JP6640966B2 - Three-layer seamless capsule - Google Patents
Three-layer seamless capsule Download PDFInfo
- Publication number
- JP6640966B2 JP6640966B2 JP2018228373A JP2018228373A JP6640966B2 JP 6640966 B2 JP6640966 B2 JP 6640966B2 JP 2018228373 A JP2018228373 A JP 2018228373A JP 2018228373 A JP2018228373 A JP 2018228373A JP 6640966 B2 JP6640966 B2 JP 6640966B2
- Authority
- JP
- Japan
- Prior art keywords
- core
- layer
- oily substance
- water
- seamless capsule
- 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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- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- General Preparation And Processing Of Foods (AREA)
Description
本発明は、三層構造シームレスカプセルに関し、より詳しくは、コアと、前記コアを被包する保護層と、前記保護層を被包する水溶性ゲル化剤を含む皮膜層とを備えた三層構造カプセルであって、前記コアは水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有し、前記保護層は第二油性物質を含有することを特徴とする三層構造シームレスカプセルに関する。 The present invention relates to a seamless capsule having a three-layer structure, and more particularly, to a three-layer seamless capsule including a core, a protective layer encapsulating the core, and a coating layer containing a water-soluble gelling agent encapsulating the protective layer. A structural capsule, wherein the core contains a substance which is incompatible with water, a first oily substance, and a porous fine particle powder, and the protective layer contains a second oily substance. It relates to a layered seamless capsule.
従来から、様々な有効成分をコアに含有させたカプセルが種々報告されている。これらのカプセルにおける皮膜の材料としては、ゼラチンや、寒天及び水溶性高分子の混合物などが広く用いられている。 Hitherto, various capsules containing various active ingredients in a core have been reported. As a material of a film in these capsules, gelatin, a mixture of agar and a water-soluble polymer, and the like are widely used.
ゼラチンや、寒天及び水溶性高分子の混合物を材料とする皮膜には水を含有しているため、水と配合禁忌の関係にある物質をコアに含有させる場合には、皮膜とコアを隔離しなければならない。 Since a film made of gelatin or a mixture of agar and a water-soluble polymer contains water, if a substance that is contraindicated with water is contained in the core, separate the film from the core. There must be.
皮膜とコアに含有される成分とを隔離したカプセルとして、例えば、内包されている腸内有用細菌が、常温において非流動性の疎水性物質を介して、カプセル皮膜から隔離されてなる腸内有用細菌含有カプセル（特許文献１参照）や、ビフィズス菌粉末に保護剤を添加し、融点３０〜４５℃、融点幅３℃以下の硬化油に懸濁してカプセル核液とし、ゼラチンを用いて皮膜を形成することを特徴とするビフィズス菌含有ソフトカプセル（特許文献２参照）や、内容物と該内容物を被覆する皮膜よりなるシームレスカプセルにおいて、該内容物が親水性物質であり、該内容物と皮膜との間にショ糖の低級脂肪酸エステルが介在することを特徴とする親水性物質を内容物とするシームレスカプセル（特許文献３参照）が提案されている。しかしながら、かかるカプセルでは皮膜とコアに含有される成分との隔離が不十分であり、コアに含有される成分が直接カプセル皮膜に接触することを一時的に防ぐことが可能であるにすぎず、皮膜や硬化油やその他の物質に含まれている水が経時的にコアに含有される成分と接するという問題があった。 As a capsule in which the film and the components contained in the core are isolated, for example, the intestinal useful bacteria contained therein are isolated from the capsule film via a non-flowable hydrophobic substance at room temperature. A protective agent is added to a bacteria-containing capsule (see Patent Document 1) or a powder of bifidobacteria, suspended in a hardened oil having a melting point of 30 to 45 ° C and a melting point width of 3 ° C or less to form a capsule nucleus solution, and a film is formed using gelatin. In a soft capsule containing bifidobacteria characterized by being formed (see Patent Document 2) or a seamless capsule comprising a content and a film covering the content, the content is a hydrophilic substance, and the content and the film A seamless capsule containing a hydrophilic substance as a content, characterized in that a lower fatty acid ester of sucrose is interposed therebetween (see Patent Document 3). However, in such a capsule, the coating and the components contained in the core are insufficiently isolated, and it is only possible to temporarily prevent the components contained in the core from directly contacting the capsule coating, There has been a problem that water contained in the film, hardened oil and other substances comes into contact with the components contained in the core over time.
また、酸、水分または熱に弱い内容物質を常温で非流動性である疎水性物質に懸濁し、これをカプセル化した後に常温通風乾燥し、ついでこの乾燥カプセルをさらに真空乾燥または真空凍結乾燥させることを特徴とする酸、水分または熱に弱い内容物質を包含するカプセル（特許文献４参照）が提案されている。かかるカプセルによって、水分に弱い内容物を保護することが可能となるが、真空乾燥や真空凍結という複雑な工程が必要であると共にコストもかかるという問題があった。 In addition, a substance that is vulnerable to acid, moisture, or heat is suspended in a hydrophobic substance that is non-flowable at room temperature, encapsulated, air-dried at room temperature, and then the dried capsule is further vacuum-dried or freeze-dried. A capsule (see Patent Literature 4), which is characterized by having a content substance that is sensitive to acid, moisture, or heat, is proposed. Such a capsule makes it possible to protect the contents that are vulnerable to moisture, but there is a problem that complicated steps such as vacuum drying and vacuum freezing are required and the cost is high.
一方、カプセルの作製において、気相法シリカなどの多孔性微粒子粉末は、アグロメレート化調合物において、活性化合物の放出速度を調整するための充填剤（特許文献５参照）や、ソフトカプセルの親油性媒体中におけるコートされた有用物質の顆粒の沈降抑制剤（特許文献６参照）や、ソフトカプセルにおける皮膜の付着性又は滑走性の改善剤（特許文献７参照）として用いることが提案されている。 On the other hand, in the production of capsules, a porous fine particle powder such as fumed silica is used as a filler for adjusting the release rate of an active compound in an agglomerated preparation (see Patent Document 5) or a lipophilic medium for soft capsules. It has been proposed to use as an agent for suppressing the sedimentation of granules of a coated useful substance in the inside (see Patent Document 6) and as an agent for improving the adhesion or sliding property of a film in a soft capsule (see Patent Document 7).
本発明の課題は、コアと皮膜層とが隔離され、コアに含有される水と配合禁忌の関係にある物質と水との接触が防止され、水と配合禁忌の関係にある物質を安定に維持することが可能な三層構造シームレスカプセルを提供することにある。 An object of the present invention is to isolate a core and a coating layer, prevent contact between water contained in a core and a substance having a contraindicated relationship with water, and stabilize a substance having a contraindicated relationship with water. It is to provide a three-layer seamless capsule that can be maintained.
本発明者らは、コアに硬化油を含有するカプセルを作製する過程で、後述する参考例に記載のように、硬化油にアエロジル（登録商標）を分散させ、かかる硬化油を融点以上に加温した状態で、冷却した中鎖脂肪酸トリグリセライド（ＭＣＴ）中に滴下したところ、硬化油とＭＣＴの間に界面が生じて硬化油がＭＣＴ中に溶解することがなく球状となり、かつ、球状を保ったまま硬化油の融点以下に冷却されて固化することを見いだした。そこで、かかる現象を応用し、ビフィズス菌と硬化油とアエロジルとを含有するコア、前記コアを被包する硬化油を含有する保護層、前記保護層を被包するゼラチンを含む皮膜層とを備えた三層構造シームレスカプセルを作製したところ、コアと皮膜層が隔離され、ビフィズス菌が安定的に維持されていることを見いだし、本発明を完成した。 The present inventors disperse Aerosil (registered trademark) in a hardened oil and add the hardened oil to a temperature higher than the melting point, as described in Reference Example described later, in the process of producing a capsule containing a hardened oil in a core. When dropped into cooled medium chain fatty acid triglyceride (MCT) in a heated state, an interface is formed between the hardened oil and the MCT, and the hardened oil does not dissolve in the MCT and becomes spherical, and the spherical shape is maintained. It was found that the hardened oil was cooled below the melting point and solidified. Therefore, applying such a phenomenon, a core containing bifidobacteria, hardened oil and aerosil, a protective layer containing hardened oil encapsulating the core, and a coating layer containing gelatin encapsulating the protective layer are provided. When the three-layer seamless capsule was prepared, the core and the coating layer were separated, and it was found that bifidobacteria were stably maintained, and the present invention was completed.
すなわち、本発明は、以下に開示されるとおりのものである。
（１）コアと、前記コアを被包する保護層と、前記保護層を被包する水溶性ゲル化剤を含む皮膜層とを備えた三層構造カプセルであって、前記コアは水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有し、前記保護層は第二油性物質を含有することを特徴とする三層構造シームレスカプセル（但し、カプセル化した後常温通風乾燥し、ついでこの乾燥カプセルをさらに真空乾燥又は真空凍結乾燥させたものは除く）。
（２）コアにおいて、第一油性物質１００質量部に対して多孔性微粒子粉末を０．１〜２０質量部含有することを特徴とする上記（１）記載の三層構造シームレスカプセル。
（３）多孔性微粒子粉末が気相法シリカであることを特徴とする上記（１）又は（２）記載の三層構造シームレスカプセル。
（４）気相法シリカがアエロジルであることを特徴とする上記（１）〜（３）のいずれか記載の三層構造シームレスカプセル。
（５）コアに含有されている第一油性物質が硬化油であることを特徴とする上記（１）〜（４）のいずれか記載の三層構造シームレスカプセル。
（６）融点が３０〜６０℃の硬化油であることを特徴とする上記（５）記載の三層構造シームレスカプセル。
（７）保護層が、第一油性物質に対して融点差が２℃以上の第二油性物質を含有することを特徴とする上記（１）〜（６）のいずれか記載の三層構造シームレスカプセル。
（８）保護層が、第一油性物質より融点が２℃以上高い第二油性物質を含有することを特徴とする上記（７）記載の三層構造シームレスカプセル。
（９）水溶性ゲル化剤がゼラチンであることを特徴とする上記（１）〜（８）のいずれか記載の三層構造シームレスカプセル。
（１０）水溶性ゲル化剤がゼラチン及びペクチンであることを特徴とする上記（１）〜（８）のいずれか記載の三層構造シームレスカプセル。
（１１）水と配合禁忌の関係にある物質が、ビフィズス菌、乳酸菌、ビタミンＢ１、ビタミンＢ２、ビタミンＢ１２、又はビタミンＣであることを特徴とする上記（１）〜（１０）のいずれか記載の三層構造シームレスカプセル。
（１２）コアと、前記コアを被包する保護層と、前記保護層を被包する皮膜層とを備えた三層構造シームレスカプセル（但し、カプセル化した後常温通風乾燥し、ついでこの乾燥カプセルをさらに真空乾燥又は真空凍結乾燥させたものは除く）の作製方法であって、以下の工程（ａ）〜（ｄ）を備えたことを特徴とする作製方法。
（ａ）水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有するコア液を調製する工程；
（ｂ）第二油性物質を含有する保護液を調製する工程；
（ｃ）水溶性ゲル化剤と水とを含有する皮膜液を調製する工程；
（ｄ）同心三重ノズルを用い、外側ノズルからは前記皮膜液を、内側ノズルからは前記コア液を、中間ノズルからは前記保護液を吐出させて三層液滴とし、かかる三層液滴を硬化液と接触させて皮膜液を硬化させる工程；
That is, the present invention is as disclosed below.
(1) A three-layer capsule comprising a core, a protective layer encapsulating the core, and a coating layer containing a water-soluble gelling agent encapsulating the protective layer, wherein the core is blended with water. A three-layer seamless capsule containing a contraindicated substance, a first oily substance, and porous fine particle powder, wherein the protective layer contains a second oily substance. Except those which were air-dried and then further dried in vacuum or freeze-dried.
(2) The three-layer seamless capsule according to the above (1), wherein the core contains 0.1 to 20 parts by mass of porous fine particle powder with respect to 100 parts by mass of the first oily substance.
(3) The three-layer seamless capsule according to the above (1) or (2), wherein the porous fine particle powder is fumed silica.
(4) The three-layer seamless capsule according to any one of (1) to (3), wherein the fumed silica is Aerosil.
(5) The three-layer seamless capsule according to any one of the above (1) to (4), wherein the first oily substance contained in the core is a hardened oil.
(6) The three-layer seamless capsule according to the above (5), which is a hardened oil having a melting point of 30 to 60 ° C.
(7) The three-layer structure seamless according to any one of the above (1) to (6), wherein the protective layer contains a second oily substance having a melting point difference of 2 ° C. or more with respect to the first oily substance. capsule.
(8) The three-layer seamless capsule according to (7), wherein the protective layer contains a second oily substance having a melting point higher than the first oily substance by 2 ° C. or more.
(9) The three-layer seamless capsule according to any one of the above (1) to (8), wherein the water-soluble gelling agent is gelatin.
(10) The seamless capsule according to any one of the above (1) to (8), wherein the water-soluble gelling agent is gelatin and pectin.
(11) The substance according to any one of the above (1) to (10), wherein the substance having a contraindicated relationship with water is bifidobacteria, lactic acid bacteria, vitamin B1, vitamin B2, vitamin B12, or vitamin C. Seamless capsule with three layers.
(12) A seamless capsule having a three-layer structure comprising a core, a protective layer enclosing the core, and a coating layer enclosing the protective layer (however, after encapsulation, dried at room temperature and then dried; (Excluding those obtained by further vacuum-drying or vacuum freeze-drying), which comprises the following steps (a) to (d).
(A) a step of preparing a core liquid containing a substance which is incompatible with water, a first oily substance, and porous fine particle powder;
(B) preparing a protective solution containing the second oily substance;
(C) preparing a coating solution containing a water-soluble gelling agent and water;
(D) A concentric triple nozzle is used to discharge the coating liquid from the outer nozzle, the core liquid from the inner nozzle, and the protective liquid from the intermediate nozzle to form three-layer droplets. A step of curing the coating liquid by contacting with a curing liquid;
本発明の三層構造シームレスカプセルによれば、コアと皮膜層とが隔離され、コアに含有される水と配合禁忌の関係にある物質と水との接触が防止され、水と配合禁忌の関係にある物質を安定に維持することが可能となる。 According to the three-layered seamless capsule of the present invention, the core and the coating layer are isolated, the contact between the water contained in the core and the substance which is incompatible with the formulation and water is prevented, and the relationship between water and the formulation is incompatible. Can be stably maintained.
本発明の三層構造シームレスカプセルとしては、コアと、前記コアを被包する保護層と、前記保護層を被包する水溶性ゲル化剤を含む皮膜層とを備えた三層構造カプセルであって、前記コアは水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有し、前記保護層は第二油性物質を含有することを特徴とする三層構造シームレスカプセルであれば特に制限されず、水と配合禁忌の関係にある物質を安定的に維持することが可能なシームレスカプセルである。 The three-layered seamless capsule of the present invention is a three-layered capsule comprising a core, a protective layer enclosing the core, and a coating layer containing a water-soluble gelling agent enclosing the protective layer. Wherein the core contains a substance which is incompatible with water, a first oily substance, and porous fine particle powder, and the protective layer contains a second oily substance. It is not particularly limited as long as it is a seamless capsule capable of stably maintaining a substance that is incompatible with water.
また、本発明の三層構造シームレスカプセルの作製方法としては、コアと、前記コアを被包する保護層と、前記保護層を被包する皮膜層とを備えた三層構造シームレスカプセルの作製方法であって、
（ａ）水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有するコア液を調製する工程；
（ｂ）第二油性物質を含有する保護液を調製する工程；
（ｃ）水溶性ゲル化剤と水とを含有する皮膜液を調製する工程；
（ｄ）同心三重ノズルを用い、外側ノズルからは前記皮膜液を、内側ノズルからは前記コア液を、中間ノズルからは前記保護液を吐出させて三層液滴とし、かかる三層液滴を硬化液と接触させて皮膜液を硬化させる工程；
の工程（ａ）〜（ｄ）を備えたことを特徴とする作製方法であれば特に制限されず、かかる作製方法により、水と配合禁忌の関係にある物質を安定的に維持することが可能な上記本発明の三層構造シームレスカプセルを作製することが可能となる。
Further, as a method for producing a three-layered seamless capsule of the present invention, a method for producing a three-layered seamless capsule including a core, a protective layer enclosing the core, and a coating layer enclosing the protective layer is provided. And
(A) a step of preparing a core liquid containing a substance which is incompatible with water, a first oily substance, and a porous fine particle powder;
(B) preparing a protective solution containing the second oily substance;
(C) preparing a coating solution containing a water-soluble gelling agent and water;
(D) Using a concentric triple nozzle, the coating liquid is discharged from the outer nozzle, the core liquid is discharged from the inner nozzle, and the protective liquid is discharged from the intermediate nozzle to form a three-layer droplet. Curing the coating liquid by contacting with a curing liquid;
The method is not particularly limited as long as the method includes the steps (a) to (d) of the step (a). By such a method, it is possible to stably maintain a substance that is incompatible with water. It is possible to produce the three-layer seamless capsule of the present invention.
本発明の三層構造シームレスカプセルや、本発明の三層構造シームレスカプセルの作製方法（以下、総称して「本件発明」ともいう。）において、コアとしては、水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有していれば特に制限されず、保護層によって被包されることによって皮膜層と隔離される。 In the three-layer seamless capsule of the present invention and the method for producing the three-layer seamless capsule of the present invention (hereinafter, also collectively referred to as “the present invention”), the core is a substance that is incompatible with water. It is not particularly limited as long as it contains the first oily substance and the porous fine particle powder, and is isolated from the coating layer by being covered with the protective layer.
上記水と配合禁忌の関係にある物質としては、水との接触により不安定となる物質であれば特に制限されないが、ビフィドバクテリアム・ロンガム、ビフィドバクテリアム・ビフィダムなどのビフィズス菌、スプレプトコックス・フェシウム、ラクトコックス・ラクチス亜種・ラクチス、ラクトバチルス・ヘルベティクス、ラクトバチルス・アシドフィルス、ラクトバチルス・カゼイなどの乳酸菌に例示される、水との接触により生育能力が低下する腸内細菌や、ビタミンＢ１、ビタミンＢ２、ビタミンＢ１２、又はビタミンＣなどの、水との接触により分解が生じるビタミンを挙げることができ、ビフィズス菌又は乳酸菌を好適に挙げることができる。 The substance which is incompatible with water is not particularly limited as long as it is a substance which becomes unstable upon contact with water, but is not limited to bifidobacterium longum, bifidobacterium bifidum, etc. Enterobacteria whose growth ability is reduced by contact with water, exemplified by lactic acid bacteria such as Ptocox fescium, Lactococcus lactis subsp. Lactis, Lactobacillus hervetics, Lactobacillus acidophilus, Lactobacillus casei, etc. And vitamins that are decomposed by contact with water, such as vitamin B1, vitamin B2, vitamin B12, and vitamin C, and preferably include bifidobacteria and lactic acid bacteria.
本件発明において、多孔性微粒子粉末としては、粒子内部に多数の細孔を有するものであれば特に制限されず、気相法シリカや湿式法シリカなどの非晶質合成シリカ、アルミナ、アルミナ水和物、炭酸カルシウム、炭酸マグネシウム、二酸化チタンなどの公知の微粒子粉末を挙げることができるが、空隙率が高い観点から、好ましくは気相法シリカや湿式法シリカなどの非晶質合成シリカ、アルミナ又はアルミナ水和物、より好ましくは気相法シリカや湿式法シリカなどの非晶質合成シリカ、さらに好ましくは気相法シリカを挙げることができる。 In the present invention, the porous fine particle powder is not particularly limited as long as it has a large number of pores inside the particle, and is amorphous synthetic silica such as fumed silica or wet silica, alumina, or alumina hydrate. Products, calcium carbonate, magnesium carbonate, known fine particle powders such as titanium dioxide, from the viewpoint of high porosity, preferably amorphous synthetic silica such as fumed silica or wet silica, alumina or Alumina hydrate, more preferably amorphous synthetic silica such as fumed silica or wet fumed silica, more preferably fumed silica can be mentioned.
非晶質合成シリカは、製造方法によって気相法シリカと湿式法シリカとその他のシリカに分類され、湿式法シリカは、更に製造方法によって沈降法シリカ、ゲル法シリカ、ゾル法シリカに分類される。 Amorphous synthetic silica is classified into fumed silica, wet silica and other silica according to the production method, and wet silica is further classified into precipitated silica, gel silica, and sol silica according to the production method. .
気相法シリカは、湿式法に対して乾式法とも呼ばれ、一般的には火炎加水分解法によって作られる。具体的には四塩化ケイ素を水素及び酸素とともに燃焼して作る方法が一般的に知られているが、四塩化ケイ素の代わりにメチルトリクロロシランやトリクロロシランなどのシラン類も、単独又は四塩化ケイ素と混合した状態で使用することができる。気相法シリカとしてはアエロジル（登録商標）（日本アエロジル社製）や、レオロシール（登録商標）（トクヤマ社製）などの市販品を用いることができる。 The fumed silica is also called a dry method with respect to a wet method, and is generally produced by a flame hydrolysis method. Specifically, a method of making silicon tetrachloride by burning it with hydrogen and oxygen is generally known, but instead of silicon tetrachloride, silanes such as methyltrichlorosilane and trichlorosilane may be used alone or silicon tetrachloride. And can be used in a mixed state. As the fumed silica, commercially available products such as Aerosil (registered trademark) (manufactured by Nippon Aerosil Co., Ltd.) and Reolosil (registered trademark) (manufactured by Tokuyama Corporation) can be used.
沈降法シリカは、ケイ酸ソーダと硫酸をアルカリ条件で反応させて製造され、粒子成長したシリカ粒子が凝集・沈降し、その後濾過、水洗、乾燥、粉砕・分級の行程を経て製造される。沈降法シリカとしては、ニップシール（登録商標）（東ソー・シリカ社製）などの市販品を用いることができる。 Precipitated silica is produced by reacting sodium silicate and sulfuric acid under alkaline conditions. The silica particles that have grown are aggregated and sedimented, and then are subjected to filtration, washing, drying, pulverization and classification steps. As the precipitated silica, commercially available products such as Nip Seal (registered trademark) (manufactured by Tosoh Silica Corporation) can be used.
ゲル法シリカは、ケイ酸ソーダと硫酸を酸性条件下で反応させて製造される。熟成中に微小粒子は溶解し、他の一次粒子同士を結合するように再析出するため、明確な一次粒子は消失し、内部空隙構造を有する比較的硬い凝集粒子を形成する。ゲル法シリカとしては、ニップジェル（登録商標）（東ソー・シリカ社製）やサイロイド（登録商標）、サイロジェット（登録商標）（グレースジャパン社製）などの市販品を用いることができる。 Gel method silica is produced by reacting sodium silicate and sulfuric acid under acidic conditions. During aging, the fine particles dissolve and re-precipitate to bind the other primary particles together, so that distinct primary particles disappear and form relatively hard aggregated particles having an internal void structure. As the gel method silica, commercially available products such as Nipgel (registered trademark) (manufactured by Tosoh Silica Co., Ltd.), Syroid (registered trademark), and Silojet (registered trademark) (manufactured by Grace Japan) can be used.
ゾル法シリカは、コロイダルシリカとも呼ばれ、ケイ酸ソーダの酸などによる複分解やイオン交換樹脂層を通して得られるシリカゾルを加熱熟成して得られる。ゾル法シリカとしては、スノーテックス（登録商標）（日産化学工業社製）などの市販品を用いることができる。 The sol method silica is also called colloidal silica, and is obtained by heating and aging a silica sol obtained by metathesis of sodium silicate with an acid or the like through an ion exchange resin layer. Commercial products such as Snowtex (registered trademark) (manufactured by Nissan Chemical Industries, Ltd.) can be used as the sol-processed silica.
多孔性微粒子粉末の比表面積は４０ｍ２／ｇ以上、好ましくは１００〜５００ｍ２／ｇを挙げることができる。 The specific surface area of the porous fine particle powder is 40 m 2 / g or more, preferably 100 to 500 m 2 / g.
本件発明において、多孔性微粒子粉末を２種以上併用することもできる。例えば、粉砕した気相法シリカと湿式法シリカとの併用や、微粉砕した湿式法シリカとアルミナあるいはアルミナ水和物との併用や、気相法シリカとアルミナあるいはアルミナ水和物との併用が挙げられる。 In the present invention, two or more kinds of porous fine particle powders can be used in combination. For example, a combination of pulverized fumed silica and wet silica, a combination of finely pulverized wet silica and alumina or alumina hydrate, or a combination of pulverized silica and alumina or alumina hydrate No.
コアにおいて、第一油性物質１００質量部に対して多孔性微粒子粉末を０．１〜２０質量部、好ましくは１〜１０質量部、より好ましくは２〜８質量部、さらに好ましくは３〜６質量部含有していることが好ましい。 In the core, 0.1 to 20 parts by mass, preferably 1 to 10 parts by mass, more preferably 2 to 8 parts by mass, and still more preferably 3 to 6 parts by mass of the porous fine particle powder with respect to 100 parts by mass of the first oily substance. It is preferable to contain a part thereof.
本件発明において、第一油性物質や第二油性物質における油性物質としては、硬化油、部分硬化油、サフラワー油、亜麻仁油、ゴマ油、オリーブ油、大豆油、からし油、ナタネ油、コーン油、ヒマシ油、月見草油、パーム核油、ホホバ油、綿実油、ヤシ油、落花生油、カカオ脂、ラード、ヘッド、ＥＰＡ、ＤＨＡ、サメ肝油、タラ肝油などの動植物油や、中鎖脂肪酸トリグリセリド（ＭＣＴ）や、グリセリン脂肪酸エステルや、脂肪酸アシルエステルや、流動パラフィンなどから選択される１種又は２種以上を用いることができ、上記硬化油としては、硬化ヒマシ油、硬化大豆油、硬化菜種油、硬化ヤシ油、カカオ脂、硬化パーム核油、牛脂硬化油、豚脂硬化油を挙げることができる。 In the present invention, as the oily substance in the first oily substance and the second oily substance, hardened oil, partially hardened oil, safflower oil, linseed oil, sesame oil, olive oil, soybean oil, mustard oil, rapeseed oil, corn oil, Animal and vegetable oils such as castor oil, evening primrose oil, palm kernel oil, jojoba oil, cottonseed oil, coconut oil, peanut oil, cocoa butter, lard, head, EPA, DHA, shark liver oil, cod liver oil, and medium chain fatty acid triglyceride (MCT) Or one or more selected from glycerin fatty acid esters, fatty acid acyl esters, and liquid paraffin, and the hardened oil may be hardened castor oil, hardened soybean oil, hardened rapeseed oil, hardened palm Examples include oil, cocoa butter, hardened palm kernel oil, tallow hardened oil, and lard hardened oil.
第一油性物質における油性物質と第二油性物質は同じ油性物質でも異なる油性物質でもよいが、第二油性物質は、第一油性物質に対して融点差が２℃以上であることや、第一油性物質より融点が２℃以上高いことが好ましい。第二油性物質として、第一油性物質に対して融点差が２℃以上である油性物質や、第一油性物質より融点が２℃以上高い油性物質を用いることで、一方の油性物質が他の油性物質よりも早く凝固し、第一油性物質と第二油性物質とが互いに溶け込むことをより防ぐことが可能となる。なお、硬化油などのように融点が一定の規格幅の温度である油性物質においては、一定の規格幅の温度における上限と下限の和の２分の１（中間）の温度を融点として採用する。 The oily substance and the second oily substance in the first oily substance may be the same oily substance or different oily substances, but the second oily substance has a melting point difference of 2 ° C or more with respect to the first oily substance, It is preferable that the melting point is higher than the oily substance by 2 ° C. or more. As the second oily substance, by using an oily substance having a melting point difference of 2 ° C. or more with respect to the first oily substance or an oily substance having a melting point of 2 ° C. or more higher than the first oily substance, one of the oily substances can be used as another oily substance. It solidifies faster than the oily substance, and it is possible to further prevent the first oily substance and the second oily substance from being dissolved into each other. In addition, in the case of an oily substance such as a hardened oil, the melting point of which is a temperature of a certain standard width, a temperature (half) of the sum of the upper limit and the lower limit of the temperature of the certain standard width is adopted as the melting point. .
第一油性物質としては、硬化油を用いることが好ましく、融点が３０〜６０℃、好ましくは３３〜３７℃の硬化油を用いることがより好ましい。 As the first oily substance, a hardened oil is preferably used, and more preferably a hardened oil having a melting point of 30 to 60C, preferably 33 to 37C.
本件発明における上記コアやコア液、及び／又は上記保護層や保護液には、レシチンや各種界面活性剤、アルコール類などの界面活性を調整できる添加剤や、ショ糖酢酸イソ酪酸エステル（ＳＡＩＢ）などの比重調整剤や、ビタミンＥ、ＢＨＴ、ＢＨＡに代表される抗酸化剤などを含有してもよい。 In the present invention, the core and the core liquid and / or the protective layer and the protective liquid may include additives such as lecithin, various surfactants, and alcohols that can adjust the surface activity, and sucrose acetate isobutyrate (SAIB). And a specific gravity adjuster, such as vitamin E, BHT, and BHA.
本件発明において、水溶性ゲル化剤としては、ゼラチン、カラギーナン、寒天、ジェランガム、ファーセレラン、ユーケマ藻類、ペクチン、アルギン酸塩類、プルラン、グルコマンナン、アラビアゴム、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、ポリビニルアルコール、デンプン類などの親水性高分子から選択される１種又は２種以上を挙げることができ、ゼラチン、カラギーナン、寒天、ジェランガム、ファーセレラン、ユーケマ藻類といった、冷却によってゲル化する水溶性ゲル化剤を好適に挙げることができる。また、腸溶性カプセルとするためには、水溶性ゲル化剤としてゼラチン、ペクチン及びアルギン酸塩類から選ばれる二種以上を用いることができ、好ましくはゼラチン及びペクチンを用いることができる。 In the present invention, as the water-soluble gelling agent, gelatin, carrageenan, agar, gellan gum, phaceleran, Euchema algae, pectin, alginate, pullulan, glucomannan, gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl One or more selected from hydrophilic polymers such as alcohols and starches may be mentioned, and examples thereof include water-soluble gelling agents that gel upon cooling, such as gelatin, carrageenan, agar, gellan gum, phacelerin, and Euchema algae. Can be suitably mentioned. Further, in order to form an enteric capsule, two or more selected from gelatin, pectin and alginates can be used as the water-soluble gelling agent, and gelatin and pectin can be preferably used.
さらに、本件発明における上記皮膜層や皮膜液には、グリセリンなどの可塑剤、リン酸ナトリウムなどのｐＨ調整剤、クエン酸三ナトリウム、メタリン酸ナトリウムなどのキレート剤、乳酸カルシウム、塩化カリウムなどのゲル化促進剤、ポリグリセリン脂肪酸エステル、レシチンなどの界面活性剤、甘味料、香料、防腐剤、着色剤などを含有してもよい。なお、水溶性ゲル化剤と水とを含有する皮膜液を用いてシームレスカプセルを作製した場合の皮膜層には水が含まれる。 Further, the coating layer and the coating liquid in the present invention include a plasticizer such as glycerin, a pH adjuster such as sodium phosphate, a chelating agent such as trisodium citrate and sodium metaphosphate, and a gel such as calcium lactate and potassium chloride. The composition may contain a surfactant such as a chelating agent, a polyglycerin fatty acid ester, lecithin, a sweetener, a flavor, a preservative, and a coloring agent. In addition, when a seamless capsule is produced using a coating solution containing a water-soluble gelling agent and water, the coating layer contains water.
本発明の三層構造シームレスカプセルの作製方法において、水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有するコア液を調製する方法としては、第一油性物質に水と配合禁忌の関係にある物質と多孔性微粒子粉末を加えて分散させる方法を挙げることができ、分散方法としては、人の手による撹拌に加え、プロペラ撹拌、タービン型撹拌、ホモミキサー型撹拌など、従来公知の方法を用いることができる。 In the method for producing a three-layered seamless capsule of the present invention, as a method for preparing a core liquid containing water and a substance having a contraindicated relationship, a first oily substance and porous fine particle powder, the first oily substance There is a method of adding and dispersing a substance having a contraindicated relationship with water and a porous fine particle powder. Examples of the dispersion method include, in addition to stirring by hand, propeller stirring, turbine stirring, and homomixer stirring. For example, a conventionally known method can be used.
本発明の三層構造シームレスカプセルの作製方法における硬化液としては、水溶性ゲル化剤と水とを含有する皮膜液に触れることで水溶性ゲル化剤と水とを含有する皮膜液を硬化させる液であれば特に制限されず、例えば冷却によってゲル化する水溶性ゲル化剤を用いる場合には、皮膜液との界面張力を生ずるＭＣＴ、流動パラフィン、大豆油、オリーブ油、サフラワー油などの植物油を含有する疎水性液体を挙げることができる。なお、例えばペクチンやアルギン酸塩など、カルシウムイオンと反応してゲル化するゲル化剤を採用する場合には、カプセル形成後に、カルシウム水溶液などのゲル化助剤に浸漬することで水溶性ゲル化剤のゲル化を強化することも可能である。 As the curing liquid in the method for producing a three-layered seamless capsule of the present invention, a coating liquid containing a water-soluble gelling agent and water is cured by touching a coating liquid containing a water-soluble gelling agent and water. It is not particularly limited as long as it is a liquid. For example, when a water-soluble gelling agent that gels upon cooling is used, vegetable oils such as MCT, liquid paraffin, soybean oil, olive oil, and safflower oil that generate interfacial tension with the coating liquid are used. And a hydrophobic liquid containing: When a gelling agent, such as pectin or alginate, which gels by reacting with calcium ions is employed, after forming the capsule, the gelling agent is immersed in a gelling auxiliary such as an aqueous calcium solution. It is also possible to enhance the gelation of.
（三層構造シームレスカプセルの作製）
同心三重ノズル（富士カプセル社製）を用い、最も外側のノズルからは表１に示す組成からなる皮膜液を、最も内側のノズルからは表２に示す組成からなるコア液を、中間のノズルからは表３に示す組成からなる保護液を吐出させて三層液滴とし、かかる三層液滴をＭＣＴからなる硬化液と接触させて皮膜液を硬化させることにより、コアと、前記コアを被包する保護層と、前記保護層を被包する皮膜層とを備えた三層構造シームレスカプセル（実施品）を作製した。得られた三層構造シームレスカプセル（実施品）の構造を図１に示す。比較例として、表２に代わって表４に示す組成（アエロジルなし）からなるコア液を用いたカプセル（比較品）を上記と同様に作製した。なお、比較品については核と皮膜層との間に界面が生じず、三層構造とならなかった。
(Production of three-layer seamless capsule)
Using a concentric triple nozzle (manufactured by Fuji Capsule), a coating liquid having the composition shown in Table 1 was applied from the outermost nozzle, a core liquid having a composition shown in Table 2 from the innermost nozzle, and a core liquid from the middle nozzle. Discharges a protective liquid having the composition shown in Table 3 into three-layer droplets, and contacts the three-layer droplet with a curing liquid composed of MCT to cure the coating liquid, thereby covering the core and the core. A three-layer seamless capsule having a protective layer for encapsulation and a coating layer for enclosing the protective layer was prepared. FIG. 1 shows the structure of the obtained three-layer seamless capsule (product). As a comparative example, a capsule (comparative product) using a core liquid having the composition shown in Table 4 (without Aerosil) instead of Table 2 was produced in the same manner as described above. Note that the comparative product did not have an interface between the core and the coating layer, and did not have a three-layer structure.
（ビフィズス菌の生存率）
ビフィズス菌は水との接触により生育能力が低下することや、死滅することが知られている。そこで、作製したカプセルに含まれるビフィズス菌の生菌数を測定し、コアと皮膜層が保護層によって隔離され、ビフィズス菌と水との接触が抑制されているかを調べた。
(Bifidobacterium viability)
It has been known that bifidobacteria have a reduced growth ability or are killed by contact with water. Then, the viable count of bifidobacteria contained in the produced capsule was measured, and it was examined whether the core and the coating layer were separated by the protective layer and contact between the bifidobacterium and water was suppressed.
上記の方法で作製した実施品及び比較品において、カプセル作製直後（初期値）、３５℃で４週間、及び３５℃で８週間保存後にビフィズス菌の生菌数を測定し、３５℃で４週間、３５℃で８週間保存後のビフィズス菌の生菌数を三層構造シームレスカプセル作製直後の生菌数（初期値）で割った値の百分率を表５に示す。生菌数の測定は、はっ酵乳・乳酸菌飲料中のビフィズス菌の菌数測定法（社団法人全国はっ酵乳乳酸菌飲料協会冊子（２０００））に記載の方法に準じて行った。 The viable count of the bifidobacteria was measured at 35 ° C. for 4 weeks immediately after capsule production (initial value), at 35 ° C. for 4 weeks, and after storage at 35 ° C. for 8 weeks. Table 5 shows the percentage of the value obtained by dividing the viable cell count of bifidobacteria after storage at 35 ° C. for 8 weeks by the viable cell count (initial value) immediately after the production of the three-layered seamless capsule. The number of viable bacteria was measured according to the method described in the method for measuring the number of bifidobacteria in fermented milk and lactic acid bacteria beverages (National Fermented Milk Lactic Acid Bacteria Beverage Association Booklet (2000)).
表５に示すように、実施品（アエロジルあり）では３５℃で８週間保存しても生菌数が８２％と高かったが、比較品（アエロジルなし）では、３５℃４週間保存で２６％、３５℃８週間ではわずか５％であった。したがって、本発明の三層構造シームレスカプセルは、コアと皮膜層が保護層によって隔離され、ビフィズス菌と水との接触が抑制されることにより、ビフィズス菌を安定的に維持可能であることが明らかとなった。 As shown in Table 5, the viable cell count was as high as 82% even when stored at 35 ° C. for 8 weeks in the working product (with Aerosil), whereas the comparative product (without Aerosil) was 26% when stored at 35 ° C. for 4 weeks. At 35 ° C. for 8 weeks was only 5%. Therefore, it is clear that the three-layer seamless capsule of the present invention can stably maintain bifidobacteria by separating the core and the coating layer by the protective layer and suppressing contact between bifidobacteria and water. It became.
（三層構造シームレスカプセルの三次元表示画像）
上記の方法で作製した三層構造シームレスカプセル（実施品）を３５℃で４週間保存後に、モリブデンターゲットによるラング法（透過法）による観察を行い、三次元表示画像を高分解能３ＤＸ線顕微鏡「ＮＡＮＯ３ＤＸ」（リガク社製）によって得た。得られた三次元表示画像を図２に示す。
(Three-dimensional display image of three-layer seamless capsule)
After storing the three-layered seamless capsule (implemented product) manufactured by the above method at 35 ° C. for 4 weeks, the sample is observed by a Lang method (transmission method) using a molybdenum target, and the three-dimensional display image is converted to a high-resolution 3DX-ray microscope “NANO3DX”. (Rigaku). FIG. 2 shows the obtained three-dimensional display image.
図２に示すように、作製した三層構造シームレスカプセルにおいて、コアと保護層、保護層と皮膜層とが混ざることなくきれいに凝固し、保護層によってコアと皮膜層が完全に隔離されていることが明らかとなった。 As shown in FIG. 2, in the prepared three-layer seamless capsule, the core and the protective layer, and the protective layer and the coating layer coagulate cleanly without mixing, and the core and the coating layer are completely separated by the protective layer. Became clear.
また、三次元表示画像に用いた三層構造シームレスカプセル（実施品：Ｎ＝１０）の核、保護層、皮膜層、総カプセルの平均質量はそれぞれ６７、４６、２５、１３８ｍｇであり、カプセル粒径は６．５ｍｍであった。 The average mass of the core, the protective layer, the coating layer, and the total capsule of the three-layer seamless capsule (Example: N = 10) used for the three-dimensional display image was 67, 46, 25, and 138 mg, respectively. The diameter was 6.5 mm.
（三層構造シームレスカプセルの崩壊試験）
上記の方法で作製した実施品の崩壊試験を文献（第１６改正日本薬局方解説書 東京広川書店刊行 Ｂ５８９（２０１１））に記載の方法に準じて行った。崩壊試験第一液を用いた試験、崩壊試験第二液を用いた試験をそれぞれ１８個の三層構造シームレスカプセルについて行った。
(Disintegration test of three-layer seamless capsule)
The disintegration test of the product prepared by the above method was performed according to the method described in the literature (16th revised Japanese Pharmacopoeia Manual, Tokyo Hirokawa Shoten B589 (2011)). A test using the first solution for the disintegration test and a test using the second solution for the disintegration test were performed on 18 seamless capsules each having a three-layer structure.
崩壊試験第一液を用いた試験により、１２０分後にも１８個の三層構造シームレスカプセル全てにおいて崩壊はみられなかった。一方、崩壊試験第二液を用いた試験により、２０分後には１８個の三層構造シームレスカプセルがすべて崩壊した。したがって、上記記載のゼラチンとペクチンを用いた本発明の三層構造シームレスカプセルは、腸溶性を有するカプセルであることが明らかとなった。 In the test using the first liquid for the disintegration test, no disintegration was observed in all of the 18 three-layered seamless capsules even after 120 minutes. On the other hand, in the test using the second liquid for the disintegration test, all of the 18 three-layered seamless capsules disintegrated after 20 minutes. Therefore, it was revealed that the three-layered seamless capsule of the present invention using the above-mentioned gelatin and pectin is an enteric capsule.
（参考例）
１０℃に冷却した融点−５℃以下のＭＣＴに、４０℃以上に加温した融点が３５℃の硬化油を滴下した。その結果、硬化油とＭＣＴとの間に界面が生じず、硬化油が瞬時にＭＣＴ中に溶け込んだ（図示なし）。
(Reference example)
Hardened oil having a melting point of 35 ° C. heated to a temperature of 40 ° C. or higher was dropped into MCTs having a melting point of −5 ° C. or lower cooled to 10 ° C. As a result, no interface was formed between the hardened oil and the MCT, and the hardened oil was instantaneously dissolved in the MCT (not shown).
一方、上記硬化油にアエロジルを分散したものを、４０℃以上に加温した状態で、１０℃に冷却した上記ＭＣＴに滴下したところ、図３に示すように硬化油がＭＣＴ中に溶解することなく球状を保ち、図４に示すように融点以下に硬化油が冷却されることによって球状を保ったまま固化した。なお、図３において、滴下した直後の硬化油は透明であるため、硬化油の位置を矢印で示した。したがって、アエロジルを分散した硬化油とＭＣＴは界面を生ずることが確認された。 On the other hand, when the aerosil dispersed in the hardened oil was dropped to the MCT cooled to 10 ° C. while being heated to 40 ° C. or higher, the hardened oil was dissolved in the MCT as shown in FIG. As shown in FIG. 4, the hardened oil was cooled below the melting point and solidified while maintaining the spherical shape. In FIG. 3, since the hardened oil immediately after dropping is transparent, the position of the hardened oil is indicated by an arrow. Therefore, it was confirmed that the hardened oil in which Aerosil was dispersed and MCT produced an interface.
本発明の三層構造シームレスカプセルは、医薬、医薬部外品、食品などの分野において、水と配合禁忌の関係にある物質を安定に保持できるカプセル製剤として利用可能である。
INDUSTRIAL APPLICABILITY The three-layered seamless capsule of the present invention can be used as a capsule preparation that can stably hold a substance that is incompatible with water in the fields of medicine, quasi-drugs, and food.
Claims (12)
（ａ）水と配合禁忌の関係にある物質と第一油性物質と多孔性微粒子粉末とを含有するコア液を調製する工程；
（ｂ）第二油性物質を含有する保護液を調製する工程；
（ｃ）水溶性ゲル化剤と水とを含有する皮膜液を調製する工程；
（ｄ）同心三重ノズルを用い、外側ノズルからは前記皮膜液を、内側ノズルからは前記コア液を、中間ノズルからは前記保護液を吐出させて三層液滴とし、かかる三層液滴を硬化液と接触させて皮膜液を硬化させる工程； A three-layer seamless capsule comprising a core, a protective layer for encapsulating the core, and a coating layer for enclosing the protective layer (however, after encapsulation, air-drying at room temperature is performed. Excluding those dried or vacuum freeze-dried), comprising the following steps (a) to (d):
(A) a step of preparing a core liquid containing a substance which is incompatible with water, a first oily substance, and a porous fine particle powder;
(B) preparing a protective solution containing the second oily substance;
(C) preparing a coating solution containing a water-soluble gelling agent and water;
(D) Using a concentric triple nozzle, the coating liquid is discharged from the outer nozzle, the core liquid is discharged from the inner nozzle, and the protective liquid is discharged from the intermediate nozzle to form a three-layer droplet. Curing the coating liquid by contacting with a curing liquid;
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| JPS5659709A (en) * | 1979-10-22 | 1981-05-23 | Grelan Pharmaceut Co Ltd | Preparation of hard capsule consisting of bean-cake essentially |
| JPH0441434A (en) * | 1990-06-07 | 1992-02-12 | Asahi Breweries Ltd | Lactobacillus tablet provided with enteric coating |
| JPH06247845A (en) * | 1993-02-25 | 1994-09-06 | Fuji Capsule Kk | Soft capsule comprising fine particulate silicon oxide blended therein |
| JP3102990B2 (en) * | 1993-07-08 | 2000-10-23 | 森下仁丹株式会社 | Method for producing capsules and capsules obtained therefrom |
| JP2005065629A (en) * | 2003-08-26 | 2005-03-17 | Mie Prefecture | Tea tablet and method for producing the same |
| JP4262057B2 (en) * | 2003-11-13 | 2009-05-13 | 俊博 野村 | Fat-soluble active ingredient combination food |
| JP2008050264A (en) * | 2004-12-21 | 2008-03-06 | Eisai Co Ltd | Dry granulated substance |
| DE602005004114T3 (en) * | 2005-02-18 | 2016-10-27 | Gnosis S.P.A. | Process for the preparation of yeast microcapsules |
| JP2006280263A (en) * | 2005-03-31 | 2006-10-19 | Snow Brand Milk Prod Co Ltd | Bacillus bifidus cell powder |
| JP2008109910A (en) * | 2006-10-31 | 2008-05-15 | Toshihiro Nomura | Enzyme-compounded granule acting in intestine, and enzyme-compounded food using the enzyme-compounded granule |
| WO2008081539A1 (en) * | 2006-12-28 | 2008-07-10 | National University Corporation Akita University | Supplement containing useful bacterium such as lactic acid bacterium with the use of porous silica |
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