JP4689970B2 - Pharmaceutical composition for inhibiting neutrophil chemotaxis - Google Patents
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本発明は、好中球走化性抑制用医薬組成物、さらに詳しくは、好中球走化性抑制作用を有し、炎症細胞の関与する疾患の治療に有用である医薬組成物に関する。 The present invention relates to a pharmaceutical composition for inhibiting neutrophil chemotaxis, and more particularly to a pharmaceutical composition having an action of inhibiting neutrophil chemotaxis and useful for the treatment of diseases involving inflammatory cells.
炎症反応において、血管反応に続いて起こってくるのが、細胞反応である。これは、まず、血流中の好中球の炎症局所への浸潤から始まる。この過程に作用するのが炎症刺激によって局所で産生されるサイトカイン、ケモカイン、LTB4や補体成分である。これらは血流中の好中球に対して走化刺激として作用したり、血管内皮細胞に働き、好中球に対するICAMなどの接着分子の発現誘導を起こす。これにより、血流中の好中球は内皮と一過性の接触を繰り返し、その上をローリングするようになり、続いて、内皮上に強く接着したあと、内皮細胞間隙を通り抜け、プロテアーゼなどで基底膜を破壊して組織中へ走化する。
炎症において、血管反応時には発赤、熱感、腫脹が起きる。それに加えて、走化および貪食の経過中に活性化された好中球が放出した活性酸素やプロテアーゼ等が疼痛、機能障害を引き起こす。したがって、好中球走化作用の抑制は炎症細胞(好中球)の関与する疾患の治療に有用である。
炎症細胞に対する作用を有する医薬組成物としては、ピリジンビニルピラゾロピリジン誘導体、アリールエテニルピラゾロピリジン誘導体を含有する治療剤(特許文献1、2)やフラボノイド系化合物として、フラバノール(カテキン)類のエピガロカテキンガレートやフラボノール類のルチン(非特許文献1、2)が知られている。しかし、フラボノイド系化合物の中でも、本発明のフラボノン類を適用し、従来の組成物または従来の組合せからなる組成物を越える好中球走化性抑制作用を得たという報告はない。
In inflammation, redness, heat, and swelling occur during vascular reactions. In addition, active oxygen and protease released by neutrophils activated during the course of chemotaxis and phagocytosis cause pain and dysfunction. Therefore, suppression of neutrophil chemotaxis is useful for the treatment of diseases involving inflammatory cells (neutrophils).
Examples of pharmaceutical compositions having an action on inflammatory cells include pyridine vinylpyrazolopyridine derivatives, therapeutic agents containing arylethenylpyrazolopyridine derivatives (Patent Documents 1 and 2), and flavonoid compounds such as flavanols (catechins). Epigallocatechin gallate and flavonol rutin (Non-Patent Documents 1 and 2) are known. However, among the flavonoid compounds, there is no report that the flavonones of the present invention are applied to obtain a neutrophil chemotaxis inhibitory action that exceeds a conventional composition or a composition comprising a conventional combination.
炎症細胞の関与する疾患は多数知られており、安全で優れた好中球走化性抑制作用を有する有効な薬剤が強く望まれている。 Many diseases involving inflammatory cells are known, and an effective drug having a safe and excellent neutrophil chemotaxis inhibitory action is strongly desired.
本発明者らは、上記目的を達成するため鋭意検討を重ねた結果、フラボノイド系化合物の中でもフラボノン類を有効成分として含有する医薬組成物が優れた好中球走化性抑制作用を有することを見だし、さらに検討を加えて本発明を完成した。 As a result of intensive studies to achieve the above object, the present inventors have found that among flavonoid compounds, a pharmaceutical composition containing flavonones as an active ingredient has an excellent inhibitory effect on neutrophil chemotaxis. As a result, the present invention was completed by further investigation.
すなわち、本発明は、
(1)フラボノン類を有効成分として含有することを特徴とする好中球走化性抑制用医薬組成物、
(2)フラボノン類が、ヘスペリジン、ナリンゲニンおよびそれらの誘導体から選ばれる上記(1)記載の医薬組成物、
(3)さらに、解熱鎮痛消炎剤を含有する上記(1)記載の医薬組成物、
(4)さらに、2種の解熱鎮痛消炎剤を含有する上記(1)記載の医薬組成物、
(5)解熱鎮痛消炎剤がアニリン誘導体および/またはプロピオン酸誘導体から選ばれる1種または2種である上記(3)または(4)記載の医薬組成物、
(6)アニリン誘導体がアセトアミノフェン、プロピオン酸誘導体がイブプロフェンである上記(5)記載の医薬組成物、
(7)感冒の予防・治療用である上記(1)〜(6)いずれか1項記載の医薬組成物、
(8)関節痛の予防・治療用である上記(1)〜(6)いずれか1項記載の医薬組成物などを提供するものである。
That is, the present invention
(1) A pharmaceutical composition for inhibiting neutrophil chemotaxis, comprising flavonones as an active ingredient,
(2) The pharmaceutical composition according to the above (1), wherein the flavonones are selected from hesperidin, naringenin and derivatives thereof,
(3) The pharmaceutical composition according to the above (1), further comprising an antipyretic analgesic / anti-inflammatory agent,
(4) The pharmaceutical composition according to the above (1), further comprising two kinds of antipyretic analgesic / anti-inflammatory agents,
(5) The pharmaceutical composition according to the above (3) or (4), wherein the antipyretic analgesic / antiinflammatory agent is one or two selected from aniline derivatives and / or propionic acid derivatives,
(6) The pharmaceutical composition according to the above (5), wherein the aniline derivative is acetaminophen and the propionic acid derivative is ibuprofen,
(7) The pharmaceutical composition according to any one of (1) to (6) above, which is used for prevention / treatment of the common cold.
(8) The pharmaceutical composition according to any one of (1) to (6) above, which is used for prevention / treatment of joint pain.
本発明の医薬組成物は、好中球走化性抑制作用を有するので、炎症細胞の関与する疾患を有効に改善または解消できる。また、解熱鎮痛消炎剤などを配合することにより、さらに有効に治療できる。 Since the pharmaceutical composition of the present invention has a neutrophil chemotaxis inhibitory effect, it can effectively improve or eliminate diseases involving inflammatory cells. Moreover, it can be further effectively treated by blending an antipyretic analgesic / anti-inflammatory agent.
本発明の医薬組成物の有効成分であるフラボノン類としては、例えば、医薬成分として公知のヘスペリジン、ナリンゲニンおよびそれらの誘導体(例、メチルヘスペリジン、ネオヘスペリジン、糖転移ヘスペリジン、ナリンジン等)等が使用でき、その配合量も医薬として通常採用される範囲から選択される。 As the flavonones that are active ingredients of the pharmaceutical composition of the present invention, for example, known hesperidin, naringenin and derivatives thereof (eg, methyl hesperidin, neohesperidin, transglycosylated hesperidin, naringin etc.) can be used as pharmaceutical ingredients. The blending amount is also selected from the range usually employed as a medicine.
本発明の医薬組成物は、さらに、解熱鎮痛消炎剤を含有することが好ましい。用いる解熱鎮痛消炎剤としては、例えば、アニリン誘導体(例、アセトアミノフェン、フェナセチン等、好ましくはアセトアミノフェン)、プロピオン酸誘導体(例、イブプロフェン、ケトプロフェン、ロキソプロフェン、プラノプロフェン、ザルトプロフェン等、好ましくはイブプロフェン)等があげられる。ことに、本発明の医薬組成物においては、2種の解熱鎮痛消炎剤を含有することが好ましく、特にアセトアミノフェンとイブプロフェンを含有するものが好ましい。これらの解熱鎮痛消炎剤も通常採用される範囲の量で使用される。 The pharmaceutical composition of the present invention preferably further contains an antipyretic analgesic / antiinflammatory agent. Examples of antipyretic analgesic / anti-inflammatory agents include aniline derivatives (eg, acetaminophen, phenacetin, etc., preferably acetaminophen), propionic acid derivatives (eg, ibuprofen, ketoprofen, loxoprofen, pranoprofen, zaltoprofen, etc., preferably Ibuprofen) and the like. In particular, the pharmaceutical composition of the present invention preferably contains two kinds of antipyretic analgesic / anti-inflammatory agents, particularly those containing acetaminophen and ibuprofen. These antipyretic analgesics and anti-inflammatory agents are also used in amounts usually employed.
本発明の医薬組成物は、フラボノイドおよび解熱鎮痛消炎剤に加えて他の有効成分を含有していてもよい。このような有効成分物としては、例えば、抗ヒスタミン剤、鎮咳剤、去痰剤、鎮咳去痰剤、気管支拡張剤およびキサンチン類から選ばれる少なくとも1つの成分が挙げられる。さらに、中枢神経興奮剤、制酸剤や粘膜保護剤等の消化器官用薬剤、ビタミン類、ミネラル類、アミノ酸、ムコ多糖類等を含んでいてもよい。また、これらの薬効成分は、生薬であってもよい。
また、通常、医薬組成物に使用される医薬上許容される担体や賦形剤、さらには製剤添加物を含有していてもよい。
The pharmaceutical composition of the present invention may contain other active ingredients in addition to the flavonoid and the antipyretic analgesic / anti-inflammatory agent. Examples of such an active ingredient include at least one component selected from antihistamines, antitussives, expectorants, antitussive expectorants, bronchodilators and xanthines. Furthermore, a central nervous stimulant, digestive organ drugs such as antacids and mucosal protective agents, vitamins, minerals, amino acids, mucopolysaccharides and the like may be included. These medicinal ingredients may be crude drugs.
Further, it may usually contain a pharmaceutically acceptable carrier or excipient used in a pharmaceutical composition, and further a formulation additive.
本発明の医薬組成物は、常法に従って経口投与用または非経口投与用の各種の剤形に製造することができ、例えば、ヒト等哺乳動物の感冒の予防・治療用、関節痛の予防・治療用に使用できる。例えば、かぜ薬、関節痛薬として治療に用いる場合は、常法により、各有効成分に関して通常採用される投与量で経口的に投与できる。
以下に実施例、試験例を挙げて、本発明をさらに詳しく説明するが、本発明はこれらの例に限定されるものではない。
The pharmaceutical composition of the present invention can be produced in various dosage forms for oral administration or parenteral administration according to a conventional method. For example, for prevention / treatment of colds in mammals such as humans, prevention / treatment of joint pain. Can be used for treatment. For example, when used for treatment as a cold medicine or a joint pain medicine, it can be administered orally at a dose usually employed for each active ingredient by a conventional method.
Hereinafter, the present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these examples.
以下、本発明の好ましい製剤例を記載するが、本発明はこれらに限定されるものではない。なお、下記例において特に断らない限り、各成分の配合量は成人1日服用量を示し、常法に従い製剤化するものとする。
以下の方法により、被験物質の好中球走化性抑制作用を測定した。
ラット好中球の調製
(1)ラットを軽くエーテル麻酔し、1w/v%カゼイン溶液を腹腔内に120 mL/kgの割合で注入する。
(2)15〜18時間後にエーテル麻酔下でラットの頚動脈を切断し、放血死させる。
(3)氷冷したPBSを腹腔内に約20 mL注入し、腹部を軽くマッサージする。腹壁を消毒用アルコールでよく拭いた後、試験管が挿入できる程度に腹部を切開する。
(4)先方に多数の小孔を開けた試験管を腹腔内に挿入し、シリンジ内に浸み込んできた腹腔内液をパスツールピペット等を用いて採取する。腹腔内液は遠心(150×g、3 min、4℃)する。
(5)細胞沈渣に赤血球が混入していた場合は溶血操作を行う。すなわち、細胞沈渣に氷冷した0.2%NaCl溶液を4 mL添加して素早く懸濁し、約20〜30秒後に同量の1.6%NaCl溶液を加え、遠心分離(150×g、3 min、4℃)する。
(6)HBSS(Ca2+、Mg2+-free Hanks balanced salt solution)で洗浄したのち、反応用培地に懸濁してラット好中球浮遊液を調製する。
(7)チュルク染色法によって算出した好中球の割合が95%以上で、かつトリパンブルー色素排除法で算出した生存率が95%以上であるものを実験に用いる。好中球は採血した当日にのみ使用する。
ラット好中球走化性の測定及び評価
(1)ラット好中球浮遊液(5×106 cells/mL)と0.2%DMSO含有反応用培地あるいは各被験物質添加液を等容量ずつ混合する。
(2)下表に従って反応用培地あるいは10-8 mol/L fMLP(N-formyl-L-methionyl-L-leucyl-L-phenylalanine)溶液を24ウェルプレートに600 μL/ウェルずつ入れ、(1)の混合液を200 μLずつ注入したケモタキセル(登録商標、倉敷紡績株式会社製ケモタキシス研究用カルチャーチャンバー、孔径3μm)をセットする。この時、ケモタキセルのフィルターとプレートウェルの液面との間に気泡が生じないように注意する。
(3)それぞれの条件について3ウェルずつを使用する。
(4)ケモタキセルをセットしたプレートをCO2インキュベーター内で37℃、90分間インキュベートする。
(5)インキュベーション後、ケモタキセルをプレートウェルから取り外し、プレートウェル内の細胞をマイクロチューブに回収する。
(6)さらに反応用培地をプレートウェルに少量加えてウェルに付着している細胞を回収し、(5)の細胞回収液に加える。
(7)遠心分離して細胞を沈降させ、0.1% Triton X-100溶液に懸濁して細胞を溶解し、細胞溶解液とする.
(8)96ウェルマイクロプレートに細胞溶解液50 μL及びOPD溶液100 μLを添加し、室温で反応後、2 mol/L H2SO4 50 μLを加えて反応を停止する。492 nmにおける吸光度をマイクロプレートリーダーを用いて測定しパーオキシダーゼ活性を求める。
(9)各群3ウェルの吸光度の平均値を算出する。平均値を用いて次式により各濃度における走化性抑制率を求める。
Preparation of rat neutrophils (1) Rats are lightly anesthetized with ether, and a 1 w / v% casein solution is injected intraperitoneally at a rate of 120 mL / kg.
(2) After 15 to 18 hours, the carotid artery of the rat is cut under ether anesthesia and exsanguinated.
(3) Inject approximately 20 mL of ice-cold PBS into the abdominal cavity and gently massage the abdomen. After the abdominal wall is thoroughly wiped with rubbing alcohol, the abdomen is opened so that the test tube can be inserted.
(4) A test tube having a large number of small holes is inserted into the abdominal cavity, and the intraperitoneal fluid immersed in the syringe is collected using a Pasteur pipette or the like. The intraperitoneal fluid is centrifuged (150 xg, 3 min, 4 ° C).
(5) If red blood cells are mixed in the cell sediment, hemolysis is performed. In other words, 4 mL of ice-cold 0.2% NaCl solution was added to the cell sediment and suspended rapidly. After approximately 20-30 seconds, the same amount of 1.6% NaCl solution was added and centrifuged (150 × g, 3 min, 4 ° C. )
(6) After washing with HBSS (Ca 2+ , Mg 2+ -free Hanks balanced salt solution), the suspension is suspended in a reaction medium to prepare a rat neutrophil suspension.
(7) The neutrophil ratio calculated by the Turku staining method is 95% or more and the survival rate calculated by the trypan blue dye exclusion method is 95% or more. Neutrophils are used only on the day of blood collection.
Measurement and evaluation of rat neutrophil chemotaxis (1) Mix rat neutrophil suspension (5 × 10 6 cells / mL) with 0.2% DMSO-containing reaction medium or each test substance addition solution in equal volumes.
(2) Add 600 μL / well of reaction medium or 10 −8 mol / L fMLP (N-formyl-L-methionyl-L-leucyl-L-phenylalanine) solution to a 24-well plate according to the table below. A chemotaxel (registered trademark, a culture chamber for chemotaxis research, manufactured by Kurashiki Boseki Co., Ltd., pore size: 3 μm) into which 200 μL each of the above mixture was injected is set. At this time, care should be taken not to generate bubbles between the chemotaxel filter and the plate well surface.
(3) Use 3 wells for each condition.
(4) Incubate the plate with chemotaxel in a CO 2 incubator at 37 ° C. for 90 minutes.
(5) After incubation, the chemotaxel is removed from the plate well, and the cells in the plate well are collected in a microtube.
(6) Further, a small amount of reaction medium is added to the plate well to recover the cells adhering to the well, and added to the cell recovery solution of (5).
(7) Centrifuge to sediment the cells, suspend in 0.1% Triton X-100 solution to lyse the cells, and use this as the cell lysate.
(8) Add 50 μL of cell lysate and 100 μL of OPD solution to a 96-well microplate, react at room temperature, and stop the reaction by adding 50 μL of 2 mol / LH 2 SO 4 . The absorbance at 492 nm is measured using a microplate reader to determine peroxidase activity.
(9) Calculate the average absorbance of 3 wells in each group. Using the average value, the chemotaxis inhibition rate at each concentration is obtained by the following formula.
試験群構成は表2のとおりである。
The test group composition is shown in Table 2.
結果を表3に示す。
表3に示すごとく、単剤の場合、被検物質A、B(1)、B(2)およびB(3)は、ラット好中球走化性を、各々、29%、49%、28%および−7%抑制するが、混合物の場合、被検物質AとB(1)では、68%、AとB(2)では57%、AとB(3)では42%ラット好中球走化性を抑制する。
The results are shown in Table 3.
As shown in Table 3, in the case of a single agent, the test substances A, B (1), B (2) and B (3) have rat neutrophil chemotaxis of 29%, 49%, 28, respectively. % And -7%, but in the case of a mixture, the test substances A and B (1) are 68%, A and B (2) are 57%, and A and B (3) are 42% rat neutrophils Inhibits chemotaxis.
炎症細胞の関与する疾患は多数知られており、安全で優れた好中球走化性抑制作用を有する有効な薬剤が強く望まれている。
Many diseases involving inflammatory cells are known, and an effective drug having a safe and excellent neutrophil chemotaxis inhibitory action is strongly desired.
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JP2000026263A (en) * | 1998-05-15 | 2000-01-25 | Coletica | Elavonoid composition and its new use in cosmetic |
JP2002509419A (en) * | 1998-01-16 | 2002-03-26 | ヴァッハアウアー・オスカル | Drives for vehicles, especially multi-lane electric vehicles |
JP2003509419A (en) * | 1999-09-14 | 2003-03-11 | メルク フロスト カナダ アンド カンパニー | Carboxylic acids and acylsulfonamides, compositions containing such compounds, and methods of treatment |
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JP2002509419A (en) * | 1998-01-16 | 2002-03-26 | ヴァッハアウアー・オスカル | Drives for vehicles, especially multi-lane electric vehicles |
JP2000026263A (en) * | 1998-05-15 | 2000-01-25 | Coletica | Elavonoid composition and its new use in cosmetic |
JP2003509419A (en) * | 1999-09-14 | 2003-03-11 | メルク フロスト カナダ アンド カンパニー | Carboxylic acids and acylsulfonamides, compositions containing such compounds, and methods of treatment |
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