JP6208332B2 - 医薬組成物及びその用途 - Google Patents
医薬組成物及びその用途 Download PDFInfo
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- JP6208332B2 JP6208332B2 JP2016512991A JP2016512991A JP6208332B2 JP 6208332 B2 JP6208332 B2 JP 6208332B2 JP 2016512991 A JP2016512991 A JP 2016512991A JP 2016512991 A JP2016512991 A JP 2016512991A JP 6208332 B2 JP6208332 B2 JP 6208332B2
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- acid
- atropine
- myopia
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- ketorolac
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Description
本出願は、2013年5月6日に出願された米国特許出願第61/819,709号の利益を主張し、その内容全体を参照により本明細書中に援用される。
この出願の発明に関連する先行技術文献情報としては、以下のものがある(国際出願日以降国際段階で引用された文献及び他国に国内移行した際に引用された文献を含む)。
(先行技術文献)
(特許文献)
(特許文献1) 欧州特許出願第0465234号
(特許文献2) 国際公開第2009/105534号
(特許文献3) 米国特許出願公開第2007/0254914号明細書
(特許文献4) 米国特許出願公開第2013/0065869号明細書
(特許文献5) 国際公開第2013/166408号
(特許文献6) 国際公開第01/95913号
(非特許文献)
(非特許文献1) Lee et al."Prevention of Myopia Progression with 0.05% Atropine Solution,"Journal of Ocular Pharmacology and Therapeutics,01 February 2006,Vol.22,Pgs.41−46.
(非特許文献2) Jin et al."Effects of prostaglandins on form deprivation myopia in the chick,"Acta Ophthalmol.Scand.2000:78:495−500
上文と公開全文中で使用される場合、下記の用語は、別段の定めがない限り、以下の意味を有するものであると理解されるべきである。
ここで、近視を治療し、目の軟骨形成蛋白質を低減させ、強膜の軟骨形成を低減させ、又は炎症で誘発された軟骨形成を減少させる医薬組成物を提供する。医薬組成物は、2種の抗軟骨形成剤の組合せを含み、理想的には、前記組合せによる優勢的な相乗作用が見られる。
を減少させる。投与される医薬組成物の投与量は、治療される状況の深刻さ、特定処方、及び受容者の体重と一般的な状況及び投与規則のようなその他の臨床要素に左右されて決定されるものである。一実施例において、投与される医薬組成物の量は、約0.001%から約1%重量のアトロピンに対応する。別の実施例において、投与される医薬組成物の量は、約0.005%、0.01%、0.015%、0.02%、0.025%、0.03%、0.035%、0.04%、0.045%、0.05%、0.055%、0.06%、0.065%、0.07%、0.075%、0.08%、0.085%、0.09%、0.095%、0.1%重量のアトロピンに対応し、又は0.001%と1%との間に0.001%ずつ増量する如何なるパーセントに対応する。別の実施例において、投与される医薬組成物の量は、約0.05%から約1%重量のケトロラクに対応する。別の実施例において、投与される医薬組成物の量は、約0.1%、0.2%、0.25%、0.3%、0.35%、0.4%、0.45%、0.5%、0.55%、0.6%、0.65%、0.7%、0.75%、0.8%、0.85%、0.9%、0.95%重量のケトロラクに対応し、又は0.01%ずつ増量する如何なるパーセントに対応する。別の実施例において、投与される医薬組成物の量は、約0.5%重量のケトロラクに対応する。別の実施例において、投与される医薬組成物の量は、約0.01%、0.025%、0.05%、0.1%、0.15%から約0.2%重量のジクロフェナクに対応し、又は0.01%ずつ増量する如何なるパーセントに対応する。ここで提供される医薬組成物の有効投与量は、動物モードにおいてその体外活性と体内活性を比較することによって決定される。マウス及びその他の動物から、ヒト内の有効投与量への外挿法に用いられる方法が当該分野に既知であり、例えばU.S.Pat.No.4,938,949を参照し、それを本明細書中で参考として援用される。
目の軟骨形成蛋白質及び/又は目の炎症マーカーのダウンレギュレーションで強膜の軟骨形成を低下させる。
特定理論に束縛されるものではないが、眼の炎症マーカーと目の軟骨形成蛋白質は、TGF−β、α−SMA及びCol2などの発現プロファイルによって、強膜の軟骨形成と近視に関連すると考えられる。限定されない例として、図1は、近視発展のメカニズムを示し、その中、脈絡膜内にTGF−βと炎症マーカー(IL−6とTNF−αなど)のレベルが増加することで、強膜内のα−SMAとCol2の形成及び強膜の軟骨形成が引き起こされる。強膜は、引き続き膜再成形と延長に伴って、近視の悪化が進んでいく。
マウス:下記の範例において、C57BL/6野生型雄性マウス(ジャクソン実験室(Jackson Labs))を使用する。全ての手順は、機構IACUCによって承認された協定及び眼科と視覚研究における動物の使用に関するARVO声明(Statement for the Use of Animals in Ophthalmic and Visual Research)に従って実行される。
前述の通り、CL・蔡氏等(CL Tsai et al)が記述する(<ネズミの強膜での多能性幹細胞/前駆細胞の同定>,調査眼科と視覚科学定期刊行物;52:5481−5487,2011年,(Identification of multipotent stem/progenitor cells in murine sclera.Invest Ophthalmol Vis Sci 52:5481−5487,2011))のように、SSPCsが分離かつ培養される。簡単に言えば、マウス由来の強膜を取得し、かつ解剖顕微鏡下に強膜を、リンバス(limbus)と視神経円板(optic disc)とから慎重に切り離す。網膜と脈絡膜組織が除去された後、強膜組織を小切れに切り分け、かつ1.5mg/ml第1型コラゲナーゼ(ワージントン・バイオケミカル社,レイクウッド,米国(Worthington Biochemical,Lakewood,USA))と、2mg/mlの中性ディスパーゼ(dispase)(ロシュ製薬会社,バーゼル,スイス(Roche,Basel,Switzerland))とにより、PBS中にて、摂氏37℃下で1時間分解して個々の細胞を放出させる。個々の細胞は、α−MEM(インビトロゲン社,カールスバド,米国(Invitrogen,Carlsbad,USA))内にて、20%多選択(lot−selected)FBS(イクイテク・バイオ,カービル,米国(Equitech−Bio,Kerrville,USA))、グルタミン、ペニシリン/ストレプトマイシンと100mM2−メルカプトエタノール(インビトロゲン社)の補助により、5%CO2にて、摂氏37℃下で8から10日間培養した。
異なる濃度のTGF−βをSSPCsの12ウェルプレート内に加える。24時間後、SSPCsの形態画像を記録する。さらなる分析をするために、総RNAを抽出する。免疫蛍光法測定に用いられるチャンバースライド(chamber slide)の培養は、同一条件下で実行される。
半合流点において、ペレットを取得するために、2ml成長培養基内に2×105個細胞のアリコートを10分間、500g遠心沈殿させるように、SSPCsがトリプシン処理され、かつ計数された。ペレットは、37℃、5%より低いCO2下で培養した。12から24時間の培養期間において、細胞が管壁に付着せずに本質的に球状の集合体に形成された。培養基に10ng/mlのTGF−β2が加わって、培養基を2から3日ごとに交換する。4週目にペレットが収集された。その後、前記ペレットをPBS中で2回洗浄して、室温下で4%パラホルムアルデヒドに3時間固定し、パラフィン包埋のために準備した。免疫組織化学法に用いられる8μm厚さの切片を取得した。
α−SMA蛋白質とCol2の軟骨形成期間での存在を証明するための免疫組織化学と免疫蛍光研究が行われた。免疫組織化学により、パラフィン切片を、20%ブロッキング用ヤギ血清(blocking goat serum)によって30分間処置し、それから一次抗体によって37℃で一晩培養し、この一次抗体は、1:200に希釈するウサギIgG抗SMAmAb(アブカム社,テメキュラ,カリフォルニア州(Abcam,Temecula,CA))と、1:100に希釈するマウスのIgG2a抗II型コラーゲン(anti−type II collagen)mAbb(アブカム社,テメキュラ,カリフォルニア州)である。前記切片は、それから1:200にするホースラディッシュペルオキシダーゼ(HRP)−結合した二次抗体(サンタクルーズバイオテクノロジー社,サンタクルーズ,カリフォルニア州(Santa Cruz Biotechnology,Santa Cruz,CA))によって1時間処置した。前記DAB試剤(ジアミノベンジジン四塩酸塩,diaminobenzidine tetrahydrochloride)を引き続いて使用して免疫活性を検出する。免疫蛍光により、クリオスタット切片と、再水和パラフィン切片とをブロッキング用血清によって処置し、一次抗体で培養し、対応のフルオレセイン・イソチオシアネート−結合した二次抗体と反応させ、最後に蛍光顕微鏡で評価した。
製造業者のプロトコルにより、Trizol(インビトロゲン社,カールスバド,カリフォルニア州)を使用してそれぞれの眼のSSPCs又は脈絡膜組織由来の総RNAを単離した。製造業者の指示に従い、定量のRT−PCR分析は、SYBR Green付きのiScript One−Step RT−PCRキット(バイオ・ラッド,ヘラクレス,米国(Bio−Rad,Hercules,USA))をABI PRISM 7900 HT配列検出システム(アプライドバイオシステムズ社,フォスターシティ,米国(Applied Biosystems,Foster City,USA))に使用して行われた。実験に用いられたプライマーは次の通りである:α−SMA(順方向プライマー:5′−ATGCCTCTGGACGTACAACTG−3′,逆方向プライマー:5′−CGGCAGTAGTCACGAAGGAAT−3′)、Col2(順方向プライマー:5′−GTCCTTCTGGCCCTAGAGGT−3′,逆方向プライマー:5′−TGTTTCTCCTGAGCGTCCA−3′)、β−actin(順方向プライマー:5′−CATTGCTGACAGGATGCAGA−3′,逆方向プライマー:5′− CTGATCCACATCTGCTGGAA−3′)と和 グリセルアルデヒド3−リン酸デヒドロゲナーゼ(glyceraldehyde 3−phosphate dehydrogenase,GAPDH)(順方向プライマー:5′−AACTTTGGCATTGTGGAAGG−3′,逆方向プライマー:5′−ACACATTGGGGGTAGGAACA−3′)。GAPDHとβ−actinを対照群とした。対照群ジーンのCt値は、α−SMAとCol2のそれらから減算して半定量分析を提供し、かつ処置なしに対する倍率変化を評価した。
実験当日(出生後日数[P]21〜24)に、C57BL/6Jマウスがケタミン(ketamine)(90mg/kg)と、キシラジン(10mg/kg)との腹腔内注射によって麻酔され、ディフューザアイパッチ(diffuser eye patch)が右眼の周囲の皮膚に縫合された一方、左眼を対照群とした。半球状プラスチックのディフューザアイパッチは、0.5mLPCRプラスチック管のキャップで作製された。マウスは、温暖パッド上に完全に動き回れるまでに回復され、かつ監視された。剥奪性近視のマウスは、透明のプラスチックケージ内に安置され、12時間光照射(200±15 lux水平照度)と12時間暗所とのサイクルで21日間続けた。形態剥奪性近視誘発の前と後、スペクトルドメインの光干渉断層撮影は、目の生物測定に用いられた。
強膜由来の総蛋白質は、RIPA蛋白質抽出緩衝剤を使用して抽出された。強膜組織の均質化後、サンプルを遠心分離して上澄液を収集した。各サンプルの蛋白質濃度は、BCATM蛋白質定量キット(バイオ・ラッド)を使用して測定した。強膜の蛋白質サンプルを正規化し、10%SDS−PAGEゲルに電気泳動し、それからポリビニルデンフルオロエチレン転写メンブレン(Immun−Blot(登録商標) PVDF Membrane,バイオ・ラッド)に21Vで1時間転写した。メンブレンは、5%ドライミルクと0.1%ツイーンを含むPBSに室温下で1時間阻害し、それから一次抗体によって4℃で一晩培養した。メンブレンを洗浄して、1:10,000にするヤギ抗マウス、又は抗ウサギIgG抗体(Santa Cruz)に結合したホースラディッシュペルオキシダーゼによって室温下で1時間培養して、再び洗浄した。メンブレンは、試剤Lumigen TMA−6(GE ヘルスケア イギリス リミテッド,バッキンガムシャー,イギリス(GE Healthcare UK limited,Buckinghamshire,UK))によって化学発光され、画像は、LAS−4000撮像システム(富士フイルム,東京,日本(Fujifilm,Tokyo,Japan))によって捕捉された。蛋白質バンドは、ImageJソフトウェアを使用して定量化された。
体外研究について、統計的顕著性は、ANOVA検定とボンフェローニ事後比較検定(Bonferroni post hoc test)によって算出される。体内研究について、統計的顕著性は、平方偏差分析(対応のある標本t検定(the paired t−test))によって算出される。統計的顕著性としては、p値が0.05より小さいと定義される。
(実施例)
TGF−β処置後のSSPCの形態変化の体外研究が行われた。SSPCは、前述のように、TGF−β2処置(0.1−10ng/ml)で24時間培養した。顕微鏡研究により、TGF−β2処置なし、又は低濃度(0.1ng/ml)のTGF−β2処置では、多数のSSPCsが薄い紡錘形状で、拡幅表現型が示されたことを示す。ほかに、SSPCsの細胞骨格線維が目立たなかった。より高い濃度のTGF−β2(1から10ng/ml)の曝露において、SSPCsが幅広くなると共に、目立つ細胞骨格線維を有する。免疫蛍光顕微鏡により、10ng/mlのTGF−β2で処置した後、α−SMA陽性のSSPCs(目立つ細胞内のα−SMA線維染色を有する)の数量が増加することを示した。
SSPCとSSPC的3−Dペレットを使用してα−SMAとCol2発現に対するTGF−β処置の効果の体外研究を実行する。SSPCとSSPC的3−Dペレットは、前述のように、TGF−β2の様々な濃度によって処置される。
FDMマウスを使用して強膜内でのCol2とα−SMAの発現を評価する体内研究が評価された。FDMは、前述のように、マウスの右眼内に導入され、かつ左眼を対照群とした。各マウスの両眼の間に眼軸長の差は、開始時に著しくなかった(p=0.378)。21日目、形態剥奪性眼は、眼軸長3055±39μmの近視を有し、その眼軸長は対側の対照群の眼よりも著しく長い(3015±40μm,p<0.001)。
FDMマウスを使用して、脈絡膜内でのTGF−βの発現を評価する体内研究を実行する。FDMは、前述のようにマウスに導入される。
ヒトのSSPCを使用して抗ムスカリン剤とNSAIDによるCol2とα−SMA発現に対する効果を検証する体内研究を実行する。SSPCsは、前述のように、1mMアトロピン、5mMケトロラクと1mMジクロフェナクで、TGF−β2(10ng/ml)の存在下にて、処置される。
アトロピン、及びアトロピンとケトロラクとを含む医薬組成物を使用して、11名の近視患者の臨床研究を行う。
近視患者は、アトロピンの副作用に耐えなくてもよく、かつ与えられるNSAIDでその方の近視を治療する。ケトロラクの投与量が単位投与量当り(約0.05から0.5ml)に約0.5%重量のケトロラクで、かつ影響された眼に夜に1滴(約0.05から0.5ml)のケトロラク眼薬水が与えられる。
FDMマウスを使用して、脈絡膜内での炎症マーカーの発現を評定する体内研究を評価する。FDMが前述のように、マウスの右眼かつ左眼に導入されて対照群とした。
SSPCを使用して、アトロピンとケトロラクとを含有する医薬組成物が、α−SMAとCol2発現に対する効果の体内研究を実行する。SSPCsが10ng/mlのTGF−β2で処置されることを前述のようにする。
Claims (6)
- 0.001%から1%重量のアトロピン;および
0.05%から1%重量のケトロラクを含む、近視治療用医薬組成物。 - 前記アトロピンが約0.005%から約0.05%重量のアトロピンである、請求項1に記載の医薬組成物。
- 近視個体における近視を治療する医薬組成物を製造するためのアトロピンおよびケトロラクの有効量の使用。
- 前記ケトロラクが約0.05%から約1%重量のケトロラクである、請求項3に記載の使用。
- 前記アトロピンが約0.001%から約1%重量のアトロピンである、請求項3または4に記載の使用。
- 前記アトロピンが約0.005%から約0.05%重量のアトロピンである、請求項3〜5のいずれか1項に記載の使用。
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HK1219691A1 (zh) | 2017-04-13 |
EP2994197A4 (en) | 2016-12-28 |
US20200113890A1 (en) | 2020-04-16 |
JP2018008991A (ja) | 2018-01-18 |
EP2994197A1 (en) | 2016-03-16 |
KR20170094552A (ko) | 2017-08-18 |
TWI562776B (en) | 2016-12-21 |
JP6450814B2 (ja) | 2019-01-09 |
TW201446245A (zh) | 2014-12-16 |
US20160067238A1 (en) | 2016-03-10 |
KR102027663B1 (ko) | 2019-10-01 |
CA2911298C (en) | 2019-09-17 |
CA2911298A1 (en) | 2014-11-13 |
KR20160004288A (ko) | 2016-01-12 |
WO2014182620A1 (en) | 2014-11-13 |
SG11201508453YA (en) | 2015-11-27 |
ES2871116T3 (es) | 2021-10-28 |
CN105555363B (zh) | 2019-03-12 |
US10888556B2 (en) | 2021-01-12 |
CA3050457C (en) | 2021-05-25 |
CN105555363A (zh) | 2016-05-04 |
EP2994197B1 (en) | 2021-04-28 |
CA3050457A1 (en) | 2014-11-13 |
TWI617306B (zh) | 2018-03-11 |
US10548887B2 (en) | 2020-02-04 |
JP2016518410A (ja) | 2016-06-23 |
US20180311227A1 (en) | 2018-11-01 |
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