JP2016505545A - 安定化されたバンコマイシン処方物 - Google Patents
安定化されたバンコマイシン処方物 Download PDFInfo
- Publication number
- JP2016505545A JP2016505545A JP2015545418A JP2015545418A JP2016505545A JP 2016505545 A JP2016505545 A JP 2016505545A JP 2015545418 A JP2015545418 A JP 2015545418A JP 2015545418 A JP2015545418 A JP 2015545418A JP 2016505545 A JP2016505545 A JP 2016505545A
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- Prior art keywords
- glycopeptide antibiotic
- lipid
- composition
- amino acid
- stabilized
- Prior art date
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- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 claims abstract description 53
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Abstract
Description
本出願は、2012年11月29日に出願された米国仮特許出願第61/731,363号の優先権の利益を請求し、これは、全ての目的に対してその全体が参照によって本明細書に組み込まれる。
バンコマイシンは、放線細菌Amycolaopsis orientalis種の発酵によって産生される分枝三環グリコシル化非リボゾームペプチド抗生物質であり、グラム陽性菌における適切な細胞壁合成の阻害によって作用すると考えられている。さらに、バンコマイシンは細胞膜透過性およびRNA合成を変化させると考えられている。したがって、バンコマイシンは、一般に、他の抗生物質タイプに無応答性のグラム陽性菌に起因する感染の防止および処置において使用される。
リポソームバンコマイシン処方物を使用した肺障害の処置方法は、米国特許出願公開第2009−0105126号および同第2009−0104257号ならびに米国仮特許出願第61/103,725号および同第60/981,990号(これらは全て、その全体が本明細書中で参考として援用される)に記載されている。より遅い速度で分解され、したがって、安定性が改善された費用効果の高いバンコマイシン処方物が当該分野で必要とされている。本発明は、これらのニーズおよび他のニーズに取り組んでいる。
本明細書中でアミノ酸について使用した略語は、慣習的に使用されている略語である:A=Ala=アラニン;R=Arg=アルギニン;N=Asn=アスパラギン;D=Asp=アスパラギン酸;C=Cys=システイン;Q=Gln=グルタミン;E=Glu=グルタミン酸(Gutamic acid);G=Gly=グリシン;H=His=ヒスチジン;I=Ile=イソロイシン(lsoleucine);L=Leu=ロイシン;K=Lys=リジン;M=Met=メチオニン;F=Phe=フェニルアラニン;P=Pro=プロリン;S=Ser=セリン;T=Thr=トレオニン;W=Trp=トリプトファン;Y=Tyr=チロシン;V=Val=バリン。本明細書中に提供した組成物中のアミノ酸は、L型またはD型アミノ酸である。1つの実施形態では、合成アミノ酸を、本明細書中に提供した組成物中で使用する。1つの実施形態では、アミノ酸は、組成物中の糖ペプチド抗生物質の半減期、有効性、および/または生物学的利用能を増大させる。さらなる実施形態では、糖ペプチド抗生物質はバンコマイシンである。
試薬および装置
コレステロール(カタログ番号700000P)およびジパルミトイルホスファチジルコリン(DPPC,カタログ番号850355P)を、Avanti Polar Lipids Certified Reference Standardから購入した。塩化バンコマイシン(ロットHVN0701303)を、North China Pharmaceutical Groupから購入した。メタノール(HPLCグレード、カタログ番号AH230−4)、アセトニトリル(HPLCグレード)、水酸化アンモニウム(HPLCグレード)を、Burdick&Jacksonから購入した。氷酢酸(HPLCグレード;JT9515−3)および塩化ナトリウム(ACS試薬;カタログ番号3628−05)を、JT Bakerから購入した。精製水を、Milli−Q18.0MΩ水の使用によって調製した。
バンコマイシン順相HILIC HPLCアッセイを、以下の条件下にてUV検出器(CADオプション)を備えたShimadzu10AVP HPLCシステムを使用して行った:
・カラム:ZIC−HILIC 150×4.6mm、3.5um、200A(SeQuant)
・カラム温度:30℃
・移動相:アセトニトリル37%、メタノール24%、水39%、酢酸0.08%、水酸化アンモニウム0.02%
・流速:0.5mL/分、定組成
・注入体積:20μL
・サンプルを移動相に溶解する。脂質含有サンプルを調製する場合、移動相のn−プロパノールとの4:1混合物を使用することができる。
・バンコマイシン標準:有効範囲10〜200mg/mL、移動相に溶解。検量線を、1次関数によってフィッティングする。
・UV検出器:波長280nm
・クロマトグラム:以下の保持時間:
CDP−I−M:約14分
CDP−I−m:約16分
バンコマイシン:約24分
さらなる主なピークは以下にある:20分、22分、27分。総記録時間は35分である。
バンコマイシン逆相HPLCアッセイ(脂質含有サンプルには使用できない)を、以下の条件下にてUV検出器(CADオプション)を備えたShimadzu 10AVP HPLCシステムを使用して行った:
・カラム:Atlantis(登録商標)dC18、5μ、250×4.6mm(Waters)
・移動相A:アセトニトリル5%、酢酸アンモニウム15mM、pH6.0。移動相B:アセトニトリル20%、酢酸アンモニウム15mM、pH6.0。酢酸アンモニウム1M溶液(pH6.0):およそ6%氷酢酸(1M)および9%水酸化アンモニウム30%溶液。
・流速:1mL/分、二成分勾配
・サンプルを移動相に溶解する。
・バンコマイシン標準:有効範囲10〜200mg/mL、移動相に溶解する。検量線を、1次関数によってフィッティングする。
・UV検出器:波長280nm
・クロマトグラム:以下の保持時間
CDP−I−M:約7分
CDP−I−m:約16分
バンコマイシン:約26分
総記録時間は55分
分析すべきサンプルを、最終バンコマイシンHCl濃度が0μg/mlと200μg/mlとの間になるようにn−プロパノール/H2O溶液(60/40、体積/体積)に溶解した。元のサンプル中のバンコマイシン濃度が10mg/mL超である場合、水での予備希釈が必要であり得る。サンプル濃度を、280nmでのその吸光度を線形検量線(標準を、0、50、100、150、および200μg/mlの原料物質から調製した)の吸光度と比較することによって計算した。
脂質HPLCアッセイを、以下の条件下およびパラメーターにてCorona荷電化粒子検出器(CAD)を備えたShimadzu 10AVP HPLCシステムを使用して行った:
・カラム:Phenomenex Luna 3μ、C8(2)、75×4.6mm
・カラム温度:30℃
・移動相:アセトニトリル43%、n−プロパノール43%、水14%、酢酸0.1%、TEA0.1%
・流速:1mL/分、定組成
・注入体積:20μL
・サンプルを以下の溶液Aに溶解した:アセトニトリル30%、n−プロパノール30%、水40%
・脂質標準(DPPC/コレステロール20/10、30/15、および40/20μg/mL)
・較正を、1次関数によってフィッティングする。
・クロマトグラム:以下についての保持時間:コレステロールは約4分、DPPCは約6分、総記録時間は10分。
バンコマイシン溶液サンプル(1mLの200mg/mL)を4mLガラスバイアルに入れ、表示の温度でインキュベートした。選択したサンプルも、より低い温度でインキュベートした(20mg/mL)。
以前に、逆相HPLCアッセイを開発し、リポソームバンコマイシン開発に関する最初の研究で使用した(発明の名称が「リポソームバンコマイシン処方物」である米国特許出願公開第2009−0104257号(その全体が本明細書中で参考として援用される))。その方法はAtlantis(登録商標)dC18カラム(Waters)を使用し、水中で7%から20%に変化するアセトニトリル濃度を使用した二成分移動相勾配を使用した。しかし、移動相は、脂質含有サンプルを溶解するには極性が高すぎた。有機相抽出を試みたが、困難であった。
濃度200mg/mLならびにpH5.0、5.5、6.0、および6.5のバンコマイシン溶液のサンプルを、適量のNaOH溶液(50mMまたは100mM)の添加によって調製した。緩衝化サンプルでは、適量の緩衝液またはアミノ酸添加物を添加した。pH値を、許容可能な最低pHと最高pHとの間の範囲を対象とするように(pH5.0(脂質安定性のため)とpH6.5(これを超えると非実用的に迅速な分解が予想される)とが含まれる)選択した。
2個または3個ほどの短さのアミノ酸を有するいくつかのペプチドがバンコマイシンに強固に結合することができ、したがって、脱アミドに対してその構造が安定化し得ることが公知である(Harrisら,1985,J.Antibiot,38(1):51−7)。2つのかかるペプチド(すなわち、Ac−D−Ala−D−AlaおよびDi−Ac−L−Lys−D−Ala−D−Ala)を同定した。これらをバンコマイシン安定性の改善のために使用できる可能性があるが、対費用効果の高いバンコマイシン安定性の改善手段ではなない。
テイコプラニン、テラバンシン、オリタバンシン、デカプラニン、またはダルババンシンを含むリポソーム糖ペプチド抗生物質の処方物を、図14に示す3ストリーム注入過程を使用して調製する。処方物中の脂質成分は、DPPC、DPPC+コレステロール、DPPG、DPPG+コレステロール、DPPC+DPPC+コレステロール、またはPOPCを含む。処方物中のアミノ酸成分は、ビシン、GLU、GLY−GLY、IDAA、ASP、またはD−ALAを含む。
本発明は、例えば以下の項目も提供する。
(項目1)
安定化された脂質ベースの糖ペプチド抗生物質組成物であって、
(a)脂質成分;
(b)糖ペプチド抗生物質成分;および
(c)アミノ酸またはその誘導体
を含み、
該アミノ酸またはその誘導体が該糖ペプチド抗生物質を安定化する、安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目2)
前記アミノ酸またはその誘導体が前記糖ペプチド抗生物質の分解速度を減少させる、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目3)
前記安定化された糖ペプチド抗生物質−アミノ酸複合体が前記脂質成分に捕捉されている、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目4)
前記抗生物質組成物が、同一の前記脂質成分および同一の前記糖ペプチド抗生物質成分を含み、アミノ酸またはその誘導体を含まない抗生物質組成物より少なくとも44%安定している、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目5)
前記抗生物質組成物が、同一の前記脂質成分および同一の前記糖ペプチド抗生物質成分を含み、アミノ酸またはその誘導体を含まない抗生物質組成物より少なくとも77%安定している、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目6)
前記抗生物質組成物が、同一の前記脂質成分および同一の前記糖ペプチド抗生物質成分を含み、アミノ酸またはその誘導体を含まない抗生物質組成物より少なくとも88%安定している、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目7)
前記組成物が4℃で1週間あたり0.05重量%未満の速度で分解生成物を生成する、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目8)
前記組成物が4℃で1週間あたり0.02重量%未満の速度で分解生成物を生成する、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目9)
前記組成物が4℃で1週間あたり0.01重量%未満の速度で分解生成物を生成する、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目10)
前記組成物が、室温で1週間あたり約0.4重量%未満の速度で分解生成物を生成する、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目11)
前記組成物が、室温で1週間あたり約0.2重量%未満の速度で分解生成物を生成する、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目12)
前記分解生成物が結晶性分解産物である、項目7〜11のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目13)
前記脂質成分がリン脂質を含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目14)
前記リン脂質が、ホスファチジルコリン(PC)、ホスファチジルグリセロール(PG)、ホスファチジルイノシトール(PI)、ホスファチジルセリン(PS)、ホスファチジルエタノールアミン(PE)、ホスファチジン酸(PA)、およびその混合物からなる群から選択される、項目13に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目15)
前記脂質成分がステロールを含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目16)
前記ステロールがコレステロールである、項目15に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目17)
前記脂質成分がリン脂質およびステロールを含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目18)
前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)を含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目19)
前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)およびコレステロールを含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目20)
前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)を含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目21)
前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)およびコレステロールを含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目22)
前記脂質成分が、ジパルミトイルホスファチジルコリン(DPPC)、ジパルミトイルホスファチジルグリセロール(DPPG)、およびコレステロールを含む、項目1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目23)
前記安定化された糖ペプチド抗生物質−アミノ酸複合体がリポソーム中に捕捉されている、項目3に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目24)
前記リポソームの平均粒径が約0.05ミクロン〜10ミクロンである、項目23に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目25)
前記安定化された糖ペプチド抗生物質−アミノ酸複合体が脂質クラスレート内に捕捉されている、項目3に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目26)
前記安定化された糖ペプチド抗生物質−アミノ酸複合体がプロリポソームによって捕捉されている、項目3に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目27)
前記糖ペプチド抗生物質がバンコマイシンである、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目28)
前記アミノ酸がD−アラニンである、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目29)
前記アミノ酸がアスパラギン酸である、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目30)
前記アミノ酸誘導体がビシンである、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目31)
前記アミノ酸がD−グルタミン酸である、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目32)
前記アミノ酸誘導体がグリシルグリシン(Gly−Gly)である、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目33)
前記アミノ酸誘導体がイミノ二酢酸(IDAA)である、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目34)
前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:4である、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目35)
前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:2である、項目34に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目36)
前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1である、項目35に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目37)
前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:2である、項目35に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目38)
前記組成物のpHが約5.5〜約6.5である、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目39)
前記組成物のpHが約5.5である、項目38に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目40)
前記組成物中の前記糖ペプチド抗生物質成分の濃度が約20mg/mL〜約200mg/mLである、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目41)
前記組成物中の前記糖ペプチド抗生物質成分の濃度が約100mg/mLである、項目40に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目42)
前記組成物中の前記糖ペプチド抗生物質成分の濃度が約200mg/mLである、項目40に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目43)
前記組成物がアミノ酸成分またはジペプチドであるその誘導体を含む、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目44)
前記組成物がアミノ酸成分またはトリペプチドであるその誘導体を含む、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目45)
前記組成物が賦形剤をさらに含む、項目1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
(項目46)
安定化された脂質ベースの糖ペプチド抗生物質組成物を調製する方法であって、
インライン様式で、溶媒中に脂質成分を含む脂質溶液の第1のストリームを糖ペプチド抗生物質およびアミノ酸またはその誘導体を含む水溶液の第2のストリームと共に注入する工程を含み、
該アミノ酸またはその誘導体が該糖ペプチド抗生物質に結合して安定化された糖ペプチド抗生物質−アミノ酸複合体を形成し、該安定化された糖ペプチド抗生物質−アミノ酸複合体が該脂質成分によって捕捉される、方法。
(項目47)
前記溶媒がエタノールである、項目46に記載の方法。
(項目48)
前記脂質溶液が約20mg/mLの前記脂質成分を含む、項目46に記載の方法。
(項目49)
前記脂質成分がリン脂質を含む、項目46に記載の方法。
(項目50)
前記リン脂質が、ホスファチジルコリン(PC)、ホスファチジルグリセロール(PG)、ホスファチジルイノシトール(PI)、ホスファチジルセリン(PS)、ホスファチジルエタノールアミン(PE)、ホスファチジン酸(PA)、およびその混合物からなる群から選択される、項目49に記載の方法。
(項目51)
前記脂質成分がステロールを含む、項目46に記載の方法。
(項目52)
前記ステロールがコレステロールである、項目51に記載の方法。
(項目53)
前記脂質成分がリン脂質およびステロールを含む、項目46に記載の方法。
(項目54)
前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)を含む、項目46に記載の方法。
(項目55)
前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)およびコレステロールを含む、項目46に記載の方法。
(項目56)
前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)を含む、項目46に記載の方法。
(項目57)
前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)およびコレステロールを含む、項目46に記載の方法。
(項目58)
前記脂質成分が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)を含む、項目46に記載の方法。
(項目59)
前記脂質成分が、ジパルミトイルホスファチジルコリン(DPPC)、ジパルミトイルホスファチジルグリセロール(DPPG)、およびコレステロールを含む、項目46に記載の方法。
(項目60)
前記第1のストリームの流速が約1L/分である、項目46に記載の方法。
(項目61)
前記糖ペプチド抗生物質と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:4である、項目46に記載の方法。
(項目62)
前記糖ペプチド抗生物質と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:2である、項目46に記載の方法。
(項目63)
前記アミノ酸がD−アラニンである、項目46に記載の方法。
(項目64)
前記アミノ酸がアスパラギン酸である、項目46に記載の方法。
(項目65)
前記アミノ酸誘導体がビシンである、項目46に記載の方法。
(項目66)
前記アミノ酸がD−グルタミン酸である、項目46に記載の方法。
(項目67)
前記アミノ酸誘導体がグリシルグリシン(Gly−Gly)である、項目46に記載の方法。
(項目68)
前記アミノ酸誘導体がイミノ二酢酸(IDAA)である、項目46に記載の方法。
(項目69)
前記水溶液が約20mg/mL〜約200mg/mLの前記糖ペプチド抗生物質を含む、項目46に記載の方法。
(項目70)
前記水溶液が約200mg/mLの糖ペプチド抗生物質を含む、項目46に記載の方法。
(項目71)
前記水溶液が約100mg/mLの糖ペプチド抗生物質を含む、項目46に記載の方法。
(項目72)
前記糖ペプチド抗生物質がバンコマイシンである、項目46に記載の方法。
(項目73)
前記水溶液のpHが約5.0〜約6.5である、項目44に記載の方法。
(項目74)
前記水溶液のpHが約5.5である、項目46に記載の方法。
(項目75)
前記第2のストリームの流速が約1.5L/分である、項目46に記載の方法。
(項目76)
生理食塩水を注入する工程をさらに含む、項目46に記載の方法。
(項目77)
細菌感染を処置する方法であって、それを必要とする被験体に、治療有効量の項目1〜45のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物を投与する工程を含む、方法。
(項目78)
前記細菌感染が肺感染である、項目77に記載の方法。
(項目79)
前記被験体が菌血症を有する、項目77に記載の方法。
(項目80)
前記被験体が骨髄炎を有する、項目77に記載の方法。
(項目81)
前記糖ペプチド抗生物質がバンコマイシンである、項目77に記載の方法。
(項目82)
前記細菌性肺感染がグラム陽性菌に起因する、項目77に記載の方法。
(項目83)
前記グラム陽性菌が、メチシリン耐性のStaphylococcus aureus(MRSA)、Streptococcus pneumoniae、大腸菌、Klebsiella、Enterobacter、Serratia、Haemophilus、Yersinia pesos、Burkholderia pseudomallei、Burkholderia cepacia、Burkholderia gladioli、Burkholderia multivorans、またはBurkholderia vietnamiensisを含む、項目82に記載の方法。
(項目84)
前記グラム陽性菌がMycobacteriaを含む、項目82に記載の方法。
(項目85)
前記Mycobacteriaが、Mycobacterium tuberculosis、非結核性抗酸菌、Mycobacterium avium複合体(MAC)、Mycobacterium kansasii、Mycobacterium xenopi、Mycobacterium marinum、Mycobacterium ulcerans、Mycobacterium fortuitum複合体、Mycobacterium abscessus、またはMycobacterium xenopiである、項目84に記載の方法。
(項目86)
前記グラム陽性菌がBurkholderiaを含む、項目82に記載の方法。
(項目87)
前記治療有効量が前記細菌性肺感染の最小阻止濃度(MIC)より多い量である、項目77に記載の方法。
(項目88)
前記治療有効量が約50mg/日〜約1000mg/日である、項目77に記載の方法。
(項目89)
前記安定化された脂質ベースの糖ペプチド抗生物質組成物を気管内に投与する、項目77に記載の方法。
(項目90)
前記安定化された脂質ベースの糖ペプチド抗生物質組成物を吸入を介して投与する、項目77に記載の方法。
(項目91)
前記安定化された脂質ベースの糖ペプチド抗生物質組成物をネブライザーを介して投与する、項目77に記載の方法。
(項目92)
前記安定化された脂質ベースの糖ペプチド抗生物質組成物を1日に1〜4回投与する、項目77に記載の方法。
Claims (92)
- 安定化された脂質ベースの糖ペプチド抗生物質組成物であって、
(a)脂質成分;
(b)糖ペプチド抗生物質成分;および
(c)アミノ酸またはその誘導体
を含み、
該アミノ酸またはその誘導体が該糖ペプチド抗生物質を安定化する、安定化された脂質ベースの糖ペプチド抗生物質組成物。 - 前記アミノ酸またはその誘導体が前記糖ペプチド抗生物質の分解速度を減少させる、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記安定化された糖ペプチド抗生物質−アミノ酸複合体が前記脂質成分に捕捉されている、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記抗生物質組成物が、同一の前記脂質成分および同一の前記糖ペプチド抗生物質成分を含み、アミノ酸またはその誘導体を含まない抗生物質組成物より少なくとも44%安定している、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記抗生物質組成物が、同一の前記脂質成分および同一の前記糖ペプチド抗生物質成分を含み、アミノ酸またはその誘導体を含まない抗生物質組成物より少なくとも77%安定している、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記抗生物質組成物が、同一の前記脂質成分および同一の前記糖ペプチド抗生物質成分を含み、アミノ酸またはその誘導体を含まない抗生物質組成物より少なくとも88%安定している、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物が4℃で1週間あたり0.05重量%未満の速度で分解生成物を生成する、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物が4℃で1週間あたり0.02重量%未満の速度で分解生成物を生成する、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物が4℃で1週間あたり0.01重量%未満の速度で分解生成物を生成する、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物が、室温で1週間あたり約0.4重量%未満の速度で分解生成物を生成する、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物が、室温で1週間あたり約0.2重量%未満の速度で分解生成物を生成する、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記分解生成物が結晶性分解産物である、請求項7〜11のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分がリン脂質を含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記リン脂質が、ホスファチジルコリン(PC)、ホスファチジルグリセロール(PG)、ホスファチジルイノシトール(PI)、ホスファチジルセリン(PS)、ホスファチジルエタノールアミン(PE)、ホスファチジン酸(PA)、およびその混合物からなる群から選択される、請求項13に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分がステロールを含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記ステロールがコレステロールである、請求項15に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分がリン脂質およびステロールを含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)を含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)およびコレステロールを含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)を含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)およびコレステロールを含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記脂質成分が、ジパルミトイルホスファチジルコリン(DPPC)、ジパルミトイルホスファチジルグリセロール(DPPG)、およびコレステロールを含む、請求項1に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記安定化された糖ペプチド抗生物質−アミノ酸複合体がリポソーム中に捕捉されている、請求項3に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記リポソームの平均粒径が約0.05ミクロン〜10ミクロンである、請求項23に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記安定化された糖ペプチド抗生物質−アミノ酸複合体が脂質クラスレート内に捕捉されている、請求項3に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記安定化された糖ペプチド抗生物質−アミノ酸複合体がプロリポソームによって捕捉されている、請求項3に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記糖ペプチド抗生物質がバンコマイシンである、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記アミノ酸がD−アラニンである、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記アミノ酸がアスパラギン酸である、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記アミノ酸誘導体がビシンである、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記アミノ酸がD−グルタミン酸である、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記アミノ酸誘導体がグリシルグリシン(Gly−Gly)である、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記アミノ酸誘導体がイミノ二酢酸(IDAA)である、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:4である、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:2である、請求項34に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1である、請求項35に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記糖ペプチド抗生物質成分と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:2である、請求項35に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物のpHが約5.5〜約6.5である、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物のpHが約5.5である、請求項38に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物中の前記糖ペプチド抗生物質成分の濃度が約20mg/mL〜約200mg/mLである、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物中の前記糖ペプチド抗生物質成分の濃度が約100mg/mLである、請求項40に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物中の前記糖ペプチド抗生物質成分の濃度が約200mg/mLである、請求項40に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物がアミノ酸成分またはジペプチドであるその誘導体を含む、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物がアミノ酸成分またはトリペプチドであるその誘導体を含む、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 前記組成物が賦形剤をさらに含む、請求項1〜26のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物。
- 安定化された脂質ベースの糖ペプチド抗生物質組成物を調製する方法であって、
インライン様式で、溶媒中に脂質成分を含む脂質溶液の第1のストリームを糖ペプチド抗生物質およびアミノ酸またはその誘導体を含む水溶液の第2のストリームと共に注入する工程を含み、
該アミノ酸またはその誘導体が該糖ペプチド抗生物質に結合して安定化された糖ペプチド抗生物質−アミノ酸複合体を形成し、該安定化された糖ペプチド抗生物質−アミノ酸複合体が該脂質成分によって捕捉される、方法。 - 前記溶媒がエタノールである、請求項46に記載の方法。
- 前記脂質溶液が約20mg/mLの前記脂質成分を含む、請求項46に記載の方法。
- 前記脂質成分がリン脂質を含む、請求項46に記載の方法。
- 前記リン脂質が、ホスファチジルコリン(PC)、ホスファチジルグリセロール(PG)、ホスファチジルイノシトール(PI)、ホスファチジルセリン(PS)、ホスファチジルエタノールアミン(PE)、ホスファチジン酸(PA)、およびその混合物からなる群から選択される、請求項49に記載の方法。
- 前記脂質成分がステロールを含む、請求項46に記載の方法。
- 前記ステロールがコレステロールである、請求項51に記載の方法。
- 前記脂質成分がリン脂質およびステロールを含む、請求項46に記載の方法。
- 前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)を含む、請求項46に記載の方法。
- 前記脂質成分がジパルミトイルホスファチジルコリン(DPPC)およびコレステロールを含む、請求項46に記載の方法。
- 前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)を含む、請求項46に記載の方法。
- 前記脂質成分がジパルミトイルホスファチジルグリセロール(DPPG)およびコレステロールを含む、請求項46に記載の方法。
- 前記脂質成分が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)を含む、請求項46に記載の方法。
- 前記脂質成分が、ジパルミトイルホスファチジルコリン(DPPC)、ジパルミトイルホスファチジルグリセロール(DPPG)、およびコレステロールを含む、請求項46に記載の方法。
- 前記第1のストリームの流速が約1L/分である、請求項46に記載の方法。
- 前記糖ペプチド抗生物質と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:4である、請求項46に記載の方法。
- 前記糖ペプチド抗生物質と前記アミノ酸またはアミノ酸誘導体とのモル比が約1:1〜約1:2である、請求項46に記載の方法。
- 前記アミノ酸がD−アラニンである、請求項46に記載の方法。
- 前記アミノ酸がアスパラギン酸である、請求項46に記載の方法。
- 前記アミノ酸誘導体がビシンである、請求項46に記載の方法。
- 前記アミノ酸がD−グルタミン酸である、請求項46に記載の方法。
- 前記アミノ酸誘導体がグリシルグリシン(Gly−Gly)である、請求項46に記載の方法。
- 前記アミノ酸誘導体がイミノ二酢酸(IDAA)である、請求項46に記載の方法。
- 前記水溶液が約20mg/mL〜約200mg/mLの前記糖ペプチド抗生物質を含む、請求項46に記載の方法。
- 前記水溶液が約200mg/mLの糖ペプチド抗生物質を含む、請求項46に記載の方法。
- 前記水溶液が約100mg/mLの糖ペプチド抗生物質を含む、請求項46に記載の方法。
- 前記糖ペプチド抗生物質がバンコマイシンである、請求項46に記載の方法。
- 前記水溶液のpHが約5.0〜約6.5である、請求項44に記載の方法。
- 前記水溶液のpHが約5.5である、請求項46に記載の方法。
- 前記第2のストリームの流速が約1.5L/分である、請求項46に記載の方法。
- 生理食塩水を注入する工程をさらに含む、請求項46に記載の方法。
- 細菌感染を処置する方法であって、それを必要とする被験体に、治療有効量の請求項1〜45のいずれか1項に記載の安定化された脂質ベースの糖ペプチド抗生物質組成物を投与する工程を含む、方法。
- 前記細菌感染が肺感染である、請求項77に記載の方法。
- 前記被験体が菌血症を有する、請求項77に記載の方法。
- 前記被験体が骨髄炎を有する、請求項77に記載の方法。
- 前記糖ペプチド抗生物質がバンコマイシンである、請求項77に記載の方法。
- 前記細菌性肺感染がグラム陽性菌に起因する、請求項77に記載の方法。
- 前記グラム陽性菌が、メチシリン耐性のStaphylococcus aureus(MRSA)、Streptococcus pneumoniae、大腸菌、Klebsiella、Enterobacter、Serratia、Haemophilus、Yersinia pesos、Burkholderia pseudomallei、Burkholderia cepacia、Burkholderia gladioli、Burkholderia multivorans、またはBurkholderia vietnamiensisを含む、請求項82に記載の方法。
- 前記グラム陽性菌がMycobacteriaを含む、請求項82に記載の方法。
- 前記Mycobacteriaが、Mycobacterium tuberculosis、非結核性抗酸菌、Mycobacterium avium複合体(MAC)、Mycobacterium kansasii、Mycobacterium xenopi、Mycobacterium marinum、Mycobacterium ulcerans、Mycobacterium fortuitum複合体、Mycobacterium abscessus、またはMycobacterium xenopiである、請求項84に記載の方法。
- 前記グラム陽性菌がBurkholderiaを含む、請求項82に記載の方法。
- 前記治療有効量が前記細菌性肺感染の最小阻止濃度(MIC)より多い量である、請求項77に記載の方法。
- 前記治療有効量が約50mg/日〜約1000mg/日である、請求項77に記載の方法。
- 前記安定化された脂質ベースの糖ペプチド抗生物質組成物を気管内に投与する、請求項77に記載の方法。
- 前記安定化された脂質ベースの糖ペプチド抗生物質組成物を吸入を介して投与する、請求項77に記載の方法。
- 前記安定化された脂質ベースの糖ペプチド抗生物質組成物をネブライザーを介して投与する、請求項77に記載の方法。
- 前記安定化された脂質ベースの糖ペプチド抗生物質組成物を1日に1〜4回投与する、請求項77に記載の方法。
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- 2013-11-27 CA CA2891487A patent/CA2891487A1/en not_active Abandoned
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- 2013-11-27 CN CN201380068974.7A patent/CN104884047A/zh active Pending
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US12016873B2 (en) | 2014-05-15 | 2024-06-25 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
JP2020520987A (ja) * | 2017-05-22 | 2020-07-16 | インスメッド インコーポレイテッドInsmed Incorporated | リポ‐グリコペプチド可切断性誘導体及びその使用 |
JP2020520986A (ja) * | 2017-05-22 | 2020-07-16 | インスメッド インコーポレイテッドInsmed Incorporated | グリコペプチド誘導体化合物およびそれらの使用 |
JP7165146B2 (ja) | 2017-05-22 | 2022-11-02 | インスメッド インコーポレイテッド | グリコペプチド誘導体化合物およびそれらの使用 |
JP7210476B2 (ja) | 2017-05-22 | 2023-01-23 | インスメッド インコーポレイテッド | リポ‐グリコペプチド可切断性誘導体及びその使用 |
JP2021523224A (ja) * | 2018-05-02 | 2021-09-02 | インスメッド インコーポレイテッド | リポソーム薬物製剤の製造方法 |
JP7449275B2 (ja) | 2018-05-02 | 2024-03-13 | インスメッド インコーポレイテッド | リポソーム薬物製剤の製造方法 |
JP2022511715A (ja) * | 2018-11-21 | 2022-02-01 | インスメッド インコーポレイテッド | グリコペプチド誘導体化合物およびそれらの使用 |
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EP4209229A4 (en) * | 2020-09-04 | 2024-07-31 | Univ Osaka | LIPOSOME PREPARATION WITH ANTIBACTERIAL ACTIVE INGREDIENT |
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ES2743039T3 (es) | 2020-02-18 |
JP6529438B2 (ja) | 2019-06-12 |
RU2015125293A (ru) | 2017-01-10 |
CN104884047A (zh) | 2015-09-02 |
CA2891487A1 (en) | 2014-06-05 |
US20190022232A1 (en) | 2019-01-24 |
EP3581186A1 (en) | 2019-12-18 |
BR112015012351A8 (pt) | 2019-10-01 |
EP2925298B1 (en) | 2019-05-29 |
AU2013352259B2 (en) | 2018-06-14 |
BR112015012351A2 (pt) | 2017-07-11 |
US10471149B2 (en) | 2019-11-12 |
HK1216008A1 (zh) | 2016-10-07 |
RU2018135921A (ru) | 2019-02-05 |
JP2019031554A (ja) | 2019-02-28 |
US20150314002A1 (en) | 2015-11-05 |
EP2925298A4 (en) | 2016-07-13 |
US10124066B2 (en) | 2018-11-13 |
MX2015006681A (es) | 2016-04-06 |
AU2013352259A1 (en) | 2015-06-04 |
EP2925298A1 (en) | 2015-10-07 |
RU2675859C2 (ru) | 2018-12-25 |
WO2014085526A1 (en) | 2014-06-05 |
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