JP5122460B2 - 治療薬の眼内輸送のための組成物および方法 - Google Patents
治療薬の眼内輸送のための組成物および方法 Download PDFInfo
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- JP5122460B2 JP5122460B2 JP2008531128A JP2008531128A JP5122460B2 JP 5122460 B2 JP5122460 B2 JP 5122460B2 JP 2008531128 A JP2008531128 A JP 2008531128A JP 2008531128 A JP2008531128 A JP 2008531128A JP 5122460 B2 JP5122460 B2 JP 5122460B2
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- A61K9/0048—Eye, e.g. artificial tears
Description
本発明に有用な生物活性物質として、レチノイド、プロスタグランジン、プロテインキナーゼインヒビター(チロシンキナーゼインヒビターなど)、αまたはβアドレナリン受容体アゴニストもしくはアンタゴニスト、ドーパミンアゴニスト、コリンアゴニスト、炭酸脱水酵素インヒビター、グアニル酸シクラーゼアクチベーター、カンナビノイド、エンドセリン、アデノシンアゴニスト、抗血管新生化合物、血管新生抑制化合物および神経保護剤が挙げられる。
本発明は、一般に、眼の後部区域を治療する方法に関する。好ましくは、眼の後部区域は、ブドウ膜、硝子体、網膜、脈絡膜、視神経および網膜色素上皮(RPE)を含むがこれらに限定されるものではない。本発明に関連する疾患または状態は、眼の後部における活性薬物の作用によって予防または治療されうる疾患または状態を含む。決して本発明の範囲を限定することを意図するものではないが、本発明によれば、眼の後部における活性薬物の作用によって予防または治療されうる疾患または状態として、黄斑浮腫、非滲出性加齢性黄斑変性症(ARMD)、滲出性加齢性黄斑変性症(ARMD)、脈絡膜血管新生、糖尿病性網膜症、急性黄斑視神経網膜症、中心性漿液性網脈絡膜症、類嚢胞黄斑浮腫および糖尿病性黄斑浮腫などの黄斑症/網膜変性症;急性多発性小板状色素上皮症、ベーチェット病、散弾網膜脈絡膜炎、感染症(梅毒、ライム病、結核、トキソプラズマ症)、中間部ブドウ膜炎(扁平部炎)、多発性脈絡膜炎、多発一過性白点症候群(mewds)、眼サルコイドーシス、後部強膜炎、蛇行性脈絡膜炎、網膜か線維症およびブドウ膜炎症候群、フォークト・小柳・原田症候群などのブドウ膜炎/網膜炎/脈絡膜炎;網膜動脈閉塞性疾患、網膜中心静脈閉塞症、播種性血管内凝固障害、網膜静脈分枝閉塞症、高血圧性眼底変化、眼虚血症候群、網膜動脈毛細血管瘤、コーツ病、傍中心窩毛細血管拡張症、半網膜(hemiretinal)静脈閉塞症、乳頭静脈炎、網膜中心動脈閉塞、網膜動脈分枝閉塞症、頸動脈疾患(CAD)、フロステッド(frosted)分枝血管炎、鎌状赤血球網膜症およびその他の異常血色素症、網膜色素線条、家族性滲出性硝子体網膜症およびイールズ病などの血管病/滲出性疾患;交感性眼炎、ブドウ膜網膜疾患、網膜剥離、外傷、レーザー処置に起因する状態、光線力学的療法に起因する状態、光凝固、手術中の血流低下、放射線網膜症および骨髄移植網膜症などの外傷性/外科的状態;増殖性硝子体網膜症および網膜上膜ならびに増殖性糖尿病性網膜症などの増殖性障害;眼ヒストプラスマ症、眼トキソカラ症、推定眼ヒストプラスマ症候群(POHS)、眼内炎、トキソプラズマ症、HIV感染関連網膜疾患、HIV感染関連脈絡膜疾患、HIV感染関連ブドウ膜疾患、ウイルス性網膜炎、急性網膜壊死、進行性外層網膜壊死、真菌性網膜疾患、眼梅毒、眼結核、びまん性片側性亜急性視神経網膜炎およびハエウジ症などの感染性障害;網膜色素変性症、関連性網膜ジストロフィーを伴う全身性障害、先天性停止性夜盲、錐体ジストロフィー、シュタルガルト病および黄色斑眼底、ベスト病、網膜色素上皮のパターンジストロフィー、X連鎖性網膜分離症、ソースビー眼底変性症、良性中心性黄斑症、ビエッティクリスタリンジストロフィー(Bietti's crystalline dystrophy)および弾力線維性仮性黄色腫などの遺伝病;網膜剥離、黄斑円孔および巨大網膜裂孔などの網膜裂孔/網膜円孔;腫瘍関連網膜疾患、網膜色素上皮の先天性肥大、後部ブドウ膜メラノーマ、脈絡膜血管腫、脈絡膜骨腫、脈絡膜転移、網膜および網膜色素上皮の混合過誤腫、網膜芽細胞腫、眼底の血管増殖性腫瘍、網膜星状細胞腫および眼内リンパ腫瘍などの腫瘍;および点状内部脈絡膜症、急性後部多発性小板状色素上皮症、近視性網膜変性および急性網膜色素上皮炎などの眼の後部に影響を及ぼす種々雑多な他の疾患が挙げられる。疾患または状態が、網膜色素変性症、増殖性硝子体網膜症(PVR)、加齢黄斑変性(ARMD)、糖尿病性網膜症、糖尿病性黄斑浮腫、網膜剥離、網膜劣孔、ブドウ膜炎またはサイトメガロウイルス網膜炎であるのが好ましい。
眼の前部構造への局所的ドラッグデリバリーは、重要な解剖学的および生理学的障害物を提供する。注入された薬物の角膜透過性の低さや前角膜クリアランスの迅速さが、通常、房水への吸収を、適用された用量のわずか2、3パーセントにしてしまう。通常の房水の代謝回転は、吸収された薬物の房水濃度を持続的に低下する。さらに、虹彩水晶体隔壁が、薬物が眼の後部に到達するのを妨げる。水晶体を通っての後部室への薬物の拡散は、通例、実行可能であると考えられていない。
局所投与は一般に、薬物の眼への眼内または結膜下投与よりも外傷性が少ないが、いくつかの場合、本発明組成物を、眼の後部区域へ、直接(または局所投与が許すよりもより直接的に)デリバリーすることが必要である。
本発明の治療薬、プロドラッグおよび/または複合体を、硝子体液の粘度に近似する粘度などの相対的に高い粘度を有する粘度製剤に懸濁させてもよい。このような粘度製剤は、粘度誘発成分を含む。本発明治療薬は、水性注射液、懸濁液、乳剤、溶液剤、ゲルまたは徐放性あるいは持続放出性インプラント(生分解性または非生分解性)として(これらに限定されるものではない)、硝子体内投与してもよい。
有用な粘度誘発成分の例として、ヒアルロン酸、カルボマー、ポリアクリル酸、セルロース誘導体、ポリカルボフィル、ポリビニルピロリドン、ゼラチン、デキストリン、多糖、ポリアクリルアミド、ポリビニルアルコール、酢酸ポリビニル、それらの誘導体およびそれらの混合物が挙げられるが、これらに限定されるものではない。
投与モードまたは治療薬の剤形(たとえば、局所、注射用またはインプラント用剤としての溶液、懸濁液など)にかかわらず、本発明の輸送体標的化治療用組成物は、医薬的に許容しうるビヒクル成分で投与される。治療薬または作用剤を、組成物の製造中に医薬的に許容しうるビヒクル成分と組み合わせてもよい。言い換えれば、本明細書に開示した組成物は、治療成分および有効量の医薬的に許容しうるビヒクル成分を含むことができる。少なくとも1つの実施態様において、ビヒクル成分は、水性である。たとえば、組成物は、水を含むことができる。
形質膜表面における特異的担体介在膜輸送タンパク質は、RPEが、脈絡膜毛細管と末梢網膜の細胞との間で、栄養素、代謝産物および生体異物を選択的に輸送するのを可能にする。これらの特殊化した膜輸送体として、アミノ酸、ペプチド、ジカルボン酸塩、グルコース、モノカルボン酸、ヌクレオシド、有機アニオンおよび有機カチオン輸送体が挙げられる。同様に、角膜、結膜およびRPEなどの堅い眼上皮上で膜輸送体を標的化することによって、これらの関門を横切る吸収を大きく増加することができ、したがって、眼のバイオアベイラビリティを増加することができる。
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Na1共役Lアルギニン輸送システムが、ウサギ結膜において特徴決定されている。この輸送システムの輸送システムは、指向性(粘膜から漿膜へ)を示し、過剰の塩基性アミノ酸、大型中性アミノ酸および一酸化窒素シンターゼ(NOS)インヒビターによって阻害される。アミノ酸輸送システムB0,+もまた、NOSインヒビターの結膜輸送において存在する。GABA、グルタミン酸塩、グリシン、タウリン、トリプトファンおよびプロリンなどの他のアミノ酸輸送体が、網膜/RPEの細胞の表面において特徴決定されている。
グリシルエステル化合物1
ビマトプロストのグリシルエステル
化合物1のトリプトフィルエステル
ペプチド輸送体は、種々の上皮を横切るβ−ラクタム抗生物質、抗がん剤、レニンインヒビターおよ数種のアンギオテンシン変換酵素インヒビターなどの種々のペプチド様またはペプチド模倣薬物の輸送に、重要な薬理学的および薬物動態学的関連を有する。1つのモデルジペプチドであるグリシルサルコシンが、RPEに存在することが明らかにされている。プロトン駆動担体介在ジペプチド輸送体が、初代培養ウサギ結膜上皮において機能的に同定されている。
酢酸塩、プロピオン酸塩、乳酸塩、ピルビン酸塩およびケトン体などのモノカルボン酸塩は、H+−共役、Na+共役またはアニオン交換担体介在モノカルボン酸輸送体によって輸送される。着色ウサギ結膜におけるNa+依存性モノカルボン酸塩輸送体の存在が明らかにされている。この輸送体は、涙から強膜方向を好む方向性を示す。
本発明のさらなる実施態様は、硝子体半減期を延長するために硝子液内へプロベネシドとともに共投与されうる有機酸輸送体のための基質である薬物を含む。この実施態様ならびに他の実施態様において、インプラントおよびマイクロスフェアの形態で、薬物をプロベネシドまたはその他の有機酸輸送体のインヒビターとともに製剤することもできる。
ヌクレオシド輸送体は、ウサギの着色結膜上皮に存在し、涙から強膜方向で、ヌクレオシド結合分子の輸送体を介在する。Na+−依存性およびNa+−依存性ヌクレオシドは、ウサギ結膜の涙に局在化しているようにみえる過程を輸送する。ヌクレオシド輸送体は、ウサギ網膜およびヒトRPE細胞系においても同定された。この輸送体の関与は、傍細胞拡散によるものよりも10〜100倍以上吸収される薬物を多くすることができる。これは、非環式シトシンヌクレオシド類縁体であるシドフォビルの場合に明らかにされた。
有機カチオンの輸送は、基質特異的ナトリウム依存性輸送体によって、およびより特異性の少ないナトリウム非依存性輸送体によって介在される。有機カチオン輸送体の2つの主要ファミリーが、同定されている:有機カチオン輸送体(OCT) および有機カチオン/カルニチン輸送体(OCTN)。有機カチオン輸送体(OCT)を特徴決定するために通例用いられる基質であるグアニジンへの着色ウサギ結膜の透過性が評価されている。漿膜から粘膜の方向とは対照的に、グアニジンの透過性が、粘膜から漿膜方向において5.4倍大きいことが明らかにされた。
ビマトプロストをN,N−ジメチルホルムアミド(DMF):ピリジンの1:1溶液および5倍過剰の塩化リシンに室温にて懸濁することによって、ビマトプロストのリシンエステルを合成する。薄層クロマトグラフィー(TLC)によって完了が確認されるまで室温にて2〜3日間反応を行う。ピリジンおよびDMFを減圧除去し、生成物を酸塩化物から沈澱させる。シリカゲルクロマトグラフィーによって沈澱を精製し、ベンゼン−メタノール混合物から再結晶して、精製生成物を得る。
65歳の男性は、左眼に進行した(滲出型)加齢性黄斑変性を呈している。網膜散瞳(dilated)検査は、黄斑の下にある微細血管および網膜浮腫の両方の存在を特徴とする発生期の血管新生および浮腫を示す。
73歳の女性は、中心視野のかすみを訴えている。彼女の眼の散瞳検査は、右眼に嚢胞性黄斑浮腫の存在を示す。
インプランテーション後、患者の右眼に、1日2回0.15%(w/v)酒石酸ブリモニジンを局所投与し、その後2週間眼内圧をモニターする。
1か月後、散瞳後、患者の右眼を検査する。患者の網膜から膿疱性黄斑浮腫の痕跡は消滅し、患者の視力に焦点の明瞭さが回復していた。
10年前に鎌状赤血球症と診断されている36歳の患者は、両目に視覚のかすみを示している。散瞳下での網膜検査により、両眼に、黄斑虚血の部位およびその結果生じる血管新生葉状体または「ウミウチワ(sea fans)」の形状での網膜血管新生の部位が明らかとなる。さらに、黄斑浮腫の部位が視認できる。
眼内注射の1か月後、患者に再度、散瞳下網膜検査を行う。網膜血管新生および浮腫の領域は、縮小しており、視力の喪失の進行は止まっていた。インプラント処理の2か月後、血管新生の領域は、さらに減少し、浮腫の領域は、消失した。患者は、有意に回復した視力を報告している。
Claims (6)
- 膜輸送体の基質に共有的に結合した生物活性物質を含む、眼の後部区域における増強された有効性を有する治療薬を含む眼科用組成物であって、生物活性物質がビマトプロストであり、膜輸送体の基質がスクシニル残基である組成物。
- 局所投与用に製剤される請求項1に記載の組成物。
- 硝子体内注入物として製剤される請求項1に記載の組成物。
- 眼内インプラントとして製剤される請求項1に記載の組成物。
- 生物活性物質および基質が、組織不安定結合で結合する請求項1に記載の組成物。
- 組織不安定結合が、加水分解可能なエステル結合を含む請求項5に記載の組成物。
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JP5567082B2 (ja) | 2014-08-06 |
US20070066541A1 (en) | 2007-03-22 |
US20100222587A1 (en) | 2010-09-02 |
CA2602440A1 (en) | 2007-04-05 |
BRPI0616041A2 (pt) | 2011-06-07 |
JP2013014600A (ja) | 2013-01-24 |
AU2006295305A1 (en) | 2007-04-05 |
WO2007037849A3 (en) | 2008-01-24 |
CA2850858A1 (en) | 2007-04-05 |
AU2006295305B2 (en) | 2013-01-31 |
US7714024B2 (en) | 2010-05-11 |
JP2009508857A (ja) | 2009-03-05 |
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