JP2017193562A - 筋萎縮性側索硬化症の治療のための新規組成物 - Google Patents
筋萎縮性側索硬化症の治療のための新規組成物 Download PDFInfo
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- JP2017193562A JP2017193562A JP2017112687A JP2017112687A JP2017193562A JP 2017193562 A JP2017193562 A JP 2017193562A JP 2017112687 A JP2017112687 A JP 2017112687A JP 2017112687 A JP2017112687 A JP 2017112687A JP 2017193562 A JP2017193562 A JP 2017193562A
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Abstract
Description
‐バクロフェンおよびシナカルセト、
‐シナカルセトおよびアカンプロセート、
‐バクロフェンおよびアカンプロセート、
‐バクロフェンおよびアカンプロセートおよびトラセミド
‐メキシレチンおよびシナカルセト、
‐トラセミドおよびバクロフェン、または、
‐トラセミドおよびスルフィソキサゾール、
またはそれらの塩、プロドラッグ、任意の純度の誘導体、もしくは徐放性製剤、のうちの少なくとも1つを含む。
グは、不活性であるか、または生じる薬剤より低活性であり、例えば、薬剤の物理化学的特性の改善、特定組織への標的化、薬剤の薬剤動態および薬力学的特性の改善、ならびに/または、望ましくない副作用の低減などに使用可能である。プロドラッグの設計に適する共通の官能基のいくつかは、カルボキシル基、ヒドロキシル基、アミン基、リン酸塩/ホスホン基およびカルボニル基を含むが、これに限らない。典型的に、これらの基の修飾を介して製造されるプロドラッグは、エステル類、炭酸塩類、カルバメート類、アミド類およびリン酸塩類を含むが、これには限らない。適切なプロドラッグ選択のための詳細な技術ガイダンスは技術常識である(参考文献19〜23)。加えて、プロドラッグの調製は当業者には既知の従来の方法によっておこなわれることが可能である。その他のプロドラッグを合成するために使用可能な方法は、本主題の数多くの先行文献に記載されている(参考文献20、24〜30)。例を挙げると、アルバクロフェン・プラカルビルは、ChemID plus Advanceデータベース(ウェブサイト:chem.sis.nlm.nih.gov/chemidplus/)に掲載されており、アルバクロフェン・プラカルビルは、バクロフェンのプロドラッグとしてよく知られている(参考文献31および32)。バクロフェンのプロドラッグの具体例は、Hanafi他の文献(参考文献33、2011年)に掲載されており、具体的には、中枢神経系(CNS)を標的に特定指向するバクロフェンエステルおよびバクロフェンエステルカルバメートが挙げられている。故に、このようなプロドラッグは本発明の組成物に特に適している。また、前述のアルバクロフェン・プラカルビルは、既知のプロドラッグであり、本発明の組成物において、バクロフェンの代わりに用いてもよい。バクロフェンのその他のプロドラッグは、特許出願である、国際公開第2010102071号、米国特許第2009197958号、国際公開第2009096985号、国際公開第2009061934号、国際公開第2008086492号、米国特許第2009216037号、国際公開第2005066122号、米国特許第2011021571号、国際公開第2003077902号、および国際公開第2010120370号において見受けられる。
‐リルゾール、バクロフェン、およびシナカルセト、
‐リルゾール、シナカルセト、およびアカンプロセート、
‐リルゾール、バクロフェン、およびアカンプロセート、
‐リルゾール、バクロフェン、およびアカンプロセート、およびトラセミド、
‐リルゾール、メキシレチン、およびシナカルセト、
‐リルゾール、トラセミド、およびバクロフェン、または
‐リルゾール、トラセミド、およびスルフィソキサゾール、
またはそれらの塩、プロドラッグ、任意の純度の誘導体、もしくは徐放性製剤、のうちの少なくとも1つを含む組成物である。
プラム〔Lexapro〕、グラチラマー酢酸塩、顆粒球コロニー刺激因子〔G−CSF〕、成長ホルモン〔ソマトロピン(Somatropin)〕、GSK1223249、インジナビル(indinavir)、インスリン様成長因子‐1〔IGF−I〕、IGF−1−AAV、KNS−760704、レテプリニム(leteprinim)、ロイプロリド(leuprolide)、レベチラセタム(levetiracetam)、MCI−186、メコバラミン(mecobalamin)、ミノサイクリン(minocycline)、モダフィニル(Modafinil)、Naaladase阻害剤、N−アセチルシステイン(N−acetylcysteine)、NBQX、ニメスリド(nimesulide)、ニモジピン(nimodipine)、オランザピン(olanzapine)、オレソキシム(olesoxime)〔TRO19622〕、ONO−2506、オキセパ(oxepa)、ピオグリタゾン(pioglitazone)、R(+)プラミペキソール二塩酸塩一水和物、オレソキシム(olesoxime)、オキサンドロロン(oxandrolone)、キニジン(quinidine)、フェニル酪酸、SB−509、スクリプタイド(Scriptaid)、sNN0029、ソマトロピン(somatropine)、タランパネル(talampanel)、タモキシフェン(tamoxifen)、タウロウルソデオキシコール酸(tauroursodeoxycholic acid)、TCH346、テストステロン、サリドマイド、トレハロース、トレチノイン、ビタミンE、YAM80、または17ベータエストラジオール、2−MPPA(2‐(3‐メルカプトプロピル)ペンタン二酸)、3,4‐ジアミノピリジン、5−ヒドロキシトリプトファン、7−ニトロインダゾール、アルファリポ酸、AM1241、アミノフィリン(aminophylline)、アンジオゲニン(angiogenin)、抗ヒトSOD1抗体、p75に対するアンチセンスペプチド核酸〔NTR〕、AP7、アポシニン(apocynin)、BAPTA−AM、BDNF、BN82451、カンナビノール(cannabinol)、カルジオトロフィン−1、CD4抗体、CNTF、コリベリン(colivelin)、食事摂取による銅、コルチコトロフィン(corticotrophin)、シクロホスファミド(cyclophosphamide)、デルタ(9)−テトラヒドロカンナビノール(Delta(9)−tetrahydrocannabinol)、DHEA、ジアゼパム(diazepam)、食事摂取による亜鉛、ジルチアゼム(diltiazem)、DMPO、DP−109、DP−460、エダラボン(edaravone)、EGCG、エピガロカテキンガレート(epigallocatechin gallate)、エチドロネート(etidronate)、FeTCPP、フルボキサミン(fluvoxamine)、葉酸、ガバペンチン(gabapentin)、ガレクチン−1(galectin−1)、GDNF、チョウセンニンジン、GPI−1046、グアニジン(guanidine)、HGF、ヒューマニン(humanin)、IFN−アルファ、インターロイキン−3、イベルメクチン(ivermectin)、L−745,870、L−カルニチン(L−carnitine)、L−DOPA、レシチン化SOD、レナリドミド(lenalidomide)、ロイペプチン(leupeptin)、LIF、L−NAME、リシンアセチルサリチル酸(lysine acetylsalicylate)、メラトニン、メピバカイン(mepivacaine)、メタンフェタミン(methamphetamine)、メチルコバラミン(methylcobalamin)、MK−801、MnTBAP、モダフィニル(modafinil)、モルヒネ(morphine)、Neu2000、NGF、ノルジヒドログアイアレチン酸(nordihydroguaiaretic acid)、ノルトリプチリン(nortriptyline)、NT3、オルメサルタン(olmesartan)、ペニシラミン(penicillamine)、ペントキシフィリン(pentoxifylline)、ピモジド(pimozide)、ポリアミン修飾カタラーゼ(polyamine−modified
catalase)、プラミペキソール(pramipexole)、プレドニゾン(prednisone)、プロゲステロン(progesterone)、プロメタジン(promethazine)、プトレシン修飾カタラーゼ(putrescine−m
odified catalase)、ピルビン酸(pyruvate)、ラサギリン(rasagiline)、RK35、Ro 28−2653、ロフェコキシブ(rofecoxib)、RPR 119990、RX77368、 SB203580、セレギリン(selegiline)、セマピモド(semapimod)、セルトラリン(sertraline)、SS−31、SSR180575、ヒトCu、Zn−スーパーオキシドジスムターゼ〔SOD1〕に対する安定化siRNA、タクロリムス(tacrolimus)、タムスロシン塩酸塩(tamsulosin hydrochloride)、TAT修飾Bcl−X(L)、TGF−ベータ2、チアネプチン(tianeptine)、トリエンチン(trientine)、TRO19622、U−74389F、VEGF、ビンクリスチン(vincristine)、WHI−P131、WIN55,212−2、WX−340、キサリプロデン(xaliproden)、ZK 187638、およびzVAD−fmkから選択される。
‐バクロフェンおよびシナカルセト、
‐シナカルセトおよびアカンプロセート、
‐バクロフェンおよびアカンプロセート、
‐バクロフェンおよびアカンプロセートおよびトラセミド、
‐メキシレチンおよびシナカルセト、
‐トラセミドおよびバクロフェン、または、
‐トラセミドおよびスルフィソキサゾール、
のうちの少なくとも1つの使用に関する。
‐バクロフェンおよびシナカルセト、
‐シナカルセトおよびアカンプロセート、
‐バクロフェンおよびアカンプロセート、
‐バクロフェンおよびアカンプロセートおよびトラセミド、
‐メキシレチンおよびシナカルセト、
‐トラセミドおよびバクロフェン、または、
‐トラセミドおよびスルフィソキサゾール、
のうちの少なくとも1つの使用に関する。
各組合せ薬剤の投与は、その他の成分と組み合わせて、患者の状態を改善可能である薬剤の濃縮物として、任意の適切な手段によっておこなわれてもよい。
。また、添付文書の封入は、医師の指示に対する患者の服薬コンプライアンスを改善することが示されている。したがって、本発明は、前述の製剤に適切な包装材料を組み合わせた、本明細書に前記の医薬製剤をさらに含む。このような患者用パックにおいて、組合せ治療のための製剤の使用意図は、その治療に対し最も適切に製剤が使用されるように、指示、仕組み、供給、適用および/または他の手段により推察されることが可能である。このような評価基準により、患者用パックは、本発明の組合せでの治療のための使用に特に適切であり、相応する。
シロスタゾールおよびリルゾールの好ましい投与経路は経口経路である。経口使用のための製剤は、医薬的に許容される非毒性の賦形剤との混合物中に活性成分を含有する錠剤を含む。これらの賦形剤は、例えば、不活性賦形剤または充填剤(例えば、ショ糖、微結晶性セルロース、バレイショデンプンを含むデンプン、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、またはリン酸ナトリウム)、顆粒剤および崩壊剤(例えば、微結晶性セルロースを含むセルロース誘導体、バレイショデンプンを含むデンプン、クロスカルメロースナトリウム、アルギネイト、またはアルギン酸)、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、α化デンプン、微結晶性セルロース、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、またはポリエチレングリコール)、ならびに潤滑剤、滑剤、および粘着防止剤(例えば、ステアリン酸、シリカ、またはタルク)であってよい。その他の医薬的に許容される賦形剤は、着色剤、香料、可塑剤、湿潤剤、緩衝剤などであってよい。
水の添加により水性懸濁液の調製に適している散剤、分散性散剤、または顆粒剤は、経口投与に便利な投与剤形である。懸濁液としての製剤は、分散剤または湿潤剤、懸濁剤、および1つ以上の保存剤との混合物として活性成分を提供する。適切な懸濁剤は、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。
またあまり好ましくはないが、本医薬組成物は、注射、点滴またはインプラント(静脈内、筋肉内、皮下など)により、従来の非毒性の薬学的に許容される担体およびアジュバントを含む、投与剤形、製剤で、または適切な送達装置もしくはインプラントを介して、非経口投与されてもよい。このような組成物の製剤および調製は、医薬品製剤の当業者には周知である。
好ましさ、便利さには欠けるが、その他の投与経路およびそのための他の製剤を考慮してもよい。これに関し、直腸内適用では、組成物に適する投与剤形として、坐剤(乳剤または懸濁剤型)、および直腸用ゼラチンカプセル剤(液剤または懸濁剤)が含まれる。典型的な坐剤製剤では、活性薬剤は、薬学的に許容される適切な坐剤基剤(カカオバター、エステル化脂肪酸、グリセリンゼラチンなど)、および種々の水溶性または分散性基剤(ポリエチレングリコールなど)と組み合わせられる。また、様々な添加剤、増強剤、または界面活性剤が組み込まれてもよい。
本組合せ薬剤は、同一もしくは異なる医薬品製剤のいずれかで同時に、または連続して投与されるとよい。連続投与である場合、活性成分のうちの1つを投与する際の遅延は、活性成分の組合せの有効な作用の恩恵を失わないようにすべきである。本詳細な説明に記載の組合せにとって最小限の要件は、組合せにおいて、活性成分の組合せの有効作用の恩恵を伴う組合せでの使用が意図されるべきであるということである。本組合せで意図される使用は、本発明の組合せの使用を補助するための仕組み、設備、適用および/または他の手段により推察されることが可能である。
‐メキシレチンは、1日当たり約6mg〜120mg、好ましくは1日当たり60mg未満、より好ましくは1日当たり30mg未満、さらにより好ましくは1日当たり15mg未満であり、特に経口投与に適する用量、
‐トラセミドは、1日当たり約0.05mg〜4mg、好ましくは1日当たり2mg未満、より好ましくは1日当たり1mg未満、さらにより好ましくは1日当たり0.5m
g未満であり、特に経口投与に適する用量、
‐アカンプロセートは、1日当たり1mg〜1000mg、好ましくは1日当たり400mg未満、より好ましくは1日当たり200mg未満、さらにより好ましくは1日当たり50mg未満、または、さらに1日当たり10mg未満であり、特に経口投与に適する用量、
‐バクロフェンは、1日当たり0.01mg〜150mg、好ましくは1日当たり100mg未満、より好ましくは1日当たり50mg未満、さらにより好ましくは1日当たり30mg未満であり、特に経口投与に適する用量、
‐シナカルセトは、1日当たり約0.3mg〜150mg、より好ましくは1日当たり100mg未満、さらにより好ましくは1日当たり36mg未満であり、特に経口投与に適する用量、
‐スルフィソキサゾールは、1日当たり約20mg〜800mgであり、特に経口投与に適する用量、
‐リルゾールは、1日当たり約0.01mg〜100mg、好ましくは1日当たり75mg未満、より好ましくは1日当たり50mg未満であり、さらにより好ましくは1日当たり25mg未満であり、特に経口投与に適する用量、
である。
本発明の組合せ療法は、神経筋肉共培養モデルのラットの皮質細胞においてインビトロで、ALSのマウスモデルにおいてインビボでテストされた。方法および結果を本項において示す。
グルタミン酸毒性はALSの発病に関連する。この実験一式で、候補化合物の、ニューロン細胞におけるグルタミン酸の毒性作用を抑止または低減する能力をテストした。薬剤について、最初に個別にテストをし、続いて組合せ作用の評価をする。
本発明の組合せ薬剤の効能は、一次皮質ニューロン細胞でまず評価された。
ase1グレードIIおよび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)の添加によって反応を停止した。その後、10mlピペットを用いて、3連続継代で、機械的に細胞を解離し、そして+4℃で、10分間、515xgで遠心分離をした。上清は廃棄され、細胞のペレットを、B27(2%)、L−グルタミン(0.2mM)、2%PS溶液、および10ng/mlのBDNFで補完したNeurobasalからなる既定培地に再懸濁した。トリパンブルー排除法を用いて、Neubauerサイトメータで生存細胞をカウントした。96ウェルプレート(ポリ‐L‐リジン(10μg/ml)で、ウェルをあらかじめコーティングした)を用いて、30,000cells/wellの密度で細胞を播種し、そして加湿空気(95%)/CO2(5%)環境において、+37℃で培養した。
化合物の神経保護作用は、グルタミン酸作動性ニューロンを特異的に示す神経突起網(ニューロフィラメント免疫染色(NF))の定量化により評価された。
テストをしたすべての組合せ薬剤は、グルタミン酸毒性に対する保護作用を皮質ニューロン細胞にもたらす。結果を下記表2に示す。
<神経および筋肉細胞の一次共培養>
先述の方法にしたがって、ヒトの筋肉を健康な対象者の生検の部分から用意する(参考文献39)。筋肉細胞を、解離細胞(ウェル毎に2万細胞)から株化し、0.1%ゼラチンコーティングした48ウェルプレート上に配置し、そして、グルタミン2mM、ウシインスリン10μg/ml、ヒト組み換え上皮増殖因子10ng/ml、ヒト組み換え繊維芽細胞増殖因子塩基性(human recombinant fibroblast growth factor basic)2ng/ml、10%ウシ胎児血清(FCS)、ならびに10000U/mlのペニシリンおよび10mg/mlのストレプトマイシンを補完した25%M199培地と75%MEM培地との混合からなる増殖培地で成長させる。
27日目に、共培養物を、20分間のグルタミン酸中毒(60μM)の1時間前に、候補化合物、その組合せ、またはリルゾールと共にインキュベートする。そして、共培養物を洗浄し、候補化合物、その組合せ、および/またはリルゾールをさらに48時間添加する。このインキュベーション時間の後、非固定共培養物を、Alexa 488と結合したα-ブンガロトキシンと共に、500nmol/Lの濃度で、室温で15分間、インキュベートする。その後、共培養物を、室温で20分間、PFAにより固定する。0.1%のサポニンで透過処理後、共培養物を、マウスモノクローナル抗ニューロフィラメント抗体(NF、1/400希釈)と共にインキュベートする。
23日目に(すなわち前処理まで4日)、共培養物をリルゾールと共にインキュベートする。4日後(すなわち27日目)、組合せ薬剤をグルタミン酸添加の1時間前に加え、そしてグルタミン酸(60μM)を20分間加える。その後共培養物は、上述のように免疫蛍光分析用に処理される。
薬剤が組合せで用いられるとき、単独で用いられる際には効果が見られない濃度で、3つのエンドポイントすべてにおいて、有意な保護作用が見受けられる。テストをした組合せ薬剤を表3に記載し、図2において例示する。この予期せぬ相乗効果によって非常に低い用量での薬剤の使用が可能になるので、潜在的副作用を克服できる。
トランスジェニックヘテロ接合型マウスのB6SJL−Tg(SOD1−G93A)1Gur/JマウスおよびWTマウス(1012系統、JAX)が、模倣ALSの実験一式において選択された。罹患マウスは、内因性ヒトSOD1プロモータにより駆動される変異型ヒトSOD1遺伝子(コドン93におけるアラニンへのグリシンの単一アミノ酸置換)で設計された、SOD1−G93A導入遺伝子を発現する。
マウスは、生後60日目から生後150日になるまで、媒体で希釈した候補薬剤の投与を受けた。候補薬剤の希釈溶液は,投与開始の直前に、室温にて水で調製される。リルゾールおよび組合せ薬剤のいずれも経口投与される。シクロデキストリンは、保存用溶液(20%シクロデキストリン)から、室温において水で希釈した5%の最終濃度で媒体として用いられる。組合せ薬剤(10ml/kg)および媒体での処置は生後60日から始まり、マウスが生後150日になるまで継続される。組合せ薬剤は、午前8〜11時および午後4〜7時の間に1日2回経口投与される。
研究用グループの準備において(すなわち、テスト、または処置される対照体)、トランスジェニックマウスは無作為にグループ化され、マウスのすべての同腹仔が1つのテストグループにならないようにして、結果全体における「同腹仔作用」を避ける。さらに、グループの雄と雌との比率を等しく釣り合うようにする。
体重の減少は疾患発現と深く関連していることを証明しており、疾患段階と連結して容易に点数化される。マウスは、生後60日〜91日のとき、各週の同じ日(月曜日)に週1回体重を計量され、生後91日(13週)に達した後は、週に3回(月曜日、水曜日、金曜日)体重を計量される。
SOD1−G93Aマウスの産生を記載した原論文(参考文献40)は、疾患の早期発症(〜100日)および平均して40日以内で最終段階に達する発症マウスの急速な衰弱(生存期間の典型は130日〜150日)を報告している。ゆえに、下記に記載するような臨床スコアリングを用いて、生後91日目までは週に1回(月曜日)、そして生後91日に達した後は週に3回(月曜日、水曜日、金曜日)、マウスは慎重に検査される。
5=健康、
4〜5=総じて健康、軽度の振戦、非常に活動的、四肢の開脚、
4=観察可能な軽度の振戦、四肢の開脚、非常に活動的、
3〜4=いくらかの軽度の硬直を伴う振戦、非常に活動的、
3=振戦、肢の硬直、いくらかの軽度の麻痺の可能性、活動的、
2〜3=振戦、部分的な麻痺、硬直、四肢の開脚への奮闘、活動的、
2=麻痺、やや活動的、
1〜2=後肢の麻痺、後肢の開脚なし、動物の行動および30秒以内に自身で正常にもどる能力次第で安楽死がおこなわれる、
1=エンドポイント、動物は自身で正常にもどれない、
である。
すべての行動テストは、媒体群のTGマウスの約70%が失われたとき、20週齢で中止される。この年齢以降、残りのマウスは運動テストをするには大変衰弱しており、体重計量、疾患段階および生存スコアリングをするのみである。
オープンフィールドテスト測定は、投与が始まる前(基準)、約90日目(13週齢)、および110日目(16週齢)におこなわれる。生後2〜4日以内のマウスがオープンフィールドテスト用に利用される。活動室(Med Associates Inc, St Albans, VT;27×27×20.3cm)にはIRビームを備える。マウスは部屋の中心に配置されて、その行動が10分間記録される。移動した距離、垂直立ち上がりの回数、および平均速度が記録される。
ロータロッドテストは、投与が始まる前(基準)、約90日目(13週齢)、および110日目(16週齢)におこなわれる。生後2〜4日以内のマウスがオープンフィールドテスト用に利用される。1日のセッションには、ロータロッド装置(AccuScan Instruments、Columbus、米国)上において4RPMで5分間の訓練試行が含まれる。動物は、1時間後に、360秒以上で0〜40RPMの速度変化および実験中の少なくとも30分の休憩を伴う、6分の3連続加速実験のテストを受ける。棒からの落下までの時間が記録される。棒上に360秒以上残っているマウスは除かれ、その時間は360秒としてスコアをつける。
組合せ療法はALSのインビボモデルで有効である。
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Claims (19)
- 原発性側索硬化症(PLS)、進行性筋萎縮(PMA)、仮性球麻痺及び進行性球麻痺(PBP)、並びに前頭側頭型認知症(FTD)から選択される関連疾患の治療に使用するための、シナカルセト、メキシレチン、スルフィソキサゾール、トラセミド、リルゾール、アカンプロセート及びバクロフェン、又はそれらの塩、プロドラッグ若しくは徐放性製剤から選択される少なくとも2つの化合物の組合せを含む組成物。
- スルフィソキサゾール又はその塩、プロドラッグ若しくは徐放性製剤と、
アカンプロセート、バクロフェン、シナカルセト、メキシレチン、トラセミド若しくはリルゾール、又はそれらの塩、プロドラッグ若しくは徐放性製剤から選択される少なくとも1つの第2化合物との組み合わせを含む、請求項1に記載の使用のための組成物。 - メキシレチン又はその塩、プロドラッグ若しくは徐放性製剤と、
アカンプロセート、バクロフェン、シナカルセト、トラセミド、スルフィソキサゾール若しくはリルゾール、又はそれらの塩、プロドラッグ若しくは徐放性製剤から選択される少なくとも1つの第2化合物との組み合わせを含む、請求項1に記載の使用のための組成物。 - シナカルセト又はその塩、プロドラッグ若しくは徐放性製剤と、
アカンプロセート、バクロフェン、メキシレチン、トラセミド、スルフィソキサゾール若しくはリルゾール、又はそれらの塩、プロドラッグ若しくは徐放性製剤から選択される少なくとも1つの第2化合物との組み合わせを含む、請求項1に記載の使用のための組成物。 - 下記の薬剤の組合せ、
‐トラセミド及びスルフィソキサゾール
‐トラセミド及びリルゾール、
‐スルフィソキサゾール及びリルゾール、
‐メキシレチン及びシナカルセト、
‐バクロフェン及びシナカルセト、
‐シナカルセト及びアカンプロセート、
‐メキシレチン及びリルゾール、
‐シナカルセト及びリルゾール、
‐メキシレチン、シナカルセト及びリルゾール、若しくは、
‐トラセミド、スルフィソキサゾール及びリルゾール、
のうちのいずれか1つを含み、上記組合せの各化合物はそれらの塩、プロドラッグ若しくは徐放性製剤であってもよい請求項1に記載の使用のための組成物。 - 前記化合物は、薬学的に許容される担体または賦形剤と共に投与される、請求項1〜5のいずれか1項に記載の使用のための組成物。
- 前記化合物は対象者に繰り返して投与される、請求項1〜6のいずれか1項に記載の使用のための組成物。
- 前記化合物は、一緒に、個別に、または連続して製剤化または投与される、請求項1〜7のいずれか1項に記載の使用のための組成物。
- 前記化合物は一緒に製剤化される、請求項8に記載の使用のための組成物。
- スルフィソキサゾール若しくはトラセミド若しくはそれらの組合せ、又はそれらの塩、プロドラッグ若しくは徐放性製剤若しくはそれらの組合せが、リルゾール又はその塩、プロドラッグ若しくは徐放性製剤と交互に投与される、請求項5に記載の使用のための組成物。
- メキシレチン若しくはシナカルセト若しくはそれらの組合せ、又はそれらの塩、プロドラッグ若しくは徐放性製剤若しくはそれらの組合せが、リルゾール又はその塩、プロドラッグ若しくは徐放性製剤と交互に投与される、請求項5に記載の使用のための組成物。
- ALSの治療のための請求項1〜11のいずれか1項に記載の使用のための組成物。
- スルフィソキサゾールは、1日当たり800mg未満の用量で投与される、請求項1〜12のいずれか1項に記載の使用のための組成物。
- トラセミドは、1日当たり0.05mg〜4mgの用量で投与される、請求項1〜13のいずれか1項に記載の使用のための組成物。
- メキシレチンは、1日当たり6mg〜120mgの用量で投与される、請求項1〜14のいずれか1項に記載の使用のための組成物。
- シナカルセトは、1日当たり0.3mg〜150mgの用量で投与される、請求項1〜15のいずれか1項に記載の使用のための組成物。
- リルゾールは、1日当たり0.01mg〜50mgの用量で投与される、請求項1〜16のいずれか1項に記載の使用のための組成物。
- 前記化合物は経口投与される、請求項1〜17のいずれか1項に記載の使用のための組成物。
- 下記の薬剤の組合せ、
‐メキシレチン及びシナカルセト、
‐バクロフェン及びシナカルセト、
‐シナカルセト及びアカンプロセート、
‐トラセミド及びスルフィソキサゾール
‐メキシレチン及びリルゾール、
‐シナカルセト及びリルゾール、
‐トラセミド及びリルゾール、
‐スルフィソキサゾール及びリルゾール、
‐メキシレチン、シナカルセト及びリルゾール、若しくは、
‐トラセミド、スルフィソキサゾール及びリルゾール、
のうちのいずれか1つを含み、上記組合せの各化合物はそれらの塩、プロドラッグ若しくは徐放性製剤であってもよい医薬組成物。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11305217 | 2011-03-01 | ||
EP11305687 | 2011-06-06 | ||
EPPCT/EP2012/053565 | 2012-03-01 | ||
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