JP5769693B2 - (r)−n−メチルナルトレキソン、その合成方法およびその医薬用途 - Google Patents
(r)−n−メチルナルトレキソン、その合成方法およびその医薬用途 Download PDFInfo
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Description
本発明は、(R)−N−メチルナルトレキソン(R−MNTX)およびその中間体の立体選択的合成、R−MNTXまたはその中間体を含む医薬製剤およびそれらの使用方法に関する。
メチルナルトレキソン(MNTX)は、純粋なオピオイドアンタゴニストであるナルトレキソンの第四級誘導体である。これは塩として存在する。文献に置いてMNTXの臭化物塩に使用される名称としては、以下が挙げられる:臭化メチルナルトレキソン;臭化N−メチルナルトレキソン;ナルトレキソンメトブロミド;ナルトレキソンメチルブロミド;MRZ 2663BR、MNTXは、70年代半ばにGoldbergらによって特許文献1に記載されるように報告された。環の窒素へのメチル基の添加が、ナルトレキソンよりも大きな極性および低い脂溶性を有する荷電化合物を形成すると考えられる。MNTXのこの特徴は、ヒトにおいて血液脳関門の通過を防ぐ。結果として、MNTXは、中枢神経系よりもむしろ末梢においてこの効果を発揮し、中枢神経系におけるオピオイドの鎮痛作用を妨げないという利点を伴う。
S−MNTXは今や高純度で製造され、このことにより、クロマトグラフィーにおけるその相対保持時間をR−MNTXのそれに対して特徴付けることが可能となる。S−MNTXが文献において報告されたMNTXの活性とは異なる活性を有することが見出された。これは、R−MNTXの製造方法および高純度への精製方法への必要性を浮かび上がらせた。
(a)R−MNTXを含む第1組成物を得ること、(b)第1組成物をクロマトグラフィー、再結晶またはこれらの組合せにより精製すること、(c)精製した第1組成物のサンプルについて、S−MNTXを標準物質として使用してHPLCを行うこと、ならびに(d)サンプル中のS−MNTXの有無を決定すること。重要な態様において、R−MNTXおよびS−MNTXの両方を標準物質として使用し、例えばR−MNTXおよびS−MNTXの相対保持時間を測定する。一態様において、精製は、多重再結晶工程または多重クロマトグラフィー工程である。別の態様において、HPLCで測定されるものとしてS−MNTXがサンプル中に存在しなくなるまで精製を行う。しかし当然のことながら、本発明のいくつかの側面において、精製した第1組成物が、必ずしも検出可能なS−MNTXを含まないわけではない。かかるS−MNTXの存在は、例えば、より純粋なR−MNTXを望む場合は、さらなる精製工程を行うべきであることを示し得る。この方法は、HPLCによって検出可能なS−MNTXの存在しない精製した第1組成物を梱包することをさらに含んでもよい。この方法は、梱包された精製した第1組成物にHPLCによって検出可能なS−MNTXが存在しないことを示す証印を、精製した第1組成物上に、またはその中に提供することを、さらに含むことが出来る。本明細書に記載された状態のいずれかを処置するために、医薬的有効量を梱包することをさらに含んでも良い。R−およびS−MNTXを含む第1組成物を、本明細書中に記載した方法によって得ることができる。
一態様において、この方法は、梱包された精製した第1組成物の上、またはその中に、梱包した第1精製組成物におけるS−MNTXのレベルを示す証印を提供する。
本発明は、R−MNTX、(モルヒナニウム、17R、17−(シクロプロピルメチル)−4,5−エポキシ−3,14−ジヒドロキシ−17−メチル−6−オキソ−、塩、(5α)−(9Cl))の立体選択的合成のための合成経路、実質的に純粋なR−MNTX、実質的に純粋なR−MNTXの結晶、実質的に純粋なR−MNTXを含む医薬製剤、およびこれらの使用方法を提供する。
(a)3−O−保護−R−MNTX塩を得るための、メチル化剤での3−O−保護ナルトレキソンのメチル化;および
(b)R−MNTXを得るための、3−ヒドロキシル保護基を除去するための加水分解
を含む、R−MNTXの立体選択的合成方法を提供する。3−O−保護−R−MNTX塩の好ましいヒドロキシル保護基は、イソブチリル、2−メチルブチリル、tertブチルカルボニル、シリルエーテル類、2−テトラヒドロピラニルエーテル類、および炭酸アルキル類を含む。
R−およびS−MNTXのHPLC分析
HPLC分析を、以下の方法を用いた、Varian Starソフトウェアによって制御されるVarian ProStar HPLCで行った:
カラム: Luna C18(2)、150×4.6mm、5μ
流速: 1mL/分
検出: UV@230nm
移動相B=0.1%メタノールTFA
TFA=トリフルオロ酢酸
クロマトグラフィーの条件およびパラメーター:分析カラムの説明:Phenomenex Inertsil ODS-3 150×4.6mm、5μm;カラム温度:50.0℃;流速:1.5mL/分;注入量:20μL;検出波長:280nm;移動層:A=水:MeOH:TFA(95:5:0.1%;v/v/v)、B=水:MeOH:TFA(35:65:0.1%;v/v/v);分析時間:50分
定量限界:0.05%
検出限界0.02%
移動相B(水:MeOH:TFA::35:65:0.1%,v/v/v)
MeOH=メタノールTFA=トリフルオロ酢酸
R−MNTXの立体選択的合成
実施例2の合成スキームを図6に示す。
一般:全ての無水反応を炉乾(130℃)ガラス製品において、乾燥窒素(N2)の雰囲気下で行った。全ての市販の試薬および溶媒は、さらなる精製なしに使用した。核磁気共鳴(NMR)スペクトルを、Varian GeminiまたはVarian Mercury 300 MHzスペクトロメータのいずれかを用いて得た。質量スペクトルは、Finnigan LCQで測定した。HPLC純度は、Waters 717 AutosamplerおよびWaters 996 Photodiode Array Detectorを用いて測定した。
ジクロロメタン/メタノール98:2(300ml)
ジクロロメタン/メタノール97:3(300ml)
ジクロロメタン/メタノール94:6(200ml)
ジクロロメタン/メタノール92:8(400ml)
分画をTLC[ジクロロメタン/メタノール9:1(v/v),順相シリカ,UV検出]で分析した。主成分のみを含んでいる分画(Rf=0.4)を混ぜ合わせてメタノールで共にリンスし、濃縮し、867mgの白色固体を得た。これは3−O−イソブチリル−ナルトレキソンに基づいて91%の収率を表す。1H NMRは一貫している。
R−MNTXの立体選択的合成
実施例3に関する合成スキームを図7に示す。実施例3において、保護基に関してGoldbergらの教示した方法に従った。Goldbergらの好ましい保護基であるアセチルを、イソブチリルの代わりに保護基として用いた。反応は実施例2に記載した通りに行った。驚くべきことに、図7に示したスキームを用いて、2(O−アセチル−ナルトレキソン)の生成の間にアセチル保護基が落ちる傾向があることを見出した。これは純粋な中間体2を得ることを困難にする。アセチル基を用いての中間体2の収率は、たったの36.3%であり、図7に示したスキームを商業的スケールアップに不適切にした。対照的に、イソブチリルを保護基として用いると(図6)、中間体2(3−O−イソブチリル−ナルトレキソン)は精製の間かなり安定し、76.8%の収率をもたらした。
R−MNTXの医薬処方物の製造方法
製造方法を以下のように要約できる:
1.必要な量の注射のための水をステンレス製タンクに加える(〜80%または最終容量)。
2.タンクにキレート剤を加え、溶解するまで撹拌する。
3.タンクに緩衝剤を加え、溶解するまで撹拌する。
4.タンクにR−MNTXを加え、溶解するまで撹拌する。
5.タンクに等張剤を加え、溶解するまで撹拌する。
6.溶液のpHをpH3.25に調製する。
7.注射用蒸留水を加えて、必要な量まで容積を増加させる。
8.材料を供給圧力容器に移動する。
9.滅菌ステンレス製圧力容器へ無菌濾過する。
10.ボトル/バイアルへ充填し、窒素でパージし、そしてボトル/バイアルに栓をする。
11.充填したバイアルを高圧蒸気殺菌法で殺菌する。
使用する賦形剤の厳密な量
エデト酸2ナトリウム=0.75mg/ml 工程2で加える。
クエン酸ナトリウム=0.199mg/ml 工程3で加える。
クエン酸=0.35mg/ml 工程3で加える。
塩化ナトリウム=8.5mg/ml 工程5で加える。
賦形剤の添加の順序を上に記載する。工程2〜5はいかなる順序で行ってもよい。
全ての賦形剤および薬物を加えたとき、工程6、溶液のpHを酸の添加によって調整する。緩衝剤を溶液において用いる場合、pH調整は必須でなくてもよい。
処方の間、温度または撹拌速度に細目はない。処方の間の温度は80℃までの高さであり得る。
R−MNTXの医薬処方物の好ましい製造方法
R−MNTX溶液の100mlの20mg/ml溶液の好ましい製造方法は以下の通りである:
1.注射のための80mlの水をステンレス製タンクに加える(〜80%または最終容量)。
2.タンクに75mgのエデト酸2ナトリウム、キレート剤、を加え、溶解するまで撹拌する。
3.タンクに19.9mgのクエン酸ナトリウムおよび35mgのクエン酸を(緩衝剤として)加え、溶解するまで撹拌する。
4.タンクに2000mgのR−MNTXを加え、溶解するまで撹拌する。
5.タンクに850mgの塩化ナトリウム、等張剤、を加え、溶解するまで撹拌する。
6.必要であれば溶液のpHを調製する。
7.注射用蒸留水を加えて、100mlまで容積を増加させる。
8.材料を供給圧力容器に移動する。
9.0.22ミクロンフィルターを用いて滅菌ステンレス製圧力容器へ無菌濾過する。
10.充填し、窒素でパージし、そしてボトル/バイアルに栓をする。
11.充填したバイアルを高圧蒸気殺菌法で殺菌する。
R−MNTXの皮下処方物の調製
低クエン酸塩/EDTA処方物のための処方を以下に示す:
成分 mg/mL
R−MNTX 30mg
塩化ナトリウム 4mg
クエン酸 0.0875mg
クエン酸三ナトリウム 0.0496mg
エデト酸2ナトリウム 0.75mg
注射用水 1gまで適量
この溶液のpHは3.5であり、高圧蒸気殺菌工程に耐えることができる。
R−MNTXの凍結乾燥医薬処方物の製造方法
凍結乾燥サイクルをR−MNTXの凍結乾燥製剤の調製のために用いた。40ミリグラムのR−MNTXを、32mgの凍結防止剤、マンニトールと混合し、注射用水を用いて、1mlまで十分量にする。
1.室温(20〜25℃)でチャンバーに入れる。
2.棚温度を、−45℃まで、1.0℃/分で下げる。
3.棚温度を−45に120分保つ。
4.冷却器が−50℃より低い場合、チャンバーを100〜125mtまで真空にする。
5.棚を−20℃まで、0.5℃/分で一定の比率で上昇(ramp)させる。
6.−20℃に16時間保つ。
7.棚を+27℃まで、0.1℃/分で一定の比率で上昇させる。
8.最低8時間保持する。チャンバーの圧力を全サイクルにわたって100〜125mtに保持する。
9.無菌濾過した窒素を用いて、チャンバーを11.0PSIA+または−1.0に戻し、そして閉鎖物を設置し(2”Hg)、そして取り外すためにN2で大気圧まで流出させる。凍結乾燥および再構成後の溶液のpHは5.0である。
Claims (31)
- X−が、ハロゲン化物イオン、硫酸イオン、リン酸イオン、硝酸イオンおよび有機アニオン荷電種からなる群から選択されるものである、請求項1に記載の3−O−保護−R−MNTX塩。
- ハロゲン化物イオンが、臭化物イオン、ヨウ化物イオン、塩化物イオンまたはフッ化物イオンである、請求項2に記載の3−O−保護−R−MNTX塩。
- 有機アニオン荷電種がスルホン酸イオンまたはカルボン酸イオンである、請求項2に記載の3−O−保護−R−MNTX塩。
- スルホン酸イオンが、メシレートイオン、ベシレートイオン、トシレートイオンまたはトリフレートイオンである、請求項4に記載の3−O−保護−R−MNTX塩。
- カルボン酸イオンが、ギ酸イオン、酢酸イオン、クエン酸イオンまたはフマル酸イオンである、請求項4に記載の3−O−保護−R−MNTX塩。
- 請求項1〜6のいずれかに記載の単離3−O−保護−R−MNTX塩を含む組成物。
- 請求項1〜6のいずれかに記載の3−O−保護−R−MNTX塩および医薬的に許容される担体を含む、医薬組成物。
- 持続放出性処方物、凍結乾燥処方物もしくは溶液であるか、または経口投与のために腸溶性にコーティングされたものである、請求項8に記載の医薬組成物。
- アルフェンタニル、アニレリジン、アシマドリン、ブレマゾシン、ブプレノルフィン、ブトルファノール、コデイン、デゾシン、ジアセチルモルフィン(ヘロイン)、ジヒドロコデイン、ジフェニルオキシレート、フェドトジン、フェンタニル、フナルトレキサミン、ヒドロコドン、ヒドロモルホン、レバロルファン、レボメタジルアセテート、レボルファノール、ロペラミド、メペリジン(ペチジン)、メタドン、モルフィン、モルフィン6−グルコロニド、ナルブフィン、ナロルフィン、オピウム、オキシコドン、オキシモルホン、ペンタゾシン、プロピラム、プロポキシフェン、レミフェンタニル、スフェンタニル、チリジン、トリメブチン、トラマドールおよびこれらの組合せからなる群から選択されるオピオイドを更に含む、請求項8または9に記載の医薬組成物。
- 抗ウイルス剤、抗感染症剤、抗癌剤、鎮痙剤、抗ムスカリン剤、抗炎症剤、運動亢進剤、5HT1アゴニスト、5HT3アンタゴニスト、5HT4アンタゴニスト、5HT4アゴニスト、胆汁酸塩捕捉剤、バルク形成剤、アルファ2−アドレナリン作動性アゴニスト、ミネラルオイル、抗うつ剤、生薬、制吐剤、止痢剤、緩下剤、便軟化剤、繊維および造血促進剤からなる群から選択される、オピオイドまたはオピオイドアンタゴニストでない少なくとも1つの医薬剤を更に含む、請求項8または9に記載の医薬組成物。
- 抗炎症剤が、非ステロイド抗炎症薬(NSAIDS)、腫瘍壊死因子阻害薬、バシリキシマブ、ダクリズマブ、インフリキシマブ、ミコフェノール酸、モフェチル、アザチオプリン、タクロリムス、ステロイド類、スルファサラジン、オルサラジン、メサラミンおよびこれらの組合せからなる群から選択される、請求項11に記載の組成物。
- 患者におけるオピオイド誘導性の副作用を処置または予防するための、請求項8に記載の医薬組成物。
- 患者が、オピオイドを急性的または慢性的に受けている、請求項13に記載の医薬組成物。
- オピオイド誘導性の副作用が内因性オピオイド誘導性である、請求項13に記載の医薬組成物。
- 副作用が、便秘、免疫抑制、胃腸運動の阻害、胃内容排出の阻害、吐き気、嘔吐、不完全排便、膨満、腹部膨満,胃食道逆流増加、低血圧、徐脈、胃腸機能障害、掻痒、不快、および尿閉からなる群から選択される、請求項13、14または15に記載の医薬組成物。
- 特発性便秘、過敏性腸症候群および術後腸機能障害からなるから選択される疾患を処置または予防するための、請求項8に記載の医薬組成物。
- 術後腸機能障害が、遅発性胃内容排出、または胃腸運動の阻害である、請求項17に記載の医薬組成物。
- 便通を誘発するため、請求項8に記載の医薬組成物。
- 請求項8に記載の医薬組成物を含む、患者管理注射デバイス。
- 請求項8に記載の医薬組成物および使用説明書を含む密封容器を含むパッケージを含むキット。
- 請求項8に記載の医薬組成物、および該組成物におけるS−MNTXのレベルを表す該パッケージ上のまたは該パッケージ内に含まれる証印を含む、パッケージ。
- 経口投与用である、請求項13に記載の医薬組成物。
- 非経口投与用である、請求項13に記載の医薬組成物。
- 皮下投与用である、請求項13に記載の医薬組成物。
- 静脈内投与用である、請求項13に記載の医薬組成物。
- 請求項9に記載の医薬組成物であって、40mg/mlの濃度で水中で再構成された凍結乾燥処方物が、pH2〜6を有する、前記組成物。
- 凍結乾燥処方物が、凍結防止剤を更に含む、請求項9に記載の医薬組成物。
- 凍結防止剤がポリオールである、請求項28に記載の医薬組成物。
- 凍結防止剤がマンニトールである、請求項28に記載の医薬組成物。
- 請求項9に記載の医薬組成物であって、30mg/mlの濃度で水中で再構成された凍結乾燥処方物が、pH2〜6を有する、前記組成物。
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