JP6990170B2 - L-オルニチンをフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つと組み合わせて用いる筋肉喪失の治療および予防 - Google Patents
L-オルニチンをフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つと組み合わせて用いる筋肉喪失の治療および予防 Download PDFInfo
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- JP6990170B2 JP6990170B2 JP2018508683A JP2018508683A JP6990170B2 JP 6990170 B2 JP6990170 B2 JP 6990170B2 JP 2018508683 A JP2018508683 A JP 2018508683A JP 2018508683 A JP2018508683 A JP 2018508683A JP 6990170 B2 JP6990170 B2 JP 6990170B2
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- muscle
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- ornithine
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Description
本出願は、35U.S.C.§119(e)に従って、2015年8月18日に出願した米国仮特許出願第62/206466号明細書の優先権を主張するものである。この関連出願の内容は、その全体が参照により本明細書に明確に組み込まれる。
本明細書で用いているように、「対象」は、治療、観察または実験の目的である動物を意味する。「動物」は、冷および温血脊椎動物ならびに魚、貝などの非脊椎動物、爬虫類、とりわけ哺乳動物を含む。「哺乳動物」は、制限なく、マウス、ラット、ウサギ、モルモット、イヌ、ネコ、ヒツジ、ヤギ、ウシ、ウマ、サル、チンパンジーおよび類人猿などの霊長類、とりわけヒトを含む。
BDL=胆管結紮
OP=オルニチンフェニル酢酸
筋肉喪失は、筋肉の量および質の低下の状態である。筋肉喪失の非限定的な症状は、筋肉量の低下もしくは減少、除脂肪筋肉の喪失もしくは減少、筋肉重量の低下もしくは減少、筋周囲長の低下もしくは減少、脂肪量の低下もしくは減少、除脂肪量の低下もしくは減少、筋肉機能の喪失もしくは減少、筋力の喪失もしくは減少、可動性の喪失もしくは減少、体重低下、筋タンパク質合成比速度(FSR)の低下、またはそれらのいずれかの組合せであり得る。いくつかの実施形態では、筋肉喪失の状態の少なくとも1つの症状は、筋肉量低下または骨格筋喪失である。いくつかの実施形態では、筋肉喪失の状態の少なくとも1つの症状は、体重減少である。いくつかの実施形態では、筋肉喪失の状態の少なくとも1つの症状は、除脂肪量の低下もしくは減少、筋周囲長の低下もしくは減少または筋タンパク質合成比速度(FSR)の低下である。筋肉喪失の様々な原因が存在する。例えば、筋肉喪失は、加齢、疾患(例えば、がんおよび肝疾患)、無活動、損傷(例えば、肝移植)またはそれらのいずれかの組合せにより引き起こされ得る。
本明細書で開示するいくつかの実施形態は、オルニチンをフェニルアセテートおよび/またはフェニルブチレートと組み合わせてそれを必要とする対象に同時投与することにより筋肉喪失の状態を治療または予防する方法を含む。いくつかのそのような実施形態は、治療処置を含み、いくつかの実施形態は、予防処置を含む。
いくつかの実施形態では、オルニチンおよびフェニルアセテートまたはフェニルブチレートを薬学的に許容される塩として投与する。「薬学的に許容される塩」という用語は、化合物の生物学的有効性および特性を保持し、医薬品に用いるのに生物学的にまたはその他の点で望ましくないものではない塩を意味する。多くの場合、本明細書で開示する化合物は、アミノおよび/もしくはカルボキシル基またはそれと類似の基の存在により酸および/または塩基塩を形成することができる。薬学的に許容される酸付加塩は、無機酸および有機酸により形成され得る。塩を得ることができる無機酸は、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸などを含む。塩を得ることができる有機酸は、例えば、酢酸、プロピオン酸、グリコール酸、ピルビン酸、シュウ酸、マレイン酸、マロン酸、コハク酸、フマル酸、酒石酸、クエン酸、安息香酸、ケイ皮酸、マンデル酸、メタンスルホン酸、エタンスルホン酸、p-トルエンスルホン酸、サリチル酸などを含む。薬学的に許容される塩は、無機および有機塩基を用いて形成させることもできる。塩を得ることができる無機塩基は、例えば、ナトリウム、カリウム、リチウム、アンモニウム、カルシウム、マグネシウム、鉄、亜鉛、銅、マンガン、アルミニウムなどを含む塩基を含み、アンモニウム、カリウム、ナトリウム、カルシウムおよびマグネシウム塩がとりわけ好ましい。いくつかの実施形態では、本明細書で開示する化合物の無機塩基による処理は、Li+、Na+、K+、Mg2+およびCa2+などのような無機陽イオンを含む塩形を得るための、化合物からの活性な水素の喪失をもたらす。塩を得ることができる有機塩基は、例えば、第一級、第二級および第三級アミン、天然に存在する置換アミンを含む置換アミン、環状アミン、塩基性イオン交換樹脂など、具体的にはイソプロピルアミン、トリメチルアミン、ジエチルアミン、トリエチルアミン、トリプロピルアミンおよびエタノールアミンなどを含む。多くのそのような塩は、1987年9月11日に公開された国際公開第87/05297号パンフレット(その全体が参照により本明細書に組み込まれる)に記載されているように、当技術分野で公知である。
オルニチン(例えば、L-オルニチン)およびフェニルアセテートまたはフェニルブチレートは、別個にまたは単一剤形で投与することができる。一実施形態では、組合せ薬をオルニチンフェニル酢酸塩としてまたはオルニチンフェニル酢酸塩の溶液として投与する。
(実施例)
慢性肝疾患(CLD)は、6週間の胆管結紮(BDL)の後にラットにおいて誘発した。次の4つの実験群を試験した:1)Sham;2)BDL;3)Sham+OP;および4)BDL+OP。BDL後1週目に、ラットにOP(1g/kg)を5週間にわたり毎日経口投与した(強制経口投与)。体重、脂肪および除脂肪量(EchoMRI)、血中アンモニア、脳浮腫(比重法)、筋肉におけるタンパク質の合成比(FSR)(D2Oを用いた)および自発運動量(昼間/夜間)を測定した。
この実施例は、L-オルニチンフェニル酢酸組合せ薬(OP)による治療がラットにおける加齢に関連する筋肉喪失を減少させるかどうかを判定するためのものである。
この実施例は、L-オルニチンフェニル酢酸組合せ薬(OP)による治療がラットにおける悪液質を治療するかどうかを判定するためのものである。
この実施例で述べる試験では、6週胆管結紮(BDL)ラットモデルを用いた。動物モデルを作製するために、胆管結紮後に雄Sprague-Dawleyラット(200~225g)(Charles River、St-Constant、QC)における肝硬変を誘発した。BDLラットの特性は、黄疸、腹水、肝機能不全、脳浮腫、高アンモニア血症および潜在性HEである。図2A~Cに示すように、BDLラットは、腓腹筋肉量の低下および周囲の減少も示した。
なお、本発明は以下の態様をも含むものである。
<1> 筋肉喪失の状態を治療する方法であって、オルニチンをフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つと組み合わせてそれを必要とする対象に投与し、それにより、前記状態を軽減することを含む、方法。
<2> 筋肉喪失の状態に罹患している対象を同定することをさらに含む、上記1に記載の方法。
<3> 前記対象が肝移植を受けている、上記2に記載の方法。
<4> 筋肉喪失の状態を予防する方法であって、オルニチンをフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つと組み合わせてそれを必要とする対象に投与し、それにより、前記状態を予防することを含む、方法。
<5> 筋肉喪失の状態を発現するリスクがある対象を同定することをさらに含む、上記4に記載の方法。
<6> 前記対象が肝移植を受けようとしている、上記5に記載の方法。
<7> 筋肉重量、筋肉周囲長、除脂肪筋肉、体重、アンモニアレベル、1つもしくは複数の肝酵素の機能(複数可)、脂肪量、除脂肪量、脳含水量、自発運動量、タンパク質合成速度、または対象のそれらのいずれかの組合せを決定することをさらに含む、上記1から6のいずれかに記載の方法。
<8> 前記1つもしくは複数の肝酵素がアルブミン、ビリルビン、アスパラギン酸アミノトランスフェラーゼ、アラニンアミノトランスフェラーゼ、アルカリホスファターゼまたはそれらのいずれかの組合せを含む、上記7に記載の方法。
<9> 前記脳含水量が前頭皮質含水量である、上記7に記載の方法。
<10> 前記筋肉喪失の状態の少なくとも1つの症状が骨格筋喪失である、上記1から9のいずれかに記載の方法。
<11> 前記筋肉喪失の状態の少なくとも1つの症状が筋肉量低下である、上記1から9のいずれかに記載の方法。
<12> 前記筋肉喪失の状態が加齢、疾患、損傷、不活動またはそれらのいずれかの組合せにより引き起こされる、上記1から9のいずれかに記載の方法。
<13> 前記筋肉喪失の状態がサルコペニア、筋委縮、悪液質、筋ジストロフィーまたはそれらのいずれかの組合せである、上記1から9のいずれかに記載の方法。
<14> 前記対象が慢性肝疾患に罹患している、上記1から9のいずれかに記載の方法。
<15> 前記慢性肝疾患が肝硬変である、上記14に記載の方法。
<16> 前記状態の治療および予防が血中アンモニアを減少させること、筋代謝を直接改善すること、またはそれらの組合せによって達成される、上記1から15のいずれかに記載の方法。
<17> 前記オルニチンならびにフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つの薬学的に許容される別個の塩を前記対象に投与する、上記1から16のいずれかに記載の方法。
<18> フェニルアセテートおよびフェニルブチレートのうちの前記少なくとも1つをフェニル酢酸ナトリウムまたはフェニル酪酸ナトリウムとして投与する、上記17に記載の方法。
<19> 前記オルニチンを遊離の単量体アミノ酸またはその生理学的に許容される塩として投与する、上記1から18のいずれかに記載の方法。
<20> 前記オルニチンおよびフェニルアセテートをオルニチンフェニル酢酸として投与する、上記1から16のいずれかに記載の方法。
<21> 前記投与が経口、静脈内、腹腔内、胃内または血管内投与である、上記1から20のいずれかに記載の方法。
<22> 前記投与が静脈内投与である、上記1から20のいずれかに記載の方法。
<23> 前記投与が経口投与である、上記1から20のいずれかに記載の方法。
Claims (18)
- オルニチンをフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つと組み合わせて含み、肝疾患を有する対象における筋肉喪失の状態を治療し、それによって筋肉喪失の状態を軽減するための医薬組成物。
- 筋肉喪失の状態を治療することが、筋肉喪失の状態に罹患していると同定された対象に対してであり、場合によって前記対象が肝移植を受けている、請求項1に記載の医薬組成物。
- オルニチンをフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つと組み合わせて含む、肝疾患を有する対象における筋肉喪失の状態を予防するための医薬組成物。
- 筋肉喪失の状態を予防することが、筋肉喪失の状態を発現するリスクがあると同定された対象に対してであり、場合によって前記対象が肝移植を受けようとしている、請求項3に記載の医薬組成物。
- 前記対象が、筋肉重量、筋肉周囲長、除脂肪筋肉、体重、アンモニアレベル、1つもしくは複数の肝酵素の機能(複数可)、脂肪量、除脂肪量、脳含水量、自発運動量、タンパク質合成速度、またはそれらのいずれかの組合せを決定することによって同定される、請求項2または4に記載の医薬組成物。
- 前記1つもしくは複数の肝酵素がアルブミン、ビリルビン、アスパラギン酸アミノトランスフェラーゼ、アラニンアミノトランスフェラーゼ、アルカリホスファターゼまたはそれらのいずれかの組合せを含む、請求項5に記載の医薬組成物。
- 前記脳含水量が前頭皮質含水量である、請求項5に記載の医薬組成物。
- 前記筋肉喪失の状態の少なくとも1つの症状が骨格筋喪失または筋肉量低下である、請求項1から7のいずれか一項に記載の医薬組成物。
- 前記筋肉喪失の状態が加齢、疾患、損傷、不活動またはそれらのいずれかの組合せにより引き起こされる、請求項1から7のいずれか一項に記載の医薬組成物。
- 前記筋肉喪失の状態がサルコペニア、筋委縮、悪液質、筋ジストロフィーまたはそれらのいずれかの組合せである、請求項1から7のいずれか一項に記載の医薬組成物。
- 前記肝疾患が慢性肝疾患であり、場合によって前記慢性肝疾患が肝硬変である、請求項1から7のいずれか一項に記載の医薬組成物。
- 前記筋肉喪失の状態の治療または予防が、血中アンモニアを減少させること、筋代謝を直接改善すること、またはそれらの組合せによって達成される、請求項1から11のいずれか一項に記載の医薬組成物。
- 前記オルニチンならびにフェニルアセテートおよびフェニルブチレートのうちの少なくとも1つの薬学的に許容される別個の塩を含む、請求項1から12のいずれか一項に記載の医薬組成物。
- フェニルアセテートおよびフェニルブチレートのうちの前記少なくとも1つが、フェニル酢酸ナトリウムまたはフェニル酪酸ナトリウムである、請求項13に記載の医薬組成物。
- 前記オルニチンが、遊離の単量体アミノ酸またはその生理学的に許容される塩である、請求項1から14のいずれか一項に記載の医薬組成物。
- 前記オルニチンおよびフェニルアセテートが、オルニチンフェニル酢酸である、請求項1から12のいずれか一項に記載の医薬組成物。
- 経口、静脈内、腹腔内、胃内または血管内投与用である、請求項1から16のいずれか一項に記載の医薬組成物。
- 静脈内投与用または経口投与用である、請求項17に記載の医薬組成物。
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CA2995823A1 (en) | 2017-02-23 |
AU2016308641A1 (en) | 2018-03-01 |
HK1249434A1 (zh) | 2018-11-02 |
EP3337473A1 (en) | 2018-06-27 |
EP3337473A4 (en) | 2019-04-17 |
AU2016308641B2 (en) | 2022-02-03 |
WO2017031131A1 (en) | 2017-02-23 |
JP2018523683A (ja) | 2018-08-23 |
US20180221320A1 (en) | 2018-08-09 |
US10835506B2 (en) | 2020-11-17 |
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