JP2021510713A - 腔内適用による結直腸がんの細菌プロモーターを排除するための組成物 - Google Patents
腔内適用による結直腸がんの細菌プロモーターを排除するための組成物 Download PDFInfo
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Abstract
Description
本発明による組成物は本質的に、抗生物質ホスホマイシンを、単独で、又はメトロニダゾール及びカルバペネム、例えばエルタペネム、メロペネム、及びイミペネムを含む非限定的リストから選択され得る1種若しくは複数の追加の抗生物質と組み合せて、含む。
ホスホマイシンは、フォスフォマイシン又はフォスフォノマイシンの名称で、ストレプトマイセス・フラジアエ(Streptomyces fradiae)株から1969年に単離され特徴付けられた、広域抗生物質の国際一般名である(Hendlinraら 1969年)。その構造は、(-)(IR, 2S)-1,2-エポキシプロピルホスホン酸であることが決定され(Christensenら 1969年)、組織(IUPAC)名は[(2R,3S)-3-メチルオキシラン-2-イル]ホスホン酸であり、式量は138.1Daであった。ホスホマイシンは殺菌性であり、MurAとしても公知の酵素UDP-N-アセチルグルコサミン-3-エノールピルビルトランスフェラーゼを不活性化することによって細菌細胞壁の生合成を阻害する(Brownら 1995年)。この酵素は、ペプチドグリカン生合成に関与する行程を触媒し、ホスホエノールピルベートをUDP-N-アセチルグルコサミンの3'-ヒドロキシル基にライゲーションしてN-アセチルムラミン酸を形成する。ホスホマイシンは、活性部位のシステイン残基をアルキル化することによってMurAを阻害する、ホスホエノールピルベート類似体である。抗生物質は、グリセロリン酸トランスポーターを介して細菌細胞に進入する。
i) ホスホマイシン二ナトリウム、式量182.0Da、5%溶液のpH9.0〜10.5。この塩は、吸湿性であり、水に高度に溶解し、高いバイオアベイラビリティを示すが、中和されない場合は局所的に刺激を与える。
ii) ホスホマイシンカルシウム一水和物、式量194.1Da、0.4%溶液のpH8.1〜9.6。この塩は、水にやや溶け難く、吸湿性ではなく、経口治療のために使用した場合には胃にそれほど刺激を与えず、全身循環への進入に関するバイオアベイラビリティは12%程度に低くなる可能性がある(Bergan 1990年)。
iii) ホスホマイシントロメタモール、式量259.2Da、5%溶液のpH3.5〜5.5。この塩は、水に高度に溶解し、経口的に与えられた場合に十分耐性があり、そのバイオアベイラビリティ約40%を示す。
B.フラギリス群及びフソバクテリウム属種の細菌を含むいくつかの嫌気性細菌に対して活性なこの半合成抗生物質は、従来技術で周知である。腹部手術後の創傷感染に対する予防のために、全身性ホスホマイシンと組み合せて全身に使用されてきた。メトロニダゾールの細胞内浸透は、急速受動拡散によってなされるようであり、したがって細胞内レベルは、15分以内で細胞外レベルと平衡に近付く(Handら 1987年)。本発明による組成物は、単回用量が100ミリグラムから1グラムの範囲にあるようにメトロニダゾールを含んでいてもよい。
カルバペネムは、抗生物質のベータ-ラクタムのクラスのメンバーであり、ペニシリン及びセファロスポリンのように、ホスホマイシンの場合とは異なるメカニズムにより細菌細胞壁合成を阻害することによって殺菌作用を発揮する。したがって、カルバペネムを含むベータ-ラクタム抗生物質は、両方のタイプの抗生物質がそれに対して活性であるほとんどの細菌種に対して、ホスホマイシンとの相乗殺菌作用を特徴的に示す。しかしカルバペネムは、ほとんどのペニシリン及びセファロスポリンよりも広範なスペクトルの活性を示し、B.フラギリス群、プレボテラ属種、及びフソバクテリウム属種等の嫌気性細菌に対して活性である。したがって、ホスホマイシンに非常に鈍感な嫌気性細菌に対して殺菌作用を発揮させるため、メトロニダゾールの代わりに使用される。カルバペネムの細胞内浸透に関し、マウスマクロファージ細胞系におけるエルタペネムの殺菌細胞内濃度は、15μg/mL程度に低い細胞外濃度で実現され(Tangら 2012年)、ヒトマクロファージにおけるメロペネムの細胞濃度の細胞外濃度に対する比は、0.125から1μg/mLの範囲の細胞外濃度で常に高かった(3〜12の範囲)(Cuffiniら 1993年)。本発明による組成物は、エルタペネム、又はメロペネム、又はイミペネムを、単回用量が100ミリグラムから1グラムの範囲にあるように含んでいてもよい。
記述される組成物を使用するための主な適応症は、結腸若しくは直腸粘膜から生ずる1つ若しくは複数の結直腸腫瘍の存在、及び/又は腺がん、腺腫、若しくはポリープ、若しくは粘膜上皮異形成に関連があるか否かに関わらず結腸若しくは直腸粘膜を覆う細菌バイオフィルムの存在である。適応症は、典型的には結腸鏡検査に関連して診断されることになる。記述される組成物での治療は、典型的には、同じセッション中に内視鏡を通して、又は粘膜病態が観察される腸セクションでの組成物の溶液の管腔内設置による後半の処置で、施すことができる。初期治療に続き、治療する医師の裁量で更なる治療を行なうことができる。
好ましい実施形態では、組成物は、供給された薬学的に許容される担体、好ましくは水性担体又は希釈剤に溶解させる、乾燥顆粒として供給されたホスホマイシントロメタモールを含む。担体は、単なる水であってもよく、又は、ホスホマイシン溶液の中性pH及び等張性を確実にするための、限定するものではないが緩衝剤及び/又は等張化剤を含む薬学的に許容される補助物質又はアジュバントを含有する水でもよい。別の実施形態では、組成物は、ホスホマイシン二ナトリウム、例えば、キャップ付きガラスバイアルに入れた凍結乾燥粉末として供給される、静脈内注射用に製剤化されたホスホマイシン二ナトリウムを含む。これは薬学的に許容される水性担体又は希釈剤に、同様に溶解する。
本発明の組成物は、粘膜CRC腫瘍、腺腫の領域、又は粘膜異形成の領域、又は結腸若しくは直腸に位置付けられた細菌バイオフィルムの領域で、腸の管腔への局所投与のために、当技術分野で従来から使用されてきた投与方法によって適用されてもよい。
本発明は、個々の症例に関する適切な投与量の、臨床医の選択の規範となるべきであるが、組成物は、本発明の組成物中のホスホマイシンの単位用量が、400ミリグラムから4mgの範囲にあるように製剤化されることが示唆される。これらの組成物中の追加の抗生物質として使用されたときの、メトロニダゾール又はカルバペネムの単位用量は、100ミリグラムから1グラムの範囲にあってもよい。これらの用量は、例えば大容量の浣腸剤が与えられることになる場合、医師の裁量で超えてもよい。
本発明は、腸内への本発明の組成物の局所投与を使用して、フソバクテリアによる結直腸がんの感染又はコロニー形成を低減し又は排除する、並びに結腸細菌バイオフィルムを排除する、方法を提供する。
1. フソバクテリア及び結直腸がん腫瘍に関連した細菌バイオフィルムによる結直腸がん腫瘍の感染又はコロニー形成を、低減させ又は排除するための活性成分として、抗生物質ホスホマイシンを含む組成物であって、腸管腔内に局所的に投与される組成物。
Claims (11)
- フソバクテリウム・ヌクレアタムを含むフソバクテリアによる結直腸がん腫瘍の感染又はコロニー形成及びそのような腫瘍に関連した細菌バイオフィルムの低減又は排除における使用のための、活性成分としてホスホマイシンを含む組成物であって、前記組成物が、腸管腔内に局所的に投与される、組成物。
- 前記組成物が、活性成分として1種又は複数の追加の抗菌剤又は抗生物質剤を更に含む、請求項1に記載の使用のための組成物。
- 前記1種又は複数の追加の抗菌剤又は抗生物質剤が、メトロニダゾール、又はカルバペネム、例えばエルタペネム若しくはメロペネム若しくはイミペネムを含むリストから選択される、請求項2に記載の使用のための組成物。
- 前記活性成分ホスホマイシンが、ホスホマイシントロメタモールの形態である、請求項1から3のいずれか一項に記載の使用のための組成物。
- 前記活性成分ホスホマイシンが、ホスホマイシン二ナトリウムの形態である、請求項1から3のいずれか一項に記載の使用のための組成物。
- 前記活性成分が、腸管腔内への送達前に、水性媒体に溶解される乾燥粉末又は顆粒として製剤化される、請求項1から5のいずれか一項に記載の使用のための組成物。
- 前記局所投与が、停留浣腸又は大容量浣腸である、請求項6に記載の使用のための組成物。
- 前記局所投与が、結腸鏡を介した腫瘍又は細菌バイオフィルムのレベルである、請求項6に記載の使用のための組成物。
- 前記乾燥粉末若しくは顆粒、及び/又は溶解のための水性媒体が、ジメチルスルホキシド、グリコフロール、ポリオキシエチレンラウリルエーテル、タウロコール酸ナトリウム、及びカプリン酸ナトリウムのリストから選択される1種又は複数の追加の物質を含有する、請求項6に記載の使用のための組成物。
- 前記組成物が、ネオアジュバント放射線療法、又は例えばベバシズマブ及び/若しくは細胞毒性薬を用いる、化学療法中に、投与される、請求項1から9のいずれか一項に記載の使用のための組成物。
- 前記組成物が、腫瘍細胞からフソバクテリア若しくはその他の生きている微生物を、又は腸壁から離れた転移を、低減又は排除するように、抗生物質の全身投与と組み合せて投与される、請求項1から10のいずれか一項に記載の使用のための組成物。
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