JP2015522601A - バクロフェン及びアカンプロセートに基づいた黄斑変性疾患の治療法 - Google Patents
バクロフェン及びアカンプロセートに基づいた黄斑変性疾患の治療法 Download PDFInfo
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Abstract
Description
本発明は、黄斑変性疾患の処置のための組み合わせ及び方法に関する。より具体的には、本発明は、バクロフェン及びアカンプロセートの組み合わせに基づいた、新規なAMDの併用療法に関する。
加齢黄斑変性(AMD)は、世界中において高齢集団に発症する失明の第一原因である。8000万人の人々が2020年までにAMDを発症すると推定されている。罹患率は66歳から74歳の患者において10%であり、75歳から85歳の患者では30%に増加する。AMDは、網膜の中心付近に位置する、黄斑の進行的な障害によって特徴付けられる変性疾病である。黄斑は、光受容体が最も集中している領域であり、それ故、中心視野及び視力に関与している。AMDに関連したリスク因子が存在し、高齢が主なリスク因子である。その他のリスク因子は、眼の要因(より暗い虹彩の色素沈着、白内障手術の前歴、屈折性遠視)又は全身性の要因(喫煙、肥満、食事、人種、網膜ストレス(日光への曝露)及び心血管疾患)からなる。いくつかの遺伝子座がAMDと関連し、これには、CFH、ARMS2/HTRA1遺伝子座、C2、CFB、C3及びCF1などの補体系の配列が含まれる。HDLコレステロール経路(LIPC、CETP及びおそらくABCA1及びLDL)、LDL経路(おそらくAPOE)、細胞外マトリックス(COL10A1、COL8A1、TIMP3)、グリア線維酸性タンパク質(GFAP)及び血管新生経路(VEGFA)の遺伝子もAMDに関連している[1,2]。
本発明の目的は、黄斑変性疾患の処置を提供することである。より正確には、本発明は、バクロフェン及びアカンプロセートの使用に基づいた、黄斑変性疾患を処置するための組成物及び方法に関する。
本発明は、黄斑変性疾患の処置のための新規な方法及び組成物を提供する。本発明は、このような疾病の効果的な矯正を可能とし、任意の哺乳動物被験体に使用され得る、新規な薬物組成物を開示する。
経口使用のための製剤としては、無毒性の薬学的に許容される賦形剤との混合物中に本発明の組成物を含む錠剤が挙げられる。これらの賦形剤は、例えば、不活性な希釈剤又は増量剤(例えばスクロース、微結晶セルロース、デンプン(ジャガイモデンプンを含む)、炭酸カルシウム、塩化ナトリウム、リン酸カルシウム、硫酸カルシウム、又はリン酸ナトリウム);造粒剤及び崩壊剤(例えばセルロース誘導体(微結晶セルロースを含む)、デンプン(ジャガイモデンプンを含む)、クロスカルメロースナトリウム、アルギネート、又はアルギン酸);結合剤(例えばアカシア、アルギン酸、アルギン酸ナトリウム、ゼラチン、デンプン、アルファ化デンプン、微結晶セルロース、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、エチルセルロース、ポリビニルピロリドン、又はポリエチレングリコール);及び潤滑剤、滑沢剤、及び粘着防止剤(例えばステアリン酸、シリカ、又はタルク)であり得る。他の薬学的に許容される賦形剤は、着色剤、芳香剤、可塑剤、湿潤剤、緩衝化剤などであり得る。
水の添加による水性懸濁液の調製に適した散剤、分散性散剤、又は顆粒剤は、経口投与のための慣用的な剤形である。懸濁剤としての製剤は、分散剤又は湿潤剤、懸濁化剤、及び1つ以上の保存剤との混合物中の活性成分を提供する。適切な懸濁化剤は、例えば、カルボキシメチルセルロースナトリウム、メチルセルロース、アルギン酸ナトリウムなどである。
剤形の製剤の、又は適切な送達装置を介した、又は慣用的で無毒性の薬学的に許容される担体及び補助剤を含む、薬学的組成物は、眼内注射によって非経口投与され得る。このような組成物の製剤化及び調製は医薬製剤の分野の技術者には周知である。
薬学的組成物はまた、慣用的で無毒性の薬学的に許容される担体及び賦形剤を含む剤形又は製剤で(ミクロスフィア及びリポソームを含む)点眼を通して局所投与され得る。前記製剤としては、ローション剤、リニメント剤、ゲル剤、ハイドロゲル剤、液剤、懸濁剤、噴霧剤、及び他の種類の薬物送達システムが挙げられる。薬学的に許容される担体又は賦形剤としては、乳化剤、抗酸化剤、緩衝化剤、保存剤、湿潤剤、浸透増強剤、キレート剤、ゲル形成剤、軟膏基剤、香料、及び皮膚保護剤が挙げられ得る。
組み合わせの薬物は、同じ又は異なる薬学的製剤のいずれかで同時に又は順次投与され得ると理解される。順次投与されるのであれば、第2の(又は追加の)活性成分の投与の遅延は、活性成分の組合せの効果的な作用の利点を失わないようなものとすべきである。本記載による組み合わせの最小限度の必要条件は、前記組み合わせが、活性成分の組合せの効果的な作用の利点を有する併用を目的とすべきであることである。組み合わせの使用目的は、施設、支給物、適応及び/又は本発明による組み合わせの使用を助ける他の手段によって推論され得る。
− 1〜1000mg/日、好ましくは500mg/日未満、より好ましくは100mg/日未満、さらにより好ましくは10mg/日未満のアカンプロセート、このような投与量が経口投与に特に適している。
− 0.01〜150mg/日、好ましくは100mg/日未満、より好ましくは75mg/日未満、さらにより好ましくは50mg/日未満のバクロフェン、このような投与量が経口投与に特に適している。
I.酸化ストレスに対する本発明の組み合わせの効果
酸化ストレスは、AMDの病因に強く関連していることが示された。この現象は、ミトコンドリアの機能不全の原因であることが疑われ、この機能不全は次に反応性酸素種を生じる。RPE細胞及び網膜神経細胞の両方が、酸化的傷害を特に受けやすい[24、25]。以下に示された実験において、本発明者らは、バクロフェン及びアカンプロセートを含む組成物が、6−ヒドロキシドーパミン(6−OHDA)又はアミロイドβ(後者は、ドルーゼンの一成分と判明した)によって誘発された酸化ストレス及びミトコンドリア機能不全を低下させるのに特に効果的であることを発見した。
6−OHDAは、細胞において反応性酸素種を生成し、ミトコンドリア死滅を誘発することによって、ニューロンを破壊する神経毒性薬物である。ドーパミンとその構造が類似していることから、6OHDAは、特異的なドーパミン活性輸送体を介してドーパミン作動性ニューロン内に特異的に侵入すると考えられる。それにも関わらず、以下の結果は、本発明の組み合わせが、酸化ストレスから神経細胞を防御するのに効果的であることを示す。
ラットドーパミン作動性ニューロンを、Schinelli et al. (1988)によって記載されているように培養した[26]。15日間の妊娠期間の妊娠雌ラットを頸部脱臼によって屠殺し(Rats Wistar; Janvier)、子宮から胎仔を取り出した。胎仔の中脳を取り出し、2%ペニシリン−ストレプトマイシン(PS; PanBiotech)及び1%のウシ血清アルブミン(BSA; PanBiotech)を含む氷冷リーボビッツ培地(L15; PanBiotech)に入れた。中脳湾曲部の腹側部だけを細胞調製物のために使用した。なぜなら、これは、ドーパミン作動性ニューロンに富んだ発達中の脳の領域であるからである。中脳を、37℃で20分間トリプシンで処理することによって解離した(トリプシンEDTA 1×;PanBiotech)。反応を、II等級のDNAaseI(0.1mg/ml;PanBiotech)及び10%ウシ胎児血清(FCS;Invitrogen)を含むダルベッコ改変イーグル培地(DMEM;PanBiotech)の添加によって停止する。その後、細胞を、10mlのピペットに3回通すことによって機械的に解離し、180×gで10分間+4℃でL15培地中のBSA(3.5%)層上で遠心分離にかけた。上清を廃棄し、ペレットの細胞を、B27(2%;Invitrogen)、L−グルタミン(2mM;PanBiotech)及び2%のPS溶液及び10ng/mlの脳由来神経栄養因子(BDNF、PanBiotech)及び1ng/mlのグリア由来神経栄養因子(GDNF、PanBiotech)の補充されたNeurobasal(Invitrogen)からなる規定の培養培地に再懸濁した。生細胞を、トリパンブルー色素排除試験を使用してノイバウエルサイトメーターで計数した。細胞を、96ウェルプレート(ポリ−L−リジンで前以てコーティングされている(Greiner))に40000個の細胞/ウェルの密度で播種し、加湿空気(95%)/CO2(5%)雰囲気中37℃で培養する。培地の半分を2日毎に新たな培地と交換した。神経細胞集団の5〜6%がドーパミン作動性ニューロンであった。
培養6日目に、培地を除去し、以下の濃度の6OHDAを含まない又は含む新たな培地を加えた:48時間の間、対照培地で希釈された20μM。試験化合物を1時間プレインキュベーションし、その後、48時間の間に6−OHDAを適用した。
6OHDAによる中毒から48時間後、細胞を、PBS(pH=7.3)中4%パラホルムアルデヒド溶液によって20分間かけて室温で固定した。細胞を、PBS中で再度2回洗浄し、その後、透過処理し、非特異的部位を、0.1%サポニン(Sigma)及び1%FCSを含むPBS溶液を用いて15分間かけて室温でブロッキングした。その後、細胞を、1%FCS、0.1%サポニンを含むPBS中で1/1000希釈度のマウス(TH、Sigma)で産生されたモノクローナル抗チロシンヒドロキシラーゼ抗体と共に室温で2時間インキュベーションした。これらの抗体を、1%FCS、0.1%サポニンを含むPBS中1/800希釈度のAlexa Fluor 488ヤギ抗マウスIgG(Molecular Probes)を用いて室温で1時間かけて明らかとした。
結果を表2に要約する。ドーパミン作動性ニューロンに対する神経保護効果が、6−OHDAによる損傷から48時間後に、THニューロン生存試験において、本発明の化合物及び組み合わせについて観察される。
アミロイドβは、ミトコンドリアの崩壊をトリガーし、酸化ストレスも引き起こすミトコンドリア毒素として知られている。興味深いことに、アミロイドβはドルーゼンにおいて見られ、その蓄積は初期のAMDの兆候と考えられている。
ラット皮質ニューロンを、Singer et al., 1999[28]によって記載されている通りに培養した。簡潔には、15日間の妊娠期間の妊娠雌ラットを頸部脱臼によって屠殺し(Rats Wistar)、子宮から胎仔を取り出した。皮質を取り出し、2%ペニシリン10.000U/ml及びストレプトマイシン10mg/ml及び1%のウシ血清アルブミン(BSA)を含む氷冷リーボビッツ培地(L15)に入れた。皮質を、37℃で20分間かけてトリプシン(0.05%)によって解離した。反応を、II等級のDNaseI(0.1mg/ml)及び10%ウシ胎児血清(FCS)を含むダルベッコ改変イーグル培地(DMEM)の添加によって停止した。その後、細胞を、10mlのピペットに3回通すことによって機械的に解離した。その後、細胞を、515×gで10分間10℃で遠心分離にかけた。上清を廃棄し、細胞のペレットを、B27(2%)、L−グルタミン(0.2mM)、2%のPS溶液及び10ng/mlのBDNFの補充されたNeurobasalからなる規定の培養培地に再懸濁する。生細胞を、トリパンブルー色素排除試験を使用してノイバウエルサイトメーターで計数した。細胞を、96ウェルプレート(ウェルは、ポリ−L−リジン(10μg/mL)で前以てコーティングされている)に30000個の細胞/ウェル(CytCの調査のために)又は15000個の細胞/ウェル(MetOの評価のために)の密度で播種し、加湿空気(95%)/CO2(5%)雰囲気中37℃で培養した。
ヒトAβ1−42を、40μMの規定の培養培地(母液)中で再構成し、暗闇の中で37℃で3日間ゆっくりと放置する。対照培地は同じ条件で調製された。
4時間かけて中毒化した後、細胞を、エタノール(95%)及び酢酸(5%)の冷溶液によって5分間かけて固定した。その後、細胞を透過処理し、非特異的部位を、0.1%のサポニン(Sigma)及び1%のウシ胎児血清(FCS)を含むリン酸緩衝食塩水(PBS;PanBiotech)溶液を用いて室温で15分間かけてブロッキングした。その後、細胞をモノクローナル抗体抗微小管会合タンパク質2(MAP−2;Sigma)と共にインキュベーションした。この抗体は、特異的にニューロンの細胞体及び神経突起を染色する。ポリクローナルMetO一次抗体(Euromedex)を使用して同時染色を行なった。これらの抗体を、Alexa Fluor 488ヤギ抗マウスIgG(Molecular probe)を用いて、及びAlexa Fluor 568ヤギ抗ウサギIgG(Molecular probe)を用いて明らかとした。ニューロンの核は、蛍光マーカー(ヘキスト液、SIGMA)によって標識される。
このアッセイは、ポリクローナルCytoC一次抗体(Abcam)を使用して細胞質チトクロムCを検出したこと以外は、実質的に上記されている通りに実施された。
データを、対照条件(中毒なし、6OHDAなし=100%)に対する比率として表現することにより、アミロイドによる損傷を表現する。全ての数値は、3つの培養液(1つの条件あたりn=6のウェル)の平均値+/−標準誤差(s.e.mean)として表現される。(Statviewソフトウェアバージョン5.0)が可能であった場合には、統計分析は、ANOVA、その後のダネット検定及びPLSDフィッシャー検定を使用して実施された。
結果を表2に要約する。本発明の組成物は、AMDの病因の構成要素である酸化ストレス及びミトコンドリア機能不全から神経細胞を防御する上で効果的である。
脈絡膜血管新生(CNV)は、ウェット型AMDを有する患者における重度の中心視野の低下の主要な原因である。ウェット型AMDに対する本発明の組み合わせの効果を、脈絡膜血管新生のマウスモデルにおいて評価した。
青色光が、RPE、杆体及び錐体においてフリーラジカルを発生する光化学反応を引き起こすことが示された。このフリーラジカル発生により、最終的に黄斑の維持システムが詰まり、ドライ型黄斑変性を生じると考えられている(25)。
Claims (10)
- 必要とされる被験者における黄斑変性疾患の処置もしくは予防において使用するための、又は前記疾患の進行を阻止もしくは停止させるための、バクロフェン及びアカンプロセート、又はその塩もしくはプロドラッグもしくは誘導体もしくは持続放出製剤を含む組成物。
- 黄斑変性疾患が、ドライ型又はウェット型加齢黄斑変性(AMD)、シュタルガルト病、若年発症型又は成人発症型卵黄様黄斑変性症、及び糖尿病性神経障害から選択される、請求項1記載の使用のための組成物。
- 被験者が、ドルーゼン又は網膜色素の変化を有すると診断された、請求項1又は2記載の使用のための組成物。
- 必要とされる被験者における初期AMDからウェット型もしくはドライ型AMDへのエボリューションを予防するための請求項1〜3のいずれか一項の使用のための組成物。
- 被験者が、網膜変性又は異常な眼の血管新生を経験している、請求項1〜4のいずれか一項の使用のための組成物。
- 薬学的に許容される担体又は賦形剤をさらに含む、請求項1〜5のいずれか一項の使用のための組成物。
- 前記組成物中の化合物が、一緒に、別々に又は順次製剤化又は投与される、請求項1〜6のいずれか一項の使用のための組成物。
- 前記組成物が被験者に繰り返し投与される、請求項1〜7のいずれか一項の使用のための組成物。
- アカンプロセートカルシウム塩が使用される、請求項1〜8のいずれか一項の使用のための組成物。
- 必要とされる被験者における黄斑変性疾患を処置もしくは予防するために、又は前記疾患の進行を阻止もしくは停止させるために使用するための、少なくともアカンプロセート、又はその塩、プロドラッグ、誘導体もしくは持続放出製剤と組み合わせた、バクロフェン、又はその塩、プロドラッグ、誘導体もしくは持続放出製剤。
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