JP5468001B2 - イブジラストを含む進行性神経変性疾患の処置用医薬組成物 - Google Patents
イブジラストを含む進行性神経変性疾患の処置用医薬組成物 Download PDFInfo
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- JP5468001B2 JP5468001B2 JP2010516198A JP2010516198A JP5468001B2 JP 5468001 B2 JP5468001 B2 JP 5468001B2 JP 2010516198 A JP2010516198 A JP 2010516198A JP 2010516198 A JP2010516198 A JP 2010516198A JP 5468001 B2 JP5468001 B2 JP 5468001B2
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Classifications
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本出願は、2007年7月11日に出願された米国仮特許出願第60/929,745号及び2008年4月3日に出願された米国仮特許出願第61/042,181号の利益を主張するものであり、その開示内容はすべて参照により本明細書に組み込まれる。
本発明を詳述する前に、添付する説明及び図から明らかであるように、本発明はそれ自体多種多様になりうるため、特定の投与方法、患者集団などに限定されないことを理解されたい。
進行性神経変性疾患の処置のための本発明の方法は、分子であるイブジラストの投与に基づく。イブジラストは下記に示される構造を有する小分子薬剤(分子量230.3)である。
上記に示されるように、本発明は、治療有効量のイブジラストを投与することにより、進行性神経変性疾患を患う被験者を処置する方法に関する。このような投与は、付随する実施例に示されるように、被験体が経験する進行性神経変性疾患の量を減少させ、即ち、進行性神経変性疾患の有意な減弱又は更には反転をもたらすのに有効である。好ましくは、イブジラストは、約30mg〜240mg/日、又は約30mg〜180mg/日、又は60mg〜120mg/日の範囲の連日投与量にて投与される。
治療量は、経験的に決定可能であり、処置すべき特定の疾患、被験体及び組成物に含まれる各活性剤の効力・毒性により異なる。実際の投与用量は、被験体の年齢、体重及び全身状態並びに処置対象疾患の重症度、医療従事者の判断及び投与される特定の組合せにより異なる。
イブジラストはグリア活性化の強力なサプレッサーである(Mizunoら(2004)Neuropharmacology 46:404−411)。用量依存的に、イブジラストは、一酸化窒素(NO)、活性酸素種、インターロイキン(IL)−1β、IL−6及び腫瘍壊死因子(TNF)の産生を抑制し、神経成長因子(NGF)、グリア由来神経栄養因子(GDNF)及び活性化ミクログリアにおけるニューロトロフィン(NT)−4を含む追加神経栄養因子とともに抑制性サイトカイン、IL−10の産生を亢進させることが示されている。従って、イブジラスト媒介性神経保護は、主に炎症性メディエータの抑制及び神経栄養因子のアップレギュレーションによるものであることが見出された。
イブジラストの進行性神経変性疾患を処置する能力は、当該技術分野において公知のいかなる標準的な進行性神経障害疾患モデルによっても評価可能である。このようなモデル例は、Animal Models of Neurological Disease:Neurodegenerative Diseases(Neuromethods)、Alan A.Boulton,Glen B.Baker及びRoger F.Butterworth(1992);Handbook of Laboratory Animal Science、第二版:第I〜III巻(Handbook of Laboratory Animal Science)、Jann Hau(編)、Jr.,Gerald L.Van Hoosier(編)(2004);Animal Models of Movement Disorders,Mark LeDoux(編)、(2005);並びにAnimal Models of Cognitive Impairment(Frontiers in Neuroscience)(2006)、Edward D.Levin(編)、Jerry J.Buccafusco(編)に述べられている。
イブジラストを含むことに加え、本発明の治療製剤は後述のように1つ以上の追加成分を任意に含んでもよい。
イブジラストに加え、進行性神経変性疾患を処置するための本発明の組成物は、1つ以上の医薬的に許容可能な賦形剤又は担体を更に含んでもよい。典型的な賦形剤には、限定するものではないが、ポリエチレングリコール(PEG)、硬化ヒマシ油(HCO)、クレモフォル(cremophors)、糖質、デンプン(例えば、コーンスターチ)、無機塩、抗菌剤、酸化防止剤、結合剤/充填剤、界面活性剤、潤滑剤(例えば、ステアリン酸カルシウム又はマグネシウム)、タルクのような流動促進剤、崩壊剤、希釈剤、緩衝剤、酸、塩基、フィルムコート、その組合せなどが含まれる。
本発明による製剤(又はキット)は、イブジラストに加え、進行性神経変性疾患を処置するのに有効な1つ以上の追加活性剤を含んでもよい。好ましくは、活性剤はイブジラストと異なる作用機序を有する活性剤である。そのような活性剤は、米国特許出願公開第2006/0160843号に列挙されている疼痛に対する組合せ及び標的疾患の処置について認識されている活性成分を含む。そのような活性成分は、FDAのOrange Book,Goodman & Gilman The Pharmacological Basis of Therapeutics,J.Griffith Hardman,L.L.Limbird,A.Gilman、第11版、2005,The Merck Manual、第18版、2007及びThe Merck Manual of Medical Information 2003に列挙されているのが見出されうる。
好ましくは、組成物はイブジラストの安定性を向上させ、イブジラストの半減期を延ばすように製剤化される。例えば、イブジラストは徐放性製剤にて送達されうる。放出制御又は徐放性製剤は、例えば、リポソームなどの担体又はビヒクル、例えば、エチレン酢酸ビニルコポリマー及びHytrel(登録商標(RTM))コポリマーなどの非吸収性不浸透性ポリマー、ヒドロゲルのような膨潤性ポリマー又はコラーゲンのような吸収性ポリマー並びに吸収性縫合糸を作製するために用いられるようなある種のポリ酸又はポリエステルにイブジラストを組み込むことによって調製される。加えて、イブジラストは微粒子担体に封入され、吸着され、又は結合されうる。微粒子担体例には、ポリメチルメタクリレートポリマー由来の微粒子担体並びにポリ(ラクチド)及びPLGとして公知のポリ(ラクチド−co−グリコリド)由来の微粒子が含まれる。例えば、Jefferyら、Pharm.Res.(1993)10:362−368;及びMcGeeら、J.Microencap.(1996)を参照されたい。
本明細書で述べられるイブジラスト組成物は、あらゆるタイプの製剤、特に、全身又はくも膜下腔内投与に適した製剤を包含する。経口剤形には、錠剤、飴、カプセル、シロップ、経口懸濁液、エマルション、顆粒及び丸薬が含まれる。別の製剤には、エアロゾル、経皮貼布、ゲル、クリーム、軟膏、坐薬、粉末又は再構成可能な凍結乾燥物(lyophilate)並びに液体が含まれる。例えば、注射前に固形組成物を再構成するのに好適な希釈剤の例には、注射用の静菌性水、水中5%ブドウ糖、リン酸緩衝生理食塩水、リンゲル液、生理食塩水、滅菌水、脱イオン水及びその組合せが含まれる。液体医薬組成物に関しては溶液及び懸濁液が想定される。好ましくは、本発明のイブジラスト組成物は経口投与に適したものである。
本明細書で更に提供されるものは、使用説明書を伴った、本発明の少なくとも1つの組合せ組成物を含むキットである。
多発性硬化症患者においてイブジラストを用いて第II相無作為化プラセボ対照二重盲検試験を行った。第一年目の間、イブジラスト0mg(プラセボ)を1日3回、イブジラスト10mgを1日3回又はイブジラスト20mgを1日3回で患者を処置した。第二年目の間、プラセボ患者を無作為化し、イブジラスト10mg又は20mgを1日3回投与した(試験第一年目の間に10mg又は20mgを1日3回の患者は第二年目の間、その用量で継続した)。処置の2週間前にベースラインMRIスキャンを行った。その後のMRIスキャンにより年間ベースで脳容積の変化を評価した。2年間2カ月毎にMRIスキャンを行い、T1及びT2病変の変化を評価した。2年間の試験の第一年目の結果を下記の表1に概略的に示す。
アルツハイマー病のラット動物モデルにイブジラストを投与し、イブジラスト投与動物群に認知機能の改善が得られ、これにより、このモデルがヒトにおけるアルツハイマー病の処置に有効でありうることが示される。
進行性多発性硬化症の動物モデルにイブジラストを投与し、イブジラスト投与動物群に機能転帰の改善が得られ、これにより、このモデルが進行性多発性硬化症の処置に有効でありうることが示される。
パーキンソン病の動物モデルにイブジラストを投与し、イブジラスト投与動物群に運動の改善が得られ、これにより、このモデルがパーキンソン病の処置に有効でありうることが示される。
下記の表2は障害の進行(連続4日間、総合障害度評価尺度(EDSS)のスコアにおける1.0ポイント以上の増加、Kurtzke JF(1983)“Rating neurologic impairment in multiple sclerosis:an expanded disability status scale(EDSS)”Neurology 33(11):1444−52を参照されたい)が、12カ月間MN−166を投与される患者より24カ月間該薬剤を投与される患者において少なかったことを示す(p=0.026)。24カ月でのp値は、2年間の活性剤(30mg及び60mg用量群のプール)対プラセボから活性剤(p=0.0264);60mg対プラセボから活性剤(p=0.0516)及び30mg対プラセボから活性剤(p=0.0832)であった。MRI上での脳容積の減少は、MS患者における臨床的進行及び障害と相関することが示された。これらの結果は、再発MS患者におけるMN−166の神経保護的効果の可能性と一致する。
表3は、多発性硬化症(MS)におけるMN−166の2年間の第II相臨床試験の処置の第一年目からのMRIデータの二重盲検解析が行われたことを示す。この解析は、MS患者における磁気共鳴画像(MRI)上にてMN−166がブラックホール(脳神経の死滅を示すと考えられる永続的な脳病変)の形成を減少させることを示した。データは、MN−166の60mg/日の投与計画が、プラセボと比べて第10カ月目に永続的なブラックホールに進展した、試験の第二カ月目に同定された新たなT1ガドリニウム増強又は新たなT2病変の割合を有意に減少させることを示した(RR 0.63,p=0.011)。MN−166の30mg/日の投与計画による処置は、プラセボと比べて新たな病変の永続的なブラックホールへの進展のリスクの低減傾向を示した(RR 0.735,p=0.074)。プラセボ(n=100)、MN−166を30mg/日(n=94)又はMN−166を60mg/日(n=98)投与された患者292人のうち、プラセボ処置患者の72人、MN−166を30mg/日投与された患者の64人及びMN−166を60mg/日を投与された患者の56人が試験の第二カ月目に新たな病変を有していた。永続的なブラックホールに進展する新たな病変の割合は、プラセボ、30mg/日のMN−166及び60mg/日のMN−166の処置群において、それぞれ0.24,0.20及び0.16であった。新たな病変の永続的なブラックホールへの進展の相対リスク(RR)は、プラセボ処置患者と比べて、MN−166を60mg/日で処置されたMS患者において有意に低く(RR 0.63,p=0.011)、MN−166を30mg/日で処置された患者において低い傾向にあった(RR 0.735,p=0.074))。
Claims (6)
- 進行性神経変性疾患を患うヒト患者における進行性神経変性疾患の負の作用を軽減するための医薬組成物であって、
イブジラスト又はその医薬的に許容可能な塩を含んで構成され、
前記進行性神経変性疾患が、一次性進行型又は二次性進行型多発性硬化症である、医薬組成物。 - 前記イブジラスト又はその医薬的に許容可能な塩は、少なくとも1日1回投与するためのものである、請求項1に記載の医薬組成物。
- 前記イブジラスト又はその医薬的に許容可能な塩は、少なくとも1日1回経腸投与するためのものである、請求項1に記載の医薬組成物。
- 前記イブジラスト又はその医薬的に許容可能な塩は、少なくとも1日1回経口投与するためのものである、請求項1に記載の医薬組成物。
- 前記イブジラスト又はその医薬的に許容可能な塩は、少なくとも1日1回非経口投与するためのものである、請求項1に記載の医薬組成物。
- 前記イブジラスト又はその医薬的に許容可能な塩は、少なくとも1日1回静脈内投与するためのものである、請求項1に記載の医薬組成物。
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JP4954085B2 (ja) * | 2004-12-06 | 2012-06-13 | メディシノバ, インコーポレイテッド | 神経障害性疼痛及びその関連する症状を治療するためのイブジラスト |
JP2009512711A (ja) | 2005-10-21 | 2009-03-26 | ブレインセルス,インコーポレイティド | Pde阻害による神経新生の調節 |
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