JP6356492B2 - Anti-inflammatory agent - Google Patents
Anti-inflammatory agent Download PDFInfo
- Publication number
- JP6356492B2 JP6356492B2 JP2014110423A JP2014110423A JP6356492B2 JP 6356492 B2 JP6356492 B2 JP 6356492B2 JP 2014110423 A JP2014110423 A JP 2014110423A JP 2014110423 A JP2014110423 A JP 2014110423A JP 6356492 B2 JP6356492 B2 JP 6356492B2
- Authority
- JP
- Japan
- Prior art keywords
- passion fruit
- seed extract
- fruit seed
- active ingredient
- inflammatory agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- 238000005292 vacuum distillation Methods 0.000 description 1
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Landscapes
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、抗炎症剤に関する。 The present invention relates to an anti-inflammatory agent.
ピセアタンノールは、スチルベン類の化合物であって、例えば、トケイソウ科トケイソウ属(Passiflora)の果物であるパッションフルーツの種子に含まれており、シミ、ソバカス、日焼けなどによる色素沈着の原因となるメラニンの生成を抑制する効果があることが報告されている(特許文献1を参照)。 Piceatannol is a stilbene compound, for example, contained in the seeds of passion fruit, a fruit of the genus Passiflora (Passiflora), and causes melanin that causes pigmentation due to spots, buckwheat, sunburn, etc. It has been reported that there is an effect of suppressing the generation of (see Patent Document 1).
このピセアタンノールは、強い抗炎症作用を有しており、ヒト末梢血単核球細胞などにおいて、LPS刺激に反応してTNF-alphaやIL-8の分泌を抑制する(非特許文献1参照)。 This piceatannol has a strong anti-inflammatory action and suppresses secretion of TNF-alpha and IL-8 in response to LPS stimulation in human peripheral blood mononuclear cells and the like (see Non-Patent Document 1). ).
本発明は、新規な抗炎症剤を提供することを目的とする。 An object of the present invention is to provide a novel anti-inflammatory agent.
本発明者らは、パッションフルーツの種子エキスの利用方法を開発しようと、鋭意努力した結果、パッションフルーツの種子エキスが強い抗炎症作用を有することを見出した。そして、ピセアタンノールの類縁体の一つであるイソラポンチゲニンも、同様に強い抗炎症作用を有することを見出し、本発明の完成に至った。 As a result of diligent efforts to develop a method for using passion fruit seed extract, the present inventors have found that passion fruit seed extract has a strong anti-inflammatory effect. And it discovered that isolapontigenin, which is one of the analogues of piceatannol, also has a strong anti-inflammatory action, leading to the completion of the present invention.
本発明の一実施態様は、パッションフルーツ種子エキスまたはイソラポンチゲニンを有効成分として含有する、抗炎症剤、IL-8産生阻害剤、またはTNF−α産生阻害剤である。 One embodiment of the present invention is an anti-inflammatory agent, an IL-8 production inhibitor, or a TNF-α production inhibitor containing passion fruit seed extract or isolapontigenin as an active ingredient.
本発明によって、新規な抗炎症剤を提供することができるようになった。 According to the present invention, a novel anti-inflammatory agent can be provided.
本発明の目的、特徴、利点、及びそのアイデアは、本明細書の記載により、当業者には明らかであり、本明細書の記載から、当業者であれば、容易に本発明を再現できる。以下に記載された発明の実施の形態及び具体的に実施例などは、本発明の好ましい実施態様を示すものであり、例示又は説明のために示されているのであって、本発明をそれらに限定するものではない。本明細書で開示されている本発明の意図並びに範囲内で、本明細書の記載に基づき、様々な改変並びに修飾ができることは、当業者にとって明らかである。 The objects, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification, and those skilled in the art can easily reproduce the present invention from the description of the present specification. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention, and are shown for illustration or explanation. It is not limited. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.
(1)イソラポンチゲニン
イソラポンチゲニン(3,4',5-Trihydroxy-3'-methoxy-trans-stilbene;3,4',5-トリヒドロキシ-3'-メトキシ-trans-スチルベン)は、以下の構造式を有する化合物である。
(1) Isolapontigenin isolapontigenin (3,4 ', 5-Trihydroxy-3'-methoxy-trans-stilbene;3,4',5-trihydroxy-3'-methoxy-trans-stilbene) It is a compound which has the following structural formula.
(2)パッションフルーツ種子エキスの製法
パッションフルーツ種子エキスの具体的な製造方法として、公知の方法を用いることができ、例えば、パッションフルーツ種子を、乾燥した後に、破砕、粉砕、または、切断などによって種子分解物を得、溶媒を用いて抽出し、残渣を除去することによって抽出液を得、さらに、抽出液から溶媒を除去することによって、抽出物を得ることができる。この段階のいずれのものも、本発明のパッションフルーツ種子エキスとして使用することができる。
(2) Production Method of Passion Fruit Seed Extract As a specific production method of the passion fruit seed extract, a known method can be used. For example, after the passion fruit seed is dried, it is crushed, pulverized, or cut. A seed decomposition product is obtained, extracted using a solvent, and an extract is obtained by removing the residue. Further, an extract can be obtained by removing the solvent from the extract. Any of these stages can be used as the passion fruit seed extract of the present invention.
抽出に用いる溶媒の種類は、当業者であれば適切に選択することができるが、例えば、水、メタノール、エタノール、アセトン、酢酸エチル、グリセリン、プロピレングリコール、ジプロピレングリコール、1,3−ブチレングリコール、ジメチルスルホキシド、アセトニトリル、N,N−ジメチルホルムアミド、2−プロパノール、1,4−ジオキサン、ヘキサン、クロロホルム、ジクロロメタン、または、これらから選択される2以上の溶媒の混合溶媒であっても良く、水、エタノール、1,3−ブチレングリコール、または、これらから選択される2以上の溶媒の混合溶媒であることが好ましく、水、エタノール、または、水およびエタノールの混合溶媒であることがより好ましい。混合溶媒を用いる場合の、各溶媒の混合比は特に限定されないが、例えば水およびエタノールの混合溶媒を用いる場合には、水とエタノールとの体積比は、1:99〜99:1であっても良く、3:97〜80:20であることが好ましく、5:95〜50:50であることがより好ましく、10:90〜40:60であることが特に好ましい。 The type of the solvent used for extraction can be appropriately selected by those skilled in the art. For example, water, methanol, ethanol, acetone, ethyl acetate, glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol , Dimethyl sulfoxide, acetonitrile, N, N-dimethylformamide, 2-propanol, 1,4-dioxane, hexane, chloroform, dichloromethane, or a mixed solvent of two or more solvents selected from these, water , Ethanol, 1,3-butylene glycol, or a mixed solvent of two or more solvents selected from these, more preferably water, ethanol, or a mixed solvent of water and ethanol. When using a mixed solvent, the mixing ratio of each solvent is not particularly limited. For example, when using a mixed solvent of water and ethanol, the volume ratio of water to ethanol is 1:99 to 99: 1. The ratio is preferably 3:97 to 80:20, more preferably 5:95 to 50:50, and particularly preferably 10:90 to 40:60.
溶媒として、水、または、水との混合溶媒を用いる場合には、熱水、または、熱水との混合溶媒であることが好ましい。水、または、水との混合溶媒は塩を含んでいても良く、塩を含む溶媒の例として、バッファー(緩衝液)であっても良い。バッファーのpHは、特に限定されず、酸性、中性、または、アルカリ性のいずれであっても良いが、酸性であることが好ましく、pH6以下の酸性であることがより好ましく、pH1〜pH5の酸性であることがさらに好ましい。バッファーに用いる塩の種類は特に限定されず、例として、クエン酸塩、リンゴ酸塩、リン酸塩、酢酸塩および炭酸塩などが挙げられる。 When water or a mixed solvent with water is used as the solvent, it is preferably hot water or a mixed solvent with hot water. Water or a mixed solvent with water may contain a salt, and may be a buffer (buffer) as an example of a solvent containing a salt. The pH of the buffer is not particularly limited, and may be acidic, neutral, or alkaline, but is preferably acidic, more preferably acidic at pH 6 or lower, and acidic from pH 1 to pH 5. More preferably. The kind of salt used for the buffer is not particularly limited, and examples thereof include citrate, malate, phosphate, acetate, and carbonate.
抽出液から溶媒を除去する方法は、特に限定されず公知の方法を用いることができる。例えば、減圧留去、凍結乾燥、または、スプレードライ(噴霧乾燥)であっても良いが、凍結乾燥、または、スプレードライであることが好ましく、スプレードライであることがより好ましい。 The method for removing the solvent from the extract is not particularly limited, and a known method can be used. For example, vacuum distillation, freeze drying, or spray drying (spray drying) may be used, but freeze drying or spray drying is preferable, and spray drying is more preferable.
抽出物の形状は、特に限定されず、例えば粉体などの固体状、アモルファス状、または、オイル状であっても良い。 The shape of the extract is not particularly limited, and may be, for example, a solid such as powder, an amorphous form, or an oil form.
(3)抗炎症剤及びIL-8産生阻害剤、またはTNF−α産生阻害剤
パッションフルーツ種子エキスまたはイソラポンチゲニンは、IL-8、またはTNF−α産生阻害効果を有するため、IL-8、またはTNF−α産生阻害剤や抗炎症剤などの薬剤として有効に利用することができる。パッションフルーツ種子エキスまたはイソラポンチゲニンの剤型化は公知の方法によって可能である。
(3) Anti-inflammatory agent and IL-8 production inhibitor, or TNF-α production inhibitor Passion fruit seed extract or isolapontigenin has an inhibitory effect on IL-8 or TNF-α production. Alternatively, it can be effectively used as a drug such as a TNF-α production inhibitor or an anti-inflammatory agent. The formulation of passion fruit seed extract or isolapontigenin is possible by a known method.
本発明に係る薬剤はまた、有効成分の他、必要に応じて、一般に用いられる各種成分をさらに含み得るものであり、例えば、1種以上の医薬的に許容され得る賦形剤、崩壊剤、希釈剤、滑沢剤、着香剤、着色剤、甘味剤、矯味剤、懸濁化剤、湿潤剤、乳化剤、分散剤、補助剤、防腐剤、緩衝剤、結合剤、安定剤、コーティング剤などを含み得る。 The drug according to the present invention may further contain various components generally used in addition to the active ingredient, if necessary, for example, one or more pharmaceutically acceptable excipients, disintegrants, Diluent, Lubricant, Flavor, Colorant, Sweetener, Flavoring Agent, Suspending Agent, Wetting Agent, Emulsifier, Dispersant, Auxiliary Agent, Preservative, Buffering Agent, Binder, Stabilizer, Coating Agent And so on.
投与経路は、全身投与または局所投与のいずれも選択することができる。この場合、疾患、症状などに応じた適当な投与経路を選択する。本発明に係る薬剤は、経口経路、非経口経路のいずれによっても投与できる。非経口経路としては、通常の静脈内投与、動脈内投与の他、皮下、皮内、筋肉内などへの投与を挙げることができる。さらに、経粘膜投与または経皮投与を実施することができる。 As the administration route, either systemic administration or local administration can be selected. In this case, an appropriate administration route is selected according to the disease, symptoms and the like. The drug according to the present invention can be administered by either oral route or parenteral route. Examples of parenteral routes include normal intravenous administration and intraarterial administration, as well as subcutaneous, intradermal and intramuscular administration. Furthermore, transmucosal administration or transdermal administration can be performed.
経口用固形製剤を調製する場合は、有効成分に賦形剤、必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤などを加えた後、常法により錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤などを製造することができる。そのような添加剤としては、当該分野で一般的に使用されるものでよく、例えば、賦形剤としては、乳糖、白糖、塩化ナトリウム、ブドウ糖、デンプン、炭酸カルシウム、カオリン、微結晶セルロース、珪酸などを、結合剤としては、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン液、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドンなどを、崩壊剤としては乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖などを、滑沢剤としては精製タルク、ステアリン酸塩、ホウ砂、ポリエチレングリコールなどを、矯味剤としては白糖、橙皮、クエン酸、酒石酸などを例示できる。 When preparing an oral solid preparation, after adding excipients, binders, disintegrating agents, lubricants, coloring agents, corrigents, flavoring agents, etc. to the active ingredient, tablets by a conventional method, Coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid As a binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. Disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and lubricants such as purified talc, stearin Salts, borax, polyethylene glycol and the like, as the corrigent sucrose, orange peel, citric acid, can be exemplified tartaric acid.
経口用液体製剤を調製する場合は、有効成分に矯味剤、緩衝剤、安定化剤、矯臭剤などを加えて常法により内服液剤、シロップ剤、エリキシル剤などを製造することができる。この場合矯味剤としては上記に挙げられたもので良く、緩衝剤としてはクエン酸ナトリウムなどが、安定化剤としてはトラガント、アラビアゴム、ゼラチンなどを挙げることができる。 When an oral liquid preparation is prepared, a liquid preparation, a syrup, an elixir or the like can be produced by a conventional method by adding a corrigent, a buffer, a stabilizer, a corrigent and the like to the active ingredient. In this case, the flavoring agent may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.
注射剤を調製する場合は、有効成分にpH調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤などを添加し、常法により皮下、筋肉内及び静脈内用注射剤を製造することができる。この場合のpH調節剤及び緩衝剤としてはクエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウムなどを挙げることができる。安定化剤としてはピロ亜硫酸ナトリウム、 エチレンジアミン四酢酸(EDTA)、チオグリコール酸、チオ乳酸などを挙げることができる。局所麻酔剤としては塩酸プロカイン、塩酸リドカインなどを挙げることができる。等張化剤としては、塩化ナトリウム、ブドウ糖などが例示できる。 When preparing injections, add pH regulators, buffers, stabilizers, tonicity agents, local anesthetics, etc. to active ingredients, and manufacture injections for subcutaneous, intramuscular and intravenous injections using conventional methods. can do. In this case, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, ethylenediaminetetraacetic acid (EDTA), thioglycolic acid, and thiolactic acid. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.
坐剤を調製する場合は、有効成分に当業界において公知の製剤用担体、例えば、ポリエチレングリコール、ラノリン、カカオ脂、脂肪酸トリグリセライドなどを、さらに必要に応じてツイーン(登録商標)のような界面活性剤などを加えた後、常法により製造することができる。 When preparing a suppository, a formulation carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, or the like, and a surfactant such as Tween (registered trademark) as necessary are used as active ingredients. After adding an agent etc., it can manufacture by a conventional method.
軟膏剤を調製する場合は、有効成分に通常使用される基剤、安定剤、湿潤剤、保存剤などが必要に応じて配合され、常法により混合、製剤化される。基剤としては、流動パラフィン、白色ワセリン、サラシミツロウ、オクチルドデシルアルコール、パラフィンなどを挙げることができる。保存剤としては、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピルなどを挙げることができる。 When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used as active ingredients are blended as necessary, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, and paraffin. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like.
貼付剤を製造する場合は、通常の支持体に前記軟膏、クリーム、ゲル、ペーストなどを常法により塗布すれば良い。支持体としては、綿、スフ、化学繊維からなる織布、不織布や軟質塩化ビニル、ポリエチレン、ポリウレタンなどのフィルムあるいは発泡体シートが適当である。 When producing a patch, the ointment, cream, gel, paste and the like may be applied to a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.
薬剤に含有される有効成分の量は、該有効成分の用量や投薬の回数などにより適宜決定できる。用量は特に限定されず、含有される成分の有効性、投与形態、投与経路、疾患の種類、対象の性質(体重、年齢、病状および他の医薬の使用の有無など)、および担当医師の判断など応じて適宜選択される。一日投与量は1日1回乃至数回に分けて投与することができる。 The amount of the active ingredient contained in the drug can be appropriately determined depending on the dose of the active ingredient, the number of doses, and the like. The dose is not particularly limited, and the effectiveness of the contained components, administration form, administration route, type of disease, nature of the subject (such as weight, age, medical condition and use of other drugs), and judgment of the doctor in charge It is appropriately selected according to the above. The daily dose can be administered once to several times a day.
ヒト末梢血単核球細胞(PBMC:Peripheral blood mononuclear cells)をFicollR gradientによりヒトから単離し、2mM L-glutamine, Penicillin/Streptomycin, 10%inactivated fetal calf serum を含んだRPMI培地で1時間培養後、各サンプル物質(ピセアタンノール、パッションフルーツ種子エキス、イソラポンチゲニン)(ピセアタンノール、イソラポンチゲニンは東京化成から入手)を所定濃度添加して、さらに1時間培養し、その後、パッションフルーツ種子エキスを添加した実験ではLPS(100ng/ml)で刺激し、イソラポンチゲニンを添加した実験ではLPS(100ng/ml)+IFNγ(20U/ml=1ng/ml)で刺激して、24時間後の培養液中のサイトカイン(IL-8、TNF−α)の産生量をELISAにより測定した。その結果を図1に示す(%阻害は100-(刺激から24時間後のサイトカインの産生量-無刺激時コントロール)/(サンプル処理時コントロール-無刺激時コントロール)×100であらわした。) ここで、パッションフルーツ種子エキスは、以下のようにして、抽出した。パッションフルーツ種子を焙煎して粉砕し、これに80%含水エタノール(80%(v/v)エタノール+20%(v/v)水)を加えて混合、攪拌した後、83meshフィルター(目開き180μm)で濾過することで固液分離した。得られた抽出液をエバポレータで濃縮して、スプレードライによって粉末化して得た。 Human peripheral blood mononuclear cells (PBMC) were isolated from humans by Ficoll R gradient and cultured for 1 hour in RPMI medium containing 2 mM L-glutamine, Penicillin / Streptomycin, 10% inactivated fetal calf serum Each sample substance (piceatannol, passion fruit seed extract, isolapontigenin) (piceatannol, isolapontigenin obtained from Tokyo Kasei) is added at a predetermined concentration, further cultured for 1 hour, and then passion fruit seeds. In the experiment in which the extract was added, stimulation was performed with LPS (100 ng / ml), and in the experiment in which isolapontigenin was added, stimulation was performed with LPS (100 ng / ml) + IFNγ (20 U / ml = 1 ng / ml), followed by culture after 24 hours. The production amount of cytokine (IL-8, TNF-α) in the liquid was measured by ELISA. The results are shown in FIG. 1 (% inhibition is expressed as 100- ( cytokine production 24 hours after stimulation-control during non-stimulation) / (control during sample treatment- control during non-stimulation) x 100). The passion fruit seed extract was extracted as follows. Passion fruit seeds were roasted and pulverized, and 80% water-containing ethanol (80% (v / v) ethanol + 20% (v / v) water) was added thereto, mixed and stirred, and then 83 mesh filter (mesh size 180 μm) ) To separate solid and liquid. The obtained extract was concentrated by an evaporator and powdered by spray drying.
なお、パッションフルーツ種子の含水エタノール抽出物中には、9.49%(w/v)のピセアタンノールが含有しており、精製ピセアタンノールの添加量に対応するパッションフルーツ種子エキスを用いた。 In addition, the aqueous ethanol extract of passion fruit seeds contained 9.49% (w / v) piceatannol, and the passion fruit seed extract corresponding to the added amount of purified piceatannol was used. .
図1に示されるように、パッションフルーツ種子エキス及びイソラポンチゲニンは、IL-8産生阻害活性やTNF−α産生阻害活性を有していた。このように、パッションフルーツ種子エキス及びイソラポンチゲニンは、抗炎症剤、IL-8産生阻害剤及びTNF−α産生阻害剤として、顕著に有効である。 As shown in FIG. 1, the passion fruit seed extract and isolapontigenin had an IL-8 production inhibitory activity and a TNF-α production inhibitory activity. Thus, passion fruit seed extract and isolapontigenin are remarkably effective as an anti-inflammatory agent, IL-8 production inhibitor and TNF-α production inhibitor.
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