JP2012041293A - Intraoral collapsible tablet containing lactobacillus or extracted ingredient thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an intraoral collapsible tablet which contains lactobacillus or an extracted ingredient thereof as an active ingredient, is minimal in the time required for collapse thereof in an oral cavity, when taken, namely excellent in intraoral easy collapsibility for quickly collapsing in an oral cavity, and holds tablet hardness needed for holding the shape of the tablet on the molding, distribution and handling of the tablets, and to provide a method for producing the same.SOLUTION: The method for producing the intraoral collapsible tablet containing lactobacillus or extracted ingredient thereof, holding intraoral easy collapsibility and tablet hardness required for preparing the tablet is characterized by mixing (a) granulated granules containing lactobacillus or an extracted ingredient thereof as an active ingredient and compounding it with a vehicle and/or a moisture-adjusting agent, with (b) easily collapsible powder, for intraoral collapsible tablets, containing sugar and/or a sugar alcohol and not containing lactobacillus or extracted ingredient thereof, and then molding the mixture. The intraoral collapsible tablet containing lactobacillus or extracted ingredient thereof holds intraoral easy collapsibility for quick collapse in oral cavity and tablet hardness necessary for holding the tablet shape.

Description

  The present invention relates to an orally disintegrating tablet containing a lactic acid bacterium or an extract component thereof as an active ingredient, and when it is ingested, the time required for disintegration in the oral cavity is minimal, that is, easily disintegrating in the oral cavity that rapidly disintegrates in the oral cavity. Furthermore, the present invention relates to an orally disintegrating tablet containing lactic acid bacteria or an extract component thereof, which retains the tablet hardness necessary for maintaining the dosage form in tablet molding, distribution and handling, and a method for producing the same.

  Lactic acid bacteria or their extracted components are known to have various pharmaceutical functions or health functions, and in terms of their own safety, they are effective ingredients for pharmaceuticals, foods, etc. as pharmaceutical components or health function components. The application as is. For example, an antiallergic composition containing a lactic acid bacterium having antiallergic activity or an extracted component thereof as an active ingredient is known (Japanese Patent Laid-Open No. 2005-137357). In the patent document, examples of the preparation for ingesting lactic acid bacteria or an extract component thereof include granules, powders, tablets (including sugar-coated tablets), pills, capsules, syrups, emulsions, and suspensions. Yes.

  As a form of ingestion of lactic acid bacteria and the like, a method of formulating and ingesting a rapidly disintegrating tablet or film is also known. For example, JP-A-2004-26816 discloses a tablet containing a sugar or sugar alcohol, a disintegrant, an abrasive, a foaming agent, a binder and a wetting agent, the abrasive, the foaming agent, the binder and Disclosed is a rapidly disintegrating oral composition that disperses rapidly in the oral cavity by setting the ratio of the total amount of the wetting agent and the other components in the range of 1: 0.5 to 1:20. Yes. In addition, WO2007 / 111375 contains a useful bacterium such as lactic acid bacteria, microcrystalline cellulose, light silicic acid anhydride and starch-containing saccharide, and has a moisture content of 3.2% by weight or less, and a rapidly disintegrating tablet in the oral cavity. Japanese Patent Application Laid-Open No. 2010-132653 discloses a first layer containing an edible water-soluble film forming agent and lactic acid bacteria, and a first layer laminated with the first layer and containing an edible water-soluble film forming agent and a fragrance. A film containing lactic acid bacteria that dissolves or disintegrates easily in the oral cavity consisting of two layers is disclosed.

  As a dosage form such as a drug, an orally disintegrating tablet is known as an easy-to-take dosage form characterized by dissolving or disintegrating in the oral cavity with saliva or a small amount of water. In general, the time required for dissolution or disintegration in the oral cavity is preferably as fast as possible, and various tablets and the like that have been improved so as to have rapid disintegration in the oral cavity have been proposed.

  For example, in WO97 / 47287, a mixture containing an active ingredient and a disintegrating agent as a main component and a sugar alcohol or saccharide such as D-mannitol or lactose having an average particle size of 30 μm or less and containing an active ingredient and a disintegrant within one minute An intraoral quick disintegrating tablet characterized by disintegrating in the oral cavity is disclosed. WO2005 / 004923 discloses that 70% by mass or more of the active ingredient and all the constituents is a tablet that rapidly disintegrates in the oral cavity by making it a tablet containing cyclodextrin or a cyclodextrin derivative. JP 2003-34655 A discloses group 1 comprising a) an active ingredient, b-1) sugar and / or sugar alcohol, and c-1) cellulose, and b-2) sugar and / or sugar alcohol. And c-2) Group 2 containing celluloses, and Group 1 and / or Group 2 discloses a rapidly disintegrating solid preparation containing d) a dissolution aid.

  Furthermore, WO03 / 074085 discloses that the powder obtained by granulating a mixture containing a water-soluble pharmacologically active ingredient and an adsorbent contains D-mannitol and a disintegrant, thereby providing excellent disintegration and practical use. Intraoral rapidly disintegrating tablets having excellent tablet hardness are disclosed. As described above, various tablets that have been provided with quick disintegration in the oral cavity have been disclosed so far in order to obtain tablets that disintegrate rapidly in the oral cavity. However, in the production of orally disintegrating tablets, it is necessary to impart a certain level of tablet hardness in order to mold, distribute and handle the tablets. For example, it is necessary to prevent the tablet from being destroyed by vibration during carrying of the shaped tablet or impact when it is taken out from the container. From such a viewpoint, the higher the tablet hardness, the more desirable.

  However, increasing tablet hardness acts in a direction that suppresses rapid disintegration in the oral cavity, and maintaining the necessary tablet hardness is a contradictory condition for providing excellent disintegration of tablets. It is a difficult task to make the two compatible. In addition, depending on the active substance such as a drug contained, it may be difficult to make both the time required for dissolution or disintegration in the oral cavity and the tablet hardness appropriate. Has been continued. Therefore, when a tablet for oral administration is formed, development of a preparation form that can satisfy these conditions is particularly desired.

JP 2003-34655 A JP 2004-26816 A JP 2005-137357 A JP 2010-132653 A WO97 / 47287 WO03 / 074085 WO2005 / 004923 WO2007 / 111375

  It is an object of the present invention to provide an orally disintegrating tablet containing lactic acid bacteria or an extract component thereof as an active ingredient. When the tablet is ingested, the time required for disintegration in the oral cavity is minimal, that is, oral disintegration that rapidly disintegrates in the oral cavity. An orally disintegrating tablet containing lactic acid bacteria or an extract component thereof, which has excellent disintegration, and which has the tablet hardness necessary for retaining the dosage form in the molding, distribution and handling of tablets, and a method for producing the same It is to provide.

  In order to solve the above-mentioned problems, the present inventor, in an orally disintegrating tablet containing lactic acid bacteria or an extract component thereof as an active ingredient, has a minimal time required for disintegration of the tablet in the oral cavity when ingested, that is, the oral cavity In the diligent study of the formulation form that can achieve both the easily disintegrating property in the oral cavity that rapidly disintegrates in the tablet and the tablet hardness conditions necessary for maintaining the dosage form in the molding, distribution, and handling of tablets, a) Effective A granulated product containing lactic acid bacteria or an extract component thereof as an ingredient, and granulated by blending an excipient and / or a wet conditioner; and b) a sugar and / or a sugar alcohol, and containing the lactic acid bacteria or an extract component thereof Lactic acid bacteria or both of which are compatible with both oral disintegration property and tablet hardness required for tablet preparation by mixing and molding with powder for easily disintegrating orally disintegrating tablets not containing Extraction It found that it is possible to produce a content orally disintegrating tablet, thereby completing the present invention.

  That is, conventionally, in the preparation of an orally disintegrating tablet, sugar or sugar alcohol is contained in the tablet, and when it is ingested, the time required for disintegration in the oral cavity is shortened. An orally disintegrating tablet excellent in easily disintegrating in the oral cavity has been used. However, when sugar or sugar alcohol is added to increase the rapid disintegration property of the tablet in the oral cavity, there is a problem that the tablet hardness is practically insufficient, while the tablet hardness is not practically problematic. When it is increased, there is a problem that the rapid disintegration property of the tablet in the oral cavity decreases. Therefore, in the present invention, a granulated product is prepared by blending an active ingredient that is a lactic acid bacterium or an extract component thereof and an excipient and / or a wet conditioner, and contains a sugar and / or a sugar alcohol. It is possible to produce an orally disintegrating tablet having both the easily disintegrating property in the oral cavity and the tablet hardness by mixing and molding the powder for the easily disintegrating orally disintegrating tablet. The headline and the present invention were completed.

  The method for producing an orally disintegrating tablet of the present invention produces an orally disintegrating tablet that has a minimal amount of time required for disintegration in the oral cavity at the time of ingestion, that is, has an easily disintegrating property in the oral cavity that rapidly disintegrates in the oral cavity. It is possible to hold the tablet hardness necessary to hold the dosage form in the molding, distribution, and handling of tablets, and it has excellent oral disintegration and tablet hardness. An orally disintegrating tablet containing lactic acid bacteria or an extracted component thereof as an active ingredient can be provided.

  In the manufacturing method of the orally disintegrating tablet of the present invention, the mixing ratio in the preparation of the orally disintegrating tablet of the granulated product of a) is 5 to 60 parts by mass with respect to 100 parts by mass of the orally disintegrating tablet, b The mixing ratio of the powder for easily disintegrating orally disintegrating tablets is 95 to 40 parts by mass. Moreover, in the manufacturing method of the orally disintegrating tablet of the present invention, the blending ratio of the excipient and / or the wet conditioner in the preparation of the orally disintegrating tablet of the granulated product of a) is the amount of lactic acid bacteria or the amount of the extract component thereof 1 mass. The total amount is 0.1 to 10 parts by mass with respect to parts. Furthermore, in the method for producing an orally disintegrating tablet of the present invention, sugar, starch, starch derivative, cellulose, cellulose derivative and sugar can be used as a preferred embodiment used as an excipient in the preparation of the orally disintegrating tablet of the granulated product of a). One or more selected from the group consisting of alcohol and / or one or more selected from the group consisting of crystalline cellulose, powdered cellulose, croscarmellose sodium and hydroxypropyl starch can be mentioned.

  In addition, in the method for producing an orally disintegrating tablet of the present invention, light anhydrous silicic acid, hydrous silicon dioxide, and metasilicic acid aluminate are used as preferred embodiments for use as a wetting control agent in the preparation of the orally disintegrating tablet of the granulated product of a). One or more selected from the group consisting of sodium can be mentioned. Furthermore, as preferred examples of b) sugar and / or sugar alcohol used in the method for producing an orally disintegrating tablet of the present invention, one or more sugars selected from lactose, sucrose, and maltose, and / or mannitol, Mention may be made of one or more sugar alcohols selected from maltitol, erythritol, sorbitol and xylitol.

  The lactic acid bacteria produced by the method for producing an orally disintegrating tablet of the present invention or its orally extracted component-containing orally disintegrating tablet has a hardness of 20 to 200 N as measured by a tablet hardness meter, and disintegrates as measured by a disintegration tester. It is preferable that the time is adjusted to 0.1 to 4.5 min, preferably 0.4 to 1.0 min. The present invention includes an orally disintegrating tablet containing lactic acid bacteria or its extract components, which retains easily disintegrable in the oral cavity and tablet hardness, and is produced by the method for producing an orally disintegrating tablet of the present invention.

  Specifically, the present invention includes (1) a) a granulated product containing lactic acid bacteria or an extracted component thereof as an active ingredient, and granulated by blending an excipient and / or a wet conditioner; b) Easily disintegrating in the oral cavity and tablet hardness, characterized by mixing and molding powders for easily disintegrating orally disintegrating tablets that contain sugar and / or sugar alcohol, and that do not contain lactic acid bacteria or extract components thereof The mixing ratio in the preparation of the orally disintegrating tablet of the orally disintegrating tablet containing the lactic acid bacterium or its extract component-containing lactic acid bacteria and the granulated product of (2) is based on 100 parts by mass of the orally disintegrating tablet The mixing ratio of the powder for b) easily disintegrating orally disintegrating tablets of 5 to 60 parts by mass is 95 to 40 parts by mass, and easily disintegrating in the oral cavity according to the above (1) And method for producing orally disintegrating tablets containing lactic acid bacteria or extract components thereof retaining tablet hardness , (3) The blending ratio of the excipient and / or the wetting regulator in the preparation of the orally disintegrating tablet of the granulated product of a) is 0.1 in total with respect to 1 part by mass of the lactic acid bacterium or the extract component thereof. It consists of the manufacturing method of the lactic acid bacteria or its extract component containing orally disintegrating tablet which hold | maintained the easily disintegratable oral cavity property and tablet hardness of the said (1) or (2) description characterized by being 10-10 mass parts.

  In addition, the present invention provides (4) a) an excipient in preparation of an orally disintegrating tablet of a granulated product, one or more selected from the group consisting of sugar, starch, starch derivatives, cellulose, cellulose derivatives and sugar alcohols, And / or one or more selected from the group consisting of crystalline cellulose, powdered cellulose, croscarmellose sodium, and hydroxypropyl starch, and easily disintegrating in the oral cavity according to any one of (1) to (3) above As a wet conditioner in the preparation of orally disintegrating tablets containing lactic acid bacteria or its extract components containing the tablet hardness and (5) a granulated product of orally disintegrating tablets, light anhydrous silicic acid, hydrous silicon dioxide And one or more selected from the group consisting of sodium aluminate metasilicate and (1) to (4) above A method for producing a lactic acid bacterium or an extractable ingredient-containing orally disintegrating tablet that retains easily disintegratable in the oral cavity and tablet hardness, and (6) b) sugar and / or sugar alcohol as lactose, sucrose, and maltose Any one of the above (1) to (5), wherein one or more sugars selected and / or one or more sugar alcohols selected from mannitol, maltitol, erythritol, sorbitol, and xylitol are used. It consists of the manufacturing method of the lactic acid bacteria or its extract component containing orally disintegrating tablet holding the oral disintegration property and tablet hardness of description.

  Furthermore, in the present invention, (7) the lactic acid bacterium or its extract component-containing orally disintegrating tablet has a hardness of 20 to 200 N as measured by a tablet hardness meter, and a disintegration time of 0.1 to 0.1 as measured by a disintegration tester. It is adjusted so that it may be 4.5 min of lactic acid bacteria or its extract component-containing orally disintegrating tablet holding the easily disintegratable oral cavity and tablet hardness in any one of said (1)-(6) characterized by the above-mentioned A lactic acid bacterium that retains easily disintegrable in the oral cavity and tablet hardness, or a manufacturing method thereof, and (8) a method for producing an orally disintegrating tablet according to any one of (1) to (7) Consists of orally disintegrating tablets containing extractive components.

  According to the present invention, in an orally disintegrating tablet containing an lactic acid bacterium or an extract thereof as an active ingredient, the time required for disintegration in the oral cavity is minimal upon ingestion, that is, oral disintegration that rapidly disintegrates in the oral cavity. An orally disintegrating tablet containing lactic acid bacteria or an extract component thereof, which has excellent disintegration, and which has the tablet hardness necessary for retaining the dosage form in the molding, distribution and handling of tablets, and a method for producing the same Can be provided.

  The present invention includes a) a lactic acid bacterium or an extract thereof as an active ingredient, and a granulated product granulated by blending an excipient and / or a wet conditioner; and b) a sugar and / or a sugar alcohol. In addition, by mixing and molding a powder for easily disintegrating orally disintegrating tablets that do not contain lactic acid bacteria or its extract components, both the easily disintegrating in the oral cavity and the tablet hardness necessary for the preparation of the tablet are retained, Orally disintegrating orally disintegrating tablets containing the lactic acid bacteria, and a method for producing the same. In the orally disintegrating tablet of the present invention, the lactic acid bacteria or the extract component thereof, the excipient and / or the wet conditioner are mixed, and further, the a) contains the lactic acid bacteria or the extract component thereof, the excipient and And / or a granulated product containing a wetness adjusting agent and b) a powder for an easily disintegrating orally disintegrating tablet containing sugar and / or sugar alcohol and not containing lactic acid bacteria or its extract components. Matching.

  Examples of the lactic acid bacteria that are active ingredients of the orally disintegrating tablet in the present invention include the genus Lactobacillus (Lactobacillus), the genus Bifidobacterium, the genus Enterococcus, the genus Lactococcus, the genus Pediococcus and the genus Leuconostoc Specifically, for example, LC1, LG21 (Lactobacillus gasseri / OLL2716 strain), LGG (Lactobacillus GG strain), L. gasseri SP strain, Bb12 [Bifidobacterium], L. reuteri, L92 Strains (Lactobacillus acidophilus L92 strain), KW3110 (Lactobacillus paracasei KW3110 strain), NY1301 strain [Kasei strain], Yakult (Lactobacillus casei shirota strain), BE80 [Bifidobacterium], BB536 (Bifidobacterium) Umm Longham BB5 36), LB81 and the like. Moreover, 1 type or 2 types or more may be sufficient as the lactic acid bacteria in the orally disintegrating tablet of this invention.

  The extraction component of lactic acid bacteria in the present invention may be any of the above-mentioned extraction components of lactic acid bacteria, and the extraction may be performed according to a conventional method. For example, water or a polar solvent is added to the collected lactic acid bacteria and stirred. If necessary, an insoluble matter is removed by an operation such as filtration or centrifugation, and the solvent is removed and concentrated to obtain an organic solvent extract of lactic acid bacteria. In addition, the lactic acid bacterial cells may be subjected to extraction with a polar solvent without being crushed, or the crushed bacterial cells may be subjected to an extraction treatment or may be extracted while being crushed. The amount of the lactic acid bacterium or the extract component thereof in the orally disintegrating tablet of the present invention is preferably 5 to 40 parts by mass and 10 to 25 parts by mass with respect to 100 parts by mass of the orally disintegrating tablet. It is more preferable.

  Examples of the excipient used in the production of the orally disintegrating tablet of the present invention include one or more selected from sugar, starch, starch derivative, cellulose, cellulose derivative and sugar alcohol, preferably lactose, sucrose. Corn starch, potato starch, crystalline cellulose, powdered cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch, hydroxypropyl starch, mannitol, maltitol and erythritol More preferred is one or more selected from crystalline cellulose, powdered cellulose, croscarmellose sodium and hydroxypropyl starch.

  The wetting conditioner used in the production of the orally disintegrating tablet of the present invention is not particularly limited. For example, a poorly water-soluble inorganic salt (for example, talc, light anhydrous silicic acid, hydrous silicon dioxide, sodium aluminate metasilicate, silica Calcium hydroxide, calcium phosphate, etc.), and preferably, one or more selected from light anhydrous silicic acid, hydrous silicon dioxide and sodium aluminate metasilicate.

  Although it does not specifically limit as sugar used for manufacture of the orally disintegrating tablet of this invention, For example, a monosaccharide, a disaccharide, an oligosaccharide etc. are mentioned. Examples of monosaccharides include glucose, xylose, galactose, and fructose. Examples of the disaccharide include trehalose, lactose, sucrose, maltose, palatinose and the like. Examples of the oligosaccharide include raffinose, inuro-oligosaccharide (chicory oligosaccharide), palatinose oligosaccharide, and cyclic oligosaccharide (for example, cyclodextrin and the like, preferably α-cyclodextrin containing 6, 7 or 8 glucose units, β- Cyclodextrin, γ-cyclodextrin, etc.). The sugar in the present invention may be an anhydride or a hydrate. For example, lactose includes lactose hydrate and anhydrous lactose listed in the Japanese Pharmacopoeia. Examples of the sugar used in the production of the orally disintegrating tablet of the present invention include lactose, sucrose, maltose, or a combination thereof, and more preferably lactose, sucrose, or a combination thereof.

  The starch in the excipient of the present invention is not particularly limited, and examples thereof include corn starch, potato starch, rice starch, wheat starch and the like, or combinations thereof. The starch derivative in the excipient of the present invention is not particularly limited, and examples thereof include pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, sodium carboxymethyl starch, cyclodextrin, and the like, or combinations thereof.

  Although it does not specifically limit as the cellulose in the excipient | filler of this invention, For example, crystalline cellulose, powdered cellulose, etc. or those combinations are mention | raise | lifted. Although it does not specifically limit as a cellulose derivative in the excipient | filler of this invention, For example, croscarmellose sodium, low substituted hydroxypropyl cellulose, carmellose calcium etc., or those combinations are mentioned.

  The sugar alcohol used in the production of the orally disintegrating tablet of the present invention is not particularly limited, and examples thereof include mannitol, maltitol, erythritol, sorbitol, xylitol, and preferably mannitol, maltitol, erythritol. .

  In the production of the orally disintegrating tablet of the present invention, b) powders for orally disintegrating tablets containing sugar and / or sugar alcohol and not containing lactic acid bacteria or extract components thereof are WO97 / 47287 pamphlet and WO2005 / 004923. Of known powders for orally disintegrating tablets, such as pamphlets, JP2003-034655A, and WO2003 / 074085 pamphlets, sugars and / or sugar alcohols must be contained, and lactic acid bacteria or extract components thereof must be contained. Any powder for orally disintegrating tablets may be used, but preferably a powder for orally disintegrating tablets containing a sugar alcohol or saccharide having an average particle size of 30 μm or less and a disintegrant (WO97 / 47287). Pamphlet), for orally disintegrating tablets containing cyclodextrin or cyclodextrin derivatives Powder (see pamphlet WO2005 / 004 923), and the like.

  In the production of the orally disintegrating tablet of the present invention, a) an lactic acid bacterium or an extract component thereof, an excipient and / or a wet condition contained in a granulated product containing an excipient and / or a wet conditioner The total amount of the agent is preferably 0.1 to 10 parts by mass, and 0.5 to 2 parts by mass with respect to 1 part by mass of the lactic acid bacterium contained in the granulated product or its extracted component. Is more preferably 0.75 to 1.5 parts by mass.

  In the production of the orally disintegrating tablet of the present invention, the amount of a granulated product containing a) lactic acid bacteria or an extract component thereof and containing an excipient and / or a wetness adjusting agent is the amount of the orally disintegrating tablet 100. It is preferable that it is 5-60 mass parts with respect to a mass part, and it is more preferable that it is 20-40 mass parts.

  In the production of the orally disintegrating tablet of the present invention, a) a granulated product containing lactic acid bacteria or an extract component thereof and containing an excipient and / or a wet conditioner, other than the excipient and the wet conditioner In addition, for example, a binder (for example, methylcellulose, carboxymethylcellulose, carboxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, dextrin, gum arabic, gelatin, etc.) , Disintegrating agents (eg, crospovidone, bentonite, etc.), lubricants (magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester, polyethylene glycol, sodium lauryl sulfate, etc.), sweeteners (eg, saccharin sodium, Lithylritin dipotassium, aspartame, stevia, thaumatin, etc.), acidulants (eg, citric acid, tartaric acid, malic acid, etc.), antioxidants (eg, tocopherol, ascorbic acid, cysteine hydrochloride, L-ascorbic acid stearate, etc.) , Coloring agents (for example, caramel, edible yellow No. 5, edible red No. 2, edible blue No. 2, carotenoid pigment, tomato pigment, etc.), fragrance (for example, lemon flavor, lemon lime flavor, grapefruit flavor, apple flavor, etc.) May be contained, and these may be used alone or in combination.

  In the production of the orally disintegrating tablet of the present invention, b) powders for orally disintegrating tablets that contain sugar and / or sugar alcohol and do not contain lactic acid bacteria or their extract components contain additives other than sugar and sugar alcohol. For example, starch, starch derivatives, cellulose, cellulose derivatives, sparingly water-soluble inorganic salts (for example, talc, light anhydrous silicic acid, hydrous silicon dioxide, sodium aluminate metasilicate, calcium silicate, calcium phosphate, etc.) , Binders (eg methylcellulose, carboxymethylcellulose, carboxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, dextrin, gum arabic, gelatin etc.), disintegrants (eg crospovidone) Bentonite etc.), lubricants (eg magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester, polyethylene glycol, sodium lauryl sulfate etc.), sweeteners (eg saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin etc. ), Acidulants (eg, citric acid, tartaric acid, malic acid, etc.), antioxidants (eg, tocopherol, ascorbic acid, cysteine hydrochloride, L-ascorbic acid stearate, etc.), colorants (eg, caramel, edible yellow) No. 5, Edible Red No. 2, Edible Blue No. 2, carotenoid pigment, tomato pigment, etc.), flavors (eg lemon flavor, lemon lime flavor, grapefruit flavor, apple flavor, etc.) etc. Al may be used alone, or two or more kinds. In addition, cellulose (eg, crystalline cellulose, powdered cellulose, etc.), cellulose derivatives (eg, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose calcium, etc.), starch (eg, corn starch, pregelatinized starch, partially pregelatinized starch, etc.) Further, starch derivatives (hydroxypropyl starch, carboxymethyl starch sodium, etc.) may be contained as disintegrants.

  In the production of the orally disintegrating tablet of the present invention, b) croscarmellose sodium as a disintegrating agent that can be contained in the powder for orally disintegrating tablets that contains sugar and / or sugar alcohol and does not contain lactic acid bacteria or its extract components Low substituted hydroxypropyl cellulose, hydroxypropyl starch, sodium carboxymethyl starch and crospovidone are preferred, and croscarmellose sodium, low substituted hydroxypropyl cellulose and crospovidone are more preferred.

  In the production of the orally disintegrating tablet of the present invention, a) a granulated product containing a lactic acid bacterium or an extract component thereof and containing an excipient and / or a wet conditioner is, for example, a lactic acid bacterium or an extract component thereof; It is obtained by granulating a mixture containing a dosage form and / or a wetness adjusting agent, and dissolving or partially or all of the excipient and / or the wetness adjusting agent in water or a binder solution used for granulation. It may be suspended and granulated.

  In the production of the orally disintegrating tablet of the present invention, b) a powder for an orally disintegrating tablet which contains sugar and / or sugar alcohol and does not contain lactic acid bacteria or its extractable component is sugar and / or sugar alcohol and the oral cavity. Although it may be a mixture in which an additive that can be contained in a powder for an internally disintegrating tablet is mixed, it is preferably a granulated powder. In the production of the orally disintegrating tablet of the present invention, b) when the powder for orally disintegrating tablet containing sugar and / or sugar alcohol and not containing lactic acid bacteria or its extract component is a granulated powder For example, it can be obtained by granulating sugar and / or sugar alcohol and an additive that can be contained in the powder for orally disintegrating tablets, and c) sugar and / or Part or all of the sugar alcohol and the necessary additives for orally disintegrating tablets may be dissolved or suspended and granulated.

  In the present invention, examples of the granulation method include a wet granulation method and a dry granulation method. Examples of the wet granulation method include an extrusion granulation method (by a screw extrusion granulation device, a roll extrusion granulation device, etc.), a rolling granulation method (a rotating drum type granulation device, a centrifugal rolling granulation device). Etc.), fluidized bed granulation method (with fluidized bed granulator, rolling fluidized bed granulator, etc.), stirring granulation method (with stirring granulator, etc.), etc., preferably stirring granulation Law. In the wet granulation method, it is preferable to use, for example, water, a binder solution or the like as the wetting solution. In the present invention, the binder liquid is a liquid obtained by suspending or dissolving the binder in water or a pharmaceutically acceptable solvent, and the concentration of the binder in the binder liquid is the total mass of the binder liquid. Generally, it is preferably 0.1 to 50 parts by mass, more preferably 0.5 to 20 parts by mass with respect to 100 parts by mass.

  An orally disintegrating tablet of the present invention comprises a) a granulated product containing a) lactic acid bacteria or an extract component thereof, and containing an excipient and / or a wet conditioner, and b) a sugar and / or a sugar alcohol. Is mixed with the powder for orally disintegrating tablets containing no lactic acid bacteria or its extract components, and if desired, the additives that can be contained in the powder for orally disintegrating tablets in the present invention are further mixed with a tableting machine. The tablet can be produced by compression molding. The tablet contains a) a lactic acid bacterium or an extract component thereof in the present invention, a granulated product containing an excipient and / or a wetness adjusting agent, and b) a saccharide and / or a sugar alcohol. Or, after applying film coating to the powder for orally disintegrating tablets that do not contain the extract component, it may be produced by the method of producing tablets in the same manner, but it does not have film coating or has film coating. Even if it is a case, it is preferable that the film coating which disintegrated or melt | dissolved quickly enough to be able to swallow without water is given.

  In the present invention, the tableting machine is not particularly limited, and for example, a tableting machine such as a rotary tableting machine or a hydraulic press machine can be used. Further, for example, a mortar coated with a very small amount of a lubricant such as stearic acid such as stearic acid, magnesium stearate, calcium stearate or a metal salt thereof, sucrose fatty acid ester or glycerin fatty acid ester, hardened oil and fat in advance. You may use the tableting machine which has, and may manufacture a tablet using what is called an external lubrication compression molding method.

  In the present invention, the tablet shape is specifically preferably, for example, a round tablet, a triangular tablet, a cannonball tablet, or the like. The size of the tablet of the present invention is not particularly limited, but is preferably 0.1 to 2 g in terms of mass and 0.3 to 2.0 cm in terms of diameter, for example.

  In the present invention, it is preferable that the tablet has a hardness that does not cause breakage, breakage, or the like. The hardness of the tablet is generally measured as a breaking strength in the diameter direction of the tablet with a tablet hardness meter, but the value is preferably 20 to 200N, more preferably 30 to 150N, and 40 to 100N. Is particularly preferred. The hardness of the tablet can be measured by a commercially available tablet breaking strength measuring machine such as TH-203CP type manufactured by Toyama Sangyo Co., Ltd., NT-40HS type manufactured by Ikeda Rika.

  Hereinafter, the present invention will be described in more detail based on test examples and examples, but the present invention is not limited to these test examples and examples. Lactobacillus paracasei KW3110 lactic acid bacteria (see JP-A-2005-137357) were cultured as an extract component of lactic acid bacteria used in Examples 1 to 10 and Comparative Examples 1 and 2, and water or a polar solvent was added to the collected lactic acid bacteria. In addition, it is an extraction component of lactic acid bacteria (hereinafter referred to as KW lactic acid bacteria extraction component) prepared by stirring, removing insolubles by operation such as filtration or centrifugation as necessary, removing the solvent and concentrating.

[Comparative Example 1]
19 kg of D-mannitol (PEARLITOL 25C, manufactured by Rocket Corporation, the same shall apply hereinafter) and 1 kg of crospovidone (produced by ISP) were charged into a stirring granulator VG-100 (manufactured by Paulek) and mixed for 5 minutes. Thereafter, 4 kg of purified water was added and granulated for 10 minutes. The obtained granulated product was wet-sized using a granulator Comil U-20 (manufactured by QUADRO) and dried using a fluidized bed granulator / dryer GPCG-60 (manufactured by Paulek). The obtained granulated material was sized using a Φ1.0 mm screen using a particle sizer Comil 194S (manufactured by QUADRO) to obtain a powder for an orally disintegrating tablet.

  2.0 g of the KW lactic acid bacteria extract component and 9.9 g of the obtained powder for orally disintegrating tablets were mixed, and then 0.1 g of magnesium stearate (manufactured by Marincklot, the same shall apply hereinafter) was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine (manufactured by Ichibashi Seiki Co., Ltd., hereinafter the same) with a Φ10 mm corner flat tablet mortar at a tablet mass of 300 mg and a tableting pressure of 12 kN.

[Comparative Example 2]
KW lactic acid bacteria extract component 2.0g and β-cyclodextrin (Celdex B, manufactured by Nippon Shokuhin Kako Co., Ltd., hereinafter the same) 9.52g are mixed, and then sucrose fatty acid ester (Ryoto Sugar Ester, manufactured by Mitsubishi Chemical Foods) 0.48 g was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 4 kN.

[Example 1]
5.0 g of KW lactic acid bacteria extract component and 5.0 g of light anhydrous silicic acid (ADSOLIDER 101, manufactured by Freund Corporation) were charged into a small stirring granulator (manufactured by Kyoritsu Kiko Co., Ltd., hereinafter the same) and mixed for 5 minutes. Thereafter, 15.0 g of purified water was added and granulated for 10 minutes. The obtained granulated product is dried at 80 ° C. for 60 minutes in a compact confidential thermostatic chamber (manufactured by Asahi Rika Seisakusho, the same shall apply hereinafter), sieved with a No. 20 sieve, containing an extractive component of lactic acid bacteria, and a moisture regulator. To obtain a granulated product. The resulting granulated product (3.0 g) containing an extract component of lactic acid bacteria and containing a wet conditioner was mixed with 5.91 g of the powder for orally disintegrating tablet obtained in Comparative Example 1, and then stearic acid. 0.09 g of magnesium was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 12 kN.

[Example 2]
KW lactic acid bacteria extract component 5.0g and D-mannitol 5.0g were put into a small stirring granulator and mixed for 5 minutes. Thereafter, 2.0 g of purified water was added and granulated for 10 minutes. The obtained granulated product was dried at 80 ° C. for 60 minutes in a compact confidential thermostatic chamber, sieved with a No. 20 sieve, a granulated product containing an extract component of lactic acid bacteria and containing an excipient. Obtained. The resulting granulated product containing an extract component of lactic acid bacteria and containing excipients was mixed with 5.91 g of the powder for orally disintegrating tablets obtained in Comparative Example 1, and then stearic acid. 0.09 g of magnesium was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 12 kN.

[Example 3]
5.0 g of KW lactic acid bacteria extract component and 5.0 g of low-substituted hydroxypropylcellulose (L-HPC LH-32, manufactured by Shin-Etsu Chemical Co., Ltd.) were put into a small stirring granulator and mixed for 5 minutes. Thereafter, 2.0 g of purified water was added and granulated for 10 minutes. The obtained granulated product was dried at 80 ° C. for 60 minutes in a compact confidential thermostatic bath to obtain a granulated product containing an extract component of lactic acid bacteria and an excipient.
The resulting granulated product containing an extract component of lactic acid bacteria and containing excipients was mixed with 5.91 g of the powder for orally disintegrating tablets obtained in Comparative Example 1, and then stearic acid. 0.09 g of magnesium was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 12 kN.

[Example 4]
5.0 g of KW lactic acid bacteria extract component and 5.0 g of partially pregelatinized starch (Starch 1500, manufactured by Colorcon) were put into a small stirring granulator and mixed for 5 minutes. Thereafter, 2.5 g of purified water was added and granulated for 10 minutes. The obtained granulated product was dried at 80 ° C. for 60 minutes in a compact confidential thermostatic chamber, sieved with a No. 20 sieve, a granulated product containing an extract component of lactic acid bacteria and containing an excipient. Obtained. The resulting granulated product containing an extract component of lactic acid bacteria and containing excipients was mixed with 5.91 g of the powder for orally disintegrating tablets obtained in Comparative Example 1, and then stearic acid. 0.09 g of magnesium was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 12 kN.

[Example 5]
5.0 g of KW lactic acid bacteria extract component and 5.0 g of crystalline cellulose (Theolas KG-1000, manufactured by Asahi Kasei Co., Ltd.) were put into a small stirring granulator and mixed for 5 minutes. Thereafter, 2.5 g of purified water was added and granulated for 10 minutes. The obtained granulated product was dried at 80 ° C. for 60 minutes in a compact confidential thermostatic chamber, sieved with a No. 20 sieve, a granulated product containing an extract component of lactic acid bacteria and containing an excipient. Obtained. The resulting granulated product containing an extract component of lactic acid bacteria and containing excipients was mixed with 5.91 g of the powder for orally disintegrating tablets obtained in Comparative Example 1, and then stearic acid. 0.09 g of magnesium was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 12 kN.

[Example 6]
A granulated product (3.0 g) containing an extract component of lactic acid bacteria obtained in Example 5 and containing an excipient was mixed with 5.91 g of β-cyclodextrin, and then 0.09 g of magnesium stearate was added. Further mixing. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 4 kN.

[Example 7]
5.0 g of KW lactic acid bacteria extract component and 5.0 g of crystalline cellulose (Theolas PH-301, manufactured by Asahi Kasei Co., Ltd.) were put into a small stirring granulator and mixed for 5 minutes. Thereafter, 2.0 g of purified water was added and granulated for 10 minutes. The obtained granulated product was dried at 80 ° C. for 60 minutes in a compact confidential thermostatic chamber, sieved with a No. 20 sieve, a granulated product containing an extract component of lactic acid bacteria and containing an excipient. Obtained. The resulting granulated product containing an extract component of lactic acid bacteria and containing an excipient was mixed with 3.09 g of β-cyclodextrin, and then 0.09 g of magnesium stearate was added and further mixed. The obtained mixture was tableted using a simple tablet molding machine with a Φ10 mm corner flat tablet mortar with a tablet mass of 300 mg and a tableting pressure of 4 kN.

  The compositions of the tablets obtained in Examples 1 to 5 and Comparative Example 1 are shown in Table 1 (composition). Moreover, Table 2 (composition) shows the composition of the tablets obtained in Examples 6 to 7 and Comparative Example 2.

(Evaluation method)
Tablet hardness: Measured twice using a tablet hardness meter PB-301 (manufactured by Japan Machinery) and averaged.
Disintegration test 1: The tablet was placed under the tongue, and the time until complete disintegration was measured with a stopwatch.
Disintegration test 2: Using a disintegration tester NT-40HS (manufactured by Ikeda Rika), the disintegration time was measured and averaged for 2 tablets according to the disintegration test method of the 15th revision Japanese Pharmacopoeia.

  The measurement results of the hardness and disintegration time of the tablets obtained in Examples 1 to 5 and Comparative Example 1 are shown in Table 3 (tablet hardness, disintegration time). Moreover, the measurement results of the hardness and disintegration time of the tablets obtained in Examples 6 to 7 and Comparative Example 2 are shown in Table 4 (tablet hardness, disintegration time).

As is clear from Tables 3 and 4, the tablets obtained in Examples 1 to 6 were excellent in both the time required for disintegration in the oral cavity and the tablet hardness, whereas they were obtained in Comparative Examples 1 and 2. The time required for disintegration in the oral cavity was inferior. Therefore, it was clarified that the orally disintegrating tablet of the present invention is an orally disintegrating tablet excellent in both time required for disintegration in the oral cavity and tablet hardness.
Examples 2 and 5 wherein a) a granulated product containing lactic acid bacteria or an extract component thereof and containing an excipient and / or a wet conditioner contains mannitol and crystalline cellulose as excipients, respectively. The tablet obtained in (1) had more preferable tablet hardness. Therefore, the orally disintegrating tablet of the present invention includes: a) a lactic acid bacterium or an extract component thereof, and a granulated product containing an excipient and / or a wet conditioner, and mannitol, maltitol as excipients. In addition, it has been clarified that one or more selected from erythritol or one or more selected from crystalline cellulose, powdered cellulose, croscarmellose sodium and hydroxypropyl starch can be used to provide a more excellent orally disintegrating tablet.

  Further, a) A granulated product containing lactic acid bacteria or an extract component thereof and containing an excipient and / or a wet conditioner, and containing light anhydrous silicic acid as a wet conditioner, is obtained in Example 1. The tablets had more favorable tablet hardness. Therefore, the orally disintegrating tablet of the present invention comprises: a) a lactic acid bacterium or an extract component thereof, and a granulated product containing an excipient and / or a wet adjuster, and light anhydrous silicic acid as a wet adjuster It has been clarified that when one or more selected from hydrous silicon dioxide and sodium aluminate metasilicate is contained, an even more orally disintegrating tablet is obtained.

[Example 8]
1500 g of KW lactic acid bacteria extract component and 1500 g of crystalline cellulose (Theolas FD-101, manufactured by Asahi Kasei Co., Ltd.) were added to an agitation granulator FM-VG-50 (manufactured by Paulec Co., Ltd.) and mixed. Then, purified water was added and granulated. The obtained granulated product was dried and sieved with a No. 24 sieve to obtain a granulated product containing an extract component of lactic acid bacteria and containing an excipient. Cyclic oligosaccharide (Seldex B-100, manufactured by Nippon Shokuhin Kako Co., Ltd.) 4830 g, caramel (produced by Amano Jitsugyo Co., Ltd.) 21 g, and citric acid (produced by Kyowa Hy-Foods Co., Ltd.) 164.5 g were fluidized bed granulator FLO-5 (Freund Corporation) 980 g of a 5% pullulan (Hayashibara) aqueous solution was sprayed and granulated and dried. The obtained granulated product was dried and sieved with No. 16 sieve to obtain a powder for orally disintegrating tablets.

  1700 g of a granulated product containing an extract component of the obtained lactic acid bacteria and containing an excipient, 4929.8 g of the powder for the orally disintegrating tablet obtained, 102 g of calcium stearate (produced by Taihei Chemical Industrial Co., Ltd.), sweetness 10.2 g of ingredients (Sun Sweet SA8020, manufactured by Saneigen FFI Co., Ltd.) and 68 g of fragrance (X-00843, manufactured by Iwata Fragrance Co., Ltd.) were mixed. The obtained mixture was tableted using a tableting machine HT-AP 15SS-U Hata Seiko Co., Ltd., with a normal R tablet mortar with Φ11 mm at a tablet mass of 400 mg and a tableting pressure of 500 to 600 kgf. . Table 5 shows the composition of the tablet. The tablet hardness of the obtained tablets was 30 to 50 N, and the disintegration time under the tongue was about 3 minutes.

  According to the present invention, in an orally disintegrating tablet containing an lactic acid bacterium or an extract thereof as an active ingredient, the time required for disintegration in the oral cavity is minimal upon ingestion, that is, oral disintegration that rapidly disintegrates in the oral cavity. An orally disintegrating tablet containing lactic acid bacteria or an extract component thereof, which is excellent in disintegration and has the tablet hardness necessary for retaining the dosage form in the molding, distribution and handling of tablets, can be provided. .

Claims (8)

  a) a granulated product containing lactic acid bacteria or an extract thereof as an active ingredient, and granulated by blending an excipient and / or a wet conditioner; and b) containing sugar and / or sugar alcohol, Lactic acid bacteria that retain oral disintegration property and tablet hardness, or its disintegration component-containing oral disintegration, characterized by mixing and molding powders for easily disintegrating orally disintegrating tablets that do not contain the extraction components A method for manufacturing tablets.   The mixing ratio in the preparation of the orally disintegrating tablet of a) the granulated product is 5 to 60 parts by mass with respect to 100 parts by mass of the orally disintegrating tablet, and b) for the easily disintegrating orally disintegrating tablet. The method for producing an orally disintegrating tablet containing lactic acid bacteria or extract components thereof, which retains easily disintegrable in the oral cavity and tablet hardness, according to claim 1, wherein the mixing ratio of the powder is 95 to 40 parts by mass.   The blending ratio of the excipient and / or the wet conditioner in the preparation of the orally disintegrating tablet of the granulated product of a) is 0.1 to 10 parts by mass in total with respect to 1 part by mass of the lactic acid bacteria or the extract component thereof. The method for producing an orally disintegrating tablet containing lactic acid bacteria or extract components thereof, which retains easily disintegratable in the oral cavity and tablet hardness according to claim 1 or 2.   As an excipient in the preparation of orally disintegrating tablets of the granulated product of a), one or more selected from the group consisting of sugar, starch, starch derivatives, cellulose, cellulose derivatives and sugar alcohols, and / or crystalline cellulose, powdered cellulose, One or more selected from the group consisting of croscarmellose sodium and hydroxypropyl starch is used. The lactic acid bacterium having oral disintegrability and tablet hardness, or an extract component thereof, according to any one of claims 1 to 3, A method for producing an orally disintegrating tablet.   2. One or more selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide and sodium aluminate metasilicate is used as a wetting regulator in the preparation of orally disintegrating tablets of the granulated product of a). The manufacturing method of the orally disintegrating tablet containing the lactic acid bacteria or its extract component which hold | maintained the easily disintegrating property in an oral cavity and tablet hardness in any one of -4.   b) As sugar and / or sugar alcohol, one or more sugars selected from lactose, sucrose, and maltose and / or one or more sugar alcohols selected from mannitol, maltitol, erythritol, sorbitol, and xylitol. The method for producing an orally disintegrating tablet containing lactic acid bacteria or extract components thereof, which retains easily disintegratable in the oral cavity and tablet hardness, according to any one of claims 1 to 5.   Lactic acid bacteria or extractable component-containing orally disintegrating tablets are adjusted to have a hardness of 20 to 200 N as measured by a tablet hardness meter and a disintegration time of 0.1 to 4.5 min as measured by a disintegration tester. The method for producing an orally disintegrating tablet containing lactic acid bacteria or its extract components, which retains easily disintegratable in the oral cavity and tablet hardness according to any one of claims 1 to 6. An orally disintegrating tablet containing a lactic acid bacterium or its extract component, which retains easily disintegratable in the oral cavity and tablet hardness, produced by the method for producing an orally disintegrating tablet according to any one of claims 1 to 7.