JP5986891B2 - MIF secretion inhibitor - Google Patents
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Description
本発明は、マクロファージ遊走阻止因子（ＭＩＦ）分泌抑制剤、炎症性疾患の改善剤に関する。 The present invention relates to a macrophage migration inhibitory factor (MIF) secretion inhibitor and an inflammatory disease ameliorating agent.
マクロファージ遊走阻止因子（以下、ＭＩＦと記載する）は、炎症・免疫のメディエーターの１つであり、マクロファージの遊走を制御し、炎症部位にマクロファージを集め、貪食能を高める液性因子である。ＭＩＦは慢性関節リウマチ(非特許文献１：Expert Opin Ther Targets, 7, 2, 153-164, 2003)、腎炎(非特許文献２：Expert Opin Ther Targets, 7, 2, 153-164, 2003)、アトピー性皮膚炎(非特許文献３：Biochem Biophys Res Commun, 240, 11, 173-8, 1997)、乾癬（非特許文献４：B J Dermatol, 141, 1061-66, 1999)、潰瘍性大腸炎、敗血症、接触性皮膚炎(非特許文献５：Eur J Immunol, 33, 1478-87, 2003)、紫外線による炎症(非特許文献６：J Invest Dermatol, 112, 2, 210-15, 1999)、遅延性アレルギー(非特許文献７：Pro Natl Acad Sci USA, 93, 7849-54, 1996)などの急性・慢性炎症疾患(J End, 179, 15-23, 2003)、関節炎、移植片拒絶反応、腫瘍成長、血管新生、貧血、脳脊髄炎等の炎症性疾患の病理過程に関与しており、ＭＩＦを阻害することにより、これら炎症性疾患を軽減させることが期待される。
ＭＩＦの活性阻害剤は種々開発されている（特許文献１：特表２００３−５１３０６５号公報、特許文献２：特表２００５−５００２６６号公報、特許文献３：特表２００６−５１７９７７号公報）。
本発明者は、ＭＩＦの分泌抑制に着目し、ＭＩＦの分泌抑制剤に関する研究開発を継続している。本発明者は、ヒメジョオン又はその抽出物をＭＩＦの分泌抑制剤とする技術(特許文献４：特開２００９−２０３２２１号)、ヒルガオ又はその抽出物をＭＩＦの分泌抑制剤とする技術(特許文献５：特開２０１０−７０４８３号)、マユマメ又はその抽出物をＭＩＦの分泌抑制剤とする技術(特許文献６：特開２０１０−７０４８４号)、アジョワン又はその抽出物をＭＩＦの分泌抑制剤とする技術(特許文献７：特開２０１０−７０４８５号)、トウガシ又はその抽出物をＭＩＦの分泌抑制剤とする技術(特許文献８：特開２０１０−７０４８６号)、シナヤグルマカエデ又はその抽出物をＭＩＦの分泌抑制剤とする技術(特許文献９：特開２０１０−７０４８７号)、を提案した。
一方、本発明で使用するローズマリー（学名：Rosmarinus officinalis L.）は、地中海沿岸地方原産で、シソ科に属する常緑性低木である。ローズマリーの薬効については様々な研究がなされている。消臭効果や抗菌作用、抗酸化作用（非特許文献８：駒沢女子大学 研究紀要 30 pp.31-38 19970）、神経成長因子の生成を高める作用（非特許文献９：Biol Pharm Bull. 2003 Nov;26(11):1620-2.）、生体防御機構を活性化させる作用（非特許文献１０：J Biol Chem. 2004 Mar 5;279(10):8919-29）効果があることなどが報告されている。
またローズマリーは、皮膚外用剤としても種々の用途に使用されている。真皮コラーゲン線維束再構築剤（特許文献１０：特開２０１１−２４６３５４号公報）としての用途、ローズマリー油を皮脂溶解剤（特許文献１１：特開２０１１−２０７８１９号公報）として用いる用途、一重項酸素消去剤（特許文献１２：特開２０１２−１８４３５７号公報）として用いる用途、アトピー性皮膚炎を治療するための治療用水和ゲル剤に配合する用途（特許文献１３：特開２００８−３７８７１号公報）、化粧料に抗菌性を付与するための用途（特許文献１４：特開２００７−８９０９号公報）など、様々の用途が提案されている。
Macrophage migration inhibitory factor (hereinafter referred to as MIF) is one of the mediators of inflammation and immunity, and is a humoral factor that controls macrophage migration, collects macrophages at the site of inflammation, and enhances phagocytic ability. MIF is rheumatoid arthritis (Non-patent document 1: Expert Opin Ther Targets, 7, 2, 153-164, 2003), nephritis (Non-patent document 2: Expert Opin Ther Targets, 7, 2, 153-164, 2003), Atopic dermatitis (Non-patent document 3: Biochem Biophys Res Commun, 240, 11, 173-8, 1997), psoriasis (Non-patent document 4: BJ Dermatol, 141, 1061-66, 1999), ulcerative colitis, Sepsis, contact dermatitis (Non-patent document 5: Eur J Immunol, 33, 1478-87, 2003), inflammation caused by ultraviolet rays (Non-patent document 6: J Invest Dermatol, 112, 2, 210-15, 1999), delayed Acute / chronic inflammatory diseases (J End, 179, 15-23, 2003) such as sexual allergy (Non-patent Document 7: Pro Natl Acad Sci USA, 93, 7849-54, 1996), arthritis, graft rejection, tumor It is involved in the pathological processes of inflammatory diseases such as growth, angiogenesis, anemia, encephalomyelitis and the like, and it is expected to reduce these inflammatory diseases by inhibiting MIF.
Various active inhibitors of MIF have been developed (Patent Document 1: Japanese Patent Publication No. 2003-513065, Patent Document 2: Japanese Patent Publication No. 2005-500266, Patent Document 3: Japanese Patent Publication No. 2006-517977).
The present inventor has focused on MIF secretion inhibition and has continued research and development on MIF secretion inhibitors. The inventor of the present invention uses a technique of using Himejoon or an extract thereof as an MIF secretion inhibitor (Patent Document 4: JP-A-2009-203221), and a technique of using convolvulus or an extract thereof as an MIF secretion inhibitor (Patent Document 5). : Japanese Patent Application Laid-Open No. 2010-70483), a technology using maya beans or an extract thereof as an MIF secretion inhibitor (Patent Document 6: Japanese Patent Application Laid-Open No. 2010-70484), a technology using Ajowan or an extract thereof as an MIF secretion inhibitor (Patent Document 7: Japanese Patent Application Laid-Open No. 2010-70485), a technique using a red pepper or an extract thereof as a MIF secretion inhibitor (Patent Document 8: Japanese Patent Application Laid-Open No. 2010-70486), a Japanese maple maple or an extract thereof using MIF A technique for producing a secretion inhibitor (Patent Document 9: Japanese Patent Application Laid-Open No. 2010-70487) has been proposed.
On the other hand, rosemary (scientific name: Rosmarinus officinalis L.) used in the present invention is an evergreen shrub native to the Mediterranean coast and belonging to the family Lamiaceae. Various studies have been conducted on the medicinal properties of rosemary. Deodorant effect, antibacterial action, antioxidant action (Non-patent Document 8: Komazawa Women's University Research Bulletin 30 pp.31-38 19970), action to enhance the generation of nerve growth factor (Non-patent Document 9: Biol Pharm Bull. 2003 Nov 26 (11): 1620-2.), An effect of activating a biological defense mechanism (Non-patent Document 10: J Biol Chem. 2004 Mar 5; 279 (10): 8919-29) has been reported. Has been.
Rosemary is also used in various applications as a skin external preparation. Use as a dermal collagen fiber bundle reconstructing agent (Patent Document 10: JP 2011-246354 A), use using rosemary oil as a sebum solubilizer (Patent Document 11: JP 2011-207919 A), singlet Use as an oxygen scavenger (Patent Document 12: Japanese Patent Application Laid-Open No. 2012-184357), Use in a hydrating gel for treatment to treat atopic dermatitis (Patent Document 13: Japanese Patent Application Laid-Open No. 2008-37871) ), Various uses such as a use for imparting antibacterial properties to cosmetics (Patent Document 14: Japanese Patent Laid-Open No. 2007-8909) have been proposed.
本発明は新しいＭＩＦ分泌抑制剤を提供することを課題とする。 An object of the present invention is to provide a novel MIF secretion inhibitor.
本発明の主な構成は、次のとおりである。
（１）ローズマリーの１，３ブチレングリコール抽出物を有効成分とするマクロファージ遊走阻止因子（ＭＩＦ）分泌抑制用組成物。
（２）ローズマリーの１，３ブチレングリコール抽出物が、全草又は花の抽出物である（１）に記載のＭＩＦ分泌抑制用組成物。
（３）（１）１又は（２）に記載のＭＩＦ分泌抑制用組成物を含有するＭＩＦ分泌抑制用の皮膚外用剤。
The main configuration of the present invention is as follows.
(1) A composition for inhibiting macrophage migration inhibitory factor (MIF) secretion comprising a rosemary 1,3-butylene glycol extract as an active ingredient.
(2) The composition for suppressing MIF secretion according to (1), wherein the 1,3 butylene glycol extract of rosemary is an extract of whole grass or flowers.
(3) A skin external preparation for suppressing MIF secretion comprising the composition for suppressing MIF secretion according to (1) 1 or (2) .
本発明により、ＭＩＦ異常分泌に伴うアトピー性皮膚炎等の新たな治療剤または予
防剤の提供が可能となる。
また、ＭＩＦの異常分泌や関与が推定されている、乾癬や紫外線による皮膚炎症、血管腫、蕁麻疹、敗血症、呼吸器炎症、潰瘍性大腸炎、慢性関節リウマチ、腎炎、接触性皮膚炎、遅延性アレルギーなどの急性・慢性炎症疾患、関節炎、移植片拒絶反応、腫瘍成長、血管新生、貧血、脳脊髄炎、その他菌感染による炎症への治療や予防に使用することが可能となる。さらに又本発明のＭＩＦ分泌抑制剤は、皮膚外用剤として皮膚の炎症部位に塗布することで、マクロファージ遊走阻止因子の働きを抑えて、炎症部位におけるマクロファージの機能を抑制し、炎症を治療することができる。
According to the present invention, it is possible to provide a new therapeutic agent or preventive agent for atopic dermatitis associated with abnormal secretion of MIF.
In addition, abnormal secretion and involvement of MIF are estimated, skin inflammation caused by psoriasis and ultraviolet rays, hemangioma, urticaria, sepsis, respiratory inflammation, ulcerative colitis, rheumatoid arthritis, nephritis, contact dermatitis, delayed It can be used for the treatment and prevention of acute and chronic inflammatory diseases such as sexual allergy, arthritis, graft rejection, tumor growth, angiogenesis, anemia, encephalomyelitis, and other inflammation caused by bacterial infection. Furthermore, the MIF secretion inhibitor of the present invention is applied to an inflammatory site of the skin as an external preparation for skin, thereby suppressing the function of macrophage migration inhibitory factor, suppressing the function of macrophages at the inflammatory site, and treating inflammation. Can do.
本発明で使用するローズマリーは前述したように民間療法に広く利用されており、またハーブとして食用されており、園芸植物としても栽培されている。 As described above, the rosemary used in the present invention is widely used in folk remedies, is edible as an herb, and is also cultivated as a garden plant.
ローズマリー抽出物としてはローズマリーの全草、あるいは葉をそのまま粉砕し、あるいは乾燥させた後に粉砕して、水あるいはエタノール等のアルコール、エーテル、アセトン、１，３−ブチレングリコール、１，２−ペンタンジオール、プロピレングリコール、酢酸エチルなどの有機溶媒により抽出した粗抽出物、および粗抽出物を分配抽出やカラムクロマトなどの各種クロマトグラフィーなどで段階的に精製して得られた抽出物画分を含む。これらは単独で用いても良く、また２種以上混合して用いても良い。
ローズマリーの全草、あるいは葉を生のまま抽出操作に供しても良いが、細切、乾燥、粉砕等の処理を行なった後、抽出を行なう方が効率がよい。抽出は抽出溶媒に浸漬して行なうことができる。抽出効率を上げる為に、抽出溶媒を攪拌したり、抽出溶媒中で破砕均一化したり、抽出溶媒中で圧力をかけることもできる。抽出温度は5〜100℃程度が適切であり、抽出時間は5分〜1ヶ月程度である。これらの条件は適宜設定することができる。
前記ローズマリー抽出物はそのまま、また、水、エタノール等の有機溶媒に溶解又は分散させた状態で、ＭＩＦ分泌抑制剤、炎症性疾患の改善剤、特に皮膚の炎症性疾患改善剤として使用できる。また、必要に応じて抽出溶媒を留去し、その乾燥物を用いてもよい。
一方、すでにローズマリー抽出物も市販されている。「ローズマリー抽出液ＢＧ」丸善製薬株式会社製のブチレングリコール抽出エキスが市販されており、これを本発明の実施に当たって使用することも可能である。
As the rosemary extract, the whole plant or leaves of rosemary are crushed as they are, or dried and then crushed, water, alcohol such as ethanol, ether, acetone, 1,3-butylene glycol, 1,2- A crude extract extracted with an organic solvent such as pentanediol, propylene glycol, and ethyl acetate, and an extract fraction obtained by stepwise purification of the crude extract by various types of chromatography such as partition extraction and column chromatography Including. These may be used alone or in combination of two or more.
The whole rosemary plant or leaf may be subjected to an extraction operation as it is, but it is more efficient to perform extraction after processing such as shredding, drying, and pulverization. Extraction can be performed by immersing in an extraction solvent. In order to increase the extraction efficiency, the extraction solvent can be stirred, crushed and homogenized in the extraction solvent, or pressure can be applied in the extraction solvent. The extraction temperature is suitably about 5 to 100 ° C., and the extraction time is about 5 minutes to 1 month. These conditions can be set as appropriate.
The rosemary extract can be used as it is, or dissolved or dispersed in an organic solvent such as water or ethanol, as an MIF secretion inhibitor, an inflammatory disease ameliorating agent, particularly a skin inflammatory disease ameliorating agent. Further, if necessary, the extraction solvent may be distilled off and the dried product may be used.
On the other hand, rosemary extract is already on the market. “Rosemary extract BG”, a butylene glycol extract, manufactured by Maruzen Pharmaceutical Co., Ltd., is commercially available and can be used in the practice of the present invention.
ローズマリー抽出物は、乾燥物として、0.0001〜1000mg／日の範囲で適用することができ、さらに、この範囲に限らず、対象、適用形態、症状に応じてその量を適宜設定することができる。
本発明のローズマリー抽出物の配合量としては、0.0001〜10質量％程度が好ましいが、用いる剤型、使用対象等の様々の条件に応じて、100質量％までの広範囲でその配合量を適宜設定できる。
The rosemary extract can be applied as a dry product in the range of 0.0001 to 1000 mg / day, and the amount can be appropriately set according to the target, application form, and symptoms, not limited to this range. .
The blending amount of the rosemary extract of the present invention is preferably about 0.0001 to 10% by weight, but the blending amount is appropriately selected over a wide range up to 100% by weight, depending on various conditions such as the dosage form to be used and the intended use Can be set.
本発明の製剤は、経口で又は非経口で投与することができる。
本発明の製剤は、例えば水溶液、油剤、乳液、懸濁液等の液剤、ゲル、クリーム等の半固形剤、粉末、顆粒、カプセル、マイクロカプセル、固形等の固形剤の形態で適用可能である。従来から公知の方法でこれらの形態に調製し、ローション剤、乳剤、ゲル剤、クリーム剤、軟膏、硬膏、ハップ剤、エアゾル剤、坐剤、注射剤、粉末剤、顆粒剤、錠剤、丸剤、シロップ剤、トローチ剤等の種々の剤型とすることができる。これらを身体に塗布、貼付、噴霧、飲用等により適用することができる。特にこれら剤型の中で、皮膚外用剤であるローション剤、乳剤、クリーム剤、軟膏剤、硬膏剤、ハップ剤、エアゾル剤等が適している。通常、医薬において使用される製剤化方法にしたがって、これらの剤型、組成物として製造することができる。
以下、実施例に基づき本発明を詳細に説明する。
The preparation of the present invention can be administered orally or parenterally.
The preparation of the present invention can be applied in the form of a solid agent such as an aqueous solution, oil agent, emulsion, suspension, etc., semi-solid agent such as gel, cream, powder, granule, capsule, microcapsule, solid, etc. . It is prepared in these forms by conventionally known methods, and lotions, emulsions, gels, creams, ointments, plasters, haps, aerosols, suppositories, injections, powders, granules, tablets, pills , Various dosage forms such as syrups and lozenges. These can be applied to the body by applying, sticking, spraying, drinking and the like. Among these dosage forms, lotions, emulsions, creams, ointments, plasters, haps, aerosols and the like, which are external preparations for skin, are suitable. Usually, these dosage forms and compositions can be produced according to the formulation method used in medicine.
Hereinafter, the present invention will be described in detail based on examples.
〔ローズマリー抽出物のケラチノサイトを用いたＵＶＢ誘導性ＭＩＦ分泌抑制試験〕
ＭＩＦは皮膚の構成細胞の一つであるケラチノサイトで強く発現することが知られている。そして、ケラチノサイトにUVBを照射することにより、ＭＩＦの分泌が促進されることが知られている(J Invest Dermatol, 112, 2, 210-15, 1999)。
ケラチノサイトにＵＶＢを照射したときのＭＩＦの分泌をローズマリー抽出物が抑制するか否かを試験した。
なお本試験で用いたローズマリー抽出物は、次のものを用いた。
製品名「ローズマリー抽出液ＢＧ」丸善製薬株式会社製、ローズマリーエキス濃度1.7%、溶媒ブチレングリコール、溶媒濃度49.15%
[UVB-induced MIF secretion inhibition test using rosemary extract keratinocytes]
It is known that MIF is strongly expressed in keratinocytes, which are one of the constituent cells of the skin. It is known that MIF secretion is promoted by irradiating UVB to keratinocytes (J Invest Dermatol, 112, 2, 210-15, 1999).
It was tested whether or not the rosemary extract inhibits MIF secretion when keratinocytes are irradiated with UVB.
The following rosemary extract was used in this test.
Product name “Rosemary extract BG” manufactured by Maruzen Pharmaceutical Co., Ltd., rosemary extract concentration 1.7%, solvent butylene glycol, solvent concentration 49.15%
＜試験方法＞
１．ヒトケラチノサイトを1.0×104 cells/cm2でφ35mm dishに播種し、EpiLife-KG2培地(倉敷紡績製)で3日間培養した。EpilLife-KG2・BPE(-)培地に各サンプルを所定の抽出物濃度を添加したサンプル添加培地に交換し、1晩培養後、HANKS(-)存在下でＵＶＢを2.0W/m2、15mJ/cm2照射し、サンプル含有EpilLife-KG2・BPE(-)培地に交換し、24時間培養した。培養上清を回収し、hMIF ELISA kit を用いて、定法に従い上清中ＭＩＦ量を測定し、ＭＩＦ分泌量を算出した。さらに、細胞をCell lysys bufferで溶解し、溶解液中のたんぱく質量をプロテインアッセイキットで測定し、dishあたりのタンパク質量を算出した。
<Test method>
1. Human keratinocytes were seeded in a φ35 mm dish at 1.0 × 10 4 cells / cm 2 and cultured in EpiLife-KG2 medium (Kurashikibo) for 3 days. Replace each sample with EpilLife-KG2 · BPE (-) medium with a sample-added medium with the specified extract concentration added, and after overnight culture, UVB in the presence of HANKS (-) is 2.0 W / m 2 , 15 mJ / After irradiation with cm 2 , the sample was replaced with a sample-containing EpilLife-KG2 · BPE (−) medium and cultured for 24 hours. The culture supernatant was collected, and the amount of MIF in the supernatant was measured using the hMIF ELISA kit according to a conventional method, and the amount of MIF secretion was calculated. Furthermore, the cells were lysed with Cell lysys buffer, the protein mass in the lysate was measured with a protein assay kit, and the amount of protein per dish was calculated.
２．ＵＶＢ照射した試料無添加で溶媒添加（0.1%ＢＧ）処理群の単位タンパク質当たりのＭＩＦ分泌率を100%とした。
ＭＩＦ分泌率(%)を求める式を以下に示す。
ＭＩＦ分泌率（％）＝(Ｍx／Ｐx)／(Ｍ0／Ｐ0)×100
Ｍ0：ＵＶＢ照射・サンプルＡ無添加で溶媒添加（0.1%ＢＧ）のＭＩＦ分泌量、
Ｐ0：Ｍ0測定時のタンパク質量、
Ｍx：各試料のＭＩＦ分泌量、
Ｐx：各試料のタンパク質量
2. The MIF secretion rate per unit protein in the solvent-added (0.1% BG) treated group with no UVB-irradiated sample was taken as 100%.
The formula for obtaining the MIF secretion rate (%) is shown below.
MIF secretion rate (%) = (M x / P x ) / (M 0 / P 0 ) × 100
M 0 : MIF secretion amount with UVB irradiation and solvent addition (0.1% BG) without sample A ,
P 0 : protein amount at the time of M 0 measurement ,
M x : MIF secretion amount of each sample ,
P x : protein amount of each sample
＜結果＞
ＭＩＦ分泌抑制率の測定結果を表１、図１に示す。なお、本試験における試料無添加群とローズマリー抽出物添加群の細胞のタンパク質の量を比較したところ、両群に差は認められなかった。したがって、ローズマリーの細胞毒性は認められないものと判断した。
<Result>
The measurement results of the MIF secretion inhibition rate are shown in Table 1 and FIG. In addition, when the amount of protein of the cells in the sample-free group and the rosemary extract-added group in this test was compared, no difference was found between the two groups. Therefore, it was judged that the cytotoxicity of rosemary was not observed.
以上の試験結果から、ケラチノサイトにローズマリー抽出物を添加することにより、紫外線誘導性のＭＩＦの分泌が顕著に抑制された。抑制はローズマリー抽出液の添加量に依存していた。
したがって、ＭＩＦの分泌量が増加することによって皮膚の症状が悪化することが知られている紫外線による皮膚障害・炎症、アトピー性皮膚炎、乾癬、接触性皮膚炎等のＭＩＦが関与する皮膚の炎症性疾患に対して改善効果が期待できる。
From the above test results, the addition of rosemary extract to keratinocytes markedly suppressed UV-induced MIF secretion. Inhibition was dependent on the amount of rosemary extract added.
Therefore, skin inflammation associated with MIF such as skin damage / inflammation due to ultraviolet rays, atopic dermatitis, psoriasis, contact dermatitis, etc., which are known to worsen skin symptoms due to increased secretion of MIF It can be expected to improve the disease.
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