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JP5089004B2 - ボリコナゾールを含有する薬剤製剤 - Google Patents

ボリコナゾールを含有する薬剤製剤 Download PDF

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JP5089004B2
JP5089004B2 JP2002088076A JP2002088076A JP5089004B2 JP 5089004 B2 JP5089004 B2 JP 5089004B2 JP 2002088076 A JP2002088076 A JP 2002088076A JP 2002088076 A JP2002088076 A JP 2002088076A JP 5089004 B2 JP5089004 B2 JP 5089004B2
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voriconazole
cyclodextrin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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Description

【０００１】
【発明の属する技術分野】
本発明は、スルホブチルエーテルβ−シクロデキストリンを含む新規なボリコナゾール薬剤製剤に関する。
【０００２】
【従来の技術】
ボナコナゾールはヨーロッパ特許出願第０４４０３７２号に開示されている(実施例７参照）。これは下記構造を有し；
【０００３】
【化２】
Figure 0005089004
真菌感染症の治療に有用である。ボリコナゾールは低い水溶性（０．２ｍｇ／ｍｌ＠ｐＨ３）を有し、水中で不安定である（加水分解のレトロ−アルドール生成物の組換えから不活性エナンチオマーが形成される）。したがって、充分な貯蔵寿命を有する静脈内注射製剤の開発は困難である。これらの問題は、この化合物が例えば油、界面活性剤又は水混和性補溶媒のような慣用的手段によって一般に可溶化されないことを意味する半極性(ｌｏｇＤ＝１．８)であることによって拡大される。
【０００４】
ヨーロッパ特許出願第０４４０３７２号は、これに開示される化合物がシクロデキストリンによって製剤化されうるが；この場合に、誘導体化されない又は代謝されないシクロデキストリンが身体に対して有害な影響を及ぼすので、シクロデキストリンが特に非経口的投与されるときに薬剤賦形剤として不適切であると述べている。
【０００５】
国際特許出願ＷＯ９１／１１１７２は、式Ａのスルホアルキルエーテルシクロデキストリン誘導体を開示している：
【０００６】
【化３】
Figure 0005089004
式中、
ｎは４、５、又は６であり；
Ｒ1〜9は独立的にＯ-又はＯ−（Ｃ2−Ｃ6アルキレン）−ＳＯ-を表す、但し、Ｒ1とＲ2の少なくとも一方はＯ−（Ｃ2−Ｃ6アルキレン）−ＳＯ-である；
Ｓ1〜9は独立的に製薬的に受容されるカチオン（例えば、Ｈ+又はＮａ+）を表す。
【０００７】
【発明が解決しようとする課題および課題解決手段】
国際特許出願ＷＯ９１／１１１７２に開示されている種類のスルホアルキルエーテルシクロデキストリン誘導体による分子カプセル封入によって、特にｎが５（β−シクロデキストリン誘導体）であり、そのシクロデキストリン環がスルホブチル基によって置換されている場合に、水中のボリコナゾール溶解性が上昇されうることが、今回判明した。
【０００８】
したがって、本発明によると、ボリコナゾール又はその製薬的に受容される誘導体と、式１：
【０００９】
【化４】
Figure 0005089004
［式中、Ｒ1a-g、Ｒ2a-g、及びＲ3a-gは独立的にＯＨ又はＯ（ＣＨ2）4ＳＯ3Ｈを表す；但し、Ｒ1a-gの少なくとも１つはＯ（ＣＨ2）4ＳＯ3Ｈを表す］
で示されるシクロデキストリン誘導体又はその製薬的に受容される塩とを含む
薬剤製剤を提供する。
【００１０】
特に重要な製薬的に受容される塩はＯ（ＣＨ2）4ＳＯ3Ｈ基の塩、例えばナトリウム塩のようなアルカリ金属塩である。
好ましくは、式Ｉの分子当りのＯ（ＣＨ2）4ＳＯ3Ｈ基の平均数は６．１〜６．９の範囲内であり、例えば６．５である。このことは分子カプセル封入を強化して、ボリコナゾールの強化された溶解性を生じる。置換度を高めることはシクロデキストリンのキャビティの周囲の立体障害を高め、錯体形成効率を減ずると考えられるので、この効果は予期されなかった。
【００１１】
存在する各Ｏ（ＣＨ2）4ＳＯ3Ｈがアルカリ金属塩（例えばナトリウム塩）の形状であることが好ましい。このことはボリコナゾールに対するアフィニティを高めるが、この効果は、ボリコナゾールが荷電されていないので、予測できない。
【００１２】
好ましくは、この製剤は非経口投与用、例えばｉ．ｖ．投与用である。
ボリコナゾール−シクロデキストリン誘導体錯体の水性安定性は凍結乾燥によってさらに強化される。本発明に用いられるシクロデキストリン誘導体は、完成した凍結乾燥製品が安定性に不利な影響を与えずに高レベルの水分（３．０％まで）を受容することを可能にする。さらに、このようなシクロデキストリン誘導体の使用はボリコナゾールの不活性なエナンチオマーの形成を制御し、最少にする。
【００１３】
一般に、本発明による静脈内及び筋肉内水性製剤では、ボリコナゾールは５ｍｇ／ｍｌ〜５０ｍｇ／ｍｌ、例えば１０ｍｇ／ｍｌ〜３０ｍｇ／ｍｌの濃度で存在する。式Ｉのシクロデキストリン誘導体は１：１から１：１０まで、例えば１：２〜１：７、特に１：２〜１：３のボリコナゾール：シクロデキストリン誘導体のモル比率で存在する。製剤は使用前の貯蔵のために凍結乾燥（フリードライイング）することができ、必要時に水によって構成することができる。
【００１４】
次の実施例では、スルホブチルエーテルβ−シクロデキストリンはシクロデキストリン分子当り６．５の平均スルホブチルエーテル置換度を有し、各スルホブチルエーテル単位はそのナトリウム塩として存在する。
【００１５】
【実施例】
実施例１ ボリコナゾールのｉ．ｖ．製剤
【００１６】
【表１】
Figure 0005089004
方法
１．絶えず撹拌しながら、注射用水の最終量の８０％にスルホブチルエーテルβ−シクロデキストリン（ＳＢＥＣＤ）を加えて、ＳＢＥＣＤの全てが溶解するまで撹拌を続ける。
２．ボリコナゾールを加えて、撹拌しながら溶解させる。
３．注射用水によって溶液を全体量にする。
４．得られた溶液を滅菌０．２ｍｍナイロンフィルターに通して濾過して、滅菌容器に入れる。
５．２０ｍｌ量を滅菌フリーズドライイング・バイアルに入れて、栓をする。凍結乾燥する。

Claims (1)

  1. ボリコナゾールと、式I；
    Figure 0005089004
    ［式中、Ｒ1a-g、Ｒ2a-g、及びＲ3a-gは独立的にＯＨ又はＯ（ＣＨ2）4ＳＯ3Ｈを表す；
    但し、Ｒ1a-gの少なくとも１つはＯ（ＣＨ2）4ＳＯ3Ｈを表す］で示されるシクロデキストリン誘導体のナトリウム塩［存在する各Ｏ（ＣＨ 2 ） 4 ＳＯ 3 Ｈがナトリウム塩である］とを含む薬剤製剤であって、
    当該式Ｉのシクロデキストリン誘導体の分子当りのＯ（ＣＨ 2 ） 4 ＳＯ 3 Ｈ基の平均数は６．１〜６．９の範囲内であり、
    当該式Ｉのシクロデキストリン誘導体が１：１から１：１０までのボリコナゾール：シクロデキストリン誘導体のモル比率で存在し、および、
    当該製剤は凍結乾燥されている、
    当該製剤。
JP2002088076A 1997-06-21 2002-03-27 ボリコナゾールを含有する薬剤製剤 Expired - Lifetime JP5089004B2 (ja)

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