JP5753435B2 - Anti-ulcer composition - Google Patents
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- JP5753435B2 JP5753435B2 JP2011096696A JP2011096696A JP5753435B2 JP 5753435 B2 JP5753435 B2 JP 5753435B2 JP 2011096696 A JP2011096696 A JP 2011096696A JP 2011096696 A JP2011096696 A JP 2011096696A JP 5753435 B2 JP5753435 B2 JP 5753435B2
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本発明は、非ステロイド性解熱鎮痛消炎剤による胃粘膜障害を軽減した医薬組成物に関する。 The present invention relates to a pharmaceutical composition that reduces gastric mucosal damage caused by a nonsteroidal antipyretic analgesic / antiinflammatory agent.
非ステロイド性解熱鎮痛消炎剤（以下、ＮＳＡＩＤｓと称することがある）は、プロスタグランジン生合成の抑制作用に基づく鎮痛・抗炎症・解熱作用を有する。そのため必然的に胃粘膜が障害され、潰瘍形成にいたる副作用を有することが知られている。 Non-steroidal antipyretic analgesic / anti-inflammatory agents (hereinafter sometimes referred to as NSAIDs) have analgesic / anti-inflammatory / antipyretic effects based on the inhibitory action of prostaglandin biosynthesis. Therefore, it is known that the gastric mucosa is inevitably damaged and has side effects leading to ulceration.
トラネキサム酸は、抗プラスミン剤として抗出血、抗アレルギー、抗炎症作用などを有し、出血・湿疹・口内炎・肝斑の内服治療薬として医療用医薬品（例えば、非特許文献１参照）やＯＴＣ医薬品（例えば、非特許文献２参照）で使用されている。また、止血用として薬用歯磨剤や、美白等の目的で薬用化粧品にも配合されている。 Tranexamic acid has anti-bleeding, anti-allergic, anti-inflammatory effects, etc. as an antiplasmin agent, and is a medical drug (for example, see Non-Patent Document 1) or an OTC drug as an internal medicine for bleeding, eczema, stomatitis, or melasma (See, for example, Non-Patent Document 2). It is also blended in medicated dentifrices for hemostasis and medicinal cosmetics for the purpose of whitening.
有胞子性乳酸菌は、胞子形成をした乳酸菌（Lactobacillus sporogenes）であり、嫌気性条件で乳酸菌の顔、好気性条件ではBacillus属の顔を持つユニークな菌である。分類学的にはBacillus coagulansであり（非特許文献３参照）、通常の乳酸菌と同様に整腸剤として配合されている（例えば、非特許文献２参照）。 Spore-forming lactic acid bacteria are spore-forming lactic acid bacteria (Lactobacillus sporogenes), which are unique bacteria having a lactic acid bacteria face under anaerobic conditions and a Bacillus face under aerobic conditions. Taxonomically, it is Bacillus coagulans (see Non-Patent Document 3), and is formulated as an intestinal adjuster in the same manner as ordinary lactic acid bacteria (see Non-Patent Document 2).
有胞子性乳酸菌が抗潰瘍作用を有することは知られていないが、乳酸菌１２菌株について酢酸潰瘍による抗潰瘍効果を調べた結果、Bifidobacterium bifidum の１菌株とBifidobacterium breveの２菌株に抗潰瘍作用が認められたことが報告されている（非特許文献４参照）。 Although it is not known that spore-forming lactic acid bacteria have anti-ulcer activity, as a result of examining the anti-ulcer effect of acetic acid ulcer on 12 lactic acid bacteria strains, 1 strain of Bifidobacterium bifidum and 2 strains of Bifidobacterium breve have anti-ulcer activity It has been reported (see Non-Patent Document 4).
これまでに、トラネキサム酸や有胞子性乳酸菌の抗潰瘍作用は知られておらず、トラネキサム酸と有胞子性乳酸菌を配合した医薬組成物も知られていない。更に、当該配合によってＮＳＡＩＤｓによる胃粘膜障害が軽減されることを記載又は示唆したものは見当たらない。 Until now, the anti-ulcer action of tranexamic acid and spore-forming lactic acid bacteria has not been known, and a pharmaceutical composition containing tranexamic acid and spore-forming lactic acid bacteria has not been known. Furthermore, there is no description or suggestion that gastric mucosal damage caused by NSAIDs is reduced by the formulation.
本発明の課題はＮＳＡＩＤｓによる胃粘膜障害を顕著に軽減する新たな医薬組成物の提供である。 An object of the present invention is to provide a new pharmaceutical composition that significantly reduces gastric mucosal damage caused by NSAIDs.
本発明者らは鋭意研究を実施した結果、ＮＳＡＩＤｓと有胞子性乳酸菌を併用した場合には、胃粘膜障害が増悪されること、しかし、ＮＳＡＩＤｓ、トラネキサム酸及び有胞子性乳酸菌を同時併用すると、胃粘膜障害が顕著に軽減され、潰瘍が抑制されるという驚くべき事実を見出し、本発明を完成するに至った。 As a result of intensive studies, the inventors have found that gastric mucosal damage is exacerbated when NSAIDs and spore-forming lactic acid bacteria are used in combination, but when NSAIDs, tranexamic acid and spore-forming lactic acid bacteria are used together, The inventors have found the surprising fact that gastric mucosal damage is remarkably reduced and ulcers are suppressed, and the present invention has been completed.
すなわち、本発明は、以下の（１）〜（４）を提供するものである。
（１）：トラネキサム酸及び有胞子性乳酸菌を含有する医薬組成物。
（２）：胃粘膜障害治療剤である（１）に記載の医薬組成物。
（３）：潰瘍治療剤である（１）に記載の医薬組成物。及び、
（４）：非ステロイド性解熱鎮痛消炎剤によって引き起こされる胃粘膜障害及び／又は潰瘍の治療剤である（１）〜（３）のいずれか１に記載の医薬組成物。
That is, the present invention provides the following (1) to (4).
(1): A pharmaceutical composition comprising tranexamic acid and spore-forming lactic acid bacteria.
(2): The pharmaceutical composition according to (1), which is a therapeutic agent for gastric mucosal disorder.
(3) The pharmaceutical composition according to (1), which is an ulcer treatment agent. as well as,
(4) The pharmaceutical composition according to any one of (1) to (3), which is a therapeutic agent for gastric mucosal disorder and / or ulcer caused by a nonsteroidal antipyretic analgesic / antiinflammatory agent.
非ステロイド性解熱鎮痛消炎剤（ＮＳＡＩＤｓ）を投与するにあたり、本発明のトラネキサム酸と有胞子性乳酸菌を含有する医薬組成物を併用すると、ＮＳＡＩＤｓによる胃粘膜障害を抑制するので、抗潰瘍剤として有用である。 When administering non-steroidal antipyretic analgesic / anti-inflammatory drugs (NSAIDs), the combined use of the pharmaceutical composition containing tranexamic acid of the present invention and spore-forming lactic acid bacteria suppresses gastric mucosal damage caused by NSAIDs and is useful as an antiulcer agent. It is.
本発明のトラネキサム酸は第１５改正日本薬局方に収載されており、有胞子性乳酸菌は日本薬局方外医薬品規格２００２に収載されている。 Tranexamic acid of the present invention is listed in the 15th revised Japanese Pharmacopoeia, and sporic lactic acid bacteria are listed in the Japanese Pharmacopoeia Standard 2002.
本発明の組成物の１回投与量における、トラネキサム酸及び有胞子性乳酸菌の含有量は特に制限はないが、それぞれ、５〜２０００ｍｇ及び０．１〜４００ｍｇで、好ましくは、それぞれ、１０〜１２００ｍｇ及び１〜１００ｍｇである。 The contents of tranexamic acid and spore-forming lactic acid bacteria in a single dose of the composition of the present invention are not particularly limited, but are 5 to 2000 mg and 0.1 to 400 mg, respectively, preferably 10 to 1200 mg, respectively. And 1 to 100 mg.
本発明におけるＮＳＡＩＤｓとしては、例えば、アスピリン、イブプロフェン、エテンザミド、ロキソプロフェンナトリウム、ジクロフェナクナトリウム、サザピリン、サリチルアミド、インドメタシン等を挙げることができる。 Examples of NSAIDs in the present invention include aspirin, ibuprofen, etenzamide, loxoprofen sodium, diclofenac sodium, sazapyrine, salicylamide, indomethacin and the like.
本発明の組成物は、常法に従って製剤されるが、投与方法に合わせて、各薬剤を別々に製剤してもよい。 The composition of the present invention is formulated according to a conventional method, but each drug may be formulated separately according to the administration method.
本発明の組成物等は、例えば、錠剤、カプセル剤、顆粒剤、散剤、液剤若しくはシロップ剤等の経口投与用組成物である。本発明の組成物には、必要に応じて、乳糖、結晶セルロース、ヒドロキシプロピルセルロース等の賦形剤、ステアリン酸マグネシウム等の滑沢剤、マクロゴール等の結合剤、クロスカルメロースナトリウム等の崩壊剤、メチルパラベン等の安定剤を適宜添加することができ、さらに、通常使用される、甘味料、酸味料、香料等の矯味矯臭剤や、希釈剤等の添加剤を用いることもできる。 The composition of the present invention is a composition for oral administration such as a tablet, capsule, granule, powder, liquid or syrup. In the composition of the present invention, if necessary, excipients such as lactose, crystalline cellulose, hydroxypropylcellulose, lubricants such as magnesium stearate, binders such as macrogol, disintegration of croscarmellose sodium and the like A stabilizer such as an agent and methylparaben can be added as appropriate, and a commonly used flavoring agent such as a sweetener, acidulant and fragrance, and an additive such as a diluent can also be used.
以下に、試験例及び製剤例を挙げて本発明を更に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。 Hereinafter, the present invention will be described more specifically with reference to test examples and formulation examples, but the present invention is not limited thereto.
（製剤例１）ハードカプセル剤 (Formulation Example 1) Hard capsule
上記成分及び分量をとり、日局製剤総則「カプセル剤」の項に準じてカプセルを製造する。 Taking the above ingredients and amounts, capsules are produced according to the section “General Capsules” of the Japanese Pharmacopoeia.
（製剤例２）錠剤 (Formulation example 2) Tablet
上記成分及び分量をとり、日局製剤総則「錠剤」の項に準じて錠剤を製造する。なお、所望により剤皮を塗布する。 Taking the above ingredients and amounts, tablets are produced according to the section “General Tablet Preparation Guidelines”. If desired, a coating is applied.
（試験例）抗潰瘍効果試験
（１）被検物質
インドメタシンはSigma-Aldrich製のものを、トラネキサム酸及び有胞子性乳酸菌は第一三共プロファーマ製のものを使用した。
被験物質はメチルセルロース（和光純薬工業製）を注射用水（大塚製薬製）に溶解した０．５％メチルセルロース溶液中に懸濁させて調製した。
(Test example) Anti-ulcer effect test (1) Test substance Indomethacin was manufactured by Sigma-Aldrich, and tranexamic acid and spore-forming lactic acid bacteria were manufactured by Daiichi Sankyo Propharma.
The test substance was prepared by suspending methylcellulose (manufactured by Wako Pure Chemical Industries) in a 0.5% methylcellulose solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical).
（２）使用動物
Ｃｒｌ：ＣＤ雄性ラット５週齢（日本チャールスリバー）を使用した。動物は温度２１−２７℃、湿度３５−７５％、照明時間７−１９時に制御されたラット飼育室内で個別飼育した。固形試料（オリエンタル酵母工業ラット用固形飼料、CRF-1）及び水道水を自由に摂取させ、１週間予備飼育した後、毛並、体重増加などの一般症状の良好な動物を選別して供試した。
(2) Animals used Crl: CD male rats 5 weeks old (Nippon Charles River) were used. The animals were individually housed in a rat breeding room controlled at a temperature of 21-27 ° C., a humidity of 35-75%, and an illumination time of 7-19. A solid sample (oriental yeast industrial rat chow, CRF-1) and tap water were freely ingested and pre-bred for 1 week, after which animals with good general symptoms such as fur and weight gain were selected and tested. .
（３）試験方法
２４時間以上絶食したラットに、フレキシブル胃管を装着したディスポーザブルシリンジを用いて、被験物質を経口投与した。なお、被験物質はスターラーを用いて撹拌しながら使用した。
被験薬投与後５時間後に、頚椎脱臼により動物を安楽死させ、速やかに胃を摘出し、内部に生理食塩液を１０ｍＬ 充填後、２％ホルマリンに浸して翌日まで固定した。固定した胃を大弯に沿って切開し、デジタルノギスを用いて胃粘膜における傷害の長さを測定した。なお、個体の胃粘膜における傷害の長さは、長径を計測し、総和を算出した。
(3) Test method A test substance was orally administered to a rat fasted for 24 hours or more using a disposable syringe equipped with a flexible gastric tube. The test substance was used with stirring using a stirrer.
Five hours after administration of the test drug, the animals were euthanized by cervical dislocation, the stomach was quickly removed, 10 mL of physiological saline was filled therein, and then immersed in 2% formalin and fixed until the next day. The fixed stomach was incised along the large vagina and the length of injury in the gastric mucosa was measured using a digital caliper. The length of the injury in the gastric mucosa of the individual was calculated by measuring the major axis and calculating the sum.
（４）試験結果
ＮＳＡＩＤｓ（インドメタシン)の投与による、胃粘膜における傷害の長さの総和（潰瘍長、ｍｍ）の結果を表３に示す。表３には、ＮＳＡＩＤｓにトラネキサム酸、又は有胞子乳酸菌を各々投与した場合、及び、ＮＳＡＩＤｓにトラネキサム酸と有胞子乳酸菌を同時に投与した場合の結果を示した。なお、いずれの投与群も１群９匹であり、潰瘍長（ｍｍ）はその平均値で示した。
(4) Test results Table 3 shows the results of the total length of injury (ulcer length, mm) in the gastric mucosa by administration of NSAIDs (indomethacin). Table 3 shows the results when tranexamic acid or spore lactic acid bacteria were respectively administered to NSAIDs, and when tranexamic acid and spore lactic acid bacteria were simultaneously administered to NSAIDs. Each administration group had 9 mice per group, and the ulcer length (mm) was shown as an average value.
表３に示したように、インドメタシンにトラネキサム酸を併用しても、インドメタシンによる胃粘膜傷害の軽減作用はほとんどみられなかった。また、インドメタシンに有胞子性乳酸菌を併用した場合には、インドメタシンによる胃粘膜傷害を増悪させる結果であった。 As shown in Table 3, even when tranexamic acid was used in combination with indomethacin, the effect of reducing gastric mucosal damage by indomethacin was hardly observed. Further, when indomethacin was used in combination with spore-forming lactic acid bacteria, the gastric mucosal damage caused by indomethacin was exacerbated.
一方、インドメタシンにトラネキサム酸及び有胞子性乳酸菌を同時併用すると、胃粘膜傷害の長さが顕著に短くなることが判明した。 On the other hand, it was found that when tranexamic acid and spore-forming lactic acid bacteria were used in combination with indomethacin, the length of gastric mucosal injury was significantly shortened.
以上の結果から、トラネキサム酸と有胞子性乳酸菌を含有する医薬組成物は、ＮＳＡＩＤｓによる胃粘膜障害を著しく軽減し、潰瘍を抑制することがわかった。 From the above results, it was found that the pharmaceutical composition containing tranexamic acid and spore-forming lactic acid bacteria significantly reduced gastric mucosal damage caused by NSAIDs and suppressed ulcers.
本発明の医薬組成物は、ＮＳＡＩＤｓによる潰瘍を抑制するので、抗潰瘍剤として利用できる。 Since the pharmaceutical composition of the present invention suppresses ulcers caused by NSAIDs, it can be used as an anti-ulcer agent.
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| JPH05942A (en) * | 1991-06-26 | 1993-01-08 | Asahi Chem Ind Co Ltd | Tranexamic acid derivative, enzyme inhibitor and antiulcer agent |
| JPH07228528A (en) * | 1994-02-16 | 1995-08-29 | Res Inst For Prod Dev | Water-soluble zinc tranexamate compound |
| JPH09154535A (en) * | 1995-12-07 | 1997-06-17 | Sanwa Kagaku Kenkyusho Co Ltd | Natto (fermented soybean)-containing composition |
| JP2002234836A (en) * | 2001-02-13 | 2002-08-23 | Kinji Ishida | Stress-responsive skin care preparation |
| AU2003272974A1 (en) * | 2002-10-11 | 2004-05-04 | Daiichi Pharmaceutical Co., Ltd. | Anti-influenza virus agent |
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| JP5232404B2 (en) * | 2006-06-07 | 2013-07-10 | 第一三共ヘルスケア株式会社 | Anti-cold virus or anti-influenza virus composition containing sporic lactic acid bacteria |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |