WO2022138257A1 - Pde5 inhibitor - Google Patents

Pde5 inhibitor Download PDF

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WO2022138257A1
WO2022138257A1 PCT/JP2021/045726 JP2021045726W WO2022138257A1 WO 2022138257 A1 WO2022138257 A1 WO 2022138257A1 JP 2021045726 W JP2021045726 W JP 2021045726W WO 2022138257 A1 WO2022138257 A1 WO 2022138257A1
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extract
pde5
powder
pde5 inhibitor
item
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PCT/JP2021/045726
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French (fr)
Japanese (ja)
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志穂 齋藤
俊一郎 畑
直子 益子
裕美 石黒
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第一工業製薬株式会社
株式会社バイオコクーン研究所
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Publication of WO2022138257A1 publication Critical patent/WO2022138257A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • PDE Phosphodiesterase
  • Non-Patent Document 1 a substance having a PDE5 inhibitory action is effective in preventing or ameliorating urinary tract disorders and pulmonary arterial hypertension.
  • Non-Patent Documents 1 and 2 Naturally-derived substances having a PDE5 inhibitory effect are also known (Patent Documents 1 and 2).
  • One issue is to provide a substance having a new PDE5 inhibitory effect.
  • Item 1 A PDE5 inhibitor comprising sardine flour or an extract thereof.
  • Item 2 Item 2.
  • the PDE5 inhibitor according to Item 1 which is a form of a food or drink composition.
  • Item 3 Item 2.
  • the PDE5 inhibitor according to Item 1 or 2 which is used for preventing or ameliorating dysuria and / or pulmonary arterial hypertension.
  • Item 4 Use of pupa flour or an extract thereof to produce PDE5 inhibitors.
  • Item 5 Use of pupal powder or an extract thereof for producing a composition for preventing or ameliorating dysuria and / or pulmonary arterial hypertension.
  • Item 6 A method of administering sardine powder or an extract thereof to a subject in need of PDE5 inhibition.
  • Item 7 Item 6. The method according to Item 6, wherein the subject requires prevention or improvement of dysuria and / or pulmonary arterial hypertension.
  • Item 8 Chrysalis flour or an extract thereof for use in PDE5 inhibition.
  • Item 9 Chrysalis powder or an extract thereof for use in the prevention or amelioration of dysuria and / or pulmonary arterial hypertension.
  • a substance having a PDE5 inhibitory action is provided.
  • a means for preventing or ameliorating dysuria and / or pulmonary arterial hypertension utilizing a PDE5 inhibitory effect is provided.
  • sample refers to a sardine powdered water extract.
  • Substrate indicates cGMP.
  • the results of measuring the PDE5 inhibitory activity of the Sanagi powder DMSO extract are shown.
  • Sample refers to Sanagi flour DMSO extract.
  • Sample indicates cGMP.
  • the PDE5 inhibitor preferably contains sanagi flour or an extract thereof.
  • Chrysalis powder is a dried silk moth pupa powder. Commercially available pupa can be used, or it can be produced from silk moth pupae and used.
  • the particle size and the like of the powder are not limited and can be appropriately set according to the purpose of use and the like.
  • the PDE5 inhibitor preferably comprises an extract of sardine flour.
  • the methods and conditions used to obtain the extract are arbitrary.
  • the sardine powder can be extracted as it is or by further pulverizing it and using a suitable solvent.
  • the type of solvent is not particularly limited, and is, for example, lower alcohols such as water, methanol, ethanol and isopropanol, polyhydric alcohols such as propylene glycol and 1,3-butylene glycol; ketones such as acetone, diethyl ethers, dioxane and acetonitrile. , Esters such as ethyl acetate esters, dimethylsulfoxide, xylene, benzene, chloroform and the like.
  • the preferred solvent in one embodiment is water.
  • the temperature of the solvent is not particularly limited, but may be, for example, 10 ° C. or higher and 20 ° C. or higher.
  • the sardine powder while applying ultrasonic waves. It is preferably obtained by the following method.
  • the mixing ratio of the pupa powder and the solvent at the time of extraction is arbitrary, but for example, 5 to 20 parts by weight or 7 to 15 parts by weight of the solvent can be used with respect to 1 part by weight of the dry powder.
  • the water content of the sardine powder or its extract is not particularly limited, but can be, for example, 20% by weight or less, 10% by weight or less, 8% by weight or less, or 5% by weight or less.
  • the PDE5 inhibitor may consist only of sardine powder or an extract thereof, or may further contain any other component.
  • Other ingredients include, for example, excipients, binders, disintegrants, lubricants, wetting agents, fluidizing agents, preservatives, surfactants, stabilizers, diluents, solubilizers, isotonic agents, etc.
  • other components such as bactericides, preservatives, flavoring agents, odorants, coloring agents, and fragrances, other components having PDE5 inhibitory activity and other physiologically active components can also be selected.
  • the form of the PDE5 inhibitor is arbitrary and can be, for example, powder, granule, tablet, capsule or liquid.
  • the amount of sardine powder or its extract contained in the PDE5 inhibitor is arbitrary, but can be set in the range of 0.1% or more and 100% or less in terms of dry weight, for example.
  • the lower limit of the content is, for example, 1% or more, 2% or more, 5% or more, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more or 70%.
  • the upper limit can be 99% or less, 95% or less, 90% or less, 80% or less, 70% or less, or 60% or less. These lower and upper limits can be combined arbitrarily.
  • the PDE5 inhibitor is preferably in the form of food and drink.
  • Food and drink includes not only general foods but also foods with health claims (specifically, foods for specified health use, foods with nutritional claims, foods with functional claims), foods for the sick, supplements and the like.
  • the PDE5 inhibitor forms are liquid forms such as liquids, emulsions, suspensions, syrups, powders, granules, fine granules, tablets, pills, capsules (including hard capsules, soft capsules). , Troche, chewable, gel, cream, paste, mousse, sheet, etc., in semi-solid or solid form.
  • General foods are not particularly limited, but for example, beverages (for example, fruit juice beverages, vegetable juices, soft beverages, alcoholic beverages, carbonated beverages, sports drinks, nourishing tonic drinks, nutritional drinks, etc.), confectionery (for example, snacks, rice). Confectionery, chocolate, gummy, candy, jelly, pudding, Japanese confectionery, Western confectionery, etc.), seasonings (for example, soy sauce, miso, mirin-style seasoning, mixed spices, sauce, soup, sauce, ketchup, etc.), dressings, noodles (For example, udon, buckwheat, spaghetti, etc.), processed meat and fish foods (for example, sausage, wiener, ham, hamburger, etc.), dairy products (yogurt, milk, cheese, cream, butter, etc.), etc. can be mentioned. ..
  • the PDE5 inhibitor described above can be used for the prevention or amelioration of dysuria and / or pulmonary arterial hypertension by inhibiting the activity of PDE5.
  • the cause and type of urinary tract disorder are not limited, but urinary tract disorders accompanied by lower urinary tract symptoms can be mentioned.
  • the PDE5 inhibitor can be in the form of a pharmaceutical.
  • Pharmaceuticals containing PDE5 inhibitors can be prepared by combining sanagi flour or an extract thereof with a pharmaceutically acceptable excipient as required.
  • the intake (administration) amount of the PDE5 inhibitor is not particularly limited as long as the desired effect is achieved, and is appropriately set according to the physique, age, symptom, application form, purpose of use, etc. of the subject (target animal). can do.
  • the daily intake (administration) amount should be set in the range of 0.001 to 8000 mg, 0.01 to 5000 mg, etc. in terms of dry weight of sanagi powder or its extract, based on an adult weighing 60 kg. Can be done.
  • the number of ingestions (administrations) is arbitrary, and may be, for example, a single ingestion (administration) or a plurality of ingestions (administrations) per day.
  • the sanagi powder or its extract can be used for producing a PDE5 inhibitor.
  • Sanagi flour or an extract thereof can also be used to produce a composition for preventing or ameliorating dysuria and / or pulmonary arterial hypertension.
  • the sardine powder or its extract has a PDE5 inhibitory action
  • PDE5 inhibition makes it possible to prevent or ameliorate dysuria and / or pulmonary arterial hypertension
  • dysuria and / or pulmonary arterial hypertension is required to be prevented or ameliorated.
  • the prevention or improvement can be performed by administering the extract.
  • pupa powder Dried silk moth pupa (obtained from Usui Raw Silk Manufacturing Co., Ltd.) was crushed with a mixer to obtain pupa powder.
  • Sanagi powder 42 g
  • 420 mL of ultrapure water or 420 mL of DMSO were placed in a reaction vessel, and the mixture was extracted for 15 minutes while applying ultrasonic waves with an ultrasonic cleaner. Then, the mixed solution was centrifuged at 5000 rpm for 10 minutes, the supernatant was collected, and spray-dried to obtain a water extract and a DMSO extract of sardine powder.
  • PDE5 inhibitory activity was performed using PDE-Glo TM Phosphodiesterase Assay (manufactured by Promega). Water extracts and DMSO extracts of sardine powder diluted with ultrapure water so that the final concentrations were 33 ⁇ g / ml, 11 ⁇ g / g, 3.7 ⁇ g / ml, and 1.2 ⁇ g / ml were used as samples.
  • As the enzyme phosphodiesterase 5A1 human (manufactured by Sigma-Aldrich) was used. 1 ⁇ l of 3100 U / ⁇ l of PDE and 205.7 ⁇ l of reaction buffer were mixed to prepare a PDE solution.
  • pupa powder is considered to be effective for the treatment or prevention of diseases such as pulmonary arterial hypertension and dysuria.

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Abstract

The present invention provides a new substance having a PDE5 inhibitory effect. This PDE5 inhibitor includes a pupae powder or an extract thereof.

Description

ＰＤＥ５阻害剤PDE5 inhibitor
　ホスホジエステラーゼ（ＰＤＥ：Phosphodiesterase）５阻害剤に関する技術が開示される。 Technology related to phosphodiesterase (PDE: Phosphodiesterase) 5 inhibitors is disclosed.
　ＰＤＥ５阻害作用を有する物質は、尿路障害や肺動脈性肺高血圧症の予防ないし改善に有効であることが知られている（非特許文献１）。ＰＤＥ５阻害作用を有する天然由来の物質も知られている（特許文献１及び２）。 It is known that a substance having a PDE5 inhibitory action is effective in preventing or ameliorating urinary tract disorders and pulmonary arterial hypertension (Non-Patent Document 1). Naturally-derived substances having a PDE5 inhibitory effect are also known (Patent Documents 1 and 2).
特開2019-34920JP 2019-34920 特開2018-154610JP 2018-154610
　新たなＰＤＥ５阻害作用を有する物質を提供することが１つの課題である。 One issue is to provide a substance having a new PDE5 inhibitory effect.
　上記課題を解決すべく鋭意研究を重ねた結果、サナギ粉にＰＤＥ５阻害作用があることが見出された。斯かる知見に基づき更なる検討を重ね、下記に代表される発明が提供される。
項１
サナギ粉又はその抽出物を含む、ＰＤＥ５阻害剤。
項２
飲食品組成物の形態である、項１に記載のＰＤＥ５阻害剤。
項３
排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善用である、項１又は２に記載のＰＤＥ５阻害剤。
項４
ＰＤＥ５阻害剤を製造するためのサナギ粉又はその抽出物の使用。
項５
排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善用組成物を製造するための、サナギ粉又はその抽出物の使用。
項６
ＰＤＥ５阻害が必要な対象にサナギ粉又はその抽出物を投与する方法。
項７
対象が排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善を必要とする、項６に記載の方法。
項８
ＰＤＥ５阻害における使用のためのサナギ粉又はその抽出物。
項９
排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善における使用のためのサナギ粉又はその抽出物。 As a result of diligent research to solve the above problems, it was found that sanagi powder has a PDE5 inhibitory effect. Further studies will be conducted based on such findings, and the inventions represented by the following will be provided.
Item 1
A PDE5 inhibitor comprising sardine flour or an extract thereof.
Item 2
Item 2. The PDE5 inhibitor according to Item 1, which is a form of a food or drink composition.
Item 3
Item 2. The PDE5 inhibitor according to Item 1 or 2, which is used for preventing or ameliorating dysuria and / or pulmonary arterial hypertension.
Item 4
Use of pupa flour or an extract thereof to produce PDE5 inhibitors.
Item 5
Use of pupal powder or an extract thereof for producing a composition for preventing or ameliorating dysuria and / or pulmonary arterial hypertension.
Item 6
A method of administering sardine powder or an extract thereof to a subject in need of PDE5 inhibition.
Item 7
Item 6. The method according to Item 6, wherein the subject requires prevention or improvement of dysuria and / or pulmonary arterial hypertension.
Item 8
Chrysalis flour or an extract thereof for use in PDE5 inhibition.
Item 9
Chrysalis powder or an extract thereof for use in the prevention or amelioration of dysuria and / or pulmonary arterial hypertension.
　ＰＤＥ５阻害作用を有する物質が提供される。一実施形態において、ＰＤＥ５阻害作用を利用した排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善の手段が提供される。 A substance having a PDE5 inhibitory action is provided. In one embodiment, a means for preventing or ameliorating dysuria and / or pulmonary arterial hypertension utilizing a PDE5 inhibitory effect is provided.
サナギ粉水抽出物についてＰＤＥ５阻害活性を測定した結果を示す。「Ｓａｍｐｌｅ」はサナギ粉水抽出物を示す。「Ｓｕｂｓｔｒａｔｅ」はｃＧＭＰを示す。The results of measuring the PDE5 inhibitory activity of the Sanagi powdered water extract are shown. "Sample" refers to a sardine powdered water extract. "Substrate" indicates cGMP. サナギ粉ＤＭＳＯ抽出物についてＰＤＥ５阻害活性を測定した結果を示す。「Ｓａｍｐｌｅ」はサナギ粉ＤＭＳＯ抽出物を示す。「Ｓｕｂｓｔｒａｔｅ」はｃＧＭＰを示す。The results of measuring the PDE5 inhibitory activity of the Sanagi powder DMSO extract are shown. "Sample" refers to Sanagi flour DMSO extract. "Substrate" indicates cGMP.
　ＰＤＥ５阻害剤は、サナギ粉又はその抽出物を含むことが好ましい。サナギ粉は、蚕の蛹を乾燥して粉末にしたものである。サナギ粉は市販されるものを使用することができ、蚕の蛹から製造して使用することもできる。粉末の粒子径等は制限されず、使用目的等に応じて適宜設定することができる。 The PDE5 inhibitor preferably contains sanagi flour or an extract thereof. Chrysalis powder is a dried silk moth pupa powder. Commercially available pupa can be used, or it can be produced from silk moth pupae and used. The particle size and the like of the powder are not limited and can be appropriately set according to the purpose of use and the like.
　一実施形態において、ＰＤＥ５阻害剤はサナギ粉の抽出物を含むことが好ましい。抽出物を得るために用いられる方法及び条件は、任意である。例えば、サナギ粉をそのまま、又は更に粉砕し、適当な溶媒を用いて抽出することができる。溶媒の種類は特に制限されず、例えば、水、メタノール、エタノール、イソプロパノール等の低級アルコール、プロピレングリコール、１，３－ブチレングリコール等の多価アルコール；アセトン等のケトン類、ジエチルエーテル、ジオキサン、アセトニトリル、酢酸エチルエステル等のエステル類、ジメチルスルホキシド、キシレン、ベンゼン、クロロホルム等が挙げられる。一実施形態において好ましい溶媒は、水である。溶媒の温度は特に制限されないが、例えば、１０℃以上、２０℃以上とすることができる。 In one embodiment, the PDE5 inhibitor preferably comprises an extract of sardine flour. The methods and conditions used to obtain the extract are arbitrary. For example, the sardine powder can be extracted as it is or by further pulverizing it and using a suitable solvent. The type of solvent is not particularly limited, and is, for example, lower alcohols such as water, methanol, ethanol and isopropanol, polyhydric alcohols such as propylene glycol and 1,3-butylene glycol; ketones such as acetone, diethyl ethers, dioxane and acetonitrile. , Esters such as ethyl acetate esters, dimethylsulfoxide, xylene, benzene, chloroform and the like. The preferred solvent in one embodiment is water. The temperature of the solvent is not particularly limited, but may be, for example, 10 ° C. or higher and 20 ° C. or higher.
　一実施形態において、サナギ粉の抽出は、超音波を与えながら行うことが好ましい。次の方法で得られたものであることが好ましい。また、抽出する際のサナギ粉と溶媒の混合比率は任意であるが、例えば、乾燥粉末１重量部に対して５～２０重量部、又は７～１５重量部の溶媒を使用することができる。 In one embodiment, it is preferable to extract the sardine powder while applying ultrasonic waves. It is preferably obtained by the following method. The mixing ratio of the pupa powder and the solvent at the time of extraction is arbitrary, but for example, 5 to 20 parts by weight or 7 to 15 parts by weight of the solvent can be used with respect to 1 part by weight of the dry powder.
　サナギ粉又はその抽出物の水分含量は特に制限されないが、例えば、２０重量％以下、１０重量％以下、８重量％以下、又は５重量％以下とすることができる。 The water content of the sardine powder or its extract is not particularly limited, but can be, for example, 20% by weight or less, 10% by weight or less, 8% by weight or less, or 5% by weight or less.
　ＰＤＥ５阻害剤は、サナギ粉又はその抽出物のみから成るものであっても、更に任意の他の成分を含むものであってもよい。他の成分としては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、湿潤剤、流動化剤、保存剤、界面活性剤、安定剤、希釈剤、溶解剤、等張化剤、殺菌剤、防腐剤、矯味剤、矯臭剤、着色剤、香料等を挙げることができる他の成分として、他のＰＤＥ５阻害活性を有する成分や他の生理活性成分を選択することもできる。ＰＤＥ５阻害剤の形態は任意であり、例えば、粉末状、顆粒状、錠剤状、カプセル状、又は液体状とすることができる。 The PDE5 inhibitor may consist only of sardine powder or an extract thereof, or may further contain any other component. Other ingredients include, for example, excipients, binders, disintegrants, lubricants, wetting agents, fluidizing agents, preservatives, surfactants, stabilizers, diluents, solubilizers, isotonic agents, etc. As other components such as bactericides, preservatives, flavoring agents, odorants, coloring agents, and fragrances, other components having PDE5 inhibitory activity and other physiologically active components can also be selected. The form of the PDE5 inhibitor is arbitrary and can be, for example, powder, granule, tablet, capsule or liquid.
　ＰＤＥ５阻害剤に含まれる、サナギ粉又はその抽出物の量は任意であるが、例えば、乾燥重量換算で、０．１％以上１００％以下の範囲で設定することができる。含有量の下限は、例えば、１％以上、２％以上、５％以上、１０％以上、１５％以上、２０％以上、３０％以上、４０％以上、５０％以上、６０％以上または７０％以上とすることができ、上限は９９％以下、９５％以下、９０％以下、８０％以下、７０％以下、又は６０％以下とすることができる。これらの下限及び上限は任意に組み合わせられる。 The amount of sardine powder or its extract contained in the PDE5 inhibitor is arbitrary, but can be set in the range of 0.1% or more and 100% or less in terms of dry weight, for example. The lower limit of the content is, for example, 1% or more, 2% or more, 5% or more, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more or 70%. The upper limit can be 99% or less, 95% or less, 90% or less, 80% or less, 70% or less, or 60% or less. These lower and upper limits can be combined arbitrarily.
　一実施形態において、ＰＤＥ５阻害剤は飲食品の形態であることが好ましい。飲食品には、一般食品だけでなく、保健機能食品（具体的には、特定保健用食品、栄養機能食品、機能性表示食品）、病者用食品、サプリメント等が含まれる。 In one embodiment, the PDE5 inhibitor is preferably in the form of food and drink. Food and drink includes not only general foods but also foods with health claims (specifically, foods for specified health use, foods with nutritional claims, foods with functional claims), foods for the sick, supplements and the like.
　一実施形態において、ＰＤＥ５阻害剤の形態は、液剤、乳剤、懸濁剤、シロップ剤等の液状形態、散剤、顆粒剤、細粒剤、錠剤、丸剤、カプセル剤（ハードカプセル、ソフトカプセルを含む）、トローチ、チュアブル、ゲル状、クリーム状、ペースト状、ムース状、シート状等の半固形または固形形態であり得る。 In one embodiment, the PDE5 inhibitor forms are liquid forms such as liquids, emulsions, suspensions, syrups, powders, granules, fine granules, tablets, pills, capsules (including hard capsules, soft capsules). , Troche, chewable, gel, cream, paste, mousse, sheet, etc., in semi-solid or solid form.
　一般食品は特に制限されないが、例えば、飲料類（例えば、果汁飲料、野菜ジュース、清涼飲料、アルコール飲料、炭酸飲料、スポーツドリンク、滋養強壮ドリンク、栄養ドリンク等）、菓子類（例えば、スナック菓子、米菓、チョコレート、グミ、キャンディー、ゼリー、プリン、和菓子、洋菓子等）、調味料類（例えば、醤油、味噌、みりん風調味料、ミックススパイス、たれ、つゆ、ソース、ケチャップ等）、ドレッシング類、麺類（例えば、うどん、そば、スパゲッティ等）、畜肉魚肉加工食品類（例えば、ソーセージ、ウインナー、ハム、ハンバーグ等）、乳製品類（ヨーグルト、牛乳、チーズ、クリーム、バター等）等を挙げることができる。 General foods are not particularly limited, but for example, beverages (for example, fruit juice beverages, vegetable juices, soft beverages, alcoholic beverages, carbonated beverages, sports drinks, nourishing tonic drinks, nutritional drinks, etc.), confectionery (for example, snacks, rice). Confectionery, chocolate, gummy, candy, jelly, pudding, Japanese confectionery, Western confectionery, etc.), seasonings (for example, soy sauce, miso, mirin-style seasoning, mixed spices, sauce, soup, sauce, ketchup, etc.), dressings, noodles (For example, udon, buckwheat, spaghetti, etc.), processed meat and fish foods (for example, sausage, wiener, ham, hamburger, etc.), dairy products (yogurt, milk, cheese, cream, butter, etc.), etc. can be mentioned. ..
　一実施形態において、上述のＰＤＥ５阻害剤は、ＰＤＥ５の活性を阻害することによって、排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善する用途で用いることができる。尿路障害の原因、種別は問わないが、下部尿路症状を伴う尿路障害を挙げることができる。 In one embodiment, the PDE5 inhibitor described above can be used for the prevention or amelioration of dysuria and / or pulmonary arterial hypertension by inhibiting the activity of PDE5. The cause and type of urinary tract disorder are not limited, but urinary tract disorders accompanied by lower urinary tract symptoms can be mentioned.
　一実施形態において、ＰＤＥ５阻害剤は医薬の形態とすることができる。ＰＤＥ５阻害剤を含む医薬は、サナギ粉又はその抽出物に必要に応じて薬学的に許容可能な賦形剤を組み合わせて調製することができる。 In one embodiment, the PDE5 inhibitor can be in the form of a pharmaceutical. Pharmaceuticals containing PDE5 inhibitors can be prepared by combining sanagi flour or an extract thereof with a pharmaceutically acceptable excipient as required.
　ＰＤＥ５阻害剤の摂取（投与）量は、目的とする効果が奏される限り特に限定されず、対象者（対象動物）の体格、年齢、症状、適用形態、使用目的等に応じて適宜設定すすることができる。例えば、１日当たりの摂取（投与）量は、体重６０ｋｇの成人を基準として、サナギ粉又はその抽出物の乾燥重量換算として、０．００１～８０００ｍｇ、０．０１～５０００ｍｇ等の範囲で設定することができる。摂取（投与）回数は任意であり、例えば、１日あたり単回摂取（投与）であってもよく複数回摂取（投与）であってもよい。 The intake (administration) amount of the PDE5 inhibitor is not particularly limited as long as the desired effect is achieved, and is appropriately set according to the physique, age, symptom, application form, purpose of use, etc. of the subject (target animal). can do. For example, the daily intake (administration) amount should be set in the range of 0.001 to 8000 mg, 0.01 to 5000 mg, etc. in terms of dry weight of sanagi powder or its extract, based on an adult weighing 60 kg. Can be done. The number of ingestions (administrations) is arbitrary, and may be, for example, a single ingestion (administration) or a plurality of ingestions (administrations) per day.
　上述のとおり、サナギ粉又はその抽出物はＰＤＥ５阻害作用を有するため、サナギ粉又はその抽出物をＰＤＥ５阻害剤を製造するために使用できる。また、排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善用組成物を製造するために、サナギ粉又はその抽出物を使用こともできる。 As described above, since the sanagi powder or its extract has a PDE5 inhibitory effect, the sanagi powder or its extract can be used for producing a PDE5 inhibitor. Sanagi flour or an extract thereof can also be used to produce a composition for preventing or ameliorating dysuria and / or pulmonary arterial hypertension.
　上述のとおり、サナギ粉又はその抽出物はＰＤＥ５阻害作用を有するため、ＰＤＥ５阻害が必要な対象にサナギ粉又はその抽出物を投与し、ＰＤＥ５阻害作用を提供することができる。また、ＰＤＥ５阻害によって、排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善が可能となるため、排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善を必要とする対象にサナギ粉又はその抽出物を投与することにより、当該予防若しくは改善を行うことができる。 As described above, since the sardine powder or its extract has a PDE5 inhibitory action, it is possible to administer the sardine powder or its extract to a subject in need of PDE5 inhibition to provide the PDE5 inhibitory action. In addition, since PDE5 inhibition makes it possible to prevent or ameliorate dysuria and / or pulmonary arterial hypertension, dysuria and / or pulmonary arterial hypertension is required to be prevented or ameliorated. The prevention or improvement can be performed by administering the extract.
　以下、実施例により本発明についてさらに詳細に説明するが、本発明はこれらに制限されるものではない。 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.
１．サナギ粉の調製
　乾燥したカイコ蛹（碓氷製糸株式会社より入手）をミキサーで粉砕し、サナギ粉を得た。反応容器に、サナギ粉（42g）および超純水420mL又はDMSO420mLを入れ、超音波洗浄機で超音波をあてながら15分間抽出した。その後、混合液を５０００ｒｐｍで１０分間遠心分離し、上澄みを採取し、スプレー乾燥を行うことによりサナギ粉の水抽出物及びDMSO抽出物を得た。 1. 1. Preparation of pupa powder Dried silk moth pupa (obtained from Usui Raw Silk Manufacturing Co., Ltd.) was crushed with a mixer to obtain pupa powder. Sanagi powder (42 g) and 420 mL of ultrapure water or 420 mL of DMSO were placed in a reaction vessel, and the mixture was extracted for 15 minutes while applying ultrasonic waves with an ultrasonic cleaner. Then, the mixed solution was centrifuged at 5000 rpm for 10 minutes, the supernatant was collected, and spray-dried to obtain a water extract and a DMSO extract of sardine powder.
２．ＰＤＥ５阻害活性の測定
　ＰＤＥ５阻害活性は、ＰＤＥ－Ｇｌｏ（商標）Ｐｈｏｓｐｈｏｄｉｅｓｔｅｒａｓｅ　Ａａｓｓａｙ（Ｐｒｏｍｅｇａ社製）を用いて行った。サナギ粉の水抽出物及びDMSO抽出物を終濃度が３３μｇ／ｍｌ、１１μｇ／ｇ、３．７μｇ／ｍｌ、１．２μｇ／ｍｌとなるように超純水に希釈したものをサンプルとして用いた。酵素は、ホスホジエステラーゼ５Ａ１ヒト（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ製）を用いた。３１００Ｕ／μｌのＰＤＥ１μｌと反応バッファー２０５．７μｌを混合し、ＰＤＥ溶液を調製した。ＰＤＥ溶液１５μｌと各サンプル１０μｌを混合し、２分間スピンダウンし、室温で５分間振盪した。この混合液２５μｌに２０μＭのｃＧＭＰを２５μｌを添加して混合し、ＰＣＲチューブに８μｌずつ分注した。これをシェーカーに載せ、室温、４００ｒｐｍで反応させた。各チューブに検出バッファーを４μｌ添加し、スピンダウン後に室温で２０分間振盪した。これとＫｉｎａｓｅ－Ｇｌｏ試薬を１０μｌを３８４ウェルプレート（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ製）の各ウェルに１０μｌずつ分注し、室温で振盪し、反応させた。サナギ粉の抽出物を添加しないサンプルを用いた試験例を０％コントロール、ＰＤＥを添加しない試験例を１００％コントロールとして、サナギ粉の水抽出物及びDMSO抽出物による相対的な阻害率を測定した。測定は４回繰り返した。結果を図１（水抽出物）及び図２（DMSO抽出物）に示す。 2. 2. Measurement of PDE5 Inhibitory Activity PDE5 inhibitory activity was performed using PDE-Glo ™ Phosphodiesterase Assay (manufactured by Promega). Water extracts and DMSO extracts of sardine powder diluted with ultrapure water so that the final concentrations were 33 μg / ml, 11 μg / g, 3.7 μg / ml, and 1.2 μg / ml were used as samples. As the enzyme, phosphodiesterase 5A1 human (manufactured by Sigma-Aldrich) was used. 1 μl of 3100 U / μl of PDE and 205.7 μl of reaction buffer were mixed to prepare a PDE solution. 15 μl of PDE solution and 10 μl of each sample were mixed, spun down for 2 minutes and shaken at room temperature for 5 minutes. To 25 μl of this mixed solution, 25 μl of 20 μM cGMP was added and mixed, and 8 μl each was dispensed into a PCR tube. This was placed on a shaker and reacted at room temperature at 400 rpm. 4 μl of detection buffer was added to each tube, and after spin-down, the mixture was shaken at room temperature for 20 minutes. 10 μl of this and 10 μl of Kinase-Glo reagent was dispensed into each well of a 384-well plate (manufactured by Thermo Fisher), shaken at room temperature, and reacted. The relative inhibition rate of the water extract and DMSO extract of the sardine powder was measured using the test example using the sample without the addition of the sardine powder extract as 0% control and the test example without the addition of PDE as the 100% control. .. The measurement was repeated 4 times. The results are shown in FIG. 1 (water extract) and FIG. 2 (DMSO extract).
　図１及び２の結果から、サナギ粉の水抽出物及びDMSO抽出物にはＰＤＥ５阻害活性が存在し、その活性が濃度依存的に上昇することが確認された。この結果から、サナギ粉は、肺動脈性肺高血圧症及び排尿障害等の疾患の治療ないし予防に有効と考えられる。 From the results of FIGS. 1 and 2, it was confirmed that the water extract and DMSO extract of pupa powder had PDE5 inhibitory activity, and the activity increased in a concentration-dependent manner. From this result, pupa powder is considered to be effective for the treatment or prevention of diseases such as pulmonary arterial hypertension and dysuria.

Claims (3)

  1. サナギ粉又はその抽出物を含む、ＰＤＥ５阻害剤。 A PDE5 inhibitor comprising sardine flour or an extract thereof.
  2. 飲食品組成物の形態である、請求項１に記載のＰＤＥ５阻害剤。 The PDE5 inhibitor according to claim 1, which is in the form of a food and drink composition.
  3. 排尿障害及び／又は肺動脈性肺高血圧症の予防若しくは改善用である、請求項１又は２に記載のＰＤＥ５阻害剤。 The PDE5 inhibitor according to claim 1 or 2, which is used for preventing or ameliorating dysuria and / or pulmonary arterial hypertension.
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