JP2011516400A - 眼および付属器組織の炎症を処置するための治療組成物 - Google Patents
眼および付属器組織の炎症を処置するための治療組成物 Download PDFInfo
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Abstract
Description
本出願は、そのそれぞれの全内容物が参照により本明細書に組み入れられる、2007年8月16日に提出された仮出願である米国特許出願第60/965,135号、および2008年6月2日に提出された米国特許出願第61/130,687号に関連する。
本発明は一般的に眼科学の分野に関する。
眼および付属器組織の炎症は、多様な機序によって起こりえて、多数の疾患状態に一次的にまたは二次的に関連する。これらの組織の炎症に関する現在の処置は、抗生物質、ステロイド、および免疫系阻害剤の全身投与を伴う。これらの全身投与薬を用いることの難しさは、ステロイドの場合では長期の障害性の副作用、抗生物質の場合には長期の薬物耐性、またはシグナル伝達阻害剤の場合には標的部位での不適切な長期間の持続を通して明らかとなっている。その上、免疫系におけるシグナル伝達の全身的阻害は、疾患に既に罹患している個体に関して有害な結末を有しえて、これらの処置の全身的な使用の結果として追加の合併症に対する個体の感受性が増加する。
後部眼瞼炎
後部眼瞼炎は、後部眼瞼縁の全般的炎症として記述され、眼表面の炎症ならびに焼灼感、刺激感、および不快感の症状に関連する一般的な慢性眼瞼状態である。後部眼瞼炎は、集合的にマイボーム腺機能障害(MGD)として知られるマイボーム腺の様々な障害に関連する。これはマイボーム腺の閉塞および炎症に関連するか、またはより一般的ではないが、マイボーム腺の萎縮に関連する(Foulks, G. et al. 2003. Ocul Surf. 107-26;Bron, A. J. et al. 2004. Ocul Surf. 2:149-65)。
本発明に含まれる組成物に接触する眼の組織または区画には、角膜、房水、虹彩、および強膜が含まれるがこれらに限定されるわけではない。「付属器」という用語は、臓器の付属体としての一般的な用語として定義される。本発明において付属器は、眼表面に直接接する多数の組織または表面を定義するが、定義によって眼表面は含まれない。例示的な付属器組織には、眼瞼、涙腺、および外眼筋が含まれるがこれらに限定されるわけではない。本発明の組成物の局所表面投与は、眼瞼内の以下の組織および構造に接する:皮膚、皮下組織、眼輪筋、眼窩隔膜、瞼板、眼瞼結膜、およびマイボーム腺。付属器組織は、眼窩および眼瞼部分が含まれる涙腺の全ての小区分と共に、これらの腺によって接触される全ての組織を含む。付属器組織のこのカテゴリーに属する外眼筋には、上および下直筋、外および内直筋、ならびに上および下斜筋が含まれるがこれらに限定されるわけではない。本発明に含まれる組成物は、局所表面に適用され、単独で、または眼の組織と共にこれらの組織に接する。
眼内圧は、眼の毛様体によって産生される液体である房水によって維持される。房水は通常、眼の後区には行かない;これは水晶体およびチン小体によってこの領域外で維持される。その代わりに、房水は、前眼房および後眼房に分けられる前区のみに留まる。前眼房および後眼房は前区および後区と非常に類似の名称であるが、それらは類義語ではない。前眼房および後眼房は、いずれも前区の一部である。
緑内障は、非可逆的失明の主な原因である。緑内障の第一の危険因子は眼内圧(IOP)の上昇であり、これは著しい視神経障害および失明に寄与しうる。房水流出の容易さの低減によるIOPの上昇は、主要な原因となる危険因子である。眼の主な房水流出経路は、小柱網(TM)、シュレム管、収集チャネル、および上強膜静脈系を含む、前眼房角における一連の内皮細胞裏打ちチャネルからなる。
IL-1ファミリーは、炎症および免疫応答の主要なメディエータとして機能するサイトカイン群である(Dinarello, C. A. 1996. Blood. 15:2095-2147)。このファミリーは、3つの型で構成される:それぞれが前駆体型を有する2つの炎症促進型、IL-1αおよびIL-1β、ならびに抗炎症型、IL-1受容体アンタゴニスト(IL-1Ra)。炎症促進性サイトカインであるIL-1は、ケモカイン産生、接着因子、マクロファージ浸潤および活性、ならびにリンパ球の増殖を増加させることによって、炎症および免疫において重要な役割を果たす。IL-1は、リウマチ性関節炎、敗血症ショック、および歯周炎などのヒトの炎症疾患の病因に関係している(Jiang, Y. et al. 2000. Arthritis Rheum. 43:1001-1009;Okusawa, S. et al. 1988. J Clin Invest. 81:1162-1172;McDevitt, M. J. et al. 2000. J. Periodontol. 71:156-163)。
IL-1Raは、活性化単球および組織マクロファージによって主に産生される内因性の受容体アンタゴニストであり、IL-1受容体に競合的に結合することによって、炎症促進型のIL-1の活性を阻害する(Gabay, C. et al. 1997. 159: 5905-5913)。IL-1Raは、リウマチ性関節炎などの炎症状態において典型的にアップレギュレートされる誘導型遺伝子である(Arend, W.P. 1993. Adv Immunol. 54: 167-223)。
組み換え型ヒトIL-1Ra(rHuIL-1Ra)は、関節炎の動物モデルにおいて開発および試験された。この型のrHuIL-1Raはまた、アナキンラまたはKineret(登録商標)としても知られ、N末端メチオニンの付加によって本来の非グリコシル化IL-1Raとは異なる。これは、IL-1βと同じ親和性でIL-1R 1型に結合する。Kineret(登録商標)は、アミノ酸153個からなり、分子量17.3キロダルトンを有する。これは、大腸菌(E.coli)細菌発現系を用いて組み換えDNA技術によって産生される。
本発明の組成物は、IL-1受容体1型または2型のいずれかをコードするポリヌクレオチドまたはポリペプチドの転写、転写物安定性、翻訳、修飾、局在化、分泌、または機能を阻害する手段を有するポリヌクレオチド、ポリペプチド、抗体、化合物、または低分子を含む。本出願において、IL-1受容体、1型(IL-1R1)は、SEQ ID NO:17のポリヌクレオチド配列またはSEQ ID NO:18のポリペプチド配列によって定義される。本出願において、IL-1受容体2型(IL-1R2)、転写物変種1および2は、SEQ ID NO:19および20のポリヌクレオチド配列またはSEQ ID NO:21のポリペプチド配列によって定義される。IL-1R2は、IL-1サイトカインに結合して、IL-1R1を阻害する「デコイ」受容体として機能しうる。ポリヌクレオチドまたはポリペプチド組成物は、SEQ ID NO:17〜21によって含まれるIL-1R1またはIL-1R2およびその関連するイソ型の1つまたは複数の領域に結合する。
本発明は、ヒトIL-1R2の活性を阻害または増強する手段を有する組成物を含む。IL-1R2アンタゴニスト、IL-1Ra3を含む組成物は、IL-1R1機能の有効性に関してアゴニストまたはアンタゴニスト活性のいずれかを有する。組成物は、IL-1Ra3をコードするポリヌクレオチドまたはポリペプチドの転写、転写物安定性、翻訳、修飾、局在化、分泌、または機能を阻害する手段を有するポリヌクレオチド、ポリペプチド、抗体、化合物、または低分子を含む。阻害性のポリヌクレオチドまたはポリペプチド組成物は、SEQ ID NO:22およびSEQ ID NO:23に含まれるIL-1Ra3の1つまたは複数の領域に結合する。
ヒトIL-1RAPの活性を阻害する組成物は、IL-1サイトカインまたはIL-1受容体に対するIL-1RAPの結合を阻害して、その後の下流の細胞内シグナルの伝達を阻害する。IL-1RAP機能の阻害剤を含む組成物は、IL-1受容体の活性に拮抗する。組成物は、IL-1RAPをコードするポリヌクレオチドまたはポリペプチドの転写、転写物安定性、翻訳、修飾、局在化、分泌、または機能を阻害する手段を有するポリヌクレオチド、ポリペプチド、抗体、化合物、または低分子を含む。阻害性ポリヌクレオチドまたはポリペプチド組成物は、SEQ ID NO:24〜27に含まれるIL-1RAPおよび関連するイソ型の1つまたは複数の領域に結合する。
本発明はまた、この受容体とIL-1とのライゲーション後にIL-1受容体に結合し、かつ炎症反応に至る下流のシグナルを伝達するこのタンパク質の能力として定義される、ヒトIRAK1の活性を阻害する組成物および方法を含む。IRAKの阻害剤を含む組成物は、IL-1受容体からの下流のシグナル伝達に拮抗する。組成物は、IRAK1をコードするポリヌクレオチドまたはポリペプチドの転写、転写物安定性、翻訳、修飾、局在化、分泌、または機能を阻害する手段を有するポリヌクレオチド、ポリペプチド、抗体、化合物、または低分子を含む。阻害性ポリヌクレオチドまたはポリペプチド組成物は、SEQ ID NO:28〜33に含まれるIRAK1および関連するイソ型の1つまたは複数の領域に結合する。
本発明は、マイクロRNA(miRNA)分子を、適当な薬学的担体と共に眼または付属器組織に送達することによって、IL-1α、IL-1b、IL-1R1、IL-1R2、IL-1Ra3、IL-1RAP、またはIRAK1の活性を阻害する手段を有する組成物を含む。IL-1α、IL-1b、IL-1R1、IL-1R2、IL-1Ra3、IL-1RAP、またはIRAK1のいずれかを標的とするmiRNAを含む組成物は、IL-1R1の機能に拮抗する。組成物は、IL-1α、IL-1b、IL-1R1、IL-1R2、IL-1Ra3、IL-1RAP、またはIRAK1の1つまたは複数の領域に結合する1つまたは複数のmiRNAを含む。以下の表は、ヒトIL-1αまたはIL-1R1の発現を部分的または完全にサイレンシングすることが示されている例示的なmiRNAを含む。
本明細書において用いられるように、「炎症性インターロイキン-1サイトカインの活性を阻害する」という用語は、IL-1受容体から開始、連絡、または伝達された細胞内シグナル伝達の阻害、防止、減損、低減、減少、抑制、または中断を記述することを意味する。本発明の1つの局面において、IL-1受容体から開始、連絡、または伝達された細胞内シグナル伝達の阻害、防止、減損、低減、減少、抑制、または中断は、IL-1サイトカインのIL-1Rに対する結合を防止または減少させることによって達成される。またはもしくは加えて、IL-1Rからの細胞内シグナル伝達の伝達は、シグナル伝達カスケード内の下流のエフェクターまたは標的を除去、サイレンシング、または変異させることによって防止される。下流のエフェクターおよび/または標的の発現および/または機能または活性は、遺伝子改変または治療化合物の投与によって、除去される(たとえば、欠失、ノックアウト、隔離、変性、分解される等)、サイレンシングされる(分解される、転写的または翻訳的に抑制される)、または変異される(活性産物をコードするヌクレオチドまたはアミノ酸配列が、非機能的産物をコードするように変更されている)。
眼または付属器組織への局所表面組成物の経皮送達を容易にしてはかどらせるために組み入れられる例示的な化合物には、アルコール(エタノール、プロパノール、およびノナノール)、脂肪アルコール(ラウリルアルコール)、脂肪酸(吉草酸、カプロン酸、およびカプリン酸)、脂肪酸エステル(イソプロピルミリステートおよびイソプロピルn-ヘキサノエート)、アルキルエステル(酢酸エチルおよび酢酸ブチル)、ポリオール(プロピレングリコール、プロパンジオンおよびヘキサントリオール)、スルホキド(ジメチルスルホキシドおよびデシルメチルスルホキシド)、アミド(ウレア、ジメチルアセトアミドおよびピロリドン誘導体)、界面活性剤(ラウリル硫酸ナトリウム、臭化セチルトリメチルアンモニウム、ポロキサマー、スパン、ツイーン、胆汁酸塩、およびレシチン)、テルペン(d-リモネン、α-テルペンオール、1,8-シネオール、およびメントン)、アルカノン(N-ヘプタンおよびN-ノナン)が含まれるがこれらに限定されるわけではない。その上、局所表面に投与された組成物は、カドヘリンアンタゴニスト、セレクチンアンタゴニスト、およびインテグリンアンタゴニストが含まれるがこれらに限定されるわけではない表面接着分子調整物質を含む。
本発明は、炎症性インターロイキン-1サイトカインの活性を阻害するコンタクトレンズおよび組成物を含む。たとえば、組成物は、レンズに組み入れられるかまたはレンズ上にコーティングされる。組成物は、コンタクトレンズポリマーに化学的に結合されるか、または物理的に捕捉される。または、着色添加剤をポリマー組成物に化学的に結合させるかまたは物理的に捕捉させて、着色添加剤の強度の変化がポリマー内で結合してまたは捕捉されて残っている治療薬組成物の量または用量の変化を示すように、これを治療薬組成物と同じ速度で放出する。または、もしくは加えて、紫外線(UV)吸収体をコンタクトレンズポリマーに化学結合させるか、またはポリマー内に物理的に捕捉させる。コンタクトレンズは疎水性または親水性のいずれかである。
実施例1:眼表面疾患指数(OSDI)
眼表面疾患指数(OSDI)は、後部眼瞼炎およびドライアイ疾患が含まれる眼表面疾患に一貫する眼の刺激感の症状、および視力関連機能に及ぼすその影響の迅速な査定を提供する12項目の質問票である(図1)。OSDI質問票の12項目は0から4までの尺度で等級付けされ、0は全くない;1はときどきある;2は半分の時間ある;3はほとんどの時間ある;および4は常にあることを示す。次に全OSDIスコアを以下の式に基づいて計算する:OSDI=[(回答があった全ての質問に関するスコアの合計)×100]/[(回答があった質問の総数)×4]。このように、OSDIは0から100までの尺度で採点され、より高いスコアはより大きい能力障害を表す。ベースラインからの負の変化は、視力関連機能および本明細書において記述される眼の炎症障害の改善を示している。本明細書において記述される治療法に関して、処置は、OSDIに関するベースラインからの平均変化(減少)が対照と比較して>10単位によって示される場合、対照(ビヒクル)より有効であると見なされる。
標準的なTBUT測定は、フルオレセイン片を滅菌非保存生理食塩液によって湿らせて、内部眼瞼結膜に適用することによって行われる。数回の瞬きの後、青色のフィルターを備えた細隙灯の広い光線を用いて涙液層を調べる。最後のまばたきからフルオレセイン染色涙液層における最初の無作為に分布した暗色のとぎれめの出現までの経過時間を3回測定して、測定の平均値を計算する。涙液層破壊時間は、いかなる点眼液も点眼する前、および眼瞼をいかなるようにも操作する前に評価する。10秒未満の破壊時間は異常であると見なされる。ベースラインからの正の変化は、本明細書において記述される眼の炎症障害の症状の改善を示す。本明細書において記述される処置は、ビヒクル単独による処置から観察された場合より有意に大きいTBUTの改善に至る。
角膜染色は、中でも後部眼瞼炎およびドライアイなどの眼表面疾患の場合に典型的に認められる、上皮疾患または眼表面の上皮障壁の破壊の測定である。重要なことに、角膜染色は、後部眼瞼炎などの有意な眼瞼疾患が存在する場合、臨床的に明確なドライアイがなくても存在しうる。角膜染色は、全ての患者ではないが多くの患者において眼の不快感と高度に相関する;一般的に角膜染色は、先に記述したようにOSDIの高いスコアに関連する。角膜フルオレセイン染色の場合、生理食塩液で湿らせたフルオレセイン片または1%フルオレセインナトリウム溶液を用いて涙液層を染色する。次に角膜全体を、黄色の障壁フィルター(#12 Wratten)およびコバルトブルー照明(染色は黄色のフィルターで観察する場合により強度である)によって細隙灯評価を用いて調べる。染色をOxford Schema(図2)に従って等級付けする。
シルマー試験は、細い濾紙片(Whatman #41濾紙の5×35 mm片)を下結膜嚢に置くことによって麻酔の存在下および非存在下で行われる。この試験は、かすかな光の部屋で行われる。患者は軽く眼を閉じて、5分が経過すると小片を取り出す。眼から取り出した後も涙液の先端は数ミリメートル進行し続けることから、正確に5分で涙液の先端にボールペンで印をつける。水層涙液層破壊を、小片が5分間のあいだに湿ったミリメートルでの長さによって測定する。非麻酔下でのシルマー試験に関して10 mmまたはそれ未満、および麻酔下でのシルマー試験の5 mmまたはそれ未満という結果は、異常であると見なされる。ベースラインからの正の変化は、本明細書において記述された眼の炎症障害の1つまたは複数の症状の改善を示している。
下位眼瞼の中心において、隣接する中心の腺10個が両側面に位置して、腺の基底部でしっかりした指圧を適用することによって腺を圧出する。それぞれの眼に関して圧出された腺の数を報告する。分泌の質を以下のように記述する:
・透明な排出物または小さい粒子を有する透明な排出物(0)
・正常な粘度の不透明の排出物(1)
・粘度が増加した不透明の排出物(2)
・圧出後に分泌物が形状を保持する(3)
眼瞼縁の血管充血(紅斑)は、周辺の眼瞼皮膚と比較して赤色の変色として定義され、以下のように等級付けされる:
なし(0):なし
軽度(1):眼瞼縁または皮膚の小さい領域に局在する赤み
中等度(2):眼瞼縁の大部分での赤み
重度(3):眼瞼縁と皮膚の大部分または全てでの赤み
非常に重度(4):眼瞼縁および皮膚の双方の顕著な散在性の赤み
瞼板の毛細管拡張症の有無も同様に記入する。眼瞼の毛細管拡張症は、眼瞼縁に沿った少なくとも2つの血管の存在として定義される。
眼球結膜充血は以下のように等級付けされる:
なし(0):なし
軽度(1):軽度の局在する充血
中等度(2):ピンク色、瞼板または眼球結膜に限定される
重度(3):瞼板および/または眼球結膜の赤み
非常に重度(4):瞼板および/または眼球結膜の顕著な暗色の赤み
瞼板の乳頭状肥大の有無も同様に記入する。
以下の試験は、公知の市販の組み換え型IL-1受容体アンタゴニスト、アナキンラ(Kineret(登録商標))を含む溶液対ビヒクルを1つまたは複数の眼および/または付属器組織を冒した炎症状態を有する被験体に局所表面投与する治療利益を評価する。
選択/除外基準によって定義されるプロスペクティブな患者を、試験の参加に関して検討する。試験設計および処置養生法を各患者に関して考察する。参加を希望する人を、以下の検査によって試験への参加に関して調べる。
・内科および眼科での既往
・患者の質問票(OSDI)(実施例1および図1を参照されたい)
・完全矯正視力(BCVA)(スネレン視力表)
・フルオレセイン涙液層破壊時間(TBUT)(実施例2を参照されたい)
・角膜および結膜染色(実施例3を参照されたい)
・非麻酔下でのシルマー試験(実施例4を参照されたい)
・麻酔下でのシルマー試験(実施例4を参照されたい)
・マイボーム腺の評価(実施例5を参照されたい)
・生体顕微鏡検査
・眼内圧
・眼底検査
各患者は2週間目にコンプライアンス診察のために戻ってくる(表2)。この診察時に、試験者は試験処置に対する患者のコンプライアンスおよび有害事象に関して直接質問する。患者は有害事象およびプロトコール違反のために試験を中止されうるが、コンプライアンスを強化して、処置プロトコールに被験体を維持するように、あらゆる努力を行う。
後部眼瞼炎の管理のために、局所表面IL-1Raの安全性および有効性を決定するために、5回の追跡診察(眼の検査)を1日目、2週目、6週目、12週目および16週目に予定する(表2を参照されたい)。患者を、試験診察スケジュールに厳密に従うように指導する。それぞれの追跡診察時に、患者にOSDI質問票(図1)に記入するように要請する。総合的な眼の検査に加えて、TBUT、角膜および結膜染色試験、マイボーム腺評価、ならびにシルマー試験が含まれる、涙液機能および眼表面の試験を行う。
もう1つの臨床治験薬または装置の試験への同時登録は禁止される。いかなる同時の薬剤、処方、または大衆薬の使用も、薬剤を使用した理由と共に記録する。試験のあいだ、全ての同時薬物処置レジメン、眼の衛生的処置(すなわち、眼をこするおよび加温圧迫)、または涙点プラグの挿入も、容認された医学の実践によって許容されるように一定に維持される。
本発明の治療化合物の投与の有効性のいくつかの徴候をモニターする。客観的徴候はマイボーム腺分泌の質、マイボーム腺閉塞、涙液層破壊時間、角膜および結膜染色、ならびにシルマー試験(麻酔下および非麻酔下)である。主観的エンドポイントは、OSDI質問票スコアである。これらの変数は全て、ベースライン時および追跡調査の終了まで全ての診察時に注意深く測定される(表2)。
モニターされる一次安全性変数は、有害事象の発生である。観察された各有害事象の重症度(眼および全身)を、軽度(徴候または症状の自覚はあるが、容易に認容される)から重度(仕事をすることができないまたは日常活動を行うことができない)まで評定をつける。事象と試験薬との関連は、治験担当者によって、なし、可能性は低い、ありうる、可能性がある、または明確として査定される。安全性変数はベースラインおよび全ての試験診察時に評価する。
有効性変数および安全性を除く他の任意の変数に関して、被験体を全員、無作為化された処置に関して分析する(治療企図集団)。安全性変数に関して、被験体を実際に受けた処置に関して分析する(安全性集団)。
IL-1Raを、野生型BALB/cマウスの片眼に投与して、処置および無処置(反対側の眼)の双方に関する平均眼内圧(IOP)を測定した。これらの実験からのデータは、IL-1Raの投与が、1回の日中に対して、および特に1回の夜間の期間に対して統計学的に有意な量でIOPを低減させるために十分であることを示している(以下の表4、および図3)。IOPは、緑内障発症の危険因子である。重要なことに、用いた組成物および方法は野生型、または正常な被験体において有効であった。そのため、本実施例は、本発明の組成物および方法が、IL-1媒介炎症が含まれるがこれらに限定されるわけではない多様な機序によって引き起こされている眼内圧上昇または高眼圧症を処置するために有効であるという概念の証明である。
本発明は、その詳細な説明に関連して説明してきたが、前述の説明は、添付の特許請求の範囲によって定義される本発明を例証することを意図しており、本発明の範囲を制限することを意図していない。他の局面、長所、および改変は、以下の特許請求の範囲に含まれる。
Claims (35)
- 炎症性インターロイキン-1サイトカインの活性を阻害する組成物を被験体の眼または付属器組織に局所投与する段階を含む、眼および付属器組織を冒す炎症障害を阻害するかまたはその重症度を低減させるための方法。
- 前記活性が、IL-1受容体に対する炎症性IL-1サイトカインの結合を含む、請求項1記載の方法。
- 眼および付属器組織を冒す炎症障害に罹っていると特徴付けされた被験体を同定する段階をさらに含む、請求項1記載の方法。
- 前記同定する段階が、炎症性サイトカインの上皮過剰発現、眼瞼縁の血管過形成もしくは肥厚、眼瞼縁もしくは角膜辺縁の新生血管形成、眼の表面での白血球の増加、または眼表面でのマトリクスメタロプロテアーゼの過剰発現からなる群より選択される徴候または症状の検出を含み、かつ方法が該徴候または症状の少なくとも1つを阻害またはその重症度を低減させる、請求項3記載の方法。
- 炎症障害が感染性眼瞼炎を含む、請求項1記載の方法。
- 炎症障害が非感染性眼瞼炎を含む、請求項1記載の方法。
- 抗生物質化合物の投与を含まない、請求項1記載の方法。
- 抗生物質化合物と、IL-1受容体に対する炎症性IL-1サイトカインの結合を阻害する組成物の双方の投与を含む、請求項1記載の方法。
- IL-1受容体に対する炎症性IL-1サイトカインの結合を阻害する組成物が、SEQ ID NO:15またはSEQ ID NO:16のアミノ酸配列を含む、請求項1記載の方法。
- 組成物が0.1〜10%(mg/ml)の濃度で存在する、請求項1記載の方法。
- 組成物の剤形が固体、パスタ剤、軟膏、ゲル、液剤、エアロゾル剤、噴霧剤、ポリマー剤、フィルム剤、乳剤、または懸濁剤である、請求項1記載の方法。
- 組成物が局所表面に投与される、請求項1記載の方法。
- 全身投与または非眼組織への実質的な散布を含まない、請求項1記載の方法。
- 組成物が、生理的に許容される塩、カルボポル(carbopol)を有するポロキサマー類似体、カルボポル/HPMC、カルボポル-メチルセルロース、カルボキシメチルセルロース(CMC)、ヒアルロン酸、シクロデキストリン、および鉱油からなる群より選択される化合物をさらに含む、請求項1記載の方法。
- 剤形が固体、パスタ剤、液剤、軟膏、ゲル、エアロゾル剤、噴霧剤、ポリマー剤、フィルム剤、乳剤、または懸濁剤であり、かつ0.1〜10%(mg/ml)の濃度で存在する、炎症性インターロイキン-1サイトカインの活性を阻害する組成物を含む、組成物。
- SEQ ID NO:15またはSEQ ID NO:16のアミノ酸配列を含むポリペプチドを含む、請求項15記載の組成物。
- 炎症性インターロイキン-1サイトカインの活性を阻害する組成物を含むコンタクトレンズであって、該組成物が該レンズに組み入れられるかまたはその上にコーティングされる、コンタクトレンズ。
- 炎症性インターロイキン-1サイトカインまたはIL-1受容体をコードするポリヌクレオチドまたはポリペプチドの転写、転写物安定性、翻訳、修飾、局在化、分泌、または機能を阻害する組成物を被験体の眼または付属器組織に局所投与する段階を含む、眼の炎症障害を阻害するかまたはその重症度を低減させるための方法。
- 前記組成物がポリヌクレオチド、ポリペプチド、抗体、または低分子を含む、請求項18記載の方法。
- 前記組成物が、モルフォリノアンチセンスオリゴヌクレオチド、マイクロRNA(miRNA)、低分子ヘアピン型RNA(shRNA)、または低分子干渉RNA(siRNA)を含む、請求項18記載の方法。
- 前記組成物が局所表面に投与される、請求項18記載の方法。
- ポリマーと、ポリマーの中にまたはその上に組み入れられた生物活性組成物とを含む装置であって、該生物活性組成物が炎症性インターロイキン-1サイトカインの活性を阻害し、かつ該装置が、眼または付属器組織の中またはその上に組み入れられる、装置。
- IL-1受容体に対する炎症性IL-1サイトカインの結合を阻害する組成物と、1つまたは複数の炎症性アンタゴニストを含む第二の組成物の双方の投与を含む、請求項1記載の方法。
- 前記第二の組成物が、腫瘍壊死因子α(TNFα)、1つもしくは複数のインターロイキンサイトカイン、血管上皮増殖因子(VEGF)ファミリーの1つもしくは複数のメンバー、インターフェロン-γ、または1つもしくは複数のケモカインおよびその受容体を阻害する、請求項23記載の方法。
- 前記第二の組成物が、エタネルセプト/Embrel、インフリキシマブ/Remicade、またはアダリムマブ/Humiraを含む、請求項23記載の方法。
- 前記第二の組成物が、TNFα、IL-2、IL-4、IL-5、IL-6、IL-8、IL-12、IL-17、IL-18、IL-23、VEGF-A、VEGF-C、VEGFR-2、VEGFR-3、インターフェロン-γ、CCR1、CCR2、CCR5、CCR7、またはCXCR3の阻害剤を含む、請求項23記載の方法。
- 前記第二の組成物が免疫抑制剤を含む、請求項23記載の方法。
- 前記第二の組成物が、シクロスポリンAもしくはその類似体、グルココルチコイド、細胞増殖抑制剤、アルキル化剤、ナイトロジェンマスタード、シクロホスファミド、ニトロソウレア、白金化合物、代謝拮抗剤、メソトレキセート、葉酸類似体、アザチオプリン、メルカプトプリン、プリン類似体、ピリミジン類似体、タンパク質合成阻害剤、細胞障害性抗生物質、ダクチノマイシン、アントラサイクリン、マイトマイシンC、ブレオマイシン、ミスラマイシン、ポリクローナル抗体、Atgam(登録商標)、Thympglobuline(登録商標)、抗リンパ球抗原に対する抗体、抗胸腺細胞抗原に対する抗体、モノクローナル抗体、OKT3(登録商標)、T細胞受容体に対する抗体、IL-2に対する抗体、バシリキシマブ/Simulect(登録商標)、デクリズマブ/Zenapax(登録商標)、タクロリムス/Prograf(商標)/FK506、シロリムス/Rapamune(商標)/ラパマイシン、インターフェロンβ、インターフェロンγ、オピオイド、TNFα結合タンパク質、ミコフェノレート(mycophenolate)、またはFTY720を含む、請求項23記載の方法。
- 上昇した眼内圧を有する被験体を同定する段階、および炎症性インターロイキン-1サイトカインの活性を阻害する組成物を該被験体の眼または付属器組織に局所投与する段階を含む、上昇した眼内圧を抑制するかまたはその重症度を低減させるための方法。
- 上昇した眼内圧を有する被験体を同定する段階、および炎症性インターロイキン-1サイトカインまたはIL-1受容体をコードするポリヌクレオチドまたはポリペプチドの転写、転写物安定性、翻訳、修飾、局在化、分泌、または機能を阻害する組成物を被験体の眼または付属器組織に局所投与する段階を含む、上昇した眼内圧を抑制するかまたはその重症度を低減させるための方法。
- 正常より上の眼内圧に関連する状態に罹っているかまたはそのリスクを有する被験体を同定する段階、および炎症性インターロイキン-1サイトカインの活性を阻害する組成物を被験体に局所投与する段階を含む、眼内圧を低減させるための方法。
- 前記状態が緑内障である、請求項31記載の方法。
- 前記炎症障害が、上昇した眼内圧、高眼圧症、または緑内障を含む、請求項1または18記載の方法。
- 前記同定する段階が、眼内圧を測定する段階、および該眼内圧が正常レベルより上に上昇しているか否かを決定する段階を含む、請求項3、29、30、または31記載の方法。
- 前記組成物が、プロスタグランジン類似体(ラタノプロスト(Xalatan)、ビマトプロスト(Lumigan)、およびトラボプロスト(Travatan)など);局所表面βアドレナリン受容体アンタゴニスト(チモロール、レボブノロール(Betagan)、およびベタキソロールなど);α2-アドレナリンアゴニスト(ブリモニジン(Alphagan)など)、交感神経模倣薬(エピネフリンおよびジピベフリン(Propine)など);縮瞳剤(副交感神経模倣薬)(ピロカルピンなど);炭酸脱水素酵素阻害剤(ドルゾラミド(Trusopt)、ブリンゾラミド(Azopt)、アセタゾラミド(Diamox)など);フィソスチグミン;魚油;ω3脂肪酸、コケモモ、ビタミンE、カンナビノイド、カルニチン、補酵素Q10、クルクミン、タンジン(Salvia miltiorrhiza)、ダークチョコレート、エリスロポエチン、葉酸、イチョウ(Ginkgo biloba)、チョウセンニンジン、L-グルタチオン、ブドウ種子抽出物、緑茶、マグネシウム、メラトニン、メチルコバラミン、N-アセチル-Lシステイン、ピクノジェノール(pycnogenol)、レスベラトロール、ケルセチン、およびフルドロコルチゾンからなる群より選択される化合物をさらに含む、請求項1、18、29、30、または31記載の方法。
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US10105441B2 (en) | 2018-10-23 |
AU2008289552B2 (en) | 2014-10-09 |
WO2009025763A2 (en) | 2009-02-26 |
JP5894364B2 (ja) | 2016-03-30 |
EP2187900A2 (en) | 2010-05-26 |
EP2187900B1 (en) | 2016-11-09 |
US20130273065A1 (en) | 2013-10-17 |
US20100203103A1 (en) | 2010-08-12 |
AU2008289552A1 (en) | 2009-02-26 |
EP2187900A4 (en) | 2011-08-17 |
JP2016065089A (ja) | 2016-04-28 |
WO2009025763A3 (en) | 2009-04-23 |
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