JP6815782B2 - α-SMA production inhibitor - Google Patents
α-SMA production inhibitor Download PDFInfo
- Publication number
- JP6815782B2 JP6815782B2 JP2016149624A JP2016149624A JP6815782B2 JP 6815782 B2 JP6815782 B2 JP 6815782B2 JP 2016149624 A JP2016149624 A JP 2016149624A JP 2016149624 A JP2016149624 A JP 2016149624A JP 6815782 B2 JP6815782 B2 JP 6815782B2
- Authority
- JP
- Japan
- Prior art keywords
- sma
- sulfated
- production inhibitor
- acid
- acetyl
- 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.)
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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 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 contractile ability by expressing α-SMA. .. In the wound healing process, fibroblasts are transformed into myofibroblasts with strong contractile ability that express α-SMA, play a role in contracting granulation tissue and reducing wounds, and promote the expression of α-SMA. Is known to contribute to wound healing. It is also known that myofibroblasts expressing α-SMA play an important role in the strength of the dermis and the firmness of the skin. Therefore, conventionally, substances that promote the production of α-SMA have been screened, 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 abnormal skin wound healing such as hypertrophic scars and keloids, the appearance of myofibroblast-like cells is observed, and it is known that excessive expression of α-SMA of the cells exerts an adverse effect. It has also been reported that α-SMA is also 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, conventionally, no substance has been found that suppresses the production of α-SMA in cells.
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 that can suppress the production of α-SMA can be found, it is possible to improve the symptoms of abnormal skin wound healing such as hypertrophic scars and keloids, and it is also effective for tumor cell metastasis and osteoporosis. However, as mentioned above, the current situation is that such a substance has not been found in the past.
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 agent for suppressing the production of α-SMA.
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 diligent studies to solve the above problems, the present inventors have found that sulfated glycosaminoglycan has an effect 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, the present invention provides the inventions of the following aspects.
Item 1. An α-SMA production inhibitor containing a sulfated glycosaminoglycan and / or a salt thereof.
Item 2. Item 2. The item 1 wherein the amino sugar constituting the sulfated glycosaminoglycan and / or a salt thereof is N-acetyl-D-galactosamine in which the hydroxyl groups at the 4- and / or 6-positions are sulfated. α-SMA production inhibitor.
Item 3. Item 2. 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 4- and 6-positions are sulfated.
Item 4. Item 3. The α-SMA production inhibitor according to any one of Items 1 to 3, wherein D-glucuronic acid is contained as a constituent sugar of the sulfated glycosaminoglycan and / or a salt thereof.
Item 5. Item 1 to 4, wherein the sulfated glycosaminoglycan and / or a 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.
Item 6. Item 4. The α-SMA production inhibitor according to any one of Items 1 to 4, wherein the sulfated glycosaminoglycan and / or a salt thereof is chondroitin sulfate E and / or a salt thereof.
Item 7. Item 2. 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, the expression of α-SMA can be suppressed, so that the symptoms and diseases caused by the overexpression of α-SMA, the symptoms and diseases associated with α-SMA, and the like. It is 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 glycosaminoglycans and / or salts 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。 Sulfated glycosaminoglycan is a disaccharide unit in which uronic acid or galactose is glycosidic-bonded to an amino sugar by β1-3 bond, β1-4 bond, or α1-4 bond (hereinafter referred to as “basic constituent unit”). It is an acidic polysaccharide having a repeating structure (which may be) and in which hydroxyl groups and / or amino groups that are not involved in glycosidic bonds in the basic structural unit are partially sulfated. Sulfated glycosaminoglycans usually have an unbranched linear skeleton.
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。 Specifically, the uronic acid constituting the basic structural unit of sulfated glycosaminoglycan is L-iduronic acid or D-glucuronic acid. The amino sugar constituting the basic constituent 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 sugars that make up the basic building blocks of sulfated glycosaminoglycans vary depending on the type of sulfated glycosaminoglycan, but are D-glucosamine, D-galactosamine, N-acetyl-D-galactosamine, or N-acetyl-. It is 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 sulfated glycosaminoglycan may be uronic acid or galactose, but uronic acid is preferable from the viewpoint of exerting an even more excellent α-SMA production inhibitory effect. More preferably, D-glucuronic acid is mentioned.
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 that constitutes the basic constituent unit of sulfated glycosaminoglycan may be any of the above-mentioned ones, but is preferable from the viewpoint of exerting an even more excellent α-SMA production inhibitory effect. Can be 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 site to be sulfated may be a hydroxyl group and / or an amino group not involved in the glycosidic bond in the basic structural unit. For example, uronic acid constituting the basic structural unit. Alternatively, the 2-position hydroxyl group, the 3-position hydroxyl group, the 4-position hydroxyl group of galactose, the 2-position amino group of the amino sugar constituting the basic structural unit, the 3-position hydroxyl group, the 4-position hydroxyl group, and the fourth hydroxyl group. A hydroxyl group at the 6-position can be mentioned.
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 sulfated sites in the sulfated glycosaminoglycan is not particularly limited, but for example, the number of sulfated sites (number of sulfate groups) in the basic structural unit is 1 to 6. The number is preferably 1 to 3, more preferably 1 or 2, and even 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 exerting an even more excellent effect of suppressing α-SMA production as a site that is sulfated in the sulfated glycosaminoglycan, preferably at least one of the hydroxyl groups at the 4- and 6-positions of the amino sugar is used. More preferably, both the 4- and 6-position hydroxyl groups of the amino sugar can be 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。 Further, as a basic constituent unit of sulfated glycosaminoglycan, the hydroxyl groups at the 4-position and / or the 6-position are preferably sulfated from the viewpoint of exerting an even more excellent effect of suppressing α-SMA production. Examples thereof include those having N-acetyl-D-galactosamine, and more preferably those having N-acetyl-D-galactosamine in which both the 4- and 6-position hydroxyl groups 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 β1-3 bond, and the hydroxyl group at the 4-position of N-acetyl-D-galactosamine is sulfated. Acidic polysaccharides)
-Basic building block of chondroitin sulfate B (D-glucuronic acid bound to N-acetyl-D-galactosamine by β1-3 bond) and L-iduronic acid bound to N-acetyl-D-galactosamine by β1-3 bond An acidic polysaccharide that has a constituent unit and the hydroxyl group at the 4-position of N-acetyl-D-galactosamine is sulfated)
-Chondroitin sulfate C (D-glucuronic acid has a basic structural unit bonded to N-acetyl-D-galactosamine by β1-3 bond, and the hydroxyl group at the 6-position of N-acetyl-D-galactosamine is sulfated. Acidic polysaccharides)
-Chondroitin sulfate D (D-glucuronic acid has a basic structural unit bonded to N-acetyl-D-galactosamine by β1-3 bond, and has a hydroxyl group at the 2-position of D-glucuronic acid and N-acetyl-D-galactosamine. Acidic polysaccharide in which the hydroxyl group at the 6th position is sulfated)
-Chondroitin sulfate E (D-glucuronic acid has a basic structural unit bonded to N-acetyl-D-galactosamine by β1-3 bond, and the hydroxyl groups at the 4- and 6-positions of N-acetyl-D-galactosamine are Acidic polysaccharides that are sulfated)
-Heparan sulfate (basic constituent 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 having a unit and in which the 2-position hydroxyl group of D-glucuronic acid and L-iduronic acid, and the 2-position amino acid and 6-position 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 β1-4 bond, the hydroxyl group at the 6-position of D-galactose, and 2 of N-acetyl-D-galactosamine. Acidic polysaccharide in which the amino group at the position and the hydroxyl group at the 6th position 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, but for example, the basic structural unit (constituent unit consisting of two sugar residues) is about 2 to 300, preferably 5 to 200. The degree of polymerization, more preferably about 10 to 150, may be 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。 The salt of sulfated glycosaminoglycan is not particularly limited as long as it is pharmaceutically acceptable, but for example, alkali metal salts such as sodium salt and potassium salt; calcium salt, magnesium salt, iron salt, etc. Metal salts such as manganese salts; salts such as ammonium salts can be mentioned. 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 of sulfated glycosaminoglycans and salts thereof may be selected and used alone, or two or more thereof 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 a salt thereof used in the present invention may be obtained by extracting from an animal and purifying as necessary, chemically synthesized or genetically engineered. It may be manufactured by a method.
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。 Among the sulfated glycosaminoglycans and salts thereof used in the present invention, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate E, are preferable from the viewpoint of exerting an even more excellent effect of suppressing α-SMA production. 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 a salt thereof is not particularly limited and may be appropriately set according to the formulation form, administration form and the like of the agent. However, for example, 0.01 to 5% by weight can be mentioned. More specifically, when the α-SMA production inhibitor of the present invention is an external preparation for skin, the content of sulfated glycosaminoglycan and / or a salt thereof is usually 0.05 to 3% by weight. It is preferably 0.1 to 3% by weight, more preferably 0.1 to 1% by weight.
［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 in addition to the sulfated glycosaminoglycan, if necessary. Examples of such pharmacological components include anti-histamines (dipotassium glycyrrhizinate, glycyrrhizic acid, difenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacine, chloroprocaine, proparacaine, meprilcaine, or salts thereof. , Orthokine, oxesazein, oxypolyentoxydecane, funnel extract, percaminpase, tesitdecitin, etc.), anti-inflammatory agents (alantin, indomethacin, fervinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (corodion, castor oil, etc.), blood circulation promotion Ingredients (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), refreshing agents (menthol, camphor, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (chondroitin sodium sulfate, glucosamine, etc.), etc. Be done.
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。 In addition, the α-SMA production inhibitor of the present invention may contain a base or an additive, if necessary, in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable, but for example, water, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene, etc.) Aqueous bases such as glycol, 1,3-butylene glycol, etc.; oils (olive oil, paraffin 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, vaseline, etc.), waxes / waxes (mitsurou, carnauba wax, candelilla wax, selecin, rice wax, microcrystallin wax, etc.), ester oil (isopropyl myristate, etc.) , Isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, bechenic acid, linoleic acid, lanolin, etc.) ), Fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, tri2-ethyl Oily bases such as glyceryl hexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10-50 mol) phytosterol ether, POE (10-50 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) ) Polyoxyethylene such as behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether Alcohol ethers, these phosphates and phosphates (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE (10-60 mol) 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), Surfactants such as glycerin fatty acid esters (glycerin monostearate, etc.), hydrogenated soybean phospholipids, hydrogenated lanolin alcohol; refreshing agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), antiseptic Agents (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-cyonel, citronellal, farnesol, etc.), colorants (tar pigments (brown 201, blue 201, etc.) , Yellow No. 4, Yellow No. 403, etc.), cocoa pigment, chlorophyll, aluminum oxide, etc.), viscous agent (carboxyvinyl polymer, hypromerose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, etc.) Conditioning agent (phosphate, hydrochloric acid, citrate, sodium citrate, succinic acid, tartrate acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (dol-pyrrolidone sodium carboxylate solution, D) -Solvitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbinate, gallic acid Addition of propyl, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, UV absorbers, chelating agents, pressure-sensitive agents, buffers, solubilizers, solubilizers, preservatives, etc. Agents can be mentioned.
［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 form]
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, a drip infusion, etc., and may be appropriately set according to the specific use of the preparation. From the viewpoint of exerting an even more excellent effect of suppressing α-SMA production, 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, but for example, it is liquid, solid, semi-solid (gel, ointment). Shape, paste shape) and the like.
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。 Further, when the α-SMA production inhibitor of the present invention is used as an external preparation for skin, the formulation form thereof is not particularly limited as long as it can be applied transdermally, but for example, an external preparation for skin and a quasi-drug for external use on skin. , Cosmetics, skin cleaning agents, etc. Specific examples of the formulation form when the α-SMA production inhibitor of the present invention is used as an external preparation for skin are creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, and packs. Topical skin preparations such as preparations; creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs and other external medicines for skin; creams, lotions, gels, Cosmetics such as emulsions, liquids, ointments, and packs; skin lotions such as body shampoos, hair shampoos, and rinses can be mentioned. Among these preparation forms, a skin external medicine is preferable, and a cream, lotion, gel, emulsion, and pack are more preferable.
［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 / Dosage]
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, and diseases and symptoms associated with α-SMA. It is effective in the prevention or treatment of. Specifically, it is known that excessive expression of α-SMA is one of the causes of abnormal skin wound healing such as hypertrophic scars and keloids. Therefore, the α-SMA production inhibitor of the present invention is used. , Can be used for the prevention or treatment of these skin wound healing abnormalities. 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 dermis-derived fibroblasts at the scar site, and thus the excessive expression of α-SMA in the cells is one of the causes. It can be particularly suitably used for the prevention or treatment of abnormal skin wound healing (hypertrophic scars, keloids, 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。 The dose of the α-SMA production inhibitor of the present invention may be appropriately set according to the administration method, formulation form, degree of symptom to be applied, and the like. For example, when the α-SMA production inhibitor of the present invention is used as an external preparation for skin, as an example of the dose, sulfated glucosaminoglycan and / or a salt thereof may be used per 1 cm 2 of the skin. 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。 The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto.
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
The following experiments were conducted to evaluate the effect of sulfated glycosaminoglycan on α-SMA expression of dermis-derived fibroblasts in the scar area.
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. 1. Experimental material (cells)
In this study, dermis-derived fibroblasts (HSF) from human scars (Cosmo Bio Co., Ltd., HYPERTROPHIC SCAR FIBROBLAST; ADULT LEFT, CRC-HSF105-1) 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, Ltd., 042-30555) to which fetal bovine serum was added so as to be 10% by volume 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) was diluted with deionized distilled water and used. Human TGF-β is a component known to induce the expression of α-SMA in HSF.
Heparan sulfate : Heparan sulfate (Funakoshi Co., Ltd., GAG-HS01) was diluted with deionized distilled water before use.
Sodium chondroitin sulfate: Sodium chondroitin sulfate (Wako Pure Chemical Industries, Ltd., derived from chicken cartilage (037-24391)) was diluted with deionized distilled water and used.
C sodium chondroitin sulfate: C sodium chondroitin sulfate (Wako Pure Chemical Industries, Ltd., (032-14613)) was diluted with deionized distilled water and used.
E-sodium chondroitin sulfate: E-sodium chondroitin sulfate (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. 2. experimental method
Sprinkle 0.5 ml of cell suspension added to the medium to 1.0 × 10 5 cells / ml of HSF into each hole of the 24-well plate, and further add TGF-β to a final concentration of 2 ng / mL. In addition, the cells were cultured in an incubator for 48 hours under the conditions of 37 ° C. and 5% CO 2 . After culturing for 48 hours, sulfated glycosaminoglycans were added to a final concentration of 1 mg / mL or 0.2 mg / mL. After addition of sulfated glucosaminoglycan, after culturing in an incubator for 9 days under 37 ° C. and 5% CO 2 conditions, 1 × Sample buffer (6 wt% sodium dodecyl sulfate, Tris-) was added to each hole. 200 μL of 3 × Sample buffer containing 0.25 M HCl, 50% by weight of glycerol and 0.1% by weight of bromophenol blue diluted 3-fold with ion-exchanged water) and 2 μL of 2-mercaptoethanol were added, and cells were collected. The obtained cell recovery solution was vortexed, further sonicated, and then boiled to obtain a cell lysate. Western blotting was performed on the obtained cell lysate to determine the expression level of α-SMA. The expression level of α-SMA was determined by adjusting the expression level by comparing with the expression level of β-actin, which is an internal standard. In addition, as a control, the test was carried out under the same conditions as above except that sulfated glucosaminoglycan was not added, and the expression level of α-SMA was determined. In this test, the test was conducted under the same conditions in five holes, and the average value of the obtained α-SMA expression levels was calculated for evaluation.
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. 3. Experimental Results Table 1 shows the obtained results. As a result, it was confirmed that the expression level of α-SMA can be reduced by coexisting sulfated glycosaminoglycan with HDF in which the expression of α-SMA was induced by TGF-β. In particular, it was revealed that chondroitin sulfate E having a sulfate group at the 4- and 6-positions 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 As α-SMA production inhibitors, creams having the compositions shown in Tables 2 to 3 (Prescription Examples 1 to 8), lotions shown in Table 4 (Prescription Examples 9 to 14), and gel agents shown in Table 5 (formulations). Examples 15-19) and the emulsions shown in Tables 6-7 (Prescription Examples 20-29) were prepared. All of these preparations are expected to have an effect of suppressing the expression level of α-SMA as in the case of Test Example 1, and are effective in suppressing the production of α-SMA.
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