200412930 ⑴ 玖、發明說明 【發明所屬之技術領域】 本發明係將食品、健康食品、醫藥、香料及香辛料等 之充塡物質’以明膠及瓊脂等所形成之皮膜物質被覆所成 之無接縫膠囊的製造方法。尤其係關於適合製造具有於口 腔內可容易地破壞皮膜而將充塡物質放出於口腔內之口腔 內可即溶性之口腔內可即溶之無接縫膠囊的製造方法。 【先前技術】 傳統以來’製造被覆層無接縫之膠囊，亦即無接縫膠 囊之技術中’尤其作爲適合製造比通常的軟膠囊小，比微 膠囊大之膠囊之技術，由二重噴嘴、三重噴嘴等之多重噴 嘴噴出多層液流，形成多層液滴，使此多層液滴之最外層 液與硬化用液接觸而硬化形成皮膜，以該皮膚被覆內層液 而得無接縫膠囊之方法及適合其製造之製造裝置係由下述 文獻所提出。 特開昭5 9 — 1 1 8 5 9號公報 特開昭6 2 — 1 7 6 5 3 6號公報 特開昭6 2 — 1 8 0 7 4 4號公報 特開平4 — 3 2 2 7 4 0號公報 特開平4 — 3 2 2 7 4 1號公報 特開平5 — 2 2 8 3 6 0號公報 特開平4 — 338230號公報 特開平5 — 200274號公報 -5- (2) (2)200412930 特開平5 — 200275號公報 特開平5 — 2 0 0 2 7 6號公報 特開平5 - 1 3 8 0 1 2號公報 特開平6 — 1 3 4 2 9 2號公報 特開平6— 154587號公報 特開平8 — 1 0 3 1 3號公報 特開平8— 26976號公報 特開平9 — 1 5 5 1 8 3號公報 近年來，於點心類、機能性食品及嗜好品等之食物領 域’於口腔內簡單地破壞皮膜，放出由該皮膜所封住之食 品、醫藥及香料等之充塡物質於口腔內，立即可得到淸涼 感或防止口臭效果之口腔內可即溶性膠囊逐漸開發。此種 口腔內可即溶性膠囊於醫藥領域中，因沒有水亦可容易服 藥’作爲適合於高齡者或小孩等之吞嚥機能低之服藥困難 之患者之劑型而受到囑目。因此，使用上述之無接縫膠囊 的製造技術，嘗試口腔內可即溶性膠囊的製造。 然而，於製造口腔內可即溶性膠囊時，爲形成於口腔 內容易破壞之皮膜，所以使皮膜變薄或於口內容易溶解時 ’製造中之皮膜未被充份硬化，即使硬化，膜的強度亦弱 ’與硬化液分離時等，膠囊容易變形或破壞，變得難以製 造。另一方面，若使皮膜具有充份的膜強度時，所得的製 品於口腔內時皮膜變得難以破壞，不能得到充份的口腔內 可即溶性。 以如此之傳統技術，具有於口腔內容易破壞之口腔內 -6- (3) 200412930 可即溶性之另一方面，製造於製造時難以發生皮膜硬化不 良或遭破壞等問題之製品係困難的。 本發明係有鑑於上述情形而實施者，係以提供具有口 腔內容易破壞之口腔內可即溶性，而且可製造於製造時難 以發生皮膜硬化不良或遭破壞等問題之製品之口腔內可即 溶之無接縫膠囊的製造方法爲目的。 【發明內容】200412930 ⑴ 发明, description of the invention [Technical field to which the invention belongs] The present invention is a jointless material formed by coating foodstuffs, health foods, medicines, spices, spices, and other filling substances with coating materials such as gelatin and agar. Manufacturing method of capsule. In particular, the present invention relates to a manufacturing method suitable for producing a seamless capsule in an oral cavity which is capable of easily destroying a film in a mouth cavity and releasing a filling substance into the oral cavity which is soluble in the oral cavity. [Previous technology] Traditionally, 'the technology of manufacturing jointless capsules, that is, jointless capsules', is especially suitable for the manufacturing of capsules smaller than ordinary soft capsules and larger than microcapsules. Multiple nozzles, such as triple nozzles, eject multiple layers of liquid flow to form multiple layers of liquid droplets. The outermost layer of the multiple layer droplets contacts the hardening liquid to harden to form a film. The inner layer of liquid is covered with the skin to obtain jointless capsule A method and a manufacturing device suitable for the manufacturing thereof are proposed by the following documents. JP 5 9 — 1 1 8 5 9 JP 6 2 — 1 7 6 5 3 6 JP 6 2 — 1 8 0 7 4 4 JP 4 — 3 2 2 7 4 Japanese Patent Publication No. 0 JP 4-3 2 2 7 4 Japanese Patent Publication No. 1 JP 5-2 2 8 3 6 Japanese Patent Publication No. 4-338230 Japanese Patent Publication No. 5-200274-5 (2) (2) 200412930 Japanese Patent Laying-Open No. 5 — 200275 Japanese Patent Laying-Open No. 5-2 0 0 2 7 Japanese Patent Laying-Open No. 5-1 3 8 0 1 Japanese Patent Laying-Open No. 6-1 3 4 2 9 Japanese Patent Laying-Open No. 6-154587 Japanese Patent Laid-Open No. 8-1 0 3 1 Japanese Patent Laid-Open No. 8-26976 Japanese Patent Laid-Open No. 9-1 5 5 1 8 In recent years, in the food field such as snacks, functional foods, and hobby products, The membrane is simply destroyed in the oral cavity, and the filling materials such as food, medicine and spices sealed by the membrane are released into the oral cavity, and the instant soluble capsules in the oral cavity which can immediately obtain a cool feeling or prevent bad breath are gradually developed. Such an intraorally soluble capsule is used in the medical field because it can be easily taken without water 'as a dosage form suitable for elderly patients or children with low swallowing ability and difficult to take medication. Therefore, using the above-mentioned manufacturing technology of the seamless capsule, an attempt was made to manufacture an instant capsule in the oral cavity. However, when manufacturing instant capsules in the oral cavity, in order to form a film that is easily damaged in the oral cavity, the film is thinned or easily dissolved in the mouth. The strength is also weak, such as when separated from the hardening liquid, the capsule is easily deformed or broken, making it difficult to manufacture. On the other hand, if the film has sufficient film strength, the film becomes difficult to break when the obtained product is in the oral cavity, and sufficient oral solubility is not obtained. With such a conventional technique, it is easy to break into the oral cavity -6- (3) 200412930. On the other hand, it is difficult to manufacture a product which is hard to cause problems such as poor film hardening or damage during manufacture. The present invention has been implemented in view of the above-mentioned circumstances, and is to provide a product that is readily soluble in the oral cavity, which is easily damaged in the oral cavity, and can be manufactured in a product that is difficult to cause problems such as poor film hardening or damage during manufacture. The purpose is to produce a jointless capsule. [Summary of the Invention]
發明之揭示 本發明之口腔內可即溶之無接縫膠囊的製造方法係具 有 調製含有充塡物質芯液之步驟； 調製溶解含有1種或2種以上選自甘油、丙二醇及聚 乙二醇之成群所形成之可塑劑及皮膜形成劑之皮膜物質之 皮膜液之步驟；DISCLOSURE OF THE INVENTION The method for manufacturing an instant instant jointless capsule in the oral cavity of the present invention includes the step of preparing a core liquid containing a substance that is filled with a substance; preparing and dissolving one or two or more selected from glycerin, propylene glycol, and polyethylene glycol The step of forming a plastic film of the plasticizer and the film forming agent,
具有內側噴嘴及上述包圍內側噴嘴之外側噴嘴之多重 噴嘴，將上述芯液由上述之內側噴嘴，將上述之皮膜液由 上述外側噴嘴噴出而分別供給，由上述之多重噴嘴噴出多 層液流形成多層液滴之步驟； 使上述之多層液滴，與流路內所流通之硬化用液接觸 ，硬化上述皮膜液，形成以上述皮膜物質被覆上述芯液所 成之無接縫膠囊之步驟； 由包含上述無接縫膠囊之上述硬化用液，分離上述無 接縫膠囊之步驟；以及 -7- (4) (4)200412930 除去由上述硬化用液所分離之上述無接縫膠囊之表面 所附著之硬化用液，以及乾燥表面，形成實質上無互相附 著性之無接縫膠囊之步驟。依此製造粒徑爲1至1 〇mm， 皮膜物質及充塡物質之質量比爲5 : 95至70 : 3 0，可塑 劑之添加量係對於除水以外之皮膜物質總量之20至70質 量％之無接縫膠囊。 依據此方法，可提供具有口腔內容易破壞之口腔內可 即溶性，而且可製造於製造時難以發生皮膜硬化不良或遭 破壞等問題之製品之口腔內可即溶之無接縫膠囊的製造方 法爲目的。上述可塑劑亦可爲甘油。 用以實施發明之最佳型態 以下，係詳細地說明本發明之實施例，但本發明並不 局限於下述之實施例，在申請的範圍內，均可作任何變更 〇 本發明者等爲得到口腔內容易破壞之口腔內可即溶性 ’對於各膠囊例如硬膠囊、軟膠囊及無接縫膠囊，作各種 檢討。硬膠囊僅於口腔內膨潤而不崩壞，不能得到口腔內 可即溶性。軟性膠囊係製法上，皮膜物質必須爲總質量中 之3 0質量％以上。另外，關於無接縫膠囊，單獨明膠時 之溶解性鈍化。但是，膠囊之皮膜物質質量比係以無接縫 膠囊爲最少，無接縫膠囊作爲口腔內可即溶性膠囊係最適 合的。一般於皮膜物質之明膠中添加可塑劑使用，但作爲 □腔內可即溶性膠囊所使用之可塑劑係以水溶性可塑劑爲 -8- (5) (5)200412930 宜。 由此等之檢討結果’本發明者等發現以含有皮膜形成 劑及可塑劑之皮膜物質，被覆充塡物質所成之粒徑爲1至 10mm，皮膜物質及充塡物質之質量比爲5: 95至70: 30 之範圍，上述可塑劑係使用1種或2種以上選自甘油、丙 二醇及聚乙二醇之成群，可塑劑之添加量係對於除水以外 之皮膜物質總量之2 0至7 0質量％之範圍之無接縫膠囊， 作爲口腔內可即溶性膠囊係特別優異的。 另外，本發明者等確立可製造於製造時難以發生皮膜 硬化不良或遭破壞等問題之製品之口腔內可即溶之無接縫 膠囊的製造方法。 此實施例之無接縫膠囊的製造方法係具備以下的步驟 〇 〈步驟A >調製含有充塡物質芯液，以及溶解皮膜物 質之皮膜液。 〈步驟B >具有內側噴嘴及包圍其內側噴嘴之外側噴 嘴之多重噴嘴，將上述芯液由內側噴嘴，將皮膜液由外側 噴嘴分別噴出而供給，由該多重噴嘴噴出多層液流形成多 層液滴。 〈步驟C >使上述多層液滴，流動於流路內所流通之 硬化用液中，硬化上述皮膜液，形成以皮膜物質被覆芯液 所成之無接縫膠囊。 〈步驟D >由包含上述無接縫膠囊之上述硬化用液， 分離無接縫膠囊 -9 - (6) (6)200412930 〈步驟E〉除去由硬化用液所分離之無接縫膠囊之表 面所附著之硬化用液，以及乾燥表面，形成實質上無互相 附著性之無接縫膠囊。 依據步驟A至E之順序進行，以含有明膠等之皮膜 形成劑及甘油等之可塑劑之皮膜物質，被覆充塡物質，製 造粒徑爲1至10mm，皮膜物質及充塡物質之質量比之範 圍爲5 : 9 5至7 0 : 3 0之無接縫膠嚢。以下，詳細說明各 步驟例。 〈步驟A〉 本發明中’只要充塡物質由步驟B之多重噴嘴作爲芯 液噴出時爲液狀即可，形成多層液滴後，該芯液可爲原本 的液體，或亦可於形成無接縫膠囊後爲凝膠狀或固體。此 充塡物質可包含因應食品、健康食品、香料、香辛料、醫 藥或芳香劑等之無接縫膠囊之用途所選擇之主要成份（醫 藥時爲有效成份）之外，其他食品製造上或藥學上所容許 之各種添加物，例如食用油等之溶媒、甘味料、酸味料、 香料、色素、增粘劑（凝膠化劑）、安定化劑及乳化劑等 。將充塡物質調製爲液狀時，可將上述主要成份溶解於溶 媒而成透明的溶液、懸濁液及乳液（乳霜）的型態。調製 液狀之充塡物質’亦即芯液之方法係可使用於食品製造領 域或醫藥品製造領域之已知方法。例如調製透明液狀之芯 液時’可使用稱量上述主要成份及添加物，與食用油等之 溶媒混合，因應需要，加溫、攪拌成均勻溶液的方法。調 -10- (7) (7)200412930 製乳液狀之芯液時，可使用將含有乳化劑之水性成份及油 性成份，使用勻化器乳化’製造油中水型乳膠之傳統已知 之方法。例如有關高甘味度甘味料，即阿斯巴甜及蔗糖素 等之可分散溶解於乙醇之物質，因爲直接分散於油所形成 之粒子徑過大，膠囊之成形性不安定，所以亦可以使用首 先於乙醇中，使用勻化器將此等分散溶解，再將其溶解於 油之方法。 本發明中，皮膜物質係含有1種或多種之明膠及瓊脂 等之食品製造上或藥學上所容許之皮膜形成劑，以及爲使 硬化後之皮膜於口腔內容易破裂之使膜柔軟，降低口腔內 之膜強度用之可塑劑。作爲可塑劑係使用1種或2種以上 選自甘油、丙二醇及聚乙二醇所成群，作爲適合之可塑劑 ，可舉例如甘油。此可塑劑之添加量係對於皮膜物質總量 (除皮膜液之水以外之成份的合計量）爲20至70質量％ ，以30至65質量％爲宜，以40至60質量％尤佳。甘油 爲可塑劑，以上述範圍內配合於皮膜物質時，硬化後之皮 膜變得柔軟而且容易溶解於口腔內。 皮膜物質中，與上述之可塑劑同樣地可提高皮膜物質 硬化後之硬度，例如可加入山梨糖醇，調製皮膜硬度。另 外，依據添加粘多糖類、凝膠化劑及蛋白質分解物等，可 提升皮膜之經時安定性。皮膜物質係可以色素著色成任意 色調’亦可加入香料、甘味料及酸味料等。此等之山梨糖 醇、粘多糖類、凝膠化劑及蛋白質分解物等之添加量，通 常對於皮膜物質總量之1 〇質量％以下，以5質量％以下 -11 - (8) (8)200412930 爲宜。 至少含有皮膜形成劑及可塑劑之皮膜物質係加入適量 的水，加溫溶解而調製皮膜液。皮膜液中之皮膜物質之配 合量（即除水以外之成份之合計量）係相對於皮膜液總量 之10至50質量％，以20至40質量％程度爲宜。皮膜形 成物質之配合量，於明膠時係相對於皮膜液總量之1 5至 35質量％，以20至30質量％程度爲宜。 並不局限於加水於皮膜形成劑中而加溫溶解的方法， 例如可使用加水於皮膜形成劑中膨潤後加溫溶解的方法， 以及將皮膜形成劑投入溫水，攪拌溶解的方法。只要爲此 溫水攪拌溶解方法，可短時間調液。加溫溫度係因應所使 用之皮膜形成劑之種類而設定，例如明膠時係可設定爲 45至90 °C，以45至55 °C程度爲宜。爲調製不含氣泡之 皮膜液，於減壓加溫槽內，投入皮膜物質及水，於減壓環 境下加溫攪拌，脫氣狀態下調製皮膜液爲宜。 如上述之各種所調製芯液及皮膜液係保管於各自的貯 液槽等之適當的容器內。皮膜液必須保溫以免冷卻而凝膠 化。皮膜液之保溫溫度係因應所使用之皮膜形成劑之種類 而設定，例如明膠時爲45至90 °C，以45至55 °C程度爲 宜。芯液及皮膜液之調製量係配合於完成之無接縫膠囊中 之皮膜物質及充塡物質之質量比爲5 : 95至70 : 3 0之範 圍所設定的任何質量比而調製、準備爲宜。 〈步驟B至D > -12- (9) 200412930 步驟B $ d係使用傳統已知之無接縫膠囊 而可連續實施。圖1係舉例表示適合連續地實施 無接縫膠囊之製造方法之步驟B至D之製造裝 構成圖。 圖1的液中噴嘴式無接縫膠囊製造裝置中， 縫膠囊用之芯液（內層液）1係貯存於芯液用槽 覆此芯液1之皮膜液（外層液）3係貯存於被覆 中〇 芯液1係以唧筒5由芯液用槽2，經由管路 至多重噴嘴7，另一方面，皮膜液3係以唧筒8 用槽4，經由管路9，壓送至上述多重噴嘴7。 上述多重噴嘴7係構成可插入於流通管1 1 ，亦即硬化用液1 0之流入處1 1 A之中，將芯液 液3噴出於流通管1 1內之硬化用液1 〇之中，生 滴。 硬化用液1 0係冷卻硬化所生成之多層液滴 接縫膠囊S C。作爲硬化用液，冷卻皮膜液使之 使用於食用油例如中鏈脂肪酸甘油酯（MCT : MCT中加入卵磷脂等之界面活性劑，改善多層: 止附著性之硬化用液等。硬化用液之溫度設定爲 溫程度。 本裝置中之流通管1 1係形成爲彎曲形狀之 以略成J子形之流入處11A’以及以嵌合處lie 入處11A互相地摺動而且嵌合成可密封之套疊式 製造裝置 本發明之 置之槪略 形成無接 2中，被 液用槽4 6，壓送 由被覆液 之入口處 1及皮膜 成多層液 ，形成無 硬化時， > ，於此 液滴之防 o°c至室 圓柱體， ，與該流 之逆J字 -13- 200412930 do) 形之流出處1 1 B所構成。因此，如後所述，流通管1 1係 於肷合處11C，流入處11A及流出處11B可互相地上下 方向相對地移動，尤其於本裝置之流出處1 1 B係構成可上 下移動的。 上述流通管11之流出處11B之出口處下方，設有略 成漏斗形狀之分離器1 2。此分離器1 2係使由流通管i i 一起流出之無接縫膠囊S C及硬化用液1 0互相分離者， 其內部中係設有不使無接縫膠囊S C通過，而且僅使硬化 用液1 0通過之濾網1 3。 分離器1 2係與流通管1 1之流出處1 1 B —起以驅動來 源1 4 ’如氣體汽缸或油壓汽缸之流體壓汽缸，或是馬達 等而可上下移動。亦即，流通管n之流出處i i B之一部 份與連接棒1 1 D結合，另一方面，分離器12與連接棒 1 2 A結合’而且此等連接棒〗丨〇及丨2 a係以連接材料j 5 互相結合，此連接材料1 5係驅動源1 4的一部份，例如結 合於汽缸之活塞杆。 因此’驅動驅動來源1 4，例如使氣體汽缸之活塞杆 上下方向來回移動時，流通管11之流出處11B及分離器 12係介由連接材料15及各連接棒丨1D及12A僅以等距離 一起上下移動。 依此’ ^通管1 1之流入處1 1 A之液面及流出處1 1 b 之液面之高度差△ h係可調節的，流通管n內之硬化用 液1 〇之流速係可調節的。 而且’流通管11之流出處11B及分離器12 —起上下 -14- (11) (11)200412930 移動時，流出處11 B中之硬化用液1 〇之液面及分離器1 2 (尤其該濾網13 )間之局度差保持一定。 以分離器1 2由無接縫膠囊s C所分離出硬化用液1 0 係回收於下方之分離槽1 6中。 上述分離器1 2下端之細管處係構成可與分離槽1 6之 上端筒狀處互相嵌合，即使該分離器1 2上下移動亦不脫 離分離槽1 6。 分離槽1 6內之硬化用液1 0係由啷筒1 9，經由管路 2 0，壓送至冷卻槽2 1。冷卻槽2 1內之硬化用液1 〇以冷 卻器2 2冷卻至所定的溫度後，以唧筒2 3經由管路2 4回 到流通管1 1之中。 因爲此無接縫膠囊製造裝置係液中噴嘴式之構造，多 重噴嘴7係構成可插入形成供給硬化用液〗〇用流路之流 通管1 1之入口處，噴出芯液1及皮膜液3於液中，後者 被覆前者之全部周圍。 因此，本實施例中，由多重噴嘴所噴出之芯液1及皮 膜液3於流通管1 1內之硬化用液1 〇中，形成多層液滴（ 步驟Β )，以隨著流通管1 1中流動之硬化用液1 〇之作用 而冷卻硬化，形成無接縫膠囊S C (步驟C )。接著，如 此形成之無接縫膠囊SC係由流通管Π之流出處1 1 Β之 出口端，分離器12之濾網1 3上方，與硬化用液1 〇 一起 流下，以該濾網1 3由硬化用液1 〇所分離（步驟D )，而 且該硬化用液1 0通過濾網1 3，回收於分離槽1 6之中。 另一方面，濾網1 3上所捕集之無接縫膠囊S C，後續達成 - 15- (12) (12)200412930 適當量時，以批式回收於圖中未表示之製品回收容器中。 本裝置中，調節流通管1 1之流入處1 1 A及流出處 1 1 B之液面高度差△ h時，因爲流通管1 1之流出處1 1 B 以驅動來源1 4對於流入處1 1 A可上下移動，所以流通管 1 1內之硬化用液1 〇之流速係依任意變化上述液面高度差 △ h於下降位置及上升位置之間，而可任意調節至最適當 的位置。 本裝置中，因爲流通管11之流出處11B與分離器12 僅能一起等距離上下移動，所以流出處1 1 B之硬化用液 10之液面及分離器12之高度差保持一定。因此，本實施 例中之無接縫膠囊S C經常成爲所需之球狀，而且亦可防 止發生無接縫膠囊S C之破壞或飛散。本發明中，無接縫 膠囊SC之粒徑爲1至l〇mm。此範圍之粒徑之無接縫膠 囊SC係製造容易，使用者容易操作膠囊，適合含於口中 之大小。 尤其，本裝置中，流通管11之流出處11]3與分離器 1 2，與連接棒1 1 D及1 2 A及連接材料1 5互相構造上結合 成一體構造，因爲整個該一體構造以如流體壓汽缸之驅動 源1 4上下移動，所以流出處1 1 B與分離器1 2經常確實地 僅等距離上下移動，其構造亦簡單且價廉。 步驟B中，多重噴嘴可爲二重噴嘴之外，亦可爲三重 噴嘴等，爲生成該多層液滴，必要的振動方式除了噴嘴加 振方式外，可利用環加振方式或管加振方式等各種方式。 當然，亦可取代多重噴嘴，僅噴出1層液滴之單噴嘴。 -16- (13) (13)200412930 步驟B中，多重噴嘴7係使用先端角度（圓錐狀部份 之角度）90 °以下者爲宜。使用先端角度90°以下之多重 噴嘴7時，接觸多重噴嘴7先端之流動硬化用液之流向不 會產生亂流，而可形成均勻粒徑之無接縫膠囊S C。 步驟B中，多重噴嘴7之外側噴嘴及內側噴嘴之各先 端可配置於同一平面上，亦可內側噴嘴先端比外側噴嘴先 端突出1至5mm之構造。 步驟B中，可使多重噴嘴7之先端位置與流通管1 1 之軸線中心一致，亦可配置偏離軸線中心。使多重噴嘴7 之先端位置與流通管1 1之軸線中心一致時，由多重噴嘴 7所噴出之多層液滴係沿著多重噴嘴7之軸線中心部份直 直地流下。另一方面，配置多重噴嘴7之先端位置偏離軸 線中心時，多層液滴係於流通管1 1之內壁附近，沿著螺 旋狀的軌道流下，所以可增長多層液滴之流下時間。將多 重噴嘴7之位置，對著流通管1 1之軸線中心，可改變位 置，而可調整無接縫膠囊之完成狀態，可防止發生不均勻 或眼洞（eyes )而得到高品質製品。眼洞係皮膜中所發生 之微小球狀液泡，若眼洞大時，乾燥後皮膜開孔，芯液漏 出之虞。 步驟B及C中，於流通管1 1之任何一處配置頻閃觀 測器（stroboscope )，希望構成可監控流下流通管1 1內 之多重液滴之粒徑及形狀。如此地以頻閃觀測器監控多重 液滴，配合應製造無接縫膠囊之粒徑，可迅速地調整由多 重噴嘴7之各液之噴出條件、振動條件及硬化用液之流速 -17- (14) (14)200412930 等，可無損失地製造具有目的之粒徑、無不均勻或眼洞之 無接縫膠囊。 步驟c中，係以構成可將硬化用液1 〇流入流通管11 之部份，以瀉滿（Ο V e r f 1 0 W )方式，由流通管1 1之全部 周圍面流入硬化用液1 〇爲宜。由流通管1 1之全部周圍面 流入硬化用液1 0，可防止流通管1 1內之硬化用液流發生 局部的亂流。 步驟C中，由循環使用之硬化用液1 0除去水份之脫 水手段係以設於與硬化溶液1 〇接觸之任何一處爲宜。於 硬化用液1 〇中，可能混入來自大氣中或多層液滴之水份 。硬化用液1 0之水份量若增加時，皮膜變形或膠囊彼此 間容易粘著，進而有引起皮膜液之硬化狀態發生不均勻等 不良狀態之虞。設置上述脫水手段，儘可能減少硬化溶液 1 〇之水份含量，可穩定地製造高品質之無接縫膠囊S C。 作爲上述之脫水手段，可選擇使用任何一種吸水材料吸收 方式、冷卻水管方式及微波加熱方式等，通常係使用使矽 膠等之吸水材料與硬化用液1 〇接觸之簡單方式。 步驟D中，取代與分離器12之濾網1 3之上方與硬 化用液1 〇 —起流下，以該濾網1 3由硬化用液1 0分離出 無接縫膠囊S C，亦可構成使用具有濾網或布製過濾器之 輸送帶之分離搬運裝置，以輸送帶接受來自流通管11之 流出物，濾下回收硬化用液，僅將無接縫膠囊S C，以輸 送帶運送。使用如此的分離搬運裝置，可避免所分離出之 無接縫膠囊S C堆積而使下側之膠囊變形或遭破壞之不良 -18- (15) (15)200412930 狀況。 〈步驟E > 經由上述步驟B至E之步驟所製造之與硬化用液分 離之無接縫膠囊係於步驟E，除去附著於無接縫膠囊表面 之硬化用液，以及乾燥表面，形成實質上無互相附著性之 無接縫膠囊。於本發明之適合實施型態，此步驟E係具備 下述之次步驟之el至e7。 步驟e 1 :將步驟D中由硬化用液所分離之無接縫膠 囊，直接或浸漬於不溶解皮膜之液體所形成之保冷液，保 冷於〇至2 0 °C，於1至1 0 °C程度爲宜，促進皮膜硬化之 步驟， 步驟e2 :離心分離保冷後之無接縫膠囊，除去附著 於膠囊表面液體之步驟， 步驟e 3 :乾燥離心分離後之無接縫膠囊之步驟， 步驟e4 :將乾燥後之無接縫膠囊，以有機溶媒洗淨 之步驟， 步驟e 5 :乾燥以有機溶媒洗淨後之無接縫膠囊之步 驟， 步驟e 6 :過篩及選別步驟e 5終了後之無接縫膠囊之 步驟， 步驟e 7 :包裝乾燥終了後或過篩及選別後之無接縫 膠囊之步驟。 步驟e 1中，保冷方法並無特別的限制，可使用將硬 -19· (16) 200412930 化用液所分離之無接縫膠囊放入托盤，放 個托盤放入冷藏庫，一定時間冷卻的方法 以輸送帶上搬送，通過墜道式冷卻機之保 卻板接觸的方法等。保冷液係不使皮膜軟 之材料，例如中鏈脂肪酸三甘油酯之食用 等之界面活性劑之食用油等爲宜。 步驟e 1中，使保冷溫度爲2 °C程度 皮膜中之水份凍結，促進膠囊皮膜之硬化 步驟e2中，離心分離條件係以使無 所附著油等之液體，由外觀上消失，另一 形或遭破裂程度之旋轉數及時間進行。以 能除去無接縫膠囊表面的油，可提升接著 步驟中之乾燥效率，縮短乾燥所需時間。 步驟e 2中，取代使用離心分離之皮 ，亦可以布、經親油處理紙及不織布等打 去皮膜表面的油。 步驟e 3中，乾燥方式並無特別的限 上乾燥粒狀物所使用的方法及裝置實施。 乾燥法（包含流動床乾燥法）、鼓式乾燥 等。使用通風乾燥法或鼓式乾燥法時，將 化皮膜溫度以下，以〇至4 0 °C爲宜，以1 空氣氣流相接觸。 步驟e3中，使用鼓式乾燥法時，爲 膠囊之滑落’以設有擋板爲宜。無接縫膠 入保冷液，將整 ，將無接縫膠囊 冷方法以及與冷 化、溶解或崩壞 油及含有卵磷脂 時，可防止膠囊 爲宜。 接縫膠囊之皮膜 方面使皮膜不變 此離心分離儘可 步驟e3之乾燥 膜表面脫油處理 磨處理膠囊，除 制，可使用傳統 例如可使用通風 法及減壓乾燥法 無接縫膠囊以軟 0至3 0 °C尤佳之 防止鼓內無接縫 囊若於鼓內滑落 -20- (17) (17)200412930 時，乾燥狀態將不均勻，有發生未乾燥部份之虞。 步驟e 3中，使用通風乾燥法或鼓式乾燥法時，所導 入空热的溫度’可由乾燥開始至終了爲同一溫度（例如室 溫之空氣），亦可中途改變溫度。例如可以乾燥開始時， 使用2 5 °C以下之冷風，經過所定時間後，供給2 5 °C以上 之空氣進行乾燥。所導入空氣係以預先降低濕度爲宜，必 要時，亦可供給通過矽膠等吸水材料層之乾燥空氣。 步驟e 3中，使用通風乾燥法或鼓式乾燥法時，承載 無接縫膠囊之通氣板或乾燥鼓之孔洞，係以因應無接縫膠 囊之粒徑而選擇使用爲宜。 步驟e4中，洗淨無接縫膠囊所使用之有機溶媒只要 可溶解附著於無接縫膠囊皮膜之油份（硬化用液，保冷液 )，並且不軟化、溶解或崩壞皮膜之有機溶媒即可，可舉 例如乙醇、醋酸乙酯、丙酮及己烷等之烴類或此等之混合 液爲宜。 步驟e4中，以有機溶媒洗淨無接縫膠囊之方法，並 無特別的限制，可使用將無接縫膠囊完全浸漬於有機溶媒 後，再撈出膠囊的方法，以及於無接縫膠囊上，散佈有機 溶媒之液滴或霧之方法等。有機溶媒之溫度爲0至4 0 °C ，以室溫爲宜。洗淨次數及洗淨時間並無特別的限制，可 以1次或多次重覆洗淨。此洗淨操作中，於不傷及無接縫 膠囊皮膜之程度下，亦可進行攪拌或加入超音波以提高洗 淨效率。洗淨後之有機溶媒，可回收、精製而再使用。 步驟e 5之乾燥（二次乾燥）主要係爲除去以有機溶 -21 - (18) (18)200412930 媒洗淨後之無接縫膠囊之有機溶媒而進行。此乾燥方式並 無特別的限制，可使用傳統上乾燥粒狀物所使用的方法及 裝置實施。例如可使用通風乾燥法（包含流動床乾燥法） 、鼓式乾燥法、減壓乾燥法及離心乾燥法等。其溫度、濕 度及使用機器等係可與步驟e3大致相同。使來自乾燥裝 置之含有有機溶媒之排氣氣體，接觸冷卻水管或適當的溶 媒吸附劑，進行脫溶媒處理。 步驟e 6中，過篩及選別二次乾燥步驟（步驟e 5 )終 了後之無接縫膠囊之方法係可使用傳統上粒狀物，尤其是 軟膠囊等之膠囊狀醫藥製品檢查所使用之手法而進行。作 爲無接縫膠囊之檢查項目，可舉例如粒徑大小、有無形狀 異常品、有無皮膜遭破壞、有無混濁或夾雜物、有無外觀 不良品（不均勻或眼洞等）、及有無複數個粘著品等。關 於內容物，取出無接縫膠囊，施以製藥上或食品衛生上所 必須之各種分析試驗。 步驟e7中，包裝乾燥終了後或過篩及選別後之無接 縫膠囊之前，例如將乳糖、甘露糖醇、糯米紙粉末及玉米 澱粉等之澱粉等之食品製造上或藥學上所容許之粉體作爲 防止附著劑，適量地灑於膠囊表面，亦可達成防止膠囊成 塊。 另外，上述實施型態不過是顯示本發明之一例，本發 明不局限於上述實施例而可作各種改變。 【貫施方式】 -22- (19) (19)200412930 實施例 以下係以實施例明確地顯示本發明之效果。但本發明 並不局限於下述之實驗例。 使用作爲充塡液（芯液）之中鏈脂肪酸三甘油酯，以 及將作爲皮膜物質之3 0質量％之表1中所述之各組成之 皮膜物質及70質量％之水混合加熱而成之皮膜液，使用 無接縫微膠囊製造裝置「SPHEREX (註冊商標）」（ Freund產業株式會社製），由該多重噴嘴以4至20個/秒 之速度，於冷卻至7 t之中鏈脂肪酸三甘油酯所形成之硬 化用液中，滴下多層液滴，製造如表1所示N 〇. 1至6之 各組成之無接縫膠囊。 關於所製造N 〇. 1至6之各膠囊，依據日局崩壞試驗 ，實施崩壞試驗。結果總結如表1所示。 -23- (20)200412930The multi-nozzle having an inner nozzle and the outer nozzle surrounding the inner nozzle, the core liquid is supplied from the inner nozzle, the coating liquid is sprayed from the outer nozzle and supplied separately, and the multi-nozzle sprays a multi-layer liquid flow to form a multilayer. The step of droplets; the step of contacting the above-mentioned multi-layered droplets with the hardening liquid circulating in the flow path to harden the coating liquid to form a seamless capsule formed by coating the core liquid with the coating material; And (4) (4) 200412930 removing the above-mentioned hardening liquid of the above-mentioned jointless capsule from the above-mentioned hardening liquid, and removing the adherence on the surface of the above-mentioned jointless capsule separated by the above-mentioned hardening liquid. A step of forming a jointless capsule with a hardening liquid and a dry surface to form substantially no mutual adhesion. According to this, the particle size is 1 to 10 mm, and the mass ratio of film material and filling material is 5: 95 to 70: 30. The amount of plasticizer added is 20 to 70 of the total film material except water. Mass% jointless capsule. According to this method, it is possible to provide a method for manufacturing a seamless capsule in a mouth that is easily soluble in the mouth and can be manufactured in a product that is difficult to cause problems such as poor film hardening or damage during manufacture. for purpose. The plasticizer may be glycerin. Best Modes for Implementing the Invention Hereinafter, the embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments, and any changes can be made within the scope of the application. The inventors, etc. In order to obtain the intra-oral instant soluble which is easily damaged in the oral cavity, various reviews are made on each capsule such as a hard capsule, a soft capsule, and a jointless capsule. Hard capsules swell only in the oral cavity and do not collapse, and cannot obtain immediate solubility in the oral cavity. In the soft capsule manufacturing method, the coating material must be 30% by mass or more of the total mass. In addition, regarding the jointless capsule, the solubility of gelatin alone is dulled. However, the mass ratio of the capsule material to the capsule is the least jointless capsule, and the jointless capsule is the most suitable as a soluble capsule in the oral cavity. Generally, plasticizer is added to the gelatin of the film material, but as the plasticizer used as the instant soluble capsule in the cavity, the water-soluble plasticizer is -8- (5) (5) 200412930. As a result of these reviews, the inventors have found that the particle size of the coating material containing the film-forming agent and the plasticizer is 1 to 10 mm, and the mass ratio of the coating material and the filling material is 5: In the range of 95 to 70: 30, the plasticizer mentioned above uses one or two or more groups selected from glycerin, propylene glycol, and polyethylene glycol. The amount of the plasticizer added is 2% of the total amount of the film material except water. The jointless capsule in the range of 0 to 70% by mass is particularly excellent as an intraorally soluble capsule. In addition, the present inventors have established a method for producing an instant jointless capsule that can be manufactured into a product that is difficult to cause problems such as poor film hardening or damage during manufacture. The method for manufacturing a seamless capsule of this embodiment includes the following steps: 〈Step A〉 A film solution containing a core-filling substance and a film-solving substance is prepared. <Step B > A multi-nozzle having an inner nozzle and a multi-nozzle surrounding the outer nozzle of the inner nozzle, the core liquid is supplied from the inner nozzle, and the coating liquid is sprayed from the outer nozzle, respectively. drop. <Step C> The multi-layered liquid droplets are caused to flow into the hardening liquid flowing in the flow path to harden the coating liquid to form a seamless capsule formed by coating the core liquid with a coating material. <Step D> Separating the jointless capsule from the above-mentioned hardening liquid containing the jointless capsule-9-(6) (6) 200412930 <Step E> Removing the jointless capsule separated by the hardening liquid The hardening liquid adhered to the surface and the dry surface form a jointless capsule with substantially no mutual adhesion. Follow steps A to E in order to cover the film-filling substance with a film-forming substance containing a film-forming agent such as gelatin and a plasticizer such as glycerin to produce a particle size of 1 to 10 mm. Range of 5: 9 5 to 7 0: 30 jointless joints. Hereinafter, each step example will be described in detail. 〈Step A〉 In the present invention, as long as the filling substance is discharged from the multiple nozzles of step B as the core liquid, the core liquid may be the original liquid after forming the multilayer liquid droplets, or After the seam capsules are gelatinous or solid. This filling substance may contain the main ingredients (effective ingredients in medicine) other than the main ingredients selected for the use of jointless capsules such as food, health food, spices, spices, medicines, or fragrances, etc. Permissible various additives, such as edible oil and other solvents, sweeteners, sour ingredients, flavors, colorants, thickeners (gelatinizers), stabilizers, and emulsifiers. When the filling material is prepared into a liquid state, the above main components can be dissolved in a solvent to form a transparent solution, suspension, and emulsion (cream). A method for preparing a liquid filling substance ', that is, a core liquid, is a known method that can be used in the field of food manufacturing or pharmaceutical manufacturing. For example, when preparing a transparent liquid core solution, a method of weighing the main components and additives mentioned above, mixing with a solvent such as edible oil, and heating and stirring to a uniform solution as required. When adjusting -10- (7) (7) 200412930 to make an emulsion-type core liquid, a conventionally known method of emulsifying a water-containing component and an oily component containing an emulsifier and using a homogenizer to manufacture a water-based latex in oil can be used. For example, high-sweetness sweeteners, such as aspartame and sucralose, disperse and dissolve in ethanol, because the diameter of the particles formed by directly dispersing in oil is too large, and the formability of the capsule is unstable, so it can also be used first A method of dispersing and dissolving these in ethanol using a homogenizer, and then dissolving them in oil. In the present invention, the film substance is a film-forming agent that is acceptable in food manufacturing or pharmacy that contains one or more types of gelatin and agar, and to soften the film and reduce the mouth in order to make the hardened film easily rupture in the mouth. Plasticizer for inner film strength. As the plasticizer, one or two or more kinds are selected from the group consisting of glycerin, propylene glycol, and polyethylene glycol. As a suitable plasticizer, for example, glycerin can be mentioned. The addition amount of the plasticizer is 20 to 70% by mass, preferably 30 to 65% by mass, and more preferably 40 to 60% by mass, with respect to the total amount of the film material (the total amount of components other than the water of the film liquid). Glycerin is a plasticizer, and when it is blended with the coating material within the above range, the hardened film becomes soft and easily dissolves in the oral cavity. The film material can increase the hardness of the film material after hardening in the same way as the plasticizer described above. For example, sorbitol can be added to adjust the film hardness. In addition, the addition of mucopolysaccharides, gelling agents, and protein degradation products can improve the stability of the membrane over time. The coating material can be colored with a pigment to an arbitrary hue ', and flavors, sweeteners, and sour agents can also be added. The addition amount of these sorbitol, mucopolysaccharides, gelling agents, and protein degradation products is usually not more than 10% by mass of the total coating material, and not more than 5% by mass -11-(8) (8 ) 200412930 is appropriate. A film material containing at least a film-forming agent and a plasticizer is prepared by adding an appropriate amount of water and dissolving at a temperature to prepare a film liquid. The compounding amount of the coating material in the coating liquid (that is, the total amount of components other than water) is preferably about 10 to 50% by mass, and preferably about 20 to 40% by mass based on the total amount of the coating solution. The compounding amount of the film-forming substance in gelatin is preferably 15 to 35% by mass with respect to the total amount of the film solution, and preferably about 20 to 30% by mass. The method is not limited to a method of adding water to the film-forming agent and dissolving it at a temperature, and for example, a method of adding water to the film-forming agent to swell and dissolve it at a temperature, and a method of adding the film-forming agent to warm water and stirring to dissolve it. As long as the dissolution method is stirred with warm water for this purpose, the liquid can be adjusted for a short time. The heating temperature is set according to the type of the film-forming agent to be used. For example, the gelatin temperature can be set to 45 to 90 ° C, preferably 45 to 55 ° C. In order to prepare a film liquid without air bubbles, put the film material and water in a decompression heating tank, and heat and stir under a reduced pressure environment. It is advisable to prepare the film liquid in a degassed state. The various core liquids and coating liquids prepared as described above are stored in appropriate containers such as respective liquid storage tanks. The membrane fluid must be kept warm to prevent cooling and gelation. The heat preservation temperature of the coating liquid is set according to the type of the film forming agent used. For example, it is 45 to 90 ° C for gelatin, and preferably 45 to 55 ° C. The preparation amount of the core liquid and the coating liquid is prepared according to any mass ratio set in the range of 5:95 to 70:30 in the mass ratio of the film material and the filling material in the finished seamless capsule. should. <Steps B to D > -12- (9) 200412930 Step B $ d can be performed continuously using conventionally known jointless capsules. Fig. 1 is a structural view showing a manufacturing apparatus suitable for continuously performing steps B to D of a manufacturing method of a seamless capsule. In the liquid-in-nozzle type seamless capsule manufacturing apparatus shown in FIG. 1, the core liquid (inner layer liquid) 1 for the capsule is stored in the core liquid tank, and the film liquid (outer layer liquid) 3 covering the core liquid 1 is stored in During the coating, the core fluid 1 is pumped from the core fluid tank 2 through the tube 5 to the multiple nozzle 7 through the pipe, and the coating liquid 3 is pumped to the multiple tank 7 through the tube 9 through the pipe 9 Nozzle 7. The multiple nozzles 7 are configured to be inserted into the flow tube 11, that is, the inflow portion 1 1 A of the hardening liquid 10, and the core liquid 3 is sprayed into the hardening liquid 1 0 in the flow tube 11. , Raw drops. The hardening liquid 10 is a multilayered liquid droplet joint capsule SC produced by cooling and hardening. As a hardening liquid, the film liquid is cooled and used in edible oils such as medium-chain fatty acid glycerides (MCT: MCT, with a surfactant such as lecithin, etc.) to improve the multi-layer: anti-adhesion hardening liquid, etc. The temperature is set to a warm degree. The flow tube 11 in this device is formed into a curved shape with a slightly J-shaped inflow 11A ′ and a joint 11A and the joint 11A are mutually folded and fitted into a sealable The telescoping manufacturing device of the present invention is formed in the non-contact 2 and the liquid tank 4 6 for pressure feeding from the inlet 1 of the coating liquid and the film into a multi-layer liquid to form a non-hardened, > here The droplet's anti-o ° c to the chamber cylinder is composed of 1 1 B with the outflow point of the shape of the inverse J-shape-13-200412930 do) of the flow. Therefore, as will be described later, the circulation tube 11 is connected to the joint 11C, and the inflow 11A and the outflow 11B can move relative to each other in the up and down direction, especially the outflow 1 1 B of the device can be moved up and down. . Below the outlet of the outflow portion 11B of the flow tube 11, a separator 12 having a funnel shape is provided. The separator 12 separates the jointless capsule SC and the hardening liquid 10 which flow out together from the flow tube ii. The separator 12 does not allow the jointless SC to pass through, and only the hardening liquid. 1 0 through the filter 1 3. The separator 1 2 is connected to the outflow 1 1 B of the flow pipe 11 1 to move up and down by driving the source 1 4 ′, such as a gas cylinder or a fluid pressure cylinder of a hydraulic cylinder, or a motor. That is, a part of the outflow portion ii B of the flow tube n is combined with the connecting rod 1 1 D, and on the other hand, the separator 12 is combined with the connecting rod 1 2 A ', and these connecting rods 〖〇 and 丨 2 a It is connected to each other by a connecting material j 5. This connecting material 15 is a part of the driving source 14, such as a piston rod of a cylinder. Therefore, when the driving source 14 is driven, for example, when the piston rod of the gas cylinder is moved up and down, the outflow 11B of the flow tube 11 and the separator 12 are connected through the connecting material 15 and the connecting rods 1D and 12A only at equal distances. Move up and down together. According to this, the difference in height between the liquid level of the inflow 1 1 A of the through pipe 1 and the liquid level of the 1 1 b outflow △ h is adjustable, and the flow rate of the hardening liquid 1 0 in the flow tube n is adjustable. Regulated. In addition, the outflow portion 11B of the circulation tube 11 and the separator 12 are up and down -14- (11) (11) 200412930 When moving, the liquid level of the hardening liquid 1 0 in the outflow portion 11 B and the separator 1 2 (especially The difference in locality between the filters 13) is kept constant. The hardening liquid 10 separated by the jointless capsule s C by the separator 12 is recovered in the lower separation tank 16. The thin tube at the lower end of the separator 12 is configured to be able to fit into the cylindrical portion at the upper end of the separation tank 16. Even if the separator 12 moves up and down, the separation tank 16 is not detached. The hardening liquid 10 in the separation tank 16 is pressure-fed to the cooling tank 21 from the drum 19 through the pipeline 20. The hardening liquid 10 in the cooling tank 21 is cooled to a predetermined temperature by the cooler 22, and then returned to the circulation pipe 11 through the tube 23 through the tube 23. Because this jointless capsule manufacturing device has a nozzle-type structure in the liquid, the multiple nozzles 7 are configured to be inserted into the supply hardening liquid. The inlet of the flow pipe 11 of the flow path is used to eject the core liquid 1 and the film liquid 3 In liquid, the latter covers the entire periphery of the former. Therefore, in this embodiment, the core liquid 1 and the coating liquid 3 sprayed from the multiple nozzles form a multilayer liquid droplet in the hardening liquid 10 in the flow tube 11 (step B) to follow the flow tube 11 The hardening liquid 10 flowing in the medium cools and hardens to form a jointless capsule SC (step C). Next, the jointless capsule SC thus formed is from the outlet end of the circulation tube Π at the outlet end of 1 1 B, above the screen 13 of the separator 12, and flows down with the hardening liquid 10 to the screen 1 3 The hardening liquid 10 is separated (step D), and the hardening liquid 10 passes through the screen 13 and is recovered in the separation tank 16. On the other hand, the seamless capsule S C captured on the filter screen 13 was subsequently reached at an appropriate amount-15- (12) (12) 200412930, and was recovered in batches in a product recovery container not shown in the figure. In this device, when the level difference Δh of the inflow point 1 1 A of the flow tube 11 and the outflow point 1 1 B is adjusted, because the outflow point 1 1 B of the flow tube 11 is used to drive the source 1 4 1 A can move up and down, so the flow rate of the hardening liquid 10 in the flow tube 11 can be arbitrarily changed. The liquid level height difference Δ h is between the lowered position and the raised position, and can be arbitrarily adjusted to the most appropriate position. In this device, because the outflow portion 11B of the flow tube 11 and the separator 12 can only move up and down at the same distance together, the liquid level of the hardening liquid 10 at the outflow portion 1 1 B and the height difference of the separator 12 are kept constant. Therefore, the jointless capsule SC in this embodiment often becomes a desired spherical shape, and the destruction or scattering of the jointless capsule SC can also be prevented. In the present invention, the jointless SC has a particle diameter of 1 to 10 mm. The jointless SC with a particle size in this range is easy to manufacture and easy to handle by the user, and is suitable for the size to be contained in the mouth. In particular, in this device, the outflow portion 11] 3 of the flow pipe 11 and the separator 12 are combined with the connecting rods 1 1 D and 1 2 A and the connecting material 15 to form an integrated structure, because the entire integrated structure is For example, the drive source 14 of the fluid pressure cylinder moves up and down, so the outflow place 1 1 B and the separator 12 often move up and down only at equal distances, and its structure is also simple and inexpensive. In step B, the multiple nozzle may be a double nozzle, a triple nozzle, etc. In order to generate the multi-layered droplets, in addition to the nozzle vibration method, a ring vibration method or a tube vibration method may be used. And so on. Of course, instead of multiple nozzles, a single nozzle that ejects only one layer of liquid droplets can also be used. -16- (13) (13) 200412930 In step B, it is advisable to use the multi-nozzle 7 with a tip angle (angle of the conical part) of 90 ° or less. When the multiple nozzles 7 with a tip angle of 90 ° or less are used, the flow of the hardening fluid flowing in contact with the tips of the multiple nozzles 7 does not cause turbulent flow, and can form a jointless capsule SC with a uniform particle diameter. In step B, the tips of the outer nozzle and the inner nozzle of the multiple nozzles 7 may be arranged on the same plane, or the tip of the inner nozzle may protrude from the tip of the outer nozzle by 1 to 5 mm. In step B, the leading end position of the multiple nozzles 7 can be aligned with the center of the axis of the flow tube 1 1, and the center of the axis can also be arranged off-axis. When the leading end position of the multiple nozzles 7 is aligned with the axis center of the flow tube 11, the multilayer liquid droplets ejected from the multiple nozzles 7 flow straight down along the center portion of the axis of the multiple nozzles 7. On the other hand, when the position of the tip of the multiple nozzles 7 is deviated from the center of the axis, the multi-layered droplets flow around the inner wall of the flow tube 11 and flow down a spiral orbit, so that the multi-layered droplet flow time can be increased. The position of the multi-nozzle 7 facing the center of the axis of the flow tube 11 can be changed, and the completion state of the jointless capsule can be adjusted, which can prevent unevenness or eyes and obtain high-quality products. Eye holes are tiny spherical vacuoles that occur in the membrane. If the eye holes are large, the membrane will open after drying and the core fluid may leak out. In steps B and C, a stroboscope is arranged at any position of the flow tube 11 to hope that the particle diameter and shape of the multiple droplets in the flow tube 11 can be monitored. In this way, multiple droplets are monitored with a stroboscope, and in accordance with the particle size of a jointless capsule, the ejection conditions, vibration conditions, and the flow rate of the hardening liquid of each liquid from the multiple nozzles 7 can be quickly adjusted -17- ( 14) (14) 200412930, etc., can produce jointless capsules with targeted particle size, non-uniformity or eye holes without loss. In step c, the hardening liquid 1 0 is poured into the flow tube 11 so that the hardening liquid 1 0 flows into the entire peripheral surface of the flow tube 11 in the manner of 0 V erf 10 W. Better. The hardening liquid 10 flows into the entire peripheral surface of the flow tube 11 to prevent local turbulent flow of the hardening liquid flow in the flow tube 11. In step C, the dehydration means for removing water from the circulating hardening solution 10 is preferably provided at any place in contact with the hardening solution 10. In the hardening liquid 10, water from the atmosphere or multiple layers of droplets may be mixed. If the water content of the hardening liquid 10 is increased, the film may be deformed or the capsules may be easily adhered to each other, which may cause an adverse state such as unevenness in the hardened state of the film liquid. By providing the above-mentioned dehydration means, the water content of the hardening solution 10 can be reduced as much as possible, and high-quality seamless capsules SC can be stably manufactured. As the above-mentioned dehydration means, any one of a water-absorbing material absorption method, a cooling water pipe method, and a microwave heating method can be selected. Generally, a simple method of contacting a water-absorbing material such as silicone with a hardening liquid 10 is used. In step D, instead of being above the filter screen 13 of the separator 12, and the hardening liquid 10 is flown down, the filter screen 13 is used to separate the seamless capsule SC from the hardening liquid 10, which can also be used. The separation and conveying device of the conveyor belt with a strainer or a cloth filter receives the effluent from the circulation pipe 11 by the conveyor belt, filters and recovers the hardening liquid, and only transports the jointless capsules SC on the conveyor belt. By using such a separation and conveying device, it is possible to avoid the undesired condition that the separated seamless capsules S C are piled up and deform or damage the lower capsule -18- (15) (15) 200412930. <Step E > The jointless capsule separated from the hardening liquid produced through the steps B to E described above is performed in Step E to remove the hardening fluid attached to the surface of the jointless capsule and dry the surface to form a substance. No jointless capsule on top of each other. In a suitable implementation form of the present invention, this step E is provided with el to e7 of the following steps. Step e 1: The jointless capsule separated from the hardening liquid in step D is directly or immersed in a liquid that does not dissolve the film, and is kept at a temperature of 0 to 20 ° C and at a temperature of 1 to 10 ° C. The degree of C is appropriate, the step of promoting the hardening of the film, step e2: a step of centrifuging the jointless capsule after cooling and removing the liquid attached to the surface of the capsule, step e3: a step of drying the jointless capsule after centrifugation, step e4: The step of washing the dried jointless capsules with organic solvent, step e5: The step of drying the jointless capsules washed with organic solvent, step e6: sieving and selection step e5 is over The next step without joint capsules, step e 7: after the package is dry or after screening and selection, the step without joint capsules. In step e1, there is no particular limitation on the method of keeping cold. You can use the jointless capsules separated by the hard-19 · (16) 200412930 chemical solution into a tray, put a tray into a refrigerator, and cool it for a certain period of time. Methods The method is carried on a conveyor belt, and the method is to contact the retaining plate of the down-channel cooler. The cooling liquid is preferably a material that does not soften the film, such as an edible oil such as a surfactant of a medium chain fatty acid triglyceride and the like. In step e1, the moisture in the film is frozen at a temperature of about 2 ° C to promote the hardening of the capsule film. In step e2, the conditions for centrifugal separation are such that no liquid such as attached oil disappears from the appearance, and the other The number of rotations and the time of the degree of deformation or fracture. The oil on the surface of the jointless capsule can be removed, which can improve the drying efficiency in the subsequent step and shorten the time required for drying. In step e2, instead of using the centrifugally separated skin, the oil on the surface of the membrane can also be removed by cloth, lipophilic treated paper, and non-woven cloth. In step e3, the drying method is not particularly limited to the method and device used for drying the granular material. Drying methods (including fluid bed drying methods), drum drying, etc. When using the ventilation drying method or the drum drying method, the temperature of the chemical film is preferably below 0 ° C to 40 ° C, and the air is brought into contact with each other. In step e3, when a drum-type drying method is used, it is preferable that a baffle is provided for the slipping of the capsules. Jointless Adhesive Fill in cold liquid, clean the jointless capsule, and prevent the capsule when it is cold, dissolved, or disintegrated with oil and contains lecithin. The membrane of the joint capsule keeps the membrane unchanged. This centrifugal separation can be done in step e3. The surface of the dried membrane is degreased and milled. The capsule can be removed by using traditional methods such as ventilation and reduced-pressure drying. 0 to 30 ° C is particularly good to prevent the seamless sac inside the drum from slipping inside the drum. When the -20- (17) (17) 200412930 is used, the dry state will be uneven and there may be undried parts. In step e 3, when the air-drying method or the drum-type drying method is used, the temperature of the air heat to be introduced may be the same temperature (for example, room temperature air) from the beginning to the end of the drying, or the temperature may be changed halfway. For example, you can use cold air at 25 ° C or lower at the beginning of drying, and supply air at 25 ° C or higher after a predetermined period of time to dry. It is advisable to reduce the humidity of the introduced air in advance. If necessary, dry air may be supplied through a layer of absorbent material such as silicone. In step e 3, when the ventilation drying method or the drum drying method is used, the ventilation plate carrying the jointless capsules or the holes of the drying drum should be selected and used according to the particle diameter of the jointless capsules. In step e4, as long as the organic solvent used for washing the jointless capsule can dissolve the oil (hardening liquid, cooling liquid) attached to the jointless capsule film and does not soften, dissolve or break the film, However, hydrocarbons such as ethanol, ethyl acetate, acetone, and hexane, or a mixed solution thereof are suitable. In step e4, the method of washing the jointless capsule with an organic solvent is not particularly limited. A method of completely immersing the jointless capsule in the organic solvent, and then removing the capsule, and the jointless capsule can be used. , Dispersing droplets or mist of organic solvents. The temperature of the organic solvent is 0 to 40 ° C, preferably room temperature. There is no particular restriction on the number of washing times and washing time, and washing can be repeated one or more times. In this washing operation, stirring or adding ultrasonic waves can be performed to the extent that the jointless capsule film is not damaged to improve the washing efficiency. The washed organic solvent can be recovered, refined and reused. The drying (secondary drying) in step e 5 is mainly performed to remove the organic solvent of the jointless capsule after washing with the organic solvent -21-(18) (18) 200412930. This drying method is not particularly limited, and it can be carried out using a method and an apparatus conventionally used for drying granules. For example, a ventilation drying method (including a fluidized bed drying method), a drum drying method, a reduced-pressure drying method, and a centrifugal drying method can be used. The temperature, humidity, and equipment used may be substantially the same as those in step e3. The exhaust gas containing the organic solvent from the drying device is brought into contact with a cooling water pipe or an appropriate solvent adsorbent to perform a desolvent treatment. In step e 6, the method of sieving and selecting the secondary drying step (step e 5) after the end of the jointless capsule can use traditionally granular materials, especially soft capsules and other capsule-shaped pharmaceutical products. By the means. The inspection items for jointless capsules include, for example, particle size, presence or absence of abnormal shapes, damage to the film, presence of turbidity or inclusions, appearance of defective products (unevenness or eye holes, etc.), and presence or absence of multiple stickies. Writing and so on. Regarding the contents, the jointless capsule was taken out and subjected to various analytical tests necessary for pharmaceutical or food hygiene. In step e7, after the packaging is dried or before the seamless capsules are sieved and selected, for example, lactose, mannitol, glutinous rice paper powder, starches such as corn starch, and the like are manufactured or pharmaceutically acceptable powder As an anti-adhesive agent, the body can be sprinkled on the surface of the capsule to prevent the capsule from blocking. In addition, the above-mentioned embodiment is merely an example showing the present invention, and the present invention is not limited to the above-mentioned embodiment and can be variously modified. [Performance Mode] -22- (19) (19) 200412930 Examples The following clearly shows the effects of the present invention with examples. However, the present invention is not limited to the following experimental examples. It is prepared by using a medium chain fatty acid triglyceride as a filling solution (core liquid), and mixing and coating film materials of each composition described in Table 1 as 30% by mass of film materials and 70% by mass of water. The coating liquid was cooled to 7 t of medium chain fatty acid three at a rate of 4 to 20 per second using a multi-nozzle manufacturing device "SPHEREX (registered trademark)" (made by Freund Industries) In the hardening liquid formed by the glyceride, a plurality of liquid droplets were dropped to produce a seamless capsule having a composition of N 0.1 to 6 as shown in Table 1. For each of the capsules No. 1 to 6 produced, a collapse test was performed in accordance with the daily local collapse test. The results are summarized in Table 1. -23- (20) 200412930
No. 1 2 3 4 5 6 膠囊直徑 5 5 5 5 5 5 (mm) 明膠 6 8 12 16 18 27 (質量％) 甘油 4 2 8 4 2 3 (質量％) 皮膜 10 10 20 20 20 30 (質量％) 充塡液 中鏈脂 中鏈脂 中鏈脂 中鏈脂肪酸 中鏈脂肪酸 中鏈脂 肪酸三 肪酸三 肪酸三 三甘油酯 三甘油酯 肪酸三 甘油酯 甘油酯 甘油酯 甘油酯 充塡液 90 90 80 80 80 70 (質量％) 崩壞時間 7 10 10 60 120 300 (秒)(*1) 備考 快速地 快速地 快速地 比No.3之 比No.4之 崩壞所 溶解 溶解 溶解 崩壞所需 崩壞所需 需時間 日寺間長 日寺間長 非常長 崩壞性 良好 良好 良好 有困難 差 差 -24- (21) (21)200412930 由表1的結果，有關本發明之No. 1至3之無接縫膠 囊之崩壞性優異，適合作爲口腔內可即溶之無接縫膠囊。 No .4之無接縫膠囊比No.3之崩壞所需時間長。No. 1 2 3 4 5 6 Capsule diameter 5 5 5 5 5 5 (mm) Gelatin 6 8 12 16 18 27 (mass%) Glycerin 4 2 8 4 2 3 (mass%) Film 10 10 20 20 20 30 (mass) %) Filling solution Medium chain fatty acid Medium chain fatty acid Medium chain fatty acid Medium chain fatty acid Medium chain fatty acid Medium fatty acid Tri fatty acid Tri fatty acid triglyceride Triglyceride Fatty acid triglyceride Glyceride Glyceride Glyceride Glyceride Filling solution 90 90 80 80 80 70 (mass%) Collapse time 7 10 10 60 120 300 (seconds) (* 1) Remarks Faster and faster than the collapse of No. 3 than the collapse of No. 4 Dissolve Dissolve Dissolve Dissolve The time required for the collapse is the time required for the collapse. The length of the temple is very long. The collapse is good. The good is good. The difficulty is poor. -24- (21) (21) 200412930 From the results in Table 1, the No. . The seamless capsules of 1 to 3 are excellent in disintegration and are suitable as instant soluble seamless capsules. The jointless capsule of No.4 takes longer than the collapse of No.3.
No. 5及 N 〇.6之無接縫膠囊之崩壞所需時間更長’稱 不上適合作爲口腔內可即溶之無接縫膠囊之組成。 產業上利用性 本發明係依據此方法，可提供具有口腔內容易破壞之 口腔內可即溶性，而且可製造於製造時難以發生皮膜硬化 不良或遭破壞等問題之製品之D腔內可即溶之無接縫膠囊 的製造方法。 【圖式簡單說明】 圖1係可使用於本發明之一個實施例之液中噴嘴式無 接縫膠囊製造裝置之槪略圖。 主要元件對照表 1 芯液 2 芯液用槽 3 皮膜液 4 被覆液用槽 5 唧筒 6 管路 7 多重噴嘴 -25- (22)200412930 8 啷筒 9 管路 10 硬化用液 11 流通管 1 1 A 流入處 1 IB 流出處 11C 嵌合處 1 ID 連接棒 12 分離器 12A 連接棒 13 濾網 14 驅動來源 15 連接材料 16 分離槽 19 啣筒 20 管路 21 冷卻槽 22 冷卻器 23 唧筒 24 管路No. 5 and No. 0.6 need no longer to collapse the jointless capsules, which is not suitable as a composition of the jointless capsules that are soluble in the oral cavity. INDUSTRIAL APPLICABILITY According to this method, the present invention can provide immediate dissolution in the oral cavity, which is easily damaged in the oral cavity, and can be manufactured in the D cavity, which is difficult to cause problems such as poor film hardening or damage during manufacture. Manufacturing method of jointless capsule. [Brief description of the drawings] FIG. 1 is a schematic diagram of a liquid-in-nozzle type seamless capsule manufacturing apparatus that can be used in an embodiment of the present invention. Comparison table of main components 1 Core fluid 2 Tank for core fluid 3 Coating fluid 4 Tank for coating fluid 5 Casing 6 Pipe 7 Multi-nozzle-25- (22) 200412930 8 Casing 9 Pipe 10 Hardening liquid 11 Flow pipe 1 1 A Inflow 1 IB Outflow 11C Fitting 1 ID Connecting rod 12 Separator 12A Connecting rod 13 Strainer 14 Driving source 15 Connecting material 16 Separation tank 19 Abutment 20 Pipe 21 Cooling tank 22 Cooler 23 Tube 24 Pipe