JP4098394B2 - Non-steroidal anti-inflammatory / analgesic side effect reducing agent - Google Patents
Non-steroidal anti-inflammatory / analgesic side effect reducing agent Download PDFInfo
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Description
【０００１】
【発明の属する技術分野】
本発明は、インドメタシン、アスピリン、ジクロフェナクナトリウム等の非ステロイド性消炎・鎮痛剤を投与した際に発生する胃腸等の消化管障害やこの消化管障害から引き起こされる皮疹等の薬剤誘発性胃腸障害を抑制する薬剤に関するものである。
【０００２】
【従来の技術】
従来より、インドメタシン、アスピリン等の非ステロイド性消炎・鎮痛薬剤(NSAIDS)は、消炎・鎮痛剤として広く用いられている。これらは、好適な作用を有するものの、副作用としてこれらの薬剤の作用によるプロスタグランジン類の低下に伴い、胃、腸管等での粘膜傷害や皮膚での発疹等の胃腸障害を発症させてしまう。特に胃粘膜障害に関してはNSAIDS潰瘍として多くの症例が報告されている。
【０００３】
このような副作用の対策として、現状では徐放剤、プロドラッグ、坐剤等による消化管への直接作用を回避するような対策が講じられている。
【０００４】
【発明が解決しようとする課題】
しかしながら、上記のような対策では充分な効果が得られず、依然として胃粘膜障害等の副作用が認められている。このため、上記のような副作用の発生の予防若しくは治療等によって低減することのできる有効な薬剤が望まれている。
【０００５】
本発明者らは鋭意研究の結果、インドメタシン、アスピリン等の投薬時に硫酸化多糖類を摂取することにより、薬剤誘発性胃腸障害を予防できることを見出し本発明を完成した。
【０００６】
即ち、本発明は非ステロイド性消炎・鎮痛剤の薬剤誘発性の胃腸障害等の副作用を低減するための新規な薬剤を得ることを目的とする。更に、非ステロイド性消炎・鎮痛成分と共に製剤化することにより、副作用の少ない消炎・鎮痛剤を得ることを目的とする。
【０００７】
【課題を解決するための手段】
本請求項１に記載された発明に係る非ステロイド性消炎・鎮痛剤の副作用低減剤は、硫酸化多糖類を有効成分とし、前記硫酸化多糖類がフコイダンであるものである。
【０００９】
本請求項２に記載された発明に係る非ステロイド性消炎・鎮痛剤の副作用低減剤は、請求項１に記載されたフコイダンが原藻を酸性領域で熱水抽出法の後に中和して抽出残渣を除去して得られたものである。
【００１０】
本請求項３に記載された発明に係る副作用の少ない経口投与用消炎・鎮痛剤は、非ステロイド性消炎・鎮痛薬から選ばれる１種又は２種以上の消炎・鎮痛成分と、フコイダンを有効成分とする副作用低減成分とを配合したものである。
【００１１】
本請求項４に記載された発明に係る副作用の少ない経口投与用消炎・鎮痛剤は、請求項３に記載された消炎・鎮痛成分が、インドメタシン、アスピリン、ジクロフェナクナトリウム、イブプロフェン、ケトプロフェン、ピロキシカム等のＮＳＡＩＤＳの１種又は２種以上から選ばれたものである。
【００１２】
【発明の実施の形態】
本発明は、硫酸化多糖類を有効成分とする非ステロイド性消炎・鎮痛剤の副作用低減剤である。このため、ヒトの発熱や鎮痛、生理痛等の治療に有効なインドメタシン、アスピリン、ジクロフェナクナトリウム等の非ステロイド性消炎・鎮痛剤を服用した際に服用することにより、発生され易い薬剤誘発性の胃腸障害や皮疹等の発症等という副作用を低減することができる。
【００１３】
本発明での、硫酸化多糖類とは、多糖分子中の水酸基の一部が硫酸化されたものであり、具体的には、フコイダン、カラギーナン、ラムナン硫酸、ヘパリン、ヘパラン硫酸、コンドロイチン硫酸などが挙げられるが、特にフコイダンが好適である。
【００１４】
本発明の副作用低減剤が、併用した場合に硫酸化多糖類の効果が期待できる薬剤は、インドメタシン、アスピリン、ジクロフェナクナトリウム、イブプロフェン、ケトプロフェン、ピロキシカム等の非ステロイド性消炎・鎮痛剤で、特にインドメタシン、アスピリンである。
【００１５】
本発明の硫酸化多糖類による作用メカニズムとしては、プロスタグランジン（ＰＧ）、特に、ＰＧＥ2と6-ketoＰＧＦ1alphaとの産生増強作用により、非ステロイド性消炎・鎮痛剤の投与による消化管でのＰＧＥ2や6-ketoＰＧＦ1alphaの減少に伴う胃粘膜障害の発生を予防若しくは回復させることによるものと考えられている。
【００１６】
本発明の副作用低減剤は、好ましくは硫酸多糖類としてフコイダンを有効成分とするものである。このフコイダンは、主としてフコースからなる粘質多糖であり、フコース残基の水酸基の一部には硫酸が半エステル型でついている。その生理作用としては、抗血液凝固活性、抗腫瘍活性（海草の本、研成社、西沢一俊著）の他、抗潰瘍活性なども見出されている。
【００１７】
フコイダンの調製法は、特に限定されるものではなく、酸抽出法、熱水抽出法、若しくは海藻の磨砕処理物等も使用可能である。フコイダンは抽出後の処理によっては糊状になるなど、使用する製品の形態によっては供し難い場合もあるため、特に、後述する実施例１、及び、実施例２乃至実施例３に示された酸性領域での熱水抽出法の後に中和して抽出残渣を除去する方法により得られるものが操作上及び得られるフコイダンの純度から好ましい。酸性領域での抽出は不純物の混入を防ぎ、低分子化に伴う粘度低下により、製造工程での操作性が向上するからである。また、用いるフコイダンの抽出源となる原藻は、モズク以外にもヒバマタ、クロメ、アラメ、昆布等の他の褐藻類を用いても良い。
【００１８】
フコイダンはインドメタシン、アスピリン等の非ステロイド性炎症・鎮痛剤に対し、0.08mg/kg〜8.0mg/kg/回の投与で良好な効果が得られる。
【００１９】
硫酸化多糖の投与時期は本薬剤の性質から、非ステロイド性抗炎症薬の投与前若しくは投与時に用いるのが効果的と考えられている。また、その投与時期から、硫酸化多糖類を非ステロイド性抗炎症薬の併用剤としての利用の他に、これらの薬剤を製剤化する際の希釈剤、添加剤などの製剤成分として用いても良い。
【００２０】
従って、本発明の副作用低減剤と、インドメタシン、アスピリン、ジクロフェナクナトリウム等の非ステロイド性消炎・鎮痛成分とを製剤化することにより、副作用の少ない消炎・鎮痛剤が得られる。即ち、本発明の副作用の少ない消炎・鎮痛剤は、非ステロイド性消炎・鎮痛薬から選ばれる１種又は２種以上の消炎・鎮痛成分と、フコイダンを有効成分とする副作用低減成分とを配合したものである。
【００２１】
この副作用の少ない消炎・鎮痛剤の形態は、経口投与薬であれば、特に制限されず、例えばシロップ剤，乳剤，懸濁剤の液剤や、錠剤，細粒剤，顆粒剤，散剤、丸剤，カプセル剤，トローチ剤等の固形製剤などとすることができる。これらの製剤の調製には、製剤の種類に応じ、慣用の担体成分を使用することができる。
【００２２】
固形製剤の調製には、例えば賦形剤、結合剤、潤沢剤、崩壊剤、崩壊助剤、糖類、保湿剤、界面活性剤などを使用することができる。また、液剤の調製には、例えば溶剤、溶解補助剤、緩衝剤、懸濁剤、等張化剤、界面活性剤、無痛化剤、ブドウ糖、アミノ酸などを使用することができる。
【００２３】
更に、固形製剤や液剤には、保存剤、抗酸化剤、可溶化剤、乳化剤、増粘剤、可塑剤、吸着剤、香料、着色剤、分散剤、矯味矯臭剤、甘味剤、防腐剤なども製剤中の各有効成分を阻害しない範囲で使用できる。
【００２４】
【実施例】
実施例１（硫酸化多糖類の調製法１）
モズクの塩蔵藻体１kgに水道水１リットルを加え、１Ｎ−ＨＣｌを用いてｐＨを３に調整し、９５℃に１時間加熱してフコイダンを抽出した。冷却後、苛性ソーダでｐＨを６に調整してから、10000Ｇで１０分間遠心分離して抽出残渣を除去し、得られた抽出液を分画分子量が、6000の限外濾過膜を用いて濾過した。フコイダンが濃縮されている非透過液は、脱イオン水２リットルを加えて再度限外濾過し、凍結乾燥した。粉末状のフコイダン２１ｇが得られた。
【００２５】
実施例２（硫酸化多糖類の調製法２）
実施例１で用いたモズクと同じモズクを同様に抽出処理し、遠心分離して抽出液を得た。得られた抽出液を減圧下に約５００mlまで濃縮し、イオン交換膜・アシプレックスカートリッジAC-110-400を装着した電気透析装置・マイクロアシライザーG3型（旭化成工業株式会社製）で処理して、低圧下に濃縮し、凍結乾燥して粉末状のフコイダン２５ｇを得た。
【００２６】
実施例３（硫酸化多糖類の調製法３）
実施例１で用いたモズクと同じモズク３００kgを実施例１と同様に抽出し、遠心分離して抽出液を得た。得られた抽出液を分画分子量6000の限外濾過膜を用いて濾過し、低分子量不純物を濾過した。次いで、フコイダンが濃縮された非透過液に脱イオン水２００リットル及び塩酸を加えてｐＨ３の希釈液とし、同じ限外濾過膜で限外濾過した。ｐＨ３の希釈液にて限外濾過する酸洗浄処理を更に２回繰り返し、最後に濃縮、凍結乾燥することにより、粉末状のフコイダン４．５kgを得た。
【００２７】
実施例４（インドメタシン胃傷害モデルにおけるフコイダンの効果検定）
インドメタシン胃傷害モデルにおけるフコイダンの効果検定は以下のようにして行った。
【００２８】
８週齢のWistar系ラットを５日間予備飼育し、１８時間の断食、２時間の絶水後、実施例３で得られたフコイダンの溶液１mlを経口投与する。投与２時間後、インドメタシン溶液１ml（５０mg/rat）を経口投与し傷害を誘発した。
【００２９】
投与２時間後に胃の傷害形成部分の面積を測定した。対照群には蒸留水のみを投与し、その効果は対照群に対して投与群の傷害形成抑制率で判定した。検定は、１wayダネット検定を行い、対照群に対して５％以下の危険率で有意差が認められた群について、効果が認められものと判定した。結果を表１に示す。
【００３０】
【表１】
実施例５（ラット胃組織中プロスタグランジン含量に対する作用の検討）
フコイダンのラット胃組織中のプロスタグランジン（ＰＧ）含量に対する作用を検討するため、ラットを試験前日より断食し、試験当日に３mg/mlのフコイダンを経口投与して、投与０，２０，６０分後の胃組織中ＰＧＥ2及び6-ketoＰＧＦ1alpha含量を測定した。
【００３２】
ラットはサンプルの最終投与の前日に断食し、最終投与後経時的にネンブタール麻酔下で開腹、素早く胃を取り出し、４℃の生理食塩水中に入れた。胃を液体窒素で凍結して、６ウエルのプレートに入れて凍結乾燥した。凍結乾燥終了後、胃組織をメタノールで抽出後、17,000rpmで３０分間遠心し、そのカラムを蒸留水と１０％メタノールで洗浄した。
【００３３】
カラムをヘキサンで洗浄後、１０％のメタノールを含む酢酸エチル溶液を用いてプロスタノイドを溶出した。溶出されたプロスタノイドを含む溶媒を乾固させた後、ケイマンのＥＩＡキットを用いてＰＧＥ2及び6-ketoＰＧＦ1alphaを測定した。測定値は平均値±標準偏差で示し、ＰＧＥ2及び6-ketoＰＧＦ1alpha含量はpg/tissueで表した。結果を次の表２に示す。
【００３４】
【表２】
表２に示す通り、フコイダンは経口投与により、胃組織中のＰＧＥ2及び6-ketoＰＧＦ1alpha含量を増加させることが示された。このＰＧＥ2及び6-ketoＰＧＦ1alphaと産生増強作用により、非ステロイド性消炎・鎮痛剤の投与による消化管でのＰＧＥ2や6-ketoＰＧＦ1alphaの減少に伴う胃粘膜障害の発生を予防若しくは回復させると認められた。
【００３６】
実施例６（消炎・鎮痛剤）
非ステロイド性消炎・鎮痛成分と、フコイダンとを含む副作用の少ない消炎・鎮痛剤を調製した。組成はアセチルサリチル酸（アスピリン）５００mg/gに対して、フコイダン１２０mg/gとして、他に賦形剤を配合した。尚、本消炎・鎮痛剤についても、実施例４と同様の傷害形成抑制効果を得た。
【００３７】
以上のように、本発明の副作用低減剤は、0.08mg/kg〜8.0mg/kg/回程度の低容量で優れた胃粘膜障害予防作用を示すことが示された。また、食用物であるモズクの抽出物であることから、安全性も高く、非ステロイド性抗炎症薬の副作用防止のための併用剤として有効な物質である。
【００３８】
【発明の効果】
本発明は以上説明したとおり、ヒトの発熱や鎮痛、生理痛等の治療に有効なインドメタシン、アスピリン、ジクロフェナクナトリウム等の非ステロイド性消炎・鎮痛剤を服用した際に服用することにより、発生され易い薬剤誘発性の胃腸障害や皮疹等の発症等の発症という副作用を低減することができるという効果がある。[0001]
BACKGROUND OF THE INVENTION
The present invention suppresses gastrointestinal disorders such as gastrointestinal tracts caused by administration of nonsteroidal anti-inflammatory / analgesic drugs such as indomethacin, aspirin, diclofenac sodium, etc., and drug-induced gastrointestinal disorders such as rash caused by this GI disorder It is related to the drug.
[0002]
[Prior art]
Conventionally, nonsteroidal anti-inflammatory / analgesic drugs (NSAIDS) such as indomethacin and aspirin have been widely used as anti-inflammatory / analgesic agents. Although these have a suitable action, as a side effect, they cause gastrointestinal disorders such as mucosal damage in the stomach, intestinal tract and the like and rashes on the skin with the reduction of prostaglandins due to the action of these drugs. Many cases of NSAIDS ulcers have been reported, particularly regarding gastric mucosal disorders.
[0003]
As measures against such side effects, currently, measures are taken to avoid direct action on the digestive tract by sustained-release agents, prodrugs, suppositories and the like.
[0004]
[Problems to be solved by the invention]
However, the above countermeasures do not provide sufficient effects, and side effects such as gastric mucosal damage are still recognized. Therefore, an effective drug that can be reduced by preventing or treating the occurrence of the side effects as described above is desired.
[0005]
As a result of intensive studies, the present inventors have found that drug-induced gastrointestinal disorders can be prevented by ingesting sulfated polysaccharides at the time of administration of indomethacin, aspirin and the like, and have completed the present invention.
[0006]
That is, an object of the present invention is to obtain a novel drug for reducing side effects such as drug-induced gastrointestinal disorders of nonsteroidal anti-inflammatory / analgesic agents. Furthermore, it aims at obtaining the anti-inflammatory / analgesic agent with few side effects by formulating with a non-steroidal anti-inflammatory / analgesic component.
[0007]
[Means for Solving the Problems]
The side effect reducing agent of the nonsteroidal anti-inflammatory / analgesic agent according to the first aspect of the present invention comprises a sulfated polysaccharide as an active ingredient, and the sulfated polysaccharide is fucoidan .
[0009]
The non-steroidal anti-inflammatory / analgesic side effect reducing agent according to the present invention described in claim 2 is obtained by extracting fucoidan according to claim 1 by neutralizing the original algae after the hot water extraction method in the acidic region. It was obtained by removing the residue.
[0010]
The anti-inflammatory / analgesic agent for oral administration according to the invention described in claim 3 having few side effects is an active ingredient comprising one or more anti-inflammatory / analgesic components selected from non-steroidal anti-inflammatory agents and analgesics, and fucoidan. And a side effect reducing component.
[0011]
The anti-inflammatory / analgesic agent for oral administration according to the invention described in claim 4 having few side effects has an anti-inflammatory / analgesic component described in claim 3 such as indomethacin, aspirin, diclofenac sodium, ibuprofen, ketoprofen, piroxicam, etc. NSAIDS are selected from one or more of NSAIDS.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a non-steroidal anti-inflammatory / analgesic side effect reducing agent containing sulfated polysaccharide as an active ingredient. For this reason, drug-induced gastrointestinal tract that is likely to occur by taking nonsteroidal anti-inflammatory / analgesic drugs such as indomethacin, aspirin, diclofenac sodium, etc. effective for the treatment of human fever, analgesia, menstrual pain, etc. It is possible to reduce side effects such as the onset of disorders and skin rashes.
[0013]
In the present invention, the sulfated polysaccharide is one in which a part of the hydroxyl group in the polysaccharide molecule is sulfated. Specifically, fucoidan, carrageenan, rhamnan sulfate, heparin, heparan sulfate, chondroitin sulfate, etc. Among them, fucoidan is particularly preferable.
[0014]
When the side effect reducing agent of the present invention is used in combination, a drug that can be expected to have an effect of a sulfated polysaccharide is a nonsteroidal anti-inflammatory / analgesic agent such as indomethacin, aspirin, diclofenac sodium, ibuprofen, ketoprofen, piroxicam, in particular indomethacin, Aspirin.
[0015]
As the action mechanism of the sulfated polysaccharide of the present invention, prostaglandin (PG), particularly in the gastrointestinal tract by administration of nonsteroidal anti-inflammatory / analgesic agent by enhancing production of PGE 2 and 6-keto PGF 1alpha It is thought to be due to preventing or reversing the occurrence of gastric mucosal damage associated with a decrease in PGE 2 or 6-keto PGF 1alpha .
[0016]
The side effect reducing agent of the present invention preferably contains fucoidan as an active ingredient as a sulfated polysaccharide. This fucoidan is a viscous polysaccharide mainly composed of fucose, and sulfuric acid is attached to a part of the hydroxyl group of the fucose residue in a half-ester form. As its physiological action, anticoagulant activity, antitumor activity (Seaweed Book, Kenseisha, Kazutoshi Nishizawa), antiulcer activity and the like have also been found.
[0017]
The method for preparing fucoidan is not particularly limited, and an acid extraction method, a hot water extraction method, a seaweed ground product, or the like can also be used. Fucoidan may become difficult to use depending on the form of the product used, such as being pasty depending on the treatment after extraction. In particular, the acidity shown in Example 1 and Examples 2 to 3 described later is used. What is obtained by the method of neutralizing after the hot water extraction method in the region and removing the extraction residue is preferable from the viewpoint of operation and the purity of fucoidan obtained. This is because extraction in an acidic region prevents impurities from being mixed in and improves the operability in the manufacturing process due to a decrease in viscosity accompanying the reduction in molecular weight. In addition to mozuku, the original algae used as the extraction source of fucoidan to be used may be other brown algae such as hibermata, chrome, alame, and kelp.
[0018]
Fucoidan is effective against nonsteroidal inflammatory / analgesic drugs such as indomethacin and aspirin when administered at 0.08 mg / kg to 8.0 mg / kg / dose.
[0019]
Due to the nature of this drug, it is considered effective to use sulfated polysaccharide before or during administration of nonsteroidal anti-inflammatory drugs. In addition to the use of sulfated polysaccharides as a concomitant agent for non-steroidal anti-inflammatory drugs from the time of administration, it may be used as a formulation component such as a diluent or additive in formulating these drugs. good.
[0020]
Therefore, an anti-inflammatory / analgesic agent with fewer side effects can be obtained by formulating the side-effect reducing agent of the present invention and a non-steroidal anti-inflammatory / analgesic component such as indomethacin, aspirin, diclofenac sodium and the like. That is, the anti-inflammatory / analgesic agent with few side effects of the present invention comprises one or more anti-inflammatory / analgesic components selected from non-steroidal anti-inflammatory / analgesic agents and a side-effect reducing component containing fucoidan as an active ingredient. Is.
[0021]
The form of anti-inflammatory / analgesic agent with few side effects is not particularly limited as long as it is an orally administered drug. For example, syrups, emulsions, suspensions, tablets, fine granules, granules, powders, pills , Solid preparations such as capsules and lozenges. In preparing these preparations, conventional carrier components can be used depending on the kind of preparation.
[0022]
For the preparation of solid preparations, for example, excipients, binders, lubricants, disintegrants, disintegration aids, sugars, humectants, surfactants and the like can be used. In addition, for example, a solvent, a solubilizing agent, a buffering agent, a suspending agent, a tonicity agent, a surfactant, a soothing agent, glucose, an amino acid, and the like can be used for preparing the liquid agent.
[0023]
Furthermore, solid preparations and liquids include preservatives, antioxidants, solubilizers, emulsifiers, thickeners, plasticizers, adsorbents, fragrances, colorants, dispersants, flavoring agents, sweeteners, preservatives, etc. Can also be used as long as each active ingredient in the preparation is not inhibited.
[0024]
【Example】
Example 1 (Preparation Method 1 of Sulfated Polysaccharide 1)
1 liter of tap water was added to 1 kg of Mozuku's salted algae, pH was adjusted to 3 with 1N-HCl, and the mixture was heated to 95 ° C. for 1 hour to extract fucoidan. After cooling, the pH was adjusted to 6 with caustic soda, centrifuged at 10,000 G for 10 minutes to remove the extraction residue, and the resulting extract was filtered using an ultrafiltration membrane with a molecular weight cut off of 6000. . The non-permeate containing the fucoidan was ultrafiltered again by adding 2 liters of deionized water and lyophilized. 21 g of powdered fucoidan was obtained.
[0025]
Example 2 (Preparation Method 2 of Sulfated Polysaccharide)
The same mozuku used in Example 1 was extracted in the same manner and centrifuged to obtain an extract. The resulting extract is concentrated to about 500 ml under reduced pressure, and treated with an electrodialysis machine / microacylator G3 type (Asahi Kasei Kogyo Co., Ltd.) equipped with an ion exchange membrane / Aciplex cartridge AC-110-400. The solution was concentrated under low pressure and freeze-dried to obtain 25 g of powdered fucoidan.
[0026]
Example 3 (Preparation Method 3 of Sulfated Polysaccharide 3)
300 kg of the same mozuku used in Example 1 was extracted in the same manner as in Example 1 and centrifuged to obtain an extract. The obtained extract was filtered using an ultrafiltration membrane having a molecular weight cut off of 6000, and low molecular weight impurities were filtered. Subsequently, 200 liters of deionized water and hydrochloric acid were added to the non-permeate enriched with fucoidan to obtain a diluted solution of pH 3, and ultrafiltered with the same ultrafiltration membrane. The acid washing treatment of ultrafiltration with a diluted solution of pH 3 was further repeated twice, and finally concentrated and freeze-dried to obtain 4.5 kg of powdered fucoidan.
[0027]
Example 4 (Efficacy test of fucoidan in indomethacin gastric injury model)
The effect test of fucoidan in the indomethacin gastric injury model was performed as follows.
[0028]
8-week-old Wistar rats are preliminarily raised for 5 days, and after 18 hours of fasting and 2 hours of water shortage, 1 ml of the fucoidan solution obtained in Example 3 is orally administered. Two hours after administration, 1 ml of indomethacin solution (50 mg / rat) was orally administered to induce injury.
[0029]
Two hours after administration, the area of the gastric lesion was measured. Only the distilled water was administered to the control group, and the effect was judged by the injury formation inhibition rate of the administration group with respect to the control group. The test was performed using a 1-way Dunnett test, and a group in which a significant difference was recognized with a risk rate of 5% or less with respect to the control group was judged to be effective. The results are shown in Table 1.
[0030]
[Table 1]
Example 5 (Study of action on prostaglandin content in rat stomach tissue)
In order to examine the effect of fucoidan on prostaglandin (PG) content in rat stomach tissue, rats were fasted from the day before the test, and 3 mg / ml fucoidan was orally administered on the day of the test. The contents of PGE 2 and 6-keto PGF 1alpha in the later stomach tissue were measured.
[0032]
The rats were fasted the day before the last administration of the sample, and after the last administration, the abdomen was opened under Nembutal anesthesia over time. The stomach was quickly removed and placed in 4 ° C. physiological saline. The stomach was frozen with liquid nitrogen and placed in a 6-well plate and lyophilized. After lyophilization, the stomach tissue was extracted with methanol, centrifuged at 17,000 rpm for 30 minutes, and the column was washed with distilled water and 10% methanol.
[0033]
After washing the column with hexane, prostanoids were eluted using an ethyl acetate solution containing 10% methanol. After elution of the eluted prostanoid-containing solvent, PGE 2 and 6-keto PGF 1alpha were measured using a Cayman EIA kit. The measured values are shown as mean ± standard deviation, and the PGE 2 and 6-keto PGF 1alpha contents are expressed in pg / tissue. The results are shown in Table 2 below.
[0034]
[Table 2]
As shown in Table 2, fucoidan was shown to increase the PGE 2 and 6-keto PGF 1alpha contents in gastric tissue by oral administration. When this PGE 2 and 6-keto PGF 1alpha and production-enhancing effect are used, the occurrence of gastric mucosal damage associated with the decrease of PGE 2 and 6-keto PGF 1alpha in the gastrointestinal tract by administration of nonsteroidal anti-inflammatory and analgesics is prevented or recovered. Admitted.
[0036]
Example 6 (Anti-inflammatory / analgesic agent)
A non-steroidal anti-inflammatory / analgesic component and an anti-inflammatory / analgesic agent with few side effects were prepared, including fucoidan. The composition was fucoidan 120 mg / g for acetylsalicylic acid (aspirin) 500 mg / g, and other excipients were blended. In addition, about this anti-inflammatory / analgesic agent, the same injury formation inhibitory effect as Example 4 was acquired.
[0037]
As described above, it was shown that the side effect reducing agent of the present invention exhibits an excellent gastric mucosal disorder preventive action at a low volume of about 0.08 mg / kg to 8.0 mg / kg / dose. Moreover, since it is an extract of mozuku, which is an edible product, it is highly safe and effective as a concomitant drug for preventing side effects of non-steroidal anti-inflammatory drugs.
[0038]
【The invention's effect】
As described above, the present invention is likely to occur when a nonsteroidal anti-inflammatory / analgesic agent such as indomethacin, aspirin, diclofenac sodium and the like effective for treating human fever, analgesia, and menstrual pain is taken. There is an effect that side effects such as onset of drug-induced gastrointestinal disorders and skin rashes can be reduced.
Claims (4)
前記硫酸化多糖類がフコイダンである非ステロイド性消炎・鎮痛剤の副作用低減剤。Sulfated polysaccharide as an active ingredient ,
A non-steroidal anti-inflammatory / analgesic side-effect reducing agent, wherein the sulfated polysaccharide is fucoidan .
フコイダンを有効成分とする副作用低減成分と
を配合した副作用の少ない経口投与用消炎・鎮痛剤。One or more anti-inflammatory / analgesic ingredients selected from non-steroidal anti-inflammatory / analgesic drugs;
An anti-inflammatory / analgesic agent for oral administration with few side effects, containing a side effect reducing component containing fucoidan as an active ingredient.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP08509998A JP4098394B2 (en) | 1998-03-17 | 1998-03-17 | Non-steroidal anti-inflammatory / analgesic side effect reducing agent |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP08509998A JP4098394B2 (en) | 1998-03-17 | 1998-03-17 | Non-steroidal anti-inflammatory / analgesic side effect reducing agent |
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| Publication Number | Publication Date |
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| JPH11263730A JPH11263730A (en) | 1999-09-28 |
| JP4098394B2 true JP4098394B2 (en) | 2008-06-11 |
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