JP2017081853A - Virus infection prophylactic and/or therapeutic agent - Google Patents
Virus infection prophylactic and/or therapeutic agent Download PDFInfo
- Publication number
- JP2017081853A JP2017081853A JP2015212160A JP2015212160A JP2017081853A JP 2017081853 A JP2017081853 A JP 2017081853A JP 2015212160 A JP2015212160 A JP 2015212160A JP 2015212160 A JP2015212160 A JP 2015212160A JP 2017081853 A JP2017081853 A JP 2017081853A
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- Prior art keywords
- lactic acid
- lactobacillus
- agent
- virus
- rotavirus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
本発明は、ウイルス感染症の予防及び／又は治療剤に関する。 The present invention relates to a preventive and / or therapeutic agent for viral infections.
病原性ウイルスによる感染症は、発展途上国においても、先進国においても、毎年多数の患者が発生しており、特に、乳児、小児においても主な死亡原因になっている。例えば、ロタウイルス下痢症は６ヶ月〜２歳の乳幼児に多発する疾病で、それが原因で発展途上国では毎年６０万人が死亡する。また、ロタウイルス下痢症は糞便を介して、乳幼児の親や保育所の職員等に感染する。さらに、ロタウイルス下痢症は豚等の家畜でも発症し、経済的な打撃が大きい。 Infectious diseases caused by pathogenic viruses occur in large numbers of patients every year, both in developing and developed countries, and are the main cause of death in infants and children in particular. For example, rotavirus diarrhea is a disease that occurs frequently in infants aged 6 months to 2 years, which causes 600,000 deaths every year in developing countries. In addition, rotavirus diarrhea infects infant parents and nursery school staff through feces. Furthermore, rotavirus diarrhea also occurs in domestic animals such as pigs, and it is an economic blow.
これまでに、ワクチンの効果を増強させるビフィドバクテリウム属菌体等のウイルス感染症の予防に有効な菌が報告されている（特許文献１、２）。また、ロタウイルスによる下痢発症の予防に効果的な菌体として特定の納豆菌株が知られている（特許文献３）。しかし、これまでに、ワクチンの非存在下、ウイルス感染症の治療に有効な乳酸菌は報告されていない。また、現在ロタウイルスに効果のある抗ウイルス剤や治療方法は存在しない。 So far, bacteria effective for preventing viral infections such as Bifidobacterium cells that enhance the effect of vaccines have been reported (Patent Documents 1 and 2). Moreover, a specific natto strain is known as a bacterial cell effective for preventing the onset of diarrhea due to rotavirus (Patent Document 3). However, no lactic acid bacteria effective for the treatment of viral infections in the absence of a vaccine have been reported so far. In addition, there are currently no antiviral agents or treatment methods effective against rotavirus.
本発明は、新規なウイルス感染症の治療剤を提供することを目的とする。 An object of the present invention is to provide a novel therapeutic agent for viral infection.
本発明者らは、上記課題を解決するために検討した結果、乳酸菌がウイルス感染症の治療に有効であることを見出し、さらに検討を重ねて、種々の新知見を得て、本発明を完成するに至った。
すなわち、本発明は以下の発明に関する。
〔１〕ワクチン非存在下で用いられる、ビフィドバクテリウム（Bifidobacterium）属、ストレプトコッカス（Streptococcus）属、ラクトバシラス アシドフィルス（Lactobacillus acidophilus）種、ラクトバシラス ガセリ（Lactobacillus gasseri）種、ラクトバシラス ジョンソニイ（Lactobacillus johnsonii）種、ラクトバシラス パラカゼイ（Lactobacillus paracasei）種又はラクトバシラス ファーメンタム（Lactobacillus fermentum）種に属する乳酸菌を含有するウイルス感染症の予防及び／又は治療剤。
〔２〕ウイルス感染症治療剤である前記〔１〕に記載の剤。
〔３〕乳酸菌が、ビフィドバクテリウム（Bifidobacterium）属に属する乳酸菌である前記〔１〕又は〔２〕に記載の剤。
〔４〕ウイルスが、ロタウイルス、ポリオウイルス、インフルエンザウイルス、エイズウイルス、Ａ型肝炎ウイルス、Ｂ型肝炎ウイルス、ノロウイルス、アデノウイルス、サポウイルス、アストロウイルス、アイチウイルス、及びパレコウイルスからなる群より選択される１以上である前記〔１〕〜〔３〕のいずれかに記載の剤。
〔５〕乳酸菌がビフィドバクテリウム ビフィダム Ｇ９−１（Bifidobacterium bifidum Ｇ９−１）であり、ウイルスがロタウイルスである前記〔２〕に記載の剤。
〔６〕ウイルス感染症による症状が、下痢、吐き気、嘔吐、発熱、腹痛、腹部膨満感、鼓腸、脱水症状、及び脳症からなる群より選択される１以上である前記〔１〕〜〔５〕のいずれかに記載の剤。
As a result of studies to solve the above-mentioned problems, the present inventors have found that lactic acid bacteria are effective for the treatment of viral infections, and have further studied to obtain various new findings, thereby completing the present invention. It came to do.
That is, the present invention relates to the following inventions.
[1] Bifidobacterium genus, Streptococcus genus, Lactobacillus acidophilus species, Lactobacillus gasseri species, Lactobacillus johnsonii, Lactobacillus johnsoni, Lactobacillus johnson, Lactobacillus johnson, A preventive and / or therapeutic agent for a viral infection containing a lactic acid bacterium belonging to Lactobacillus paracasei species or Lactobacillus fermentum species.
[2] The agent according to [1], which is a therapeutic agent for viral infection.
[3] The agent according to [1] or [2], wherein the lactic acid bacterium is a lactic acid bacterium belonging to the genus Bifidobacterium.
[4] From the group consisting of rotavirus, poliovirus, influenza virus, AIDS virus, hepatitis A virus, hepatitis B virus, norovirus, adenovirus, sapovirus, astrovirus, aichivirus, and parecovirus The agent according to any one of [1] to [3], which is one or more selected.
[5] The agent according to [2], wherein the lactic acid bacterium is Bifidobacterium bifidum G9-1 and the virus is rotavirus.
[6] The above [1] to [5], wherein the symptom due to viral infection is at least one selected from the group consisting of diarrhea, nausea, vomiting, fever, abdominal pain, abdominal fullness, flatulence, dehydration, and encephalopathy The agent in any one of.
本発明は、さらに以下の発明を包含する。
〔７〕ウイルス感染症の予防及び／又は治療用医薬製造のための前記〔１〕〜〔５〕のいずれかに記載の剤の使用。
〔８〕ウイルス感染症の予防及び／又は治療のために使用される前記〔１〕〜〔５〕のいずれかに記載の剤。
〔９〕前記〔１〕〜〔５〕のいずれかに記載の剤を、ヒトを含む哺乳動物に投与するウイルス感染症の予防及び／又は治療方法。
〔１０〕ウイルス感染症の予防及び／又は治療のための前記〔１〕〜〔５〕のいずれかに記載の剤の使用。
The present invention further includes the following inventions.
[7] Use of the agent according to any one of [1] to [5] for the manufacture of a medicament for prevention and / or treatment of viral infection.
[8] The agent according to any one of [1] to [5], which is used for prevention and / or treatment of viral infection.
[9] A method for preventing and / or treating a viral infection, comprising administering the agent according to any one of [1] to [5] to mammals including humans.
[10] Use of the agent according to any one of [1] to [5] for prevention and / or treatment of viral infection.
本発明は、新規なウイルス感染症の予防及び／又は治療剤を提供することができる。本発明の剤は、ロタウイルス感染症の治療が可能であり、ロタウイルスの二次感染予防も可能である点において、特に顕著な効果を有する。 The present invention can provide a novel preventive and / or therapeutic agent for viral infections. The agent of the present invention has a particularly remarkable effect in that it can treat rotavirus infection and can prevent secondary infection of rotavirus.
本発明は、ビフィドバクテリウム（Bifidobacterium）属、ストレプトコッカス（Streptococcus）属、ラクトバシラス アシドフィルス（Lactobacillus acidophilus）種、ラクトバシラス ガセリ（Lactobacillus gasseri）種、ラクトバシラス ジョンソニイ（Lactobacillus johnsonii）種、ラクトバシラス パラカゼイ（Lactobacillus paracasei）種又はラクトバシラス ファーメンタム（Lactobacillus fermentum）種に属する乳酸菌を含有するウイルス感染症の予防及び／又は治療剤（以下、本発明の剤という）を提供する。本発明の剤は、上記乳酸菌を含有していればよく、さらに他の成分を含有していてもよい。上記乳酸菌は、１種単独で使用してもよく、２種以上を混合して用いてもよい。本発明の剤は、ワクチン非存在下で用いられる。 The present invention relates to a genus Bifidobacterium, a genus Streptococcus, a Lactobacillus acidophilus species, a Lactobacillus gasseri species, a Lactobacillus johnsonii species, a Lactobacillus johnsonii species, a Lactobacillus johnsonii species, Alternatively, a prophylactic and / or therapeutic agent for a viral infection (hereinafter referred to as the agent of the present invention) containing a lactic acid bacterium belonging to Lactobacillus fermentum species is provided. The agent of this invention should just contain the said lactic acid bacteria, and may contain the other component further. The said lactic acid bacteria may be used individually by 1 type, and may mix and use 2 or more types. The agent of the present invention is used in the absence of a vaccine.
本発明において、乳酸菌は、ビフィドバクテリウム（Bifidobacterium）属、ラクトバシラス アシドフィルス（Lactobacillus acidophilus）種、ラクトバシラス ガセリ（Lactobacillus gasseri）種、ラクトバシラス ジョンソニイ（Lactobacillus johnsonii）種、ラクトバシラス パラカゼイ（Lactobacillus paracasei）種、ラクトバシラス ファーメンタム（Lactobacillus fermentum）種又はストレプトコッカス（Streptococcus）属に属する菌である。ビフィドバクテリウム（Bifidobacterium）属に属する乳酸菌としては、ビフィドバクテリウム ビフィダム（Bifidobacterium bifidum）また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 ビフィダム Ｇ９−１（Bifidobacterium bifidum G9-1）またはビフィドバクテリウム ロンガム ＭＭ−２（Bifidobacterium longum MM-2）がさらに好ましい。また、ビフィドバクテリウム（Bifidobacterium）属に属する乳酸菌は、B. breve、B. adolescentis、B. infantis、B.pseudolongum、B.thermophilum等であってもよい。ラクトバシラス アシドフィルス（Lactobacillus acidophilus）種に属する乳酸菌としては、例えばラクトバシラス アシドフィルス ＫＳ−１３（Lactobacillus acidophilus KS-13）が好ましい。ストレプトコッカス（Streptococcus）属に属する乳酸菌としては、ストレプトコッカス フェーカリス（Streptococcus(Enterococcus) faecalis）が好ましく、ストレプトコッカス フェーカリス１２９ ＢＩＯ ３Ｂ（Streptococcus(Enterococcus) faecalis 129 BIO 3B）またはストレプトコッカス フェーカリス１２９ ＢＩＯ ３Ｂ−Ｒ（Streptococcus(Enterococcus) faecalis 129 BIO 3B-R）がさらに好ましい。また、ストレプトコッカス（Streptococcus）属に属する乳酸菌は、Streptococcus(Enterococcus) faecium、 Streptococcus(Enterococcus) hirae、Streptococcus(Enterococcus) thermophilus等であってもよい。 これらの菌体は、例えばＡＴＣＣ又はＩＦＯ等の機関や財団法人 日本ビフィズス菌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。
なお、本明細書中においては、ストレプトコッカス（Streptococcus）属とは、ストレプトコッカス（Streptococcus）属及びエンテロコッカス(Enterococcus)属を包含する。
In the present invention, the lactic acid bacteria include Bifidobacterium genus, Lactobacillus acidophilus species, Lactobacillus gasseri species, Lactobacillus johnsonii species, Lactobacillus johnsonii species, Lactobacillus parasonis (Lactobacillus species) It is a bacterium belonging to the genus Mental (Lactobacillus fermentum) or Streptococcus. As the lactic acid bacteria belonging to the genus Bifidobacterium, Bifidobacterium bifidum or Bifidobacterium longum is preferable, and Bifidobacterium bifidum G9-1 (Bifidobacterium bifidum G9-1) Or Bifidobacterium longum MM-2. The lactic acid bacteria belonging to the genus Bifidobacterium may be B. breve, B. adolescentis, B. infantis, B. pseudolongum, B. thermophilum, and the like. As a lactic acid bacterium belonging to Lactobacillus acidophilus species, for example, Lactobacillus acidophilus KS-13 (Lactobacillus acidophilus KS-13) is preferable. As the lactic acid bacteria belonging to the genus Streptococcus, Streptococcus faecalis (Streptococcus (Enterococcus) faecalis) is preferable, Streptococcus faecalis 129 BIO 3B (Streptococcus (Enterococcus) faecalis 129 BIO 3 oc) or Streptococcus faecalis 129 BIO 3 octo ) faecalis 129 BIO 3B-R) is more preferred. The lactic acid bacteria belonging to the genus Streptococcus may be Streptococcus (Enterococcus) faecium, Streptococcus (Enterococcus) hirae, Streptococcus (Enterococcus) thermophilus, or the like. These cells can be easily obtained from, for example, an organization such as ATCC or IFO or the Japan Bifidobacteria Center. Moreover, what is marketed can also be used suitably.
In the present specification, the genus Streptococcus includes the genus Streptococcus and the genus Enterococcus.
本発明の効果を奏する限り、上記乳酸菌以外の有用菌を含んでもよい。例えば、Bacillus subtilis 129 BIO H(α)等のBacillus subtilis、Bacillus mesentericus、Bacillus polyformenticus等の糖化菌；例えば、Bacillus coagulans等の有胞子性乳酸菌； Bacillus toyoi、B．licheniformis、Clostridium butyricum等の酪酸菌；Leuconostoc mesenteroides等のリューコノストック属、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；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。
As long as the effects of the present invention are exhibited, useful bacteria other than the lactic acid bacteria may be included. For example, saccharified bacteria such as Bacillus subtilis 129 BIO H (α), Bacillus subtilis, Bacillus mesentericus, Bacillus polyformenticus; for example, spore-forming lactic acid bacteria such as Bacillus coagulans; Bacillus toyoi, B. butyric acid bacteria such as licheniformis and Clostridium butyricum; genus Leuconostoc such as Leuconostoc mesenteroides; genus Lactococcus such as Lactococcus lactis and L. cremoris; Lactococcus such as genus Pediococcus such as pentosaceus, and genus Oenococcus such as Oenococcus oeni; other useful bacteria.
These cells can be easily obtained from institutions such as ATCC or IFO. Moreover, what is marketed can also be used suitably.
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、通常、グルコ−ス、酵母エキス、ペプトン等を含む液体培地で上記乳酸菌の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, usually, one or more of the above lactic acid bacteria are usually aerobically or anaerobically cultured at about 25-45 ° C. for about 4-72 hours in a liquid medium containing glucose, yeast extract, peptone, etc. Bacteria are collected from the culture 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、該細胞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。上記死菌体は、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。これらの技術は従来充分に確立されていて、本発明において、そのような技術に従ってよい。 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 bacterial cells by ultrasonic waves, the cell culture solution or the culture supernatant. . 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. These techniques are well established in the past, and such techniques may be followed in the present invention.
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り、その結果、ウイルス感染症の予防及び／又は治療効果が高くなる。シングルミクロンの乳酸菌の製造方法も従来公知であり、本発明の実施においても、公知の方法に従ってよい。 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 increases, and as a result, the effect of preventing and / or treating viral infections is enhanced. A method for producing a single micron lactic acid bacterium is also conventionally known, and in the practice of the present invention, a known method may be followed.
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から、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、公知技術に従ってさらに賦形剤、結合剤、崩壊剤、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。
賦形剤としては、例えば、乳糖、白糖、Ｄ−マンニトール、トウモロコシデンプン、粉末セルロース、リン酸水素カルシウム、炭酸カルシウム等が挙げられる。結合剤としては、例えばヒドロキシプロピルセルロース、ポビドン（ポリビニルピロリドン）、キサンタンガム等が挙げられる。崩壊剤としては、例えば、低置換度ヒドロキシプロピルセルロース、カルメロースカルシウム、部分アルファー化デンプン、クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチ等が挙げられる。静電気防止剤としては、例えば微粉または非微粉タルク、コロイド状シリカ、加工シリカ、沈降シリカ等が挙げられる。
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 an excipient | filler, a binder, a disintegrating agent, and an antistatic agent, to the said microbial cell liquid at a normal compounding ratio according to a well-known technique.
Examples of the excipient include lactose, sucrose, D-mannitol, corn starch, powdered cellulose, calcium hydrogen phosphate, calcium carbonate and the like. Examples of the binder include hydroxypropylcellulose, povidone (polyvinylpyrrolidone), xanthan gum and the like. Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose calcium, partially pregelatinized starch, croscarmellose sodium, crospovidone, carboxymethyl starch and the like. Examples of the antistatic agent include fine powder or non-fine powder talc, colloidal silica, processed silica, precipitated silica and the like.
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、好ましく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 single-micron droplet preferably means a spray droplet whose particle size is 1 to 10 μm rounded off 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、例えば４流体ノズルの構造としては、好ましく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, for example, the structure of the four-fluid nozzle is preferably a gas flow path and a liquid flow path in one system, which are provided symmetrically at the 2-system nozzle edge. The slant surface is a fluid flow 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。 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.
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.
本発明の剤は、乳酸菌を単独で使用または他の成分を混合することにより容易に製造され得る。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。他の成分としては、例えば、Bacillus subtilis、Bacillus mesentericus、Bacillus polyformenticus等の糖化菌；例えば、Bacillus coagulans等の有胞子性乳酸菌； Bacillus toyoi、B．licheniformis、Clostridium butyricum等の酪酸菌；その他の有用菌、医薬用の賦形剤等が挙げられる。本発明の剤は、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、本発明の剤を含む医薬品も、本発明の好ましい実施態様の１つである。 The agent of the present invention can be easily produced by using lactic acid bacteria alone or by mixing other components. Other components are not particularly limited as long as the effects of the present invention are exhibited. Examples of other components include saccharifying bacteria such as Bacillus subtilis, Bacillus mesentericus and Bacillus polyformenticus; for example, spore-forming lactic acid bacteria such as Bacillus coagulans; Bacillus toyoi, B. et al. Examples include butyric acid bacteria such as licheniformis and Clostridium butyricum; other useful bacteria and pharmaceutical excipients. The agent of this invention can be used as forms, such as a pharmaceutical, a quasi-drug, food-drinks, and feed. Such a medicament containing the agent of the present invention is also one of the preferred embodiments of the present invention.
本発明の剤の剤形は、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、経口投与に適しており、内服剤とすることが好ましい。内服剤の剤型としては、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、本発明の剤は、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、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。製剤中に含まれる乳酸菌の合計量は、通常、最終製剤中に約０．０００００１〜９９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 agent of the present invention may be a dosage form suitable for administration in consideration of the physicochemical properties and biological properties of each component. In the case of a pharmaceutical, it is suitable for oral administration and is preferably an internal preparation. Examples of the internal dosage form 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 lactic acid bacteria, the agent of the present invention includes 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. It may be. The total amount of lactic acid bacteria contained in the preparation can usually be determined by appropriately selecting from the range of about 0.000001 to 99% by mass in the final preparation.
なお、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。 Lactic acid bacteria are generally anaerobic and are weak against air or oxygen in the dry state, and are vulnerable to high temperatures and humidity. Therefore, in the formulation of the composition, in the presence of an inert gas or in a vacuum at a low temperature as much as possible. It is preferable to process.
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 a composition containing lactic acid bacteria is made into a solid preparation, the powders may be simply mixed together 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（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 mix a small amount of an active ingredient (lactic acid bacterium) with a large amount of other powders to obtain a uniform mixture, 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、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１０３〜１０１２個／大人／回、好ましくは１０５〜１０１０個／大人／回、より好ましくは１０６〜１０１０個／大人／回である。本発明において、乳酸菌の投与回数は、１０３〜１０１２個／大人／回の場合において、１日当たり１〜数回が好ましい。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。 In the present invention, the dose of lactic acid bacteria is usually about 10 3 to 10 12 cells / adult / time, preferably 10 5 to 10 10 cells / adult / time, when viable cells are used. More preferably, it is 10 6 to 10 10 pieces / adult / time. In the present invention, the number of administrations of lactic acid bacteria is preferably 1 to several times per day in the case of 10 3 to 10 12 cells / adult / time. 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.
本発明におけるウイルスは特に限定されないが、例えば、ロタウイルス、ポリオウイルス、インフルエンザウイルス、エイズウイルス、Ａ型肝炎ウイルス、Ｂ型肝炎ウイルス、ノロウイルス、アデノウイルス、サポウイルス、アストロウイルス、アイチウイルス、パレコウイルス等が挙げられ、中でもロタウイルスが好ましい。 The virus in the present invention is not particularly limited. For example, rotavirus, poliovirus, influenza virus, AIDS virus, hepatitis A virus, hepatitis B virus, norovirus, adenovirus, sapovirus, astrovirus, eye virus, pareco A virus etc. are mentioned, A rotavirus is especially preferable.
ウイルス感染症による症状としては特に限定されず、下痢、吐き気、嘔吐、発熱、腹痛、腹部膨満感、鼓腸、脱水症状、脳症等が挙げられる。 Symptoms due to viral infection are not particularly limited, and include diarrhea, nausea, vomiting, fever, abdominal pain, abdominal fullness, flatulence, dehydration, encephalopathy and the like.
本発明の剤は、ウイルス感染症の治療のために好適に用いられる。中でも、ロタウイルス感染症を発症した後の治療が可能であり、ロタウイルスの二次感染予防も可能である点で、その臨床的意義は計り知れない程大きいものと言える。さらには、本発明の剤は、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。ウイルス感染症の治療効果の有無は、ウイルス感染動物に本発明の剤を、経口投与などの方法により投与し、下痢症状、糞便スコア、その動物の盲腸及び結腸内容物のウイルス価等を対照群と比較することにより確認することができる。 The agent of the present invention is suitably used for the treatment of viral infections. Among them, the clinical significance is immensely great in that treatment after the onset of rotavirus infection is possible and secondary infection of rotavirus is possible. Furthermore, the agent of the present invention is easy to administer and has few side effects. The presence or absence of a therapeutic effect on a viral infection is determined by administering the agent of the present invention to a virus-infected animal by a method such as oral administration. It can confirm by comparing with.
本発明の剤は、上記の通り、ウイルス感染により生じる症状のある個体（動物）に好適に適用することができる。さらに、本発明の剤は、副作用がなく安全であることから、予防目的で長期間投与することもできる。ウイルス感染症の予防効果の有無は、ウイルス感染動物に本発明の剤を、経口投与などの方法により投与し、下痢症状、糞便スコア、その動物の盲腸及び結腸内容物のウイルス価等を対照群と比較することにより確認することができる。このため、本発明の剤は、ウイルス感染した個体だけでなく、健常な個体、該症状を発症するおそれのある個体（動物）等にも好適に適用することができる。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、サル等の哺乳動物が好ましく、特にヒトが好ましい。 As described above, the agent of the present invention can be suitably applied to individuals (animals) having symptoms caused by viral infection. Furthermore, since the agent of the present invention has no side effects and is safe, it can be administered for a long time for the purpose of prevention. The presence or absence of the effect of preventing viral infection is determined by administering the agent of the present invention to a virus-infected animal by a method such as oral administration, and controlling the diarrhea symptoms, fecal score, virus value of the cecum and colon contents of the animal, etc. It can confirm by comparing with. Therefore, the agent of the present invention can be suitably applied not only to individuals infected with viruses, but also to healthy individuals, individuals (animals) that may develop the symptoms, and the like. As the individual, mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs and monkeys are preferable, and humans are particularly preferable.
本発明の剤は、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、食品添加物、ドリンク剤などの飲食品として用いることができるものである。本発明の剤を含むウイルス感染症の予防及び／又は治療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、ウイルス感染症を発症した、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、ウイルス感染症を予防及び／又は治療することができる。飲食品組成物中に含まれる乳酸菌の合計量は、通常、最終組成物中に約０．０００００１〜９９質量％の範囲から適宜選択して決定することができる。 The agent of the present invention can be used as a pharmaceutical product as described above, and can also be used as a food and drink such as a functional food, a food for specified health use, a food additive, and a drink. A food and drink composition for preventing and / or treating a viral infection containing the agent of the present invention is also one aspect of the present invention. Viral infection can be prevented and / or treated by ingesting the food / beverage product composition according to the present invention to mammals including humans who have developed or are likely to develop viral infection. The total amount of lactic acid bacteria contained in the food / beverage product composition can be determined by appropriately selecting from the range of about 0.000001 to 99% by mass in the final composition.
本発明に係る飲食品組成物の形態は特に限定されないが、例えば、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。また、本発明に係る飲食品組成物は、ウイルス感染の予防及び／又は治療、ウイルス感染による下痢、吐き気、嘔吐、発熱、腹痛、脱水症状、腹部膨満感、鼓腸、脳症等の予防及び／又は治療をコンセプトとし、その旨を表示した特定保健用食品、サプリメント、栄養補助食品、機能性食品等が含まれる。また、本発明に係る飲食品組成物は、乳糖、デンプン、結晶セルロース、リン酸ナトリウム等の医薬用賦形剤を含んでいてもよい。さらに、本発明に係る飲食品組成物は、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。 Although the form of the food-drinks composition which concerns on this invention is not specifically limited, For example, it can also be set as processed forms, such as a natural liquid food, a semi-digested nutrient food, a component nutrient food, or a drink. In addition, the food and drink composition according to the present invention can be used for the prevention and / or treatment of viral infection, diarrhea due to viral infection, nausea, vomiting, fever, abdominal pain, dehydration, abdominal fullness, flatulence, encephalopathy and / or the like. Foods for specified health use, supplements, dietary supplements, functional foods, etc. that indicate the concept of treatment are included. Moreover, the food-drinks composition which concerns on this invention may contain pharmaceutical excipient | fillers, such as lactose, starch, crystalline cellulose, sodium phosphate. Furthermore, the food-drinks composition which concerns on 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, for example, under the control of a dietitian based on a doctor's meal, adds the food / beverage composition of the present invention to any food at the time of cooking in a hospital meal, It can also be given to patients in the form of food prepared in 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。上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、乳酸菌を、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。 The intake of the food / beverage composition according to the present invention varies depending on the lifestyle-related disease state, age, sex, etc. of the mammal to be ingested. It is preferable to take a large amount.
本発明は、本発明の効果を奏する限り、本発明の技術的範囲内において、上記の構成を種々組み合わせた態様を含む。 The present invention includes embodiments in which the above-described configurations are variously combined within the technical scope of the present invention as long as the effects of the present invention are exhibited.
次に、実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの実施例により何ら限定されるものではなく、多くの変形が本発明の技術的思想内で当分野において通常の知識を有する者により可能である。本実施例中、「％」は、特に断らない限り「質量％」を意味する。 EXAMPLES Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples at all, and many variations are within the technical idea of the present invention. This is possible by those with ordinary knowledge. In this example, “%” means “% by mass” unless otherwise specified.
［実施例１］（乳酸菌菌体乾燥物の調製及び該菌体乾燥物中の生菌数の測定）
１．菌（BBG9-1：Bifidobacterium bifidum G9-1）の調製方法
ＢＢＧ９−１の菌体乾燥物の調製は以下のように行った。すなわち、ＢＢＧ９−１の凍結保存菌株（ビオフェルミン製薬社保存菌株）を３７℃で２４時間静置培養後、ビフィズス菌試験用液体培地（１）（日本薬局方外医薬品規格「ビフィズス菌」の項に記載）にこの培養菌液をビフィズス菌試験用液体培地（１）１００に対して１の割合（容量比）で接種し、３７℃で１８時間静置培養した。得られた培養菌液を遠心分離し、水で３回洗浄後、適量の水を加え、湿菌体１ｋｇに対し、グルタミン酸塩０．１ｋｇ及びデキストリン０．５ｋｇの割合で加えて噴霧乾燥装置にて菌体乾燥物とした。なお、ビフィズス菌ＢＢＧ９−１株は、医療用医薬品のビオフェルミン錠剤（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。
[Example 1] (Preparation of dried lactic acid bacterial cells and measurement of the number of viable bacteria in the dried bacterial cells)
1. Preparation Method of Bacteria (BBG9-1: Bifidobacterium bifidum G9-1) BBG9-1 dry cells were prepared as follows. That is, after the BBG9-1 cryopreserved strain (Biofermin Pharmaceutical Co., Ltd.) was allowed to stand at 37 ° C. for 24 hours, the Bifidobacterium test liquid medium (1) This culture was inoculated at a ratio (volume ratio) of 1 with respect to the liquid medium for bifidobacterial test (1) 100, and cultured at 37 ° C. for 18 hours. The obtained culture solution is centrifuged, washed three times with water, an appropriate amount of water is added, and 0.1 kg of glutamate and 0.5 kg of dextrin are added to 1 kg of wet cells, and the mixture is added to the spray drying apparatus. The cells were dried. The Bifidobacterium BBG9-1 strain is contained as a component of a biopharmaceutical drug Biofermin tablet (trade name, manufactured by Biofermin Pharmaceutical Co., Ltd.) and can be obtained by purification from the tablet or the like by a usual method. is there.
２．菌体乾燥物中の生菌数の測定
日本薬局方外医薬品規格「ビフィズス菌」の項に記載されているビフィズス菌の定量法に準じて測定した。すなわち、菌体乾燥物５ｇを精密に量り、希釈液（２）３０ｍＬ中に加え、強く振り混ぜ、更に同希釈液を加えて正確に５０ｍＬとし、よく振り混ぜ、この菌液１ｍＬを正確に量り、別に正確に分注した同希釈液９ｍＬ中に加える操作（１０倍希釈法）を繰り返し、１ｍＬ中の生菌数が２０〜２００個となるよう希釈した。この液１ｍＬをペトリ皿にとり、ここに５０℃に保ったビフィズス菌試験用カンテン培地を２０ｍＬ加えてすばやく混和し、固化させた。これを３７℃で４８〜７２時間嫌気培養し、出現したコロニー数及び希釈倍率から菌体乾燥物中の生菌数を求めた。これにより求めた上記１．で得られた菌体乾燥物の菌数は、生菌数３．４×１０１１ＣＦＵ／ｇであった。
2. Measurement of the number of viable bacteria in the dried microbial cell body The measurement was performed according to the method for quantifying bifidobacteria described in the section of the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacteria”. That is, weigh accurately 5 g of the dried bacterial cell product, add it to 30 mL of diluent (2), shake vigorously, add the same diluent to make exactly 50 mL, shake well, and accurately measure 1 mL of this bacterial solution. Then, the operation (10-fold dilution method) of addition into 9 mL of the same diluted solution that was accurately dispensed was repeated, and diluted so that the number of viable bacteria in 1 mL was 20 to 200. 1 mL of this solution was placed in a Petri dish, and 20 mL of an agar medium for bifidobacteria test maintained at 50 ° C. was added thereto and quickly mixed to solidify. This was anaerobically cultured at 37 ° C. for 48 to 72 hours, and the number of viable cells in the dried microbial cell was determined from the number of colonies that appeared and the dilution rate. The above-described 1. The cell count of the dried microbial cell product obtained in (1) was 3.4 × 10 11 CFU / g viable count.
実施例中で用いた希釈液（２）の調製方法を、以下に示す。
希釈液（２）の調製方法
日本薬局方外医薬品規格「ビフィズス菌」の項に記載された方法に従い、下記の成分を混合し、高圧蒸気滅菌器を用いて１２１℃で１５分間加熱して滅菌して調製した。
無水リン酸一水素ナトリウム ６．０ｇ
リン酸二水素カリウム ４．５ｇ
ポリソルベート８０ ０．５ｇ
Ｌ−塩酸システイン ０．５ｇ
カンテン １．０ｇ
精製水 １０００ｍＬ
ｐＨ ６．８〜７．０
The preparation method of the diluent (2) used in the examples is shown below.
Preparation of Diluent (2) According to the method described in the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacteria”, the following components are mixed and sterilized by heating at 121 ° C. for 15 minutes using a high-pressure steam sterilizer Prepared.
Anhydrous sodium monohydrogen phosphate 6.0 g
4.5g potassium dihydrogen phosphate
Polysorbate 80 0.5g
L-cysteine hydrochloride 0.5g
Kang 1.0g
Purified water 1000mL
pH 6.8-7.0
［実施例２］（使用動物、乳酸菌及びロタウイルス）
１．動物
実施例３〜５の各実施例において、２匹の妊娠ＢＡＬＢ/ｃマウスを日本ＳＬＣ社より購入後、室温２２±５℃、湿度５５±５％、１２時間周期の照明（７〜１９時）条件下で、固形飼料（ＣＥ−２：日本クレア社製）及び上水道を自由に摂取させ飼育した。乳飲みマウスが生後２日齢である日に２群（各群当たり一腹単位、即ち母親マウス１匹及び乳飲みマウス６〜８匹）に分けた。そのうちの乳飲みマウスを実験に供した。
[Example 2] (Animals used, lactic acid bacteria and rotavirus)
1. Animals In each of Examples 3 to 5, after 2 pregnant BALB / c mice were purchased from Japan SLC, room temperature 22 ± 5 ° C., humidity 55 ± 5%, 12 hour lighting (7-19 o'clock) ) Under conditions, solid feed (CE-2: manufactured by CLEA Japan, Inc.) and water supply were freely ingested and bred. The group was divided into two groups (one abdominal unit for each group, that is, one mother mouse and 6-8 suckling mice) on the day when the suckling mice were 2 days old. Of these, the suckling mice were subjected to experiments.
２．乳酸菌
上記ＢＢＧ９−１の菌体乾燥物を、ＰＢＳ（Phosphate Buffered Saline）（−）（日水製薬社）を用いて溶解させることによって得た、ＢＢＧ９−１が６．０×１０８ＣＦＵ（Colony Forming Unit）／ｍＬの乳酸菌溶液を実験に供した。
2. Lactic acid bacteria BBG9-1 obtained by dissolving the dried BBG9-1 cells using PBS (Phosphate Buffered Saline) (-) (Nissui Pharmaceutical Co., Ltd.) was 6.0 × 10 8 CFU (Colony Forming Unit) / mL lactic acid bacteria solution was used for the experiment.
３．ロタウイルス
サル由来ＳＡ−１１株（藤田保健衛生大学）をＰＢＳ（＋）（シグマアルドリッチジャパン社）で希釈して得た、２．９×１０７（ＰＦＵ（Plaque Forming Unit）／ｍＬ）のロタウイルス溶液を実験に供した。
3. A rota of 2.9 × 10 7 (PFU (Plaque Forming Unit) / mL) obtained by diluting Rotavirus monkey-derived SA-11 strain (Fujita Health University) with PBS (+) (Sigma Aldrich Japan) The virus solution was subjected to the experiment.
［実施例３］（乳酸菌によるロタウイルス感染症の予防効果）
１．試験方法
図２は実施例３の試験スケジュールを示す説明図である。即ち、図２は、分娩、群分け、乳飲みマウスへの乳酸菌又はＰＢＳ（−）の投与、ロタウイルス感染及び下痢の症状観察のスケジュールを示す。具体的には、乳飲みマウスが生後２日齢の日に、乳酸菌投与群と対照群とに群分けした。群分け後の各群は乳飲みマウスとその母親マウスからなる。乳飲みマウスが生後５日齢の日から生後１４日齢の日まで乳酸菌投与群の乳飲みマウスに乳酸菌溶液を、対照群の乳飲みマウスにＰＢＳ（−）を、５０μＬずつ一日一回経口投与した。さらに、生後７日齢の両群の乳飲みマウスに５０μＬのロタウイルス溶液を経口投与して、両群の乳飲みマウスをロタウイルス感染させた。ロタウイルス感染後８日間、毎日各乳飲みマウスの腹部を押して、下記表１に示す通り、糞便の性状を４段階でスコア化した。糞便のスコアが２以上のものを下痢と評価して、各腹の下痢発症率を算出した。また、糞便スコアに関しても、各腹の平均値を算出した。なお、下痢の症状観察及び糞便のスコア評価を各群乳飲みマウス６腹ずつ行った。
[Example 3] (Preventive effect of rotavirus infection by lactic acid bacteria)
1. Test Method FIG. 2 is an explanatory diagram showing a test schedule of Example 3. That is, FIG. 2 shows a schedule for observing symptoms of parturition, grouping, administration of lactic acid bacteria or PBS (−) to suckling mice, rotavirus infection and diarrhea. Specifically, the milking mice were divided into a lactic acid bacteria administration group and a control group on the day 2 days after birth. Each group after grouping consists of a suckling mouse and its mother mouse. From the day 5 days after birth to the day 14 days after birth, the lactic acid bacteria solution was given to the milked mice in the lactic acid bacteria administration group, the PBS (-) was given to the control group's milked mice once a day. Administered. Furthermore, 50 μL of rotavirus solution was orally administered to both groups of 7-day-old suckling mice to infect both groups of suckling mice with rotavirus infection. For 8 days after rotavirus infection, the abdomen of each suckling mouse was pushed daily, and the fecal properties were scored in 4 stages as shown in Table 1 below. A stool score of 2 or more was evaluated as diarrhea, and the incidence of diarrhea in each belly was calculated. Moreover, the average value of each belly was also calculated regarding the stool score. In addition, the diarrhea symptom observation and the fecal score evaluation were performed for 6 suckling mice in each group.
２．結果及び考察
結果を図３及び４に示す。図３に示す通り、ロタウイルス感染後３日、４日での下痢の発症率が対照群では７４．２％、５２．５％であったのに対して、乳酸菌投与群では３４．８％、１４．６％と、統計学的に有意に下痢の発症率が減少した（ｐ＜０．０５）。さらに、図４に示す通り、ロタウイルス感染３日後、４日後での糞便スコアが対照群では１．９、１．２であったのに対して、乳酸菌投与群では０．８、０．３と、統計学的に有意に糞便スコアが改善した（ｐ＜０．０５）。
以上のように、乳飲みマウスに対してロタウイルス感染前２日より乳酸菌株を予防的に経口投与することによって、下痢の発症率の減少および糞便スコアの改善が認められ、乳酸菌がロタウイルス感染症の予防に有効であることが明らかとなった。
2. Results and Discussion The results are shown in FIGS. As shown in FIG. 3, the incidence of diarrhea on days 3 and 4 after rotavirus infection was 74.2% and 52.5% in the control group, compared with 34.8% in the lactic acid bacteria administration group. 14.6%, a statistically significant decrease in the incidence of diarrhea (p <0.05). Furthermore, as shown in FIG. 4, the stool score 3 days and 4 days after rotavirus infection was 1.9 and 1.2 in the control group, whereas 0.8 and 0.3 in the lactic acid bacteria administration group. And the stool score improved statistically significantly (p <0.05).
As described above, the preventive oral administration of lactic acid strains to suckling mice from day 2 before rotavirus infection resulted in a decrease in the incidence of diarrhea and improvement in stool score. It became clear that it was effective in the prevention of symptoms.
［実施例４］（乳酸菌によるロタウイルス感染症の治療効果）
１．試験方法
図５は実施例４の試験スケジュールを示す説明図である。即ち、実施例３における乳酸菌又はＰＢＳ（−）の投与期間を「乳飲みマウスが生後５日齢の日から生後１４日齢の日まで」から「乳飲みマウスが生後８日齢の日から生後１４日齢の日まで」に変更し、下痢の症状観察及び糞便のスコア評価を行う各群乳飲みマウスを「６腹ずつ」から「７腹ずつ」に変更した以外は、実施例３と同じ方法で試験を行った。
[Example 4] (Therapeutic effect of rotavirus infection by lactic acid bacteria)
1. Test Method FIG. 5 is an explanatory diagram showing a test schedule of Example 4. That is, the administration period of lactic acid bacteria or PBS (−) in Example 3 was changed from “from the day when the suckling mouse was 5 days old to the day of 14 days after birth” to “from the day when the milking mouse was 8 days old. It is the same as Example 3 except that each group of suckling mice for diarrhea symptom observation and fecal score evaluation was changed from “6 stomachs” to “7 stomachs”. The method was tested.
２．結果及び考察
結果を図６及び７に示す。図６に示す通り、ロタウイルス感染後３日での下痢の発症率が対照群では９０．５％であったのに対して、乳酸菌投与群では６０．５％と、統計学的に有意に下痢の発症率が減少した（ｐ＜０．０５）。さらに、図７に示す通り、ロタウイルス感染後３日、４日での糞便スコアが対照群では２．０、１．１であったのに対して、乳酸菌投与群では１．３、０．６と、統計学的に有意に糞便スコアが改善した（ｐ＜０．０５）。
以上のように、乳飲みマウスに対してロタウイルス感染後１日より乳酸菌株を経口投与することによって、下痢の発症率の減少および糞便スコアの改善が認められ、乳酸菌がロタウイルス感染症の治療に有効であることが明らかとなった。
2. Results and Discussion The results are shown in FIGS. As shown in FIG. 6, the incidence of diarrhea 3 days after rotavirus infection was 90.5% in the control group, compared with 60.5% in the lactic acid bacteria administration group, which was statistically significant. The incidence of diarrhea decreased (p <0.05). Furthermore, as shown in FIG. 7, the stool scores at 3 days and 4 days after rotavirus infection were 2.0 and 1.1 in the control group, whereas 1.3 and 0. 6, the fecal score improved statistically significantly (p <0.05).
As mentioned above, oral administration of a lactic acid strain from day 1 after rotavirus infection to a suckling mouse resulted in a decrease in the incidence of diarrhea and an improvement in fecal score, and lactic acid bacteria treated rotavirus infection It became clear that it was effective.
［実施例５］（乳酸菌の治療的投与によるロタウイルス感染価の減弱効果）
１．試験方法
乳飲みマウスが生後２日齢の日に、乳酸菌投与群と対照群とに群分けした。群分け後の各群は乳飲みマウスとその母親マウスからなる。生後７日齢の両群の乳飲みマウスにロタウイルス溶液を５０μＬ経口投与して、両群の乳飲みマウスをロタウイルス感染させた。乳飲みマウスが生後８日齢の日に乳酸菌投与群の乳飲みマウスに乳酸菌溶液を、対照群の乳飲みマウスにＰＢＳ（−）を、５０μＬずつ一回経口投与した。生後９日齢の両群の乳飲みマウスから盲腸及び結腸内容物を採取した。なお、盲腸及び結腸内容物の採取を各群乳飲みマウス６腹ずつ行った。
[Example 5] (Attenuating effect of rotavirus infection titer by therapeutic administration of lactic acid bacteria)
1. Test Method On the day when the suckling mice were 2 days old, they were divided into a lactic acid bacteria administration group and a control group. Each group after grouping consists of a suckling mouse and its mother mouse. 50 μL of rotavirus solution was orally administered to both groups of 7-day-old suckling mice to infect both groups of suckling mice with rotavirus. On the day when the suckling mice were 8 days old, the lactobacillus solution was orally administered to the sucking mice in the lactobacillus-administered group once and 50 μL of PBS (−) was once orally administered to the suckling mice in the control group. Cecum and colon contents were collected from both groups of 9-day-old suckling mice. The contents of the cecum and colon were collected from 6 suckling mice in each group.
２．プラークアッセイ法
６ウェルプレートに１．０×１０５ｃｅｌｌs／ｍＬに播いたＣＶ−１細胞（理化学研究所）溶液を２日間培養した。盲腸及び結腸内容物５ｍｇを、終濃度３０μｇ／ｍＬのアセチル化トリプシン（シグマアルドリッチジャパン社）を添加したＥ−ＭＥＭ（シグマアルドリッチジャパン社）中で分散させて、３７℃で３０分間盲腸及び結腸内容物に含まれるロタウイルスを活性化させた。ＣＶ−１細胞をＥ−ＭＥＭを用いて二度洗浄した。ＣＶ−１細胞から培地を除いた後、Ｅ−ＭＥＭを用いて１０倍に段階希釈した活性化ロタウイルス溶液を３００μＬ／ウェルになるように添加して、３７℃で１時間感染させた。Ｅ−ＭＥＭを用いて細胞を一度洗浄した後、１．４％ Ｓｅａｋｅｍ ＭＥアガロース溶液（ロンザジャパン社）と終濃度２μｇ／ｍＬにてブタ膵臓由来トリプシン（シグマアルドリッチジャパン社）を添加した２×Ｅ−ＭＥＭをそれぞれ１：１で混合して、２．５ｍＬ／ウェルになるように添加した。室温で３０分間寒天を凝固させた後、３７℃で３晩インキュベートした。遮光下で、２×Ｅ−ＭＥＭに０．１％ Ｎｅｕｔｒａｌ ｒｅｄ溶液（シグマアルドリッチジャパン社）および１．４％ Ｓｅａｋｅｍ ＭＥアガロース溶液をそれぞれ２×Ｅ−ＭＥＭ：０．１％ Ｎｅｕｔｒａｌ ｒｅｄ溶液：１．４％ Ｓｅａｋｅｍ ＭＥアガロース溶液が１０：１：１０になるように混合して、２ｍＬ/ウェルになるように添加し、室温で３０分間寒天を凝固させた。３７℃で一晩インキュベーションさせた後、プラークをカウントした。
2. Plaque assay method A CV-1 cell (RIKEN) solution seeded in a 6-well plate at 1.0 × 10 5 cells / mL was cultured for 2 days. The cecum and colon contents 5 mg were dispersed in E-MEM (Sigma Aldrich Japan) supplemented with acetylated trypsin (Sigma Aldrich Japan) at a final concentration of 30 μg / mL, and the cecum and colon contents at 37 ° C. for 30 minutes. The rotavirus contained in the product was activated. CV-1 cells were washed twice with E-MEM. After removing the medium from the CV-1 cells, an activated rotavirus solution serially diluted 10-fold with E-MEM was added to 300 μL / well and infected at 37 ° C. for 1 hour. After washing the cells once using E-MEM, 2 × E supplemented with porcine pancreatic trypsin (Sigma Aldrich Japan) at a final concentration of 2 μg / mL with a 1.4% Seake ME agarose solution (Lonza Japan). -MEM was mixed 1: 1 each and added to 2.5 mL / well. The agar was coagulated for 30 minutes at room temperature and then incubated at 37 ° C. for 3 nights. Under shading, 2 × E-MEM was mixed with 0.1% Neutral red solution (Sigma Aldrich Japan) and 1.4% Seake ME agarose solution, respectively. 2 × E-MEM: 0.1% Neutral red solution: 1. A 4% Seake ME agarose solution was mixed at 10: 1: 10, added to 2 mL / well, and the agar was allowed to solidify for 30 minutes at room temperature. Plaques were counted after overnight incubation at 37 ° C.
３．結果及び考察
図８に示す通り、ロタウイルス感染後２日での盲腸及び結腸内容物中のウイルス価は、対照群では中央値９．５（ＰＦＵ／ｍｇ）であったのに対して、乳酸菌投与群では中央値１．７（ＰＦＵ／ｍｇ）であり、統計学的に有意なウイルス価の減少が認められた（ｐ＜０．０１）。したがって、乳酸菌はロタウイルスの感染によって引き起こされる腸管上皮の損傷及び、それに伴う下痢などのロタウイルス感染症状の緩和に有効であることが明らかとなった。
また、ロタウイルスは他のウイルスと比較して、感染性が極めて高く、その感染経路はロタウイルスが多量に存在する糞便を介した経口及び／又は接触感染であることから、ウイルス価の減弱効果を有する乳酸菌はロタウイルスの二次感染を予防する上でも有効であることが明らかとなった。
3. Results and Discussion As shown in FIG. 8, the virus titer in the cecum and colon contents at 2 days after rotavirus infection was median 9.5 (PFU / mg) in the control group, whereas lactic acid bacteria In the administration group, the median was 1.7 (PFU / mg), and a statistically significant reduction in virus titer was observed (p <0.01). Therefore, it has been clarified that lactic acid bacteria are effective in alleviating intestinal epithelial damage caused by rotavirus infection and associated rotavirus infection symptoms such as diarrhea.
In addition, rotavirus is extremely infectious compared to other viruses, and its infection route is oral and / or contact infection via feces in which a large amount of rotavirus is present. It has been clarified that the lactic acid bacteria having an effective in preventing secondary infection of rotavirus.
本発明の剤は、ウイルス感染の予防及び／又は治療に有用である。 The agent of the present invention is useful for prevention and / or treatment of viral infection.
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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| CN117402794A (en) * | 2023-12-12 | 2024-01-16 | 四川厌氧生物科技有限责任公司 | Lactobacillus gasseri and application thereof |
| CN117402794B (en) * | 2023-12-12 | 2024-02-27 | 四川厌氧生物科技有限责任公司 | Lactobacillus gasseri and application thereof |
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