WO2023276866A1 - Therapeutic composition for barrett's esophagus - Google Patents
Therapeutic composition for barrett's esophagus Download PDFInfo
- Publication number
- WO2023276866A1 WO2023276866A1 PCT/JP2022/025231 JP2022025231W WO2023276866A1 WO 2023276866 A1 WO2023276866 A1 WO 2023276866A1 JP 2022025231 W JP2022025231 W JP 2022025231W WO 2023276866 A1 WO2023276866 A1 WO 2023276866A1
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- WIPO (PCT)
- Prior art keywords
- esophagus
- barrett
- mek inhibitor
- composition
- mek
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Abstract
The present invention pertains to a therapeutic composition for Barrett's esophagus and addresses the problem of providing a therapeutic composition for restoring Barrett's esophagus to normal esophagus and a method for treating Barrett's esophagus using the therapeutic composition. More specifically, the present invention pertains to a therapeutic composition for Barrett's esophagus, said composition containing an MEK inhibitor. Further, the present invention pertains to a composition for preventing esophageal adenocarcinoma, said composition containing an MEK inhibitor.
Description
本発明は、バレット食道の治療用組成物に関する。より具体的には、本発明は、扁平上皮の再生を促すことにより、バレット食道に特徴的な組織形態である円柱上皮を食道本来の組織形態である扁平上皮に復帰させるための治療用組成物に関する。
The present invention relates to a composition for treating Barrett's esophagus. More specifically, the present invention is a therapeutic composition for restoring columnar epithelium, which is the tissue morphology characteristic of Barrett's esophagus, to squamous epithelium, which is the original tissue morphology of the esophagus, by promoting regeneration of squamous epithelium. Regarding.
バレット食道（Barrett’s esophagus）は、下部食道から上部食道の粘膜組織が扁平上皮から円柱上皮に変化したもので、 胃食道逆流症（gastroesophagealreflux disease：GERD）に伴って引き起こされる。バレット食道を発症すると、食道腺癌を発症するリスクが高まることが知られている。バレット食道から発症する食道腺癌が進行してしまった場合、その予後は不良である。バレット食道の治療法として、円柱上皮に変化した粘膜組織の切除療法および焼却療法などが行われている。しかし、粘膜切除を全周性に行うと食道狭窄を来す。また、焼却療法においては、表層のみが焼却され深部に残存したバレット食道粘膜組織から発がんすることがあり、このような場合には、腫瘍部が再生した表層に覆われて、発見が遅れるおそれがある。予後不良の食道腺癌の発症を予防するためにも、バレット食道を本来の食道に復帰させることは、非常に重要であると考えられる。しかしながら、現在のところ、上記の外科的な治療法以外のより非侵襲的で、効果的な治療法は開発されていない。
Barrett's esophagus is a change in the mucosal tissue from the lower to the upper esophagus from squamous epithelium to columnar epithelium, and is caused by gastroesophagealreflux disease (GERD). Developing Barrett's esophagus is known to increase the risk of developing esophageal adenocarcinoma. If esophageal adenocarcinoma that develops from Barrett's esophagus has progressed, the prognosis is poor. Treatment methods for Barrett's esophagus include excision therapy and ablation therapy for mucosal tissue that has changed to columnar epithelium. However, circumferential mucosal resection results in esophageal stricture. In addition, in incineration therapy, carcinogenesis may occur from Barrett's esophageal mucosa tissue that remains deep after only the superficial layer is incinerated. be. In order to prevent the development of esophageal adenocarcinoma with a poor prognosis, it is considered very important to restore Barrett's esophagus to the original esophagus. However, to date, no more non-invasive and effective treatments other than the surgical treatments described above have been developed.
ところで、バレット食道から食道腺癌へ移行する過程において機能する分子メカニズムの解明も行われている。Dulakらは、変異スペクトラム解析により、食道腺癌に関連すると考えられる26の変異した遺伝子を同定した（非特許文献１）。その中には、例えば、TP53、CDKN2A、SMAD4、PIK3CA、SPG20、TLR4、ELMO1およびDOCK2などが含まれていた。Chaoらは、TP53の両アレル不活性化（biallelic inactivation）がバレット食道から食道腺癌への進行に関与していると報告している（非特許文献２）。また、Sommererらは、バレット食道から発症した食道腺癌の約32%において、BRAFおよびKRAS2の変異が存在することを見出し、Raf/MEK/ERK(MAPK)キナーゼパスウェイの異常がバレット食道から発症する食道腺癌の初期段階において関与していると結論付けている（非特許文献３）。
By the way, elucidation of the molecular mechanism that functions in the process of transition from Barrett's esophagus to esophageal adenocarcinoma is also underway. Dulak et al. identified 26 mutated genes thought to be associated with esophageal adenocarcinoma by mutation spectrum analysis (Non-Patent Document 1). These included, for example, TP53 , CDKN2A , SMAD4 , PIK3CA , SPG20 , TLR4 , ELMO1 and DOCK2 . Chao et al. reported that biallelic inactivation of TP53 is involved in progression from Barrett's esophagus to esophageal adenocarcinoma (Non-Patent Document 2). Also, Sommerer et al. found that approximately 32% of esophageal adenocarcinoma originating from Barrett's esophagus have mutations in BRAF and KRAS2 , suggesting that abnormalities in the Raf/MEK/ERK (MAPK) kinase pathway develop from Barrett's esophagus. It is concluded that it is involved in the early stages of esophageal adenocarcinoma (Non-Patent Document 3).
以上のように、バレット食道から食道腺癌への進行に関与する可能性のある遺伝子変異について、徐々に解明されつつあるが、正常な食道からバレット食道へ変化する原因となる分子メカニズムについては、現在のところ明らかになっていない。そのため、バレット食道の治療において、外科的方法以外で有効な非侵襲的な治療法の開発はあまり進んでいない。
As described above, genetic mutations that may be involved in the progression from Barrett's esophagus to esophageal adenocarcinoma are being gradually elucidated. It is not clear at present. Therefore, in the treatment of Barrett's esophagus, development of effective non-invasive treatments other than surgical methods has not made much progress.
上記事情に鑑み、本発明は、バレット食道の治療用組成物、より具体的には、バレット食道を正常な食道に復帰させる治療用組成物の提供、および当該治療用組成物を用いたバレット食道の治療方法の提供を課題とする。
In view of the above circumstances, the present invention provides a therapeutic composition for Barrett's esophagus, more specifically, a therapeutic composition for restoring Barrett's esophagus to a normal esophagus, and Barrett's esophagus using the therapeutic composition. The objective is to provide a therapeutic method for
発明者は、ラットの胃食道逆流症モデルに対し、MEK阻害剤を投与したところ、バレット食道の長さが短縮すること、およびバレット食道のびらん内に扁平上皮が再生することを見出した。
MEK（MAPK/ERK kinase）は、MAPKシグナル伝達経路において、ERK（extracellular signal-regulated Kinase）をリン酸化し活性化するキナーゼである。これまでに多くのがんにおいて、MAPKシグナル伝達経路を構成するRas、Raf、MEKなどの活性型変異・遺伝子増幅が数多く報告されている。今回、発明者は、正常な食道がバレット食道へ変化する過程においても、MAPKシグナル伝達経路を構成する因子が関与することを初めて見出し、本発明を完成させた。 The inventor found that administration of a MEK inhibitor to a rat gastroesophageal reflux disease model shortened the length of Barrett's esophagus and that squamous epithelium regenerated within the erosion of Barrett's esophagus.
MEK (MAPK/ERK kinase) is a kinase that phosphorylates and activates ERK (extracellular signal-regulated kinase) in the MAPK signaling pathway. To date, many reports have reported activating mutations/gene amplifications of Ras, Raf, MEK, etc. that constitute the MAPK signaling pathway in many cancers. This time, the inventors have found for the first time that factors constituting the MAPK signaling pathway are involved in the process of transformation of normal esophagus into Barrett's esophagus, and have completed the present invention.
MEK（MAPK/ERK kinase）は、MAPKシグナル伝達経路において、ERK（extracellular signal-regulated Kinase）をリン酸化し活性化するキナーゼである。これまでに多くのがんにおいて、MAPKシグナル伝達経路を構成するRas、Raf、MEKなどの活性型変異・遺伝子増幅が数多く報告されている。今回、発明者は、正常な食道がバレット食道へ変化する過程においても、MAPKシグナル伝達経路を構成する因子が関与することを初めて見出し、本発明を完成させた。 The inventor found that administration of a MEK inhibitor to a rat gastroesophageal reflux disease model shortened the length of Barrett's esophagus and that squamous epithelium regenerated within the erosion of Barrett's esophagus.
MEK (MAPK/ERK kinase) is a kinase that phosphorylates and activates ERK (extracellular signal-regulated kinase) in the MAPK signaling pathway. To date, many reports have reported activating mutations/gene amplifications of Ras, Raf, MEK, etc. that constitute the MAPK signaling pathway in many cancers. This time, the inventors have found for the first time that factors constituting the MAPK signaling pathway are involved in the process of transformation of normal esophagus into Barrett's esophagus, and have completed the present invention.
すなわち、本発明は以下の（１）～（５）である。
（１）バレット食道の治療用組成物であって、MEK阻害剤を含む前記組成物。
（２）前記MEK阻害剤が、トラメチニブ、ビニメチニブ、セルメチニブ、コビメチニブ、ピマセルチブ、レファメチニブ、ウリキセルチニブ、アベマシクリブ、U0126、PD184352（CI-1040）、PD98059およびBIX 02189からなるグループから選択される1または複数であることを特徴とする上記（１）に記載の組成物。
（３）食道腺癌の予防用組成物であって、MEK阻害剤を含む前記組成物。
（４）前記MEK阻害剤が、トラメチニブ、ビニメチニブ、セルメチニブ、コビメチニブ、ピマセルチブ、レファメチニブ、ウリキセルチニブ、アベマシクリブ、U0126、PD184352（CI-1040）、PD98059およびBIX 02189からなるグループから選択される1または複数であることを特徴とする上記（３）に記載の組成物。
（５）バレット食道を発症している患者に投与することを特徴とする上記（３）または（４）に記載の組成物。
なお、本明細書において「～」の符号は、その左右の値を含む数値範囲を示す。 That is, the present invention is the following (1) to (5).
(1) A composition for treating Barrett's esophagus, said composition comprising a MEK inhibitor.
(2) the MEK inhibitor is one or more selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, pimasertib, refametinib, urixertinib, abemaciclib, U0126, PD184352 (CI-1040), PD98059 and BIX 02189 The composition according to (1) above, characterized in that:
(3) A composition for preventing esophageal adenocarcinoma, which comprises a MEK inhibitor.
(4) the MEK inhibitor is one or more selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, pimasertib, refametinib, urixertinib, abemaciclib, U0126, PD184352 (CI-1040), PD98059 and BIX 02189 The composition according to (3) above, characterized in that:
(5) The composition according to (3) or (4) above, which is administered to a patient suffering from Barrett's esophagus.
In this specification, the sign "-" indicates a numerical range including the values on the left and right of it.
（１）バレット食道の治療用組成物であって、MEK阻害剤を含む前記組成物。
（２）前記MEK阻害剤が、トラメチニブ、ビニメチニブ、セルメチニブ、コビメチニブ、ピマセルチブ、レファメチニブ、ウリキセルチニブ、アベマシクリブ、U0126、PD184352（CI-1040）、PD98059およびBIX 02189からなるグループから選択される1または複数であることを特徴とする上記（１）に記載の組成物。
（３）食道腺癌の予防用組成物であって、MEK阻害剤を含む前記組成物。
（４）前記MEK阻害剤が、トラメチニブ、ビニメチニブ、セルメチニブ、コビメチニブ、ピマセルチブ、レファメチニブ、ウリキセルチニブ、アベマシクリブ、U0126、PD184352（CI-1040）、PD98059およびBIX 02189からなるグループから選択される1または複数であることを特徴とする上記（３）に記載の組成物。
（５）バレット食道を発症している患者に投与することを特徴とする上記（３）または（４）に記載の組成物。
なお、本明細書において「～」の符号は、その左右の値を含む数値範囲を示す。 That is, the present invention is the following (1) to (5).
(1) A composition for treating Barrett's esophagus, said composition comprising a MEK inhibitor.
(2) the MEK inhibitor is one or more selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, pimasertib, refametinib, urixertinib, abemaciclib, U0126, PD184352 (CI-1040), PD98059 and BIX 02189 The composition according to (1) above, characterized in that:
(3) A composition for preventing esophageal adenocarcinoma, which comprises a MEK inhibitor.
(4) the MEK inhibitor is one or more selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, pimasertib, refametinib, urixertinib, abemaciclib, U0126, PD184352 (CI-1040), PD98059 and BIX 02189 The composition according to (3) above, characterized in that:
(5) The composition according to (3) or (4) above, which is administered to a patient suffering from Barrett's esophagus.
In this specification, the sign "-" indicates a numerical range including the values on the left and right of it.
本発明により、バレット食道の治療用組成物、および当該治療用組成物を用いた非侵襲的なパレット食道の治療方法が提供される。
The present invention provides a therapeutic composition for Barrett's esophagus and a non-invasive treatment method for Barrett's esophagus using the therapeutic composition.
バレット食道は、下部食道から上部食道の粘膜組織の少なくとも一部が扁平上皮から円柱上皮に変化した食道のことであり、胃食道逆流症などに伴い発症することが多い。本発明者は、胃食道逆流症ラットモデルにMEK阻害剤を投与したところ、バレット食道の長さが短縮すること、およびバレット食道のびらん内に扁平上皮が再生してバレット食道が正常な食道に復帰することを明らかにした。すなわち、本発明者は、MEK阻害剤がバレット食道の治療剤としての効果を有することを初めて明らかにした。
Barrett's esophagus is an esophagus in which at least part of the mucosal tissue from the lower esophagus to the upper esophagus has changed from squamous epithelium to columnar epithelium, and it often develops with gastroesophageal reflux disease. The present inventors have found that when a MEK inhibitor was administered to a rat model of gastroesophageal reflux disease, the length of Barrett's esophagus was shortened, and that squamous epithelium regenerated within the erosion of Barrett's esophagus to transform it into a normal esophagus. announced that he would return. That is, the present inventors revealed for the first time that MEK inhibitors are effective as therapeutic agents for Barrett's esophagus.
MEK（MAPK/ERK kinase）は、RAS/RAF/MEK/ERKシグナル伝達経路において、ERK（extracellular signal-regulated Kinase）1およびERK2のセリン残基およびスレオニン残基をリン酸化し、ERK1/2を活性化する二重特異性セリン／スレオニンキナーゼである。正常な細胞において、細胞外からの増殖因子刺激により活性化されたRasは、Rafと結合してその活性化を促し、RafはMEKをリン酸化して活性化し、次いで、MEKがERKをリン酸化して活性化する。活性化されたERKは、細胞質から核へと移行して、ELK、CREB、c-Myc、c-Fos、Sp-1などの転写因子を活性化して遺伝子の発現を誘導する。このようにRASからERKに至るリン酸化カスケードによって、遺伝子発現のための情報が伝達される経路をRAS/RAF/MEK/ERKシグナル伝達経路という。MEKには、MEK1およびMEK2の2つのサブタイプが存在する。本明細書に記載される「MEK」には、MEK1およびMEK2の両方が含まれる。
MEK (MAPK/ERK kinase) phosphorylates serine and threonine residues of ERK (extracellular signal-regulated kinase) 1 and ERK2 in the RAS/RAF/MEK/ERK signaling pathway, and activates ERK1/2. It is a dual specificity serine/threonine kinase that In normal cells, Ras activated by extracellular growth factor stimulation binds to Raf and promotes its activation, Raf phosphorylates and activates MEK, and MEK then phosphorylates ERK. to activate. Activated ERK translocates from the cytoplasm to the nucleus and activates transcription factors such as ELK, CREB, c-Myc, c-Fos and Sp-1 to induce gene expression. The pathway in which information for gene expression is transmitted by the phosphorylation cascade from RAS to ERK is called the RAS/RAF/MEK/ERK signaling pathway. There are two subtypes of MEK, MEK1 and MEK2. As used herein, "MEK" includes both MEK1 and MEK2.
第１の実施形態は、バレット食道の治療用組成物であって、MEK阻害剤を含む、組成物（以下「本実施形態にかかる治療用組成物」とも記載する）である。バレット食道の「治療」とは、バレット食道を本来の食道に復帰させることで、具体的には、主として円柱上皮から構成されるバレット食道の粘膜組織を、扁平上皮からなる本来の食道の粘膜組織へ戻すこと、または、食道に扁平上皮からなる粘膜組織を再生させることである。
The first embodiment is a composition for treating Barrett's esophagus, which contains a MEK inhibitor (hereinafter also referred to as "therapeutic composition according to this embodiment"). "Treatment" of Barrett's esophagus means returning Barrett's esophagus to its original esophagus. or to regenerate mucosal tissue consisting of squamous epithelium in the esophagus.
本実施形態のMEK阻害剤としては、特に限定はしないが、例えば、トラメチニブ（CAS：871700-17-3）、ビニメチニブ（CAS：606143-89-9）、セルメチニブ（CAS：606143-52-6）、コビメチニブ（CAS：934660-93-2）、ピマセルチブ（CAS：1236699-92-5）、レファメチニブ（CAS：923032-37-5）、ウリキセルチニブ（CAS：869886-67-9）、アベマシクリブ（CAS：1231929-97-7）、U0126（CAS：1173097-76-1）、PD184352（CI-1040）（CAS：212631-79-3）、PD98059（CAS：167869-21-8）およびBIX 02189（CAS：1094614-85-3）などを挙げることができる。さらに、これらの化合物以外にも、MEKの活性を抑制または阻害する抗体、ペプチドアプタマーの他、MEK遺伝子の発現を抑制もしくは阻害する物質、例えば、siRNA、miRNAなどが挙げられる。
The MEK inhibitor of this embodiment is not particularly limited, but for example, trametinib (CAS: 871700-17-3), binimetinib (CAS: 606143-89-9), selumetinib (CAS: 606143-52-6) , cobimetinib (CAS: 934660-93-2), pimasertib (CAS: 1236699-92-5), lefametinib (CAS: 923032-37-5), urixertinib (CAS: 869886-67-9), abemaciclib (CAS: 1231929) -97-7), U0126 (CAS: 1173097-76-1), PD184352 (CI-1040) (CAS: 212631-79-3), PD98059 (CAS: 167869-21-8) and BIX 02189 (CAS: 1094614 -85-3). In addition to these compounds, antibodies that suppress or inhibit MEK activity, peptide aptamers, and substances that suppress or inhibit MEK gene expression, such as siRNA and miRNA.
上述の通り、MEK阻害剤は、バレット食道を正常な食道に復帰させる効果を有しており、バレット食道から食道腺癌への進行を阻止することができる。
第２の実施形態は、食道腺癌の予防用組成物であって、MEK阻害剤を含む、組成物（以下「本実施形態にかかる予防用組成物」とも記載する）である。本実施形態にかかる予防用組成物は、バレット食道を発症している者の食道腺癌の発症の予防に特に効果を発揮する。
本実施形態にかかる治療用組成物および予防用組成物（以下「本実施形態にかかる組成物等」とも記載する）は、有効成分であるMEK阻害剤の他、１もしくは２以上の製剤用添加物、薬学的に許容可能な担体などを含んでもよく、また、バレット食道の病態を改善するために有効な他の薬剤等を含んでもよい。 As described above, MEK inhibitors have the effect of reverting Barrett's esophagus to a normal esophagus, and can prevent progression from Barrett's esophagus to esophageal adenocarcinoma.
The second embodiment is a preventive composition for esophageal adenocarcinoma containing a MEK inhibitor (hereinafter also referred to as "the preventive composition according to this embodiment"). The preventive composition according to this embodiment is particularly effective in preventing the development of esophageal adenocarcinoma in patients with Barrett's esophagus.
The therapeutic composition and prophylactic composition according to the present embodiment (hereinafter also referred to as "composition etc. according to the present embodiment") include an MEK inhibitor as an active ingredient and one or more pharmaceutical additives. , a pharmaceutically acceptable carrier, etc., and may also contain other agents effective to ameliorate the condition of Barrett's esophagus.
第２の実施形態は、食道腺癌の予防用組成物であって、MEK阻害剤を含む、組成物（以下「本実施形態にかかる予防用組成物」とも記載する）である。本実施形態にかかる予防用組成物は、バレット食道を発症している者の食道腺癌の発症の予防に特に効果を発揮する。
本実施形態にかかる治療用組成物および予防用組成物（以下「本実施形態にかかる組成物等」とも記載する）は、有効成分であるMEK阻害剤の他、１もしくは２以上の製剤用添加物、薬学的に許容可能な担体などを含んでもよく、また、バレット食道の病態を改善するために有効な他の薬剤等を含んでもよい。 As described above, MEK inhibitors have the effect of reverting Barrett's esophagus to a normal esophagus, and can prevent progression from Barrett's esophagus to esophageal adenocarcinoma.
The second embodiment is a preventive composition for esophageal adenocarcinoma containing a MEK inhibitor (hereinafter also referred to as "the preventive composition according to this embodiment"). The preventive composition according to this embodiment is particularly effective in preventing the development of esophageal adenocarcinoma in patients with Barrett's esophagus.
The therapeutic composition and prophylactic composition according to the present embodiment (hereinafter also referred to as "composition etc. according to the present embodiment") include an MEK inhibitor as an active ingredient and one or more pharmaceutical additives. , a pharmaceutically acceptable carrier, etc., and may also contain other agents effective to ameliorate the condition of Barrett's esophagus.
本実施形態にかかる組成物等の剤形としては、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、懸濁剤、座剤、軟膏、クリーム剤、ゲル剤、貼付剤、吸入剤、注射剤等が挙げられる。これらの製剤は常法に従って調製される。なお、液体製剤にあっては、用時、水または他の適当な溶媒に溶解または懸濁するものであってもよい。また、錠剤、顆粒剤は周知の方法でコーティングしてもよい。注射剤の場合には、有効成分を水に溶解させて調製されるが、必要に応じて生理食塩水あるいはブドウ糖溶液に溶解させてもよく、また、緩衝剤や保存剤を添加してもよい。
Dosage forms of the composition according to this embodiment include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, and injections. etc. These formulations are prepared according to a conventional method. Liquid formulations may be dissolved or suspended in water or other suitable solvents at the time of use. Moreover, tablets and granules may be coated by a well-known method. Injections are prepared by dissolving the active ingredient in water, but if necessary, they may be dissolved in physiological saline or glucose solution, and buffers and preservatives may be added. .
経口投与用または非経口投与用の製剤は、任意の製剤形態で提供される。製剤形態としては、例えば、顆粒剤、細粒剤、散剤、硬カプセル剤、軟カプセル剤、シロップ剤、乳剤、懸濁剤もしくは液剤等の形態の経口投与用治療薬または治療用組成物、静脈内投与用、筋肉内投与用もしくは皮下投与用などの注射剤、点滴剤、経皮吸収剤、経粘膜吸収剤、点鼻剤、吸入剤、坐剤などの形態の非経口投与用治療薬または治療用組成物として調製することができる。注射剤や点滴剤などは、凍結乾燥形態などの粉末状の剤形として調製し、用時に生理食塩水などの適宜の水性媒体に溶解して用いることもできる。
Formulations for oral or parenteral administration are provided in any formulation form. Formulations include, for example, granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, liquid formulations, therapeutic agents for oral administration or therapeutic compositions, intravenous therapeutic agents for parenteral administration in the form of injections, drops, transdermal absorptions, transmucosal absorptions, nasal drops, inhalants, suppositories, etc. for intramuscular, intramuscular or subcutaneous administration, or It can be prepared as a therapeutic composition. Injections and infusions can also be prepared in the form of a powder such as a freeze-dried form and dissolved in an appropriate aqueous medium such as physiological saline at the time of use.
本実施形態にかかる組成物等の製造に用いられる製剤用添加物の種類、有効成分に対する製剤用添加物の割合、あるいは、治療用組成物および予防用組成物の製造方法は、その形態に応じて当業者が適宜選択することが可能である。製剤用添加物としては無機または有機物質、あるいは、固体または液体の物質を用いることができ、一般的には、有効成分重量に対して1重量％から90重量％の間で配合することができる。具体的には、製剤用添加物の例として乳糖、ブドウ糖、マンニット、デキストリン、シクロデキストリン、デンプン、蔗糖、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルデンプン、カルボキシメチルセルロースカルシウム、イオン交換樹脂、メチルセルロース、ゼラチン、アラビアゴム、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、ポリビニルアルコール、軽質無水ケイ酸、ステアリン酸マグネシウム、タルク、トラガント、ベントナイト、ビーガム、酸化チタン、ソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、グリセリン、脂肪酸グリセリンエステル、精製ラノリン、グリセロゼラチン、ポリソルベート、マクロゴール、植物油、ロウ、流動パラフィン、白色ワセリン、フルオロカーボン、非イオン性界面活性剤、プロピレングルコール、水等が挙げられる。
The type of pharmaceutical additive used in the production of the composition according to the present embodiment, the ratio of the pharmaceutical additive to the active ingredient, or the method for producing the therapeutic composition and the prophylactic composition depend on the form. can be appropriately selected by those skilled in the art. Inorganic or organic substances, or solid or liquid substances can be used as pharmaceutical additives, and can generally be blended between 1% and 90% by weight based on the weight of the active ingredient. . Specifically, examples of pharmaceutical additives include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, and calcium carboxymethylcellulose. , ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, veegum, titanium oxide, sorbitan fatty acid ester, Sodium lauryl sulfate, glycerin, fatty acid glycerin ester, refined lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, liquid paraffin, white petrolatum, fluorocarbon, nonionic surfactant, propylene glycol, water and the like.
経口投与用の固形製剤を製造するには、有効成分と賦形剤成分、例えば、乳糖、デンプン、結晶セルロース、乳酸カルシウム、無水ケイ酸などと混合して散剤とするか、さらに必要に応じて白糖、ヒドロキシプロピルセルロース、ポリビニルピロリドンなどの結合剤、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウムなどの崩壊剤などを加えて湿式または乾式造粒して顆粒剤とする。錠剤を製造するには、これらの散剤および顆粒剤をそのまま、あるいは、ステアリン酸マグネシウム、タルクなどの滑沢剤を加えて打錠すればよい。これらの顆粒または錠剤はヒドロキシプロピルメチルセルロースフタレート、メタクリル酸－メタクリル酸メチルポリマーなどの腸溶剤基剤で被覆して腸溶剤製剤、あるいは、エチルセルロース、カルナウバロウ、硬化油などで被覆して持続性製剤とすることもできる。また、カプセル剤を製造するには、散剤または顆粒剤を硬カプセルに充填するか、有効成分をそのまま、あるいは、グリセリン、ポリエチレングリコール、ゴマ油、オリーブ油などに溶解した後ゼラチン膜で被覆し軟カプセルとすることができる。
In order to produce a solid preparation for oral administration, the active ingredient is mixed with excipient ingredients such as lactose, starch, crystalline cellulose, calcium lactate, silicic anhydride, etc. to form a powder, or if necessary, Binders such as sucrose, hydroxypropyl cellulose and polyvinylpyrrolidone, and disintegrants such as carboxymethyl cellulose and carboxymethyl cellulose calcium are added and wet or dry granulated to form granules. In order to produce tablets, these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate and talc. These granules or tablets are coated with an enteric base such as hydroxypropyl methylcellulose phthalate, methacrylic acid-methyl methacrylate polymer to form an enteric preparation, or ethylcellulose, carnauba wax, hardened oil or the like to form a sustained release preparation. can also To manufacture capsules, powders or granules are filled into hard capsules, or active ingredients are dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc. and coated with a gelatin film to form soft capsules. can do.
注射剤を製造するには、有効成分を必要に応じて塩酸、水酸化ナトリウム、乳糖、乳酸、ナトリウム、リン酸一水素ナトリウム、リン酸二水素ナトリウムなどのｐＨ調整剤、塩化ナトリウム、ブドウ糖などの等張化剤と共に注射用蒸留水に溶解し、無菌濾過してアンプルに充填するか、さらにマンニトール、デキストリン、シクロデキストリン、ゼラチンなどを加えて真空凍結乾燥し、用時溶解型の注射剤としてもよい。また、有効成分にレチシン、ポリソルベート８０、ポリオキシエチレン硬化ヒマシ油などを加えて水中で乳化せしめ注射剤用乳剤とすることもできる。
In order to manufacture an injection, the active ingredient is mixed with pH adjusters such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, glucose, etc. Dissolve in distilled water for injection together with an isotonizing agent, filter aseptically and fill into an ampoule, or add mannitol, dextrin, cyclodextrin, gelatin, etc. and lyophilize in vacuum to prepare an injection that dissolves before use. good. Alternatively, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. may be added to the active ingredient and emulsified in water to prepare an emulsion for injection.
直腸投与剤を製造するには、有効成分をカカオ脂、脂肪酸のトリ、ジおよびモノグリセリド、ポリエチレングリコールなどの座剤用基材と共に加湿して溶解し型に流し込んで冷却するか、有効成分をポリエチレングリコール、大豆油などに溶解した後、ゼラチン膜で被覆すればよい。
For the preparation of rectal formulations, the active ingredient is moistened with a suppository base such as cocoa butter, tri-, di- and monoglycerides of fatty acids, polyethylene glycol and the like, poured into molds and allowed to cool, or the active ingredient is extruded in polyethylene. After dissolving in glycol, soybean oil, etc., it may be coated with a gelatin film.
本実施形態にかかる組成物等の投与量および投与回数は特に限定されず、治療および予防の目的、疾患の種類、患者の体重や年齢などの条件に応じて、医師の判断により適宜選択することが可能である。
一般的には、経口投与における成人一日あたりの投与量は0.01～1000mg（有効成分重量）程度であり、一日１回または数回に分けて、あるいは、数日ごとに投与することができる。注射剤として用いる場合には、成人に対して一日量0.001～100mg（有効成分重量）を連続投与または間欠投与することが望ましい。 The dosage and administration frequency of the composition according to the present embodiment are not particularly limited, and may be appropriately selected by a doctor's judgment according to conditions such as the purpose of treatment and prevention, the type of disease, and the patient's weight and age. is possible.
In general, the daily dose for adults in oral administration is about 0.01 to 1000 mg (weight of active ingredient), and can be administered once or divided into several times a day, or every few days. . When used as an injection, it is desirable to administer 0.001 to 100 mg (active ingredient weight) daily for adults continuously or intermittently.
一般的には、経口投与における成人一日あたりの投与量は0.01～1000mg（有効成分重量）程度であり、一日１回または数回に分けて、あるいは、数日ごとに投与することができる。注射剤として用いる場合には、成人に対して一日量0.001～100mg（有効成分重量）を連続投与または間欠投与することが望ましい。 The dosage and administration frequency of the composition according to the present embodiment are not particularly limited, and may be appropriately selected by a doctor's judgment according to conditions such as the purpose of treatment and prevention, the type of disease, and the patient's weight and age. is possible.
In general, the daily dose for adults in oral administration is about 0.01 to 1000 mg (weight of active ingredient), and can be administered once or divided into several times a day, or every few days. . When used as an injection, it is desirable to administer 0.001 to 100 mg (active ingredient weight) daily for adults continuously or intermittently.
本実施形態にかかる組成物等は、植込錠およびマイクロカプセルに封入された送達システムなどの徐放性製剤として、体内から即時に除去されることを防ぎ得る薬学的に許容可能な担体を用いて調製してもよい。そのような担体として、エチレンビニル酢酸塩、ポリ酸無水物、ポリグリコール酸、コラーゲン、ポリオルトエステルおよびポリ乳酸などの生物分解性、生物適合性ポリマーを用いることができる。このような材料は、当業者によって容易に調製することができる。また、リポソームの懸濁液も薬学的に許容可能な担体として使用することができる。リポソームは、限定はしないが、ホスファチジルコリン、コレステロールおよびPEG誘導ホスファチジルエタノール（PEG-PE）を含む脂質組成物として、使用に適するサイズになるように、適当なポアサイズのフィルターを通して調製され、逆相蒸発法によって精製することができる。
The composition, etc. according to this embodiment uses a pharmaceutically acceptable carrier capable of preventing immediate elimination from the body as a sustained-release preparation such as an implant and a microcapsule-encapsulated delivery system. may be prepared using Biodegradable, biocompatible polymers can be used as such carriers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such materials can be readily prepared by those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. Liposomes are prepared through filters of suitable pore size to a suitable size for use as a lipid composition containing, but not limited to, phosphatidylcholine, cholesterol and PEG-derived phosphatidylethanol (PEG-PE), followed by reverse-phase evaporation. can be refined by
本実施形態にかかる組成物等は、投与方法等の説明書と共にキットの形態で提供してもよい。キット中に含まれる薬剤は、当該薬剤の活性を長期間有効に持続し、容器内側に吸着することなく、また、構成成分を変質することのない材質で製造された容器により供給される。例えば、封着されたガラスアンプルは、窒素ガスのような中性で不反応性を示すガスの存在下で封入されたバッファーなどを含んでもよい。
また、キットには使用説明書が添付されてもよい。当該キットの使用説明は、紙などに印刷されたものであっても、CD-ROM、DVD-ROMなどの電磁的に読み取り可能な媒体に保存されて使用者に供給されてもよい。 The composition and the like according to this embodiment may be provided in the form of a kit together with an instruction such as an administration method. The drug contained in the kit is supplied in a container manufactured from a material that effectively maintains the activity of the drug for a long period of time, does not adsorb to the inside of the container, and does not alter the constituent components. For example, a sealed glass ampoule may contain a buffer or the like sealed in the presence of a neutral, non-reactive gas such as nitrogen gas.
The kit may also be accompanied by instructions for use. Instructions for use of the kit may be printed on paper or the like, or stored in an electromagnetically readable medium such as a CD-ROM or DVD-ROM and supplied to the user.
また、キットには使用説明書が添付されてもよい。当該キットの使用説明は、紙などに印刷されたものであっても、CD-ROM、DVD-ROMなどの電磁的に読み取り可能な媒体に保存されて使用者に供給されてもよい。 The composition and the like according to this embodiment may be provided in the form of a kit together with an instruction such as an administration method. The drug contained in the kit is supplied in a container manufactured from a material that effectively maintains the activity of the drug for a long period of time, does not adsorb to the inside of the container, and does not alter the constituent components. For example, a sealed glass ampoule may contain a buffer or the like sealed in the presence of a neutral, non-reactive gas such as nitrogen gas.
The kit may also be accompanied by instructions for use. Instructions for use of the kit may be printed on paper or the like, or stored in an electromagnetically readable medium such as a CD-ROM or DVD-ROM and supplied to the user.
第３の実施形態は、本実施形態にかかる治療用組成物（第１の実施形態）を患者に投与することを含むバレット食道の治療方法である。
ここで「治療」とは、バレット食道を本来の食道に復帰させることで、具体的には、主として円柱上皮から構成されるバレット食道の粘膜組織を、扁平上皮からなる本来の食道の粘膜組織へ戻すこと、または、扁平上皮からなる粘膜組織を再生させることである。 A third embodiment is a method for treating Barrett's esophagus, comprising administering a therapeutic composition according to this embodiment (first embodiment) to a patient.
Here, "treatment" means returning Barrett's esophagus to the original esophagus. It is to return, or to regenerate mucosal tissue consisting of squamous epithelium.
ここで「治療」とは、バレット食道を本来の食道に復帰させることで、具体的には、主として円柱上皮から構成されるバレット食道の粘膜組織を、扁平上皮からなる本来の食道の粘膜組織へ戻すこと、または、扁平上皮からなる粘膜組織を再生させることである。 A third embodiment is a method for treating Barrett's esophagus, comprising administering a therapeutic composition according to this embodiment (first embodiment) to a patient.
Here, "treatment" means returning Barrett's esophagus to the original esophagus. It is to return, or to regenerate mucosal tissue consisting of squamous epithelium.
第４の実施形態は、本実施形態にかかる予防用組成物（第２の実施形態）を患者に投与することを含む、食道腺癌の予防方法である。
ここで「予防」とは、食道腺癌を発症するおそれがあるほ乳動物において、その発症を予め阻止することを意味し、特に、食道の粘膜組織の少なくとも一部にバレット食道に特徴的な円柱上皮からなる組織を含むほ乳動物が食道腺癌を発症するのを予め阻止することを意味する。 The fourth embodiment is a method for preventing esophageal adenocarcinoma, comprising administering the preventive composition (second embodiment) according to this embodiment to a patient.
The term "prevention" as used herein means to prevent the development of esophageal adenocarcinoma in advance in mammals at risk of developing esophageal adenocarcinoma. It means to prevent in advance the development of esophageal adenocarcinoma in mammals containing tissue consisting of epithelium.
ここで「予防」とは、食道腺癌を発症するおそれがあるほ乳動物において、その発症を予め阻止することを意味し、特に、食道の粘膜組織の少なくとも一部にバレット食道に特徴的な円柱上皮からなる組織を含むほ乳動物が食道腺癌を発症するのを予め阻止することを意味する。 The fourth embodiment is a method for preventing esophageal adenocarcinoma, comprising administering the preventive composition (second embodiment) according to this embodiment to a patient.
The term "prevention" as used herein means to prevent the development of esophageal adenocarcinoma in advance in mammals at risk of developing esophageal adenocarcinoma. It means to prevent in advance the development of esophageal adenocarcinoma in mammals containing tissue consisting of epithelium.
本実施形態にかかるバレット食道の治療方法および食道腺癌の予防方法の対象となる「ほ乳動物」は、ほ乳類に分類される任意の動物を意味し、特に限定はしないが、例えば、ヒトの他、イヌ、ネコ、ウサギ、フェレットなどのペット動物、ウシ、ブタ、ヒツジ、ウマなどの家畜動物などのことである。特に好ましい「ほ乳動物」は、ヒトである。
The “mammal” that is the target of the method for treating Barrett's esophagus and the method for preventing esophageal adenocarcinoma according to the present embodiment means any animal classified as a mammal, and is not particularly limited. , pet animals such as dogs, cats, rabbits and ferrets, and livestock animals such as cows, pigs, sheep and horses. A particularly preferred "mammal" is a human.
本明細書が英語に翻訳されて、単数形の「a」、「an」および「the」の単語が含まれる場合、文脈から明らかにそうでないことが示されていない限り、単数のみならず複数のものも含むものとする。
以下に実施例を示してさらに本発明の説明を行うが、本実施例は、あくまでも本発明の実施形態の例示にすぎず、本発明の範囲を限定するものではない。 When this specification is translated into English and contains the words "a", "an" and "the" in the singular, the singular as well as the plural unless the context clearly indicates otherwise. shall also include those of
EXAMPLES The present invention will be further described below with reference to Examples, but these Examples are merely illustrations of embodiments of the present invention and do not limit the scope of the present invention.
以下に実施例を示してさらに本発明の説明を行うが、本実施例は、あくまでも本発明の実施形態の例示にすぎず、本発明の範囲を限定するものではない。 When this specification is translated into English and contains the words "a", "an" and "the" in the singular, the singular as well as the plural unless the context clearly indicates otherwise. shall also include those of
EXAMPLES The present invention will be further described below with reference to Examples, but these Examples are merely illustrations of embodiments of the present invention and do not limit the scope of the present invention.
１．ラット胃食道逆流症モデル
既報（Miyashitaら, Dig Dis Sci 56:1309-1314：Miyashitaら, Surgery 164:49-55 2018）に従い、外科的手術によりラット胃食道逆流症モデルを作成した。
本実施例では、6週齢のオスのSprague-Dawleyラット（日本クレア）を使用した。ラットは2週間、馴化させたのち、温度20-22℃、湿度30-50%、12時間毎の明暗周期で飼育した。一晩絶食させたラットは、ジエチルエーテルで麻酔した後、開腹し、食道胃接合部を結紮した後、食道側で食道を切断した。トライツ（treitz）靱帯より5 cm肛門側空腸をloopで食道断端部へ挙上した。食道断端と挙上した空腸を端側吻合し、胃液、腸液が食道へ逆流するように処置を行った。上記外科手術を施したラットのほぼ100%にバレット食道が認められることが報告されている（Miyashitaら, Dig Dis Sci 56:1309-1314）、手術後17週で、トラメチニブ（trametinib）またはセルメチニブ（selumetinib）を含有する徐放ペレットまたはプラセボペレット（トラメチニブおよびセルメチニブ不含有）を皮下に挿入した。トラメチニブ投与実験の場合には手術後20週で、セルメチニブ投与実験の場合には手術後21週で、ラットを安楽死させ、食道の組織学的観察を行った。
トラメチニブの徐放ペレットは、3.4 mgのトラメチニブを含有し、28日間かけてトラメチニブを徐放する。トラメチニブは、Selleck社から購入し、徐放ペレットの作製は、Innovative Research of America社に委託した。
また、セルメチニブの徐放ペレットは、3.4 mgのセルメチニブを含有し、28日間かけてセルメチニブを徐放する。セルメチニブは、Selleck社から購入し、徐放ペレットの作製は、Innovative Research of America社に委託した。
以下、外科的手術等を行わなかった無処置のラットを「コントロールラット」（n=3；トラメチニブ投与実験）、プラセボペレットを皮下に挿入したラットを「プラセボ処置ラット」（n=12；トラメチニブ投与実験、n=3；セルメチニブ投与実験）、トラメチニブ含有ペレットを皮下に挿入したラットを「MEK阻害剤処置ラット」（n=12；トラメチニブ投与実験、n=1；セルメチニブ投与実験）とも記載する。 1. Rat gastroesophageal reflux disease model According to previous reports (Miyashita et al., Dig Dis Sci 56:1309-1314; Miyashita et al., Surgery 164:49-55 2018), a rat gastroesophageal reflux disease model was created by surgical operation.
In this example, 6-week-old male Sprague-Dawley rats (CLEA Japan) were used. After acclimation for 2 weeks, the rats were maintained at a temperature of 20-22°C, a humidity of 30-50%, and a light-dark cycle every 12 hours. Rats fasted overnight were anesthetized with diethyl ether, the abdomen was opened, the esophagogastric junction was ligated, and the esophagus was cut at the esophageal side. The jejunum 5 cm from the anal side of the treitz ligament was lifted to the esophageal stump with a loop. The esophageal stump and the elevated jejunum were anastomosed end-to-side, and treatment was performed to allow gastric and intestinal juices to flow back into the esophagus. Barrett's esophagus was reported to be present in nearly 100% of rats subjected to the above surgery (Miyashita et al., Dig Dis Sci 56:1309-1314), and treated with trametinib or selumetinib 17 weeks after surgery. Sustained-release pellets containing selumetinib) or placebo pellets (without trametinib and selumetinib) were inserted subcutaneously. At 20 weeks post-surgery for trametinib administration experiments and at 21 weeks post-surgery for selumetinib administration experiments, rats were euthanized and histological observation of the esophagus was performed.
Trametinib extended release pellets contain 3.4 mg of trametinib and provide sustained release of trametinib over 28 days. Trametinib was purchased from Selleck, Inc., and manufacturing of sustained-release pellets was outsourced to Innovative Research of America.
The selumetinib extended release pellets also contain 3.4 mg of selumetinib and provide sustained release of selumetinib over 28 days. Selumetinib was purchased from Selleck, Inc., and production of sustained-release pellets was outsourced to Innovative Research of America.
In the following, untreated rats that did not undergo surgery, etc., were "control rats" (n = 3; trametinib administration experiment), and rats subcutaneously inserted with placebo pellets were "placebo-treated rats" (n = 12; trametinib administration). Experiment, n=3; selumetinib administration experiment), rats subcutaneously inserted trametinib-containing pellets are also described as "MEK inhibitor-treated rats"(n=12; trametinib administration experiment, n=1; selumetinib administration experiment).
既報（Miyashitaら, Dig Dis Sci 56:1309-1314：Miyashitaら, Surgery 164:49-55 2018）に従い、外科的手術によりラット胃食道逆流症モデルを作成した。
本実施例では、6週齢のオスのSprague-Dawleyラット（日本クレア）を使用した。ラットは2週間、馴化させたのち、温度20-22℃、湿度30-50%、12時間毎の明暗周期で飼育した。一晩絶食させたラットは、ジエチルエーテルで麻酔した後、開腹し、食道胃接合部を結紮した後、食道側で食道を切断した。トライツ（treitz）靱帯より5 cm肛門側空腸をloopで食道断端部へ挙上した。食道断端と挙上した空腸を端側吻合し、胃液、腸液が食道へ逆流するように処置を行った。上記外科手術を施したラットのほぼ100%にバレット食道が認められることが報告されている（Miyashitaら, Dig Dis Sci 56:1309-1314）、手術後17週で、トラメチニブ（trametinib）またはセルメチニブ（selumetinib）を含有する徐放ペレットまたはプラセボペレット（トラメチニブおよびセルメチニブ不含有）を皮下に挿入した。トラメチニブ投与実験の場合には手術後20週で、セルメチニブ投与実験の場合には手術後21週で、ラットを安楽死させ、食道の組織学的観察を行った。
トラメチニブの徐放ペレットは、3.4 mgのトラメチニブを含有し、28日間かけてトラメチニブを徐放する。トラメチニブは、Selleck社から購入し、徐放ペレットの作製は、Innovative Research of America社に委託した。
また、セルメチニブの徐放ペレットは、3.4 mgのセルメチニブを含有し、28日間かけてセルメチニブを徐放する。セルメチニブは、Selleck社から購入し、徐放ペレットの作製は、Innovative Research of America社に委託した。
以下、外科的手術等を行わなかった無処置のラットを「コントロールラット」（n=3；トラメチニブ投与実験）、プラセボペレットを皮下に挿入したラットを「プラセボ処置ラット」（n=12；トラメチニブ投与実験、n=3；セルメチニブ投与実験）、トラメチニブ含有ペレットを皮下に挿入したラットを「MEK阻害剤処置ラット」（n=12；トラメチニブ投与実験、n=1；セルメチニブ投与実験）とも記載する。 1. Rat gastroesophageal reflux disease model According to previous reports (Miyashita et al., Dig Dis Sci 56:1309-1314; Miyashita et al., Surgery 164:49-55 2018), a rat gastroesophageal reflux disease model was created by surgical operation.
In this example, 6-week-old male Sprague-Dawley rats (CLEA Japan) were used. After acclimation for 2 weeks, the rats were maintained at a temperature of 20-22°C, a humidity of 30-50%, and a light-dark cycle every 12 hours. Rats fasted overnight were anesthetized with diethyl ether, the abdomen was opened, the esophagogastric junction was ligated, and the esophagus was cut at the esophageal side. The jejunum 5 cm from the anal side of the treitz ligament was lifted to the esophageal stump with a loop. The esophageal stump and the elevated jejunum were anastomosed end-to-side, and treatment was performed to allow gastric and intestinal juices to flow back into the esophagus. Barrett's esophagus was reported to be present in nearly 100% of rats subjected to the above surgery (Miyashita et al., Dig Dis Sci 56:1309-1314), and treated with trametinib or selumetinib 17 weeks after surgery. Sustained-release pellets containing selumetinib) or placebo pellets (without trametinib and selumetinib) were inserted subcutaneously. At 20 weeks post-surgery for trametinib administration experiments and at 21 weeks post-surgery for selumetinib administration experiments, rats were euthanized and histological observation of the esophagus was performed.
Trametinib extended release pellets contain 3.4 mg of trametinib and provide sustained release of trametinib over 28 days. Trametinib was purchased from Selleck, Inc., and manufacturing of sustained-release pellets was outsourced to Innovative Research of America.
The selumetinib extended release pellets also contain 3.4 mg of selumetinib and provide sustained release of selumetinib over 28 days. Selumetinib was purchased from Selleck, Inc., and production of sustained-release pellets was outsourced to Innovative Research of America.
In the following, untreated rats that did not undergo surgery, etc., were "control rats" (n = 3; trametinib administration experiment), and rats subcutaneously inserted with placebo pellets were "placebo-treated rats" (n = 12; trametinib administration). Experiment, n=3; selumetinib administration experiment), rats subcutaneously inserted trametinib-containing pellets are also described as "MEK inhibitor-treated rats"(n=12; trametinib administration experiment, n=1; selumetinib administration experiment).
２．食道の組織学的観察
２－１．トラメチニブ投与の結果
円柱上皮の組織学的特徴を呈するバレット食道部分の長さを測定した結果、MEK阻害剤（トラメチニブ）処置ラットのバレット食道の長さは、プラセボ処置ラットのバレット食道と比較して、有意に短縮していることが明らかとなった（図１）。
また、MEK阻害剤（トラメチニブ）処置ラットの食道組織をヘマトキシリン＋エオジン染色（HE染色）し、組織観察を行ったところ、びらんの中に扁平上皮が再生している組織像が観察された（図２中、破線で囲んだ領域）。他方、プラセボ処置ラットの食道組織においては、このような扁平上皮の再生は認められなかった。プラセボ処置ラットの食道組織像とMEK阻害剤（トラメチニブ）処置ラットの食道組織像を比較すると、プラセボ処置ラットの食道組織には円柱上皮が観察された（図３Ａの破線で囲んだ領域）のに対し、MEK阻害剤（トラメチニブ）処置ラットの食道組織には、円柱上皮の他、再生した扁平上皮が観察された（図３Ｂの破線で囲んだ領域が円柱上皮、実線で囲んだ領域が扁平上皮）。
以上の結果から、MEK阻害剤は、バレット食道の長さを短縮させ、食道粘膜組織における扁平上皮の再生を促すことが確認された。 2. Histological observation of esophagus 2-1. Trametinib Administration Results Measurement of the length of the segment of Barrett's esophagus, which exhibits columnar epithelial histology, showed that the length of Barrett's esophagus in MEK inhibitor (trametinib)-treated rats was significantly greater than that in placebo-treated rats. , was significantly shortened (Fig. 1).
In addition, when the esophageal tissue of MEK inhibitor (trametinib)-treated rats was stained with hematoxylin and eosin (HE staining) and histological observation was performed, a histological image of regenerated squamous epithelium in the erosion was observed (Fig. 2, area enclosed by a dashed line). On the other hand, no such regeneration of squamous epithelium was observed in the esophageal tissue of placebo-treated rats. Comparing the histology of the esophagus of placebo-treated rats with that of MEK inhibitor (trametinib)-treated rats, columnar epithelium was observed in the esophageal tissue of placebo-treated rats (the area enclosed by the dashed line in FIG. 3A). In contrast, in the esophageal tissue of MEK inhibitor (trametinib)-treated rats, in addition to columnar epithelium, regenerated squamous epithelium was observed (in FIG. ).
From the above results, it was confirmed that MEK inhibitors shorten the length of Barrett's esophagus and promote regeneration of squamous epithelium in esophageal mucosal tissue.
２－１．トラメチニブ投与の結果
円柱上皮の組織学的特徴を呈するバレット食道部分の長さを測定した結果、MEK阻害剤（トラメチニブ）処置ラットのバレット食道の長さは、プラセボ処置ラットのバレット食道と比較して、有意に短縮していることが明らかとなった（図１）。
また、MEK阻害剤（トラメチニブ）処置ラットの食道組織をヘマトキシリン＋エオジン染色（HE染色）し、組織観察を行ったところ、びらんの中に扁平上皮が再生している組織像が観察された（図２中、破線で囲んだ領域）。他方、プラセボ処置ラットの食道組織においては、このような扁平上皮の再生は認められなかった。プラセボ処置ラットの食道組織像とMEK阻害剤（トラメチニブ）処置ラットの食道組織像を比較すると、プラセボ処置ラットの食道組織には円柱上皮が観察された（図３Ａの破線で囲んだ領域）のに対し、MEK阻害剤（トラメチニブ）処置ラットの食道組織には、円柱上皮の他、再生した扁平上皮が観察された（図３Ｂの破線で囲んだ領域が円柱上皮、実線で囲んだ領域が扁平上皮）。
以上の結果から、MEK阻害剤は、バレット食道の長さを短縮させ、食道粘膜組織における扁平上皮の再生を促すことが確認された。 2. Histological observation of esophagus 2-1. Trametinib Administration Results Measurement of the length of the segment of Barrett's esophagus, which exhibits columnar epithelial histology, showed that the length of Barrett's esophagus in MEK inhibitor (trametinib)-treated rats was significantly greater than that in placebo-treated rats. , was significantly shortened (Fig. 1).
In addition, when the esophageal tissue of MEK inhibitor (trametinib)-treated rats was stained with hematoxylin and eosin (HE staining) and histological observation was performed, a histological image of regenerated squamous epithelium in the erosion was observed (Fig. 2, area enclosed by a dashed line). On the other hand, no such regeneration of squamous epithelium was observed in the esophageal tissue of placebo-treated rats. Comparing the histology of the esophagus of placebo-treated rats with that of MEK inhibitor (trametinib)-treated rats, columnar epithelium was observed in the esophageal tissue of placebo-treated rats (the area enclosed by the dashed line in FIG. 3A). In contrast, in the esophageal tissue of MEK inhibitor (trametinib)-treated rats, in addition to columnar epithelium, regenerated squamous epithelium was observed (in FIG. ).
From the above results, it was confirmed that MEK inhibitors shorten the length of Barrett's esophagus and promote regeneration of squamous epithelium in esophageal mucosal tissue.
２－２．セルメチニブ投与の結果
MEK阻害剤（セルメチニブ）処置ラットおよびプラセボ処置ラットの食道における癌の発生の有無を、肉眼的および触診的に調べた。その結果、3匹のプラセボ処置ラットの食道には、明らかな癌の発生が確認されたのに対し、MEK阻害剤（セルメチニブ）処置ラットの食道には、肉眼的にも触診的にも癌の発生は認められなかった（図４）。
さらに、MEK阻害剤（セルメチニブ）処置ラットおよびプラセボ処置ラットの食道の組織学的観察を行った。各食道組織をHE染色し観察したところ、プラセボ処置ラットの食道では癌化した組織や異型腺管などが観察されたのに対し、MEK阻害剤（セルメチニブ）処置ラットの食道では、癌化した組織は認められず、食道本来の組織である扁平上皮で覆われていることが確認できた（図５）。
以上の結果から、MEK阻害剤は、バレット食道組織における扁平上皮の再生を促し、さらには、食道組織の癌化を防ぐことが確認された。 2-2. Results of Selumetinib Administration The presence or absence of cancer development in the esophagus of MEK inhibitor (selumetinib)-treated and placebo-treated rats was examined macroscopically and palpably. As a result, the esophagus of 3 placebo-treated rats was confirmed to have obvious cancer, whereas the esophagus of the MEK inhibitor (selumetinib)-treated rats showed no cancer both macroscopically and palpably. No development was observed (Fig. 4).
In addition, histological observations of the esophagus of MEK inhibitor (selumetinib)-treated and placebo-treated rats were performed. When each esophageal tissue was observed by HE staining, cancerous tissue and atypical ducts were observed in the esophagus of placebo-treated rats, whereas cancerous tissue was observed in the esophagus of MEK inhibitor (selumetinib)-treated rats. was not observed, and it was confirmed that the esophagus was covered with squamous epithelium, which is the original tissue of the esophagus (Fig. 5).
From the above results, it was confirmed that the MEK inhibitor promotes regeneration of squamous epithelium in Barrett's esophageal tissue and prevents canceration of the esophageal tissue.
MEK阻害剤（セルメチニブ）処置ラットおよびプラセボ処置ラットの食道における癌の発生の有無を、肉眼的および触診的に調べた。その結果、3匹のプラセボ処置ラットの食道には、明らかな癌の発生が確認されたのに対し、MEK阻害剤（セルメチニブ）処置ラットの食道には、肉眼的にも触診的にも癌の発生は認められなかった（図４）。
さらに、MEK阻害剤（セルメチニブ）処置ラットおよびプラセボ処置ラットの食道の組織学的観察を行った。各食道組織をHE染色し観察したところ、プラセボ処置ラットの食道では癌化した組織や異型腺管などが観察されたのに対し、MEK阻害剤（セルメチニブ）処置ラットの食道では、癌化した組織は認められず、食道本来の組織である扁平上皮で覆われていることが確認できた（図５）。
以上の結果から、MEK阻害剤は、バレット食道組織における扁平上皮の再生を促し、さらには、食道組織の癌化を防ぐことが確認された。 2-2. Results of Selumetinib Administration The presence or absence of cancer development in the esophagus of MEK inhibitor (selumetinib)-treated and placebo-treated rats was examined macroscopically and palpably. As a result, the esophagus of 3 placebo-treated rats was confirmed to have obvious cancer, whereas the esophagus of the MEK inhibitor (selumetinib)-treated rats showed no cancer both macroscopically and palpably. No development was observed (Fig. 4).
In addition, histological observations of the esophagus of MEK inhibitor (selumetinib)-treated and placebo-treated rats were performed. When each esophageal tissue was observed by HE staining, cancerous tissue and atypical ducts were observed in the esophagus of placebo-treated rats, whereas cancerous tissue was observed in the esophagus of MEK inhibitor (selumetinib)-treated rats. was not observed, and it was confirmed that the esophagus was covered with squamous epithelium, which is the original tissue of the esophagus (Fig. 5).
From the above results, it was confirmed that the MEK inhibitor promotes regeneration of squamous epithelium in Barrett's esophageal tissue and prevents canceration of the esophageal tissue.
３．MEK阻害剤の効果の確認
MEK阻害剤であるトラメチニブが、投与された食道組織において、MEKキナーゼ活性を阻害したかどうかの確認を行った。MEKは、MAPKシグナル伝達経路において、ERKをリン酸化し、活性化するキナーゼである。トラメチニブなどのMEK阻害剤は、MEKキナーゼ活性を阻害する。そのため、食道組織内においてMEK阻害剤が機能したかどうかは、ERKのリン酸化の有無を指標にして確認することができる。
MEK阻害剤処置ラットおよびプラセボ処置ラットの各々から切除した食道組織を4%パラフォルムアルデヒド固定後、パラフィンブロックを作成し、パラフィン切片を作製した。作製した切片をスライドに貼り付けた後、風乾した。ヒストクリア（登録商標）（コスモ・バイオ株式会社）にて脱パラフィン後、100%エタノールにて水和させ、3%過酸化水素水にてブロッキング後、マイクロウェーブにて抗原賦活を行なった。PBSで切片を洗浄した後、3%ヤギ血清中、室温で1時間静置してブロッキングを行った。スライドをPBSで洗浄後、抗pERK抗体（アブカム社）溶液を添加し、4℃で一晩インキュベーションした。その後、PBSで洗浄後、ABC法にてビオチン標識二次抗体（Vector社）をスライドに添加し、室温で60分間インキュベーションした。PBSでスライドを洗浄後、HRP標識アビジン－ビオチン複合体をスライドに添加し、室温で30分間インキュベーションした。その後、PBSでスライドを洗浄後、HRPの基質としてDAB（3,3’‐ジアミノベンジジン四塩酸塩）を用いて発色を行った。免疫染色後のスライドは、共焦点顕微鏡で観察を行った。 3. Confirmation of Effect of MEK Inhibitor It was confirmed whether trametinib, a MEK inhibitor, inhibited MEK kinase activity in the administered esophageal tissue. MEK is a kinase that phosphorylates and activates ERK in the MAPK signaling pathway. MEK inhibitors such as trametinib inhibit MEK kinase activity. Therefore, whether or not the MEK inhibitor functions in the esophageal tissue can be confirmed using the presence or absence of ERK phosphorylation as an index.
The esophageal tissues excised from each of the MEK inhibitor-treated rats and the placebo-treated rats were fixed with 4% paraformaldehyde, paraffin blocks were prepared, and paraffin sections were prepared. After attaching the prepared section to a slide, it was air-dried. After deparaffinization with Histoclear (registered trademark) (Cosmo Bio Co., Ltd.), the cells were hydrated with 100% ethanol, blocked with 3% hydrogen peroxide solution, and then subjected to antigen retrieval with microwaves. After washing the sections with PBS, they were left standing in 3% goat serum at room temperature for 1 hour for blocking. After washing the slides with PBS, anti-pERK antibody (Abcam) solution was added and incubated overnight at 4°C. Then, after washing with PBS, a biotin-labeled secondary antibody (Vector) was added to the slide by the ABC method and incubated at room temperature for 60 minutes. After washing the slides with PBS, HRP-labeled avidin-biotin complex was added to the slides and incubated for 30 minutes at room temperature. Then, after washing the slide with PBS, color development was performed using DAB (3,3'-diaminobenzidine tetrahydrochloride) as a substrate for HRP. After immunostaining, the slides were observed with a confocal microscope.
MEK阻害剤であるトラメチニブが、投与された食道組織において、MEKキナーゼ活性を阻害したかどうかの確認を行った。MEKは、MAPKシグナル伝達経路において、ERKをリン酸化し、活性化するキナーゼである。トラメチニブなどのMEK阻害剤は、MEKキナーゼ活性を阻害する。そのため、食道組織内においてMEK阻害剤が機能したかどうかは、ERKのリン酸化の有無を指標にして確認することができる。
MEK阻害剤処置ラットおよびプラセボ処置ラットの各々から切除した食道組織を4%パラフォルムアルデヒド固定後、パラフィンブロックを作成し、パラフィン切片を作製した。作製した切片をスライドに貼り付けた後、風乾した。ヒストクリア（登録商標）（コスモ・バイオ株式会社）にて脱パラフィン後、100%エタノールにて水和させ、3%過酸化水素水にてブロッキング後、マイクロウェーブにて抗原賦活を行なった。PBSで切片を洗浄した後、3%ヤギ血清中、室温で1時間静置してブロッキングを行った。スライドをPBSで洗浄後、抗pERK抗体（アブカム社）溶液を添加し、4℃で一晩インキュベーションした。その後、PBSで洗浄後、ABC法にてビオチン標識二次抗体（Vector社）をスライドに添加し、室温で60分間インキュベーションした。PBSでスライドを洗浄後、HRP標識アビジン－ビオチン複合体をスライドに添加し、室温で30分間インキュベーションした。その後、PBSでスライドを洗浄後、HRPの基質としてDAB（3,3’‐ジアミノベンジジン四塩酸塩）を用いて発色を行った。免疫染色後のスライドは、共焦点顕微鏡で観察を行った。 3. Confirmation of Effect of MEK Inhibitor It was confirmed whether trametinib, a MEK inhibitor, inhibited MEK kinase activity in the administered esophageal tissue. MEK is a kinase that phosphorylates and activates ERK in the MAPK signaling pathway. MEK inhibitors such as trametinib inhibit MEK kinase activity. Therefore, whether or not the MEK inhibitor functions in the esophageal tissue can be confirmed using the presence or absence of ERK phosphorylation as an index.
The esophageal tissues excised from each of the MEK inhibitor-treated rats and the placebo-treated rats were fixed with 4% paraformaldehyde, paraffin blocks were prepared, and paraffin sections were prepared. After attaching the prepared section to a slide, it was air-dried. After deparaffinization with Histoclear (registered trademark) (Cosmo Bio Co., Ltd.), the cells were hydrated with 100% ethanol, blocked with 3% hydrogen peroxide solution, and then subjected to antigen retrieval with microwaves. After washing the sections with PBS, they were left standing in 3% goat serum at room temperature for 1 hour for blocking. After washing the slides with PBS, anti-pERK antibody (Abcam) solution was added and incubated overnight at 4°C. Then, after washing with PBS, a biotin-labeled secondary antibody (Vector) was added to the slide by the ABC method and incubated at room temperature for 60 minutes. After washing the slides with PBS, HRP-labeled avidin-biotin complex was added to the slides and incubated for 30 minutes at room temperature. Then, after washing the slide with PBS, color development was performed using DAB (3,3'-diaminobenzidine tetrahydrochloride) as a substrate for HRP. After immunostaining, the slides were observed with a confocal microscope.
抗pERK抗体で染色されるリン酸化ERKは、プラセボ処置ラット由来の食道組織内においてその分布が認められたのに対し（図６Ａ）、MEK阻害剤処置ラット由来の食道組織内においては、染色強度の減弱が認められた（図６Ｂ）。この結果から、MEK阻害剤処置ラットの食道組織において、MEK阻害剤によりMEKキナーゼ活性が阻害されたことが確認できた。
Phosphorylated ERK stained with anti-pERK antibody was distributed in esophageal tissue from placebo-treated rats (Fig. 6A), whereas staining intensity in esophageal tissue from MEK inhibitor-treated rats was low. Attenuation of was observed (Fig. 6B). This result confirmed that the MEK inhibitor inhibited the MEK kinase activity in the esophageal tissue of MEK inhibitor-treated rats.
以上の結果から、MEK阻害剤は、円柱上皮からなるバレット食道の長さを短縮し、扁平上皮の再生を促し、かつ、バレット食道の癌化を防ぐ効果を有することが分かった。
From the above results, it was found that MEK inhibitors have the effect of shortening the length of Barrett's esophagus, which consists of columnar epithelium, promoting regeneration of squamous epithelium, and preventing canceration of Barrett's esophagus.
本発明にかかる治療組成物は、バレット食道の粘膜組織を正常な食道の粘膜組織に復帰させ、さらには、食道腺癌への進行を予防する効果を発揮する。従って、本発明は、医学分野（特に、がん治療分野）における利用が期待される。
The therapeutic composition of the present invention restores the mucosal tissue of Barrett's esophagus to normal esophageal mucosal tissue, and further exerts the effect of preventing progression to esophageal adenocarcinoma. Therefore, the present invention is expected to be used in the medical field (particularly in the cancer treatment field).
The therapeutic composition of the present invention restores the mucosal tissue of Barrett's esophagus to normal esophageal mucosal tissue, and further exerts the effect of preventing progression to esophageal adenocarcinoma. Therefore, the present invention is expected to be used in the medical field (particularly in the cancer treatment field).
Claims (5)
- バレット食道の治療用組成物であって、MEK阻害剤を含む前記組成物。 A composition for treating Barrett's esophagus, said composition comprising a MEK inhibitor.
- 前記MEK阻害剤が、トラメチニブ、ビニメチニブ、セルメチニブ、コビメチニブ、ピマセルチブ、レファメチニブ、ウリキセルチニブ、アベマシクリブ、U0126、PD184352（CI-1040）、PD98059およびBIX 02189からなるグループから選択される1または複数であることを特徴とする請求項１に記載の組成物。 wherein the MEK inhibitor is one or more selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, pimasertib, lefametinib, urixertinib, abemaciclib, U0126, PD184352 (CI-1040), PD98059 and BIX 02189 The composition of claim 1, comprising:
- 食道腺癌の予防用組成物であって、MEK阻害剤を含む前記組成物。 A composition for preventing esophageal adenocarcinoma, which composition contains a MEK inhibitor.
- 前記MEK阻害剤が、トラメチニブ、ビニメチニブ、セルメチニブ、コビメチニブ、ピマセルチブ、レファメチニブ、ウリキセルチニブ、アベマシクリブ、U0126、PD184352（CI-1040）、PD98059およびBIX 02189からなるグループから選択される1または複数であることを特徴とする請求項３に記載の組成物。 wherein the MEK inhibitor is one or more selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, pimasertib, lefametinib, urixertinib, abemaciclib, U0126, PD184352 (CI-1040), PD98059 and BIX 02189 4. The composition of claim 3, wherein
- バレット食道を発症している患者に投与することを特徴とする、請求項３または請求項４に記載の組成物。
5. The composition according to claim 3 or 4, characterized in that it is administered to a patient suffering from Barrett's esophagus.
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