JP2018016596A - α-SMA PRODUCTION INHIBITOR - Google Patents
α-SMA PRODUCTION INHIBITOR Download PDFInfo
- Publication number
- JP2018016596A JP2018016596A JP2016149624A JP2016149624A JP2018016596A JP 2018016596 A JP2018016596 A JP 2018016596A JP 2016149624 A JP2016149624 A JP 2016149624A JP 2016149624 A JP2016149624 A JP 2016149624A JP 2018016596 A JP2018016596 A JP 2018016596A
- Authority
- JP
- Japan
- Prior art keywords
- sma
- sulfated
- production inhibitor
- acid
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
Description
本発明は、α−SMA産生抑制剤に関する。より具体的には、本発明は、α−SMAの産生を抑制することにより、α−SMAの過剰な発現等によってもたらされる症状や疾患を改善できるα−SMA産生抑制剤に関する。 The present invention relates to an α-SMA production inhibitor. More specifically, the present invention relates to an α-SMA production inhibitor that can improve the symptoms and diseases caused by excessive expression of α-SMA by suppressing the production of α-SMA.
α−SMA(α−平滑筋アクチン)は、筋線維芽細胞において多く発現しているタンパク質であり、α−SMAを発現することによって筋線維芽細胞は収縮能を獲得することが知られている。創傷治癒過程では、線維芽細胞が、α−SMAを発現する強い収縮能をもつ筋線維芽細胞に変化して、肉芽組織を収縮させ、傷口を小さくする役割を果たし、α−SMAの発現促進が創傷治癒に寄与することが知られている。また、α−SMAを発現する筋線維芽細胞は、真皮の強度や皮膚のハリに重要な役割を果たしていることも知られている。そこで、従来、α−SMAの産生を促進する物質についてスクリーニングされており、種々のα−SMA産生促進剤が報告されている(例えば、特許文献1及び2参照)。 α-SMA (α-smooth muscle actin) is a protein that is highly expressed in myofibroblasts, and it is known that myofibroblasts acquire contractility by expressing α-SMA. . In the wound healing process, fibroblasts change to myofibroblasts with strong contractive ability to express α-SMA, play a role in contracting granulation tissue and making wounds smaller, and promoting α-SMA expression Is known to contribute to wound healing. It is also known that myofibroblasts expressing α-SMA play an important role in dermis strength and skin firmness. Therefore, screening for substances that promote the production of α-SMA has been conducted, and various α-SMA production promoters have been reported (see, for example, Patent Documents 1 and 2).
一方、肥厚性瘢痕やケロイド等の皮膚創傷治癒異常では、筋繊維芽様細胞の出現が認められ、当該細胞のα−SMAの過剰な発現が悪影響を示すことが知られている。また、α−SMAは、腫瘍細胞の転移や骨粗鬆症にも関与していることが報告されている(特許文献3参照)。また、PDGF(血小板由来成長因子)は、α−SMAを阻害する作用があり、α−SMA阻害剤として使用できることも知られている(特許文献3参照)。しかしながら、従来、細胞におけるα−SMAの産生自体を抑制する物質については見出されていない。 On the other hand, in skin wound healing abnormalities such as hypertrophic scars and keloids, the appearance of myofibroblast-like cells is recognized, and it is known that excessive expression of α-SMA in the cells has an adverse effect. In addition, α-SMA has been reported to be involved in tumor cell metastasis and osteoporosis (see Patent Document 3). It is also known that PDGF (platelet-derived growth factor) has an action of inhibiting α-SMA and can be used as an α-SMA inhibitor (see Patent Document 3). However, a substance that suppresses α-SMA production itself in cells has not been found so far.
そのため、α−SMAの産生を抑制できる物質を見出すことができれば、新たな手法で、肥厚性瘢痕やケロイド等の皮膚創傷治癒異常の症状を改善でき、更に腫瘍細胞の転移や骨粗鬆症等にも有効になると期待できるが、前述するように、従来、このような物質は見出されていないのが現状である。 Therefore, if a substance capable of suppressing the production of α-SMA can be found, a new technique can improve symptoms of abnormal skin wound healing such as hypertrophic scars and keloids, and it is also effective for metastasis of tumor cells, osteoporosis, etc. However, as described above, such a substance has not been found so far.
本発明の目的は、α−SMAの産生を抑制できる物質を見出し、α−SMA産生抑制剤を提供することである。 An object of the present invention is to find a substance capable of suppressing the production of α-SMA and to provide an α-SMA production inhibitor.
本発明者等は、前記課題を解決すべく鋭意検討を行ったところ、硫酸化グリコサミノグリカンには、α−SMAの産生を抑制する作用があり、α−SMA産生抑制剤として使用できることを見出した。本発明は、かかる知見に基づいてさらに検討を重ねることにより完成したものである。
即ち、本発明は、下記に掲げる態様の発明を提供する。
項1. 硫酸化グリコサミノグリカン及び/又はその塩を含有する、α−SMA産生抑制剤。
項2. 硫酸化グリコサミノグリカン及び/又はその塩を構成するアミノ糖が、第4位及び/又は第6位の水酸基が硫酸化されているN−アセチル−D−ガラクトサミンである、項1に記載のα−SMA産生抑制剤。
項3. 前記アミノ糖は、第4位及び第6位の水酸基が硫酸化されているN−アセチル−D−ガラクトサミンである、項2に記載のα−SMA産生抑制剤。
項4. 前記硫酸化グリコサミノグリカン及び/又はその塩の構成糖としてD−グルクロン酸が含まれる、項1〜3のいずれかに記載のα−SMA産生抑制剤。
項5. 前記硫酸化グリコサミノグリカン及び/又はその塩が、コンドロイチン硫酸A、コンドロイチン硫酸C、コンドロイチン硫酸E、ヘパラン硫酸、及びそれらの塩よりなる群から選択される少なくとも1種である、項1〜4のいずれかに記載のα−SMA産生抑制剤。
項6. 前記硫酸化グリコサミノグリカン及び/又はその塩が、コンドロイチン硫酸E及び/又はその塩である、項1〜4のいずれかに記載のα−SMA産生抑制剤。
項7. 皮膚外用剤である、項1〜6のいずれかに記載のα−SMA産生抑制剤。
As a result of intensive studies to solve the above problems, the present inventors have found that sulfated glycosaminoglycan has an action of suppressing the production of α-SMA and can be used as an α-SMA production inhibitor. I found it. The present invention has been completed by further studies based on such findings.
That is, this invention provides the invention of the aspect hung up below.
Item 1. The alpha-SMA production inhibitor containing a sulfated glycosaminoglycan and / or its salt.
Item 2. Item 2. The amino sugar constituting the sulfated glycosaminoglycan and / or salt thereof is N-acetyl-D-galactosamine in which the hydroxyl group at the 4-position and / or the 6-position is sulfated. α-SMA production inhibitor.
Item 3. Item 3. The α-SMA production inhibitor according to Item 2, wherein the amino sugar is N-acetyl-D-galactosamine in which the hydroxyl groups at the 4th and 6th positions are sulfated.
Item 4. Item 4. The α-SMA production inhibitor according to any one of Items 1 to 3, wherein D-glucuronic acid is included as a constituent sugar of the sulfated glycosaminoglycan and / or salt thereof.
Item 5. Item 1-4, wherein the sulfated glycosaminoglycan and / or salt thereof is at least one selected from the group consisting of chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate E, heparan sulfate, and salts thereof. The α-SMA production inhibitor according to any one of the above.
Item 6. Item 5. The α-SMA production inhibitor according to any one of Items 1 to 4, wherein the sulfated glycosaminoglycan and / or salt thereof is chondroitin sulfate E and / or salt thereof.
Item 7. Item 7. The α-SMA production inhibitor according to any one of Items 1 to 6, which is an external preparation for skin.
本発明のα−SMA産生抑制剤によれば、α−SMAの発現を抑制できるので、α−SMAの過剰発現に起因して生じる症状や疾患、α−SMAが関与している症状や疾患や症状等の予防又は治療に有効である。 According to the α-SMA production inhibitor of the present invention, since the expression of α-SMA can be suppressed, the symptoms and diseases caused by overexpression of α-SMA, the symptoms and diseases associated with α-SMA, Effective for prevention or treatment of symptoms.
本発明のα−SMA産生抑制剤は、硫酸化グリコサミノグリカン及び/又はその塩を含有することを特徴とする。以下、本発明のα−SMA産生抑制剤について詳述する。 The α-SMA production inhibitor of the present invention is characterized by containing a sulfated glycosaminoglycan and / or a salt thereof. Hereinafter, the α-SMA production inhibitor of the present invention will be described in detail.
[硫酸化グリコサミノグリカン及び/又はその塩]
本発明のα−SMA産生抑制剤では、α−SMAの産生を抑制させるための有効成分として、硫酸化グリコサミノグリカン及び/又はその塩を含有する。
[Sulfated glycosaminoglycan and / or salt thereof]
The α-SMA production inhibitor of the present invention contains sulfated glycosaminoglycan and / or a salt thereof as an active ingredient for suppressing the production of α-SMA.
硫酸化グリコサミノグリカンとは、ウロン酸又はガラクトースがアミノ糖にβ1−3結合、β1−4結合、又はα1−4結合でグリコシド結合した二糖単位(以下、「基本構成単位」と表記することがある)の繰り返し構造を有し、当該基本構成単位においてグリコシド結合に関与していない水酸基及び/又はアミノ基が部分的に硫酸化されている酸性多糖である。硫酸化グリコサミノグリカンは、通常は、枝分かれしていない直鎖状の骨格を有している。 A sulfated glycosaminoglycan is a disaccharide unit in which uronic acid or galactose is glycosidically linked to an amino sugar by β1-3 bond, β1-4 bond, or α1-4 bond (hereinafter referred to as “basic structural unit”). The hydroxyl group and / or the amino group that is not involved in the glycosidic bond in the basic structural unit is partially sulfated. Sulfated glycosaminoglycans usually have a linear skeleton that is not branched.
硫酸化グリコサミノグリカンの基本構成単位を構成するウロン酸は、具体的には、L−イズロン酸又はD−グルクロン酸である。また、硫酸化グリコサミノグリカンの基本構成単位を構成するアミノ糖は、硫酸化グリコサミノグリカンの種類によって異なるが、D−グルコサミン、D−ガラクトサミン、N−アセチル−D−グルコサミン又はN−アセチル−D−ガラクトサミンである。硫酸化グリコサミノグリカンの基本構成単位を構成するアミノ糖は、硫酸化グリコサミノグリカンの種類によって異なるが、D−グルコサミン、D−ガラクトサミン、N−アセチル−D−ガラクトサミン、又はN−アセチル−D−グルコサミンである。 The uronic acid constituting the basic structural unit of the sulfated glycosaminoglycan is specifically L-iduronic acid or D-glucuronic acid. The amino sugar constituting the basic structural unit of sulfated glycosaminoglycan varies depending on the type of sulfated glycosaminoglycan, but is D-glucosamine, D-galactosamine, N-acetyl-D-glucosamine or N-acetyl. -D-galactosamine. The amino sugar constituting the basic structural unit of the sulfated glycosaminoglycan varies depending on the type of the sulfated glycosaminoglycan, but D-glucosamine, D-galactosamine, N-acetyl-D-galactosamine, or N-acetyl- D-glucosamine.
硫酸化グリコサミノグリカンの基本構成単位を構成する一方の糖は、ウロン酸又はガラクトースであればよいが、より一層優れたα−SMA産生抑制作用を発揮させるという観点から、好ましくはウロン酸、更に好ましくはD−グルクロン酸が挙げられる。 One sugar constituting the basic structural unit of the sulfated glycosaminoglycan may be uronic acid or galactose, but from the viewpoint of exhibiting a more excellent α-SMA production inhibitory action, preferably uronic acid, More preferred is D-glucuronic acid.
硫酸化グリコサミノグリカンの基本構成単位を構成する他方のアミノ糖は、前述するものの内、いずれであってもよいが、より一層優れたα−SMA産生抑制作用を発揮させるという観点から、好ましくはN−アセチル−D−ガラクトサミン又はN−アセチル−D−グルコサミン、更に好ましくはN−アセチル−D−ガラクトサミンが挙げられる。 The other amino sugar constituting the basic structural unit of the sulfated glycosaminoglycan may be any of those described above, but is preferably from the viewpoint of exhibiting an even more excellent α-SMA production inhibitory action. N-acetyl-D-galactosamine or N-acetyl-D-glucosamine, more preferably N-acetyl-D-galactosamine.
硫酸化グリコサミノグリカンにおいて、硫酸化されている部位については、基本構成単位においてグリコシド結合に関与していない水酸基及び/又はアミノ基であればよいが、例えば、基本構成単位を構成するウロン酸又はガラクトースの第2位の水酸基、第3位の水酸基、第4位の水酸基、基本構成単位を構成するアミノ糖の第2位のアミノ基、第3位の水酸基、第4位の水酸基、第6位の水酸基等が挙げられる。 In the sulfated glycosaminoglycan, the sulfated site may be any hydroxyl group and / or amino group that is not involved in the glycosidic bond in the basic structural unit. For example, uronic acid constituting the basic structural unit Or the 2nd hydroxyl group, the 3rd hydroxyl group, the 4th hydroxyl group, the 2nd amino group of the amino sugar constituting the basic structural unit, the 3rd hydroxyl group, the 4th hydroxyl group, the galactose Examples include a hydroxyl group at the 6-position.
硫酸化グリコサミノグリカンにおいて硫酸化されている部位の数については、特に制限されないが、例えば、基本構成単位における硫酸化されている部位の数(硫酸基の数)として、1〜6個、好ましくは1〜3個、より好ましくは1又は2個、更に好ましくは2個が挙げられる。 The number of sites that are sulfated in the sulfated glycosaminoglycan is not particularly limited. For example, the number of sites that are sulfated in the basic structural unit (the number of sulfate groups) is 1 to 6, The number is preferably 1 to 3, more preferably 1 or 2, and still more preferably 2.
硫酸化グリコサミノグリカンにおいて硫酸化されている部位として、より一層優れたα−SMA産生抑制作用を発揮させるという観点から、好ましくはアミノ糖の第4位及び第6位の水酸基の少なくとも一方、更に好ましくはアミノ糖の第4位及び第6位の水酸基の双方が挙げられる。 From the viewpoint of exhibiting a more excellent α-SMA production inhibitory action as a sulfated site in the sulfated glycosaminoglycan, preferably at least one of the hydroxyl groups at the 4th and 6th positions of the amino sugar, More preferably, both the 4th and 6th hydroxyl groups of the amino sugar are mentioned.
また、硫酸化グリコサミノグリカンの基本構成単位として、より一層優れたα−SMA産生抑制作用を発揮させるという観点から、好ましくは、第4位及び/又は第6位の水酸基が硫酸化されているN−アセチル−D−ガラクトサミンを有するもの、更に好ましくは第4位及び第6位の双方の水酸基が硫酸化されているN−アセチル−D−ガラクトサミンを有するものが挙げられる。 In addition, as a basic structural unit of sulfated glycosaminoglycan, from the viewpoint of exhibiting a more excellent α-SMA production inhibitory action, the hydroxyl group at the 4th and / or 6th position is preferably sulfated. Those having N-acetyl-D-galactosamine, more preferably those having N-acetyl-D-galactosamine in which both hydroxyl groups at the 4th and 6th positions are sulfated.
本発明で使用される硫酸化グリコサミノグリカンとして、具体的には、以下の酸性多糖が挙げられる:
・コンドロイチン硫酸A(D−グルクロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位を有し、N−アセチル−D−ガラクトサミンの第4位の水酸基が硫酸化されている酸性多糖)
・コンドロイチン硫酸B(D−グルクロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位とL−イズロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位とを有し、N−アセチル−D−ガラクトサミンの第4位の水酸基が硫酸化されている酸性多糖)
・コンドロイチン硫酸C(D−グルクロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位を有し、N−アセチル−D−ガラクトサミンの第6位の水酸基が硫酸化されている酸性多糖)
・コンドロイチン硫酸D(D−グルクロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位を有し、D−グルクロン酸の第2位の水酸基とN−アセチル−D−ガラクトサミンの第6位の水酸基が硫酸化されている酸性多糖)
・コンドロイチン硫酸E(D−グルクロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位を有し、N−アセチル−D−ガラクトサミンの第4位と第6位の水酸基が硫酸化されている酸性多糖)
・ヘパラン硫酸(D−グルクロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位とL−イズロン酸がN−アセチル−D−ガラクトサミンにβ1−3結合によって結合した基本構成単位とを有し、D−グルクロン酸及びL−イズロン酸の第2位の水酸基、並びにN−アセチル−D−ガラクトサミンの2位のアミノ酸及び第6位の水酸基が硫酸化されている酸性多糖)
・ケラタン硫酸(D−ガラクトースがN−アセチル−D−ガラクトサミンにβ1−4結合によって結合した基本構成単位を有し、D−ガラクトースの第6位の水酸基、並びにN−アセチル−D−ガラクトサミンの2位のアミノ基及び第6位の水酸基が硫酸化されている酸性多糖)
Specific examples of the sulfated glycosaminoglycan used in the present invention include the following acidic polysaccharides:
Chondroitin sulfate A (D-glucuronic acid has a basic structural unit bonded to N-acetyl-D-galactosamine by a β1-3 bond, and the hydroxyl group at the 4-position of N-acetyl-D-galactosamine is sulfated. Acidic polysaccharide)
Chondroitin sulfate B (basic structural unit in which D-glucuronic acid is bound to N-acetyl-D-galactosamine by β1-3 bond and basic unit in which L-iduronic acid is bound to N-acetyl-D-galactosamine by β1-3 bond An acidic polysaccharide having a structural unit and wherein the hydroxyl group at the 4-position of N-acetyl-D-galactosamine is sulfated)
Chondroitin sulfate C (having a basic structural unit in which D-glucuronic acid is bonded to N-acetyl-D-galactosamine by a β1-3 bond, and the hydroxyl group at the 6th position of N-acetyl-D-galactosamine is sulfated Acidic polysaccharide)
Chondroitin sulfate D (having a basic structural unit in which D-glucuronic acid is bonded to N-acetyl-D-galactosamine by a β1-3 bond, the second hydroxyl group of D-glucuronic acid and N-acetyl-D-galactosamine Acidic polysaccharide in which the hydroxyl group at position 6 is sulfated)
Chondroitin sulfate E (having a basic structural unit in which D-glucuronic acid is bonded to N-acetyl-D-galactosamine by a β1-3 bond, and the hydroxyl groups at positions 4 and 6 of N-acetyl-D-galactosamine are Sulfated acidic polysaccharide)
Heparan sulfate (basic constitutional unit in which D-glucuronic acid is bound to N-acetyl-D-galactosamine by β1-3 bond and L-iduronic acid is bound to N-acetyl-D-galactosamine by β1-3 bond An acidic polysaccharide in which the 2nd hydroxyl group of D-glucuronic acid and L-iduronic acid, and the 2nd amino acid and 6th hydroxyl group of N-acetyl-D-galactosamine are sulfated)
Keratan sulfate (D-galactose has a basic structural unit bonded to N-acetyl-D-galactosamine by a β1-4 bond, the 6-position hydroxyl group of D-galactose, and 2 of N-acetyl-D-galactosamine Acidic polysaccharide in which the amino group at position 6 and the hydroxyl group at position 6 are sulfated)
これらの硫酸化グリコサミノグリカンは、1種単独で使用してもよく、また2種以上を組み合わせて使用してもよい。 These sulfated glycosaminoglycans may be used alone or in combination of two or more.
本発明で使用される硫酸化グリコサミノグリカンの重合度については、特に制限されないが、例えば、基本構成単位(2つの糖残基からなる構成単位)が2〜300程度、好ましくは5〜200程度、更に好ましくは10〜150程度重合しているものが挙げられる。 The degree of polymerization of the sulfated glycosaminoglycan used in the present invention is not particularly limited. For example, the basic structural unit (the structural unit composed of two sugar residues) is about 2 to 300, preferably 5 to 200. Those having a degree of polymerization, more preferably about 10 to 150 are mentioned.
また、硫酸化グリコサミノグリカンの塩については、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩、鉄塩、マンガン塩等の金属塩;アンモニウム塩等の塩が挙げられる。これらの硫酸化グリコサミノグリカンの塩は、1種単独で使用してもよく、また2種以上を組み合わせて使用してもよい。 Further, the sulfated glycosaminoglycan salt is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include alkali metal salts such as sodium salt and potassium salt; calcium salt, magnesium salt, iron salt, Metal salts such as manganese salts; salts such as ammonium salts. These sulfated glycosaminoglycan salts may be used alone or in combination of two or more.
本発明のα−SMA産生抑制剤では、硫酸化グリコサミノグリカン及びその塩の中から、1種を選択して単独で使用してもよく、2種以上を組み合わせて使用してもよい。 In the α-SMA production inhibitor of the present invention, one type may be selected from sulfated glycosaminoglycans and salts thereof, or two or more types may be used in combination.
本発明で使用される硫酸化グリコサミノグリカン及び/又はその塩は、動物から抽出し、必要に応じて精製して得られたものであってもよく、また化学合成したものや遺伝子工学的手法を用いて製造したものであってもよい。 The sulfated glycosaminoglycan and / or salt thereof used in the present invention may be one obtained by extracting from an animal and purifying as necessary, or chemically synthesized or genetically engineered. It may be manufactured using a technique.
本発明で使用される硫酸化グリコサミノグリカン及びその塩の中でも、より一層優れたα−SMA産生抑制作用を発揮させるという観点から、好ましくは、コンドロイチン硫酸A、コンドロイチン硫酸C、コンドロイチン硫酸E、ヘパラン硫酸、及びそれらの塩;更に好ましくはコンドロイチン硫酸E及びその塩が挙げられる。 Of the sulfated glycosaminoglycans and salts thereof used in the present invention, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate E, Heparan sulfate and salts thereof; more preferably chondroitin sulfate E and salts thereof.
本発明のα−SMA産生抑制剤において、硫酸化グリコサミノグリカン及び/又はその塩の含有量については、特に制限されず、該剤の製剤形態や投与形態等に応じて適宜設定すればよいが、例えば、0.01〜5重量%が挙げられる。より具体的には、本発明のα−SMA産生抑制剤が皮膚外用剤の場合であれば、硫酸化グリコサミノグリカン及び/又はその塩の含有量として、通常0.05〜3重量%、好ましくは0.1〜3重量%、更に好ましくは0.1〜1重量%が挙げられる。 In the α-SMA production inhibitor of the present invention, the content of sulfated glycosaminoglycan and / or its salt is not particularly limited, and may be appropriately set according to the preparation form, administration form, etc. of the agent. However, 0.01 to 5 weight% is mentioned, for example. More specifically, if the α-SMA production inhibitor of the present invention is a skin external preparation, the content of sulfated glycosaminoglycan and / or a salt thereof is usually 0.05 to 3% by weight, Preferably 0.1 to 3 weight%, More preferably, 0.1 to 1 weight% is mentioned.
[その他の成分]
本発明のα−SMA産生抑制剤は、前記硫酸化グルコサミノグリカンの他に、必要に応じて、他の薬理成分を含有していてもよい。このような薬理成分としては、例えば、抗ヒスタミン剤(グリチルリチン酸二カリウム、グリチルリチン酸、ジフェンヒドラミン、塩酸ジフェンヒドラミン等)、局所麻酔剤(プロカイン、テトラカイン、ブピパカイン、メピパカイン、クロロプロカイン、プロパラカイン、メプリルカイン又はこれらの塩、オルソカイン、オキセサゼイン、オキシポリエントキシデカン、ロートエキス、ペルカミンパーゼ、テシットデシチン等)、抗炎症剤(アラントイン、インドメタシン、フェルビナク、ジクロフェナクナトリウム、ロキソプロフェンナトリウム等)、皮膚保護剤(コロジオン、ヒマシ油等)、血行促進成分(ノニル酸ワニリルアミド、ニコチン酸ベンジルエステル、カプサイシン、トウガラシエキス等)、清涼化剤(メントール、カンフル等)、ビタミン類(ビタミンA等)、ムコ多糖類(コンドロイチン硫酸ナトリウム、グルコサミン等)等が挙げられる。
[Other ingredients]
The α-SMA production inhibitor of the present invention may contain other pharmacological components as necessary in addition to the sulfated glucosaminoglycan. Examples of such pharmacological components include antihistamines (dipotassium glycyrrhizinate, glycyrrhizic acid, diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilucaine or salts thereof. , Orthocaine, oxesasein, oxypolyentoxydecane, funnel extract, percamin ase, tesit decite, etc.), anti-inflammatory agents (allantoin, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promotion Ingredients (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, pepper extract, etc.), cooling agents (menthol, canned Le etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.) and the like.
また、本発明のα−SMA産生抑制剤は、所望の製剤形態にするために、必要に応じて、基剤や添加剤が含まれていてもよい。このような基剤や添加剤については、薬学的に許容されることを限度として特に制限されないが、例えば、水、低級アルコール(エタノール、イソプロパノール等)、多価アルコール(グリセリン、プロピレングリコール、ジプロピレングリコール、1,3−ブチレングリコール等)等の水性基剤;油類(オリーブ油、サフラワー油、大豆油、つばき油、とうもろこし油、なたね油、ひまわり油、綿実油、落花生油、ラード、スクワラン、魚油等)、鉱物油(流動パラフィン、パラフィン、ゲル化炭化水素、ワセリン等)、ワックス類・ロウ類(ミツロウ、カルナウバロウ、キャンデリラロウ、セレシン、ライスワックス、マイクロクリスタリンワックス等)、エステル油(ミリスチン酸イソプロピル、アジピン酸イソプロピル、セバシン酸ジエチル、セバシン酸イソプロピル、パルミチン酸イソプロピル、パルミチン酸セチル、オレイン酸エチル等)、脂肪酸アルキルエステル、脂肪酸(ステアリン酸、オレイン酸、パルミチン酸、ベヘン酸、リノール酸、ラノリン等)、脂肪酸エステル(パルミチン酸セチル、パルミチン酸イソプロピル、リノール酸エチル等)、高級アルコール(ステアリルアルコール、セタノール、ベヘニルアルコール、ミリスチルアルコール、オレイルアルコール、ヘキサデシルアルコール、ラノリンアルコール等)、コレステロール、トリ2−エチルヘキサン酸グリセリル、2−エチルヘキサン酸セチル、シリコーンオイル(ジメチルポリシロキサン、環状シリコーン等)等の油性基剤;POE(10〜50モル)フィトステロールエーテル、POE(10〜50モル)ジヒドロコレステロールエーテル、POE(10〜50モル)2−オクチルドデシルエーテル、POE(10〜50モル)デシルテトラデシルエーテル、POE(10〜50モル)オレイルエーテル、POE(2〜50モル)セチルエーテル、POE(5〜50モル)ベヘニルエーテル、POE(5〜30モル)ポリオキシプロピレン(5〜30モル)2−デシルテトラデシルエーテル、POE(10〜50モル)ポリオキシプロピレン(2〜30モル)セチルエーテルなどのポリオキシエチレンアルキルエーテル、これらのリン酸・リン酸塩(POEセチルエーテルリン酸ナトリウムなど)、POE(20〜60モル)ソルビタンモノオレート、POE(10〜60モル)ソルビタンモノイソステアレート、POE(10〜80モル)グリセリルモノイソステアレート、POE(10〜30モル)グリセリルモノステアレート、POE(20〜100モル)・ポリオキシプロピレン変性シリコーン、POE・アルキル変性シリコーン、モノラウリン酸ポリエチレングリコール、モノパルミチン酸ポリエチレングリコール、モノステアリン酸ポリエチレングリコール、ジラウリン酸ポリエチレングリコール、ジパルミチン酸ポリエチレングリコール、ジステアリン酸ポリエチレングリコール、ジオレイン酸ポリエチレングリコール、ジリシノレイン酸ポリエチレングリコール、ポリオキシエチレン硬化ヒマシ油(5〜100)、ポリソルベート(20〜85)、グリセリン脂肪酸エステル(モノステアリン酸グリセリン等)、水素添加大豆リン脂質、水素添加ラノリンアルコール等の界面活性剤;清涼化剤(メントール、カンフル、ボルネオール、ハッカ水、ハッカ油等)、防腐剤(メチルパラベン、プロピルパラベン、安息香酸、安息香酸ナトリウム、ソルビン酸等)、着香剤(シトラール、1,8−シオネール、シトロネラール、ファルネソール等)、着色剤(タール色素(褐色201号、青色201号、黄色4号、黄色403号等)、カカオ色素、クロロフィル、酸化アルミニウム等)、粘稠剤(カルボキシビニルポリマー、ヒプロメロース、ポリビニルピロリドン、アルギン酸ナトリウム、エチルセルロース、カルボキシメチルセルロースナトリウム、キサンタンガム、カラギーナン等)、pH調整剤(リン酸、塩酸、クエン酸、クエン酸ナトリウム、コハク酸、酒石酸、水酸化ナトリウム、水酸化カリウム、トリエタノールアミン、トリイソプロパノールアミン等)、湿潤剤(dl−ピロリドンカルボン酸ナトリウム液、D−ソルビトール液、マクロゴール等)、安定化剤(ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エデト酸ナトリウム、メタリン酸ナトリウム、L−アルギニン、L−アスパラギン酸、DL−アラニン、グリシン、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム、二酸化硫黄、クロロゲン酸、カテキン、ローズマリー抽出物等)、酸化防止剤、紫外線吸収剤、キレート剤、粘着剤、緩衝剤、溶解補助剤、可溶化剤、保存剤等の添加剤が挙げられる。 Moreover, in order to make the alpha-SMA production inhibitor of this invention into a desired formulation form, the base and the additive may be contained as needed. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, water, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene) Aqueous bases such as glycol and 1,3-butylene glycol; oils (olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc. ), Mineral oil (liquid paraffin, paraffin, gelled hydrocarbon, petroleum jelly, etc.), waxes and waxes (honey bees, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oil (isopropyl myristate) , Isopropyl adipate, sebacic acid Ethyl, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc., fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (palmitic acid) Cetyl, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, 2-ethyl Oily bases such as cetyl hexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10-50 mol) phytosterol ether, POE ( 0-50 mol) Dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) ) Cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2- 30 mol) polyoxyethylene alkyl ethers such as cetyl ether, phosphoric acid / phosphate thereof (such as POE cetyl ether sodium phosphate), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan Monoisostearate, POE (10 80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol) polyoxypropylene-modified silicone, POE alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene monopalmitate Glycol, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20 -85), glycerin fatty acid ester (glyceryl monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanoli Surfactants such as alcohol; refreshing agents (menthol, camphor, borneol, mint water, mint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral) , 1,8-shioner, citronellal, farnesol, etc.), coloring agent (tar pigment (brown 201, blue 201, yellow 4, yellow 403, etc.), cacao pigment, chlorophyll, aluminum oxide, etc.), thickener (Carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjuster (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, Hydroxy Potassium, triethanolamine, triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidonecarboxylate, D-sorbitol, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, metalin) Acid sodium, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidant, UV absorption Additives such as agents, chelating agents, pressure-sensitive adhesives, buffers, solubilizers, solubilizers, preservatives, etc.
[製剤形態]
本発明のα−SMA産生抑制剤の剤型は、皮膚外用剤、内服剤、注射剤、点滴剤等のいずれであってもよく、該剤の具体的用途に応じて適宜設定すればよいが、より一層優れたα−SMA産生抑制作用を発揮させるという観点から、好ましくは皮膚外用剤が挙げられる。
[Formulation]
The dosage form of the α-SMA production inhibitor of the present invention may be any of an external preparation for skin, an internal preparation, an injection, an instillation, etc., and may be appropriately set according to the specific use of the agent. From the viewpoint of exhibiting a more excellent α-SMA production inhibitory action, an external preparation for skin is preferable.
本発明のα−SMA産生抑制剤を皮膚外用剤として使用する場合、その形状については、経皮適用できることを限度として特に制限されないが、例えば、液状、固形状、半固形状(ゲル状、軟膏状、ペースト状)等が挙げられる。 When the α-SMA production inhibitor of the present invention is used as an external preparation for skin, its shape is not particularly limited as long as it can be applied transdermally. For example, liquid, solid, semisolid (gel, ointment) And paste).
また、本発明のα−SMA産生抑制剤を皮膚外用剤として使用する場合、その製剤形態については、経皮適用できることを限度として特に制限されないが、例えば、皮膚外用医薬品、皮膚外用医薬部外品、化粧料、皮膚洗浄料等が挙げられる。本発明のα−SMA産生抑制剤を皮膚外用剤にする場合の製剤形態として、具体的には、クリーム剤、ローション剤、ジェル剤、乳液剤、液剤、貼付剤、エアゾール剤、軟膏剤、パック剤等の皮膚外用医薬品;クリーム剤、ローション剤、ジェル剤、乳液剤、液剤、貼付剤、エアゾール剤、軟膏剤、パック剤等の皮膚外用医薬部外品;クリーム剤、ローション剤、ジェル剤、乳液剤、液剤、軟膏剤、パック剤等の化粧料;ボディーシャンプー、ヘアシャンプー、リンス等の皮膚洗浄料等が挙げられる。これらの製剤形態の中でも、好ましくは皮膚外用医薬品、更に好ましくはクリーム剤、ローション剤、ジェル剤、乳液剤、パック剤が挙げられる。 In addition, when the α-SMA production inhibitor of the present invention is used as a skin external preparation, the formulation form is not particularly limited as long as it can be applied transdermally. For example, a skin external pharmaceutical, a skin external pharmaceutical quasi-drug , Cosmetics, skin cleansing agents and the like. As a preparation form when the α-SMA production inhibitor of the present invention is used as an external preparation for skin, specifically, creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments, packs Skin external medicines such as creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments, packs, etc .; external drugs for skin external use such as creams, lotions, gels, Cosmetics such as emulsions, liquids, ointments and packs; skin cleansing agents such as body shampoos, hair shampoos and rinses. Among these preparation forms, preferably a skin external medicine, more preferably a cream, a lotion, a gel, an emulsion, or a pack.
[用途・用量]
本発明のα−SMA産生抑制剤は、α−SMAの発現を抑制できるので、α−SMAの過剰な発現が一因となっている疾患や症状、α−SMAが関与している疾患や症状の予防又は治療に有効である。具体的には、肥厚性瘢痕やケロイド等の皮膚創傷治癒異常では、α−SMAの過剰な発現が一因となっていることが知られているので、本発明のα−SMA産生抑制剤は、これらの皮膚創傷治癒異常の予防又は治療に使用できる。更に、α−SMAは、腫瘍細胞の転移や骨粗鬆症にも関与していることが知られているので、本発明のα−SMA産生抑制剤は、腫瘍の転移や骨粗鬆症の予防又は治療にも使用することができる。
[Use / Dose]
Since the α-SMA production inhibitor of the present invention can suppress the expression of α-SMA, diseases and symptoms caused by excessive expression of α-SMA, diseases and symptoms related to α-SMA, and the like. It is effective for prevention or treatment. Specifically, it is known that excessive expression of α-SMA is a cause in abnormal skin wound healing such as hypertrophic scars and keloids. Therefore, the α-SMA production inhibitor of the present invention is These can be used for prevention or treatment of abnormal skin wound healing. Furthermore, since α-SMA is known to be involved in tumor cell metastasis and osteoporosis, the α-SMA production inhibitor of the present invention is also used for prevention or treatment of tumor metastasis and osteoporosis. can do.
とりわけ、本発明のα−SMA産生抑制剤は、傷痕部の真皮由来の繊維芽細胞におけるα−SMAの発現を効果的に抑制できるので、当該細胞のα−SMAの過剰な発現が一因となっている皮膚創傷治癒異常(肥厚性瘢痕やケロイド等)の予防又は治療用途に特に好適に使用できる。 In particular, the α-SMA production inhibitor of the present invention can effectively suppress the expression of α-SMA in fibroblasts derived from the dermis of the scar, and this is due to the excessive expression of α-SMA in the cells. It can be particularly suitably used for the prevention or treatment of abnormal skin wound healing (hypertrophic scar, keloid, etc.).
また、本発明のα−SMA産生抑制剤の用量については、投与方法、製剤形態、適用する症状の程度等に応じて適宜設定すればよい。例えば、本発明のα−SMA産生抑制剤を皮膚外用剤として使用する場合であれば、その用量の一例として、1回当たり、皮膚1cm2当たり、硫酸化グルコサミノグリカン及び/又はその塩が0.1〜3mg程度となる量で、1日1〜数回程度の頻度が挙げられる。 Moreover, what is necessary is just to set suitably about the dosage of the alpha-SMA production inhibitor of this invention according to an administration method, a formulation form, the grade of the symptom to apply, etc. For example, when the α-SMA production inhibitor of the present invention is used as an external preparation for skin, as an example of its dosage, per 1 cm 2 of skin, sulfated glucosaminoglycan and / or a salt thereof may be used. The amount is about 0.1 to 3 mg, and the frequency is about 1 to several times a day.
以下に実施例を示して本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.
試験例1
硫酸化グルコサミノグリカンが傷痕部の真皮由来の繊維芽細胞のα−SMA発現に与える影響を評価するために以下の実験を行った。
Test example 1
In order to evaluate the effect of sulfated glucosaminoglycan on α-SMA expression of fibroblasts derived from the dermis of the scar, the following experiment was conducted.
1.実験材料
(細胞)
本試験では、ヒト傷痕部の真皮由来の繊維芽細胞(HSF)(コスモバイオ株式会社、HYPERTROPHIC SCAR FIBROBLAST; ADULT LEFT、CRC−HSF105−1)を使用した。
1. Experimental material (cell)
In this test, dermal fibroblasts (HSF) (Cosmo Bio Inc., HYPERTROPHIC SCAR FIBROBLAST; ADULT LEFT, CRC-HSF105-1) derived from human scars were used.
(培地)
ウシ胎児血清を10容量%となるように添加したD-MEM/Ham's F-12(和光純薬工業株式会社、042−30555)を使用した。
(Culture medium)
D-MEM / Ham's F-12 (Wako Pure Chemical Industries, 042-30555) supplemented with 10% by volume of fetal bovine serum was used.
(試薬)
ヒトTGF−β(Human Transforming Growth Factor−β1):ヒトTGF−β(PERPROTECH、PTI−100−21C−10)を脱イオン蒸留水で希釈して使用した。なお、ヒトTGF−βは、HSFにおけるα−SMAの発現を誘導することが知られている成分である。
ヘパラン硫酸:ヘパラン硫酸(フナコシ株式会社、GAG−HS01)を脱イオン蒸留水で希釈して使用した。
コンドロイチン硫酸Aナトリウム:コンドロイチン硫酸Aナトリウム(和光純薬工業株式会社、ニワトリ軟骨由来(037−24391))を脱イオン蒸留水で希釈して使用した。
コンドロイチン硫酸Cナトリウム:コンドロイチン硫酸Cナトリウム(和光純薬工業株式会社、(032−14613))を脱イオン蒸留水で希釈して使用した。
コンドロイチン硫酸Eナトリウム:コンドロイチン硫酸Eナトリウム(和光純薬工業株式会社、イカ軟骨由来(034−23061))を脱イオン蒸留水で希釈して使用した。
(reagent)
Human TGF-β (Human Transforming Growth Factor-β1) : Human TGF-β (PERPROTECH, PTI-100-21C-10) diluted with deionized distilled water was used. Human TGF-β is a component known to induce α-SMA expression in HSF.
Heparan sulfate : Heparan sulfate (Funakoshi Co., Ltd., GAG-HS01) diluted with deionized distilled water was used.
Chondroitin sulfate A sodium : Chondroitin sulfate A sodium (Wako Pure Chemical Industries, Ltd., derived from chicken cartilage (037-24391)) was diluted with deionized distilled water and used.
Chondroitin sulfate C sodium : Chondroitin sulfate C sodium (Wako Pure Chemical Industries, Ltd., (032-14613)) diluted with deionized distilled water was used.
Chondroitin sulfate E sodium : Chondroitin sulfate E sodium (Wako Pure Chemical Industries, Ltd., derived from squid cartilage (034-23061)) was diluted with deionized distilled water and used.
2.実験方法
HSFを1.0×105cells/mlとなるように培地に添加した細胞懸濁液0.5mlを24穴プレ−トの各穴に撒き、更にTGF−βを最終濃度が2 ng/mLになるように加え、37℃、5%CO2条件下で48時間インキュベ−タ−にて培養した。48時間の培養後、最終濃度が1 mg/mL又は0.2 mg/mLとなるように硫酸化グルコサミノグリカンを添加した。硫酸化グルコサミノグリカンの添加後に、37℃、5%CO2条件下で9日間インキュベ−タ−にて培養した後に、各穴に、1×Sample buffer(ドデシル硫酸ナトリウム6重量%、Tris-HCl 0.25M、グリセロール50重量%、ブロモフェノールブルー0.1重量%を含有する3×Sample bufferをイオン交換水で3倍に希釈したもの)200μL及び2−メルカプトエタノール2μLを加え、細胞を回収した。得られた細胞回収液に対して、ボルテックスを行い、更にソニケ−ションを行った後に、煮沸することにより、細胞溶解液を得た。得られた細胞溶解液についてウエスタンブロッティングを行い、α−SMAの発現量を求めた。α−SMA発現量は、内部標準であるβ−actinの発現量と比較して補正することにより求めた。また、コントロールとして、硫酸化グルコサミノグリカンを添加しなかったこと以外は、前記と同条件で試験を行い、α−SMAの発現量を求めた。なお、本試験では、同一条件での試験を5つの穴で行い、得られたα−SMAの発現量の平均値を算出することによって評価した。
2. experimental method
Spread 0.5 ml of cell suspension with HSF added to the medium to 1.0 × 10 5 cells / ml in each well of the 24-well plate, and add TGF-β to a final concentration of 2 ng / mL. In addition, the cells were cultured in an incubator for 48 hours at 37 ° C. and 5% CO 2 . After 48 hours of culture, sulfated glucosaminoglycan was added so that the final concentration was 1 mg / mL or 0.2 mg / mL. After the addition of sulfated glucosaminoglycan, the cells were cultured in an incubator for 9 days under conditions of 37 ° C. and 5% CO 2 , and 1 × Sample buffer (6% by weight of sodium dodecyl sulfate, Tris- 200 μL of 3 × Sample buffer containing HCl 0.25M, 50% by weight of glycerol and 0.1% by weight of bromophenol blue was diluted 3-fold with ion-exchanged water) and 2 μL of 2-mercaptoethanol were added to recover the cells. The obtained cell recovery solution was vortexed and further sonicated, and then boiled to obtain a cell lysate. The obtained cell lysate was subjected to Western blotting to determine the expression level of α-SMA. The α-SMA expression level was determined by correcting it relative to the expression level of β-actin, which is an internal standard. As a control, a test was performed under the same conditions as above except that sulfated glucosaminoglycan was not added, and the expression level of α-SMA was determined. In addition, in this test, it evaluated by calculating the average value of the expression level of the obtained (alpha) -SMA, performing the test on the same conditions with five holes.
3.実験結果
得られた結果を表1に示す。この結果、TGF−βによってα−SMAの発現が誘導されたHDFに硫酸化グルコサミノグリカンを共存させることにより、α−SMAの発現量を低減できることが確認された。特に、基本構成単位中のN−アセチルガラクトサミンの4位と6位に硫酸基を持つコンドロイチン硫酸Eは、α−SMAの発現を顕著に抑制できることが明らかとなった。
3. The results obtained are shown in Table 1. As a result, it was confirmed that the expression level of α-SMA can be reduced by allowing the sulfated glucosaminoglycan to coexist in HDF in which the expression of α-SMA was induced by TGF-β. In particular, it was revealed that chondroitin sulfate E having sulfate groups at positions 4 and 6 of N-acetylgalactosamine in the basic structural unit can remarkably suppress the expression of α-SMA.
処方例
α−SMA産生抑制剤として、表2〜3に示す組成のクリーム剤(処方例1〜8)、表4に示すローション剤(処方例9〜14)、表5に示すジェル剤(処方例15〜19)、及び表6〜7に示す乳液剤(処方例20〜29)を調製した。これらの製剤は、いずれも、前記試験例1の場合と同様に、α−SMAの発現量を抑制させる効果が期待され、α−SMAの産生抑制に有効である。
Formulation examples α-SMA production inhibitors, creams (formulation examples 1 to 8) having the compositions shown in Tables 2 to 3, lotions (formulation examples 9 to 14) shown in Table 4, gel agents (formulations) shown in Table 5 The emulsions (Prescription Examples 20 to 29) shown in Examples 15 to 19) and Tables 6 to 7 were prepared. As in the case of Test Example 1, each of these preparations is expected to have an effect of suppressing the expression level of α-SMA, and is effective in suppressing α-SMA production.
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