JP2017082015A - 徐放性抗感染剤 - Google Patents
徐放性抗感染剤 Download PDFInfo
- Publication number
- JP2017082015A JP2017082015A JP2017027482A JP2017027482A JP2017082015A JP 2017082015 A JP2017082015 A JP 2017082015A JP 2017027482 A JP2017027482 A JP 2017027482A JP 2017027482 A JP2017027482 A JP 2017027482A JP 2017082015 A JP2017082015 A JP 2017082015A
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- Japan
- Prior art keywords
- lipid
- amikacin
- infective
- formulation
- liposomal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
【課題を解決するための手段】陰イオン脂質を実質的に含まず、かつ脂質と抗感染薬との比率は、約1:1から約4:1であり、平均直径が約1μm未満である抗感染脂質製剤が提供される。さらに、注入プロセスを含む、抗感染脂質製剤を調製する方法が提供される。さらに、薬物に対する脂質の比率が約1:1以下、約0.75:1以下、または約0.50:1以下である、インライン注入プロセスによって調製される、抗感染脂質製剤が提供される。本発明はさらに、肺感染症に罹患した患者を治療する方法であって、該患者に治療的有効量の本発明の抗感染脂質製剤を投与することを含む方法に関する。本発明はさらに、嚢胞性線維症に罹患した患者を治療する方法であって、該患者に治療的有効量の本発明の抗感染脂質製剤を投与することを含む方法に関する。
【選択図】なし
Description
本出願は、2002年10月29日に出願された米国特許出願第60/421,923号の利益の権利を主張している、2003年10月29日に出願された米国特許出願第10/696,389号の部分継続出願である、2004年12月28日に出願された米国特許出願第11/023,971号の部分継続出願である。
吸入法による投与に適した、ある徐放性のテクノロジーは、そして肺において、全身的に徐放性及び目的とする部位に向けそして病巣への薬の取り込みを促進する能力により、薬の持続性のある治療効果を提供する、リポソーム及び脂質複合体を採用している。本発明は、リポソーム化された抗感染薬、及びリポソーム化された抗感染薬、又は脂質と複合体化された抗感染薬を使用する、肺感染症の治療方法を包含する。
の発生は、アミノ配糖体類が蓄積する濃度と関連しているので、腎機能が損なわれている患者におけるこれらの薬の維持投与量を減らすことが欠く事ができない。」アミノ配糖体類は、患者の欠陥に関係なく耳の前庭又は聴覚の機能不全を引き起こすので、一般的に維持投薬量を減らすことが重要である。本発明は、劇的に毒性を減らすことができるので、通常の投与量よりも高い投与量が可能になる。
ここで開示された注入法によって、典型的には脂質/抗感染薬の重量比が約4:1から約5:1で抗感染薬を封入する適度の大きさ(<1μm)の陰イオン脂質を実質的に含まないリポソームが創製された。リポソームの捕捉された量は定量されており、これらの数値に基づいて、その理論封入量が前記の抗感染薬が理想的な溶質として振舞う(すなわち、リポソーム膜と相互作用することなく、水と共に理想的に封入される)かどうかをを算出することができる。この比較によれば、予測より3〜5倍高い封入数が観察される。これは、特殊な相互作用が起こり、予測した封入より大きな封入と、低い脂質/抗感染薬比が可能になることを示すものである。リポソームが形成する溶液は、ある濃度の抗感染薬を含有している。このリポソーム中の抗感染薬の濃度は、溶液中の抗感染薬の濃度とほぼ同じであるはずである。しかしながら、内部の抗感染薬の濃度は、少なくとも3倍高いことが計算されている。
本発明は、その大きさおよび脂質対薬物の比率が、これまでに知られているものより小さい、抗感染薬を含む脂質製剤を開示している。さらに本発明は、これらの脂質製剤を調製する方法を開示している。
本発明をさらに説明する前に、便宜上、本明細書、実施例および添付の請求の範囲において用いられるいくつかの用語をここに集めている。これらの定義を、当業者は本開示の他の部分に照らして読み取り、理解するであろう。他に特に規定しない限り、ここで用いられる全ての技術および科学用語は、当業者が通常理解するものと同じ意味を有する。
but not limitedto(限定されないが、〜を含んでいる)」の意味で用いられている。「
including(含んでいる)」は、「including
but not limitedto(限定されないが、〜を含んでいる)」は、交換可能に用いられる。
Basis ofTherapeuticsなどの公知の参考文献に記載があり、限定されないが、医薬品;
ビタミン類;ミネラルサプリメント類;疾患もしくは疾病の治療、予防、診断、治癒もしくは軽減のために用いられる物質;または生物学的に活性のある、もしくはそれらが生理学的環境におかれたときにより活性的になるプロドラッグがあげられる。
抗感染薬は、細菌性、ミコバクテリア性、真菌性、ウイルス性、または原生動物性感染などの感染に対して作用する作用物質である。本発明で論じる抗感染薬としては、限定されないが、アミノ配糖体類(例えば、ストレプトマイシン、ゲンタマイシン、トブラマイシン、アミカシン、ネチルマイシン、カナマイシン、など)、テトラサイクリン類(例えば、クロルテトラサイクリン、オキシテトラサイクリン、メタサイクリン、ドキシサイクリン、ミノサイクリン、など)、スルホンアミド類(例えば、スルファニルアミド、スルファジアジン、スルファメタジン、スルフイソキサゾール、スルファセタミド、など)、パラアミノ安息香酸、ジアミノピリミジン(例えば、トリメトプリム、スルファメトキサゾール、ピラジンアミド、などと組み合わせて使用されることが多い)、キノロン類(例えば、ナリジキシ酸、シノキサシン、シプロフロキサシン、およびノルフロキサシン、など)、ペニシリン類(例えば、ペニシリンG、ペニシリンクロルV、アンピシリン、アモキシシリン、バカンピシリン、カルベニシリン、カルベニシリンインダニル、チカルシリン、アズロシリン、メズロシリン、ピペラシリン、など)、ペニシリナーゼ耐性ペニシリン(例えば、メチシリン、オキサシリン、クロキサシリン、ジクロキサシリン、ナフシリン、など)、第1世代セファロスポリン系物質(例えば、セファドロキシル、セファレキシン、セフラジン、セファロチン、セファピリン、セファゾリン、など)、第2世代セファロスポリン系物質(例えば、セファクロール、セファマンドール、セフォニシド、セフォキシチン、セフォテタン、セフロキシム、セフロキシムアクセチル;セフメタゾール、セフプロジル(原語:cefprozil)、ロラカルベフ(原語:loracarbef)、セホラニド、など)、第三世代セファロスポリン系物質(例えば、セフェプリム(原語:cefepime)、セホペラゾン、セフォタキシム、セフチゾキシム、セフトリアキソン、セフタジジム、セフィキシム、セフポドキシム、セフチゾキシム、など)、他のベータ−ラクタム系物質(例えば、イミペネム、メロペネム(原語:meropenem)、アズトレオナム、クラブラン酸、スルバクタム、タロバクタム(原語:tazobactam)、など)、ベータ−ラクタマーゼ阻害剤(例えば、クラブラニン酸)、クロラムフェニコール、マクロライド類(例えば、エリスロマイシン、アジスロマイシン、クラリスロマイシン、など)、リンコマイシン、クリンダマイシン、スペクチノマイシン、ポリミキシンB、ポリミキシン類(例えば、ポリミキシンA、B、C、D、El(コリスチンA)、もしくはE2、コリスチンBもしくはC、など)、コリスチン、バンコマイシン、バシトラシン、イソニアジド、リファンピン、エタンブトール、エチオナミド、アミノサリチル酸、サイクロセリン、カプレオマイシン、スルホン類(例えば、ダプソン、スルホキソンナトリウム、など)、クロファジミン、サリドマイド、または他の脂質カプセル化が可能な抗細菌剤が含まれる。抗感染薬は、抗真菌性物質を含むことができ、それは、ポリエン抗真菌性物質(例えば、アンホテリシンB、ナイスタチン、ナタマイシン、など)、フルシトシン、イミダゾール類(例えば、n−チコナゾール(原語:ticonazole)、クロトリマゾール、エコナゾール、ケトコナゾール、など)、トリアゾール類(例えば、イトラコナゾール、フルコナゾール、など)、グリセオフルビン、テルコナゾール、ブトコナゾール(原語:butoconazole)、シクロピロックス、シクロピロクスオラミン、ハロプロジン、トルナフテート、ナフチフィン、テルビナフィン、または他の脂質カプセル化もしくは複合体化することが可能な抗真菌性の物質が含まれる。説明と例は、主にアミカシンについて行うが、適用範囲はこの抗感染薬に限定されることを意図するものではない。薬物の併用も可能である。
る担体であると考えられている。
本発明の方法を用いて治療することができる肺感染症(例えば、嚢胞性線維症患者)には、シュードモナス(例えば、シュードモナス・アエルギノーザ(P.aeruginosa)、シュードモナス・パウシモビリス(P.Paucimobilis)、シュードモナス・プチダ(P.putida)、シュードモナス-フルオレッセンス(P.fluorescens)、およびシュードモナス・アシドボランス(P.acidovorans)、ブドウ球菌(staphylococcal)、耐性黄色ブドウ球菌(MethicillinresistantStaphylococcusaureus(MRSA))、連鎖球菌(streptococcal)(連鎖球菌性肺炎(Streptococcuspneumoniae)によるものを含む)、大腸菌(Escherichiacoli)、クレブシエラ(Klebsiella)、エンテロバクター(Enterobacter)、セラチア属(Serratia)、ヘモフィルス属(Haemophilus)、エルシニア属ペソス(Yersiniapesos)、ブルクホルデリア・プセウドマレイ(Burkholderiapseudomallei)、ブルクホルデリア・セパシア(B.cepacia)、ブルクホルデリア・グラディオリ(B.gladioli)、ブルクホルデリア・マルチボランス(B.multivorans)、ブルクホルデリア・ベトナミエンシス(B.vietnamiensis)、マイコバクテリウム・ツベルクローシス(Mycobacteriumtuberculosis)、マイコバクテリウムアビウム複合体(M.avium(MAC)(マイコバクテリウム・アビウム(Mavium)およびマイコバクテリウム・イントラセルラーレ(M.intracellular))、マイコバクテリウム・カンサシイ(M.kansasii)、マイコバクテリウム-キセノピー(M.xenopi)、マイコバクテリウム・マリナム(M.marinum)、マイコバクテリウム-ウルセランス(M.ulcerans)、またはマイコバクテリウム・フォルツイタム複合体(M.fortuitumcomplex)(マイコバクテリウム・フォルツイタム(M.fortuitum)およびマイコバクテリウム・ケロネイ(M.chelonei))感染がある。
ある実施態様において、本発明は、抗感染脂質製剤の治療的有効量を投与することを含む治療方法を含む。
本発明の組成物に用いられる資質は、合成脂質、半合成脂質、または天然に存在する脂質であることができ、リン脂質類、トコフェロール類、ステロイド類、脂肪酸類、アルブミンなどのグリコプロテイン類、陰イオン脂質および陽イオン性脂質があげられる。該脂質は、陰イオン性でも、陽イオン性でも、中性でもよい。ある実施態様において、当該脂質製剤は、実質的に陰イオン脂質を含まない。ある実施態様において、当該脂質製剤は、中性脂質のみを含む。別の実施態様において、当該脂質製剤は、陰イオン脂質を含まない。別の実施態様において、当該脂質は、リン脂質である。リン脂質は、卵ホスファチジルコリン(EPC)、卵ホスファチジルグリセロール(EPG)、卵ホスファチジルイノシトール(EPI)、卵ホスファチジルセリン(EPS)、ホスファチジルエタノールアミン(EPE)、および卵ホスファチド酸(EPA);その大豆の対応物、大豆ホスファチジルコリン(SPC);SPG,SPS、SPI、SPE、およびSPA;その硬化卵および大豆対応物(例えば、HEPC、HSPC)、炭素数12〜26の鎖を含有する2および3のグリセロール位置における脂肪酸のエステル結合、およびコリン、グリセロール、イノシトール、セリン、エタノールアミンを含むグリセロールの1位置における異なる頭基(headgroup)から構成された他のリン脂質、ならびに対応するホスファチジン酸が
あげられる。これらの脂肪酸の鎖は、飽和であっても不飽和であってもよく、そのリン脂質は、異なる鎖長および異なる不飽和度の脂肪酸で構成してもよい。特に、製剤の組成物は、ジパルミトイルホスファチジルコリン(DPPC)、天然に存在する肺表面活性剤の主要な構成要素、ならびにジオレイルホスファチジルコリン(DOPC)を含むことができる。他の例としては、ジミリストイルホスファチジルコリン(DMPC)およびジミリストイルホスファチジルグリセロール(DMPG)、ジパルミトイルホスファチジルコリン(DPPC)およびジパルミトイルホスファチジルグリセロール(DPPG)、ジステアロイルホスファチジルコリン(DSPC)およびジステアロイルホスファチジルグリセロール(DSPG)、ジオレイルホスファチジル−エタノールアミン(DOPE)およびパルミトイルステアロイルホスファチジルコリン(PSPC)やパルミトイルステアロイルホスファチジルグリセロール(PSPG)のような混合リン脂質、トリアシルグリセロール(原語:driacylglycerol)、ジアシルグリセロール、セラニド(原語:seranide)、スフィンゴシン、スフィンゴミエリンおよびモノオレイル−ホスファチジルエタノールアミン(MOPE)のような単一アシル化リン脂質を含むことができる。
リポソームまたは抗感染脂質製剤を作製するプロセスには、「溶媒注入」プロセスが含まれる。これは、1以上の脂質を少量、好ましくは微量のプロセス適合性溶媒に溶解して、脂質懸濁液もしくは溶液(好ましくは、溶液)を作製し、その後該溶液を、抗感染薬を含有する水性媒体に注入することを含むプロセスである。典型的には、プロセス適合性溶媒は、水性プロセス、例えば、透析法によって洗い流すことができるものである。「エタノール注入」は、溶媒注入の1つのタイプであり、1以上の脂質を少量、好ましくは微量のエタノールに溶解して、脂質溶液を作製し、その後該溶液を、抗感染薬を含有する水性媒体に添加することを含むプロセスである。溶媒の「少」量とは、注入プロセスにおけるリポソームまたは脂質複合体の作製に適合する量である。こうしたプロセスについては、2003年8月4日に出願されたLeeらの米国特許第10/634,144号、2003年3月5日に出願されたPilkiewiczらの米国特許第10/383,173号、および2003年3月5日に出願されたBoniらの米国特許第10/383,004号に記載がある。その全てを、引用を以って本明細書に引用する。
ーを用いることもできる。
たんぱく質(SP)は、構造を維持するための機能を示し、呼吸中におこる肺の界面活性物質の拡張および収縮を容易にする。もちろん、SP−BおよびSP−Cは、特にリポソームを分解する(Hagwoodetal., 1998;Johansson, 1998)。この分解の振る舞いは、リポソームを徐々に分解することを容易にするであろう。さらにリポソームはまた、ファゴサイトーシスを介してマクロファージによって直接的に消化されることもある(Couveuretal.,1991; Gonzales-Roth et al., 1991; Swenson et al, 1991)。肺胞マクロファージによるリポソームの取り込みは、薬物が疾患部位に送達される別の手段である。
ある特に好ましい実施態様において、本発明のリポソーム性抗感染薬製剤は、インライン注入法によって作製される。そこでは、脂質溶液の流れと抗感染薬溶液の流れとを1つの流れに混合する。例えば、2つの溶液を、図8に示すように、先の方がY字コネクターになった混合チューブ内のインラインに混合するとよい。このようにインライン注入法は、上記注入法とは異なり、そこでは、脂質溶液は、大量の抗感染薬用液の流れの中に注入される。驚くべきことに、この注入法の結果、脂質対薬物の比率を低くし、閉じ込め効果を高めることができる。該プロセスは、流速、温度、抗感染薬濃度、注入ステップ後の塩添加といったパラメーターを最適化することによって、さらに改良することができる。
流速の合計を800mL/分に保ちながら、個別の流速を変化させた。そうするために、ポンピングスピードの異なる2つの別々のポンプを用いた。NaClの最終濃度が1.5%、エタノールの最終濃度が30%を超えないようにしながら、NaCl溶液の入ったビーカーに、混合溶液を10秒間注入した。混合後、1mLのアリコートをセファデックス(Sephadex)G−75ゲル濾過カラムに通して、閉じ込められたものから遊離アミカシンを分離させた。(視覚混濁度による測定によって)密度の最も高い1mLの画分を回収し、さらに分析した。得られた結果を表1に示す。脂質/アミカシン流速比率が増加した結果、300/500mL/分までほぼL/Dは一定であった。さらに脂質率を増やしたところ、L/Dは、上昇し、粒径は大きくなり始めた。同時に脂質の流速が大きくなり、脂質の質量を大きくするにつれて、アミカシン回収率(カプセル化効率)が上昇した。
mLとした。注入前にNaClの10%溶液を添加し、最終的に1.5%とした。注入時間は、10秒に設定した。混合チューブを10cm、6−エレメントインラインミキサーを0cmのところに位置づけた。
実施例6乃至10)、または30秒間注入した(実施例11乃至18)。追加の水性液(NaClまたは水)を添加した(500部のアミカシン体積に対する部)。
各種設定は、添加するNaCl溶液の量を少なくし、最終濃度を1.0%とした以外は、バッチ3と同じとした。注入開始前に溶液を再び添加した。注入時間が短いと、注入中に添加することが難しいからである。さらに、注入中に、インラインミキサーを流れの圧力の下で混合チューブの端に移動させた。ミキサーの位置は、バッチ3では0cmとしていたが、ここではチューブの前端から5cmのところとした。バッチ20において同じ温度条件(40/40℃)で得られたL/D比率が0.55、すなわち、バッチ3のほぼ半分であったことから、このことは重要かもしれない。異なる注入温度で、アミカシンカプセル化の比較を行ったところ、驚くべきことに、温度が低いほど、L/Dが良好であった。試験した温度のうち、脂質/アミカシン温度30/30℃および50/RTのとき、類似のL/D比率0.32および0.37が得られた。また、バッチ1〜5に見られるように、より低いゲル濾過で洗浄したものは、おそらくバッチをダイアフィルトレーションで洗浄した場合よりも低いであろう。
次にNaCl溶液添加および洗浄プロセスのステップに注目した。プロセスパラメーターは、種々の方向において変化させた。流速300/500で注入ステップを行った直後、混合物中のエタノール濃度は、34%に達する。この濃度においては、アミカシンの安定性は限定されていた(図9参照)。
これまで、50mg/mLのアミカシンの保存溶液を用いることで、最もよく閉じ込めを行うことがわかっている。アミカシン保存濃度を40mg/mLまで下げると、従来のプロセスにおいて用いられた場合、L/Dが上昇する。2つの流れのインライン注入プロセスによって、エタノール濃度が高いレベルに達することから、現在の50mg/mLアミカシンは、最適濃度ではないかもしれない。
抗感染薬(例えば、アミカシン、トブラマイシン、ゲンタマイシンなどのアミノ配糖体)のリポソームへの閉じ込めを増加させるための方法がいくつかある。1つの方法は、脂質の量あたりの閉じ込めの体積が大きい場合、より大きなリポソーム(>1μm)とすることである。より小さなL/D比率を達成するためのこのアプローチは、リポソームの吸引(噴霧)には適用できない。なぜなら、1)より大きなリポソーム(>0.5μm)が大きな放出をしようとした場合、噴霧中の剪断応力がリポソームをサイズ依存的に破裂させる可能性があるからである。2)肺での良好な蓄積のために必要なより小さな液滴のサイズは、約3μmまでである。だから、吸引の場合、放出しすぎることを避けるために、リポソームサイズをできるだけ小さくすることが望ましい。現在、ここに開示しているリポソームの平均粒径は、約0.4μm未満である(表4を参照されたい)。
8.1 肺感染のバイオフィルム障壁
シュードモナス-アエルギノーザなどの感染の疾患の治療にとっての障害である、嚢胞性線維症患者における慢性疾患の主な原因は、上皮細胞上の喀痰/バイオフィルム関門内の薬物調製である(図1)。図1において、ドーナツ形は、リポソーム性抗感染薬製剤を表している。「+」印は、遊離状態の抗感染薬を表し、「−」印は、ムチン、アルギン酸塩およびDNAを表し、太線は、シュードモナス・アエルギノーザを表している。この関門は、アルギン酸塩に埋設した、コロニー化した、またはプランクトン様のシュードモナス・アエルギノーザ、または、細菌からのエキソポリサッカライド、ならびに損傷した白血球からのDNA、および肺上皮細胞からのムチンからなり、これらは全て正味で負に帯電している(Costerton,etal., 1999)。この負の電荷は、正に帯電した薬物、例えば、アミノ配糖体に結合し、その通過を阻止し、それらが生物学的に影響力を持たないようにしている(Mendelmanet al., 1985)。抗感染薬をリポソーム性製剤または脂質製剤に閉じ込めることによって、抗感染薬が、喀痰/バイオフィルムに非特異的な結合をするのを遮断したり、または部分的に遮断したりすることができ、リポソーム性製剤または脂質製剤を(閉じ込めたアミノ配糖体とともに)貫通するようにしている(図1)。
遊離のトブラマイシンまたはリポソーム性のアミカシン製剤のいずれかを気管内(IT)投与した後のラットにおいて、アミカシンの薬物動態を測定した。これらのデータを、トブラマイシンを尾の静脈注射した後の肺で得られた分散と比較した。全てのケースにおいて、ラット1匹あたり4mgを投与した。図2から、注射と比較して、ITによるとアミノ配糖体をはるかに多く送達可能であることがわかる。リポソーム性抗感染薬技術のデポー効果はさらに、ITもしくはIVで投与されたトブラマイシンと比較した場合、投与の24時間後に肺に残留するリポソーム性のアミカシン製剤は100倍であることを示す。したがって、薬物の肺での治療効果は、遊離のトブラマイシンと比較した場合、リポソーム性のアミカシン製剤では長時間持続する。
Hintonブロス希釈アッセイ(シュードモナス・アエルギノーザ)を用いて、生物活性を測定した。この結果を表7に示す。
吸引)炭疽病におけるホストの自己破壊の主な原因となっている。徐放および標的化というそれがもつ属性に加えて、リポソーム性抗感染薬製剤技術は、薬物標的化と送達において細胞の取り込みを高め、肺胞マクロファージと肺上皮細胞を用いることができる。これらの特徴を持つことは、これらの、肺でおこり、マクロファージによって輸送される細胞内感染を促進する。より重要なことは、これらの特徴は、抗感染薬をより有効なものとするはずであるということである。リポソーム性抗感染薬が、疾患を含有するまさにその細胞によって食作用を受けるはずである。該抗感染薬は、標的化されて細胞内に放出され、それによって、散剤する前に感染を攻撃することができるであろう。カプセル化された薬物は、既に認可されている製剤シプロフロキサシン、テトラサイクリン、エリスロマイシン(原語:erthyromycin)またはアミカシンであってよい。リポソーム性シプロフロキサシン製剤が開発された。
適用する脂質をエタノールに溶解し、脂質−エタノール溶液を作製する。該脂質−エタノール溶液を、閉じ込められた生物活性物質の分子を含有する水溶性またはエタノール性溶液中に注入する。該脂質は、自発的に小胞を形成する。
**:L/Dの計算においては、閉じ込められたアミカシンの量のみを考慮した。
感染の近隣での活性形態の薬物の放出は、本発明のリポソーム性の薬物の活性の局面において重要である。そのような標的化された放出の可能性は、CF患者からの喀痰とともにインキュベートしたときの薬物の放出、P.アエルギノーザとともにプレインキュベートしたときのラット肺での薬物の放出、ならびにP.アエルギノーザの培養に対する活性をモニターすることによって、試験した。
ある実施態様においては、本発明のリポソーム性アミカシン製剤は、嚢胞性線維症患者の慢性P.アエルギノーザ感染を治療するために製剤されたナノスケール(200〜300nm)のリポソームカプセル化形態のアミカシンである。吸引に際しては、肺でアミカシンが持続的に放出されることが好ましい。なぜなら、肺胞マクロファージは、このサイズ範囲で積極的に粒子を取り込むことが知られており、リポソーム製剤がこれらの細胞に及ぼす影響は、特に興味深い。洗浄法によって取得したラット肺胞マクロファージの基本的かつ刺激的な機能を、リポソーム性アミカシン製剤を投与して、および投与せずに研究し、種々の対照と比較した。
本発明の組成物の投与量は、患者の徴候、年齢および体重、治療もしくは予防すべき障害の性質および重篤度、投与経路、ならびに対象組成物の形態によって変わる。対象となる製剤は全て、単回投与でもよいし、分けて投与してもよい。本発明の組成物の投与は、当業で公知の技術または本明細書において教示している技術によって容易に決定すればよい。
本発明の抗感染脂質製剤は、リポソームの水性分散液を含んでもよい。該製剤は、脂質添加剤を含有し、リポソームおよび塩/緩衝剤を形成して、適切な浸透圧およびpHを提供することもできる。該製剤は、薬学的添加剤を含んでもよい。薬学的添加剤は、いずれかの対象の組成物またはその成分の、ある器官または身体部分から別の器官または身体部分への運搬または輸送に関与する、流体、希釈液、溶媒、またはカプセル化剤であることができる。各添加剤は、対象組成物およびその成分と相溶性があるという意味において、「許容可能」でなければならず、患者にとって有害であってはならない。好適な添加剤としては、トレハロース、ラフィノース、マンニトール、スクロース、ロイシン、トリロイシン、および塩化カルシウムがある。他の好適な添加剤の例には:(1)乳糖、ブドウ糖およびショ糖などの糖類;(2)コーンスターチおよびいもでんぷんなどのでんぷん;(3)セルロースおよび、例えばカルボキシメチルセルロースナトリウム、エチルセルロースおよび酢酸セルロースなどのその誘導体;(4)粉末トラガカント;(5)麦芽;(6)ゼラチン;(7)タルク;(8)ココアバターおよび座薬用ろうなどの添加物;(9)ピーナッツ油、綿実油、紅花油、ごま油、オリーブ油、コーン油および大豆油などの油類;(10)プロピレングリコールなどのグリコール;(11)グリセリン、ソルビトール、マンニトールおよびポリエチレングリコールなどのポリオール;(12)オレイン酸エチルおよびラウリル酸エチルなどのエステル;(13)寒天;(14)水酸化マグネシウムおよび水酸化アルミニウムなどの緩衝剤;(15)アルギン酸;(16)無発熱源水;(17)等張生理食塩水;(18)リンガー液;(19)エチルアルコール;(20)リン酸緩衝液;および(21)薬剤処方に用いられる他の無毒性の適合性物質、がある。
当初の合計体積=1.5L
エタノール成分=23.5%(v/v)
脂質組成物:DPPC/Chol(1:1モル比)
当初[脂質]=7.6mg/mL
当初[アミカシンスルフェート]=57.3mg/mL
最終生成物体積=150mL
7.47gのDPPCおよび3.93gのコレステロールを、50C水浴中352.5mLのエタノールに直接溶解した。85.95gのアミカシンスルフェートを1147.5mLのPBS緩衝剤中に直接溶解した。次いで該溶液を、IONNaOHまたはKOHを用いて滴定し、pHを約6.8とした。
混合容器をぜん動ポンプおよびダイアフィルトレーションカートリッジに引っ掛けた。該ダイアフィルトレーションカートリッジは、分子量の遮断が500キロダルトンの中空膜ファイバーである。該生成物を反応容器からダイアフィルトレーションカートリッジを介してポンピングし、室温で混合容器に戻した。カートリッジを介して約7psiの逆圧が生じる。リポソーム性のアミカシン(生成物)を残しながら、遊離アミカシンおよびエタノールを、逆圧によって中空ファイバー膜に通した。該生成物を室温で8回洗浄した。浸透除去を補填し、一定の生成物の体積を維持するために、新鮮なPBS緩衝剤を(別のぜん動ポンプを介して)反応容器に添加した。該生成物を濃縮した。
サンプル#5。ゲンタマイシンスルフェート20.0gを230mLの食塩水溶液に溶解し(0.9%NaCl)、必要量の硫酸を加えてpHを6.5に調整した。脂質−0.982gのDPPCおよび0.518gのコレステロールを70mLのエタノールに溶解した。脂質溶液をゲンタマイシン溶液に注入し(〜500mL/分)、一定に撹拌しながらリポソームを形成した。捕捉されていないアミカシンおよびエタノールを、AmershamHollowFiber カートリッジを用いたダイアフィルトレーションによって除去した。該懸濁液を最終体積が〜35mLとなるように濃縮した。
サンプル#7。実施例2のサンプル#2と同様の処置を行った。アミカシン塩基10.7gおよびクエン酸4.2gを230mLの食塩水溶液に溶解し(0.9%NaCl)、得られたアミカシン−クエン酸塩溶液のpHを6.2に調整した。脂質−0.982gのDPPCおよび0.518gのコレステロールを70ミリリットルのエタノールに溶解した。脂質溶液を〜500ml/分の速度でアミカシン溶液に注入し、一定に撹拌しながらリポソームを形成した。捕捉されていないアミカシンおよびエタノールをAmershamHollowFiber カートリッジを用いたダイアフィルトレーションによって除去した。該懸濁液を最終体積が〜35mLとなるように濃縮した。
インライン注入プロセスの本質は、脂質溶液の流れと、抗感染薬溶液の流れとが、例えば、そこでさらなる混合を行うことができる混合チューブと呼ばれるチュービングの長手方向に結合するY字コネクターによって「インライン」に混合することである。この意味で、この新たなプロセスは、大量のアミカシン溶液の流れとして脂質溶液を注入する「従来の」エタノール注入プロセスとは異なる。
アミカシンスルフェート12.0gを200mLの水に溶解し、必要量の25%のNaOH溶液を加えてpHを6.5に調整した。脂質、1.480gのDPPCおよび0.520gのコレステロールを60mLのエタノールと10mLの水の混合物中に溶解した。これらの量は、脂質/アミカシンの流速をそれぞれ300/500mL/分で注入した後、300mLのバッチとする。より大きなスケールまたは異なる流速が望ましければ、それにあわせて体積を調整することができる。
注入システムの一実施態様を図8に示す。
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限定されないが特許および特許出願を含む、本明細書に引用されている文献および引例を、個々の出願または引例が特別に、かつ個別に引用によって本明細書に援用されるのと同程度に、その全体、その部分全体を引用によってここに援用する。この出願が優先権を主張する特許出願もまた、出願および引例について上記したように、ここに引用を以って援用する。
好ましい実施態様を強調して本発明を説明してきたが、好ましいデバイスおよび方法における変形を用いてもよいこと、ならびに本発明は本明細書に特に記載したもの以外の方法で行ってもよいことが意図されていることが当業者には明らかであろう。したがって、本発明は、以下に示す請求項によって定義されている本発明の精神および範囲に包含されるすべての変形を含む。
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