JP5258583B2 - 放射性画像診断剤の製造方法 - Google Patents
放射性画像診断剤の製造方法 Download PDFInfo
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- JP5258583B2 JP5258583B2 JP2008558082A JP2008558082A JP5258583B2 JP 5258583 B2 JP5258583 B2 JP 5258583B2 JP 2008558082 A JP2008558082 A JP 2008558082A JP 2008558082 A JP2008558082 A JP 2008558082A JP 5258583 B2 JP5258583 B2 JP 5258583B2
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
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Description
一般的な医薬品の場合、その有効成分の最大一日投与量が1mg以下と微量な場合であって、製剤中の分解物が1.0%を超えるものについては、該分解物の構造決定を行うべきことが、ICHのガイドラインで推奨されている(非特許文献1)。しかし、製剤中の配合量そのものが少ない放射性医薬品では、製剤中の分解物が1.0%を超える場合であっても、製剤中における放射線分解による不純物は、その物理量が10−12mol程度と非常に少ない場合が多い。そのため、該分解物の構造を推定すること、並びに該分解物が腫瘍集積等の製剤の有効性に影響するかどうかの検証を行うことは一般的には極めて困難である。
また、特に放射性画像診断剤において、分解により生じた不純物が放射性化合物であった場合には、その生成量が少量であっても、得られる画像に大きな影響を与える場合がある。このことからも、放射性画像診断剤における不純物は、できるだけ少なくする必要があり、その生成原因となる放射線分解についてもできるだけ抑制することが好ましい。
国際公開第03/090789号パンフレットには、[18F]FDG溶液に弱酸ベースの緩衝液を添加することにより、[18F]FDGの放射線分解を抑制する方法及び該方法により調製された注射剤が開示されている(特許文献1)。また、国際公開04/043497号パンフレットには、[18F]FDG溶液にエタノールを添加することにより、[18F]FDGの放射線分解を抑制し、安定性を向上させ得る注射剤組成が開示されている(特許文献2)。
また、特開平10−147542号公報には、生理的認容性の高い有機化合物を、放射性医薬品における放射線防護剤として利用する技術について開示されている。しかし、[18F]FACBCをはじめとする放射性フッ素標識された一連のアミノ酸化合物の放射線分解を防ぐために、生理的認容性の高い有機化合物としてどのような化合物を選択すべきか、あるいはどの程度加えればいいかなどといった技術に関する開示はない。
さらに、国際公開第06/134822号パンフレットには、種々の糖または糖アルコールを放射性画像診断剤に配合させることにより、放射線分解を抑制する技術が開示されている。しかし、この公報においても、[18F]FACBCをはじめとする放射性フッ素標識された一連のアミノ酸化合物の放射線分解を効果的に抑制するための条件についての開示はない。
しかしながら、糖ラクトンは、その分子内に環状エステルを有する化合物であるため、放射性画像診断剤のように注射液として用いる場合、その加水分解が起こる。この問題は糖ラクトンにおいては回避し得ない。また、糖ラクトンの一つであるアスコルビン酸などは、その分子内に二重結合を有し還元作用を発揮しうる化合物であり、溶存酸素などにより容易に酸化されてしまう。このことから、その使用に当っては、酸素を出来るだけ排除する必要があり、取扱操作が煩雑になるといった問題がある。
さらに発明者らは、放射線分解を抑制する医薬品添加物を添加することにより、重畳的に放射線分解を抑制することが可能となることをも見出した。
これらの知見に基づき、製造工程中であって濃度調整前の[18F]FACBC溶液に一定量の酸及び所望により医薬品添加物を添加することにより、製造工程中及び製剤調製後における放射性分解を抑制し得ることを見出し、本発明を完成させた。
本発明において、前記希釈工程は、例えば、前記放射性フッ素標識有機化合物を含有した液に、水、生理食塩液、又はリンゲル液を加えることで行うことができる。
[18F]フッ化物イオン含有H2 18O(放射能量138〜158GBq、製造開始時、詳細は表1参照)を、陰イオン交換カラムに通液し、[18F]フッ化物イオンを、吸着捕集した。次いで、該カラムを水で洗浄した後、定法(例えば、文献(Radioisotopes,50,(2001),p205−227,Radioisotopes,50,(2001),p.228−556「PET用放射性薬剤の製造および品質管理−合成と臨床使用へのてびき−(第2版)」、PET化学ワークショップ編)記載の方法)に従って、[18F]フッ化物イオンと炭酸カリウム水溶液と相間移動触媒とを含む混合溶液を得た。
結果を、表4に示す。表4に示すように、マンニトールを10mmol/Lの割合で含有した最終製剤に対して塩酸を0.40〜2.8mmol/L相当添加した試料(実施例1〜7)は、pHが2.8〜5.9であり、放射線分解抑制効果を有するpHの範囲内に入っていた。
以上の結果より、マンニトールを10mmol/Lの割合で含有した最終製剤に対して塩酸を0.40〜2.8mmol/L相当添加することにより、放射線分解抑制効果を有するpHで、最終製剤を調製し得る事が示された。
実施例1と同様の方法にて、[18F]FACBC原液を調製し、室温下で72時間以上放置して、放射能を減衰させた。
この液をそれぞれ1.0mL(実施例8〜9)、1.5mL(実施例10〜12)、2.5mL(比較例1)ずつ分注し、それぞれに、表5記載の濃度でマンニトールを含有したマンニトール含有塩酸を表5記載の量添加し、混合した。
[18F]フッ化物イオン含有H2 18Oを、陰イオン交換カラムに通液し、[18F]フッ化物イオンを、吸着捕集した。次いで、該カラムを水で洗浄した後、定法(例えば、文献(Radioisotopes, 50, (2001), p.205−227、Radioisotopes, 50, (2001), p.228−256、「PET用放射性薬剤の製造および品質管理−合成と臨床使用へのてびき−(第2版)」、PET化学ワークショップ編)記載の方法)に従って、[18F]フッ化物イオンと炭酸カリウム水溶液と相間移動触媒とを含む混合溶液を得た。
展開溶媒:アセトニトリル/水/100%酢酸=4/1/1
TLCプレート:Silica Gel 60F254(商品名、膜厚:0.25mm、メルク社製)
展開長: 10cm
TLCスキャナー: Rita Star(Raytest社製)
分析回数:3回
一方、pH6.28以上では、pHの増加とともに急激な放射化学的純度の低下が起こっていた。近似直線の傾きを計算すると、−1.000であった。この値は、pH2.00から4.88の場合の約6.7倍であり、pH5.03から5.94の場合の約100倍であった。
これらのことから、pH6.28以上では、pH2.00から5.94の場合と比較して、急激に放射化学的純度の低下が起こることが示された。
[18F]フッ化物イオン含有H2 18Oを用い、参考例1と同様の方法でanti−[18F]−FACBC原液を調製した。その後、調製したanti−[18F]−FACBC原液に、設定した実験開始時間(表11における0時間)において、放射能濃度が約500MBq/mL、pHが約4.8となるよう塩酸および生理食塩液を添加した。得られた溶液を、容量5mLのバイアルに2.23mLずつに分注し、表10に記載した濃度のマンニトール溶液又は塩酸を、表10記載の量添加し、試料溶液とした。調製直後の試料溶液の放射能濃度は、553〜565MBq/mLであった。
加えて、pH4.78においてよりも、pH3.44においての方が、いずれのマンニトール濃度においても放射化学的純度の低下が抑えられていた。
以上の結果より、放射化学的安定性に溶液のpHが寄与していることが確認された。加えて、マンニトールを添加することにより、重畳的に放射線分解を抑制し得ることが示された。
Claims (4)
- 前記希釈工程が、前記放射性フッ素標識有機化合物を含有した溶液に、水、生理食塩液、またはリンゲル液を加えるものである、請求項1に記載の方法。
- 前記酸添加工程において、さらに糖又は糖アルコールを、希釈工程後の液中における濃度が0.5mmol/L以上となるように添加し、
および/または、
前記希釈工程において、希釈に用いる液に加えて、さらに糖又は糖アルコールを、希釈工程後の液中における濃度が0.5mmol/L以上となるように添加する、請求項1又は2に記載の方法。 - 前記酸添加工程または前記希釈工程において添加する糖アルコールが、エリスリトール、キシリトール、ソルビトール又はマンニトールである、請求項3に記載の方法。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11534494B2 (en) | 2011-12-21 | 2022-12-27 | Ge Healthcare Limited | Formulation and method of synthesis |
US10023525B2 (en) | 2012-08-09 | 2018-07-17 | Ge Healthcare Limited | Preparation of 18F-fluciclovine |
US11077216B2 (en) | 2014-06-30 | 2021-08-03 | Ge Healthcare Limited | Formulation and method of synthesis |
Also Published As
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EP2119458A1 (en) | 2009-11-18 |
US20100119448A1 (en) | 2010-05-13 |
CA2678020C (en) | 2015-03-24 |
KR101485445B1 (ko) | 2015-01-22 |
EP2119458A4 (en) | 2010-03-24 |
TWI406674B (zh) | 2013-09-01 |
WO2008099800A1 (ja) | 2008-08-21 |
US8658132B2 (en) | 2014-02-25 |
HK1138504A1 (en) | 2010-08-27 |
EP2119458B1 (en) | 2013-05-15 |
US8343459B2 (en) | 2013-01-01 |
CA2678020A1 (en) | 2008-08-21 |
CN101636183B (zh) | 2014-03-19 |
KR20090111331A (ko) | 2009-10-26 |
JPWO2008099800A1 (ja) | 2010-05-27 |
EP2119458B9 (en) | 2013-08-21 |
CN101636183A (zh) | 2010-01-27 |
US20120301399A1 (en) | 2012-11-29 |
TW200833362A (en) | 2008-08-16 |
ES2421886T3 (es) | 2013-09-06 |
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