WO2011065300A1 - 抗ウイルス剤及び飲食品組成物 - Google Patents
抗ウイルス剤及び飲食品組成物 Download PDFInfo
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- WO2011065300A1 WO2011065300A1 PCT/JP2010/070666 JP2010070666W WO2011065300A1 WO 2011065300 A1 WO2011065300 A1 WO 2011065300A1 JP 2010070666 W JP2010070666 W JP 2010070666W WO 2011065300 A1 WO2011065300 A1 WO 2011065300A1
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- Prior art keywords
- food
- antiviral
- neutral polysaccharide
- beverage composition
- lactic acid
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to an antiviral agent and a food / beverage product composition, and particularly to an antiviral agent and a food / beverage product composition containing a neutral polysaccharide produced by a specific lactic acid bacterium.
- antiviral drugs that are effective by acting on the virus itself are used. These antiviral drugs are extremely effective against each viral infection, and symptoms can be quickly alleviated by taking early after the onset of illness.
- neuraminidase inhibitors have been developed that inhibit neuraminidase proteins on the surface of viruses and prevent the growth of viruses in the body.
- osetamivir trade name: Tamiflu; Tamiflu is a registered trademark
- zanamivir trademark: Relenza; Relenza
- these drugs are drugs that suppress the growth of viruses and need to be taken early after infection. For example, it must be taken within 48 hours after symptoms appear. In addition, these drugs must be taken continuously for a certain period.
- vaccination prevention by vaccination is also carried out.
- vaccines must be manufactured by specifying the target virus species in advance, and mass production is very time consuming.
- vaccination has the only effect of reducing the risk of increasing severity after infection.
- vaccination requires a certain period of time for the antibody to become established, must be vaccinated before it becomes epidemic, and if the type of vaccine inoculated differs from the type of virus actually infected, There is also a problem that the effect cannot be exhibited.
- NK cells also referred to as natural killer cells
- NK cells spontaneously attack infected cells while the virus infection is small, and suppress the proliferation and spread of the virus.
- type I IFN including interferon (IFN) - ⁇ is produced.
- IFN interferon
- NK cells are activated by type I IFN released from virus-infected cells. Therefore, by enhancing the degree of NK cell activity by virus detection, it is possible to suppress subsequent virus growth and prevent the spread of infection.
- NK cells are also known to attack any virus-infected cell. Therefore, it can be said that NK cells are effective not only for specific viruses such as vaccines but also for a wide variety of viral infections.
- Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (hereinafter sometimes abbreviated as “1073R-1 strain”) is a neutral polysaccharide (NPS) and an acidic polysaccharide (APS) in which a phosphate group is added to the neutral polysaccharide. : Acidic polysaccharide).
- NPS neutral polysaccharide
- APS acidic polysaccharide
- APS acidic polysaccharide
- the present inventors have clarified that acidic polysaccharides (APS) have an effect of enhancing the activity of NK cells (Patent Document 2).
- NK activity is measured by FACS (fluorescence activated cell sorter). Evaluating.
- NPS neutral polysaccharide
- NPS neutral polysaccharide
- an object of the present invention is to provide an antiviral agent that can be safely and easily ingested and enhances the increase in activity that occurs when NK cells responsible for a part of innate immunity obtain a viral stimulus. There is.
- the present inventors have conducted intensive research and found that they can be safely and easily ingested in daily life if they are derived from materials used as food.
- food-grade microorganisms used for yogurt fermentation can produce various useful substances.
- the present inventors pay attention to these food-use microorganisms, isolate a polysaccharide produced by a certain type of fungus, clarify the structure of the polysaccharide, and that the polysaccharide has antiviral activity. I found. That is, the present inventors have found that an increase in the activity of NK cells after stimulation with IFN- ⁇ is enhanced by orally administering this polysaccharide to mice before stimulation with IFN- ⁇ .
- the present invention has been completed.
- one embodiment of the present invention is an antiviral agent containing a neutral polysaccharide produced by lactic acid bacteria as an active ingredient.
- lactic acid bacterium used for the preparation of the antiviral agent of the present invention Lactobacillus delbrueckii ssp. Bulgaricus.
- Particularly preferred examples of the lactic acid bacteria include Lactobacillus delbrueckii ssp. Bulgaricus OLL1073R-1.
- the antiviral agent of the present invention is an antiviral agent comprising a neutral polysaccharide produced by lactic acid bacteria and capable of increasing the activity of NK cells in response to stimulation with IFN- ⁇ as an active ingredient. It is preferable that it is an agent.
- the neutral polysaccharide has a structural unit represented by the following formula (1).
- an antiviral food or beverage composition containing an effective amount of neutral polysaccharide produced by lactic acid bacteria.
- Preferred examples of the lactic acid bacteria used for the preparation of the antiviral food and beverage composition of the present invention include Lactobacillus delbrueckii ssp. Bulgaricus. Particularly preferred examples of the lactic acid bacteria include Lactobacillus delbrueckii ssp. Bulgaricus OLL1073R-1 (may be abbreviated as “1073R-1 strain” in this specification).
- the antiviral food and beverage composition of the present invention is a neutral polysaccharide produced by lactic acid bacteria, and an effective amount of a neutral polysaccharide that can increase the activity of NK cells in response to stimulation with IFN- ⁇ . It is preferable that it is an antiviral food / beverage composition containing.
- the antiviral food or drink composition of the present invention is preferably a fermented milk food or drink.
- yogurt foods and drinks such as yogurt and yogurt drink are particularly preferable.
- the neutral polysaccharide is 0.002 to 0.014% (w / w), particularly 0.002 to 0.004, relative to the total amount of the composition. It is preferably contained in an amount of% (w / w).
- the neutral polysaccharide contained in the antiviral food or beverage composition of the present invention has a structural unit represented by the formula (1).
- the antiviral agent and antiviral food / drink composition of the present invention can be safely and easily ingested, and when NK cells responsible for part of innate immunity have obtained viral stimulation, the activity of NK cells Increase the degree of increase.
- the lactic acid bacteria used in the present invention are not limited as long as they are lactic acid bacteria that produce neutral polysaccharides. Lactic acid bacteria may be used individually by 1 type, and may be used in combination of 2 or more type. Examples of lactic acid bacteria that produce neutral polysaccharides include Lactobacillus delbrueckii ssp. Is mentioned. Among these, Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (deposit number: FERM BP-10741) is preferred.
- the neutral polysaccharide in the antiviral agent or antiviral food or beverage composition of the present invention one kind may be contained alone, or two or more kinds of different kinds may be contained.
- a culture of lactic acid bacteria containing the neutral polysaccharide may be used without being purified as it is, or by using a method described in JP-A-2000-247895.
- neutral polysaccharides isolated from a culture of lactic acid bacteria containing neutral polysaccharides or further purified as necessary may be used.
- the isolation method or the purification method is not particularly limited, and examples thereof include an isolation and purification method according to the following procedure.
- Trichloroacetic acid is added to the medium to a final concentration of 10% to denature the protein and obtain a culture containing the denatured protein.
- the denatured protein and microbial cells are removed from the culture by centrifugation to obtain a polysaccharide-containing product.
- the high molecular weight polysaccharide in the polysaccharide-containing material is precipitated by ethanol precipitation, and the precipitate is collected. 4).
- the acidic polysaccharide in the liquid obtained in 3 above is adsorbed with an anion exchange resin, and the neutral polysaccharide-containing material is recovered from the remaining eluate. 5.
- the neutral polysaccharide-containing material is treated with DNase and RNase to decompose the nucleic acid. 6).
- the neutral polysaccharide-containing material after the treatment in 5 is subjected to proteinase treatment to decompose the protein. 7).
- the neutral polysaccharide-containing material after the treatment of 6 is heated at 90 ° C. for 10 minutes to inactivate the enzyme. 8).
- the neutral polysaccharide-containing material after the treatment of 7 is subjected to ethanol precipitation and dialysis to purify the neutral polysaccharide.
- the neutral polysaccharide obtained from the culture of the 1073R-1 strain by the above isolation and purification method is a polysaccharide having a structural unit represented by the following formula (1) and an estimated molecular weight of about 4.3 MDa.
- the neutral polysaccharide used in the present invention is not only used as a culture of the lactic acid bacteria, but is also a concentrate of the culture, a pasted product processed into a paste, a spray-dried product, a freeze-dried product, a vacuum-dried product, a drum
- the present invention can be used as an object to be processed such as a dried product, a liquid material dispersed in a medium, a diluted product diluted with a diluent, or a crushed product obtained by crushing a dried product with a mill or the like.
- the said process process may be individual or may use multiple together.
- the dosage of the antiviral agent of the present invention containing a neutral polysaccharide as an active ingredient can be appropriately set in consideration of various factors such as the route of administration and the age, weight, and symptoms of animals to be administered including humans. it can.
- the dosage of the antiviral agent of the present invention is not particularly limited, but is preferably 1 mg / kg / day (day) or more, more preferably 5 mg / kg / day or more, as the amount of the neutral polysaccharide as the active ingredient. Particularly preferably, it is 10 mg / kg / day or more. However, when it is taken for the purpose of prevention and / or treatment over a long period of time, the dose of the antiviral agent may be smaller than the above preferred amount.
- the dosage of the antiviral agent is that of the neutral polysaccharide as the active ingredient.
- the amount may be an amount (for example, 100 mg / kg / day) that greatly exceeds the above amount (1 mg / kg / day).
- each value (for example, 1 mg / kg / day or more) regarding the quantity of the said neutral polysaccharide is applied not only to an antiviral agent but also to the food / beverage product composition described later.
- the antiviral agent of the present invention can be administered either orally or parenterally (intramuscular, subcutaneous, intravenous, suppository, transdermal, etc.).
- the dosage form of the antiviral agent of the present invention can be selected according to the therapeutic purpose, administration route, etc., for example, tablets, coated tablets, pills, capsules, granules, powders, liquids, suspensions. , Emulsion, syrup, injection, suppository, soaking agent, decoction, tincture and the like.
- These various preparations are prepared in accordance with conventional methods, as necessary, with respect to the active ingredient, fillers, extenders, excipients, binders, humectants, disintegrants, surfactants, lubricants, coloring agents, flavoring agents. It can be formulated using known adjuvants that can be generally used in the pharmaceutical formulation technical field, such as agents, solubilizers, suspensions, and coating agents.
- the food / beverage product composition of the present invention contains an effective amount of a neutral polysaccharide produced by lactic acid bacteria.
- Examples of the form of the food / beverage composition include fermented milk such as yogurt, beverages, health functional foods, foods for the sick, and the like.
- Japan's health functional food system covers not only ordinary foods but also foods with shapes such as tablets and capsules, based on trends in Japan and overseas and consistency with conventional food systems for specified health use. It is provided and consists of two types of foods for specific health use (individual permission type) and nutritional functional foods (standard type).
- it is possible to prevent and / or treat viral infection by directly ingesting a food or drink containing a neutral polysaccharide that activates NK cells as a food for specified health use or a food with nutritional function.
- various food / beverage products for example, milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crusts, prepared powdered milk, liquid foods, food for the sick, for infants, etc.
- Foods such as powdered milk, foods such as milk powder for breastfeeding women, and nutritional foods
- the neutral polysaccharide as an active ingredient may be added as it is, or may be added after mixing with other foods or food ingredients.
- Neutral polysaccharides can be used according to conventional methods in ordinary food compositions.
- the property of the food / beverage product composition of the present invention may be a normal property of the food / beverage product, for example, solid (powder, granule, etc.), paste, liquid or suspension.
- the main component of the food and drink composition of the present invention is not particularly limited, but water, protein (including degradation products), carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, and flavors. Etc. can be used.
- protein or its degradation products include whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, ⁇ -casein, ⁇ -casein, ⁇ -casein , ⁇ -lactoglobulin, ⁇ -lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and vegetable proteins; hydrolysates thereof; whey, cream, non-protein nitrogen and other milk-derived components .
- sugars include processed starch (in addition to text phosphorus, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and lactose.
- lipids include various milk-derived components such as butter, cream, and phospholipid; animal oils such as lard and fish oil, fractionated oils thereof, hydrogenated oils and transesterified oils; Examples thereof include vegetable oils such as oil, rapeseed oil, coconut oil, fractionated oils thereof, hydrogenated oils and transesterified oils.
- vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline.
- folic acid examples include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and whey mineral.
- the organic acid examples include malic acid, citric acid, lactic acid, and tartaric acid. These components can be used in combination of two or more.
- the main component of the food-drinks composition of this invention may be a synthetic product, and may contain many synthetic products.
- the content of the neutral polysaccharide can be arbitrarily determined according to its purpose, application (antiviral agent, food / beverage product composition) and the like, and is not particularly limited. It is preferably 0.002 to 0.014% (w / w), more preferably 0.002 to 0.004% (w / w) based on the total amount of the product.
- NPS neutral polysaccharide
- the supernatant was recovered by centrifuging the obtained culture solution (12000 g, 4 ° C., 20 minutes). While stirring the supernatant well, an equal volume of cold ethanol was added. Thereafter, the resulting liquid was allowed to stand at 4 ° C. overnight, thereby precipitating a mixture of neutral polysaccharide (NPS) and acidic polysaccharide (APS). The precipitated mixture was recovered by centrifuging the precipitate-containing material. The collected mixture was dissolved in MilliQ water. The obtained aqueous solution was dialyzed against MilliQ water using a dialysis membrane (MWCO 3500, manufactured by SPECTRAM). Further, the aqueous solution after dialysis was 0.02 M Tris-HCl (pH 8.6) solution.
- NPS neutral polysaccharide
- APS acidic polysaccharide
- This aqueous solution was charged into a column packed with an anion exchange resin DEAE Sepharose Fast Flow (trade name; manufactured by GE Healthcare) to adsorb the acidic polysaccharide (APS) to the column.
- DEAE Sepharose Fast Flow trade name; manufactured by GE Healthcare
- APS acidic polysaccharide
- the aqueous solution that passed through the column at this time contained neutral polysaccharide (NPS), and the aqueous solution containing this neutral polysaccharide (NPS) was recovered.
- the recovered aqueous solution containing neutral polysaccharide (NPS) was dialyzed against MilliQ water using a dialysis membrane.
- NPS neutral polysaccharide
- the enzyme was inactivated by heating the solution at 90 ° C. for 10 minutes.
- the obtained aqueous solution containing the neutral polysaccharide (NPS) is cooled to 4 ° C., and then added with an equal amount of cold ethanol while stirring well, and then allowed to stand at 4 ° C. overnight, whereby the neutral polysaccharide ( NPS) was precipitated.
- the neutral polysaccharide (NPS) was recovered as a precipitate by centrifugation, and the recovered neutral polysaccharide (NPS) was dissolved in MilliQ water to obtain a neutral polysaccharide (NPS) aqueous solution.
- a neutral polysaccharide (NPS) aqueous solution was dialyzed against MilliQ water using a dialysis membrane and then freeze-dried.
- NPS neutral polysaccharide
- the prepared spleen cells were measured for NK activity using FACS with YAC-1 cells as target cells.
- the ratio of spleen cells to YAC-1 cells was set to 50: 1.
- the NK activity of spleen cells was measured before and after stimulation with IFN- ⁇ . Stimulation with IFN- ⁇ was performed by incubating spleen cells seeded in a 96-well (round bottom) microplate in a medium supplemented with IFN- ⁇ at 1000 units / ml for 4 hours.
- Example 2 Using 1073R-1 strain, which is a lactic acid bacterium producing NPS in which an effect of enhancing NK activity after stimulation with IFN- ⁇ in Example 1 was used, yogurt was produced as a lactic acid bacterium food and drink by a conventional method.
- NPS neutral polysaccharide
- Example 3 A lactic acid bacterium concentrate was prepared by a conventional method using the 1073R-1 strain, which is a lactic acid bacterium producing NPS, in which the enhancement effect of NK activity after stimulation with IFN- ⁇ was observed in Example 1, and this lactic acid bacterium concentrate A desired antiviral tablet containing a neutral polysaccharide (NPS) corresponding to the antiviral agent of the present invention, wherein a tablet is produced using an appropriate pharmaceutical additive in combination with a conventional method. Got. In addition, you may use the lactic acid bacteria dried material instead of the said lactic acid bacteria concentrate. Moreover, it can also formulate as a capsule or a syrup instead of the said tablet.
- NPS neutral polysaccharide
- Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (1073R-1 strain) in which neutral polysaccharide purified from nonfat dry milk culture was administered the NK activity of spleen cells when stimulated with IFN- ⁇ was higher than that in the group with distilled water Significantly increased. Therefore, it is suggested that the neutral polysaccharide produced by the 1073R-1 strain exhibits antiviral activity by enhancing the increase in NK activity in response to IFN- ⁇ produced when a living body is infected with a virus. Is done. Further, since yogurt using 1073R-1 strain for fermentation contains the neutral polysaccharide, antiviral activity can also be obtained with this yogurt. That is, by taking safe and inexpensive foods every day, it is possible to expect a prophylactic effect that is possible before the virus infection, in which natural immunity is normally increased, and there is no virus specificity like a vaccine.
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Abstract
Description
なお、中性多糖体(NPS)の単離方法は、種々の文献の中で報告されている(特許文献3)。
中性多糖体を生産する乳酸菌の例としては、ラクトバチルス・デルブリュッキー・サブスピーシーズ・ブルガリカス(Lactobacillus delbrueckii ssp. bulgaricus)、ラクトコッカス・ラクティス・サブスピーシーズ・クレモリス(Lactococcus lactis ssp. cremoris)等が挙げられる。これらの中でも、Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1(寄託番号:FERM BP-10741)が好ましい。
本発明の抗ウイルス剤または抗ウイルス用飲食品組成物中の中性多糖体は、1種が単独で含まれていてもよいし、種類の異なる2種以上が含まれていてもよい。
1.培地にトリクロロ酢酸を最終濃度が10%になるように加えて、タンパク質を変性させ、変性タンパク質を含む培養物を得る。
2.遠心分離によって、前記培養物から変性タンパク質と菌体を除去し、多糖体含有物を得る。
3.エタノール沈殿によって、前記多糖体含有物中の高分子量の多糖体を沈殿させ、沈殿物を回収する。
4.陰イオン交換樹脂によって、前記3で得られた液分中の酸性多糖体を吸着させ、残りの溶出液から中性多糖体含有物を回収する。
5.前記中性多糖体含有物に対して、DNase、RNase処理を行い、核酸を分解する。
6.前記5の処理後の中性多糖体含有物に対して、プロテイナーゼ処理を行い、タンパク質を分解する。
7.前記6の処理後の中性多糖体含有物を90℃、10分間加熱して、酵素を失活させる。
8.前記7の処理後の中性多糖体含有物に対して、エタノール沈殿及び透析を行い、中性多糖体を精製する。
なお、前記の中性多糖体の量に関する各値(例えば、1mg/kg/日以上)は、抗ウイルス剤のみならず、後述の飲食品組成物においても適用される。
また、本発明の抗ウイルス剤は、経口投与と非経口投与(筋肉内、皮下、静脈内、坐薬、経皮等)のいずれでも投与できる。
飲食品組成物の形態としては、ヨーグルトのような発酵乳や、飲料や、保健機能食品や、病者用食品等が挙げられる。我国の保健機能食品制度は、国内外の動向、及び、従来からの特定保健用食品制度との整合性を踏まえて、通常の食品のみならず、錠剤、カプセル等の形状を有する食品を対象として設けられたものであり、特定保健用食品(個別許可型)と栄養機能食品(規格基準型)の2種類の類型からなる。本発明においては、NK細胞を活性化する中性多糖体を含有する飲食品を、特定保健用食品または栄養機能食品として直接摂取することによって、ウイルス感染に対する予防および/または治療が可能となる。
タンパク質またはその分解物としては、例えば、全脂粉乳、脱脂粉乳、部分脱脂粉乳、カゼイン、ホエイ粉、ホエイタンパク質、ホエイタンパク質濃縮物、ホエイタンパク質分離物、α―カゼイン、β―カゼイン、κ-カゼイン、β―ラクトグロブリン、α―ラクトアルブミン、ラクトフェリン、大豆タンパク質、鶏卵タンパク質、肉タンパク質等の動植物性タンパク質、これら加水分解物;ホエイ、クリーム、非タンパク態窒素等の各種乳由来成分等が挙げられる。
糖類としては、加工澱粉(テキストリンのほか、可溶性澱粉、ブリティッシュスターチ、酸化澱粉、澱粉エステル、澱粉エーテル等)、食物繊維、乳糖などが挙げられる。
脂質としては、例えば、バター、クリーム、リン脂質等の各種乳由来成分;ラード、魚油等、これらの分別油、水素添加油、エステル交換油等の動物性油脂;パーム油、サフラワー油、コーン油、ナタネ油、ヤシ油、これらの分別油、水素添加油、エステル交換油等の植物性油脂などが挙げられる。
ビタミン類としては、例えば、ビタミンA、カロチン類、ビタミンB群、ビタミンC、ビタミンD群、ビタミンE、ビタミンK群、ビタミンP、ビタミンQ、ナイアシン、ニコチン酸、パントテン酸、ビオチン、イノシトール、コリン、葉酸などが挙げられる。
ミネラル類としては、例えば、カルシウム、カリウム、マグネシウム、ナトリウム、銅、鉄、マンガン、亜鉛、セレン、乳清ミネラルなどが挙げられる。
有機酸としては、例えば、リンゴ酸、クエン酸、乳酸、酒石酸などが挙げられる。
これらの成分は、2種以上を組み合わせて使用することができる。また、本発明の飲食品組成物の主成分は、合成品でもよいし、合成品を多く含むものでもよい。
脱脂粉乳を10%(w/v)でMilliQ水に溶解し、120℃、7分間滅菌して、培地を作製した。本培地を用いて、Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1(1073R-1株)を37℃、18時間、好気条件下で静置培養した。
培養液に100%トリクロロ酢酸(和光純薬工業社製)を最終濃度が10%となるように加え、粘性が無くなるまで、よくかき混ぜた。得られた培養液を遠心分離(12000g、4℃、20分間)することにより、上清を回収した。上清をよくかき混ぜながら、等量の冷エタノールを加えた。その後、得られた液体を4℃で一晩静置することで、中性多糖体(NPS)と酸性多糖体(APS)の混合物を沈澱させた。この沈殿物含有物を遠心分離することによって、沈殿した混合物を回収した。回収した混合物は、MilliQ水に溶解した。得られた水溶液を、透析膜(MWCO3500、SPECTRAM社製)を用いて、MilliQ水に対して透析を行った。さらに、透析後の水溶液を、0.02MのTris-HCl(pH8.6)溶液とした。
この水溶液を、陰イオン交換樹脂DEAE Sepharose Fast Flow(商品名;GE Healthcare社製)を充填したカラムにチャージして、酸性多糖体(APS)をカラムに吸着させた。この時カラムを通過した水溶液には、中性多糖体(NPS)が含まれており、この中性多糖体(NPS)を含む水溶液を回収した。回収した中性多糖体(NPS)を含む水溶液を、透析膜を用いて、MilliQ水に対して透析を行った。透析終了後、中性多糖体(NPS)を含む水溶液を、1mMのMgCl2を含む0.05MのTris-HCl(pH8.0)の溶液とした。この溶液に、最終濃度が2μg/mlとなるように、DNaseI(TypeII、Sigma社製)、及び、RNaseA(Sigma社製)を加えて、37℃、6時間インキュベートすることで、核酸の消化を行った。その後、最終濃度が0.1mg/mlとなるようにProteinase K(Sigma社製)を加えて、37℃、16時間インキュベートすることで、タンパク質の消化を行った。酵素処理の終了後、この溶液を90℃、10分間加熱することで、酵素を失活させた。得られた中性多糖体(NPS)を含む水溶液を、4℃まで冷却後、よくかき混ぜながら、等量の冷エタノールを加え、その後4℃で一晩静置することで、中性多糖体(NPS)を沈澱させた。遠心分離によって、中性多糖体(NPS)を沈澱として回収し、回収した中性多糖体(NPS)をMilliQ水に溶解し、中性多糖体(NPS)水溶液とした。中性多糖体(NPS)水溶液を、透析膜を用いて、MilliQ水に対して透析を行った後、凍結乾燥させた。
[マウスへの経口投与によるNK活性の評価例]
20匹のBALB/cマウス(メス、7週齢)を1週間馴化後、体重を測定し、n=10で平均体重がほぼ同じとなる2群(平均体重:約21g)に群分けした。一方の群はコントロール群として、蒸留水を各個体に0.4ml/day投与し、他方の群には各個体に中性多糖体(NPS)を20μg(0.4ml)/dayの用量で3週間経口投与を行った。その後、マウスを頸椎脱臼にて安楽死させ、脾臓細胞を採取し調製した。
調製した脾臓細胞について、YAC-1細胞をターゲット細胞として、FACSを用いてNK活性の測定を行った。脾臓細胞とYAC-1細胞の比率は50:1になるように設定した。また、脾臓細胞のNK活性の測定は、IFN-αによる刺激前と刺激後の各時点で行った。IFN-αによる刺激は、96穴(丸底)のマイクロプレートに播種した脾臓細胞を、1000unit/mlでIFN-αを添加した培地で4時間インキュベートすることにより行った。
実施例1にてIFN-αによる刺激後のNK活性の増強効果が認められたNPSを産生する乳酸菌である1073R-1株を用いて、常法により、乳酸菌飲食品としてヨーグルトを製造したところ、本発明の飲食品組成物に該当する、中性多糖体(NPS)を含有する所望の抗ウイルス用のヨーグルト食品を得ることができた。
実施例1にてIFN-αによる刺激後のNK活性の増強効果が認められたNPSを産生する乳酸菌である1073R-1株を用いて、常法により乳酸菌濃縮物を作製し、この乳酸菌濃縮物を用いて、常法により適宜の医薬品用添加剤を併用して錠剤を製造して、本発明の抗ウイルス剤に該当する、中性多糖体(NPS)を含有する所望の抗ウイルス用の錠剤を得た。
なお、上記乳酸菌濃縮物の代わりに乳酸菌乾燥物を用いてもよい。また、上記錠剤の代わりにカプセル剤またはシロップ剤として製剤することもできる。
Claims (14)
- 乳酸菌が産生する中性多糖体を有効成分として含む抗ウイルス剤。
- 前記乳酸菌がLactobacillus delbrueckii ssp. bulgaricusである請求項1記載の抗ウイルス剤。
- 前記乳酸菌がLactobacillus delbrueckii ssp. bulgaricus OLL1073R-1である請求項2記載の抗ウイルス剤。
- 乳酸菌が産生する中性多糖体であって、IFN-αによる刺激に応答してNK細胞の活性を上昇させることができる中性多糖体を有効成分として含む抗ウイルス剤。
- 前記抗ウイルス剤は、前記中性多糖体の量が1mg/kg/日以上となるように投与するためのものである、請求項1~4のいずれか1項に記載の抗ウイルス剤。
- 乳酸菌が産生する中性多糖体を有効量含む抗ウイルス用飲食品組成物。
- 前記乳酸菌がLactobacillus delbrueckii ssp. bulgaricusである請求項6記載の抗ウイルス用飲食品組成物。
- 前記乳酸菌がLactobacillus delbrueckii ssp. bulgaricus OLL1073R-1である請求項7記載の抗ウイルス用飲食品組成物。
- 乳酸菌が産生する中性多糖体であって、IFN-αによる刺激に応答してNK細胞の活性を上昇させることができる中性多糖体を有効成分として含む抗ウイルス用飲食品組成物。
- 前記飲食品組成物が発酵乳飲食品である請求項6~9のいずれか1項に記載の抗ウイルス用飲食品組成物。
- 前記発酵乳飲食品がヨーグルト飲食品である請求項10記載の抗ウイルス用飲食品組成物。
- 前記飲食品組成物の全体量中の前記中性多糖体の含有割合が、0.002~0.014%(w/w)である請求項6~11のいずれか1項に記載の抗ウイルス用飲食品組成物。
- 前記飲食品組成物の全体量中の前記中性多糖体の含有割合が、全体量に対して0.002~0.004%(w/w)である請求項6~11のいずれか1項に記載の抗ウイルス用飲食品組成物。
- 前記抗ウイルス用飲食品組成物は、前記中性多糖体の量が1mg/kg/日以上となるように摂取するためのものである、請求項6~13のいずれか1項に記載の抗ウイルス用飲食品組成物。
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WO2015029967A1 (ja) * | 2013-08-26 | 2015-03-05 | 株式会社明治 | 乳酸菌を用いた抗体価上昇剤 |
JPWO2015137501A1 (ja) * | 2014-03-14 | 2017-04-06 | 株式会社明治 | レチノイン酸産生剤 |
US11759485B2 (en) | 2018-06-14 | 2023-09-19 | Meiji Co., Ltd. | Composition for enhancing immune checkpoint blockade therapy |
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Cited By (5)
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JP2014027925A (ja) * | 2012-06-25 | 2014-02-13 | Meiji Co Ltd | 菌体外多糖産生乳酸菌用培地、菌体外多糖産生菌の製造方法、菌体外多糖、菌体外多糖の製造方法、及びヨーグルトの製造方法 |
WO2015029967A1 (ja) * | 2013-08-26 | 2015-03-05 | 株式会社明治 | 乳酸菌を用いた抗体価上昇剤 |
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JPWO2015137501A1 (ja) * | 2014-03-14 | 2017-04-06 | 株式会社明治 | レチノイン酸産生剤 |
US11759485B2 (en) | 2018-06-14 | 2023-09-19 | Meiji Co., Ltd. | Composition for enhancing immune checkpoint blockade therapy |
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HK1174834A1 (en) | 2013-06-21 |
JP5971949B2 (ja) | 2016-08-17 |
JPWO2011065300A1 (ja) | 2013-04-11 |
JP2015070855A (ja) | 2015-04-16 |
CN102647991B (zh) | 2015-05-06 |
CN102647991A (zh) | 2012-08-22 |
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