Tablets and manufacturing method thereof

Abstract

To provide a tablet obtained by compression molding using a microbial powder containing live bacteria as a raw material, which has a high survival rate of microorganisms while having sufficient hardness for practical use, and to provide a manufacturing method thereof.SOLUTION: Provided are a tablet containing cellulose powder and a powder of a microorganism, the diameter R (mm) and density D (mg / mm3) of the tablet satisfy 6≤R≤14 and D≤-0.01R+1.30; and a method for producing the tablet, including preparing a mixture containing cellulose powder and a powder of a microorganism, and tabletting the mixture to produce a tablet, the tabletting being performed at a tabletting pressure of 128 MPa or less per unit tablet area, and the diameter R (mm) and density D (mg / mm3) of the tablet satisfying 6≤R≤14 and D≤-0.01R+1.30.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a tablet containing cellulose powder and a powder of live microorganisms and a method for producing the same. [Background technology]

[0002] It has been known for some time that lactic acid bacteria, bifidobacteria, and the like, when orally ingested, have useful effects such as intestinal regulation. In recent years, these microorganisms have been actively ingested as probiotics (live microorganisms that benefit the host's health by improving the balance of intestinal flora) as functional foods and medicines. For example, medicines containing probiotics include powder preparations (powders) made from dried bacterial powder as is, capsules filled with dried bacterial powder, granules made from dried bacterial powder, and tablets compressed and molded from dried bacterial powder as is or after granulation.

[0003] Tablets are preparations that can be taken more easily than powders or capsules. However, the active ingredient may be affected during compression molding. Probiotic preparations also have a problem that the probiotics are killed by high impact pressure during compression molding, resulting in a decrease in the number of live bacteria. One method for solving this problem is, for example, to lower the impact pressure. However, if the impact pressure is simply lowered, sufficient hardness for tablets cannot be obtained, and the degree of friability increases. In addition, Patent Document 1 describes that a tablet with a high number of live bacteria and a suitable hardness can be produced by granulating an excipient composition containing starch, adding and mixing 0.15 to 1.0 parts by mass of a powder composition containing disaccharides, polysaccharides, and calcium carbonate per part by mass of the obtained granules without granulation, and further adding and mixing live bacteria to obtain a live bacteria-containing composition, and compressing the obtained live bacteria-containing composition.

[0004] Meanwhile, in the fields of medicine, food, and other chemical industries, it has been widely practiced to prepare compacts containing active ingredients by using cellulose powders such as crystalline cellulose and powdered cellulose as excipients. For example, Patent Document 2 discloses that when tableting a drug that becomes unstable due to the pressure applied during tableting, i.e., a so-called crushing-sensitive drug, the destabilization of the crushing-sensitive drug can be suppressed even when the drug is produced into a tablet having a practical hardness or higher by direct tableting by blending a cellulose powder having an average L / D (average value of the ratio of the major axis to the minor axis (L / D) of the particle) of 2.0 to 4.5. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2011-102250 A [Patent Document 2] JP 2013-224265 A Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention has been made in consideration of the above circumstances, and provides a tablet obtained by compression molding using a microbial powder containing live bacteria as a raw material, which has a hardness sufficient for practical use while increasing the survival rate of the microorganisms, and a method for producing the tablet. [Means for solving the problem]

[0007] As a result of intensive research in light of the above-mentioned current situation, the present inventors have found that cellulose powder is used as an excipient and that the diameter (mm) and density (mg / mm 3 The inventors have found that by adjusting the above relationship so that the above formula satisfies a certain relational expression, it is possible to obtain tablets having a sufficient hardness while suppressing the death of microorganisms, and have thus completed the present invention.

[0008] That is, the present invention includes the following aspects. [1] A tablet containing cellulose powder and microbial powder, The diameter R (mm) and density D (mg / mm 3 ) satisfies the following formulas (1) and (2). Formula (1): 6≦R≦14 Formula (2): D≦-0.01R+1.30 [2] The tablet of [1], wherein the cellulose powder is a powder of crystalline cellulose. [3] The tablet of [2], wherein the powder of crystalline cellulose has an average ratio of the long axis to the short axis (L / D) of the particles of 2.0 or more and 4.5 or less. [4] The cellulose powder has a loose bulk density of 0.250 g / cm 3 The tablet according to any one of [1] to [3] above, which is as follows: [5] The tablet according to any one of [1] to [4] above, wherein the diameter R (mm) and hardness H (N) of the tablet satisfy the following formula (3): Formula (3): H≧12.5R-50 [6] Any of the tablets according to [1] to [5] above, having a friability of 0.2% or less. [7] The tablet according to any one of [1] to [6], wherein the ratio (mass ratio) of the content of the cellulose powder to the total amount of the tablet is 10 mass% or more and 60 mass% or less. [8] Any of the tablets according to [1] to [7], wherein the ratio (mass ratio) of the content of the microbial powder to the total weight of the tablet is 10 mass% or more and 60 mass% or less. [9] The number of viable bacteria of the microorganism per gram of tablet is 1.0 × 10 9 The tablet according to any one of [1] to [8] above, which has a CFU / g or more.

[10] The tablet according to any one of [1] to [9], wherein the survival rate of the microorganism is 35% or more.

[11] The tablet according to any one of the above [1] to

[10] , wherein the microorganism is one or more species selected from the group consisting of lactic acid bacteria, bifidobacteria, saccharifying bacteria, butyric acid bacteria, and yeast.

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

[11] above, wherein the microorganism is a probiotic.

[13] It also contains a lubricant. The tablet according to any one of the above [1] to

[12] , wherein the ratio (mass ratio) of the content of the lubricant to the total amount of the tablet is 0.1 mass % or more and 3.0 mass % or less.

[14] A step of preparing a mixture containing a cellulose powder and a powder of a microorganism; compressing the mixture to produce tablets; having The tableting is carried out at a tablet pressure of 128 MPa or less per tablet unit area, The diameter R (mm) and density D (mg / mm 3 ) satisfies the following formulas (1) and (2). Formula (1): 6≦R≦14 Formula (2): D≦-0.01R+1.30

[15] The cellulose powder is a powder of crystalline cellulose and has a loose bulk density of 0.250 g / cm 3 A method for producing the tablet according to

[14] above, which is as follows:

[16] The method for producing a tablet according to

[15] , wherein the powder of crystalline cellulose has an average ratio of the long axis to the short axis (L / D) of the particles of 2.0 or more and 4.5 or less.

[17] The method for producing a tablet according to any one of the above

[14] to

[16] , wherein the diameter R (mm) and hardness H (N) of the tablet satisfy the following formula (3): Formula (3): H≧12.5R-50

[18] The ratio (mass ratio) of the content of the cellulose powder to the total amount of the tablet is 10% by mass or more and 60% by mass or less, The method for producing a tablet according to any one of the above

[14] to

[17] , wherein the ratio (mass ratio) of the content of the microbial powder to the total amount of the tablet is 10 mass% or more and 60 mass% or less.

[19] The viable cell count of the microorganism per gram of the tablet is 1.0 × 10 9 The method for producing any one of the tablets according to

[14] to

[18] above, wherein the tablet content is 50% or more CFU / g.

[20] The method for producing a tablet according to any one of

[14] to

[19] above, wherein the microbial survival rate of the tablet is 35% or more. Effect of the Invention

[0009] According to the tablet and the manufacturing method thereof of the above aspect, it is possible to provide a tablet which has a high survival rate of microorganisms, sufficient hardness, and is less likely to crack or chip. [Brief description of the drawings]

[0010] [Figure 1] FIG. 2 is a diagram showing a schematic diagram of the shape of a tablet. [Diagram 2] 1 is a diagram in which tablets from test plots 1-1 to 1-4 and 2-1 to 2-8 in Example 1 are plotted with tablet density D (mg / mm3) on the vertical axis and tablet diameter R (mm) on the horizontal axis. [Diagram 3] (A) An SEM image of a cross section of a divided tablet of test plot 3-1 in Reference Example 1. (B) An SEM image of a cross section of a divided tablet of test plot 3-2 in Reference Example 1. (C) An SEM image of a cross section of a divided tablet of test plot 3-3 in Reference Example 1. (D) An SEM image of a cross section of a divided tablet of test plot 3-4 in Reference Example 1. (E) An SEM image of a cross section of a divided tablet of test plot 3-5 in Reference Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] <Tablets> The tablet of this embodiment is a tablet containing cellulose powder and a powder of a microorganism, and has a tablet diameter R (mm) and a tablet density D (mg / mm 3 ) satisfy the following formulae (1) and (2). The tablet of this embodiment is compression-molded so that the tablet diameter R and tablet density D satisfy the following formulae (1) and (2), and thus has sufficient hardness as a tablet and a high microbial survival rate ([number of living microorganisms in the tablet] / [number of living microorganisms blended in the tablet as raw materials]×100(%)).

[0012] Formula (1): 6≦R≦14 Formula (2): D≦-0.01R+1.30

[0013] The diameter R (mm) of the tablet of this embodiment is not particularly limited as long as it satisfies the above formula (1), that is, is 6 mm or more and 14 mm or less. From the viewpoint of ease of administration, etc., the diameter R of the tablet of this embodiment is preferably 7 mm or more and 13 mm or less, and more preferably 8 mm or more and 12 mm or less.

[0014] The density D (mg / mm 3 ) is not particularly limited as long as it satisfies the above formula (2). 3 ) is 0.85mg / mm because it provides sufficient hardness. 3 More than 0.90 mg / mm 3 More preferably, 0.95 mg / mm 3 More preferably, 1.00 mg / mm 3 The above is particularly preferred. 3 ) is 1.45 mg / mm3 because it is easier to maintain the survival rate of microorganisms at a high level. 3 Less than 1.40 mg / mm is preferred. 3 Less than 1.35 mg / mm is more preferable. 3 More preferably, 1.30 mg / mm 3 Even more preferably, it is 1.25 mg / mm 3 The following is particularly preferred: 1.20 mg / mm 3 The following are most preferred:

[0015] The thickness T (mm) of the tablet of this embodiment is not particularly limited. The thickness T (mm) of the tablet of this embodiment can be, for example, 3 mm or more.

[0016] The hardness H(N) of the tablet of this embodiment is not particularly limited as long as the tablet diameter R and tablet density D satisfy formulas (1) and (2). The tablet hardness H(N) of the tablet of this embodiment is preferably such that the tablet diameter R(mm) and tablet hardness H(N) satisfy the following formula (3) in order to more effectively suppress the occurrence of cracking and chipping. A tablet that satisfies the following formula (3) satisfies the practical hardness of the tablet, so that cracking and chipping are unlikely to occur and the degree of abrasion is small. In addition, the hardness H(N) of the tablet of this embodiment is preferably 150N or less, more preferably 140N or less, and even more preferably 130N or less in terms of balance with disintegration.

[0017] Formula (3): H≧12.5R-50

[0018] Tablet hardness can be measured, for example, using a commonly used tablet hardness tester (Tablet Tester 8M / manufactured by DR. SCHLEUNIGER).

[0019] The tablet tensile strength TS (MPa) of the tablet of this embodiment can be calculated according to the following formula, where H (N) is the tablet hardness, R (mm) is the tablet diameter, T (mm) is the tablet thickness, and W (mm) is the thickness of the cylindrical portion of the tablet.

[0020]

number

[0021] The tablet tensile strength TS (MPa) of the tablet of this embodiment is preferably 1.0 MPa or more from the viewpoint of more effectively suppressing the occurrence of cracking and chipping, and is preferably 2.2 MPa or less from the viewpoint of balance with disintegration property. The tablet tensile strength TS (MPa) is more preferably 1.1 MPa or more and 2.0 MPa or less, and further preferably 1.2 MPa or less and 1.8 MPa or less.

[0022] The friability of the tablet of this embodiment is not particularly limited. The friability of the tablet of this embodiment is preferably 1.0% by mass or less, more preferably 0.5% by mass or less, even more preferably 0.4% by mass or less, and even more preferably 0.2% by mass or less. On the other hand, the smaller the friability, the more preferable, and the lower limit is not particularly limited, but may be, for example, 0.00% by mass or more, or 0.01% by mass or more.

[0023] The friability of the tablet can be measured, for example, by the method described in the Examples below.

[0024] The tablet weight variation (CV) of the tablet of this embodiment has a practical value of 1.0% or less, the lower the better, and 0.8% or less is extremely stable, but is not particularly limited.

[0025] The tablet of this embodiment has a tablet diameter R (mm) and a tablet density D (mg / mm 3 ) does not satisfy at least one of the formulas (1) and (2), particularly does not satisfy the formula (2). The microbial survival rate (%) of the tablet of this embodiment is not particularly limited, but is preferably 35% or more, more preferably 40% or more, even more preferably 45% or more, even more preferably 50% or more, particularly preferably 55% or more, and most preferably 70% or more. The higher the microbial survival rate (%), the more preferable, and the upper limit is not particularly limited, and 100% is most preferable.

[0026] The viable cell count of the microorganism contained in the tablet of this embodiment is not particularly limited, and depends on the amount of the microorganism blended as a raw material. For the tablet of this embodiment, the viable cell count of the microorganism per 1 g of the tablet is 1.0 × 10 9 CFU / g or more is preferable, 6.0×10 9 CFU / g or more is preferable, and 1.0×10 10 CFU / g or more is more preferable, and 3.0×10 10The upper limit of the viable cell count of the microorganism contained in the tablet of this embodiment is not particularly limited, and for example, the viable cell count of the microorganism per 1 g of the tablet is 1.0 × 10 12 CFU / g or less, and 1.0×10 11 It can also be less than CFU / g.

[0027] The microorganism contained in the tablet of this embodiment is not particularly limited as long as it is a microorganism to be orally ingested by animals. The microorganism contained in the tablet of this embodiment may be one type or two or more types. The microorganism may be, for example, one or more types selected from the group consisting of lactic acid bacteria, bifidobacteria, saccharifying bacteria, butyric acid bacteria, and yeast. In addition, it may be useful bacteria other than these.

[0028] Among the microorganisms that can be included in the tablet of the present embodiment, examples of lactic acid bacteria include Lactobacillus acidophilus, L. casei, L. gasseri, L. plantarum, L. delbrueckii subsp bulgaricus, L. delbrueckii subsp lactis, L. fermentum, L. helveticus, L. johnsonii, L. paracasei subsp. Lactobacillus reuteri, L. rhamnosus, L. salivarius, L. brevis, etc.; Leuconostoc mesenteroides, Streptococcus (Enterococcus) faecalis, Streptococcus (Enterococcus) faecium, Streptococcus (Enterococcus) hirae, Streptococcus thermophilus, Lactococcus lactis, L. cremoris, Tetragenococcus halophilus, Pediococcus Examples of the bifidobacteria include Bifidobacterium bifidum, B. longum, B. breve, B. adolescentis, B. infantis, B. pseudolongum, B. thermophilum, etc. Examples of the saccharifying bacteria include Bacillus subtilis, Bacillus mesentericus, Bacillus polyfermenticus, etc. Examples of the butyric acid bacteria include Bacillus toyoi, B. licheniformis, Clostridium butyricum, etc.

[0029] Since the tablet of the present embodiment can retain a large number of live bacteria, the microorganism contained in the tablet is preferably a probiotic. As the microorganism contained in the tablet of the present embodiment, among the probiotics, lactobacilli or bifidobacteria are particularly preferred, and lactobacilli are more preferred.

[0030] The viable cell count and survival rate of microorganisms in a tablet can be measured, for example, by the method described in the Examples below.

[0031] The amount of the microbial powder contained in the tablet of this embodiment is not particularly limited. In order to easily contain a sufficient amount of living microorganisms and to easily mix other components such as cellulose powder in a sufficient amount, the tablet of this embodiment preferably has a content ratio (mass ratio) of the microbial powder to the total amount of the tablet of 1% by mass or more and 80% by mass or less, more preferably 10% by mass or more and 60% by mass or less, even more preferably 20% by mass or more and 50% by mass or less, even more preferably 20% by mass or more and 40% by mass or less, and particularly preferably 20% by mass or more and 30% by mass or less.

[0032] The cellulose powder in this specification is generally referred to as crystalline cellulose, powdered cellulose, etc., and is preferably used as a pharmaceutical additive or food additive. The cellulose powder contained in the tablet of this embodiment is preferably a powder of crystalline cellulose. Known examples of crystalline cellulose include microcrystalline cellulose described in the 9th edition of the Food Additives Standards, crystalline cellulose described in the Japanese Pharmacopoeia (18th revision), and crystalline cellulose described in the United States Pharmacopoeia, European Pharmacopoeia, etc.

[0033] The crystalline cellulose powder contained in the tablet of this embodiment may have an average value of the ratio of the long axis to the short axis (L / D) of the particle (hereinafter sometimes referred to as "average L / D") of 1.5 to 4.5, preferably 2.0 to 4.5. By using a crystalline cellulose powder having an average L / D within the above range, it is easy to manufacture a tablet that satisfies the above formulas (1) and (2), and it is easy to obtain a tablet that has both a high microbial survival rate and good moldability (sufficient hardness). The average L / D of the crystalline cellulose powder contained in the tablet of this embodiment is more preferably 2.0 to 4.0, even more preferably 2.0 to 3.5, and particularly preferably 2.0 to 3.0.

[0034] The L / D of a particle is determined by using an air jet sieve (ALPINE, A200LS type) to sieve particles through a JIS standard sieve of 75 μm, dispersing the particles in advance so that the individual particles do not become entangled, and processing the optical microscope image of the particle with image analysis (Interquest, Imagehyper), and determining the ratio of the long side to the short side (long side / short side) of the rectangle that circumscribes the particle and has the smallest area. The average L / D of a particle is determined by calculating the L / D of at least 400 particles, and taking the average of these.

[0035] The loose bulk density of the crystalline cellulose powder contained in the tablet of this embodiment is not particularly limited, but is preferably 0.250 g / cm 3 Less than 0.200 g / cm is preferable. 3 Less than 0.150 g / cm is more preferable. 3 The loose bulk density is preferably equal to or less than the upper limit. By having the loose bulk density equal to or less than the upper limit, sufficient mechanical strength can be imparted to a sufficient molded body. On the other hand, the lower limit of the loose bulk density is not particularly limited, but is, for example, 0.03 g / cm. 3 and 0.05 g / cm 3 and 0.07 g / cm 3 0.08g / cm 3 , 0.10g / cm 3 and 0.12 g / cm 3 It can be said that:

[0036] The loose bulk density of the cellulose powder can be measured by the following method. Using a Scott volumeter (Model ASTM B-329-85, manufactured by Tsutsui Rikagaku Kikai Co., Ltd.), cellulose powder is filled into a 25 mL cylindrical metal container. The cellulose powder in the 25 mL cylindrical metal container is leveled off, and the mass (g) of the cellulose powder in the container is divided by 25 mL to obtain the loose bulk density (g / cm 3 ) is calculated. Specifically, it can be measured using the method described in the Examples below.

[0037] The repose angle (°) of the crystalline cellulose powder contained in the tablet of this embodiment is not particularly limited, but is preferably 35° to 60°, more preferably 38° to 60°, and even more preferably 40° to 60°. When the repose angle is equal to or greater than the lower limit, the moldability is improved. On the other hand, when the repose angle is equal to or less than the upper limit, the flowability is improved.

[0038] The angle of repose of crystalline cellulose can be measured with a powder tester (manufactured by Hosokawa Micron Corporation) after adjusting the powder moisture content to 3.5% by mass or more and 4.5% by mass or less.

[0039] The angle of repose (°) of the raw material mixture (powder) constituting the tablet of this embodiment is not particularly limited, but is preferably 30° to 60°, more preferably 35° to 60°, and even more preferably 38° to 60°. When the angle of repose is equal to or greater than the lower limit, the moldability is improved. On the other hand, when the angle of repose is equal to or less than the upper limit, the flowability of the raw material mixture (powder) is improved, and the tablet weight variation (CV) after tableting is reduced.

[0040] The amount of cellulose powder contained in the tablet of this embodiment is not particularly limited. In order to fully demonstrate the high moldability of the cellulose powder and to easily mix other components such as microbial powder in sufficient amounts, the tablet of this embodiment preferably has a content ratio (mass ratio) of cellulose powder to the total tablet amount of 10% by mass or more and 80% by mass or less, more preferably 10% by mass or more and 70% by mass or less, even more preferably 10% by mass or more and 60% by mass or less, even more preferably 20% by mass or more and 60% by mass or less, even more preferably 20% by mass or more and 50% by mass or less, particularly preferably 30% by mass or more and 50% by mass or less, and most preferably 40% by mass or more and 50% by mass or less.

[0041] The ratio (mass ratio) of the content of the microbial powder and the ratio (mass ratio) of the content of the cellulose powder relative to the total amount of the tablet can be calculated based on the blending ratio of the raw materials used in the production of the tablet.

[0042] The tablet of this embodiment may contain other ingredients in addition to the microorganism powder and cellulose powder, provided that the effect of the present invention is not impaired. As the other ingredients, various additives that are generally blended in tablets can be used. As the other additives, for example, excipients (excluding cellulose powder), lubricants, disintegrants, flow agents, binders, flavorings, flavorings, colorants, and sweeteners can be included.

[0043] Examples of excipients include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, powdered gum arabic, alginic acid, sodium alginate, pregelatinized starch, pumice granules, inositol, ethylcellulose, ethylene-vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrated silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate, dry magnesium sulfate, agar, powdered agar, and ketchup. Silitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, crospovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, sodium carmellose, crystalline cellulose (granules), genmai koji, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ flour, rice Co, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, calcined gypsum, sucrose fatty acid ester, magnesium alumina hydroxide, aluminium hydroxide gel, aluminium hydroxide-sodium bicarbonate coprecipitate, magnesium hydroxide, squalane, stearyl alcohol, stearic acid , calcium stearate, polyoxyl stearate, magnesium stearate, hardened soybean oil, refined gelatin, refined shellac, refined white sugar, refined white sugar spherical granules, cetostearyl alcohol, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, D-sorbitol, tribasic calcium phosphate, soybean oil, soybean unsaponifiable matter, soybean lecithin, skimmed milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropyl cellulose, dextran, dextrin,Maltodextrin, natural aluminum silicate, corn starch, tragacanth powder, silicon dioxide, calcium lactate, lactose, lactose granules, Perfiller 101, white shellac, white petrolatum, hakudo, white sugar, white sugar and starch spherical granules, naked barley leaf extract powder, naked malt leaf green juice dried powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose syrup, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) poly Examples of excipients include oxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltitol, maltose, D-mannitol, starch syrup, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium aluminometasilicate, methylcellulose, cottonseed flour, cottonseed oil, Japanese laurel, aluminum monostearate, glycerin monostearate, sorbitan monostearate, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular corn starch, liquid paraffin, dl-malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, and the like, which are classified as excipients in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha). These excipients may be used alone or in combination of two or more.

[0044] Examples of disintegrants include celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose; starches such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, and partially pregelatinized starch; and synthetic polymers such as crospovidone and crospovidone copolymer, which are classified as disintegrants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha). These disintegrants may be used alone or in combination of two or more.

[0045] When the tablet of this embodiment contains a disintegrant, the content of the disintegrant in the tablet is preferably 0.1% by mass or more and 10% by mass or less, more preferably 0.5% by mass or more and 5% by mass or less, and even more preferably 1.0% by mass or more and 2.0% by mass or less, based on the total amount (mass) of the tablet. When the content of the disintegrant is equal to or more than the lower limit, the disintegration property is more excellent. On the other hand, when the content of the disintegrant is equal to or less than the upper limit, the moldability is more excellent.

[0046] Examples of binders include sugars such as sucrose, glucose, lactose, and fructose; sugar alcohols such as mannitol, xylitol, maltitol, erythritol, and sorbitol; water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin, sodium alginate, and gum arabic; celluloses such as crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, and methylcellulose; starches such as pregelatinized starch and starch paste; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and polyvinyl alcohol; inorganic compounds such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminosilicate, which are classified as binders in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha). These binders may be used alone or in combination of two or more.

[0047] Examples of the fluidizing agent include silicon compounds such as hydrous silicon dioxide and light anhydrous silicic acid, which are classified as fluidizing agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha). These fluidizing agents may be used alone or in combination of two or more kinds.

[0048] When the tablet of this embodiment contains a fluidizer, the content of the fluidizer in the tablet is preferably 0.1% by mass or more and 3.0% by mass or less, and more preferably 0.5% by mass or more and 2.0% by mass or less, based on the total amount (mass) of the tablet. When the content of the fluidizer is more than the lower limit, the fluidity is more excellent. On the other hand, when the content of the fluidizer is equal to or less than the upper limit, the moldability is more excellent.

[0049] Examples of lubricants include those classified as lubricants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha), such as calcium phosphate, magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, talc, etc. These lubricants may be used alone or in combination of two or more kinds.

[0050] When the tablet of this embodiment contains a lubricant, the content of the lubricant in the tablet is preferably 0.1% by mass or more and 3.0% by mass or less, and more preferably 0.5% by mass or more and 2.0% by mass or less, based on the total amount (mass) of the tablet. When the content of the lubricant is equal to or more than the above lower limit, it is easy to suppress tableting trouble. On the other hand, when the content of the lubricant is equal to or less than the above upper limit, the moldability is more excellent.

[0051] The disintegration time of the tablet of this embodiment may be within 60 minutes, preferably within 50 minutes, more preferably within 40 minutes, even more preferably within 30 minutes, even more preferably within 20 minutes, and particularly preferably within 15 minutes. On the other hand, the shorter the disintegration time, the more preferable, and the lower limit is not particularly limited, but is usually about 10 seconds.

[0052] The disintegration time of a tablet can be measured, for example, by the method described in the Examples below.

[0053] <Tablet manufacturing method> The tablet manufacturing method of the present embodiment includes a step of preparing a mixture containing a cellulose powder and a powder of a microorganism, and a step of compressing the mixture to manufacture tablets. By adjusting the compression pressure during compression and the cellulose powder as a raw material, the diameter R (mm) and density D (mg / mm 3 ) is a method for producing tablets that satisfy the following formulas (1) and (2).

[0054] Formula (1): 6≦R≦14 Formula (2): D≦-0.01R+1.30

[0055] The cellulose powder used in the tablet manufacturing method of this embodiment can be the same as the cellulose powder contained in the tablet of this embodiment. In the tablet manufacturing method of this embodiment, in particular, a cellulose powder having a loose bulk density of 0.250 g / cm 3 It is preferable to use a crystalline cellulose powder having a loose bulk density of 0.250 g / cm3 or less. 3 It is more preferable to use a crystalline cellulose powder having an average L / D of 2.0 to 4.5.

[0056] The microbial powder used in the tablet manufacturing method of this embodiment can be the same as the microbial powder contained in the tablet of this embodiment. In the tablet manufacturing method of this embodiment, it is preferable to use one or more microbial powders selected from the group consisting of lactic acid bacteria, bifidobacteria, saccharifying bacteria, butyric acid bacteria, and yeast, and it is more preferable to use one or more microbial powders selected from the group consisting of lactic acid bacteria and bifidobacteria. In particular, it is preferable to use one or more probiotic powders in the tablet manufacturing method of this embodiment.

[0057] In the tablet manufacturing method of this embodiment, first, a mixture containing cellulose powder and microbial powder is prepared. The entire amount of the solid raw materials of the tablet is mixed into the mixture. That is, in addition to the cellulose powder and the microbial powder, other additives are also contained in the mixture as necessary. As the other additives, those listed as additives that can be contained in the tablet of this embodiment can be appropriately used. The order of mixing each component is not particularly limited. The ratio (mass ratio) of the content of each component to the total amount of the mixture becomes the ratio (mass ratio) of the content of the component to the total amount of the tablet to be manufactured.

[0058] In the tablet manufacturing method of this embodiment, the content ratio of the microbial powder to the total amount of the mixture is preferably 1% by mass or more and 80% by mass or less, more preferably 10% by mass or more and 60% by mass or less. In the tablet manufacturing method of this embodiment, the content ratio of the cellulose powder to the total amount of the mixture is preferably 10% by mass or more and 80% by mass or less, more preferably 10% by mass or more and 70% by mass or less, even more preferably 10% by mass or more and 60% by mass or less, and even more preferably 20% by mass or more and 60% by mass or less.

[0059] In the tablet manufacturing method of this embodiment, the mixture preferably contains a flow agent, a lubricant, and a disintegrant in addition to the microorganism powder and the cellulose powder. The content ratio of the flow agent to the total amount of the mixture is preferably 0.1% by mass or more and 3.0% by mass or less, more preferably 0.5% by mass or more and 2.0% by mass or less. The content ratio of the lubricant to the total amount of the mixture is preferably 0.1% by mass or more and 3.0% by mass or less, more preferably 0.5% by mass or more and 2.0% by mass or less. The content ratio of the disintegrant to the total amount of the mixture is preferably 0.1% by mass or more and 10% by mass or less, more preferably 0.5% by mass or more and 5% by mass or less, and even more preferably 1.0% by mass or more and 2.0% by mass or less.

[0060] In preparing the mixture, the mixing operation can be performed using a mixer that is generally used in pharmaceutical manufacturing, such as a tumbler mixer, a V-type mixer, etc. Also, for laboratory level experiments, mixing using a plastic bag may be used.

[0061] The prepared mixture (powder) is compressed and molded into tablets using a tablet press. The tablet press may be a rotary tablet press generally used for tablet production or a single punch tablet press used for laboratory level experiments.

[0062] There are various methods for manufacturing tablets, such as direct compression, dry granulation, and wet granulation. However, since the microbial powder is unstable to moisture, the wet granulation method may reduce the survival rate of the microorganisms. In addition, in the dry granulation method, the mixture of raw materials is compressed, then crushed and granulated to the desired particle size, and then tableted. Therefore, the microbial powder is subjected to strong forces many times during the manufacturing process, and is likely to die. For this reason, in the manufacturing method of the tablet of this embodiment, it is preferable to use a direct compression method in which a mixture (powder) of the microbial powder, the cellulose powder, and various additives to be added as necessary is directly compressed and molded.

[0063] In the tablet manufacturing method of this embodiment, a mixture consisting of all the solid raw materials of the tablet is subjected to a pressure of 128 MPa (N / mm 2 ) or less to produce tablets. By compressing with a compressing pressure within the above range, it is possible to suppress the annihilation of microorganisms and maintain a high number of live bacteria in the tablet. The compressing pressure during compression in the tablet manufacturing method of this embodiment is preferably 120 MPa or less per tablet unit area, more preferably 100 MPa or less, and even more preferably 80 MPa or less, from the viewpoint of improving the survival rate of microorganisms. The compressing pressure during compression in the tablet manufacturing method of this embodiment is preferably 32 MPa or more, more preferably 40 MPa or more, and even more preferably 48 MPa or more, from the viewpoint of easily obtaining a practical hardness.

[0064] According to the tablet manufacturing method of this embodiment, it is possible to manufacture tablets whose tablet diameter R (mm) and tablet hardness H (N) satisfy the following formula (3). Tablets that satisfy the formula (3) have sufficient hardness, are less likely to crack or chip, and have low friability.

[0065] In the tablet manufacturing method of this embodiment, a cellulose powder having a loose bulk density and average L / D within a predetermined range is used, and the tablet is compressed with a predetermined compression force, thereby making it possible to manufacture tablets in which microorganisms are unlikely to be killed and which have sufficient hardness. The tablet manufacturing method of this embodiment makes it possible to manufacture tablets in which the survival rate of microorganisms is 35% or more, more preferably 40% or more, and even more preferably 45% or more. Furthermore, by using a microbial powder containing a sufficient amount of viable bacteria as a raw material, the tablet manufacturing method of this embodiment makes it possible to manufacture tablets in which the survival rate of the microorganisms is 1.0×10 9 CFU / g or more, preferably 6.0×10 9 CFU / g or more, more preferably 1.0×10 10 Tablets can be produced that contain greater than or equal to CFU / g. EXAMPLES

[0066] The present invention will be described with reference to examples. However, the embodiment of the present invention is not limited to the description of these examples. The methods for measuring and evaluating the various physical properties in the examples and comparative examples are as follows.

[0067] [Long diameter / short diameter (L / D) of cellulose powder] Images taken using a digital microscope (VHX-6000, Keyence, using a VH-501 lens) were saved in TIFF file format with 1360 × 1024 pixels. Next, the short and long diameters of 200 particles were measured using the saved images with image processing and analysis software (Image HyperII, Digimo), the ratio of the long diameter to the short diameter L / D was calculated, and the average value of L / D for the 200 particles was taken.

[0068] [Loose bulk density of cellulose powder (g / cm 3 )] The loose bulk density of the cellulose powder was measured by the method described below. The cellulose powder was filled into a 25 mL cylindrical metal container using a Scott volumeter (Model ASTM B-329-85, manufactured by Tsutsui Rikagaku Kikai Co., Ltd.). The cellulose powder in the 25 mL cylindrical metal container was leveled off, and the mass (g) of the cellulose powder in the container was divided by 25 mL to obtain the loose bulk density (g / cm 3 ) was calculated and shown as the average of two measurements.

[0069] [Angle of repose of cellulose powder (°)] The moisture content in the powder sample was measured using an infrared moisture meter (Kett Electric Laboratory, FD-220 model, sample: 1 g, 105 °C) and adjusted to 3.5% by mass or more and 4.5% by mass or less. The powder sample was then dropped into a commercially available powder property measuring instrument (Hosokawa Micron, Powder Tester TR model) using a metal funnel with an orifice diameter of 0.8 cm (must be made of a material that does not generate static electricity) and a vibration scale of 1.5, and the ridge angle of the mountain made by the powder sample (2 ridge angle measurements, measurement interval 3 °) was measured and used as the angle of repose (°). The angle of repose (°) was shown as the average value of three measurements.

[0070] [Tablet density] Tablet volume (mm 3 ) was measured by dividing the tablet into the upper and lower cap (spherical notch) parts and the cylindrical part sandwiched between them, calculating the volumes of each part, and adding them up, as shown in Figure 1. In Figure 1, R is the tablet diameter (mm), r is the tablet radius (mm:R / 2), and T is the tablet thickness (mm). h is the height of the tablet cap part (spherical notch), and k is the distance from the end of the cylindrical part of the tablet to the end of the tablet cap part. h and k are values ​​specific to the mortar and pestle used for tablet formation.

[0071] [Table 1]

[0072] The R, h, and k of a tablet can also be determined by observing the formed tablet under an optical microscope and performing image analysis.

[0073] The volume of the tablet was calculated as the sum of the spherical cavity and cylindrical cavity by the following formula: cap is the volume of the recess (mm 3 ), V cyl is the volume of the cylindrical part (mm 3 ), V tab is the volume of the tablet (mm 3 ), m tab means tablet weight (mg). The tablet weight was 200 mg for the 200 mg tablet and 500 mg for the 500 mg tablet.

[0074]

number

[0075] [Tablet hardness] The hardness of the sampled tablets was measured using a commonly used tablet hardness tester (Tablet Tester 8M / manufactured by DR. SCHLEUNIGER). The tablet hardness (N) of 10 tablets was measured, and the average tablet hardness of the 10 tablets was calculated.

[0076] [Tablet tensile strength] The tablet hardness H (N), tablet diameter R (mm), tablet thickness T (mm), and thickness W (mm: T-2H) of the cylindrical part of the tablet measured above were used to calculate the tablet tensile strength TS (MPa) according to the following formula.

[0077]

number

[0078] [Tablet friability] The mass (Wa) of 33 tablets was measured for the 200 mg tablets, and the mass (Wa) of 13 tablets was measured for the 500 mg tablets. For the tablets whose mass had been measured, 33 tablets of the 200 mg tablets and 13 tablets of the 500 mg tablets were placed in a tablet friability tester (PTER-A, manufactured by PHARMA TEST) and rotated at 25 rpm for 4 minutes. After that, the fine powder adhering to the tablets was removed, and the mass (Wb) was measured again. The friability of the tablets was then calculated using the following formula.

[0079] [Friability (mass%)]=(Wa-Wb) / Wa×100(mass%)

[0080] [Disintegrability of tablets] A tablet disintegration test was carried out according to the general test method "Disintegration Test" of the 18th Edition of the Japanese Pharmacopoeia, and the average disintegration time of six tablets was calculated. Pure water was used as the test liquid.

[0081] [Measurement of viable microbial count] The viable cell count in the lactic acid bacteria powder and tablets was measured by the following method. A sample solution was prepared by adding 99 mL of sterile phosphate buffered saline to 1 g of sample and mixing. 0.1 mL of each of the prepared sample solution and its serial dilutions were smeared on two MRS agar plates and anaerobically cultured at 30°C for three days. The grown colonies were confirmed to be gram-positive, catalase-negative acid-producing bacteria, and the number of gram-positive, catalase-negative colonies multiplied by the dilution factor was calculated as the number of lactic acid bacteria (CFU) per 1 g of sample.

[0082] [Tablet weight variation (CV)] The weights of 10 tablets obtained by rotary tableting were measured, and the average weight and standard deviation of the weights were calculated. The coefficient of variation (%) defined as (standard deviation / average weight)×100 was calculated to evaluate the tablet weight variation.

[0083] [Angle of repose of raw material mixture (powder) (°)] The repose angle (°) of the raw material mixture (powder) was measured using a commercially available powder property measuring instrument (Powder Tester TR model, manufactured by Hosokawa Micron Co., Ltd.) in the same manner as described in [Repose angle (°) of cellulose powder] above. The repose angle (°) is shown as the average value of three measurements.

[0084] [Example 1] Probiotic tablets were produced using cellulose powders with various physical properties as excipients, and their effects on the survival rate of the probiotics and the physical properties of the tablets were investigated.

[0085] <Lactic acid bacteria> As probiotics, live lactic acid bacteria Lactobacillus acidophilus powder (manufactured by Seti Co., Ltd.) was used. The live bacteria count was previously measured and found to be 6.1 x 10 10 CFU / g.

[0086] <Cellulose powder> As the cellulose powder, crystalline celluloses 1 to 3 produced by the following production method, CEOLUS PH-101 (manufactured by Asahi Kasei Corporation), and CEOLUS PH-102 (manufactured by Asahi Kasei Corporation) were used. The physical properties of each cellulose powder are shown in Table 2.

[0087] [Production of crystalline cellulose 1] (1) Production of wet floc (X) 2 kg of shredded commercial SP pulp and 30 L of hydrochloric acid solution were placed in a low-speed mixer (30LGL Reactor (product name) manufactured by Ikebukuro Horo Kogyo Co., Ltd.) and hydrolyzed while stirring (reaction conditions: hydrochloric acid concentration 0.05%, reaction temperature 80°C, reaction time 6 hours, stirring speed 5 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue was thoroughly washed with pure water until the electrical conductivity of the filtrate was less than 100 μS / cm, and then filtered to obtain wet floc X.

[0088] (2) Production of wet flock (Y) Separately, 2 kg of shredded commercially available SP pulp and 30 L of hydrochloric acid solution were placed in a low-speed mixer (product name: 30LGL reactor, manufactured by Ikebukuro Horo Kogyo Co., Ltd.) and hydrolyzed with stirring (reaction conditions: hydrochloric acid concentration 1.0%, reaction temperature 130°C, reaction time 2 hours, stirring speed 220 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue was thoroughly washed with pure water until the electrical conductivity of the filtrate was less than 100 μS / cm, and then filtered to obtain wet floc (Y).

[0089] (3) Preparation of crystalline cellulose 1 The wet floc (X) and the wet floc (Y) were mixed at 60:40 (mass ratio of solid content) and introduced into a 90 L plastic bucket, and pure water was added so that the total solid content concentration became 25 mass %. Next, the mixture in the plastic bucket was neutralized with ammonia water (pH after neutralization was 7.5 to 8.0) while stirring with a three-one motor, and this was spray-dried (conditions: dispersion liquid supply rate 6 kg / hour, inlet temperature 180°C to 220°C, outlet temperature 50°C to 70°C) to obtain a powder of crystalline cellulose 1.

[0090] [Production of crystalline cellulose 2] A powder of crystalline cellulose 2 was obtained in the same manner as in the preparation of crystalline cellulose 1, except that the wet floc (X) and the wet floc (Y) were mixed at a ratio of 50:50 (mass ratio of solid contents).

[0091] [Production of crystalline cellulose 3] A powder of crystalline cellulose 3 was obtained in the same manner as in the preparation of crystalline cellulose 1, except that the wet floc (X) and the wet floc (Y) were mixed at a ratio of 40:60 (mass ratio of solid contents).

[0092] [Table 2]

[0093] <Tablet manufacturing> A raw material mixture (powder) was prepared with the composition shown in Table 3. The maltodextrin used was "(trade name) Sandec #150" (manufactured by Sanwa Starch Co., Ltd.), the croscarmellose sodium used was "(trade name) Kiccolate (registered trademark) ND-2HS" (manufactured by Nichirin Chemical Industry Co., Ltd.), and the light anhydrous silicic acid used was "(trade name) Aerosil 200" (manufactured by Nippon Aerosil Co., Ltd.). As a control, the anhydrous calcium phosphate used was "(trade name) Fujicalin" (manufactured by Fuji Chemical Industry Co., Ltd.).

[0094] [Table 3]

[0095] All ingredients except magnesium stearate were placed in a polyethylene bag and mixed for 3 minutes, after which magnesium stearate was added and mixed for another minute before being fed into a tablet press.

[0096] Each raw blend was used to prepare 200 mg and 500 mg tablets. The 200 mg tablets were produced using a single punch tablet press (product name: Autotab500, Ichihashi Seiki Co., Ltd., φ=8 mm, 12R mortar and punch) at a tableting speed of 30 T / min and the compression pressure shown in Table 5 (test plots 2-1 to 2-8). The 500 mg tablets were produced using a rotary tablet press (product name: LIBRA2, Kikusui Seisakusho Co., Ltd., φ=12 mm, 16R mortar and punch) at a rotating plate speed of 30 rpm and the compression pressure shown in Table 5 (test plots 1-1 to 1-4). In Table 4, the compression pressure in parentheses in the compression pressure column for test plots 1-1 to 1-4 indicates the residual pressure. The tablet weight (mg) and tablet diameter (mm) of each tablet produced are shown in Table 4. The tablet thickness (mm) and the V tab Tablet volume (mm) calculated according to the formula 3 ) are also shown in Table 5.

[0097] [Table 4]

[0098] [Table 5]

[0099] The density D (mg / mm 3 ) was calculated according to the above formula. The tablet hardness (N), tablet tensile strength (MPa), friability (mass%), viable cell count (CFU / g), survival rate (%), and disintegration time (min) of each tablet obtained were also measured. The results are shown in Table 6. For all tablets in the test groups, the tablet diameter R and tablet hardness H (N) satisfied the relationship of the above formula (3), and thus met the practical hardness.

[0100] [Table 6]

[0101] For the tablets in test areas 1-1 to 1-4 and 2-1 to 2-8, the vertical axis represents the tablet density D (mg / mm 3 ) and the horizontal axis is the tablet diameter R (mm), as shown in FIG. 2. In the figure, among the test plots 1-1 to 1-4, the test plots 1-3 to 1-4 with a survival rate of 50% or more are plotted with black circles, and the test plots 1-1 to 1-2 with a survival rate of less than 50% are plotted with white circles. Among the test plots 2-1 to 2-8, the test plots 2-1 to 2-5 with a survival rate of 40% or more are plotted with black circles, and the test plots 2-6 to 2-8 with a survival rate of less than 40% are plotted with white circles. As shown in FIG. 2, for tablets with the same tablet diameter, the smaller the tablet density, the higher the survival rate and viable cell count tended to be. In particular, it was confirmed that tablets within the range satisfying the above formula (1) and the above formula (2) had high viable cell counts and survival rates, and by satisfying the relationship between the two, the tablets had a high viable cell count and were hard enough to be less likely to crack or chip.

[0102] The tablet weight variation (CV) was measured for the tablets of test plots 1-1 to 1-4. In addition, the angle of repose of the raw material mixture (powders) constituting the tablets of test plots 1-1 to 1-4 was measured at the time when the raw materials other than magnesium stearate were mixed for 3 minutes. The results are shown in Table 7. The tablet weight variation of the tablets of each test plot was extremely stable at 0.8% or less, and the flowability of the raw material mixture (powders) was also good.

[0103] [Table 7]

[0104] [Reference example 1] <Tablet manufacturing> Spray-dried lactose and cellulose powder were mixed in a predetermined ratio to prepare a raw material mixture (powder) having the composition shown in Table 8. The spray-dried lactose used was "(trade name) Supertab 11SD" (manufactured by DFE Pharma), and the cellulose powder used was the crystalline cellulose 1 produced in [Production of crystalline cellulose 1] in Example 1 and "(trade name) Ceolus PH-102" (manufactured by Asahi Kasei Corporation).

[0105] [Table 8]

[0106] All raw materials were placed in a polyethylene bag and mixed for 3 minutes. Then, magnesium stearate was added to each raw material mixture (powder) so that the raw material mixture (powder):magnesium stearate ratio was 99:1 (mass ratio), and the mixture was mixed for another minute and then fed to a tablet press.

[0107] Each raw material mixture (powders) was used to manufacture 200 mg tablets. The 200 mg tablets were produced using the same single punch tablet press used in the production of the 200 mg tablets described in Example 1, at a tableting speed of 30 T / min and a tableting pressure of 3 kN.

[0108] <Observation of tablet cross section> The obtained tablets were each divided using a tablet cutter, and the cross sections were observed using a scanning electron microscope (SEM) (manufactured by Keyence Corporation). The results of SEM images observed at a magnification of 500 times are shown in Figures 3(A) to (E).

[0109] As shown in Table 2, crystalline cellulose 1 has a high average particle long axis to short axis ratio (L / D), and is prone to plastic deformation during compression molding. This allows it to flexibly deform within the tablet, filling the gaps between particles and increasing tablet hardness and friability. In fact, a comparison of SEM images of tablet cross sections clearly shows that in tablets containing crystalline cellulose 1, domains made of fibrous particles exist between amorphous particles. [Industrial Applicability]

[0110] According to the tablet and the manufacturing method thereof of this embodiment, it is possible to provide a tablet that has a high survival rate of microorganisms, has sufficient hardness, and is less likely to crack or chip.

Claims

1. A tablet containing cellulose powder and a powder of a microorganism, The diameter R (mm) and density D (mg / mm ３ ) satisfies the following formulas (1) and (2). Formula (1): 6≦R≦14 Formula (2): D≦-0.01R+1.30

2. The tablet according to claim 1 , wherein the cellulose powder is a powder of crystalline cellulose.

3. The tablet according to claim 2, wherein the powder of crystalline cellulose has an average ratio of the long axis to the short axis (L / D) of the particles of 2.0 or more and 4.5 or less.

4. The cellulose powder has a loose bulk density of 0.250 g / cm ３ 2. The tablet of claim 1, wherein:

5. The tablet according to claim 1, wherein the diameter R (mm) and hardness H (N) of the tablet satisfy the following formula (3). Formula (3): H≧12.5R-50

6. 2. The tablet of claim 1, having a friability of 0.2% or less.

7. The tablet according to claim 1, wherein the ratio (mass ratio) of the content of the cellulose powder to the total amount of the tablet is 10% by mass or more and 60% by mass or less.

8. The tablet according to claim 1, wherein the ratio (mass ratio) of the content of the microbial powder to the total amount of the tablet is 10% by mass or more and 60% by mass or less.

9. The viable cell count of the microorganism per gram of tablet is 1.0 x 10 ９ The tablet according to claim 1, having a CFU / g or more.

10. 2. The tablet of claim 1, wherein the microbial viability is 35% or more.

11. The tablet according to claim 1 , wherein the microorganism is one or more selected from the group consisting of lactic acid bacteria, bifidobacteria, saccharifying bacteria, butyric acid bacteria, and yeast.

12. The tablet of claim 1 , wherein the microorganism is a probiotic.

13. In addition, it contains a lubricant, The tablet according to claim 1, wherein the ratio (mass ratio) of the content of the lubricant to the total amount of the tablet is 0.1 mass% or more and 3.0 mass% or less.

14. preparing a mixture containing a cellulose powder and a powder of a microorganism; compressing the mixture to produce tablets; having The tableting is carried out at a tablet pressure of 128 MPa or less per tablet unit area, The diameter R (mm) and density D (mg / mm ３ ) satisfies the following formulas (1) and (2). Formula (1): 6≦R≦14 Formula (2): D≦-0.01R+1.30

15. The cellulose powder is a powder of crystalline cellulose and has a loose bulk density of 0.250 g / cm ３ The method for producing a tablet according to claim 14, wherein:

16. The method for producing a tablet according to claim 15, wherein the powder of crystalline cellulose has an average ratio of the major axis to the minor axis (L / D) of the particles of 2.0 or more and 4.5 or less.

17. The method for producing a tablet according to claim 14, wherein the diameter R (mm) and hardness H (N) of the tablet satisfy the following formula (3). Formula (3): H≧12.5R-50

18. The ratio (mass ratio) of the content of the cellulose powder to the total amount of the tablet is 10% by mass or more and 60% by mass or less, The method for producing a tablet according to claim 14, wherein the ratio (mass ratio) of the content of the microbial powder to the total amount of the tablet is 10% by mass or more and 60% by mass or less.

19. The viable cell count of the microorganism per 1 g of the tablet is 1.0 x 10 ９ The method for producing a tablet according to claim 14, wherein the CFU / g or more.

20. The method of claim 14, wherein the microbial viability of the tablet is 35% or more.

Images