JP4886233B2 - Method for solubilizing ebselen - Google Patents
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- JP4886233B2 JP4886233B2 JP2005211810A JP2005211810A JP4886233B2 JP 4886233 B2 JP4886233 B2 JP 4886233B2 JP 2005211810 A JP2005211810 A JP 2005211810A JP 2005211810 A JP2005211810 A JP 2005211810A JP 4886233 B2 JP4886233 B2 JP 4886233B2
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Description
本発明は、エブセレンの可溶化方法に関する。 The present invention relates to a method for solubilizing ebselen.
下記の構造式で示されるエブセレン（Ｅｂｓｅｌｅｎ：２−ｐｈｅｎｙｌ−１，２−ｂｅｎｚｏｉｓｏｓｅｌｅｎａｚｏｌ−３−（２Ｈ）−ｏｎｅ）は、抗酸化作用を有するセレニウム有機化合物として公知の薬物である。その主な薬理作用は、グルタチオン・ペルオキシダーゼ様作用およびチオレドキシン・レダクターゼの基質になることによる酸化物質消去作用である。さらに、エブセレンには、スーパーオキサイド・活性酸素消去作用、リポキシゲナーゼ阻害作用（抗ロイコトリエン作用）、ペルオキシナイトライト還元作用（ＮＯ拮抗作用）などがあることも知られている。エブセレンは、細胞内のチオール基との反応性により、細胞内ミトコンドリアに分布し、細胞内酸化還元調節作用などを発現する唯一の薬物とされている。 Ebselen (Ebselen: 2-phenyl-1,2-benzoisoselenazol-3- (2H) -one) represented by the following structural formula is a known drug as a selenium organic compound having an antioxidant action. Its main pharmacological action is glutathione peroxidase-like action and oxidant scavenging action by becoming a substrate for thioredoxin reductase. Further, ebselen is also known to have a superoxide / active oxygen scavenging action, a lipoxygenase inhibitory action (anti-leukotriene action), a peroxynitrite reducing action (NO antagonism), and the like. Ebselen is considered to be the only drug that is distributed in intracellular mitochondria due to its reactivity with intracellular thiol groups and expresses intracellular redox regulation and the like.
エブセレンは、上記のように他の薬物にはない極めて特異的な薬理作用を有することから、脳梗塞急性期の治療薬、抗炎症剤、免疫抑制剤といったような医薬品としての幅広い利用価値が期待される。しかしながら、エブセレンは、水に不溶で、アルコールに難溶であり、極性溶媒に対する溶解性が極めて悪く、液状製剤化が困難であるという物理化学的特性を有する。 Since ebselen has a very specific pharmacological action not found in other drugs as described above, it is expected to have a wide range of utility values as a pharmaceutical agent such as a therapeutic agent for acute cerebral infarction, an anti-inflammatory agent, and an immunosuppressive agent. Is done. However, ebselen has physicochemical properties that it is insoluble in water, hardly soluble in alcohol, has extremely poor solubility in polar solvents, and is difficult to form into a liquid formulation.
そこで、エブセレンを液状製剤化する方法として、例えば、特許文献１ではエブセレンのエマルション製剤が、特許文献２ではエブセレンのシクロデキストリン製剤が提案されている。
しかしながら、上記の方法では、製剤が高分子量となることに加え、エブセレンとエマルジョンを構成する油脂やシクロデキストリンとの相互作用が強固であるため、エブセレンが円滑に担体から遊離して細胞内に移行しにくいという欠点があった。
そこで本発明は、エブセレンを高分子量な担体を用いることなく簡易に液状製剤化することが可能となる可溶化方法を提供することを目的とする。
However, in the above method, in addition to the high molecular weight of the preparation, the interaction between ebselen and the fats and oils that make up the emulsion is strong, so that ebselen can be smoothly released from the carrier and transferred into the cell. There was a drawback that it was difficult to do.
Therefore, an object of the present invention is to provide a solubilization method that makes it possible to easily form ebselen into a liquid formulation without using a high molecular weight carrier.
本発明者らは、上記の点に鑑みて鋭意研究を重ねた結果、エブセレンとＮ−アセチルシステインを反応させると、両者は高収率で１：１の化学量論的に複合体を形成すること、得られる複合体は、エブセレンのアルコールへの溶解性を向上させ、中でもエタノールに対して極めて高い溶解性を示すことを見出した。 As a result of intensive studies in view of the above points, the present inventors have reacted ebselen and N-acetylcysteine to form a 1: 1 stoichiometric complex in high yield. In addition, it has been found that the resulting composite improves the solubility of ebselen in alcohol and exhibits extremely high solubility in ethanol.
上記の知見に基づいてなされた本発明は、請求項１記載の通り、エブセレンとＮ−アセチルシステインとの複合体である。
また、本発明は、請求項２記載の通り、エブセレンをＮ−アセチルシステインと複合体を形成させることで、エブセレンのアルコールへの溶解性を向上させる方法である。
また、請求項３記載の方法は、請求項２記載の方法において、アルコールがエタノールであるものである。
The present invention made based on the above findings is a complex of ebselen and N-acetylcysteine as described in
Moreover, this invention is the method of improving the solubility to the alcohol of ebselen by forming a complex with N-acetylcysteine as described in
The method according to
本発明によれば、エブセレンを高分子量な担体を用いることなく簡易に液状製剤化することが可能となる可溶化方法を提供することができる。 According to the present invention, it is possible to provide a solubilization method that makes it possible to easily prepare ebselen in a liquid formulation without using a high molecular weight carrier.
本発明のエブセレンとＮ−アセチルシステインとの複合体は、例えば、エブセレンのエタノール溶液乃至懸濁液とＮ−アセチルシステインのエタノール溶液とを混合し、室温で１時間〜１０日攪拌した後、反応溶液（エブセレンはＮ−アセチルシステインと複合体を形成することでエタノールに溶解する）を酢酸エチルに添加し、エブセレンとＮ−アセチルシステインとの複合体を沈殿物として析出させてこれを遠心分離によって回収することで得ることができる。エブセレンとＮ−アセチルシステインとの混合モル比は、例えば、１：１〜１．５とすればよい。なお、エブセレンは自体公知の方法によって合成したものを用いればよい（必要であれば特公平６−２５０５９号公報を参照のこと）。 The complex of ebselen and N-acetylcysteine of the present invention is prepared by, for example, mixing an ethanol solution or suspension of ebselen with an ethanol solution of N-acetylcysteine and stirring at room temperature for 1 hour to 10 days. A solution (ebselen dissolves in ethanol by forming a complex with N-acetylcysteine) is added to ethyl acetate, and a complex of ebselen and N-acetylcysteine is precipitated as a precipitate, which is centrifuged. It can be obtained by collecting. The mixing molar ratio of ebselen and N-acetylcysteine may be, for example, 1: 1 to 1.5. Note that ebselen synthesized by a method known per se may be used (see Japanese Patent Publication No. 6-25059 if necessary).
本発明のエブセレンとＮ−アセチルシステインとの複合体は、エブセレンのアルコールへの溶解性を向上させ、中でもエタノールに対して極めて高い溶解性を示すことから、注射剤などの液状製剤を容易に調製することが可能となる。従って、脳梗塞急性期の治療薬、抗炎症剤、免疫抑制剤といったようなエブセレンの医薬品としての利用価値を高め、実用化を容易なものとする。 The complex of ebselen and N-acetylcysteine of the present invention improves the solubility of ebselen in alcohol, and in particular, exhibits extremely high solubility in ethanol, so liquid preparations such as injections can be easily prepared. It becomes possible to do. Therefore, the useful value of ebselen as a pharmaceutical agent such as a therapeutic agent, an anti-inflammatory agent, an immunosuppressive agent for acute cerebral infarction is increased, and the practical application becomes easy.
以下、本発明を実施例によって詳細に説明するが、本発明は以下の記載によって何ら限定して解釈されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited at all by the following description.
エブセレンの７％エタノール溶液乃至懸濁液２ｍＬ（０．５ｍｍｏｌ）にＮ−アセチルシステインの１６％エタノール溶液０．５ｍＬ（０．５ｍｍｏｌ）をゆっくりと滴下し、室温にて２４時間攪拌した。得られた反応溶液を大過剰の酢酸エチルに添加し、析出した沈殿物を遠心分離によって回収した。得られた沈殿物を酢酸エチルで洗浄し、２４時間減圧乾燥することで、目的物であるエブセレンとＮ−アセチルシステインとの複合体を淡黄色粉末として得た（収量０．２０ｇ）。1Ｈ−ＮＭＲ（日本電子社製ＡＬ−３００，３００ＭＨｚ，ＤＭＳＯ−ｄ６）とＨＰＬＣ（水−アセトニトリル）の結果から、エブセレンとＮ−アセチルシステインは、９０％以上の高収率で複合体を形成することがわかった。また、ＵＶ測定と質量分析の結果から、両者は１：１の化学量論的に複合体を形成することがわかった。1Ｈ−ＮＭＲとＨＰＬＣの結果をそれぞれ図１と図２に示す（図中、ＮＡＣはＮ−アセチルシステインを意味する）。 0.5 mL (0.5 mmol) of a 16% ethanol solution of N-acetylcysteine was slowly added dropwise to 2 mL (0.5 mmol) of a 7% ethanol solution or suspension of ebselen and stirred at room temperature for 24 hours. The obtained reaction solution was added to a large excess of ethyl acetate, and the deposited precipitate was collected by centrifugation. The obtained precipitate was washed with ethyl acetate and dried under reduced pressure for 24 hours to obtain a complex of ebselen and N-acetylcysteine, which was the target product, as a pale yellow powder (yield 0.20 g). From the results of 1 H-NMR (manufactured by JEOL Ltd. AL-300, 300 MHz, DMSO-d6) and HPLC (water-acetonitrile), ebselen and N-acetylcysteine form a complex with a high yield of 90% or more. I found out that Moreover, it was found from the results of UV measurement and mass spectrometry that both form a complex with a stoichiometric ratio of 1: 1. The results of 1 H-NMR and HPLC are shown in FIGS. 1 and 2, respectively (in the figure, NAC means N-acetylcysteine).
エブセレンとＮ−アセチルシステインとの複合体の、水、メタノール、エタノール、イソプロピルアルコールに対する溶解性（１００ｇの溶媒に対する溶解量：単位ｇ）を表１に示す。表１から明らかなように、エブセレンとＮ−アセチルシステインとの複合体は、エブセレンのアルコールへの溶解性を向上させ、中でもエタノールに対して極めて高い溶解性（エブセレンの溶解性の約１００倍）を示すことがわかった。また、エブセレンとＮ−アセチルシステインとの複合体の、酢酸エチル、１，４−ジオキサン、アセトンに対する溶解性（同上）を表１にあわせて示す。表１から明らかなように、エブセレンとＮ−アセチルシステインとの複合体は、エブセレンのこれらの極性溶媒への溶解性を向上させることもわかった。 Table 1 shows the solubility of ebselen and N-acetylcysteine complex in water, methanol, ethanol, and isopropyl alcohol (dissolution amount in 100 g of solvent: unit g). As is apparent from Table 1, the complex of ebselen and N-acetylcysteine improves the solubility of ebselen in alcohol, and extremely high solubility in ethanol (about 100 times the solubility of ebselen). It was found that Table 1 also shows the solubility of ebselen and N-acetylcysteine complex in ethyl acetate, 1,4-dioxane and acetone (same as above). As is apparent from Table 1, it was also found that the complex of ebselen and N-acetylcysteine improves the solubility of ebselen in these polar solvents.
本発明は、エブセレンを高分子量な担体を用いることなく簡易に液状製剤化することが可能となる可溶化方法を提供することができる点において産業上の利用可能性を有する。 INDUSTRIAL APPLICABILITY The present invention has industrial applicability in that it can provide a solubilization method that makes it possible to easily prepare ebselen in a liquid formulation without using a high molecular weight carrier.
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