JP2021169537A - Dry granule, and solid formulation containing dry granule and method for producing the same - Google Patents

Abstract

To provide a dry granule that contains a medicine, particularly a hygroscopic medicine, specifically a crude drug extract and/or a Chinese medicine extract, and presents no problem in production; and a solid formulation containing the dry granule (chewable tablet, intraoral disintegrable tablet or the like); and a method for producing the same.SOLUTION: A dry granule contains (A) a medicine, (B) a silicate compound and (C) dicarboxylate higher alcohol monoester or a salt thereof.SELECTED DRAWING: None

Description

The present invention relates to a dry granulated product obtained from a drug, a silicic acid compound, a dicarboxylic acid higher alcohol monoester or a salt thereof, and a solid preparation such as a chewable tablet or an orally disintegrating tablet containing the dry granulated product. And related to their manufacturing method.

Granulation methods for solid preparations include (1) a wet granulation method in which a solvent is added to granulate powder (Patent Document 1), and (2) a binder that dissolves by heat is added to powder and heated. Examples thereof include a melt granulation method for granulating (Patent Document 2), and (3) a dry granulation method for compressing and granulating powder (Patent Document 3).

Judging from the effects of these granulation methods on drugs, the wet granulation method uses a solvent, is not suitable for drugs that are unstable to the solvent, and requires heat for drying. It has the disadvantage that it is not suitable for heat-unstable drugs. Similarly, the melt granulation method does not use a solvent, but has the disadvantage that it is not suitable for heat-unstable drugs because it requires heat for dissolution. On the contrary, unlike those granulation methods, the dry granulation method has an advantage that it is suitable for a drug that is unstable to a solvent or heat because it does not require a solvent or heat.

However, as described above, the dry granulation method is suitable for drugs that are unstable to solvents and heat, but on the other hand, there is a problem in the fluidity of the powder in addition to the compression formability of the powder. In some cases, an excellent dry granulated product cannot be obtained, and the final form of a solid preparation may not be obtained. In particular, when a herbal extract and / or a Chinese herbal extract, which are hygroscopic drugs, are blended as a drug, the drug in the powder adsorbs water in the air and the adhesiveness of the powder increases, so that the powder becomes There is concern that it will cause problems with fluidity.

Japanese Unexamined Patent Publication No. 2015-134838 Japanese Unexamined Patent Publication No. 2013-10751 Japanese Unexamined Patent Publication No. 2007-33207

The present invention is a dry granulated product containing a drug, particularly a hygroscopic drug, specifically a crude drug extract and / or a Chinese herbal extract, which has no problem in production, and a solid preparation (chewable) containing the dry granulated product. It is an object of the present invention to provide tablets, orally disintegrating tablets, etc.) and methods for producing them.

As a result of intensive studies to solve this problem, the present inventors carry out dry granulation by combining a drug, particularly a hygroscopic drug, specifically a crude drug extract and / or a Chinese herbal extract, with an excipient. At that time, by adding a silicic acid compound and a dicarboxylic acid higher alcohol monoester or a salt thereof as excipients, the fluidity and / or compression moldability can be improved, and a dry granulator can be used. We have found that it is possible to produce excellent dry granules.
Further, after sizing the obtained dry granulated product, an additive is additionally mixed, and further compression molding is performed to obtain a solid preparation such as a chewable tablet and an orally disintegrating tablet having excellent hardness and / or wearability. It was found that the production of

The present invention has been completed based on the above findings, and includes the following dry granulated product, a solid preparation containing the dry granulated product, and a method for producing the same.
[1] A dry granulated product containing (A) a drug, (B) a silicic acid compound, and (C) a dicarboxylic acid higher alcohol monoester or a salt thereof.
[2] The dry granulated product according to the above [1], wherein the drug (A) is a hygroscopic drug.
[3] The dry granulated product according to the above [1] or [2], wherein the drug (A) is a crude drug extract and / or a Chinese herbal extract.
[4] The dry granulated product according to any one of the above [1] to [3], wherein the (B) silicic acid compound is 1% by mass to 90% by mass with respect to the entire dry granulated product.
[5] The above-mentioned [1] to [4], wherein the (C) dicarboxylic acid higher alcohol monoester or a salt thereof is 0.1% by mass to 9% by mass based on the entire dry granulated product. Dry granulated product.
[6] The dry granulated product according to any one of the above [1] to [5], which further contains an excipient.
[7] The dry granulated product according to the above [6], wherein the excipient is at least one selected from the group consisting of sugars, sugar alcohols, and celluloses.
[8] The dry granulated product according to any one of the above [1] to [7], which is for a solid preparation.
[9] The (B) silicic acid compound is at least one selected from the group consisting of synthetic aluminum silicate, light anhydrous silicic acid, and magnesium aluminometasilicate, and the salt of (C) dicarboxylic acid higher alcohol monoester is The dry granule according to any one of the above [1] to [8], which is stearyl sodium fumarate and is for a solid preparation.
[10] A solid preparation containing the dry granulated product according to any one of the above [1] to [9].
[11] The solid preparation according to the above [10], which further contains a binder and / or a disintegrant.
[12] The solid preparation according to the above [11], wherein the binder is at least one selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose.
[13] The solid according to the above [11] or [12], wherein the disintegrant is at least one selected from the group consisting of crospovidone, carmellose, carmellose calcium, croscarmellose sodium, and low-degree-of-substitution hydroxypropyl cellulose. pharmaceutical formulation.
[14] The solid preparation according to any one of the above [10] to [13], which is in the form of a chewable tablet or an orally disintegrating tablet.
[15] (A) The dry granulated product according to any one of the above [1] to [9], or (B) the dry granulated product and the additive according to any one of the above [1] to [9]. A method for producing a solid preparation, which comprises a step of compression molding a mixture containing.
[16] The production method according to the above [15], wherein the additive is a binder and / or a disintegrant.
[17] (A) Chinese herbal extract selected from the group consisting of Shakuyakukanzoto, Tokishakuyakusan, Hochuekkito, and Yokukansan, or Ougi, Ogon, Kanzo, Kikyo, Keigai, Psycho, Saishin, Sansounin, At least one crude drug extract selected from the group consisting of peony, ginger, animal gall, ginger, yokukansan, senkyu, sojutsu, daiou, taiso, chimpi, angelica acutiloba, carrot, hakka, byakujutsu, bukuryo, maou, and renkyo. A solid preparation containing a silicic acid compound and (C) a dicarboxylic acid higher alcohol monoester or a salt thereof and in the form of a chewable tablet or an orally disintegrating tablet.
[18] The solid preparation according to the above [1], wherein (A) is a Chinese herbal extract selected from the group consisting of shakuyakukanzoto, tokishakuyakusan, hochuekkito, and yokukansan.
[19] The solid preparation according to the above [17] or [18], wherein the Chinese herbal extract is shakuyakukanzoto.
[20] The solid preparation according to the above [17] or [18], wherein the Chinese herbal extract is Tokishakuyakusan.
[21] The solid preparation according to the above [17] or [18], wherein the Chinese herbal extract is Hochuekkito.
[22] The solid preparation according to the above [17] or [18], wherein the Chinese herbal extract is yokukansan.
[23] (A) is Ougi, Ogon, Kanzo, Kikyo, Schizonepeta, Psycho, Saishin, Sansonin, Shakuyaku, Shouma, Beast, Shokyo, Sekko, Senkyu, Sojutsu, Daiou, Taisou, Chimpi, Touki, Carrot, The solid preparation according to the above [17], which is at least one crude drug extract selected from the group consisting of Atractylodes lanceolata, Atractylodes lanceolata, Atractylodes lanceolata, Atractylodes lanceolata, and Forsythia.
[24] (A) The crude drug extract is at least one selected from the group consisting of peony, licorice, psycho, peony, ginger, ginger, senkyu, sojutsu, taiso, chimpi, angelica acutiloba, carrot, and bukuryo. 17] The solid preparation according to.
[25] The solid preparation according to any one of [17] to [24] above, which further contains a binder and / or a disintegrant.
[26] The solid preparation according to the above [25], wherein the binder is at least one selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose.
[27] The solid according to the above [25] or [26], wherein the disintegrant is at least one selected from the group consisting of crospovidone, carmellose, carmellose calcium, croscarmellose sodium, and low-degree-of-substitution hydroxypropyl cellulose. pharmaceutical formulation.
[28] The solid preparation according to any one of the above [17] to [27], wherein the (B) silicic acid compound is 1% by mass to 90% by mass with respect to the entire dry granulated product.
[29] The above-mentioned [17] to [28], wherein the (C) dicarboxylic acid higher alcohol monoester or a salt thereof is 0.1% by mass to 9% by mass with respect to the entire dry granulated product. Solid formulation.
[30] The solid preparation according to any one of the above [17] to [29], which further contains an excipient.
[31] The solid preparation according to the above [30], wherein the excipient is at least one selected from the group consisting of sugars, sugar alcohols, and celluloses.
[32] The (B) silicic acid compound is at least one selected from the group consisting of synthetic aluminum silicate, light anhydrous silicic acid, and magnesium aluminometasilicate, and (C) a salt of a dicarboxylic acid higher alcohol monoester. The solid preparation according to any one of the above [17] to [31], which is sodium stearyl fumarate.
[33] The step of compression molding the dry granulated product according to the above [17], or (B) the mixture containing the dry granulated product and the additive according to the above [17]. ]. The method for producing a solid preparation according to.
[34] The production method according to the above [33], wherein the additive is a binder and / or a disintegrant.

By applying the new constitution of the dry granulated product according to the present invention or the method for producing the same, it is possible to satisfactorily obtain the dry granulated product having improved fluidity and / or compression moldability. Further, the solid preparations such as chewable tablets and orally disintegrating tablets containing the dry granulated products obtained by further mixing the additives after sizing the dry granulated products and further compression-molding have appropriate hardness and appropriate hardness. / Or has a degree of abrasion and can also provide a good chewing feeling or mouth melting feeling.

FIG. 1 shows the flake formation rate (%) of Examples 1 to 6 and Comparative Examples 1 to 5. FIG. 2 shows the hardness (N) of Examples 7 to 12. FIG. 3 shows the degree of wear (%) of Examples 7 to 12. FIG. 4 shows the flake formation rate (%) of Examples 13 to 17 and Comparative Examples 6 to 9. FIG. 5 shows the hardness (N) of Examples 18 to 22. FIG. 6 shows the degree of wear (%) of Examples 18 to 22.

Hereinafter, the present invention will be described in detail.
(I) Dry Granulation The dry granulation of the present invention is a dry granulation containing (A) a drug, (B) a silicic acid compound, and (C) a dicarboxylic acid higher alcohol monoester or a salt thereof. .. The "dry granulated product" in the present invention is also referred to as a granular product that does not contain water and / or a binder-containing aqueous solution added from the outside. In the present invention, the dry granulated product may contain flakes and crushed granules thereof, may consist only of flakes and crushed granules thereof, or may consist only of flakes. In the present invention, "flakes" and "molded articles" can be paraphrased with each other. In the dry granulated product of the present invention, for example, (A) drug, (B) silicic acid compound and (C) dicarboxylic acid higher alcohol monoester or a salt thereof are mixed and compression-molded using a dry granulator, etc. Can be manufactured by Commercially available products (A), (B) and (C) may be used, or can be obtained by producing them by a known method. Examples of the dry granulator required for producing the dry granulation product of the present invention include a roller compactor, a pharmacopactor, a chillsonator, and the like, and among these, the roller compactor is particularly preferable. The compression molding pressure during the production of dry granulated products varies depending on the type of dry granulator, but the range is usually 1 to 100 MPa, preferably 2 to 50 MPa, and more preferably 4 to 25 MPa. Is.

The drug (A) in the present invention is not particularly limited, but is preferably a hygroscopic drug, and more preferably a crude drug extract and / or a Chinese herbal extract. Further, the hygroscopic drug used in the present invention means a drug that absorbs more than 3% of water in the air at 25 ° C., 75% RH, and 7 days.
The crude drug extract used in the present invention may be used by oral administration and may be pharmaceutically, pharmacologically, or physiologically acceptable, and is a combination of constituent crude drugs and a blending ratio thereof. There is no particular limitation on the above, and the type of crude drug used for the crude drug extract may be not only a plant-based crude drug but also an animal-based or mineral-based crude drug, but it is particularly described in the Japanese Pharmacopoeia. Crude drugs are preferred. Further, the crude drug extract can be obtained by extracting the extract from the crude drug powder using an organic solvent such as water or ethanol and a mixed solvent thereof, concentrating and drying the extract, and may be extracted from a single crude drug. The mixture may be extracted from a plurality of crude drugs.

Specific examples of crude drug extract raw materials include Asenyaku, Ireisen (Plantago seeds), Uikyo (Plantago seeds), Engosaku (Ginger), Ougi (Ginger), Ougon (Huangyu), Atractylodes lanceolata (Atractylodes lanceolata), Ohi (Sakura bark), Ouren (yellow ream), Onji (distant soul), Gajutsu, Kankyo (dry ginger), Kakkon (Kuzune), Kakkou, Karonin, Kanokosou, Kanzo (licorice), Kamitsure, Kikyo (Kikyou), Kikuka (Kikuhana), Kijitsu (Kijitsu) ), Kyonin (Apricot), Kyokatsu, Kujin (Bitter), Keigai (荊芥), Keihi (Keihi), Gentiana, Kouka (Red Flower), Kobushi (Kabushi), Koubei, Koboku (Park), Goou, Gositsu ( Beef knee), Goshuyu (Wu 茱萸), Goboushi (Beef 蒡子), Gomishi (Gomiko), Psycho (Shibahu), Saishin (Spicy), Sanshishi (Sanjoko), Sanshuyu (Sansho), Sansho (Sansho), Sanzashi (Yamasuko), Sandscon (Yamazukon), Sansounin (Sourjin), Sanyaku (Yamayaku), Sanna (Yamana), Jio (Jihuang), Zion, Shakuyaku, Jakou, Ginger (Masuma), Shitsurishi, Shazenshi, Shazensou , Shajin (shukusha (shrinked sand)), beast ginger (including yutan), ginger (ginger), jiryu (earth dragon), shinii (spicy), jicoppi (earth bone skin), shikon, sexan (stone 蒜), Sekko (plaster), Senega, Senkotsu (river bone), Zenko (maehu), Senkyu, Senburi, Soujutsu (Aoi), Souhakuhi (Kuwashirohide), Soyo (Suha), Daiou (Daio), Taisou, Chikujo, Chikusetsu carrot (Takebushi carrot), Chouji (Choco), Chorei (Inori), Chinpi (Chen skin), Tennansho (Tennansei), Tougashi (Fuyu Ginger), Touki (Toki), Tounin (Momojin), Tokon, Tochu, Nantenjitsu, Carrot (Ginger), Nindou (Shinobi Fuyu), Baimo, Bakumondou, Hacka (Light load), Hange (Half-summer), Byakushi, Byakushaku, Byakujutsu (White 朮), Biwayou (Ginger leaf), Binrouji (Ginger), Bukuryo (茯 蓓), Buttonpi (peony skin), Maou (mao), Mashinin (asakojin), Mokko (wooden incense), Yokuinin, Ryugannik (dragon eye meat), Ryokyo (ginger), Ryukotsu (dragon bone), Ryutan (Ryutan) Ryuji), Rennik (lotus meat), Renkyo (ream), etc.

The Chinese herbal extract used in the present invention may be used by oral administration and may be pharmaceutically, pharmacologically, or physiologically acceptable, and is a combination of constituent crude drugs and a blending ratio thereof. There are no particular restrictions on the above, as well as the "Revised General-Purpose Chinese Medicine Prescription Guide" (supervised by the Japanese Pharmacopoeia Association, edited by the Japanese Pharmacopoeia Herbal Medicine Association, published by Jiho Co., Ltd.) and the "Revised General-Purpose Chinese Medicine Prescription Guide 2010". Japanese Pharmacopoeia using the herbal medicines listed in "April 1st Notification (Additional Additions) Supplementary Edition" (supervised by the Japan Official Publications Association, edited by the Japan Herbal Medicines Association, published by Jiho Co., Ltd.) It can be obtained according to the manufacturing method of the crude drug. The Chinese herbal extract is obtained by extracting an extract from crude drug powder (mainly a mixture of crude drug powder) using an organic solvent such as water or ethanol and a mixed solvent thereof, concentrating the extract, and drying the extract. It may be a mixture of crude drug extracts, or may be extracted from a plurality of crude drugs.

Specific examples of the raw material for the Chinese herbal extract include the following.

The content of the drug (A) is preferably about 1% by mass or more, more preferably about 5% by mass or more, and even more preferably about 10% by mass or more, based on the total amount of the dry granulated product.
The upper limit of the total amount of the dry granulated product is preferably about 90% by mass or less, more preferably about 80% by mass or less, and even more preferably about 70% by mass or less. Further, the drug (A) may be used alone or in combination of two or more.

The (B) silicic acid compound in the present invention includes synthetic aluminum silicate, aluminum silicate such as natural aluminum silicate, magnesium aluminometasilicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, and light anhydrous silicic acid. Examples thereof include heavy anhydrous silicic acid, silicon dioxide, and hydrous silicon dioxide. Of these, aluminum silicate (particularly synthetic aluminum silicate), light anhydrous silicic acid, and magnesium aluminometasilicate are preferable.
The content of the (B) silicic acid compound is preferably about 1% by mass or more, more preferably about 5% by mass or more, and about 10% by mass or more as the lower limit value with respect to the total amount of the dry granulated product. Even more preferable. The upper limit of the total amount of the dry granulated product is preferably about 90% by mass or less, more preferably about 80% by mass or less, and even more preferably about 70% by mass or less. Within the above range, practically sufficient powder moldability can be obtained.

The (C) dicarboxylic acid higher alcohol monoester or a salt thereof in the present invention is not particularly limited as long as it is an ester bond of one molecule of dicarboxylic acid and one molecule of higher alcohol or a salt thereof. The number of carbon atoms of the dicarboxylic acid constituting the ester may be about 3 to 25. The dicarboxylic acid constituting the ester is not particularly limited as long as it is an organic compound having two carboxyl groups, and for example, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and the like. Examples thereof include suberic acid, azelaic acid, sebacic acid, phthalic acid, isophthalic acid and terephthalic acid. The dicarboxylic acid is preferably fumaric acid, maleic acid or the like, and more preferably fumaric acid. The higher alcohol constituting the ester may have about 8 to 22 carbon atoms. The higher alcohol constituting the ester may be a linear alcohol such as lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, or cetostearyl alcohol, and monostearyl glycerin ether (bacyl alcohol), 2. -It may be a branched alcohol such as decyltetradecinol, lanolin alcohol, cholesterol, phytosterol, hexyldodecanol, isostearyl alcohol, octyldodecanol and the like. The ions constituting the salt of the dicarboxylic acid higher alcohol monoester include alkali metal ions such as lithium, sodium, potassium, rubidium, cesium and francium; alkaline earth metal ions such as calcium, strontium, barium and radium; ammonium ions; Examples thereof include organic ions such as phosphonium, pyrrolidinium, and imidazolium. The combination of the dicarboxylic acid constituting the ester and the higher alcohol is not particularly limited, but it is preferable that the ester composed of these or a salt thereof can be used in the pharmaceutical or food pharmaceutical field. The dicarboxylic acid higher alcohol monoester or a salt thereof is particularly preferably stearyl sodium fumarate.
The content of (C) dicarboxylic acid higher alcohol monoester or a salt thereof is preferably about 0.1% by mass or more, preferably about 0.5% by mass or more, with respect to the total amount of the dry granulated product. Is more preferable, and about 1% by mass or more is even more preferable. The upper limit of the total amount of the dry granulated product is preferably about 9% by mass or less, more preferably about 6% by mass or less, and even more preferably about 3% by mass or less. Within the above range, practically sufficient powder fluidity can be obtained.

Mass ratio The mass ratio (A): (B) is not particularly limited, but may be, for example, (1:10) to (100: 1) or (1: 2) to (20: 1). good. The mass ratio (A): (C) is not particularly limited, but may be, for example, (2: 1) to (1000: 1) or (10: 1) to (100: 1). The mass ratio (B): (C) is not particularly limited, but may be, for example, (1000: 1) to (1:20) or (20: 1) to (1: 1). The mass ratio (A) :( B) :( C) is not particularly limited, but may be, for example, 100: (2 to 90) :( 0.1 to 10), and 100: (5 to 90) :( It may be 0.5 to 10), or 100: (10 to 90) :( 1 to 10).

In addition to the above components (A), (B) and (C), the dry granulated product preferably contains an additive commonly used in the field of pharmaceuticals or foods, thereby. It is possible to further improve the moldability and disintegration property of dry granulated products and solid formulations. Additives include binders, disintegrants, excipients, lubricants, colorants, flavoring agents, sweeteners, flavors, preservatives and the like.
Examples of the binder include water-soluble binders such as povidone, hydroxypropyl cellulose, purulan, polyvinyl alcohol / polyethylene glycol graft copolymer, polyvinyl alcohol and copolyvidone, as well as magnesium aluminometasilicate, synthetic aluminum silicate and light anhydrous silicic acid. , Silicic acids such as calcium silicate; insoluble binders such as crystalline cellulose, powdered cellulose, and celluloses such as low-substituted hydroxypropyl cellulose. Examples of excipients include sugar alcohols such as D-mannitol, sorbitol, xylitol, erythritol, powdered reduced starch syrup, candy, and isomalu; lactose hydrate, anhydrous lactose, sucrose, purified sucrose, fructose, glucose, and glucose hydrate. , Sugars such as trehalose; starches such as corn starch, potato starch, wheat starch, rice starch; amino acids such as glycine and alanine. Examples of the lubricant include magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester. Examples of the colorant include edible pigments, edible lake pigments, iron sesquioxide, yellow iron sesquioxide, titanium oxide and the like. Examples of the flavoring agent include citric acid hydrate, tartaric acid, malic acid, ascorbic acid and the like. Examples of the sweetener include aspartame, acesulfame potassium, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, taumatin, sucralose and the like. Examples of the fragrance include uikyo oil, orange oil, chamomile oil, sparemint oil, kehi oil, butterfly oil, peppermint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roma chamomile oil, menthol and the like. Preservatives include benzoic acid, sodium benzoate, benzyl benzoate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, propyl sodium paraoxybenzoate, paraoxybenzoic acid. Methyl, methyl sodium paraoxybenzoate and the like can be mentioned. As the additive, one kind may be used alone, or two or more kinds may be used.

The size of the dry granulated product can be appropriately adjusted according to the purpose of use of the dry granulated product. The average particle size of the dry granulated product may be 0.05 to 3.0 mm, 0.1 to 2.0 mm, or 0.2 to 1.0 mm. The average particle size is, for example, the cumulative 50% average particle size after measuring the particle size distribution using a sieve with an appropriate opening according to the 16th revised Japanese Pharmacopoeia particle size measurement method (second method: sieving method). It is obtained by calculating the diameter. The mass percentage (%) of the molded product (flakes) remaining on the sieve with respect to the total amount of the dry granulated product, that is, the flake formation ratio (%) is preferably 70 or more, more preferably 75 or more, and 80. The above is even more preferable.

The dry granulated product is preferably for a solid formulation. In the present invention, "for solid preparation" means that it has a use as a constituent material of a solid preparation such as a chewable tablet and an orally disintegrating tablet.

(II) Solid preparation and method for producing the same The present invention includes the solid preparation containing the above-mentioned dry granulated product. In order to produce a chewable tablet or an orally disintegrating tablet (hereinafter, abbreviated as "tablet of the present invention") as a solid preparation of the present invention using the above-mentioned dry granulated product, the dry-type preparation of the present invention described above. If necessary, the granules may be compression-molded by additionally mixing additives such as a binder and a disintegrant.
A rotary type lock machine, a single-shot lock machine, or the like can be used for compression molding, and the lock pressure at that time is preferably 1 to 25 kN, more preferably 2 to 20 kN, and even more preferably 4 to 15 kN. .. Further, within this range, the burden on the usuki at the time of locking is small, and it is easy to maintain the locking pressure at the time of locking.

Prior to the above compression molding, the dry granulated product is dried using a fluidized bed dryer, a shelf dryer, etc .; granulation using a screen mill, a jet mill, a hammer mill, a pin mill, etc.; a vibrating sieve is used. If desired, it may be attached to the production of tablets such as sieving.

The tablets of the present invention may be composed substantially only of the above-mentioned dry granulated products, but may also contain other additives such as binders and disintegrants. Even when other additives are contained, the content of the dry granulated product in the tablet of the present invention is preferably about 70% by mass or more, more preferably about 80% by mass or more, with respect to the total amount of the tablet. , About 90% by mass or more is even more preferable. That is, when the tablet of the present invention contains components other than the dry granulated product, the content other than the dry granulated product is preferably about 30% by mass or less, preferably about 20% by mass, with respect to the total amount of the tablet. % Or less is more preferable, and about 10% by mass or less is even more preferable. Within the above range, practically sufficient moldability and disintegration property can be obtained.

Since the tablet of the present invention is produced by further compression-molding the dry granulated product, the shape of the dry granulated product and the shape of the dry granulated product in the tablet of the present invention are usually different.

Binder The tablets of the present invention can contain a binder. The binder has an action of binding the granulated products to each other at the time of compression. Examples of the binder include insoluble binders such as magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, crystalline cellulose, powdered cellulose, and low-substituted hydroxypropyl cellulose. Of these, magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose are preferred.
The content of the binder is preferably about 0.01% by mass or more, more preferably about 0.1% by mass or more, and even more preferably about 1% by mass or more, based on the total amount of the tablets. .. The upper limit of the total amount of tablets is preferably about 30% by mass or less, more preferably about 20% by mass or less, and even more preferably about 10% by mass or less. Within the above range, practically sufficient moldability can be obtained. As the binder, one type may be used alone, or two or more types may be used.

Disintegrant The tablets of the present invention can contain a disintegrant. The disintegrant is a component that swells with water or a component that collapses with water. Disintegrants include crospovidone, carmellose calcium, carmellose, alginic acid, croscarmellose sodium, low-substituted hydroxypropyl cellulose, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and carboxy. Examples include methyl starch sodium. Of these, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, and low-degree-of-substitution hydroxypropyl cellulose are preferred.
The content of the disintegrant is preferably about 0.01% by mass or more, more preferably about 0.1% by mass or more, and even more preferably about 1% by mass or more, based on the total amount of the tablets. .. The upper limit of the total amount of tablets is preferably about 30% by mass or less, more preferably about 20% by mass or less, and even more preferably about 10% by mass or less. Within the above range, practically sufficient disintegration can be obtained. As the disintegrant, one type may be used alone, or two or more types may be used.

Other Additives The tablets of the present invention are additives commonly used in the fields of pharmaceuticals and foods such as binders, excipients, lubricants, colorants, flavoring agents, sweeteners, flavors and preservatives. Can also be included in an appropriate amount. Further, a drug may be contained, and the additive and the drug may be used alone or in combination of two or more.

The size of the tablet of the present invention can be appropriately adjusted according to the purpose of use thereof.

The hardness of the tablet of the present invention can be measured using, for example, a load cell type tablet hardness tester (for example, manufactured by Okada Seiko Co., Ltd.). The lower limit of the hardness of the tablet of the present invention may be 5N or more, 10N or more, 20N or more, 30N or more, or 40N or more. It may be 50 N or more. Further, the upper limit of the hardness of the tablet of the present invention may be 300 N or less, 250 N or less, or 200 N or less.

The degree of abrasion of the tablet of the present invention may be measured using an abrasion degree tester (for example, manufactured by Toyama Sangyo Co., Ltd.) in accordance with the "tablet abrasion degree test method" of the Japanese Pharmacopoeia reference information. Regarding the lower limit of the abrasion degree of the tablet of the present invention, the abrasion degree (%) may be -1.0 or more, -0.5 or more, or -0.1 or more. It may be −0.05 or more. Regarding the upper limit of the abrasion degree of the tablet of the present invention, the abrasion degree (%) may be 1.0 or less, 0.5 or less, or 0.1 or less. It may be 0.05 or less.

Usage The dry granules and tablets of the present invention can be applied in the field of pharmaceuticals or foods. In particular, by applying the tablet of the present invention to the field of pharmaceuticals or foods, it is possible to impart a good chewing feeling to these.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but these are not intended to limit the present invention.

(1-1) Manufacture of dry granulated products (Chinese medicine extract: Shakuyakukanzoto extract)
The dry granulator (manufactured by Freund) shown below used the model "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm].
Example 1
Based on the composition shown in Table 1 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 8.75 g of synthetic aluminum silicate, 26.25 g of crystalline cellulose, 36.55 g of powdered reduced malt sugar water candy and 0.075 g of taumatin. After mixing, 5.25 g of stearyl sodium fumarate was further added and mixed so that the whole became uniform, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) ( A dry granulated product containing a molded product (flakes) was obtained from Freund Co., Ltd.).

Example 2
Based on the composition shown in Table 1 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 71.55 g of synthetic aluminum silicate and 0.075 g of taumatin are mixed, and then 5.25 g of stearyl sodium fumarate is further added. A dry granulation machine (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) was used to obtain a dry granulated product containing a molded product (flakes).

Example 3
Based on the composition shown in Table 1 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 45.3 g of synthetic aluminum silicate, 26.25 g of crystalline cellulose and 0.075 g of taumatin are mixed, and then stearyl fumarate is further mixed. 5.25 g of sodium is added and mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) is used to dry-form the product (flake). Obtained grains.

Example 4
Based on the composition shown in Table 1 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 8.75 g of synthetic aluminum silicate, 62.8 g of crystalline cellulose and 0.075 g of taumatin are mixed, and then stearyl fumarate is further mixed. 5.25 g of sodium is added and mixed, and a dry granulator (roll compression pressure: 5 Mpa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) is used for dry fabrication including a molded body (flakes). Obtained grains.

Example 5
Based on the composition shown in Table 1 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 35 g of synthetic aluminum silicate, 36.55 g of powdered reduced maltose water candy and 0.075 g of taumatin are mixed, and then fumaric acid is further added. Add 5.25 g of stearyl sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry the product (flakes). Granulated material was obtained.

Example 6
Based on the composition shown in Table 1 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 8.75 g of synthetic aluminum silicate, 62.8 g of powdered reduced maltose water candy and 0.075 g of taumatin are mixed, and then further. Add 5.25 g of stearyl silicate, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to separate the molded product (flakes). A dry granulated product containing was obtained.

Comparative Example 1
Based on the composition shown in Table 2 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 71.55 g of crystalline cellulose and 0.075 g of taumatin are mixed, and then 5.25 g of stearyl fumarate is further added and mixed. Then, a dry granulation machine (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) was used to obtain a dry granulated product containing a molded product (flakes).

Comparative Example 2
Based on the composition shown in Table 2 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 71.55 g of powdered reduced maltose water candy and 0.075 g of taumatin were mixed, and then 5.25 g of stearyl sodium fumarate was further added. In addition, they were mixed to obtain a dry granulated product containing a molded product (flakes) with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). ..

Comparative Example 3
Based on the composition shown in Table 2 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 26.25 g of crystalline cellulose, 45.3 g of powdered reduced maltose water candy and 0.075 g of taumatin are mixed, and then fumaric acid is further mixed. Add 5.25 g of stearyl sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry the product (flakes). Granulated material was obtained.

Comparative Example 4
Based on the composition shown in Table 2 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 35 g of crystalline cellulose, 36.55 g of powdered reduced maltose water candy and 0.075 g of taumatin are mixed, and then stearyl fumarate is further mixed. Add 5.25 g, mix, and use a dry granulator (roll compression pressure: 5 Mpa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to perform dry granulation containing the molded product (flakes). I got something.

Comparative Example 5
Based on the composition shown in Table 2 below, 100 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 8.75 g of synthetic aluminum silicate, 26.25 g of crystalline cellulose, 36.55 g of powdered reduced malt sugar water candy and 0.075 g of taumatin. After mixing, 5.25 g of magnesium stearate was further added and mixed, and molded with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). A dry granulated product containing the body (flakes) was obtained.

(2-1) Manufacture of solid product (Chinese medicine extract: Shakuyakukanzoto extract)
The chewable tablets of the present invention were produced using the dry granulated products obtained in Examples 1 to 6.
Example 7
Based on the composition shown in Table 3 below, the dry granulated product obtained in Example 1 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 70.75 g of the product, 3.5 g of calcium carmellose, 1.05 g of magnesium aluminometasilicate and 0.35 g of sucralose were added and mixed, and 0.35 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 8
Based on the composition shown in Table 3 below, the dry granulated product obtained in Example 2 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 70.75 g of the product, 3.5 g of calcium carmellose, 1.05 g of magnesium aluminometasilicate and 0.35 g of sucralose were added and mixed, and 0.35 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 9
Based on the composition shown in Table 3 below, the dry granulated product obtained in Example 3 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 70.75 g of the product, 3.5 g of calcium carmellose, 1.05 g of magnesium aluminometasilicate and 0.35 g of sucralose were added and mixed, and 0.35 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 10
Based on the composition shown in Table 3 below, the dry granulated product obtained in Example 4 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 70.75 g of the product, 3.5 g of calcium carmellose, 1.05 g of magnesium aluminometasilicate and 0.35 g of sucralose were added and mixed, and 0.35 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 11
Based on the composition shown in Table 3 below, the dry granulated product obtained in Example 5 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 70 g of the product, 3.5 g of calcium carmellose, 1.05 g of magnesium aluminometasilicate and 0.35 g of sucralose were added and mixed, and 0.35 g of magnesium stearate was further added and mixed. Tableting was performed with a pressure of 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 12
Based on the composition shown in Table 3 below, the dry granulated product obtained in Example 6 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 70.75 g of the product, 3.5 g of calcium carmellose, 1.05 g of magnesium aluminometasilicate and 0.35 g of sucralose were added and mixed, and 0.35 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

(3-1) Evaluation of physical properties
Dry granulated product <Flake formation rate>
After collecting the dry granulated product for 2 minutes, the whole amount is passed through a 12-mesh sieve (opening: 1.41 mm) to calculate the mass percentage (%) of the molded product (flakes) remaining on the sieve. , A flake formation rate measurement test was conducted.
Solid formulation <hardness>
A hardness measurement test was performed by using a load cell type tablet hardness tester (manufactured by Okada Seiko Co., Ltd.) to set the number of tests to 10 and calculating the average value of the hardness.
<Abrasion degree>
According to the "Tablet Abrasion Test Method" in the Japanese Pharmacopoeia Reference Information, this was carried out using an Abrasion Tester (manufactured by Toyama Sangyo), and 20 tablets were rotated at 25 rotations for 1 minute for 4 minutes to determine the Abrasion degree. By calculating, the abrasion degree measurement test was performed.

(4-1) Test results of physical property evaluation
The composition of the dry granulation of Examples 1 to 6, and dry granules of Comparative Examples 1-5, as well as the test results of the flake formation rate in Tables 1 and 2 below.

As is clear from Tables 1 and 2, in Examples 1 to 6, the flake formation rate of the dry granulated product was as high as 86 to 93%, showing 80% or more. Further, in Comparative Examples 1 to 4, the flake formation rate of the dry granulated product was extremely low at 25 to 67%, and in Comparative Example 5, the fluidity was poor and the adhesiveness was strong, so that the flakes were formed. It was difficult [flake formation impossible].

Solid Formula The composition of the solid pharmaceuticals (chewable tablets) of Examples 7 to 12 and the test results of hardness and abrasion degree are shown in Table 3 below.

In Examples 7 to 12 in Table 3 using Examples 1 to 6 in Table 1, the hardness of the solid preparation (chewable tablet) was 30 N or more (111 to 233 N), and the degree of abrasion was less than 1.0% (abrasion degree). It showed a very good value of −0.05 to 0.05%). Moreover, when the solid preparation (chewable tablet) obtained from Examples 7 to 12 was actually taken, a good chewing feeling could be obtained.

(1-2) Manufacture of dry granules (Chinese extract: Yokukansan extract)
The dry granulator (manufactured by Freund) shown below used the model "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm].
Example 13
Based on the composition shown in Table 4 below, 114 g of hepatic powder extract (manufactured by Nippon Powder Chemicals), 10.5 g of synthetic aluminum silicate, 31.5 g of crystalline cellulose, 49.91 g of powdered reduced malt sugar water candy and 0.09 g of taumatin. After mixing, 6.3 g of stearyl sodium fumarate was further added and mixed, and the mixture was mixed with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). A dry granulated product containing a molded product (flakes) was obtained.

Example 14
Based on the composition shown in Table 4 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 91.91 g of synthetic aluminum silicate and 0.09 g of taumatin are mixed, and then 6.3 g of stearyl sodium fumarate is further added. A dry granulation machine (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) was used to obtain a dry granulated product containing a molded product (flakes).

Example 15
Based on the composition shown in Table 4 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 60.41 g of synthetic aluminum silicate, 31.5 g of crystalline cellulose and 0.09 g of taumatin are mixed, and then stearyl fumarate is further mixed. Add 6.3 g of sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry-form including the molded product (flakes). Obtained grains.

Example 16
Based on the composition shown in Table 4 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 42 g of synthetic aluminum silicate, 49.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then fumaric acid is further mixed. Add 6.3 g of stearyl sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry the product (flakes). Granulated material was obtained.

Example 17
Based on the composition shown in Table 4 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 10.5 g of synthetic aluminum silicate, 81.41 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then further. Add 6.3 g of stearyl silicate, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to separate the molded product (flakes). A dry granulated product containing was obtained.

Comparative Example 6
Based on the composition shown in Table 5 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 91.91 g of crystalline cellulose and 0.09 g of taumatin are mixed, and then 6.3 g of stearyl fumarate is further added and mixed. Then, a dry granulation machine (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) was used to obtain a dry granulated product containing a molded product (flakes).

Comparative Example 7
Based on the composition shown in Table 5 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 91.91 g of powdered reduced maltose water candy and 0.09 g of taumatin were mixed, and then 6.3 g of stearyl fumarate was further added. In addition, they were mixed to obtain a dry granulated product containing a molded product (flakes) with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). ..

Comparative Example 8
Based on the composition shown in Table 5 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 31.5 g of crystalline cellulose, 60.41 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then fumaric acid is further mixed. Add 6.3 g of stearyl sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry the product (flakes). Granulated material was obtained.

Comparative Example 9
Based on the composition shown in Table 5 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 42 g of crystalline cellulose, 49.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then stearyl sodium fumarate is further mixed. Add 6.3 g, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to perform dry granulation including the molded product (flakes). I got something.

Comparative Example 10
Based on the composition shown in Table 5 below, 114 g of hepatic powder extract (manufactured by Nippon Powder Chemicals), 10.5 g of synthetic aluminum silicate, 31.5 g of crystalline cellulose, 49.91 g of powdered reduced malt sugar water candy and 0.09 g of taumatin. After mixing, 6.3 g of magnesium stearate was further added and mixed, and molded with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). A dry granulated product containing the body (flakes) was obtained.

(2-2) Manufacture of solid product (Chinese medicine extract: Yokukansan extract)
The chewable tablets of the present invention were produced using the dry granulated products obtained in Examples 13 to 17.
Example 18
Based on the composition shown in Table 6 below, the dry granulated product obtained in Example 13 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 106.15 g of the product, 5.25 g of calcium carmellose, 1.58 g of magnesium aluminometasilicate and 0.51 g of sucralose were added and mixed, and 0.51 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 19
Based on the composition shown in Table 6 below, the dry granulated product obtained in Example 14 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 106.15 g of the product, 5.25 g of calcium carmellose, 1.58 g of magnesium aluminometasilicate and 0.51 g of sucralose were added and mixed, and 0.51 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 20
Based on the composition shown in Table 6 below, the dry granulated product obtained in Example 15 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 106.15 g of the product, 5.25 g of calcium carmellose, 1.58 g of magnesium aluminometasilicate and 0.51 g of sucralose were added and mixed, and 0.51 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 21
Based on the composition shown in Table 6 below, the dry granulated product obtained in Example 16 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 106.15 g of the product, 5.25 g of calcium carmellose, 1.58 g of magnesium aluminometasilicate and 0.51 g of sucralose were added and mixed, and 0.51 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

Example 22
Based on the composition shown in Table 6 below, the dry granulated product obtained in Example 17 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 106.15 g of the product, 5.25 g of calcium carmellose, 1.58 g of magnesium aluminometasilicate and 0.51 g of sucralose were added and mixed, and 0.51 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 10 mm and a mass of 380 mg.

(3-2) Evaluation of physical properties
Dry granulated product <Flake formation rate>
After collecting the dry granulated product for 2 minutes, the whole amount is passed through a 12-mesh sieve (opening: 1.41 mm) to calculate the mass percentage (%) of the molded product (flakes) remaining on the sieve. A flake formation rate measurement test was performed.
Solid formulation <hardness>
Using a tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), the number of tests was 10 tablets, and the hardness measurement test was performed by calculating the average value of the hardness.
<Abrasion degree>
According to the "Tablet Abrasion Test Method" in the Japanese Pharmacopoeia Reference Information, 20 tablets are rotated at 25 rpm for 4 minutes using an abrasion tester (manufactured by Toyama Sangyo), and the abrasion is calculated. Therefore, the abrasion degree measurement test was carried out.

(4-2) Test results of physical property evaluation
The composition of the dry granulation of Examples 13 to 17, and dry granulation of Comparative Example 6-10, as well as the test results of the flake formation rate in Tables 4 and 5 below.

As is clear from Tables 4 and 5, in Examples 13 to 17, the flake formation rate of the dry granulated product was as high as 84 to 91%, showing 80% or more. Further, in Comparative Examples 6 to 9, the flake formation rate of the dry granulated product was extremely low, 0.12 to 23%, and in Comparative Example 10, the fluidity was poor and the adhesiveness was strong, so that the flakes of the flake It was difficult to form [flakes could not be formed].

Solid Formula The composition of the solid pharmaceuticals (chewable tablets) of Examples 18 to 22 and the test results of hardness and abrasion degree are shown in Table 6 below.

As is clear from Table 6, in Examples 18 to 22, the hardness of the solid formulation (chewable tablet) was 30 N or more (80 to 192 N), and further, in Examples 18 to 22, using the formulation formulation having a high flake formation rate of the dry granulated product. The degree of abrasion was 1.0% or less (0.11 to 0.32%), which was a very good value. Moreover, when the solid preparation (chewable tablet) obtained from Examples 18 to 22 was actually taken, a good chewing feeling could be obtained.

(1-3) Manufacture of dry granules (Chinese extract: Yokukansan extract)
The dry granulator (manufactured by Freund) shown below used the model "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm].
Example 23
Based on the composition shown in Table 7 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 26 g of synthetic aluminum silicate, 77.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then fumaric acid is further mixed. Add 6.3 g of stearyl sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry the product (flakes). Granulated material was obtained.

Example 24
Based on the composition shown in Table 7 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 26 g of light anhydrous silicic acid, 77.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then fumaric acid is further mixed. Add 6.3 g of stearyl sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry the product (flakes). Granulated material was obtained.

Example 25
Based on the composition shown in Table 7 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 26 g of magnesium aluminometasilicate, 77.91 g of powdered reduced malt sugar water candy and 0.09 g of taumatin are mixed, and then Fumaru. Add 6.3 g of stearyl acid acid, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to include the molded product (flakes). A dry granulated product was obtained.

Example 26
Based on the composition shown in Table 7 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 26 g of synthetic aluminum silicate, 77.91 g of D-mannitol and 0.09 g of taumatin are mixed, and then stearyl sodium fumarate is further mixed. Add 6.3 g, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to perform dry granulation including the molded product (flakes). I got something.

Example 27
Based on the composition shown in Table 7 below, 114 g of hepatic powder extract (manufactured by Nippon Powder Chemicals), 26 g of synthetic aluminum silicate, 77.91 g of lactose hydrate and 0.09 g of taumatin are mixed, and then stearyl fumarate is further mixed. Add 6.3 g of sodium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry-form with a molded body (flakes). Obtained grains.

Example 28
Based on the composition shown in Table 7 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 26 g of synthetic aluminum silicate, 77.91 g of isomal and 0.09 g of taumatin are mixed, and then stearyl sodium fumarate is further 6. Add 3 g and mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to prepare a dry granulation product containing a molded product (flakes). Obtained.

Comparative Example 11
Based on the composition shown in Table 8 below, 114 g of yokukansan extract (manufactured by Nippon Powder Chemicals), 26 g of synthetic aluminum silicate, 77.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then calcium stearate is further mixed. Add 6.3 g, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to perform dry granulation including the molded product (flakes). I got something.

Comparative Example 12
Based on the composition shown in Table 8 below, 114 g of hepatic powder extract (manufactured by Nippon Powder Chemicals), 26 g of synthetic aluminum silicate, 77.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then stearate is further mixed. Add 6.3 g of magnesium, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to dry-form including the molded product (flakes). Obtained grains.

(2-3) Manufacture of solid product (Chinese medicine extract: Yokukansan extract)
The chewable tablets of the present invention were produced using the dry granulated products obtained in Examples 23 to 28.
Example 29
Based on the composition shown in Table 9 below, the dry granulated product obtained in Example 23 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 30
Based on the composition shown in Table 9 below, the dry granulated product obtained in Example 24 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 31
Based on the composition shown in Table 9 below, the dry granulated product obtained in Example 25 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 32
Based on the composition shown in Table 9 below, the dry granulated product obtained in Example 26 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 33
Based on the composition shown in Table 9 below, the dry granulated product obtained in Example 27 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 34
Based on the composition shown in Table 9 below, the dry granulated product obtained in Example 28 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

(3-3) Evaluation of physical properties
Dry granulated product <Flake formation rate>
After collecting the dry granulated product for 2 minutes, the whole amount is passed through a 12-mesh sieve (opening: 1.41 mm) to calculate the mass percentage (%) of the molded product (flakes) remaining on the sieve. A flake formation rate measurement test was performed.
Solid formulation <hardness>
Using a tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), the number of tests was 10 tablets, and the hardness measurement test was performed by calculating the average value of the hardness.
<Abrasion degree>
According to the "Tablet Abrasion Test Method" in the Japanese Pharmacopoeia Reference Information, 20 tablets are rotated at 25 rpm for 4 minutes using an abrasion tester (manufactured by Toyama Sangyo), and the abrasion is calculated. Therefore, the abrasion degree measurement test was carried out.

(4-3) Test results of physical property evaluation
The composition of the dry granulation of Examples 23-28, and dry granulation of Comparative Example 11-12, and the test results of the flake formation rate shown in Tables 7 and 8 below.

As is clear from Tables 7 and 8, in Examples 23 to 28, the flake formation rate of the dry granulated product was as high as 88 to 91%, showing 80% or more. Further, in Comparative Examples 11 to 12, it was difficult to form flakes [flakes could not be formed] because the fluidity was poor and the adhesiveness was strong.

Solid Formula The composition of the solid pharmaceuticals (chewable tablets) of Examples 29 to 34, and the test results of hardness and abrasion degree are shown in Table 9 below.

As is clear from Table 9, in Examples 29 to 34 using the formulation formulation having a high flake formation rate of the dry granulated product, the hardness of the solid formulation (chewable tablet) was 30 N or more (44 to 142 N), and further. The degree of abrasion was 1.0% or less (-0.09 to 0.77%), which was a very good value. Moreover, when the solid preparations (chewable tablets) obtained from Examples 29 to 34 were actually taken, a good chewing feeling could be obtained.

(1-4) Manufacture of dry granules (Chinese medicine extract: Shakuyakukanzoto extract, Hochuekkito extract, and Tokishakuyakusan extract)
The dry granulator (manufactured by Freund) shown below used the model "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm].
Example 35
Based on the composition shown in Table 10 below, 80 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 34.5 g of synthetic aluminum silicate, 103.41 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then further. Add 6.3 g of stearyl silicate, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to separate the molded product (flakes). A dry granulated product containing was obtained.

Example 36
Based on the composition shown in Table 10 below, 80 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 34.5 g of magnesium aluminometasilicate, 103.41 g of powdered reduced malt sugar water candy and 0.09 g of taumatin were mixed. Further, 6.3 g of stearyl sodium fumarate was added and mixed, and a molded product (flake) was used in a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). A dry granulated product containing the above was obtained.

Example 37
Based on the composition shown in Table 10 below, 80 g of shakuyakukanzoto extract (manufactured by Alps Pharmaceutical Co., Ltd.), 34.5 g of light silicic acid anhydride, 103.41 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then further. Add 6.3 g of stearyl sodium fumarate, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to separate the molded product (flakes). A dry granulated product containing the mixture was obtained.

Example 38
Based on the composition shown in Table 10 below, 166.8 g of Hochuekkito extract (manufactured by Nippon Powder Chemicals), 12.9 g of synthetic aluminum silicate, 38.21 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed. After that, 6.3 g of stearyl sodium fumarate was further added and mixed, and the compact was molded by a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). A dry granulated product containing (flakes) was obtained.

Example 39
Based on the composition shown in Table 10 below, 166.8 g of Hochuekkito extract (manufactured by Nippon Powder Chemicals), 12.9 g of magnesium aluminometasilicate, 38.21 g of powdered reduced maltose water candy and 0.09 g of taumatin were added. After mixing, 6.3 g of stearyl sodium fumarate was further added and mixed, and molded with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). A dry granulated product containing the body (flakes) was obtained.

Example 40
Based on the composition shown in Table 10 below, 166.8 g of Hochuekkito extract (manufactured by Nippon Powder Chemicals), 12.9 g of light silicic acid anhydride, 38.21 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed. After that, 6.3 g of stearyl sodium fumarate was further added and mixed, and the compact was molded by a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund). A dry granulated product containing (flakes) was obtained.

Example 41
Based on the composition shown in Table 10 below, 150 g of Tokishakuyakusan extract (manufactured by Alps Pharmaceutical Co., Ltd.), 17 g of synthetic aluminum silicate, 50.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then Fumaru. Add 6.3 g of stearyl silicate, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to include the molded product (flakes). A dry granulated product was obtained.

Example 42
Based on the composition shown in Table 10 below, 150 g of Tokishakuyakusan extract (manufactured by Alps Pharmaceutical Co., Ltd.), 17 g of magnesium aluminometasilicate, 50.91 g of powdered reduced malt sugar water candy and 0.09 g of taumatin were mixed, and then further. Add 6.3 g of stearyl sodium fumarate, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to separate the molded product (flakes). A dry granulated product containing was obtained.

Example 43
Based on the composition shown in Table 10 below, 150 g of Tokishakuyakusan extract (manufactured by Alps Pharmaceutical Co., Ltd.), 17 g of light anhydrous silicic acid, 50.91 g of powdered reduced maltose water candy and 0.09 g of taumatin are mixed, and then Fumaru. Add 6.3 g of stearyl acid acid, mix, and use a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Freund) to include the molded product (flakes). A dry granulated product was obtained.

(2-4) Manufacture of solid product (Chinese medicine extract: Shakuyakukanzoto extract, Hochuekkito extract, and Tokishakuyakusan extract)
The chewable tablets of the present invention were produced using the dry granulated products obtained in Examples 35 to 43.
Example 44
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 35 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 45
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 36 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 46
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 37 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 47
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 38 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 48
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 39 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 49
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 40 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 50
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 41 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 51
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 42 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

Example 52
Based on the composition shown in Table 11 below, the dry granulated product obtained in Example 43 was sized with an oscillator-type sizing machine (screen size: 0.8 mm) (manufactured by Freund), and then sized. To 168.225 g of the product, 7.875 g of carmellose calcium, 2.37 g of magnesium aluminometasilicate and 0.765 g of sucralose were added and mixed, and 0.765 g of magnesium stearate was further added and mixed. The tableting pressure was 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable tablet having a diameter of 12 mm and a mass of 600 mg.

(3-4) Evaluation of physical properties
Dry granulated product <Flake formation rate>
After collecting the dry granulated product for 2 minutes, the whole amount is passed through a 12-mesh sieve (opening: 1.41 mm) to calculate the mass percentage (%) of the molded product (flakes) remaining on the sieve. A flake formation rate measurement test was performed.
Solid formulation <hardness>
Using a tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), the number of tests was 10 tablets, and the hardness measurement test was performed by calculating the average value of the hardness.
<Abrasion degree>
According to the "Tablet Abrasion Test Method" in the Japanese Pharmacopoeia Reference Information, 20 tablets are rotated at 25 rpm for 4 minutes using an abrasion tester (manufactured by Toyama Sangyo), and the abrasion is calculated. Therefore, the abrasion degree measurement test was carried out.

(4-4) Test results of physical property evaluation
Dry Granulation The composition of the dry granulation of Examples 35 to 43 and the test results of the flake formation rate are shown in Table 10 below.

As is clear from Table 10, in Examples 35 to 40, the flake formation rate of the dry granulated product was as high as 80% to 91%, showing 80% or more.

Solid Formula The composition of the solid pharmaceuticals (chewable tablets) of Examples 44 to 52, and the test results of hardness and abrasion degree are shown in Table 11 below.

As is clear from Table 11, in Examples 44 to 52 using the formulation formulation having a high flake formation rate of the dry granulated product, the hardness of the solid formulation (chewable tablet) was 30 N or more (37 to 122 N), and further. The degree of abrasion was 1.0% or less (-0.14 to 0.49%), which was a very good value. Moreover, when the solid preparations (chewable tablets) obtained from Examples 44 to 52 were actually taken, a good chewing feeling could be obtained.

The method for producing a dry granulated product using the dry granulation method and a solid preparation having the same as the core according to the present invention is a chewable tablet containing a hygroscopic drug, specifically a crude drug extract and / or a Chinese herbal extract. Furthermore, it enables the industrial large-scale production of orally disintegrating tablets. Moreover, by using this technology, it can be used not only for pharmaceutical products but also for food products.

Claims (18)

(A) Chinese herbal extract selected from the group consisting of Shakuyakukanzoto, Tokishakuyakusan, Hochuekkito, and Yokukansan, or Ougi, Ogon, Kanzo, Kikyo, Keigai, Psycho, Saishin, Sansounin, Peony, Shouma. , Beast gall, ginger, peony, senkyu, sojutsu, daiou, taiso, chimpi, angelica, carrot, peony, biakujutsu, bukuro, maou, and renkyo, at least one crude drug extract selected from the group, (B) Kei A solid preparation containing an acid compound and (C) dicarboxylic acid higher alcohol monoester or a salt thereof and in the form of a chewable tablet or an orally disintegrating tablet. The solid preparation according to claim 1, wherein (A) is a Chinese herbal extract selected from the group consisting of shakuyakukanzoto, tokishakuyakusan, hochuekkito, and yokukansan. (A) The solid preparation according to claim 1 or 2, wherein the Chinese herbal extract is shakuyakukanzoto. (A) The solid preparation according to claim 1 or 2, wherein the Chinese herbal extract is Tokishakuyakusan. (A) The solid preparation according to claim 1 or 2, wherein the Chinese herbal extract is Hochuekkito. (A) The solid preparation according to claim 1 or 2, wherein the Chinese herbal extract is yokukansan. (A) is Ougi, Ogon, Kanzo, Kikyo, Schizonepeta, Psycho, Saishin, Sansounin, Shakuyaku, Shouma, Beast, Shokyo, Sekko, Senkyu, Sojutsu, Daiou, Taisou, Chimpi, Touki, Carrot, Hakka, Byakujutsu The solid preparation according to claim 1, which is at least one crude drug extract selected from the group consisting of Atractylodes lanceolata, Atractylodes lanceolata, and Forsythia. (A) The invention according to claim 1, wherein the crude drug extract is at least one selected from the group consisting of ogi, licorice, psycho, peony, ginger, ginger, senkyu, sojutsu, taiso, chimpi, touki, carrot, and bukuryo. Solid formulation. The solid preparation according to any one of claims 1 to 8, further containing a binder and / or a disintegrant. The solid preparation according to claim 9, wherein the binder is at least one selected from the group consisting of magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose. The solid preparation according to claim 9 or 10, wherein the disintegrant is at least one selected from the group consisting of crospovidone, carmellose, carmellose calcium, croscarmellose sodium, and low-degree-of-substitution hydroxypropyl cellulose. (B) The solid preparation according to any one of claims 1 to 11, wherein the silicic acid compound is 1% by mass to 90% by mass with respect to the entire dry granulated product. (C) The solid preparation according to any one of claims 1 to 12, wherein the dicarboxylic acid higher alcohol monoester or a salt thereof is 0.1% by mass to 9% by mass with respect to the entire dry granulated product. The solid preparation according to any one of claims 1 to 13, further comprising an excipient. The solid preparation according to claim 14, wherein the excipient is at least one selected from the group consisting of sugars, sugar alcohols, and celluloses. The (B) silicic acid compound is at least one selected from the group consisting of synthetic aluminum silicate, light anhydrous silicic acid, and magnesium aluminometasilicate, and the salt of (C) dicarboxylic acid higher alcohol monoester is stearyl fumarate. The solid preparation according to any one of claims 1 to 15, which is sodium. The solid preparation according to claim 1, which comprises a step of compression-molding (A) the dry granulated product according to claim 1 or (B) the mixture containing the dry granulated product and the additive according to claim 1. Manufacturing method. The production method according to claim 17, wherein the additive is a binder and / or a disintegrant.

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