JP2019116447A - Solid preparation and production method thereof - Google Patents

Abstract

To provide solid preparations comprising starch with a moisture of 10 mass% as a raw material, which is conventionally considered to be unsuitable as a raw material for solid preparations comprising enteric useful bacteria.SOLUTION: Provided is a solid preparation comprising granules of a mixture comprising starch with a moisture of 10 mass% and an excipient, and an enteric useful bacterium. Provided is a method for producing an enteric useful bacterium-containing solid preparation, comprising: granulating a mixture comprising starch with a moisture of 10 mass% and an excipient to obtain granules; and mixing the obtained granules with an enteric useful bacterium.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a solid preparation and a method for producing the same.

Patent Document 1 discloses a solid preparation characterized by containing enteric bacteria and starch having a loss on drying value of 4% or less in a range of 5 to 35% by mass.
However, there is no disclosure of a granulated product of a mixture containing starch having a water content of 10% by mass or more and an excipient, a solid preparation containing enteric useful bacteria, and a method for producing the same.

JP, 2016-193894, A

  An object of the present invention is to provide a solid preparation which can be industrially advantageously implemented and a method for producing the same.

  As a result of intensive studies to solve the above problems, the present inventors have found that 10% by mass of moisture is obtained by using a granulated mixture of starch containing 10% by mass or more of moisture and an excipient. It has been found that even if the above starches are used, it is possible to provide an excellent solid preparation containing pharmaceutically useful enteric bacteria, and based on this finding, further studies are conducted to complete the present invention. .

That is, the present invention relates to the following inventions.
[1] A granulated product of a mixture containing starch having a water content of 10% by mass or more and an excipient, and a solid preparation containing enteric useful bacteria.
[2] (1) Granulating a mixture containing 10% by mass or more of starch and an excipient to obtain a granulated product, and (2) the obtained granulated product and useful enteric bacteria A method for producing a solid preparation containing enteric useful bacteria, comprising the step of mixing.

  The present invention can provide a solid preparation which can be industrially advantageously implemented and a method for producing the same. In particular, the solid preparation containing enteric useful bacteria of the present invention is solid even using starch having a water content of 10% by mass or more, which is a raw material conventionally thought to be unsuitable as a raw material of solid preparation containing enteric useful bacteria. It is excellent in that it can be advantageously used industrially without any hindrance for preparation of a preparation. The present invention also enriches the art of formulation technology.

FIG. 1 shows the results of comparing the particle size distribution of the sized powder.

  The solid preparation of the present invention is characterized in that it comprises a granulated product of a mixture containing starch having a water content of 10% by mass or more and an excipient, and enterofungal bacteria. The mixture is usually a mixture of starch and an excipient, and may contain, for example, other components described below.

Mixture-containing component 1: A starch having a water content of 10% by mass or more, for example, a commercially available starch is purchased, and the loss on drying 10 determined according to the method described in the 17th Amendment of the Japanese Pharmacopoeia 2.4.1 [Dry loss test method] is 10 When it is not less than% by mass, it can be used as a starch having a water content of not less than 10% by mass. That is, the loss on drying may be determined as the water content ratio. Moreover, when the water content of the starch calculated | required using moisture analyzers, such as a Karl-Fisher moisture meter, is 10 mass% or more, it can be used as a starch of 10 mass% or more of water content.
The lower limit of the water content of the starch used in the present invention may be, for example, 11% by mass or 12% by mass.
The upper limit of the water content of the starch used in the present invention may be, for example, 30% by mass, 20% by mass, or 15% by mass.
The moisture content ratio of starch in the present invention includes the range of the ratio of any combination of the above lower limit value and the upper limit value.

  As starch, for example, corn starch, potato starch, rice starch, wheat starch, sweet potato starch, tapioca starch, sago starch, bracken starch, kudzu starch, green bean starch or green bean starch, or a combination of two or more of these can be mentioned. Among them, corn starch is preferred. For example, starch having a moisture content of about 11 to 13% by mass such as the commercially available Eclipse Bureau corn starch (made by Japan Food Chemical Industries Co., Ltd.) or cornstarch white (made by Japan Cornstarch) or a moisture content of about 18% by mass Starch etc. can be used as it is. Furthermore, a combination of starch having a low water content rate and a high starch content or a combination of different types of starch may be used to make the water content rate 10% by mass or more as a whole mixture.

  The content ratio of starch is not particularly limited as long as the effects of the present invention are not impaired, but it is usually 1.0 to 99.0% by mass, preferably 2.0 to 98.5% by mass with respect to the whole solid preparation. And particularly preferably 2.4 to 98.0% by mass.

Mixture-Containing Component 2: Excipient The excipient is not particularly limited as long as it is pharmaceutically or food-acceptable, and a commonly used excipient can be appropriately selected and used. As an excipient, for example, sucrose; lactose hydrate, maltose (including candy powder), sucrose (sucrose), disaccharides such as trehalose; polysaccharides such as cyclodextrin, dextrin; calcium carbonate such as precipitated calcium carbonate Cellulose or cellulose derivatives such as hydroxypropyl cellulose; sugar alcohols such as D-mannitol, erythritol, maltitol, xylitol; sodium phosphate etc., among which sucrose, candy powder, precipitated calcium carbonate, crystals One or more selected from cellulose and erythritol is preferable.

  The content of the excipient is not particularly limited as long as the effects of the present invention are not impaired, but it is usually 1.0 to 99.0% by mass, preferably 2.0 to 98.5% by mass with respect to the whole solid preparation. %, Particularly preferably 2.4 to 98.0% by mass.

Mixture-containing component 3: The medicinal component mixture other than enteric useful bacteria may further contain a medicinal component other than enteral useful bacteria. As such a pharmaceutically active ingredient, preferably, an enteric agent, antacid agent, stomach stomach agent, digestive agent, antipruritic agent, analgesic anticonvulsant agent, vitamin agent, mucous membrane repair agent, antifoam agent, antipyretic analgesic anti-inflammatory agent, psychotropic drug, anti-anxiety drug Antidepressants, hypnotic sedatives, anticonvulsants, central nervous system agonists, cerebral metabolism improvers, cerebral circulation improvers, antiepileptics, sympathomimetics, gastrointestinal drugs, antiulcers, antitussives, antiemetics, antiemetics, Respiratory enhancer, bronchodilator, allergy medicine, dental oral medicine, antihistamine, cardiotonic, arrhythmia, diuretic, antihypertensive, vasoconstrictor, coronary vasodilator, peripheral vasodilator, hyperlipidemia Medicines, chores, antibiotics, chemotherapeutics, diabetes, osteoporosis, anti-rheumatics, skeletal muscle relaxants, antiseptics, hormones, alkaloid narcotics, sulfa drugs, gout medications, Selected from anticoagulants and antineoplastic agents Or more, and the like. By combining them with useful intestinal bacteria, these medicinal ingredients and useful intestinal bacteria can exhibit additive effects or synergistic effects.

  As an enteric agent, for example, ketsumeishi, gennoshoko, red locust, asenyak or ubai or a combination of two or more of these can be mentioned.

  As an antacid agent, for example, magnesium oxide, synthetic aluminum silicate, synthetic hydrotalcite, aluminum hydroxide / sodium bicarbonate coprecipitate, magnesium hydroxide, magnesium carbonate, precipitated calcium carbonate, magnesium aluminometasilicate, hydrogen carbonate Sodium, Rohto extract, dried aluminum hydroxide gel, aluminum hydroxide gel, alumina magnesium hydroxide, magnesium silicate, magnesium aluminum silicate, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co Precipitate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, volley, stone determination, pith bone, aminoacetic acid or dihydroxyaluminum aminoacetate or a combination of two or more of them. It is.

  As a stomach stomach agent, for example, carnitine chloride, dried yeast, aloe, turmeric, oatbacus, guagetsu, keihi, gentian, kobok, germinating, fessial, aniseed, perennial grass, long-lived grass, ougon, ouren, processed vat, cuckoo, rhubarb root, dried Amber, rice husk, pheasant, kojin, goshyu, pepper, columbo, condurango, sansho, Yamana, shisoshi, shiksha, shosui, shozo, shochu, blue peel, centrum root grass, centaurium grass, jujube, soio, sage, spruce, keihi oil, Rash, Ginseng Ginseng, Choji, Chimpo, Chili pepper, Spruce, Animal gall, Nigaki, Niggazuki, Carrot, Mint, Beak, Boiled, Boiled, Hops, Homicha Extract, Water Lily, Mosquito, Yakuchi, Rytan, Red Rose, Pomegranate Oil, Ginger Oil Cardamom oil, clove oil, peppermint oil, lemon oil, l-menthol, dl-menthol, betaine hydrochloride, glutamic acid hydrochloride, and bethanechol or glutamic hydrochloride or a combination of two or more of these chloride.

  The digestive agent includes, for example, biodiastase, ursodeoxycholic acid, oxychoric acid salts, dehydrocholic acid, cholic acid, bile powder, bile extract (powder) or animal bile or a combination of two or more of these.

  As an antidiarrheal agent, for example, guaiacol, calcium lactate, creosote, calcium hydrogen phosphate, precipitated calcium carbonate, ovary, scurvy, acrinol, acrinol, berberine chloride, bismuth subsalicylic acid, bismuth subsitrate, bismuth subcarbonate, bismuth subsulphate , Tannic acid, tannic acid albumin, methylene thymol tannin, phenyl salicylate, guaiacol carbonate, berberine tan tanate, kaolin, natural aluminum silicate, hydroxynaphthoate aluminum, pectin, medicinal charcoal, asenyak, ubai, ginshoko, five times child, hawthorn or beehive Or the combination of two or more of these is mentioned.

  Analgesic and antispasmodic agents such as oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, methylatropine bromide, methyl anisotropin bromide bromide, methyl scopolamine bromide, methyl-l-hyohistamine bromide, odor Alkylated benzalidium iodide, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, roto extract, veradonna extract, papaverine hydrochloride, ethyl aminobenzoate, engosac, licorice, licorice, kobok or peony or combinations of two or more of these. .

  Vitamins, for example, nicotinamide, calcium pantothenate, biotin, vitamin B1 (including derivatives and salts thereof), vitamin B2 (derivatives and salts including salts thereof), vitamin B6 (derivatives and salts including salts thereof) Or vitamin C (derivatives and salts including the salts thereof) or combinations of two or more of these.

  Mucosal repair agents include, for example, sodium azulene sulfonate, aldioxa, glycyrrhizinic acid and salts thereof and licorice extract, L-glutamine, copper chlorophyllin potassium, histidine hydrochloride, pig gastric wall pepsin degradation product, methyl methionine sulfonium chloride, red hair or red pepper or A combination of two or more of these can be mentioned.

  As an antifoamer, for example, a mixture of dimethylpolysiloxane, dimethylpolysiloxane and silicon dioxide, dimethylpolysiloxane or silicone resin emulsion, or a combination of two or more thereof can be mentioned.

  The content ratio of the pharmaceutically active ingredient other than enteric useful bacteria is not particularly limited as long as the effects of the present invention are not impaired, but is usually 0.5 to 93.5% by mass with respect to the whole solid preparation, preferably 1.0. It is -93.0 mass%, and preferably 1.5 to 92.6 mass%.

Mixture-Containing Component 4: Additives other than Excipients The mixture of components used in the present invention may further contain additives other than excipients. The additives are appropriately selected according to the type of enteric useful bacteria or excipients, and those commercially available can be used appropriately. Additives include, for example, disintegrants, taste masking agents, stabilizing agents, sweeteners, fluidizers, lubricants, buffers, solubilizers, binders, and coatings. The content ratio of the additive is not particularly limited as long as the effects of the present invention are not impaired.

  As the disintegrant, for example, carmellose calcium, croscarmellose sodium, carmellose, carmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose or agar powder, or a combination of two or more of them can be mentioned. The content ratio of the disintegrant is usually 2.0 to 9.0% by mass, preferably 2.5 to 8.5% by mass, particularly preferably 3.0 to 8.0% by mass with respect to the whole solid preparation. It is mass%.

  Examples of the flavoring agent include fructooligosaccharides, ascorbic acid, citric acid, succinic acid, menthol or peppermint powder. The content ratio of the flavoring agent is usually 0.1 to 5.0% by mass, preferably 0.1 to 4.0% by mass, particularly preferably 0.1 to 3.0% with respect to the whole solid preparation. It is mass%.

  As the stabilizing agent, for example, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid or dibutylhydroxytoluene or a combination of two or more of them can be mentioned.

  As the sweetening agent, for example, saccharin sodium, dipotassium glycyrrhizinate, stevia, aspartame, erythritol, sucrose, powdered reduced maltose starch syrup, sucralose, acesulfame potassium or advantame or a combination of two or more of them can be mentioned. The content ratio of the sweetening agent is usually 1.5 to 24.5% by mass, preferably 2.0 to 24.0% by mass, particularly preferably 2.2 to 23.6% with respect to the whole solid preparation. It is mass%.

  The fluidizing agent includes, for example, light anhydrous silicic acid, stearic acid, magnesium stearate, calcium stearate or talc, or a combination of two or more thereof.

  Lubricants include, for example, magnesium stearate, calcium stearate, talc or colloidal silica, or a combination of two or more thereof. The content ratio of the lubricant is usually 0.1 to 5.5% by mass, preferably 0.5 to 5.0% by mass, particularly preferably 0.9 to 4% with respect to the whole solid preparation. It is 6% by mass.

  Buffering agents include, for example, disodium citrate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, tartaric acid or sodium acetate, or a combination of two or more thereof.

  As a solubilizer, for example, sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol or povidone or a combination of two or more of them can be mentioned.

  As the binder, there may be mentioned, for example, starch, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, pullulan, gelatin, povidone or gum arabic, or a combination of two or more thereof. The content ratio of the binder is usually 1.0 to 35.0% by mass, preferably 1.5 to 30.0% by mass, particularly preferably 1.7 to 29.4% with respect to the whole solid preparation. It is mass%.

  Coating agents include, for example, hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl cellulose, methacrylic acid copolymer, macrogol, triethyl citrate or propylene glycol or a combination of two or more thereof.

Mixture containing component 5: mixture of the components used in the water present invention may further contain water. The water is preferably purified water or distilled water. Depending on the granulation method, if water is required for granulate production, the required amount of water is used.

Production of Mixture A mixture is obtained by mixing starch with a moisture content of 10% by mass or more and an excipient according to a known method such as stirring using, for example, a mixer or a granulator. If necessary, a starch having a water content of 10% by mass or more and an excipient may be mixed together with a medicinal ingredient other than enteric useful bacteria, an additive other than an excipient and / or water. The mixture preferably has a uniform content.

Production of Granulated Product A granulated product is obtained by granulating the above mixture. The granulated product may be sieved to form a sized product.
The granulation method may be a dry granulation method or a wet granulation method, but a wet granulation method is preferable in that the granulation of granules can be suppressed or the surface is finished smoothly. preferable.

  Examples of a dry granulation apparatus for performing dry granulation include, for example, types such as a roller compactor, a pharmacopactor, and a chillsonator.

  The method used for wet granulation is particularly limited as long as it is a wet granulation method generally used for pharmaceuticals etc. such as fluidized bed granulation, stirring granulation, extrusion granulation or rotary granulation (roll granulation). I will not. Preferably, it is fluid bed granulation. Wet granulation can be performed, for example, using a general fluidized bed granulator, a rolling agitation granulator, an extrusion granulator, and the like. The fluid bed granulator may perform the above mixing and granulation and drying in the same apparatus. As a solvent in the case of performing wet granulation, water, ethanol or the like is preferable. As water, purified water is preferable. As ethanol, about 50 to 100% by mass of ethanol is usually used. Among them, in the present invention, it is preferable to carry out wet granulation using water (preferably purified water), but ethanol may be added if desired. The solvent used for wet granulation may contain known binders such as sucrose, hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), etc., as necessary.

  The size of the granulated product (which may be a sized product) is usually 125 to 850 μm, more preferably 125 to 500 μm.

  The water content of the granulated product (which may be a sized product) is usually about 1 to 3% by mass, preferably 1.5 to 2.5% by mass. The moisture content of the granulated product (which may be a sized product) can be determined according to the method described in the 17th Amended Japanese Pharmacopoeia 2.4.1 (Dry loss test method) or using a Karl Fischer moisture meter It can be measured. The water content of the granulated product (which may be a sized product) is the water content of the granulated product (which may be a sized product) manufactured using starch having a water content of less than 10% by mass as the starch. It is preferred that there is almost no difference compared to the proportions.

The loosening bulk density of the granulated product (which may be a sized product) is usually about 0.4 to 0.5 g / cm ³ , preferably 0.45 to 0.50 g / cm ³ . The loosened bulk density of the granulated product (which may be a sized product) can be measured, for example, using a Konishi FK type repose angle measuring instrument (model: 1421, manufactured by Konishi Medical Instruments Co., Ltd.). Loosening bulk density of granulated product (which may be sized product), loosening bulk of granulated product (which may be sized product) manufactured using starch having a water content of less than 10% by mass as starch It is preferred that there is almost no difference compared to the density.

  The repose angle of the granulated product (which may be a sized product) is usually about 30 to 40 °, preferably 33 to 39 °. The angle of repose of the granulated material (which may be a sized material) can be measured, for example, using a Konishi FK type repose angle measuring device (model: 1421, manufactured by Konishi Medical Instruments Co., Ltd.). The angle of repose of granules (which may be sized) is the angle of repose of granules (which may be sized) prepared using starch having a water content of less than 10% by mass as starch. In comparison, it is preferable that there is almost no difference.

  It is preferable that the particle size distribution of the granulated product (which may be a sized product) is usually a monomodal distribution. The particle size distribution of the granulated product (which may be a sized product) can be measured, for example, using an electronic sieving machine (model: M-2, manufactured by Tsutsui Rikagaku Co., Ltd.). The particle size distribution of the granulated product (which may be a sized product) is the particle size distribution of the granulated product (which may be a sized product) manufactured using starch having a water content of less than 10% by mass as starch. In comparison, it is preferable that there is almost no difference.

Useful Enteric Bacteria The useful bacteria in the intestine are not particularly limited, and examples thereof include bifidobacteria, lactic acid bacteria, glycated bacteria, butyric acid bacteria, natto bacteria, yeast and the like. Among them, the useful intestinal bacteria are preferably at least one selected from Bifidobacterium, lactic acid bacteria, saccharifying bacteria, butyric acid bacteria and yeast. More preferably, the useful intestinal bacteria is at least one selected from bifidobacteria, lactic acid bacteria, glycated bacteria and butyric acid bacteria. Useful enteric bacteria may be living bacteria or dead bacteria, but preferably contain living bacteria, and more preferably contain many living bacteria.

In the case of containing at least one type of bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, butyric acid bacteria and yeast, the dried bacterial cell used in the present invention has a viable cell count of about 10 ^{6, for example.} It is preferable that it is -10 < ¹² > CFU / g. More preferably, the viable count is about 10 ⁸ to 10 ¹² CFU / g.

  As preferred bacteria in the present invention, specifically, for example, Bifidobacteriums such as Bifidobacterium bifidum, B. longum, B. breve, B. adolescentis, B. infantis, B. pseudolongum, B. thermophilum etc., for example, 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. paracasei, L. reuteri, L. rhamnosus, Lactobacilli, such as L. salivarius, L. brevis; eg, Lactococci such as P. pentosaceus, Oenococcus oeni etc .; for example, glycated bacteria such as Bacillus subtilis, Bacillus mesentericus, Bacillus polyfermenticus etc .; Bacillus toyoi, B. Butyrate bacteria such as licheniformis, Clostridium butyricum, etc .; and other useful bacteria. In the present invention, it is preferable to use at least one type of bacteria selected from the group consisting of such bifidobacteria, lactic acid bacteria, glycated bacteria and butyric acid bacteria.

  These bacteria have, for example, morphological characteristics (for example, shape of colony, shape of cell, etc.), physiology, biochemical properties (for example, assimilability of sugar, growth temperature, optimum pH, etc.), chemical taxonomical Properties such as properties (cell fatty acid composition, etc.) may be compared with specific enteric useful bacteria known, and may be bacteria identified based on the comparison results of the properties, based on analysis of the nucleotide sequence of the 16S rRNA gene It may be the identified bacteria or the like. The fungi may be used alone or in combination of two or more.

  These bacteria can be easily obtained, for example, from an organization such as ATCC (registered trademark) or IFO, the Japan Bifidobacterium Center, the National Institute of Technology and Evaluation, Patent Microorganisms Depositary, and the like. Moreover, what is marketed can also be used suitably.

  As live bacteria used in the present invention, lactic acid bacteria and / or bifidobacteria are more preferable. Among them, Bifidobacterium is more preferable, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium infantis, and Bifidobacterium breve are more preferable, and Bifidobacterium bifidum and Bifidobacterium longum are particularly preferable. When a plurality of bacteria are used in combination, a combination of bifidobacteria and lactic acid bacteria and glycated bacteria, bifidobacteria and lactic acid bacteria, bifidobacteria and glycated bacteria, or lactic acid bacteria and glycated bacteria is preferable, among which (i) Bifidobacterium bifidum, ( ii) Lactobacillus acidophilus, (iii) Lactobacillus gasseri, (iv) Streptococcus (Enterococcus) faecalis, (v) Streptococcus (Enterococcus) faecium, (vi) Bacillus subtilis, (vii) of Bacillus mesentericus (i) to (vii) A combination of two or more of these is more preferred. The blending ratio in the case of using two or more of Bifidobacterium, lactic acid bacteria, saccharifying bacteria and butyric bacteria in combination is not particularly limited.

  The above bacteria can be obtained by culturing under known conditions or conditions equivalent thereto. For example, in the case of bifidobacteria or lactic acid bacteria, one or two or more of the above bifidobacteria and lactic acid bacteria are generally used in a liquid medium containing glucose, yeast extract, peptone and the like at a temperature of about 25 to 45 ° C. After aerobic or anaerobic culture for about 72 hours, cells are collected from the culture solution to obtain wet cells. In addition, in the case of glycated bacteria, one or two types of agar medium containing meat extract, casein peptone, sodium chloride and the like are generally cultured aerobically for about 4 to 72 hours at about 25 to 45 ° C. The cells are collected from the culture medium to obtain wet cells.

  In the present invention, in general, a dried product (dried product of dried cells) obtained by subjecting the above-mentioned viable fungi to dry processing is blended. Cell dry matter usually refers to dried individual cells or a collection of dried cells. Drying treatment of viable bacteria can be performed by a conventional method, for example, heat drying, lyophilization, spray drying and the like. In order to obtain the dry matter of the cells, the cells are suspended in a neutral buffer solution to which a suitable stabilizer such as monosodium glutamate, adonitol and the like is added, and dried by a known method or a method known per se. You can also.

  In the present invention, it is preferable to use a powder of the dried cell or a single-micron dried cell. The single micron is a range of 1 to 10 μm by rounding off the first decimal place. When at least one type of bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, butyric acid bacteria and yeast used in the present invention, the viable cell ratio in the preparation obtained using a single-micron dry cell material Is preferable because it improves.

Dosage forms of the solid preparation solid preparation is not particularly limited, and examples thereof include tablets, powders, granules or capsules. Among them, tablets are preferred.

  Examples of tablets include general uncoated tablets, sugar-coated tablets, film tablets etc. Uncoated tablets include, in addition to ordinary uncoated tablets, fast-dissolving tablets, which rapidly dissolve or disintegrate in saliva or digestive fluid, fast-disintegrating tablets, An orally disintegrating tablet, a chewable tablet to be taken by chewing, and the like can be mentioned. In addition, the form may be a laminated tablet, a dry coated tablet, a divided tablet or the like.

Production of solid preparation In the present invention, the method of producing a solid preparation comprises the steps of: (1) granulating a mixture containing 10% by mass or more of starch and an excipient to obtain a granulated product, and (2) The process of mixing the obtained granulated material and enteric useful bacteria is included.

  For step (1), reference may be made to the preparation of the above mixture and the preparation of granulates.

  In the step (2), the granulated product and enteral useful bacteria obtained in the step (1) are mixed by a known method such as stirring using, for example, a mixer or a granulator. The mass ratio of the granulated product to the enteric useful bacteria (granulated product: enteric useful bacteria) may be, for example, 1: (0.000001 to 2) or 1: (0.000001 to 1) .

  The content ratio of the granulated product is usually 50 to 95% by mass, preferably 60 to 95% by mass, and particularly preferably 65 to 95% by mass, based on the whole solid preparation.

  The content ratio of useful enteric bacteria is not particularly limited, and, for example, the dry matter of normally useful enteral useful bacteria is appropriately selected so as to be in the range of about 0.1 to 10% by mass with respect to the whole solid preparation. Can be determined. Preferably, the dry matter of enteric useful bacteria is about 1 to 6% by mass with respect to the whole solid preparation.

  When mixing the granulated product obtained in step (1) with enteric useful bacteria, additives generally used for medicinal ingredients other than enterable useful bacteria and / or solid preparations may be further added. Such additives include, for example, lubricants, disintegrants and / or excipients.

  For the medicinal components other than the enteric useful bacteria, the description of the medicinal components other than the enteral useful bacteria can be referred to. The content ratio of the pharmacologically active ingredient other than enteric useful bacteria is usually 1 to 50% by mass, preferably 1 to 30% by mass, and particularly preferably 1 to 20% by mass with respect to the whole solid preparation.

  Lubricants include, for example, magnesium stearate, calcium stearate, talc or colloidal silica, or a combination of two or more thereof. The content ratio of the lubricant is usually 0.1 to 5% by mass, preferably 1 to 3% by mass, and particularly preferably 1.0 to 1.5% by mass, based on the whole solid preparation.

  As a disintegrant, for example, croscarmellose, croscarmellose sodium, carmellose calcium, carmellose sodium, carmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose or agar powder, or a combination of two or more of these It can be mentioned. The content ratio of the disintegrant is usually 0.1 to 5% by mass, preferably 0.5 to 3% by mass, and particularly preferably 1 to 2% by mass with respect to the whole solid preparation.

  For the excipients, reference can be made to the description of said excipients and the description of said starch. The content ratio of the excipient is usually 1 to 20% by mass, preferably 1 to 15% by mass, particularly preferably 1 to 10% by mass, based on the whole solid preparation.

  It is preferable that the manufacturing method of a solid preparation includes the process of tableting the granule and the enteric useful microbe which were further mixed with (3) following said (1) and (2). Tableting is usually compression-molded at a tableting pressure of about 5 to 30 kN. In compression molding, a known tableting machine can be used. As a tableting machine, a single-shot type tableting machine or a rotary type tableting machine etc. are mentioned, for example.

The hardness of the obtained tablet is usually about 40 to 200 N, preferably 65 to 80 N. The hardness of the tablet can be measured using a tablet breaking strength measuring device or a tablet hardness tester (for example, model: TH-203RP, manufactured by Toyama Sangyo Co., Ltd.).
It is preferred that the hardness of the tablets in the present invention be substantially the same as that of tablets made using starch with less than 10% water by weight as starch.

The water content of the solid preparation is usually about 1 to 5%, preferably 2 to 3%. The water content of the solid preparation can be measured by the method described in the 17th Amended Japanese Pharmacopoeia 2.4.1 [Determination of Loss on Drying], or using a Karl Fischer moisture meter.
The water content of the solid preparation of the present invention is preferably substantially the same as that of a solid preparation produced using starch having a water content of less than 10% by mass as the starch.

The mass of the solid preparation is usually about 100 to 600 mg, preferably 200 to 600 mg.
The average particle size of the solid preparation is usually about 5 to 20 mm, preferably 5 to 15 mm.

  The present invention includes embodiments in which the above-described configurations are variously combined within the technical scope of the present invention as long as the effects of the present invention can be obtained.

  EXAMPLES The present invention will next be described in more detail by way of examples, which should not be construed as limiting the present invention in any way, and many modifications may be made within the technical scope of the present invention. It is possible by the person of ordinary knowledge.

"%" In this example means "mass%" unless otherwise specified.
(1) Drying weight loss test (17th edition Japanese Pharmacopoeia 2.4.1 [drying weight loss testing method])
The balance bottle was dried in advance for 30 minutes, and its mass was accurately measured. The sample is taken in the range of 1 g ± 10%, put in a weighing bottle, spread out so that the layer is 5 mm or less, accurately measure its mass, put it in a dryer at 105 ° C., 4 hours It was dry. After drying, it was removed from the dryer, allowed to cool for 30 minutes in a desiccator (silica gel), and accurately weighed.
(2) Loosen bulk density test / rest angle test It was measured using a Konishi FK type rest angle measuring instrument (model: 1421, manufactured by Konishi Medical Instruments Co., Ltd.).
Bulk density: A 25 mL stainless steel cylindrical container was used. The sample was allowed to flow freely until it overflowed the measuring vessel. After the inflow, excess powder was carefully scraped off the top of the container. The bulk density was calculated by measuring the mass of the powder by subtracting the mass of the measuring container from that previously measured.
Repose angle: The angle with the slope plate formed when it was dropped with a funnel and deposited in a flat plate shape was measured.
(3) Particle size distribution test It measured using the electronic sifter (model | type: M-2 and the Tsutsui Rikagaku company make).
First, sieves of 1700, 1400, 850, 500, 355, 250, 150, 125, 106, 90 and 75 μm were prepared, respectively. 10 g of the sample was weighed, and the correctly weighed sample was placed on the top sieve and covered. The sieve was shaken for 5 minutes. The sieves of each stage were carefully removed from the screen to ensure no sample loss. The mass of each sieve was weighed again, and the sample mass on the sieve was measured.
(4) Hardness test The hardness was measured using a tablet hardness tester (model: TH-203RP, manufactured by Toyama Sangyo Co., Ltd.).

[Examples 1 and 2]
Corn starch with a loss on drying value of 0.7% or 12.6%, precipitated calcium carbonate (manufactured by Bihoku Powder Industry Co., Ltd.), crystalline cellulose (manufactured by Asahi Kasei Corp.), fructooligosaccharide (manufactured by Meiji Food Materia Co., Ltd.), light anhydrous silica An acid (manufactured by Fuji Silysia Chemical Co., Ltd.), ame powder (manufactured by Hayashibara Co., Ltd.), and white sugar (manufactured by Saline Port Sugar Co., Ltd.) were weighed according to the compositions shown in Table 1. In addition, 0.7% of corn starch used Matsutani-Bokuho corn starch (made by Matsutani Chemical Industry Co., Ltd.), and 12.6% of corn starch used the Eclipse Bureau method corn starch (made by Nippon Food Chemical Co., Ltd.).

[Examples 3 and 4]
The raw materials weighed in Examples 1 and 2 are granulated with a fluidized bed granulator (FLO-5, manufactured by Freund Corporation), and the obtained granulated powder has a sieve of 850 μm (A-10677, manufactured by Iida Works) The sieved powder was obtained by passing through.

[Test Example 1]
The results of dry weight loss value, loose bulk density, and repose angle of the obtained sized granules are shown in Table 2.

  Desiccated powder using corn starch having a drying loss value of 0.7% (Example 3) and corn starch having a drying loss value of 12.6% at all of the drying loss value, loosening bulk density, and repose angle No major pharmaceutical differences were observed between the particles of the present invention and the sized granules (Example 4).

[Test Example 2]
The result of the particle size distribution test of the obtained granulated powder is shown in FIG.
As a result of measuring the particle size distribution, a sieved powder using corn starch having a loss on drying value of 0.7% (Example 3) and a sieved particle using corn starch having a loss on drying value of 12.6% (Example 4) In both cases, the peak was a 250 μm monomodal distribution, and it was found that the homology was high.

[Examples 5, 6]
Grain-sized powder (Example 3, Example 4), Bifidobacterium (Bifidobacterium bifidum G9-1), croscarmellose sodium, and magnesium stearate were weighed and mixed according to the composition shown in Table 3 to obtain a mixed powder. The sized powder obtained in Example 3 was used in Example 5 and the sized powder manufactured in Example 4 was used in Example 6.

[Examples 7 and 8]
The mixed powder of Examples 5 and 6 was tableted by a rotary tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) so as to have a hardness of about 80 N, and tablets of Examples 7 and 8 were obtained.
(Weight 22 mg / tablet, tablet shape: 8.0 mmφ, 1 step R)

[Test Example 3]
The tableting pressure and tablet hardness of the tablets obtained in Examples 7 and 8 and the drying loss test were conducted, and the results are shown in Table 4.

Tablets made of sized powder using corn starch with a loss on drying value of 0.7% (Example 7) and tablets made with sized powder using corn starch having a loss on drying value of 12.6% (implementation In Example 8), as a result of tableting so as to have the same hardness, it was found that there is no large difference in tableting pressure and the moldability is also the same. In addition, no difference was observed in the loss on drying.
From the above, when wet granulation is used, corn starch having a loss on drying of 10% or more and corn starch having a loss on drying of 1% or less are used, and their pharmaceutical properties are similar. It was shown that it was possible to obtain a sieved powder, and there was no difference between the two in the tableting process.

  The solid preparation of the present invention is useful in the pharmaceutical and food fields as a preparation containing enteric useful bacteria.

Claims (2)

  A granulated product of a mixture containing starch having a water content of 10% by mass or more and an excipient, and a solid preparation containing enteric useful bacteria. (1) Granulating a mixture containing 10% by mass or more of starch and an excipient to obtain a granulated product, and (2) mixing the obtained granulated product with enteric useful bacteria A method of producing a solid preparation containing enteric useful bacteria, comprising: