JP6448214B2 - 皮膚バリア機能改善剤 - Google Patents
皮膚バリア機能改善剤 Download PDFInfo
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- JP6448214B2 JP6448214B2 JP2014089906A JP2014089906A JP6448214B2 JP 6448214 B2 JP6448214 B2 JP 6448214B2 JP 2014089906 A JP2014089906 A JP 2014089906A JP 2014089906 A JP2014089906 A JP 2014089906A JP 6448214 B2 JP6448214 B2 JP 6448214B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- 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
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Description
[1]JAK阻害剤を有効成分として含有する、老人性乾皮症、皮脂欠乏症、湿疹及び接触皮膚炎からなる群から選択される皮膚疾患の治療剤又は予防剤。
有機酸との塩として、例えば、シュウ酸、マレイン酸、クエン酸、フマル酸、乳酸、リンゴ酸、コハク酸、酒石酸、酢酸、トリフルオロ酢酸、グルコン酸、アスコルビン酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸等との塩が挙げられる。
有機塩基との塩として、例えば、メチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、エチレンジアミン、トリス(ヒドロキシメチル)メチルアミン、ジシクロヘキシルアミン、N,N’−ジベンジルエチレンジアミン、グアニジン、ピリジン、ピコリン、コリン、シンコニン、メグルミン等との塩が挙げられる。
アミノ酸との塩として、例えば、リジン、アルギニン、アスパラギン酸、グルタミン酸等との塩が挙げられる。
化合物A、B又はC、或いはその医薬上許容される塩としては、実質的に精製された、化合物A、B又はC、或いはその医薬上許容される塩が好ましい。さらに好ましくは、80%以上の純度に精製された、化合物A、B又はC、或いはその医薬上許容される塩である。
「崩壊剤」としては、例えば、カルメロース、カルメロースカルシウム、カルメロースナトリウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、結晶セルロース等が挙げられる。
「結合剤」としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポビドン、結晶セルロース、白糖、デキストリン、デンプン、ゼラチン、カルメロースナトリウム、アラビアゴム等が挙げられる。
「流動化剤」としては、例えば、軽質無水ケイ酸、ステアリン酸マグネシウム等が挙げられる。
「滑沢剤」としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク等が挙げられる。
「溶解補助剤」としては、例えば、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。
「懸濁化剤」としては、例えば、塩化ベンザルコニウム、カルメロース、ヒドロキシプロピルセルロース、プロピレングリコール、ポビドン、メチルセルロース、モノステアリン酸グリセリン等が挙げられる。
「等張化剤」としては、例えば、ブドウ糖、D−ソルビトール、塩化ナトリウム、D−マンニトール等が挙げられる。
「緩衝剤」としては、例えば、リン酸水素ナトリウム、酢酸ナトリウム、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。
「無痛化剤」としては、例えば、ベンジルアルコール等が挙げられる。
「抗酸化剤」としては、例えば、亜硫酸ナトリウム、アスコルビン酸等が挙げられる。
「着色剤」としては、例えば、食用色素(例えば食用赤色2号又は3号、食用黄色4号又は5号等)、β−カロテン等が挙げられる。
「甘味剤」としては、例えば、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテーム等が挙げられる。
カルシウム刺激により分化することが知られている新生児正常ヒト表皮角化細胞(Lonza社)を実験に用いた(非特許文献8)。新生児正常ヒト表皮角化細胞(Lonza社)を、Human Keratinocyte Growth Supplement(Cascade Biologics社)を添加したEpiLife Medium with 0.06mM Calcium(Cascade Biologics社))にて、細胞の取扱説明書に従い、培養した。新生児正常ヒト表皮角化細胞を、5×105個/wellで12ウェルプレートに播種し、37℃、5%CO2下で2時間培養した。上記細胞から培養上清を除いた後、各最終濃度100ng/mL ヒトIL−4及びヒトIL−13(R&D社)の存在下又は非存在下で、各種濃度の被験物質及び1.3mmol/L 塩化カルシウムを含む培養培地を添加し、細胞を37℃、5%CO2下で5日間培養した。化合物A、化合物Bの一クエン酸塩又は化合物Cの一リン酸塩を被験物質として用いた。
Total RNAを、GenElute Mammalian Total RNA Miniprep Kit(Sigma−Aldrich社)を用いて、取扱説明書に従い、上記培養細胞から精製した。
上記RNAをHigh Capacity cDNA Reverse Transcription Kit with RNase Inhibitor(Applied Biosystems社)を用いて、取扱説明書に従い、cDNAに逆転写した。上記cDNAをリアルタイムPCR法により、Taqman Gene Expresion Master Mix(Applied Biosystems社)を用いて、取扱説明書に従い、ABI Prism 7900HT sequence detectorで分析し、ヒトプロフィラグリン、ロリクリン、インボルクリン、ベータ‐デフェンシン3及びグリセルアルデヒド‐3‐リン酸デヒドロゲナーゼ(GAPDH)のCt値(Threshold Cycle)をそれぞれ求めた。GAPDHは内部標準として使用した。プライマー及びプローブは、Applied Biosystems社から購入したものを使用した(TaqMan Gene Expression Assays)。
ヒトプロフィラグリン、ロリクリン、インボルクリン及びベータ‐デフェンシン3の各相対mRNA量は比較Ct法により算出した。各被験物質を添加した細胞のmRNA量は、ヒトIL−4、ヒトIL−13及び被験物質を添加しなかった細胞における各遺伝子のmRNA量に対する比として、示した。結果を図1〜4に示す。
Tape Stripping処置マウス(非特許文献9)を用いて、JAK阻害剤によるNMF産生促進作用を評価した。実験動物は、8−10週齢の雌性C57BL/6jマウス(清水実験材料株式会社)を用いた。
マウス左耳介内側にセロハンテープ(NICHIBAN)を貼付し剥離すること(Tape Stripping)を5回繰り返し、角質を剥離した。Tape Stripping6日後まで1日1回、アセトン(Vehicle)または0.5%(w/v)の被験物質を、Tape Strippingした部位にそれぞれ0.02mLずつ塗布した。Tape Stripping1日目は、Tape Stripping1時間後にアセトン(Vehicle)または被験物質を塗布した。化合物A又は化合物Bの一クエン酸塩を被験物質として用いた。
Tape Stripping1、5及び7日後に、左耳介内側の総NMF量を、in vivo共焦点ラマン分光装置(model 3510、RiverDiagnostics社)で求めた。
左耳介内側表面より8マイクロメータの深さまで1マイクロメータ間隔で、励起波長を785nmとして400〜1800cm−1領域のラマンスペクトルを測定した。総NMF量は、Skin Tools 2.0(RiverDiagnostics社)を用いてケラチンあたりの量として定量した。各測定時には個体毎に2−5回測定を行った。測定深度毎に総NMF量の平均値を算出し、各深度における個体値として示した。化合物Aの結果を図5に、化合物Bの一クエン酸塩の結果を図6に示した。
DNFBに対する接触皮膚炎モデルマウス(非特許文献10)を用いて、JAK阻害剤の耳介腫脹抑制作用を評価した。実験動物は、8週齢の雌性C57BL/6jマウス(清水実験材料株式会社)を用いた。
マウス腹部を剃毛し、AOO(アセトンとオリーブオイルを4:1で混合した溶液)で希釈した0.5%(w/v)DNFB(2,4−Dinitrofluorobenzene、Sigma−Aldrich社)をそれぞれ0.025mLずつ腹部に塗布した(感作)。5日後、AOOで希釈した0.3%(w/v)DNFBをマウス両耳介の表裏にそれぞれ0.01mLずつ塗布した(惹起)。感作日より1日1回5日間、Vehicle群に0.5%(w/v)メチルセルロース(MC)を、化合物A投与群に0.5%(w/v)MCに懸濁した0.3mg/mLまたは3mg/mLの化合物Aを10mL/Kgの投与用量で経口投与した。各群は3匹ずつとした。感作及び惹起日は、感作及び惹起の1時間前に0.5%(w/v)MCまたは化合物Aを経口投与した。
惹起前及び惹起24時間後に両耳介の厚さをシックネスゲージ(TECLOCK社)で1回測定し、惹起前の各耳介の厚さからの変化量の平均を個体値とした。結果を図7に示した。
三次元培養皮膚モデルとして、TESTSKIN LSE−high(東洋紡社、TMLSE−013A)を用いた(非特許文献11)。TESTSKIN LSE−highの取扱い説明書に従い、トランスウェル上のLiving Skin Equivalent(LSE)組織を、キットに含まれているアッセイ培地にて、37℃、5%CO2下で24時間培養した。
LSE組織培養系より培地を除いた後、各最終濃度20ng/mLのヒトIL−4及びヒトIL−13(R&D社)存在下又は非存在下で、最終濃度1000nmol/Lの化合物Aを含むアッセイ培地を添加し、LSE組織を37℃、5%CO2下で3日間培養した。上記と同様に培地交換を行い、LSE組織を37℃、5%CO2下でさらに2日間培養した。
LSE組織の表皮層をチューブにそれぞれ回収し、9mol/L 尿素、2% Triton X−100、プロテアーゼインヒビターカクテル(シグマ社、P8340)及びホスファターゼインヒビターカクテル(ナカライテスク社、07575−51)を含む50mmol/L Tris−HCl(pH8.0)緩衝液を0.1mLずつ添加し、超音波処理で溶解した。組織溶解液に1.73mmol/L 2−メルカプトエタノールを含むラミニSDS−PAGEサンプルバッファーを0.08mLずつ添加し、95度で5分間加熱し、タンパク質を熱変性させた。
熱変性させたタンパク質(0.015mg/lane)を、4−12% NuPAGE Bis−Tris gel(Life technologies社)上でSDS−ポリアクリルアミド電気泳動(SDS−PAGE)により分離し、ウエスタンブロット法でフィラグリンタンパク質及びロリクリンタンパク質を検出した。内部標準としてGAPDHタンパク質を検出した。常法に従い、SDS−PAGEで分離したタンパク質をPVDF膜(GE Healthcare社)へブロッティングし、PVDF膜を5%スキムミルク(ナカライテスク社)でブロッキングした。PVDF膜を一次抗体(マウス抗ヒトフィラグリン抗体(Santa Cruz Biotechnology社、sc−66192、300倍希釈)、ウサギ抗ヒトロリクリン抗体(Covance社、PRB−145P、1000倍希釈)もしくはウサギ抗ヒトGAPDH抗体(Genetex社、GTX100118、1000倍希釈))でインキュベーションした後、西洋ワサビペルオキシダーゼ(HRP)で標識された二次抗体(ヒツジ抗マウスIgG抗体(GE Healthcare社、RPN2124、10000倍希釈)もしくはヤギ抗ウサギIgG抗体(Cell Signaling Technology社、7074、3000倍希釈))でインキュベーションした。化学発光基質(ECL Western Blotting Detection Reagents;GE Healthcare、RPN2232)を取扱い説明書に従って使用して、PVDF膜よりオートラジオグラフィー用フィルムAmersham Hyperfilm ECL(GE Healthcare社)へ露光し、目的とするタンパク質を検出した。結果を図8及び9に示した。
「ドライスキンモデルマウスの作製」
ドライスキンモデルマウス(非特許文献12)を用いて、JAK阻害剤の皮膚バリア機能の改善効果を評価した。実験動物は、8週齢の雌性C57BL/6JJmsSlcマウス(日本エスエルシー社)を用いた。
アセトンとジエチルエーテルの混合液(1:1)に浸漬した脱脂綿をマウスの右または両耳介内側の表面に30秒間置いた後、水に浸漬した脱脂綿を同じ領域に30秒間置いた(以下、A/E/W処理と略す)。この処理を各群とも1日2回、7日間行い、ドライスキンモデルを作製した。A/E/W処理を開始した日をDay0とした。正常対照群にはA/E/W無処置のマウスを使用した。
1%(v/v)DMSO含有アセトンに溶解した最終濃度0.5%(w/v)の化合物Aを、Day0から、1日1回7日間、A/E/W処理直後に、A/E/W処理した領域に0.02mLずつ塗布した(化合物A投与群)。Vehicle群には、1%(v/v)DMSO含有アセトンを、Day0から、1日1回7日間、A/E/W処理直後に、A/E/W処理した領域に0.02mLずつ塗布した。
「定量的リアルタイムPCR」
右耳介にA/E/W処理を行ったマウスを実験に用いた。Day0、3及び6のA/E/W処置直前に、マウス右耳介(化合物A投与群及びVehicle群;各n=4)からTotal RNAをRNeasy mini kit(QIAGEN社)を用いて、取扱い説明書に従い、抽出した後、DNase I(タカラバイオ社)で消化した。Total RNAを、Prime Script RT reagent kit(タカラバイオ社)を用いて、取扱い説明書に従い、cDNAに逆転写した。cDNAを、LightCycler 480 SYBR Green I Master(ロッシュ社)とLightCycler 480 II(ロッシュ社)を用いたリアルタイムPCR法(インターカレーター法)により分析し、マウスプロフィラグリン及びGAPDHのCt値をそれぞれ求めた。GAPDHは内部標準として使用した。用いたプライマーはすべてグライナージャパン社から購入した。マウスプロフィラグリンのフォワードプライマーとして、5’−ATG TCC GCT CTC CTG GAA AG−3’を、リバースプライマーとして5’−TGG ATT CTT CAA GAC TGC CTG TA−3’をマウスGAPDHのフォワードプライマーとして、5’−GGC CTC ACC CCA TTT GAT GT−3’を、リバースプライマーとして5’−CAT GTT CCA GTA TGA CTC CAC TC−3’を用いた。サンプル毎に2回測定し、その平均値を各サンプル値とした。マウスプロフィラグリンの相対mRNA量は比較Ct法により算出した。各サンプルのmRNA量は、Day0におけるマウスプロフィラグリンのmRNA量に対する比として、示した。結果を図10に示した。
「NMFの測定」
両耳介にA/E/W処理を行ったマウスを実験に用いた。Day7に、マウス両耳介角質層の総NMF量を、in vivo共焦点ラマン分光装置(model 3510、RiverDiagnostics社)で求めた(化合物A投与群及びVehicle群;各n=3)。
耳介内側表面より8マイクロメータの深さまで1マイクロメータ間隔で、励起波長を785nmとして400〜1800cm−1領域のラマンスペクトルを測定した。総NMF量は、Skin Tools 2.0(RiverDiagnostics社)を用いてケラチンあたりの量として定量した。耳介毎にそれぞれ4回測定を行った。測定深度毎に総NMF量の平均値を算出し、各深度における個体値とした。正常対照として、A/E/W無処理マウス(n=1)の耳介角質層の総NMF量を測定した。結果を図11に示した。
「TEWLの測定」
右耳介にA/E/W処理を行ったマウスを実験に用いた。A/E/W処理した領域からのTEWLの測定は、Day0、1、3及び4のA/E/W処置直前とDay7に行なった(化合物A投与群及びVehicle群;各n=4)。TEWLの測定は、室温(摂氏23度から26度)、湿度40%から60%で、水分蒸散量測定装置VAPOSCAN AS−VT100RS(アサヒバイオメッド)を用いて測定した。個体毎に2回測定を行い、その平均値を各個体値とした。結果を図12に示した。
Claims (6)
- 下記化学構造式:
- 請求項1において選択される皮膚疾患が老人性乾皮症である請求項1に記載の治療剤又は予防剤。
- 請求項1において選択される皮膚疾患が皮脂欠乏症である請求項1に記載の治療剤又は予防剤。
- 請求項1において選択される皮膚疾患が尋常性魚鱗癬である請求項1に記載の治療剤又は予防剤。
- 請求項1において選択される皮膚疾患がネザートン症候群である請求項1に記載の治療剤又は予防剤。
- 請求項1において選択される皮膚疾患がB型ピーリング皮膚症候群である請求項1に記載の治療剤又は予防剤。
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LT3352734T (lt) * | 2015-09-24 | 2020-04-10 | Leo Pharma A/S | Židininės alopecijos gydymas |
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JP6185041B2 (ja) * | 2015-12-04 | 2017-08-23 | 一丸ファルコス株式会社 | 表皮ブドウ球菌由来のグリセロール産生促進剤、皮膚表皮角化細胞由来の抗菌ペプチド産生促進剤、およびそれらの皮膚保護用外用剤への利用 |
BR112018014769A2 (pt) * | 2016-01-21 | 2018-12-11 | Leo Pharma A/S | ?composto, composição farmacêutica, e, método para tratamento do eczema nas mãos? |
US11339181B2 (en) * | 2016-12-21 | 2022-05-24 | Japan Tobacco Inc. | Crystalline forms of a Janus kinase inhibitor |
CN107022549B (zh) * | 2017-04-19 | 2021-06-01 | 华中农业大学 | 黄颡鱼β防御素基因及其β防御素抗菌肽及其应用 |
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AU2020275208A1 (en) | 2019-05-15 | 2021-10-28 | Leo Pharma A/S | Treatment of cutaneous lupus erythematosus |
CA3149558A1 (en) * | 2019-09-05 | 2021-03-11 | Universitat Bern | Tricyclic janus kinase (jak) inhibitors and their use in the treatment of autoimmune diseases |
CN116635026A (zh) * | 2020-12-29 | 2023-08-22 | 上海岸阔医药科技有限公司 | 治疗与抗肿瘤剂相关的皮肤疾病或病症的试剂和方法 |
CN117500504A (zh) * | 2021-05-03 | 2024-02-02 | 因赛特公司 | 用于治疗结节性痒疹的鲁索替尼 |
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