JP2010535797A - 非経口用抗菌剤 - Google Patents
非経口用抗菌剤 Download PDFInfo
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- JP2010535797A JP2010535797A JP2010520259A JP2010520259A JP2010535797A JP 2010535797 A JP2010535797 A JP 2010535797A JP 2010520259 A JP2010520259 A JP 2010520259A JP 2010520259 A JP2010520259 A JP 2010520259A JP 2010535797 A JP2010535797 A JP 2010535797A
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- Prior art keywords
- infection
- formulation
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- resistant
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- 238000011105 stabilization Methods 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
抗菌剤の注射剤(parenteral injection)は、感染症、特にメチシリン耐性黄色ブドウ球菌(Staphylococcus aureus)または多剤耐性肺炎球菌(Streptococcus pneumoniae)による感染症を治療するのに最も有効な方法の一つである。抗菌剤の注射剤は、安定した溶液である水性製剤を使用する必要がある。
一態様によると、本発明は、下記式I:
本発明を実施するのに使用される式Iの化合物は、公知の方法によって合成できる。下記実施例1を参照。
(3S,5S)−7−[3−アミノ−5−メチル−ピペリジニル]−1−シクロプロピル−1,4−ジヒドロ−8−メトキシ−4−オキソ−3−キノリンカルボン酸[(3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid](化合物1)のリンゴ酸塩を以下のようにして合成した。
化合物10を、米国特許第6,329,391号に記載の方法に従って調製した。
デキストロース及び塩化ナトリウム製剤を調製し、研究した:
1.5%デキストロース溶液における製剤
化合物1を5%滅菌デキストロース水溶液に溶解した(5mg/mL)。この溶液を濾過し、100−mLのポリプロピレンボトルに移した。このボトルにふたをし、密閉し、110℃で35分間滅菌し、60℃のオーブンに貯蔵した。ボトル内のこの溶液を、0、5、及び10日目に分析した。その結果を下記に示すが、これから、化合物1の5%デキストロース溶液では、活性成分の含量が減少し、pH値が増加し、溶液が変色し、茶色の沈殿物が形成することが示される。
化合物1を0.9%生理食塩水に溶解した(5mg/mL)。この溶液を濾過し、100−mLのポリプロピレンボトルに移した。このボトルにふたをし、密閉し、110℃で35分間滅菌し、60℃のオーブンに貯蔵した。ボトル内のこの溶液を、0、5、及び10日目に分析した。その結果を下記に示すが、これから、この製剤は予想外に安定であったことが示される。より詳しくは、外観及びpH値は60℃で10日間同じであり続けた。化合物1の含有量は、ボトルのプラスチック壁を通して水が蒸発することにより、経時的に若干増加した。全体的な純度は、10日後、若干増加したのみであった。
製剤への活性炭(charcoal)、pH値、及び鉄含有量の効果を研究した:
1.活性炭の効果
13.85gの化合物1及び18gのNaClを、滅菌水に溶解した。攪拌しながら滅菌水をさらに加えて、溶液の最終容積を2000mLとし、5mg/mLの化合物1を含む溶液を得た。この溶液を500mLずつ4つに分けた。これらの4つの画分に、0%、0.02%、0.05%及び0.5%(g/mL)の活性炭を添加した。得られた混合物を攪拌しながら25分間煮沸し、0.45ミクロンの濾紙で濾過した。濾液を、一連の100mLのポリプロピレンボトルに加え、これにふたをし、密閉し、110℃で35分間滅菌した。これら4ボトルそれぞれについて化合物1の含有量及びpHを分析し、下記に示す。0.05%(g/mL)の活性炭を下記配合プロセスに選択した。
0.9%生理食塩水における化合物1の溶液2000mLを、上記したのと同様にして調製した。この溶液を6つに等量に分けた。これらの6画分のpHを、希塩酸または水酸化ナトリウムを添加することによって、2.43、3.00、3.76、4.51、6.01及び7.13に調節した。これらの溶液の外観及び含有量を分析し、下記に示す。結果から、生理食塩水において5mg/mL濃度の化合物1は、pHが6.6で沈殿したことが示される。
0.9%生理食塩水における化合物1の溶液1000mLを、上記したのと同様にして調製した。この溶液を2つに等量に分けた。一方の6画分に、0.25gの活性炭を加え、他方の画分に、0.25gの活性炭及び0.1gの鉄粉末を加えた。得られた混合物を、それぞれ、攪拌し、100mLのポリプロピレンボトルに濾過して入れた。これらの満たされたボトルにふたをし、密閉し、110℃で35分間滅菌した。各溶液のpH及び外観を下記に示す。結果から、非経口製剤用のプロセスには、鉄との接触は避けるべきである。
0.9%生理食塩水における化合物1の溶液3000mLを、上記したのと同様にして調製した。この溶液に、1.5gの活性炭を添加した(0.05%g/mL)。この混合物を15分間攪拌し、濾過した。濾液を、一連の100mLのポリプロピレンボトルに添加した。これらの満たされたボトルにふたをし、密閉し、4グループに分けた(7ボトル/グループ)。サンプルの滅菌を115℃/35分間、110℃/35分間、105℃/35分間で、行った。各グループ(コントロールグループを含む)のpHに加えて、化合物1の含有量及び不純物レベルを、測定し、下記に示す。研究結果によると、非経口製剤の滅菌は、110℃で35分間を選択する。
0.9%生理食塩水において5mg/mLの化合物を含むボトルを、−15℃フリーザーに貯蔵した。サンプルを、0、5及び10日目に分析した。結果を下記に示すが、これから、外観、化合物の含有量、pH及び全不純物量は−15℃で10日間は同等に維持されたことが示される。
0.9%生理食塩水における化合物1の溶液(遊離塩基に対して5mg/mL)を含むボトルを、4500Lx+/−500Lx下でライトボックス中に置いた。サンプルを、0、5及び10日目に分析した。結果を下記に示すが、これから、強い光照射下での変化はなかったことが示される。
0.9%生理食塩水における化合物1の溶液(遊離塩基に対して5mg/mL)を調製し、濾過し、100mLのポリプロピレンボトルに移した。これらのボトルにふたをし、密閉し、110℃で35分間滅菌し、40℃で20%相対湿度(RH)で6カ月および25℃で60%RHで12カ月貯蔵し、下記表に示されるように試験した。
化合物1のインビトロ及びインビボでの活性を以下のようにして調べた。
嫌気性で非定型病原菌である、グラム陽性細菌(例えば、クロストリジウム属(Clostridium)、スタフィロコッカス属(Staphylococcus )及びストレプトコッカス属(Streptococcus))、グラム陰性細菌(例えば、モラクセラ属(Moraxella)、ヘモフィルス属(Haemophilus)、シュードモナス属(Pseudomonas)、プロテウス属(Proteus)、及びバクテリオイデス属(Bacteriodes))などの、様々な細菌を、臨床サンプルから単離した。式Iの化合物の、これらの細菌に対する抗菌活性を、U.S. National Committee for Clinical Laboratory, M7-A6, 2003, and M11-A5, 2001に記載される寒天希釈アッセイ法を用いて測定した。
化合物1のインビボでの抗菌効力をマウスモデルで評価した。マウスに麻酔をかけ、致死量の肺炎連鎖球菌 Stp 6301(S. pneumoniae Stp 6301)を鼻腔内に感染させた。感染させてから12、18、及び24時間後に、化合物1またはモキシフロキサシン(moxifloxacin)(ポジティブコントロールとして)、0.7%乳酸、及び3%デキストロースを含む組成物を、50、25、12.5、または6.25mg/kgの全投与量でマウスの皮下に投与した。処置されたマウスの半数を、化合物1またはモキシフロキサシンで最後に処置してから4時間後に安楽死させ、これらの血液及び肺組織を集めた。次に、血液及び肺組織中の生菌の数を測定した。また、肺組織について組織病理学的評価を行った。マウスの残りの半分を6日間モニターし、生存したマウスの数を記録した。
本明細書に記載されるすべての態様は、いずれの組み合わせで結合されてもよい。同じ、等価の、または同様の目的を果たす別の態様を本明細書に記載される各態様の代わりに使用してもよい。ゆえに、特記しない限り、開示される各態様は、一般的な一連の等価のまたは同様の態様の例にすぎない。
Claims (27)
- 前記感染症は、尿路感染症、前立腺炎、呼吸器感染症、骨髄炎、淋病、ヒト型結核菌、MAC症(mycobacterium avium complex)、慢性気管支炎の急性増悪、肺炎、副鼻腔炎、感染性下痢症、ヘリコバクター・ピロリ(helicobacter pylori)、皮膚感染症、産婦人科感染症、または腹部感染症である、請求項1に記載の方法。
- 前記感染症は、グラム陰性またはグラム陽性細菌による感染症である、請求項1に記載の方法。
- 前記感染症は、嫌気性細菌による感染症である、請求項1に記載の方法。
- 前記感染症は、メチシリン耐性黄色ブドウ球菌(methicillin-resistant S. aureus)または多剤耐性肺炎球菌(multi-resistant S. pneumoniae)による感染症である、請求項1に記載の方法。
- 前記化合物は、D,L−リンゴ酸塩の形態である、請求項1に記載の方法。
- 前記等張剤は、塩化ナトリウムである、請求項6に記載の方法。
- 前記製剤における前記化合物の濃度は0.2〜45mMであり、前記製剤における前記塩化ナトリウムの濃度は0.2〜1.3%v/wである、請求項7に記載の方法。
- 前記製剤は、静脈内注射または輸液によって投与される、請求項8に記載の方法。
- 前記製剤における前記塩化ナトリウムの濃度は0.9%w/vである、請求項9に記載の方法。
- 前記感染症は、尿路感染症、前立腺炎、呼吸器感染症、骨髄炎、淋病、ヒト型結核菌、MAC症(mycobacterium avium complex)、慢性気管支炎の急性増悪、肺炎、副鼻腔炎、感染性下痢症、ヘリコバクター・ピロリ(helicobacter pylori)、皮膚感染症、産婦人科感染症、または腹部感染症である、請求項9に記載の方法。
- 前記感染症は、グラム陰性またはグラム陽性細菌による感染症である、請求項9に記載の方法。
- 前記感染症は、嫌気性細菌による感染症である、請求項9に記載の方法。
- 前記感染症は、メチシリン耐性黄色ブドウ球菌(methicillin-resistant S. aureus)または多剤耐性肺炎球菌(multi-resistant S. pneumoniae)による感染症である、請求項9に記載の方法。
- 前記製剤は、ヒスチジン、リジン、グリシン、スクロース、フルクトース、トレハロース、及びこれらの混合物からなる群より選択される安定化剤をさらに含む、請求項9に記載の方法。
- 前記製剤は、酢酸塩、クエン酸塩、酒石酸塩、乳酸塩、コハク酸塩、リンゴ酸塩、またはリン酸塩からなる群より選択される緩衝剤をさらに含む、請求項9に記載の方法。
- 前記製剤は、亜硫酸水素ナトリウム、ブチル化ヒドロキシアニソール、システイン、ゲンチシン酸、グルタミン酸1ナトリウム、チオグリコール酸ナトリウム、及びアスコルビン酸からなる群より選択される抗酸化剤をさらに含む、請求項9に記載の方法。
- 前記製剤は、0.1〜1.0%w/v濃度の安定化剤および0.01〜5%w/v濃度の緩衝剤をさらに含む、請求項11に記載の方法。
- 前記等張剤は、グリセリン、ラクトース、マンニトール、デキストロース、硫酸ナトリウム、及びソルビトールからなる群より選択される、請求項6に記載の方法。
- 前記等張剤はデキストロースであり、その製剤における濃度は1〜7%w/vである、請求項19に記載の方法。
- 前記製剤は、0.1〜1.0%w/v濃度の安定化剤および0.01〜5%w/v濃度の緩衝剤をさらに含む、請求項20に記載の方法。
- 前記製剤は、静脈内注射または輸液によって投与される、請求項20に記載の方法。
- 前記感染症は、尿路感染症、前立腺炎、呼吸器感染症、骨髄炎、淋病、ヒト型結核菌、MAC症(mycobacterium avium complex)、慢性気管支炎の急性増悪、肺炎、副鼻腔炎、感染性下痢症、ヘリコバクター・ピロリ(helicobacter pylori)、皮膚感染症、産婦人科感染症、または腹部感染症である、請求項6に記載の方法。
- 前記感染症は、グラム陰性またはグラム陽性細菌による感染症である、請求項6に記載の方法。
- 前記感染症は、嫌気性細菌による感染症である、請求項6に記載の方法。
- 前記感染症は、メチシリン耐性黄色ブドウ球菌(methicillin-resistant S. aureus)または多剤耐性肺炎球菌(multi-resistant S. pneumoniae)による感染症である、請求項6に記載の方法。
- 前記等張剤は塩化ナトリウムであり、その製剤における濃度は0.2〜1.3%w/vである、請求項1に記載の方法。
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WO2010059658A1 (en) | 2008-11-20 | 2010-05-27 | Glaxosmithkline Llc | Chemical compounds |
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