JP2022504098A - Composition for prevention or treatment of macular degeneration - Google Patents
Composition for prevention or treatment of macular degeneration Download PDFInfo
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- JP2022504098A JP2022504098A JP2021518126A JP2021518126A JP2022504098A JP 2022504098 A JP2022504098 A JP 2022504098A JP 2021518126 A JP2021518126 A JP 2021518126A JP 2021518126 A JP2021518126 A JP 2021518126A JP 2022504098 A JP2022504098 A JP 2022504098A
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- Prior art keywords
- macular degeneration
- fursultiamine
- neovascular
- pharmaceutical composition
- neovascularization
- Prior art date
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Abstract
本発明は、フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）又はその塩（ｓａｌｔｓ）を含む、黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）予防又は治療用薬剤学的組成物に関する。フルスルチアミンは、網膜色素上皮細胞において増加したＨＩＦ－１αの発現を減少させ、脈絡膜血管内皮細胞成長を抑制する。本発明のフルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）又はその塩（ｓａｌｔｓ）を含む薬剤学的組成物は、様々な新生血管性眼疾患の治療剤にも利用可能である。
【選択図】図１
The present invention relates to a pharmaceutical composition for the prevention or treatment of macular degeneration, which comprises fursultiamine or a salt thereof. Fursultiamine reduces the increased expression of HIF-1α in retinal pigment epithelial cells and suppresses choroidal vascular endothelial cell growth. The pharmaceutical composition containing fursultiamine or a salt thereof (salts) of the present invention can also be used as a therapeutic agent for various neovascular eye diseases.
[Selection diagram] Fig. 1
Description
本発明は、保健福祉部の支援下で課題番号ＨＩ１６Ｃ１５０１によってなされたものであり、前記課題の研究管理専門機関は韓国保健産業振興院、研究事業名は“先導型特性化研究開発事業”、研究課題名は“糖尿病性心血管合併症治療剤及び効能評価システム開発”、主管機関はキョンブク大学校病院、研究期間は２０１６．０４．０１～２０２１．０３．３１である。 The present invention was made by the subject number HI16C1501 with the support of the Ministry of Health and Welfare. The title of the project is "Development of therapeutic agent for diabetic cardiovascular complications and efficacy evaluation system", the main institution is Kyungbuk University Hospital, and the research period is 2016.04.01 to 2021.03.31.
また、本発明は、教育部の支援下で課題番号２０１７Ｒ１Ｄ１Ａ１Ｂ０３０２７９６６によってなされたものであり、前記課題の研究管理専門機関は韓国研究財団、研究事業名は“理工学個人基礎研究支援事業”、研究課題名は“Ｓｅｍａｐｈｏｒｉｎ ３Ａ及びＡｎｇｉｏｐｏｉｅｔｉｎ－ｌｉｋｅ ４を標的にするｍｉｃｒｏＲＮＡ制御による脈絡膜網膜新生血管及び血管透過性亢進調節効能評価”、主管機関はキョンブク大学校産学協力団、研究期間は２０１７．０６．０１～２０２０．０５．３１である。 Further, the present invention was made by the subject number 2017R1D1A1B030279666 with the support of the Ministry of Education. The name is "Evaluation of choroidal retinal neovascular and vascular hyperpermeability regulation efficacy by microRNA control targeting Semiphorin 3A and Angiopoietin-like 4", the main institution is Kyonbuku University Industry-Academia Cooperation Group, research period is 2017.06.01 ~ It is 2020.05.31.
また、本発明は、教育部の支援下で課題番号２０１９Ｒ１Ａ２Ｃ１０８４３７１によってなされたものであり、前記課題の研究管理専門機関は韓国研究財団、研究事業名は“理工学中堅研究者支援事業”、研究課題名は“免疫細胞のミトコンドリアエネルギー代謝リプログラミング及び炎症活性化制御を用いた新生血管性加齢黄斑変性新規治療機転研究”、主管機関はキョンブク大学校産学協力団、研究期間は２０１９．０９．０１～２０２４．０２．２９である。 Further, the present invention was made by the subject No. 2019R1A2C1084371 with the support of the Ministry of Education. The name is "Research on new therapeutic mechanism of neovascular age-related yellow spot degeneration using mitochondrial energy metabolism reprogramming and inflammation activation control of immune cells", the main institution is Kyungbuk University Industry-Academia Cooperation Group, and the research period is 2019.09.01 It is ~ 2024.02.29.
本特許出願は、２０１８年１１月２日に大韓民国特許庁に提出された大韓民国特許出願第１０－２０１８－０１３３６７７号に対して優先権を主張し、この特許出願の開示事項は本明細書に参照によって組み込まれる。 This patent application claims priority to the Republic of Korea Patent Application No. 10-2018-0133677 filed with the Republic of Korea Patent Office on November 2, 2018, and the disclosure items of this patent application are referred to in this specification. Incorporated by.
本発明は、黄斑変性予防又は治療用組成物に関する。より詳細には、本発明は、フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）又はその塩（ｓａｌｔｓ）を含む黄斑変性予防又は治療用組成物に関する。 The present invention relates to a composition for preventing or treating macular degeneration. More specifically, the present invention relates to a composition for preventing or treating macular degeneration containing fursultiamine or a salt thereof (salts).
黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）は、黄斑部分に変性が起きて視力障害を起こす眼球疾患で、発病原因は、加齢、家族力、人種、喫煙と関連があると知られている。発病初期には視野がぼやけ、近くの物が歪んで見えるが、最後には失明に至る。 Macular degeneration is an eye disease in which degeneration occurs in the macula and causes visual acuity, and the cause of the disease is known to be related to aging, family strength, race, and smoking. In the early stages of illness, the visual field is blurred and nearby objects appear distorted, but eventually blindness occurs.
加齢黄斑変性（ａｇｅ－ｒｅｌａｔｅｄ ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ，ＡＭＤ）は、重症の非可逆的な視力喪失を引き起こし、５０歳以上の人口における失明の主要原因と知られている。疫学研究において有病率は、米国内５２～６４歳人口の１．２％であると報告されており、７５歳以上ではその比率が２０～３７％とより高いと報告され、平均年齢が増加するほど有病率は増加していくと考えられる。 Age-related macular degeneration (AMD) causes severe and irreversible vision loss and is known to be the leading cause of blindness in the population over the age of 50. Epidemiological studies have reported a prevalence of 1.2% of the population aged 52-64 years in the United States, with a higher prevalence of 20-37% for people aged 75 and over, increasing average age. It is thought that the prevalence increases as the disease increases.
加齢黄斑変性には２類型がある。その第一は非新生血管性加齢黄斑変性で、最も通常のものであり、全加齢黄斑変性事例の８５％を占める。このような乾性類型は、網膜色素上皮の油カスと萎縮性変化を特徴とする。その第二は新生血管性加齢黄斑変性であり、脈絡膜新生血管を特徴とする。脈絡膜新生血管は新しく形成された血管に血液と体液を流出させる傾向がある。これは、網膜組織に繊維組織が増殖し、光受容体が消失された病変の形成を誘導し、進行し続けて重症且つ非可逆的な視力喪失を招く。 There are two types of age-related macular degeneration. The first is non-neovascular age-related macular degeneration, which is the most common and accounts for 85% of all age-related macular degeneration cases. Such drytypes are characterized by oil debris and atrophic changes in the retinal pigment epithelium. The second is neovascular age-related macular degeneration, which is characterized by choroidal neovascularization. Choroidal neovascularization tends to drain blood and fluid into newly formed blood vessels. This leads to the growth of fibrous tissue in the retinal tissue, inducing the formation of lesions in which photoreceptors have disappeared, and continues to progress, leading to severe and irreversible loss of vision.
特に、２０１０年に発表された韓国内加齢黄斑変性に対する基礎疫学調査によれば、加齢黄斑変性の有病率は、初期変性が２．９２％、後期変性が０．１９％であるが、後期黄斑変性のうち、非新生血管性黄斑変性は３．９％で、残りはいずれも新生血管性と観察され、新生血管性黄斑変性の頻度が海外に比べて非常に高いことが分かる。 In particular, according to the basic epidemiological survey on age-related macular degeneration in Korea published in 2010, the prevalence of age-related macular degeneration is 2.92% for early degeneration and 0.19% for late degeneration. Of the late-stage macular degeneration, non-neovascular macular degeneration was observed to be 3.9%, and the rest were observed to be neovascular, indicating that the frequency of neovascular macular degeneration is much higher than in other countries.
新生血管性加齢黄斑変性の治療法には、光力学療法と血管内皮成長因子を遮断するための薬物を眼球中に注射する方法がある。しかし、多くの大規模多機関臨床研究では、光力学療法に比べて、硝子体腔内血管内皮成長因子（ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ ｇｒｏｗｔｈ ｆａｃｔｏｒ，ＶＥＧＦ）注射術を施行する方がより良い結果を示した。 Treatments for neovascular age-related macular degeneration include photodynamic therapy and injection of a drug to block vascular endothelial growth factor into the eyeball. However, many large multi-institutional clinical studies have shown better results with vascular endothelial growth factor (VEGF) injection than with photodynamic therapy.
これによって、新生血管性加齢黄斑変性の治療のために様々な抗血管内皮成長因子薬物が開発されたが、その代表的な薬剤がラニビズマブ（Ｒａｎｉｂｉｚｕｍａｂ，Ｌｕｃｅｎｔｉｓ（登録商標））であり、細胞外の血管内皮成長因子と結合して活性を抑制させる。ラニビズマブは、様々な臨床研究から、新生血管性加齢黄斑変性患者にとって効果的で安全な治療であることが報告され、全世界的に広く用いられている。 As a result, various anti-vascular endothelial growth factor drugs have been developed for the treatment of neovascular age-related macular degeneration, and the representative drug is ranibizumab (Lucentis®), which is extracellular. It binds to vascular endothelial growth factor and suppresses its activity. Ranibizumab has been reported by various clinical studies to be an effective and safe treatment for patients with neovascular age-related macular degeneration, and is widely used worldwide.
しかしながら、病変がよく再発し、注射回数の増加によって患者に相当な負担を与える。一部の患者では、注射術にもかかわらず病変が好転しない場合もある。 However, the lesions often recur and the increased number of injections puts a considerable burden on the patient. In some patients, the lesion may not improve despite the injection.
一方、血管内皮成長因子（ＶＥＧＦ）は強力な血管拡張剤の役割を担い、心臓の冠状動脈の弛緩と血液循環を維持させる。加齢黄斑変性患者たちは高齢で、心血管疾患の危険が高い群であるため、血管内皮成長因子注射術は深刻な副作用の危険性もある。 Vascular Endothelial Growth Factor (VEGF), on the other hand, acts as a potent vasodilator, maintaining relaxation of the coronary arteries of the heart and maintenance of blood circulation. Vascular Endothelial Growth Factor Injection also carries the risk of serious side effects, as age-related macular degeneration patients are older and at increased risk of cardiovascular disease.
そこで、本発明では、副作用の危険性を減らし、黄斑変性に対して効率的な治療効果をもたらす新しい治療組成物を提案しようとする。 Therefore, the present invention attempts to propose a new therapeutic composition that reduces the risk of side effects and brings about an efficient therapeutic effect on macular degeneration.
本発明者らは、副作用の危険性が低減した黄斑変性治療剤を開発するために鋭意研究努力した。その結果、本発明者らは、フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）が網膜色素上皮細胞で増加したＨＩＦ－１αの発現を減少させ、脈絡膜血管内皮細胞成長を抑制することを確認し、本発明を完成するに至った。 The present inventors have made diligent research efforts to develop a therapeutic agent for macular degeneration with a reduced risk of side effects. As a result, the present inventors confirmed that fursultiamine reduced the expression of increased HIF-1α in retinal pigment epithelial cells and suppressed the growth of choroidal vascular endothelial cells, and completed the present invention. It came to.
そこで、本発明の目的は、黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）予防又は治療用薬剤学的組成物を提供することである。 Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating macular degeneration.
本発明の他の目的は、黄斑変性予防又は改善用食品組成物を提供することである。 Another object of the present invention is to provide a food composition for preventing or improving macular degeneration.
本発明のさらに他の目的は、新生血管性眼疾患（ｎｅｏｖａｓｃｕｌａｒ ｏｃｕｌａｒ ｄｉｓｅａｓｅ）予防又は治療用薬剤学的組成物を提供することである。 Yet another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of neovascular ocular disease.
本発明のさらに他の目的は、新生血管性眼疾患予防又は改善用食品組成物を提供することである。 Yet another object of the present invention is to provide a food composition for preventing or ameliorating neovascular eye disease.
本発明のさらに他の目的は、黄斑変性治療方法を提供することである。 Yet another object of the present invention is to provide a method for treating macular degeneration.
本発明のさらに他の目的は、新生血管性眼疾患治療方法を提供することである。 Yet another object of the present invention is to provide a method for treating neovascular eye disease.
本発明の一様態は、フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）又はその塩（ｓａｌｔｓ）を含む黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）予防又は治療用薬剤学的組成物に関する。 The uniformity of the present invention relates to a pharmaceutical composition for preventing or treating macular degeneration, which comprises fursultiamine or a salt thereof.
本発明者らは副作用の危険性が低減した黄斑変性治療剤を開発するために鋭意研究努力した。その結果、本発明者らは、フルスルチアミンが網膜色素上皮細胞で増加したＨＩＦ－１αの発現を減少させ、脈絡膜血管内皮細胞成長を抑制することを確認した。 The present inventors have made diligent research efforts to develop a therapeutic agent for macular degeneration with a reduced risk of side effects. As a result, the present inventors confirmed that fursultiamine reduced the expression of HIF-1α increased in retinal pigment epithelial cells and suppressed the growth of choroidal vascular endothelial cells.
本発明の特徴及び利点を要約すると、次の通りである：
（ａ）本発明は、フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）又はその塩（ｓａｌｔｓ）を含む、黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）予防又は治療用薬剤学的組成物に関する。
（ｂ）フルスルチアミンは、網膜色素上皮細胞で増加されたＨＩＦ－１αの発現を減少させ、脈絡膜血管内皮細胞成長を抑制する。
（ｃ）本発明のフルスルチアミン又はその塩を含む薬剤学的組成物は、様々な新生血管性眼疾患の治療剤にも用いることができる。
The features and advantages of the present invention can be summarized as follows:
(A) The present invention relates to a pharmaceutical composition for preventing or treating macular degeneration, which comprises fursultiamine or a salt thereof.
(B) Fursultiamine reduces the increased expression of HIF-1α in retinal pigment epithelial cells and suppresses choroidal vascular endothelial cell growth.
(C) The pharmaceutical composition containing fursultiamine or a salt thereof of the present invention can also be used as a therapeutic agent for various neovascular eye diseases.
フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ；ｔｈｉａｍｉｎｅ ｔｅｔｒａｈｙｄｒｏｆｕｒｆｕｒｙｌ ｄｉｓｕｌｆｉｄｅ，ＴＴＦＤ）は、チアミン欠乏症の治療に用いられるビタミンＢ１の活性ビタミンであり、チアミンジスルフィド誘導体である。ビタミンＢ１に比べて細胞内によく吸収され、多量のコカルボキシラーゼ（ｃｏ－ｃａｒｂｏｘｙｌａｓｅ）を生成して、生理学的にビタミンＢ１の欠乏や代謝障害に関連した神経機能障害、心筋代謝障害などを改善させるものと知られている。 Fursultiamine (thiamine ttrahydrofuryl disulfide, TTFD) is an active vitamin of vitamin B1 used in the treatment of thiamine deficiency and is a thiamine disulfide derivative. It is better absorbed into cells than vitamin B1 and produces a large amount of co-carboxylase, which physiologically causes neurological dysfunction and myocardial metabolic disorders related to vitamin B1 deficiency and metabolic disorders. It is known to improve.
黄斑変性（Ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）の発病原因は、加齢、家族力、人種、喫煙などがあるが、主に加齢によって発生する。黄斑変性では網膜色素上皮と脈絡膜との間の黄斑（網膜の一部）にドルーゼン（ｄｒｕｓｅｎ、細胞外タンパク質と脂質の蓄積）という黄色沈殿物が蓄積されていく。 The causes of macular degeneration include aging, family power, race, smoking, etc., but it mainly occurs with aging. In macular degeneration, a yellow precipitate called drusen (accumulation of extracellular proteins and lipids) accumulates in the macula (part of the retina) between the retinal pigment epithelium and the choroid.
年齢の増加によって発生する加齢黄斑変性（ａｇｅ－ｒｅｌａｔｅｄ ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ，ＡＭＤ）は、ドルーゼンの程度（サイズ及び数）に部分的に基づいて初期（ｅａｒｌｙ）、中期（ｉｎｔｅｒｍｅｄｉａｔｅ）、及び後期（ｌａｔｅ）の３段階に分けられる。 Age-related macular degeneration (AMD), which occurs with increasing age, is early, intermediate, and late, partly based on the degree (size and number) of drusen. It can be divided into three stages.
本発明の一具現例によれば、前記黄斑変性は、加齢黄斑変性（ａｇｅ－ｒｅｌａｔｅｄ ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ，ＡＭＤ）である。 According to one embodiment of the present invention, the macular degeneration is age-related macular degeneration (AMD).
本発明の他の具現例によれば、前記黄斑変性は、後期加齢黄斑変性（ｌａｔｅ ａｇｅ－ｒｅｌａｔｅｄ ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ，ｌａｔｅ ＡＭＤ）である。 According to another embodiment of the present invention, the macular degeneration is late age-related macular degeneration (late AMD).
後期ＡＭＤでは、網膜損傷が起き、ドルーゼンの他にも有症状の視力損失が発生する。後期ＡＭＤは、損傷類型によって乾式ＡＭＤと湿式ＡＭＤとに区別される。乾式ＡＭＤは、地図状萎縮症（Ｇｅｏｇｒａｐｈｉｃ ａｔｒｏｐｈｙ）を特徴とし、非血管新生性ＡＭＤである。一方、湿式ＡＭＤは、脈絡膜新生血管が現れる血管新生性ＡＭＤ（Ｎｅｏｖａｓｃｕｌａｒ ＡＭＤ）である。 Late AMD causes retinal damage and causes symptomatic visual loss in addition to drusen. Late AMD is divided into dry AMD and wet AMD according to the type of injury. Dry AMD is a non-angiogenic AMD characterized by geographic atrophy. On the other hand, the wet AMD is an angiogenic AMD (Neovascular AMD) in which choroidal neovascularization appears.
本発明の他の具現例によれば、前記黄斑変性は、新生血管性加齢黄斑変性（Ｎｅｏｖａｓｃｕｌａｒ ａｇｅ－ｒｅｌａｔｅｄ ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ，Ｎｅｏｖａｓｃｕｌａｒ ＡＭＤ）又は非血管新生性加齢黄斑変性（Ｎｏｎ－ｎｅｏｖａｓｃｕｌａｒ ａｇｅ－ｒｅｌａｔｅｄ ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ，Ｎｏｎ－ｎｅｏｖａｓｃｕｌａｒ ＡＭＤ）である。 According to other embodiments of the present invention, the macular degeneration is neovascular age-related macular degeneration (Neovascalar AMD) or non-neovascular age-relate. macular degeneration, Non-neovascular AMD).
本発明の他の具現例によれば、前記黄斑変性は、新生血管性加齢黄斑変性である。 According to another embodiment of the present invention, the macular degeneration is neovascular age-related macular degeneration.
本発明の薬剤学的組成物は、フルスルチアミン又はその塩の有効量が１００ｍｇ／６０ｋｇ／日～２４０ｍｇ／６０ｋｇ／日である。 The pharmaceutical composition of the present invention has an effective amount of fursultiamine or a salt thereof of 100 mg / 60 kg / day to 240 mg / 60 kg / day.
本発明において有効成分として用いられるフルスルチアミンは、それ自体又は塩の形態、好ましくは薬剤学的に許容可能な塩の形態で用いられてよい。 The fursultiamine used as the active ingredient in the present invention may be used by itself or in the form of a salt, preferably in the form of a pharmaceutically acceptable salt.
前記塩としては、遊離酸（ｆｒｅｅ ａｃｉｄ）によって形成された酸付加塩が好ましい。 As the salt, an acid addition salt formed by a free acid is preferable.
前記遊離酸は、有機酸及び／又は無機酸でよい。 The free acid may be an organic acid and / or an inorganic acid.
前記有機酸は、クエン酸、酢酸、乳酸、酒石酸、マレイン酸、フマル酸、ギ酸、プロピオン酸、シュウ酸、トリフルオロ酢酸、ベンゾ酸、グルコン酸、メタスルホン酸、グリコール酸、コハク酸、４－トルエンスルホン酸、グルタミン酸及びアスパラギン酸などであり得るが、これに制限されない。 The organic acids include citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid and 4-toluene. It can be, but is not limited to, sulfonic acid, glutamic acid, aspartic acid, and the like.
前記無機酸は、塩酸、臭素酸、硫酸及びリン酸などであり得るが、これに制限されない。 The inorganic acid may be, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like.
本発明の薬剤学的組成物は、フルスルチアミン又はその塩の他に、薬剤学的に許容される担体（ｃａｒｒｉｅｒ）を含むことができる。 The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier in addition to fursultiamine or a salt thereof.
前記薬剤学的に許容される担体は、製剤時に通常用いられるものであり、ラクトース、デキストロース、スクロース、ソルビトール、マンニトール、澱粉、アカシアガム、リン酸カルシウム、アルジネート、ゼラチン、ケイ酸カルシウム、微結晶性セルロース、ポリビニルピロリドン、セルロース、水、シロップ、メチルセルロース、ヒドロキシ安息香酸メチル、ヒドロキシ安息香酸プロピル、滑石、ステアリン酸マグネシウム及びミネラルオイルなどを含むが、これに限定されない。 The pharmaceutically acceptable carrier is one commonly used at the time of formulation, such as lactose, dextrose, syrup, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, Includes, but is not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oils.
本発明の薬剤学的組成物は、これらの成分の他に、潤滑剤、湿潤剤、甘味剤、香味剤、乳化剤、懸濁剤、保存剤などをさらに含むことができる。好適な薬剤学的に許容される担体及び製剤はＲｅｍｉｎｇｔｏｎ’ｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅｓ（１９ｔｈ ｅｄ．，１９９５）に詳細に記載されている。 In addition to these components, the pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
本発明の薬剤学的組成物は、経口又は非経口で投与できる。 The pharmaceutical composition of the present invention can be administered orally or parenterally.
非経口投与では、静脈内注入、皮下注入、筋肉注入、腹腔注入、経皮投与、眼球投与又は眼球局所投与などで投与できる。 In parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, peritoneal injection, transdermal administration, eyeball administration, topical eyeball administration, or the like.
眼球局所投与は、例えば、直接に眼球内投薬されたり、眼球周囲、眼球後ろ、網膜下（ｓｕｂｒｅｔｉｎａｌ）、網膜中心（ｃｅｎｔｒａｌ ｒｅｔｉｎａｌ）、中心窩（ｆｏｖｅａ）外部、結膜下（ｓｕｂｃｏｎｊｕｎｃｔｉｖａｌ）、硝子体内（ｉｎｔｒａｖｉｔｒｅｏｕｓ）、前房内（ｉｎｔｒａｃａｍｅｒａｌ）又は脈絡膜上（ｓｕｐｒａｃｈｏｒｏｉｄａｌ）などに投与することを含む。 Topical ocular administration may be, for example, direct intraocular medication, periocular, posterior, subretinal, central retina, outside the fovea, subconjunctival, intravitreal (subconjunctival). Includes administration to intravitreous, intravitreal or suprachoroidal, and the like.
本発明の薬剤学的組成物は、挿入装置を介して投薬されてもよい。 The pharmaceutical composition of the present invention may be administered via an insertion device.
本発明の薬剤学的組成物の好適な投与量は、製剤化方法、投与方式、患者の年齢、体重、性別、病的状態、飲食、投与時間、投与経路、排泄速度及び放射線反応感応性のような要因によって様々であり、通常熟練した医師は所望の治療に効果的な投与量を容易に決定及び処方できる。 Suitable doses of the pharmaceutical composition of the present invention include formulation method, administration method, patient age, body weight, sex, pathological condition, eating and drinking, administration time, administration route, excretion rate and radiation response sensitivity. Depending on such factors, a skilled physician can easily determine and prescribe an effective dose for the desired treatment.
本発明の薬剤学的組成物は、当該発明の属する技術の分野における通常の知識を有する者が容易に実施できる方法によって、薬剤学的に許容される担体及び／又は賦形剤を用いて製剤化することによって、単位容量形態で製造されてもよく、又は多回容量容器内に内入して製造されてもよい。このとき、剤形は、オイル又は水性媒質中の溶液、懸濁液又は乳化液の形態であるか、軟膏剤、エキス剤、粉末剤、顆粒剤、錠剤又はカプセル剤の形態であってもよく、分散剤又は安定化剤をさらに含むことができる。 The pharmaceutical composition of the present invention is formulated using a pharmaceutically acceptable carrier and / or excipient by a method that can be easily carried out by a person having ordinary knowledge in the field of the technique to which the invention belongs. It may be manufactured in the form of a unit capacity, or it may be manufactured by putting it in a multi-volume container. At this time, the dosage form may be in the form of a solution, suspension or emulsion in an oil or an aqueous medium, or in the form of an ointment, an extract, a powder, a granule, a tablet or a capsule. , Dispersants or stabilizers can be further included.
本発明の他の様態は、フルスルチアミン又はその塩を含む黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）予防又は改善用食品組成物に関する。 Another aspect of the invention relates to a food composition for preventing or ameliorating macular degeneration comprising fursultiamine or a salt thereof.
本発明の組成物が食品組成物である場合には、粉末、顆粒、錠剤、カプセル又は飲料などの形態で製造されてよい。 When the composition of the present invention is a food composition, it may be produced in the form of powder, granules, tablets, capsules, beverages and the like.
本発明において、前記食品は、キャンディ類、飲料、ガム、茶、ビタミン複合剤、又は健康補助食品類でよい。 In the present invention, the food may be candy, beverage, gum, tea, vitamin complex, or dietary supplement.
本発明の食品組成物は、有効成分としてフルスルチアミン又はその塩の他にも、食品製造時に通常添加される成分を含むことができ、例えば、タンパク質、炭水化物、脂肪、栄養素、調味剤及び香味剤を含む。上述した炭水化物の例は、モノサッカライド、例えば、ブドウ糖、果糖など；ジサッカライド、例えば、マルトース、スクロース、オリゴ糖など；及びポリサッカライド、例えば、デキストリン、シクロデキストリンなどのような通常の糖、及びキシリトール、ソルビトール、エリトリトールなどの糖アルコールである。 In addition to fursultiamine or a salt thereof as an active ingredient, the food composition of the present invention may contain ingredients normally added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavors. Contains agents. Examples of carbohydrates mentioned above include monosaccharides such as glucose, fructose; dissaccharides such as maltose, sucrose, oligosaccharides; and polysaccharides such as dextrin, cyclodextrin and the like, and erythritol. , Sorbitol, erythritol and other sugar alcohols.
香味剤として天然香味剤［タウマチン、ステビア抽出物（例えば、レバウジオシドＡ、グリチルリチンなど］）及び合成香味剤（サッカリン、アスパルテームなど）を用いることができる。 As a flavoring agent, a natural flavoring agent [taumatin, stevia extract (for example, rebaugioside A, glycyrrhizin, etc.]) and a synthetic flavoring agent (saccharin, aspartame, etc.) can be used.
本発明の食品組成物がドリンク剤として製造される場合には、フルスルチアミン又はその塩の他に、クエン酸、液状果糖、砂糖、ブドウ糖、酢酸、リンゴ酸、果汁、杜沖抽出液、ナツメ抽出液、甘草抽出液などをさらに含むことができる。 When the food composition of the present invention is produced as a drink, in addition to fluthiamine or a salt thereof, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, Toki extract, Natsume It can further contain an extract, a licorice extract and the like.
本発明のさらに他の態様は、フルスルチアミン又はその塩を含む新生血管性眼疾患（ｎｅｏｖａｓｃｕｌａｒ ｏｃｕｌａｒ ｄｉｓｅａｓｅ）予防又は治療用薬剤学的組成物に関する。 Yet another aspect of the present invention relates to a pharmaceutical composition for the prevention or treatment of neovascular ocular disease, which comprises fursultiamine or a salt thereof.
本発明のさらに他の態様は、フルスルチアミン又はその塩を含む新生血管性眼疾患予防又は改善用食品組成物に関する。 Yet another aspect of the present invention relates to a food composition for preventing or ameliorating neovascular eye disease, which comprises fursultiamine or a salt thereof.
本発明の新生血管性眼疾患予防又は治療用薬剤学的組成物及び食品組成物は、上述した本発明の黄斑変性予防又は治療用薬剤学的組成物と同じ有効成分であるフルスルチアミン又はその塩を含むので、この両者に共通する内容は、反復記載による明細書の過度な複雑性を避けるために、その記載を省略する。 The pharmaceutical composition and food composition for the prevention or treatment of neovascular eye disease of the present invention are fursultiamine or fursultiamine, which is the same active ingredient as the above-mentioned pharmaceutical composition for the prevention or treatment of yellow spot degeneration of the present invention. Since it contains salt, the content common to both is omitted in order to avoid excessive complexity of the specification due to repeated description.
本明細書において用語“新生血管性眼疾患”は、眼球で発生する病理学的血管新生関連疾患であり、例えば、角膜血管新生（ｃｏｒｎｅａｌ ｎｅｏｖａｓｃｕｌａｒｉｚａｔｉｏｎ）、網膜血管新生（ｒｅｔｉｎａｌ ｎｅｏｖａｓｃｕｌａｒｉｚａｔｉｏｎ）、脈絡膜血管新生（ｃｈｏｒｏｉｄａｌ ｎｅｏｖａｓｃｕｌａｒｉｚａｔｉｏｎ）、眼球内血管新生（ｉｎｔｒａｏｃｕｌａｒ ｎｅｏｖａｓｃｕｌａｒｉｚａｔｉｏｎ）、新生血管性緑内障（ｎｅｏｖａｓｃｕｌａｒ ｇｌａｕｃｏｍａ）、増殖性糖尿病性網膜症（ｐｒｏｌｉｆｅｒａｔｉｖｅ ｄｉａｂｅｔｉｃ ｒｅｔｉｎｏｐａｔｈｙ）、新生血管性黄斑変性（ｎｅｏｖａｓｃｕｌａｒ ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）、及び未熟児網膜病症（ｒｅｔｉｎｏｐａｔｈｙ ｏｆ ｐｒｅｍａｔｕｒｉｔｙ）を含む。 As used herein, the term "neovascularization ocular disease" is a pathological neovascularization-related disease that occurs in the eyeball, and is, for example, corneal neovascularization, retinal neovascularization, choroidal neovascularization (). choroidal neovascularization, intraovascular neovascularization, neovascular neovascularization, proliferative diabetic retinopathy (proliferative neovascularization), neovascularization, neovascularization, neovascularization, neovascularization, neovascularization (Retinopathy of prematurity) is included.
本発明のさらに他の態様は、フルスルチアミン又はその塩を含む薬剤学的組成物をそれを必要とする個体（ｓｕｂｊｅｃｔ）に投与する段階を含む黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）治療方法に関する。 Yet another aspect of the invention relates to a method of treating macular degeneration comprising the step of administering a pharmacological composition comprising fursultiamine or a salt thereof to an individual in need thereof (subject).
本発明のさらに他の態様は、フルスルチアミン又はその塩を含む薬剤学的組成物をそれを必要とする個体（ｓｕｂｊｅｃｔ）に投与する段階を含む新生血管性眼疾患治療方法に関する。 Yet another aspect of the invention relates to a method of treating neovascular eye disease comprising the step of administering a pharmacological composition comprising fursultiamine or a salt thereof to an individual in need thereof (subject).
本明細書において用語“投与”は、任意の適切な方法で個体に所定の物質を提供することを意味する。本発明の薬剤学的組成物の投与経路は、目的組織に到達できる限り、通常のいかなる経路を通じても経口又は非経口投与できる。また、本発明の薬剤学的組成物は、有効成分を標的細胞又は器官に伝達できる任意の装置を用いて投与されてもよい。 As used herein, the term "administration" means providing an individual with a given substance in any suitable manner. The route of administration of the pharmaceutical composition of the present invention can be administered orally or parenterally through any ordinary route as long as it can reach the target tissue. In addition, the pharmaceutical composition of the present invention may be administered using any device capable of transmitting the active ingredient to target cells or organs.
本明細書において用語“個体（ｓｕｂｊｅｃｔ）”は、特に限定されるものではないが、例えば、ヒト、サル、ウシ、ウマ、ヒツジ、ブタ、ニワトリ、シチメンチョウ、ウズラ、ネコ、イヌ、マウス、ネズミ、ウサギ又はギニアピッグを含み、好ましくは哺乳類、より好ましくはヒトを意味する。 As used herein, the term "mammal" is not particularly limited, but for example, humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, etc. Includes rabbits or turkey pigs, preferably mammals, more preferably humans.
本発明は、フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）又はその塩（ｓａｌｔｓ）を含む黄斑変性（ｍａｃｕｌａｒ ｄｅｇｅｎｅｒａｔｉｏｎ）予防又は治療用薬剤学的組成物に関する。 The present invention relates to a pharmaceutical composition for the prevention or treatment of macular degeneration, which comprises fursultiamine or a salt thereof.
以下、本発明を下記の実施例によってさらに詳しく説明する。ただし、これらの実施例は本発明を例示するためのものに過ぎず、本発明の範囲がこれらの実施例によって限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are merely for exemplifying the present invention, and the scope of the present invention is not limited to these examples.
実施例１：フルスルチアミンの新生血管抑制効果－ＨＩＦ－１α減少
新生血管性加齢黄斑変性は、脈絡膜新生血管を特徴とする。網膜又は脈絡膜の低酸素（ｈｙｐｏｘｉａ）環境がＨＩＦ－１α（ｈｙｐｏｘｉａ ｉｎｄｕｃｉｂｌｅ ｆａｃｔｏｒ１ａｌｐｈａ）を発現させ、これが血管内皮細胞因子を促進させて脈絡膜の新生血管の発生を誘導すると知られている。このような脈絡膜内新生血管の発生は、結局、視力損傷を引き起こす。
Example 1: Suppressive effect of fursultiamine on neovascularization-decreased HIF-1α Neovascular age-related macular degeneration is characterized by choroidal neovascularization. It is known that the hypoxia environment of the retina or choroid expresses HIF-1α (hypoxia inducible factor1alpha), which promotes vascular endothelial cell factors and induces the development of new blood vessels in the choroid. The development of such intrachoroidal neovascularization eventually causes visual impairment.
本発明では、チアミン誘導体であるフルスルチアミンによるＨＩＦ－１α抑制及びフルスルチアミンの脈絡膜内新生血管発生予防効果を確認しようとした。網膜細胞ＡＲＰＥ－１９（Ａｄｕｌｔ Ｒｅｔｉｎａｌ Ｐｉｇｍｅｎｔ Ｅｐｉｔｈｅｌｉａｌ ｃｅｌｌ ｌｉｎｅ－１９）を用いたインビトロ実験を行った。 In the present invention, an attempt was made to confirm the inhibitory effect of fursultiamine, which is a thiamine derivative, on HIF-1α and the preventive effect of fursultiamine on intrachoroidal neovascularization. In vitro experiments were performed using retinal cells ARPE-19 (Adult Retinal Pigment Epithelial cell line-19).
ＡＲＰＥ－１９細胞を６０ｍｍ皿（ｄｉｓｈ）に分注し、１日程度付着するようにした。翌日、フルスルチアミン塩酸塩（Ｔｏｒｏｎｔｏ ｒｅｓｅａｒｃｈ ｃｈｅｍｉｃａｌ，Ｆ８６５２３０）０μＭ、２０μＭ、５０μＭ及び１００μＭとビークル（ｖｅｈｉｃｌｅ）（Ｄｉｍｅｔｈｙｌ ｓｕｌｆｏｘｉｄｅ（ＤＭＳＯ）、Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）を各細胞に濃度別に処置した。１時間後に、低酸素チャンバー（ＩＮＶＩＶＯ２ ４００，Ｂａｋｅｒ）に入れて１％酸素条件に露出させた。そして、４時間～６時間後に細胞を取り出してタンパク質溶解バッファー（ｐｒｏｔｅｉｎ ｌｙｓｉｓ ｂｕｆｆｅｒ）を処理し、細胞を溶解後にタンパク質を分離した。
ARPE-19 cells were dispensed into a 60 mm dish and allowed to adhere for about 1 day. The next day, each cell was treated with fursultiamine hydrochloride (Toronto relief chemical, F856230) 0 μM, 20 μM, 50 μM and 100 μM and vehicle (Dimethyl sulfoxide (DMSO), Sigma-Aldrich) at different concentrations. After 1 hour, they were placed in a hypoxic chamber (
ＢＣＡタンパク質分析キット（Ｐｉｅｒｃｅ ＢＣＡ ｐｒｏｔｅｉｎ ａｓｓａｙ ｋｉｔ，Ｔｈｅｒｍｏ Ｆｉｓｈｅｒ Ｓｃｉｅｎｔｉｆｉｃ）を用いてタンパク質を定量分析した後、同一のタンパク質の量のサンプルと４Ｘローディングバッファーと混ぜて加熱してタンパク質を１次構造に変性させた。ＳＤＳ－ＰＡＧＥゲルに同一量のタンパク質サンプルをローディングし、ＰＶＤＦメンブレン（ｍｅｍｂｒａｎｅ）に伝達（ｔｒａｎｓｆｅｒ）させた。ＨＩＦ－１ａ抗体（Ｎｏｖｕｓ，ＮＢ１００－４７９）を５％ ＢＳＡ（ｂｏｖｉｎｅ ｓｅｒｕｍ ａｌｂｕｍｉｎ）溶液に希釈して４℃で一晩インキュベートした。 After quantitative analysis of the protein using the BCA protein assay kit (Pierce BCA protein assay kit, Thermo Fisher Scientific), the protein is denatured into a primary structure by mixing with a sample of the same amount of protein and a 4X loading buffer and heating. rice field. The same amount of protein sample was loaded onto an SDS-PAGE gel and transferred to a PVDF membrane (membrane). HIF-1a antibody (Novus, NB100-479) was diluted in 5% BSA (bovine serum albumin) solution and incubated overnight at 4 ° C.
翌日、メンブレンを、ＨＲＰ（Ｈｏｒｓｅｒａｄｉｓｈ ｐｅｒｏｘｉｄａｓｅ）が結合している２次抗体とインキュベートし、ＥＣＬ（ｅｎｈａｎｃｅｄ ｃｈｅｍｉｌｕｍｉｎｅｓｃｅｎｃｅ）溶液と反応させて化学発光を誘導した。化学蛍光イメージ分析装備（ＧＥ Ｈｅａｌｔｈｃａｒｅ，ＬＡＳ－４０００）でタンパク質の量に従う発光程度を探知し、イメージを得た。ローディングコントロール（ｌｏａｄｉｎｇ ｃｏｎｔｒｏｌ）遺伝子としてはβ－チューブリンを用いて同一の量のタンパク質がローディングされたことを示した。 The next day, the membrane was incubated with a secondary antibody bound to HRP (Horseradish peroxidase) and reacted with an ECL (enhanced chemiluminescence) solution to induce chemiluminescence. The chemiluminescence image analysis equipment (GE Healthcare, LAS-4000) was used to detect the degree of luminescence according to the amount of protein, and an image was obtained. It was shown that the same amount of protein was loaded using β-tubulin as the loading control gene.
その結果、低酸素条件（１％酸素）で増加するＨＩＦ－１αの発現がフルスルチアミン処置時に減少することを確認した（図１）。 As a result, it was confirmed that the expression of HIF-1α, which increases under hypoxic conditions (1% oxygen), decreases during fursultiamine treatment (Fig. 1).
実施例２：フルスルチアミンの新生血管抑制効果－脈絡膜血管内皮細胞成長減少
加齢黄斑変性のｅｘ ｖｉｖｏモデルであるマウス脈絡膜スプラウティングアッセイ（ｍｏｕｓｅ ｃｈｏｒｏｉｄ ｓｐｒｏｕｔｉｎｇ ａｓｓａｙ）から、脈絡膜血管内皮細胞成長に及ぼすフルスルチアミンの効果を確認した。
Example 2: Neovascular inhibitory effect of flusultiamine-decreased choroidal vascular endothelial cell growth From a mouse choroid sprouting assay, which is an ex-vivo model of age-related macular degeneration, it affects choroidal vascular endothelial cell growth. The effect of flusultiamine was confirmed.
３週齢又は４週齢のＪａｃｋｓｏｎ Ｌａｂｏｒａｔｏｒｙ社のＣ５７ブラック／６Ｊ（Ｃ５７ＢＬ／６Ｊ）の眼球を摘出して脈絡膜／鞏膜を分離し、１ｍｍ×１ｍｍのサイズに切断した。一方、氷で溶かして液体状態であるマトリゲル（Ｂｅｃｔｏｎ Ｄｉｃｋｉｎｓｏｎ，ＢＤ ｍａｔｒｉｇｅｌ）を２４ウェルプレートに３００μｌずつ入れ、切断しておいた脈絡膜／鞏膜を１枚ずつ植えた。その後、３７℃インキュベーターに１０分間置いてマトリゲルを固めた後、ＥＧＭ培地（Ｌｏｎｚａ，Ｅｎｄｏｔｈｅｌｉａｌ Ｇｒｏｗｔｈ Ｍｅｄｉｕｍ）を５００μｌずつ入れた。 A 3-week or 4-week-old Jackson Laboratory C57 Black / 6J (C57BL / 6J) eyeball was removed to separate the choroid / sclera and cut to a size of 1 mm x 1 mm. On the other hand, 300 μl of Becton Dickinson (BD matrigel), which was melted with ice and was in a liquid state, was placed in a 24-well plate, and the cut choroid / sclera was planted one by one. Then, after placing in a 37 ° C. incubator for 10 minutes to harden the Matrigel, 500 μl of EGM medium (Lonza, Endothelial Growth Medium) was added.
その後、３７℃インキュベーターで血管内皮細胞の成長を誘導した。２日に１回ずつ培地を交換し、この時、フルスルチアミン塩酸塩を２０μＭ又は５０μＭ濃度で処置した。脈絡膜／鞏膜を植えた日から３日～５日後に観察し、脈絡膜から生長した血管内皮細胞の成長を確認した。組織からスプラウティングした範囲までの距離を、イメージＪ（ＩｍａｇｅＪ）プログラムを用いて総４ヶ所の位置における距離を測定して平均した。統計処理は、Ｐｒｉｓｍプログラムを用いて、ｐ値０．０５以下（ｐ＜０．０５）の場合を有意性があると表示した。 Then, the growth of vascular endothelial cells was induced in a 37 ° C. incubator. The medium was changed once every two days, at which time fursultiamine hydrochloride was treated at a concentration of 20 μM or 50 μM. Observation was performed 3 to 5 days after the day when the choroid / sclera was planted, and the growth of vascular endothelial cells grown from the choroid was confirmed. The distances from the tissue to the sprout range were averaged by measuring the distances at all four positions using the ImageJ program. For statistical processing, the Prism program was used to indicate that a p-value of 0.05 or less (p <0.05) was significant.
その結果、血管内皮細胞成長がフルスルチアミンによって減少することを確認した（図２ａ～図２ｂ及び表１）。 As a result, it was confirmed that vascular endothelial cell growth was decreased by fursultiamine (FIGS. 2a to 2b and Table 1).
実施例３：フルスルチアミンのＶＥＧＦ分泌抑制効果
ＡＲＰＥ－１９細胞を６０ｍｍ皿（ｄｉｓｈ）に分注し、１日程度付着するようにした。翌日、無血清（ｓｅｒｕｍ－ｆｒｅｅ）培地に交換した後、フルスルチアミン塩酸塩０μＭ、５０μＭ、及び１００μＭ（Ｔｏｒｏｎｔｏ ｒｅｓｅａｒｃｈ ｃｈｅｍｉｃａｌ）とビークル（ＤＭＳＯ，Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）を各細胞に濃度別に処置し、低酸素チャンバー（ＩＮＶＩＶＯ２ ４００，Ｂａｋｅｒ）に入れて１％酸素条件に露出させた。
Example 3: VEGF secretion inhibitory effect of fursultiamine ARPE-19 cells were dispensed into a 60 mm dish (dish) so that they could adhere to the cells for about 1 day. The next day, after exchanging with serum-free medium, each cell was treated with
そして、１２時間後に培地を回収し、ヒトＶＥＧＦ酵素免疫測定キット（Ｅｎｚｙｍｅ ｌｉｎｋｅｄ ｉｍｍｕｎｏａｓｓａｙ（ＥＬＩＳＡ）、Ｒ＆Ｄ ｓｙｓｔｅｍｓ）で培地に分泌されたＶＥＧＦの量を測定した。測定方法及び濃度計算は、キットに提供されたマニュアルに従った。統計処理は、Ｐｒｉｓｍプログラムを用いて、ｐ値０．０５以下（ｐ＜０．０５）の場合を有意性があると表示した。 Then, after 12 hours, the medium was collected, and the amount of VEGF secreted into the medium was measured with a human VEGF enzyme-linked immunoassay (ELISA), R & D systems. The measurement method and concentration calculation followed the manual provided with the kit. For statistical processing, the Prism program was used to indicate that a p-value of 0.05 or less (p <0.05) was significant.
その結果、フルスルチアミンが低酸素条件（１％酸素）によって増加するＶＥＧＦ分泌を抑制することを確認した（図３及び表２）。 As a result, it was confirmed that fursultiamine suppresses VEGF secretion that is increased by hypoxic conditions (1% oxygen) (Fig. 3 and Table 2).
実施例４：フルオレセイン血管造影法を用いて血管漏出程度比較
黄斑変性の動物モデルであるレーザー誘導脈絡膜網膜病症モデルにおける薬物効能を調べるために、７～８週齢のＣ５７ブラック／６Ｊ（Ｃ５７ＢＬ／６Ｊ）マウスを使用した。フルスルチアミン（Ｆｕｒｓｕｌｔｉａｍｉｎｅ）投与群と対照群（Ｃｏｎｔｒｏｌ）をそれぞれ１０匹ずつ使用し、レーザー照射１日前からレーザー照射後１週までの総８日間フルスルチアミン５０ｍｇ／ｋｇを経口投与した。対照群は、溶媒として用いた滅菌蒸留水を同じ方法で投与した。
Example 4: Comparison of Degree of Vascular Leakage Using Fluorescein Angiography To investigate drug efficacy in a laser-induced choroidal retinal disease model, which is an animal model of macular degeneration, C57 Black / 6J (C57BL / 6J) at 7-8 weeks of age ) A mouse was used. Ten animals each of the fursultiamine-administered group and the control group (Control) were used, and 50 mg / kg of fursultiamine was orally administered for a total of 8 days from 1 day before laser irradiation to 1 week after laser irradiation. The control group was administered sterile distilled water used as a solvent in the same manner.
アバチン（Ａｖｅｒｔｉｎ，Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）でマウスを麻酔し、両眼に散瞳剤（ミドリンＰ、テジュン製薬）を投与して瞳孔を拡張させた。アルゴンレーザー（Ｏｃｕｌｉｇｈｔ ＧＬ，ＩＲＩＤＥＸ）を両眼に照射して１眼球当たりに４個のレーザー斑点（ｓｐｏｔ）を作った。 Mice were anesthetized with Avatin (Sigma-Aldrich), and mydriatic agents (Midrin P, Tae-joon Pharmaceutical) were administered to both eyes to dilate the pupils. Both eyes were irradiated with an argon laser (Oculight GL, IRIDEX) to create four laser spots per eyeball.
１週後にマウスを麻酔後に、フルオレセイン（ＡＫ－ＦＬＵＯＲ １０％，Ａｋｏｒｎ）を腹腔に投与し、ＭＩＣＲＯＮ ＩＶ Ｂａｓｉｃ Ｓｙｓｔｅｍ（Ｐｈｏｅｎｉｘ Ｒｅｓｅａｒｃｈ Ｌａｂｓ）を用いて網膜基底部及びフルオレセイン血管造影イメージを撮影した。
After 1 week, the mice were anesthetized, fluorescein (AK-
フルオレセイン注射後、３分以内に現れる初期（ｅａｒｌｙ ｐｈａｓｅ）と７分程度で現れる後期（ｌａｔｅ ｐｈａｓｅ）に血管漏出（ｖａｓｃｕｌａｒ ｌｅａｋａｇｅ）程度を撮影し、両時期間に見られる蛍光輝度とサイズの変化程度を確認した。 After injection of fluorescein, vascular leakage is photographed in the early phase that appears within 3 minutes and the late phase that appears in about 7 minutes, and the degree of change in fluorescence brightness and size seen between the two periods. It was confirmed.
斑点の蛍光輝度とサイズの両方とも増加すれば２Ｂ、輝度だけ増加すれば２Ａ、差異ががなければ１、斑点が出来なければ０とスコア（ｓｃｏｒｉｎｇ）して比較した。２Ｂとスコアされた斑点が多いほど新生血管漏出が増加したことを意味する。統計処理は、Ｐｒｉｓｍプログラムを用いて、ｐ値０．０５以下（ｐ＜０．０５）の場合を有意性があると表示した。 When both the fluorescence brightness and the size of the spots increased, they were scored as 2B, when only the brightness increased, they were scored as 2A, when there was no difference, they were scored as 1, and when there were no spots, they were scored as 0. The more spots scored 2B, the more neovascular leakage. For statistical processing, the Prism program was used to indicate that a p-value of 0.05 or less (p <0.05) was significant.
その結果、脈絡膜網膜病症モデルにおいて、フルスルチアミン処理時に新生血管漏出程度が後期（ｌａｔｅ ｐｈａｓｅ）で減少し、この結果から、フルスルチアミンによって血管漏出程度が減少することを確認した（図４ａ及び図４ｂ）。 As a result, in the choroidal retinal disease model, the degree of neovascular leakage decreased in the late phase during fursultiamine treatment, and from this result, it was confirmed that the degree of vascular leakage was reduced by fursultiamine (Fig. 4a and). FIG. 4b).
実施例５：レーザー誘導脈絡膜新生血管モデル（ｌａｓｅｒ－ｉｎｄｕｃｅｄ ＣＮＶ）においてフルスルチアミンによるＣＮＶ病変サイズ確認
レーザー誘導脈絡膜網膜病症モデル誘導のために、７～８週齢のＣ５７ブラック／６Ｊ（Ｃ５７ＢＬ／６Ｊ）マウスをアバチン（Ａｖｅｒｔｉｎ，Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）で麻酔し、両眼に散瞳剤（ミドリンＰ、テジュン製薬）を投与して瞳孔を拡張させた。アルゴンレーザー（Ｏｃｕｌｉｇｈｔ ＧＬ，ＩＲＩＤＥＸ）を両眼に照射して１眼球当たりに４個のレーザー斑点（ｓｐｏｔ）を作った。フルスルチアミン（Ｆｕｒｓｕｌｔｉａｍｉｎｅ）投与群と対照群（Ｃｏｎｔｒｏｌ）をそれぞれ１０匹ずつ使用し、レーザー照射１日前からレーザー照射後１週までの８日間フルスルチアミン５０ｍｇ／ｋｇを経口投与した。対照群は、溶媒として用いた滅菌蒸留水を同じ方法で投与した。
Example 5: Confirmation of CNV lesion size by flusultiamine in a laser-guided choroidal neovascular model (laser-induced CNV) 7-8 weeks old C57 Black / 6J (C57BL / 6J) for laser-guided choroidal retinal disease model guidance ) Mice were anesthetized with Abatin (Sigma-Aldrich), and mydriatic agents (Midrin P, Taejun Pharmaceutical Co., Ltd.) were administered to both eyes to dilate the pupils. Both eyes were irradiated with an argon laser (Oculight GL, IRIDEX) to create four laser spots per eyeball. Ten animals each of the fursultiamine-administered group and the control group (Control) were used, and 50 mg / kg of fursultiamine was orally administered for 8 days from 1 day before laser irradiation to 1 week after laser irradiation. The control group was administered sterile distilled water used as a solvent in the same manner.
レーザー照射１週後にマウスを麻酔後、フルオレセイン血管造影撮影後に組織染色のために眼球を摘出し、４％パラホルムアルデヒド（４％ ＰＦＡ，ＥＭＳ）に３０分間固定した。角膜とレンズを除去した後、網膜と脈絡膜を分離した。分離された脈絡膜をブロッキングバッファー（ｂｌｏｃｋｉｎｇ ｂｕｆｆｅｒ，０．２％ウシ血清アルブミン、５％正常ヤギ血清、０．５％ Ｔｒｉｔｏｎ Ｘ－１００）に入れて１時間反応させた。血管のマーカーの一つであるイソレクチン（ｉｓｏｌｅｃｔｉｎ）抗体（Ｉｓｏｌｅｃｔｉｎ ＩＢ４－Ａｌｅｘａ Ｆｌｕｏｒ ４８８，Ｉｎｖｉｔｒｏｇｅｎ）をブロッキングバッファーに希釈した後、組織に入れて反応させた。その後、脈絡膜を扁平に展開し、その上にマウント溶液（Ｍｏｕｎｔａｎｔ，Ｔｈｅｒｍｏ ｓｃｉｅｎｔｉｆｉｃ）を置き、カバーガラスを覆って安定化させた。 One week after laser irradiation, the mice were anesthetized, and after fluorescein angiography, the eyeballs were removed for tissue staining and fixed in 4% paraformaldehyde (4% PFA, EMS) for 30 minutes. After removing the cornea and lens, the retina and choroid were separated. The separated choroid was placed in blocking buffer (blocking buffer, 0.2% bovine serum albumin, 5% normal goat serum, 0.5% Triton X-100) and reacted for 1 hour. Isolectin antibody (Isolectin IB4-Alexa Fluor 488, Invitrogen), which is one of the markers of blood vessels, was diluted in a blocking buffer and then placed in a tissue for reaction. Then, the choroid was spread flat, and a mount solution (Mountant, Thermo Scientific) was placed on the choroid, and the cover glass was covered to stabilize the choroid.
翌日、共焦点顕微鏡（ＬＳＭ８００，Ｚｅｉｓｓ）を用いて１００倍の倍率で撮影した。各レーザー斑点のサイズは、イメージＪ（Ｉｍａｇｅ Ｊ）プログラムを用いて定量化した。統計処理は、Ｐｒｉｓｍプログラムを用いて、ｐ値０．０５以下（ｐ＜０．０５）の場合を有意性があると表示した。 The next day, images were taken with a confocal microscope (LSM800, Zeiss) at a magnification of 100 times. The size of each laser spot was quantified using the ImageJ program. For statistical processing, the Prism program was used to indicate that a p-value of 0.05 or less (p <0.05) was significant.
その結果、フルスルチアミンによってＣＮＶ病変サイズが減少することを確認した（図５及び表３）。 As a result, it was confirmed that fursultiamine reduced the CNV lesion size (Fig. 5 and Table 3).
実施例６：網膜色素上皮においてフルスルチアミンによるミトコンドリア代謝変化確認
新生血管性加齢黄斑変性は炎症が主要病理的メカニズムであると知られており、フルスルチアミン処理によるミトコンドリア代謝回復の有無とこれによる炎症抑制効果を確認した。ミトコンドリアの代謝変化は炎症の誘発又は悪化を引き起こすこともあるので、フルスルチアミンがミトコンドリアの代謝を回復させる場合、それを炎症を伴う新生血管性眼疾患の予防又は治療に適用できると予測した。
Example 6: Confirmation of changes in mitochondrial metabolism by fursultiamine in retinal pigment epithelium It is known that inflammation is the main pathological mechanism in neovascular age-related macular degeneration, and the presence or absence of recovery of mitochondrial metabolism by fursultiamine treatment and this. The effect of suppressing inflammation was confirmed. Since mitochondrial metabolic changes can also induce or exacerbate inflammation, we predicted that if fursultiamine restores mitochondrial metabolism, it could be applied to the prevention or treatment of inflammatory neovascular eye disease.
具体的に、ＡＲＰＥ－１９細胞を９６ウェルＸＦプレート（ｐｌａｔｅ）に分注し、２日に１回ずつ培地を交換した。細胞を植えて５日目にＬＰＳ（Ｌｉｐｏｐｏｌｙｓａｃｃｈａｒｉｄｅｓ，Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）を１０μｇ／ｍｌ処理し、６日目にフルスルチアミンを５０μＭ処理した。７日目にＸＦ培地（Ｓｅａｈｏｒｓｅ ＸＦ ＤＭＥＭ ｍｅｄｉｕｍ，Ａｇｉｌｅｎｔ）に交換し、３７℃、Ｎｏｎ－ＣＯ２インキュベーター（ｉｎｃｕｂａｔｏｒ）に３０分間置いた。 Specifically, ARPE-19 cells were dispensed into 96-well XF plates and the medium was changed once every two days. On the 5th day after planting the cells, LPS (Lipoporysaccharides, Sigma-Aldrich) was treated with 10 μg / ml, and on the 6th day, fursultiamine was treated with 50 μM. On the 7th day, the medium was replaced with XF medium (Seahorse XF DMEM medium, Agilent), and the medium was placed in a Non-CO 2 incubator (incubator) at 37 ° C. for 30 minutes.
ミトコンドリア予備容量（Ｓｐａｒｅ ｃａｐａｃｉｔｙ）を確認するために、ミトコンドリア電子伝達抑制剤（Ｉｎｈｉｂｉｔｏｒ）及び細胞呼吸阻害剤としてオリゴマイシン（Ｏｌｉｇｏｍｙｃｉｎ）２μＭ、ＦＣＣＰ ０．５μＭ、ロテノン（Ｒｏｔｅｎｏｎｅ）２μＭ、アンチマイシン（Ａｎｔｉｍｙｃｉｎ）Ａ ２μＭをそれぞれ段階別に使用した。 To confirm the mitochondrial reserve capacity, oligomycin 2 μM, FCCP 0.5 μM, rotenone 2 μM, antimycin (Antimycin) as mitochondrial electron transfer inhibitors (Inhibitor) and cellular respiration inhibitors. A 2 μM was used for each step.
Ｓｅａｈｏｒｓｅ ＸＦ分析機（Ｓｅａｈｏｒｓｅ ＸＦｅ ９６ａｎａｌｙｚｅｒ，Ａｇｉｌｅｎｔ）で細胞内酸素消耗率（Ｏｘｙｇｅｎ Ｃｏｍｓｕｍｐｔｉｏｎ Ｒａｔｅ，ＯＣＲ）を測定した。測定方法は、Ｓｅａｈｏｒｓｅ ＸＦ分析機（Ｓｅａｈｏｒｓｅ ＸＦｅ９６ ａｎａｌｙｚｅｒ，Ａｇｉｌｅｎｔ）で提供されたマニュアルに従って行った。 The intracellular oxygen consumption rate (Oxygen Measurement Rate, OCR) was measured with a Seahorse XF analyzer (Seahorse XFe 96analyzer, Agilent). The measurement method was carried out according to the manual provided by the Seahorse XF analyzer (Seahorse XFe96 analyzer, Agilent).
その結果、ＬＰＳによって減少したミトコンドリア予備容量（Ｓｐａｒｅ ｃａｐａｃｉｔｙ）が、フルスルチアミン処置時に回復することを確認した。このことから、フルスルチアミンによるミトコンドリアエネルギー代謝の変化が炎症抑制効果に関与できるという点を確認した（図６ａ～図６ｂ及び表４）。 As a result, it was confirmed that the mitochondrial reserve capacity reduced by LPS was restored during the treatment with fursultiamine. From this, it was confirmed that changes in mitochondrial energy metabolism due to fursultiamine can be involved in the anti-inflammatory effect (FIGS. 6a to 6b and Table 4).
以上の結果は、新生血管性加齢黄斑変性発病メカニズムにおいてフルスルチアミンの阻害効果を示し、フルスルチアミンを含む組成物の処置時に黄斑変性の予防及び治療効果を奏することを示唆する。 The above results suggest that it exhibits an inhibitory effect on fursultiamine in the pathogenic mechanism of neovascular age-related macular degeneration, and that it exerts a preventive and therapeutic effect on macular degeneration when treated with a composition containing fursultiamine.
本発明は、黄斑変性予防又は治療用組成物に関する。より詳細には、本発明は、フルスルチアミン（ｆｕｒｓｕｌｔｉａｍｉｎｅ）又はその塩（ｓａｌｔｓ）を含む黄斑変性予防又は治療用組成物に関する。 The present invention relates to a composition for preventing or treating macular degeneration. More specifically, the present invention relates to a composition for preventing or treating macular degeneration containing fursultiamine or a salt thereof (salts).
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