JP2022528734A - 粘土鉱物複合体を含む炎症性大腸炎の予防、改善及び治療用組成物、組成物の製造方法、及び炎症性大腸炎の改善及び治療方法 - Google Patents
粘土鉱物複合体を含む炎症性大腸炎の予防、改善及び治療用組成物、組成物の製造方法、及び炎症性大腸炎の改善及び治療方法 Download PDFInfo
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Abstract
Description
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、炎症性大腸炎の予防及び治療用薬学的組成物を提供する。
化1の化合物又はその薬学的に許容可能な塩を含む溶液、酸性である反応溶液及び粘土鉱物懸濁液を混合し、前記化合物を粘土鉱物に吸着させて複合体を製造するステップを含む、
炎症性大腸炎の予防及び治療用薬学的組成物の製造方法を提供する。
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、炎症性大腸炎の予防及び改善用食品組成物を提供する。
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、薬学的組成物を対象に投与するステップを含む炎症性大腸炎の治療方法を提供する。
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、薬学的組成物を対象に投与するステップを含む炎症性大腸炎の改善方法を提供する。
化1の化合物(以下、「バクトセルチブ」と言う。)又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、炎症性大腸炎の予防及び治療用薬学的組成物及びその製造方法に関する。
化1の化合物又はその薬学的に許容可能な塩を含む溶液、酸性である反応溶液及び粘土鉱物懸濁液を混合し、前記化合物を粘土鉱物に吸着させて複合体を製造するステップを含む、
炎症性大腸炎の予防及び治療用薬学的組成物の製造方法に関する。
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、炎症性大腸炎の予防及び改善用食品組成物に関する。
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、薬学的組成物を対象に投与するステップを含む炎症性大腸炎の治療方法に関する。
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、薬学的組成物を対象に投与するステップを含む炎症性大腸炎の改善方法に関する。
化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む、炎症性大腸炎の予防、改善及び治療用途に関する。
本発明の化1の化合物は、公知の方法を利用して製造することができる。例えば、化1の化合物は、N-((4-([1,2,4]トリアゾロ[1,5-a]ピリジン-6-イル)-5-(6-メチルピリジン-2-イル)-1H-イミダゾール-2-イル)メチル)-2-フルオロアニリン(N-((4-([1,2,4]triazolo[1,5-a]pyridine-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline)である。前記化合物の分子式はC22H18FN7であり、25±3℃における飽和水溶液のpHはpH7.2で、溶解度(aqueous solubility)は<0.02Mg/mlである。溶解度は、低いpH範囲でさらに高く(つまり、pH2.81における25.05mg/ml)、pH4.9以上、かつ溶解度は0.02Mg/ml以下である。分配係数(オクタノール/水)Log Do/wは3.31である。化1の化合物は、韓国特許公開公報10-2013-0028749号に開示の方法を利用して製造することができる。
一般的に粘土鉱物は、ケイ酸板(silica sheet)とアルミナ板(alumina sheet)とが結合して形成された結晶単位が積層された層状構造、つまり板状構造を有するが、このような粘土鉱物のうち層間膨脹性を有する粘土鉱物では、結晶単位の間に水素結合が存在せず、結晶単位の間の結合力が弱いため、これら結晶単位の間に水分が吸入すると膨脹され得る。よって、層間膨脹性を有する粘土鉱物の結晶単位の間には、相対的に大きな大きさを有するイオンであっても容易に流入させることができる。一方、層間膨脹性を有する粘土鉱物においては、4価正電荷を有する四面体のSiが、3価正電荷を有するAl又はFeと同型置換(isomorphic substitution)されるか、3価正電荷を有する八面体のAl又はFe3+が、2価正電荷を有するMg又はFe2+に同型置換されることで、負の層電荷が発生するが、層と層との間又は表面にカルシウムイオン(Ca2+)、マグネシウムイオン(Mg2+)、ナトリウムイオン(Na+)、カリウムイオン(K+)などのカチオンが結合して、全体的としては電気的中性を帯びるようになる。本発明の粘土鉱物は、カチオン性物質に対する吸着に優れ、このような吸着パターンは周辺のpHによって変わる。
本発明の粘土鉱物/バクトセルチブ複合体において、粘土鉱物は、バクトセルチブを胃腸(pH1.5~2.0)と小腸(pH7.2~7.5)を経て大腸(pH7.9~8.5)まで伝達して、大腸で作用するようにする伝達体、つまり担体として用いられる。すなわち、本発明の粘土鉱物/バクトセルチブ複合体は、上部消化管でバクトセルチブが吸収されることを抑制して、大腸部位までバクトセルチブを伝達する。本発明の粘土鉱物は、層状粘土鉱物であって、層状表面は、負電荷を帯びて、バクトセルチブは、粘土鉱物に無定形状態で吸着する。前記複合体は、粘土鉱物及び化1の化合物又はその薬学的に許容可能な塩を1:0.02~0.26の重量比で含んでいてもよい。
本発明は、化1の化合物又はその薬学的に許容可能な塩;及び粘土鉱物の複合体を含む組成物に関する。
本発明の組成物を投与する対象は、炎症性大腸炎の診断を受けるか、炎症性大腸炎の発病可能性のある人間又は人間のほか動物、特に哺乳動物を意味する。
本発明は、化1の化合物又はその薬学的に許容可能な塩を含む溶液、酸性である反応溶液及び粘土鉱物懸濁液を混合し、前記化合物を粘土鉱物に吸着させて複合体を製造するステップを含む、炎症性大腸炎の予防、改善又は治療用組成物の製造方法に関する。このとき、化1の化合物が層状粘土鉱物に無定形状態で吸着するためには、前記化合物と粘土鉱物を同じ水溶液に溶解、分散して混合する方法を用いることができる。このとき、粘土鉱物(例えば、ベントナイト)の層状表面は、負電荷を帯びるため、水溶液に溶解された薬物がカチオンを帯びる場合、吸着がより効果的に行われ得る。
化1の化合物(以下、「バクトセルチブ」と言う。)は、韓国株式会社メドペクトより提供された。ベントナイトは、韓国地質資源研究院より提供されて使用した。
<1-1>
溶媒のpHによるバクトセルチブとベントナイトの吸着率を評価した。このとき、バクトセルチブが中性ではあまり溶けず、pH3から約1mg/mL程度に溶け始める点を勘案して、反応pHをpH1、pH2及びpH3に選定して試験を行った。
バクトセルチブとベントナイトの比率による吸着率を評価した。これは、バクトセルチブの損失を最小化しつつ、ベントナイトに最大限に吸着させ得る組成を見つけるためである。
反応pH及びベントナイト/バクトセルチブの比率が固定された状態で、使用されるバクトセルチブ及びベントナイトの絶対濃度による吸着率の変化を評価した。
<2-1>
pH1の溶媒を用いて、バクトセルチブの濃度1mg/ml及びベントナイトの濃度5mg/mlの条件で、実験例1の方法によりベントナイト/バクトセルチブ複合体を製造した。そして、これを凍結乾燥した後、実際のバクトセルチブの含量を測定するためにバクトセルチブの抽出及び分析を行った。
前記 <2-1>で製造したベントナイト/バクトセルチブ複合体の形態学的特性を評価した。このために、<2-1>で製造したベントナイト/バクトセルチブ複合体とバクトセルチブをそれぞれ銅テープに接着させた後、表面に白金コーティング処理して、走査電子顕微鏡(scanning electron microscopy、SEM)撮影した。
XRDによってベントナイト/バクトセルチブ複合体の結晶学的特性を分析した。バクトセルチブ、ベントナイト、バクトセルチブとベントナイトの物理的混合物、それからベントナイト/バクトセルチブ複合体のXRDパターンを分析、比較することによって、薬物吸着現象による結晶構造変化を確認した。
<3-1>
バクトセルチブがベントナイトに吸着した後に放出される変化を確認するために、バクトセルチブの溶出試験を行った。
ベントナイト/バクトセルチブ複合体を実際に経口投与時、血中濃度変化を確認するために、約7週齢のSDラットを利用して薬物動態分析実験を行った。既存のバクトセルチブ粉末及びこれをpH3緩衝液に溶解した水溶液、それからベントナイト/バクトセルチブ複合体を試料として用いて行っており、投与用量は、薬物(つまり、バクトセルチブ)量を基準に10Mg/kgと設定した。各試料をラットに経口投与した後、時間別に採血しており、これを前処理して血中薬物濃度を分析した。
バクトセルチブを10Mg/mLで0.1N塩酸水溶液に溶かし、これをpH1の0.1N塩酸水溶液に希釈して、濃度を1mg/mLに合わせた。該薬物(つまり、バクトセルチブ)溶液1mLと、0.1N塩酸水溶液8mL、ベントナイトを蒸留水に懸濁した5mg/mLの懸濁液1mLを混合し、30分間放置して、薬物がベントナイトに吸着するようにした。その後、遠心分離して(3,000rpm、5分)上層液を得て、これを凍結乾燥し、ベントナイト/バクトセルチブ複合体を製造した。
<5-1>
DSS(dextran sulfate sodium)により誘導された潰瘍性大腸炎ラットモデルにおけるバクトセルチブの薬物動態を把握し、ベントナイトの結合有無によるバクトセルチブ剤形の生物薬剤学的差異を評価した。
データは、平均±標準偏差と示しており、統計分析は、SPSS statistic 19(Mann-Whitney test)を利用して行った。
*p<0.05、G1群に比べて相当な差異
#p<0.05、G2群に比べて相当な差異
G1群:n=10、G2群:n=9、G3群:n=9、G4群:n=10
時間によるバクトセルチブの血中濃度変化を測定して、薬物体内動態を評価した。これは、図9のように、(○G1群、◇G2群、●G3群、◆G4群)薬物成分の体内吸収量指標である血中薬物濃度曲線下面積(AUC、area under the concentration-time curve)と、どれ程速やかに吸収されるかを示す指標である最高濃度に到逹した時間(tmax)、血中薬物の最高濃度(Cmax,maximum plasma concentration)により評価した。
炎症性腸疾患の一つである潰瘍性大腸炎のマウスモデルを利用して、バクトセルチブ/ベントナイト複合体の抗炎症、抗腺窩細胞の損傷、抗潰瘍、抗浮腫、抗線維化の効果を確認する動物試験を行った。動物実験を行うための炎症誘導方法及び薬物投与計画は、図14のとおりである。C57BL/6マウスを試験動物として選定し、潰瘍性大腸炎を誘導するために炎症誘導物質であるDSSを飲水に入れて7日間供給した後、14日間正常な飲水を供給するサイクルを繰り返した。かかる炎症誘導サイクルを3回繰り返して、大腸内慢性炎症、潰瘍及び線維化状態を誘導した。対照群を除く試験動物群らに最初の炎症誘導サイクルが過ぎた3週後からベントナイト、バクトセルチブ又はバクトセルチブ/ベントナイト複合体を1日2回(午前10時、午後4時)、週5日、計6週間投与した。換算したマウス体重1kg当たりのベントナイトは106,8mg、バクトセルチブは20.0mg、複合体は126.8Mgを投与した。このとき、バクトセルチブ/ベントナイト複合体としては、実験例5で製造した複合体を使用した。潰瘍性大腸炎動物試験に使用された試験群別炎症誘導物質、試験物質、試験物質投与量及び試験動物数は、下記の表7のとおりである。
Claims (24)
- 前記組成物の経口投与時の最高血中濃度到達時間(tmax)は、化1の化合物水溶液の経口投与時の最高血中濃度到達時間(tmax)よりも2~10倍長いことを特徴とする、
請求項1記載の薬学的組成物。 - 前記組成物の経口投与時の最高血中濃度到達時間(tmax)は、化1の化合物水溶液の経口投与時の最高血中濃度到達時間(tmax)よりも長いことを特徴とする、
請求項1記載の薬学的組成物。 - 前記組成物の経口投与時の最高血中濃度(Cmax)は、化1の化合物水溶液の経口投与時の最高血中濃度(Cmax)の20~80%であることを特徴とする、
請求項1記載の薬学的組成物。 - 前記組成物の経口投与時の最高血中濃度(Cmax)は、化1の化合物水溶液の経口投与時の最高血中濃度(Cmax)よりも低いことを特徴とする、
請求項1記載の薬学的組成物。 - 前記組成物を経口投与時、化1の化合物の大腸での炎症、腺窩細胞の損傷、潰瘍、浮腫及び線維化で構成される群から選択される症状に対する薬物の改善効果が、化1の化合物水溶液の経口投与時、大腸での薬物の改善効果よりも高いことを特徴とする、
請求項1記載の薬学的組成物。 - 前記組成物を経口投与時、化1の化合物の小腸での吸収速度(rate)は、化1の化合物水溶液の経口投与時、小腸での吸収速度よりも低いことを特徴とする、
請求項1記載の薬学的組成物。 - 前記複合体をpH1.2の溶出液に添加時の溶出速度は、化1の化合物をpH1.2の溶出液に添加時の溶出速度よりも遅いことを特徴とする、
請求項1記載の薬学的組成物。 - 前記複合体をpH7.4の溶出液に添加時の溶出速度は、化1の化合物をpH7.4の溶出液に添加時の溶出速度よりも早いことを特徴とする、
請求項1記載の薬学的組成物。 - 前記炎症性大腸炎は、クローン病又は潰瘍性大腸炎であることを特徴とする、
請求項1記載の薬学的組成物。 - 前記反応溶液のpHは、pH0.5~pH3.5のpHであることを特徴とする、
請求項11記載の薬学的組成物の製造方法。 - 前記組成物の経口投与時の最高血中濃度到達時間(tmax)は、化1の化合物水溶液の経口投与時の最高血中濃度到達時間(tmax)よりも2~10倍長いことを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記組成物の経口投与時の最高血中濃度到達時間(tmax)は、化1の化合物水溶液の経口投与時の最高血中濃度到達時間(tmax)よりも長いことを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記組成物の経口投与時の最高血中濃度(Cmax)は、化1の化合物水溶液の経口投与時の最高血中濃度(Cmax)の20~80%であることを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記組成物の経口投与時の最高血中濃度(Cmax)は、化1の化合物水溶液の経口投与時の最高血中濃度(Cmax)よりも低いことを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記組成物を経口投与時、化1の化合物の大腸での炎症、腺窩細胞の損傷、潰瘍、浮腫及び線維化で構成される群から選択される症状に対する薬物の改善効果が、化1の化合物水溶液の経口投与時、大腸での薬物の改善効果よりも高いことを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記組成物を経口投与時、化1の化合物の小腸での吸収速度(rate)は、化1の化合物水溶液の経口投与時、小腸での吸収速度よりも低いことを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記複合体をpH1.2の溶出液に添加時の溶出速度は、化1の化合物をpH1.2の溶出液に添加時の溶出速度よりも遅いことを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記複合体をpH7.4の溶出液に添加時の溶出速度は、化1の化合物をpH7.4の溶出液に添加時の溶出速度よりも早いことを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。 - 前記炎症性大腸炎は、クローン病又は潰瘍性大腸炎であることを特徴とする、
請求項14記載の炎症性大腸炎の治療方法。
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KR102035479B1 (ko) * | 2019-04-12 | 2019-10-23 | 한국지질자원연구원 | 점토광물 복합체를 포함하는 방출성이 제어된 경구투여용 조성물 |
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WO2020209476A1 (ko) | 2020-10-15 |
KR102424761B1 (ko) | 2022-07-25 |
EP3954391A1 (en) | 2022-02-16 |
KR102035481B1 (ko) | 2019-10-23 |
CN113710278A (zh) | 2021-11-26 |
EP3954392A4 (en) | 2022-06-22 |
JP7367057B2 (ja) | 2023-10-23 |
EP3954391A4 (en) | 2022-06-15 |
KR20200120472A (ko) | 2020-10-21 |
US20220175745A1 (en) | 2022-06-09 |
KR102424766B1 (ko) | 2022-07-25 |
KR102035479B1 (ko) | 2019-10-23 |
EP3954391B1 (en) | 2024-05-29 |
JP7367056B2 (ja) | 2023-10-23 |
US20220193049A1 (en) | 2022-06-23 |
JP2022528448A (ja) | 2022-06-10 |
CN113710279A (zh) | 2021-11-26 |
EP3954392A1 (en) | 2022-02-16 |
WO2020209475A1 (ko) | 2020-10-15 |
EP3954392B1 (en) | 2024-06-05 |
KR20200120471A (ko) | 2020-10-21 |
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