JP5947041B2 - Safe IL-17 production inhibitor - Google Patents
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- JP5947041B2 JP5947041B2 JP2012001092A JP2012001092A JP5947041B2 JP 5947041 B2 JP5947041 B2 JP 5947041B2 JP 2012001092 A JP2012001092 A JP 2012001092A JP 2012001092 A JP2012001092 A JP 2012001092A JP 5947041 B2 JP5947041 B2 JP 5947041B2
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Description
本発明は、パンテチンを含有するＩＬ−１７産生抑制剤に関する。 The present invention relates to an IL-17 production inhibitor containing pantethine.
生体の免疫応答の主体をなすリンパ球がＴ細胞であり、Ｔ細胞には免疫反応を調節するヘルパーＴ細胞（以下、Ｔｈと称することがある)がある。ヘルパーＴ細胞としてはＴｈ１細胞やＴｈ２細胞がよく知られているが、最近になって、慢性関節リウマチ等にＴｈ１７細胞が関与することが報告され（非特許文献１）、これはインターロイキン（以下、ＩＬと称することがある）１７を産生する細胞であることも知られている。また、変形性関節症の病態にもＩＬ−１７が関与することが報告されている（非特許文献２）。 Lymphocytes that form the body's immune response are T cells, and T cells include helper T cells (hereinafter sometimes referred to as Th) that regulate immune responses. As helper T cells, Th1 cells and Th2 cells are well known. Recently, it has been reported that Th17 cells are involved in rheumatoid arthritis and the like (Non-patent Document 1). It is also known to be a cell that produces 17). In addition, it has been reported that IL-17 is also involved in the pathophysiology of osteoarthritis (Non-patent Document 2).
ＩＬ−１７は、真菌に対する感染防御などの生体防御に重要な役割をはたすが、異常に産生が亢進すると生体に有害な影響を及ぼす。変形性関節症は、進行的な軟骨の破壊を特徴とする疾患であるが、ＩＬ−１７は、この軟骨細胞の破壊に関与するサイトカインの１つであり（非特許文献３）、変形性関節症における重要性が注目されている。例えば、ＩＬ−１７は、ヒトの変形性関節症軟骨細胞のＮＯ産生を増強し（非特許文献４）、関節組織の破壊を起こすcollagenase3の産生を誘導する（非特許文献５）。 IL-17 plays an important role in defense of organisms such as defense against fungi, but has an adverse effect on the body when production is abnormally increased. Osteoarthritis is a disease characterized by progressive cartilage destruction, but IL-17 is one of the cytokines involved in this chondrocyte destruction (Non-patent Document 3). Attention has been focused on the importance of the disease. For example, IL-17 enhances NO production of human osteoarthritic chondrocytes (Non-Patent Document 4) and induces the production of collagenase 3 that causes destruction of joint tissues (Non-Patent Document 5).
慢性関節リウマチは、Ｔｈ１７細胞の異常亢進によるＩＬ−１７等のサイトカインの産生過多により、本来はウイルス、バクテリア等に対する感染防御などの細胞性免疫が、自己の関節の組織を攻撃し、関節破壊により歩行障害などが生じる疾患である（非特許文６及び非特許文献７）。 Rheumatoid arthritis is caused by excessive production of cytokines such as IL-17 due to abnormal increase in Th17 cells, and originally cellular immunity such as defense against infections against viruses, bacteria, etc. attacks the tissues of its own joints and destroys joints. It is a disease that causes gait disturbance (Non-Patent Document 6 and Non-Patent Document 7).
一方、免疫抑制剤であるシクロスポリンやタクロリムスは、Ｔｈの活性化を強く抑制することが知られており、慢性関節リウマチ、アレルギー性疾患であるアトピー性皮膚炎などの自己免疫疾患の治療薬として使用されている。しかし、これらの薬物は副作用が多く、治療の途中で投与を中断したり、別の薬剤に切り替えたりしなければならず、より安全な治療薬が望まれている。 On the other hand, cyclosporine and tacrolimus, which are immunosuppressants, are known to strongly inhibit Th activation and are used as therapeutic agents for autoimmune diseases such as rheumatoid arthritis and allergic diseases such as atopic dermatitis. Has been. However, these drugs have many side effects, and administration must be interrupted or switched to another drug during the treatment, and a safer therapeutic drug is desired.
パンテチンはＣｏＡの前駆物質であるため極めて安全な薬剤であり、粥状硬化進展抑制作用、血清脂質改善作用、脂肪酸酸化促進作用、血小板数改善作用、腸管運動促進作用等が知られている。 Since pantethine is a precursor of CoA, it is an extremely safe drug, and is known to have atherosclerosis progress inhibiting action, serum lipid improving action, fatty acid oxidation promoting action, platelet number improving action, intestinal motility promoting action, and the like.
しかし、これまでに、パンテチンのＩＬ−１７産生抑制作用はもとより、変形性関節症、自己免疫性関節炎、リウマチ様関節炎、接触型過敏症、遅延型過敏症、気道過敏症、多発性硬化症、自己免疫性脳炎等の抑制作用は報告されておらず、示唆もされていない。 However, to date, pantethine has not only inhibited IL-17 production, but also osteoarthritis, autoimmune arthritis, rheumatoid arthritis, contact-type hypersensitivity, delayed-type hypersensitivity, airway hypersensitivity, multiple sclerosis, No inhibitory action such as autoimmune encephalitis has been reported or suggested.
本発明の課題は、Ｔｈ１７細胞の免疫応答の異常亢進に起因する疾患、又は、インターロイキン１７の産生亢進による疾患を治療又は予防することができる、新規かつ安全な関節炎抑制剤組成物を提供することである。 An object of the present invention is to provide a novel and safe arthritis inhibitor composition capable of treating or preventing a disease caused by abnormally increased immune response of Th17 cells or a disease caused by increased production of interleukin-17. That is.
発明者らは、ヘルパーＴ細胞（Ｔｈ）の異常な免疫応答を抑制する組成物を探索すべく長年にわたり鋭意研究を重ねてきた。今回、マウスより摘出した脾臓細胞からＴｈを分離し、抗原特異的刺激によりＴ細胞から産生されるサイトカイン（Ｔｈ１７）を指標として、ＩＬ−１７の産生を抑制する物質について、鋭意スクリーニングを行ってきた。 The inventors have conducted extensive research for many years to search for a composition that suppresses an abnormal immune response of helper T cells (Th). In this study, Th was isolated from spleen cells isolated from mice, and intensive screening was conducted for substances that suppress IL-17 production using cytokine (Th17) produced from T cells by antigen-specific stimulation as an index. .
その結果、驚くべきことに、パンテチン単独で、既存の免疫抑制剤のシクロスポリンに匹敵するほどのＩＬ−１７の産生抑制効果が発現することを見出し、本発明を完成させるに至った。 As a result, it was surprisingly found that pantethine alone exerts an IL-17 production inhibitory effect comparable to that of the existing immunosuppressive agent cyclosporine, and thus completed the present invention.
すなわち、本発明は、
（１）パンテチンを含有することを特徴とする、ＩＬ−１７に起因する炎症を治療または改善する医薬組成物、
（２）ＩＬ−１７に起因する前記炎症が、変形性関節症、自己免疫性関節炎、リウマチ様関節炎、接触型過敏症、遅延型過敏症、気道過敏症、多発性硬化症又は自己免疫性脳炎である、上記（１）に記載の医薬組成物、
（３）ＩＬ−１７に起因する炎症が、変形性関節症又はリウマチ様関節炎である、上記（１）に記載の医薬組成物、又は、
（４）ＩＬ−１７に起因する炎症が、変形性関節症である、上記（１）に記載の医薬組成物である。
（５）ＩＬ−１７に起因する炎症が、変形性膝関節症である、上記（１）に記載の医薬組成物である。
That is, the present invention
(1) A pharmaceutical composition for treating or ameliorating inflammation caused by IL-17, comprising pantethine,
(2) The inflammation caused by IL-17 is osteoarthritis, autoimmune arthritis, rheumatoid arthritis, contact hypersensitivity, delayed hypersensitivity, airway hypersensitivity, multiple sclerosis or autoimmune encephalitis The pharmaceutical composition according to the above (1),
(3) The pharmaceutical composition according to the above (1), wherein the inflammation caused by IL-17 is osteoarthritis or rheumatoid arthritis, or
(4) The pharmaceutical composition according to (1), wherein the inflammation caused by IL-17 is osteoarthritis.
(5) The pharmaceutical composition according to (1), wherein the inflammation caused by IL-17 is knee osteoarthritis.
また、本発明は、
（６）上記（１）乃至（５）に記載された医薬組成物の有効量を哺乳動物に投与する、Ｔ細胞の異常亢進による疾患を予防又は治療する方法であり、
好適には、
（７）Ｔ細胞が、Ｔｈ１７である、上記（６）に記載の方法、又は、
（８）Ｔ細胞の異常亢進による疾患が、変形性関節症又は慢性関節リウマチである、上記（６）又は（７）に記載の方法である。
The present invention also provides:
(6) A method for preventing or treating a disease caused by abnormally elevated T cells, wherein an effective amount of the pharmaceutical composition described in (1) to (5) above is administered to a mammal.
Preferably,
(7) The method according to (6) above, wherein the T cell is Th17, or
(8) The method according to (6) or (7) above, wherein the disease caused by abnormal increase in T cells is osteoarthritis or rheumatoid arthritis.
本発明の、パンテチンを含有する医薬組成物は、ヘルパーＴ細胞、特に、Ｔｈ１７の免疫応答の異常亢進を顕著に抑制して、ＩＬ−１７の産生を顕著に抑制するため、ＩＬ−１７に起因する炎症、例えば、変形性関節症、自己免疫性関節炎、リウマチ様関節炎、接触型過敏症、遅延型過敏症、気道過敏症、多発性硬化症や自己免疫性脳炎の治療薬又は予防薬として有用である。 Since the pharmaceutical composition containing pantethine of the present invention remarkably suppresses abnormal enhancement of immune response of helper T cells, particularly Th17, and remarkably suppresses the production of IL-17, it is attributed to IL-17. Useful as a therapeutic or prophylactic agent for inflammatory inflammation such as osteoarthritis, autoimmune arthritis, rheumatoid arthritis, contact hypersensitivity, delayed hypersensitivity, airway hypersensitivity, multiple sclerosis and autoimmune encephalitis It is.
本発明のパンテチンは、第１５改正日本薬局方に収載されている。 The pantethine of the present invention is listed in the 15th revised Japanese Pharmacopoeia.
パンテチンを含有する本発明のＩＬ−１７産生抑制剤は、変形性関節症又は慢性関節リウマチ等を治療するのに好ましい投与経路に適した薬学的に許容される媒体を含んでいてもよい。また、本発明のＩＬ−１７産生抑制剤は、通常許容される賦形剤、結合剤、安定化剤などと共に配合することにより製造することができる。また、注射剤形で用いる場合は、通常許容される緩衝剤、溶解補助剤、等張剤等を添加することもできる。 The IL-17 production inhibitor of the present invention containing pantethine may contain a pharmaceutically acceptable vehicle suitable for a preferable administration route for treating osteoarthritis or rheumatoid arthritis. In addition, the IL-17 production inhibitor of the present invention can be produced by blending it with commonly acceptable excipients, binders, stabilizers and the like. In addition, when used in an injection form, generally acceptable buffering agents, solubilizing agents, isotonic agents and the like can be added.
投与法としては、経口投与及び注射のいずれも使用可能である。経口投与の場合はカプセル剤または錠剤、顆粒剤などの剤形で投与することができ、注射の場合は水溶性溶液による注射剤として皮下、筋肉内、又は、静脈内投与として用いることができる。 As the administration method, either oral administration or injection can be used. In the case of oral administration, it can be administered in the form of capsules, tablets, granules, etc. In the case of injection, it can be used as an injection with an aqueous solution, subcutaneously, intramuscularly or intravenously.
投与量は、対象疾患を有効に治療するに充分な量を使用することが可能であるが、一般に、症状、年齢、体重等により異なるが、経口投与の場合、大人では１日当たり５ｍｇ〜２０００ｍｇ、好ましくは２０〜１０００ｍｇを1回または数回に分けて投与することができる。 The dose may be an amount sufficient to effectively treat the target disease, but generally varies depending on symptoms, age, body weight, etc., but in the case of oral administration, 5 mg to 2000 mg per day for an adult, Preferably, 20 to 1000 mg can be administered once or divided into several times.
注射の場合、５％乃至１０％濃度の水溶液を０．１〜１０ｍＬ、好ましくは、０．２〜５ｍＬを1回または数回に分けて投与する。 In the case of injection, 0.1 to 10 mL, preferably 0.2 to 5 mL, of a 5% to 10% aqueous solution is administered once or divided into several times.
以下に、実施例等を示し、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples and the like, but the scope of the present invention is not limited thereto.
（実施例１）錠剤
（１）成分
（表１）
１日量（３錠）中（ｍｇ）
――――――――――――――――――――――――
パンテチン ３０
結晶セルロース １５０
低置換度ヒドロキシプロピルセルロース １００
ステアリン酸マグネシウム ４０
乳糖 適量
Example 1 Tablet (1) Ingredient (Table 1)
In daily dose (3 tablets) (mg)
――――――――――――――――――――――――
Pantethine 30
Crystalline cellulose 150
Low-substituted hydroxypropylcellulose 100
Magnesium stearate 40
Lactose appropriate amount
（２）製法
上記成分及び分量をとり、第１５改正日本薬局方製剤総則「錠剤」の項に準じて錠剤を製した。
(2) Manufacturing method Taking the said component and quantity, the tablet was manufactured according to the 15th revision Japanese Pharmacopoeia preparation general rule "Tablet".
（実施例２）注射剤
（１）成分
（表２）
１日量（％）
――――――――――――――――――――――――
パンテチン １０
氷酢酸 適量
塩化ナトリウム 適量
注射用精製水 残部
(Example 2) Injection (1) component (Table 2)
Daily amount (%)
――――――――――――――――――――――――
Panthecin 10
Glacial acetic acid Appropriate amount Sodium chloride Appropriate amount Purified water for injection The remainder
（２）製法
上記成分及び分量をとり、第１５改正日本薬局方製剤総則「注射剤」の項に準じて注射剤を製した。
(2) Manufacturing method Taking the said component and quantity, the injection was manufactured according to the 15th revision Japanese Pharmacopoeia preparation general rule "injection".
（試験例）マウス脾臓細胞から分離したCD4陽性T細胞のサイトカイン産生に対する作用
１．実験方法
１）動物
BALB/cマウスは日本チャールスリバー（横浜）より購入し、５週齢の雄を使用した。
２）培地
RPMI1640培地（Gibco社製）に、非働化した牛胎児血清（Fetal Bovine Serum,ＤＳファーマバイオメディカル株式会社）を10％になるように使用した。
３）薬剤
パンテチン（第一三共プロファーマ製）が0.167, 1.67,16.7, 167μg/mLになるように、さらに両薬物の併用されるように培地により希釈、調製した。また対照薬としてシクロスポリン（和光純薬製）10μg/mLを使用した。
４）脾臓細胞からCD4陽性T細胞（Ｔｈ細胞）の分離
脾臓から脾細胞を分離し、溶血、白血球を分離した。さらにDynabeads FlowComp Mouse CD4(invitrogen社製)を用いてCD4陽性T細胞を分離した。
５）CD4陽性T細胞の刺激によるサイトカイン産生
調製したCD4陽性T細胞浮遊液（8×105 cells/mL）に、上記３）にて調製した薬剤に、Dynabeads Mouse T-Activator CD3/CD28(invtorogen社製)を4μL、IL-6 20ng/mL TGFβ 2ng/mL添加し、37℃、5% CO2存在下で3日間培養した（0.2ml/well）。その後、上清中に産生されるサイトカインを、ELISA法により定量した。その際、IL-17を、それぞれ定量した。ELISA法にはeBio science社製のサイトカイン測定キットを使用した。
(Test example) Effect of CD4 positive T cells isolated from mouse spleen cells on cytokine production Experimental method 1) Animals
BALB / c mice were purchased from Japan Charles River (Yokohama), and 5-week-old males were used.
2) Medium
Inactivated fetal bovine serum (Fetal Bovine Serum, DS Pharma Biomedical Co., Ltd.) was used at 10% in RPMI1640 medium (Gibco).
3) Drug The pantethine (manufactured by Daiichi Sankyo Propharma Co., Ltd.) was diluted and prepared in a medium so that both drugs could be used in combination so as to be 0.167, 1.67, 16.7, 167 μg / mL. In addition, 10 μg / mL of cyclosporine (manufactured by Wako Pure Chemical Industries) was used as a control drug.
4) Separation of CD4-positive T cells (Th cells) from spleen cells Spleen cells were separated from the spleen, and hemolysis and leukocytes were separated. Further, CD4 positive T cells were separated using Dynabeads FlowComp Mouse CD4 (manufactured by Invitrogen).
5) Cytokine production by stimulation of CD4 positive T cells The prepared CD4 positive T cell suspension (8 × 10 5 cells / mL) is added to the drug prepared in 3) above with Dynabeads Mouse T-Activator CD3 / CD28 (invtorogen 4 μL, IL-6 20 ng / mL TGFβ 2 ng / mL was added and cultured at 37 ° C. in the presence of 5% CO 2 for 3 days (0.2 ml / well). Thereafter, cytokines produced in the supernatant were quantified by ELISA. At that time, IL-17 was quantified. For the ELISA method, a cytokine measurement kit manufactured by eBio science was used.
２．結果
結果を図１に示す。Dynabeads Mouse T-Activator CD3/CD28、IL-6、TGFβ添加により、IL-17が産生され、パンテチンは用量に依存してIL-17産生を抑制し、シクロスポリンのような非常に強いサイトカインの抑制が認められた。従って、パンテチンが本発明の目的たるＴｈ１７細胞分化抑制作用を有することが判明した。
2. Results The results are shown in FIG. Addition of Dynabeads Mouse T-Activator CD3 / CD28, IL-6, and TGFβ produces IL-17, and pantethine suppresses IL-17 production in a dose-dependent manner, suppressing very strong cytokines such as cyclosporine. Admitted. Therefore, it was found that pantethine has the Th17 cell differentiation inhibitory action which is the object of the present invention.
本発明の、パンテチンを含有する医薬組成物は、ヘルパーＴ細胞、特に、Ｔｈ１７の免疫応答の異常亢進を顕著に抑制して、ＩＬ−１７の産生を顕著に抑制するため、ＩＬ−１７に起因する炎症、例えば、変形性関節症、自己免疫性関節炎、リウマチ様関節炎、接触型過敏症、遅延型過敏症、気道過敏症、多発性硬化症や自己免疫性脳炎の治療薬又は予防薬として有用である。 Since the pharmaceutical composition containing pantethine of the present invention remarkably suppresses abnormal enhancement of immune response of helper T cells, particularly Th17, and remarkably suppresses the production of IL-17, it is attributed to IL-17. Useful as a therapeutic or prophylactic agent for inflammatory inflammation such as osteoarthritis, autoimmune arthritis, rheumatoid arthritis, contact hypersensitivity, delayed hypersensitivity, airway hypersensitivity, multiple sclerosis and autoimmune encephalitis It is.
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