JP2009539941A - Slv308およびl−dopaを含んでなる組み合わせ製剤 - Google Patents
Slv308およびl−dopaを含んでなる組み合わせ製剤 Download PDFInfo
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- JP2009539941A JP2009539941A JP2009514809A JP2009514809A JP2009539941A JP 2009539941 A JP2009539941 A JP 2009539941A JP 2009514809 A JP2009514809 A JP 2009514809A JP 2009514809 A JP2009514809 A JP 2009514809A JP 2009539941 A JP2009539941 A JP 2009539941A
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Abstract
本発明は、ドーパミン作動性機能の回復が必要な疾患、特にパーキンソン病およびむずむず脚症候群の処置に同時に、別々にまたは順次に使用するためのSLV308もしくそのN−オキシド、またはそれら化合物(I)、(II)の薬理学的に許容され得る塩、およびL−DOPAの組み合わせ製剤の使用に関する。
Description
発明の名称 1
目次 1
要約:発明の技術分野 1
発明の背景 2
発明の詳細な説明 5
定義 7
実施例 10
実施例1:薬理学的方法 10
実施例2:薬理学的試験結果 12
実施例3:製薬学的製剤 13
図1〜7の説明 15
参考文献 16
特許請求の範囲 19
要約 20
図面1〜7 21
本発明は、ドーパミン作動性機能の回復を必要とする疾患、特にパーキンソン病およびむずむず脚症候群(restless leg syndrome)の処置に同時に、別々に、もしくは順次に使用するためのSLV308もしくはそのN−オキシド、またはそのような化合物の薬理学的に許容され得る塩:
手足の絶え間無い振せん、次第に硬く、遅く、そして弱くなる身体の運動、および仮面様の表情は、人類の歴史を通じて観察されてきた症状である。1817年にJames Parkinsonがこの一群の症状を“paralysis agitans”と記載し、その直後、最初に詳細にこの疾患を記載した医師にちなんで病名が付けられた。パーキンソン病の病理学的原因には、筋肉運動が関係する脳の部分の黒質の神経細胞の破壊が関与する。パーキンソン病において約80%の線条体ドーパミンの損失は、運動不能、硬直および運動緩徐の重要な症状を生じる(Hornykiewicz,1966)。患者は運動を始めることに問題があり、そして***の不安定性および協調の損失を現す。
耐性および症状の増大が起こる(Allen,1996);この合併症はドーパミンアゴニストにも共通する(Earley,1996)。他の選択であるベンゾジアゼピン、アヘン剤および鎮痙薬はドーパミン作用剤のように均一に効果的ではない(Chesson,1999;Hening,1999)。それらの処置計画の変更にもかかわらず、15〜20%の患者には副作用および処置の利益の限界からすべての投薬療法が不十分であることが分かる。
本発明の目標は、L−DOPAのように効果的であるが、その副作用が無い、特に「オン」期間中に運動異常症候群を、そして「オフ」期間中に運動緩徐なエピソードを引き起こすその特徴的な「オン−オフ(on−off)効果」無しの処置を開発することであった。
(i)SLV308、そのN−オキシドまたはそれらの薬理学的に許容され得る塩、水和物および溶媒和物、および:
(ii)製薬学的に許容され得る補助物質、希釈剤もしくは担体との混合物でのL−DOPA
を含んでなる製薬学的製剤に関する。
(i)SLV308、そのN−オキシドまたはそれらの薬理学的に許容され得る塩、水和物および溶媒和物を、任意に製薬学的に許容され得る補助物質、希釈剤もしくは担体との混合物で含む容器、および;
(ii)L−DOPAを任意に製薬学的に許容され得る補助物質、希釈剤もしくは担体との混合物で含む容器、および;
(iii)必要な患者へのSLV308およびL−DOPAの順次の、別々の、または同時の投与に関する使用説明書、
を含んでなるキットの部分に関する。
(i)別個の製剤として提供され(すなわち互いに独立して)、これは引き続き併用療法において互いに連合して使用するために一緒にされる;あるいは
(ii)併用療法で互いに連合して使用するために「組み合わせパック」の別個の成分として一緒に包装され、そして提示される。
(i)SLV308、そのN−オキシドまたはそれらの薬理学的に許容され得る塩、水和物および溶媒和物を、任意に製薬学的に許容され得る補助物質、希釈剤もしくは担体との混合物で;
(ii)L−DOPAを任意に製薬学的に許容され得る補助物質、希釈剤もしくは担体との混合物と連合して投与することを含んでなる。
(i)SLV308、そのN−オキシドまたはそれらの薬理学的に許容され得る塩、水和物および溶媒和物;および
(ii)L−DOPAを製薬学的に許容され得る補助物質、希釈剤もしくは担体との混合物で含んでなる製薬学的製剤の使用に関する。
脱炭酸酵素インヒビターの例は、カルビドパおよびベンセラジドである。カテコールアミン−O−メチルトランスフェラーゼ(COMT)インヒビターの例はエンタカポン(entacapone)、ニテカポン(nitecapone)およびトルカポン(tolcapone)であり、モノアミンオキシダーゼB(MAO−B)インヒビターの例には、デプレニール、(−)−デプレニール(セレジリン)、デスメチルデプレニール、N−プロパルギル−1−(R)−アミノインダン(ラサガリン:rasagaline)、フェネルジン(ナルジル:nardil)、トラニルシプロミン(パルネート:parnate)、CGP3466、フラゾリドン、イソカルボキサジド(isocarboxazid)、パルジリン、メチクロチアジドおよびプロカルバジンがある。
物は、疾患の進行または状態に望ましい効果を生じるために十分な活性の目的化合物を含む。したがって本発明の製薬学的組成物は、本発明の化合物および製薬学的に許容され得る担体を混合することにより作成される任意の組成物を包含する。「製薬学的に許容され得る」とは、担体、希釈剤または賦形剤が製剤の他の成分と適合し、そしてその受容者に有害であってはならないことを意味する。
方が他方の成分を投与する前、後および/または同時に投与できることを含む(場合により繰り返して)。この内容で使用する場合、用語「同時に投与する(administered simultaneously)」および「同時に投与する(administered at the same time as)」とは、SLV308およびL−DOPAの個別用量が48時間、例えば24時間、18時間、12時間、6時間、3時間、2時間、1時間または30分以内に互いに投与されることを含む。
動物:雄雌両方の一般的な成体のマーモセット(Callithrix jacchus;n=6、320〜450g、2〜3年齢)をこの実験に使用した。動物は単独または対で24±2℃の温度および50%の相対湿度の標準的条件下で収容し、12時間の明暗サイクルを使用し、食料と水を自由に与えた。すべての実験作業はアニマル(サイエンティフィック プロセデュアーズ アクト:Scientific Procedures
Act)1986、プロジェクトライセンスnrPPL70/4986に従い行った。
ドン(シグマ、英国)を10%のシュクロースに溶解して2ml/kgの容量を得、そして動物の口に直接投与した。投薬用量はSLV308を用いた事前の実験に基づき、ここでSLV308の運動活性に及ぼす最適な効果および疾患スコアが0.26mg/kg,po.で達成されることが示された。L−DOPAの投薬用量はL−DOPAの中および高用量を反映するために選択された(それぞれ7.5および12.5mg/kg,po)。
自然な運動活性:SLV308(0.26mg/kg,po)は投与の30分以内に運動活性を増大した(図1)。ピーク活性は処置から180分後に見られ、そして運動活性は7時間の観察期間持続した。L−DOPA(7.5および12.5mg/kg,po)は運動活性に即座の上昇を生じ、この上昇は投与から60〜90分後にピークとなった(図1および2)。活性の期間は150〜240分であった。L−DOPA(7.5および12.5mg/kg,po)後のピーク活性は、SLV308(0.26mg/kg,po)単独後に見られた活性よりも大きかった。SLV308(0.26mg/kg,po)での前処置後、L−DOPA(7.5mg/kg,po)後の活性のピークおよび期間
は、SLV308(0.26mg/kg,po)単独後で見られるピークおよび期間に類似した(図1)。L−DOPA(7.5mg/kg,po)に加えてSLV308(0.26mg/kg,po)を用いた組み合わせ処置は、L−DOPA(7.5mg/kg,po)単独後のピーク運動活性を、SLV308(0.26mg/kg,po)単独後に見られるレベルに下げたので、機能亢進は観察されなかった(図1)。SLV308(0.26mg/kg,po)はL−DOPA(12.5mg/kg,po)後に見られるピーク活性を下げることができなかったが、上昇させなかった。しかしL−DOPA(7.5および12.5mg/kg,po)後の活性の期間(「オン」時間)は、SLV308(0.26mg/kg,po)の同時投与により増加し、SLV308活性の期間を反映している(図3)。全運動活性は、賦形剤で処置した群に比べてすべての処置で増加したが(図4)、他の差異は観察されなかった。
使用することができる製薬学的組成物の種類には、限定するわけではないが錠剤、チュワブル錠剤、カプセル(マイクロカプセルを含む)、溶液、非経口溶液、軟膏(クリームおよびゲル)、座薬、懸濁液、および本明細書に開示された、あるいは本明細書および当該技術分野での一般的知識から当業者に明白な他の種類を含む。組成物は投与するために経口、静脈内、皮下、気管、気管支、鼻内、肺、経皮、頬内、直腸、非経口または他の経路が使用される。製薬学的製剤は少なくとも1つの本発明の製剤を製薬学的に許容され得る補助剤、希釈剤および/または担体との混合物で含む。適切な有効成分の総量は製剤の約0.1(重量/重量)%〜約95(重量/重量)%の範囲であり、適切には0.5%〜50(重量/重量)%であり、そして好ましくは1%〜25(重量/重量)%である。SLV308(またはそのN−オキシド)とL−DOPAの間のモル比は、約1000:1〜約1:1000、適切には約300:1〜1:300の範囲にあり、そして好ましくは50:1〜1:50である。
Claims (10)
- ドーパミン作動性機能の回復を必要とする疾患の治療に同時に、別々に、もしくは順次に使用するための:
(i)SLV308もしくはそのN−オキシド
- さらに脱炭酸酵素インヒビターを含んでなる請求項1に記載の製剤。
- さらにCOMTインヒビターを含んでなる請求項1または2に記載の製剤。
- さらにMAO−Bインヒビターを含んでなる請求項1、2または3のいずれかに記載の製剤。
- ドーパミン作動性機能の回復を必要とする疾患を処置する薬剤を製造するための請求項1ないし4のいずれかに記載の製剤の使用。
- 疾患がパーキンソン病である請求項5に記載の使用。
- 疾患がむずむず脚症候群である請求項5に記載の使用。
- 製薬学的に許容され得る担体および/または少なくとも1つの製薬学的に許容され得る補助物質に加えて、有効成分として請求項1ないし4のいずれかに記載の製剤を薬理学的に活性な量で含んでなる製薬学的組成物。
- パーキンソン病またはむずむず脚症候群の処置が必要なヒトまたは動物患者において、ある量のSLV308もしくはそのN−オキシドまたはそれらの薬理学的に許容され得る塩、およびある量のL−DOPAを同時に、別々に、もしくは順次に患者に投与することを含んでなり、その量が処置に有効である、パーキンソン病またはむずむず脚症候群の処置方法。
- さらにある量の脱炭酸酵素インヒビターおよび/またはCOMTインヒビターおよび/またはMAO−Bインヒビターが投与される請求項9に記載方法。
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PCT/EP2007/055955 WO2007144421A1 (en) | 2006-06-16 | 2007-06-15 | Combination preparations comprising slv308 and a l-dopa |
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JPN5009007779; JOHNSTON L C: BRITISH JOURNAL OF PHARMACOLOGY V133 N.SUPPL, 200105, BASINGSTOKE * |
JPN5009007783; JOST W H: AKTUELLE NEUROLOGIE V32 N.SUPPL6, 200511, P.S318-S325, THIEME * |
JPN6012045091; 医学と薬学 52(3), 2004, 331-335 * |
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KR20090031908A (ko) | 2009-03-30 |
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MY148457A (en) | 2013-04-30 |
NO20090164L (no) | 2009-01-14 |
CA2654719A1 (en) | 2007-12-21 |
AU2007259255A1 (en) | 2007-12-21 |
EA015073B1 (ru) | 2011-04-29 |
WO2007144421A1 (en) | 2007-12-21 |
EA200970021A1 (ru) | 2009-06-30 |
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