Citrus unshiu (scientific name: C.unshiu Marcov.) Is an evergreen shrub of the mandarin family that is widely cultivated in the warm and warm areas of central and southern Japan. Used for the treatment or prevention of gallstones.

<Grapefruit>
Grapefruit (scientific name: C. paradisii) is an American mandarin orange plant.

<Valencia Orange>
Valencia orange (scientific name: C. sinensis cv. Valencia) is a plant of the mandarin orange family and has the highest production in orange and is cultivated all over the world.

<Seek Arthur>
Shiku Arthur (scientific name: C.depressa Hayata) is also known as Hiramemon, a plant of the native Okinawan mandarin.

<Ponkan>
Ponkan (scientific name: C. reticulata Blanco) is an evergreen small Takagi tree in the mandarin orange family, and is cultivated in southern China, Taiwan, India, Sri Lanka, the Philippines, etc., and also in Japan in Kagoshima, Miyazaki, Kochi, etc. It is cultivated.

<Lemon>
Lemon (scientific name: C. limon (Linn.) Burm.) Is a plant belonging to the mandarin orange family and is known to have a bactericidal and disinfecting action.

<Marcot>
A marcot is a plant of the mandarin family that is a kind of a hybrid of oranges and oranges. Florida in the United States is the birthplace, and in Japan it is also cultivated in Nagasaki, Kumamoto, Saga, etc.

<Shiranui>
Shiranui is a plant of the mandarin family that is a hybrid between Kiyomi Orange and Ponkan, and is cultivated in Kumamoto, Aichi, Kagoshima, Ehime, and others. Of the Shiranui, those with a sugar content of 13 degrees or more and a sourness of 1.0% or less are called Decopon (registered trademark).

  Hereinafter, the preferable purification method of nobiletin which uses the said citrus fruits as a raw material is demonstrated.

  Examples of the citrus part that can be used as an extraction raw material include fruits, pericarps, leaves, and the like, and one or more of these can be used as the extraction raw material. It is preferable to use as. As the fruit, it is preferable to use the whole fruit including the skin. As the fruit or pericarp, any of immature fruit (plucked fruit) or pericarp and mature fruit or pericarp may be used. The extraction raw material can be subjected to pretreatment such as cutting, crushing, and drying.

  Examples of the extraction solvent include lower aliphatic alcohols having 1 to 5 carbon atoms such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, lower aliphatic ketones such as acetone and methyl ethyl ketone, 1,3-butylene glycol, propylene glycol, and glycerin. A mixed solvent of a hydrophilic organic solvent and water, such as a polyhydric alcohol having 2 to 5 carbon atoms such as, can be used, and it is particularly preferable to use an aqueous ethanol solution having an ethanol concentration of 0 to 40% by volume. In the ethanol aqueous solution, the ethanol concentration can be appropriately changed within the range of 0 to 40% by volume.

  The ethanol aqueous solution having an ethanol concentration of 0% by volume means water. The water includes pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, and the like, as well as those subjected to various treatments. Examples of the treatment applied to water include purification, heating, sterilization, sterilization, filtration, ion exchange, adjustment of osmotic pressure, buffering, and the like.

  The extraction treatment is not particularly limited as long as nobiletin contained in the citrus can be extracted, and can be performed according to a conventional method. For example, by immersing the extraction raw material in an extraction solvent 1 to 20 times the mass of the extraction raw material (mass ratio), extracting for 0.1 to 3 hours at room temperature or under reflux heating, and then filtering to remove the residue, An extract containing nobiletin can be obtained. The obtained extract may be concentrated according to a conventional method. The obtained extract may be treated with activated carbon for the purpose of decolorization and the like. The extract obtained here can be a “citrus extract” in the present invention.

  When the extraction raw material is extracted with an aqueous ethanol solution having an ethanol concentration of 0 to 40% by volume, the extraction raw material is preferably extracted with hot water before or after the treatment. Thereby, the nobiletin yield from an extraction raw material can be improved.

  The temperature of the hot water is usually 40 to 100 ° C, preferably 60 to 90 ° C. When extracting with hot water before extraction with an aqueous ethanol solution with an ethanol concentration of 0 to 40% by volume, the extraction raw material is extracted with hot water and filtered to obtain an extract containing nobiletin, then the residue Is extracted with an aqueous ethanol solution having an ethanol concentration of 0 to 40% by volume and filtered to obtain an extract containing nobiletin, and both extracts are mixed. In the case of extracting with hot water after extracting with an ethanol aqueous solution with an ethanol concentration of 0 to 40% by volume, the raw material for extraction is extracted with an aqueous ethanol solution with an ethanol concentration of 0 to 40% by volume and filtered to contain nobiletin. After obtaining the extract, the residue is extracted with hot water and filtered to obtain an extract containing nobiletin, and the two extracts are mixed.

  An extract obtained by the above method, particularly an extract obtained using an aqueous ethanol solution having an ethanol concentration of 0 to 40% by volume or a mixture of the extract and an extract obtained using hot water, It is preferable that the nobiletin adsorbed on the porous adsorption resin is eluted after passing through the porous adsorption resin to adsorb nobiletin onto the porous adsorption resin.

  The porous adsorption resin is not particularly limited as long as it can adsorb nobiletin. Examples of the porous adsorption resin include synthetic adsorption resin, activated carbon, and the like. Among these, one type or two or more types can be used, and it is preferable to use a synthetic adsorption resin.

  The extract is preferably passed through a porous adsorption resin after being concentrated. Thereby, the liquid passing time to porous adsorption resin can be shortened. Concentration can be carried out according to a conventional method such as vacuum concentration, and is usually concentrated 3 to 10 times, preferably 4 to 6 times.

  The space velocity of the extract is usually 0.1 to 4, preferably 0.8 to 1.5. In addition, the space velocity (Space Velocity; SV) = 1 sets the speed | rate which passes 1 time of resin amount per hour.

  The extraction liquid is passed through the porous adsorption resin, and the liquid flowing out of the porous adsorption resin may contain nobiletin that has not been adsorbed on the porous adsorption resin. It is preferable to collect it.

  Examples of the solvent capable of eluting nobiletin adsorbed on the porous adsorption resin include an ethanol aqueous solution, a methanol aqueous solution, and an isopropanol aqueous solution. Among these, it is preferable to use an ethanol aqueous solution. The ethanol concentration of the aqueous ethanol solution used for elution of nobiletin is usually 55 to 95% by volume, preferably 60 to 90% by volume.

  Before eluting nobiletin adsorbed on the porous adsorption resin, it is preferable to wash the porous adsorption resin and elute components other than nobiletin adsorbed on the porous adsorption resin. Examples of the cleaning liquid for the porous adsorption resin include water, an aqueous ethanol solution, an aqueous methanol solution, an aqueous isopropanol solution, and an aqueous sodium hydroxide solution. Of these, an aqueous ethanol solution is preferably used. The ethanol concentration of the aqueous ethanol solution used for washing the porous adsorption resin is usually 10 to 50% by volume, preferably 30 to 50% by volume.

  A crude nobiletin product can be obtained by drying the eluate from the porous adsorption resin according to a conventional method such as drying under reduced pressure. A nobiletin crude product can also be obtained by mixing the porous adsorbent resin washing solution with the eluate from the porous adsorbent resin and drying the mixed solution.

  The nobiletin crude product usually contains polymethoxyflavonoids other than nobiletin contained in the raw material for extraction (for example, tangeretin, pentamethoxyflavone, tetramethoxyflavone, heptamethoxyflavone, etc.).

  The extract from the citrus has an androgen receptor binding inhibitory action, and in particular, the nobiletin crude product has an extremely high androgen receptor binding inhibitory action, as it is or with other active substances and moldings. It can be formulated with auxiliary agents according to conventional methods and provided as an arbitrary dosage form such as powder, granule, tablet, etc. Used as a skin preparation, internal solution, internal solid preparation, injection, suppository, etc. can do.

  When formulating the obtained citrus extract or crudely purified nobiletin product, a pharmaceutically acceptable carrier such as dextrin or cyclodextrin may be added in order to facilitate storage and handling. it can.

  The androgen receptor binding inhibitor in the present invention may be used as an active ingredient by blending with other natural extracts having testosterone 5α-reductase inhibitory action and / or androgen receptor binding inhibitory action as necessary. it can. As an example of the blending ratio in this case, nobiletin: natural extract = 1: 0.01-1: 5 (mass ratio) can be mentioned.

  The androgen receptor binding inhibitor of the present invention can suppress the action of androgen through the androgen receptor binding inhibitory action possessed by nobiletin, a specific citrus extract or a purified nobiletin as an active ingredient. Therefore, the androgen receptor binding inhibitor of the present invention can be used for various diseases in which male hormones are involved, such as androgenetic baldness, hirsutism, seborrhea, acne, benign prostatic hyperplasia, prostate tumor, premature maleity, etc. It is useful for prevention or treatment.

  In addition to these uses, the androgen receptor binding inhibitor of the present invention can be used for all uses that are meaningful in inhibiting the binding between 5α-DHT and the androgen receptor.

[Hair nourishing agent, sebum secretion inhibitor]
The hair nourishing agent and sebum secretion inhibitor of the present invention contain the above-mentioned androgen receptor binding inhibitor (including those composed only of nobiletin, a specific citrus extract or a nobiletin purified product) as an active ingredient.

  Nobiletin, specific citrus extract or purified nobiletin has an androgen receptor binding inhibitory action, and can prevent and / or improve diseases such as male type baldness, seborrhea, Since it is excellent in usability and safety when applied, it is suitable for blending into a hair nourishing agent or sebum secretion inhibitor as a skin external preparation. In this case, nobiletin, a specific citrus extract or a purified nobiletin product may be added as it is, or an androgen receptor binding inhibitor formulated from nobiletin, a specific citrus extract or a purified nobiletin product.

  The form of the hair nourishing agent and sebum secretion inhibitor of the present invention is not particularly limited, but specific examples thereof include hair tonic, shampoo, rinse, lotion, cream, emulsion, pack, ointment, bath preparation, and the like. . The sebum secretion inhibitor can also be used as an internal preparation, and the dosage form in this case can be tablets, capsules, powders, liquids, and the like. The compounding amount of the active ingredient in the hair nourishing agent or sebum secretion inhibitor can be appropriately adjusted in consideration of the purpose of use, sex, symptoms, etc., but is about 0.0001 to 10% by mass in terms of nobiletin.

  A hair nourishing agent and sebum secretion inhibitor as an external preparation for skin, together with the above-mentioned androgen receptor binding inhibitor, any physiologically active substance or auxiliary agent according to the application, such as astringent, bactericidal, antibacterial agent, whitening agent, ultraviolet absorber If a moisturizer, cell activator, anti-inflammatory / antiallergic agent, antioxidant / active oxygen scavenger, etc. are used in combination, the product becomes more general. In addition, this may lead to a synergistic effect with other active ingredients used in combination, which is more excellent than normally expected.

[Prostatic hypertrophy inhibitor]
The prostatic hypertrophy inhibitor of the present invention contains the above androgen receptor binding inhibitor (including nobiletin, a specific citrus extract or a purified nobiletin product) as an active ingredient.

  Nobiletin, a specific citrus extract or purified nobiletin has an androgen receptor binding inhibitory action, and can prevent and / or ameliorate diseases such as prostatic hypertrophy and prostate tumor, and is orally administered Since it is excellent in safety in cases, it is suitable for blending into a prostatic hypertrophy inhibitor as an internal use. In this case, nobiletin, a specific citrus extract or a purified nobiletin product may be added as it is, or an androgen receptor binding inhibitor formulated from nobiletin, a specific citrus extract or a purified nobiletin product.

  The prostatic hypertrophy inhibitor of the present invention can be used as general foods, health foods, health functional foods, quasi drugs, and pharmaceuticals. In consideration of the general intake amount of the product to be formulated, it is appropriate that the amount of the active ingredient in them is converted to nobiletin so that the daily intake amount for adults is about 1-1000 mg.

  Examples of the prostate hypertrophy inhibitor of the present invention include beverages such as soft drinks, carbonated drinks, nutrition drinks, fruit drinks, and lactic acid drinks (including concentrated concentrates and powders for adjustment of these drinks); ice cream, ice sherbet, shaved ice Noodles such as buckwheat, udon, harsame, gyoza skin, sushi mai, Chinese noodles, instant noodles; rice cakes, chewing gum, candy, gum, chocolate, tablet confectionery, snacks, biscuits, jelly, jam, cream, Pastries such as baked goods; processed fishery and livestock products such as kamaboko, ham, sausage; dairy products such as processed milk and fermented milk; fats and oils such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, dressing Processed foods; seasonings such as sauces and sauces; soups, stews, salads, prepared dishes, pickles; other species Can be manufactured by blending the above androgen receptor binding inhibitor with pharmaceuticals such as tablets, capsules, drinks, lozenges, quasi-drugs, etc. Supplementary raw materials and additives to be used can be used in combination.

  In addition, although the androgen receptor binding inhibitor of the present invention is suitably applied to humans, it can also be applied to animals other than humans as long as a desired action and effect are exhibited. For example, the androgen receptor binding inhibitor of the present invention can be added to pet foods such as dog foods and cat foods and livestock feed to prevent and treat hair loss of pet animals and livestock.

  Hereinafter, although a manufacture example, a test example, and a compounding example are shown and this invention is demonstrated concretely, this invention is not limited to each following example at all.

[Production Example 1] Production of nobiletin crude product 50 L of 30% by volume ethanol (mass ratio of water and ethanol 7: 3) as an extraction solvent is added to 2500 kg of Ponkan fruit (whole fruit), and a reflux extractor. And heated at 80 ° C. for 2 hours and filtered while hot. The obtained extract was concentrated under reduced pressure and further dried to obtain an extract (hereinafter referred to as “nobiletin crude product A”). The nobiletin content in the obtained crude nobiletin product A was 0.08% by mass. In addition, identification of nobiletin was performed by measuring by liquid chromatography (HPLC) (carrier: 50% acetonitrile (0.1% phosphoric acid), detection wavelength: 334 nm, column: WAKOSIL-II 5C18HG (Wako Pure Chemical Industries, Ltd.) Made by Co., Ltd.)).

  The crude nobiletin product A was treated with column chromatography (Diaion HP-20, manufactured by Mitsubishi Chemical Corporation) and then eluted with 70% by mass aqueous methanol to obtain a fraction. The obtained fraction was treated with activated carbon, further concentrated under reduced pressure, and dried to obtain 1.3 kg of a crude nobiletin product (hereinafter referred to as “nobiletin crude product B”). In addition, the nobiletin content in the crude nobiletin purified product B was 45.6% by mass.

[Test Example 1] Androgen receptor binding inhibitory action test The crude purified nobiletin obtained in Production Example 1 was tested for its androgen receptor binding inhibitory action by the following test method.

96 wells of androgen-dependent mouse breast cancer cells SC-3 cells at a cell density of 1.0 × 10 ⁴ cells / well / 100 μL using MEM medium containing 2% FBS (hereinafter referred to as “MEM-2 medium”). The cells were seeded on a microplate and cultured at 37 ° C. under 5% CO ₂ -95% air. After 24 hours, the medium was changed to 0.5% BSA-containing HamF12 + MEM medium (hereinafter referred to as “HMB medium”) supplemented with the sample and 10 ⁻⁹ molar DHT, and cultured for 48 hours.

  Thereafter, the medium was replaced with a MEM-2 medium containing 0.97 mM MTT. After culturing for 2 hours, the medium was replaced with isopropanol, and blue formazan produced in the cells was extracted. About isopropanol containing the extracted blue formazan, the light absorbency of 570 nm with the absorption maximum of blue formazan was measured.

  In order to correct the influence of adherent cells, the absorbance at 650 nm was also measured at the same time, and the difference between the two absorbances was taken as a value proportional to the amount of blue formazan produced (the absorbance in the formula for calculating the binding inhibition rate is the corrected absorbance below). Is).

  In parallel with the above, in order to examine the effect of the sample alone on the SC-3 cells, the same culture and measurement were performed by adding only the sample without adding DHT to the HMB medium. Further, as a control, the same measurement was performed when culturing in an HMB medium not added with a sample and DHT, and when culturing in an HMB medium added with only DHT without adding a sample.

From the measurement results, the binding inhibition rate showing antiandrogenic activity was calculated by the following formula.
Binding inhibition rate (%) = {1− (C−D) / (A−B)} × 100
In the above formula, “A” is the absorbance when DHT is added and no sample is added, “B” is the absorbance when DHT is not added and the sample is not added, and “C” is the absorbance when DHT is added and the sample is not added. “D” represents the absorbance when DHT is not added and the sample is added.

Next, the concentration of the sample solution is decreased stepwise to measure the inhibition rate, and the androgen binding inhibition rate (%) at each concentration is determined. From the result, androgen binding is 50% by interpolation. The inhibitory sample concentration IC ₅₀ (ppm; μg / mL) was determined. The results are shown in Table 1.

[Table 1]
Sample 50% inhibitory concentration (ppm; μg / mL)
Nobiletin crude product A (0.08%) 50.0
Nobiletin crude product B (45.6%) 1.6

From the results in Table 1, excellent androgen receptor binding inhibitory action was observed in the nobiletin crude product, particularly nobiletin crude product B. Thus, since the sample concentration IC ₅₀ that inhibits androgen binding by 50% decreases with an increase in nobiletin content, it is considered that nobiletin has an excellent androgen receptor binding inhibitory action.

[Test Example 2] Hair loss inhibitory action test 10 males aged 35 to 51 who have symptoms of androgenetic alopecia and head seborrheic dermatitis are divided into a use group of 5 people and a non-use group, In the use group, instead of the hair tonic that is usually used, 70% ethanol aqueous solution containing 0.2% by mass of the nobiletin crude product B obtained in Production Example 1 is used twice a day in the morning and at night for 3 weeks. In the non-use group, 70% ethanol aqueous solution was used under the same conditions in place of the hair tonic normally used.

  All members were allowed to wash their hair under the same conditions on the test start date and the test end date, and the number of hair removal at that time was measured. In order to make the conditions uniform, the hair was washed under the same conditions 24 hours before washing for counting the number of hair removal. Table 2 shows the test results of the use group, and Table 3 shows the test results of the non-use group.

[Table 2]
Test start date the day of study termination reduction rate (%)
Subject A 76 55 55 27.6
Subject B 65 52 52 20.0
Subject C 75 44 44 41.3
Subject D 80 70 70 12.5
Test subject E 83 68 68 18.1
Mean ± SE 23.9 ± 4.5

[Table 3]
Test start date the day of study termination reduction rate (%)
Subject F 71 68 68 4.2
Subject G 77 68 68 11.7
Subject H 65 57 57 12.3
Subject I 69 61 61 11.6
Subject J 80 76 76
Mean ± SE 9.0 ± 1.6

  As shown in Tables 2 and 3, the use group (Table 2) and the non-use group (Table 3) have a significant difference in the rate of hair loss, and apparently hair loss was achieved by using the nobiletin crude product. It was confirmed that hair loss can be prevented when a hair nourishing agent containing nobiletin crude product is used.

  In addition, in the above use test, no irritation or sensitization to the skin or scalp was observed by using 70% ethanol aqueous solution containing 0.2% by mass of nobiletin crude product B of Production Example 1, and its side effects were I was not able to admit.

[Formulation Example 1]
The following raw materials were processed by a conventional method for producing hair tonics to produce hair nourishing hair tonics.
Nobiletin crude purified product B (Production Example 1) 0.002 parts by mass Pyridoxine hydrochloride 0.1 parts by mass Resorcin 0.01 parts by mass D-pantothenyl alcohol 0.1 parts by mass Dipotassium glycyrrhizinate 0.1 parts by mass 1-menthol 0 .05 parts by mass 1,3-butylene glycol 4.0 parts by mass carrot extract 0.5 parts by mass ethanol 25.0 parts by mass perfume appropriate amount purified water 70.0 parts by mass

[Formulation Example 2]
The following raw materials were processed by a conventional method for producing lotions to produce a lotion having a sebum secretion-inhibiting action.
Nobiletin crude product B (Production Example 1) 0.001 parts by mass Dipotassium glycyrrhizinate 0.2 parts by mass 1,3-butylene glycol 4.0 parts by mass oleyl alcohol 4.0 parts by mass polyoxyethylene sorbitan monolaurate (20E .0.) 1.5 parts by weight polyoxyethylene lauryl ether (20E.0.) 0.5 parts by weight ethanol 15.0 parts by weight preservative appropriate amount perfume appropriate amount purified water 70.0 parts by weight

[Composition Example 3]
The following raw materials were processed by a conventional method for producing cream to produce a cream having a sebum secretion-inhibiting action.
Nobiletin crude purified product B (Production Example 1) 0.01 parts by mass stearyl glycyl retinate 0.1 parts by mass beeswax 10.0 parts by mass cetanol 5.0 parts by mass hydrophilic lanolin 8.0 parts by mass squalane 35.5 parts by mass Parts glyceryl monostearate 2.0 parts by mass γ-oryzanol 0.05 parts by mass purified water 40.0 parts by mass polyoxyethylene sorbitan monolaurate (20E.0.) 2.0 parts by mass polyethylene glycol 0.5 parts by mass Preservative Appropriate amount Fragrance Appropriate amount

[Formulation Example 4]
The following raw materials were processed by a conventional method for producing sputum to produce a sputum having an action to suppress prostate hypertrophy.
Nobiletin crude purified product B (Production Example 1) 0.01 parts by mass Sucrose 70 parts by mass Minamata 30 parts by mass Citric acid 1 part by mass Fragrance 0.1 parts by mass

[Formulation Example 5]
The following raw materials were processed by a conventional method for producing chewing gum to produce a chewing gum having an action to suppress prostate hypertrophy.
Nobiletin crude purified product B (Production Example 1) 1 part by weight chewing gum base 70 parts by weight sucrose 54 parts by weight starch syrup 20 parts by weight softener 4 parts by weight fragrance (mint oil) 1 part by weight The hair nourishing agent and sebum secretion inhibitor as an external preparation and the foods according to the above Formulation Examples 4 and 5 all showed good storage stability.

The androgen receptor binding inhibitor according to the present invention relates to the improvement or prevention of symptoms such as androgenetic baldness, hirsutism, seborrhea, acne, benign prostatic hyperplasia, prostate tumor, premature boyhood, etc. The hair nourishing agent is used to improve or prevent male buns, the sebum secretion inhibitor according to the present invention is used to improve or prevent seborrhea, acne, etc., and the prostatic hypertrophy inhibitor according to the present invention is prostatic hypertrophy, prostate It can greatly contribute to the improvement or prevention of tumors.

Claims (3)

An androgen receptor binding inhibitor characterized by containing Ponkan extract as an active ingredient (except for hair restoration and hair growth applications) . A sebum secretion inhibitor comprising a purified nobiletin obtained by purifying a Ponkan extract or a Ponkan extract . A prostatic hypertrophy inhibitor characterized by containing a purified nobiletin obtained by purifying a Ponkan extract or a Ponkan extract .