JP2018080118A - Injury therapeutic agent - Google Patents
Injury therapeutic agent Download PDFInfo
- Publication number
- JP2018080118A JP2018080118A JP2016221422A JP2016221422A JP2018080118A JP 2018080118 A JP2018080118 A JP 2018080118A JP 2016221422 A JP2016221422 A JP 2016221422A JP 2016221422 A JP2016221422 A JP 2016221422A JP 2018080118 A JP2018080118 A JP 2018080118A
- Authority
- JP
- Japan
- Prior art keywords
- group
- phosphatidic acid
- injury
- therapeutic agent
- damage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
Description
本発明は、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸を有効成分とする損傷治療剤に関する。 The present invention relates to a therapeutic agent for injury comprising cyclic phosphatidic acid, carbacyclic phosphatidic acid or thiacyclic phosphatidic acid as an active ingredient.
1992年に、真性粘菌Physarum polycephalumの単相体ミクソアメーバから、真核細胞のDNA複製酵素であるDNAポリメラーゼαの活性を抑え、動物培養細胞の増殖を抑制する脂溶性物質が見いだされ、単離・精製された(非特許文献1))。この物質はグリセロール骨格のsn-1位にシクロプロパンを含むヘキサデカン酸が結合し、2位と3位にリン酸が環状エステル結合した物質であることがわかり、Physarum由来のLPA様物質であることから、PHYLPAと命名された。PHYLPAがsn-1位に特徴的な脂肪酸を有することから、一般的な脂肪酸に置換した誘導体を化学合成し、その活性を検討した結果、細胞増殖を抑制することが示され、PHYLPAの増殖抑制作用が、2位と3位の環状リン酸基によることが明らかになった。現在では、このような環状リン酸基を持つLPA類似体を総称して、環状ホスファチジン酸(cPA、cyclic phosphatidic acid)と呼んでいる。 In 1992, a monophasic myxomycoba of the true slime mold Physarum polycephalum was found to be a fat-soluble substance that suppresses the activity of DNA polymerase α, a DNA replication enzyme of eukaryotic cells, and suppresses the growth of cultured animal cells. Separated and purified (Non-patent Document 1)). This substance is an LPA-like substance derived from Physarum, which is found to be a substance in which hexadecanoic acid containing cyclopropane is bonded to the sn-1 position of the glycerol skeleton and phosphoric acid is bonded to the 2nd and 3rd positions by a cyclic ester bond. And was named PHYLPA. Since PHYLPA has a characteristic fatty acid at the sn-1 position, chemical synthesis of a derivative substituted with a general fatty acid and investigation of its activity showed that it suppresses cell growth and suppresses PHYLPA growth. It was revealed that the action was due to the cyclic phosphate groups at the 2nd and 3rd positions. At present, LPA analogs having such a cyclic phosphate group are collectively called cyclic phosphatidic acid (cPA).
環状ホスファチジン酸及びその誘導体については、神経栄養因子作用と神経変性疾患への適用(特許文献1及び2)、癌細胞の増殖と浸潤・転移の抑制(特許文献3)、鎮痛作用(特許文献4)、並びにアトピー性皮膚炎への適用(特許文献5)、脱髄疾患への適用(特許文献6及び非特許文献2)についての報告があるが、損傷治療に及ぼす影響についての知見はない。 Regarding cyclic phosphatidic acid and its derivatives, neurotrophic factor action and application to neurodegenerative diseases (Patent Documents 1 and 2), suppression of proliferation and invasion / metastasis of cancer cells (Patent Document 3), analgesic action (Patent Document 4) ) As well as application to atopic dermatitis (Patent Document 5) and application to demyelinating disease (Patent Document 6 and Non-Patent Document 2), but there is no knowledge about the effect on damage treatment.
外傷性損傷などの損傷からの血液成分の漏出を抑制する作用を有する薬剤を見出すことができれば、新規な損傷治療剤を開発することが可能である。特に、外傷性脳損傷は修復機構が十分に明らかになっておらず、外傷性脳損傷の治療剤は見つかっていない。本発明は、損傷からの血液成分の漏出を抑制する作用を有する新規な損傷治療剤を提供することを解決すべき課題とする。 If a drug having an action of suppressing the leakage of blood components from damage such as traumatic injury can be found, a novel therapeutic agent for damage can be developed. In particular, the repair mechanism of traumatic brain injury has not been fully clarified, and no therapeutic agent for traumatic brain injury has been found. An object of the present invention is to provide a novel therapeutic agent for damage that has an action of suppressing leakage of blood components from damage.
本発明者らは、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸及びその誘導体が、損傷からの血液成分の漏出を抑制する作用を有することを見いだし、本発明を完成するに至った。 The present inventors have found that cyclic phosphatidic acid, carbacyclic phosphatidic acid or thiacyclic phosphatidic acid and derivatives thereof have an action of suppressing leakage of blood components from damage, and have completed the present invention.
すなわち、本発明によれば、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩を含有する、損傷治療剤が提供される。
好ましくは、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸は、式(1)で示される化合物である。
Preferably, the cyclic phosphatidic acid, the carbacyclic phosphatidic acid or the thiacyclic phosphatidic acid is a compound represented by the formula (1).
好ましくは、式(1)において、X及びYの一方が−CH2−であり、X及びYの他方が−O−である。
好ましくは、損傷が外傷性損傷である。
好ましくは、損傷が、外傷性脳損傷である。
好ましくは、本発明の損傷治療剤は、止血作用を有する止血剤として使用される。
Preferably, in Formula (1), one of X and Y is —CH 2 —, and the other of X and Y is —O—.
Preferably, the injury is a traumatic injury.
Preferably, the injury is traumatic brain injury.
Preferably, the therapeutic agent for injury of the present invention is used as a hemostatic agent having a hemostatic action.
本発明によれば、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩を、損傷を有する患者に投与することを含む、損傷を治療する方法が提供される。 According to the present invention, there is provided a method of treating an injury comprising administering a cyclic phosphatidic acid, a carbacyclic phosphatidic acid or a thiacyclic phosphatidic acid or a salt thereof to a patient having an injury.
本発明によればさらに、損傷治療剤の製造のための、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩の使用が提供される。
本発明によればさらに、損傷の治療において使用するための、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩が提供される。
The present invention further provides the use of cyclic phosphatidic acid, carbacyclic phosphatidic acid or thiacyclic phosphatidic acid or a salt thereof for the manufacture of a therapeutic agent for injury.
The present invention further provides cyclic phosphatidic acid, carbacyclic phosphatidic acid or thiacyclic phosphatidic acid or salts thereof for use in the treatment of damage.
本発明によれば、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸を有効成分として含有することを特徴とする損傷治療剤を提供できる。 ADVANTAGE OF THE INVENTION According to this invention, the damage therapeutic agent characterized by containing cyclic phosphatidic acid, carbacyclic phosphatidic acid, or thiacyclic phosphatidic acid as an active ingredient can be provided.
以下、本発明について更に具体的に説明する。
本発明は、環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩を有効成分として含有する、損傷治療剤に関する。本発明の損傷治療剤は、損傷を治療するために使用することができ、環状ホスファチジン酸カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸、あるいはその塩を有効成分として含む。環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸としては本発明の効果を示すものであれば特に限定されないが、好ましくは、下記式(I)で示される環状ホスファチジン酸を使用することができる。
Hereinafter, the present invention will be described more specifically.
The present invention relates to a therapeutic agent for injury containing cyclic phosphatidic acid, carbacyclic phosphatidic acid, thiacyclic phosphatidic acid or a salt thereof as an active ingredient. The injury therapeutic agent of the present invention can be used to treat injury, and contains cyclic phosphatidic acid carbacyclic phosphatidic acid or thiacyclic phosphatidic acid, or a salt thereof as an active ingredient. The cyclic phosphatidic acid, the carbacyclic phosphatidic acid, or the thiacyclic phosphatidic acid is not particularly limited as long as it exhibits the effects of the present invention. Preferably, a cyclic phosphatidic acid represented by the following formula (I) can be used. .
(式中、Rは、炭素数1〜30の直鎖状若しくは分岐状アルキル基、炭素数2〜30の直鎖状若しくは分岐状アルケニル基、又は炭素数2〜30の直鎖状若しくは分岐状アルキニル基であり、これらの基はシクロアルカン環又は芳香環を含んでいてもよい。X及びYはそれぞれ独立に、−O−、−S−又は−CH2−を示すが、X及びYが同時に−CH2−になることはない。Mは、水素原子又は対カチオンである。) (In the formula, R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms. An alkynyl group, which may contain a cycloalkane ring or an aromatic ring, wherein X and Y each independently represent —O—, —S— or —CH 2 —, at the same time -CH 2 - not to become that .M represents a hydrogen atom or a counter cation).
式(I)において、置換基Rが示す炭素数1〜30の直鎖状若しくは分岐状アルキル基の具体例としては、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基、トリデシル基、テトラデシル基、ペンタデシル基、ヘキサデシル基、ヘプタデシル基、オクタデシル基、ノナデシル基、エイコシル基などが挙げられる。 In the formula (I), specific examples of the linear or branched alkyl group having 1 to 30 carbon atoms represented by the substituent R include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. , Heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and the like.
置換基Rが示す炭素数2〜30の直鎖状若しくは分岐状アルケニル基の具体例としては、例えば、アリル基、ブテニル基、オクテニル基、デセニル基、ドデカジエニル基、ヘキサデカトリエニル基などが挙げられ、より具体的には、8−デセニル基、8−ウンデセニル基、8−ドデセニル基、8−トリデセニル基、8−テトラデセニル基、8−ペンタデセニル基、8−ヘキサデセニル基、8−ヘプタデセニル基、8−オクタデセニル基、8−イコセニル基、8−ドコセニル基、ヘプタデカ−8,11−ジエニル基、ヘプタデカ−8,11,14−トリエニル基、ノナデカ−4,7,10,13−テトラエニル基、ノナデカ−4,7,10,13,16−ペンタエニル基、ヘニコサ−3,6,9,12,15,18−ヘキサエニル基などが挙げられる。 Specific examples of the linear or branched alkenyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, an allyl group, a butenyl group, an octenyl group, a decenyl group, a dodecadienyl group, a hexadecatrienyl group, and the like. More specifically, 8-decenyl group, 8-undecenyl group, 8-dodecenyl group, 8-tridecenyl group, 8-tetradecenyl group, 8-pentadecenyl group, 8-hexadecenyl group, 8-heptadecenyl group, 8- Octadecenyl group, 8-icosenyl group, 8-docosenyl group, heptadec-8,11-dienyl group, heptadec-8,11,14-trienyl group, nonadeca-4,7,10,13-tetraenyl group, nonadeca-4, 7,10,13,16-pentaenyl group, henicosa-3,6,9,12,15,18-hexaenyl group, etc. It is.
置換基Rが示す炭素数2〜30の直鎖状若しくは分岐状アルキニル基の具体例としては、例えば、8−デシニル基、8−ウンデシニル基、8−ドデシニル基、8−トリデシニル基、8−テトラデシニル基、8−ペンタデシニル基、8−ヘキサデシニル基、8−ヘプタデシニル基、8−オクタデシニル基、8−イコシニル基、8−ドコシニル基、ヘプタデカ−8,11−ジイニル基などが挙げられる。 Specific examples of the linear or branched alkynyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, 8-decynyl group, 8-undecynyl group, 8-dodecynyl group, 8-tridecynyl group, and 8-tetradecynyl group. Group, 8-pentadecynyl group, 8-hexadecynyl group, 8-heptadecynyl group, 8-octadecynyl group, 8-icosinyl group, 8-docosinyl group, heptadec-8,11-diynyl group and the like.
上記のアルキル基、アルケニル基又はアルキニル基に含有されうるシクロアルカン環の具体例としては、例えば、シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、シクロオクタン環などが挙げられる。シクロアルカン環は、1個以上のヘテロ原子を含んでいてもよく、そのような例としては、例えば、オキシラン環、オキセタン環、テトラヒドロフラン環、N−メチルプロリジン環などが挙げられる。 Specific examples of the cycloalkane ring that can be contained in the alkyl group, alkenyl group, or alkynyl group include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and a cyclooctane ring. The cycloalkane ring may contain one or more heteroatoms, and examples thereof include an oxirane ring, an oxetane ring, a tetrahydrofuran ring, and an N-methylprolysine ring.
上記のアルキル基、アルケニル基又はアルキニル基に含有されうる芳香環の具体例としては、例えば、ベンゼン環、ナフタレン環、ピリジン環、フラン環、チオフェン環などが挙げられる。 Specific examples of the aromatic ring that can be contained in the alkyl group, alkenyl group, or alkynyl group include a benzene ring, a naphthalene ring, a pyridine ring, a furan ring, and a thiophene ring.
従って、置換基Rがシクロアルカン環によって置換されたアルキル基である場合の具体例としては、例えば、シクロプロピルメチル基、シクロヘキシルエチル基、8,9−メタノペンタデシル基などが挙げられる。 Therefore, specific examples when the substituent R is an alkyl group substituted with a cycloalkane ring include, for example, a cyclopropylmethyl group, a cyclohexylethyl group, an 8,9-methanopentadecyl group, and the like.
置換基Rが芳香環によって置換されたアルキル基である場合の具体例としては、ベンジ
ル基、フェネチル基、p−ペンチルフェニルオクチル基などが挙げられる。
Specific examples when the substituent R is an alkyl group substituted by an aromatic ring include a benzyl group, a phenethyl group, a p-pentylphenyloctyl group, and the like.
Rは、好ましくは、炭素数9〜17の直鎖状若しくは分岐状アルキル基、炭素数9〜17の直鎖状若しくは分岐状アルケニル基、又は炭素数9〜17の直鎖状若しくは分岐状アルキニル基である。Rは、さらに好ましくは、炭素数9、11、13、15又は17の直鎖状若しくは分岐状アルキル基、又は炭素数9、11、13、15又は17の直鎖状若しくは分岐状アルケニル基である。Rは、特に好ましくは、炭素数9、11、13、15又は17の直鎖状若しくは分岐状アルケニル基である。 R is preferably a linear or branched alkyl group having 9 to 17 carbon atoms, a linear or branched alkenyl group having 9 to 17 carbon atoms, or a linear or branched alkynyl group having 9 to 17 carbon atoms. It is a group. R is more preferably a linear or branched alkyl group having 9, 11, 13, 15 or 17 carbon atoms, or a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms. is there. R is particularly preferably a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms.
一般式(1)で示される化合物中のX及びYはそれぞれ独立に、−O−、−S−又は−CH2−を示すが、X及びYが同時に−CH2−になることはない。即ち、X及びYの組み合わせは以下の3通りである。
(1)Xが−O−であり、Yが−O−である。
(2)Xが−CH2−であり、Yが−O−である(2カルバcPA(2ccPAとも略記))。またはXが−S−であり、Yが−O−である。
(3)Xが−O−であり、Yが−CH2−である(3カルバcPA(3ccPAとも略記))。またはXが−O−であり、Yが−S−である。
上記の中でも、Xが−CH2−でありYが−O−である(2カルバcPA)が特に好ましい。
X and Y in the compound represented by the general formula (1) each independently represent —O—, —S— or —CH 2 —, but X and Y are not simultaneously —CH 2 —. That is, there are the following three combinations of X and Y.
(1) X is —O— and Y is —O—.
(2) X is —CH 2 — and Y is —O— (2-carba cPA (also abbreviated as 2ccPA)). Or X is -S- and Y is -O-.
(3) X is —O— and Y is —CH 2 — (3-carba cPA (also abbreviated as 3ccPA)). Or X is -O- and Y is -S-.
Among the above, (2-carba cPA) in which X is —CH 2 — and Y is —O— is particularly preferable.
式(I)で示される環状ホスファチジン酸誘導体中のMは、水素原子又は対カチオンである。Mが対カチオンである場合の例としては、例えば、アルカリ金属原子、アルカリ土類金属原子、置換若しくは無置換アンモニウム基が挙げられる。アルカリ金属原子としては、例えば、リチウム、ナトリウム、カリウムなどが挙げられ、アルカリ土類金属原子としては、例えば、マグネシウム、カルシウムなどが挙げられる。置換アンモニウム基としては、例えば、ブチルアンモニウム基、トリエチルアンモニウム基、テトラメチルアンモニウム基などが挙げられる。 M in the cyclic phosphatidic acid derivative represented by the formula (I) is a hydrogen atom or a counter cation. Examples of the case where M is a counter cation include, for example, an alkali metal atom, an alkaline earth metal atom, and a substituted or unsubstituted ammonium group. Examples of the alkali metal atom include lithium, sodium, and potassium, and examples of the alkaline earth metal atom include magnesium and calcium. Examples of the substituted ammonium group include a butyl ammonium group, a triethyl ammonium group, and a tetramethyl ammonium group.
式(I)の化合物はその置換基の種類に応じて、位置異性体、幾何異性体、互変異性体、又は光学異性体のような異性体が存在する場合があるが、全ての可能な異性体、並びに2種類以上の該異性体を任意の比率で含む混合物も本発明の範囲内のものである。 The compounds of formula (I) may have isomers such as positional isomers, geometric isomers, tautomers, or optical isomers depending on the type of substituent, but all possible Isomers and mixtures containing two or more of these isomers in any ratio are also within the scope of the present invention.
また、式(I)の化合物は、水あるいは各種溶媒との付加物(水和物又は溶媒和物)の形で存在することもあるが、これらの付加物も本発明の範囲内のものである。さらに、式(I)の化合物及びその塩の任意の結晶形も本発明の範囲内のものである。 The compound of formula (I) may exist in the form of an adduct (hydrate or solvate) with water or various solvents, and these adducts are also within the scope of the present invention. is there. Furthermore, any crystalline form of the compound of formula (I) and salts thereof is within the scope of the invention.
好ましくは、式(1)で示される化合物は、1−オレオイル環状ホスファチジン酸、又は1−パルミトオレオイル環状ホスファチジン酸である。本発明で用いられる式(1)で示される化合物の具体例としては、オレオイル2カルバcPA(△Ole-2ccPA)、パルミトオレオイル2カルバcPA(△Pal-2ccPA)などを挙げることができる。 Preferably, the compound represented by the formula (1) is 1-oleoyl cyclic phosphatidic acid or 1-palmioleoyl cyclic phosphatidic acid. Specific examples of the compound represented by the formula (1) used in the present invention include oleoyl 2-carba cPA (ΔOle-2ccPA), palmitooleoyl 2-carba cPA (ΔPal-2ccPA) and the like.
式(1)で示される化合物のうちX及びYが−O−である化合物は、例えば、Kobayashi, S., 他: Tetrahedron Lett., 34, 4047-4050 (1993)、特開平5−230088号公報、特開平7−149772号公報、特開平7−258278号公報、特開平9−25235号公報に記載の方法等に準じて化学的に合成することができる。 Among the compounds represented by the formula (1), compounds in which X and Y are —O— are, for example, Kobayashi, S., et al .: Tetrahedron Lett., 34, 4047-4050 (1993), JP-A-5-230088. It can be chemically synthesized according to the methods described in JP-A-7-149772, JP-A-7-258278, and JP-A-9-25235.
また、式(1)で示される化合物のうちX及びYが−O−である化合物は、特開2001−178489号公報に記載の方法に準じてリゾ型リン脂質にホスホリパーゼDを作用させることによって合成することもできる。ここで用いるリゾ型リン脂質は、ホスホリパーゼDを作用しうるリゾ型リン脂質であれば特に限定されない。リゾ型リン脂質は多くの種類が知られており、脂肪酸種が異なるもの、エーテル又はビニルエーテル結合をもった分子種などが知られており、これらは市販品として入手可能である。ホスホリパーゼDとしては、キャベツや落花生などの高等植物由来のものやStreptomyces chromofuscus, Actinomadula sp.などの微生物由来のものが市販試薬として入手可能であるが、Actinomadula sp. No.362由来の酵素によって極めて選択的にcPAが合成される(特開平11−367032号明細書)。リゾ型リン脂質とホスホリパーゼDとの反応は、酵素が活性を発現できる条件であれば特に限定されないが、例えば、塩化カルシウムを含有する酢酸緩衝液(pH5〜6程度)中で室温から加温下(好ましくは37℃程度)で1から5時間程度反応させることにより行う。生成したcPA誘導体は、常法に準じて、抽出、カラムクロマトグラフィー、薄層クロマトグラフィー(TLC)などにより精製することができる。 Further, among the compounds represented by the formula (1), a compound in which X and Y are —O— can be obtained by allowing phospholipase D to act on lyso-type phospholipid according to the method described in JP-A No. 2001-178489. It can also be synthesized. The lyso-type phospholipid used here is not particularly limited as long as it is a lyso-type phospholipid capable of acting on phospholipase D. Many types of lyso-type phospholipids are known, those having different fatty acid types, and molecular types having ether or vinyl ether bonds are known, and these are available as commercial products. As phospholipase D, those derived from higher plants such as cabbage and peanuts, and those derived from microorganisms such as Streptomyces chromofuscus and Actinomadula sp. Are available as commercially available reagents, but are extremely selected by the enzyme derived from Actinomadula sp. CPA is synthesized (Japanese Patent Laid-Open No. 11-367032). The reaction between lyso-type phospholipid and phospholipase D is not particularly limited as long as the enzyme can exhibit its activity. For example, it is heated from room temperature in an acetic acid buffer solution (about pH 5 to 6) containing calcium chloride. (Preferably at about 37 ° C.) for about 1 to 5 hours. The produced cPA derivative can be purified by extraction, column chromatography, thin layer chromatography (TLC) or the like according to a conventional method.
また、式(1)で示される化合物のうちX又はYが−S−である化合物は、Bioorganic & Medicinal Chemistry Letters 21 (2011) 4180-4182、又はBioorganic & Medicinal Chemistry 20 (2012) 3196-3201の記載に準じて合成することができる。 Further, among the compounds represented by the formula (1), a compound in which X or Y is —S— is represented by Bioorganic & Medicinal Chemistry Letters 21 (2011) 4180-4182 or Bioorganic & Medicinal Chemistry 20 (2012) 3196-3201. It can be synthesized according to the description.
また、式(1)で示される化合物のうちXが−CH2−であり、Yが−O−である化合物は、特開2004−010582号公報又は国際公開WO03/104246号公報に記載の方法により合成することができる。 Further, among the compounds represented by the formula (1), a compound in which X is —CH 2 — and Y is —O— is a method described in Japanese Patent Application Laid-Open No. 2004-010582 or International Publication WO 03/104246. Can be synthesized.
また、式(1)で示される化合物のうちXが−O−であり、Yが−CH2−である化合物は、文献記載の方法(Uchiyama A. et al., Biochimica et Biophysica Acta 1771 (2007) 103-112;並びに「日本薬学会 第23回 反応と合成の進歩シンポジウム1997年11月17、18日(熊本市民会館)環状ホスファチジン酸およびカルバ体誘導体の合成と生理作用、要旨集ページ101−104」)に準じて合成することができ、また国際公開WO2002/094286号公報に記載の方法により合成することができる。具体的な合成経路の一例を以下に示す。 Further, among the compounds represented by the formula (1), a compound in which X is —O— and Y is —CH 2 — can be obtained by a method described in the literature (Uchiyama A. et al., Biochimica et Biophysica Acta 1771 (2007 103-112; and “The Pharmaceutical Society of Japan 23rd Symposium on Progress in Reactions and Synthesis, November 17 and 18, 1997 (Kumamoto Civic Center) Synthesis and Physiological Actions of Cyclic Phosphatidic Acid and Carba Derivatives, Abstracts Page 101- 104 ") and can be synthesized by the method described in International Publication No. WO2002 / 094286. An example of a specific synthesis route is shown below.
上記においては、先ず、市販の(R)-ベンジルグリシジルエーテル(1)をBF3・Et2Oで活性化させ、メチルホスホン酸ジメチルエステルにn-BuLiを作用させて得られるリチオ体を反応させることでアルコール(2)を得る。
得られたアルコールを、トルエン中で過剰のp-トルエンスルホン酸のピリジニウム塩を用いて80℃で反応させることにより、環化体(3)を得る。この環化体を、水素雰囲気下で20% Pd(OH)2-Cを用いて加水素分解し、脱ベンジル化を行う(4)。縮合剤として1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩を用いて、脂肪酸と反応させてカップリング体(5)を得る。次に、求核剤としてブロモトリメチルシランを用いて、メチル基だけを位置選択的に除去し、環状ホスホン酸(6)を得る。これをエーテルを用いて分液ロートに移しこみ、少量の0.02Nの水酸化ナトリウム水溶液を滴下して、分液操作を行い、ナトリウム塩(7)として目的化合物を抽出、精製する。
In the above, first, the commercially available (R) -benzyl glycidyl ether (1) is activated with BF 3 .Et 2 O, and the thio compound obtained by reacting n-BuLi with methylphosphonic acid dimethyl ester is reacted. To obtain alcohol (2).
The obtained alcohol is reacted at 80 ° C. with an excess of pyridinium salt of p-toluenesulfonic acid in toluene to obtain a cyclized product (3). This cyclized product is subjected to hydrogenolysis using 20% Pd (OH) 2 —C under hydrogen atmosphere to perform debenzylation (4). Using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride as a condensing agent, it is reacted with a fatty acid to obtain a coupled product (5). Next, using bromotrimethylsilane as a nucleophile, only the methyl group is regioselectively removed to obtain cyclic phosphonic acid (6). This is transferred to a separatory funnel using ether, and a small amount of 0.02N aqueous sodium hydroxide solution is added dropwise to carry out a liquid separation operation to extract and purify the target compound as a sodium salt (7).
本発明において有効成分として用いる環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩は、外傷性損傷などの損傷からの血液成分の漏出を抑制する作用を有することから損傷治療剤(損傷修復剤)として使用することができる。特に、本発明において有効成分として用いる環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩は、損傷部位(傷口)において止血作用を有することにより、止血剤として使用することができる。 Cyclic phosphatidic acid, carbacyclic phosphatidic acid, thiacyclic phosphatidic acid or a salt thereof used as an active ingredient in the present invention has an action of suppressing the leakage of blood components from damage such as traumatic injury, so that it is a therapeutic agent for damage (damage It can be used as a restorative agent). In particular, cyclic phosphatidic acid, carbacyclic phosphatidic acid, thiacyclic phosphatidic acid or salts thereof used as active ingredients in the present invention can be used as a hemostatic agent by having a hemostatic action at the damaged site (wound).
本発明の損傷治療剤(損傷修復剤)の投与対象となる損傷としては、中枢神経損傷(例えば、外傷性脳損傷等の脳損傷、又は脊髄損傷)、組織損傷、臓器損傷(肝損傷、脾損傷、膵損傷、腎損傷、消化管損傷、間膜・小網・大網損傷、胸郭損傷、気管・気管支損傷、肺損傷、横隔膜損傷、心損傷、大血管損傷、骨盤損傷等)、皮膚損傷(例えば、熱傷、裂傷、創傷、穿刺又は外傷等)等が挙げられるが、これらに限定されない。本発明の損傷治療剤は、これらの中でも特に、外傷性脳損傷の治療薬として有用である。 Examples of the damage to be administered with the damage treatment agent (damage repair agent) of the present invention include central nerve damage (for example, brain damage such as traumatic brain damage or spinal cord damage), tissue damage, organ damage (liver damage, spleen). Injury, pancreatic damage, kidney damage, gastrointestinal damage, mesentery, omentum, omental damage, thorax damage, trachea / bronchial damage, lung damage, diaphragm damage, heart damage, large blood vessel damage, pelvic damage, etc.), skin damage (For example, but not limited to, burns, lacerations, wounds, punctures, or traumas). Among these, the injury therapeutic agent of the present invention is particularly useful as a therapeutic agent for traumatic brain injury.
本発明の損傷治療剤は、1又は2以上の製剤学的に許容される製剤用添加物と有効成分である環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸(好ましくは、式(1)で示される化合物)あるいはその塩とを含む医薬組成物の形態で提供することが好ましい。 The therapeutic agent for injury of the present invention comprises one or more pharmaceutically acceptable pharmaceutical additives and an active ingredient cyclic phosphatidic acid, carbacyclic phosphatidic acid or thiacyclic phosphatidic acid (preferably represented by the formula (1) And a salt thereof are preferably provided in the form of a pharmaceutical composition.
本発明の損傷治療剤は、種々の形態で投与することができるが、好適な投与形態としては、経口投与でも非経口投与(例えば、静脈内、筋肉内、皮下又は皮内等への注射、直腸内投与、経粘膜投与など)でもよいが、好ましくは非経口投与であり、特に好ましくは損傷部位への局所投与である。 The agent for treating damage according to the present invention can be administered in various forms, and suitable administration forms include oral administration and parenteral administration (for example, intravenous, intramuscular, subcutaneous or intradermal injection, (Intrarectal administration, transmucosal administration, etc.) may be used, but parenteral administration is preferred, and local administration to the site of injury is particularly preferred.
経口投与に適する医薬組成物としては、例えば、錠剤、顆粒剤、カプセル剤、散剤、溶液剤、懸濁剤、シロップ剤などを挙げることができ、非経口投与に適する医薬組成物としては、例えば、注射剤、点滴剤、坐剤、経皮吸収剤などを挙げることができるが、本発明の損傷治療剤の剤形はこれらに限定されることはない。さらに、公知の技術によって持続性製剤とすることもできる。例えば、ゼラチンを基剤としたハイドロゲル中に、有効成分である環状ホスファチジン酸、カルバ環状ホスファチジン酸又はチア環状ホスファチジン酸あるいはその塩を封入することによって、徐放性製剤とすることができる。 Examples of the pharmaceutical composition suitable for oral administration include tablets, granules, capsules, powders, solutions, suspensions, syrups, etc. Examples of the pharmaceutical composition suitable for parenteral administration include , Injections, infusions, suppositories, transdermal absorption agents, and the like, but the dosage form of the therapeutic agent for injury of the present invention is not limited thereto. Furthermore, it can also be set as a continuous formulation by a well-known technique. For example, a sustained-release preparation can be obtained by encapsulating cyclic phosphatidic acid, carbacyclic phosphatidic acid, thiacyclic phosphatidic acid or a salt thereof as an active ingredient in a hydrogel based on gelatin.
本発明の損傷治療剤の製造に用いられる製剤用添加物の種類は特に限定されず、当業者が適宜選択可能である。例えば、賦形剤、崩壊剤又は崩壊補助剤、結合剤、滑沢剤、コーティング剤、基剤、溶解剤又は溶解補助剤、分散剤、懸濁剤、乳化剤、緩衝剤、抗酸化剤、防腐剤、等張化剤、pH調節剤、溶解剤、安定化剤などを用いることができ、これらの目的で使用される個々の具体的成分は当業者に周知されている。 There are no particular limitations on the type of formulation additive used in the production of the injury treatment agent of the present invention, and a person skilled in the art can appropriately select it. For example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, bases, solubilizers or solubilizers, dispersants, suspending agents, emulsifiers, buffers, antioxidants, antiseptics Agents, isotonic agents, pH adjusters, solubilizers, stabilizers, and the like can be used, and the specific components used for these purposes are well known to those skilled in the art.
経口投与用の製剤の調製に用いることができる製剤用添加物として、例えば、ブドウ糖、乳糖、D-マンニトール、デンプン、又は結晶セルロース等の賦形剤;カルボキシメチルセルロース、デンプン、又はカルボキシメチルセルロースカルシウム等の崩壊剤又は崩壊補助剤;ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、又はゼラチン等の結合剤;ステアリン酸マグネシウム又はタルク等の滑沢剤;ヒドロキシプロピルメチルセルロース、白糖、ポリエチレングリコール又は酸化チタン等のコーティング剤;ワセリン、流動パラフィン、ポリエチレングリコール、ゼラチン、カオリン、グリセリン、精製水、又はハードファット等の基剤を用いることができる。 Pharmaceutical additives that can be used in the preparation of formulations for oral administration include, for example, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; carboxymethylcellulose, starch, carboxymethylcellulose calcium, etc. Disintegrating agents or disintegrating aids; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coatings such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide Agents: Bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used.
注射あるいは点滴用の製剤の調製に用いることができる製剤用添加物としては、注射用蒸留水、生理食塩水、プロピレングリコール、界面活性剤等の水性あるいは用時溶解型注射剤を構成しうる溶解剤又は溶解補助剤;ブドウ糖、塩化ナトリウム、D-マンニトール、グリセリン,等の等張化剤;無機酸、有機酸、無機塩基又は有機塩基等のpH調節剤等の製剤用添加物を用いることができる。 Examples of pharmaceutical additives that can be used for the preparation of pharmaceutical preparations for injection or infusion include aqueous solutions such as distilled water for injection, physiological saline, propylene glycol, surfactants, etc. Agents or solubilizers; isotonic agents such as glucose, sodium chloride, D-mannitol, glycerin, etc .; use of pharmaceutical additives such as pH regulators such as inorganic acids, organic acids, inorganic bases or organic bases it can.
本発明の損傷治療剤はヒトなどの哺乳動物に投与することができる。
本発明の損傷治療剤の投与量は患者の年齢、性別、体重、症状、及び投与経路などの条件に応じて適宜増減されるべきであるが、一般的には、成人一日あたりの有効成分の量として1μg/kgから1,000mg/kg程度の範囲であり、好ましくは10μg/kgから100mg/kg程度の範囲である。上記投与量の損傷治療剤は一日一回に投与してもよいし、数回(例えば、2〜4回程度)に分けて投与してもよい。
The therapeutic agent for injury of the present invention can be administered to mammals such as humans.
The dose of the therapeutic agent for injury according to the present invention should be appropriately increased or decreased depending on conditions such as the age, sex, weight, symptoms, and administration route of the patient. Is in the range of about 1 μg / kg to 1,000 mg / kg, and preferably in the range of about 10 μg / kg to 100 mg / kg. The above-mentioned dose of the therapeutic agent for injury may be administered once a day, or may be administered in several times (for example, about 2 to 4 times).
以下の実施例により本発明を具体的に説明するが、本発明は実施例によって限定されることはない。 The present invention will be specifically described by the following examples, but the present invention is not limited to the examples.
実施例1:
(1)被験化合物
実験で用いたカルバcPAは2ccPA (18:1)である。2ccPA (18:1)の構造は以下の通りである。ここで−C17H33は、−(CH2)7CH=CH(CH2)7CH3(シス体)を示す。2ccPA (18:1)は、特開2004−010582号公報に記載の方法により合成した。
Example 1:
(1) Test compound Carba cPA used in the experiment is 2ccPA (18: 1). The structure of 2ccPA (18: 1) is as follows. Here, —C 17 H 33 represents — (CH 2 ) 7 CH═CH (CH 2 ) 7 CH 3 (cis isomer). 2ccPA (18: 1) was synthesized by the method described in JP-A-2004-010582.
(2)マウス
6週齢雌性ICRマウス(チャールスリバー)を、プラスチック製ケージを用いて動物飼育室内で飼育した。飼育環境は温度を22℃で一定とし、明暗は12時間周期とした。実験は、文部科学省およびお茶の水女子大学動物実験委員会によって承認を受け、これらのガイドラインに従って行った。
(2) Mouse
Six-week-old female ICR mice (Charles River) were raised in an animal breeding room using a plastic cage. The breeding environment was a constant temperature of 22 ° C., and the light and dark were cycled 12 hours. The experiment was approved by the Ministry of Education, Culture, Sports, Science and Technology and the Ochanomizu University Animal Experiment Committee, and was conducted according to these guidelines.
(3)脳損傷
穿刺傷害は、6週齢雌マウスに対して行った。マウスに三種混合麻酔薬(0.75 mg/kg ドミトール(日本全薬工業), 4.0 mg/kg ミダゾラム(サンド), 5.0 mg/kg ベトルファール(Meiji Seika ファルマ))を腹腔投与し麻酔をかけた後、後頭部頭蓋骨を露出させ、注射針(テルモ注射針19G×1 1/2", テルモ)を用いて後頭部の右脳側の頭蓋骨に穴を開けた。次に、注射針(テルモ注射針27G×3/4", テルモ)を用いて頭蓋骨の穴から大脳皮質に水平に刺傷した。刺傷後、麻酔に対する拮抗薬アンチセダン(0.75 mg/kg)(日本全薬工業)を腹腔投与した。左脳を対照実験として扱った。損傷直後から24時間おきに、500 μg/ml 2ccPAを1.8 mg/kg/day量腹腔投与した。またControl群として、リン酸緩衝液(PBS; 0.135M NaCl, 8.1mM Na2HPO4, 2.685mM KCl, 1.47mM KH2PO4)を同量腹腔投与したものを作製した。
(3) Brain injury The puncture injury was performed on 6-week-old female mice. Three anesthetics (0.75 mg / kg domitol (Nippon Zenyaku Kogyo), 4.0 mg / kg midazolam (sand), 5.0 mg / kg betorfal (Meiji Seika Pharma)) were intraperitoneally administered to mice, and then the occipital region The skull was exposed, and a hole was made in the skull on the right brain side of the occipital region using a syringe needle (Terumo needle 19G × 1 1/2 ”, Terumo). Next, the needle (Terumo needle 27G × 3/4) ", Terumo) was used to puncture the cerebral cortex horizontally from the skull hole. After the stab wound, an anti-anedan against anesthesia (0.75 mg / kg) (Nippon Zenyaku Kogyo) was administered intraperitoneally. The left brain was treated as a control experiment. 500 μg / ml 2ccPA was intraperitoneally administered at a dose of 1.8 mg / kg / day every 24 hours immediately after the injury. As a Control group, a phosphate buffer solution (PBS; 0.135 M NaCl, 8.1 mM Na 2 HPO 4 , 2.685 mM KCl, 1.47 mM KH 2 PO 4 ) was administered intraperitoneally.
(4)固定
穿刺傷害1、3、5、7日後にそれぞれCO2を用いてマウスを安楽死させ、PBSを50ml、固定液(4%パラホルムアルデヒド, 80mM Na2HPO4, 20mM NaH2PO4) 50mlの順に左心室に注入し、灌流固定を行った。全脳を摘出した後、固定液に入れ室温で一晩振盪させた。固定液を15%スクロースに置換し4℃で一晩振盪し、さらにその後30% スクロースに置き換え4℃で一晩振盪を行った。
(4) Fixation After puncture injury 1, 3, 5, and 7 days, mice were euthanized using CO 2 , 50 ml of PBS, fixative (4% paraformaldehyde, 80 mM Na 2 HPO 4 , 20 mM NaH 2 PO 4 ) Injection into the left ventricle in the order of 50 ml, and perfusion fixation was performed. After removing the whole brain, it was placed in a fixative and shaken overnight at room temperature. The fixative was replaced with 15% sucrose and shaken overnight at 4 ° C., and then replaced with 30% sucrose and shaken overnight at 4 ° C.
(5)包埋・凍結組織切片作製
包埋剤(O.C.T Compound)(サクラファインテック)を、全脳を入れたクリオモルド(TED PELLA, Inc.)に入れ、4℃で30分振盪させ、ドライアイスとイソペンタンを入れた発砲スチロール箱内で全脳を凍結させ、-80℃で保管した。凍結組織切片作製装置クライオスタット(CM1850, ライカ)を用いて凍結組織切片を作製し、スライドグラス(Superfrost Plus, Fisher Scientific)に貼り付けた。切片は、厚さ20μmの冠状断切片とした。
(5) Preparation of embedding / frozen tissue section Embedding agent (OCT Compound) (Sakura Finetech) is placed in cryomold (TED PELLA, Inc.) containing whole brain, shaken at 4 ° C for 30 minutes, and dried ice And the whole brain were frozen in a foamed polystyrene box containing isopentane and stored at -80 ° C. A frozen tissue section was prepared using a cryostat section preparation apparatus cryostat (CM1850, Leica) and attached to a slide glass (Superfrost Plus, Fisher Scientific). The section was a coronal section having a thickness of 20 μm.
(6)IgGを用いた免疫組織染色
損傷修復の指標として、損傷部から脳組織への血液の漏出を観察した。穿刺傷害1、3、5、7日後のマウス脳の冠状断凍結切片において抗マウスIgG抗体を用いた酵素抗体染色を行い、IgGを発色させることで血液の漏出を可視化させた。さらに発色強度から2ccPA投与群及びControl群での血液漏出量を解析した。酵素抗体染色の方法を以下に示す。まず、冠状断凍結切片を37℃で1時間乾燥させた。後の操作は全て室温で行った。固定液で30分間固定し、PBSで5分×2回、トリス緩衝液(TBS;25mM Tris, 137mM NaCl, 2.68mM KCl, pH 7.4)で5分×2回洗浄を行った。10%メタノール、3% H2O2を含むTBS混合液を添加し、10分反応させることで内在性ペルオキシダーゼを不活性化させた後、TBSで5分×3回洗浄した。その後、ブロッキング溶液(10% 仔ウシ血清, 3% ウシ血清アルブミン,133mM グリシン, 0.4% トリトンX-100:in TBS)を用いてブロッキングを1時間行った。次にビオチン標識抗マウスIgG抗体(AP124B, メルクミリポア)をブロッキング溶液で希釈し、1時間反応させた。さらにVECTASTAIN Elite ABC Standard Kit試薬(ベクターラボラトリーズ)を1時間反応させることでアビジン−ビオチン標識酵素複合体を形成させた後、0.1M Tris-HCl(pH 8.0)を用いて5分×3回洗浄した。発色は0.05% ジアミノベンジジン, 0.003% H2O2, 0.1M Tris-HCl(pH 8.0)混合液で一晩反応させることで行った。翌日、蒸留水で洗浄後、70% エタノール, 95% エタノール, 100% エタノール, キシレンの順に置換していき、最後にカナダバルサムで封入した。
(6) Immunohistochemical staining using IgG As an index for repairing damage, leakage of blood from the damaged part to the brain tissue was observed. Enzyme antibody staining with anti-mouse IgG antibody was performed on coronal sections frozen sections of mouse brain 1, 3, 5, and 7 days after puncture injury, and blood leakage was visualized by coloring IgG. Furthermore, the amount of blood leakage in the 2ccPA administration group and the Control group was analyzed from the color intensity. The method of enzyme antibody staining is shown below. First, frozen coronal sections were dried at 37 ° C. for 1 hour. All subsequent operations were performed at room temperature. The solution was fixed with a fixative for 30 minutes, washed with PBS for 5 minutes × 2 times, and with Tris buffer (TBS; 25 mM Tris, 137 mM NaCl, 2.68 mM KCl, pH 7.4) for 5 minutes × 2 times. A TBS mixed solution containing 10% methanol and 3% H 2 O 2 was added and reacted for 10 minutes to inactivate endogenous peroxidase, and then washed with TBS for 5 minutes × 3 times. Thereafter, blocking was performed for 1 hour using a blocking solution (10% calf serum, 3% bovine serum albumin, 133 mM glycine, 0.4% Triton X-100: in TBS). Next, biotin-labeled anti-mouse IgG antibody (AP124B, Merck Millipore) was diluted with a blocking solution and allowed to react for 1 hour. Furthermore, after forming an avidin-biotin labeled enzyme complex by reacting with VECTASTAIN Elite ABC Standard Kit reagent (Vector Laboratories) for 1 hour, it was washed 5 times x 3 times with 0.1M Tris-HCl (pH 8.0) . The color was developed by reacting overnight with a mixed solution of 0.05% diaminobenzidine, 0.003% H 2 O 2 , 0.1M Tris-HCl (pH 8.0). The next day, after washing with distilled water, 70% ethanol, 95% ethanol, 100% ethanol, and xylene were replaced in this order, and finally sealed with Canadian balsam.
(7)観察・定量化
2ccPA投与群及びControl群の穿刺傷害1、3、5、7日後における酵素抗体染色画像は、倒立顕微鏡(FSX-100, オリンパス)を用いて明視野で観察、撮影を行った。結果を図1に示す。
IgGの発色強度はImageJを用いて以下のように定量化した。まず、各切片において撮影した画像を8ビットに変換し、グレースケール画像にした。さらに白黒を反転させた。その後、右脳損傷領域周辺の5つの領域(8×8 μm2)をランダムに選択し、各領域内のMean Gray Valueを計測した。また、損傷していない左脳の大脳皮質領域からも5つの領域を選択し、Mean Gray Valueを計測した。染色のバックグラウンドを取り除くために右脳側から左脳側のMean Gray Valueを引き、その値をIgGの発色強度とした。上記の操作は、各個体から摘出した全脳の損傷部位を含む切片(1個体あたり8から10枚)に対して行った。各切片から得られたIgGの発色強度の平均値をその個体の数値とし、それぞれ3個体の数値を平均した結果を図2に示している。
(7) Observation and quantification
Enzyme antibody-stained images after 1, 3, 5, and 7 days after puncture injury in the 2ccPA administration group and the Control group were observed and photographed in a bright field using an inverted microscope (FSX-100, Olympus). The results are shown in FIG.
The color development intensity of IgG was quantified using ImageJ as follows. First, the image photographed in each section was converted to 8 bits to obtain a grayscale image. Furthermore, the black and white were reversed. Thereafter, five regions (8 × 8 μm 2 ) around the right brain injury region were randomly selected, and the mean gray value in each region was measured. In addition, five regions were selected from the cerebral cortex region of the left brain that was not damaged, and the mean gray value was measured. In order to remove the background of staining, the mean gray value of the left brain side was subtracted from the right brain side, and the value was used as the color intensity of IgG. The above operation was performed on sections (8 to 10 pieces per individual) including the damaged sites of the whole brain extracted from each individual. The average value of the color development intensity of IgG obtained from each section is taken as the value of that individual, and the results of averaging the values of three individuals are shown in FIG.
(8)結果
穿刺傷害後に2ccPAを腹腔投与することにより、血液漏出量はControl群と比較して1日目 28%、3日目 34%、5日目 42%、7日目 60% 有意に減少していた。このことから2ccPAは血液漏出を抑制し、修復を促進することが示された。
(8) Result By intraperitoneal administration of 2ccPA after puncture injury, the amount of blood leakage was significantly 28% on the 1st day, 34% on the 3rd day, 42% on the 5th day, 60% on the 7th day compared with the Control group It was decreasing. This indicates that 2ccPA suppresses blood leakage and promotes repair.
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