JP7037205B2 - 幹細胞由来のエキソソームを有効成分として含む組成物のかゆみの抑制又は改善の用途 - Google Patents
幹細胞由来のエキソソームを有効成分として含む組成物のかゆみの抑制又は改善の用途 Download PDFInfo
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- JP7037205B2 JP7037205B2 JP2019566946A JP2019566946A JP7037205B2 JP 7037205 B2 JP7037205 B2 JP 7037205B2 JP 2019566946 A JP2019566946 A JP 2019566946A JP 2019566946 A JP2019566946 A JP 2019566946A JP 7037205 B2 JP7037205 B2 JP 7037205B2
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Description
ヒト皮膚繊維芽細胞(human dermal fibroblast)であるHS68細胞はATCCから購入し、10%ウシ胎児血清(fetal bovine serum:ThermoFisher Scientificから購入)及び1%抗生剤-抗真菌剤(antibiotics-antimycotics:ThermoFisher Scientificから購入)が含有されたDMEM(ThermoFisher Scientificから購入)培地に5%CO2、37℃の条件で継代培養した。また、ヒト皮膚角質細胞(human keratinocyte)であるHaCaT細胞は、10%のFBS(Fetal Bovine Serum)及び1体積%のペニシリン-ストレプトマイシンが補充されたDMEM培地に5%CO2、37℃の条件で継代培養した。
実施例1で0.22μmフィルタでろ過された培養液からエキソソームを分離、濃縮、脱塩とバッファー交換(diafiltration)をするためにTFF(Tangential Flow Filtration)法を使用した。TFF法を用いてエキソソームを分離、濃縮する前に培養液を超音波処理(sonication)して潜在的なエキソソームの塊を解いた。TFF法のためのフィルタとしては、カートリッジフィルタ(cartridge filter、別名hollow fiber filter;GE Healthcareから購入)、又はカセットフィルタ(cassette filter;Pall又はSartorius又はMerck Milliporeから購入)を使用した。TFFフィルタは、様々な分画分子量(molecular weight cutoff;MWCO)によって選択されてもよい。選択されたMWCOによって選別的にエキソソームを分離、濃縮し、MWCOよりも小さい粒子やタンパク質、脂質、核酸、低分子化合物等は除去した。
分離されたエキソソーム、培養液、及びTFF分離過程の分画物におけるタンパク質の量は、BCA発色法(ThermoFisher Scientificから購入)、又はフルオロプロファイル(FluoroProfile)蛍光法(Sigmaから購入)を用いて測定した。本発明の一具体例のTFF法によりエキソソームが分離、濃縮されてタンパク質、脂質、核酸、低分子化合物等が除去される程度は、タンパク質定量法によってモニタリングし、その結果を図2に示した。その結果、本発明の一具体例のTFF法によって非常に効果的に培養液に存在するタンパク質が除去されることが分かった。
ヒト皮膚繊維芽細胞であるHS68細胞で本発明の一具体例の分離方法によって得られたエキソソームの毒性を評価するために、細胞に濃度別にエキソソームを処理し、細胞の増殖率を確認した。HS68細胞を、10%FBSを含むDMEMに懸濁させた後、80~90%の密集度(confluency)を有するように分株し、37℃、5%CO2インキュベーターで24時間培養した。24時間後、培養液を除去し、実施例2で準備されたエキソソームを濃度別に処理して、24~72時間培養しながら細胞生存率を評価した。細胞生存率をWST-1試薬(WST-1 reagent)(Takaraから購入)、MTT試薬(Sigmaから購入)、セルタイターグロ試薬(CellTiter-Glo reagent)(Promegaから購入)、又はアラマールブルー試薬(alamarBlue reagent)(ThermoFisher Scientificから購入)とマイクロプレートリーダー(microplate reader)(Molecular Devicesから購入)を用いて測定した。
雄NC/Ngaマウス(16~18g、5週齢;中央実験動物から購入)を購入して7日間の適応期を通じて本実験に使用した。適応期を経たマウスはかゆみを伴う皮膚炎誘発後、以下のようにそれぞれ5群に分類した。
(1)Normal:正常対照群
(2)Vehicle(皮膚炎誘発群):イエダニ抽出物によりかゆみを伴う皮膚炎を誘発した陰性対照群
(3)IV:イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に2.8μgの用量で週3回ずつ2週間、血管内投与(IV:intravenous injection)した実験群
(4)SC:イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に2.8μgの用量で週3回ずつ2週間、皮下投与(SC:subcutaneous injection)した実験群
(5)Pred:イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、プレドニゾロン(prednisolone)を毎日経口投与した実験群
NC/Ngaマウス(中央実験動物から購入)の耳介部分をカミソリで除毛した後、除毛剤を適量塗布して除毛した。除毛剤をふき取った後、AD誘発試薬(イエダニ抽出物;BioStir Inc.から購入)をマイクロピペットチップ(micro pipet tip)を用いて、耳介部分に均一に塗布した。必要に応じてカミソリで除毛した後、4%SDS水溶液150μLをマイクロピペットチップ(micro pipet tip)を用いて、耳介部分に均一に塗布した。ドライヤーを用いて冷風で乾燥させた後、約2~3時間自然乾燥させた後、AD誘発試薬をマイクロピペットチップ(micro pipet tip)を用いて耳介部分に均一に塗布した。すべての前処理は、1週間に2回、計3週間、6回の処理で行った。
エキソソームの用量依存的な効果を確認するために、実施例5と同様に、かゆみを伴う皮膚炎を誘発した後、以下のように9群に分類した。
(1)Normal:正常対照群(図8で「N」と表記)
(2)Control(皮膚炎誘発群):イエダニ抽出物によりかゆみを伴う皮膚炎を誘発した陰性対照群(図8で「C」と表記)
(3)IV、L(exosome、low):イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に0.14μgの用量で週3回ずつ4週間、血管内投与(IV:intravenous injection)した実験群
(4)IV、M(exosome、medium):イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に1.4μgの用量で週3回ずつ4週間、血管内投与(IV:intravenous injection)した実験群
(5)IV、H(exosome、high):イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に10μgの用量で週3回ずつ4週間、血管内投与(IV:intravenous injection)した実験群
(6)SC、L(exosome、low):イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に0.14μgの用量で週3回ずつ4週間、皮下投与(SC:subcutaneous injection)した実験群
(7)SC、M(exosome、medium):イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に1.4μgの用量で週3回ずつ4週間、皮下投与(SC:subcutaneous injection)した実験群
(8)SC、H(exosome、high):イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、実施例2で準備されたエキソソームを個体別に10μgの用量で週3回ずつ4週間、皮下投与(SC:subcutaneous injection)した実験群
(9)Pred:イエダニ抽出物によりかゆみを伴う皮膚炎誘発後、プレドニゾロン(prednisolone)を毎日経口投与した実験群(図8で「P」と表記)
本発明のエキソソームがかゆみを抑制及び緩和させる効果があるか否かと、様々な原因に起因するかゆみに対して広範囲の適用が可能か否かを確認するために、IL-4 mRNA及びIL-31のmRNA発現レベルを分析した。IL-4は、かゆみを誘発するサイトカインとして広く知られており、表皮でIL-4を発現する形質転換マウスで皮膚のかゆみが誘発されることが報告されたところがある(非特許文献5)。そしてIL-31は、かゆみを示すアトピー性皮膚炎患者で過発現され、IL-31を過発現するように形質転換されたマウスでかゆみが誘発されることが報告されたところがある(非特許文献6)。また、IL-31は、IL-31RA/OSMR受容体と結合して、かゆみを引き起こすことが報告されており(非特許文献7)、IL-31受容体Aに対する抗体を処理した場合、かゆみが緩和されることが報告されたところがある(非特許文献8)。したがって、候補物質処理後、皮膚組織や血液内のIL-4及びIL-31の生成量や発現量を分析すると、候補物質のかゆみ抑制及び緩和に対する効能を評価することができる。
TSLPは、かゆみがひどい患者の上皮細胞や皮膚角質細胞(human keratinocytes)で過度に増加しており、皮膚のかゆみの原因となる物質として知られている。したがって、特定の候補物質が皮膚角質細胞で誘導されるTSLPを抑制するか否かを確認すれば候補物質のかゆみ抑制ないし緩和効果を確認することができる。ヒト皮膚角質細胞であるHaCaT細胞を、10%FBS(fetal bovine serum)、1%アムホテリシンB(Sigmaから購入)及び1%ペニシリン-ストレプトマイシンが補充されたDMEM(ThermoFisher Scientificから購入)培地に懸濁させた後、12ウェルプレート(12 well plate)の各ウェルに1×105の密度で接種し、24時間培養した。その後、無血清DMEM培地でさらに24時間培養した後、付着した細胞をPBSで2回洗浄し、図9Aに示された実験群の分類に基づいて無血清培地でポリI:C(Poly I:C)(Sigmaから購入)及びヒスタミン(Histamine)(Sigmaから購入)と、本発明のエキソソーム(実施例2で準備されたエキソソーム)を処理して、24時間培養した。各実験群のHaCaT細胞から分離したRNAからcDNAを製造してリアルタイムPCR法を用いて、かゆみの主な原因となるTSLPのmRNAの変化量を測定した。TSLP遺伝子を定量するための標準遺伝子としてβ-アクチン遺伝子を使用した。リアルタイムPCRに使用したプライマーの種類と配列は下記表2の通りである。
蛍光染色されたエキソソームを製造するためにPKH67染料(Sigmaから購入)を使用した。1mMのPKH67をDiluent C(Sigmaから購入)に希釈して、10μMのPKH67溶液を製造した後、適正濃度のエキソソーム溶液と混合して、常温で光を遮断した状態で10分間反応させた。反応が終わった後、PKH67で染色されたエキソソーム(以下、「PKH-エキソソーム」と略称)から残りのPKH67染料を除去するためにMW3000スピンカラム(ThermoFisher Scientificから購入)を使用した。蛍光測定器(Molecular Devicesから購入)を用いて確認した結果、エキソソームと反応しないPKH67を除去した後、PKH-エキソソームで十分な強度の蛍光が検出されることを確認した(図10)。
本発明の一具体例の分離方法によって得られたエキソソームを含有するアンプル(半透明乳液状組成物を含む)、液状浸漬シートマスク(前記半透明乳液状が浸漬された白色シートマスク)及び経皮透過促進シートマスク(イオントフォレシスデバイスを含む銀色シートマスク)で構成された「試験製品」をかゆみと関連のある紅潮症状と皮膚のトラブルがひどい人(以下、「ケース1」という)の顔に1回適用して皮膚のトラブルと紅潮症状が緩和ないしは改善されるかを評価した。また、前記試験製品を紅潮症状のある人(以下、「ケース2」という)の顔に1回適用して、全体的な皮膚のトーンと紅潮症状が改善されるかを評価した。
前記実施例2で準備された1704μg/mLの濃度のエキソソームを下記表3に記載された成分と混合して懸濁した後、化粧料組成物(ローション)を製造した。各成分の含有量は下記表3の通りである。
Claims (13)
- 脂肪由来幹細胞培養液から分離された、脂肪由来幹細胞由来のエキソソームを有効成分として含む、TSLP(Thymic stromal lymphopoietin)を媒介とするかゆみの予防、抑制、緩和、改善、又は治療用薬学組成物。
- 前記エキソソームは、皮膚組織又は皮膚細胞でIL-4、IL-31、及びTSLP(Thymic stromal lymphopoietin)の発現量を減少させることを特徴とする、請求項1に記載の薬学組成物。
- 脂肪由来幹細胞培養液から分離された、脂肪由来幹細胞由来のエキソソームを有効成分として含む、TSLP(Thymic stromal lymphopoietin)を媒介とするかゆみの予防、抑制、緩和、改善、又は治療用の皮膚外用剤。
- 前記エキソソームは、ハイドロゲル、ヒアルロン酸、ヒアルロン酸塩、又はヒアルロン酸ゲルのうち少なくとも1種に担持又は混合されている、請求項3に記載の皮膚外用剤。
- 前記ハイドロゲルは、ゲル化ポリマーを多価アルコールに分散させて得られたハイドロゲルであることを特徴とする、請求項4に記載の皮膚外用剤。
- 前記ゲル化ポリマーは、プルロニック、精製寒天、アガロース、ゲランガム、アルギン酸、カラギーナン、カシアガム、キサンタンガム、ガラクトマンナン、グルコマンナン、ペクチン、セルロース、グアーガム、及びローカストビーンガムからなる群から選ばれた少なくとも1種であり、前記多価アルコールは、エチレングリコール、プロピレングリコール、1,3-ブチレングリコール、イソブチレングリコール、ジプロピレングリコール、ソルビトール、キシリトール、及びグリセリンからなる群から選ばれた少なくとも1種であることを特徴とする、請求項5に記載の皮膚外用剤。
- 脂肪由来幹細胞培養液から分離された、脂肪由来幹細胞由来のエキソソームを有効成分として含む、TSLP(Thymic stromal lymphopoietin)を媒介とするかゆみの予防、抑制、緩和、又は改善用の化粧料組成物。
- パッチ、マスクパック、シートマスク、クリーム、トニック、軟膏、懸濁液、乳濁液、ペースト、ローション、ゲル、オイル、パック、スプレー、エアゾール、ミスト、ファンデーション、パウダー、及び油紙で構成された群から選ばれた少なくとも1種の形態に適用することを特徴とする、請求項7に記載の化粧料組成物。
- パッチ、マスクパック又はシートマスクの少なくとも一面に塗布又は浸漬されることを特徴とする、請求項8に記載の化粧料組成物。
- (a)請求項7に記載の化粧料組成物を哺乳動物の皮膚に直接塗布すること、(b)前記化粧料組成物が塗布又は浸漬されたパッチ、マスクパック又はシートマスクを哺乳動物の皮膚に接触又は付着すること、若しくは前記(a)及び(b)を順次進行することを含む、治療用を除くTSLP(Thymic stromal lymphopoietin)を媒介とするかゆみによる哺乳動物の皮膚の紅潮症状、皮膚のトラブル又は紅斑を緩和させる美容方法。
- (c)前記化粧料組成物が適用された哺乳動物の皮膚に微細電流を流してイオントフォレシス(iontophoresis)を行うことをさらに含む、請求項10に記載の美容方法。
- イオントフォレシス装置を前記哺乳動物の皮膚に接触又は付着させることをさらに含む、請求項11に記載の美容方法。
- 前記イオントフォレシス装置は、可撓性電池、リチウムイオン二次電池、アルカリ電池、乾電池、水銀電池、リチウム電池、ニッケルカドミウム電池、及び逆電気透析(reverse electrodialysis)電池で構成された群から選ばれた少なくとも1種の電池を含むか、前記少なくとも1種の電池が装着されたパッチ、マスクパック又はシートマスクを含む、請求項12に記載の美容方法。
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