JP2016528218A - 低水溶性薬剤の低融解イオン性塩の組成物および調製方法 - Google Patents
低水溶性薬剤の低融解イオン性塩の組成物および調製方法 Download PDFInfo
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Abstract
Description
低融解イオン性塩は、適切な薬剤および対イオンを用いることにより、方法#1〜5として以下に記載の例示的な適用と同様の方法に従って、またはその方法により、調製し得る。
方法#1
・有機溶剤中にわずかに可溶性である対イオンに関して開発。
・薬剤:有機溶剤(例えばクロロホルム)中に可溶性である薬剤に適用可能、例えば、シンナリジン・HClおよびハロファントリン・HCl。
シンナリジン(5.83g、15.83mmol)をジエチルエーテル(300mL)中に溶解させ、HCl溶液(ジエチルエーテル中2M、7.92ml、15.83mmol)を、シリンジを介して滴下して添加した。オフホワイトの沈殿物が直ちに形成された。吸引濾過を介して生じた沈殿物を回収し、ジエチルエーテルで洗浄し、真空下で乾燥させた。生じたシンナリジン・HCl塩(6.35g、15.68mmol)をCHCl3(500mL)中に溶解させ、デシル硫酸アンモニウム塩(4.01g、15.68mmol)を添加した。得られた懸濁液を2日間還流した。反応混合物を室温まで冷却し、陰性のAgNO3試験が得られるまで蒸留水(4×300mL)で洗浄した。それから、有機相を乾燥させ(無水MgSO4)、フィルター濾過し、そして蒸発させて所望の産物(油)を得て、60℃にて高真空下で乾燥させた。収率96%。
・水溶性(またはわずかに有機可溶性)の対イオンに関して開発。
・利点:方法#1と比較して、より短い反応時間、室温で反応が進行する。
・特に、水溶性対イオン、例えば、デシル硫酸アンモニウム、ドデシル硫酸ナトリウム、オクタデシル硫酸アンモニウム塩に使用。
・薬剤:有機溶剤(例えばジクロロメタン、クロロホルム)中に可溶性である薬剤に適用可能、例えば、シンナリジン・HClおよびハロファントリン・HCl。
・水に不溶性の対イオンに関して開発。高い水感受性を有する化合物にも有用。
・水に不溶性だがメタノールに可溶性である対イオン、例えば、オレエートナトリウムおよびジオクチルスルホスクシネートナトリウムのために、特に有用な方法。
・薬剤:シンナリジン・HCl、ハロファントリン・HClおよびイトラコナゾール・HClなどの薬剤に適用可能。
シンナリジンデシルサルフェート
HRMS +ve mode: calcd. for C35H39Cl2N8O4 + 705.2471 found 705.2443. HRMS -ve mode: calcd. for C10H17O4S- 233.0848 found 233.0852.
方法#2を用いて、デキストロメトルファンドデシルサルフェートを製造した。
・酸性薬剤に関して開発。
・特に、アルキルピリジニウム塩および四級アンモニウム塩のような水溶性の対イオンに使用。
・薬剤:イブプロフェン、ジクロフェナク、メクロフェナムおよびトルフェナム酸のような、酸性薬剤に適用可能。
・酸性薬剤を用いたメタセシス反応は、アルカリ塩(例えば炭酸ナトリウム、炭酸水素ナトリウムなど)の添加によって塩基性条件下で理想的に行なわなければならない。
・酸性薬剤を用いたメタセシス反応は、高脂溶性の対イオン(水に不溶性)を用いる場合、水およびメタノール中で理想的に行なわなければならない。
・酸性薬剤を用いたメタセシス反応は、酸性薬剤塩の代わりに遊離酸を出発原料として用いる場合、強塩基(NaOH、KOHなど)を添加することによって理想的に行なわなければならない。
例示の適用:イブプロフェンオクチルアンモニウム塩:
表1〜10は、さまざまな低融解イオン性塩に関する融点抑制データを要約する。低融解イオン性塩の形成に起因して可能な、溶解度における可能性のある利点の示度を提供するために、例示の脂質製剤も製造し、その製剤における最大の薬剤溶解度を測定した。脂質系製剤を用いた場合、製剤は、適切な量の賦形剤を直接バイアル中に計量した後に混ぜ合わせることにより、ガラスバイアル中に作った。
LC2SEDDS:30% w/w SBO、30% w/w Maisine、30% CrEL w/w、10% w/w EtOH
MCSEDDS:15% w/w Captex 355、15% w/w Capmul MCM、60% w/w CrEL、10% w/w EtOH。
シンナリジン遊離塩基(FB)およびデシルサルフェートイオン性液体(IL)の様々な製剤を、表2−1に従って調製した。遊離塩基として、脂質ビヒクルにおけるシンナリジンの溶解度は、およそ44mg/gである。製剤は、脂質ビヒクル中に薬剤を100%のそれらの溶解度で負荷することは稀であり、保管温度が変動する場合などは、これは製剤からの薬剤沈殿の危険性を与えるので、典型的に、薬剤は、約80%の飽和で負荷し得る。この場合、これは約35mg/gの最大負荷を定める。対照的に、シンナリジンのデシルサルフェートILは、製剤と本質的に混和性であり、ほとんど任意の薬剤負荷で負荷することができた。この例では、薬剤は、FBを用いて達成され得るものに匹敵するように35mg/gで、および、ILを用いて達成可能なより高レベルの例として約125mg/gでの、いずれかで負荷した。また、コントロール製剤は、シンナリジンデシルサルフェートILの水性懸濁液として125mg/gで、および、SEDDS製剤中のFBの懸濁液として125mg/gで製造した。
#15% w/w 大豆油、15% w/w Maisine 35−1、60% w/w Cremophor EL、10% w/w EtOH。界面活性剤および共溶剤とともに極性および非極性脂質の組み合わせを用いて、消化管における構成要素の分散を助ける。
全ての場合において、SEDDS製剤は、15%(w/w)の大豆油、15%(w/w)のMaisine 35−1TM、60%(w/w)のCremophor ELおよび10%(w/w)のエタノールから構成された。
製剤(4g)を、以下を含んで調製した:
製剤(4g)を、以下を含んで調製した:
シンナリジンに関して出されたものと同様のデータが、イトラコナゾール遊離塩基の水性懸濁液(ITZ FB)、SEDDS製剤中のイトラコナゾール(itraconzole)遊離塩基の懸濁液(LC2SEDDS:30% w/w SBO、30% w/w Maisine、30% CrEL w/w、10% w/w EtOH)、同じSEDDS製剤中のイトラコナゾールドキュセートIL(ITZ IL)の溶液、および、ITZの市販の噴霧乾燥された分散製剤(Sporanox)に関して得られた。ITZ遊離塩基の非常に低い溶解度が、脂質系製剤としての製剤化を妨げることに注意が必要である。脂質製剤におけるITZ ILの溶解度はさらにいっそうより高いので、この可能性が認識されるのは、ILとしての分離を介してのみである。全て、同一の投与量(20mg/kg)で投薬した。製剤の詳細を表5−1に示す。
Claims (31)
- 低水溶性薬剤の脂質製剤であって、
前記低水溶性薬剤の低融解イオン性塩を、実質的に非水性の脂質ビヒクルとともに含む、
脂質製剤。 - 請求項1に記載の脂質製剤であって、
前記低融解イオン性塩は、前記低水溶性薬剤のイオン性液体塩である、
脂質製剤。 - 請求項2に記載の脂質製剤であって、
前記イオン性液体塩は、約90℃またはそれ未満の融点を有する、
脂質製剤。 - 請求項2に記載の脂質製剤であって、
前記イオン性液体塩は、約70℃またはそれ未満の融点を有する、
脂質製剤。 - 請求項2に記載の脂質製剤であって、
前記イオン性液体塩は、約50℃またはそれ未満の融点を有する、
脂質製剤。 - 請求項2に記載の脂質製剤であって、
前記イオン性液体塩は、約40℃またはそれ未満の融点を有する、
脂質製剤。 - 請求項2に記載の脂質製剤であって、
前記イオン性液体塩は、約30℃またはそれ未満の融点を有する、
脂質製剤。 - 請求項2に記載の脂質製剤であって、
前記イオン性液体塩は、約25℃またはそれ未満の融点を有する、
脂質製剤。 - 請求項2に記載の脂質製剤であって、
前記イオン性液体塩は、室温で油である、
脂質製剤。 - 請求項1から9のいずれか一項に記載の脂質製剤であって、
前記低水溶性薬剤の前記低融解イオン性塩は、イオン化されていない薬剤の少なくとも2倍、前記の非水性の脂質ビヒクル中に可溶性である、
脂質製剤。 - 請求項10に記載の脂質製剤であって、
前記低水溶性薬剤の前記低融解イオン性塩は、イオン化されていない薬剤の少なくとも4〜5倍、前記の非水性の脂質ビヒクル中に可溶性である、
脂質製剤。 - 請求項1から11のいずれか一項に記載の脂質製剤であって、
前記低水溶性薬剤は、前記低融解イオン性塩のカチオンを形成し、少なくとも1つの塩基性のイオン化可能な窒素原子を含む、
脂質製剤。 - 請求項12に記載の脂質製剤であって、
前記低水溶性薬剤は、カルボン酸(RC(O)O−)、ホスフェート(ROP(O)O− 2)、ホスホネート(RP(O)O− 2)、スルホネート(RS(O)2O−)、サルフェート(ROS(O)2O−)、テトラゾリル(R−テトラゾレート)またはビス(スルホニル)イミド(RSO2−N−−SO2R)から形成されるアニオンと、低融解イオン性塩を形成し、
ここで、Rは、少なくとも2個の炭素原子を有する、場合により置換された炭化水素基である、
脂質製剤。 - 請求項13に記載の脂質製剤であって、
前記低水溶性薬剤は、ホスフェート(ROP(O)O2 −)、または、サルフェート(ROS(O)2O−)から形成されるアニオンと、低融解イオン性塩を形成する、
脂質製剤。 - 請求項12または13に記載の脂質製剤であって、
Rは、場合により置換され、アルキル、アルケニルまたはアルキニル(alkynl)基(それぞれ4〜40個の炭素原子を有する)、および、シクロアルキルまたは不飽和環状炭化水素基(それぞれ3〜10個の炭素原子を有する)からなる群から選択される、
脂質製剤。 - 請求項15に記載の脂質製剤であって、
Rは、4〜24個の炭素原子を有する、場合により置換されたアルキル基である、
脂質製剤。 - 請求項1から11のいずれか一項に記載の脂質製剤であって、
前記低水溶性薬剤は、前記低融解イオン性塩の前記アニオンを形成し、少なくとも1つの酸性基を含む、
脂質製剤。 - 請求項17に記載の脂質製剤であって、
前記低水溶性薬剤は、+NR’4および+PR’4から選択されるカチオンと、低融解イオン性塩を形成し、
ここで、R’は、それぞれ独立に、水素およびR”から選択され、
ここで、R”は、アルキル、アルケニルまたはアルキニル(alkynl)基(それぞれ4〜40個の炭素原子を有する)、および、シクロアルキルまたは不飽和環状炭化水素基(それぞれ3〜10個の炭素原子を有する)の群から選択される、
脂質製剤。 - 請求項1から18のいずれか一項の脂質製剤であって、
前記の実質的に非水性の脂質ビヒクルは、少なくとも1つの油または脂質を含む、
脂質製剤。 - 請求項1から18のいずれか一項の脂質製剤であって、
前記の実質的に非水性の脂質ビヒクルは、少なくとも1つの油または脂質から本質的になる、
脂質製剤。 - 請求項19の脂質製剤であって、
前記の実質的に非水性の脂質ビヒクルは、少なくとも1つの油または脂質、および、少なくとも1つの界面活性剤を含む、
脂質製剤。 - 請求項20の脂質製剤であって、
前記の実質的に非水性の脂質ビヒクルは、少なくとも1つの油または脂質、少なくとも1つの界面活性剤、および、少なくとも1つの共溶剤を含む、
脂質製剤。 - 請求項1から18のいずれか一項の脂質製剤であって、
前記の実質的に非水性の脂質ビヒクルは、少なくとも1つの界面活性剤、および、場合により少なくとも1つの共溶剤を含む、
脂質製剤。 - 請求項1から18のいずれか一項の脂質製剤であって、
前記の実質的に非水性の脂質ビヒクルは、少なくとも1つの界面活性剤および/または溶剤から本質的になり、場合により、1つまたは複数の共界面活性剤または共乳化剤を有する、
脂質製剤。 - 請求項1から18のいずれか一項の脂質製剤であって、
1つまたは複数の油および/または液体をともに、前記低水溶性薬剤のイオン性液体塩から本質的になる、
脂質製剤。 - 請求項1から18のいずれか一項の脂質製剤であって、
1つまたは複数の界面活性剤および/または溶剤をともに、前記低水溶性薬剤のイオン性液体塩から本質的になり、場合により、1つまたは複数の共界面活性剤または共乳化剤を含む、
脂質製剤。 - 請求項1から26のいずれか一項の脂質製剤であって、
単一相の形態である、
脂質製剤。 - 脂質製剤請求項1から27のいずれか一項に記載の脂質製剤の使用であって、
カプセルの充填としての、
使用。 - 請求項1から27のいずれか一項に記載の脂質製剤を含む、
カプセル、小袋、シリンジまたはドロッパ装置、アンプル、チューブまたはボトル。 - 請求項1から16のいずれか一項に記載の低水溶性薬剤の脂質製剤を製造する方法であって、
前記方法は、前記低水溶性薬剤の低融解イオン性塩を、非水性の脂質ビヒクルと混合するステップを含む、
方法。 - 請求項30の方法であって、
生じる脂質製剤が、単一相の液体、固体または半固体である、
脂質製剤。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007046544A1 (ja) * | 2005-10-21 | 2007-04-26 | Medrx Co., Ltd. | カルボキシル基を有する肥満細胞脱顆粒抑制剤と有機アミンとの塩を含有する外用剤 |
WO2008093686A1 (ja) * | 2007-01-29 | 2008-08-07 | Medrx Co., Ltd. | 非ステロイド系抗炎症薬と有機アミン化合物との塩とその用途 |
JP2009511497A (ja) * | 2005-10-07 | 2009-03-19 | ザ ユニバーシティ オブ アラバマ | 多機能イオン性液体組成物 |
WO2010111397A1 (en) * | 2009-03-24 | 2010-09-30 | Adds Pharmaceuticals Llc | Stabilized solubility-enhanced formulations for oral delivery |
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WO2010143199A1 (en) * | 2009-06-11 | 2010-12-16 | Suven Nishtaa Pharma Private Limited | Solid lipid dispersion for aqueous solubility enhancement of poorly water soluble drugs |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009511497A (ja) * | 2005-10-07 | 2009-03-19 | ザ ユニバーシティ オブ アラバマ | 多機能イオン性液体組成物 |
WO2007046544A1 (ja) * | 2005-10-21 | 2007-04-26 | Medrx Co., Ltd. | カルボキシル基を有する肥満細胞脱顆粒抑制剤と有機アミンとの塩を含有する外用剤 |
WO2008093686A1 (ja) * | 2007-01-29 | 2008-08-07 | Medrx Co., Ltd. | 非ステロイド系抗炎症薬と有機アミン化合物との塩とその用途 |
WO2010111397A1 (en) * | 2009-03-24 | 2010-09-30 | Adds Pharmaceuticals Llc | Stabilized solubility-enhanced formulations for oral delivery |
Non-Patent Citations (2)
Title |
---|
ORAL FORMULATIONS FOR POORLY WATER SOLUBLE COMPOUNDS, JPN6018003958, 2009, ISSN: 0003952234 * |
PHARMACIE GLOBALE(IJCP), vol. Vol.02,Issue 09,08, JPN6018003956, 2011, pages 1 - 6, ISSN: 0003952233 * |
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EP3027216A1 (en) | 2016-06-08 |
WO2015013772A1 (en) | 2015-02-05 |
JP6666840B2 (ja) | 2020-03-18 |
CA2914841A1 (en) | 2015-02-05 |
US20160151503A1 (en) | 2016-06-02 |
JP6852204B2 (ja) | 2021-03-31 |
CA2914841C (en) | 2021-11-02 |
JP2020105183A (ja) | 2020-07-09 |
EP3027216A4 (en) | 2017-03-01 |
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