JP2005247842A - Therapeutic agent for xeroderma - Google Patents
Therapeutic agent for xeroderma Download PDFInfo
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- JP2005247842A JP2005247842A JP2005029171A JP2005029171A JP2005247842A JP 2005247842 A JP2005247842 A JP 2005247842A JP 2005029171 A JP2005029171 A JP 2005029171A JP 2005029171 A JP2005029171 A JP 2005029171A JP 2005247842 A JP2005247842 A JP 2005247842A
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Abstract
Description
本発明は、乾皮症治療剤に関し、さらに詳しくは角質水分量減少、角質間脂質低下などによる皮膚傷害の解消に効果がある薬剤に関する。 The present invention relates to a therapeutic agent for xeroderma, and more particularly, to a drug effective in relieving skin damage caused by a decrease in keratin water content, a decrease in interkeratin lipid, and the like.
近年、加齢などにより、皮膚角質間脂質の減少、角質水分量低下により惹起される乾燥肌、乾皮症などの慢性皮膚疾患の患者数が増加している。これらの疾患は原因不明の強い痒み感を伴い、そのために行う掻痒行動（引っ掻き行動）により悪化するものと考えられている。したがって、これら慢性疾患の解消には角質水分量を保持し、掻痒感を解消することが非常に重要である。 In recent years, due to aging and the like, the number of patients with chronic skin diseases such as dry skin and xeroderma caused by a decrease in lipids between the stratum corneum and a decrease in the amount of stratum corneum is increasing. These diseases are accompanied by a strong itching of unknown cause, and are thought to be exacerbated by pruritus behavior (scratching behavior). Therefore, in order to eliminate these chronic diseases, it is very important to maintain the amount of keratinous water and eliminate itching.
従来、これらの慢性皮膚炎に対しては、外用ステロイド剤、抗ヒスタミン剤、抗アレルギー剤および保湿剤などの薬剤が使用されている。しかし、ステロイド剤は強い副作用からその使用が制限されており、抗ヒスタミン剤、抗アレルギー剤、保湿剤などでは、十分満足のいく治療効果が得られていなかった。また、それらの薬剤は、一時的に症状が改善されても再発する事があり治療効果が不十分なものであった。 Conventionally, drugs such as external steroids, antihistamines, antiallergic agents and moisturizers have been used for these chronic dermatitis. However, the use of steroids is limited due to strong side effects, and antihistamines, antiallergic agents, moisturizers, etc. have not been able to provide a sufficiently satisfactory therapeutic effect. In addition, these drugs may recur even if symptoms are temporarily improved, and the therapeutic effect is insufficient.
従来、皮膚の乾燥については、その原因が不明なことから十分な評価ができていなかったのが現状である。 Conventionally, the dryness of the skin has not been sufficiently evaluated because the cause is unknown.
したがって、乾皮症が関与する皮膚からの水分蒸散量もしくは皮膚角質水分量を指標にして薬物を評価し、皮膚からの水分蒸散量を効果的に低減させることができる薬物を見出せば、乾皮症の発症を抑制することができる薬物が得られると考えられる。 Therefore, if the drug is evaluated using the amount of moisture transpiration from the skin involved in xeroderma or the amount of skin horny moisture as an index, and a drug that can effectively reduce the amount of moisture transpiration from the skin is found, It is considered that a drug capable of suppressing the onset of the disease can be obtained.
従来、プロスタグランジン類が痒み惹起成分であるという報告は多数なされている。一方、プロスタグランジン類を有効成分とする止痒剤としては、プロスタグランジン受容体アゴニストが、アトピー性皮膚炎による痒みに対する外用止痒剤として有用であることが報告されている（特許文献１）。 Conventionally, there have been many reports that prostaglandins are stagnation-inducing components. On the other hand, as an antidiarrheal agent containing prostaglandins as an active ingredient, it has been reported that a prostaglandin receptor agonist is useful as an external antidiarrheal agent against itching due to atopic dermatitis (Patent Document 1). ).
本願発明の化合物の一部は眼圧降下剤などとして開示されている化合物である（特許文献２〜４）。しかしそれらが乾皮症に有効であるという報告はなされていない。
Some of the compounds of the present invention are compounds disclosed as intraocular pressure-lowering agents (
一般的にプロスタグランジン受容体に作用する成分は、一つの受容体だけでなく複数の受容体に作用することが多い。したがって目的とする薬効を発現する受容体に対する作用だけでなく、他の受容体に対しても作用することから、目的外の生理反応が副作用や作用低減という形で発現するリスクがある。プロスタグランジンＤ2がＤＰ受容体だけでなくＴＰ受容体に対しても作動物質であることは報告されている（非特許文献１、２）。
In general, a component that acts on a prostaglandin receptor often acts not only on one receptor but also on a plurality of receptors. Therefore, since it acts not only on the receptor that exhibits the intended medicinal effect but also on other receptors, there is a risk that an unintended physiological reaction is manifested in the form of side effects or reduced action. It has been reported that prostaglandin D 2 is an agonist for not only the DP receptor but also the TP receptor (
ＴＰ受容体作動物質には強力な血管収縮作用、血小板凝集を引き起こす可能性がある。このため、ＤＰ受容体以外にもＴＰ受容体等にも作動物質として作用するＰＧＤ2においては薬剤としての有用性が制限される。 TP receptor agonists can cause potent vasoconstriction and platelet aggregation. For this reason, the usefulness as a drug is limited in PGD 2 which acts as an agonist on not only the DP receptor but also the TP receptor and the like.
本発明は、主に加齢により皮膚角質間脂質及び角質水分量が低下することによる原因不明の皮膚過敏、掻痒感及び皮膚乾皮症の発症を予防または治療することができる、高い安全性と有効性を併せ持った薬剤の提供を目的とする。 The present invention is capable of preventing or treating the development of skin irritability, pruritus sensation and dry skin disease of unknown cause mainly due to the decrease of interkeratin lipid and keratin water content due to aging. The purpose is to provide a drug with effectiveness.
本発明者らは種々検討した結果、プロスタグランジンＤ受容体選択的作動薬が皮膚乾燥を効果的に抑制でき、角質水分量低下などの症状の治療または予防に有効であることを見出し本発明を完成した。 As a result of various studies, the present inventors have found that a prostaglandin D receptor selective agonist can effectively suppress skin dryness and is effective in the treatment or prevention of symptoms such as a decrease in keratin water content. Was completed.
すなわち本発明は
１．ＤＰ受容体選択的アゴニストを有効成分とする乾皮症治療剤。
２．ＤＰ受容体選択的アゴニストであるプロスタグランジン類を有効成分とする乾皮症治療剤。
３．式
That is, the present invention is 1. A therapeutic agent for xeroderma comprising a DP receptor selective agonist as an active ingredient.
2. A therapeutic agent for xeroderma, comprising prostaglandins that are DP receptor selective agonists as active ingredients.
3. formula
[式中Ｒ1は
-(CH2)4-S-CH2-CO2H
で示される基、
-(CH2)4-S-CH2-CO2CH3
で示される基、
-(CH2)4-C≡C-CO2H
で示される基、
-CH2-S-(CH2)2-S-CH2-CO2H
で示される基または
-CH2-S-(CH2)4-CO2H
で示される基のいずれかの基を示す。]
で示される化合物を有効成分とする乾皮症治療剤。
４．式
[Wherein R 1 is
-(CH 2 ) 4 -S-CH 2 -CO 2 H
A group represented by
-(CH 2 ) 4 -S-CH 2 -CO 2 CH 3
A group represented by
-(CH 2 ) 4 -C≡C-CO 2 H
A group represented by
-CH 2 -S- (CH 2 ) 2 -S-CH 2 -CO 2 H
A group represented by
-CH 2 -S- (CH 2 ) 4 -CO 2 H
Any one of the groups represented by ]
A therapeutic agent for xeroderma comprising the compound represented by the formula:
4). formula
で示される化合物を有効成分とする乾皮症治療剤。
５．乾皮症が、老人性乾皮症である１〜４のいずれかに記載の乾皮症治療剤。
である。
A therapeutic agent for xeroderma comprising the compound represented by the formula:
5). The therapeutic agent for xeroderma according to any one of 1 to 4, wherein the xeroderma is senile xeroderma.
It is.
本発明者らは、本発明の作用機序を検討したところ、皮膚炎を自然発症するＮＣ/Ｎｇaマウスは、皮膚組織中のプロスタグランジンのうち、ＰＧＥ2、ＰＧＦ2α、ＰＧＩ2量については加齢に伴う変化がないにも拘わらず、ＰＧＤ2量のみが加齢により低下することを見出した。この結果より皮膚炎を自然発症するＮＣ/Ｎｇaマウスでは加齢により低下した生体内ＰＧＤ2量が痒み及び皮膚乾燥の引き金になっている可能性を示唆した。即ち、内因性のＰＧＤ2量が生理的に皮膚バリアー機能の保持に作用しており、外因性のＰＧＤ2安定誘導体を補給することにより、乾皮症の発症を予防または治療するものと考えられる。 The present inventors have examined the mechanism of action of the present invention. As a result, NC / Nga mice that spontaneously develop dermatitis are among the prostaglandins in the skin tissue with respect to the amounts of PGE 2 , PGF 2 α, and PGI 2 . Found that only the amount of PGD 2 decreased with aging, even though there was no change with aging. From these results, it was suggested that in vivo NC / Nga mice that spontaneously develop dermatitis, the amount of in vivo PGD 2 decreased by aging may trigger itchiness and dry skin. That is, the amount of endogenous PGD 2 acts physiologically to maintain the skin barrier function, and it is considered that the onset of xeroderma is prevented or treated by supplementing with an exogenous PGD 2 stable derivative. .
本願発明で効果がある乾皮症には老人性乾皮症、皮脂欠乏性湿疹などがあげられるが、本発明は老人性乾皮症に対して特に有効である。 Xeroderma dermatosis effective in the present invention includes senile xeroderma and sebum-deficient eczema. The present invention is particularly effective for senile xeroderma.
本発明において、ＤＰ受容体選択的アゴニストとは、プロスタグランジン受容体のうち、ＤＰ受容体に対して強い作動薬として作用し、ＴＰ受容体に対する作用が弱い物質である。具体的には、ヒト血小板ＡＤＰ凝集抑制作用がIC50値で１０nM未満、ヒトＴＰ拮抗作用がIC50値で１０μM以上の物質を示す物質である。 In the present invention, the DP receptor selective agonist is a prostaglandin receptor that acts as a strong agonist for the DP receptor and weakly acts on the TP receptor. Specifically, it is a substance that exhibits a human platelet ADP aggregation inhibitory action with an IC 50 value of less than 10 nM and a human TP antagonistic action with an IC 50 value of 10 μM or more.
その様な作用を持つＤＰ受容体選択的アゴニストである化合物としては、具体的には、式１
As a compound that is a DP receptor selective agonist having such an action, specifically, a compound represented by
[式中Ｒ1は
-(CH2)4-S-CH2-CO2H、
-(CH2)4-S-CH2-CO2CH3、
-(CH2)4-C≡C-CO2H、
-CH2-S-(CH2)2-S-CH2-CO2H、または
-CH2-S-(CH2)4-CO2H
で示されるいずれかの基を示す。]
で示される化合物が好ましく、その中でも特に式
[Wherein R 1 is
-(CH 2 ) 4 -S-CH 2 -CO 2 H,
-(CH 2 ) 4 -S-CH 2 -CO 2 CH 3 ,
-(CH 2 ) 4 -C≡C-CO 2 H,
-CH 2 -S- (CH 2 ) 2 -S-CH 2 -CO 2 H, or
-CH 2 -S- (CH 2 ) 4 -CO 2 H
Any one of the groups represented by ]
The compounds represented by
で示される化合物（以下「化合物１」という）が好ましい。
(Hereinafter referred to as “
本願発明の好ましい化合物である、式１の化合物はＷＯ９５／１８１０１号公報、ＷＯ９９／６１４１９号公報およびＷＯ０１／１９７９０号公報に記載された化合物であり、それらの公報に開示された方法で製造することができる。
The compound of
本発明の乾皮症治療剤は外用剤として患部に塗布して使用することができる。したがって、患部に速やかに投与できるだけでなく、代謝による無効化や副作用などが発生しにくいという特徴を有している。 The therapeutic agent for xeroderma of the present invention can be used as an external preparation applied to the affected area. Therefore, not only can it be administered promptly to the affected area, but it also has the feature that it is unlikely to cause invalidation or side effects due to metabolism.
本発明の乾皮症治療剤の投与量は、年齢、性別、体重等により異なるが、有効成分濃度が０．１〜０．０００１％程度の製剤を患部に適量塗布することにより投与する。 The dose of the therapeutic agent for xeroderma of the present invention varies depending on age, sex, weight, etc., but is administered by applying an appropriate amount of a preparation having an active ingredient concentration of about 0.1 to 0.0001% to the affected area.
本発明の乾皮症治療剤は、有効成分のほか必要な基剤、ゲル化剤、溶解剤、溶解補助剤、ｐＨ調節剤、他の薬効成分などを配合し、一般的な方法で、軟膏剤、クリーム剤、ゲル剤、液剤、エアゾール剤、貼付剤などの外用剤にすることができる。 The therapeutic agent for xeroderma of the present invention contains an active ingredient, a necessary base, a gelling agent, a solubilizing agent, a solubilizing agent, a pH adjusting agent, other medicinal ingredients, and the like. It can be used as an external preparation such as an agent, cream, gel, liquid, aerosol, or patch.
本発明により、乾皮症を予防または改善することができた。また、本発明により、乾皮症により発生する皮膚炎を予防または改善することが可能になった。 According to the present invention, xeroderma can be prevented or ameliorated. In addition, the present invention makes it possible to prevent or improve dermatitis caused by xeroderma.
以下実施例および試験例により、本発明をさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
化合物１を０．０１ｇ秤量しグリセリン２０ｇに溶解後、白色ワセリン８０ｇに均一に混合し１００ｇの軟膏剤を得た。
化合物１ ０．０１ｇ
白色ワセリン ８０ｇ
グリセリン ２０ｇ
0.01 g of
80g white petrolatum
Glycerin 20g
下記の成分を秤量し均一に混合した後、精製水とエタノールの下記容量を加え１０００ｍｌの液剤を得た。
化合物１ ０．１ｇ
エタノール ２００ｍL
精製水 ８００ｍL
The following components were weighed and mixed uniformly, and then the following volumes of purified water and ethanol were added to obtain 1000 ml of liquid.
Ethanol 200mL
800 ml of purified water
下記の成分をそれぞれ混合し均一に乳化し、更に香料を適量加えクリーム剤
５００ｇを得た。
化合物１ ０．０５ｇ
マレイン酸カルビノキサミン ５ｇ
エラグ酸ナトリウム ５ｇ
ヒヤルロン酸ナトリウム ３ｇ
メチルパラベン ２ｇ
精製水 ２１８．５ｇ
流動パラフィン（＃７０） ５０ｇ
スクワラン １００ｇ
セトステアリルアルコール ６０ｇ
蜜蝋 ２０ｇ
モノステアリン酸グリセリン １５ｇ
ソルビタンモノラウレート ２０ｇ
プロピルパラベン １ｇ
The following components were mixed and uniformly emulsified, and an appropriate amount of fragrance was added to obtain 500 g of a cream.
Carbinoxamine maleate 5g
5g sodium ellamate
Sodium hyaluronate 3g
Methyl paraben 2g
218.5 g of purified water
Liquid paraffin (# 70) 50g
Squalane 100g
Setostearyl alcohol 60g
20g of beeswax
15g glyceryl monostearate
Sorbitan monolaurate 20g
1g propylparaben
以下の各成分を組成とするエアゾール剤を調製した。
化合物１ ０．０１（Ｗ／Ｖ％）
アジピン酸ジイソプロピル ３
モノラウリン酸ポリエチレングリコール ８
エタノール １０
イソプロパノール １０
マクロゴール４００ ５
ジブチルヒドロキシトルエン ０．１
ジイソプロパノールアミン ０．２
精製水 ２５
液化石油ガス 全１００
An aerosol agent comprising the following components was prepared.
Macrogol 400 5
Dibutylhydroxytoluene 0.1
Diisopropanolamine 0.2
Purified water 25
100 liquefied petroleum gas
参考例１：マウス皮膚組織中のＰＧｓ量の変化
ＮＣ/Ｎｇa系雄性マウス(５、１０、１５、２０週齢)を試験に用いた。内因性のプロスタグランジン（ＰＧ）を正確に測定するため、インドメタシン(１０ｍｇ／ｋｇ)を静脈内注射して新たな内因性のＰＧ産生を抑制し、５分後に鋏を用いて背部皮膚を採取した。皮膚片をチューブに移しＰＢＳ（１００μＭ インドメタシンを含む）1ｍＬを添加した後、ポリトロンホモジェナイザーを用いて組織を粉砕した。アセトンを４ｍＬ添加して５分間静置した後、３０００ｒｐｍで１０分間遠心した。上清を回収後、溶媒を蒸発させてELISA bufferに再溶解し、ELISA kit（Cayman chemical、R&D systems）にて各ＰＧｓ量(ＰＧＤ2、ＰＧＥ2、ＰＧＦ2α、６ketoＰＧＦ1α)を測定し、皮膚１mg中の各ＰＧｓ量を求めた。
Reference Example 1: Change in the amount of PGs in mouse skin tissue NC / Nga male mice (5, 10, 15, 20 weeks old) were used in the test. To accurately measure endogenous prostaglandins (PG), indomethacin (10 mg / kg) is injected intravenously to suppress new endogenous PG production, and after 5 minutes, the dorsal skin is collected using scissors did. The skin piece was transferred to a tube, 1 mL of PBS (containing 100 μM indomethacin) was added, and the tissue was pulverized using a polytron homogenizer. After adding 4 mL of acetone and allowing to stand for 5 minutes, the mixture was centrifuged at 3000 rpm for 10 minutes. After collecting the supernatant, the solvent is evaporated and redissolved in ELISA buffer, and the amount of each PGs (PGD 2 , PGE 2 , PGF 2α , 6 keto PGF 1α ) is measured with ELISA kit (Cayman chemical, R & D systems), and the skin The amount of each PGs in 1 mg was determined.
結果を図１に示した。 The results are shown in FIG.
図１から明らかなようにＮＣ／Ｎｇａマウスは加齢により皮膚中のＰＧＤ2量が低下することがわかった。 As is apparent from FIG. 1, it was found that the amount of PGD 2 in the skin of NC / Nga mice decreased with aging.
試験例１
以下の方法で本願発明有効成分である化合物１と対照例としてＰＧＤ2を用いて、各種プロスタグランジン受容体結合選択性を求めた。
Test example 1
With PGD 2 as a control example with the
１．ヒト血小板凝集抑制作用
ヒト血小板ＡＤＰ凝集抑制作用
試験は購入した多血小板血漿（ＰＲＰ）(６×１０8 platelets／mL)を用い、血小板凝集の測定はＢｏｒｎの方法（Nature，第１９４巻，第９２７頁，１９６２年）に準じて行なった。ＰＲＰ １００μＬに、エタノールに溶解した１nM〜３μMの被検薬物溶液５μＬを加え、３７℃、１０００ｒｐｍ攪拌下、１分間インキュベートした。これに５μＬの凝集惹起剤［ＡＤＰ（３μＭ）］を添加して血小板凝集を惹起し、血小板凝集計（アグリゴメーター）により最大凝集率（血小板の凝集を惹起してから５分以内の光透過度の最大変化）を求めた。被検薬物の凝集抑制率を、被検薬物溶液のかわりにエタノールを用いた場合の最大凝集率に対する被検薬物の最大凝集率から算出し、その用量反応曲線からＩＣ50値を求めた。その結果、化合物１のＩＣ50値は４．２７ｎＭ、ＰＧＤ2のＩＣ50値は１１ｎＭであった。
1. Human platelet aggregation inhibitory action Human platelet ADP aggregation inhibitory action The purchased platelet-rich plasma (PRP) (6 × 10 8 platelets / mL) was used for the test, and the platelet aggregation was measured by the method of Born (Nature, 194, 927). Page, 1962). To 100 μL of PRP, 5 μL of a 1 nM to 3 μM test drug solution dissolved in ethanol was added and incubated at 37 ° C. under stirring at 1000 rpm for 1 minute. To this was added 5 μL of an aggregation inducer [ADP (3 μM)] to induce platelet aggregation, and the maximum aggregation rate (platelet aggregation within 5 minutes after inducing aggregation of platelets) was measured with a platelet aggregometer (aggregometer). Maximum degree of change). The aggregation inhibition rate of the test drug was calculated from the maximum aggregation rate of the test drug relative to the maximum aggregation rate when ethanol was used instead of the test drug solution, and the IC 50 value was obtained from the dose-response curve. As a result, the IC 50 value of
２．モルモット血小板凝集抑制作用
モルモット血小板ＡＤＰ凝集抑制作用
採血およびplatelet rich plasma（ＰＲＰ）とplatelet poor plasma（ＰＰＰ）の調製
９〜１０週齢ハートレー系雄性モルモットをペントバルビタール(３０mg／kg、腹腔内投与)により麻酔し、腹大動脈より３．８％クエン酸ナトリウム２．０ｍＬ含有注射筒に血液を２０ｍＬ採血した。血液は直ちに２０℃、９００ｒｐｍ、１０分間遠心分離し上清であるＰＲＰを回収した。さらに２０℃、３０００ｒｐｍ、１０分間遠心分離し上清であるＰＰＰを回収した。
2. Guinea pig platelet aggregation inhibitory action Guinea pig platelet ADP aggregation inhibitory action Blood collection and preparation of platelet rich plasma (PRP) and platelet poor plasma (PPP) Anesthesia was performed, and 20 mL of blood was collected from the abdominal aorta into a syringe containing 2.0 mL of 3.8% sodium citrate. The blood was immediately centrifuged at 20 ° C., 900 rpm for 10 minutes, and the supernatant PRP was collected. Furthermore, it centrifuged at 3000 rpm for 10 minutes at 20 degreeC, and collect | recovered PPP which is a supernatant liquid.
血小板凝集能の測定には、血小板凝集能測定装置（ＰＡＭ−８Ｃ）を使用した。ＰＲＰ ２７４μＬにエタノールに溶解した０．２８７〜９５．７nMの被験物質1μＬを添加し、３７℃、１０００ｒｐｍの攪拌下に３分間インキュベートした。インキュベート後、２５μＬのＡＤＰ（３μＭ）にて血小板凝集を惹起し、５分間の最大凝集率を測定した。 For measurement of platelet aggregation ability, a platelet aggregation ability measuring apparatus (PAM-8C) was used. 1 μL of 0.287 to 95.7 nM test substance dissolved in ethanol was added to 274 μL of PRP and incubated for 3 minutes at 37 ° C. with stirring at 1000 rpm. After incubation, platelet aggregation was induced with 25 μL of ADP (3 μM), and the maximum aggregation rate for 5 minutes was measured.
その結果、化合物１のＩＣ50値は６．２±２．３ｎＭ、ＰＧＤ2のＩＣ50値は５４．３±２３．０ｎＭであった。
As a result, the IC 50 value of
３．ヒトＴＰ拮抗作用
文献（Ｊ.Pharmacol.Exp.Ther．、第２４５巻、第７８６−７９２頁、１９８８年）に記載された方法に準拠して、ヒト洗浄血小板への[3Ｈ]ＳＱ２９５４８結合に対する被検薬の拮抗作用を検討した。
3. Human TP antagonism According to the method described in the literature (J. Pharmacol. Exp. Ther., 245, 786-792, 1988), the [ 3 H] SQ29548 binding to human washed platelets The antagonism of the test drug was examined.
その結果、化合物１は１０μＭで２８％、１μＭで７％の結合阻害率を示した。一方、陽性対照薬として用いたトロンボキサンアゴニストであるＵ４４０６９のＩＣ50値は２．４μＭであった。
As a result,
参考例２
上記１で示された本願発明有効成分及びＰＧＤ2の血小板凝集抑制作用がプロスタグランジンＤ受容体アゴニスト作用であることを確認するために、化合物１及びＰＧＤ2の血小板凝集抑制作用がプロスタグランジンＤ受容体選択的アンタゴニストによって拮抗されるかを試験した。
Reference example 2
In order to confirm that the platelet aggregation inhibitory action of the present invention active ingredient and PGD 2 shown in 1 above is a prostaglandin D receptor agonistic action, the platelet aggregation inhibitory action of
被験薬物：
プロスタグランジンＤ受容体選択的アンタゴニストとして、((+/-)-3-ベンジル-5-(6-カルボキシヘキシル)-1-(2-シクロヘキシル-2-ヒドロキシエチルアミノ)-ヒダントイン) (以下「BW A868C」という)（シグマアルドリッチジャパン株）を用いた。
Study drug:
As a prostaglandin D receptor selective antagonist, ((+/−)-3-benzyl-5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) -hydantoin) (hereinafter “ BW A868C ”(Sigma Aldrich Japan Co., Ltd.) was used.
BW A868Cは、エタノールで希釈して、終濃度が０．０３μmol／L、０．１μmol／L、０．３μmol／L、１μmol／L、３μmol／L及び１０μmol／Lとなるようにした。 BW A868C was diluted with ethanol so that the final concentrations were 0.03 μmol / L, 0.1 μmol / L, 0.3 μmol / L, 1 μmol / L, 3 μmol / L and 10 μmol / L.
化合物１及びPGD2は、エタノールで希釈して、287 nmol/L及び300 nmol/Lに調整して用いた。
陰性対照としてエタノールを用いた。 Ethanol was used as a negative control.
血小板の調製：
ヒト健常男子の肘静脈から採血し、３．１３％クエン酸ナトリウムを入れたチューブに血液を採取した。これを２０℃にて１，０００ｒｐｍにて1０分間遠心分離することで上澄（ＰＲＰ、多血小板血漿）を分取し、残さをさらに２０℃にて、３，０００ｒｐｍにて1０分間遠心分離することで上澄（ＰＰＰ、乏血小板血漿）を得た。ＰＲＰの血小板数を任意にＰＰＰで希釈して30×104 血小板/μLに調整して用いた。
Platelet preparation:
Blood was collected from the cubital vein of a healthy human male and collected in a tube containing 3.13% sodium citrate. The supernatant (PRP, platelet-rich plasma) is separated by centrifuging at 1,000 rpm for 10 minutes at 20 ° C., and the residue is further centrifuged at 3,000 rpm for 10 minutes at 20 ° C. The supernatant (PPP, platelet poor plasma) was obtained. The platelet count of PRP was arbitrarily adjusted with PPP and adjusted to 30 × 10 4 platelets / μL.
血小板凝集能の測定
血小板凝集能は，血小板凝集能測定装置(PAM-8C：エム・シー・メディカル株式会社)を使用し，Ｂｏｒｎの方法（Ｎａｔｕｒｅ，第１９４巻，第９２７ページ，１９６２年）にて測定した。PRP 273 μL（BW A868C群の場合は各濃度のBW A868Cを１μL添加）を1,000 rpmの攪拌下37 ℃で3分間プレインキュベートした。プレインキュベート後，エタノールまたは試験物質を１μL（化合物１：最終濃度 95.7 nmol/L、PGD2：最終濃度 1000 nmol/L）添加し、1,000 rpmの攪拌下37℃で３分間インキュベートした。インキュベート後、25 μLのADP(最終濃度３ μmol/L)にて血小板凝集を惹起し、５分間の最大凝集率を測定した。
Measurement of platelet aggregation ability Platelet aggregation ability is measured by the method of Born (Nature, 194, 927, 1962) using a platelet aggregation ability measuring device (PAM-8C: MC Medical Co., Ltd.). Measured. PRP 273 μL (in the case of the BW A868C group, 1 μL of each concentration of BW A868C was added) was preincubated for 3 minutes at 37 ° C. with stirring at 1,000 rpm. After pre-incubation, 1 μL of ethanol or test substance (compound 1: final concentration 95.7 nmol / L, PGD 2 : final concentration 1000 nmol / L) was added, and the mixture was incubated at 37 ° C. for 3 minutes with stirring at 1,000 rpm. After incubation, platelet aggregation was induced with 25 μL of ADP (
その結果を図２に示した。 The results are shown in FIG.
化合物１及びPGD2は、それぞれの対照群（エタノール）に対して有意な血小板凝集抑制作用を示した。
化合物１による血小板凝集抑制作用は、BW A868Cの添加濃度の増加に伴って拮抗され、0.1 μmol/L以上により有意に拮抗された。PGD2による血小板凝集抑制作用も、BW A868Cの添加濃度の増加に伴って拮抗され、0.3 μmol/L以上により有意に拮抗された。
The platelet aggregation inhibitory action by
以上の結果より、本願発明有効成分はプロスタグランジンＤ受容体選択的アゴニスト作用を有することが明らかとなった。 From the above results, it was revealed that the active ingredient of the present invention has a prostaglandin D receptor selective agonistic action.
試験例２
マウス皮膚バリアー機能に対する作用（治療試験）
６週齢のＢＡＬＢ／ｃ系雄性マウス、８匹の吻側背部の４ｃｍ2（２ｃｍ×２ｃｍ）を電気バリカンで剃毛し、アセトン：ジエチルエーテル＝1：1混液を浸した脱脂綿（２ｃｍ×２ｃｍ）で６０秒間被覆した。上記皮膚バリアー機能破壊（バリアー破壊）処理を１日１回、連続して３日間行った。３日目のバリアー破壊処理完了翌日から１日１回、２日間、溶媒（エタノール，１００μＬ）または溶媒に溶解した薬剤（化合物１,ＰＧＤ2，ＰＧＦ2α及びＰＧＥ1，全て０．０１％，１００μＬ）をバリアー破壊部位に塗布した。２回目の溶媒及び薬剤塗布翌日に同部位の経表皮水分蒸散量をTewameter（商品名）により測定し、薬剤の作用を評価した。結果を図３に示した。
Test example 2
Effect on mouse skin barrier function (treatment test)
6-week-old BALB / c male mice, 8 rostral back 4cm 2 (2cm x 2cm) shaved with electric clippers, cotton wool soaked with acetone: diethyl ether = 1: 1 mixture (2cm x 2cm) ) For 60 seconds. The skin barrier function destruction (barrier destruction) treatment was performed once a day for 3 consecutive days. On the third day after the completion of the barrier disruption treatment, once a day for 2 days, the solvent (ethanol, 100 μL) or the drug dissolved in the solvent (
図から明らかなように、正常群と比較し、バリアー破壊した対照群は有意に経表皮水分蒸散量が増加した。バリアー破壊した対照群と比較し、化合物１塗布群は、有意に経表皮水分蒸散量が減少した。一方、ＰＧＤ2，ＰＧＦ2α及びＰＧＥ1塗布群は、対照群との間に有意差は認められなかった。
As is clear from the figure, the transepidermal water transpiration amount was significantly increased in the control group in which the barrier was destroyed as compared with the normal group. Compared with the control group in which the barrier was destroyed, the transepidermal water transpiration amount was significantly reduced in the
以上の結果より、化合物１は、破壊された皮膚バリアーの治癒促進作用を示すことがわかった。
From the above results, it was found that
試験例３
マウス皮膚バリアー機能に対する作用（予防試験）
６週齢のＢＡＬＢ／ｃ系雄性マウス、６匹の吻側背部の４ｃｍ2（２ｃｍ×２ｃｍ）を電気バリカンで剃毛し、皮膚炎を発症したＮＣ／Ｎｇａマウスと同居飼育した。同居飼育開始翌日から１日１回7日間、溶媒（エタノール、１００μＬ）または溶媒に溶解した薬剤（化合物１、ＰＧＤ2、ＰＧＦ2α及びＰＧＥ1、全て０．０１％、１００μＬ）を上記剃毛部位に塗布した。
Test example 3
Effect on mouse skin barrier function (prevention test)
6-week-old BALB / c male mice and 6 rostral backs of 4 cm 2 (2 cm × 2 cm) were shaved with an electric clipper and reared together with NC / Nga mice that developed dermatitis. From the day following the start of cohabitation, once a day for 7 days, the solvent (ethanol, 100 μL) or a drug dissolved in the solvent (
7回目の溶媒または薬剤塗布翌日に同部位の経表皮水分蒸散量をTewameter（商品名）により測定し、薬剤の作用を評価した。結果を図４に示した。 The transepidermal water transpiration amount at the same site was measured with Tewameter (trade name) on the day after the seventh solvent or drug application, and the effect of the drug was evaluated. The results are shown in FIG.
図から明らかなように、正常群と比較し、対照群は有意に経表皮水分蒸散量が増加していることが認められた。対照群と比較し、化合物１、ＰＧＤ2及びＰＧＥ1塗布群は、有意な経表皮水分蒸散量の減少が認められた。一方、ＰＧＦ2α塗布群は対照群との間に有意な差は認められなかった。
As is clear from the figure, it was found that the amount of transepidermal water transpiration was significantly increased in the control group compared to the normal group. Compared with the control group, the
以上の結果は化合物１の皮膚バリアー傷害予防作用を示すものであり、化合物１は乾皮症などの皮膚バリアー傷害に対し、予防作用を示すことがわかった。
The above results show the skin barrier injury preventive action of
試験例４
加齢マウス皮膚バリアー機能に対する作用（治療試験）
50週齢のBALB/c系雄性マウス、８匹の吻側背部の４cm2（２cm×２cm）を電気バリカンで剃毛した。翌日から１日１回３日間、溶媒（エタノール，200μL）または溶媒に溶解した薬剤（化合物１及びPGD2，全て0.0001%，200μL）を上記剃毛部位に塗布した。
Test example 4
Effect on skin barrier function in aging mice (treatment test)
50 cm-old BALB / c male mice, 8 rostral backs of 4 cm 2 (2 cm × 2 cm) were shaved with an electric clipper. From the next day, once a day for 3 days, a solvent (ethanol, 200 μL) or a drug dissolved in the solvent (
３回目の溶媒または薬剤塗布翌日に同部位の経表皮水分蒸散量をTewameter（商品名）により測定し、薬剤の作用を評価した。結果を図５に示した。 On the day after the third solvent or drug application, the transepidermal water transpiration of the same site was measured by Tewameter (trade name) to evaluate the action of the drug. The results are shown in FIG.
図から明らかなように、対照群と比較し、化合物１塗布群は、有意な経表皮水分蒸散量の減少が認められた。一方、PGD2塗布群は対照群との間に有意な差は認められなかった。
As is clear from the figure, a significant reduction in transepidermal water transpiration was observed in the
以上の結果は化合物１の皮膚バリアー修復促進作用を示すものであり、化合物１は老人性乾皮症などの皮膚バリアー傷害に対し、治療作用を示すことがわかった。
The above results show the skin barrier repair promoting action of
参考例３
加齢による皮膚障害
6，12，24及び50週齢のBALB/c系雄性マウスの経表皮水分蒸散量（皮膚バリアー機能の指標）を試験例４と同様の方法で測定した。結果を図６に示した。
Reference example 3
Skin damage due to aging
Transepidermal water transpiration (index of skin barrier function) of BALB / c male mice aged 6, 12, 24 and 50 weeks was measured in the same manner as in Test Example 4. The results are shown in FIG.
図から明らかなように、加齢に伴い、皮膚バリアーの指標である経表皮水分蒸散量（TEWL）が増加を示し、皮膚機能が加齢とともに破壊されることを確認した。 As is clear from the figure, with aging, transepidermal water transpiration (TEWL), which is an index of skin barrier, increased, and it was confirmed that skin function was destroyed with aging.
本願発明により、安全性が高く優れた効果を示す乾皮症治療または予防剤の提供が可能になったので、医薬品などに利用可能である。 According to the present invention, it has become possible to provide a therapeutic or preventive agent for xeroderma that exhibits high safety and excellent effects, and thus can be used for pharmaceuticals.
Claims (5)
-(CH2)４-S-CH2-CO２H
で示される基、
-(CH2)４-S-CH2-CO２CH3
で示される基、
-(CH2)４-C≡C-CO２H
で示される基、
-CH2-S-(CH２)2-S-CH2-CO２H
で示される基または
-CH2-S-(CH２)４-CO２H
で示される基のいずれかの基を示す。]
で示される化合物を有効成分とする乾皮症治療剤。 formula
-(CH 2 ) 4 -S-CH 2 -CO 2 H
A group represented by
-(CH 2 ) 4 -S-CH 2 -CO 2 CH 3
A group represented by
-(CH 2 ) 4 -C≡C-CO 2 H
A group represented by
-CH 2 -S- (CH 2) 2 -S-CH 2 -CO 2 H
A group represented by
-CH 2 -S- (CH 2 ) 4 -CO 2 H
Any one of the groups represented by ]
A therapeutic agent for xeroderma comprising the compound represented by the formula:
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006085655A1 (en) * | 2005-02-14 | 2006-08-17 | Taisho Pharmaceutical Co., Ltd. | Ointment |
| WO2008018592A1 (en) * | 2006-08-11 | 2008-02-14 | Taisho Pharmaceutical Co., Ltd. | External preparation comprising prostaglandin derivative |
| WO2009004873A1 (en) * | 2007-06-29 | 2009-01-08 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivative-containing aqueous liquid agent |
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| WO1995018101A1 (en) * | 1993-12-29 | 1995-07-06 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivative, salt thereof, and use thereof |
| WO1999061419A1 (en) * | 1998-05-25 | 1999-12-02 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivative |
| WO2001019790A1 (en) * | 1999-09-10 | 2001-03-22 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivatives |
| WO2003070252A1 (en) * | 2002-02-22 | 2003-08-28 | Taisho Pharmaceutical Co., Ltd. | Antipruritics |
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2005
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995018101A1 (en) * | 1993-12-29 | 1995-07-06 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivative, salt thereof, and use thereof |
| WO1999061419A1 (en) * | 1998-05-25 | 1999-12-02 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivative |
| WO2001019790A1 (en) * | 1999-09-10 | 2001-03-22 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivatives |
| WO2003070252A1 (en) * | 2002-02-22 | 2003-08-28 | Taisho Pharmaceutical Co., Ltd. | Antipruritics |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006085655A1 (en) * | 2005-02-14 | 2006-08-17 | Taisho Pharmaceutical Co., Ltd. | Ointment |
| JPWO2006085655A1 (en) * | 2005-02-14 | 2008-06-26 | 大正製薬株式会社 | Ointment |
| US7888392B2 (en) | 2005-02-14 | 2011-02-15 | Taisho Pharmaceutical Co., Ltd. | Ointment |
| WO2008018592A1 (en) * | 2006-08-11 | 2008-02-14 | Taisho Pharmaceutical Co., Ltd. | External preparation comprising prostaglandin derivative |
| WO2009004873A1 (en) * | 2007-06-29 | 2009-01-08 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin derivative-containing aqueous liquid agent |
| US8044104B2 (en) | 2007-06-29 | 2011-10-25 | Taisho Pharmaceutical Co., Ltd | Prostaglandin derivative-containing aqueous liquid preparation |
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