TWI781921B - Dry granulated material and solid preparation containing dry granulated material and method for producing the same - Google Patents

Abstract

By using a dry granulated material containing (A) a drug, (B) a silicic acid compound and (C) dicarboxylic acid higher alcohol mono ester or salt thereof, it is possible to formulat a drug, especially a hygroscopic drug, specially herbal medicine extract and/or traditional Chinese medicine extract, to produce a solid preparation (chewable tablet or oral distinguishable tablet and the like) without problems in production. Further, the present invention provides a method for producing a solid preparation containing a step of compression molding a dry granulate material containing (A) a drug, (B) a silicic acid compound and (C) dicarboxylic acid higher alcohol mono ester or salt thereof, or a mixture comprising the above dry granulated material and other ingredients (addition and the like).

Description

Dry granulation, solid preparation containing the dry granulation, and manufacturing method thereof

The present invention relates to solid preparations such as dry granules obtained from medicines, silicic acid compounds, dicarboxylic acid higher alcohol monoesters or salts thereof, chewable tablets containing the dry granules, oral collapse tablets, and the preparations The manufacturing method.

The granulation method of solid preparations includes (1) wet granulation method (Patent Document 1) in which a solvent is added to the powder to granulate, (2) heating granulation by adding a thermally soluble binder to the powder The melt granulation method (Patent Document 2), (3) the dry granulation method (Patent Document 3) in which the powder is compressed and granulated.

If the granulation method is judged from the influence on the drug, the wet granulation method is not suitable for drugs that are unstable in the solvent because of the use of solvents. In addition, it is not suitable for heating because it must be heated during drying. Disadvantages of heat labile drugs. Similarly, although the melt granulation method does not use a solvent, but, Heating is necessary for dissolution, and it has the disadvantage of being unsuitable for heat-labile drugs. On the contrary, the dry granulation method, which is different from these granulation methods, has the advantage of being suitable for drugs that are unstable to solvents or heat because it does not require the use of solvents and heat.

However, as mentioned above, the dry granulation method is suitable for drugs that are unstable to solvents or heat. Relatively, in addition to powder compression formability, if the fluidity of the powder is not good, superior dry granulation cannot be obtained. Granular matter, unable to reach the final solid preparation form. Especially if the prepared drug is the crude drug extract and/or Chinese herbal extract of a hygroscopic drug, the drug in the powder will absorb the moisture in the atmosphere, which will increase the adhesion of the powder and cause poor fluidity of the powder. .

[Prior Art Literature] [Patent Document]

[Patent Document 1] Japanese Patent Laid-Open No. 2015-134838

[Patent Document 2] Japanese Unexamined Patent Publication No. 2013-10751

[Patent Document 3] Japanese Patent Laid-Open No. 2007-332074

The present invention is to provide a compounded drug, especially a hygroscopic drug, specifically a crude drug extract and/or a herbal extract, which can produce a dry granulated product and a solid preparation containing the dry granulated product. (Chewable tablets, oral collapse tablets, etc.) and their production methods are the subject.

In order to solve the related problems, the inventors of the present invention have repeatedly carried out As a result of in-depth research, it has been found that silicic acid compounds, dicarboxylic acid higher alcohols and Monoesters or their salts are used as excipients to improve fluidity and/or compression formability, and dry granulators can be used to produce superior dry granulated products.

In addition, it has been found that the obtained dry granules are sized and then mixed with additives to further produce solid preparations such as chewable tablets and oral disintegration tablets with excellent hardness and/or friability during compression molding.

The present invention is based on the above findings and includes the following dry granules, solid preparations containing the dry granules, and their production methods.

[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 herbal medicine extract.

[4] The dry granulated product according to any one of [1] to [3] above, wherein the (B) silicic acid compound is 1% by mass to 90% by mass based on the entire dry granulated product.

[5] The dry granulated product according to any one of [1] to [4] above, wherein the (C) dicarboxylic acid higher alcohol monoester or its salt is 0.1 to the whole dry granulated product. % by mass to 9% by mass.

[6] The dry granulated product described in any one of [1] to [5] above, which is further Contains excipients.

[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 as described in any one of [1] to [7] above, which is for solid preparation.

[9] The dry granulated product according to any one of the above [1] to [8], wherein the (B) silicic acid compound is made of synthetic aluminum silicate, light anhydrous silicic acid, and aluminum magnesium silicate At least one selected from the group, (C) salt of higher alcohol monoester of dicarboxylic acid is sodium stearyl fumarate, and it is used for solid preparations.

[10] A solid preparation comprising the dry granulated product described in any one of [1] to [9] above.

[11] The solid preparation as described in [10] above, which further contains a binder and/or a disintegrating agent.

[12] The solid preparation as described in [11] above, wherein the binder is selected from the group consisting of aluminum magnesium metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose At least one of them.

[13] The solid preparation as described in [11] or [12] above, wherein the disintegrating agent is composed of crospovidone, carboxymethylcellulose, carboxymethylcellulose calcium, crosslinked At least one selected from the group consisting of sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose.

[14] The solid preparation according to any one of the above-mentioned [10] to [13], which is in the form of a chewable tablet or an oral collapse tablet.

[15] A method for producing a solid preparation, comprising (A) the dry granulated product described in any one of [1] to [9] above or (B) A step of compression molding a mixture containing the dry granulated product described in any one of the above [1] to [9] and additives.

[16] The production method according to the above [15], wherein the additive is a binder and/or a disintegrating agent.

A novel composition of dry granules can be obtained by the present invention, and dry granules with improved fluidity and/or compression formability can be obtained by applying the production method. In addition, solid preparations such as chewable tablets, oral collapse tablets and other solid preparations containing dry granules obtained by adding mixed additives after granulation and compression molding can also provide appropriate hardness and/or friability and Good chewing or mouth melting.

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 friability (%) 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 friability (%) of Examples 18 to 22.

Hereinafter, the present invention will be described in detail.

(I) dry granulation

The dry granulated product of the present invention is a dry granulated product containing (A) drug, (B) silicic acid compound and (C) dicarboxylic acid higher alcohol monoester or its salt. In addition, the "dry granulated product" of the present invention is also a granulated product that does not contain water and/or an aqueous solution added from the outside. In the present invention, the dry granulated product may contain flakes and their broken particles, may only consist of flakes and their broken particles, or may only consist of flakes. In addition, in the present invention, "sheet" and "molded body" may be used interchangeably. The dry granulated product of the present invention can be produced by, for example, mixing (A) drug, (B) silicic acid compound, and (C) dicarboxylic acid higher alcohol monoester or its salt, and performing compression molding using a dry granulator. Each of (A), (B) and (C) can be a commercially available product, or can be produced by a known method. The dry granulator necessary for producing the dry granulated product of the present invention may include a roller compactor, a pharmaceutical compression granulator (Phamapaktor), and a Chilsonator. good. Also, the compression molding pressure in the production of dry granules varies depending on the type of dry granulator, and generally ranges from 1 to 100 MPa, preferably from 2 to 50 MPa, more preferably from 4 to 25 MPa.

The drug (A) of the present invention is not particularly limited, but is preferably a hygroscopic drug, and more specifically, is a crude drug extract and/or a Chinese herbal medicine extract. In addition, the hygroscopic drug used in the present invention refers to a drug that absorbs more than 3% of the moisture in the air at 25°C, 75% RH, and 7 days.

The crude drug extract used in the present invention can be administered to users by oral administration, as long as it is acceptable in medicine, pharmacology or physiology, and there is no special limitation on the combination of the crude drugs or the blending ratio of the crude drugs. The types of crude drugs used in the extract are not only plant-based crude drugs, but also animal or Mineral crude drugs, however, are preferably crude drugs recorded in the Japanese Pharmacopoeia. In addition, crude drug extracts are obtained by extracting, concentrating, and drying crude drug raw materials using organic solvents such as water, ethanol, or mixed solvents, and may be extracted from a single crude drug, or a mixture thereof, or extracted from a plurality of crude drugs. By.

As raw materials of crude drug extracts, specifically, axianyao, clematis, fennel, corydalis, astragalus, scutellaria, phellodendron, cherry skin, berberine, polygala, zedoary, dried ginger, kudzu root, rhododendron, and coriander , Jicao root, licorice, German chamomile, bellflower, chrysanthemum, citrus aurantium, almond, notopterygium, flavescens, Nepeta, cinnamon, gentian, safflower, Cyperus radix, japonica rice, Magnolia officinalis, Bezoar, Achyranthes bidentata, Evodia, burdock , schisandra, bupleurum, asarum, gardenia, dogwood, pepper, wild hawthorn, mountain bean root, jujube seed, yam, kaempferia, rehmannia, aster, peony, musk, cohosh, tribulus, plantain seed, plantain, sand Ginseng (shrinking sand), animal gallbladder (including bear bile), ginger, earthworm, magnolia, digubark, purple root, lycoris, gypsum, Polygala, Chuangu, Peucedanum, Chuanxiong, Japanese herbal medicine, atractylodes, Morus alba Peel, Perilla, Rhubarb, Jujube, Bamboo Whisk, Bamboo Ginseng, Clove, Polyporus, Tangerine Peel, Araceae, Winter Melon Seeds, Angelica, Peach Kernel, Ipekac, Eucommia, Nantianshi, Ginseng, Honeysuckle, Fritillaria, Ophiopogon japonicus , mint, Pinellia, Angelica dahurica, White peony root, Atractylodes macrocephala, loquat leaves, betel nut, Poria cocos, Moutan bark, ephedra, pockmark kernels, woody fragrance, coix seed, longan meat, galangal, keel, gentian, lotus seeds, forsythia Wait.

The Chinese herbal extract used in the present invention can be administered to the user by oral administration, as long as it is acceptable in medicine, pharmacology or physiology, and there is no special limitation on the herbal medicine combination or its blending ratio. Revision of the guidelines for the general use of Kampo prescriptions" (Nippon Corporation Public Documents Association Supervised, edited by Japan Kampo Herbal Medicine Association, published by Jiho Co., Ltd.) and "Revised Guidelines for Kampo Prescriptions for General Use, Notice on April 1, 2012 (adding additions and subtractions) Corresponding Supplementary Version" (Japanese Foundation The herbal medicines of the Kampo prescriptions recorded in the Kampo Herbal Medicine Association supervised by the Official Documents Association, edited by the Japan Kampo Herbal Medicines Association, and published by Jiwa Co., Ltd., are obtained in accordance with the Japanese Pharmacopoeia extract preparation method, etc. In addition, Chinese herbal extracts can be obtained from crude drug extracts (mainly a mixture of crude drug extracts), using organic solvents such as water, ethanol, and their mixed solvents to extract, concentrate, and dry the extracts. It can be a mixture of crude drug extracts, or It can be an extract extracted from multiple herbal medicines.

As a raw material of a Chinese medicine extract, the following etc. are mentioned specifically,.

Anzhong Powder, Anzhong Powder plus Poria, Weifeng Decoction, Weiling Decoction, Yinchenhao Decoction, Yinchen Wuling Powder, Wuyao Shunqi Powder, Wuling Tongqi Powder, Wenjing Decoction, Wenqing Drink, Wendan Decoction, Yuepi Jiashu Decoction, Yuepi Jiashufu Decoction, Yannian Banxia Decoction, Huangqi Jingpi Wuwu Decoction, Huangqi Jianzhong Decoction, Huangqin Decoction, Yingzhong Powder, Huanglian Ejiao Decoction, Huanglian Jiedu Decoction, Huanglian Decoction, Yizi Decoction, Yizi Decoction Removing Rhubarb, Jieji Shujiao Decoction, Jielaosan, Modified Liangge San (Asada), Modified Liangge San (Gong Tingxian), Huashi Yangpi Decoction, Huoxiangzhengqi San, Gegen Huanglian Huangqin Decoction, Gegen Honghua Decoction, Pueraria Decoction, Pueraria Decoction plus Chuanxiong Xinyi, Modified Wendan Decoction, Modified Guipi Decoction, Modified Jiedu Decoction, Modified Siwu Decoction, Modified Xiaoyao San, Modified Xiaoyao San plus Chuanxiong Dihuang, Modified Pingwei San, Cuanlou Xiongbai Soup, Guilou Xiebai Baijiu Soup, Dried Ginger and Ginseng Pinellia Pills, Licorice Dried Ginger Soup, Licorice Xiexin Soup, Licorice Soup, Licorice Aconite Soup, Ganmai Jujube Soup, Ganlu Drink, Guiqi Jianzhong Soup, Bellflower Soup, Hovenia Erchen Decoction, Guipi Decoction, Xionggui Jiaoai Decoction, Xionggui Tiaoxue Drink, Xionggui Tiaoxue Drink the first addition and subtraction, sound broken flute pills, apricot susan, bitter ginseng soup, dispelling wind and detoxification powder, nine flavor betel nut soup, nepeta forsythia soup, chicken liver pills, cinnamon twig jujube huang xinfu soup, cinnamon yuepi soup, Guizhi plus Astragalus Soup, Guizhi plus Gegen Soup, Guizhi plus Magnolia and Almond Soup, Guizhi plus Peony Ginger and Ginseng Soup, Guizhi plus Shaoyao Dahuang Soup, Guizhi plus Shaoyao Soup, Guizhi plus Shufu Decoction, Guizhi plus Longgu Muli Decoction, Guizhi plus Lingzhufu Decoction, Guipi Shaoyaozhimu Decoction, Guizhi Decoction, Guipi Eryuepi Decoction, Guipi Eryuepi Decoction plus Shufu, Guizhi Ginseng Decoction, Guizhi Fuling Pills , Guizhi Fuling pills with coix seed, Qipi decoction, Jingfangbaidu powder, half of Guima decoction, Jiming powder with Poria cocos, Waitai Siwu decoction with flavor, Jianzhong decoction, Jiazi decoction, Xiangshaping Weisan, Xiangsha Yangwei Decoction, Xiangsha Liujunzi Decoction, Xiangsu Powder, Magnolia Ginger Pinellia Ginseng and Licorice Decoction, Qiju Dihuang Pills, Wuhu Decoction, Nixie Powder, Wuji Powder, Niuche Shenqi Pills, Evodia Decoction, Wuwu Jiedu Powder, Wulin Powder, Wuling Powder, Chaige Jieji Decoction, Chaige Decoction plus Chuanxiong Xinyi, Chaixin Decoction, Bupleurum Pinellia Decoction, Bupleurum Plus Longgu Oyster Soup, Bupleurum Citrus Soup, Bupleurum Guizhi Dried Ginger Decoction, Chaihu Guizhi Decoction, Chaihu Qinggan Decoction, Chaihu Shugan Decoction, Chai Shao Liujunzi Decoction, Chai Su Decoction, Chai Pu Decoction, Chai Ling Decoction, Zuo Tu Gao, Sanhuang Powder, Sanhuang Xiexin Decoction, Suanzao Ren Decoction, Sanwu Huangqin Decoction, Nourishing Yin and Lowering Fire Decoction, Nourishing Yin Zhibao Decoction, Ziyun Paste, Sini Plus Ginseng Decoction, Sini Powder, Sini Decoction, Sijunzi Decoction, Nourishing Blood and Moistening Intestine Decoction, Purple Root Oyster Decoction, Gardenia Ziqi Soup, Gardenia Bopi Soup, Zishen Tonger Soup, Nourishing Kidney and Eyesight Soup, Qiwu Jiangxia Soup, Persimmon Stalk Soup, Siwu Soup, Roasted Licorice Soup, Shaoyao Licorice Soup, Shaoyao Licorice Aconite Soup, Partridge Soup, Cnidium Decoction, Shiquan Dabu Decoction, Shiwei Baidu Decoction, Runchang Decoction, Steamed Eye Decoction, Ginger Xiexin Decoction, Xiaojianzhong Decoction, Xiaochaihu Decoction, Xiaochaihu Decoction plus Campanulaceae Gypsum, Xiaochengqi Decoction , Xiaoqinglong Decoction, Xiaoqinglong Decoction plus Almond Gypsum, Xiaoqinglong Decoction plus Gypsum, Xiaoxuanming Soup, Jiaomei Decoction, Xiaobanxiajia Fuling Decoction, Xiaofeng Powder, Cimicifuga Gegen Decoction, Xiaoyao Powder, Siling Decoction, Xinyi Qingfei Decoction, Gentiana Qianghuo Decoction, Gentiana Fangfeng Decoction, Shenxian Taiyi Cream, Shensu Drink, Mysterious Decoction, Zhenwu Decoction, Shenling Baizhu Powder, Qingji Anhuan Decoction, Qingshi Huatan Decoction, Qingshang Juantong Decoction, Qingshangfangfeng Decoction, Qingshu Yiqi Decoction, Qingxin Lotus Seed Drink, Qingre Tonifying Qi Decoction, Clearing Heat Buxue Decoction, Qingfei Decoction, Zhe Chong Drink, Xigan Mingmu Decoction, Chuanxiong Tea Blending Powder, Qianjin Jiming Powder, Qianjin Neituo Powder, Chuansijunzi Decoction, Qianshi Baizhu Powder, Xuming Decoction, Shujing Huoxue Decoction, Su Zijiangqi Decoction, Rhubarb Licorice Decoction, Rhubarb Fuzi Decoction, Rhubarb Moutan Peel Decoction, Dajianzhong Decoction, Da Bupleurum Decoction, Da Bupleurum Decoction to remove rhubarb, Dabanxia Decoction, Dafangfeng Decoction, Alisma Decoction, Bamboo Decoction Ruwendan Decoction, Bamboo Leaf Gypsum Decoction, Treatment of Dapu, Treatment of Head Sores, Treatment of Head Sores, Rhubarb, Zhibai Dihuang Pills, Zhonghuang Paste, Zhongjianzhong Decoction, Tiaowei Chengqi Decoction, Clove Persimmon Di Decoction, Diao Teng San, Zhu Ling Decoction, Zhu Ling Decoction combined with Siwu Decoction, Tongdao San, Dingpal Drink, Taohe Chengqi Decoction, Danggui Yinzi, Danggui Jianzhong Decoction, Danggui Powder, Danggui Sini plus Evodia Ginger Decoction, Danggui Sini Decoction, Danggui Shaoyao Powder, Danggui Shaoyao Powder plus Huangqin Fishing Teng, Danggui Shaoyao Powder plus Ginseng, Danggui Shaoyao Powder plus Aconite, Danggui Decoction, Danggui Fritillaria Kushen Pills, Duhuo Pueraria Decoction, Duhuo Huotang, Ershu Decoction, Erchen Decoction, Goddess Powder, Ginseng Soup, Ginseng Yangrong Soup, Paifu Powder, Paifu Powder and Soup, Paifu Soup, Maimendong Soup, Bajie San, Bawei Dihuang Pills, Bawei Weixianqi Recipe, Banxia Houpu Decoction, Banxia Powder and Decoction, Banxia Xiexin Decoction, Banxia Baizhu Tianma Decoction, Baizhu Fuzi Decoction, Baihujia Guizhi Decoction, Baihujia Ginseng Decoction, Baihu Decoction, Baihu Decoction, Buchang Jinzhengqi Powder . Powder, Fenxiao Decoction, Pingwei Powder, Fangji Huangqi Decoction, Fangji Poria Decoction, Fangfeng Tongsheng San, Buqi Jianzhong Decoction, Buzhong Yiqi Decoction, Bufei Decoction, Buyang Huanwu Decoction, Bentun Decoction (Golden Chamber Synopsis), Bentun Decoction (behind the elbow), Mahuang Decoction, Mahuang Fuzi Xixin Decoction, Maxing Ganshi Decoction, Maxing Coix Gan Decoction, Maziren Pills, Weimai Dihuang Pills, Minglang Drink, Mufangji Decoction, Yang Baisan, Coix Ren Decoction, Coix Fuzi Baijiang San, Yigan San, Yigan San plus Shaoyaohuanglian, Yigan San plus Chenpi Pinellia, Liujunzi Decoction, Lixiao San, Longdan Xiegan Decoction, Linggan Jiang Weixin Xiaren Decoction, Ling Jiangshugan Decoction, Linggui Ganzao Decoction, Linggui Zhugan Decoction, Linggui Weigan Decoction, Lize Tongqi Decoction, Lize Tongqi Decoction plus magnolia, Lianzhuyin, Liuwei Wan.

For the total amount of the dry granulated product, the lower limit of (A) drug content is preferably at least about 1% by mass, more preferably at least about 5% by mass, most preferably at least about 10% by mass.

Also, the upper limit is preferably at most about 90% by mass, more preferably at most about 80% by mass, most preferably at most about 70% by mass, with respect to the total amount of the dry granulated product. In addition, (A) drugs may be used alone or in combination of two or more.

The (B) silicic acid compound of the present invention includes synthetic aluminum silicate, aluminum silicate such as natural aluminum silicate, aluminum magnesium metasilicate, calcium silicate, magnesium silicate, magnesium aluminum silicate, light anhydrous silicic acid, Heavy anhydrous silicic acid, silicon dioxide, hydrated silicon dioxide, etc. Among them, aluminum silicate (especially synthetic aluminum silicate), light anhydrous silicic acid, and aluminum magnesium metasilicate are preferred.

The lower limit of the content of the (B) silicic acid compound is preferably at least about 1% by mass, more preferably at least about 5% by mass, most preferably at least about 10% by mass of the total amount of the dry granulated product. Also, with respect to the total amount of the dry granulated material, the upper limit is preferably at most about 90% by mass, preferably at most about 80% by mass, most preferably at most about 70% by mass. Mass% or less. As long as it is within the above range, practically sufficient powder formability can be obtained.

The (C) dicarboxylic acid higher alcohol monoester or salt thereof in the present invention is not particularly limited as long as one molecule of dicarboxylic acid and one molecule of higher alcohol are ester-bonded or the salt thereof. The dicarboxylic acid constituting the ester may have about 3 to 25 carbon atoms. The dicarboxylic acid constituting the ester is not particularly limited as long as it is an organic compound having two carboxyl groups, and examples thereof include fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, and adipic acid , pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid, etc. The dicarboxylic acid is preferably fumaric acid, maleic acid, etc., more preferably fumaric acid. The higher alcohol constituting the ester may have about 8 to 22 carbon atoms. The higher alcohols constituting the esters can be linear alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetearyl alcohol, etc., and can also be glycerol monostearyl ether (squalyl alcohol). Hepatic Alcohol), 2-Decyltetradecanol, Lanolin Alcohol, Cholesterol, Phytosterol, Hexyldodecanol, Isostearyl Alcohol, Octyldodecanol and other branched chain alcohols. The ions constituting the salt of the dicarboxylic acid higher alcohol monoester include alkali metal ions such as lithium, sodium, potassium, rubidium, cesium, and argonium; alkaline earth metal ions such as calcium, strontium, barium, and radium; ammonium ions; phosphonium, pyrrolidine, etc. Onium, imidazolium and other organic ions, etc. The combination of dicarboxylic acid and higher alcohol constituting the ester is not particularly limited, and the ester or its salt formed by such formation is preferably used in the field of medicine or food preparation. The dicarboxylic acid higher alcohol monoester or its salt is preferably sodium stearyl fumarate.

Also, the lower limit of the content of (C) higher alcohol monoester of dicarboxylic acid or its salt is preferably at least about 0.1% by mass, more preferably at least about 0.5% by mass, most preferably at least about 1 Mass% or more. Also, for dry granulation The total amount of the substance, the upper limit is preferably at most about 9% by mass, more preferably at most about 6% by mass, most preferably at most about 3% by mass. As long as it is within the above range, practically sufficient powder fluidity can be obtained.

mass ratio

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

In addition to the above-mentioned (A) component, (B) component and (C) component, the dry granulation preferably contains additives commonly used in the field of pharmaceuticals or food, so that the dry granulation and solid Formability and collapsibility of preparations. Additives include binders, disintegrating agents, excipients, lubricants, coloring agents, flavoring agents, sweeteners, spices, preservatives, etc.

Adhesives include water-soluble adhesives such as povidone, hydroxypropyl cellulose, pullulan, polyvinyl alcohol/polyethylene glycol/graft copolymer, polyvinyl alcohol, copovidone, and partial silicon Aluminum magnesium acid, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate and other silicic acids; crystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose and other cellulose-based insoluble binders. Examples of excipients include sugar alcohols such as D-mannitol, sorbitol, xylitol, erythritol, powdered reduced maltose syrup, and isomalt; lactose hydrate, anhydrous lactose, White sugar, refined white sugar, fructose, glucose, glucose hydrate, trehalose and other sugars; corn starch, potato starch, wheat starch, rice starch and other starches; amino acids such as glycine and alanine, etc. Lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and the like. Examples of the coloring agent include food coloring, food lake coloring, ferric oxide, yellow ferric oxide, titanium oxide, and the like. Examples of flavoring agents include citric acid hydrate, tartaric acid, malic acid, and ascorbic acid. Examples of sweeteners include aspartame, acesulfame potassium, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, and sucralose. Fragrances include anise oil, orange peel oil, chamomile oil, spearmint oil, cinnamon oil, clove oil, peppermint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, Roman chamomile oil, menthol, etc. . Preservatives include benzoic acid, sodium benzoate, benzyl benzoate, isobutyl p-hydroxybenzoate, isopropyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, butyl p-hydroxybenzoate, p-hydroxybenzoic acid Propyl ester, sodium propylparaben, methylparaben, sodium methylparaben, etc. One type of additive may be used alone, or two or more types may be used.

The size of the dry granules can be adjusted appropriately according to the purpose of use of the dry granules. 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. In addition, the average particle size can be obtained by calculating the cumulative 50% average particle size after measuring the particle size distribution using a sieve with appropriate meshes according to the particle size measurement method (second method: screening method) of the Japanese Pharmacopoeia Revised 16th, for example. For the total amount of dry granulation, the mass percentage (%) of the formed body (flake) remaining on the sieve, that is, the flake formation rate (%), is preferably at least 70, more preferably at least 75, and most preferably at least 80.

Dry granules are preferably used for solid preparations. In the present invention, "for solid preparations" refers to the use as a constituent material of solid preparations such as chewable tablets or oral collapse tablets.

(II) Solid preparation and its manufacturing method

The present invention includes a solid preparation comprising the above-mentioned dry granulation. The above-mentioned dry granulation is used to manufacture the chewable tablet or the oral disintegrating tablet of the solid preparation of the present invention (hereinafter referred to as "the tablet of the present invention"), as long as the above-mentioned dry granulation of the present invention is added if necessary. Mix additives such as binders and collapsing agents, and then compress and shape.

Compression molding can use a rotary ingot machine, a single ingot machine, etc. The ingot pressure at this time is preferably 1 to 25 kN, more preferably 2 to 20 kN, most preferably 4 to 15 kN. Also, as long as it is within this range, the burden on the mortar and pestle during ingot beating is small, and the ingot pressure during ingot beating can be easily maintained.

In addition, before the above-mentioned compression molding, the dry granulated material can be dried using a fluidized bed dryer, a shed dryer, etc.; a sieve mill, a jet mill, or a hammer mill can be used in the manufacture of tablets according to expectations. , Corner column grinder, etc.; use vibrating sieve to sieve and other operations.

The lozenge of the present invention can be composed of only the above-mentioned dry granules in essence, but it can also contain other additives such as binders and disintegrating agents. Even in the case of containing other additives, the lower limit of the dry granulation content in the tablet of the present invention is preferably at least about 70% by mass, more preferably at least about 80% by mass, most preferably at least about 80% by mass of the total amount of the tablet. More than 90% by mass. That is, when the tablet of the present invention contains ingredients other than dry granules, for The upper limit of the total amount of the tablet, other than dry granules, is preferably at most about 30% by mass, more preferably at most about 20% by mass, most preferably at most about 10% by mass. As long as it is in the above-mentioned range, practically sufficient formability and collapsibility can be obtained.

Also, since the tablet of the present invention is produced by separately compressing the dry granulated product, the shape of the dry granulated product is usually different from that of the dry granulated product in the tablet of the present invention.

Adhesive

The lozenges of the present invention may contain a binder. The binder has the effect of combining the granules with each other during compression. Binders include insoluble binders such as aluminum magnesium metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, crystalline cellulose, powdered cellulose, and low-substituted hydroxypropyl cellulose. Among them, aluminum magnesium metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate and crystalline cellulose are preferred.

Also, the lower limit of the binder content is preferably at least about 0.01% by mass, more preferably at least about 0.1% by mass, most preferably at least about 1% by mass, with respect to the total amount of the tablet. Also, the upper limit is preferably at most about 30% by mass, more preferably at most about 20% by mass, most preferably at most about 10% by mass, with respect to the total amount of the tablet. As long as it is within the above range, practically sufficient formability can be obtained. One type of binder may be used alone, or two or more types may be used.

Collapsing agent

The lozenges of the present invention may contain disintegrants. The disintegrating agent contains water to make it expand Ingredients or ingredients that contain water to cause disintegration. Disintegrating agents include crospovidone, carmellose calcium, carboxymethyl cellulose, alginic acid, croscarmellose sodium, low-substituted hydroxypropyl cellulose, corn starch, and potato starch , wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, sodium carboxymethyl starch, etc. Among them, crospovidone, carboxymethyl cellulose, carmellose calcium, croscarmellose sodium, and low-substituted hydroxypropyl cellulose are preferred.

Also, the lower limit of the disintegrating agent content is preferably at least about 0.01% by mass, more preferably at least about 0.1% by mass, most preferably at least about 1% by mass with respect to the total amount of the tablet. Also, the upper limit is preferably at most about 30% by mass, more preferably at most about 20% by mass, most preferably at most about 10% by mass, with respect to the total amount of the tablet. As long as it is within the above range, practically sufficient collapse properties can be obtained. The disintegrating agents may be used alone or in combination of two or more.

other additives

The lozenge of the present invention may contain an appropriate amount of additives commonly used in the pharmaceutical or food fields, such as binders, excipients, lubricants, coloring agents, flavoring agents, sweeteners, fragrances, and preservatives. In addition, a drug may be contained, and each of the additive and the drug may be used alone or in two or more types.

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

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

The friability of the tablet of the present invention can be measured using a friability tester (for example, manufactured by Toyama Sangyo Co., Ltd.) according to the "Test method for tablet friability" in the Japanese Pharmacopoeia Reference Information. The lower limit of the friability of the tablet of the present invention, the friability (%) can be above -1.0, above -0.5, above -0.1, or above -0.05. The upper limit of the friability of the tablet of the present invention, the friability (%) can be below 1.0, below 0.5, below 0.1, or below 0.05.

Instructions

The dry granulation and lozenge of the present invention can be applied in the field of medicine or food. In particular, the lozenge of the present invention can impart a good chewing sensation when applied to the field of medicine or food.

[Example]

Hereinafter, examples and comparative examples are given to describe the present invention in more detail, but the present invention is not limited to these examples.

(1-1) Manufacture of dry granulation (Kampo extract: peony licorice decoction extract)

The type "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm] used in the dry granulator shown below (manufactured by Freund Co., Ltd.).

Example 1

Based on the composition shown in Table 1 below, the extract of Shaoyao Gancao Decoction (Manufactured by Alps Pharmaceutical Industry Co., Ltd.) 100g, 8.75g of synthetic aluminum silicate, 26.25g of crystalline cellulose, 36.55g of powdered reduced maltose syrup and 0.075g of thaumatin, and then add stearyl fumaric acid Mix 5.25g of sodium to make the whole composition uniform, and obtain a molded body containing ( flakes) dry granulation.

Example 2

Based on the composition shown in Table 1 below, 100 g of Shaoyao Gancao Tang extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 71.55 g of synthetic aluminum silicate, and 0.075 g of thaumatin were mixed, and stearyl fumaric acid was added. Sodium 5.25g is mixed, with dry-type granulator (roller compression pressure: 5MPa, roller rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Feinde Company), obtain the dry-type granulation containing molded body (flake). particulate matter.

Example 3

Based on the composition shown in Table 1 below, mix 100 g of Shaoyao Gancao Tang extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 45.3 g of synthetic aluminum silicate, 26.25 g of crystalline cellulose, and 0.075 g of thaumatin, and then add 5.25 g of sodium stearyl fumarate was mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Corporation) was used to obtain a molded body containing (Flake) dry granulation.

Example 4

Based on the composition shown in Table 1 below, mix 100 g of Shaoyao Gancao Decoction (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 8.75 g of synthetic aluminum silicate, 62.8 g of crystalline cellulose, and 0.075 g of thaumatin, and then add 5.25 g of sodium stearyl fumarate was mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Corporation) was used to obtain a molded body containing (Flake) dry granulation.

Example 5

Based on the composition shown in Table 1 below, mix 100 g of Shaoyao Gancao Tang extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 35 g of synthetic aluminum silicate, 36.55 g of powdered reduced maltose syrup, and 0.075 g of thaumatin, and then add 5.25 g of sodium stearyl fumarate was mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Corporation) was used to obtain a molded body containing (Flake) dry granulation.

Example 6

Based on the composition shown in Table 1 below, 100 g of Shaoyao Gancao Tang extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 8.75 g of synthetic aluminum silicate, 62.8 g of powdered reduced maltose syrup, and 0.075 g of thaumatin were mixed. Add 5.25 g of sodium stearyl fumarate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain the granulation containing Dry granulation of body (flake).

Comparative example 1

Based on the composition shown in Table 2 below, mix 100 g of Shaoyao Gancao Tang extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 71.55 g of crystalline cellulose, and 0.075 g of thaumatin, and then add sodium stearyl fumarate Mix 5.25g of it, and obtain dry granulation containing shaped bodies (flakes) with a dry granulator (roller compression pressure: 5MPa, roller rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Frynd Company) things.

Comparative example 2

Based on the composition shown in Table 2 below, mix 100 g of Shaoyao Gancao Decoction Extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 71.55 g of powdered reduced maltose syrup, and 0.075 g of thaumatin, and then add stearyl fumaric acid Sodium 5.25g is mixed, with dry-type granulator (roller compression pressure: 5MPa, roller rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Feinde Company), obtain the dry-type granulation containing molded body (flake). particulate matter.

Comparative example 3

Based on the composition shown in Table 2 below, mix 100 g of Shaoyao Gancao Tang extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 26.25 g of crystalline cellulose, 45.3 g of powdered reduced maltose syrup, and 0.075 g of thaumatin, and then add 5.25 g of sodium stearyl fumarate was mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Corporation) was used to obtain a molded body containing (Flake) dry granulation.

Comparative example 4

Based on the composition shown in Table 2 below, 100 g of Paeoniae Glycyrrhizae Decoction (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 35 g of crystalline cellulose, 36.55 g of powdered reduced maltose syrup, and 0.075 g of thaumatin were mixed, and hard Sodium fatty acid fumarate 5.25g is mixed, with a dry granulator (roll compression pressure: 5MPa, roll rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain a molded body containing ( flakes) dry granulation.

Comparative Example 5

Based on the composition shown in Table 2 below, 100 g of Shaoyao Gancao Decoction (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 8.75 g of synthetic aluminum silicate, 26.25 g of crystalline cellulose, 36.55 g of powdered reduced maltose syrup, and thaumatin After mixing 0.075g, add 5.25g of magnesium stearate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), A dry granulation containing shaped bodies (flakes) is obtained.

(2-1) Manufacture of solid preparations (Kampo extract: peony licorice decoction extract)

The dry granules obtained in Examples 1 to 6 were used to manufacture chewable tablets of the present invention.

Example 7

Based on the composition shown in Table 3 below, the dry granulated material obtained in Example 1 was sized with an oscillating granulator (sieve size: 0.8 mm) (manufactured by Floyd Co., Ltd.), and the granulated material was Add 3.5g of carboxymethyl cellulose calcium, 1.05g of aluminum magnesium metasilicate and 0.35g of sucralose to 70.75g, mix them, and add 0.35 g of magnesium stearate was mixed, and ingotized with a rotary ingot machine (ingot pressure: 10 kN) (manufactured by Kikusui Seisakusho) to obtain a chewable ingot with 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 material obtained in Example 2 was sized with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd Co., Ltd.), and the granulated material was Add 3.5g of carboxymethylcellulose calcium, 1.05g of aluminum magnesium metasilicate and 0.35g of sucralose to 70.75g, mix it, and add 0.35g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with 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 material obtained in Example 3 was sized with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd Co., Ltd.), and the granulated material was Add 3.5g of carboxymethylcellulose calcium, 1.05g of aluminum magnesium metasilicate and 0.35g of sucralose to 70.75g, mix it, and add 0.35g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 10 mm and a mass of 380 mg.

Example 10

Based on the composition shown in Table 3 below, the result obtained in Example 4 After the dry granulation is sized by an oscillating granulator (sieve size: 0.8 mm) (manufactured by Frynd), 3.5 g of carboxymethylcellulose calcium and aluminum metasilicate are added to 70.75 g of the granulated product. 1.05 g of magnesium and 0.35 g of sucralose were mixed, and 0.35 g of magnesium stearate was added and mixed, and ingots were made with a rotary tablet machine (ingot pressure: 10kN) (manufactured by Kikusui Seisakusho) to obtain a diameter of 1 ingot Chewable tablets with a size of 10mm and a mass of 380mg.

Example 11

Based on the composition shown in Table 3 below, the dry granulated material obtained in Example 5 was sized with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd Co., Ltd.), and the granulated material was Add 3.5g of carboxymethylcellulose calcium, 1.05g of aluminum magnesium metasilicate and 0.35g of sucralose to 70g, mix it, and add 0.35g of magnesium stearate, mix it, and use a rotary tablet machine (tabletting pressure: 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with 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 material obtained in Example 6 was sized with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd Co., Ltd.), and the granulated material was Add 3.5g of carboxymethylcellulose calcium, 1.05g of aluminum magnesium metasilicate and 0.35g of sucralose to 70.75g, mix it, and add 0.35g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 10 mm and a mass of 380 mg.

(3-1) Evaluation of physical properties dry granulation <Flake Formation Rate>

After collecting the dry granulation for 2 minutes, put the whole amount on a 12-mesh sieve (mesh opening: 1.41mm), and calculate the mass percentage (%) of the molded body (flake) remaining on the sieve to form flakes Rate determination test.

Solid preparation <hardness>

By using a load cell type tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), the number of tests was 10 tablets, and the average value of the hardness was calculated to perform a hardness measurement test.

<Friability>

According to the "tablet friability test method" based on the Japanese Pharmacopoeia reference information, using a friability tester (manufactured by Toyama Sangyo Co., Ltd.), 20 tablets were rotated for 4 minutes at 25 rotations per minute to calculate the Friability The friability test was carried out.

(4-1) Test results of physical property evaluation dry granulation

The following Tables 1 and 2 show the test results of the composition and flake formation rate of the dry granules of Examples 1 to 6 and Comparative Examples 1 to 5.

From Tables 1 to 2, it is clear that in Examples 1 to 6, the formation rate of dry granulated product flakes is as high as 86 to 93%, showing 80% or more. Also, in Comparative Examples 1 to 4, the formation rate of dry granulated flakes was extremely low, ranging from 25 to 67%. In Comparative Example 5, due to poor fluidity and strong adhesion, the formation of flakes was difficult [unable to form flakes].

Solid preparation

The following Table 3 shows the groups of solid preparations (chewable tablets) of Examples 7 to 12 Formation and hardness and friability test results.

In Examples 7 to 12 using Table 3 of Examples 1 to 6 in Table 1, the hardness of the solid preparation (chewable tablet) is above 30N (111 to 233N), and the friability does not reach 1.0% (-0.05 to 0.05%) , showing very good values. In addition, a good chewing sensation can also be obtained by actually taking the solid preparations (chewable tablets) obtained from Examples 7 to 12.

(1-2) Manufacture of dry granulation (Kampo extract: Yigansan extract)

The type "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm] used in the dry granulator (manufactured by Floyd Corporation) shown below.

Example 13

Based on the composition shown in the following Table 4, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 10.5 g of synthetic aluminum silicate, 31.5 g of crystalline cellulose, 49.91 g of powdered reduced maltose syrup, and 0.09 g of thaumatin After mixing, add 6.3 g of sodium stearyl fumarate and mix it with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Co., Ltd.) to obtain a dry granulated product containing a molded body (flake).

Example 14

Based on the composition shown in Table 4 below, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 91.91 g of synthetic aluminum silicate, and 0.09 g of thaumatin were mixed, and 6.3 g of sodium stearyl fumarate was added. g mixed, with a dry granulator (roller compression pressure: 5MPa, roller rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Frynd Company), to obtain dry granulation containing shaped bodies (flakes) .

Example 15

Based on the composition shown in Table 4 below, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 60.41 g of synthetic aluminum silicate, 31.5 g of crystalline cellulose, and 0.09 g of thaumatin were mixed, and stearin was added. 6.3 g of sodium fumarate was mixed, and with a dry granulator (roller compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Company), obtain a molded body (sheet) ) dry granulation.

Example 16

Based on the composition shown in Table 4 below, mix 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 42g of synthetic aluminum silicate, 49.91g of powdered reduced maltose syrup, and 0.09g of thaumatin, and then add stearin Sodium amide fumarate 6.3g mixed it, with a dry granulator (roll compression pressure: 5MPa, roll rotation Rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Fjond Co.), to obtain a dry granulated product containing a molded body (flake).

Example 17

Based on the composition shown in the following Table 4, 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 10.5g of synthetic aluminum silicate, 81.41g of powdered reduced maltose syrup, and 0.09g of thaumatin were mixed. Sodium fatty acid fumarate 6.3g is mixed, with a dry granulator (roll compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain a molded body containing ( flakes) dry granulation.

Comparative example 6

Based on the composition shown in the following Table 5, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 91.91 g of crystalline cellulose, and 0.09 g of thaumatin were mixed, and 6.3 g of sodium stearyl fumarate was added. After mixing, a dry granulated product containing a molded body (flake) was obtained with a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Frynd).

Comparative Example 7

Based on the composition shown in the following Table 5, after mixing 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 91.91g of powdered reduced maltose syrup, and 0.09g of thaumatin, 6.3 sodium stearyl fumarate was added. g mixed it, with a dry granulator (roller compression pressure: 5MPa, roller rotation speed: 2rpm, into Material screw rotation speed: 40 rpm) (manufactured by Floyd Co.), to obtain a dry granulated product containing a molded body (flake).

Comparative Example 8

Based on the composition shown in Table 5 below, mix 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 31.5g of crystalline cellulose, 60.41g of powdered reduced maltose syrup, and 0.09g of thaumatin, and then add stearin 6.3 g of sodium fumarate was mixed, and with a dry granulator (roller compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Company), obtain a molded body (sheet) ) dry granulation.

Comparative Example 9

Based on the composition shown in the following Table 5, 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 42g of crystalline cellulose, 49.91g of powdered reduced maltose syrup, and 0.09g of thaumatin were mixed, and stearyl was added. Sodium fumarate 6.3g was mixed, and with a dry granulator (roller compression: 5MPa, roller rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Floyd Company), obtained a molded body (sheet) containing dry granulation.

Comparative Example 10

Based on the composition shown in Table 5 below, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 10.5 g of synthetic aluminum silicate, 31.5 g of crystalline cellulose, 49.91 g of powdered reduced maltose syrup, and 0.09 g of thaumatin After mixing, add 6.3g of magnesium stearate and mix it, and use a dry granulator (roller compression Pressure: 5 MPa, roller rotation speed: 2 rpm, feeding screw rotation speed: 40 rpm) (manufactured by Frynd Co.), to obtain a dry granulated product containing a molded body (flake).

(2-2) Manufacture of solid preparations (Kampo extract: Yigansan extract)

Using the dry granules obtained in Examples 13 to 17, chewable tablets of the present invention were manufactured.

Example 18

Based on the composition shown in the following Table 6, after the dry granulation obtained in Example 13 was sized with an oscillating granulator (sieve size: 0.8 mm) (manufactured by Floyd Co.), the granulated Add 5.25g of carboxymethylcellulose calcium, 1.58g of aluminum magnesium metasilicate and 0.51g of sucralose to 106.15g, mix it, and add 0.51g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 10 mm and a mass of 380 mg.

Example 19

Based on the composition shown in the following Table 6, after the dry granulation obtained in Example 14 was sized with an oscillating granulator (screen size: 0.8 mm) (manufactured by Floyd), the granulated Add 5.25g of carboxymethylcellulose calcium, 1.58g of aluminum magnesium metasilicate and 0.51g of sucralose to 106.15g, mix it, and add 0.51g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 10 mm and a mass of 380 mg.

Example 20

Based on the composition shown in the following Table 6, after the dry granulation obtained in Example 15 was sized with an oscillating granulator (screen size: 0.8mm) (manufactured by Floyd Co.), the granulated Add 5.25g of carboxymethylcellulose calcium, 1.58g of aluminum magnesium metasilicate and 0.51g of sucralose to 106.15g, mix it, and add 0.51g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 10 mm and a mass of 380 mg.

Example 21

Based on the composition shown in the following Table 6, after the dry granulated material obtained in Example 16 was sized with an oscillating granulator (screen size: 0.8mm) (manufactured by Floyd Co., Ltd.), the sized material was Add 5.25g of carboxymethylcellulose calcium, 1.58g of aluminum magnesium metasilicate and 0.51g of sucralose to 106.15g, mix it, and add 0.51g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 10 mm and a mass of 380 mg.

Example 22

Based on the composition shown in the following Table 6, after the dry granulation obtained in Example 17 was sized with an oscillating granulator (sieve size: 0.8 mm) (manufactured by Floyd), the granulated Add 5.25g of carboxymethylcellulose calcium, 1.58g of aluminum magnesium metasilicate and 0.51g of sucralose to 106.15g, mix it, and add 0.51g of magnesium stearate, mix it, and use a rotary tablet making machine (tabletting press : 10kN) (manufactured by Kikusui Seisakusho) was tabletted to obtain a chewable tablet with a diameter of 10 mm and a mass of 380 mg.

(3-2) Evaluation of physical properties dry granulation <Flake Formation Rate>

After collecting the dry granulation for 2 minutes, put the whole amount on a 12-mesh sieve (mesh opening: 1.41mm), and calculate the mass percentage (%) of the molded body (flake) remaining on the sieve to form flakes Rate determination test.

<hardness>

Using a tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), the number of test pieces was 10, and the average value of the hardness was calculated to perform a hardness measurement test.

<Friability>

According to the "Test method for friability of tablets" based on the Japanese Pharmacopoeia reference information, using a friability tester (manufactured by Toyama Sangyo Co., Ltd.), 20 tablets were rotated at 25 rotations for 1 minute and rotated for 4 minutes to calculate the friability. The friability test was carried out.

(4-2) Test results of physical property evaluation dry granulation

The following Table 4 and Table 5 show the test results of the composition and flake formation rate of the dry granules of Examples 13 to 17 and Comparative Examples 6 to 10.

From Tables 4 to 5, it is clear that in Examples 13 to 17, the formation rate of dry granulated product flakes is high at 84 to 91%, showing 80% or more. Also, in Comparative Examples 6 to 9, the yield of dry granulated flakes was extremely low, ranging from 0.12 to 23%. In Comparative Example 10, due to poor fluidity and strong adhesiveness, it was difficult to form flakes [unable to form flakes].

Solid preparation

The following Table 6 shows the solid preparations (chewable tablets) of Examples 18 to 22 The composition, hardness and friability test results.

As can be seen from Table 6, in Examples 18 to 22 that use formulations with a high dry granulation flake formation rate, the hardness of the solid formulation (chewable tablet) is above 30N (80 to 192N), and the friability is below 1.0% ( 0.11 to 0.32%), showing very good values. In fact, a good chewing sensation can also be obtained by taking the solid preparations (chewable tablets) obtained from Examples 18 to 22.

(1-3) Manufacture of dry granulation (Kampo extract: Yigansan extract)

The type "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm] used in the dry granulator (manufactured by Floyd Corporation) shown below.

Example 23

Based on the composition shown in Table 7 below, mix 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 26g of synthetic aluminum silicate, 77.91g of powdered reduced maltose syrup, and 0.09g of thaumatin, and then add stearin Mix it with 6.3 g of sodium acyl fumarate, and mix it with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Frynd Company) Manufacture) to obtain dry granules containing shaped bodies (flakes).

Example 24

Based on the composition shown in Table 7 below, 114g of Yokokansan extract (manufactured by Japan Powder Pharmaceutical Co., Ltd.), 26g of light anhydrous silicic acid, 77.91g of powdered reduced maltose syrup and 0.09g of thaumatin were mixed, and hard Sodium fatty acid fumarate 6.3g is mixed, with a dry granulator (roll compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain a molded body containing ( flakes) dry granulation.

Example 25

Based on the composition shown in Table 7 below, mix 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 26g of aluminum magnesium silicate, 77.91g of powdered reduced maltose syrup, and 0.09g of thaumatin, and then add stearin 6.3 g of sodium fumarate was mixed, and with a dry granulator (roller compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (manufactured by Floyd Company), obtain a molded body (sheet) ) dry granulation.

Example 26

Based on the composition shown in Table 7 below, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 26 g of synthetic aluminum silicate, 77.91 g of D-mannitol, and 0.09 g of thaumatin were mixed, and stearin was added. Sodium acyl fumarate 6.3g is mixed, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain the Dry granulation of shaped bodies (flakes).

Example 27

Based on the composition shown in Table 7 below, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 26 g of synthetic aluminum silicate, 77.91 g of lactose hydrate, and 0.09 g of thaumatin were mixed, and stearyl was added. Sodium fumarate 6.3g was mixed, and with a dry granulator (roller compression: 5MPa, roller rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Floyd Company), obtained a molded body (sheet) containing dry granulation.

Example 28

Based on the composition shown in Table 7 below, 114 g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 26 g of synthetic aluminum silicate, 77.91 g of isomalt, and 0.09 g of thaumatin were mixed, and then added 6.3 g of sodium stearyl fumarate was mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feeding screw rotation speed: 40 rpm) (manufactured by Floyd Corporation) was used to obtain a molded body containing (Flake) dry granulation.

Comparative Example 11

Based on the composition shown in Table 8 below, mix 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 26g of synthetic aluminum silicate, 77.91g of powdered reduced maltose syrup, and 0.09g of thaumatin, and then add stearin Calcium acid 6.3g mixes it, with dry granulator (roll compression pressure: 5MPa, roll rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain A dry granulated product containing shaped bodies (flakes) was obtained.

Comparative Example 12

Based on the composition shown in Table 8 below, mix 114g of Yokokansan extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 26g of synthetic aluminum silicate, 77.91g of powdered reduced maltose syrup, and 0.09g of thaumatin, and then add stearin Magnesium acid 6.3g is mixed, with dry type granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feeding screw rotation speed: 40rpm) (manufactured by Feynde Company), obtain the dry type that contains molded body (flake). Granulated matter.

(2-3) Manufacture of solid preparations (Kampo extract: Yigansan extract)

Using the dry granules obtained in Examples 23 to 28, chewable tablets of the present invention were manufactured.

Example 29

Based on the composition shown in the following Table 9, after sizing the dry granulated material obtained in Example 23 with an oscillating granulator (screen size: 0.8mm) (manufactured by Floyd Co., Ltd.), the granulated material was Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 30

Based on the composition shown in the following Table 9, the result obtained in Example 24 After the dry granulation is sized with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd), 7.875 g of carboxymethylcellulose calcium and aluminum metasilicate are added to 168.225 g of the granulated material. Mix 2.37g of magnesium and 0.765g of sucralose, and add 0.765g of magnesium stearate, mix it, and ingot it with a rotary ingot machine (ingot pressure: 10kN) (manufactured by Kikusui Seisakusho) to obtain a diameter of 1 ingot Chewable tablets with a size of 12mm and a mass of 600mg.

Example 31

Based on the composition shown in the following Table 9, after the dry granulation obtained in Example 25 was sized with an oscillating granulator (screen size: 0.8mm) (manufactured by Floyd), the granulated Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 32

Based on the composition shown in the following Table 9, after the dry granulated material obtained in Example 26 was sized with an oscillating granulator (screen size: 0.8 mm) (manufactured by Floyd Co., Ltd.), the sized material was Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 33

Based on the composition shown in the following Table 9, after the dry granulation obtained in Example 27 was sized with an oscillating granulator (screen size: 0.8 mm) (manufactured by Floyd), the granulated Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 34

Based on the composition shown in the following Table 9, after the dry granulation obtained in Example 28 was sized with an oscillating granulator (screen size: 0.8 mm) (manufactured by Floyd), the granulated Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

(3-3) Physical property evaluation dry granulation <Flake Formation Rate>

After collecting the dry granulation for 2 minutes, put the whole amount on a 12-mesh sieve (mesh opening: 1.41mm), and calculate the molded body (flake) remaining on the sieve The mass percentage (%) was tested for the determination of flake formation rate.

Solid preparation <hardness>

Using a tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), the number of test pieces was 10, and the average value of the hardness was calculated to perform a hardness measurement test.

<Friability>

According to the "Test method for friability of tablets" based on the Japanese Pharmacopoeia reference information, using a friability tester (manufactured by Toyama Sangyo Co., Ltd.), 20 tablets were rotated at 25 rotations for 1 minute and rotated for 4 minutes to calculate the friability. The friability test was carried out.

(4-3) Test results of physical property evaluation dry granulation

The following Tables 7 and 8 show the test results of the composition and flake formation rate of the dry granules of Examples 23 to 28 and Comparative Examples 11 to 12.

From Tables 7 and 8, it is clear that in Examples 23 to 28, the formation rate of dry granulated product flakes is high at 88 to 91%, showing 80% or more. Also, in Comparative Examples 11 to 12, since the fluidity was poor and the adhesiveness was strong, it was difficult to form a sheet [it was not possible to form a sheet].

Solid preparation

Table 9 below shows the test results of the composition, hardness and friability of the solid preparations (chewable tablets) of Examples 29 to 34.

As can be seen from Table 9, in Examples 29 to 34 of formulations with a high dry granulation flake formation rate, the hardness of the solid formulation (chewable tablet) is above 30N (44 to 142N), and the friability is below 1.0% ( -0.09 to 0.77%), showing very good values. In fact, a good chewing sensation can also be obtained by taking the solid preparations (chewable tablets) obtained from Examples 29 to 34.

(1-4) Manufacture of dry granulation (Chinese herbal medicine extracts: Shaoyao Gancao Decoction Extract, Buzhong Yiqi Decoction Extract and Danggui Shaoyao Powder Extract)

The type "TF-LABO" [roll diameter: 50 mm, roll width: 24 mm] used in the dry granulator (manufactured by Floyd Corporation) shown below.

Example 35

Based on the composition shown in Table 10 below, 80 g of Shaoyao Gancao Decoction Extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 34.5 g of synthetic aluminum silicate, 103.41 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed. Add 6.3g of sodium stearyl fumarate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain the containing molding Dry granulation of body (flake).

Example 36

Based on the composition shown in Table 10 below, 80 g of Paeoniae Glycyrrhiza Decoction (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 34.5 g of aluminum magnesium silicate, 103.41 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed. Add 6.3g of sodium stearyl fumarate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain the containing molding Dry granulation of body (flake).

Example 37

Based on the composition shown in Table 10 below, 80 g of Paeoniae Glycyrrhizae Decoction Extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 34.5 g of light anhydrous silicic acid, 103.41 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed. In addition, add 6.3 g of sodium stearyl fumarate and mix it with a dry granulator (roller compression pressure: 5 MPa, roll rotation speed: 2 rpm, feed screw rotation speed: 40 rpm) (Eph. Yinde Co., Ltd.) to obtain a dry granulated product containing a molded body (flake).

Example 38

Based on the composition shown in Table 10 below, 166.8 g of Buzhong Yiqi Decoction (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 12.9 g of synthetic aluminum silicate, 38.21 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed, and then added 6.3 g of sodium stearyl fumarate was mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feeding screw rotation speed: 40 rpm) (manufactured by Floyd Corporation) was used to obtain a molded body containing (Flake) dry granulation.

Example 39

Based on the composition shown in Table 10 below, 166.8 g of Buzhong Yiqi Decoction (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 12.9 g of aluminum magnesium metasilicate, 38.21 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed. Add 6.3g of sodium stearyl fumarate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain the containing molding Dry granulation of body (flake).

Example 40

Based on the composition shown in the following Table 10, 166.8 g of Buzhong Yiqi Decoction (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), 12.9 g of light anhydrous silicic acid, 38.21 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed. Add 6.3g of sodium stearyl fumarate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) company), to obtain dry granules containing shaped bodies (flakes).

Example 41

Based on the composition shown in Table 10 below, 150 g of Danggui Shaoyao Powder Extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 17 g of synthetic aluminum silicate, 50.91 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed, and then added 6.3 g of sodium stearyl fumarate was mixed, and a dry granulator (roll compression pressure: 5 MPa, roll rotation speed: 2 rpm, feeding screw rotation speed: 40 rpm) (manufactured by Floyd Corporation) was used to obtain a molded body containing (Flake) dry granulation.

Example 42

Based on the composition shown in the following Table 10, 150 g of Danggui Shaoyao Powder Extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 17 g of aluminum magnesium metasilicate, 50.91 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed. Add 6.3g of sodium stearyl fumarate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (manufactured by Fynd Company), obtain the containing molding Dry granulation of body (flake).

Example 43

Based on the composition shown in Table 10 below, 150 g of Danggui Shaoyao Powder Extract (manufactured by Aps Pharmaceutical Industry Co., Ltd.), 17 g of light anhydrous silicic acid, 50.91 g of powdered reduced maltose syrup, and 0.09 g of thaumatin were mixed, and Add 6.3g of sodium stearyl fumarate and mix it, with a dry granulator (roller compression pressure: 5MPa, roll rotation speed: 2rpm, feed screw rotation speed: 40rpm) (Eph. Yinde Co., Ltd.) to obtain a dry granulated product containing a molded body (flake).

(2-4) Manufacture of solid preparations (Chinese herbal extracts: Shaoyao Gancao Decoction Extract, Buzhong Yiqi Decoction Extract and Danggui Shaoyao Powder Extract)

The dry granules obtained in Examples 35 to 43 were used to manufacture chewable tablets of the present invention.

Example 44

Based on the composition shown in the following Table 11, the dry granulated material obtained in Example 35 was sized with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd Co., Ltd.). Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 45

Based on the composition shown in the following Table 11, after the dry granulation obtained in Example 36 was sized with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd), the granulated Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 46

Based on the composition shown in the following Table 11, after the dry granulation obtained in Example 37 was sized with an oscillating granulator (screen size: 0.8 mm) (manufactured by Floyd), the granulated Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 47

Based on the composition shown in the following Table 11, after sizing the dry granulated material obtained in Example 38 with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd Co.), the granulated material was Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 48

Based on the composition shown in the following Table 11, after the dry granulation obtained in Example 39 was sized with an oscillating granulator (screen size: 0.8 mm) (manufactured by Floyd), the granulated Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 49

Based on the composition shown in the following Table 11, after the dry granulation obtained in Example 40 was sized with an oscillating granulator (sieve size: 0.8 mm) (manufactured by Floyd), the granulated Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 50

Based on the composition shown in the following Table 11, after sizing the dry granulated material obtained in Example 41 with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd Co.), the granulated material was Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

Example 51

On the basis of the composition shown in the following Table 11, the dry granulation obtained in Example 42 was oscillating granulator (screen size: 0.8mm) (Floyd Co., Ltd. After granulation), 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose were added to 168.225g of the granulated material and mixed, and 0.765g of magnesium stearate was added and mixed. , ingot with a rotary ingot machine (ingot pressure: 10kN) (manufactured by Kikusui Seisakusho) to obtain a chewable ingot with a diameter of 12 mm and a mass of 600 mg.

Example 52

Based on the composition shown in the following Table 11, after sizing the dry granulated material obtained in Example 43 with an oscillating granulator (sieve size: 0.8mm) (manufactured by Floyd), the granulated material was Add 7.875g of carboxymethylcellulose calcium, 2.37g of aluminum magnesium metasilicate and 0.765g of sucralose to 168.225g, mix it, and add 0.765g of magnesium stearate, mix it, and use a rotary tablet making machine (tablet pressing : 10 kN) (manufactured by Kikusui Seisakusho Co., Ltd.), to obtain a chewable tablet with a diameter of 12 mm and a mass of 600 mg.

(3-4) Physical property evaluation dry granulation <Flake Formation Rate>

After collecting the dry granulation for 2 minutes, put the whole amount on a 12-mesh sieve (mesh opening: 1.41mm), and calculate the mass percentage (%) of the molded body (flake) remaining on the sieve to form flakes Rate determination test.

Solid preparation <hardness>

By using a tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), the number of tests is 10 ingots, calculate the average value of the hardness and carry out the hardness test.

<Friability>

According to the "Test method for friability of tablets" based on the Japanese Pharmacopoeia reference information, using a friability tester (manufactured by Toyama Sangyo Co., Ltd.), 20 tablets were rotated at 25 rotations for 1 minute and rotated for 4 minutes to calculate the friability. The friability test was carried out.

(4-4) Test results of physical property evaluation dry granulation

Table 10 below shows the composition of the dry granules of Examples 35 to 43 and the test results of the flake formation rate.

It is clear from Table 10 that in Examples 35 to 40, the formation rate of dry granulated product flakes is high, ranging from 80% to 91%, showing 80% or more.

Solid preparation

The following Table 11 shows the test results of the composition, hardness and friability of the solid preparations (chewable tablets) of Examples 44 to 52.

As can be seen from Table 11, in Examples 44 to 52 of formulation formulations using dry granules with a high flake formation rate, the hardness of the solid formulation (chewable tablet) was above 30N (37 to 122N), and the friability was below 1.0% ( -0.14 to 0.49%), showing very good values. In fact, a good chewing sensation can also be obtained by taking the solid preparations (chewable tablets) obtained from Examples 44 to 52.

[Industrial Utilization Possibility]

According to the present invention, the dry granulation method is used to manufacture the dry granulation and the solid preparation using the granulation as the core can produce and formulate hygroscopic drugs, specifically, chewable herbal extracts and/or herbal extracts Ingots can be industrially produced on a large scale in the oral cavity. In addition, this technology can be used not only for pharmaceuticals but also for food.

Since the figure in this case is the result data of the test compound, it is not a representative figure in this case. Therefore, there is no designated representative figure in this case.

Claims (16)

A dry granulated product, which contains (A) drug, (B) silicic acid compound and (C) sodium stearyl fumarate; wherein, the (B) silicic acid compound is made of synthetic aluminum silicate, light anhydrous At least one selected from the group consisting of silicic acid and aluminum magnesium metasilicate. The dry granulated product as described in item 1 of the patent application, wherein the drug (A) is a hygroscopic drug. The dry granulated product described in item 1 or item 2 of the scope of the patent application, wherein the drug (A) is a crude drug extract and/or a Chinese herbal medicine extract. The dry granulated product described in claim 1 or 2, wherein the (B) silicic acid compound is 1% by mass to 90% by mass relative to the entire dry granulated product. The dry granulated product described in claim 1 or 2, wherein the (C) sodium stearyl fumarate is 0.1% by mass to 9% by mass relative to the entire dry granulated product. The dry granulated product as described in item 1 or item 2 of the patent application, which additionally contains excipients. The dry granulated product described in claim 6 of the patent application, wherein the excipient is at least one selected from the group consisting of sugars, sugar alcohols and cellulose. The dry granulated product described in item 1 or item 2 of the scope of the patent application is for solid preparations. The dry granulated product described in item 1 or item 2 of the scope of the patent application is for solid preparations. A solid preparation, containing the dry granulation described in any one of the first to ninth items of the patent application. The solid preparation as described in claim 10 of the patent application, which additionally contains a binder and/or a disintegrating agent. The solid preparation as described in item 11 of the scope of the patent application, wherein the binder is selected from the group consisting of aluminum magnesium metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate and crystalline cellulose At least 1 species. The solid preparation as described in item 11 or item 12 of the scope of patent application, wherein the disintegrating agent is made of crospovidone, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose At least one selected from the group consisting of sodium sulfite and low-substituted hydroxypropyl cellulose. The solid preparation as described in any one of items 10 to 12 of the patent application, which is in the form of a chewable tablet or an oral disintegrating tablet. A method for manufacturing a solid preparation, comprising (A) dry granulation as described in any one of the first to ninth items of the patent application, or (B) containing the A step of compressing the mixture of the dry granulated material and additives described in any one of the items. The manufacturing method as described in claim 15 of the patent application, wherein the additive is a binder and/or a disintegrating agent.

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