JP5681533B2 - Gastrointestinal pain prevention or alleviation agent - Google Patents
Gastrointestinal pain prevention or alleviation agent Download PDFInfo
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- JP5681533B2 JP5681533B2 JP2011055458A JP2011055458A JP5681533B2 JP 5681533 B2 JP5681533 B2 JP 5681533B2 JP 2011055458 A JP2011055458 A JP 2011055458A JP 2011055458 A JP2011055458 A JP 2011055458A JP 5681533 B2 JP5681533 B2 JP 5681533B2
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- lactic acid
- acid bacteria
- pain
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- gastrointestinal
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Description
本発明は、消化管痛（消化管内臓痛）を効果的に予防又は軽減する作用を有する組成物に関する。 The present invention relates to a composition having an action of effectively preventing or reducing gastrointestinal pain (gastrointestinal visceral pain).
近年、不規則な生活習慣、精神的ストレスなどの原因によって、過敏性腸症候群（以下、ＩＢＳともいう）等の機能性消化管障害の患者が増加している。機能性消化管障害とは、消化管に炎症、潰瘍等の器質的疾患が認められないにもかかわらず、消化管痛（消化管内臓痛）、腹部不快感、下痢又は便秘等の症状を呈する疾患である。例えば、ＩＢＳの主な症状は、慢性的な腹痛又は腹部不快感や、下痢又は便秘を来たしたり、下痢と便秘を繰り返したりする便通異常であるが、結腸組織に潰瘍などの器質的疾患の存在は認められない。 In recent years, patients with functional gastrointestinal disorders such as irritable bowel syndrome (hereinafter also referred to as IBS) are increasing due to irregular lifestyles and mental stress. Functional gastrointestinal dysfunction refers to symptoms such as gastrointestinal pain (gastrointestinal visceral pain), abdominal discomfort, diarrhea or constipation, despite the absence of organic diseases such as inflammation and ulcers in the gastrointestinal tract Is a disease. For example, the main symptoms of IBS are chronic abdominal pain or abdominal discomfort, diarrhea or constipation abnormalities such as diarrhea or constipation, but the presence of organic diseases such as ulcers in the colon tissue It is not allowed.
また、ＩＢＳ等の機能性消化管障害の病因の１つとして、内臓知覚過敏が挙げられている。「内臓知覚過敏」とは、消化管伸展刺激による知覚の閾値が低下して、より痛みを強く感じる状態である。つまりＩＢＳ患者では、消化管内腔からのより弱い刺激にて知覚が生じている。従って、ＩＢＳの治療において、内臓知覚過敏による内臓痛を軽減することは非常に重要である。ＩＢＳ等の機能性消化管障害の症状の改善には時間がかかることが多いため、機能性消化管障害における消化管痛を効果的に軽減でき、しかも副作用が少ない薬剤が切望されている。 Moreover, visceral hypersensitivity is mentioned as one of the etiology of functional gastrointestinal disorders such as IBS. “Visceral hypersensitivity” is a state in which the threshold of perception due to gastrointestinal tract extension stimulation is lowered and pain is felt more strongly. In other words, in IBS patients, perception occurs with weaker stimuli from the digestive tract lumen. Therefore, it is very important to reduce visceral pain due to visceral hypersensitivity in the treatment of IBS. Improvement of symptoms of functional gastrointestinal disorders such as IBS often takes time, and therefore there is a strong demand for drugs that can effectively reduce gastrointestinal pain in functional gastrointestinal disorders and have few side effects.
非特許文献１には、ドキサントラゾールが、ラットの腸管知覚過敏に有効であることが開示されている。非特許文献２には、モルヒネが用量依存的にラットの腸管知覚過敏を改善したことが開示されている。非特許文献３には、Ｎ−［（１Ｓ）−１−（アミノカルボニル）−２，２−ジメチルプロピル］−３−（３−ヒドロキシ−３−メチルブチル）−２−オキソ−２，３−ジヒドロ−１Ｈ−ベンズイミダゾール−１−カルボキサミド（ＰＦ−０３５５００９６）がラットの腸管知覚過敏に有効であることが開示されている。しかしながら、これらの化合物は合成化合物であり、副作用等の問題があった。また、より高い消化管痛軽減作用を示す有効成分が望まれていた。 Non-Patent Document 1 discloses that doxantrazole is effective for intestinal hypersensitivity in rats. Non-Patent Document 2 discloses that morphine improved intestinal hypersensitivity in rats in a dose-dependent manner. Non-Patent Document 3 describes N-[(1S) -1- (aminocarbonyl) -2,2-dimethylpropyl] -3- (3-hydroxy-3-methylbutyl) -2-oxo-2,3-dihydro. It has been disclosed that -1H-benzimidazole-1-carboxamide (PF-03550096) is effective for intestinal hypersensitivity in rats. However, these compounds are synthetic compounds and have problems such as side effects. Moreover, an active ingredient that exhibits a higher action for reducing gastrointestinal pain has been desired.
乳酸菌及びその発酵物に痛みを軽減する作用があることが報告されている。例えば、特許文献１には、ラクトバチルス・ヘルベティカスを含む菌体により乳を発酵して得た発酵乳を有効成分とする筋肉痛抑制剤が開示されている。特許文献２には、乳酸菌から分泌される、抗炎症活性を含んでなる化合物が開示されている。特許文献３には、プロバイオティック細菌と発酵穀物を含むＩＢＳの治療に使用可能な組成物が開示されている。 It has been reported that lactic acid bacteria and their fermented products have an action to reduce pain. For example, Patent Document 1 discloses a muscle pain inhibitor containing fermented milk obtained by fermenting milk with bacterial cells containing Lactobacillus helveticus as an active ingredient. Patent Document 2 discloses a compound comprising anti-inflammatory activity secreted from lactic acid bacteria. Patent Document 3 discloses a composition that can be used for the treatment of IBS, including probiotic bacteria and fermented cereals.
特許文献４には、エンテロコッカス属に属する乳酸菌の水溶性抽出物が鎮痛作用を有することが開示されている。特許文献５には、ストレス軽減作用を有するラクトバチルス属微生物を含有する乳酸菌製剤が開示されている。特許文献６には、小麦発酵抽出物及び乳酸菌殺菌菌体が混合されている乳酸菌配合物が、免疫増強効果、鎮痛作用等を有することが開示されている。特許文献７には、ラクトバチルス・ロイテリの菌株を含む乳児疝痛を低減するための製品が開示されている。しかしながら、乳酸菌が機能性消化管障害における消化管痛に優れた効果を発揮するとの報告はない。 Patent Document 4 discloses that a water-soluble extract of lactic acid bacteria belonging to the genus Enterococcus has an analgesic action. Patent Document 5 discloses a lactic acid bacteria preparation containing a Lactobacillus microorganism having a stress reducing action. Patent Document 6 discloses that a lactic acid bacterium blend in which a wheat fermented extract and lactic acid bacteria sterilized cells are mixed has an immune enhancing effect, an analgesic effect, and the like. Patent Document 7 discloses a product for reducing infant colic containing a strain of Lactobacillus reuteri. However, there is no report that lactic acid bacteria exert an excellent effect on gastrointestinal pain in functional gastrointestinal disorders.
本発明は、上記現状に鑑み、消化管痛、特に過敏性腸症候群等の機能性消化管障害における消化管痛等を効果的に予防又は軽減でき、かつ副作用が少なく長期にわたって服用できる安全な薬剤を提供することを目的とする。 In view of the present situation, the present invention is a safe drug that can effectively prevent or reduce gastrointestinal pain, particularly gastrointestinal pain in functional gastrointestinal disorders such as irritable bowel syndrome, and can be taken for a long time with few side effects. The purpose is to provide.
本発明者らは、上記課題に鑑み鋭意研究を重ね、ストレプトコッカス（エンテロコッカス）属の乳酸菌、及びビフィドバクテリウム（Bifidobacterium）属の乳酸菌が、それぞれＴＮＢＳ誘発内臓痛モデルラットの腸管知覚過敏を改善する効果が高いことを見出した。中でも特に、ストレプトコッカス（エンテロコッカス）属の乳酸菌は、ＴＮＢＳ誘発内臓痛モデルラットの腸管知覚過敏を有意に改善することから、過敏性腸症候群における内臓痛等の消化管痛を効果的に予防又は軽減することができることを見出した。このストレプトコッカス（エンテロコッカス）属の乳酸菌による消化管痛の軽減作用は、例えば既存薬であるドキサントラゾール（上述した非特許文献１）等の腸管知覚過敏軽減作用よりも高いと考えられた。さらに、ストレプトコッカス（Streptococcus）属の乳酸菌と共にビフィドバクテリウム（Bifidobacterium bifidum）属の乳酸菌、及びラクトバシラス（Lactobacillus）属の乳酸菌を投与することによっても、過敏性腸症候群における内臓痛等の消化管痛を顕著に軽減できることを見出した。前記乳酸菌は副作用が少ないため、長期的に摂取しても安全性が高いものである。このため前記乳酸菌を用いることにより、過敏性腸症候群等の患者の生活の質を副作用なく改善できることに想到した。
本発明者らは、上記知見に基づきさらに研究を重ね、本発明を完成するに至った。
The present inventors have made extensive studies in view of the above problems, and lactic acid bacteria belonging to the genus Streptococcus (Enterococcus) and lactic acid bacteria belonging to the genus Bifidobacterium each improve intestinal hypersensitivity in TNBS-induced visceral pain model rats. It was found that the effect is high. Among these, lactic acid bacteria belonging to the genus Streptococcus (Enterococcus) significantly improve intestinal hypersensitivity in TNBS-induced visceral pain model rats, and thus effectively prevent or reduce gastrointestinal pain such as visceral pain in irritable bowel syndrome. I found that I can do it. It was considered that the action to reduce gastrointestinal pain by lactic acid bacteria belonging to the genus Streptococcus (enterococcus) is higher than the action to reduce intestinal hypersensitivity such as doxantrazole (non-patent document 1 described above) which is an existing drug. In addition, administration of lactic acid bacteria of the genus Bifidobacterium bifidum and lactic acid bacteria of the genus Lactobacillus together with lactic acid bacteria of the genus Streptococcus also reduces gastrointestinal pain such as visceral pain in irritable bowel syndrome. We found that it can be significantly reduced. Since the lactic acid bacteria have few side effects, they are highly safe even if taken for a long time. For this reason, it was conceived that the quality of life of patients such as irritable bowel syndrome can be improved without side effects by using the lactic acid bacteria.
The present inventors have further studied based on the above findings and have completed the present invention.
すなわち、本発明は、以下の（１）〜（１２）に関する。
（１）ストレプトコッカス（Streptococcus）属又はビフィドバクテリウム（Bifidobacterium）属の乳酸菌を有効成分として含むことを特徴とする消化管痛の予防又は軽減剤。
（２）消化管痛が、機能性消化管障害における消化管痛である前記（１）に記載の予防又は軽減剤。
（３）消化管痛が、過敏性腸症候群における内臓痛である前記（１）又は（２）に記載の予防又は軽減剤。
（４）消化管痛が、過敏性腸症候群における内臓知覚過敏による内臓痛である前記（１）〜（３）のいずれか一項に記載の予防又は軽減剤。
（５）乳酸菌が、ストレプトコッカス（Streptococcus）属の乳酸菌である前記（１）〜（４）のいずれか一項に記載の予防又は軽減剤。
（６）ストレプトコッカス属の乳酸菌が、ストレプトコッカス・フェーカリス（Streptococcus faecalis）である前記（１）〜（５）のいずれか一項に記載の予防又は軽減剤。
（７）ストレプトコッカス属の乳酸菌が、ストレプトコッカス・フェーカリス（Streptococcus faecalis） １２９ ＢＩＯ ３Ｂである前記（１）〜（６）のいずれか一項に記載の予防又は軽減剤。
（８）さらに、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及び／又はラクトバシラス（Lactobacillus）属の乳酸菌を含む前記（５）〜（７）のいずれか一項に記載の予防又は軽減剤。
（９）乳酸菌が、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌である前記（１）〜（４）のいずれか一項に記載の予防又は軽減剤。
（１０）ビフィドバクテリウム（Bifidobacterium）属の乳酸菌が、ビフィドバクテリウム・ロンガム（Bifidobacterium longum）である前記（１）〜（４）及び（９）のいずれか一項に記載の予防又は軽減剤。
（１１）ビフィドバクテリウム（Bifidobacterium）属の乳酸菌が、ビフィドバクテリウム・ロンガム（Bifidobacterium longum） ＭＭ−２である前記（１）〜（４）及び（９）〜（１０）のいずれか一項に記載の予防又は軽減剤。
（１２）経口投与の剤形である前記（１）〜（１１）のいずれか一項に記載の予防又は軽減剤。
That is, the present invention relates to the following (1) to (12).
(1) A preventive or alleviating agent for gastrointestinal pain comprising an lactic acid bacterium of the genus Streptococcus or Bifidobacterium as an active ingredient.
(2) The preventive or alleviating agent according to (1), wherein the gastrointestinal pain is gastrointestinal pain in a functional gastrointestinal disorder.
(3) The preventive or alleviating agent according to (1) or (2), wherein the gastrointestinal pain is visceral pain in irritable bowel syndrome.
(4) The preventive or alleviating agent according to any one of (1) to (3), wherein the digestive tract pain is visceral pain due to visceral hypersensitivity in irritable bowel syndrome.
(5) The preventive or alleviating agent according to any one of (1) to (4), wherein the lactic acid bacterium is a lactic acid bacterium of the genus Streptococcus.
(6) The preventive or alleviating agent according to any one of (1) to (5), wherein the lactic acid bacterium belonging to the genus Streptococcus is Streptococcus faecalis.
(7) The preventive or alleviating agent according to any one of (1) to (6), wherein the lactic acid bacterium of the genus Streptococcus is Streptococcus faecalis 129 BIO 3B.
(8) The preventive or alleviating agent according to any one of (5) to (7), further comprising lactic acid bacteria belonging to the genus Bifidobacterium and / or lactic acid bacteria belonging to the genus Lactobacillus.
(9) The preventive or alleviating agent according to any one of (1) to (4), wherein the lactic acid bacterium is a lactic acid bacterium of the genus Bifidobacterium.
(10) The prevention or reduction according to any one of (1) to (4) and (9), wherein the lactic acid bacterium belonging to the genus Bifidobacterium is Bifidobacterium longum. Agent.
(11) Any one of the above (1) to (4) and (9) to (10), wherein the lactic acid bacterium of the genus Bifidobacterium is Bifidobacterium longum MM-2 The preventive or alleviating agent according to Item.
(12) The preventive or alleviating agent according to any one of (1) to (11), which is a dosage form for oral administration.
本明細書中においては、１９８４年以前の分類学においてストレプトコッカス（Streptococcus）属と分類されていた乳酸菌を、ストレプトコッカス（Streptococcus）属という（例えば、Schleifer,K.H. and R.Kilpper-Balz. 1984.Int.J.Syst.Bacteriol.34:31-34.参照）。このストレプトコッカス（Streptococcus）属の一部が、現在乳酸菌の分類に使用されている１９８４年以降の分類学上、エンテロコッカス (Enterococcus)属に分類される乳酸菌となった（例えば、Schleifer,K.H. and R.Kilpper-Balz. 1984.Int.J.Syst.Bacteriol.34:31-34（上記文献と同じ）参照）。例えば、本明細書中に記載されるストレプトコッカス・フェーカリス １２９ ＢＩＯ ３Ｂ等のストレプトコッカス・フェーカリス（Streptococcus faecalis）は、現在の分類学上エンテロコッカス・フェシウム(Enterococcus faecium)に分類される乳酸菌である。例えばストレプトコッカス・フェーカリス １２９ ＢＩＯ ３Ｂは、現在の分類学上では、エンテロコッカス・フェシウム１２９ ＢＩＯ ３Ｂとされている。本発明においては、上記ストレプトコッカス（Streptococcus）属に属する乳酸菌として、現在乳酸菌の分類に使用されている１９８４年以降の分類学上、エンテロコッカス (Enterococcus)属に分類される乳酸菌を用いることが好ましい。 In the present specification, a lactic acid bacterium classified as a genus Streptococcus in taxonomy before 1984 is referred to as a genus Streptococcus (for example, Schleifer, KH and R. Kilpper-Balz. 1984. Int. J. Syst. Bacteriol. 34: 31-34.). A part of the genus Streptococcus has become a lactic acid bacterium classified as Enterococcus genus after 1984, which is currently used for classification of lactic acid bacteria (for example, Schleifer, KH and R. Kilpper-Balz. 1984. Int. J. Syst. Bacteriol. 34: 31-34 (same as above)). For example, Streptococcus faecalis such as Streptococcus faecalis 129 BIO 3B described herein are lactic acid bacteria that are currently classified as Enterococcus faecium. For example, Streptococcus faecalis 129 BIO 3B is considered to be Enterococcus faecium 129 BIO 3B in the current taxonomy. In the present invention, as the lactic acid bacterium belonging to the genus Streptococcus, it is preferable to use a lactic acid bacterium classified into the genus Enterococcus since 1984, which is currently used for classification of lactic acid bacteria.
本明細書中においては、１９８０年以前の分類学においてラクトバチルス・アシドフィルス（Lactobacillus acidophilus）に分類されていた乳酸菌を、ラクトバチルス・アシドフィルス（Lactobacillus acidophilus）という（例えば、Lauer,E.and O.Kandler. 1980.Zbl.Bakt.,I.Abt.Orig.C1:75-78.参照）。このラクトバチルス・アシドフィルス（Lactobacillus acidophilus）の一部が、現在乳酸菌の分類に使用されている１９８０年以降の分類学上、ラクトバチルス・ガッセリ（Lactobacillus gasseri）に分類される乳酸菌となった（例えば、Lauer,E.and O.Kandler. 1980.Zbl.Bakt.,I.Abt.Orig.C1:75-78.（上記文献と同じ）参照）。本明細書中に記載されるラクトバシラス・アシドフィルス ＫＳ−１３（Lactobacillus acidophilus KS-13）等のラクトバシラス・アシドフィルス（Lactobacillus acidophilus）は、現在の分類学上ラクトバチルス・ガッセリ（Lactobacillus gasseri）に分類される乳酸菌である。 In the present specification, a lactic acid bacterium classified as Lactobacillus acidophilus in taxonomy before 1980 is referred to as Lactobacillus acidophilus (for example, Lauer, E. and O. Kandler). 1980. Zbl.Bakt., I.Abt.Orig.C1: 75-78.). A part of this Lactobacillus acidophilus has become a lactic acid bacterium classified as Lactobacillus gasseri on the taxonomy after 1980, which is currently used for classification of lactic acid bacteria (for example, Lauer, E. and O. Kandler. 1980. Zbl. Bakt., I. Abt. Orig. C1: 75-78 (same as above)). Lactobacillus acidophilus such as Lactobacillus acidophilus KS-13 described in the present specification is a lactic acid bacterium classified as Lactobacillus gasseri according to the current taxonomy. It is.
乳酸菌の分類体系は１９８０年頃までは細胞形態、細胞配列、乳酸発酵形式、糖の資化性、ＤＮＡ−ＤＮＡ相同性などによって分類されていたが、現在では化学分類学的性質や１６ＳｒＲＮＡ遺伝子の塩基配列を用いた遺伝学的手法により、新規属の提案や既知属の再分類が活発に行われるようになったため、現在の分類学では、例えばストレプトコッカス・フェーカリス １２９ ＢＩＯ ３Ｂはエンテロコッカス・フェシウム(Enterococcus faecium)に、ラクトバシラス・アシドフィルス ＫＳ−１３（Lactobacillus acidophilus KS-13）はラクトバチルス・ガッセリ（Lactobacillus gasseri）に、それぞれ属している。 The classification system of lactic acid bacteria was classified by cell morphology, cell sequence, lactic acid fermentation format, sugar utilization, DNA-DNA homology, etc. until around 1980, but now it has chemical taxonomic properties and bases of 16S rRNA gene. As a result of genetic approaches using sequences, proposals for new genera and reclassification of known genera have been actively carried out. In current taxonomy, for example, Streptococcus faecalis 129 BIO 3B is enterococcus faecium. ), Lactobacillus acidophilus KS-13 (Lactobacillus acidophilus KS-13) belongs to Lactobacillus gasseri, respectively.
本発明によれば、過敏性腸症候群における内臓痛等の機能性消化管障害における消化管痛を効果的に軽減することができ、過敏性腸症候群等の機能性消化管障害の患者等の生活の質を向上させることができる。また、本発明の予防又は軽減剤は、長期間服用しても副作用がなく安全なものである。 According to the present invention, gastrointestinal pain in functional gastrointestinal disorders such as visceral pain in irritable bowel syndrome can be effectively reduced, and life of patients with functional gastrointestinal disorders such as irritable bowel syndrome Quality can be improved. The preventive or alleviating agent of the present invention is safe without side effects even when taken for a long time.
本発明の消化管痛（消化管内臓痛）の予防又は軽減剤は、ストレプトコッカス（Streptococcus）属又はビフィドバクテリウム（Bifidobacterium）属の乳酸菌を有効成分として含む。前記乳酸菌を有効成分とすることにより、消化管痛、特に胃、小腸、大腸等の消化管における痛みを効果的に軽減することができる。ストレプトコッカス（Streptococcus）属の乳酸菌、及びビフィドバクテリウム（Bifidobacterium）属の乳酸菌は、それぞれ１種であってもよく、２種以上であってもよい。 The preventive or alleviating agent for gastrointestinal pain (gastrointestinal visceral pain) of the present invention contains lactic acid bacteria belonging to the genus Streptococcus or Bifidobacterium as an active ingredient. By using the lactic acid bacteria as an active ingredient, digestive tract pain, particularly pain in the digestive tract such as stomach, small intestine, large intestine, etc. can be effectively reduced. Each of the lactic acid bacteria belonging to the genus Streptococcus and the lactic acid bacteria belonging to the genus Bifidobacterium may be one kind or two or more kinds.
本発明の好ましい態様の１つは、ストレプトコッカス（Streptococcus）属の乳酸菌を有効成分として含む消化管痛の予防又は軽減剤である。
ストレプトコッカス（Streptococcus）属の乳酸菌として、例えば、ストレプトコッカス・フェーカリス（Streptococcus faecalis）、ストレプトコッカス・フェシウム（Streptococcus faecium）、ストレプトコッカス・ヒラエ（Streptococcus hirae）、ストレプトコッカス・サーモフィルス（Streptococcus thermophilus）等の乳酸菌が挙げられる。中でも、本発明においては、ストレプトコッカス・フェーカリス（Streptococcus faecalis）が好適に用いられる。これにより、優れた内臓痛の予防又は軽減効果が得られる。より好ましくは、ストレプトコッカス・フェーカリス（Streptococcus faecalis） １２９ ＢＩＯ ３Ｂを用いる。
これらの菌体は、例えばＡＴＣＣ又はＩＦＯなどの機関や財団法人 日本ビフィズス菌センター又は独立行政法人製品評価技術基盤機構 特許生物寄託センターなどから容易に入手することができる。また、市販されているものを適宜使用することもできる。また、例えばストレプトコッカス・フェーカリス（Streptococcus faecalis） １２９ ＢＩＯ ３Ｂは、医薬部外品の新ビオフェルミンＳ錠（商品名、ビオフェルミン製薬社製）等の成分として含まれており、該錠剤等から通常行われる方法で精製することによっても入手可能である。
One of the preferred embodiments of the present invention is a preventive or alleviating agent for gastrointestinal pain comprising a lactic acid bacterium of the genus Streptococcus as an active ingredient.
Examples of lactic acid bacteria belonging to the genus Streptococcus include Streptococcus faecalis, Streptococcus faecium, Streptococcus hirae, and Streptococcus thermophile. Of these, Streptococcus faecalis is preferably used in the present invention. Thereby, the prevention or reduction effect of the excellent visceral pain is acquired. More preferably, Streptococcus faecalis 129 BIO 3B is used.
These cells can be easily obtained from, for example, an organization such as ATCC or IFO, the Japan Bifidobacteria Center, or the National Institute for Product Evaluation Technology Patent Organism Depositary. Moreover, what is marketed can also be used suitably. In addition, for example, Streptococcus faecalis 129 BIO 3B is included as a component of quasi-drug new Biofermin S tablets (trade name, manufactured by Biofermin Pharmaceutical Co., Ltd.), and a method usually performed from the tablets or the like It can also obtain by refine | purifying by.
本発明においては、本発明の効果を奏することになる限り、上記ストレプトコッカス（Streptococcus）属の乳酸菌以外にも、ビフィズス菌等の乳酸菌、糖化菌、酪酸菌等の菌を使用してもよい。例えば、Bifidobacterium longum、 B. breve、B. adolescentis、B. infantis、B.pseudolongum、B.thermophilum等のビフィドバクテリウム（Bifidobacterium）属の乳酸菌；例えば、Lactobacillus casei、L. gasseri、L. plantarum、L. delbrueckii subsp bulgaricus、L. delbrueckii subsp lactis、L. fermentum、L. helveticus、L. johnsonii、L. paracasei subsp. paracasei、L. reuteri、L. rhamnosus、L. salivarius、L. brevis等のラクトバシラス（Lactobacillus）属の乳酸桿菌；例えば、Leuconostoc mesenteroides等のリューコノストック（Leuconostoc）属、Lactococcus lactis、L. cremoris等のラクトコッカス（Lactococcus）属、Tetragenococcus halophilus等のテトラジェノコッカス（Tetragenococcus）属、Pediococcus acidilactici、P. pentosaceus等のペディオコッカス（Pediococcus）属、Oenococcus oeni等のオエノコッカス（Oenococcus）属等の乳酸球菌；例えば、Bacillus subtilis、Bacillus mesentericus、Bacillus polyformenticus等のバシラス（Bacillus）属等の糖化菌；例えば、Bacillus coagulans等のバシラス（Bacillus）属等の有胞子性乳酸菌； 例えば、Bacillus toyoi、B．licheniformis、Clostridium butyricum等のバシラス（Bacillus）属、クロストリジウム（Clostridium）属等の酪酸菌；その他の有用菌が挙げられる。
これらの菌体は、例えばＡＴＣＣ又はＩＦＯなどの機関や財団法人 日本ビフィズス菌センター又は独立行政法人製品評価技術基盤機構 特許生物寄託センターなどから容易に入手することができる。また、市販されているものを適宜使用することもできる。
In the present invention, lactic acid bacteria such as bifidobacteria, saccharifying bacteria, butyric acid bacteria and the like may be used in addition to the lactic acid bacteria belonging to the genus Streptococcus as long as the effects of the present invention are exhibited. For example, lactic acid bacteria belonging to the genus Bifidobacterium such as Bifidobacterium longum, B. breve, B. adolescentis, B. infantis, B. pseudolongum, B. thermophilum; for example, Lactobacillus casei, L. gasseri, L. plantarum, L. delbrueckii subsp bulgaricus, L. delbrueckii subsp lactis, L. fermentum, L. helveticus, L. johnsonii, L. paracasei subsp. Paracasei, L. reuteri, L. rhamnosus, L. salivarius, L. brevis, etc. Lactobacillus genus Lactobacillus; for example, Leuconostoc mesenteroides, etc. Lactococci such as Pediococcus genus such as P. pentosaceus, Oenococcus genus such as Oenococcus oeni; for example, Bacillus subtilis, Bacillus mesenter saccharified bacteria such as Bacillus genus such as Bacillus polyformenticus; for example, sporic lactic acid bacteria such as Bacillus genus such as Bacillus coagulans; Examples include butyric acid bacteria such as Bacillus and Clostridium such as licheniformis and Clostridium butyricum; and other useful bacteria.
These cells can be easily obtained from, for example, an organization such as ATCC or IFO, the Japan Bifidobacteria Center, or the National Institute for Product Evaluation Technology Patent Organism Depositary. Moreover, what is marketed can also be used suitably.
本発明の予防又は軽減剤がストレプトコッカス（Streptococcus）属の乳酸菌以外の菌を含む場合には、さらに、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及び／又はラクトバシラス（Lactobacillus）属の乳酸菌を含むことが好ましい。より好ましくは、さらに、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及びラクトバシラス（Lactobacillus）属の乳酸菌を含む。
ビフィドバクテリウム（Bifidobacterium）属の乳酸菌としては、ビフィドバクテリウム・ビフィダム（Bifidobacterium bifidum）、ビフィドバクテリウム・ロンガム（Bifidobacterium longum）等が好ましい。より好ましくは、ビフィドバクテリウム・ビフィダム（Bifidobacterium bifidum）である。ラクトバシラス（Lactobacillus）属の乳酸菌としては、ラクトバシラス・アシドフィルス（Lactobacillus acidophilus）等が好ましい。
When the preventive or alleviating agent of the present invention contains bacteria other than lactic acid bacteria belonging to the genus Streptococcus, it further contains lactic acid bacteria belonging to the genus Bifidobacterium and / or lactic acid bacteria belonging to the genus Lactobacillus. Is preferred. More preferably, a lactic acid bacterium belonging to the genus Bifidobacterium and a lactic acid bacterium belonging to the genus Lactobacillus are further included.
As lactic acid bacteria belonging to the genus Bifidobacterium, Bifidobacterium bifidum, Bifidobacterium longum, and the like are preferable. More preferably, it is Bifidobacterium bifidum. As the lactic acid bacteria belonging to the genus Lactobacillus, Lactobacillus acidophilus and the like are preferable.
本発明の別の好ましい態様は、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌を有効成分として含む消化管痛の予防又は軽減剤である。
ビフィドバクテリウム（Bifidobacterium）属の乳酸菌として、上述したビフィドバクテリウム・ロンガム（Bifidobacterium longum）、ビフィドバクテリウム・ブレーベ（Bifidobacterium breve）、ビフィドバクテリウム・アドレセンティス（Bifidobacterium adolescentis）、ビフィドバクテリウム・インファンティス（Bifidobacterium infantis）、ビフィドバクテリウム・シュードロンガム（Bifidobacterium pseudolongum）、ビフィドバクテリウム・サーモフィルム（Bifidobacterium thermophilum）等が挙げられる。中でも、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌は、ビフィドバクテリウム・ロンガム（Bifidobacterium longum）が好ましく、ビフィドバクテリウム・ロンガム（Bifidobacterium longum） ＭＭ−２がより好ましい。
本発明の予防又は軽減剤は、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌以外にも、上述した乳酸菌、糖化菌、酪酸菌等の菌を含んでもよい。
Another preferred embodiment of the present invention is an agent for preventing or reducing gastrointestinal pain comprising a lactic acid bacterium of the genus Bifidobacterium as an active ingredient.
Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium adolescentis, Bifido as lactic acid bacteria belonging to the genus Bifidobacterium Examples include Bifidobacterium infantis, Bifidobacterium pseudolongum, Bifidobacterium thermophilum, and the like. Among these, lactic acid bacteria belonging to the genus Bifidobacterium are preferably Bifidobacterium longum, and more preferably Bifidobacterium longum MM-2.
The preventive or alleviating agent of the present invention may contain bacteria such as the above-mentioned lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria in addition to the lactic acid bacteria belonging to the genus Bifidobacterium.
上記菌体は、公知の条件又はそれに準じる条件で培養することにより得ることができる。例えば、乳酸菌の場合は、通常、グルコ−ス、酵母エキス、及びペプトン等を含む液体培地で前記乳酸菌の１種又は２種以上を通常約２５〜４５℃程度で約４〜７２時間程度、好気又は嫌気培養し、培養液から菌体を集菌し、洗浄し、湿菌体を得る。また、糖化菌の場合は、通常、肉エキス、カゼイン製ペプトン、塩化ナトリウム等を含む寒天培地で１種又は２種以上を通常約２５〜４５℃程度で約４〜７２時間程度、好気培養し、培地から菌体を集菌し、洗浄し、湿菌体を得る。 The said microbial cell can be obtained by culture | cultivating on well-known conditions or the conditions according to it. For example, in the case of a lactic acid bacterium, one or more of the lactic acid bacteria are usually preferred at about 25 to 45 ° C. for about 4 to 72 hours in a liquid medium containing glucose, yeast extract, peptone and the like. Aerial or anaerobic culture is performed, and the cells are collected from the culture solution and washed to obtain wet cells. In the case of saccharifying bacteria, aerobic culture is usually carried out at about 25 to 45 ° C. for about 4 to 72 hours in an agar medium containing meat extract, casein peptone, sodium chloride and the like. Then, the cells are collected from the medium and washed to obtain wet cells.
本発明において用いる乳酸菌としては、生菌が好ましいが、菌の処理物を用いてもよい。菌の処理物とは、乳酸菌に何らかの処理を加えたものをいい、その処理は特に限定されない。該処理物として具体的には、該菌体の超音波などによる破砕液、該菌体の培養液又は培養上清、それらを濾過又は遠心分離など固液分離手段によって分離した固体残渣などが挙げられる。また、細胞壁を酵素又は機械的手段により除去した処理液、トリクロロ酢酸処理又は塩析処理などして得られるタンパク質複合体（タンパク質、リポタンパク質、糖タンパク質など）又はペプチド複合体（ペプチド、糖ペプチド等）なども該処理物として挙げられる。さらに、これらの濃縮物、これらの希釈物又はこれらの乾燥物なども該処理物に含まれる。また、該菌体の超音波などによる破砕液、該菌体の培養液又は培養上清などに対し、例えば各種クロマトグラフィーによる分離などの処理をさらに加えたものも本発明における該処理物に含まれる。乳酸菌の死菌体も、本発明における該処理物に含まれる。前記死菌体は、例えば、酵素処理、約１００℃程度の熱をかける加熱処理、抗生物質などの薬物による処理、ホルマリンなどの化学物質による処理、γ線などの放射線による処理などにより得ることができる。 The lactic acid bacterium used in the present invention is preferably a living bacterium, but a processed product of the bacterium may be used. The treated product of bacteria refers to a product obtained by adding some treatment to lactic acid bacteria, and the treatment is not particularly limited. Specific examples of the treated product include a disruption solution of the microbial cells by ultrasonic waves, a culture solution or a culture supernatant of the microbial cells, and a solid residue obtained by separating them by solid-liquid separation means such as filtration or centrifugation. It is done. In addition, a treatment solution obtained by removing a cell wall by an enzyme or mechanical means, a protein complex (protein, lipoprotein, glycoprotein, etc.) or a peptide complex (peptide, glycopeptide, etc.) obtained by trichloroacetic acid treatment or salting-out treatment, etc. ) Etc. are also mentioned as the treated product. Furthermore, these concentrates, these dilutions, or these dried products are also included in the treated product. In addition, the treated product in the present invention includes those obtained by further adding, for example, various chromatographic separations to the disrupted solution of the microbial cells by ultrasonic waves, the culture solution or culture supernatant of the microbial cells. It is. Dead cells of lactic acid bacteria are also included in the treated product in the present invention. The dead cells can be obtained by, for example, enzyme treatment, heat treatment at about 100 ° C., treatment with drugs such as antibiotics, treatment with chemicals such as formalin, treatment with radiation such as γ rays. it can.
本発明において使用される乳酸菌は、乾燥物（菌体乾燥物）であってもよく、菌体乾燥物としては、シングルミクロンの菌体乾燥物が好ましい。菌体乾燥物とは、通常は乾燥された個々の菌体又は乾燥された菌体の集合物をいう。また、シングルミクロンとは、小数第１位を四捨五入して１〜１０μｍをいう。本発明に使用される乳酸菌として、シングルミクロンの菌体乾燥物を使用すると、製剤中の生菌率が上がるため、消化管痛の予防効果及び軽減効果がより高くなる。 The lactic acid bacterium used in the present invention may be a dried product (bacterial cell dried product), and the microbial cell dried product is preferably a single micron dried cell product. The dried microbial cell usually refers to a dried individual microbial cell or a collection of dried microbial cells. Single micron means 1-10 μm by rounding off the first decimal place. When a single micron dried microbial cell product is used as the lactic acid bacterium used in the present invention, the viable cell rate in the preparation is increased, and thus the gastrointestinal pain prevention effect and reduction effect are enhanced.
菌体乾燥物の好ましい製造方法について説明する。上記菌体を溶媒に分散して菌体液とする。溶媒は、当業界で用いられる公知の溶媒を用いてよいが、水が好ましい。また、所望によりエタノールを加えてよい。エタノールを加えることによって、最初にエタノールが気化し、ついで水が気化するため、段階的な乾燥が可能となる。さらに、菌体液は、懸濁液であってもよい。溶媒は上記で示したものと同じでよい。また、懸濁させる際、懸濁剤、例えばアルギン酸ナトリウム等を使用してもよい。
また、上記菌体液には、さらに保護剤、賦形剤、結合剤、崩壊剤、又は静電気防止剤など当業界で一般に用いられている添加剤を通常の配合割合で添加してもよい。
A preferred method for producing a dried microbial cell product will be described. The said microbial cell is disperse | distributed to a solvent and it is set as a microbial cell liquid. As the solvent, a known solvent used in the art may be used, but water is preferable. If desired, ethanol may be added. By adding ethanol, ethanol is vaporized first, and then water is vaporized, so that stepwise drying is possible. Further, the bacterial cell liquid may be a suspension. The solvent may be the same as shown above. When suspending, a suspending agent such as sodium alginate may be used.
Moreover, you may add the additive generally used in this industry, such as a protective agent, an excipient | filler, a binder, a disintegrating agent, or an antistatic agent, to the said microbial cell liquid by a normal compounding ratio.
上記菌体液を、菌体乾燥物を製造するために噴霧乾燥装置による乾燥操作に付する。噴霧乾燥装置は、シングルミクロンの噴霧液滴を形成できる微粒化装置を備えた噴霧乾燥装置が好ましい。非常に粒径の小さな噴霧液滴にすると、噴霧液滴の単位質量あたりの表面積が大きくなり、乾燥温風との接触が効率よく行われるため、生産性が向上する。
ここでシングルミクロンの液滴とは、噴霧液滴の粒径が小数第１位を四捨五入して１〜１０μｍであるものをいう。
The bacterial cell liquid is subjected to a drying operation by a spray dryer in order to produce a dried bacterial cell product. The spray drying apparatus is preferably a spray drying apparatus equipped with a atomizing apparatus capable of forming single micron spray droplets. When spray droplets having a very small particle diameter are used, the surface area per unit mass of the spray droplets is increased, and contact with dry hot air is efficiently performed, so that productivity is improved.
Here, the droplet of single micron means that the particle size of the spray droplet is 1 to 10 μm rounded to the first decimal place.
噴霧乾燥装置には、微粒化装置が、例えばロータリーアトマイザー（回転円盤）、加圧ノズル、又は圧縮気体の力を利用した２流体ノズルや４流体ノズルである噴霧乾燥装置が挙げられる。
噴霧乾燥装置は、シングルミクロンの噴霧液滴を形成できるものであれば、上記形式のいずれの噴霧乾燥装置であってもよいが、４流体ノズルを有する噴霧乾燥装置を使用するのが好ましい。
Examples of the spray drying device include a spray drying device in which the atomization device is, for example, a rotary atomizer (rotary disk), a pressurized nozzle, or a two-fluid nozzle or a four-fluid nozzle using the force of compressed gas.
The spray drying apparatus may be any spray drying apparatus of the above type as long as it can form single micron spray droplets, but it is preferable to use a spray drying apparatus having a four-fluid nozzle.
４流体ノズルを有する噴霧乾燥装置では、４流体ノズルの構造としては、気体流路と液体流路とを１系統として、これを２系統ノズルエッジにおいて対称に設けたもので、ノズルエッジに流体流動面となる斜面を構成している。
また、ノズルエッジの先端の衝突焦点に向かって、両サイドから圧縮気体と液体を一点に集合させる外部混合方式の装置がよい。この方式であれば、ノズル詰まりがなく長時間噴霧することが可能となる。
In a spray drying apparatus having a four-fluid nozzle, the four-fluid nozzle has a gas flow channel and a liquid flow channel as one system, which are provided symmetrically at the two-system nozzle edge. It constitutes the slope that becomes the surface.
Also, an external mixing type apparatus that gathers compressed gas and liquid from one side toward the collision focus at the tip of the nozzle edge is preferable. With this method, it is possible to spray for a long time without nozzle clogging.
４流路ノズルを有する噴霧乾燥装置の１例について図１を用いてさらに詳しく説明する。４流路ノズルのノズルエッジにおいて、液体流路３又は４から湧き出るように出た菌体液が、気体流路１又は２から出た高速気体流により流体流動面５で薄く引き伸ばされ、引き伸ばされた液体はノズルエッジ先端の衝突焦点６で発生する衝撃波で微粒化させることにより、シングルミクロンの噴霧液滴７を形成する。 An example of a spray drying apparatus having a four-channel nozzle will be described in more detail with reference to FIG. At the nozzle edge of the four-channel nozzle, the bacterial cell liquid that springed out from the liquid channel 3 or 4 was thinly stretched and stretched on the fluid flow surface 5 by the high-speed gas flow exiting from the gas channel 1 or 2. The liquid is atomized by a shock wave generated at the collision focal point 6 at the tip of the nozzle edge to form a single micron spray droplet 7.
圧縮気体としては、例えば、空気、炭酸ガス、窒素ガス又はアルゴンガス等の不活性ガス等を用いることができる。とくに、酸化されやすいもの等を噴霧乾燥させる場合は、炭酸ガス、窒素ガス又はアルゴンガス等の不活性ガスを用いるのが好ましい。
圧縮気体の圧力としては、通常約１〜１５ｋｇ重／ｃｍ２、好ましくは約３〜８ｋｇ重／ｃｍ２である。
ノズルにおける気体量は、ノズルエッジ１ｍｍあたり、通常約１〜１００Ｌ／分、好ましくは約１０〜２０Ｌ／分である。
As the compressed gas, for example, an inert gas such as air, carbon dioxide, nitrogen gas, or argon gas can be used. In particular, when spray-drying a material that is easily oxidized, it is preferable to use an inert gas such as carbon dioxide, nitrogen gas, or argon gas.
The pressure of the compressed gas is usually about 1 to 15 kgf / cm 2 , preferably about 3 to 8 kgf / cm 2 .
The gas amount in the nozzle is usually about 1 to 100 L / min, preferably about 10 to 20 L / min per 1 mm of the nozzle edge.
通常、その後、乾燥室において、その噴霧液滴に乾燥温風を接触させることで水分を蒸発させ菌体乾燥物を得る。
乾燥室の入り口温度は、通常約２〜４００℃、好ましくは約５〜２５０℃、より好ましくは約５〜１５０℃である。入り口温度が約２００〜４００℃の高温であっても、水分の蒸発による気化熱により乾燥室内の温度はそれほど高くならず、また、乾燥室内の滞留時間を短くすることにより、生菌の死滅や損傷をある程度抑えることができる。
出口温度は、通常約０〜１２０℃、好ましくは約５〜９０℃、より好ましくは約５〜７０℃である。
Usually, after that, in the drying chamber, the sprayed droplets are brought into contact with dry hot air to evaporate the water and obtain a dried bacterial cell product.
The entrance temperature of the drying chamber is usually about 2 to 400 ° C, preferably about 5 to 250 ° C, more preferably about 5 to 150 ° C. Even if the inlet temperature is about 200 to 400 ° C., the temperature in the drying chamber is not so high due to the heat of vaporization due to the evaporation of moisture, and the residence time in the drying chamber is shortened to Damage can be suppressed to some extent.
The outlet temperature is usually about 0 to 120 ° C, preferably about 5 to 90 ° C, more preferably about 5 to 70 ° C.
４流路ノズルを有する噴霧乾燥装置では、液体流路が２流路あるので、異なった２種の菌体液又は菌体液と他の溶液若しくは懸濁液をそれぞれの液体流路から、同時に噴霧することにより、これらが混合された菌体乾燥物を製造できる。
例えば、異なった２種類の菌体の菌体液を同時に噴霧することにより、該２種の菌体を含有する菌体乾燥物が得られる。
In the spray drying apparatus having a four-channel nozzle, since there are two liquid channels, two different types of bacterial cell liquids or bacterial cell liquids and other solutions or suspensions are sprayed simultaneously from the respective liquid channels. Thus, a dried microbial cell product in which these are mixed can be produced.
For example, by simultaneously spraying two different types of bacterial cell solutions, a dried bacterial cell product containing the two types of bacterial cells can be obtained.
上記のように菌体乾燥物の粒径を小さくすることにより、生菌率が上がり、生菌率の多い製剤を提供できるという利点がある。
すなわち、シングルミクロンの菌体乾燥物を得るためにはシングルミクロンの噴霧液滴を噴霧するのが好ましい。噴霧液滴の粒径を小さくすると、噴霧液滴の単位質量あたりの表面積が大きくなるので、乾燥温風との接触が効率よく行われ、乾燥温風の熱による菌体の死滅又は損傷を極力抑えることができる。その結果として、生菌率が上がり生菌数の多い菌体乾燥物が得られる。
By reducing the particle size of the dried bacterial cell as described above, there is an advantage that the viable cell rate is increased and a preparation having a high viable cell rate can be provided.
That is, it is preferable to spray single micron spray droplets in order to obtain a single micron dried cell. When the particle size of the spray droplets is reduced, the surface area per unit mass of the spray droplets increases, so that contact with the dry hot air is performed efficiently, and killing or damaging the cells due to the heat of the dry hot air as much as possible. Can be suppressed. As a result, the viable cell rate is increased and a dried cell body having a large number of viable cells is obtained.
本発明の消化管痛の予防又は軽減剤は、有効成分である乳酸菌と、他の成分とを混合することにより容易に製造される。他の成分は、本発明の効果を奏する限り特に限定されない。本発明の消化管痛の予防又は軽減剤は、医薬品、医薬部外品、飲食品、飼料等の形態として用いることができる。このような、本発明の消化管痛の予防又は軽減剤を含む医薬品も、本発明の１つである。 The agent for preventing or reducing gastrointestinal pain according to the present invention is easily produced by mixing lactic acid bacteria, which are active ingredients, with other ingredients. Other components are not particularly limited as long as the effects of the present invention are exhibited. The agent for preventing or reducing gastrointestinal pain according to the present invention can be used in the form of pharmaceuticals, quasi drugs, foods and drinks, feeds and the like. Such a pharmaceutical comprising the agent for preventing or reducing gastrointestinal pain of the present invention is also one of the present invention.
本発明の消化管痛の予防又は軽減剤の剤形は、それぞれの成分の物理化学的性質、生物学的性質等を考慮して投与に好適な剤形とすればよい。医薬品の場合には、経口投与の剤形に適しており、内服剤とすることが好ましい。内服剤の剤形としては、例えば、錠剤、ペレット、細粒剤、散剤、顆粒剤、丸剤、チュアブル剤、トローチ剤、液剤、懸濁剤等が挙げられる。中でも、錠剤又は散剤が好ましい。さらに、それぞれの製剤は、前記乳酸菌の他に、賦形剤（例えば、乳糖、デンプン、結晶セルロース又はリン酸ナトリウム等）、結合剤（例えば、デンプン、ゼラチン、カルメロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン等）、崩壊剤（例えばデンプン、カルメロースナトリウム等）、滑沢剤（例えばタルク、ステアリン酸マグネシウム、ステアリン酸カルシウム、マクロゴール、ショ糖脂肪酸エステル等）、安定剤（亜硫酸水素ナトリウム、チオ硫酸ナトリウム、エデト酸ナトリウム、クエン酸ナトリウム、アスコルビン酸、ジブチルヒドロキシトルエン等）、着色剤、賦香剤、光沢剤等、当業界で使用される公知の添加剤等を適宜含有していてもよい。ストレプトコッカス（Streptococcus）属の乳酸菌を有効成分とする場合、製剤中に含まれるストレプトコッカス（Streptococcus）属の乳酸菌の量は、通常、最終製剤中に約０．００００００１〜９９質量％の範囲から適宜選択して決定することができる。
ストレプトコッカス（Streptococcus）属の乳酸菌と共に、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及び／又はラクトバシラス（Lactobacillus）属の乳酸菌を用いる場合、ストレプトコッカス（Streptococcus）属の乳酸菌、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及びラクトバシラス（Lactobacillus）属の乳酸菌の合計量を、最終製剤中に約０．００００００１〜９９質量％とすることが好ましい。
ビフィドバクテリウム（Bifidobacterium）属の乳酸菌を必須の有効成分として含有する場合、製剤中に含まれるビフィドバクテリウム（Bifidobacterium）属の乳酸菌の量は、通常、最終製剤中に約０．００００００１〜９９質量％の範囲から適宜選択して決定することができる。
The dosage form of the gastrointestinal pain prevention or alleviation agent of the present invention may be a dosage form suitable for administration in consideration of the physicochemical properties, biological properties and the like of each component. In the case of a pharmaceutical product, it is suitable for a dosage form for oral administration and is preferably an internal preparation. Examples of the dosage form of the internal preparation include tablets, pellets, fine granules, powders, granules, pills, chewables, troches, liquids, suspensions and the like. Among these, tablets or powders are preferable. In addition to the above-mentioned lactic acid bacteria, each preparation has excipients (eg, lactose, starch, crystalline cellulose, sodium phosphate, etc.), binders (eg, starch, gelatin, carmellose sodium, methylcellulose, hydroxypropylmethylcellulose) , Hydroxypropylcellulose, polyvinylpyrrolidone, etc.), disintegrating agents (eg, starch, carmellose sodium, etc.), lubricants (eg, talc, magnesium stearate, calcium stearate, macrogol, sucrose fatty acid ester, etc.), stabilizers (sulfurous acid) Sodium thiosulfate, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxytoluene, etc.), coloring agents, flavoring agents, brighteners, and other known additives used in the industry. Even if There. When lactic acid bacteria belonging to the genus Streptococcus are used as active ingredients, the amount of lactic acid bacteria belonging to the genus Streptococcus contained in the preparation is usually appropriately selected from the range of about 0.0000001 to 99% by mass in the final preparation. Can be determined.
When using lactic acid bacteria of the genus Bifidobacterium and / or lactic acid bacteria of the genus Lactobacillus together with lactic acid bacteria of the genus Streptococcus, lactic acid bacteria of the genus Streptococcus (Bifidobacterium) The total amount of lactic acid bacteria and Lactobacillus lactic acid bacteria is preferably about 0.0000001 to 99% by mass in the final preparation.
When a lactic acid bacterium belonging to the genus Bifidobacterium is contained as an essential active ingredient, the amount of the lactic acid bacterium belonging to the genus Bifidobacterium is usually about 0.0000001- It can be determined by appropriately selecting from the range of 99% by mass.
なお、前記乳酸菌は、一般に嫌気性で乾燥状態では空気又は酸素に対して弱く、また、高温と湿気に弱いため、組成物の製剤化に際してはできるだけ、不活性ガスの存在下又は真空、低温下で、処理することが好ましい。 The lactic acid bacteria are generally anaerobic, weak in air or oxygen in the dry state, and weak in high temperature and humidity. Therefore, in the formulation of the composition, in the presence of an inert gas or in vacuum or at low temperature as much as possible. It is preferable to process.
前記乳酸菌を含有する組成物を固形製剤にする場合、乾燥法によって、単に粉末同士を混合してもよいし、またその粉末を圧縮して顆粒にしたり、錠剤にしたりしてもよい。湿式法により顆粒、錠剤を製造する場合は、結合剤の水溶液を用いて練合、乾燥し、目的の固形剤とすることができる。さらに、この様にして得られた粉末又は顆粒をカプセルに充填して、カプセル剤とすることもできる。 When the composition containing the lactic acid bacteria is made into a solid preparation, the powders may be simply mixed by a drying method, or the powder may be compressed into granules or tablets. When granules and tablets are produced by a wet method, they can be kneaded and dried using an aqueous solution of a binder to obtain a desired solid agent. Furthermore, the powder or granule obtained in this way can be filled into a capsule to form a capsule.
例えば、錠剤を製造する場合は、公知の打錠機を用いるとよい。該打錠機としては、例えば単発式打錠機又はロータリー型打錠機等が挙げられる。また、丸剤、チュアブル剤又はトローチ剤の製造方法は、公知の方法に従って行われてよく、例えば錠剤を製造するのと同じ手段で作ることができる。 For example, when manufacturing a tablet, it is good to use a well-known tableting machine. Examples of the tableting machine include a single-shot tableting machine and a rotary tableting machine. Moreover, the manufacturing method of a pill, a chewable agent, or a troche agent may be performed in accordance with a well-known method, for example, can be made with the same means as manufacturing a tablet.
微量の有効成分（前記乳酸菌）を大量の他の粉末と混合し均一な混合物を得るためには、いわゆる段階的混合法を採るのがよい。例えば、有効成分をその１００〜２００容量倍の粉末と混合して均一な粉末を得、これを残りの粉末と混合すると均一な粉末を得ることができる。
含水物からの乾燥には、Ｌ−乾燥、凍結乾燥、噴霧乾燥などの手段をとることができる。乳酸菌の乾燥菌体を得るには、適当な安定剤、例えばグルタミン酸モノナトリウム塩、アドニトールなどを加えた中性の緩衝液に菌を懸濁させておき、自体公知の方法で乾燥することもできる。
In order to obtain a uniform mixture by mixing a small amount of active ingredient (the lactic acid bacterium) with a large amount of other powders, a so-called stepwise mixing method is preferably employed. For example, the active ingredient can be mixed with 100 to 200 times its volume of powder to obtain a uniform powder, and this can be mixed with the remaining powder to obtain a uniform powder.
For drying from the hydrated material, means such as L-drying, freeze-drying and spray-drying can be employed. In order to obtain dry cells of lactic acid bacteria, the bacteria can be suspended in a neutral buffer solution containing an appropriate stabilizer such as monosodium glutamate or adonitol and dried by a method known per se. .
本発明において、有効成分である乳酸菌の投与量は、例えばストレプトコッカス（Streptococcus）属の乳酸菌であれば、生菌を用いる場合には、生菌の菌数にして通常約１０３〜１０１１個／大人／回、好ましくは約１０６〜１０１１個／大人／回、より好ましくは約１０９〜１０１１個／大人／回である。この量を、通常１日１〜３回経口投与することが好ましい。投与するタイミングは特に限定されない。ビフィドバクテリウム（Bifidobacterium）属の乳酸菌を有効成分とする予防又は治療剤を用いる場合にも、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌の投与量は、生菌を用いる場合には、生菌の菌数にして通常約１０３〜１０１１個／大人／回、好ましくは約１０６〜１０１１個／大人／回、より好ましくは約１０９〜１０１１個／大人／回である。この量を、通常１日１〜３回経口投与することが好ましい。投与するタイミングは特に限定されない。 In the present invention, the dosage of lactic acid bacteria as an active ingredient is, for example, lactic acid bacteria belonging to the genus Streptococcus, and when viable bacteria are used, the number of viable bacteria is usually about 10 3 to 10 11 / Adult / time, preferably about 10 6 to 10 11 / adult / time, more preferably about 10 9 to 10 11 / adult / time. This amount is usually preferably administered orally 1-3 times a day. The timing of administration is not particularly limited. Even when a preventive or therapeutic agent containing a lactic acid bacterium belonging to the genus Bifidobacterium as an active ingredient is used, the dose of the lactic acid bacterium belonging to the genus Bifidobacterium should be The number of bacteria is usually about 10 3 to 10 11 cells / adult / time, preferably about 10 6 to 10 11 cells / adult / time, more preferably about 10 9 to 10 11 cells / adult / time. This amount is usually preferably administered orally 1-3 times a day. The timing of administration is not particularly limited.
ストレプトコッカス（Streptococcus）属の乳酸菌と共に、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及び／又はラクトバシラス（Lactobacillus）属の乳酸菌を用いる場合、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及びラクトバシラス（Lactobacillus）属の乳酸菌の投与量は、生菌を用いる場合には、それぞれの乳酸菌につき、生菌の菌数にして通常約１０３〜１０１１個／大人／回、好ましくは１０６〜１０１１個／大人／回、より好ましくは１０９〜１０１１個／大人／回である。各菌ごとにこの量を、通常１日１〜３回、ストレプトコッカス（Streptococcus）属の乳酸菌と共に経口投与するのが効果的である。
ここで、製剤中の生菌数の測定は菌体によって異なるが、例えば日本薬局方外医薬品規格に記載されたそれぞれの菌体の定量方法により容易に測定できる。
When using lactic acid bacteria belonging to the genus Bifidobacterium and / or lactic acid bacteria belonging to the genus Lactobacillus together with lactic acid bacteria belonging to the genus Streptococcus, lactic acid bacteria belonging to the genus Bifidobacterium and Lactobacillus The dose of lactic acid bacteria belonging to the genus is usually about 10 3 to 10 11 cells / adult / time, preferably 10 6 to 10 11 cells / live cell number for each lactic acid bacterium when the bacterium is used. Adult / times, more preferably 10 9 to 10 11 / adult / time. It is effective to orally administer this amount for each bacterium together with lactic acid bacteria belonging to the genus Streptococcus, usually 1 to 3 times a day.
Here, the measurement of the number of viable bacteria in the preparation varies depending on the bacterial cells, but can be easily measured by, for example, each bacterial cell quantification method described in the Japanese Pharmacopoeia Pharmaceutical Standards.
本発明においては、上記量の有効成分を哺乳類に連続投与することが好ましい。連続投与により、より優れた消化管痛の予防作用又は軽減作用を発揮することができる。例えば、本発明の予防又は軽減剤を、約１週間以上連続投与することが好ましく、約２週間以上連続投与することがより好ましく、約３週間以上連続投与することがさらに好ましい。上記乳酸菌は副作用がほとんどないことから、連続投与する場合の期間の上限は特に限定されない。 In the present invention, it is preferable to continuously administer the above-mentioned amount of the active ingredient to the mammal. By continuous administration, a more excellent gastrointestinal pain prevention or alleviation effect can be exhibited. For example, the preventive or alleviating agent of the present invention is preferably administered continuously for about 1 week or longer, more preferably continuously administered for about 2 weeks or longer, and further preferably continuously administered for about 3 weeks or longer. Since the lactic acid bacteria have almost no side effects, the upper limit of the period for continuous administration is not particularly limited.
ストレプトコッカス（Streptococcus）属の乳酸菌と共に、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及び／又はラクトバシラス（Lactobacillus）属の乳酸菌を用いる場合、各乳酸菌の比率は特に限定されない。例えば、ストレプトコッカス（Streptococcus）属の乳酸菌の生菌数を１とした場合に、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌は、生菌数で０．００００１〜１０００００程度とすることが好ましく、０．０１〜１００程度とすることがより好ましい。また、ストレプトコッカス（Streptococcus）属の乳酸菌の生菌数を１とした場合に、ラクトバシラス（Lactobacillus）属の乳酸菌は、生菌数で０．００００１〜１０００００程度とすることが好ましく、０．０１〜１００程度とすることがより好ましい。ストレプトコッカス（Streptococcus）属の乳酸菌と共に、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及びラクトバシラス（Lactobacillus）属の乳酸菌を使用する場合、各乳酸菌を前記比率で投与することが好ましい。 When a lactic acid bacterium of the genus Bifidobacterium and / or a lactic acid bacterium of the genus Lactobacillus is used together with a lactic acid bacterium of the genus Streptococcus, the ratio of each lactic acid bacterium is not particularly limited. For example, when the number of living lactic acid bacteria belonging to the genus Streptococcus is 1, the number of lactic acid bacteria belonging to the genus Bifidobacterium is preferably about 0.00001 to 100,000. More preferably, it is about 01-100. Further, when the number of living lactic acid bacteria belonging to the genus Streptococcus is 1, the number of lactic acid bacteria belonging to the genus Lactobacillus is preferably about 0.00001 to 100,000, and 0.01 to 100 More preferably, it is about. When lactic acid bacteria belonging to the genus Bifidobacterium and lactic acid bacteria belonging to the genus Lactobacillus are used together with lactic acid bacteria belonging to the genus Streptococcus, it is preferable to administer each lactic acid bacterium at the above-mentioned ratio.
本発明の予防又は軽減剤は、消化管痛を効果的に軽減できる効果を奏することから、消化管痛を呈する胃腸障害又は消化管疾患を発症した個体（動物）、又は該胃腸障害又は消化管疾患を発症するおそれのある個体に好適に適用される。消化管痛には、消化管知覚過敏による消化管痛も含まれる。個体としてはヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル等の哺乳類が好ましく、特にヒトが好ましい。中でも、本発明の予防又は軽減剤は、消化管系の内臓に炎症、潰瘍等の器質的疾患が認められないにもかかわらず、消化管痛（消化管内臓痛）又は消化管知覚過敏を呈する胃腸障害又は消化管疾患、例えば機能性消化管障害における消化管痛の軽減又は予防に特に好適に用いられる。本発明の好ましい態様の１つは、機能性消化管障害における消化管痛の軽減又は予防剤である。 Since the prophylactic or alleviating agent of the present invention has an effect of effectively reducing gastrointestinal pain, an individual (animal) who developed gastrointestinal disorder or gastrointestinal disorder exhibiting gastrointestinal pain, or the gastrointestinal disorder or digestive tract It is preferably applied to an individual who is likely to develop a disease. Gastrointestinal pain includes gastrointestinal pain due to gastrointestinal hypersensitivity. As the individual, mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs and monkeys are preferable, and humans are particularly preferable. Among them, the preventive or alleviating agent of the present invention exhibits gastrointestinal pain (gastrointestinal visceral pain) or gastrointestinal hypersensitivity even though organic diseases such as inflammation and ulcer are not observed in the internal organs of the gastrointestinal tract. It is particularly preferably used for the reduction or prevention of gastrointestinal pain in gastrointestinal disorders or gastrointestinal disorders, such as functional gastrointestinal disorders. One of the preferred embodiments of the present invention is an agent for reducing or preventing gastrointestinal pain in functional gastrointestinal disorders.
上記機能性消化管障害として、例えば、食道由来機能性胸痛、機能性ディスペプシア、心窩部痛症候群、過敏性腸症候群、機能性腹痛症候群、機能性胆嚢障害、機能性胆道・オッディ括約筋障害、機能性膵・オッディ括約筋障害、機能性直腸肛門痛等が挙げられる。中でも、本発明の予防又は軽減剤は、過敏性腸症候群における内臓痛（消化管痛）の予防又は軽減剤として好適に用いられる。 Examples of functional gastrointestinal disorders include esophageal functional chest pain, functional dyspepsia, epigastric pain syndrome, irritable bowel syndrome, functional abdominal pain syndrome, functional gallbladder disorder, functional biliary / oddy sphincter disorder, functional Examples include pancreatic / oddy sphincter disorder and functional rectal anal pain. Among them, the preventive or alleviating agent of the present invention is suitably used as an agent for preventing or reducing visceral pain (gastrointestinal pain) in irritable bowel syndrome.
本発明の予防又は軽減剤は、例えば、過敏性腸症候群又はそのおそれのある個体（動物）に特に好適に適用することができる。中でも、過敏性腸症候群を発症した個体が特に好適である。また、過敏性腸症候群を発症していない個体であっても、本発明の予防又は軽減剤を例えば連続投与することにより、その発症を予防することができる。 The prophylactic or alleviating agent of the present invention can be particularly suitably applied to, for example, irritable bowel syndrome or an individual (animal) that may have it. Among them, an individual who has developed irritable bowel syndrome is particularly suitable. Moreover, even in an individual who has not developed irritable bowel syndrome, its onset can be prevented by, for example, continuous administration of the preventive or alleviating agent of the present invention.
本発明の予防又は軽減剤は、過敏性腸症候群における腸管知覚過敏を効果的に改善することができる。このため過敏性腸症候群における内臓痛の予防、改善又は治療に有効なものであり、投与の方法も簡単で、しかも副作用がほとんどないものである。 The preventive or alleviating agent of the present invention can effectively improve intestinal hypersensitivity in irritable bowel syndrome. For this reason, it is effective for the prevention, improvement or treatment of visceral pain in irritable bowel syndrome, the administration method is simple, and there are almost no side effects.
本発明の予防又は軽減剤は、上述した医薬品として用いることができるほか、機能性食品、特定保健用食品又はドリンク剤などの飲食品に用いることができるものである。本発明の予防又は軽減剤を含む消化管痛の予防又は軽減用飲食品組成物も、本発明の１つである。本発明に係る飲食品組成物を、消化管痛又は消化管知覚過敏がある哺乳動物、好ましくは機能性消化管障害又はそのおそれのあるヒトを含む哺乳動物に摂取させることにより、消化管痛を予防又は改善することができる。飲食品組成物中に含まれる有効成分であるストレプトコッカス（Streptococcus）属又はビフィドバクテリウム（Bifidobacterium）属の乳酸菌の量は、通常、最終組成物中に約０．００００００１〜９９質量％の範囲から適宜選択して決定することができる。ストレプトコッカス（Streptococcus）属の乳酸菌と共に、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及び／又はラクトバシラス（Lactobacillus）属の乳酸菌を用いる場合、ストレプトコッカス（Streptococcus）属の乳酸菌、ビフィドバクテリウム（Bifidobacterium）属の乳酸菌、及びラクトバシラス（Lactobacillus）属の乳酸菌の合計量を、最終組成物中に約０．００００００１〜９９質量％とすることが好ましい。これらの乳酸菌の配合比率等は、上述した医薬の場合と同様とすることが好ましい。 The preventive or alleviating agent of the present invention can be used as a pharmaceutical as described above, and can also be used for food and drink such as functional food, food for specified health use, and drink. A food or drink composition for preventing or reducing gastrointestinal pain comprising the preventive or alleviating agent of the present invention is also one aspect of the present invention. By ingesting the food and drink composition according to the present invention to a mammal having gastrointestinal pain or gastrointestinal hypersensitivity, preferably a mammal including a human having a functional gastrointestinal dysfunction or a risk of such gastrointestinal pain, Can be prevented or ameliorated. The amount of lactic acid bacteria belonging to the genus Streptococcus or Bifidobacterium, which is an active ingredient contained in the food or drink composition, is usually from about 0.0000001 to 99% by mass in the final composition. It can be selected and determined as appropriate. When using lactic acid bacteria of the genus Bifidobacterium and / or lactic acid bacteria of the genus Lactobacillus together with lactic acid bacteria of the genus Streptococcus, lactic acid bacteria of the genus Streptococcus (Bifidobacterium) The total amount of lactic acid bacteria and Lactobacillus lactic acid bacteria is preferably about 0.0000001 to 99% by mass in the final composition. The blending ratio of these lactic acid bacteria is preferably the same as in the case of the above-mentioned medicine.
本発明の予防又は軽減剤を飲食品組成物として用いる場合、その形態は特に限定されない。また、飲食品組成物は、自然流動食、半消化態栄養食若しくは成分栄養食、又はドリンク剤等の加工形態とすることもできる。さらに、本発明にかかる飲食品組成物は、アルコール飲料又はミネラルウォーターに用時添加する易溶性製剤としてもよい。より具体的には、本発明に係る飲食品組成物は、例えばビスケット、クッキー、ケーキ、キャンディー、チョコレート、チューインガム、和菓子などの菓子類；パン、麺類、米飯又はその加工品；清酒、薬用酒などの発酵食品；ヨーグルト、ハム、ベーコン、ソーセージ、マヨネーズなどの畜農食品；果汁飲料、清涼飲料、スポーツ飲料、アルコール飲料、茶などの飲料等の形態とすることができる。 When using the prevention or reduction agent of this invention as a food-drinks composition, the form is not specifically limited. Moreover, food-drinks compositions can also be made into processing forms, such as a natural liquid food, a semi-digested nutrient food, a component nutrient food, or a drink agent. Furthermore, the food-drinks composition concerning this invention is good also as an easily soluble formulation added to an alcoholic beverage or mineral water at the time of use. More specifically, the food / beverage composition according to the present invention includes, for example, confectionery such as biscuits, cookies, cakes, candy, chocolate, chewing gum, Japanese confectionery; bread, noodles, cooked rice or processed products thereof; sake, medicinal liquor, etc. Fermented foods; livestock farming foods such as yogurt, ham, bacon, sausage, mayonnaise; beverages such as fruit juice drinks, soft drinks, sports drinks, alcoholic drinks, and tea.
また、本発明に係る飲食品組成物は、例えば、医師の食事箋に基づく栄養士の管理の下に、病院給食の調理の際に任意の食品に本発明の予防又は軽減剤又は飲食品組成物を加え、その場で調製した食品の形態で患者に与えることもできる。本発明の飲食品組成物は、液状であっても、粉末や顆粒などの固形状であってもよい。 In addition, the food / beverage composition according to the present invention is, for example, a preventive or alleviating agent or food / beverage composition according to the present invention applied to any food during cooking for a hospital meal under the control of a dietitian based on a doctor's meal. Can be given to the patient in the form of food prepared on the spot. The food / beverage composition of the present invention may be liquid or solid such as powder or granule.
本発明に係る飲食品組成物は、食品分野で慣用の補助成分を含んでいてもよい。前記補助成分としては、例えば乳糖、ショ糖、液糖、蜂蜜、ステアリン酸マグネシウム、オキシプロピルセルロース、各種ビタミン類、微量元素、クエン酸、リンゴ酸、香料、無機塩などが挙げられる。 The food-drinks composition which concerns on this invention may contain the auxiliary component conventionally used in the foodstuff field | area. Examples of the auxiliary component include lactose, sucrose, liquid sugar, honey, magnesium stearate, oxypropylcellulose, various vitamins, trace elements, citric acid, malic acid, fragrance, and inorganic salt.
本発明に係る飲食品組成物の摂取量は、摂取する哺乳動物の生活習慣病の状態、年齢、性別などによって異なるので、一概には言えないが、前記乳酸菌を、それぞれ上述した医薬品の場合と同様の量摂取させることが好ましい。 Since the intake of the food and beverage composition according to the present invention varies depending on the state of the lifestyle-related disease, age, sex, etc. of the mammal to be ingested, it cannot be said unconditionally, It is preferable to take the same amount.
以下実施例を示してさらに詳しく説明を行うが、本発明はこれによりなんら制限されるものではない。本実施例中、「％」は、特に断らない限り「質量％」を意味する。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. In this example, “%” means “% by mass” unless otherwise specified.
＜実施例１＞
１．菌体の培養及び保存
Bifidobacterium bifidum Ｇ９−１（乳酸菌Ａ）、Lactobacillus acidophilus ＫＳ−１３（乳酸菌Ｂ）、Streptococcus faecalis １２９ ＢＩＯ ３Ｂ（乳酸菌Ｃ）及びBifidobacterium longum ＭＭ−２（乳酸菌Ｄ）それぞれの菌液の調製は以下のように行った。すなわち、乳酸菌Ａ、乳酸菌Ｂ、乳酸菌Ｃ、及び乳酸菌Ｄの凍結保存菌株（いずれもビオフェルミン製薬社保存菌株）をそれぞれ３７℃で２４時間培養後、１％グルコース含ＧＡＭ培地１０ｍＬにこの培養液を培地１００に対して１の割合（容量比）で接種し、３７℃で２４時間培養した。培養後、１％グルコース含ＧＡＭ培地１０００ｍＬにこの培養液を培地１００に対して１の割合（容量比）で接種し、３７℃で１８時間培養した。得られた培養菌液１０００ｍＬを遠心分離（２６００×ｇ、１５分）し、菌体を回収した。回収した菌体はCa2+及びMg2+を含まないリン酸緩衝液生理食塩水（Dulbecco’s phosphate buffered saline Ca2+, Mg2+ free）（以下、ＰＢＳともいう）で３回洗浄後、３０〜４０ｍＬのＰＢＳに再度懸濁し、７５０μＬずつマイクロチューブに分注し、遠心（２６００×ｇ、１５分）後、上清を取り除き培養菌体として−８０℃にて使用直前まで保存した。
<Example 1>
1. Cell culture and storage
Bifidobacterium bifidum G9-1 (lactic acid bacteria A), Lactobacillus acidophilus KS-13 (lactic acid bacteria B), Streptococcus faecalis 129 BIO 3B (lactic acid bacteria C) and Bifidobacterium longum MM-2 (lactic acid bacteria D) are prepared as follows. went. That is, cryopreserved strains of lactic acid bacteria A, lactic acid bacteria B, lactic acid bacteria C, and lactic acid bacteria D (all of which were stored by Biofermin Pharmaceutical Co., Ltd.) were cultured at 37 ° C. for 24 hours, and then the culture solution was added to 10 mL of 1% glucose-containing GAM medium. Inoculated at a ratio of 1 to 100 (volume ratio) and cultured at 37 ° C. for 24 hours. After the culture, 1000 mL of 1% glucose-containing GAM medium was inoculated with this culture solution at a ratio (volume ratio) of 1 to the medium 100 and cultured at 37 ° C. for 18 hours. 1000 mL of the obtained culture solution was centrifuged (2600 × g, 15 minutes), and the cells were collected. The recovered cells are Ca 2+ and Mg 2+ do not contain a phosphate buffered saline (Dulbecco's phosphate buffered saline Ca 2+ , Mg 2+ free) ( hereinafter, also referred to as PBS) After washing three times with 30 The suspension was resuspended in ˜40 mL of PBS, dispensed in 750 μL aliquots into microtubes, centrifuged (2600 × g, 15 minutes), and the supernatant was removed and stored as cultured cells at −80 ° C. until immediately before use.
上記それぞれの保存培養菌体にＰＢＳを７５０μＬ加え十分撹拌後、液中の生存菌数（生菌数）を測定した。そのときの菌数は下記表１に示すとおりであった。生菌数の測定は、日本薬局方外医薬品規格 ビフィズス菌の項及びラクトミンの項に記載の方法に従って行った。 750 μL of PBS was added to each of the above stored cultured cells, and after sufficient stirring, the viable cell count (viable cell count) in the solution was measured. The number of bacteria at that time was as shown in Table 1 below. The number of viable bacteria was measured according to the method described in the Japanese Pharmacopoeia Standards for Bifidobacteria and Lactamine.
なおBifidobacterium bifidum Ｇ９−１株（乳酸菌Ａ）、及びLactobacillus acidophilus ＫＳ−１３株（乳酸菌Ｂ）、Streptococcus faecalis １２９ ＢＩＯ ３Ｂ株（乳酸菌Ｃ）は、医薬部外品の新ビオフェルミンＳ錠（商品名、ビオフェルミン製薬社製）等の成分として含まれており、該錠剤等から通常行われる方法で精製することによって入手可能である。Bifidobacterium longum MM-2（乳酸菌Ｄ）は、日本国千葉県木更津市かずさ鎌足2-5-8（郵便番号292-0818）の独立行政法人製品評価技術基盤機構 特許生物寄託センターに寄託されている（受付日：２００９年９月１７日、受託番号：ＮＩＴＥ ＢＰ−８１８）。 Bifidobacterium bifidum G9-1 strain (lactic acid bacteria A), Lactobacillus acidophilus KS-13 strain (lactic acid bacteria B), and Streptococcus faecalis 129 BIO 3B strain (lactic acid bacteria C) are quasi-drug new biofermin S tablets (trade name, biofermin) And the like, and can be obtained by purifying the tablets or the like by a method usually performed. Bifidobacterium longum MM-2 (lactic acid bacteria D) is deposited at the Patent Biological Depository Center of the National Institute of Technology and Evaluation, 2-5-8 Kazusa Kamashi, Kisarazu, Chiba, Japan (zip code 292-0818) (Reception date: September 17, 2009, accession number: NITE BP-818).
２．被験薬の調製
乳酸菌Ａ、Ｂ、Ｃ及びＤそれぞれの菌液のチューブにＰＢＳを７５０μＬ加え十分撹拌して懸濁液を得た。乳酸菌Ａ懸濁液５２７μＬにＰＢＳ １１４７３μＬを、乳酸菌Ｂ懸濁液７６７μＬにＰＢＳ １０２７３μＬを、乳酸菌Ｃ懸濁液７６６μＬにＰＢＳ ９７９４μＬを、乳酸菌Ｄ懸濁液４００μＬにＰＢＳ １１６００μＬをそれぞれ加え、十分撹拌し、乳酸菌Ａ、Ｂ、Ｃ及びＤのいずれかを含む４種の乳酸菌懸濁液を調製した。各調製液をそれぞれ被験薬Ａ（乳酸菌Ａ）、被験薬Ｂ（乳酸菌Ｂ）、被験薬Ｃ（乳酸菌Ｃ）、及び被験薬Ｄ（乳酸菌Ｄ）とし、３７℃の水浴で３０分間加温した後、１回につき各懸濁液６００μＬ（１０９ｃｆｕ）を動物に投与した。
2. Preparation of Test Drug A suspension was obtained by adding 750 μL of PBS to each bacterial solution tube of lactic acid bacteria A, B, C, and D and stirring sufficiently. Add 11473 μL of PBS to 527 μL of lactic acid bacteria A suspension, 10273 μL of PBS to 767 μL of lactic acid bacteria B suspension, 9794 μL of PBS to 766 μL of lactic acid bacteria C suspension, and 11600 μL of PBS to 400 μL of lactic acid bacteria D suspension. Four types of lactic acid bacteria suspensions containing any of lactic acid bacteria A, B, C and D were prepared. After preparing each preparation liquid as the test drug A (lactic acid bacteria A), the test drug B (lactic acid bacteria B), the test drug C (lactic acid bacteria C), and the test drug D (lactic acid bacteria D), it heats for 30 minutes in a 37 degreeC water bath. Animals were dosed with 600 μL (10 9 cfu) of each suspension at a time.
３．使用動物
実験には、Ｃｒｌ：ＣＤ（ＳＤ）系雄性ラット（５週齢、日本チャールス・リバー株式会社：入荷時）を用いた。
実験に用いる動物は、飼育ケージ（４６０ｍｍ×２５０ｍｍ×Ｈ２００ｍｍ）で２〜３匹飼いとし、温度：２０〜２５℃、湿度：４０〜７０％、換気回数：１３回以上／時間、照明時間：１２時間（７：００〜１９：００）の環境に調節された動物飼育室で飼育し、餌は固型飼料ＣＲＦ−１（オリエンタル酵母株式会社）を自由摂取させた。飲水はフィルター濾過水を自由に摂取させた。
3. Animals used Crl: CD (SD) male rats (5-week-old, Charles River Japan, Inc .: upon arrival) were used in the experiments.
The animals used in the experiment are 2 to 3 animals in a breeding cage (460 mm × 250 mm × H200 mm), temperature: 20 to 25 ° C., humidity: 40 to 70%, ventilation rate: 13 times / hour, lighting time: 12 The animals were raised in an animal breeding room adjusted to the time (7:00 to 19:00) environment, and the solid feed CRF-1 (Oriental Yeast Co., Ltd.) was freely fed. For drinking water, the filtered water was freely consumed.
４．使用薬物及び試薬
２，４，６−トリニトロベンゼンスルホン酸（2,4,6-trinitrobenzene sulfonic acid (TNBS)）はFlukaより、Dulbecco’s phosphate buffered saline(PBS) Ca2+, Mg2+ free（ＰＢＳ）はSigmaより、大塚生理食塩水は大塚製薬株式会社より、ソムノペンチルは共立製薬株式会社より、イソフルランはマイラン製薬株式会社より、エタノールは和光純薬工業株式会社よりそれぞれ購入した。
4). Drugs and reagents used 2,4,6-trinitrobenzene sulfonic acid (TNBS) from Fluka, Dulbecco's phosphate buffered saline (PBS) Ca 2+ , Mg 2+ free (PBS) Was purchased from Sigma, Otsuka Saline from Otsuka Pharmaceutical Co., Ltd., Somnopentyl from Kyoritsu Pharmaceutical Co., Ltd., Isoflurane from Mylan Pharmaceutical Co., Ltd., and Ethanol from Wako Pure Chemical Industries, Ltd.
５．群構成
試験に供した動物の群構成は、表２に示す通りである。Ｓｈａｍ群とは、後述するＴＮＢＳ誘発内臓痛モデルの作製において外科的処置（手術）のみ行い、ＴＮＢＳを投与しなかった動物に、ＰＢＳを経口投与した群である。溶媒対照群とは、ＴＮＢＳ誘発内臓痛モデルにＰＢＳを経口投与した群である。
被験薬群とは、ＴＮＢＳ誘発内臓痛モデルに、上記１．および２．で調製した被験薬Ａ〜Ｄのいずれかを経口投与した群である。
5. Group composition The group composition of the animals subjected to the test is as shown in Table 2. The Sham group is a group in which PBS was orally administered to animals that were subjected only to surgical treatment (surgery) in the preparation of a TNBS-induced visceral pain model described later and that were not administered with TNBS. The solvent control group is a group in which PBS was orally administered to a TNBS-induced visceral pain model.
The test drug group includes the TNBS-induced visceral pain model described above in 1. And 2. It is the group which orally administered any one of the test drugs AD prepared in 1.
６．馴化
動物は導入後約１週間馴化し、実験に供した。
6). Acclimatization Animals were acclimatized for about one week after introduction and subjected to experiments.
７．被験薬の２２日間連続経口投与試験
馴化後、動物に被験薬又は溶媒（ＰＢＳ）を２２日間連続で１日１回経口投与（１回につき６００μＬを投与）した。被験薬群においては、被験薬投与開始１５日目に、後述する方法によりＴＮＢＳを投与し、ＴＮＢＳ誘発内臓痛モデルを作製した。ＴＮＢＳ誘発内臓痛モデル作製日は、ＴＮＢＳ投与後、動物が覚醒してから被験薬を経口投与した。また、内臓痛閾値（痛覚閾値）測定日は、内臓痛閾値測定３時間前に被験薬を経口投与した。
溶媒対照群においては、被験薬の代わりに溶媒を投与した以外は、被験薬群と同様にしてＴＮＢＳ誘発内臓痛モデルを作製した。具体的には、溶媒投与開始１５日目にＴＮＢＳ誘発内臓痛モデルを作製した。ＴＮＢＳ誘発内臓痛モデル作製日は、ＴＮＢＳ投与後、動物が覚醒してから溶媒を経口投与した。また、内臓痛閾値測定日は、内臓痛閾値測定３時間前に溶媒を経口投与した。
7). 22 days continuous oral administration test of test drug After habituation, the test drug or solvent (PBS) was orally administered to the animal once a day for 22 consecutive days (600 μL per dose). In the test drug group, TNBS was administered by the method described later on the 15th day from the start of test drug administration, and a TNBS-induced visceral pain model was prepared. On the day of preparation of the TNBS-induced visceral pain model, the test drug was orally administered after the animal was awakened after TNBS administration. On the day of measurement of the visceral pain threshold (pain threshold), the test drug was orally administered 3 hours before the measurement of the visceral pain threshold.
In the solvent control group, a TNBS-induced visceral pain model was prepared in the same manner as in the test drug group except that a solvent was administered instead of the test drug. Specifically, a TNBS-induced visceral pain model was created on the 15th day after the start of solvent administration. On the day of preparation of the TNBS-induced visceral pain model, the solvent was orally administered after the animal was awakened after TNBS administration. On the day of measuring the visceral pain threshold, the solvent was orally administered 3 hours before the measurement of the visceral pain threshold.
作製したＴＮＢＳ誘発内臓痛モデルは、内臓痛閾値が正常動物に比べて有意に低下しており、過敏性腸症候群における内臓知覚過敏のモデル動物として使用されている（例えば、Ohashi et al., J. Vet. Med. Sci. 69(12):1223-1228, 2007、Ohashi et al., J. Vet. Med. Sci. 70(1):43-49, 2008、Kikuchi et al., J Pharmacol Sci 106, 219-224 (2008)等）。 The created TNBS-induced visceral pain model has a significantly reduced threshold of visceral pain compared to normal animals, and is used as a model animal for visceral hypersensitivity in irritable bowel syndrome (eg, Ohashi et al., J Vet. Med. Sci. 69 (12): 1223-1228, 2007, Ohashi et al., J. Vet. Med. Sci. 70 (1): 43-49, 2008, Kikuchi et al., J Pharmacol Sci 106, 219-224 (2008) etc.).
Ｓｈａｍ群については、動物に溶媒（ＰＢＳ）を２２日間連続で１日１回経口投与した。溶媒投与開始１５日目にＴＮＢＳ誘発内臓痛モデルの作製において外科的処置のみを行った。この外科的処置を行った日には、動物が覚醒してから溶媒を経口投与した。また、内臓痛閾値測定日は、内臓痛閾値測定３時間前に溶媒を経口投与した。 For the Sham group, the animals were orally administered the solvent (PBS) once a day for 22 consecutive days. On the 15th day from the start of solvent administration, only surgical treatment was performed in the preparation of the TNBS-induced visceral pain model. On the day of this surgical procedure, the animals were orally administered after the animals awakened. On the day of measuring the visceral pain threshold, the solvent was orally administered 3 hours before the measurement of the visceral pain threshold.
ＴＮＢＳ誘発内臓痛に対する乳酸菌の作用を調べる試験のタイムテーブルを、図２に示す。図２においては、被験薬を投与する場合が例として示されているが、溶媒対照群においては、被験薬の代わりに溶媒を投与した。また、Ｓｈａｍ群においては、被験薬の代わりに溶媒を投与し、かつＴＮＢＳの投与を行わなかった。 FIG. 2 shows a timetable of a test for examining the effect of lactic acid bacteria on TNBS-induced visceral pain. In FIG. 2, a case where a test drug is administered is shown as an example, but in the solvent control group, a solvent was administered instead of the test drug. In the Sham group, a solvent was administered instead of the test drug, and TNBS was not administered.
８．ＴＮＢＳ溶液の調製
ＴＮＢＳ（１Ｍ、１ｍＬ）は室温にて溶解させ、５０ｍｇ／ｋｇの用量になるよう３０％エタノール溶液で希釈し、１頭当たり０．５ｍＬ（０．５ｍＬ／ｈｅａｄ）の投与量とした。ＴＮＢＳ溶液は、用時調製した。
8). Preparation of TNBS solution TNBS (1M, 1 mL) was dissolved at room temperature, diluted with a 30% ethanol solution to a dose of 50 mg / kg, and a dose of 0.5 mL (0.5 mL / head) per head was used. did. The TNBS solution was prepared at the time of use.
９．ＴＮＢＳ誘発内臓痛モデルの作製
ＴＮＢＳ誘発内臓痛モデルの作製には、１６−１８時間絶食させた動物を用いた。ソムノペンチル（５０ｍｇ／ｋｇ、腹腔内投与（i.p.））麻酔下で、術部を剪毛後、腹部正中を切開し、開復部から盲腸を体外に露出させた。回盲腸より約１ｃｍ肛門側の近位結腸にＴＮＢＳの３０％エタノール溶液を５０ｍｇ／ｋｇの用量で注入した。ＴＮＢＳ溶液が盲腸に逆流しないように注意し、消化管を腹腔内に戻し縫合した。
Ｓｈａｍ群については、ＴＮＢＳ溶液を投与しなかった以外は、上記と同様の処置を行った。
9. Preparation of TNBS-induced visceral pain model For the preparation of the TNBS-induced visceral pain model, animals fasted for 16-18 hours were used. Under anesthesia with somnopentyl (50 mg / kg, intraperitoneal administration (ip)), the surgical site was shaved, the midline of the abdomen was opened, and the cecum was exposed outside the body from the revival site. A 30% ethanol solution of TNBS was injected at a dose of 50 mg / kg into the proximal colon approximately 1 cm from the ileum. Care was taken so that the TNBS solution did not flow back into the cecum, and the digestive tract was returned into the abdominal cavity and sutured.
The Sham group was treated in the same manner as above except that the TNBS solution was not administered.
１０．内臓痛閾値（痛覚閾値）の測定
被験薬投与開始２１日目に動物を一晩絶食させた。内臓痛閾値の測定には１６−１８時間絶食させた動物を用い、測定（バルーン伸展刺激）の３時間前に被験薬の２２日目の投与を行った。測定は覚醒下で行い、５ｃｍのラテックスバルーン（オカモト社製）をポリエチレンチューブの端に付けたカニューレを肛門より、先端から１０ｃｍまで挿入した。挿入から３０分後、バロスタット（Ｇ＆Ｊ社製、Canada）装置を用い、３０秒に５ｍｍＨｇの割合で最大７０ｍｍＨｇまで伸展刺激を加えた。動物が痛み行動（alpha-position）を示したバルーン内圧を内臓痛閾値（痛覚閾値）とした。痛み行動（alpha-position）については、Neurosci Lett. 1988, 246: 73-76の記載に従って評価した。すなわち、図３ａ〜ｃに示すごとく、ラットが痛みを感じるとき、痛みを感じる側の尾の方に顔を向け、半円を描くような形になり、顔を向けた側の後肢を内捻する行動を示す。このような行動を示したときに、痛み行動を示すと判定した。
10. Measurement of Visceral Pain Threshold (Pain Perception Threshold) Animals were fasted overnight on the 21st day from the start of test drug administration. For measurement of the visceral pain threshold, animals fasted for 16 to 18 hours were used, and the test drug was administered on the 22nd day 3 hours before the measurement (balloon extension stimulation). The measurement was performed under awakening, and a cannula with a 5 cm latex balloon (Okamoto) attached to the end of the polyethylene tube was inserted from the anus up to 10 cm from the tip. Thirty minutes after the insertion, extension stimulation was applied to a maximum of 70 mmHg at a rate of 5 mmHg in 30 seconds using a barostat (G & J, Canada) apparatus. The balloon internal pressure at which the animal showed pain behavior (alpha-position) was defined as the visceral pain threshold (pain threshold). Pain behavior (alpha-position) was evaluated according to the description of Neurosci Lett. 1988, 246: 73-76. That is, as shown in FIGS. 3A to 3C, when the rat feels pain, the face is directed toward the tail on which the pain is felt, and a semicircle is formed. Show the action to take. When such behavior was exhibited, it was determined that pain behavior was exhibited.
１１．統計解析方法
データは平均値±標準誤差で示し、群間の有意差検定にはMann-WhitneyのＵ検定を用いた。統計処理は統計解析アドインソフト「エクセル統計２００８」（株式会社社会情報サービス社製）を用い、危険率（Ｐ値）が０．０５以下で有意差有りと判定した。
11. Statistical analysis method Data are shown as mean ± standard error, and Mann-Whitney U test was used for significant difference test between groups. For statistical processing, statistical analysis add-in software “Excel Statistics 2008” (manufactured by Social Information Service Co., Ltd.) was used, and it was determined that there was a significant difference when the risk rate (P value) was 0.05 or less.
結果を、表３及び図４に示す。図４に示すデータは、各群（それぞれｎ＝８）の平均値±標準誤差（ＳＥＭ）で表される。図４中、「＊」は、有意差があることを示す。 The results are shown in Table 3 and FIG. The data shown in FIG. 4 is represented by the average value ± standard error (SEM) of each group (each n = 8). In FIG. 4, “*” indicates that there is a significant difference.
Ｓｈａｍ群は、ＴＮＢＳによる内臓知覚過敏が誘発されていない対照群である。Ｓｈａｍ群では、内臓痛閾値は４４．４ｍｍＨｇであった。溶媒対照群（Ｖｅｈｉｃｌｅ）では、内臓痛閾値（痛覚閾値）は３３．８ｍｍＨｇであった。これに対して、乳酸菌Ａ、乳酸菌Ｂ、乳酸菌Ｃ及び乳酸菌Ｄをそれぞれ投与した群においては、いずれも溶媒対照群と比較して内臓痛閾値が高くなり、内臓痛が軽減されていた。中でも、乳酸菌Ｃ投与群及び乳酸菌Ｄ投与群では、内臓痛が効果的に軽減された。特に乳酸菌Ｃ（Streptococcus faecalis １２９ ＢＩＯ ３Ｂ）投与群では、内臓痛閾値（痛覚閾値）は４２．５ｍｍＨｇであり、溶媒対照群に対して内臓痛閾値が有意に高かった。
また、乳酸菌Ｃ投与群では、内臓知覚過敏が減少し、Ｓｈａｍ群の内臓痛閾値の約９６％まで内臓痛閾値が回復していた。この内臓痛閾値の改善は、例えば、Ohashi et al., J. Vet. Med. Sci. 69(12):1223-1228, 2007で報告されているドキサントラゾール、Ohashi et al., J. Vet. Med. Sci. 70(1):43-49, 2008で報告されているモルヒネ、及びKikuchi et al., J Pharmacol Sci 106, 219-224 (2008)で報告されているＰＦ−０３５５００９６の内臓痛閾値改善効果よりも高いと考えられた。
このことから、Streptococcus faecalis １２９ ＢＩＯ ３Ｂには、過敏性腸症候群における内臓痛等の機能性消化管障害における消化管痛を軽減させる優れた作用があることが分かった。
The Sham group is a control group in which visceral hypersensitivity induced by TNBS is not induced. In the Sham group, the visceral pain threshold was 44.4 mmHg. In the solvent control group (Vehicle), the visceral pain threshold (pain threshold) was 33.8 mmHg. On the other hand, in the group to which lactic acid bacteria A, lactic acid bacteria B, lactic acid bacteria C and lactic acid bacteria D were respectively administered, the visceral pain threshold value was higher and the visceral pain was alleviated as compared with the solvent control group. Among them, visceral pain was effectively reduced in the lactic acid bacteria C administration group and the lactic acid bacteria D administration group. In particular, in the lactic acid bacteria C (Streptococcus faecalis 129 BIO 3B) administration group, the visceral pain threshold (pain threshold) was 42.5 mmHg, and the visceral pain threshold was significantly higher than the solvent control group.
In the lactic acid bacteria C administration group, visceral hypersensitivity decreased, and the visceral pain threshold was recovered to about 96% of the visceral pain threshold of the Sham group. This improvement in visceral pain threshold is described, for example, by Doxantrazole, Ohashi et al., J. Vet reported in Ohashi et al., J. Vet. Med. Sci. 69 (12): 1223-1228, 2007. Med. Sci. 70 (1): 43-49, 2008 Morphine reported, and PF-03550096 visceral pain reported in Kikuchi et al., J Pharmacol Sci 106, 219-224 (2008) It was considered higher than the threshold improvement effect.
This indicates that Streptococcus faecalis 129 BIO 3B has an excellent effect of reducing gastrointestinal pain in functional gastrointestinal disorders such as visceral pain in irritable bowel syndrome.
＜実施例２＞
１．菌体の培養及び保存
Bifidobacterium bifidum Ｇ９−１（乳酸菌Ａ）、Lactobacillus acidophilus ＫＳ−１３（乳酸菌Ｂ）及びStreptococcus faecalis １２９ ＢＩＯ ３Ｂ（乳酸菌Ｃ）菌液の調製は以下のように行った。すなわち、乳酸菌Ａ、乳酸菌Ｂ及び乳酸菌Ｃの凍結保存菌株（いずれもビオフェルミン製薬社保存菌株）をそれぞれ３７℃で２４時間培養後、１％グルコース含ＧＡＭ培地１０ｍＬにこの培養液を培地１００に対して１の割合（容量比）で接種し、３７℃で２４時間培養した。培養後、１％グルコース含ＧＡＭ培地１０００ｍＬにこの培養液を培地１００に対して１の割合（容量比）で接種し、３７℃で１８時間培養した。得られた培養菌液１０００ｍＬを遠心分離（２６００×ｇ、１５分）し、菌体を回収した。回収した菌体は、Ca2+及びMg2+を含まないリン酸緩衝液生理食塩水（Dulbecco’s phosphate buffered saline Ca2+, Mg2+ free）（ＰＢＳ）で３回洗浄後、３０〜４０ｍＬのＰＢＳに再度懸濁し、７５０μＬずつマイクロチューブに分注し、遠心（２６００×ｇ、１５分）後、上清を取り除き培養菌体として−８０℃にて使用直前まで保存した。
<Example 2>
1. Cell culture and storage
Bifidobacterium bifidum G9-1 (lactic acid bacteria A), Lactobacillus acidophilus KS-13 (lactic acid bacteria B) and Streptococcus faecalis 129 BIO 3B (lactic acid bacteria C) bacterial solutions were prepared as follows. That is, cryopreserved strains of lactic acid bacteria A, lactic acid bacteria B, and lactic acid bacteria C (all of which were stored by Biofermin Pharmaceutical Co., Ltd.) were cultured at 37 ° C. for 24 hours, respectively, and this culture solution was added to 10 mL of 1% glucose-containing GAM medium. Inoculated at a ratio of 1 (volume ratio) and cultured at 37 ° C. for 24 hours. After the culture, 1000 mL of 1% glucose-containing GAM medium was inoculated with this culture solution at a ratio (volume ratio) of 1 to the medium 100 and cultured at 37 ° C. for 18 hours. 1000 mL of the obtained culture solution was centrifuged (2600 × g, 15 minutes), and the cells were collected. The collected cells were washed three times with Dulbecco's phosphate buffered saline Ca 2+ and Mg 2+ free (PBS) (PBS), and 30-40 mL of Ca 2+ and Mg 2+ were not contained. The suspension was resuspended in PBS, dispensed in 750 μL aliquots into microtubes, centrifuged (2600 × g, 15 minutes), the supernatant was removed, and the cells were stored as cultured cells at −80 ° C. until just before use.
上記それぞれの保存培養菌体にＰＢＳを７５０μＬ加え十分撹拌後、液中の生存菌数（生菌数）を測定したときの菌数は下記表４に示すとおりであった。生菌数の測定は、日本薬局方外医薬品規格 ビフィズス菌の項及びラクトミンの項に記載の方法に従って行った。 When 750 μL of PBS was added to each of the above stored cultured cells and sufficiently stirred, the number of bacteria when the number of viable cells (viable cells) in the liquid was measured was as shown in Table 4 below. The number of viable bacteria was measured according to the method described in the Japanese Pharmacopoeia Standards for Bifidobacteria and Lactamine.
２．被験薬の調製
乳酸菌Ａ、Ｂ及びＣそれぞれの菌液のチューブにＰＢＳを７５０μＬ加え十分撹拌して懸濁液を得た。ＰＢＳ １０２５２μＬ、乳酸菌Ａ懸濁液４６６μＬ、乳酸菌Ｂ懸濁液７４１μＬ及び乳酸菌Ｃ懸濁液５４１μＬを混ぜ、３種の乳酸菌を含む懸濁液を調製し、十分撹拌した。本調製液を被験薬とし、３７℃の水浴で３０分間加温した後、１回につき６００μＬ（各菌１０９ｃｆｕ、合計３×１０９ｃｆｕ）を動物に投与した。
2. Preparation of test drug 750 μL of PBS was added to each bacterial solution tube of lactic acid bacteria A, B, and C, and sufficiently stirred to obtain a suspension. A suspension containing 3 types of lactic acid bacteria was prepared by mixing 10252 μL of PBS, 466 μL of lactic acid bacteria A suspension, 741 μL of lactic acid bacteria B suspension and 541 μL of lactic acid bacteria C suspension, and sufficiently stirred. This preparation was used as a test drug, heated in a 37 ° C. water bath for 30 minutes, and then 600 μL (10 9 cfu of each bacterium, 3 × 10 9 cfu in total) was administered to the animal at a time.
３．使用動物
実験には、Ｃｒｌ：ＣＤ（ＳＤ）系雄性ラット（５週齢、日本チャールス・リバー株式会社：入荷時）を用いた。
実験に用いた動物は、飼育ケージ（４６０ｍｍ×２５０ｍｍ×Ｈ２００ｍｍ）で２〜３匹飼いとし、温度：２０〜２５℃、湿度：４０〜７０％、換気回数：１３回以上／時間、照明時間：１２時間（７：００〜１９：００）の環境に調節された動物飼育室で飼育し、餌は固型飼料ＣＲＦ−１（オリエンタル酵母株式会社）を自由摂取させた。飲水はフィルター濾過水を自由に摂取させた。
3. Animals used Crl: CD (SD) male rats (5-week-old, Charles River Japan, Inc .: upon arrival) were used in the experiments.
The animals used in the experiment are 2 to 3 animals in a breeding cage (460 mm × 250 mm × H200 mm), temperature: 20 to 25 ° C., humidity: 40 to 70%, ventilation frequency: 13 times / hour, lighting time: The animals were raised in an animal breeding room adjusted to an environment of 12 hours (7:00 to 19:00), and the solid feed CRF-1 (Oriental Yeast Co., Ltd.) was ingested freely. For drinking water, the filtered water was freely consumed.
４．使用薬物及び試薬
実施例１と同じものを使用した。
4). Drugs and Reagents Used The same ones as in Example 1 were used.
５．群構成
試験に供した動物の群構成は、表５に示す通りである。溶媒対照群とは、ＴＮＢＳ誘発内臓痛モデルにＰＢＳを経口投与した群である。被験薬投与群とは、ＴＮＢＳ誘発内臓痛モデルに、上記１．および２．で調製した被験薬を経口投与した群である。
5. Group composition The group composition of the animals subjected to the test is as shown in Table 5. The solvent control group is a group in which PBS was orally administered to a TNBS-induced visceral pain model. The test drug administration group refers to the TNBS-induced visceral pain model described above in 1. And 2. This is a group in which the test drug prepared in (1) was orally administered.
６．馴化
動物は導入後約１週間馴化し、実験に供した。
6). Acclimatization Animals were acclimatized for about one week after introduction and subjected to experiments.
７．被験薬の２２日間連続経口投与試験
馴化後、動物に被験薬又は溶媒（ＰＢＳ）を２２日間連続で経口投与した。被験薬群においては、被験薬投与開始１５日目に、実施例１と同様にしてＴＮＢＳを投与し、ＴＮＢＳ誘発内臓痛モデルを作製した。ＴＮＢＳ誘発内臓痛モデル作製日は、ＴＮＢＳ投与後、動物が覚醒してから被験薬を経口投与した。また、内臓痛閾値（痛覚閾値）測定日は、内臓痛閾値測定３時間前に被験薬を経口投与した。
溶媒対照群においては、被験薬の代わりに溶媒を投与した以外は、被験薬群と同様にしてＴＮＢＳ誘発内臓痛モデルを作製した。具体的には、溶媒投与開始１５日目にＴＮＢＳ誘発内臓痛モデルを作製した。ＴＮＢＳ誘発内臓痛モデル作製日は、ＴＮＢＳ投与後、動物が覚醒してから溶媒を経口投与した。また、内臓痛閾値測定日は、内臓痛閾値測定３時間前に溶媒を経口投与した。
試験のタイムテーブルを、図２に示す。図２においては、被験薬を投与する場合が例として示されているが、溶媒対照群においては、被験薬の代わりに溶媒を投与した。
7). 22-day continuous oral administration test of test drug After habituation, the test drug or solvent (PBS) was orally administered to animals for 22 consecutive days. In the test drug group, on the 15th day from the start of test drug administration, TNBS was administered in the same manner as in Example 1 to prepare a TNBS-induced visceral pain model. On the day of preparation of the TNBS-induced visceral pain model, the test drug was orally administered after the animal was awakened after TNBS administration. On the day of measurement of the visceral pain threshold (pain threshold), the test drug was orally administered 3 hours before the measurement of the visceral pain threshold.
In the solvent control group, a TNBS-induced visceral pain model was prepared in the same manner as in the test drug group except that a solvent was administered instead of the test drug. Specifically, a TNBS-induced visceral pain model was created on the 15th day after the start of solvent administration. On the day of preparation of the TNBS-induced visceral pain model, the solvent was orally administered after the animal was awakened after TNBS administration. On the day of measuring the visceral pain threshold, the solvent was orally administered 3 hours before the measurement of the visceral pain threshold.
The time table for the test is shown in FIG. In FIG. 2, a case where a test drug is administered is shown as an example, but in the solvent control group, a solvent was administered instead of the test drug.
８．ＴＮＢＳ溶液の調製
実施例１と同様にして、ＴＮＢＳ溶液を用時調製した。
8). Preparation of TNBS solution A TNBS solution was prepared in use in the same manner as in Example 1.
９．ＴＮＢＳ誘発内臓痛モデルの作製
ＴＮＢＳ誘発内臓痛モデルの作製は、実施例１と同様に行った。
9. Preparation of TNBS-induced visceral pain model A TNBS-induced visceral pain model was prepared in the same manner as in Example 1.
１０．内臓痛閾値（痛覚閾値）の測定
実施例１と同様の方法で、内臓痛閾値（痛覚閾値）を測定した。
10. Measurement of Visceral Pain Threshold (Pain Perception Threshold) By the same method as in Example 1, the visceral pain threshold (pain perception threshold) was measured.
１１．統計解析方法
実施例１と同様の方法で、統計処理を行った。
11. Statistical analysis method Statistical processing was performed in the same manner as in Example 1.
結果を、表６及び図５に示す。図５に示すデータは、各群（それぞれｎ＝８）の平均値±標準誤差（ＳＥＭ）で表される。図５中、「＊」は、有意差があることを示す。図５中、「Ｖｅｈｉｃｌｅ」は、溶媒対照群であり、「被験薬」は被験薬投与群である。 The results are shown in Table 6 and FIG. The data shown in FIG. 5 is expressed as an average value ± standard error (SEM) of each group (each n = 8). In FIG. 5, “*” indicates that there is a significant difference. In FIG. 5, “Vehicle” is a solvent control group, and “Test drug” is a test drug administration group.
溶媒対照群では、内臓痛閾値（痛覚閾値）は３０．０ｍｍＨｇであった。それに対して、被験薬投与群では、内臓痛閾値（痛覚閾値）の平均値が５０．６ｍｍＨｇであり、溶媒対照群と比較して有意に内臓痛閾値が高かった。この結果から、乳酸菌Ｃと共に乳酸菌Ａ及び乳酸菌Ｂを含む被験薬は、内臓知覚過敏を軽減し、過敏性腸症候群における内臓痛を効果的に軽減できることが分かった。 In the solvent control group, the visceral pain threshold (a pain threshold) was 30.0 mmHg. On the other hand, in the test drug administration group, the average value of the visceral pain threshold (pain sensation threshold) was 50.6 mmHg, which was significantly higher than that of the solvent control group. From these results, it was found that a test drug containing lactic acid bacteria A and B together with lactic acid bacteria C can reduce visceral hypersensitivity and can effectively reduce visceral pain in irritable bowel syndrome.
本発明は、消化管痛、特に過敏性腸症候群等の機能性消化管障害における内臓痛の予防又は軽減に有用である。 The present invention is useful for preventing or reducing gastrointestinal pain, particularly visceral pain in functional gastrointestinal disorders such as irritable bowel syndrome.
１、２ 圧縮気体が供給される気体流路
３、４ 被乾燥体を含む液体が供給される液体流路
５ 流体流動面
６ 衝突焦点
７ 噴霧液滴
DESCRIPTION OF SYMBOLS 1, 2 Gas flow path 3 to which compressed gas is supplied, 4 Liquid flow path to which the liquid containing a to-be-dried body is supplied 5 Fluid flow surface 6 Collision focus 7 Spray droplet
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