200824708 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種固形組合物，直從 口物其係调配具有昇華性或 氣味之成分，且防止晶鬚析出或防止氣味產生。 【先前技術】 若於醫藥品或食品等之固形組合物中調配薄荷腦、咖啡 因或異布洛芬等昇華性成分，則較多的情形是於固形組合 物之表面或玻璃瓶等保存容器壁之内侧，產生因昇華所造 成之瓶壁之模糊不清或晶鬚析出。因&，較多的情形是保 存中含量產生變化’或者變成不均勻之品質，或者外觀產 生變化，而無法長時間維持製造時之品質，導致商品價值 下降。又，若於醫藥品或食品等之固形組合物中含有產生 氣味之成分，則攝取時或攝取後抱有不快之感覺，或者固 形組合物不容易通過喉嚨，而難以服用，不僅於此，且亦 有保存中氣味重新產生或增強，而無法長時間維持製造時 之品質之情形，因而無法充分發揮醫藥品之效果或商品價 值下降。 至今為止，為了於固形組合物中防止因昇華性成分所造 成之晶鬚析出，而設計有對固形組合物實施糖衣（專利文 獻1、2)或高分子薄膜（專利文獻3)等被覆膜之方法。又， 設計有與碳、無水矽酸及/或蒙脫石未加混和而共存之方 法（專利文獻4)，與碳、無水矽酸及/或蒙脫石共存之方法 (專利文獻5及6) ’含有特定大小及比表面積之1，心葡聚 糖粉末之方法（專利文獻7)，調配抗酸劑之方法（專利文獻 125840.doc 200824708 8) ’調配水合二氧化矽之方法（專利文獻9)，於密閉系統中 保存聚乙烯吡咯烷酮、氧化鎂及碳酸氫鈉之一種或兩種以 上之物質之方法（專利文獻10)，使昇華性成分、抗酸劑、 水δ 一氧化石夕之一種或兩種以上之物質共存之方法（專利 文獻11)，於密閉系統中保存乾燥劑之方法（專利文獻12)， 调配聚乙烯吡咯烷酮類之方法（專利文獻13)，乾式調配無 水礼糖之方法（專利文獻14)，調配酵母細胞壁餾分之方法 • (專利文獻15)，及調配羧甲基纖維素或其鹽之方法（專利文 獻16)等調配晶鬚之吸附劑或防止產生之物質或者使其共 存的方法。 又’為了於固形組合物中防止因具有氣味之成分所造成 之不快氣味，嘗試有對顆粒或片劑等固形製劑實施糖衣或 /專膜等被覆膜之方法，例如，進行有實施以蔗糖為基質之 糖衣製成糖衣片之方法（專利文獻17)，以油脂層及蛋白質 層之2層覆蓋之方法（專利文獻18)，以甲基丙烯酸胺基烷基 φ 酯共聚物RS之塗佈層及僅由疏水性物質與水不溶性無機質 構成之塗佈層之2層覆蓋之方法（專利文獻19)，含有普魯蘭 及界面活性劑而進行薄膜塗佈之方法（專利文獻20)，以胺 k 基酸粒子進行塗佈之方法（專利文獻21)，以含有水溶性纖 維素何生物之被覆劑覆蓋之方法（專利文獻22)，使用腸溶 性塗佈基質等高分子基質實施塗佈之方法（專利文獻23)， 以向分子化合物覆蓋環孢靈與脂肪酸蔗糖酯之混合物之方 =(專利文獻24)等。又，作為同時含有消氣味或防氣味成 分之方法，嘗試有含有氯系氧化劑或過氧化物系氧化劑之 125840.doc 200824708 方法（專利文獻25)，添加杉科、柏科、松科、樺科、蓴麻 科棒科、设鬥科、芸香科、柿樹科、唇形科、韻廬科、 菊科禾本科及百合科之植物組織之萃取物的方法（專利 文獻26) ’添加蔗糖素之方法（專利文獻27)，於絲蛋白及蠶 酶分解物中添加海藻糖之方法（專利文獻28)，除亞硫酸鹽 類以外，添加環糊精及/或環糊精衍生物之方法（專利文獻 29) ’添加巴拉金糖加熱物之方法（專利文獻3〇)，添加亞硫 酸鹽類之方法（專利文獻31)，添加羧甲基纖維素或其鹽之 方法（專利文獻16)等；又，亦進行有同時密封固形除氣味 劑之方法（專利文獻32)等。 [專利文獻1]日本專利特開2〇〇2_179559號公報 [專利文獻2]曰本專利特開2002-241275號公報 [專利文獻3]日本專利特開昭61_129138號公報 [專利文獻4]曰本專利特公昭56_53525號公報 [專利文獻5]日本專利特公昭56」797〇號公報 [專利文獻6]曰本專利特公昭56-53525號公報 [專利文獻7]日本專利特開昭63-267733號公報 [專利文獻8]日本專利特開平2_85214號公報 [專利文獻9]曰本專利特開平5_339158號公報 [專利文獻10]曰本專利特開平8-193027號公報 [專利文獻11]日本專利特開平8_301764號公報 [專利文獻12]曰本專利特開平8_333247號公報 [專利文獻13]曰本專利特開2〇〇〇_247870號公報 [專利文獻14]日本專利特開2〇〇2-154960號公報 125840.doc 200824708 [專利文獻15]日本專利特開2003-95987號公報 [專利文獻16]日本專利特開2005-162619號公報 [專利文獻17]曰本專利特開昭61-257923號公報 [專利文獻18]日本專利特開平6-24963號公報 [專利文獻19]日本專利特開平6-256170號公報 [專利文獻20]曰本專利特開2002-12541號公報 [專利文獻21]曰本專利特開2003-221326號公報 [專利文獻22]W02005/000358號公報 ® [專利文獻23]曰本專利特開2005-4 181 8號公報 [專利文獻24]日本專利特開2005-289825號公報 [專利文獻25]日本專利特開平6-157260號公報 [專利文獻26]曰本專利特開平9-275934號公報 [專利文獻27] WOOO/24273號公報 [專利文獻28]曰本專利特開2002-187900號公報 [專利文獻29]曰本專利特開2003-12439號公報 ^ [專利文獻30]曰本專利特開2004-2241號公報 [專利文獻31]日本專利特開2004-33 1524號公報 [專利文獻32]曰本專利特開2004-3 15046號公報 ‘ 【發明内容】 • [發明所欲解決之問題] 然而，上述防止晶鬚析出之方法均存在效果不充分之情 形，進而，存在製造步驟複雜且產品成本上升之問題。 又，上述防止氣味產生之方法中，實施糖衣或薄膜等被 覆膜之方法或同時密封除氣味劑之方法，亦存在製造步驟 I25840.doc 200824708 複雜或者產品成本上升之問題，或存在經時性防氣味效果 之持續不充分之情形。進而，同時含有消氣味或防氣味成 分之方法’存在很多對具有特定之不快氣味之成分發揮有 政丨生之^开^，若具有氣味之成分種類不同，則存在很多效 果減半，或者並非是具有通用性之防氣味方法之情形，亦 存在對消氣味或防氣味成分本身之氣味抱有不適感之情 ^ 進而’個人的嗜好性較大地受氣味之不適感影響，因BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a solid composition which is formulated to have a sublimation or odor component directly from a mouthpiece, and to prevent the precipitation of whiskers or the prevention of odor generation. [Prior Art] When a sublimation component such as menthol, caffeine or isobuprofen is blended in a solid composition such as a pharmaceutical or a food, there are many cases in which a solid container is placed on a surface of a solid composition or a glass bottle or the like. On the inner side of the wall, the blurring of the bottle wall caused by sublimation or the precipitation of whiskers occurs. Since &, there are many cases where the content in the storage changes or becomes uneven, or the appearance changes, and the quality at the time of manufacture cannot be maintained for a long time, resulting in a decrease in the value of the product. Further, when a solid composition such as a pharmaceutical or a food contains an odor-causing component, it may be unpleasant at the time of ingestion or after ingestion, or the solid composition may not easily pass through the throat, and it is difficult to take it, and There is also a situation in which the odor is regenerated or enhanced during storage, and the quality at the time of manufacture cannot be maintained for a long period of time, so that the effect of the pharmaceutical product or the decline in the value of the commodity cannot be fully exerted. In order to prevent the precipitation of whiskers by the sublimation component in the solid composition, a coating film such as a sugar coating (Patent Documents 1 and 2) or a polymer film (Patent Document 3) is applied to the solid composition. The method. Further, a method in which carbon, anhydrous citric acid, and/or montmorillonite are coexisted without being mixed (Patent Document 4), and a method of coexisting with carbon, anhydrous citric acid, and/or montmorillonite are designed (Patent Documents 5 and 6) 'Method of containing a specific size and specific surface area of 1, a glucan powder (Patent Document 7), a method of formulating an antacid (Patent Document 125840.doc 200824708 8) 'Method of formulating hydrated cerium oxide (Patent Document 9) A method of storing one or two or more kinds of polyvinylpyrrolidone, magnesium oxide, and sodium hydrogencarbonate in a closed system (Patent Document 10), and sublimating a component, an antacid, and water δ A method in which one or two or more substances coexist (Patent Document 11), a method in which a desiccant is stored in a closed system (Patent Document 12), a method of blending polyvinylpyrrolidone (Patent Document 13), and a dry blending of anhydrous sugar Method (Patent Document 14), a method of preparing a yeast cell wall fraction (Patent Document 15), and a method of blending carboxymethylcellulose or a salt thereof (Patent Document 16), etc. The method of qualitative or made coexist. Further, in order to prevent the unpleasant odor caused by the odorous component in the solid composition, there is a method of applying a coating film such as a sugar coating or a film to a solid preparation such as a granule or a tablet, for example, sucrose is carried out. A method of preparing a sugar-coated tablet by a sugar coating of a substrate (Patent Document 17), a method of covering two layers of a grease layer and a protein layer (Patent Document 18), and coating with an aminoalkyl methacrylate copolymer of RS A method in which a layer and a coating layer composed of only a hydrophobic substance and a water-insoluble inorganic substance are covered by two layers (Patent Document 19), and a method of coating a film by using pullulan and a surfactant (Patent Document 20) A method of coating an amine-k-acid particle (Patent Document 21), and coating it with a polymer matrix containing an enteric coating substrate (Patent Document 22) The method (Patent Document 23) covers a mixture of cyclosporine and a sucrose ester of a fatty acid to a molecular compound (Patent Document 24). Further, as a method of simultaneously containing an odor-eliminating or odor-preventing component, an attempt is made to have a chlorine-based oxidizing agent or a peroxide-based oxidizing agent, 125840.doc 200824708 (Patent Document 25), adding Cedaraceae, Cypressaceae, Pineaceae, and Betaceae Method for extracting plant tissues of ramie, genus, genus, genus, persimmon, genus, genus, genus, genus, genus, genus, genus (Patent Document 27), a method of adding trehalose to silk protein and silkworm enzyme decomposition product (Patent Document 28), and a method of adding a cyclodextrin and/or a cyclodextrin derivative in addition to a sulfite salt ( Patent Document 29) A method of adding a prasate heating material (Patent Document 3), a method of adding a sulfite (Patent Document 31), and a method of adding carboxymethylcellulose or a salt thereof (Patent Document 16) Further, a method of simultaneously sealing the solid deodorant (Patent Document 32) and the like is also performed. [Patent Document 1] Japanese Patent Laid-Open Publication No. JP-A-2002-241275 (Patent Document 3) Japanese Patent Laid-Open Publication No. SHO 61-129138 (Patent Document 4) Japanese Patent Publication No. Sho 56-53525 [Patent Document 6] Japanese Patent Laid-Open Publication No. SHO 56-53525 (Patent Document 7) Japanese Patent Laid-Open No. 63-267733 [Patent Document 8] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. [Patent Document 15] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Patent Document 18] Japanese Patent Laid-Open Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. [Patent Document No. 2] Japanese Patent Laid-Open Publication No. 2005-289825 [Patent Document No. 2005] Japanese Patent Laid-Open Publication No. 2005-289825 [Patent Document 25] Japanese Patent Laid-Open Patent Publication No. 2005-289825 Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Japanese Laid-Open Patent Publication No. 2003-12439 [Patent Document No. 30] Japanese Patent Laid-Open No. 2004-2241 [Patent Document 31] Japanese Patent Laid-Open Publication No. 2004-33-1524 [Patent Document 32] [Invention Summary] [Problems to be Solved by the Invention] However, the above methods for preventing the precipitation of whiskers have insufficient effects, and further, there are problems in that the manufacturing steps are complicated and the product cost rises. . Further, in the method for preventing odor generation, a method of applying a coating film such as a sugar coating or a film or a method of simultaneously sealing the odor removing agent, there is also a problem that the manufacturing step I25840.doc 200824708 is complicated or the product cost is increased, or there is a lapse of time. The situation in which the anti-odor effect continues to be insufficient. Furthermore, there are many methods for odor-eliminating or odor-preventing ingredients, and there are many ingredients that have a specific unpleasant odor. If there are different types of odor components, there are many effects halved, or not It is a versatile anti-odor method, and there is also a feeling of discomfort in the smell of the odor or the odor-preventing component itself. Further, the personal hobby is greatly affected by the odor of the odor.
此不論何種氣味，無氣味對醫藥品或健康食品等連曰服用 之製劑較好。 口此，本發明之目的在於提供一種可較先前之技術簡便 地防止因昇華性成分所造成之晶鬚析出及因具有氣味之成 分所造成之氣味的固形組合物。 [解決問題之技術手段]Regardless of the odor, odorless is preferred for pharmaceutical preparations such as pharmaceuticals or health foods. Accordingly, it is an object of the present invention to provide a solid composition which can prevent the precipitation of whiskers due to sublimation components and the odor caused by the odor component, which is simpler than the prior art. [Technical means to solve the problem]
本發明者等人對防止來自含有 之晶鬚析出的方法及防止來自含有具有 昇華性成分之固形組合物 氣味之成分之固形 組合物之氣味的方法進行各種 華性或氣味之成分及膨潤劑， 研九’結果發現含有具有昇 利用水或含水醇進行濕製粒 而得之固形組合物， 有氣味之成分的氣味 可意想不到地防止晶鬚析出或來自具 ’從而完成本發明。 卩本發月提ί、種包含具有昇華性或氣味之成分及膨 潤劑’利用水或含水醇進行濕製粒而得之固形組合物。 [發明之效果] 125840.doc •10- 200824708 有氣味之成分者’可簡便地防止該成分所引起之 味。 不快氡 【實施方式】 以下，對本發明加以詳細說明。 於本發明中，所謂昇華性成分意指該成分本身為 性，或者該成分及/或分解物之一部分為昇華性之物 若為如此之物質，則並無特別限定。若更具體地例卞:’ 性成分’則例如可列舉：異布洛芬（ibupr〇fen)、乙=華 酚、2-乙氧苯甲醯胺（Ethenzamide)、茶鹼、卡巴氮平p胺 來酸氯菲安明、安嗽寧（tipepidine hibenzate)諾司卡賓馬 咳必清（carbetapentane citrate)、愈創木酚磺酸鉀、非=西 汀、異丙安替比林、咖啡因類(咖啡因(―水合物)、無水: 啡因、苯甲酸鈉咖啡因等）、樟腦類（丨·掉腦、d·掉腦、^ 樟腦等）、薄荷腦類（1-薄荷腦、d-薄荷腦、dl_薄荷腦等）、· 苯甲酸類(苯甲酸異戊醋、苯甲酸雌二醇醋、苯甲酸乙 酯、笨甲酸苯酯、苯甲酸丙酯、笨甲酸节酯、苯甲酸甲 酷、苯甲酸鈉、苯甲酸鈉咖D非因等）、水揚酸類（水楊酸、 阿司匹林、水揚酸異丁自旨、水楊酸鋼、水揚酸毒扁豆驗、 水揚酸甲醋等）、草藥萃取物（麻黃、桂皮、地龍、人寨、 甘草、牛黃等萃取物）、中藥萃取物（葛根湯、小紫胡湯、 :青龍湯、紫胡桂枝湯等）等。《中，尤其好的是異布洛 分、乙醯胺朌、茶驗、馬來酸氯菲安明、無水咖哪因、卜 薄荷腦。 又於本發明中’所謂具有氣味之成分，若係該成分本 125840.doc 200824708 〃有氣未或者该成分及/或分解物之一部分具有氣味 之：貝’則亚無特別限定，m常意指經口攝取之具有氣味 之醫藥品原料或食品原料，不僅為化學合成品或醱酵品， 亦可為草藥萃取物、中藥萃取物等天然物或其萃取物。若 更具體地例示具有氣味之成分，則例如可列舉:葛根湯、 藏風解毒湯、響聲破笛丸料、小柴胡湯、小青龍湯、酸襄 仁湯、十味敗毒湯等中藥萃取物，蘆薈、菌香、薑黃、烏 =、莪術、纈草、乾薑、甘草、菊花、桂皮、苟藥、生 量、大棗、釣藤鉤、西番蓮、蛇麻草、大蒜、人蔘、地龍 等源自草藥或生物之萃取物，甲基甲硫胺酸氯化銕等抗潰 瘍藥’硫胺、硝酸硫胺、鹽酸硫胺、雙苯醯硫胺 (Bisbentiamine)、呋喃硫胺、奥托硫胺、苯磷硫胺、二苯 石瓜胺、二硫硫胺、雙異丁硫胺（Bisibuthiamine)、鹽酸基 世甲命等維生素B1群，異白胺酸、白胺酸、纈胺酸等胺基 酸，異布洛芬等解熱鎮痛藥，葡糖胺、玻尿酸、硫酸皮膚 素、硫酸軟骨素等黏多糖類，抗壞企酸或其鹽或者異抗壞 企酸或其鹽等維生素C群，dl-α-生育酚、天然維生素E(d 體）、生育酚乙酸酯、生育酚琥珀酸酯、生育酚琥珀酸 鈣、生育酚菸鹼酸酯等維生素E群等。其中，尤其好的是 葛根湯、人蔘等源自草藥或生物之萃取物，硝酸硫胺、白 胺酸、生育酚琥珀酸酯。 於本發明之固形組合物中，昇華性成分或具有氣味之成 分，較好的是含有1〜95質量％，更好的是含有2〜90質量 % ’尤其好的是含有5〜65質量％。 125840.doc -12- 200824708 本發明中所使用之膨潤劑’若係於添加水或 潤且可保持大量水或含水醇之物質，則並無特別限定M: 為合有具有氣味之成分之組合物的情形時，當然較 無氣味性之膨_。作為更具體的無氣味性之膨潤劑之 例，可列舉：低取代度經丙基纖維素、結晶纖維素、交聯 竣甲基纖維素鈉、交聯聚乙㈣㈣1甲基纖維㈣、 敌甲基纖維素納、緩甲基纖維素等，該等可使用i種或者 將2種以上混合使用。作為較好的膨潤劑，可列舉自低取 錢經丙基纖維素1甲基纖維㈣、羧甲基纖維素納、 父聯竣甲基纖維素納及結晶纖維素中所選擇之丨種或2種以 上。作為更好的膨潤劑’可列舉低取代度經丙基纖維素， 較理想的是以其占膨潤劑總體之4()質量％以上之量使用， 尤其好的是以其占膨潤劑總體之6〇質量％以上之量使用。 ，於使用低取代度經丙基纖維素作為膨濁劑之情形時，就 製造性之方面而言，齡接沾 。奴好的疋羥丙氧基為5·0〜16.0質量％ 者，更好的是6.0〜14.5質量％者，尤其好的是7純.〇質量 %者。作為如此之低取代度_基纖維素，可列舉信越化 學股份有限公司製造之LH.3 1(_氧基為iQm9 f量 %)、LH'32(㈣氧基為7·°〜9.9質均。進而，低取代度 經丙基纖維素之平均粒徑較好的是6()叫以下，更好的是 45哗以下’特別好的是25 _以下，尤其好的是4〜25 μιη 〇 於本心明之固形組合物中，膨潤劑較好的是含有5〜的質 量。/。’更好的是含有1G〜98質量％，尤其好的是含有35〜95 125840.doc -13- 200824708 質量％。 又’就防止晶鬚析出或不快氣味之效果之方面而言，具 有昇華性或氣味之成分與膨潤劑之質量比，相對於該成分 1質量份，較好的是設定膨潤劑為01〜10〇質量份，更好的 是設為〇·2〜90質量份，尤其好的是設為0.5〜80質量份。The present inventors have carried out various kinds of scent or scenting agents and swelling agents for a method for preventing precipitation from containing whiskers and for preventing odor from a solid composition containing a component having a scent of a solid composition having a sublimating component, The results of the study were found to contain a solid composition obtained by wet granulation with water or aqueous alcohol, and the odor of the odorous component unexpectedly prevented the precipitation of the whiskers or the sufficiency of the present invention. The present invention provides a solid composition comprising a sublimation or odor component and a swell agent by wet granulation with water or an aqueous alcohol. [Effects of the Invention] 125840.doc •10- 200824708 The odorous component can easily prevent the taste caused by the component. Unpleasant 氡 Embodiments Hereinafter, the present invention will be described in detail. In the present invention, the sublimation component means that the component itself is a property, or a part of the component and/or the decomposition product is a sublimation property, and is not particularly limited as long as it is such a substance. More specifically, for example, 'sexual component' can be exemplified by isoprofen (ibupr〇fen), ethyl b-phenol, 2-therein (Ethenzamide), theophylline, and kappazepine p. Tipepidine hibenzate, carbetapentane citrate, guaiacol sulfonate, non-west, isopropyl antipyrine, caffeine (coffee) ((hydrate), anhydrous: morphine, sodium benzoate, caffeine, etc.), camphor (丨·shed brain, d·shed brain, ^ camphor, etc.), menthol (1-Menthol, d-menthol) , dl_menthol, etc.), benzoic acid (isoamyl benzoate, estradiol benzoate, ethyl benzoate, phenyl benzoate, propyl benzoate, benzoic acid ester, benzoic acid , sodium benzoate, sodium benzoate, coffee, D, etc.), salicylic acid (salicylic acid, aspirin, salicylic acid, isobutylate, salicylic acid, salicylic acid, lentils, salicylic acid, etc.) , herbal extracts (ephedra, cinnamon, earthworm, human village, licorice, bezoar and other extracts), Chinese herbal extracts (Gegen soup, Xiaozihu soup) : Dragon soup, purple Hu Guizhi soup, etc.) and so on. Among them, especially, it is isobromo, acetaminophen, tea, chlorpheniramine maleate, anhydrous ganache, and menthol. Further, in the present invention, the term "scented component", if the component is present, is not smothered, or a part of the component and/or the decomposition product has an odor: the shell is not particularly limited, m is always It refers to an odorous pharmaceutical raw material or food raw material that is ingested by mouth, and is not only a chemical synthetic product or a fermented product, but also a natural product such as an herbal extract or a Chinese herbal extract or an extract thereof. More specifically, the odor-causing component can be exemplified by: keigen soup, Tibetan style detoxification soup, squeaking smashing granules, Xiaochaihu soup, Xiaoqinglong soup, sour glutinous rice soup, Shiwei fangdu soup, etc. Aloe vera, aloe vera, turmeric, turmeric, black berry, medlar, valerian, dried ginger, licorice, chrysanthemum, cinnamon, peony, raw, jujube, vine hook, passionflower, hop, garlic, human cockroach , Earthworm and other extracts derived from herbs or organisms, anti-ulcer drugs such as methyl methionine and barium chloride 'thiamine, thiamine nitrate, thiamine hydrochloride, Bisbentiamine, furan thiamine , oltipamide, phenylphosphine thiamine, diphenyl citrate, dithiothiamine, bisisobutyl thiamine (Bisibuthiamine), vitamin B1 group, vitamin B1 group, isoleucine, leucine, An amino acid such as lysine, an antipyretic analgesic such as isoprofen, a mucopolysaccharide such as glucosamine, hyaluronic acid, dermatan sulfate or chondroitin sulfate, or a bad acid or a salt thereof or a different acid or acid Vitamin C group such as salt, dl-α-tocopherol, natural vitamin E (d body), tocopherol acetate, tocopherol Vitamin E group such as crotonate, tocopheryl succinate, and tocopherol nicotinic acid ester. Among them, particularly preferred are extracts derived from herbs or organisms such as pueraria soup and human sputum, thiamine nitrate, leucine, and tocopheryl succinate. In the solid composition of the present invention, the sublimable component or the odor-containing component preferably contains 1 to 95% by mass, more preferably 2 to 90% by mass, and particularly preferably contains 5 to 65% by mass. . 125840.doc -12- 200824708 The swelling agent used in the present invention is not particularly limited as long as it is a substance which adds water or moisturizes and can retain a large amount of water or an aqueous alcohol: a combination of odor-containing components In the case of things, of course, it is less odorless. Examples of more specific odorless swells include: low substitution degree propyl cellulose, crystalline cellulose, crosslinked 竣methylcellulose sodium, crosslinked polyethylene (tetra) (tetra) 1 methyl fiber (four), enemy armor The cellulose may be used, or the methyl cellulose may be used in combination, and these may be used in combination of two or more kinds. Preferred examples of the swelling agent include those selected from the group consisting of propyl cellulose 1 methyl fiber (IV), carboxymethyl cellulose sodium, parent conjugated methyl cellulose nano and crystalline cellulose. 2 or more types. As a better swelling agent, a low degree of substitution with propyl cellulose may be mentioned, and it is preferably used in an amount of 4% by mass or more based on the total amount of the swelling agent, and particularly preferably, it accounts for a total amount of the swelling agent. Use in an amount of 6 〇 mass% or more. When using a low degree of substitution with propylcellulose as a swelling agent, it is age-sensitive in terms of manufacturability. The slave hydroxypropoxy group is 5.0 to 16.0% by mass, more preferably 6.0 to 14.5% by mass, and particularly preferably 7 pure. 〇 mass %. As such a low degree of substitution-based cellulose, LH.3 1 (_oxy group is iQm9 f amount %) and LH'32 ((tetra)oxy group is 7·° to 9.9 mass average manufactured by Shin-Etsu Chemical Co., Ltd. Further, the average particle diameter of the propylene cellulose having a low degree of substitution is preferably 6 () or less, more preferably 45 Å or less, particularly preferably 25 Å or less, particularly preferably 4 to 25 μm 〇 In the solid composition of the present invention, the swelling agent preferably contains 5 to a mass. /. 'More preferably contains 1G to 98% by mass, particularly preferably 35 to 95 125840.doc -13- 200824708 % by mass. In terms of the effect of preventing the precipitation of whiskers or the effect of unpleasant odor, the mass ratio of the component having sublimation property or odor to the swelling agent is preferably set to be 1% by mass based on the mass of the component. 01 to 10 parts by mass, more preferably 〇 2 to 90 parts by mass, particularly preferably 0.5 to 80 parts by mass.
明之固形組合物中，除昇華性成分或具有氣味之 成分及膨潤劑以外，可根據其目的適當調配其他藥理活性 成分或通常醫藥品或食品中所使用之成分。例如，作為藥 理活性成分，可麟:解熱鎮痛消炎藥、催眠鎮靜藥：抗 睡眠劑、鎮暈藥、小兒鎮痛藥、健胃藥、抗酸藥、消化 =、強心藥、心率不齊用藥、降壓藥、血管擴張藥、利尿 藥、調整腸胃藥、骨f疏鬆症治療藥、镇咳去 =、抗哮喘藥、抗_、尿頻改善劑、營養強化劑、維 令所使用之藥理活性成分…作為醫藥品或食 :二吏：之成分’可列舉賦形劑(稀釋劑)、黏合劑、崩 =、：劑、著色劑等。例如，作為賦形劑，可列舉： '''化白糖 '㈣糖、海藻糖等糖類 山梨糖醇、太播妒 土 # 甘路糖％、 列n 木料、赤鮮糖醇等糖醇等。作為黏合劑，可 牛歹工丙基纖維素、羥丙基甲基纖 乙埽吡叹〜， 纖维素、甲基纖維素、聚 米戮粉浪子作為朋解劑，可列舉玉 馬鈴薯澱粉、米澱粉、小麥 為甜味料，可列舉糖精納、阿斯類等。作 蔗糖素、甘草# 乙醯磺胺酸鉀、 著色劑，帛衫^物。作為 …化鈦、天然之食用色素、適於食品、 i25840.doc •14- 200824708 藥品之用途的染料等。 亦可於本發明之固形組合物中，使用著香劑.香料等， 、玲好丨生良好的氣味。於該情形時，較好的是採用如下 • 有昇華性或氣味之成分及無氣味性之膨潤劑， 、 或3水醇進行濕製粒而製造濕潤顆粒狀組合物，於 進=乾燥而得之固形組合物中，添加著香劑·香料等。作 2香4香料，可列舉料錢檬等柑m料或咖啡 二楚；:+奶系香料’或胡椒薄荷油、綠薄荷油、香辛料 油等植物精油等。 :發明之固形組合物，藉由於含有具有昇華性或氣味之 IM…上 加混練液進行混練，並進行濕 =毛揮抑制晶鬚析出或氣味之效果。為僅混合該成 ::广：劑而成之組合物或將該成分與膨潤劑進行乾製粒 r :r” t法獲得充分之效果。作為此處所使用之混練 义好的是使用水切含量為_量％以下之含水醇， 更好的是《水或醇含量為25f量％以下 ，尤 Γ是使用水或醇含量為15質量％以下之含水醇。又; :本發明中所使用之含水醇中之醇，彳列舉乙醇、甲醇、 =醇等醫藥品或其製造時可使用之醇，於製成經口投鱼 形時’較好的是使用乙醇。混練液之添加量，相 對於膨潤劑，較好的θ 不目 2〜5質量倍。的^為1〜_量倍，尤其好的是設為 作為製造本發明之_彡組合㈣ 製粒、流動層製教、^ ▲ 才了古#係棵掉 杈出製粒等通常用於醫藥品或食品等 125840.doc -15- 200824708 領域之濕製粒法，則並無特 法及擠出製粒法。 "讀的是擾拌製粒 本發明之固形組合物’例如可如下述進行製造。首先， 添昇華性或氣味之成分及膨潤劑，繼而根據需要添 加，、他添加物，利用授拌型混合 :嶋x股份有限公司製造）等混合—合後^ 广之1倍至H)倍左右之量添加純化水或醇含量為5〇重量 =之：水醇進行混練，將膨潤劑製成膨潤狀態。將該 用擠出製粒機’例如贿E RYUZER(Fujipaudal = 造?擠出製粒機進行製粒，製造濕潤顆粒 利用相形乾煉機或流動層製粒乾燥機進行乾 餘：又，亦可使用筛製成目標粒度之顆粒，進而，擠出製 =斤利用球形整粒機（Fujipaudal股份有限公司製造）實施 ”处理後，利用箱形乾燥機或流動層乾燥機進行乾燥， 取後，亦可使用筛製造目標粒度之球形顆粒。 粒。顆粒之二:使用薛製成"粒度之顆 <拉度凋即，可精由調節水或含水 於0 3〜1 〇 ^ ^ …：mm之範圍内改變擠出製粒時之筛徑，從而可獲 :藥== 罐而獲得顆粒劑。進一步考慮到服用感受 進行塗佈:疋4，可以糖類或高分子等對所得之顆粒劑 二$月中進行濕製粒所得之顆粒之平均粒徑，於夢 由師分法測定粒獲之情形時，較好的是25叫以上，更‘ 125840.doc -16- 200824708 的是50〜1500叫1，尤其妤的是100〜1000 μηι。 如此所製造之固形組合物，具有顆粒狀之形狀，抑制因 昇華性成分所造成之晶鬚析出，抑制因具有氣味之成分所 仏成之氣味之產生，進而流動性良好，因此可將固形組合 物之顆粒直接用作散劑、細粒劑、顆粒劑等，可填充至硬 膠囊或軟膠囊而用作膠囊劑，亦可將固形組合物之顆粒打 片而用作片劑。進而，可以糖類或高分子等塗佈該等膠囊 d或片』。於製備該等製劑時，可適時調配通常用於醫藥 品或食品之製劑添加物，作為穩定劑、穩定化劑、界面活 性劑、塑化劑、潤滑化劑、潤滑劑、還原齊】、甜味劑、稀 釋劑、吸附劑、調味劑、黏合劑、抗氧化齊Η勉光劑、塗 佈劑、悉祖、^ i 7 匕衣、填充劑、消泡劑、清涼化劑、咀嚼 劑、著多南|、| I ' 添 ^ 片者香蜊、糖衣劑、發泡劑、賦形劑、崩解 :解助剤、朋解延長劑、芳香劑、P方濕劑、P方腐劑、 料2 =動化劑、抗靜電劑、增量劑、調味料、酸味 :甜未料、者色料.顯色劑、著香料、強化劑、膨脹 =保存料.殺_、氧化抑制劑.漂白劑、增 吉味料、it、古，> % π先劑、製造用劑等。又，如此所製造之本 ^明組合物及含有其之製劑，即使填充於玻璃瓶等 、乳密容器或透明的ρτρ包裝中， 析出所造成之交哭辟 、 ^ 味產生· σ 土之模糊不清或結晶析出，或者防止氣 即使填充於玻璃瓶等氣密容器或ΡΤΡ包裝 亦無經時性氣味。 [實施例] 125840.doc -17- 200824708 繼而，表示實施例及比較例，更具體說明本發明，但本 發明並不限定於該等。 實施例1In the solid composition of the present invention, in addition to the sublimation component or the odor-containing component and the swelling agent, other pharmacologically active ingredients or ingredients used in usual pharmaceuticals or foods may be appropriately formulated according to the purpose. For example, as a pharmacologically active ingredient, Kelin: antipyretic analgesic anti-inflammatory drugs, hypnotic sedatives: anti-sleep agents, anti-aesthetics, pediatric analgesics, stomach drugs, antacids, digestion =, cardiotonic drugs, arrhythmia medication, drop Drugs, vasodilators, diuretics, gastrointestinal drugs, osteoporosis treatments, antitussives, anti-asthma drugs, anti-drugs, urinary frequency improvers, nutritional supplements, pharmacologically active ingredients used in vitamins... Examples of the pharmaceutical product or food include the excipient (diluent), the binder, the collapse, the agent, and the coloring agent. For example, examples of the excipient include: '''--------------------------- As a binder, burdock propyl cellulose, hydroxypropyl methyl ketone oxime ~, cellulose, methyl cellulose, rice bran powder prodigal as a friend, can be cited as jade potato starch, Rice starch and wheat are sweeteners, and examples thereof include saccharin sodium and aspen. As sucralose, licorice # 醯 sulfonate potassium, coloring agent, 帛 ^ ^. As a dye for titanium, natural food coloring, food, i25840.doc •14- 200824708 for pharmaceutical use. It is also possible to use a flavoring agent, a perfume, etc. in the solid composition of the present invention, and to give a good odor. In this case, it is preferred to use a sublimation or odor component and an odorless swelling agent, or a trihydrate to wet granulate to produce a wet granule composition, which is obtained by drying in a dry state. In the solid composition, a fragrance, a fragrance, and the like are added. As the fragrance of the fragrant 4, it can be exemplified by a citrus or a coffee such as a lemon or a milk; a + milk-based flavor ‘ or a plant essential oil such as peppermint oil, spearmint oil, or spice oil. The solid composition of the invention is obtained by kneading a mixture containing a sublimation property or an odor, and performing the effect of suppressing the precipitation of whiskers or the odor by wetness. A sufficient effect is obtained by mixing only the composition of the composition: the broad agent: or the dry granulation of the component with the swelling agent. The r:r" t method is sufficient to use the water cut content as the kneading used herein. More preferably, the water or alcohol content is 25% by volume or less, and particularly water or an alcohol having an alcohol content of 15% by mass or less. Further: used in the present invention The alcohol in the aqueous alcohol is exemplified by a pharmaceutical product such as ethanol, methanol or alcohol, or an alcohol which can be used in the production of the alcohol. When the fish is formed into a mouth shape, it is preferred to use ethanol. The amount of the kneading liquid is relatively In the case of the swelling agent, the preferred θ is not 2 to 5 times the mass. The amount of ^ is 1 to _ times, particularly preferably as the _ 彡 combination (4) for the production of the present invention, granulation, flow layer teaching, ^ ▲ There is no special method and extrusion granulation method for wet granulation in the field of 125840.doc -15- 200824708, which is commonly used in pharmaceuticals or foods, such as granules, granules, etc. "Reading Is a turbid granulation of the solid composition of the present invention', for example, can be produced as follows. First, adding sublimation or odor Adding purified water or alcohol in an amount of about 1 to H times the amount of the mixture and the swelling agent, and then adding it as needed, and adding it, using a blending type: 嶋x Co., Ltd.) The content is 5 〇 weight = which: the hydroalcohol is kneaded, and the swelling agent is made into a swelled state. The granulator for the use of the granulator can be granulated to produce a wet granulation machine, for example, by emulsifier E RYUZER (Fujipaudal = granulation machine) The granules are dried by a phase dryer or a fluidized layer granulating dryer: in addition, sieves can be used to form granules of a target particle size, and further, the extrusion granules are implemented by a spherical granulator (manufactured by Fujipaudal Co., Ltd.). After the treatment, drying is carried out by a box dryer or a fluidized bed dryer. After the sieve, a spherical particle of a target particle size can also be produced by using a sieve. Particles: Two of the particles: using a Xue made "particle size< The fineness can be changed by adjusting the water or water in the range of 0 3~1 〇^ ^ ...:mm to change the sieve diameter during extrusion granulation, so that the granule can be obtained by the medicine == can. Further taking into account the feeling of taking Coating: 疋4, can The average particle size of the particles obtained by wet granulation in the obtained granules for two months, such as a polymer or a polymer, is preferably 25 or more, and more '125840 when the granule is determined by the division method. .doc -16- 200824708 is 50~1500 called 1, especially 100~1000 μηι. The solid composition thus produced has a granular shape, inhibits the precipitation of whiskers due to sublimation components, and inhibits Since the odor generated by the odorous component is generated and the fluidity is good, the granules of the solid composition can be directly used as a powder, a fine granule, a granule, etc., and can be filled into a hard capsule or a soft capsule for use as a granule. For capsules, the granules of the solid composition can also be tableted for use as a tablet. Further, these capsules d or tablets may be applied by a saccharide or a polymer. In the preparation of the preparations, the preparation additives usually used for pharmaceuticals or foods can be formulated as a stabilizer, a stabilizer, a surfactant, a plasticizer, a lubricant, a lubricant, a reduction, and a sweetness. Flavoring agent, diluent, adsorbent, flavoring agent, adhesive, anti-oxidation coating agent, coating agent, ancestor, i 7 、, filler, defoamer, cooling agent, chewing agent,多多南|,| I ' Add ^ tablets 蜊 蜊, sugar coating agent, foaming agent, excipients, disintegration: 剤 剤, 朋 solution extender, fragrance, P-wet agent, P , material 2 = kinetic agent, antistatic agent, extender, seasoning, sour: sweet, unsweetened, coloring agent, coloring agent, spice, fortifier, expansion = preservation material. Kill _, oxidation inhibitor Bleaching agent, Zengji flavoring material, it, ancient, > % π pre-agent, manufacturing agent, etc. Moreover, the composition of the present invention and the preparation containing the same are filled in a glass bottle or the like, in a condensed container or a transparent ρτρ package, and the precipitation caused by the precipitation, the odor is generated, and the σ soil is blurred. Unclear or crystallized, or prevent the gas from filling in an airtight container such as a glass bottle or a package without a time odor. [Examples] 125840.doc -17- 200824708 Next, the present invention will be more specifically described by way of examples and comparative examples, but the present invention is not limited thereto. Example 1
利用垂直製粒機VG-10(POWREX股份有限公司），混合 作為昇華性成分之乙醯胺酚（山本化學工業股份有限公司 製造）3 00 g、無水咖啡因（靜岡咖啡因股份有限公司製 造）80 g，及作為膨潤劑之低取代度羥丙基纖維素（LHPC : LH-31 :信越化學股份有限公司製造）420 g，其後，添加 • 1622 g之純化水加以混練後，利用TWIN DOME GRAN TDG-80(Fuji paudal股份有限公司製造）0·5 mm篩進行擠出 製粒後，利用流動層乾燥裝置FLO-5A/2(Freund產業股份 有限公司製造）進行乾燥，獲得平均粒徑約420 μιη之顆粒 劑。將該顆粒10 g放入透明玻璃之5號規格瓶中，蓋上栓 進行密閉，試驗室溫下保存6個月後之外觀，結果並未觀 察到瓶壁之模糊不清等晶鬚析出。 ^ 比較例1 混合乙醯胺酚（山本化學工業股份有限公司製造）30 g、 無水咖啡因（靜岡咖啡因股份有限公司製造）8 g，及低取代 ， 度羥丙基纖維素（LHPC : LH-3 1 :信越化學股份有限公司 ， 製造）42 g。將該混合物10 g放入透明玻璃之5號規格瓶 中，蓋上栓進行密閉，試驗室溫下保存6個月後之外觀， 結果觀察到瓶壁之模糊不清。 實施例2 利用垂直製粒機VG-10(POWREX股份有限公司），混合 125840.doc -18- 200824708 作為昇華性成分之茶鹼（白鳥製藥股份有限公司製造）200 g ’及作為膨潤劑之低取代度羥丙基纖維素（LHPC ·· LH-32 :信越化學股份有限公司製造）8〇〇 g，其後，添加24〇6 g之純化水進行混練後，利用TWIN DOME GRAN TDG-80(Fuji paudal股份有限公司製造）〇·6 mm篩進行擠出製粒 後’利用流動層乾燥裝置FL〇-5A/2(Freund產業股份有限 公司製造）進行乾燥，獲得平均粒徑約5〇〇 μπι之顆粒劑。 將該顆粒10 g放入透明玻璃之5號規格瓶中，蓋上栓進行 • 密閉’試驗室溫下保存6個月後之外觀，結果並未觀察到 瓶壁之模糊不清等晶鬚析出。 比較例2 混合茶鹼（白鳥製藥股份有限公司製造）2〇 g，及低取代 度經丙基纖維素（LHPC : LH-32 :信越化學股份有限公司 製造）80 g。將該混合物1〇 g放入透明玻璃之5號規格瓶 中’蓋上栓進行密閉，試驗室溫下保存6個月後之外觀， 結果觀察到瓶壁之模糊不清。 實施例3 利用垂直製粒機VG-10(P〇WREX股份有限公司），混合 作為昇華性成分之異布洛芬（BASF曰本股份有限公司製 造）300 g ’及作為膨潤劑之低取代度羥丙基纖維素 (LHPC : LH-31 :信越化學股份有限公司製造）600 g，其 後，添加1895 g之純化水進行混練後，利用TWIN DOME GRAN TDG-80(Fuji paudal股份有限公司製造）0·6 mm篩進 行擠出製粒後，利用流動層乾燥裝置FLO-5A/2(Freund產 125840.doc -19- 200824708 業股份有限公司製造）進行乾燥，獲得平均粒徑約500 μπι 之顆粒劑。將該顆粒10 g放入透明玻璃之5號規格瓶中， 蓋上栓進行密閉，試驗室溫下保存6個月後之外觀，結果 並未觀察到瓶壁之模糊不清等晶鬚析出。 比較例3 混合異布洛芬（BASF日本股份有限公司製造）30 g，及低 取代度羥丙基纖維素（LHPC : LH-3 1 :信越化學股份有限 公司製造）60 g。將該混合物10 g放入透明玻璃之5號規格 瓶中，蓋上栓進行密閉，試驗室溫下保存6個月後之外 觀，結果觀察到瓶壁之模糊不清。 實施例4 利用垂直製粒機VG-25(POWREX股份有限公司），混合 作為昇華性成分之無水咖啡因（靜岡咖啡因工業股份有限 公司）500 g、1-薄荷腦（高砂香料股份有限公司）45 g，及作 為膨潤劑之低取代度羥丙基纖維素（LHPC : LH-32 :信越 化學股份有限公司製造）955 g，其後，添加303 1 g之純化 水進行混練後，利用TWIN DOME GRAN TDG-80(Fuji paudal股份有限公司製造）0.6 mm篩進行擠出製粒後，利用 流動層乾燥裝置FLO-5A/2(Freund產業股份有限公司製造） 進行乾燥，獲得平均粒徑約500 μπι之顆粒劑。將該顆粒10 g放入透明玻璃之5號規格瓶中，蓋上栓進行密閉，試驗室 溫下保存6個月後之外觀，結果並未觀察到瓶壁之模糊不 清等晶鬚析出。 比較例4 125840.doc -20- 200824708 混合無水咖啡因（靜岡咖啡因工業股份有限公司）5〇 g、μ 薄荷腦（高砂香料股份有限公司）4·5 g，及作為膨潤劑之低 取代度羥丙基纖維素（LHPC : LH-32 :信越化學股份有限 公司製造）95.5 g。將該混合物10 g放入透明玻璃之5號規 格瓶中’蓋上栓進行密閉，試驗室溫下保存6個月後之外 觀’結果觀察到瓶壁之模糊不清。 實施例5Using a vertical granulator VG-10 (POWREX Co., Ltd.), mixing acetaminophen (manufactured by Yamamoto Chemical Co., Ltd.) as a sublimation component, 300 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Co., Ltd.) 80 g And 420 g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) as a swelling agent, and then, after adding 1622 g of purified water, and kneading, using TWIN DOME GRAN TDG -80 (manufactured by Fuji Paudal Co., Ltd.) After extrusion granulation, a 0.55 mm sieve was used for drying by a fluidized bed drying apparatus FLO-5A/2 (manufactured by Freund Industries Co., Ltd.) to obtain an average particle diameter of about 420 μm. Granules. 10 g of the pellet was placed in a No. 5 size bottle of clear glass, and the plug was sealed with a plug, and the appearance of the sample was stored at room temperature for 6 months. As a result, the blurring of the bottle wall and the like were not observed. ^Comparative Example 1 Mixed acetaminophen (manufactured by Yamamoto Chemical Co., Ltd.) 30 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Co., Ltd.) 8 g, and low-substituted, hydroxypropylcellulose (LHPC: LH-3) 1: Shin-Etsu Chemical Co., Ltd., manufactured) 42 g. 10 g of this mixture was placed in a No. 5 size bottle of clear glass, and the plug was sealed with a plug, and the appearance after 6 months of storage at room temperature was observed, and as a result, the bottle wall was observed to be blurred. Example 2 Using a vertical granulator VG-10 (POWREX Co., Ltd.), mixing 125840.doc -18- 200824708 as a sublimation component of theophylline (manufactured by White Bird Pharmaceutical Co., Ltd.) 200 g ' and low as a swelling agent Substituted hydroxypropylcellulose (LHPC ·· LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) 8 〇〇 g, after which 24 〇 6 g of purified water was added for kneading, and then TWIN DOME GRAN TDG-80 was used. (manufactured by Fuji paudal Co., Ltd.) 〇·6 mm sieve was subjected to extrusion granulation and then dried by a fluidized bed drying device FL〇-5A/2 (manufactured by Freund Industries Co., Ltd.) to obtain an average particle diameter of about 5 〇〇μπι Granules. 10 g of the granules were placed in a No. 5 bottle of clear glass, and the plug was placed on the lid. The appearance of the test was sealed for 6 months at room temperature. As a result, no blurring of the bottle wall was observed. . Comparative Example 2 Mixed theophylline (manufactured by White Bird Pharmaceutical Co., Ltd.) 2 〇 g, and a low degree of substitution by 80 g of propylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.). 1 μg of this mixture was placed in a No. 5 size bottle of clear glass. The plug was sealed and sealed, and the appearance after 6 months of storage at room temperature was observed. As a result, the bottle wall was observed to be blurred. Example 3 Using a vertical granulator VG-10 (P〇WREX Co., Ltd.), ibuprofen (manufactured by BASF Co., Ltd.) 300 g ' as a sublimation component and a low degree of substitution as a swelling agent were mixed. 600 g of hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.), and then, after mixing 1895 g of purified water, TWIN DOME GRAN TDG-80 (manufactured by Fuji Paudal Co., Ltd.) was used. After the extrusion granulation of the 0·6 mm sieve, it was dried by a fluidized bed drying device FLO-5A/2 (manufactured by Freund, Inc., 125840.doc -19-200824708 Co., Ltd.) to obtain granules having an average particle diameter of about 500 μm. Agent. 10 g of the pellet was placed in a No. 5 size bottle of transparent glass, and the plug was sealed with a plug, and the appearance after 6 months of storage at room temperature was examined. As a result, no whisker such as blurring of the bottle wall was observed. Comparative Example 3 30 g of isobuprofen (manufactured by BASF Japan Co., Ltd.) and 60 g of low-substituted hydroxypropylcellulose (LHPC: LH-3 1 : manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed. 10 g of this mixture was placed in a No. 5 size bottle of clear glass, and the plug was sealed with a plug. The test was allowed to stand at room temperature for 6 months, and the appearance of the bottle wall was observed to be blurred. Example 4 Using a vertical granulator VG-25 (POWREX Co., Ltd.), mixing anhydrous caffeine as a sublimation component (Shizuoka Caffeine Industry Co., Ltd.) 500 g, 1-Menthol (High Sand Spice Co., Ltd.) 45 g, and 955 g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) as a swelling agent, after which 303 g of purified water was added for kneading, and TWIN was used. DOME GRAN TDG-80 (manufactured by Fuji Paudal Co., Ltd.) was subjected to extrusion granulation using a 0.6 mm sieve, and dried by a fluidized bed drying apparatus FLO-5A/2 (manufactured by Freund Industries Co., Ltd.) to obtain an average particle diameter of about 500. Ππι granules. 10 g of the pellet was placed in a No. 5 size bottle of transparent glass, and the plug was sealed, and the appearance of the test chamber was maintained for 6 months. As a result, no blurring of the bottle wall and the like were observed. Comparative Example 4 125840.doc -20- 200824708 Mixed anhydrous caffeine (Shizuoka Caffeine Industry Co., Ltd.) 5〇g, μ menthol (Gaosha Fragrance Co., Ltd.) 4·5 g, and low substitution as a swelling agent Hydroxypropyl cellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) 95.5 g. 10 g of this mixture was placed in a clear glass No. 5 gauge bottle, and the plug was sealed and sealed. After the test was carried out for 6 months at room temperature, the bottle wall was obscured. Example 5
利用垂直製粒機VG-25(P〇WREX股份有限公司），混合 作為昇華性成分之異布洛芬（BASF曰本股份有限公司製 造）450 g、馬來酸氯菲安明（金剛化學股份有限公司）7 5 g、及無水咖啡因（靜岡咖啡因工業股份有限公司g，作 為路潤劑之低取代度羥丙基甲基纖維素（LHpc : LH_3 1 : 仏越化學股份有限公司製造）14〇〇 g、及羧甲基纖維素鈣 (五德藥品股份有限公司）56.5 g，此外，磷酸二氫可待因 (二共股份有限公司）24 g、dl_鹽酸甲基麻黃鹼（ALps藥品 工業股份有限公司）60 g、異丙碘胺（稻畑產業股份有限公 司）6 g、抗壞血酸（武田藥品丄業股份有限公司）3〇〇 §、硝 酸硫胺（BASF日本股份有限公司）24 g，其後，於其中添加 2 g之純化水進行混練，繼而，利用 GRAN TDG-8G(Fuji paudal股份有限公司製造5醒筛進 行擠出製㈣，利用流動層乾燥裝置FLO-5A/2(Fr_d產 業股份有限公司製造）進行乾燥，製作平均粒徑約420 _ ^顆粒顆粒。向該顆粒2162.7§中，添加結晶纖維素（旭化 成化學股份有限公司）361.8g、乳糖（DMV_an)⑽g、 125840.doc -21· 200824708 滑石（KIHARA化成股份有限公司）27 g及硬脂酸鎂（太平化 學產業股份有限公司）13.5 g並加以混合，利用旋轉式打片 機（菊水製作所）製造330 mg/片之裸片。利用高速塗佈機 (Freund產業製造）對該裸片喷霧由羥丙基甲基纖維素（信越 化學股份有限公司）、氧化鈦（石原產業股份有限公司）、純 化水、乙醇（7 : 3 : 20 : 70)構成之薄膜塗佈劑，獲得335 mg/片之薄膜塗佈片。將該片劑30片放入透明玻璃之5號規 格瓶中，蓋上栓進行密閉，試驗室溫下保存6個月後之外 觀，結果並未觀察到瓶壁之模糊不清等晶鬚析出。 實施例6 利用垂直製粒機VG-10(POWREX股份有限公司），混合 作為具有不快氣味之成分之硝酸硫胺（BASF曰本股份有限 公司製造）50 g，及作為無氣味性之膨潤劑之低取代度羥丙 基纖維素（LHPC : LH-31 :信越化學股份有限公司製 造）850 g，其後，添加2620 g之純化水進行混練後，利用 • TWIN DOME GRAN TDG-80(Fuji paudal股份有限公司製 造）0.6 mm篩進行擠出製粒後，利用流動層乾燥裝置FLO-5A/2(Freund產業股份有限公司製造）進行乾燥，獲得平均 粒徑約500 μιη之顆粒劑。將該顆粒10 g放入玻璃5號規格 瓶中，蓋上栓進行密閉，試驗氣味，結果於製造後及40°C 下保存6個月後並未觀察到不快氣味。 比較例5 混合硝酸硫胺（BASF日本股份有限公司製造）5 g，及低 取代度羥丙基纖維素（LHPC : LH-3 1 :信越化學股份有限 125840.doc -22- 200824708 公司製造）85 g。將該混合物1 0 g放入玻璃5號規格瓶中’ 蓋上栓進行密閉，試驗氣味，結果於製造後及4〇°C下保存 6個月後觀察到硫胺特有之不快維生素氣味。 實施例7 利用垂直製粒機VG-10(POWREX股份有限公司），混合 作為具有不快氣味之成分之白胺酸（味之素（AJIN0M0T0) 股份有限公司製造）200 g，及作為無氣味性之膨潤劑之低 取代度羥丙基纖維素（LHPC : LH-32 :信越化學股份有限 公司製造）800 g，其後，添加2094 g之15%乙醇/純化水進 行混練後，利用 TWIN DOME GRAN TDG-80(Fuji paudal股 份有限公司製造）0.6 mm篩進行擠出製粒後，利用流動層 乾燥裝置FLO_5A/2(Freund產業股份有限公司製造）進行乾 燥，獲得平均粒徑約500 μπι之顆粒劑。將該顆粒10 g放入 玻璃5號規格瓶中，蓋上栓進行密閉，試驗氣味，結果於 製造後及40°C下保存6個月後並未觀察到不快氣味。 比較例6 混合白胺酸(味之素股份有限公司製造）20 g，及低取代 度羥丙基纖維素（LHPC : LH-32 :信越化學股份有限公司 製造）80 g。將該混合物10 g放入玻璃5號規格瓶中，蓋上 栓進行密閉，試驗氣味，結果於製造後及40°C下保存6個 月後觀察到胺基酸特有之不快氣味。 實施例8 利用垂直製粒機VG-10(POWREX股份有限公司），混合 作為具有不快氣味之成分之d-α-生育酚琥珀酸酯（EISAI股 125840.doc -23- 200824708 份有限公司製造）1 00 g，及作為無氣味性之膨潤劑之低取 代度羥丙基纖維素（LHPC : LH-31 :信越化學股份有限公 司製造）900 g，其後，添加1902 g之純化水進行混練後， 利用 TWIN DOME GRAN TDG-80(Fuji paudai股份有限公司 製造）0.6 mm篩進行擠出製粒後，利用流動層乾燥裝置 FLO-5A/2(Freund產業股份有限公司製造）進行乾燥，獲得 平均粒徑約500 μιη之顆粒劑。將該顆粒1〇 g放入玻璃5號 規格瓶中，蓋上栓進行密閉，試驗氣味，結果於製造後及 40°C下保存6個月後並未觀察到不快氣味。 比較例7 混合d-α-生育酚琥珀酸酯（EISAI股份有限公司製造）10 g，及低取代度羥丙基纖維素（LHPC : LH-3 1 :信越化學股 份有限公司製造）90 g。將該混合物1 〇 g放入玻璃5號規格 瓶中，蓋上栓進行密閉，試驗氣味，結果於製造後及40°C 下保存6個月後觀察到特有之不快氣味。 實施例9 利用垂直製粒機VG-10(POWREX股份有限公司），混合 作為具有不快氣味之成分之人蔘乾燥萃取物（日本粉末藥 品股份有限公司製造）149.8 g(作為原草藥人蔘為1000 g)， 作為無氣味性之膨潤劑之低取代度羥丙基纖維素（LHPC : LH-32 :信越化學股份有限公司製造）280 g、及羧甲基纖 維素鈣（五德藥品股份有限公司）50.2 g，其後，添加952 g 之純化水進行混練後，利用TWIN DOME GRAN TDG-8〇(Fuji paudai股份有限公司製造）〇.6 mm篩進行擠出製粒 125840.doc -24- 200824708 後’利用流動層乾燥裝置FLO-5A/2(Freund產業股份有限 公司製造）進行乾燥，獲得平均粒徑約500 μπι之顆粒劑。 將該顆粒1 〇 g放入玻璃5號規格瓶中，蓋上栓進行密閉， 試驗氣味，結果於製造後及40°C下保存6個月後並未觀察 到不快氣味。 比較例8 混合人蔘乾燥萃取物（日本粉末藥品股份有限公司製 瞻造）7·49 g，低取代度羥丙基纖維素（LHPC ·· LH-32 :信越 化學股份有限公司製造）14 g、及羧甲基纖維素鈣（五德藥 w股份有限公司）2·51 g。將該混合物1〇 g放入玻璃5號規 格瓶中，蓋上栓進行密閉，試驗氣味，結果於製造後及 4〇°C下保存6個月後觀察到特有之不快氣味。 實施例10 利用垂直製粒機VG-l〇(p〇WREX股份有限公司），混合 2為具有不快氣味之成分之葛根湯乾燥萃取物（日本粉末 • 藥的股份有限公司）400 g(作為原草藥為2000 g)，作為無氣 綠之膨潤劑之低取代度經丙基甲基纖維素（LHpc : ^ _ 31 · ^越化學股份有限公司製造）14G g、及魏甲基纖維素 .五德藥品股份有限公司）21〇 g，其後，於其中添加973 g之、、、屯化水進仃混練，繼而，利用则⑽龍 TDG-SOCFuji paudal股份有限公司製造)〇.6匪筛進行擠出 製粒後，利用流動層 乾知裝置FLO-5A/2(Freund產業股份 有限公司製造）進行菸 、 米’獲得平均粒徑約500 μπι之顆粒 劑。將該顆粒10 8放Α木+ 玻璃5號規格瓶中，蓋上栓進行密 125840.doc •25· 200824708 閉’試驗氣味，結果於製造後及40°C下保存6個月後並未 觀察到不快氣味。 比較例9 混合葛根湯乾燥萃取物（日本粉末藥品股份有限公司）2〇 g ’低取代度羥丙基甲基纖維素（LHPC : LH-31 :信越化學 股份有限公司製造）7 g、及羧甲基纖維素鈣（五德藥品股份 有限公司）10.5 g。將該混合物1〇 g放入玻璃5號規格瓶 中，盍上栓進行密閉，試驗氣味，結果於製造後及4〇。〇下 保存6個月後觀察到特有之不快氣味。 [產業上之可利用性] 含有具有昇華性或氣味之成分及膨潤劑，並進行濕製粒 而仵之本發明之固形組合物，可藉由抑制昇華性成分之昇 華’而抑制晶鬚析出、容器壁之模糊不清，又，可簡便且 有效地防止因具有氣味之成分所引起之不快氣味。進而， 本發明之固形組合物，具有顆粒狀之形狀，且流動性良 3 ’因此不僅可將固形組合物之顆粒直接製成散劑、 劑、顆粒劑等’且即使製成膠囊劑或片劑，亦易於加工， :廣泛用於醫樂品、食品等。進而，本發明之固形组人 物’即使長時間保存於氣密性之透明容… 因昇華性$ # t曰彩Μ φ σ中，亦未發現 幵華I·生成刀之曰曰須析出所造成的保存 或結晶之析出，未發現不快氣 之拉糊不>月 的品質。進而，本發明之固：广：產生’可長期維持穩定 十知d乏固形組合物， 係不僅易於服用，且具有各 ’、；；，因此 厭地服用之製劑。 Μ賈者可長期不 125840.doc * 26 -Using a vertical granulator VG-25 (P〇WREX Co., Ltd.), mixed as a sublimation component, isobuprofen (manufactured by BASF Co., Ltd.) 450 g, chlorpheniramine maleate (King Kong Chemical Co., Ltd.) Ltd.) 7 5 g, and anhydrous caffeine (Shizuoka Caffeine Industry Co., Ltd., low-substituted hydroxypropyl methylcellulose as a lubricity agent (LHpc: LH_3 1 : manufactured by Min Yue Chemical Co., Ltd.) ) 14〇〇g, and carboxymethylcellulose calcium (Wude Pharmaceutical Co., Ltd.) 56.5 g, in addition, dihydrocodeine phosphate (two companies) 24 g, dl_methylephedrine hydrochloride (ALps Pharmaceutical Industry Co., Ltd.) 60 g, isopropyl iodide (rice industry) 6 g, ascorbic acid (Wuta Pharmaceutical Co., Ltd.) 3 〇〇 §, thiamine nitrate (BASF Japan Co., Ltd. 24 g, after which 2 g of purified water was added thereto for kneading, and then, using GRAN TDG-8G (manufactured by Fuji Paudal Co., Ltd., 5 sifting, extrusion (4), using a fluidized bed drying device FLO-5A/ 2(Fr_d Industry Co., Ltd. (manufacturing) drying to produce granules having an average particle diameter of about 420 Å. To the 2162.7 §, adding crystal cellulose (Asahi Kasei Chemical Co., Ltd.) 361.8 g, lactose (DMV_an) (10) g, 125840.doc -21· 200824708 27 g of talc (KIHARA Chemical Co., Ltd.) and 13.5 g of magnesium stearate (Taiping Chemical Industry Co., Ltd.) were mixed, and a 330 mg/piece of bare piece was produced by a rotary tableting machine (Kikyo Seisakusho Co., Ltd.). The coating machine (manufactured by Freund Industries) sprays the die from hydroxypropylmethylcellulose (Shin-Etsu Chemical Co., Ltd.), titanium oxide (Ishihara Sangyo Co., Ltd.), purified water, and ethanol (7:3:20). : 70) A film coating agent is formed, and a film-coated sheet of 335 mg/piece is obtained. 30 pieces of the tablet are placed in a No. 5 size bottle of transparent glass, and the plug is sealed, and the test is carried out at room temperature. After the appearance of the month, the result was that no obscuration such as blurring of the bottle wall was observed. Example 6 Using a vertical granulator VG-10 (POWREX Co., Ltd.), nitric acid mixed as a component having an unpleasant odor was mixed. 50 g of an amine (manufactured by BASF Co., Ltd.), and 850 g of low-substituted hydroxypropylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) as an odorless swelling agent, after that, After adding 2620 g of purified water and kneading, it was subjected to extrusion granulation using a 0.6 mm sieve of TWIN DOME GRAN TDG-80 (manufactured by Fuji Paudal Co., Ltd.), and then using a fluidized bed drying device FLO-5A/2 (Freund Industrial Co., Ltd.) Drying was carried out to obtain granules having an average particle diameter of about 500 μm. 10 g of the pellet was placed in a glass No. 5 bottle, and the plug was sealed to test the odor. As a result, no unpleasant odor was observed after storage for 6 months at 40 °C. Comparative Example 5 Mixed thiamine nitrate (manufactured by BASF Japan Co., Ltd.) 5 g, and low-substituted hydroxypropylcellulose (LHPC: LH-3 1 : Shin-Etsu Chemical Co., Ltd. 125840.doc -22-200824708) 85 g. 10 g of this mixture was placed in a glass No. 5 size bottle, and the plug was sealed to test the odor. As a result, the unpleasant vitamin odor of thiamine was observed after storage for 6 months at 4 ° C. Example 7 Using a vertical granulator VG-10 (POWREX Co., Ltd.), 200 g of leucine (manufactured by Ajino M. Co., Ltd.) as a component having an unpleasant odor was mixed, and as odorless Low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) 800 g of a swelling agent, and then, after mixing 2094 g of 15% ethanol/purified water, TWIN DOME GRAN TDG was used. -80 (manufactured by Fuji Paudal Co., Ltd.), 0.6 mm sieve was subjected to extrusion granulation, and then dried by a fluidized bed drying apparatus FLO_5A/2 (manufactured by Freund Industries Co., Ltd.) to obtain granules having an average particle diameter of about 500 μm. 10 g of the pellet was placed in a glass No. 5 size bottle, and the plug was sealed to test the odor. As a result, no unpleasant odor was observed after storage for 6 months at 40 °C. Comparative Example 6 20 g of leucine (manufactured by Ajinomoto Co., Ltd.) and 80 g of low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed. 10 g of this mixture was placed in a glass No. 5 size bottle, and the plug was sealed to test the odor. As a result, the unpleasant odor of the amino acid was observed after storage for 6 months at 40 °C. Example 8 Using a vertical granulator VG-10 (POWREX Co., Ltd.), d-α-tocopherol succinate mixed as a component having an unpleasant odor (EISAI shares 125840.doc -23-200824708 Co., Ltd.) 1 00 g, and 900 g of low-substituted hydroxypropyl cellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) as a odorless swelling agent, after which 1,902 g of purified water was added for kneading After extrusion granulation using a 0.6 mm sieve of TWIN DOME GRAN TDG-80 (manufactured by Fuji Paudai Co., Ltd.), it was dried by a fluidized bed drying apparatus FLO-5A/2 (manufactured by Freund Industries Co., Ltd.) to obtain an average granule. Granules with a diameter of about 500 μηη. The pellet 1 g was placed in a glass No. 5 size bottle, and the plug was sealed to test the odor. As a result, no unpleasant odor was observed after storage for 6 months at 40 ° C. Comparative Example 7 10 g of d-α-tocopherol succinate (manufactured by EISAI Co., Ltd.) and 90 g of low-substituted hydroxypropylcellulose (LHPC: LH-3 1 : manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed. The mixture 1 〇 g was placed in a glass No. 5 size bottle, and the plug was sealed to test the odor. As a result, a characteristic unpleasant odor was observed after storage for 6 months at 40 ° C. Example 9 Using a vertical granulator VG-10 (POWREX Co., Ltd.), a human dry extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.), which is a component having an unpleasant odor, was mixed with 149.8 g (as the original herbal medicinal 蔘 1000 g), low-substituted hydroxypropylcellulose (LHPC: LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) 280 g, and carboxymethylcellulose calcium as a odorless swell agent 50.2 g, after that, 952 g of purified water was added and kneaded, and then extruded and granulated using TWIN DOME GRAN TDG-8(R) (manufactured by Fuji Paudai Co., Ltd.) 6.6 mm sieve 125840.doc -24- 200824708 After that, it was dried by a fluidized bed drying apparatus FLO-5A/2 (manufactured by Freund Industries Co., Ltd.) to obtain granules having an average particle diameter of about 500 μm. The pellet 1 〇 g was placed in a glass No. 5 size bottle, and the plug was sealed to test the odor. As a result, no unpleasant odor was observed after storage for 6 months at 40 °C. Comparative Example 8 Mixed human dried extract (manufactured by Nippon Powder Pharmaceutical Co., Ltd.) 7.49 g, low-substituted hydroxypropyl cellulose (LHPC ·· LH-32: manufactured by Shin-Etsu Chemical Co., Ltd.) 14 g And carboxymethylcellulose calcium (Wude Pharmaceutical Co., Ltd.) 2. 51 g. The mixture was placed in a glass No. 5 gauge bottle, and the plug was sealed to test the odor. As a result, a characteristic unpleasant odor was observed after storage for 6 months at 4 °C. Example 10 Using a vertical granulator VG-l〇 (p〇WREX Co., Ltd.), mixing 2 as a component of an unpleasant odor, a dried extract of Kudzu Soup (Japanese Powder Pharmaceutical Co., Ltd.) 400 g (as the original Herbal medicine is 2000 g), as a low-degree substitution of serotonin-free swelling agent, propylmethylcellulose (LHpc: ^ _ 31 · ^ Vietnam Chemical Co., Ltd.) 14G g, and Wei methyl cellulose. Wude drug Co., Ltd.) 21〇g, after which, 973 g of it, and phlegded water were mixed and kneaded, and then, using (10) Dragon TDG-SOC Fuji paudal Co., Ltd.) 〇.6 匪 sieve for extrusion After the granulation, the granules having an average particle diameter of about 500 μm were obtained by using a fluidized layer drying device FLO-5A/2 (manufactured by Freund Industries Co., Ltd.). The granules 10 8 were placed in a eucalyptus + glass No. 5 size bottle, and the plug was covered with a plug to carry out the immersion test of 125840.doc •25·200824708, and the result was not observed after being stored for 6 months at 40 ° C. Unpleasant smell. Comparative Example 9 Mixed kudzu decoction dried extract (Japan Powder Pharmaceutical Co., Ltd.) 2〇g 'low-substituted hydroxypropyl methylcellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) 7 g, and carboxy Methylcellulose calcium (Wude Pharmaceutical Co., Ltd.) 10.5 g. The mixture was placed in a glass No. 5 size bottle, and the plug was sealed to test the odor. The result was 4 hours after the production. A unique unpleasant odor was observed after 6 months of storage. [Industrial Applicability] The solid composition of the present invention containing a sublimation or odor component and a swelling agent and wet granulation can suppress the precipitation of whiskers by suppressing the sublimation of the sublimation component The container wall is illegible, and the unpleasant odor caused by the odorous component can be easily and effectively prevented. Further, the solid composition of the present invention has a granular shape and has good fluidity 3', so that not only the granules of the solid composition can be directly formed into powders, agents, granules, etc., and even if it is made into a capsule or a tablet. It is also easy to process, and is widely used in medical music and food. Further, the solid-shaped group character of the present invention is stored in a transparent and transparent space for a long time... Because of the sublimation property $# t曰彩Μ φ σ, no precipitation of the 幵华I·production knife is found. The preservation or crystallization of the precipitation, did not find the unpleasantness of the paste does not > the quality of the month. Further, the present invention is broadly prepared to produce a composition which is stable for a long period of time and which is not only easy to take, but also has various preparations. Μ Jia may not be long-term 125840.doc * 26 -