Lactic acid bacteria-containing tablet

Abstract

Provided is a lactic acid bacteria-containing tablet comprising: lactic acid bacteria (component A); a first excipient (component B) that has an average particle size of less than 60 μm; and a second excipient (component C) that has an average particle size of not less than 60 μm. Component B and component C are preferably different from each other. The content of component A in one tablet is preferably not less than 30 mass%. Component A is preferably a sterilized dry powder of lactic acid bacteria.

Description

Lactic acid bacteria-containing tablets

[0001] The present invention relates to lactic acid bacteria-containing tablets.

[0002] Lactic acid bacteria are a general term for Gram-positive bacteria that decompose sugars to produce lactic acid and obtain energy, and include many genera and species of bacteria. In addition to playing a role in regulating the intestinal environment as indigenous bacteria in the intestines of humans and animals, lactic acid bacteria are also attracting attention as probiotics because they have effects such as cholesterol reduction and immune activation.

[0003] So far, as foods containing probiotics, for example, an intestinal environment-improving food (Patent Document 1) containing a large intestine-disintegrating preparation containing Bifidobacterium and a lactic acid bacteria preparation, and a viable bacteria-containing preparation (Patent Document 2) containing viable bacteria of useful intestinal bacteria are known.

[0004] However, the powder of lactic acid bacteria has poor fluidity, and the filling suitability during the production of lactic acid bacteria-containing tablets was poor. In addition, since the powder of lactic acid bacteria has a weak binding force, it has been a problem that it is difficult to maintain sufficient hardness as a tablet after production. So far, as a lactic acid bacteria-containing tablet with high ingestion efficiency and excellent hardness, a lactic acid bacteria-containing tablet (Patent Document 3) containing lactic acid bacteria, an excipient, and a lubricant, with the content of the lubricant being less than 10% by mass based on the mass of the tablet and the mass per tablet being 200 mg or more has been proposed.

[0005] JP-A-2013-226095 JP-A-2018-158947 WO 2023 / 149554

[0006] An object of the present invention is to provide a lactic acid bacteria-containing tablet that is excellent in filling suitability during production and has sufficient hardness as a tablet after production.

[0007] According to the present invention, the following inventions are provided. [1] A lactic acid bacteria-containing tablet containing lactic acid bacteria (component A), a first excipient (component B) having an average particle diameter of less than 60 μm, and a second excipient (component C) having an average particle diameter of 60 μm or more. [2] The tablet according to [1] above, wherein the component B and the component C are different from each other. [3] The tablet according to [1] or [2] above, wherein the content of the component A in one tablet is 30% by mass or more. [4] The number of bacteria of the component A in one tablet is 1×10 ８[1] to [2] above, a tablet containing one or more of the above [1] to [2]. [3] A tablet according to any one of the above [1] to [2] above, wherein the content of component B in one tablet is 5% by mass or more. [4] A tablet according to any one of the above [1] to [2] above, wherein the content of component C in one tablet is 45% by mass or less. [5] A tablet according to any one of the above [1] to [2] above, wherein the average particle diameter of component A is 10 μm or more and 40 μm or less. [6] A tablet according to any one of the above [1] to [2] above, wherein the average particle diameter of component B is 20 μm or more and less than 60 μm. [7] A tablet according to any one of the above [1] to [2] above, wherein the angle of repose of component B is 50° or more. [8] A tablet according to any one of the above [1] to [2] above, wherein the average particle diameter of component C is 90 μm or more. [9] A tablet according to any one of the above [1] to [2] above, wherein the angle of repose of component C is 30° or more.

[12] A tablet according to any one of [1] to

[11] above, wherein the mass per tablet is less than 200 mg.

[13] A tablet according to any one of [1] to

[12] above, wherein component A is a sterilized dried powder of lactic acid bacteria.

[14] A tablet according to any one of [1] to

[13] above, wherein component B is one or more selected from the group consisting of cellulose and cellulose derivatives.

[15] A tablet according to any one of [1] to

[14] above, wherein component C is one or more selected from the group consisting of cellulose, maltose and maltitol.

[16] A tablet according to any one of [1] to

[15] above, wherein the ratio of the content of component B (mass%) in one tablet to the content of component C (mass%) in one tablet (B / C) is 0.1 or more.

[17] A tablet according to any one of [1] to

[16] above, wherein the ratio of the content of component A in one tablet (A / (B+C)) to the sum of the content of component B (mass%) and the content of component C (mass%) in one tablet is 2.0 or less.

[0008] According to the present invention, it is possible to provide a lactic acid bacteria-containing tablet that has excellent filling suitability during manufacturing and sufficient hardness as a tablet after manufacturing.

[0009] <<Lactic Acid Bacteria-Containing Tablets>> <Lactic Acid Bacteria (Component A)> The lactic acid bacteria contained in the lactic acid bacteria-containing tablets of the present invention (which may be simply referred to as "tablets" in this specification) are not particularly limited. Lactic acid bacteria are bacteria that produce lactic acid as a metabolite, and examples include bacteria of the genera Lactobacillus, Oenococcus, Bifidobacterium, Lentilactobacillus, Weissella, Tetragenococcus, Lactococcus, Leuconostoc, Pediococcus, Streptococcus, Enterococcus, Lactiplantibacillus, Heyndrickxia, and Bacillus.

[0010] Among the above, Lactobacillus, Oenococcus, Bifidobacterium, Lentilactobacillus, Weissella, Tetragenococcus, Lactococcus, Leuconostoc, Pediococcus, Enterococcus, and Lactiplantibacillus are preferred as lactic acid bacteria. Among the above, Lactococcus is particularly preferred as the lactic acid bacteria in this embodiment.

[0011] In this specification, the term "Lactobacillus" includes bacteria that were classified under the genus Lactobacillus before the reclassification of the genus. Lactobacillus bacteria, for example, have been reclassified into new genera such as Acetilactobacillus, Agrilactobacillus, Amylolactobacillus, Apilactobacillus, Bombilactobacillus, Companilactobacillus, Dellaglioa, Fructilactobacillus, Furfurilactobacillus, Holzapfelia, Lacticaseibacillus, Lactiplantibacillus, and Lapi This includes bacteria classified under genera such as Lapidilactobacillus, Latilactobacillus, Lentilactobacillus, Levilactobacillus, Ligilactobacillus, Limosilactobacillus, Liquorilactobacillus, Loigolactobacillus, Paralactobacillus, Paucilactobacillus, Schleiferilactobacillus, and Secundilactobacillus.

[0012] Examples of Lactobacillus species include Lactobacillus paracasei, Lactobacillus delbrueckii, Lactobacillus casei, Lactobacillus fructivorans, Lactobacillus hilgardii, Lactobacillus rhamnosus, Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus parakefiri, and Lactobacillus plantarum. Examples of Lactobacillus species include Lactobacillus plantarum and Lactobacillus pentosus. Specific examples of Lactobacillus species include Lactobacillus paracasei KW3110, Lactobacillus paracasei MCC1849, Lactobacillus paracasei K71, Lactobacillus paracasei K-2, Lactobacillus rhamnosus GG, Lactobacillus rhamnosus CRL1505, Lactobacillus gasseri SBT2055, Lactobacillus acidophilus L-92, and Lactobacillus casei subspecies. Examples include Lactobacillus casei 327, Lactobacillus casei Shirota (Lactobacillus casei in the new classification), Lactobacillus parakefilii (Lentilactobacillus parakefilii in the new classification) JCM8573, Lactobacillus plantarum (Lactiplantibacillus plantarum in the new classification) L-137, and Lactobacillus pentosa (Lactiplantibacillus pentosa in the new classification) ONRICb0240.

[0013] Examples of the genus Oenococcus include Oenococcus oeni. A specific example of an Oenococcus species is Oenococcus oeni JCM6125.

[0014] Examples of Bifidobacterium species include Bifidobacterium animalis subsp. lactis and Bifidobacterium longum subsp. infantis. Specific examples of Bifidobacterium species include, for example, Bifidobacterium animalis subspecies lactis JCM10602, Bifidobacterium animalis subspecies lactis BB-12, Bifidobacterium longum subspecies infantis JCM1222, Bifidobacterium longum subspecies infantis M-63, Bifidobacterium longum subspecies longum BB536, Bifidobacterium longum subspecies longum N61, Bifidobacterium breve M-16V, and Bifidobacterium breve MCC1274.

[0015] Examples of species belonging to the genus Weissella include Weissella paramesenteroides and Weissella viridescens. Specific examples of Weissella species include Weissella paramesenteroides JCM9890 and Weissella viridescens JCM1174.

[0016] Examples of Tetragenococcus species include Tetragenococcus halophilus. Specific examples of Tetragenococcus species include Tetragenococcus halophilus NRIC0098 and Tetragenococcus halophilus No. 1.

[0017] Examples of Lactococcus species include Lactococcus lactis, Lactococcus lactis subsp. lactis, Lactococcus garvieae, Lactococcus lactis subsp. cremoris, Lactococcus lactis subsp. hordniae, and Lactococcus plantarum.Specific examples of Lactococcus species include, for example, Lactococcus lactis subspecies lactis JCM5805, Lactococcus lactis subspecies lactis NBRC12007, Lactococcus lactis subspecies lactis NRIC1150, Lactococcus lactis subspecies lactis JCM20101, Lactococcus lactis subspecies lactis JCM7638, Lactococcus lactis subspecies lactis ATCC 7963, Lactococcus lactis subspecies lactis ATCC 7962, Lactococcus lactis subspecies lactis ATCC 29146, Lactococcus lactis subspecies lactis ATCC 27861, Lactococcus lactis subspecies lactis ATCC 19435, Lactococcus lactis subspecies lactis ATCC 15346, Lactococcus lactis subspecies lactis ATCC 13675, Lactococcus lactis subspecies lactis ATCC 12929, Lactococcus lactis subspecies lactis ATCC 11955, Lactococcus lactis subspecies lactis ATCC 11454, Lactococcus lactis subspecies lactis ATCC Examples include Lactococcus garbieae NBRC100934, Lactococcus lactis subspecies cremoris JCM16167, Lactococcus lactis subspecies cremoris NBRC100676, Lactococcus lactis subspecies heldniae JCM1180, Lactococcus lactis subspecies heldniae JCM11040, and Lactococcus plantarum JCM11056.

[0018] Examples of Leuconostoc species include Leuconostoc carnosum and Leuconostoc lactis. Specific examples of Leuconostoc species include Leuconostoc carnosum JCM9695 and Leuconostoc lactis NBRC12455.

[0019] Examples of species belonging to the genus Pediococcus include Pediococcus acidilactici, Pediococcus pentosaceus, Pediococcus cellicola, Pediococcus claussenii, Pediococcus damnosus, Pediococcus ethanolidurans, Pediococcus inopinatus, Pediococcus parvulus, and Pediococcus stilesii. Specific examples of Pediococcus species include Pediococcus acidilactici JCM8797, Pediococcus acidilactici K15, and Pediococcus damnosus JCM5886.

[0020] Examples of Streptococcus species include Streptococcus thermophilus. Specific examples of Streptococcus species include Streptococcus thermophilus SBC8781.

[0021] Examples of Enterococcus species include Enterococcus alcedinis and Enterococcus faecalis. A specific example of an Enterococcus species is Enterococcus faecalis EC-12.

[0022] While not limited to Bacillus species, examples include Bacillus coagulans. A specific example of a Bacillus species is Bacillus coagulans SANK70258, also known as Hendricksia coagulans SANK70258.

[0023] The lactic acid bacteria contained in the lactic acid bacteria-containing tablets of this embodiment may be one type of lactic acid bacteria, or a mixture of two or more types of lactic acid bacteria.

[0024] The above-mentioned lactic acid bacteria strains can be obtained from public depositary institutions, etc. For example, the JCM strain can be obtained from the Microbial Materials Development Laboratory, BioResource Center, RIKEN (3-1-1 Takanodai, Tsukuba, Ibaraki Prefecture), the NBRC strain from the Biological Genetic Resources Division, National Institute of Technology and Evaluation (2-5-8 Kazusa-Kamatari, Kisarazu, Chiba Prefecture), the NRIC strain from the Strain Preservation Room, Tokyo University of Agriculture (1-1-1 Sakuragaoka, Setagaya-ku, Tokyo), and the ATCC strain from the American Type Culture Collection (USA).

[0025] Furthermore, Lactobacillus paracasei KW3110 is deposited as FERM BP-08634 at the Patent Organism Depository Center of the National Institute of Advanced Industrial Science and Technology (AIST) (1-1-1 Higashi, Tsukuba, Ibaraki, Japan 305-8566, Central Building 6) (currently, the Patent Organism Depository Center of the National Institute of Technology and Evaluation (NITE-IPOD) (2-5-8 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Room 120)) as the international depositary authority under the Budapest Convention for the Deposit of Patent Microorganisms (Deposit date: February 20, 2004). In addition, a derivative strain of Lactobacillus paracasei KW3110 is deposited at the same Patent Organism Depository Center as FERM BP-08635 (Deposit date: February 20, 2004).

[0026] As mentioned above, Lactococcus lactis subspecies lactis JCM5805 can be obtained from the Microbial Materials Development Laboratory at the RIKEN BioResource Center. However, in this invention, the same strain of Lactococcus lactis subspecies lactis JCM5805 stored at institutions other than the RIKEN BioResource Center Microbial Materials Development Laboratory can be used. Specifically, the same strain of Lactococcus lactis subspecies lactis JCM5805 can be obtained from the National Institute of Technology and Evaluation (NIITE) Biological Genetics Division (2-5-8 Kazusa-Kamatari, Kisarazu City, Chiba Prefecture), Tokyo University of Agriculture Strain Preservation Room (1-1-1 Sakuragaoka, Setagaya-ku, Tokyo), and the American Type Culture Collection (USA), among others. Lactococcus lactis subspecies lactis JCM5805 is deposited in the American Type Culture Collection as Lactococcus lactis subspecies lactis ATCC9936 and Lactococcus lactis subspecies lactis ATCC19435.

[0027] The lactic acid bacteria contained in the tablets of the present invention may be live cells, dead cells, or both, or lactic acid bacteria cells and their processed products, or the lactic acid bacteria cells may be in isolated form or in culture form.

[0028] Lactic acid bacteria can be cultured using known methods with known culture media. MRS medium, GAM medium, or LM17 medium can be used as the culture medium, and inorganic salts, vitamins, amino acids, antibiotics, and serum can be added as appropriate. Culturing can be carried out at 25-40°C for several hours to several days.

[0029] After culturing, lactic acid bacteria can be collected by centrifugation or filtration. If used as dead bacteria, they may be sterilized by heating in an autoclave or similar device before use.

[0030] Examples of lactic acid bacteria cell treatment products include crushed live or dead cells (e.g., ultrasonically crushed cells), dried live or dead cells (e.g., freeze-dried cells), crushed dried cells, and enzyme-treated live or dead cells. Dead cells can be obtained, for example, by heat treatment, treatment with drugs such as antibiotics, treatment with chemical substances such as formalin, treatment with ultraviolet light, and treatment with radiation such as gamma rays. Enzyme-treated products also include products in which the cell wall of lactic acid bacteria has been removed by enzymes or mechanical means. Furthermore, nucleic acid-containing fractions of lactic acid bacteria (e.g., DNA, RNA) are also included in lactic acid bacteria cell treatment products and can be obtained by dissolving lactic acid bacteria cells with a surfactant and then precipitating them with ethanol. In the present invention, "lactic acid bacteria" is used to mean live and dead lactic acid bacteria cells, lactic acid bacteria cells and their treatment products, and the isolated and cultured forms of lactic acid bacteria cells.

[0031] In the present invention, the lower limit (greater than or equal to) of the lactic acid bacteria content in one tablet can be, for example, 5% by mass, 10% by mass, 15% by mass, 20% by mass, 25% by mass, 30% by mass, 31% by mass, 32% by mass, 33% by mass, 34% by mass, 35% by mass, 36% by mass, 37% by mass, 38% by mass, 39% by mass, 40% by mass, 41% by mass, 42% by mass, 43% by mass, 44% by mass, or 45% by mass, and the upper limit (less than or equal to) can be, for example, 65% by mass, 64% by mass, 63% by mass, 62% by mass, 61% by mass, 60% by mass, 59% by mass, 58% by mass, 57% by mass, 56% by mass, 55% by mass, 54% by mass, 53% by mass, 52% by mass, 51% by mass, or 50% by mass. These lower and upper limits can be combined arbitrarily, and the lactic acid bacteria content in one tablet can be, for example, 5-65% by mass, 5-60% by mass, 5-55% by mass, 5-50% by mass, 10-65% by mass, 10-60% by mass, 10-55% by mass, 10-50% by mass, 20-65% by mass, 20-60% by mass, 20-55% by mass, and 20-50% by mass. The content can be 30-65% by mass, 30-60% by mass, 30-55% by mass, 30-50% by mass, 35-65% by mass, 35-60% by mass, 35-55% by mass, 35-50% by mass, 40-65% by mass, 40-60% by mass, 40-55% by mass, 40-50% by mass, 45-65% by mass, 45-60% by mass, 45-55% by mass, or 45-50% by mass. When one tablet contains two or more types of lactic acid bacteria (component A), the above lower limit, upper limit, and combination thereof shall apply to the total content of the two or more types of lactic acid bacteria (component A). That is, with respect to lactic acid bacteria (component A), the term "content" refers to the total content when one tablet contains two or more types of lactic acid bacteria (component A).

[0032] When two or more kinds of lactic acid bacteria (component A) are contained in one tablet, the content of each component is as follows. That is, when two or more components are contained as lactic acid bacteria (component A) in one tablet, the lower limit value (greater than or equal to) of the content of each component is independently, for example, 1% by mass, 3% by mass, 5% by mass, 10% by mass, 15% by mass, 20% by mass, 25% by mass, 30% by mass, 31% by mass, 32% by mass, 33% by mass, 34% by mass, 35% by mass, 36% by mass, 37% by mass, 38% by mass, 39% by mass, 40% by mass, 41% by mass, 42% by mass, 43% by mass, 44% by mass or 45% by mass, and the upper limit value (less than or equal to) is, for example, 65% by mass, 64% by mass, 63% by mass, 62% by mass, 61% by mass, 60% by mass, 59% by mass, 58% by mass, 57% by mass, 56% by mass, 55% by mass, 54% by mass, 53% by mass, 52% by mass, 51% by mass or 50% by mass. These lower limit values and upper limit values can be arbitrarily combined, and the content of each component in one tablet can be independently, for example, 1 to 60% by mass, 5 to 60% by mass, 10 to 60% by mass, 1 to 55% by mass, 5 to 55% by mass, 10 to 55% by mass, 1 to 50% by mass, 5 to 50% by mass or 10 to 50% by mass.

[0033] In the present invention, from the viewpoint of proper filling and / or hardness of the tablet, the lower limit value (greater than or equal to) of the number of lactic acid bacteria in one tablet is, for example, 1×10 ８ cells,​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​１３ pieces, 4×10 １３ pieces, 3×10 １３ pieces, 2×10 １３ pieces, 1×10 １３ pieces, 5×10 １２ pieces, 4×10 １２ pieces, 3×10 １２ pieces, 2×10 １２ pieces, 1×10 １２ pieces, 5×10 １１ pieces, 4×10 １１ pieces, 3×10 １１ individual or 2 x 10 １１ The number of bacteria in one lactic acid bacteria tablet can be, for example, 1 × 10⁶. These lower and upper limits can be combined arbitrarily, and the number of bacteria in one lactic acid bacteria tablet can be, for example, 1 × 10⁶. ８ ~1 x 10 １４ pieces, 1×10 ９ ~1 x 10 １３ pieces, 1×10 １０ ~1 x 10 １２ pieces, 5×10 １０ ~3 x 10 １１ pieces, 1×10 １１ ~1 x 10 １２ individual or 1 x 10 １１ ~2 x 10 １１ The number of lactic acid bacteria can be measured by, for example, fluorescence staining, flow cytometry, or culture, and measurement by flow cytometry is preferred from the viewpoint of measurement accuracy. When one tablet contains two or more types of lactic acid bacteria (component A), the lower limit, upper limit, and combination thereof of the bacterial count shall apply to the total bacterial count of the two or more types of lactic acid bacteria (component A). That is, with respect to lactic acid bacteria (component A), the term "bacterial count" shall refer to the total bacterial count of the two or more types of lactic acid bacteria (component A) when one tablet contains two or more types of lactic acid bacteria (component A).

[0034] When one tablet contains two or more types of lactic acid bacteria (component A), the number of bacteria in each individual component is as follows. That is, when one tablet contains two or more types of lactic acid bacteria (component A), the lower limit (greater than or equal to) the number of bacteria in each individual component is independently, for example, 1 × 10⁻⁶. ４ pieces, 1×10 ５ pieces, 1×10 ６ pieces, 1×10７ pieces, 1×10 ８ pieces, 2×10 ８ pieces, 3×10 ８ pieces, 4×10 ８ pieces, 5×10 ８ pieces, 1×10 ９ pieces, 2×10 ９ pieces, 3×10 ９ pieces, 4×10 ９ pieces, 5×10 ９ pieces, 1×10 １０ pieces, 2×10 １０ pieces, 3×10 １０ pieces, 4×10 １０ pieces, 5×10 １０ pieces or 1×10 １１ pieces, and the upper limit value (hereinafter or less) is, for example, 1×10 １４ pieces, 5×10 １３ pieces, 4×10 １３ pieces, 3×10 １３ pieces, 2×10 １３ pieces, 1×10 １３ pieces, 5×10 １２ pieces, 4×10 １２ pieces, 3×10 １２ pieces, 2×10 １２ pieces, 1×10 １２ pieces, 5×10 １１ pieces, 4×10 １１ pieces, 3×10 １１ pieces or 2×10 １１ pieces, and these lower limit values and upper limit values can be arbitrarily combined respectively. The number of bacteria of each individual component in one tablet can be independently, for example, 1×10 ４ to 1×10 １４ pieces, 1×10 ６ to 1×10 １４ pieces, and 1×10 ８ to 1×10 １４ pieces, 1×10 ９ to 1×10 １３ pieces, 1×10 １０ to 1×10<00*********]]pieces, 5×10 １０ to 3×10 １１ pieces, 1×10 １１ to*********]] １２ pieces or 1×10 １１ to 2×10 １１It can be considered as an individual.

[0035] In the present invention, the average particle size of lactic acid bacteria can be, from the viewpoint of tablet filling suitability and / or hardness, set as follows: lower limit (greater than or equal to) 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, or 20 μm, and upper limit (less than or equal to) 40 μm, 39 μm, 38 μm, 37 μm, 36 μm, 35 μm, 34 μm, 33 μm, 32 μm, 31 μm, or 30 μm. These lower and upper limits can be combined in any way, and the average particle size of the lactic acid bacteria can be, for example, 10-40 μm, 15-40 μm, 20-40 μm, 10-35 μm, 15-35 μm, 20-35 μm, 10-30 μm, 15-30 μm, or 20-30 μm. When one tablet contains two or more types of lactic acid bacteria (component A), the above lower and upper limits of the average particle size and their combinations can be applied to each type of lactic acid bacteria (component A) contained in one tablet.

[0036] From the viewpoint of storage stability, lactic acid bacteria are preferably in the form of sterilized and dried powder. The method for producing sterilized and dried lactic acid bacteria powder is not limited as long as it does not impair the effects of the present invention. For example, the bacterial cells may be cultured, the bacterial solution obtained from the culture may be washed, and the bacterial cells may be sterilized by, for example, heat treatment, pressurization treatment, high-pressure steam treatment, electromagnetic wave treatment, electron beam treatment, radiation treatment, ultraviolet treatment, alcohol treatment, or electrolyzed water treatment, and then the sterilized bacterial solution may be subjected to, for example, spray drying, freeze-drying, drum drying, hot air drying, or vacuum drying.

[0037] When lactic acid bacteria are used as a sterilized and dried powder, the fluidity during the manufacturing of lactic acid bacteria-containing tablets is poor, resulting in poor filling suitability during manufacturing. Furthermore, the weak binding properties make it difficult to maintain sufficient hardness as a tablet after manufacturing. According to the present invention, by incorporating the components described below into the lactic acid bacteria-containing tablets, it is possible to provide lactic acid bacteria-containing tablets with improved filling suitability and hardness.

[0038] <Excipients (Components B and C)> In the present invention, excipients are used to improve the handling or molding of the composition. The lactic acid bacteria-containing tablets of the present invention contain two types of excipients with different average particle sizes, namely, a first excipient (component B) with an average particle size of less than 60 μm, and a second excipient (component C) with an average particle size of 60 μm or more. In the present invention, by using a combination of excipients with different average particle sizes, binding force can be imparted, and lactic acid bacteria-containing tablets with improved hardness can be provided. Furthermore, by combining excipients with different average particle sizes, the fluidity of the tablet component containing lactic acid bacteria can be increased, improving the suitability of filling during manufacturing.

[0039] The first and second excipients contained in the tablets of the present invention are not particularly limited and include, for example, starch or its derivatives such as starch, pregelatinized starch, partially pregelatinized starch, and starch hydrolysates; sugar alcohols such as dextrin, β-cyclodextrin, reduced palatinose, reduced maltose, and reduced maltose syrup; polysaccharides such as pullulan; disaccharides such as lactose and maltose; brewer's yeast; cellulose or its derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; refined sucrose; silicon dioxide (light anhydrous silicic acid); calcium silicate; titanium dioxide; precipitated calcium carbonate; phosphates (tricalcium phosphate, monocalcium phosphate, dicalcium phosphate, etc.); and corn protein. Any one of these may be used, or a combination of two or more. Commercially available products can be used for the first and second excipients.

[0040] The first excipient (component B) and the second excipient (component C) may be the same type of compound or a combination of the same type of compound, but it is preferable that they be different from each other. "Different from each other" means that the types of compounds constituting the excipients do not match between the two components. Examples include: Component B: x, Component C: z; Component B: x and y, Component C: z; Component B: x, Component C: z and w; Component B: x and y, Component C: z and w. (In the above, x, y, z, and w each represent excipients with different types of compounds.)

[0041] Component B and component C are different from each other, meaning that the types of compounds constituting the excipients in both components are partially the same (partially different). Examples include: Component B: x, Component C: x and z; Component B: x and y, Component C: x; Component B: x and y, Component C: x and z; Component B: x, y and z, Component C: x, y and w. (In the above examples, x, y, z, and w each represent excipients with different types of compounds.)

[0042] <First Excipient (Component B)> In the present invention, from the viewpoint of proper filling and / or hardness of the tablets, the first excipient (component B) is preferably a sugar selected from the group consisting of starch or its derivatives, cellulose or its derivatives, sugar alcohols and disaccharides, more preferably one or more selected from the group consisting of cellulose and cellulose derivatives, and even more preferably one or more selected from the group consisting of hydroxypropyl cellulose and crystalline cellulose.

[0043] In the present invention, the content of the first excipient (component B) in one tablet can be, from the viewpoint of proper filling and / or hardness of the tablet, set as follows: lower limit (greater than or equal to) can be, for example, 5% by mass, 6% by mass, 7% by mass, 8% by mass, 9% by mass, or 10% by mass; upper limit (less than or equal to) can be, for example, 30% by mass, 28% by mass, 26% by mass, 24% by mass, 22% by mass, 20% by mass, 19% by mass, 18% by mass, 17% by mass, 16% by mass, 15% by mass, 14% by mass, 13% by mass, 12% by mass, 11% by mass, or 10% by mass. These lower and upper limits can be combined in any way, and the content of the first excipient in one tablet can be, for example, 5-30% by mass, 10-30% by mass, 5-26% by mass, 10-26% by mass, 5-20% by mass, 10-20% by mass, 5-15% by mass, 10-15% by mass, or 5-10% by mass. If one tablet contains two or more types of the first excipient (component B), the above lower and upper limits and their combinations shall apply to the total content of the two or more types of the first excipient (component B). That is, with respect to the first excipient (component B), the term "content" refers to the total content when one tablet contains two or more types of the first excipient (component B).

[0044] When one tablet contains two or more types of the first excipient (component B), the content of each individual component is as follows. That is, when one tablet contains two or more types of components as the first excipient (component B), the lower limit of the content of each individual component can be independently set to, for example, 1% by mass, 2% by mass, 3% by mass, 4% by mass, 5% by mass, 6% by mass, 7% by mass, 8% by mass, 9% by mass, or 10% by mass, and the upper limit of the content of each individual component can be independently set to, for example, 30% by mass, 28% by mass, 26% by mass, 24% by mass, 22% by mass, 20% by mass, 19% by mass, 18% by mass, 17% by mass, 16% by mass, 15% by mass, 14% by mass, 13% by mass, 12% by mass, 11% by mass, 10% by mass, 9% by mass, 8% by mass, 7% by mass, 6% by mass, 5% by mass, or 4% by mass. These lower and upper limits can be combined in any way, and the content of each individual component in one tablet can be independently set to, for example, 1-15% by mass, 1-10% by mass, 3-15% by mass, 3-10% by mass, 5-15% by mass, 5-10% by mass, or 1-5% by mass.

[0045] In the present invention, the average particle size of the first excipient (component B) can be, from the viewpoint of tablet filling suitability and / or hardness, set to a lower limit (greater than or equal to) of, for example, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, or 20 μm, and its upper limit (less than or equal to) can be, for example, 60 μm, 59 μm, 58 μm, 57 μm, 56 μm, 55 μm, 54 μm, 53 μm, 52 μm, 51 μm, or 50 μm. These lower and upper limits can be combined arbitrarily, and the average particle size of the first excipient can be, for example, 10-60 μm, 15-60 μm, 20-60 μm, 10-55 μm, 15-55 μm, 20-55 μm, 10-50 μm, 15-50 μm, or 20-50 μm. When one tablet contains two or more types of the first excipient (component B), the above lower and upper limits of the average particle size and their combinations can be applied to each of the first excipients (component B) contained in one tablet.

[0046] In the present invention, the angle of repose of the first excipient (component B) can be, from the viewpoint of proper filling and / or hardness of the tablet, set to a lower limit (greater than or equal to) of 40°, 41°, 42°, 43°, 44°, 45°, 46°, 47°, 48°, 49°, or 50°, preferably 50°. Its upper limit (less than or equal to) can be, for example, 65°, 63°, 60°, 59°, 58°, 57°, 56°, 55°, 54°, 53°, 52°, 51°, or 50°. These lower and upper limits can be combined arbitrarily, and the angle of repose of the first excipient can be, for example, 40-65°, 45-65°, 40-60°, 45-60°, or 50-60°. When a tablet contains two or more types of the first excipient (component B), the lower limit, upper limit, and combination thereof of the angle of repose can be applied to each of the first excipients (component B) contained in the tablet.

[0047] <Second Excipient (Component C)> In the present invention, from the viewpoint of proper filling and / or hardness of the tablets, the second excipient (component C) is preferably one or more sugars selected from the group consisting of starch or its derivatives, cellulose or its derivatives, sugar alcohols and disaccharides, more preferably one or more selected from the group consisting of cellulose, cellulose derivatives, sugar alcohols and disaccharides, and even more preferably one or more selected from the group consisting of cellulose, maltose and maltitol.

[0048] In the present invention, the content of the second excipient (component C) in one tablet can be, from the viewpoint of proper filling and / or hardness of the tablet, set as follows: lower limit (greater than or equal to) can be, for example, 10% by mass, 15% by mass, 20% by mass, 21% by mass, 22% by mass, 23% by mass, 24% by mass, or 25% by mass; upper limit (less than or equal to) can be, for example, 45% by mass, 44% by mass, 43% by mass, 42% by mass, 41% by mass, 40% by mass, 39% by mass, 38% by mass, 37% by mass, 36% by mass, 35% by mass, 34% by mass, 33% by mass, 32% by mass, 31% by mass, or 30% by mass. These lower and upper limits can be combined in any way, and the content of the second excipient in one tablet can be, for example, 10-45% by mass, 15-45% by mass, 20-45% by mass, 25-45% by mass, 10-40% by mass, 15-40% by mass, 20-40% by mass, 25-40% by mass, 10-35% by mass, 15-35% by mass, 20-35% by mass, 25-35% by mass, 10-30% by mass, 15-30% by mass, 20-30% by mass, or 25-30% by mass. If one tablet contains two or more types of the second excipient (component C), the above lower and upper limits and their combinations shall apply to the total content of the two or more types of the second excipient (component C). In other words, with respect to the second excipient (component C), the term "content" refers to the total content of two or more types of the second excipient (component C) when one tablet contains them.

[0049] When one tablet contains two or more second excipients (component C), the content of each component is as follows: That is, when one tablet contains two or more components as the second excipient (component C), the lower limit of the content of each component (greater than or equal to) can be independently set to, for example, 1% by mass, 2% by mass, 3% by mass, 4% by mass, 5% by mass, 6% by mass, 7% by mass, 8% by mass, 9% by mass, 10% by mass, 11% by mass, 12% by mass, 13% by mass, 14% by mass, 15% by mass, 16% by mass, 17% by mass, 18% by mass, 19% by mass, 20% by mass, 21% by mass, 22% by mass, 23% by mass, 24% by mass, or 25% by mass, and the upper limit of the content of each component (less than or equal to) can be independently set to, For example, 45 mass%, 44 mass%, 43 mass%, 42 mass%, 41 mass%, 40 mass%, 39 mass%, 38 mass%, 37 mass%, 36 mass%, 35 mass%, 34 mass%, 33 mass%, 32 mass%, 31 mass%, 30 mass%, 29 mass%, 28 mass%, 27 mass%, 26 mass%, 25 mass%, It can be 24% by mass, 23% by mass, 22% by mass, 21% by mass, 20% by mass, 19% by mass, 18% by mass, 17% by mass, 16% by mass, 15% by mass, 14% by mass, 13% by mass, 12% by mass, 11% by mass, 10% by mass, 9% by mass, 8% by mass, 7% by mass, 6% by mass, 5% by mass or 4% by mass. These lower and upper limits can be combined in any way, and the content of each individual component in one tablet can be independently set to, for example, 1-45% by mass, 5-45% by mass, 10-45% by mass, 15-45% by mass, 20-45% by mass, 1-30% by mass, 5-30% by mass, 10-30% by mass, 15-30% by mass, 20-30% by mass, 1-20% by mass, 5-20% by mass, 10-20% by mass, 1-15% by mass, 5-15% by mass, 10-15% by mass, 1-10% by mass, or 5-10% by mass.

[0050] In the present invention, the average particle size of the second excipient (component C) can be, from the viewpoint of tablet filling suitability and / or hardness, set to a lower limit (greater than or equal to) of, for example, 70 μm, 71 μm, 72 μm, 73 μm, 74 μm, 75 μm, 76 μm, 77 μm, 78 μm, 79 μm, 80 μm, 81 μm, 82 μm, 83 μm, 84 μm, 85 μm, 86 μm, 87 μm, 88 μm, 89 μm, or 90 μm, preferably 90 μm. The upper limit (less than or equal to) is, for example, 200 μm, 195 μm, 190 μm, 185 μm, 180 μm, 175 μm, 170 μm, 165 μm, 160 μm, 155 μm, 150 μm, 145 μm, 140 μm, 139 μm, 138 μm, 137 μm, 136 μm, 135 μm, 134 μm, 133 μm, 132 μm, 131 μm, 130 μm, 129 μm, 128 μm, 127 μm The particle size can be 126 μm, 125 μm, 124 μm, 123 μm, 122 μm, 121 μm, 120 μm, 119 μm, 118 μm, 117 μm, 116 μm, 115 μm, 114 μm, 113 μm, 112 μm, 111 μm, 110 μm, 109 μm, 108 μm, 107 μm, 106 μm, 105 μm, 104 μm, 103 μm, 102 μm, 101 μm, or 100 μm. These lower and upper limits can be combined in any way, and the average particle size of the second excipient can be, for example, 70-200 μm, 75-180 μm, 80-150 μm, or 90-130 μm. When a tablet contains two or more second excipients (component C), the lower limit, upper limit, and combination thereof of the average particle size can be applied to each second excipient (component C) contained in the tablet.

[0051] In the present invention, the angle of repose of the second excipient (component C) can be set, from the viewpoint of proper filling and / or hardness of the tablet, with a lower limit (greater than or equal to) of 30°, 31°, 32°, 33°, 34°, 35°, 36°, 37°, 38°, 39°, or 40°, and with an upper limit (less than or equal to) of 50°, 49°, 48°, 47°, 46°, 45°, 44°, 43°, 42°, 41°, or 40°. These lower and upper limits can be combined arbitrarily, and the angle of repose of the second excipient can be set, for example, to 30-50°, 35-50°, 40-50°, 45-50°, 30-45°, 35-45°, or 40-45°. When a tablet contains two or more second excipients (component C), the lower limit, upper limit, and combination thereof of the angle of repose can be applied to each second excipient (component C) contained in the tablet.

[0052] <Disintegrant (Component D)> In the present invention, the disintegrant (Component D) is used to disintegrate the tablet by water absorption and to promote the release of the active ingredient, etc. The disintegrant contained in the tablet of the present invention is not particularly limited as long as it is an ingredient that can achieve the above purpose, for example, polysaccharides, more specifically agar and corn starch, etc., and one of these may be used, or a combination of two or more of them may be used. Commercially available disintegrants can be used. In the present invention, agar is preferred from the viewpoint of proper filling and / or hardness of the tablet. The disintegrant (Component D) may be a formulation containing the above-executed ingredients as the main component.

[0053] In the present invention, the content of the disintegrant (component D) in one tablet can be, from the viewpoint of proper filling and / or hardness of the tablet, set as follows: lower limit (greater than or equal to) can be, for example, 0% by mass, 1% by mass, 2% by mass, 3% by mass, 4% by mass, or 5% by mass; upper limit (less than or equal to) can be, for example, 20% by mass, 19% by mass, 18% by mass, 17% by mass, 16% by mass, 15% by mass, 14% by mass, 13% by mass, 12% by mass, 11% by mass, or 10% by mass. These lower and upper limits can be combined arbitrarily, and the content of the disintegrant (component D) in one tablet can be, for example, 0 to 20% by mass, 0 to 16% by mass, 0 to 15% by mass, 0 to 10% by mass, 5 to 20% by mass, 5 to 16% by mass, 5 to 15% by mass, or 5 to 10% by mass. When a tablet contains two or more types of disintegrants (component D), the lower limit, upper limit, and combination thereof of the above-mentioned content shall apply to the total content of the two or more types of disintegrants (component D). In other words, with respect to disintegrants (component D), the term "content" shall refer to the total content of the disintegrants (component D) when a tablet contains two or more types of disintegrants (component D).

[0054] When one tablet contains two or more disintegrants (component D), the content of each component is as follows: That is, when one tablet contains two or more components as disintegrants (component D), the lower limit (greater than or equal to) the content of each component can be independently set to, for example, 0% by mass, 0.5% by mass, 1% by mass, 2% by mass, 3% by mass, 4% by mass, or 5% by mass, and the upper limit (less than or equal to) can be, for example, 20% by mass, 19% by mass, 18% by mass, 17% by mass, 16% by mass, 15% by mass, 14% by mass, 13% by mass, 12% by mass, 11% by mass, 10% by mass, 8% by mass, or 6% by mass. These lower and upper limits can be combined in any way, and the content of each individual component in one tablet can be independently set to, for example, 0-20% by mass, 0-16% by mass, 0-15% by mass, 0-10% by mass, 0-6% by mass, 2-20% by mass, 2-16% by mass, 2-15% by mass, 2-10% by mass, 2-6% by mass, 5-20% by mass, 5-16% by mass, 5-15% by mass, 5-10% by mass, or 5-6% by mass.

[0055] In the present invention, the average particle size of the disintegrant (component D) can be, from the viewpoint of tablet filling suitability and / or hardness, set to a lower limit (greater than or equal to) of, for example, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, or 100 μm, and its upper limit (less than or equal to) can be, for example, 200 μm, 195 μm, 190 μm, 185 μm, 180 μm, 175 μm, 170 μm, 165 μm, 160 μm, 155 μm, 150 μm, 145 μm, 140 μm, 135 μm, 130 μm, 125 μm, 120 μm, 115 μm, or 110 μm. These lower and upper limits can be combined in any way, and the average particle size of the disintegrant (component D) can be, for example, 60-200 μm, 70-180 μm, 80-150 μm, 90-130 μm, or 100-110 μm. When one tablet contains two or more types of disintegrants (component D), the above lower and upper limits of the average particle size and their combinations can be applied to each disintegrant (component D) contained in one tablet.

[0056] In the present invention, the angle of repose of the disintegrant (component D) can be set, from the viewpoint of proper filling and / or hardness of the tablet, with a lower limit (greater than or equal to) of, for example, 30°, 31°, 32°, 33°, 34°, 35°, 36°, 37°, 38°, 39°, or 40°, and an upper limit (less than or equal to) of, for example, 50°, 49°, 48°, 47°, 46°, 45°, 44°, 43°, 42°, 41°, or 40°. These lower and upper limits can be combined arbitrarily, and the angle of repose of the disintegrant (component D) can be set, for example, 30-50°, 35-50°, 40-50°, 45-50°, 30-45°, 35-45°, or 40-45°. When a tablet contains two or more disintegrants (component D), the lower limit, upper limit, and combination thereof of the angle of repose described above can be applied to each disintegrant (component D) contained in the tablet.

[0057] <Lubricant (Component E)> In the present invention, the lubricant is used to reduce friction between the tablet press die and the tablet when compressing the tablet powder, and to prevent tableting defects such as sticking. The lubricant contained in the tablets of the present invention is not particularly limited as long as it is a component that can achieve the above purpose. Examples include stearic acid, calcium stearate, magnesium stearate, and other stearic acid or its salts, sodium stearyl fumarate, polyethylene glycol, fatty acid esters such as glycerin fatty acid esters and sucrose fatty acid esters, vegetable oils and fats, hydrogenated oils, and talc. One of these may be used, or a combination of two or more. Commercially available lubricants can be used. In the present invention, from the viewpoint of proper filling and / or hardness of the tablets, stearic acid or its salts and fatty acid esters are preferred, and calcium stearate or sucrose fatty acid esters are more preferred.

[0058] In the present invention, the content of the lubricant (component E) in one tablet can be less than 5% by mass from the viewpoint of preventing tableting defects. The lower limit (greater than or greater than) of the content of the lubricant (component E) in one tablet can be, for example, 0.1% by mass, 0.2% by mass, 0.5% by mass, 1% by mass, 1.5% by mass, or 2% by mass, and the upper limit (less than or less than) can be, for example, 5% by mass, 4.5% by mass, 4% by mass, 3.5% by mass, 3% by mass, 2.5% by mass, or 2% by mass. These lower and upper limits can be arbitrarily combined, and the content of the lubricant (component E) in one tablet can be, for example, 0.1 to 5% by mass, 0.5 to 4% by mass, 1 to 3% by mass, or 2 to 3% by mass. If a tablet contains two or more types of lubricants (component E), the lower limit, upper limit, and combination thereof of the above-mentioned content shall apply to the total content of the two or more types of lubricants (component E). In other words, with respect to lubricants (component E), the term "content" shall refer to the total content of the lubricants (component E) when a tablet contains two or more types of lubricants (component E).

[0059] When one tablet contains two or more lubricants (component E), the content of each component is as follows. For example, when one tablet contains two or more components as lubricants (component E), the lower limit (greater than or equal to) the content of each component can be independently set to, for example, 0.1% by mass, 0.2% by mass, 0.5% by mass, 1% by mass, 1.5% by mass, or 2% by mass, and the upper limit (less than or equal to) the content of each component can be independently set to, for example, 5% by mass, 4.5% by mass, 4% by mass, 3.5% by mass, 3% by mass, 2.5% by mass, 2% by mass, 1.5% by mass, 1% by mass, 0.5% by mass, or 0.2% by mass. These lower and upper limits can be combined in any way, and the content of each individual component in one tablet can be independently set to, for example, 0.1 to 5% by mass, 0.1 to 3% by mass, 0.1 to 2% by mass, 0.5 to 5% by mass, 0.5 to 3% by mass, 0.5 to 2% by mass, 1 to 3% by mass, or 1 to 2% by mass.

[0060] <Adsorbent (Component F)> In the present invention, the adsorbent is used for purposes such as preventing moisture absorption or solidification. The adsorbent contained in the tablets of the present invention is not particularly limited as long as it is a component that can achieve the above purpose. Examples include silicon dioxide, tricalcium phosphate, etc., and one of these may be used, or a combination of two or more. Commercially available adsorbents can be used. In the present invention, silicon dioxide is preferred from the viewpoint of proper filling and / or hardness of the tablets.

[0061] In the present invention, the content of the adsorbent (component F) in one tablet may be less than 5% by mass from the viewpoint of preventing tableting problems. The lower limit (greater than or greater than) of the content of the adsorbent (component F) in one tablet may be, for example, 0.5% by mass, 1% by mass, 1.5% by mass, or 2% by mass, and the upper limit (less than or less than) may be, for example, 5% by mass, 4.5% by mass, 4% by mass, 3.5% by mass, 3% by mass, 2.5% by mass, or 2% by mass. These lower and upper limits can be combined arbitrarily, and the content of the adsorbent (component F) in one tablet may be, for example, 1 to 5% by mass, 2 to 4% by mass, or 2 to 3% by mass. When one tablet contains two or more types of adsorbent (component F), the above lower limit, upper limit, and combination thereof shall apply to the total content of the two or more types of adsorbent (component F). In other words, with respect to the adsorbent (component F), the term "content" refers to the total content of two or more adsorbents (component F) when one tablet contains them.

[0062] When one tablet contains two or more adsorbents (component F), the content of each component is as follows. That is, when one tablet contains two or more components as adsorbents (component F), the lower limit (greater than or equal to) the content of each component can be independently set to, for example, 0.25% by mass, 0.5% by mass, 1% by mass, 1.5% by mass, or 2% by mass, and the upper limit (less than or equal to) can be, for example, 5% by mass, 4.5% by mass, 4% by mass, 3.5% by mass, 3% by mass, 2.5% by mass, or 2% by mass. These lower and upper limits can be combined arbitrarily, and the content of each component in one tablet can be independently set to, for example, 0.5 to 5% by mass, 1 to 5% by mass, 2 to 4% by mass, or 2 to 3% by mass.

[0063] <Ratio of constituent components> In the tablets of the present invention, the ratio (B / C) of the content (mass%) of the first excipient (component B) in one tablet to the content (mass%) of the second excipient (component C) in one tablet can be set to a predetermined range. From the viewpoint of the proper filling and / or hardness of the tablet, the lower limit (greater than or equal to) of the ratio (B / C) of the content (mass%) of the first excipient (component B) in one tablet to the content (mass%) of the second excipient (component C) in one tablet can be, for example, 0.1, 0.2, 0.3, 0.4, or 0.5, and the upper limit (less than or equal to) can be, for example, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, or 0.6. These lower and upper limits can be combined in any way, and the ratio (B / C) of the content (mass%) of the first excipient (component B) in one tablet to the content (mass%) of the second excipient (component C) in one tablet can be, for example, 0.1 to 2.0, 0.2 to 1, or 0.3 to 0.8.

[0064] In the tablets of the present invention, the ratio of the content of lactic acid bacteria (component A) in one tablet (A / (B+C)) to the sum of the content of the first excipient (component B) and the second excipient (component C) in one tablet (A / (B+C)) can be set to a predetermined range. The ratio of the content of lactic acid bacteria (component A) in one tablet (A / (B+C)) to the sum of the content of the first excipient (component B) and the second excipient (component C) in one tablet (A / (B+C)) can be, from the viewpoint of proper filling and / or hardness of the tablet, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5 as the lower limit (greater than or equal to) is 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, or 1.7. These lower and upper limits can be combined in any way, and the ratio of the content of lactic acid bacteria (component A) in one tablet (A / (B+C)) to the sum of the content of the first excipient (component B) and the second excipient (component C) in one tablet can be, for example, 0.5 to 2.5, 0.8 to 2, 0.9 to 1.8, or 1.0 to 1.7.

[0065] <Method for Measuring Average Particle Size> In this specification, "average particle size" refers to the particle size (d50) at 50% of the cumulative value in the particle size distribution obtained by laser diffraction and scattering. The average particle size d50 of the raw materials to be incorporated into the tablets can be measured using a laser diffraction particle size distribution analyzer, such as MASTERSIZER 3000 (manufactured by Malvern Panalogical), as shown in the examples below. The measurement procedure and conditions for the average particle size can be appropriately set based on common technical knowledge in the field.

[0066] <Method for Measuring the Angle of Repose> The angle of repose (°) of the raw materials to be incorporated into the tablets can be measured using a multi-functional powder property measuring instrument, such as the Multi-Tester MT-1001K (manufactured by Seishin Corporation), as shown in the examples below. The measurement procedure and conditions for the angle of repose can be appropriately set based on common technical knowledge in the field.

[0067] <Other Formulation Components> The tablets of the present invention may contain components other than those listed above. Formulation components necessary for the manufacture of tablets are well known and can be selected and used as appropriate, but examples include fragrances, colorants, stabilizers, and emulsifiers.

[0068] <Other Functional Ingredients> The tablets of the present invention may contain other functional ingredients besides lactic acid bacteria (component A). Other functional ingredients can be appropriately selected from known ingredients or novel ingredients, and examples include vitamins, carotenoids, minerals, amino acids, amino acid derivatives, pharmacoactive ingredients, plant extracts, health food ingredients, etc.

[0069] In the present invention, examples of vitamins include coenzyme Q10, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D (vitamin D3), vitamin E, nicotinamide, calcium pantothenate, vitamin K2, folic acid, and pyrroloquinoline quinone. Examples of vitamin C include L-ascorbic acid, sodium L-ascorbate, L-ascorbic acid stearate, L-ascorbic acid-2-glucoside, rapeseed oil-processed L-ascorbic acid, and corn starch-processed L-ascorbic acid. Examples of vitamin E include the α, β, γ, and δ isomers of the d-form, which is a natural product of tocopherol, and the dl-form, which is a synthetic product of tocopherol, as well as mixtures of one or more of these, all of which can be used as tocopherol.

[0070] In the present invention, carotenoids include, for example, β-carotene, α-carotene, lutein, cryptoxanthin, zeaxanthin, lycopene, astaxanthin, and multicarotenes.

[0071] In the present invention, examples of minerals include calcium, magnesium, dolomite, manganese, zinc, iron, copper, selenium, chromium, sulfur, and iodine.

[0072] In the present invention, examples of amino acids include aliphatic amino acids (specifically, glycine, alanine, etc.), branched-chain amino acids (specifically, valine, leucine, isoleucine, norleucine, etc.), hydroxy amino acids (specifically, serine, threonine, etc.), acidic amino acids (specifically, aspartic acid, glutamic acid, etc.), acidic amino acid amides (specifically, asparagine, glutamine, etc.), basic amino acids (specifically, lysine, hydroxylysine, arginine, ornithine, etc.), sulfur-containing amino acids (specifically, cysteine, cystine, methionine, etc.), aromatic amino acids (specifically, phenylalanine, tyrosine, thyronine, etc.), heterocyclic amino acids (specifically, tryptophan, histidine, etc.), imino acids (specifically, proline, 4-hydroxyproline, etc.), and their salts (e.g., ornithine hydrochloride) and their hydrates.

[0073] In the present invention, examples of amino acid derivatives include acetylglutamine, acetylcysteine, carboxymethylcysteine, acetyltyrosine, acetylhydroxyproline, 5-hydroxyproline, glutathione, creatine, S-adenylmethionine, glycylglycine, glycylglutamine, dopa, alanylglutamine, carnitine, γ-aminobutyric acid, 3-hydroxyisovaleric acid, and their salts (e.g., calcium 3-hydroxyisovalerate) and their hydrates.

[0074] In the present invention, the pharmaceutically active ingredients include, for example, aspirin, acetaminophen, ethenzamide, ibuprofen, diphenhydramine, chlorpheniramine, dihydrocodeine, noscapine, methyl ephedrine, caffeine, serrapeptase, lysozyme, diclofenac sodium, ketoprofen, indomethacin, bucolome, pentazocine, chlorpromazine, reserpine, alprazolam, chlordiazepoxide, diazepam, imipramine, maprotiline, estazolam, nitrazepam, phenobarbital sodium, scopo Lamin, papaverine, citicoline, meclofenoxate, phenytoin, carbamazepine, isoproterenol, diastase, lansoprazole, omeprazole, rabeprazole, famotidine, cimetidine, ranitidine, dextromethorphan, guanfacine, codeine, diphenidol, metoclopramide, levallorphan, theophylline, salbutamol, anlexanox, seratrodast, oxytetracycline, triamcinolone acetonide, chlorhexidine, lidocaine, diphenhydramine, promethazine, isotipene Digoxin, Procainamide, Propranolol, Pindolol, Isosorbide, Furosemide, Delapril, Captopril, Hydralazine, Labetalol, Manidipine, Candesartan Cilexetil, Methyldopa, Losartan, Valsartan, Eprosartan, Irbesartan, Tasosartan, Telmisartan, Forasartan, Phenylephrine, Carbochromen, Morcidomin, Verapamil, Simvastatin, Pravastatin, Trepibuton, Cephalexin, Amoxicillin, Pipmecilinum, Cefotiam, Cefozopran, Cefme Noxim, cefsulosin sodium, ampicillin, cyclacillin, sulbenicillin sodium, nalidixic acid, enoxacin, carmonam sodium, tolbutamide, voglibose, pioglitazone, troglitazone, acarbose, miglitol, emiglitate, ipriflavone, methocarbamol, meclizine, dimenhydrinate, liothyronine sodium, dexamethasone, prednisolone, oxendron, leuprorelin, opium, morphine, tocon, oxycodone, opium alkaloids, cocaine, allopurinol, colchicine,Examples include 5-fluorouracil, mitomycin, and their salts and hydrates.

[0075] In the present invention, examples of plant extracts include aloe, chlorella, prune, propolis, agaricus, ginseng, ginkgo leaf, kale, reishi, saw palmetto, turmeric, curcumin, plum extract, grape seed, pine resin extract, germinated brown rice, shiitake mushroom mycelium, sweet tea, hydrangea, Phellinus linteus, sesame, garlic, champignon, Garcinia, milk thistle extract, silymarin, St. John's wort, mulberry leaf, Gymnema sylvestre, perilla, plantain, Eucommia ulmoides tea, oolong tea, bamboo grass, guava, Panax notoginseng, citrus, cat's claw, Eleutherococcus senticosus, red yeast rice, maca, cordyceps sinensis, chamomile, chili pepper, and kudzu. Furthermore, the method for producing the plant extract is not particularly limited, but includes the raw plant material for the plant extract and its processed products. Processed products include crushed materials such as the fruits, seeds, or leaves of plants, or products obtained by separating and concentrating extracts obtained from the fruits, seeds, or leaves of plants using an aqueous ethanol solution or the like.

[0076] In the present invention, examples of health food ingredients include royal jelly, dietary fiber, protein, bifidobacteria, chitosan, health vinegar, yeast, nucleic acids, glucosamine, lecithin, polyphenols, egg yolk oil, phytosterols, docosahexaenoic acid, animal and fish cartilage, soft-shelled turtle, phosphatidylserine, lactoferrin, clams, eicosapentanoic acid, germanium, enzymes, nattokinase, creatine, carnitine, citric acid, raspberry ketone, coenzyme Q10, methylsulfonylmethane, phospholipid-bound soy peptide, and the like.

[0077] <Tablets and their characteristics> The tablets of the present invention can be administered orally to humans and non-human animals, and the typical form of administration is as food. In this specification, "food" is used to mean health foods, functional foods, nutritional supplements, health functional foods (e.g., Foods for Specified Health Uses, Foods with Nutritional Function Claims, Foods with Function Claims), foods for special dietary uses (e.g., foods for infants, foods for pregnant and lactating women, foods for the sick), and supplements. It goes without saying that when the tablets of the present invention are administered to animals other than humans, the food referred to in the present invention is used as feed (including pet food). The tablets of the present invention can also be administered orally to humans and non-human animals, and the form of administration can also be as pharmaceuticals and quasi-drugs.

[0078] Because the tablets of the present invention contain lactic acid bacteria, they can be used as a food having an immune-boosting effect, an intestinal-regulating effect, or a related function. Such foods can be labeled with claims such as: helping to maintain the immune function of healthy people or supporting the maintenance of the immune function of healthy people (immune care); for people concerned about a decline in immune function; suppressing a decline in immune function; preventing a decline in immune function; for people concerned about sunburn; for people concerned about skin damage in daily life; for people concerned about dry skin; for people concerned about skin flushing; for people concerned about skin erythema; for people concerned about redness of the skin; for people concerned about facial redness; for people concerned about rough hands; improving the intestinal flora; for digestive health; and for regulating bowel movements.

[0079] The tablets of the present invention have excellent filling properties during manufacturing and possess sufficient hardness as tablets, thus allowing for a reduction in the mass per tablet. However, from the viewpoint of efficient intake of lactic acid bacteria, the lower limit (greater than or equal to) can be, for example, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg, and the upper limit (less than or equal to) can be, for example, 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, or 100 mg. These lower and upper limits can be combined in any way, and the mass per tablet can be, for example, 40-200 mg, 50-200 mg, 80-200 mg, 100-200 mg, 40-150 mg, 60-150 mg, 80-150 mg, 100-150 mg, 40-100 mg, 60-100 mg, or 80-100 mg.

[0080] As shown in the examples below, the tablets of the present invention have excellent filling suitability during manufacturing. In the present invention, filling suitability during manufacturing is improved by improving the fluidity of the powder raw material. Here, "filling suitability" is evaluated by the ease with which the powder raw material fills the die during tableting, and the stability of the tableting pressure value during automatic operation of the tablet press.

[0081] As shown in the embodiments described below, the tablets of the present invention have sufficient hardness as tablets. From the viewpoint of preventing tableting defects and maintaining the quality of the tablets, the lower limit (greater than or equal to) of the hardness of the tablets of the present invention can be, for example, 10N, 15N, 20N, 25N, 30N, 35N, 40N, 45N, 50N, 55N, 60N, 65N, 70N, or 75N, and the upper limit (less than or equal to) can be, for example, 120N, 110N, 100N, 95N, 90N, 85N, 80N, 75N, 70N, 65N, or 60N. These lower and upper limits can be combined arbitrarily, and the tablet hardness can be, for example, 10-120N, 20-100N, 30-90N, or 20-85N. The hardness of a tablet can be measured using a commercially available tablet break strength tester, such as a digital hardness tester (KHT-40N, Fujiwara Seisakusho).

[0082] The form of the tablets of the present invention is not particularly limited as long as they are in tablet form. Examples include uncoated tablets, sugar-coated tablets, gel-coated tablets, film-coated tablets, and chewable tablets, but uncoated tablets are preferred. The tablets of the present invention are also preferably swallowable tablets.

[0083] The shape of the tablet of the present invention can be specified by the shape of the cylindrical surface of the tablet, and examples include round (round tablet), elliptical (irregularly shaped tablet), oblong (irregularly shaped tablet), and square (irregularly shaped tablet). However, from the viewpoint of intake efficiency, prevention of tableting problems, and tablet hardness, a round or elliptical shape is preferred. When the shape of the tablet of the present invention is round, a diameter (φ) of 5 to 13 mm is preferred, 5 to 11 mm is more preferred, 5 to 10 mm is even more preferred, and 5 to 9 mm is most preferred.

[0084] <<Manufacturing Method>> The tablets of the present invention can be manufactured by mixing raw materials containing lactic acid bacteria, a first excipient, and a second excipient, and then compressing the resulting mixture (tableting). There are no particular restrictions on the tableting method, and examples include using a tableting die, an upper punch and a lower punch, and compressing using a hydraulic hand press, a single-stroke tablet press, and a rotary tablet press. Tableting can be performed in a manner that ensures the resulting tablets have sufficient hardness as tablets and that no tableting problems occur. The tableting pressure can be appropriately adjusted according to the tableting method, the equipment used for tableting, the size and mass of the tablets, and the ingredients contained. For example, when compressing tablets containing 100 mg each using the tablet press (φ7 mm punch) described in the later examples, the lower limit (greater than or equal to) of the compression pressure can be, for example, 1 kN, 2 kN, 3 kN, 4 kN, or 5 kN, and the upper limit (less than or equal to) can be, for example, 20 kN, 17 kN, 15 kN, 13 kN, or 10 kN. These lower and upper limits can be combined arbitrarily, and the compression pressure can be, for example, 1 to 20 kN, 2 to 17 kN, 3 to 15 kN, 4 to 13 kN, or 5 to 10 kN.

[0085] The present invention will be described more specifically based on the following examples, but the present invention is not limited to these examples.

[0086] <<Ingredients for Tablets>> Tablets of the examples and comparative examples were manufactured using the following ingredients. The average particle size d50 of the lactic acid bacteria, excipients, and disintegrants, as well as the angles of repose of the excipients and disintegrants, were measured according to the method described later.

[0087] Ingredient A: Lactococcus lactis subsp. lactis JCM5805 (Plasma Lactobacillus K, manufactured by Koiwai Dairy Co., Ltd.), average particle size 10-40 μm, number of lactic acid bacteria per 1 g 3.3 x 10 １２Particles / g Component B: First excipient: Hydroxypropyl cellulose (Cellny SSL-SFP, manufactured by Nippon Soda Co., Ltd.), average particle size 20 μm, angle of repose 50° or more. Cellulose (Ceolus ST100, manufactured by Asahi Kasei Corporation), average particle size 50 μm, angle of repose 57°. Component C: Second excipient: Cellulose (Ceolus UF-F702, manufactured by Asahi Kasei Corporation), average particle size 90 μm, angle of repose 34°. Maltose (Sanmalto S, manufactured by Hayashibara Corporation), average particle size 90 μm, angle of repose 33°. Maltitol (Amalti MR50, manufactured by Mitsubishi Corporation Life Sciences), average particle size 130 μm, angle of repose 41°. Component D: Disintegrant: Agar preparation (Fibersat, manufactured by Ina Food Industry Co., Ltd.), average particle size 105 μm, angle of repose 44°. Ingredient E: Lubricant sucrose fatty acid ester (Lyoto sugar ester S-370F, manufactured by Mitsubishi Chemical Corporation) Calcium stearate (Ca stearate, manufactured by Taihei Chemical Industry Co., Ltd.) Ingredient F: Adsorbent silicon dioxide (Silopage 720, manufactured by Fuji Silicia Co., Ltd.)

[0088] The above-mentioned lactic acid bacteria (component A) is prepared by culturing the cells of Lactococcus lactis subsp. lactis JCM5805, washing the bacterial solution obtained from the culture, sterilizing the cells by heat-treating the bacterial solution, and then spray-drying the heat-treated bacterial solution to prepare a sterilized and dried lactic acid bacteria powder.

[0089] <Measurement of Average Particle Size d50> The particle size d50 of each sample was measured using a laser diffraction particle size distribution analyzer (MASTERSIZER 3000, Malvern Panalogical). The test was performed three times, and the average value was calculated and shown as the measured value of the average particle size d50.

[0090] <Measurement of Angle of Repose> The angle of repose (°) of each sample was measured using a multi-functional powder property analyzer (Multi-Tester MT-1001K, manufactured by Seishin Corporation). In the test, angles were measured at three locations using the angle measurement unit, and the average value was calculated and shown as the measured angle of repose.

[0091] <<Tablet Manufacturing>> Tablets of the Examples and Comparative Examples were manufactured using the above raw materials according to the formulations listed in Table 1.

[0092] The raw materials were mixed and passed through a sieve with a mesh size of 500 μm to obtain a tablet mixture. The obtained mixture was compressed into tablets with a tablet mass of 100 mg using a fully automatic single-shot tablet press (AUTOTAB-535, manufactured by Ichihashi Seiki Co., Ltd., the same applies hereafter) with a φ7 mm R10 mold and a compression pressure of 10 kN.

[0093]

[0094] <<Evaluation of Tablets>> The hardness and filling suitability of the tablets of the examples and comparative examples were evaluated according to the method described below. The evaluation results for each tablet are shown in Table 1.

[0095] <Hardness> The hardness (N) of each sample was measured using a digital hardness tester (KHT-40N, manufactured by Fujiwara Seisakusho Co., Ltd.). Measurements were taken 10 times, and the average of these measurements was used as the hardness value.

[0096] The hardness ranking was evaluated as follows: 5: hardness of 40.0 N or higher, 4: hardness of 30.0 N or higher and 39.9 N or lower, 3: hardness of 20.0 N or higher and 29.9 N or lower, 2: hardness of 10.0 N or higher and 19.9 N or lower, 1: hardness of 9.9 N or lower.

[0097] <Filling Suitability> The powder filling properties into the die were tested when tablets were compressed using a φ7 mm R10 die with a compression pressure of 10 kN to produce tablets with a mass of 100 mg, using a fully automatic single-shot tablet press (AUTOTAB-535, manufactured by Ichihashi Seiki Co., Ltd.). The stability of the compression pressure value during automatic operation of the tablet press (15 shots / min) was also tested.

[0098] The filling suitability was evaluated as follows: A: Good powder filling performance into the die during tableting, and stable tableting pressure during automatic operation. B: Somewhat unstable powder filling performance into the die during tableting and tableting pressure during automatic operation, requiring manual adjustment of the powder filling depth into the die, but automatic operation of the tablet press is possible. C: Unstable powder filling performance into the die and tableting pressure during tableting, making automatic operation of the tablet press impossible.

[0099] Table 1 shows that while the comparative tablets exhibited excellent filling suitability during manufacturing, they failed to maintain sufficient hardness as tablets after manufacturing. On the other hand, the example tablets were confirmed to have excellent filling suitability during manufacturing and to have sufficient hardness as tablets after manufacturing.

[0100] The lactic acid bacteria raw material used in the above test was a sterilized and dried powder (aggregated powder of bacterial cells) obtained by spray-drying the bacterial cells. In tablet manufacturing, it had very weak binding properties, making it difficult to achieve sufficient hardness in the tablets. In addition, because the average particle size was fine, 20 to 30 μm, the fluidity during filling in the tablet manufacturing process was poor, making it difficult to increase the content in the tablets. In the example, by using a combination of multiple excipients with different average particle sizes, it was possible to improve the fluidity during filling while also providing binding properties, resulting in tablets with excellent filling suitability during manufacturing and superior hardness after manufacturing.

Claims

1. A lactic acid bacteria-containing tablet comprising lactic acid bacteria (component A), a first excipient (component B) with an average particle size of less than 60 μm, and a second excipient (component C) with an average particle size of 60 μm or more.

2. The tablet according to claim 1, wherein component B and component C are different from each other.

3. The tablet according to claim 1 or 2, wherein the content of component A in one tablet is 30% by mass or more.

4. The number of bacteria in component A per tablet is 1 × 10 ８ A tablet according to claim 1 or 2, wherein there are one or more tablets.

5. The tablet according to claim 1 or 2, wherein the content of component B in one tablet is 5% by mass or more.

6. The tablet according to claim 1 or 2, wherein the content of component C in one tablet is 45% by mass or less.

7. The tablet according to claim 1 or 2, wherein the average particle size of component A is 10 μm or more and 40 μm or less.

8. The tablet according to claim 1, wherein the average particle size of component B is 20 μm or more and less than 60 μm.

9. The tablet according to claim 1 or 8, wherein the angle of repose of component B is 50° or more.

10. The tablet according to claim 1, wherein the average particle size of component C is 90 μm or more.

11. The tablet according to claim 1 or 10, wherein the angle of repose of component C is 30° or more.

12. The tablet according to claim 1 or 2, wherein the mass per tablet is less than 200 mg.

13. The tablet according to claim 1 or 2, wherein component A is a sterilized dried powder of lactic acid bacteria.

14. The tablet according to claim 1 or 2, wherein component B is one or more selected from the group consisting of cellulose and cellulose derivatives.

15. The tablet according to claim 1 or 2, wherein component C is one or more selected from the group consisting of cellulose, maltose, and maltitol.

16. The tablet according to claim 1 or 2, wherein the ratio of the content of component B (mass%) in one tablet to the content of component C (mass%) in one tablet (B / C) is 0.1 or more.

17. The tablet according to claim 1 or 2, wherein the ratio of the content of component A in one tablet (A / (B+C)) to the sum of the content of component B (mass%) and the content of component C (mass%) in one tablet is 2.0 or less.

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