JP7057039B2 - Agents for preventing or ameliorating dementia and compositions containing them - Google Patents
Agents for preventing or ameliorating dementia and compositions containing them Download PDFInfo
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- JP7057039B2 JP7057039B2 JP2021562610A JP2021562610A JP7057039B2 JP 7057039 B2 JP7057039 B2 JP 7057039B2 JP 2021562610 A JP2021562610 A JP 2021562610A JP 2021562610 A JP2021562610 A JP 2021562610A JP 7057039 B2 JP7057039 B2 JP 7057039B2
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- dementia
- lactic acid
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- preventing
- ameliorating
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Description
本発明は、認知症を予防、治療又は改善するための剤及び組成物に関し、さらに具体的には、乳酸菌及び／又は乳酸菌由来成分を有効成分とする認知症の予防、治療又は改善用剤及びそれを含む組成物に関する。 The present invention relates to an agent and a composition for preventing, treating or ameliorating dementia, and more specifically, an agent for preventing, treating or ameliorating dementia containing lactic acid bacteria and / or a component derived from lactic acid bacteria as an active ingredient. With respect to the composition containing it.
認知症とは、物忘れや認知機能の低下が起こり、日常生活に支障をきたしている状態をいう。物忘れや認知機能の低下は、脳の神経細胞が障害を受けて死滅し、正常な神経細胞の数が減少していくことで起こる。認知症を発症すると、行動面・心理面の変化が生じる。 Dementia is a condition in which forgetfulness or deterioration of cognitive function occurs, which interferes with daily life. Forgetfulness and cognitive decline occur when nerve cells in the brain are damaged and die, and the number of normal nerve cells decreases. When dementia develops, behavioral and psychological changes occur.
認知症は、正常な脳神経細胞の数が減少する原因に応じて、大きく二つに分けられる。その一方は、脳の神経細胞の変性・脱落が変化することによって発症する変性性認知症である。変性性認知症には、アルツハイマー型認知症、レビー小体型認知症、認知症を伴うパーキンソン病、前頭側頭型認知症などが含まれる。他方は、なんらかの外傷や病気を原因として発症する二次性認知症である。二次性認知症には、脳血管性認知症、正常圧水頭症、慢性硬膜下血腫、脳腫瘍、自発性低血糖症などが含まれる。これらの中で、アルツハイマー型認知症、レビー小体型認知症及び脳血管性認知症が三大認知症であり、その合計は、認知症全体の八割前後を占めていると考えられている。 Dementia can be broadly divided into two types depending on the cause of the decrease in the number of normal brain nerve cells. One is degenerative dementia, which is caused by changes in the degeneration and shedding of nerve cells in the brain. Degenerative dementia includes Alzheimer's disease, Lewy body dementia, Parkinson's disease with dementia, frontotemporal dementia and the like. The other is secondary dementia, which develops due to some trauma or illness. Secondary dementia includes cerebrovascular dementia, normal pressure hydrocephalus, chronic subdural hematoma, brain tumors, spontaneous hypoglycemia and the like. Among these, Alzheimer-type dementia, Lewy body dementia and cerebrovascular dementia are the three major dementias, and the total is considered to account for about 80% of the total dementia.
認知症であるか否かの診断方法には、米国精神医学会による精神疾患の診断・統計マニュアル第５版（ＤＳＭ－５）をはじめとして、多種の方法が知られている。それらの診断方法の中で、アルツハイマー型認知症に関しては、米国アルツハイマー協会によって示された「１０の症状」の有無に基づく診断方法が、理解しやすく、国際的に用いられている。当該「１０の症状」を表１に示す。 Various methods are known for diagnosing whether or not dementia, including the American Psychiatric Association's 5th Edition (DSM-5) of the Diagnosis and Statistics Manual for Mental Diseases. Among these diagnostic methods, for Alzheimer-type dementia, the diagnostic method based on the presence or absence of "10 symptoms" indicated by the American Alzheimer's Association is easy to understand and is used internationally. The "10 symptoms" are shown in Table 1.
ところで、我が国においては、認知症、特にアルツハイマー型認知症の治療薬として、従来は、コリンエステラーゼ阻害剤のみが認可されていた。その作用機序は、アルツハイマー型認知症の脳内ではアセチルコリンの分泌不足からアセチルコリンの減少が生じていることに鑑み、コリンエステラーゼ阻害剤によって、脳内アセチルコリンの分解を阻害するというものであった（非特許文献１）。 By the way, in Japan, only cholinesterase inhibitors have been previously approved as therapeutic agents for dementia, especially Alzheimer's disease. The mechanism of action was to inhibit the degradation of acetylcholine in the brain by cholinesterase inhibitors in view of the decrease in acetylcholine caused by insufficient secretion of acetylcholine in the brain of Alzheimer's disease (non-). Patent Document 1).
その後、中等度及び高度のアルツハイマー型認知症の進行を抑制する薬剤として、Ｎ－メチル－Ｄ－アスパラギン酸（N-methyl-D-aspartate；ＮＭＤＡ）受容体に対する拮抗剤が認可された（非特許文献１）。その作用機序は次のとおりである。アルツハイマー型認知症では、グルタミン酸受容体のサブタイプであるＮＭＤＡ受容体が過剰に活性化しており、その活性化によってシナプティックノイズが増大しているため、伝達シグナルがノイズに隠れ、情報が伝わりにくくなっていると考えられている。よって、ＮＭＤＡ受容体に対する拮抗剤により、ＮＭＤＡ受容体の活性を低下させるのである。 Subsequently, an antagonist against the N-methyl-D-aspartate (NMDA) receptor was approved as a drug that suppresses the progression of moderate to severe Alzheimer's disease (non-patented). Document 1). Its mechanism of action is as follows. In Alzheimer's disease, the NMDA receptor, which is a subtype of glutamate receptor, is excessively activated, and the activation increases synaptic noise, so that the transmission signal is hidden by the noise and information is difficult to transmit. It is believed that it has become. Therefore, antagonists to the NMDA receptor reduce the activity of the NMDA receptor.
しかし、これまでに我が国で認可されている上記の薬剤によって、認知症からの回復や進行の停止が十分になされているとはいえない。また、上記薬剤には、肝機能障害、悪心や下痢などの消化器系障害、めまい、不整脈などの副作用が生じることがある。したがって、より有効で且つ副作用の少ない、認知症の予防、治療又は改善用剤が望まれている。 However, it cannot be said that the above-mentioned drugs approved in Japan have sufficiently recovered from dementia and stopped its progression. In addition, the above-mentioned drugs may cause side effects such as liver dysfunction, digestive system disorders such as nausea and diarrhea, dizziness, and arrhythmia. Therefore, there is a demand for a preventive, therapeutic or ameliorating agent for dementia, which is more effective and has few side effects.
近年、健康の維持及び改善において機能性乳酸菌が注目されており、多数の菌株が単離され、それらの有用性が検討されている。ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティス ＫＬＡＢ－４株（Lactobacillus delbrueckii subsp. lactis KLAB-4）は、発酵乳から分離された菌株であり、ラクトバチルス属デルブリッキー種亜種ラクティスに属する新規な乳酸菌として、独立行政法人製品評価技術基盤機構（日本国千葉県木更津市かずさ鎌足２－５－８）に寄託されている（受託番号ＮＩＴＥ ＢＰ－３９４；原寄託日２００７年８月９日の国内寄託株をブダペスト条約に基づく国際寄託へ移管（２００８年９月２２日））。この乳酸菌は、優れた抗アレルギー機能を有し、さらに抗自己免疫疾患機能、糖尿病改善機能及び低血糖改善機能を有することが知られている（特許文献１及び３、非特許文献２）。
In recent years, functional lactic acid bacteria have been attracting attention in the maintenance and improvement of health, and a large number of strains have been isolated and their usefulness is being investigated. Lactobacillus delbrueckii subsp. Lactis KLAB-4 is a strain isolated from fermented milk and is a novel lactic acid bacterium belonging to the Lactobacillus delbrueckii subspecies lactis. Deposited with the National Institute of Technology and Evaluation (2-5-8 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan) (trust number NITE BP-394; original deposit date August 9, 2007 domestic deposit stock Was transferred to an international deposit based on the Budapest Convention (September 22, 2008). It is known that this lactic acid bacterium has an excellent anti-allergic function, and further has an anti-autoimmune disease function, a diabetes improving function and a hypoglycemia improving function (
また、特許文献２には、キムチから分離された乳酸菌である、ラクトバチルス・ペントーサス変種プランタルムＣ２９及びラクトバチルス・カルバタスＣ３が、老化及び認知症の予防及び／又は治療活性を有することが記載されている。
Further,
本発明は、安全性及び有効性が高く、副作用が少なく、長期連用の可能な認知症の予防又は改善用剤を提供することを目的とする。 An object of the present invention is to provide an agent for preventing or ameliorating dementia, which is highly safe and effective, has few side effects, and can be used continuously for a long period of time.
本発明者は、上記課題を解決すべく鋭意研究した結果、特定の乳酸菌が、優れた認知症の予防又は改善作用を示すことを見出し、本発明を完成した。 As a result of diligent research to solve the above problems, the present inventor has found that a specific lactic acid bacterium exhibits an excellent preventive or ameliorating effect on dementia, and completed the present invention.
本発明によれば、
〔１〕 乳酸菌ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティス又はその乳酸菌由来成分を有効成分とする認知症の予防又は改善用剤；
〔２〕 前記乳酸菌が、ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティスＫＬＡＢ－４株（ＮＩＴＥ ＢＰ－３９４）及びその変異体からなる群から選択される乳酸菌を含む、前記〔１〕記載の認知症の予防又は改善用剤；
〔３〕 水溶性食物繊維成分をさらに含有する、又は水溶性食物繊維成分と併用される、前記〔１〕又は〔２〕記載の認知症の予防又は改善用剤；
〔４〕 前記水溶性食物繊維成分が、グルコマンナン、ペクチン、グアーガム、アルギン酸、ポリデキストロース、βグルカン、フルクタン、イヌリン、レバン、グラミナン、アラビアガム、マルチトール、サイリウム、難消化性オリゴ糖、難消化性デキストリン、アガロース、アルギン酸ナトリウム、カラギーナン、フコイダン、ポルフィラン、ラミナラン、海藻、及び寒天からなる群から選択される、前記〔３〕記載の認知症の予防又は改善用剤；
〔５〕 前記水溶性食物繊維成分が、グルコマンナンである、前記〔４〕記載の認知症の予防又は改善用剤；
〔６〕 前記〔１〕～〔５〕のいずれか１項記載の認知症の予防又は改善用剤を含む、組成物；
〔７〕 前記〔１〕～〔５〕のいずれか１項記載の認知症の予防又は改善用剤を含む、医薬品組成物；
〔８〕 前記〔１〕～〔５〕のいずれか１項記載の認知症の予防又は改善用剤を含む、飲食品組成物；
〔９〕 前記〔１〕～〔５〕のいずれか１項記載の認知症の予防又は改善用剤を含む、動物用飼料又は動物用医薬品組成物；及び
〔１０〕 前記〔１〕～〔５〕のいずれか１項記載の認知症の予防又は改善用剤、あるいは前記〔６〕～〔９〕のいずれか１項記載の組成物を、対象に投与することを含む、認知症の予防又は改善方法；
が提供される。According to the present invention
[1] A preventive or ameliorating agent for dementia containing the lactic acid bacterium Lactobacillus delbricky subspecies lactis or a component derived from the lactic acid bacterium as an active ingredient;
[2] The dementia according to the above [1], wherein the lactic acid bacterium contains a lactic acid bacterium selected from the group consisting of Lactobacillus delbricky Subspecies Lactis KLAB-4 strain (NITE BP-394) and a mutant thereof. Preventive or ameliorating agent;
[3] The agent for preventing or ameliorating dementia according to the above [1] or [2], which further contains a water-soluble dietary fiber component or is used in combination with the water-soluble dietary fiber component;
[4] The water-soluble dietary fiber component is glucomannan, pectin, guar gum, alginic acid, polydextrose, β-glucan, fructan, inulin, levan, graminan, arabic gum, martitol, psyllium, indigestible oligosaccharide, and indigestible. The agent for preventing or ameliorating dementia according to the above [3], which is selected from the group consisting of sex dextrin, agarose, sodium alginate, carrageenan, fucoidan, porphyran, laminarin, seaweed, and agar;
[5] The agent for preventing or ameliorating dementia according to the above [4], wherein the water-soluble dietary fiber component is glucomannan.
[6] A composition comprising the agent for preventing or ameliorating dementia according to any one of the above [1] to [5];
[7] A pharmaceutical composition containing the agent for preventing or ameliorating dementia according to any one of the above [1] to [5];
[8] A food or drink composition containing the agent for preventing or ameliorating dementia according to any one of the above [1] to [5];
[9] An animal feed or an animal pharmaceutical composition containing the agent for preventing or ameliorating dementia according to any one of the above [1] to [5]; and [10] the above [1] to [5]. ], The prevention or amelioration of dementia according to any one of the above, or the composition according to any one of [6] to [9] above, which comprises administering to the subject. How to improve;
Is provided.
認知症は、変性性認知症、特にアルツハイマー型認知症であることができる。認知症の予防又は改善用剤は、認知症の改善剤であることができる。 Dementia can be degenerative dementia, especially Alzheimer's disease. The dementia preventive or ameliorating agent can be a dementia ameliorating agent.
本発明の認知症の予防又は改善用剤及びそれを含む組成物は、認知症を有効に改善することができる。本発明の、認知症の改善用剤及びそれを含む組成物は、安全性が高い乳酸菌又はその乳酸菌由来成分を有効成分とするため、長期的に投与又は摂取しても、副作用の心配がなく安全性が高い。また、水溶性食物繊維成分、例えばグルコマンナンもまた、人間にとって長年の食経験がある有益成分であり、安全性が高い。したがって、本発明の認知症の改善用剤及びそれを含む組成物は、予防的に使用することも可能であり、治療に使用することも可能である。 The agent for preventing or improving dementia of the present invention and the composition containing the same can effectively improve dementia. Since the agent for improving dementia and the composition containing it of the present invention contain highly safe lactic acid bacteria or a component derived from the lactic acid bacteria as an active ingredient, there is no concern about side effects even if they are administered or ingested for a long period of time. Highly safe. In addition, a water-soluble dietary fiber component such as glucomannan is also a beneficial component having many years of eating experience for humans and is highly safe. Therefore, the agent for improving dementia of the present invention and the composition containing the same can be used prophylactically or therapeutically.
本発明の認知症の予防又は改善用剤は、乳酸菌ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティス又はその乳酸菌由来成分を有効成分とする。したがって、本発明の剤は、乳酸菌ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティス又はその乳酸菌由来成分のみからなることができ、他の有効成分を含むこともできる。 The agent for preventing or ameliorating dementia of the present invention contains the lactic acid bacterium Lactobacillus delbricky Subspecies Lactis or a component derived from the lactic acid bacterium as an active ingredient. Therefore, the agent of the present invention can consist only of the lactic acid bacterium Lactobacillus delbricky subspecies lactis or a component derived from the lactic acid bacterium, and can also contain other active ingredients.
＜乳酸菌＞
本発明において使用される乳酸菌ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティスは、発酵乳又はチーズなどの発酵食品などから単離することができ、あるいは、単離された菌株を入手して使用することもできる。本発明において使用される乳酸菌としては、ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティス ＫＬＡＢ－４株（Lactobacillus delbrueckii subsp. lactis KLAB-4、以下「ＫＬＡＢ－４株」ともいう）及びその変異体からなる群から選択される乳酸菌を含むことが望ましい。<Lactic acid bacteria>
The lactic acid bacterium Lactobacillus delbricky subspecies lactis used in the present invention can be isolated from fermented milk or fermented foods such as cheese, or the isolated strain can be obtained and used. can. The lactic acid bacterium used in the present invention includes a group consisting of Lactobacillus delbrueckii subsp. Lactis KLAB-4 (hereinafter also referred to as "KLAB-4 strain") and its variants. It is desirable to contain lactic acid bacteria selected from.
ＫＬＡＢ－４株は、特許文献１（特許第５５５４９９４号公報）に詳細に記載されている菌株である。この菌株は、その１６ｓ ｒＲＮＡ遺伝子の５'末端の塩基より５４４番目の塩基までの配列が、ラクトバチルス属デルブリッキー種亜種ラクティス標準株と９０％以上の相同性を有することが確認されたため、ラクトバチルス属デルブリッキー種亜種ラクティスと同定された。 The KLAB-4 strain is a strain described in detail in Patent Document 1 (Patent No. 5554994). This strain was confirmed to have 90% or more homology with the lactobacillus delbricky subspecies lactis standard strain in the sequence from the 5'end base to the 544th base of the 16s rRNA gene. It was identified as Lactis, a subspecies of the genus Delbricky.
本発明における使用に関して好ましい乳酸菌は、ＫＬＡＢ－４株だけでなく、その変異体であってもよい。このような変異体は、特に限定されず、自然突然変異によるもの、放射線や突然変異誘導物質への曝露などの公知の方法で人為的に突然変異を誘導させて得られたものなどであることができる。変異体は、ＫＬＡＢ－４乳酸菌と比較して同等の特性（特に、認知症の予防又は改善作用）を有するものであれば、本発明において使用することができる。 The preferred lactic acid bacterium for use in the present invention may be not only the KLAB-4 strain but also a mutant thereof. Such mutants are not particularly limited, and are those obtained by spontaneous mutation, those obtained by artificially inducing a mutation by a known method such as exposure to radiation or a mutation-inducing substance, and the like. Can be done. The mutant can be used in the present invention as long as it has the same characteristics as that of KLAB-4 lactic acid bacterium (particularly, it has a preventive or ameliorating effect on dementia).
乳酸菌ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティス、例えばＫＬＡＢ－４株又はその変異体は、公知の一般的な培地及び方法により培養することができる。これらの乳酸菌は、これらの菌が生育可能な培地、例えば、ＭＲＳ培地を用い、一般的な培養条件下で、通常使用される発酵ジャー、試験管、ボトル、フラスコ等の容器で通常の乳酸菌培養を行うことにより、培養することができる。 Lactobacillus lactobacillus delbricky subspecies lactis, such as the KLAB-4 strain or variants thereof, can be cultivated using known media and methods. These lactic acid bacteria are cultured in a medium such as MRS medium in which these bacteria can grow, and under general culture conditions, in a container such as a fermentation jar, a test tube, a bottle, or a flask, which is usually used. Can be cultivated by performing the above.
本発明において使用される乳酸菌は、生菌であってもよく、死菌であってもよい。生菌とは、生きている菌体を指し、死菌とは、加熱、加圧、薬物などによる処理で殺菌された菌体を指す。 The lactic acid bacterium used in the present invention may be a live bacterium or a dead bacterium. Live bacteria refer to live cells, and dead bacteria refer to cells that have been sterilized by heating, pressurization, treatment with drugs, or the like.
さらに、乳酸菌から得られる乳酸菌由来成分も、同等の機能を有する限り、菌体と同様に本発明において使用することができる。乳酸菌由来成分とは、菌体の部分又は成分、あるいはそれらのいずれかを含むものをいい、例えば、乳酸菌に磨砕、破砕、抽出、分画、乾燥、加熱、凍結、冷却、濃縮、希釈などの処理の少なくとも一つを施して得られる菌体処理物などをいう。乳酸菌由来成分は、液体、ペースト、粉末、顆粒など、いずれの形態であってもよい。菌体から何らかの成分を抽出した後の残渣を使用してもよく、例えば、熱水抽出後の残渣を使用してもよい。 Furthermore, the lactic acid bacterium-derived component obtained from the lactic acid bacterium can also be used in the present invention in the same manner as the bacterial cell as long as it has the same function. The lactic acid bacterium-derived component means a part or component of a lactic acid bacterium, or a component containing any of them, for example, grinding, crushing, extraction, fractionation, drying, heating, freezing, cooling, concentration, dilution, etc. of lactic acid bacterium. Refers to a cell-treated product obtained by performing at least one of the above treatments. The lactic acid bacterium-derived component may be in any form such as liquid, paste, powder, and granules. The residue after extracting some component from the cells may be used, and for example, the residue after hot water extraction may be used.
ＫＬＡＢ－４株乳酸菌粉末は、商品名「乳酸菌ＬＡＢ４」（株式会社カネカ製）として市販されているので、これを使用してもよい。 Since the KLAB-4 strain lactic acid bacterium powder is commercially available under the trade name "lactic acid bacterium LAB4" (manufactured by Kaneka Corporation), this may be used.
＜水溶性食物繊維成分＞
本発明の認知症の予防又は改善用剤には、上記のとおりの乳酸菌又は乳酸菌由来成分に加えて、水溶性食物繊維成分を含ませることができる。このような成分をさらに含むことにより、本発明の剤の効果が増強されることが見出された。<Water-soluble dietary fiber component>
The agent for preventing or ameliorating dementia of the present invention may contain a water-soluble dietary fiber component in addition to the lactic acid bacterium or a component derived from the lactic acid bacterium as described above. It has been found that the effect of the agent of the present invention is enhanced by further containing such a component.
水溶性食物繊維成分とは、水溶性食物繊維、又はそれを含む食品／医薬品もしくは食品／医薬品素材をいう。水溶性食物繊維成分の具体例としては、例えば、グルコマンナン、ペクチン、グアーガム、アルギン酸、ポリデキストロース、βグルカン、フルクタン、イヌリン、レバン、グラミナン、アラビアガム、マルチトール、サイリウム、難消化性オリゴ糖、難消化性デキストリン、アガロース、アルギン酸ナトリウム、カラギーナン、フコイダン、ポルフィラン、ラミナラン、ならびに海藻及び寒天などの、天然又は合成の水溶性食物繊維又は水溶性食物繊維含有材料が挙げられる。 The water-soluble dietary fiber component refers to a water-soluble dietary fiber or a food / pharmaceutical product or a food / pharmaceutical material containing the same. Specific examples of the water-soluble dietary fiber component include glucomannan, pectin, guar gum, alginic acid, polydextrose, β-glucan, fructan, inulin, levan, graminan, arabic gum, martitol, psyllium, and indigestible oligosaccharides. Examples include natural or synthetic water-soluble or synthetic fiber-containing materials such as refractory dextrin, agarose, sodium alginate, carrageenan, fucoidan, porphyran, laminaran, and seaweed and agar.
水溶性食物繊維成分は、本発明の剤に含有させておいてもよく、投与又は摂取時に乳酸菌又は乳酸菌由来成分と一緒にしてもよい。あるいは、それぞれを含有する別々の調製物として投与又は摂取することもでき、その場合、両方を同時に、又は時間的に前後して投与又は摂取してもよい。言い換えれば、本発明の剤又は組成物は、乳酸菌又は乳酸菌由来成分と、水溶性食物繊維成分とを同一の組成物中に含む場合だけでなく、別々の剤又は組成物として、同時又は前後して投与又は摂取してもよい。例えば、カプセルに封入された形態の本発明の剤を、水溶性食物繊維成分を含む飲料で服用させることができる。 The water-soluble dietary fiber component may be contained in the agent of the present invention, or may be combined with lactic acid bacteria or a component derived from lactic acid bacteria at the time of administration or ingestion. Alternatively, they can be administered or ingested as separate preparations containing each, in which case both may be administered or ingested simultaneously or at back and forth in time. In other words, the agent or composition of the present invention is not only when the lactic acid bacterium or the component derived from the lactic acid bacterium and the water-soluble dietary fiber component are contained in the same composition, but also as separate agents or compositions at the same time or before and after. May be administered or ingested. For example, the agent of the present invention in the form of being encapsulated can be taken in a beverage containing a water-soluble dietary fiber component.
本発明の剤に水溶性食物繊維成分を含有させる場合又は本発明の剤と水溶性食物繊維成分とを併用する場合、その割合（重量比）は、特に限定されないが、例えば乳酸菌又は乳酸菌由来成分１部に対し、水溶性食物繊維成分０．１～２部程度が好ましい。 When the agent of the present invention contains a water-soluble dietary fiber component or when the agent of the present invention is used in combination with a water-soluble dietary fiber component, the ratio (weight ratio) is not particularly limited, but for example, lactic acid bacteria or a component derived from lactic acid bacteria. About 0.1 to 2 parts of the water-soluble dietary fiber component is preferable with respect to 1 part.
水溶性食物繊維成分によって乳酸菌の効果が増強される作用機序は不明であり、本発明は、特定の作用機序に拘束されるものではない。例えば、グルコマンナンは、親水性が高く、グルコマンナンの重量に対して約１００倍の重量の水を吸収することができるため、グルコマンナンは胃内で吸水することにより約１００倍に体積が増加して、胃粘膜に薄い膜が張られた状態となると考えられる。したがって、一つの可能性として、水溶性食物繊維成分が存在することにより乳酸菌の吸収を調節することができると考えられる。 The mechanism of action in which the effect of lactic acid bacteria is enhanced by the water-soluble dietary fiber component is unknown, and the present invention is not bound by a specific mechanism of action. For example, glucomannan is highly hydrophilic and can absorb about 100 times as much water as the weight of glucomannan, so that the volume of glucomannan increases about 100 times by absorbing water in the stomach. Then, it is considered that a thin film is put on the gastric mucosa. Therefore, one possibility is that the presence of a water-soluble dietary fiber component can regulate the absorption of lactic acid bacteria.
＜その他の成分＞
本発明の認知症の予防又は改善用剤は、上記のとおりの乳酸菌又は乳酸菌由来成分を唯一の必須成分とするが、水溶性食物繊維成分のような他の有効成分を含有又は併用することができる。本発明の認知症の予防又は改善用剤を含む組成物は、本発明の剤に加えて、一以上の他の成分を含む。<Other ingredients>
The agent for preventing or improving dementia of the present invention contains lactic acid bacteria or a component derived from lactic acid bacteria as described above as the only essential component, but may contain or use other active ingredients such as a water-soluble dietary fiber component. can. The composition containing the agent for preventing or ameliorating dementia of the present invention contains one or more other components in addition to the agent of the present invention.
本発明の組成物は、医薬品組成物、飲食品組成物、動物用飼料組成物又は動物用医薬品組成物などであることができ、それらの具体的な形態は、特に限定されない。例えば、本発明の組成物を医薬品として用いる場合は、その形態又は剤型として、カプセル剤、錠剤、丸剤、散剤、顆粒剤、ドリンク剤、シロップ剤、注射剤、輸液、点鼻剤、点眼剤、座薬、貼付剤、噴霧剤などが挙げられる。本発明の組成物を飲食品組成物として用いる場合は、各種の食品原材料又は成分と共に一般食品の形態にしてもよく、また、カプセル剤又は錠剤などの形態のサプリメントなどの機能性食品とすることもできる。 The composition of the present invention may be a pharmaceutical composition, a food or drink composition, an animal feed composition, an animal pharmaceutical composition, or the like, and the specific form thereof is not particularly limited. For example, when the composition of the present invention is used as a pharmaceutical product, it may be in the form or dosage form of capsules, tablets, pills, powders, granules, drinks, syrups, injections, infusions, nasal drops, eye drops. Examples include agents, suppositories, patches, sprays and the like. When the composition of the present invention is used as a food or drink composition, it may be in the form of a general food together with various food raw materials or ingredients, or it may be a functional food such as a supplement in the form of a capsule or a tablet. You can also.
本発明の組成物に含まれる任意の成分は、組成物の性質、形態、製造方法などに応じて適宜選択することができ、製薬、食品、化粧品などの業界で公知の種々の成分や添加剤であることができる。本発明の組成物が含んでいてもよい添加剤としては、薬剤学的に許容される、又は製薬、食品、化粧品などの業界で日常的に使用されている、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、流動性促進剤、着色剤、溶剤、増粘剤、分散剤、ｐＨ調整剤、保湿剤、安定化剤、保存料、香料などを挙げることができる。 Any component contained in the composition of the present invention can be appropriately selected depending on the properties, form, production method, etc. of the composition, and various components and additives known in the industry such as pharmaceuticals, foods, and cosmetics. Can be. Additives that may be included in the compositions of the invention include excipients, disintegrants, and lubricants that are pharmaceutically acceptable or routinely used in the pharmaceutical, food, cosmetic and other industries. Examples include swamps, binders, surfactants, fluidity promoters, colorants, solvents, thickeners, dispersants, pH regulators, moisturizers, stabilizers, preservatives, fragrances and the like.
これらの添加剤は、所望の剤型などに応じて、適宜選択される。例えば、本発明の医薬品組成物又は飲食品組成物などの組成物が、粉末剤、顆粒剤、錠剤、カプセル剤などの形態である場合には、用いる賦形剤としては、乳糖、蔗糖、グルコース、ソルビトール、ラクチトールなどの単糖又は二糖類、コーンスターチ、ポテトスターチのような澱粉類、結晶セルロース、無機物としては軽質シリカゲル、合成珪酸アルミニウム、メタ珪酸アルミン酸マグネシウム、リン酸水素カルシウム、二酸化ケイ素などがある。また、必要に応じ、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、酸化防止剤、凝集防止剤、吸収促進剤、溶解補助剤、安定化剤、防腐剤、防湿剤、着色料、香料などを適宜使用することができる。 These additives are appropriately selected according to the desired dosage form and the like. For example, when the composition such as the pharmaceutical composition or the food or drink composition of the present invention is in the form of powder, granule, tablet, capsule or the like, the excipient to be used is lactose, starch or glucose. , Monosaccharides or disaccharides such as sorbitol and lactose, starches such as corn starch and potato starch, crystalline cellulose, light silica gel as inorganic substances, synthetic aluminum silicate, magnesium aluminometasilicate, calcium hydrogen phosphate, silicon dioxide and the like. be. In addition, if necessary, binders, disintegrants, surfactants, lubricants, fluidity promoters, antioxidants, antiaggregating agents, absorption promoters, lysis aids, stabilizers, preservatives, moisture proofing agents. , Colorants, fragrances and the like can be used as appropriate.
結合剤としては、例えば、澱粉、デキストリン、アラビアガム末、ゼラチン、ヒドロキシプロピルスターチ、カルボキシメチルセルロース・ナトリウム塩、メチルセルロース、結晶性セルロース、エチルセルロース、ポリビニルピロリドンが挙げられる。 Examples of the binder include starch, dextrin, arabic gum powder, gelatin, hydroxypropyl starch, carboxymethyl cellulose sodium salt, methyl cellulose, crystalline cellulose, ethyl cellulose and polyvinylpyrrolidone.
崩壊剤としては、澱粉類、カルボキシメチルセルロース（ＣＭＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、カルボキシメチルセルロース・ナトリウム塩、ポリビニルピロリドンなどがある。 Examples of the disintegrant include starches, carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose sodium salt, polyvinylpyrrolidone and the like.
界面活性剤としては、大豆レシチン、蔗糖脂肪酸エステルなどが、滑沢剤としては、タルク、ロウ、蔗糖脂肪酸エステル、水素添加植物油、ステアリン酸カルシウム、ステアリン酸マグネシウムなどが、流動性促進剤としては、無水ケイ酸、乾燥水酸化アルミニウム、ケイ酸マグネシウムなどが、それぞれ挙げられる。 Soy lecithin, citrus fatty acid ester and the like are used as surface active agents, talc, wax, citrus fatty acid ester, hydrogenated vegetable oil, calcium stearate, magnesium stearate and the like are used as lubricants, and anhydrous as a fluidity promoter. Examples thereof include stearic acid, dry aluminum hydroxide, magnesium silicate and the like.
本発明の組成物を動物用飼料又は動物用医薬品組成物として用いる場合も、上記と同様であり、各種飼料原材料又は薬剤学的に許容される成分を使用して、飼料、サプリメント、医薬などの所望の形態又は剤型にすることができる。 The same applies to the case where the composition of the present invention is used as a feed for animals or a pharmaceutical composition for animals, and various feed raw materials or pharmaceutically acceptable ingredients are used to prepare feeds, supplements, pharmaceuticals and the like. It can be in the desired form or dosage form.
本発明の剤又は組成物は、単独で投与又は使用してもよく、他の薬剤と併用してもよい。また、本発明の剤又は組成物を他の薬剤と併用する場合は、両者を同時に用いてもよく、前後して用いてもよい。 The agent or composition of the present invention may be administered or used alone or in combination with other agents. When the agent or composition of the present invention is used in combination with another agent, both may be used at the same time, or both may be used before and after.
本発明の認知症の予防又は改善用剤、あるいは組成物の投与（又は摂取もしくは適用）経路は、例えば、経口、経皮、経腸、直腸内経路などから適宜選択することができる。認知症の予防又は改善に有効な本発明の剤又は組成物の１日当たりの投与（又は摂取もしくは適用）量は、その製剤形態、投与などの方法や経路、対象者の年齢及び体重、疾患の重症度などによって異なるが、たとえば経口経路の場合、ヒトでは、一般的には、有効成分の乳酸菌又は乳酸菌由来成分量として約０．１ｍｇ～約１０００ｍｇ／ｋｇ体重／日、好ましくは約１ｍｇ～約５００ｍｇ／ｋｇ体重／日、最も好ましくは約２ｍｇ～約３００ｍｇ／ｋｇ体重／日を、一度に又は分割して、投与又は摂取することができる。投与又は摂取のタイミングは、特に限定されず、例えば、食事と同時、食直後、食直前、睡眠前などであることができる。 The administration (or ingestion or application) route of the agent for preventing or ameliorating dementia of the present invention or the composition can be appropriately selected from, for example, oral, transdermal, enteral, rectal routes and the like. The daily dose (or ingestion or application) of the agent or composition of the present invention effective for the prevention or amelioration of dementia is the form of the pharmaceutical product, the method and route of administration, the age and body weight of the subject, and the disease. Although it varies depending on the severity and the like, for example, in the case of the oral route, in humans, the amount of the active ingredient lactic acid bacterium or the lactic acid bacterium-derived component is generally about 0.1 mg to about 1000 mg / kg body weight / day, preferably about 1 mg to about. 500 mg / kg body weight / day, most preferably about 2 mg to about 300 mg / kg body weight / day, can be administered or ingested at once or in divided portions. The timing of administration or ingestion is not particularly limited, and may be, for example, at the same time as a meal, immediately after a meal, immediately before a meal, before sleep, or the like.
本発明の剤又は組成物は、非常に安全性が高いので、患者だけでなく健常者に与えることもできる。また、本発明の剤又は組成物は、対象、具体的にはヒト及びヒト以外の動物、好ましくは哺乳類に同様に投与（又は摂取もしくは適用）することができる。ヒト以外の動物の例としては、ウシ、ウマ、ブタ、ヒツジなどの家畜、及びイヌ、ネコなどのコンパニオン動物が挙げられる。投与量については上記と同様の量を基準として、動物の特性に応じて調整することができる。例えば、小動物の場合、乳酸菌又は乳酸菌由来成分量として、約０．０１～約１０００ｍｇ／ｋｇ体重／日、より好ましくは約０．１～約３０ｍｇ／ｋｇ体重／日に相当する投与又は摂取量になるよう調整して与えることができる。 Since the agent or composition of the present invention is extremely safe, it can be given not only to patients but also to healthy subjects. In addition, the agent or composition of the present invention can be similarly administered (or ingested or applied) to a subject, specifically a human or a non-human animal, preferably a mammal. Examples of animals other than humans include domestic animals such as cows, horses, pigs and sheep, and companion animals such as dogs and cats. The dose can be adjusted according to the characteristics of the animal based on the same amount as above. For example, in the case of small animals, the amount of lactic acid bacteria or components derived from lactic acid bacteria is about 0.01 to about 1000 mg / kg body weight / day, more preferably about 0.1 to about 30 mg / kg body weight / day. It can be adjusted and given.
本発明の剤又は組成物により、認知症が改善されたか否かは、投与又は摂取の前と後、又は投与又は摂取中もしくは後などの異なる時点において、前の時点と比較して後の時点において症状が変化したか否かを調べることにより、評価することができる。例えば、投与開始前と、一定期間（例えば、６ヶ月）の投与後に、米国アルツハイマー協会によって示された「１０の症状」の有無によって認知症の程度を診断することにより、評価することができる。 Whether or not the agent or composition of the present invention has improved dementia is determined at different time points, such as before and after administration or ingestion, or during or after administration or ingestion, at a later time point as compared with the previous time point. It can be evaluated by examining whether or not the symptom has changed in. For example, it can be evaluated by diagnosing the degree of dementia by the presence or absence of "10 symptoms" indicated by the American Alzheimer's Association before the start of administration and after administration for a certain period (for example, 6 months).
以下に例を示し、本発明をより具体的に説明するが、本発明はこれらの実施例に何ら限定されるものではない。 The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
１．カプセル剤の製造
乳酸菌ラクトバチルス・デルブリッキー・サブスピーシーズ・ラクティスとして、ＫＬＡＢ－４乳酸菌粉末（商品名「乳酸菌ＬＡＢ４」（株式会社カネカ製））を、水溶性食物繊維成分としてグルコマンナン（商品名「レオレックスＲＳ」（清水化学株式会社製））を使用し、以下の３種のカプセル剤を製造した。 1. 1. Manufacture of capsules Lactobacillus lactobacillus delbricky subspecies lactis, KLAB-4 lactic acid bacterium powder (trade name "Lactobacillus LAB4" (manufactured by Kaneka Co., Ltd.)), and glucomannan (trade name "Leo") as a water-soluble dietary fiber component The following three types of capsules were manufactured using "Rex RS" (manufactured by Shimizu Chemical Co., Ltd.).
製造例１：
１カプセル当たり、乳酸菌粉末１００ｍｇ、グルコマンナン粉末５０ｍｇ、結晶セルロース粉末１７．５ｍｇ、ステアリン酸カルシウム粉末２ｍｇ、二酸化ケイ素粉末０．５ｍｇを混合、撹拌して均一にした後、市販のカプセル（商品名「ブタゼラチンクリア３号」（クオリカプス株式会社製））に充填した。
製造例２：
１カプセル当たり、乳酸菌粉末１００ｍｇ、乳糖５０ｍｇ、結晶セルロース粉末１７．５ｍｇ、ステアリン酸カルシウム粉末２ｍｇ、二酸化ケイ素粉末０．５ｍｇを混合、撹拌して均一にした後、製造例１で使用したものと同じ市販のカプセルに充填した。
比較例：
乳酸菌粉末及びグルコマンナン粉末の代わりに、乳糖１５０ｍｇを含む以外は製造例１と同じカプセル剤を製造した。Production Example 1:
A capsule containing 100 mg of lactic acid bacteria powder, 50 mg of glucomannan powder, 17.5 mg of crystalline cellulose powder, 2 mg of calcium stearate powder, and 0.5 mg of silicon dioxide powder is mixed and stirred to make them uniform, and then a commercially available capsule (trade name "Pig"). It was filled in "Gelatin Clear No. 3" (manufactured by Qualicaps Co., Ltd.).
Production example 2:
One capsule contains 100 mg of lactic acid bacteria powder, 50 mg of lactose, 17.5 mg of crystalline cellulose powder, 2 mg of calcium stearate powder, and 0.5 mg of silicon dioxide powder. Was filled into capsules.
Comparative example:
Instead of lactic acid bacteria powder and glucomannan powder, the same capsules as in Production Example 1 were produced except that they contained 150 mg of lactose.
これら３種のカプセル剤は、外見、味、匂いともに差がなく、区別がつかないものであった。 These three types of capsules had no difference in appearance, taste, and odor, and were indistinguishable.
２．認知症に対する効果の試験
本研究は、（公財）国際全人医療研究所の倫理委員会の承認のうえで、十分なインフォームド・コンセントを得て実施した（２０１７年）。 2. 2. Test of effect on dementia This study was conducted with sufficient informed consent with the approval of the Institutional Review Board of the International Institute for All-Personal Medicine (2017).
＜被験者＞
被験者は、専門医により認知症と診断され、未治療の患者３３名（男性１７名、女性１６名）であった。これらを、封筒法によって、プラセボ（Ｐ）群、乳酸菌群（Ｌ）群、及び乳酸菌＋グルコマンナン（Ｍ）群の３群に分けた。<Subject>
The subjects were 33 untreated patients (17 males and 16 females) who were diagnosed with dementia by a specialist. These were divided into three groups by the envelope method: a placebo (P) group, a lactic acid bacterium group (L) group, and a lactic acid bacterium + glucomannan (M) group.
各群の被験者の年齢及び性別に統計学的有意差はなかった。各群を構成する被験者の内訳を、表２に示す。 There were no statistically significant differences in the age and gender of the subjects in each group. Table 2 shows the breakdown of the subjects constituting each group.
＜試験方法＞
二重盲検法を採用した。Ｐ群、Ｌ群、又はＭ群に、それぞれ、上記のとおりの比較例、製造例２、又は製造例１のカプセルを、１日３カプセル（１回１カプセル）の量で食直後に服用させた。投与期間は、６カ月であった。<Test method>
A double-blind method was adopted. Group P, L, or M were allowed to take the capsules of Comparative Example, Production Example 2, or Production Example 1 as described above in an amount of 3 capsules (1 capsule at a time) immediately after meals. rice field. The administration period was 6 months.
試験開始直前と試験終了直後に、各被験者について、米国アルツハイマー協会によって示された「１０の症状」の中で、当てはまるものの数を数えた。 Immediately before the start of the study and immediately after the end of the study, the number of "10 symptoms" presented by the American Alzheimer's Association was counted for each subject.
＜試験結果＞
（１）各群の被験者における認知症の症状の数の変化
各群の被験者について、試験開始直前と試験終了直後の各々において数えた、認知症の「１０の症状」の中の当てはまるものの数の平均値の変化を、図１に示す。なお、統計数字は、平均値±標準偏差で表現し、ＭＡＣ版の統計ソフトＳＳＭＣにより解析した。<Test results>
(1) Changes in the number of dementia symptoms in each group of subjects The number of subjects in each group that apply to the "10 symptoms" of dementia counted immediately before the start of the test and immediately after the end of the test. The change in the average value is shown in FIG. The statistical figures were expressed by the average value ± standard deviation and analyzed by the MAC version of the statistical software SSMC.
図１から明らかなように、Ｌ群及びＰ群では、試験開始直前と試験終了直後における認知症の症状の数に有意差はないものの、Ｌ群において症状の数が減少する傾向が見られた。Ｍ群については、試験開始直前に比べて試験終了直後には、危険率１％で、認知症の症状の数が有意に減少した。 As is clear from FIG. 1, there was no significant difference in the number of dementia symptoms immediately before the start of the test and immediately after the end of the test between the L group and the P group, but the number of symptoms tended to decrease in the L group. .. For group M, the risk rate was 1% immediately after the end of the test compared to immediately before the start of the test, and the number of symptoms of dementia was significantly reduced.
（２）カプセル剤の服用前後における、認知症の症状の数の変化率（％）
認知症の症状の数の変化率（％）を、式：〔（服用後の症状の数－服用前の症状の数）／服用前の症状の数〕×１００で算出した。結果を図２に示す。(2) Rate of change in the number of dementia symptoms before and after taking capsules (%)
The rate of change (%) in the number of symptoms of dementia was calculated by the formula: [(number of symptoms after administration-number of symptoms before administration) / number of symptoms before administration] × 100. The results are shown in FIG.
図２から明らかなように、Ｐ群とＬ群との間には、試験前後における認知症の症状の数の変化に有意差はないものの、Ｌ群において症状の数が減少する傾向が見られた。Ｐ群とＭ群との間には、試験前後における認知症の症状の数の変化に、危険率１％で有意差があった。また、Ｌ群とＭ群との間にも、試験前後における認知症の症状の数の変化に、危険率１％で有意差があった。Ｍ群は、試験前に対する試験後の、認知症の症状の数の変化率（低下率）（％）が最も大きかった。 As is clear from FIG. 2, there is no significant difference in the change in the number of dementia symptoms before and after the test between the P group and the L group, but the number of symptoms tends to decrease in the L group. rice field. There was a significant difference in the number of dementia symptoms before and after the study between the P and M groups at a risk rate of 1%. In addition, there was a significant difference in the change in the number of dementia symptoms before and after the test between the L group and the M group at a risk rate of 1%. Group M had the largest change rate (decrease rate) (%) in the number of dementia symptoms before and after the test.
（３）副作用
副作用は、軟便がＬ群に１例、Ｍ群に１例観られたのみであった。
＜安全性の検討＞
被験者すべてについて、試験開始直前と試験終了直後に採血を行い、血算（赤血球、白血球、ヘモグロビン、ヘマトクリット、血小板）、Ａｌｂ、ＧＯＴ、ＧＰＴ、ＬＤＨ、ＡｌＰ、γ－ＧＴＰ、アミラーゼ、ＢＵＮ、クレアチニン、血糖値及びヘモグロビンＡ１ｃを測定した。また、試験開始直前と試験終了直後に採尿を行い、蛋白、糖及びウロビリノーゲンを測定した。すべての患者において、試験開始直前と試験終了直後のいずれにおいても、異常値は認められなかった。(3) Side effects As for side effects, only 1 case of loose stool was observed in the L group and 1 case in the M group.
<Consideration of safety>
Blood was collected from all subjects immediately before the start of the test and immediately after the end of the test, and blood counts (erythrocytes, leukocytes, hemoglobin, hematocrit, platelets), Alb, GOT, GPT, LDH, AlP, γ-GTP, amylases, BUN, creatinine, Blood glucose level and hemoglobin A1c were measured. In addition, urine was collected immediately before the start of the test and immediately after the end of the test, and protein, sugar and urobilinogen were measured. No abnormal values were observed in all patients either immediately before the start of the study or immediately after the end of the study.
＜結論＞
上記の結果より、本発明の剤及び組成物は、認知症の改善に有効であると考えられた。また、本発明の剤及び組成物は、いずれも安全であり、それらの内容物は、安全な素材であると考えられた。<Conclusion>
From the above results, it was considered that the agent and composition of the present invention are effective in improving dementia. In addition, the agents and compositions of the present invention are all safe, and their contents are considered to be safe materials.
この出願は、２０１９年１２月２日出願の日本特許出願、特願２０１９－２１８２１７に基づくものであり、特願２０１９－２１８２１７の明細書及び特許請求の範囲に記載された内容は、すべてこの出願明細書に包含される。 This application is based on the Japanese patent application filed on December 2, 2019, Japanese Patent Application No. 2019-218217, and all the contents described in the specification and claims of Japanese Patent Application No. 2019-218217 are included in this application. Included in the specification.
Claims (8)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019218217 | 2019-12-02 | ||
| JP2019218217 | 2019-12-02 | ||
| PCT/JP2020/044054 WO2021111981A1 (en) | 2019-12-02 | 2020-11-26 | Agent for prevention or remediation of dementia and composition containing same |
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| Publication Number | Publication Date |
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| JPWO2021111981A1 JPWO2021111981A1 (en) | 2021-06-10 |
| JP7057039B2 true JP7057039B2 (en) | 2022-04-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2021562610A Active JP7057039B2 (en) | 2019-12-02 | 2020-11-26 | Agents for preventing or ameliorating dementia and compositions containing them |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024096644A1 (en) * | 2022-11-02 | 2024-05-10 | 주식회사 종근당바이오 | Novel use of lactobacillus delbrueckii subsp. lactis strain |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009066681A1 (en) | 2007-11-19 | 2009-05-28 | Kaneka Corporation | Lactic acid bacterium-containing preparation |
| WO2017179225A1 (en) | 2016-04-13 | 2017-10-19 | 味の素株式会社 | Composition for suppressing or improving age-related physical hypofunction or physical dysfunction or age-related mental hypofunction or mental dysfunction |
-
2020
- 2020-11-26 WO PCT/JP2020/044054 patent/WO2021111981A1/en not_active Ceased
- 2020-11-26 JP JP2021562610A patent/JP7057039B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009066681A1 (en) | 2007-11-19 | 2009-05-28 | Kaneka Corporation | Lactic acid bacterium-containing preparation |
| WO2017179225A1 (en) | 2016-04-13 | 2017-10-19 | 味の素株式会社 | Composition for suppressing or improving age-related physical hypofunction or physical dysfunction or age-related mental hypofunction or mental dysfunction |
Non-Patent Citations (2)
| Title |
|---|
| BULACIOS, G.A. et al.，Selection of lactic acid bacterial strains able to modulate the host central nervous system，Biocell，2019年11月07日，Vol. 43, Suppl. 5，p. 116. Abstract Number: MI-P33 |
| NAKAMURA, Sadako et al.，Daily Feeding of Fructooligosaccharide or Glucomannan Delays Onset of Senescence in SAMP8 Mice，Gastroenterol. Res. Pract.，2014年06月02日，Vol. 2014, Article ID 303184，p. 1-11 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024096644A1 (en) * | 2022-11-02 | 2024-05-10 | 주식회사 종근당바이오 | Novel use of lactobacillus delbrueckii subsp. lactis strain |
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| Publication number | Publication date |
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| WO2021111981A1 (en) | 2021-06-10 |
| JPWO2021111981A1 (en) | 2021-06-10 |
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