JP4601745B2 - Formulation with synergistic enhancement of immunostimulatory effect - Google Patents
Formulation with synergistic enhancement of immunostimulatory effect Download PDFInfo
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- JP4601745B2 JP4601745B2 JP23543199A JP23543199A JP4601745B2 JP 4601745 B2 JP4601745 B2 JP 4601745B2 JP 23543199 A JP23543199 A JP 23543199A JP 23543199 A JP23543199 A JP 23543199A JP 4601745 B2 JP4601745 B2 JP 4601745B2
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- ascorbic acid
- lactobacillus plantarum
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- nigerosyl
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Description
【０００１】
【発明の属する技術分野】
本発明は、免疫賦活効果を相乗的に増強した製剤、さらに詳しくは、相乗的に増強した免疫賦活作用により、優れた免疫増強、生体機能の調節、保健強壮効果を発揮する医薬品、医薬部外品、食品、飼料、化粧料として有用な製剤に関する。
【０００２】
【従来の技術】
従来から、免疫賦活作用を有する物質が種々知られており、アスコルビン酸も免疫賦活作用を有することが知られている（Int. J. Vitam. Nutr. Res. Suppl., 1982, 23:49-52；Am. J. Clin. Nutr., 1976, 29(7), 762-765等）。また、乳酸菌や、ニゲロオリゴ糖も、免疫賦活作用を有することが知られている（Can. J. Microbiol., 1992, 38:774-778; J. Allergy Clin. Immunol., 1998, 102:57-64; Biosci. Biotechnol. Biochem., 1999, 63:373-378等）。一方、これらの免疫賦活作用を有する物質を有効成分とする医薬品、食品等として有用な免疫増強剤や、生体機能調節剤が提案されている（特開平３−２２９５８号、特開平９−３０９８１号、特開平９−５２８３４号、特開平１０−１６７９７２号等）。
【０００３】
【発明が解決しようとする課題】
本発明は、より優れた免疫賦活作用を発揮する免疫増強剤や生体機能調節剤を提供することを目的とする。
【０００４】
【課題を解決する手段】
本発明者らは、免疫賦活物質について種々研究した結果、アスコルビン酸と、他の免疫賦活物質、特に、乳酸菌やニゲロオリゴ糖を併用した場合、免疫賦活効果が相乗的に増強されることを見出した。アスコルビン酸とこれらを組み合わせた場合、免疫賦活効果が相乗的に増強されることは、未だ、報告されていない。
本発明は、このような本発明者らの新規な知見に基づいて完成されたものであって、
【０００５】
アスコルビン酸および他の免疫賦活物質を含有してなることを特徴とする医薬品、医薬部外品、食品、飼料または化粧料用製剤、特に、他の免疫賦活物質が、乳酸菌、とりわけ、ラクトバチルス（Lactobacillus）属に属する菌、それらの処理物、および３−Ｏ−α−Ｄ−グルコピラノシル−Ｄ−グルコースを構成単位として含有する糖類からなる群から選択される１種以上の免疫賦活物質である製剤を提供するものである。
【０００６】
【発明の実施の形態】
本発明において用いるアスコルビン酸は、遊離のアスコルビン酸のみならず、例えば、そのナトリウム、カリウム、カルシウム、マグネシウム等のアルカリ金属およびアルカリ土類金属塩、Ｌ−アスコルビン酸−２−リン酸エステルのような誘導体の１種または２種以上が使用できる。その製剤への配合量は、所望の免疫賦活作用により適宜選択できるが、経口剤の場合、吸収率を考慮して、遊離のアスコルビン酸として、成人１日当り、１０ｍｇ〜１０ｇ、好ましくは、５０ｍｇ〜５ｇ、さらに好ましくは、２００ｍｇ〜２ｇ摂取されるよう設定するのが望ましい。すなわち、通常、その製剤への配合量は、１日摂取量の目安が４ｇの錠剤の場合、製剤に対して遊離のアスコルビン酸として、０．２５〜９５重量％、好ましくは、１．２５〜９５重量％、さらに好ましくは、５〜５０重量％であり、５０ｍｌ程度のドリンク剤の場合、製剤に対して遊離のアスコルビン酸として、０．０２〜２０重量％、好ましくは、０．１〜１０重量％、さらに好ましくは、０．４〜４重量％であり、５００ｍｌ程度の飲料の場合、製剤に対して遊離のアスコルビン酸として、０．００２〜２重量％、好ましくは、０．０１〜１重量％、さらに好ましくは、０．０４〜０．４重量％である。また、注射剤、輸液剤の場合は遊離のアスコルビン酸として、成人１日当り、５ｍｇ〜５ｇ、好ましくは、２５ｍｇ〜２．５ｇ、さらに好ましくは、１００ｍｇ〜１ｇ投与されるよう設定するのが望ましい。すなわち、通常、５ｍｌ程度の注射剤の場合、製剤に対して遊離のアスコルビン酸として、０．１〜１０重量％、好ましくは、０．５〜１０重量％、さらに好ましくは２〜１０重量％であり、５００ｍｌ程度の輸液剤の場合、製剤に対して遊離のアスコルビン酸として、０．００１〜１重量％、好ましくは、０．００５〜０．５重量％、さらに好ましくは、０．０２〜０．２重量％である。
【０００７】
他の免疫賦活物質としては、乳酸菌、その処理物および３−Ｏ−α−Ｄ−グルコピラノシル−Ｄ−グルコースを構成単位として含有する糖類からなる群から選択される１種以上の免疫賦活物質である。
乳酸菌としては、とりわけ、ラクトバチルス（Lactobacillus）属に属する菌、例えば、ラクトバチルス・プランタラム（Lactobacillus plantarum）があげられ、具体的には、ラクトバチルス・プランタラムＬ−１３７株（Lactobacillus plantarum L-137）（平成７年１１月３０日より、受託番号ＦＥＲＭ Ｐ−１５３１７の下、工業技術院生命工学工業技術研究所に寄託してある）が好適に使用できる。
乳酸菌の処理物としては、本発明において用いる菌により食品を発酵させてなる、菌体を含んだ発酵物をそのまま用いてもよいし、発酵物から菌体を採取し、生菌のまま、または、例えば、加熱、紫外線照射等により不活性化し、ペースト状態あるいは乾燥して用いることもできる。分離した生菌体、死菌体をさらに摩砕、破砕、酵素分解、抽出処理をし、得られた処理物を必要により加熱滅菌、乾燥して用いることもできる。
これらの配合量も適宜選択できるが、経口剤の場合、吸収率を考慮して、成人１日当り、乾燥菌体として０．２ｍｇ〜１ｇ、好ましくは、１ｍｇ〜５００ｍｇ、さらに好ましくは、５ｍｇ〜２００ｍｇ摂取されるよう設定するのが望ましい。すなわち、通常、その製剤への配合量は、１日摂取量の目安が４ｇの錠剤の場合、製剤に対して乾燥菌体として、０．００５〜２５重量％、好ましくは、０．０２５〜１２．５重量％、さらに好ましくは、０．１２５〜５重量％であり、５０ｍｌ程度のドリンク剤の場合、製剤に対して乾燥菌体として、０．０００４〜２重量％、好ましくは、０．００２〜１重量％、さらに好ましくは、０．０１〜０．４重量％であり、５００ｍｌ程度の飲料の場合、製剤に対して乾燥菌体として、０．００００４〜０．２重量％、好ましくは、０．０００２〜０．１重量％、さらに好ましくは、０．００１〜０．０４重量％である。また、注射剤、輸液剤の場合は、乾燥菌体として、成人１日当り、０．００４ｍｇ〜５０ｍｇ、好ましくは、０．０２ｍｇ〜２５ｍｇ、さらに好ましくは、０．１ｍｇ〜１０ｍｇ投与されるよう設定するのが望ましい。すなわち、通常、５ｍｌ程度の注射剤の場合、製剤に対して乾燥菌体として、０．００００８〜１重量％、好ましくは、０．０００４〜０．５重量％、さらに好ましくは、０．００２〜０．２重量％であり、５００ｍｌ程度の輸液剤の場合、製剤に対して乾燥菌体として、０．００００００８〜０．０１重量％、好ましくは、０．０００００４〜０．００５重量％、さらに好ましくは、０．００００２〜０．００２重量％である。
【０００８】
３−Ｏ−α−Ｄ−グルコピラノシル−Ｄ−グルコースを構成単位として含有する糖類としては、例えば、ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースおよびこれらのニゲロオリゴ糖の混合物が挙げられる。これらの配合量も適宜選択できるが、経口剤の場合、吸収率を考慮して、ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、成人１日当り、４ｍｇ〜４０ｇ、好ましくは、１０ｍｇ〜１０ｇ、さらに好ましくは、５０ｍｇ〜５ｇ摂取されるよう設定するのが望ましい。すなわち、通常、その製剤への配合量は、１日摂取量の目安が４ｇの錠剤の場合、製剤に対してニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．１〜９５重量％、好ましくは、０．２５〜９５重量％、さらに好ましくは、１．２５〜９５重量％であり、５０ｍｌ程度のドリンク剤の場合、製剤に対してニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．００８〜４０重量％、好ましくは、０．０２〜２０重量％、さらに好ましくは、０．１〜１０重量％であり、５００ｍｌ程度の飲料の場合、製剤に対してニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．０００８〜８重量％、好ましくは、０．００２〜２重量％、さらに好ましくは、０．０１〜１重量％である。また、注射剤、輸液剤の場合はニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、成人１日当り、０．４ｍｇ〜４ｇ、好ましくは、１ｍｇ〜１ｇ、さらに好ましくは、５ｍｇ〜５００ｍｇ投与されるよう設定するのが望ましい。すなわち、通常、５ｍｌ程度の注射剤の場合、製剤に対してニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．００８〜２０重量％、好ましくは、０．０２〜２０重量％、さらに好ましくは、０．１〜１０重量％であり、５００ｍｌ程度の輸液剤の場合、製剤に対してニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．００００８〜０．８重量％、好ましくは、０．０００２〜０．２重量％、さらに好ましくは、０．００１〜０．１重量％である。
本発明においては、アスコルビン酸と上記の乳酸菌および３−Ｏ−α−Ｄ−グルコピラノシル−Ｄ−グルコースを構成単位として含有する糖類とを併用してもよく、その場合の配合量も適宜選択することができるが、通常、１日摂取量の目安が４ｇの錠剤の場合、製剤に対して遊離のアスコルビン酸として、０．１２５〜５０重量％、好ましくは、０．６７５〜５０重量％、さらに好ましくは、２．５〜２５重量％であり、乳酸菌の乾燥菌体として、０．００２５〜１２．５重量％、好ましくは、０．０１２５〜６．７５重量％、さらに好ましくは、０．０６７５〜２．５重量％であり、ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．０５〜５０重量％、好ましくは、０．１２５〜５０重量％、さらに好ましくは、０．６７５〜５０重量％である。５０ｍｌ程度のドリンク剤の場合、製剤に対して遊離のアスコルビン酸として、０．０１〜１０重量％、好ましくは、０．０５〜５重量％、さらに好ましくは、０．２〜２重量％であり、乳酸菌の乾燥菌体として、０．０００２〜１重量％、好ましくは、０．００１〜０．５重量％、さらに好ましくは、０．００５〜０．２重量％であり、ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．００４〜２０重量％、好ましくは、０．０１〜１０重量％、さらに好ましくは、０．０５〜５重量％である。５００ｍｌ程度の飲料の場合、製剤に対して遊離のアスコルビン酸として、０．００１〜１重量％、好ましくは、０．００５〜０．５重量％、さらに好ましくは、０．０２〜０．２重量％であり、乳酸菌の乾燥菌体として、０．００００２〜０．１重量％、好ましくは、０．０００１〜０．０５重量％、さらに好ましくは、０．０００５〜０．０２重量％であり、ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．０００４〜４重量％、好ましくは、０．００１〜１重量％、さらに好ましくは、０．００５〜０．５重量％である。５ｍｌ程度の注射剤の場合、製剤に対して遊離のアスコルビン酸として、０．０５〜５重量％、好ましくは、０．２５〜５重量％、さらに好ましくは、１〜５重量％であり、乳酸菌の乾燥菌体として０．００００４〜０．５重量％、好ましくは、０．０００２〜０．２５重量％、さらに好ましくは、０．００１〜０．１重量％であり、ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として、０．００４〜１０重量％、好ましくは、０．０１〜１０重量％、さらに好ましくは、０．０５〜５重量％である。５００ｍｌ程度の輸液剤の場合、製剤に対して遊離のアスコルビン酸として、０．０００５〜０．５重量％、好ましくは、０．００２５〜０．２５重量％、さらに好ましくは、０．０１〜０．１重量％であり、乳酸菌の乾燥菌体として、０．００００００４〜０．００５重量％、好ましくは、０．０００００２〜０．００２５重量％、さらに好ましくは０．００００１〜０．００１重量％であり、ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖混合物として０．００００４〜０．４重量％、好ましくは、０．０００１〜０．１重量％、さらに好ましくは、０．０００５〜０．０５重量％である。
【０００９】
本発明の製剤は、公知の賦形剤ないしは担体を用い、自体公知の方法に従い、例えば、経口、非経口、外用等の経路で適用できる、例えば、錠剤、顆粒、カプセル入り、粉末、クリーム、ペーストのような固体または溶液、シロップ、乳液、懸濁液のような液体の剤形の医薬品、医薬部外品、食品または化粧料用製剤とすることができる。
用いる賦形剤ないしは担体としては、例えば、デキストリン、コーンスターチ、乳糖、セルロース、メチルセルロースのような固体賦形剤、水、生理食塩水、プロピレングリコール、エタノールのような液体賦形剤が挙げられる。
【００１０】
本発明の製剤は、経口、非経口、外用等で適用することにより、相乗的に増強された免疫賦活作用から、ウイルス、バクテリア等の微生物による感染症、例えば、経口感染によるコレラ菌、毒素原性大腸菌、赤痢菌、サルモネラ菌、ウイルス等の感染性腸炎や、気道感染によるインフルエンザ、かぜ症候群等や、口腔内感染による口内炎、歯周疾患等、また、各種悪性腫瘍、例えば、消化管や呼吸器粘膜、肝・腎等の実質臓器に発生する上皮性悪性腫瘍や、運動器や軟部組織等に発生する非上皮性悪性腫瘍の予防や治療に有効である。また、本発明の製剤はＩＬ−１２および／またはＩＦＮ−γ産生誘導作用を有し、Ｔヘルパー機能をＴｈ１型に傾けるために、腫瘍により誘導される免疫抑制状態や抗癌剤治療により誘導される免疫機能低下からの回復に適しており、後天性免疫不全症候群（ＡＩＤＳ）の発症予防にも有効であり、リステリア菌、サルモネラ菌、結核菌、癩菌等の細胞内寄生性細菌に対しても有効であり、Ｉ型アレルギーの予防や治療に有効であり、ストレスに起因するＴｈ１型免疫機能低下の改善に有効であり、加齢に伴う免疫機能低下の抑制等にも適しており、また、細胞内寄生性細菌のクラミジア菌に対する感染防御作用により、クラミジア菌感染との関わりが強く示唆されている動脈硬化発症に対しても予防的にはたらくなど、種々の生体機能調節、各種疾患に対する抵抗性の向上、日常の保健強壮の促進に有効である。
【００１１】
【実施例】
以下に試験例および実施例を挙げて、本発明をさらに詳しく説明するが、本発明はこれらに限定されるものではない。
試験例１
本試験例では、ラクトバチルス・プランタラムＬ−１３７乾燥死菌体とアスコルビン酸を用いて、マウス脾臓細胞のインターロイキン１２およびインターフェロンγ産生誘導に対するラクトバチルス・プランタラムＬ−１３７乾燥死菌体とアスコルビン酸の相乗効果を検証した。
マウス（ＢＡＬＢ／ｃ、雌、２２週齡）から脾臓を摘出し、ＲＰＭＩ１６４０培地中で押し潰し、♯２００メッシュに通し脾臓細胞浮遊液を得た。脾臓細胞浮遊液の細胞数を自動血球計測装置で測定した後、細胞数を５×１０6／ｍｌの濃度にＲＰＭＩ１６４０培地で調製し、９６穴組織培養プレートに１穴あたり１００μｌを播種した。
これにラクトバチルス・プランタラムＬ−１３７乾燥死菌体を０．４μｇ／ｍｌの濃度でＲＰＭＩ１６４０培地に分散させた液またはＲＰＭＩ１６４０培地をそれぞれ１穴あたり５０μｌ加えた。さらに、ＲＰＭＩ１６４０培地（対照）またはアスコルビン酸を２０、４０または８０μｇ／ｍｌ濃度でＲＰＭＩ１６４０培地に溶解した液をそれぞれ１穴あたり５０μｌ加え、３７℃の５％炭酸ガス培養器内で７日間培養し、培養後の培養上清のインターロイキン１２およびインターフェロンγをエンザイムイムノアッセイで測定した。
エンザイムイムノアッセイは、ラット抗マウスインターロイキン１２ＩｇＧ２ａ抗体（Genzyme社製）またはハムスター抗マウスインターフェロンγ抗体（Genzyme社製）をホウ酸緩衝液で２μｇ／ｍｌに調製した溶液を、９６穴組織培養プレート１穴あたり１００μｌ加え３７℃で１夜放置しラット抗マウスインターロイキン１２ＩｇＧ２ａ抗体またはハムスター抗マウスインターフェロンγ抗体を各穴に付着させたプレートを用いて行った。培養上清を１穴あたり５０μｌ加え室温で９０分間放置し、培養上清のインターロイキン１２またはインターフェロンγをプレートに付着したラット抗マウスインターロイキン１２ＩｇＧ２ａ抗体またはハムスター抗マウスインターフェロンγ抗体と結合させた。洗浄後、ラット抗マウスインターロイキン１２ＩｇＧ１抗体（Genzyme社製）またはラット抗マウスインターフェロンγＩｇＧ１抗体（Upstate Biotechnology社製）を加え、プレートに結合させたインターロイキン１２またはインターフェロンγに結合させた。洗浄後ペルオキシダーゼで標識した抗ラットＩｇＧ１抗体を加え、プレートに結合させたラット抗マウスインターロイキン１２ＩｇＧ１抗体またはラット抗マウスインターフェロンγＩｇＧ１抗体に結合させた。洗浄後、過酸化水素０．００６％とオルトフェニレンジアミン０．１％を含有するリン酸緩衝液を１穴あたり１００μｌ加え、室温で４０分間反応させ、反応を１．５Ｎ硫酸で停止し、マイクロプレートリーダーで吸光度４９２ｎｍを測定し、リコンビナントマウスインターロイキン１２またはインターフェロンγで作成した標準曲線から、培養上清中のインターロイキン１２またはインターフェロンγの濃度を求めた。
表１にその結果を示す。
【００１２】
【表１】
表１から明らかなごとく、アスコルビン酸単独ではインターロイキン１２並びにインターフェロンγの産生を誘導しなかったが、ラクトバチルス・プランタラムＬ−１３７乾燥死菌体で誘導されたインターロイキン１２およびインターフェロンγの産生をアスコルビン酸は有意に上昇させた。インターロイキン１２およびインターフェロンγ産生誘導におけるラクトバチルス・プランタラムＬ−１３７乾燥死菌体とアスコルビン酸の相乗効果が検証された。
【００１４】
試験例２
本試験例では、ラクトバチルス・プランタラムＬ−１３７乾燥死菌体とニゲロオリゴ糖とアスコルビン酸を用いて、マウス脾臓細胞のインターロイキン１２およびインターフェロンγ産生誘導に対するラクトバチルス・プランタラムＬ−１３７乾燥死菌体とニゲロオリゴ糖（ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖の混合物）とアスコルビン酸の相乗効果を検証した。
マウス（ＢＡＬＢ／ｃ、雌、２２週齡）から脾臓を摘出し、ＲＰＭＩ１６４０培地中で押し潰し、♯２００メッシュに通し脾臓細胞浮遊液を得た。脾臓細胞浮遊液の細胞数を自動血球計測装置で測定した後、細胞数を１０×１０6／ｍｌの濃度にＲＰＭＩ１６４０培地で調製し、９６穴組織培養プレートに１穴あたり５０μｌを播種した。
これにラクトバチルス・プランタラムＬ−１３７乾燥死菌体を０．４μｇ／ｍｌの濃度で分散させ、ニゲロオリゴ糖を４μｇ／ｍｌ濃度で溶解したＲＰＭＩ１６４０培地をそれぞれ１穴あたり５０μｌ加えた。さらに、ＲＰＭＩ１６４０培地（対照）またはアスコルビン酸を２０、４０、８０または１６０μｇ／ｍｌ濃度でＲＰＭＩ１６４０培地に溶解した液をそれぞれ１穴あたり５０μｌ加え、３７℃の５％炭酸ガス培養器内で７日間培養し、培養後の培養上清のインターロイキン１２およびインターフェロンγをエンザイムイムノアッセイで測定した。
表２にその結果を示す。
【００１５】
【表２】
表２から明らかなごとくラクトバチルス・プランタラムＬ−１３７乾燥死菌体とニゲロオリゴ糖からなる組成物で誘導されたインターロイキン１２およびインターフェロンγの産生をアスコルビン酸は有意に上昇させた。インターロイキン１２およびインターフェロンγ産生誘導におけるラクトバチルス・プランタラムＬ−１３７乾燥死菌体とニゲロオリゴ糖とアスコルビン酸の相乗効果が検証された。
【００１７】
実施例１
アスコルビン酸、ニゲロースおよび乳酸菌配合の清涼飲料水
下記配合に従い、ニゲロース、ラクトバチルス・プランタラムＬ−１３７乾燥菌体、レモン果汁、グラニュー糖、果糖ブドウ糖液糖、精製ハチミツ、アスコルビン酸、クエン酸、レモンフレーバーに純水を５００ｍｌ加え攪拌後、１０分間超音波処理し懸濁溶解させ、１０００ｍｌに調整した後、６５℃で１０分間殺菌して清涼飲料水を得た。得られた清涼飲料水はニゲロースを約１．５％、アスコルビン酸を１％、ラクトバチルス・プランタラムＬ−１３７菌体を約０．０２％含有する。
成 分 量
ニゲロース １５．０ｇ
アスコルビン酸 １０．０ｇ
ラクトバチルス・プランタラムＬ−１３７乾燥菌体 ０．２ｇ
レモン果汁 ９．４ｇ
グラニュー糖 １５．４ｇ
果糖ブドウ糖液糖 ７４．０ｇ
精製ハチミツ ２２．２ｇ
クエン酸 １．５ｇ
レモンフレーバー １．６ｇ
【００１８】
実施例２
アスコルビン酸および乳酸菌配合の顆粒剤
下記配合に従い、各成分を均一に混合し、造粒破砕後、乾燥して顆粒剤とした。
成 分 量
アスコルビン酸 ６０ｇ
ラクトバチルス・プランタラムＬ−１３７乾燥菌体 １ｇ
乳糖 １５０ｇ
結晶セルロース １５ｇ
ブドウ糖 ７１ｇ
【００１９】
実施例３
アスコルビン酸および乳酸菌配合の錠剤
実施例２で得られた顆粒剤９９ｇにステアリン酸カルシウム１ｇを混合し、打錠機で圧縮整形して９００ｍｇの錠剤を得た。得られた錠剤は一錠あたり、アスコルビン酸を約１８０ｍｇ、ラクトバチルス・プランタラムＬ−１３７菌体を約３ｍｇ含有する。
【００２０】
実施例４
アスコルビン酸、乳酸菌およびニゲロオリゴ糖配合の注射剤
アスコルビン酸１０ｇ、ニゲロオリゴ糖（ニゲロース、ニゲロシルグルコース、ニゲロシルマルトースからなるニゲロオリゴ糖の混合物）２ｇ、ラクトバチルス・プランタラムＬ−１３７乾燥菌体０．０５ｇを精製水１０００ｍｌに懸濁させ、超音波処理した後、凍結乾燥した。この凍結乾燥物を５００本のバイアル瓶に分注して注射剤を得た。この注射剤１バイアルには凍結乾燥物２４．１ｍｇが含まれており、２ｍｌの生理食塩水に容易に懸濁溶解した。
【００２１】
実施例５
アスコルビン酸、乳酸菌およびニゲロオリゴ糖配合のカプセル剤
下記の配合に従い、各成分を均一に混合し、ゼラチンカプセルに充填し、カプセル１個あたり、ニゲロオリゴ糖を１００ｍｇ、アスコルビン酸５０ｍｇ、ラクトバチルス・プランタラムＬ−１３７菌体を３ｍｇ含有するカプセル剤を得た。
成 分 量
ニゲロオリゴ糖 １００ｍｇ
アスコルビン酸 ５０ｍｇ
ラクトバチルス・プランタラムＬ−１３７乾燥菌体 ３ｍｇ
コーンスターチ ３０ｍｇ
ステアリン酸マグネシウム １０ｍｇ[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a preparation that synergistically enhances the immunostimulatory effect, and more specifically, a pharmaceutical that exhibits superior immune enhancement, biological function regulation, health tonic effect, and quasi-drug by synergistically enhanced immunostimulatory action. The present invention relates to a preparation useful as a product, food, feed or cosmetic.
[0002]
[Prior art]
Conventionally, various substances having an immunostimulatory action are known, and ascorbic acid is also known to have an immunostimulatory action (Int. J. Vitam. Nutr. Res. Suppl., 1982, 23: 49- 52; Am. J. Clin. Nutr., 1976, 29 (7), 762-765, etc.). Lactic acid bacteria and nigerooligosaccharides are also known to have an immunostimulatory effect (Can. J. Microbiol., 1992, 38: 774-778; J. Allergy Clin. Immunol., 1998, 102: 57- 64; Biosci. Biotechnol. Biochem., 1999, 63: 373-378). On the other hand, immunopotentiators and biological function regulators useful as pharmaceuticals, foods, etc., containing these substances having an immunostimulatory action as active ingredients have been proposed (JP-A-3-22958, JP-A-9-30981). JP-A-9-52834, JP-A-10-167972, etc.).
[0003]
[Problems to be solved by the invention]
An object of this invention is to provide the immunopotentiator and biological function regulator which exhibit the more superior immunostimulatory effect.
[0004]
[Means for solving the problems]
As a result of various studies on immunostimulatory substances, the present inventors have found that when ascorbic acid and other immunostimulatory substances, particularly lactic acid bacteria and nigerooligosaccharides are used in combination, the immunostimulatory effect is synergistically enhanced. . It has not yet been reported that when these are combined with ascorbic acid, the immunostimulatory effect is synergistically enhanced.
The present invention has been completed based on such novel findings of the present inventors,
[0005]
A pharmaceutical, quasi-drug, food, feed or cosmetic preparation characterized in that it contains ascorbic acid and other immunostimulatory substances, in particular, other immunostimulatory substances are lactic acid bacteria, especially lactobacilli ( Lactobacillus), a processed product thereof, and a preparation that is one or more immunostimulatory substances selected from the group consisting of saccharides containing 3-O-α-D-glucopyranosyl-D-glucose as a constituent unit Is to provide.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
Ascorbic acid used in the present invention is not only free ascorbic acid but also, for example, alkali metal and alkaline earth metal salts such as sodium, potassium, calcium, magnesium, L-ascorbic acid-2-phosphate, etc. One or more of the derivatives can be used. The amount to be added to the preparation can be appropriately selected depending on the desired immunostimulatory action, but in the case of an oral preparation, considering the absorption rate, free ascorbic acid is 10 mg to 10 g per day for an adult, preferably 50 mg to It is desirable to set 5 g, more preferably 200 mg to 2 g. That is, normally, the amount of compounded in the preparation is 0.25 to 95% by weight, preferably 1.25 to 95% by weight as free ascorbic acid with respect to the preparation when the daily intake is 4 g. 95% by weight, more preferably 5 to 50% by weight. In the case of a drink of about 50 ml, 0.02 to 20% by weight as free ascorbic acid with respect to the preparation, preferably 0.1 to 10% % By weight, more preferably 0.4 to 4% by weight. In the case of a beverage of about 500 ml, 0.002 to 2% by weight as free ascorbic acid with respect to the preparation, preferably 0.01 to 1%. % By weight, more preferably 0.04 to 0.4% by weight. In the case of injections and infusions, it is desirable to set the dose of free ascorbic acid such that 5 mg to 5 g, preferably 25 mg to 2.5 g, more preferably 100 mg to 1 g per day for an adult. That is, usually in the case of an injection of about 5 ml, the free ascorbic acid is 0.1 to 10% by weight, preferably 0.5 to 10% by weight, more preferably 2 to 10% by weight as the free preparation. In the case of an infusion of about 500 ml, 0.001 to 1% by weight, preferably 0.005 to 0.5% by weight, more preferably 0.02 to 0% as free ascorbic acid with respect to the preparation .2% by weight.
[0007]
The other immunostimulatory substance is one or more immunostimulatory substances selected from the group consisting of lactic acid bacteria, processed products thereof, and saccharides containing 3-O-α-D-glucopyranosyl-D-glucose as a structural unit. .
Examples of lactic acid bacteria include bacteria belonging to the genus Lactobacillus, such as Lactobacillus plantarum, and specifically, Lactobacillus plantarum L-137 strain (Lactobacillus plantarum L-137). 137) (from November 30, 1995 under the deposit number FERM P-15317 has been deposited with the Institute of Biotechnology, Industrial Technology Institute).
As a processed product of lactic acid bacteria, a fermented product containing bacterial cells obtained by fermenting food with the bacteria used in the present invention may be used as it is, or the bacterial cells are collected from the fermented product and remain live, or For example, it can be inactivated by heating, ultraviolet irradiation, etc., and used in a paste state or dried. The separated live cells and dead cells can be further ground, crushed, enzymatically decomposed, and extracted, and the resulting processed product can be used after heat sterilization and drying, if necessary.
Although these compounding amounts can also be selected as appropriate, in the case of oral preparations, considering the absorption rate, 0.2 mg to 1 g, preferably 1 mg to 500 mg, more preferably 5 mg to 200 mg as dry cells per day for an adult. It is desirable to set it to be ingested. That is, normally, when the tablet is a tablet with a daily intake standard of 4 g, the blending amount in the preparation is 0.005 to 25% by weight, preferably 0.025 to 12% as dry cells with respect to the preparation. 0.5 wt%, more preferably 0.125 to 5 wt%, and in the case of a drink of about 50 ml, 0.0004 to 2 wt%, preferably 0.002 -1% by weight, more preferably 0.01-0.4% by weight. In the case of a beverage of about 500 ml, 0.00004-0.2% by weight, 0.0002 to 0.1% by weight, more preferably 0.001 to 0.04% by weight. In the case of injections and infusions, it is set so that 0.004 mg to 50 mg, preferably 0.02 mg to 25 mg, more preferably 0.1 mg to 10 mg is administered per day as an adult dry cell. Is desirable. That is, usually, in the case of an injection of about 5 ml, 0.00008 to 1% by weight, preferably 0.0004 to 0.5% by weight, more preferably 0.002 to 0.002% by weight as dry cells relative to the preparation. In the case of an infusion of about 500 ml, it is 0.0000008 to 0.01% by weight, preferably 0.000004 to 0.005% by weight, more preferably Is 0.00002 to 0.002% by weight.
[0008]
Examples of the saccharide containing 3-O-α-D-glucopyranosyl-D-glucose as a structural unit include nigerose, nigerosyl glucose, nigerosyl maltose, and a mixture of these nigerooligosaccharides. Although these compounding amounts can also be selected as appropriate, in the case of oral preparations, taking into account the absorption rate, a nigerooligosaccharide mixture comprising nigerose, nigerosyl glucose, nigerosyl maltose, 4 mg to 40 g, preferably 10 mg per adult day -10 g, more preferably 50 mg to 5 g. That is, normally, when the tablet is a tablet with a daily intake standard of 4 g, the blending amount in the preparation is 0.1 to 95 as a nigerooligosaccharide mixture comprising nigerose, nigerosyl glucose and nigerosyl maltose with respect to the preparation. % By weight, preferably 0.25 to 95% by weight, more preferably 1.25 to 95% by weight. In the case of a drink of about 50 ml, from the preparations nigerose, nigerosyl glucose, nigerosyl maltose As a nigerooligosaccharide mixture, it is 0.008 to 40% by weight, preferably 0.02 to 20% by weight, more preferably 0.1 to 10% by weight. As a nigerooligosaccharide mixture composed of nigerose, nigerosyl glucose, nigerosyl maltose, 0.0008-8 wt%, Mashiku is 0.002 wt%, more preferably 0.01 to 1 wt%. In the case of injections and infusions, a nigerooligosaccharide mixture consisting of nigerose, nigerosyl glucose and nigerosyl maltose is 0.4 mg to 4 g, preferably 1 mg to 1 g, more preferably 5 mg to 500 mg per day for an adult. It is desirable to set it to be administered. That is, in the case of an injection of about 5 ml, usually, a nigerooligosaccharide mixture comprising nigerose, nigerosyl glucose and nigerosyl maltose is 0.008 to 20% by weight, preferably 0.02 to 20% by weight. More preferably, it is 0.1 to 10% by weight. In the case of an infusion solution of about 500 ml, 0.00008 to 0.8 as a nigerooligosaccharide mixture comprising nigerose, nigerosyl glucose and nigerosyl maltose with respect to the preparation. % By weight, preferably 0.0002 to 0.2% by weight, more preferably 0.001 to 0.1% by weight.
In the present invention, ascorbic acid may be used in combination with the above-mentioned lactic acid bacteria and saccharides containing 3-O-α-D-glucopyranosyl-D-glucose as a structural unit, and the blending amount in that case is also appropriately selected. However, in general, in the case of a tablet with a daily intake standard of 4 g, 0.125 to 50% by weight, preferably 0.675 to 50% by weight, more preferably as free ascorbic acid to the preparation. Is 2.5 to 25% by weight, and is 0.0025 to 12.5% by weight, preferably 0.0125 to 6.75% by weight, more preferably 0.0675 to dry lactic acid bacteria. As a nigerooligosaccharide mixture comprising 2.5% by weight and comprising nigerose, nigerosyl glucose and nigerosyl maltose, 0.05 to 50% by weight, preferably 0.125 to 5% Wt%, more preferably from 0.675 to 50% by weight. In the case of a drink of about 50 ml, it is 0.01 to 10% by weight, preferably 0.05 to 5% by weight, more preferably 0.2 to 2% by weight as free ascorbic acid with respect to the preparation. The dry cells of lactic acid bacteria are 0.0002 to 1% by weight, preferably 0.001 to 0.5% by weight, more preferably 0.005 to 0.2% by weight, and nigerose and nigerosyl glucose. The nigerooligosaccharide mixture composed of nigerosyl maltose is 0.004 to 20% by weight, preferably 0.01 to 10% by weight, and more preferably 0.05 to 5% by weight. In the case of a beverage of about 500 ml, 0.001 to 1% by weight, preferably 0.005 to 0.5% by weight, more preferably 0.02 to 0.2% by weight as free ascorbic acid with respect to the preparation And 0.00002 to 0.1% by weight, preferably 0.0001 to 0.05% by weight, more preferably 0.0005 to 0.02% by weight, as dried lactic acid bacteria. The mixture of nigerooligosaccharides composed of nigerose, nigerosyl glucose and nigerosyl maltose is 0.0004 to 4 wt%, preferably 0.001 to 1 wt%, more preferably 0.005 to 0.5 wt%. . In the case of an injection of about 5 ml, it is 0.05 to 5% by weight, preferably 0.25 to 5% by weight, more preferably 1 to 5% by weight as free ascorbic acid for the preparation. 0.00004 to 0.5% by weight, preferably 0.0002 to 0.25% by weight, and more preferably 0.001 to 0.1% by weight as dry cells of nigerose, nigerosyl glucose, The mixture of nigerooligosaccharides composed of nigerosyl maltose is 0.004 to 10% by weight, preferably 0.01 to 10% by weight, and more preferably 0.05 to 5% by weight. In the case of an infusion of about 500 ml, as free ascorbic acid with respect to the preparation, 0.0005 to 0.5% by weight, preferably 0.0025 to 0.25% by weight, more preferably 0.01 to 0%. 0.1 wt%, and 0.0000004 to 0.005 wt%, preferably 0.000002 to 0.0025 wt%, more preferably 0.00001 to 0.001 wt%, as dry lactic acid bacteria. A nigerooligosaccharide mixture comprising nigerose, nigerosyl glucose and nigerosyl maltose is 0.00004 to 0.4 wt%, preferably 0.0001 to 0.1 wt%, more preferably 0.0005 to 0.00. 05% by weight.
[0009]
The preparation of the present invention can be applied using known excipients or carriers according to a method known per se, for example, oral, parenteral, external use, etc., for example, tablets, granules, capsules, powders, creams, It can be a solid or solution such as a paste, a pharmaceutical preparation in a liquid dosage form such as a syrup, emulsion, suspension, quasi-drug, food or cosmetic preparation.
Examples of the excipient or carrier to be used include solid excipients such as dextrin, corn starch, lactose, cellulose and methylcellulose, and liquid excipients such as water, physiological saline, propylene glycol and ethanol.
[0010]
The preparation of the present invention has a synergistically enhanced immunostimulatory effect by applying it orally, parenterally, externally, etc., to infections caused by microorganisms such as viruses and bacteria, for example, cholera and toxins caused by oral infection. Infectious enteritis such as Escherichia coli, Shigella, Salmonella, virus, etc., influenza due to respiratory tract infection, cold syndrome, stomatitis due to oral infection, periodontal disease, etc., and various malignant tumors such as digestive tract and respiratory organs It is effective for the prevention and treatment of epithelial malignant tumors that occur in solid organs such as mucous membranes, liver and kidney, and non-epithelial malignant tumors that occur in motor organs and soft tissues. Further, the preparation of the present invention has an IL-12 and / or IFN-γ production-inducing action, and in order to tilt the T helper function to the Th1 type, the immunosuppressed state induced by the tumor or the immunity induced by the anticancer drug treatment Suitable for recovery from functional decline, effective in preventing the occurrence of acquired immune deficiency syndrome (AIDS), and effective against intracellular parasitic bacteria such as Listeria monocytogenes, Salmonella, Mycobacterium tuberculosis, and Neisseria gonorrhoeae Yes, effective in preventing and treating type I allergies, effective in reducing Th1-type immune function decline caused by stress, suitable for suppressing immune function decline associated with aging, etc. Control of various biological functions, such as the prevention of the development of arteriosclerosis, which is strongly suggested to be related to Chlamydia infection by the protective effect of parasitic bacteria against Chlamydia. Improvement of resistance to various diseases, it is effective in promoting daily health tonic.
[0011]
【Example】
Hereinafter, the present invention will be described in more detail with reference to test examples and examples, but the present invention is not limited thereto.
Test example 1
In this test example, using Lactobacillus plantarum L-137 dried dead cells and ascorbic acid, Lactobacillus plantarum L-137 dried dead cells against induction of interleukin 12 and interferon γ production in mouse spleen cells and The synergistic effect of ascorbic acid was verified.
The spleen was removed from a mouse (BALB / c, female, 22 weeks old), crushed in RPMI 1640 medium, and passed through # 200 mesh to obtain a spleen cell suspension. After the number of cells in the spleen cell suspension was measured with an automatic hemocytometer, the number of cells was adjusted to a concentration of 5 × 10 6 / ml in RPMI 1640 medium, and 100 μl per well was seeded in a 96-well tissue culture plate.
To this, 50 μl of a solution obtained by dispersing Lactobacillus plantarum L-137 dried dead cells in a RPMI1640 medium at a concentration of 0.4 μg / ml or RPMI1640 medium was added. Furthermore, 50 μl of RPMI1640 medium (control) or a solution of ascorbic acid dissolved in RPMI1640 medium at a concentration of 20, 40 or 80 μg / ml was added to each well and cultured in a 5% carbon dioxide incubator at 37 ° C. for 7 days. Interleukin 12 and interferon γ in the culture supernatant after the culture were measured by enzyme immunoassay.
In the enzyme immunoassay, a solution prepared by preparing rat anti-mouse interleukin 12 IgG2a antibody (Genzyme) or hamster anti-mouse interferon gamma antibody (Genzyme) to 2 μg / ml with borate buffer was added to one well of a 96-well tissue culture plate. 100 μl was added, and the plate was allowed to stand at 37 ° C. overnight, using a plate having rat anti-mouse interleukin 12 IgG2a antibody or hamster anti-mouse interferon γ antibody attached to each hole. The culture supernatant was added in an amount of 50 μl per well and allowed to stand at room temperature for 90 minutes. The culture supernatant interleukin 12 or interferon γ was bound to the rat anti-mouse interleukin 12 IgG2a antibody or hamster anti-mouse interferon γ antibody attached to the plate. After washing, rat anti-mouse interleukin 12 IgG1 antibody (Genzyme) or rat anti-mouse interferon γ IgG1 antibody (Upstate Biotechnology) was added to bind to interleukin 12 or interferon γ bound to the plate. After washing, an anti-rat IgG1 antibody labeled with peroxidase was added and bound to a rat anti-mouse interleukin 12 IgG1 antibody or a rat anti-mouse interferon γ IgG1 antibody bound to the plate. After washing, 100 μl of phosphate buffer containing 0.006% hydrogen peroxide and 0.1% orthophenylenediamine was added per well, reacted at room temperature for 40 minutes, and the reaction was stopped with 1.5N sulfuric acid. The absorbance at 492 nm was measured with a plate reader, and the concentration of interleukin 12 or interferon γ in the culture supernatant was determined from a standard curve prepared with recombinant mouse interleukin 12 or interferon γ.
Table 1 shows the results.
[0012]
[Table 1]
As is clear from Table 1, ascorbic acid alone did not induce production of interleukin 12 and interferon γ, but production of interleukin 12 and interferon γ induced by Lactobacillus plantarum L-137 dry dead cells. Ascorbic acid was significantly increased. The synergistic effect of Lactobacillus plantarum L-137 dried dead cells and ascorbic acid in inducing interleukin 12 and interferon γ production was verified.
[0014]
Test example 2
In this test example, Lactobacillus plantarum L-137 dry dead cells, nigerooligosaccharide and ascorbic acid were used to induce Lactobacillus plantarum L-137 dry death for induction of interleukin 12 and interferon γ production in mouse spleen cells. The synergistic effect of the ascorbic acid with the cells, nigerooligosaccharide (mixture of nigerooligosaccharide consisting of nigerose, nigerosyl glucose, nigerosyl maltose) and ascorbic acid was verified.
The spleen was removed from a mouse (BALB / c, female, 22 weeks old), crushed in RPMI 1640 medium, and passed through # 200 mesh to obtain a spleen cell suspension. After the number of cells in the spleen cell suspension was measured with an automatic hemocytometer, the number of cells was adjusted to a concentration of 10 × 10 6 / ml in RPMI 1640 medium, and 50 μl per well was seeded in a 96-well tissue culture plate.
To this, Lactobacillus plantarum L-137 dried dead cells were dispersed at a concentration of 0.4 μg / ml, and RPMI 1640 medium in which nigerooligosaccharide was dissolved at a concentration of 4 μg / ml was added in an amount of 50 μl per well. Furthermore, RPMI1640 medium (control) or a solution of ascorbic acid dissolved in RPMI1640 medium at a concentration of 20, 40, 80 or 160 μg / ml was added 50 μl per well, respectively, and cultured in a 5% carbon dioxide incubator at 37 ° C. for 7 days. Then, interleukin 12 and interferon γ in the culture supernatant after the culture were measured by enzyme immunoassay.
Table 2 shows the results.
[0015]
[Table 2]
As is apparent from Table 2, ascorbic acid significantly increased the production of interleukin 12 and interferon γ induced by a composition comprising dry dead cells of Lactobacillus plantarum L-137 and nigerooligosaccharide. The synergistic effect of Lactobacillus plantarum L-137 dried dead cells, nigerooligosaccharide and ascorbic acid in inducing interleukin-12 and interferon γ production was verified.
[0017]
Example 1
Soft drink containing ascorbic acid, nigerose and lactic acid bacteria In accordance with the following composition, nigerose, Lactobacillus plantarum L-137 dry cells, lemon juice, granulated sugar, fructose glucose liquid sugar, purified honey, ascorbic acid, citric acid, lemon After adding 500 ml of pure water to the flavor and stirring, the suspension was dissolved by sonication for 10 minutes, adjusted to 1000 ml, and then sterilized at 65 ° C. for 10 minutes to obtain a soft drink. The resulting soft drink contains about 1.5% nigerose, 1% ascorbic acid, and about 0.02% Lactobacillus plantarum L-137 cells.
Component Amount Nigerose 15.0g
Ascorbic acid 10.0g
Lactobacillus plantarum L-137 dry cells 0.2g
Lemon juice 9.4g
Granulated sugar 15.4g
Fructose dextrose liquid sugar 74.0g
Purified honey 22.2g
Citric acid 1.5g
Lemon flavor 1.6g
[0018]
Example 2
Granules containing ascorbic acid and lactic acid bacteria According to the following formulation, each component was uniformly mixed, granulated and crushed, and dried to give granules.
Component amount Ascorbic acid 60g
Lactobacillus plantarum L-137 dried cells 1g
Lactose 150g
Crystalline cellulose 15g
Glucose 71g
[0019]
Example 3
Tablets containing ascorbic acid and lactic acid bacteria 99 g of the granules obtained in Example 2 were mixed with 1 g of calcium stearate and compressed by a tableting machine to obtain 900 mg tablets. The obtained tablet contains about 180 mg of ascorbic acid and about 3 mg of Lactobacillus plantarum L-137 cells per tablet.
[0020]
Example 4
Ascorbic acid, lactic acid bacterium and nigerooligosaccharide combination injection ascorbic acid 10 g, nigerooligosaccharide (a mixture of nigerooligosaccharide consisting of nigerose, nigerosylglucose and nigerosylmaltose) 2 g, dried lactobacillus plantarum L-137 0.05 g Was suspended in 1000 ml of purified water, sonicated, and lyophilized. This lyophilized product was dispensed into 500 vials to obtain an injection. One vial of this injection contained 24.1 mg of lyophilized product and was easily suspended and dissolved in 2 ml of physiological saline.
[0021]
Example 5
Capsules containing ascorbic acid, lactic acid bacteria and nigerooligosaccharides According to the following formulation, each component is uniformly mixed and filled into gelatin capsules. Each capsule contains 100 mg of nigerooligosaccharides, 50 mg of ascorbic acid, Lactobacillus plantarum L A capsule containing 3 mg of -137 cells was obtained.
Component Nigero-oligosaccharide 100mg
Ascorbic acid 50mg
Lactobacillus plantarum L-137 dry cells 3mg
Corn starch 30mg
Magnesium stearate 10mg
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| JP23543199A JP4601745B2 (en) | 1999-08-23 | 1999-08-23 | Formulation with synergistic enhancement of immunostimulatory effect |
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| JP2007099572A Division JP2007204488A (en) | 2007-04-05 | 2007-04-05 | Pharmaceutical preparation synergistically enhancing immunopotentiating effect |
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| JP4601745B2 true JP4601745B2 (en) | 2010-12-22 |
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| JP4782385B2 (en) * | 2003-05-29 | 2011-09-28 | 昭和産業株式会社 | Immunostimulator |
| DE602004030922D1 (en) | 2003-08-21 | 2011-02-17 | Otsuka Pharma Co Ltd | MILKY ACID BACTERIA WITH MUCOSA IMMUNOTHOTE EFFECT |
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| JP2009191276A (en) * | 2009-05-27 | 2009-08-27 | Taiyo Corp | Lactic bacterium exhibiting peroxide decomposition characteristic |
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| CN116322350A (en) | 2020-09-25 | 2023-06-23 | 好侍健康食品株式会社 | Feed and composition containing lactic acid bacteria and fatty acid |
| WO2023195569A1 (en) * | 2022-04-08 | 2023-10-12 | 이왕재바이오연구소 주식회사 | Immune-boosting composition comprising vitamin c |
| WO2025239378A1 (en) * | 2024-05-17 | 2025-11-20 | キリンホールディングス株式会社 | Immunostimulatory composition and immunostimulation method |
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