JP5118302B2 - 抗感染剤の徐放 - Google Patents
抗感染剤の徐放 Download PDFInfo
- Publication number
- JP5118302B2 JP5118302B2 JP2005500829A JP2005500829A JP5118302B2 JP 5118302 B2 JP5118302 B2 JP 5118302B2 JP 2005500829 A JP2005500829 A JP 2005500829A JP 2005500829 A JP2005500829 A JP 2005500829A JP 5118302 B2 JP5118302 B2 JP 5118302B2
- Authority
- JP
- Japan
- Prior art keywords
- formulation
- liposomal
- phosphatidylcholine
- amikacin
- aminoglycoside
- 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.)
- Expired - Lifetime
Links
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Description
Pharmaceutical Basis of Therapeutics, 第8版で報告されるように、腎毒性及び聴器毒性の発生はアミノグリコシドが蓄積する濃度に関係するため、腎機能不全のある患者でこれらの薬物の維持量を低くすることが重要である。アミノグリコシドは、患者の障害に関係なく、前庭又は聴覚の機能不全や腎毒性を生じることがあるため、一般に維持量を減らすことが重要である。本発明は、維持量の劇的な減少を提供するものである。
とりわけ、有効量のリポソーム性/複合体形成した抗感染剤を、患者に肺投与するステップを含む、嚢胞性線維症患者における肺感染症を治療又は改善する方法が提供され、この場合、(i)投与される量は、相対的遊離薬物量の50%以下であるか、又は(ii)投薬は1日一回以下であるか、又は(iii)両者、である。
本出願は、脂質ベースの粒子に封入された抗感染剤(例えば抗生物質)の投与を含む、嚢胞性線維症患者などにおいて肺感染を治療又は改善する方法を開示するものである。
pneumoniae)を含む)、エシェリヒア-コリ(原語:Escherichia
coli)、クレブシエラ(原語:Klebsiella )、エンテロバクター(原語:Enterobacter)、セラチア(原語:Serratia )、ヘモフィルス(原語:Haemophilus )、エルシニア-ペスティス(原語Yersinia pestis)、ブルクホルデリア-シュードマレイ(原語:Burkholderia pseudomallei)、B.セパシア(原語:B.
cepacia )、B.グラディオリ(原語:B. gladioli )、B.ムルチヴォランス(原語:B. multivorans )、B.ヴェトナミエンシス(原語:B.
vietnamiensis)、マイコバクテリウム-ツベルキュローシス(原語:Mycobacterium tuberculosis)、 M.アヴィウム複合
(MAC)(M.アヴィウム(原語:M. avium)及びM.イントラセルラ(原語:M. intracellulare)、M.カンサシ(原語:M. kansasii)、M.ゼノピ(原語:M. xenopi)、M.マリナム(原語:M. marinum)、M.ウルセランス(原語:M. ulcerans)、又はM.フォルテュイタム(原語:M. fortuitum )複合体(M.フォルテュイタム及びM.ケロネイ(原語:M. chelonei)感染、がある。
(DOTAP)、がある。ステロイドの例には、コレステロール及びエルゴステロールがある。PGs、PAs、PIs、PCs 及び PSs の例には、DMPG、DPPG、DSPG、DMPA、DPPA、DSPA、DMPI、DPPI、DSPI、DMPS、DPPS 及びDSPS、DSPC、DPPG、DMPC、DOPC、卵PC、がある。
多層ベシクル(それぞれ隣のものから水相により隔てられた、複数の膜二重層を特徴とする玉葱様の構造)であってもよい。二重層は疎水性の「尾」の領域と、親水性の「頭部」の領域とを柚須得る2つの脂質単層から成る。この膜二重層の構造は、脂質単層の疎水性(非極性)の「尾」が、二重層の中心に向かい、親水性の「頭部」が水相を向いているようなものである。脂質複合体は、脂質と、取り込ませようとする抗感染剤との間の結合である。この結合は共有結合でも、イオン結合でも、静電結合でも、非共有結合でも、又は立体的結合であってもよい。これらの複合体は、非リポソーム性であり、更なる水溶性の溶質を捉えることができない。このような複合体の例には、アンフォテンシンBの脂質複合体 (Janoff et al., Proc. Nat Acad. Sci., 85:6122 6126, 1988) や、ドキソルビシンと複合体形成したカルジオリピンがある。
Cullis et al., Biotechnol Adv. 5(1):194, 1987を参照されたい)。Banghamの方法 (J. Mol. Biol., J Mol Biol. 13(1):238-52, 1965) では通常の多層ベシクル (MLVs)が作製される。Lenk ら
(米国特許第4,522,803号、第5,030,453号及び第5,169,637号)、Fountain ら(米国特許第4,588,578号)及びCullis ら(米国特許第4,975,282号)は、それらの水性区画のそれぞれに実質的に同等な層間溶質分布を有する多層リポソームを作製する方法を開示している。Paphadjopoulos らは、米国特許第4,235,871号で、逆相蒸発によるオリゴラメラ・リポソームの調製を開示している。
Deamer, 米国特許第4,515,736号;及びChapman
et al., Liposome Technol., 1984, pp. 1-18を参照されたい)。
ら (Biochim. Biophys, Acta., 1967, 135:624-638)が解説した小型の音波破砕された単層ラメラベシクルや、大型の単層ラメラベシクルの開発に基礎となる。
1991)。肺胞マクロファージによるリポソームの取り込みは、薬物を罹患部位に送達することのできる別の手段である。
(Costerton, et al., 1999)。この負の電荷が結び付き合って、 アミノグリコシドなどの性の電荷を持つ薬物の透過を妨げることで、それらを生物学的に無効にする (Mendelman et al., 1985)。抗感染剤をリポソーム又は脂質複合体内に捕捉すると、痰/バイオフィルムへの非特異的結合から抗感染剤を遮蔽もしくは部分的に遮蔽でき、こうして(捕捉されたアミノグリコシドと一緒に)リポソーム又は脂質複合体の透過が可能になるであろう(図1)。
、1 mg/ラット又は10 mg/ラットの投与アミノグリコシド
又は 1 mg/ラットのリポソーム性/複合体形成したアミカシンにして、コントロールとしての盲検リポソーム(脂質賦形剤)も並行して、1群当たり5匹のラットに投薬した。
リポソーム性/複合体形成したアミカシンの、肺内におけるこのような百倍を越える抗感染剤の増加は、現在認められているTOBITM調合物よりも摂取頻度が少なくてもすむ徐放性リポソーム性/複合体形成した抗感染剤という発想の裏付けとなる。
(DPPC/Chol., 1:1) の吸入(上述の通り、ラットにおいて、1群当たり3匹のラット)による4時間である。投薬は1日目;3日目及び5日目に行うか、あるいは、1日目、2日目、3日目、4日目及び5日目である。所定のデータ棒を出したラットは、データ棒の各投薬後にと殺された。調合物は実施例の通りに作製されている。
mg/ml のシプロで入れ、当該の調合物は実施例の通りに作製された。脂質対薬物比は重量で 12.5:1 だった。経口投与されたシプロフロキサシンに比較して、リポソーム性/複合体形成したシプロフロキサシンは、マウス肺内に、遊離シプロフロキサシンよりも2桁多い量、存在した。さらに、リポソーム性/複合体形成したシプロフロキサシンのみが、24時間後に肺内の薬物レベルを示し、他方、経口投与されたこの薬物は、2時間未満で検出不能となった。このデータは、リポソーム性/複合体形成したシプロフロキサシンや、バイオテロリストが用いる細胞内疾患の治療及び予防のための他のアミノグリコシド、テトラサイクリン及びマクロライドなどの抗感染剤の使用を裏付けるものである。
蠕動ポンプで-30mL/分(輸注速度とも呼ばれる)で、室温の攪拌プレート上に載せた反応容器中の、150RPMで高速攪拌中のアミカシン/緩衝溶液に入れた。
Possmayer, F., The Role of Lipids in Pulmonary Surfactant, Biochim. Biophys.
Acta 1408:90-108 (1998).2. Hagwood,
S., Derrick, M. and Poulain, F., Structure and Properties of Surfactant Protein
B, Biochim. Biophys. Acta 1408:150-160 (1998).3. Johansson, J., Structure and Properties of Surfactant ProteinC,
Biochim. Biophys. Acta 1408:161-172 (1998).4. Ikegami,
M. and Jobe, A.H., Surfactant Protein Metabolism in vivo, Biochim. Biophys.
Acta 1408:218-225 (1998).5. Couveur, P.,
Fattel, E. and Andremont,A., Liposomes and Nanoparticles in the Treatment of
Intracellular Bacterial Infections, Pharm. Res. 8:1079-1085 (1991).6. Gonzales-Rothi, R.J., Casace, J.,
Straub, L., and Schreier, H., Liposomes and Pulmonary Alveolar Macrophages:
Functional and Morphologic Interactions, Exp. Lung Res. 17:685-705 (1991).7. Swenson, C.E.,
Pilkiewicz, F.G., and Cynamon, M.H., Liposomal Aminoglycosides and TLC-65 Aids
Patient Care 290-296 (Dec., 1991).8. Costerton,
J.W., Stewart, P.S., and Greenberg, E.P., Bacterial Biofilms: A Common Cause of
Persistent Infections, Science 284:1318-1322 (1999).9. Cash, H.A., Woods, D.E., McCullough, W.G., Johanson,
J.R., and Bass, J.A., A Rat Model of Chronic Respiratory Infection with
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A.M. and Woods, D.E. Aerosolized Prolastin Suppresses Bacterial Proliferation
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B.W., Dorkin, H.L., Eisenberg, J.D., Gibson, R.L., Harwood, I.R., Kravitz,
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Claims (17)
- 肺感染症を治療又は改善する際に使用するリポソーム性アミノグリコシド調合物であって、前記リポソーム性アミノグリコシド調合物は患者への肺内投与用であり、アミノグリコシドおよびリポソームを含み、前記リポソームがホスファチジルコリン及びステロールを含み、そしてホスファチジルコリン及びステロールのアミノグリコシドに対する重量比が2.5:1未満である、リポソーム性アミノグリコシド調合物。
- 前記アミノグリコシドが、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、ネチルミシン又はカナマイシンである、請求項1に記載の調合物。
- 前記アミノグリコシドがアミカシン又はアミカシンスルフェートである、請求項2に記載の調合物。
- ホスファチジルコリン及びステロールのアミカシンに対する重量比が、重量で1.1:1未満である、請求項3に記載の調合物。
- 前記投薬が2日に一回以下の頻度である、請求項1乃至4のいずれか一つに記載の調合物。
- 前記投薬が3日に一回以下の頻度である、請求項1乃至4のいずれか一つに記載の調合物。
- 前記治療又は改善しようとする感染症が、シュードモナス、ブドウ球菌、メチシリン耐性スタフィロコッカス・アウレウス(MRSA)、連鎖球菌、エシェリヒア-コリ、クレブシエラ、エンテロバクター、セラチア、ヘモフィルス、エルシニア-ペスティス、ブルクホルデリア-シュードマレイ、B.セパシア、B.グラディオリ、B.ムルチヴォランス、B.ヴェトナミエンシス、マイコバクテリウム-ツベルキュローシス、M.アヴィウム複合体(MAC)(M.アヴィウム及びM.イントラセルラ)、M.カンサシ、M.ゼノピ、M.マリナム、M.ウルセランス、又はM.フォルテュイタム複合体(M.フォルテュイタム及びM.ケロネイ)による感染症である、請求項1乃至6のいずれか一つに記載の調合物。
- 前記調合物の有効量が、肺感染症の症状が起きた後に治療又は改善するのに有効な量である、請求項1乃至7のいずれか一つに記載の調合物。
- 前記ホスファチジルコリンが、卵ホスファチジルコリン(EPC)、大豆ホスファチジルコリン(SPC)、水素化卵ホスファチジルコリン(HEPC)、水素化大豆ホスファチジルコリン(HSPC)、ジパルミトイルホスファチジルコリン(DPPC)、ジオレオイルホスファチジルコリン(DOPC)、ジミリストイルホスファチジルコリン(DMPC)、ジステアロイルホスファチジルコリン(DSPC)、パルミトイルステアロイルホスファチジルコリン(PSPC)、及びこれらの混合物、から成る群より選択される、請求項1乃至8のいずれか一つに記載の調合物。
- 前記ステロールがコレステロールである、請求項1乃至9のいずれか一つに記載の調合物。
- 前記リポソームが、DPPC及びコレステロールを含み、DPPC対コレステロールのモル比が19:1、9:1、4:1、13:7又は1:1である、請求項10に記載の調合物。
- 前記患者が嚢胞性線維症患者である、請求項1乃至11のいずれか一つに記載の調合物。
- 肺感染症を治療又は改善する医薬の製造におけるリポソーム性アミノグリコシド調合物の使用であって、前記リポソーム性アミノグリコシド調合物は患者への肺内投与用であり、アミノグリコシドおよびリポソームを含み、前記リポソームがホスファチジルコリン及びステロールを含み、そしてホスファチジルコリン及びステロールのアミノグリコシドに対する重量比が2.5:1未満である、使用。
- 前記調合物が、請求項2乃至12のいずれか一つに記載された調合物である、請求項13に記載の使用。
- 前記感染症がミコバクテリア感染症である、請求項1、4乃至6および8−12のいずれかに記載の調合物。
- 前記シュードモナスが、P.アエルギノーサ、P.パウシモビリス、P.プチーダ、P.フルオレセンスまたはP.アシドヴォランスである、請求項7に記載の調合物。
- 前記連鎖球菌が、ストレプトコッカス・ニューモニエである、請求項7に記載の調合物。
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