JP7120691B2 - 非アルコール性脂肪肝炎の予防または治療用の薬学組成物 - Google Patents
非アルコール性脂肪肝炎の予防または治療用の薬学組成物 Download PDFInfo
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Description
また、本発明は、肝線維化を治療、改善または予防するための薬学組成物を提供することを他の目的とする。
本発明の化合物は口腔に投与可能であり、口腔は嚥下(swallowing)を含む概念である。口腔投与によって、本発明の化合物が胃腸管(gastrointestinal tract)に入るか、例えば、口腔(buccal)または舌下(sublingual)投与のように、口から血流へ直接的に吸収され得る。
本発明の化合物は、血流、筋肉または内臓内へ直接投与され得る。非経口投与のための望ましい方法は、静脈内(intravenous)、筋肉内(intra-muscular)、皮下動脈内(subcutaneous intra-arterial)、腹腔内(intraperitoneal)、髄腔内(intrathecal)、頭蓋内(intracranial)注射などを含む。非経口投与のための望ましい装置は、(針及び無針注射器を含む)注射器(injector)及び注入方法(infusion method)を含む。
非経口剤形は、乾燥された形態(例えば、凍結乾燥)または滅菌非水溶液として製造され得る。これらの剤形は、滅菌水(sterile water)のような適したビヒクル(vehicle)と共に使用され得る。また、溶解度増強剤(solubility-enhancing agents)も、非経口溶液の製造に使用可能である。
本発明の化合物は、皮膚または経皮で局所的に投与され得る。このような局所投与のための剤形は、ローション、溶液、クリーム、ゲル、ハイドロゲル、軟膏、フォーム(foam)、インプラント(implant)、パッチなどを含む。局所投与剤形のための薬学的に許容可能な担体は、水、アルコール、ミネラルオイル、グリセリン、ポリエチレングリコールなどを含み得る。また、局所投与は、電気穿孔法(electroporation)、イオン導入法(iontophoresis)、音波泳動(phonophoresis)などによって行われ得る。
疾病または状態の適切な治療または予防のための薬学組成物の製造方法は、本発明が属した分野における通常の知識を有する者によく知られている。例えば、Handbook of Pharmaceutical Excipients(7th ed.),Remington:The Science and Practice of Pharmacy(20th ed.),Encyclopedia of Pharmaceutical Technology (3rd ed.),Sustained and Controlled Release Drug Delivery Systems (1978)などにおける記載に従って、薬学的に許容可能な担体、運搬体、添加剤などを本発明による化合物と適切に混合して本発明の目的のための薬学組成物を製造し得る。
脂肪肝炎の動物モデルであるMCD(methionine-choline deficient)モデルを用いた。C57BL/6マウスを用いて、MCD飼料を5日間供給し、その後の2日間は正常飼料を供給する方式で10週間MCD飼料と正常飼料とを交互に摂取させた。動物は、順化期間(青色)、投与及び観察期間(赤色)の間に、尾部標識法を用いて識別した。飼育箱には、色で区別される個体識別カードを付着し、飼育室の入口には、動物室使用記録紙を付着した。
(1)体重測定
投与開始日、その後には、週一回及び剖検日に測定した。
試験物質の投与を開始する前、その後には週一回測定した。測定方法は、飼料を定量給与した翌日、残量を飼育箱単位で測定してその差を計算し、一匹当たりの平均摂取量を算出した。
試験物質を投与する前、試験物質の投与後6週目(剖検日)に採血して分離した血清を、生化学自動分析装置(7180 Hitachi,Japan)を用いて下記の項目を検査した。
投与前の検査項目:アラニントランスアミナーゼ(alanine transaminase,ALT)、アスパラギン酸トランスアミナーゼ(aspartate transaminase,AST)
試験物質投与後6週目:ALT、AST、トリグリセリド(triglyceride,TG)、総コレステロール(Total cholesterol,TCHO)、高比重リポ蛋白(High-density lipoprotein,HDL)、低比重リポ蛋白(Low-density lipoprotein,LDL)、γ-グルタミルトランスフェラーゼ(Gamma-glutamyltransferase,GGT)、乳酸脱水素酵素(Lactate dehydrogenase,LDH)
(4)剖検
剖検日にピモニダゾール(Pimonidazole)を30mg/mlの濃度で生理食塩水(saline)に希釈した後、60mg/kgの投与量で静脈内に投与した。投与90分後、動物を安楽死させた。各剖検時点で動物をエーテルで吸入麻酔し、麻酔が確認された後に開腹して後大静脈から注射器を用いて採血を行った。その後、腹大動脈及び後代静脈を切断して放血し、致死させた。血液は、クロットアクティベーター(clot activator)が入っている真空採血管(vacutainer tube)に注入し、約15分間室温に放置して凝固させた後、3,000rpmで10分間遠心分離して血清を分離した。血清は、分析前まで-70℃以下に設定されている冷凍庫(Deep freezer)に保管し、血液の生化学的検査に使用した。
剖検時、肝は摘出して重量を測定し、肝の右葉は10%中性緩衝ホルマリン液に固定し、左葉は半分に分けて液体窒素を用いて急速冷凍した。急速冷凍した検体は、ELISA分析前まで-70℃以下に設定されている超低温冷凍庫に保管した。
剖検時、摘出した肝を用いて肝組織内のTG及びTCHOの含量を分析した。分析は、商用化したELISAキットを用いて行った。
固定された組織は、切り出し、脱水、パラフィン包埋、薄切などの通常の組織処理過程を経て組織病理学的検査のための検体を製作した後、Hematoxylin&Eosin(H&E)、オイルレッドO染色及びマッソントリクローム染色(Masson trichrome stain)を行い、光学顕微鏡(Olympus BX53,Japan)を用いて組織病理学的変化を観察した。
本実験結果に対して、資料の正規性を仮定し、パラメトリック多重比較法(parametric multiple comparison procedures)またはノンパラメトリック多重比較法(non-parametric multiple comparison procedures)を用いて分析した。
パラメトリック一元配置分散分析(One-way ANOVA)の結果が有意義な場合、ダネットの検定(Dunnett’s multiple comparison test)を用いて事後検定を行い、ノンパラメトリッククラスカル・ウォリス検定(Kruskal-Wallis’H-test)の分析結果が有意義な場合、ダンの検定(Dunn’s multiple comparison test)を用いて事後検定を行った。
(1)体重測定
体重測定結果、全体の実験期間中における全てのMCD飼料給与群G2~G5の体重水準は、正常対照群G1に比べて有意義に低く示された(p<0.001)。これは、MCD飼料給与時、通常観察される現象である。
飼料摂取量の測定結果、全体の実験期間中における正常対照群G1、賦形剤対照群G2及び陽性対照群G3に対し、全ての試験群から有意義な差は観察されなかった。
血液の生化学的検査結果、試験物質の投与開始日に、全てのMCD飼料給与群G2~G5のALT及びAST水準は、正常対照群G1に比べて有意義に高く(p<0.001)、TG、TCHO及びHDL水準は、正常対照群G1に比べて統計学的に有意義に低かった(p<0.001)。試験物質投与後6週目に、全てのMCD飼料給与群G2~G5のALT及びAST水準は、正常対照群G1に比べて有意義に高く(p<0.001またはp<0.01)、G5のALT及びAST水準は、賦形剤対照群G2に比べて有意義に低かった(p<0.001またはp<0.05)。試験物質投与後6週目に、G3及びG4のALT水準は、賦形剤対照群G2に比べて有意義に低く(p<0.05)、全てのMCD飼料給与群G2~G5のTG、TCHO及びHDL水準は、正常対照群G1に比べて有意義に低かった(p<0.001)。試験物質投与後6週目に、全てのMCD飼料給与群G2~G5のLDL水準は、正常対照群G1に比べて有意義に低く(p<0.001またはp<0.01)、G4及びG5のLDL水準は、賦形剤対照群G2及び陽性対照群G3に比べて有意義に低かった(p<0.01)。試験物質投与後6週目に、G3のLDH水準は、正常対照群G1に比べて有意義に高かった(p<0.05)。
結果値である絶対重量及び相対重量を図3に示した。肝の重量測定結果、全てのMCD飼料給与群の肝の重量水準は、正常対照群G1に比べて有意義に低く(p<0.001)、G5の肝の重量水準は、賦形剤対照群G2に比べて有意義に低かった(p<0.05)。G2の肝の相対重量水準は、正常対照群G1に比べて有意義に高く(p<0.05)、G5の肝の相対重量水準は、賦形剤対照群G2及び陽性対照群G3に比べて有意義に低かった(p<0.01またはp<0.05)。
分析結果を図4に示した。ELISA分析結果、全てのMCD飼料給与群G2~G5のTG及びTCHO水準は、正常対照群G1に比べて有意義に高く(p<0.001)、G4及びG5のTG及びTCHO水準は、賦形剤対照群G2に比べて有意義に低かった(p<0.001,p<0.01またはp<0.05)。
組織病理学的検査結果を図5に示した。全てのMCD飼料給与群G2~G5の微小空胞性脂肪変性(Microvesicular steatosis)及び炎症(Inflammation)水準は、正常対照群に比べて有意義に高く(p<0.01またはp<0.05)、G5の微小空胞性脂肪変性の水準は、賦形剤対照群に比べて有意義に低く観察された(p<0.05)。
本試験条件下でMCD飼料によって誘発した非アルコール性脂肪肝炎のC57BL/6マウスモデルに、試験物質を6週間繰り返して投与したとき、試験物質投与群から、賦形剤対照群に対する肝機能関連数値であるALT、AST及びLDL水準の容量相関性のある統計学的に有意義な変化様相が観察され、試験物質投与群の肝の相対重量水準も容量相関性を示し、賦形剤対照群に比べて有意義に低く観察された。また、組織病理学的検査結果、微小空胞性脂肪変性水準、オイルレッドOの面積水準及びヒドロキシプロリン水準における有意義な減少が観察され、肝組織内のTG及びTCHO分析結果から、試験物質投与群の肝組織内のTCHO及びTG水準は、賦形剤対照群に対して有意義に低く観察された。特に、試験物質の高容量投与群の場合、血液の生化学検査、肝の相対重量、肝組織内のTG、TCHO含量分析結果及び微小空胞性脂肪変性水準などの多数の項目で陽性対照群に比べて低い水準を示した。
試験物質に対する非アルコール性脂肪肝炎の予防効能を評価した。7週令のマウスC57BL/6を用いて、正常群G1には一般飼料を供給し、賦形剤対照群G2と陽性対照群G3及び試験群G4、G5には、MCD飼料を12週間にわたって供給した。MCD飼料と共に試験物質を対照群に1日1回経口投与し、総5個の群に分けて各群当たり15匹ずつ総75匹を実験に使用した。
(実施例5.非アルコール性脂肪肝炎予防モデルにおける試験結果)
(1)体重測定
体重測定結果、全体の実験期間中における全てのMCD飼料給与群G2~G5の体重水準は、正常対照群G1に比べて有意義に低く示された(p<0.001)。これは、MCD飼料給与時、通常観察される現象である。
飼料摂取量の測定結果は、全体の実験期間中における正常対照群G1、賦形剤対照群G2及び陽性対照群G3に対する全ての試験群から有意義な差は観察されなかった。
5個群に対して、マウスの肝組織を摘出し、脂質抽出キット(Lipid Extraction Kit,Cell biolabs,USA)を用いて検体を抽出した後、生化学分析機(7020,Hitachi,Japan)を用いて肝組織内の中性脂肪を分析した。
前記結果から、本発明による化合物は、非アルコール性脂肪肝炎の予防効果を有することを確認することができた。
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