201249481 六、發明說明： 【發明所屬之技術領域】 本發明係關於-種雙叉乳酸桿菌（肺―⑽⑷聰）大 腸遞送朦囊及其製造方法，該膠囊係於填充雙叉乳酸桿菌 的硬膠囊之表面，具有含有幾丁聚糖（chit〇san)之層、及 含有腸溶性基材之層。 【先前技術】 向來已有在服用、攝取益活菌劑及使益活菌作為醫禁 品或食品的作用而獲得的醫藥品製劑、保健食品、健康輔 助食品#。作為如此益活菌之—種雙叉乳酸桿菌，已知且 有於腸内抑制有害菌的增殖、改善腸内環境，盖排 便性等的整腸仙。因此，已嘗試尋求藉由攝取各式^ 腸作用等的醫療絲或健效果。 ，㈣件整 然而’雙又乳酸桿菌_達消化道下部，尤其 大腸為止須通過具有強大的殺菌仙之胃酸，已知的雜叉 =酸桿菌無法於胃酸等低阳環境下生存。因此，直接ς用 形，要以活菌的樣子到達能發生反應的 ::::::的，而有所謂無法賴分的醫療效果或保 作=以解決此問題的手段’已考慮使用於大腸内會 破特別地分解而溶出内容物的大腸藥物遞送系統。 就大腸藥物遞送系統而言，例如，已知將生理活性物 201249481 質（活性成分）與賦形劑一起成形的固態製劑以幾丁聚糖 塗佈液作為塗佈大腸藥物遞送系統製劑（例如，參照專利 文獻1〜2)。然而，該固態製劑之幾丁聚糖塗佈層二:塗佈 層皮膜存有細孔，腸液會由此侵入而活性成分之一部份會 由此冷出，其僅於大腸内能快速地溶出的效果不能說是充 分。又’由於幾丁聚糖塗佈皮膜之細孔侵入的腸液及水分， 在到達大腸内之前’雙叉乳酸桿菌亦有所謂會失活的問題。 因此，考量不使用該固態製劑而使用硬膠囊，將雙叉 乳酸^菌封人此膠射，該膠囊係為雙又乳酸桿菌到達大 腸之前不會失活的大腸遞送膠囊。 就該硬膠囊而言，例如，已提議含有幾丁聚糖的硬谬 囊（參照專利文獻3)。使用該硬膠囊的情形，與該固能f 劑的情形比較，因可減少活性成分以外之添加物，可提高、 „的摻合率’而且’因於製造步驟中不須加熱、加 壓、乾無等步驟，故有所謂活性成分於製造步驟不會劣化 :而’關於該手段’由於幾丁聚糖膠囊脆弱，所以有 =自泡殼包裝(PTP，press th削gh⑽卿)取出時膠囊會 破損的問題。為了解決此^ v θ 但製編…： 考置將膠囊皮膜加厚’ Μ ’力本上亦為不利。而且’由於增加該膠囊的 Ιΐ合#σ σ卩的段差變A，以腸溶性基材之塗佈層埋入此 二之：掠！難。再者’膠囊皮膜變厚時，會有增加於大腸 内之朋壞時間等的問題。 而且’就其他解決方法而言，已考量進行用以增加幾 201249481 丁聚糖膠囊強度的塗佈。然而，此方法有使塗佈層增厚、 製造步驟繁雜、成本上不利的問題。 因此，目前正強烈地冀求一種雙叉乳酸桿菌大腸遞送 膠囊之開發，該膠囊係一種於硬膠囊内包含雙叉乳酸桿菌 的雙叉乳酸桿菌大腸遞送膠囊，其係不會於胃及小腸中溶 出，而於大腸中快速地溶出，且於胃及小腸中可抑制水分 對硬膠囊内之侵入，抑制雙叉乳酸桿菌失活，且該膠囊具 有充分強度，不需用以增大強度的塗佈，進而抑制塗佈量， 可於有利的製造成本下製造此膠囊。 [先前技術文獻] [專利文獻] [專利文獻1] 特公平08-013748號公報 [專利文獻2]國際公開第2008/075448號小冊 [專利文獻3]日本專利第2555520號公報 【發明内容】 [發明所欲解決的問題] 本發明係以解決習知的各個問題，以達成以下目的。 即，本發明之目的為提供一種雙叉乳酸桿菌大腸遞送膠囊 及其製造方法，該膠囊係一種於硬鰺囊内包含雙叉乳酸桿 菌的雙叉乳酸桿菌大腸遞送膠囊，其係不會於胃及小腸中 溶出，而於大腸中快速地溶出，且抑制胃及小腸中之水分 對硬膠囊内之侵入，可抑制雙叉乳酸桿菌失活，且該膠囊 具有充分強度，不需用以增大強度的塗佈，進而抑制塗佈 5 201249481 量，並可以有利的製造成本製造該膠囊；。 [用以解決問題的手段] 為了解決該問題’本發明者們專心檢討的結果獲得以 下的見解。即，此大腸遞送膠囊係將填充雙叉乳酸桿菌之 以明膠或纖維素衍生物作為基材的膠囊之嵌合部施予帶式 ^(bandSealing)H膠囊的表面藉由依序被覆含有 &丁聚糖之層及含有腸溶性基材 s，藉由薄的含有幾丁 聚糖之皮膜，於大腸中具有有效的溶出性。 成丁 本發明者們基於前述的知識， 手段而言，本發_如以下所示。^相崎決該問題的 <π> -種雙叉乳酸桿菌大腸二送膠囊， 节 膠囊係為以明膠或纖維素衍生物彳八，马該 户為基材的硬膠囊，於i 内含有雙叉乳酸㈣’該膠囊^合部具有帶式封合，、ς 該膠囊的表面，依序具有含有幾、 基材之層。' 0聚糖之層及含有腸溶性 臺：二如該…所述之雙又乳酸桿菌大腸遞送膠 囊’其中纖維素衍生物為織Μ甲基纖維素。 <3>如該<1>至<2>項中& 桿菌大腸遞送膠囊，其中含有幾丁項：述之雙又礼酸 聚糖之塗佈液塗佈於膠囊表面上而形成係將含有幾丁 < 4>如該< 3 >所述之雙又乳酸桿菌大腸遞送 囊’其中含有幾丁《之塗佈液係將幾丁聚糖溶解 性有機酸水溶液而形成。 χ <5> 一種雙叉乳酸桿菌大腸遞送膠囊之製造方法， 201249481 其特徵為該膠囊係為以明膠或 膠囊，於其内填充雙又乳酸h 生物作為基材的硬 部加以鼓合，將該嵌合囊的本體部及帽 面塗佈或喷霧含有幾丁聚糖 於該膠囊之表 之層，於該含有幾丁聚糖之居'^飞形成含有幾丁聚糖 之層上塗佈或哨'霞, 材之塗佈液而形成含有腸溶性基材之層。、S有腸溶性基 [發明效果] i θ 依據本發明，可解決習知的各個問題 可提供-種雙叉乳酸桿菌大腸遞送膠囊f成:二 係為一種树膠囊内包含雙叉乳酸桿g的雙菌^ 腸遞送膠囊，其係*會於胃及极柃函大 速地溶出，且抑制胃及小腸中二 ==谢快 可抑制雙叉乳酸囊内之侵入’ 雙又找W失活，且該膠囊具有充分強产雨 用以增大強度的塗佈，進而抑制塗佈量，並可 ； 造成本來製造。 【實施方式】 (雙叉乳酸桿菌大腸遞送膠囊及其製造方法） 本發明之雙又乳酸桿菌大腸遞送膠囊至少於以明膠或 纖維素衍生物作為基材的硬膠囊内含有雙又乳酸桿菌，於 該膠囊之嵌合部具有帶式封合，於該膠囊之表面依序具有 含有幾丁聚糖之層及含有腸溶性基材之層而成，更因應必 要，而具有其他層。 本發明之雙又乳酸桿菌大腸遞送膠囊之製造方法至少 201249481 包含下列步驟：於以明膠或纖維素衍生物作為基材的硬膠 囊内填充雙叉乳酸桿菌，將該膠囊之本體部與帽部加以嵌 合，該嵌合部以帶式封合密封，於該膠囊之表面塗佈含有 幾丁聚糖之塗佈液而形成含有幾丁聚糖之層，於該含有幾 丁聚糖之層上塗佈含有腸溶性基材之塗佈液而形成含有腸 溶性基材之層的步驟，且進一步包含因應必要而適當選擇 的其他步驟。 <硬膠囊> 本發明所使用的硬膠囊係以使來自明膠或植物之纖維 素變性的纖維素衍生物作為基材。 而且，該硬膠囊係由本體部及帽部而成，藉由於該本 體部覆蓋該帽部而使兩者嵌合可加以膠囊化。 就該明膠而言，並未特別限定，可因應目的加以適當 選擇，例如，可例舉來自牛皮、豬皮、牛骨等所含動物性201249481 VI. Description of the Invention: [Technical Field] The present invention relates to a large intestine delivery sac and a method for producing the same, which is a hard capsule filled with a lactic acid bacillus The surface has a layer containing chitosan and a layer containing an enteric substrate. [Prior Art] Pharmaceutical preparations, health foods, and health supplement foods which have been obtained by taking, ingesting, and utilizing probiotics as a medical contraband or food. The lactic acid bacterium of the genus Bifidobacterium is known as a bacterium, and it is known that it inhibits the proliferation of harmful bacteria in the intestine, improves the intestinal environment, and improves the intestinal tract. Therefore, attempts have been made to seek medical wires or health effects by ingesting various types of intestinal action and the like. (4) whole piece However, 'double and Lactobacillus _ to the lower part of the digestive tract, especially the large intestine must pass through a strong bactericidal stomach acid, the known miscellaneous fork = acid bacillus can not survive in low-positive environment such as stomach acid. Therefore, the direct use of the shape, to the way of living bacteria to reach the reaction::::::, and the so-called medical effects or insurance = can be used to solve this problem 'has been considered for use A large intestine drug delivery system that specifically decomposes to dissolve the contents is broken in the large intestine. In the case of a large intestine drug delivery system, for example, a solid preparation in which a physiological active substance 201249481 (active ingredient) is formed together with an excipient is known as a coated drug delivery system preparation using a chitosan coating liquid (for example, Refer to Patent Documents 1 to 2). However, the chitosan coating layer 2 of the solid preparation has pores in the coating layer, and the intestinal juice may invade thereby a part of the active ingredient will be cooled out, which can be rapidly only in the large intestine. The effect of dissolution cannot be said to be sufficient. Further, the intestinal juice and water invaded by the pores of the chitosan coating film have a problem of being deactivated before reaching the large intestine. Therefore, it is considered that a hard capsule is used without using the solid preparation, and the bifurcated lactic acid is sealed by a gel, which is a large intestine delivery capsule which does not inactivate before the lactobacilli reaches the large intestine. For the hard capsule, for example, a hard capsule containing chitosan has been proposed (see Patent Document 3). In the case of using the hard capsule, compared with the case of the solid energy agent, the additive other than the active ingredient can be reduced, and the blending ratio can be increased, and the heating and pressurization are not required in the manufacturing step. There is no such step as dry, so there is a so-called active ingredient that does not deteriorate in the manufacturing step: and 'about this means' because the chitosan capsule is fragile, so there is a capsule that is taken out from the blister pack (PTP, press th cut gh(10)qing) The problem that will be broken. In order to solve this ^ v θ but the knitting...: It is also unfavorable to thicken the capsule film ' Μ ' force. And 'Because of the increase of the capsule's # σ σ σ # 变 变 变 变In the coating layer of the enteric-coated substrate, it is buried in the second: it is difficult to get rid of. In addition, when the capsule film becomes thick, there is a problem that the time in the large intestine is bad, and the other solutions are In other words, coatings for increasing the strength of several buttose capsules of 201249481 have been considered. However, this method has the problems of thickening the coating layer, complicated manufacturing steps, and disadvantageous cost. Therefore, it is currently strongly demanding a kind of Bifidobacterium lactis Development of a capsule which is a double-crossed Lactobacillus large intestine delivery capsule containing Bifidobacterium breve in a hard capsule, which does not dissolve in the stomach and small intestine, but dissolves rapidly in the large intestine, and is in the stomach and In the small intestine, the intrusion of water into the hard capsule can be suppressed, the inactivation of the bifidobacteria can be inhibited, and the capsule has sufficient strength, and coating for increasing the strength is not required, thereby suppressing the coating amount, which is advantageous in manufacturing cost. [The prior art] [Patent Document] [Patent Document 1] Japanese Patent Publication No. 2008-075448 [Patent Document 2] International Publication No. 2008/075448 (Patent Document 3) Japanese Patent No. 2555520 SUMMARY OF THE INVENTION [Problems to be Solved by the Invention] The present invention has been made to solve the above problems in order to achieve the following objects. That is, an object of the present invention is to provide a bifurcated Lactobacillus large intestine delivery capsule and a method of manufacturing the same, The capsule is a Bifidobacterium breve large intestine delivery capsule containing Bifidobacterium breve in a hard sac, which does not dissolve in the stomach and small intestine, but dissolves rapidly in the large intestine. And inhibiting the invasion of the stomach and the small intestine into the hard capsule, inhibiting the inactivation of the bifidobacteria, and the capsule has sufficient strength, and does not need to increase the strength of the coating, thereby inhibiting the amount of coating 5 201249481 The capsule can be manufactured at a favorable manufacturing cost. [Means for Solving the Problem] In order to solve the problem, the inventors have focused on the results of the review to obtain the following findings: that is, the large intestine delivery capsule will be filled with bifurcated lactic acid. a surface of a band-shaped band Sealing H capsule of a capsule in which a gelatin or a cellulose derivative is used as a substrate, by sequentially coating a layer containing & butan and an enteric substrate s, It has an effective dissolution property in the large intestine by a thin film containing chitosan. Cheng Ding The present inventors have based on the above-mentioned knowledge and means, and the present invention is as follows. ^Sakisaki's problem of <π> - a kind of Bifidobacterium breve large intestine two-feed capsule, which is a hard capsule containing gelatin or a cellulose derivative, which is a substrate, and contains double in i The fork lactic acid (four) 'the capsule portion has a band seal, and the surface of the capsule has a layer containing a plurality of substrates. a layer of 'glycans and an enteric-coated table: as described herein. The bismuth-Lactobacillus large intestine delivery capsule </ RTI> wherein the cellulose derivative is woven methyl cellulose. <3> The <1> to <2>>& bacilli large intestine delivery capsule containing a plurality of coatings: the coating liquid of the bis-glycolic acid coated on the surface of the capsule A solution containing a small amount of <4> as described in <3> of the Lactobacillus large intestine delivery capsule, wherein the coating solution containing chitosan dissolved organic acid is formed. χ <5> A method for producing a Bifidobacterium breve large intestine delivery capsule, 201249481, characterized in that the capsule is a gelatin or a capsule filled with a hard part of a lactic acid h-base as a substrate, and The body portion and the cap surface of the chimeric capsule are coated or sprayed with a layer containing chitosan on the surface of the capsule, and coated on the layer containing chitosan to form a chitosan-containing layer. The cloth or whistle 'Xia, the coating liquid of the material forms a layer containing an enteric substrate. , S has an enteric-soluble group [Effect of the invention] i θ According to the present invention, various problems can be solved by providing a kind of Bifidobacterium breve large intestine delivery capsule f into two types: a tree capsule containing a bifurcated lactic acid rod g Double bacteria ^ intestinal delivery capsule, its system will dissolve in the stomach and the sputum, and inhibit the stomach and small intestine two == thank you can inhibit the invasion of the bifurcated lactic acid sac And the capsule has a coating which is sufficiently strong to produce rain for increasing the strength, thereby suppressing the amount of coating, and may cause the original manufacture. [Embodiment] (Bifidobacterium lactis large intestine delivery capsule and method for producing the same) The lactic acid bacillus large intestine delivery capsule of the present invention contains at least a lactobacillus in a hard capsule containing gelatin or a cellulose derivative as a substrate. The fitting portion of the capsule has a band seal, and has a layer containing chitosan and a layer containing an enteric substrate on the surface of the capsule, and further has other layers as necessary. The method for producing a Bifidobacterium large intestine delivery capsule of the present invention at least 201249481 comprises the steps of: filling a hard capsule of gelatin or a cellulose derivative as a base material with Lactobacillus bifidum, and applying the body portion and the cap portion of the capsule The fitting portion is sealed with a band seal, and a coating liquid containing chitosan is applied onto the surface of the capsule to form a layer containing chitosan on the layer containing chitosan. The step of applying a coating liquid containing an enteric substrate to form a layer containing an enteric substrate, and further including other steps appropriately selected as necessary. <Hard Capsule> The hard capsule used in the present invention is a cellulose derivative which denatures cellulose from gelatin or plant as a substrate. Further, the hard capsule is formed by a main body portion and a cap portion, and the body portion covers the cap portion to fit the two to be encapsulated. The gelatin is not particularly limited and may be appropriately selected depending on the purpose. For example, animal origins such as cowhide, pigskin, and bovine bone may be exemplified.
• V 膠原蛋白（collagen )者、來自魚之明膠等。此等例舉之中， 以來自牛以外之動物的明膠，且不會有狂牛病感染之虞者 為較佳。 就該纖維素衍生物而言，例如，可例舉烷基纖維素（例 如，曱基纖維素等）、羥基烷基纖維素（例如，羥基乙基纖 維素、羥基丙基纖維素等）、羥基烷基烷基纖維素（例如， 羥基丙基曱基纖維素（HPMC)、羥基乙基甲基纖維素、羥 基乙基乙基纖維素等）等。上述此等可以單獨使用一種， 亦可併用兩種以上。上述此等中，以羥基烷基烷基纖維素 為較佳，具體而言，以作為膠囊之強度為優異的觀點及含 201249481 有幾丁聚糖之層溶解後於大腸内快速溶解的觀點，HPMC 為最佳。 該硬膠囊可藉由下列方式製造，例如，將該明膠或纖 維素衍生物作成水溶液，於此溶液内浸潰金屬製的栓，拉 出該栓’確保形狀後，經乾燥可加以製造。 通常可以纖維素衍生物約5質量％〜25質量％、水約 74質量％〜94質量％、膠化劑約〇.〇1質量％〜0.5質量％、 膠化輔助劑約0.01質量％〜0.5質量。/〇調製該纖維素衍生物 之水溶液’更視需要適當地摻合著色劑（例如，氧化鈦、 鐵丹（rouge)、藍色2號、黄色5號等）、不透明化劑（例 如’氧化鈦等）、香料等。 就該硬膠囊之大小而言，有〇〇號、〇號、1號、2號、 3號、4號、5號等’但本發明亦可使用任一種大小的硬膠 囊。 <雙叉乳酸桿菌> ' 就該雙叉乳酸桿菌而言，只要具有對人有用的作用者 即可，並未特別限定，可因應目的加以適當選擇，例如， 可例舉雙叉乳酸桿菌屬（)之龍根菌 {Bifidobacterium longum)、也赛德氏遠[Bifidobacterium 、短雙叉桿菌、青春雙叉桿 壤（Bifidobacterium αί/ο/esce«沿）、嬰兒雙叉桿菌 [Bifidobacterium infantis)、動物雙义择蛰（Bifidobacterium animalisV、散長雙又择議{Bifidobacterium pseudolongum') 等。上述此等可單獨使用一種，亦可併用兩種以上。上述 201249481 此等中，於可利用於食品的觀點，以龍根菌（及 longum)、也养德氏溘 Q Bifid〇bacterium bifidum)、短雙又 桿菌(Bifidobacterium breve )為較佳。 該雙叉乳酸桿菌係直接以活的狀態填充於該硬膠囊者 為較佳。而且’該雙叉乳酸桿菌亦可密封於膠囊内後，進 一步於膠囊内增殖。 就5亥雙叉乳酸桿菌之形狀而言，只要可填充於該膠囊 内即可’並未特別限定，可因應目的加以適當選擇，例如， 可例舉懸浮於適合的培養基之液狀物、硬化油脂等混合的 固態物、乾燥粉末等。 該雙叉乳酸桿菌為乾燥粉末的情形’就填充膠囊之際 的雙叉乳酸桿菌濃度而言，以1 X 1 06cfu/g以上為較佳， 1X10 cfu/g以上為更佳。此外，cfu表示菌落形成單位。 該雙叉乳酸桿菌為液狀物的情形，液狀物中的雙叉乳 酸桿菌之濃度過高時’該液狀物之黏度會變高’而難以膠 囊化，故與適合的培養基作膠囊化後，進一步增殖為較佳。 就該液狀物中之雙又乳酸桿菌濃度而言，1X106 C fu / g以上為 較佳，lxl09cfu/g〜lxi〇i2cfu/g 為更佳。 就可與該雙叉乳酸桿菌一起填充炱該硬膠囊内的其他 成分而言’可例舉將該雙叉乳酸桿菌作成液狀物的情形使 懸浮的培養基、將雙又乳酸桿菌作成固態物的情形所使用 的硬化油脂、將雙叉乳酸桿菌作成乾嫖粉末的情形所使用 的乳糖、乾燥馬鈴薯澱粉等之稀釋劑、乳酸菌、粉糖、寡 糖、纖維素等。上述此等可單獨使用〆種，亦可併用兩種 201249481 以上。上述此等中，以使水分活性降低者或水分活性為低 者較佳，具體而言，乾燥馬鈴薯澱粉為較佳。 就該雙又乳酸桿菌之膠囊内含量而言，依雙叉乳酸桿 菌之形狀、膠囊之容量等不能一概而論地決定，但相對於 膠囊内包含的組成物全量，以3質量％〜9〇質量％為較佳， 質里°/〇〜60質量％為更佳。該含量低於3質量％時，為 了獲得雙又乳酸桿菌所產生的整腸效果等，而產生服用多 量膠囊的必要性，超過90質量〇/〇時，亦擔心對腸内細菌叢 之平衡有影響。 -雙叉乳酸桿菌之對硬膠囊的填充及膠囊之嵌合_ 雙又乳酸桿菌之填充係於該硬膠囊之本體部填充該雙 又乳酸桿菌來進行’例如’可藉由下列方法進行：於雙叉 乳酸桿菌為液狀物的情形作注入、滴下的方法、於雙叉乳 酸桿菌為乾燥粉末的情形使過濾器一邊震盪一邊落下填充 的方法等。 其次’於以前述方法填充雙叉乳酸桿菌的膠囊之本體 部’蓋上膠囊的帽部而使兩者嵌合，藉由接合本體部及帽 部’可製作包含雙叉乳酸桿菌的膠囊。 該雙又乳酸桿菌對硬膠囊内之填充及膠囊之嵌合可使 用眾所皆知的膠囊填充機，例如，全自動膠囊填充機 (Qualicaps股份有限公司製，LIQFIL super 100型）、膠囊 填充密封機（Qualicaps股份有限公司製，LIQFIL super FS 型）等來實施。 <帶式封合> 201249481 該帶式封合係於硬膠囊内填充内容物後，使用於此膠 囊的本體部及帽部之嵌合部的封口之密封劑（封口劑）。 藉由該帶式封合’使用幾丁聚糖塗佈液而形成含有幾 丁聚糖之層之際，幾丁聚糖塗佈液不會由嵌合部侵入膠囊 内部，再者，藉由嵌合部被平滑化，可形成薄且均一的含 有幾丁聚糖之層。 就該帶式封合之材料而言，並未特別限定，可自眾所 皆知者中適當選擇，例如，可例舉明膠、纖維素衍生物、 聚乙二醇（PEG )、聚乙烯醇（p VA )等。 就該明膠及纖維素衍生物而言，使用與該硬膠囊 料相同者為較佳。 你中叭珂甘只要不防礙本發明之效果，除了上 述成分外’更因應必要’可摻合著色劑（例如，氧 :丹、：油系色素等)、不透明化劑、香料等之鄉囊之製 造上通常使用的添加劑。就該添加劑對帶式封合的換人^ 例而言，通常為0.1質量％〜7 t ^ /口 式封合性而加以適當選擇。質夏/°’可由此乾圍考量帶 一般而言’㈣帶式封合㈣ 調製液），塗佈於該硬膠量$ 饮式封合 乾燥而可形以封合囊之讀料帽部《合部，使其 猎由於至溫或加、;w 水、親水性溶媒、或水與親帶H合材料溶解於 該帶式封合調製液。 4、之混合液中，可調製 就該親水性溶媒而言，可物有與水之相溶性的有 12 201249481 機溶媒，具體而言，可例舉乙醇、異丙醇等的碳數為1〜6 之低級醇。上述此等中，以乙醇為較佳。此外，該親水性 溶媒係呈與水之混合液來使用者為較佳。 該帶式封合調製液之調製使用水與親水性溶媒之混合 液的情形，就該混合液100質量％中之親水性溶媒之比率 而言，通常為5質量％〜80質量％，8質量％〜65質量％為 較佳，10質量％〜50質量％為更佳。 就該帶式封合調製液而言，調製液之最終黏度係通常 為 lOOmPa · s〜5,000mPa · s，125mPa · s〜4,700mPa · s 為較佳，150mPa · s〜4,500mPa · s為更佳。該黏度低於 lOOmPa · s時，於硬膠囊之嵌合部表面以未滴液的情況來 塗佈帶式封合調製液係有困難的，有無法形成封口力優異 的帶式封合之可能性。而且，該黏度超過5,000mPa· s時， 黏度過高而有以機械無法形成帶式封合的可能性。另一方 V , ，· 面，該黏度於該較佳範圍内時，於硬膠囊劑之本體部與帽 部之嵌合部可形成密封力（封口力）大的強固帶式封合， 而且製造時不會拖絲，製造中的處理亦容易。此外，該黏 度意指使用回轉型黏度計（例如，英弘精機股份有限公司 製VT550型），於20°c、測量時間2分鐘的條件下測量時 的黏度。 -經由帶式封合膠囊的封口- 該帶式封合係對經由該方法製作包含雙叉乳酸桿菌的 膠囊，以其帽部之端緣部作為中心的一定寬度下於本體部 的表面及帽部的表面上，將該帶式封合調製液以本體部及 13 201249481 帽部之圓周方向塗佈一次至數次，較佳為一次至兩次，而 將嵌合部密封。於此情形，如後述控制密封劑之溫度於— 定溫度範圍者為較佳。 使遠硬膠囊之本體部及帽部兩者嵌合時，就本體部之 外周及帽部之内周重疊的嵌合寬度而言，並未特別限定， 可因應目的加以適當選擇，但就膠囊之軸線方向的距離而 吕，於3號膠囊為約4.5mm〜6.5mm、4號膠囊為約4.0mm 〜6.0mm者較佳。而且，就封口寬度而言，3號膠囊為約 1.5mm〜4.〇mm、4號膠囊為約l.5mm〜2.8mm者較佳。 一般而言，該帶式封合調製液可於室溫或加熱下使 用，就此溫度而言，14C〜28°C為較佳，；[5〇C〜25°C為更 佳，16 C〜22 C為最佳。該溫度於該較佳範圍内時，可賦 予硬膠囊之内容物防漏效果。就該調製液之溫度調節而 言，並未特別限定，可以面板加熱器、溫水加熱器等眾所 皆知之方法來實施’例如’將循環式溫水加熱器、該一體 型膠囊填充密封機之密封盤單元使用於循環式溫水加熱器 型改造者，於可微妙地調節溫度範圍為較佳。此外，帶式 封合調製液中之醇（例如，乙醇），因會依溫度條件而揮發， 故適當補充帶式封合調製液的組成為一定量者較佳。 該帶式封合硬膠囊的封口，可使用其眾所皆知的膠囊 填充密封機，例如，該膠囊填充密封機（Qualicaps股份有 限公司製、LIQFIL super FS型）、膠囊密封機（Qualicaps 股份有限公司製、HICAPSEAL 100型）來實施。 <含有幾丁聚糖之層（幾丁聚糖皮膜）> 14 201249481 該含有幾丁聚糖之層至少含有幾丁聚糖，因應必要進 一步含有其他成分而成。 藉由將至少含有幾丁聚糖的幾丁聚糖塗佈液塗佈或喷 霧於該硬膠囊之表面，而形成該含有幾丁聚糖之層。 -幾丁聚糖塗佈液- 該幾丁聚糖塗佈液至少含有幾丁聚糖，因應必要含有 其他成分。 —幾丁聚糖一 就該幾丁聚糖之脱乙醯基化度、分子量而言，並未特 別限定，可因應目的加以適當選擇。 就該幾丁聚糖之脱乙醯基化度而言，對酸之溶解性及 對塗佈法之適性的觀點，70莫耳％以上為較佳。 就該含有幾丁聚糖之層之厚度而言，可因應膠囊形 狀、大小、質量等而適當選擇，但相對於膠囊之質量，幾 丁聚糖之質量為相當於0.5質量％〜6.0質量％的厚度為較 佳，相當於0.8質量％〜5.0質量％的厚度為更佳，相當於 0.8質量％〜3.0質量％的厚度為最佳。該厚度低於相當於 0.5質量％的厚度時，因未形成充分厚度之含有幾丁聚糖之 層，故於小腸内含有腸溶性基材之層崩壞後，雙叉乳酸桿 菌大腸遞送膠囊被送達大腸之前，含有幾丁聚糖之層舍有 崩壞的情形，超過相當於6.0質量％的厚度時，為了於膠囊 表面形成含有幾丁聚糖之層而進行塗佈時，恐怕塗佈時間 會增長。另一方面，該厚度於前述之更佳範圍内時，雙叉 乳酸桿菌大腸遞送膠囊之對大腸的送達確實成為可能，企 15 201249481 圖獲得有利於含有必要的幾丁聚糖之層的塗佈時間之縮短 的觀點。 就該含有幾丁聚糖之層中的幾丁聚糖之含量而言，並 未特別限定，可因應目的加以適當選擇，但30質量％〜95 質量％為較佳。該幾丁聚糖之含量低於30質量％時，獲得 的幾丁聚糖皮膜之強度並不充分，而無實用性，超過95質 量％時，有機酸殘存量的降低並不充分，幾丁聚糖皮膜之 耐水性有變低的情形。另一方面，該幾丁聚糖之含量於該 較佳範圍内時，可有利於將含有幾丁聚糖之層的厚度變薄 之觀點。 --酸-- 該幾丁聚糖因不溶於水及有機溶媒，故使其與酸共存 而溶解於水。 就該酸而言，可例舉無機酸及有機酸，但因無機酸與 幾丁聚糖之相互作用極為不適，故以有機酸為較佳。 就該有機酸而言，並未特別限定，可因應目的加以適 當選擇，但於常壓具有充分揮發性的觀點，以曱酸、乙酸、 丙酸、三氯乙酸為較佳。上述此等中，於便宜、處理容易、 且即使殘留於含有幾丁聚糖之層對人體之影響亦少的觀 點，以乙酸為更佳。 就該有機酸之使用量而言，並未特別限定，可因應目 的加以適當選擇，但每當量之幾丁聚糖之胺基，以0.8莫 耳當量至2.0莫耳當量為較佳。該有機酸之使用量低於0.8 莫耳當量時，幾丁聚糖之溶解性變低，超過2.0莫耳當量• V collagen (collagen), gelatin from fish, etc. Among these examples, it is preferred to use gelatin from animals other than cattle, and there is no risk of infection with mad cow disease. The cellulose derivative may, for example, be an alkyl cellulose (for example, mercapto cellulose or the like), a hydroxyalkyl cellulose (for example, hydroxyethyl cellulose, hydroxypropyl cellulose, or the like), A hydroxyalkylalkylcellulose (for example, hydroxypropylmercaptocellulose (HPMC), hydroxyethylmethylcellulose, hydroxyethylethylcellulose, etc.) or the like. These may be used alone or in combination of two or more. In the above, the hydroxyalkylalkylcellulose is preferred, and in particular, the viewpoint that the strength of the capsule is excellent and that the layer containing 201249481 having chitosan is dissolved and rapidly dissolved in the large intestine is used. HPMC is the best. The hard capsule can be produced, for example, by using the gelatin or the cellulose derivative as an aqueous solution, impregnating the metal plug in the solution, and pulling the plug to ensure the shape, and drying can be carried out. Generally, the cellulose derivative may be from about 5% by mass to 25% by mass, water is from about 74% by mass to 94% by mass, the gelling agent is about 〇. 〇1% by mass to 0.5% by mass, and the gelling aid is about 0.01% by mass to 0.5% by weight. quality. /〇 modulating the aqueous solution of the cellulose derivative', more appropriately blending a coloring agent (for example, titanium oxide, rouge, blue No. 2, yellow No. 5, etc.), an opaque agent (for example, 'oxidation Titanium, etc.), spices, etc. As for the size of the hard capsule, there are nicknames, nicknames, No. 1, No. 2, No. 3, No. 4, No. 5, etc. However, any size of the hard capsule can be used in the present invention. <Lactobacillus bifidum> 'The Bifidobacterium breve is not particularly limited as long as it has a useful effect on humans, and can be appropriately selected depending on the purpose, and for example, Lactobacillus bifidum can be exemplified. Bifidobacterium longum (Bifidobacterium longum), also known as Bifidobacterium, Bifidobacterium, Bifidobacterium αί/ο/esce«, Bifidobacterium infantis, Bifidobacterium animalis V, Bifidobacterium pseudolongum', etc. These may be used alone or in combination of two or more. In the above-mentioned 201249481, it is preferable to use R. solani (and longum), Q Bifid〇bacterium bifidum, and Bifidobacterium breve from the viewpoint of being usable in food. It is preferred that the Bifidobacterium breve is directly filled in the hard capsule in a living state. Further, the Bifidobacterium breve can be further encapsulated in the capsule and further propagated in the capsule. The shape of the Lactobacillus brevisii is not particularly limited as long as it can be filled in the capsule, and can be appropriately selected depending on the purpose. For example, a liquid suspended in a suitable medium and hardened can be exemplified. a mixed solid such as oil or fat, a dry powder, or the like. In the case where the Bifidobacterium breve is a dry powder, the concentration of the Bifidobacterium breve at the time of filling the capsule is preferably 1 X 1 06 cfu/g or more, more preferably 1 X 10 cfu/g or more. In addition, cfu represents a colony forming unit. When the Bifidobacterium breve is in the form of a liquid, when the concentration of the Bifidobacterium breve in the liquid is too high, the viscosity of the liquid becomes high, and it is difficult to be encapsulated, so that it is encapsulated with a suitable medium. After that, further proliferation is preferred. With respect to the concentration of the Lactobacillus in the liquid, 1X106 C fu / g or more is preferable, and lxl09 cfu/g to lxi〇i2 cfu/g is more preferable. In the case where the other components in the hard capsule are filled together with the Bifidobacterium breve, 'the suspension medium can be exemplified, and the suspension medium can be made into a solid body. The hardened fats and oils used in the case, the lactose used for the case where the Bifidobacterium breve is used as a dry powder, the diluent such as dry potato starch, lactic acid bacteria, powdered sugar, oligosaccharide, cellulose, or the like. These may be used alone or in combination with two types of 201249481 or more. In the above, it is preferred that the water activity is lowered or the water activity is low, and specifically, the potato starch is preferably dried. In terms of the content of the capsule of the lactic acid bacillus, the shape of the lactic acid bacillus, the capacity of the capsule, and the like cannot be determined in a general manner, but the total amount of the composition contained in the capsule is 3% by mass to 9% by mass. Preferably, the quality is in the range of °/〇 to 60% by mass. When the content is less than 3% by mass, in order to obtain the effect of the whole intestine produced by the lactic acid bacillus, it is necessary to take a large amount of capsules, and when it exceeds 90 mass 〇/〇, it is also feared that the balance of the intestinal flora is influences. - Filling of hard capsules with Lactobacillus bifidum and fitting of capsules - Filling of Lactobacillus and Lactobacillus in the body of the hard capsule is carried out by filling the Lactobacillus bacterium to 'for example' by the following method: In the case where the Bifidobacterium breve is in the form of a liquid, the method of injecting and dropping is used, and when the Bifidobacterium breve is a dry powder, the filter is swayed while being swayed and filled. Then, the cap portion of the capsule filled with the lactic acid bacillus in the above-described method is covered with the cap portion of the capsule, and the cap portion of the capsule is fitted, and the capsule containing the Bifidobacterium breve can be produced by joining the body portion and the cap portion. The Lactobacillus can be used for the filling of the hard capsule and the fitting of the capsule, and a well-known capsule filling machine, for example, a fully automatic capsule filling machine (manufactured by Qualicaps Co., Ltd., LIQFIL super 100 type), a capsule filling seal can be used. It is implemented by a machine (made by Qualicaps Co., Ltd., LIQFIL super FS type). <Band Sealing> 201249481 This tape seal is used as a sealant (sealing agent) for sealing the fitting portion of the main body portion and the cap portion of the capsule after filling the contents in the hard capsule. When the chitin coating layer is used to form a layer containing chitosan by the band sealing, the chitosan coating liquid does not intrude into the capsule by the fitting portion, and further, The fitting portion is smoothed to form a thin and uniform layer containing chitosan. The material to be band-sealed is not particularly limited and may be appropriately selected from those well-known, and examples thereof include gelatin, cellulose derivatives, polyethylene glycol (PEG), and polyvinyl alcohol. (p VA ) and so on. In the case of the gelatin and the cellulose derivative, it is preferred to use the same as the hard capsule. As long as it does not hinder the effects of the present invention, in addition to the above-mentioned components, it is more necessary to blend colorants (for example, oxygen: Dan, oily pigments, etc.), opaque agents, spices, etc. Additives commonly used in the manufacture of pouches. In the case of the substitution of the additive to the tape seal, it is usually 0.1% by mass to 7 t ^ / mouth sealability and is appropriately selected. The quality of summer / ° ' can be considered as a dry circumference of the general ('four) belt seal (four) preparation liquid), coated in the amount of hard plastic $ drink-type sealed dry and can be shaped to seal the reading cap of the capsule "The joint, so that it is due to warm or add; w water, hydrophilic solvent, or water and pro-band H material dissolved in the band seal solution. 4. In the mixed liquid, it is possible to prepare a solvent which is compatible with water in the case of the hydrophilic solvent. Specifically, the carbon number of ethanol, isopropyl alcohol or the like is 1 ~6 lower alcohol. Among the above, ethanol is preferred. Further, it is preferred that the hydrophilic solvent is a mixture with water. In the case where the mixture of the water and the hydrophilic solvent is used for the preparation of the band-sealing preparation liquid, the ratio of the hydrophilic solvent in 100% by mass of the mixed liquid is usually 5% by mass to 80% by mass, and 8 masses. More preferably, it is more preferably from 100% by mass to 50% by mass. In the case of the belt-sealing preparation liquid, the final viscosity of the preparation liquid is usually from 100 mPa·s to 5,000 mPa·s, 125 mPa·s to 4,700 mPa·s is preferable, and 150 mPa·s to 4,500 mPa·s is more. good. When the viscosity is less than 100 mPa·s, it is difficult to apply the band seal liquid to the surface of the fitting portion of the hard capsule without dripping, and there is a possibility that a band seal excellent in sealing strength cannot be formed. Sex. Further, when the viscosity exceeds 5,000 mPa·s, the viscosity is too high and there is a possibility that the belt cannot be formed by mechanical sealing. The other side V, , · surface, when the viscosity is within the preferred range, a strong band seal can be formed in the fitting portion of the body portion and the cap portion of the hard capsule, and the sealing force (sealing force) is large, and is manufactured. It does not drag the wire, and the handling in manufacturing is also easy. In addition, the viscosity means a viscosity measured under a condition of 20 ° C and a measurement time of 2 minutes using a rotary viscometer (for example, VT550 type manufactured by Hidehiro Seiki Co., Ltd.). - Sealing via a band-sealing capsule - This cap-type sealing system is used to produce a capsule containing a bifidobacterium lactobacillus by this method, and a cap having a certain width centering on the end portion of the cap portion on the surface of the body portion and a cap On the surface of the portion, the belt-sealing preparation liquid is applied once to several times, preferably once to twice, in the circumferential direction of the body portion and the cap portion of 2012-0481, and the fitting portion is sealed. In this case, it is preferred to control the temperature of the sealant to a predetermined temperature range as will be described later. When the main body portion and the cap portion of the distal hard capsule are fitted, the fitting width of the outer circumference of the main body portion and the inner circumference of the cap portion is not particularly limited, and may be appropriately selected depending on the purpose, but the capsule is appropriately selected. The distance in the direction of the axis is preferably about 4.5 mm to 6.5 mm for the No. 3 capsule and about 4.0 mm to 6.0 mm for the No. 4 capsule. Further, in terms of the sealing width, the No. 3 capsule is preferably about 1.5 mm to 4. 〇 mm, and the No. 4 capsule is preferably about 1.5 mm to 2.8 mm. In general, the tape sealing solution can be used at room temperature or under heating, and at this temperature, 14C to 28 ° C is preferred; [5 〇 C 〜 25 ° C is better, 16 C 〜 22 C is the best. When the temperature is within the preferred range, the content of the hard capsule can be imparted with a leak-proof effect. The temperature adjustment of the preparation liquid is not particularly limited, and a method such as a panel heater or a warm water heater can be used to carry out 'for example, a circulating type warm water heater, the integral type capsule is filled and sealed. The sealing disc unit of the machine is used in the reformer of the circulating hot water heater, and it is preferable to finely adjust the temperature range. Further, the alcohol (e.g., ethanol) in the band-sealing preparation liquid is volatilized depending on temperature conditions, so that it is preferable to appropriately supplement the composition of the belt-sealing preparation liquid to a certain amount. The sealing of the band-sealed hard capsule can be carried out using a well-known capsule filling and sealing machine, for example, the capsule filling and sealing machine (manufactured by Qualicaps Co., Ltd., LIQFIL super FS type), capsule sealing machine (Qualicaps shares limited) Company system, HICAPSEAL 100 type) to implement. <Latex-containing layer (chitosan coating)> 14 201249481 The chitosan-containing layer contains at least chitosan, and further contains other components as necessary. The chitosan-containing layer is formed by coating or spraying a chitosan coating solution containing at least chitosan on the surface of the hard capsule. - Chitosan coating liquid - The chitosan coating liquid contains at least chitosan, and other components are necessary as necessary. - Chitosan - The degree of deacetylation and molecular weight of the chitosan is not particularly limited and may be appropriately selected depending on the purpose. The degree of deacetylation of the chitosan is preferably 70 mol% or more from the viewpoints of the solubility of the acid and the suitability for the coating method. The thickness of the layer containing the chitosan may be appropriately selected depending on the shape, size, quality, and the like of the capsule, but the mass of the chitosan is equivalent to 0.5% by mass to 6.0% by mass based on the mass of the capsule. The thickness is preferably from 0.8% by mass to 5.0% by mass, more preferably from 0.8% by mass to 3.0% by mass. When the thickness is less than 0.5% by mass, the layer containing chitosan having a sufficient thickness is not formed, so that the layer containing the enteric substrate in the small intestine collapses, and the Bifidobacterium breve large intestine delivery capsule is Before the large intestine is delivered, the layer containing chitosan may be collapsed. When the thickness is more than 6.0% by mass, the coating time may be applied in order to form a layer containing chitosan on the surface of the capsule. Will grow. On the other hand, when the thickness is within the above-mentioned preferable range, the delivery of the big intestine delivery capsule to the large intestine is indeed possible, and the application of the layer containing the necessary chitosan is obtained. The idea of shortening the time. The content of the chitosan in the chitosan-containing layer is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferably 30% by mass to 95% by mass. When the content of the chitosan is less than 30% by mass, the strength of the obtained chitosan film is not sufficient, and there is no practicality. When the content exceeds 95% by mass, the decrease in the residual amount of the organic acid is not sufficient. The water resistance of the polysaccharide film is lowered. On the other hand, when the content of the chitosan is within the preferred range, the viewpoint of thinning the thickness of the layer containing chitosan can be favored. - Acid - The chitosan is insoluble in water and an organic solvent, so it coexists with acid and dissolves in water. The acid may, for example, be an inorganic acid or an organic acid. However, since the interaction between the inorganic acid and the chitosan is extremely uncomfortable, an organic acid is preferred. The organic acid is not particularly limited and may be appropriately selected depending on the intended purpose. From the viewpoint of sufficient volatility at normal pressure, citric acid, acetic acid, propionic acid or trichloroacetic acid is preferred. Among these, it is preferable to use acetic acid because it is inexpensive, easy to handle, and even if the layer containing the chitosan has little influence on the human body. The amount of the organic acid to be used is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferably from 0.8 mole equivalent to 2.0 mole equivalent per equivalent of the amine group of the chitosan. When the amount of the organic acid used is less than 0.8 mol equivalent, the solubility of chitosan becomes low, exceeding 2.0 m.
S 201249481 時，未能有效率地進行酸的去除，獲得呈現耐水性的幾丁 聚糖皮膜（含有幾丁聚糖之層）有變困難的情形。 於可有效率地除去該有機酸的觀點，以該幾丁聚糖塗 佈液包含甘油脂肪酸酯者為較佳。 該甘油脂肪酸酯係包含脂肪酸與甘油（glycerol)或聚 甘油（polyglycerol)之酯及其衍生物。就該甘油脂肪酸酯 之具體例而言，可例舉甘油脂肪酸酯、甘油乙酸脂肪酸酯、 甘油乳酸脂肪酸酯、甘油檸檬酸脂肪酸酯、甘油琥珀酸脂 肪酸酯、甘油乙酸酯、聚甘油脂肪酸酯、聚甘油縮合篦麻 子油酸醋等。 就該甘油脂肪酸酯所使用的脂肪酸而言，並未特別限 定’可因應目的加以適當選擇，例如，可例舉辛酸（caprylie acid)、癸酸（capric acid)、月桂酸（lauric acid)、肉豆惹 酸（myristic acid )、棕櫚酸（palmitic acid)、硬脂酸（stearic ， ' , acid)、山窬酸（behenic acid)、油酸（oleic acid)、亞麻仁 油酸（linolic acid )、芥酸（erucic acid )、異棕橺酸（isopalmitic acid)、異硬脂酸（isostearic acid)等。上述此等中，以肉 豆蔻酸、棕櫚酸或硬脂酸為較佳。 就該聚甘油脂肪酸酯中之甘油之聚合數而言，只要為 單體至20量體的範圍即可’並未特別限定，可因應目的加 以適當選擇，例如，可例舉單甘油、二甘油、三甘油、四 甘油、五甘油、六甘油、十甘油等。脂肪酸單體對水的溶 解有變困難的情形，21量體以上者於製造所需成本會變高。 就該脂肪酸之取代度而言，只要該甘油脂肪酸酯可溶 17 201249481 解或分散於水即可，並未特別限定，可因應目的加以適當 選擇，但單g旨至三g旨的範圍為較佳。 就該幾丁聚糖皮膜中的甘油脂肪酸酯的含量而言，並 未特別限定，可因應目的加以適當選擇，但於可使有機酸 殘存量降低的觀點，相對於幾丁聚糖之質量，以5質量％ 〜200質量％為較佳。該甘油脂肪酸酯之含量低於5質量％ 時，有機酸殘存量的降低並不充分，幾丁聚糖皮膜之耐水 性有變低的情形，超過200質量％時，所得幾丁聚糖皮膜 之強度並不充分，而不實用。 --其他成分一 就該其他成分而言，只要不損及本發明效果，並未特 別限定，可因應目的加以適當選擇，例如，可例舉填充劑 或可塑劑等。 藉由使用該填充劑或可塑劑，可更防止水分侵入膠囊 . 1 - 内，而可更抑制大腸到達前之崩壞及雙叉乳酸桿菌之溶出。 就該填充劑而言，並未特別限定，可因應目的加以適 當選擇，例如，可例舉滑石、皂土（bentonite)或碳數為 10以上之有機酸的金屬鹽等。 就該可塑劑而言，並未特別限定，可因應目的加以適 當選擇，例如，可例舉甘油、二甘油、二乙二醇、丙二醇、 三乙二醇、聚乙二醇等之多元醇等。上述此等中，為了於 醫藥品領域中使用，以甘油、丙二醇或聚乙二醇為較佳。 -含有幾丁聚糖之層之形成- 該含有幾丁聚糖之層係藉由於該膠囊表面上塗佈或喷In S 201249481, the acid was not efficiently removed, and it was difficult to obtain a water-resistant chitosan film (a layer containing chitosan). From the viewpoint of efficiently removing the organic acid, it is preferred that the chitosan coating liquid contains a glycerin fatty acid ester. The glycerin fatty acid esters include esters of fatty acids with glycerol or polyglycerol and derivatives thereof. Specific examples of the glycerin fatty acid ester include glycerin fatty acid ester, glycerin acetate fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citrate fatty acid ester, glyceryl succinate fatty acid ester, and glycerin acetate. , polyglycerin fatty acid ester, polyglycerin condensed castor oil vinegar and the like. The fatty acid to be used for the glycerin fatty acid ester is not particularly limited, and may be appropriately selected depending on the intended purpose. For example, caprylie acid, capric acid, lauric acid, and the like may be mentioned. Myristic acid, palmitic acid, stearic, ', acid, behenic acid, oleic acid, linolic acid , erucic acid, isopalmitic acid, isostearic acid, and the like. Among the above, it is preferred to use myristic acid, palmitic acid or stearic acid. The number of polymerization of the glycerin in the polyglycerin fatty acid ester is not particularly limited as long as it is in the range of from 20 to 20, and may be appropriately selected depending on the intended purpose. For example, monoglycerin or two may be mentioned. Glycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerol, decaglycerin, and the like. It is difficult to dissolve the water in the fatty acid monomer, and the cost required for the production of 21 or more is high. The degree of substitution of the fatty acid is not particularly limited as long as the glycerin fatty acid ester is soluble or dispersible in water, and may be appropriately selected depending on the purpose, but the range from the single g to the third g is Preferably. The content of the glycerin fatty acid ester in the chitosan film is not particularly limited, and may be appropriately selected depending on the purpose, but the quality of the chitosan may be lowered from the viewpoint of reducing the residual amount of the organic acid. It is preferably 5 mass% to 200 mass%. When the content of the glycerin fatty acid ester is less than 5% by mass, the decrease in the residual amount of the organic acid is insufficient, and the water resistance of the chitosan film may be lowered. When the content exceeds 200% by mass, the resulting chitosan film may be obtained. The strength is not sufficient and not practical. (Other components) The other components are not particularly limited as long as they do not impair the effects of the present invention, and may be appropriately selected depending on the purpose. For example, a filler or a plasticizer may, for example, be mentioned. By using the filler or the plasticizer, it is possible to further prevent moisture from intruding into the capsule. In the inside, the collapse of the large intestine and the dissolution of the lactobacilli can be more inhibited. The filler is not particularly limited and may be appropriately selected depending on the intended purpose. For example, talc, bentonite or a metal salt of an organic acid having 10 or more carbon atoms may, for example, be mentioned. The plasticizer is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include polyols such as glycerin, diglycerin, diethylene glycol, propylene glycol, triethylene glycol, and polyethylene glycol. . Among these, glycerin, propylene glycol or polyethylene glycol is preferred for use in the pharmaceutical field. - formation of a layer containing chitosan - the layer containing chitosan is coated or sprayed on the surface of the capsule
18 201249481 霧至少含有幾丁聚糖的幾丁聚糖塗佈液而形成。 例如，使用流動層造粒塗佈裝置（Flow coater，FREUND 產業股份有限公司製）、離心轉動造粒塗佈裝置（CF GRANULATOR，GRANUREX，FREUND 產業股份有限公 司製）、複合型造粒塗佈裝置（Spiraflow，FREUND產業股 份有限公司製）、糖衣薄膜塗佈裝置（Hicoater，Aqua coater ; FREUND產業股份有限公司製）等之各種塗佈裝 置，使膠囊於裝置内流動’給予乾燥空氣的同時，使用喷 霧等，於膠嚢表面喷霧該幾丁聚糖塗佈液之塗佈方法。 就該幾丁聚糖塗佈液之黏度、幾丁聚糖濃度而言，只 要適合塗佈裝置者即可，並未特別限定，可因應目的加以 適當選擇。 就該幾丁聚糖塗佈液之黏度而言，於溶液溫度23°C， 10mPa · s〜l，〇〇〇mPa · s 為較佳。18 201249481 A mist is formed by a chitosan coating solution containing at least chitosan. For example, a fluidized layer granulation coating device (Flow coater, manufactured by FREUND Industries Co., Ltd.), a centrifugal tumbling granulation coating device (CF GRANULATOR, GRANUREX, manufactured by FREUND Industries Co., Ltd.), and a composite granulation coating device are used. (Spiraflow, manufactured by FREUND Industries Co., Ltd.), various coating devices such as a sugar-coated film coating device (Hicoater, Aqua coater; manufactured by FREUND Industries Co., Ltd.), which allows the capsule to flow in the device, while using dry air. Spraying or the like, spraying the chitosan coating liquid on the surface of the capsule. The viscosity of the chitosan coating liquid and the chitosan concentration are not particularly limited as long as they are suitable for the coating apparatus, and may be appropriately selected depending on the purpose. With respect to the viscosity of the chitosan coating liquid, at a solution temperature of 23 ° C, 10 mPa · s to l, 〇〇〇mPa · s is preferred.
. ' V 就該幾丁聚糖塗佈液之幾丁聚糖濃度而言，以0.1質 量％〜20質量％為較佳。 就該含有幾丁聚糖之層之形成（塗佈）中的進氣溫度 而言’並未特別限定’可因應目的加以適當選擇，但4〇〇c 〜95°C為較佳。該進氣溫度低於40Ϊ：時，因不能充分去除 有機酸，故無法對幾丁聚糖皮膜賦予耐水性，超過1〇〇〇c 時，因於幾丁聚糖皮膜有產生著色、變形等之外觀上的問 題，故不佳。又，水系塗佈下，進氣溫度超過1 〇〇°C並非一 般的溫度’對塗佈裴置的負担亦變大，故不可行。 就該含有幾丁聚糖之層之形成（塗佈）中的排氣溫度 19 201249481 並未特別限定，可因應目 而言’只要為30°C〜90。(：即可， 的加以適當選擇。 <含有腸溶性基材之層> 該含有腸溶性基材之層係至少含有腸溶性基材 必要進一步含有其他成分而成。 … 該含有腸溶性基材之層係藉由於該含有幾丁聚 表面塗佈或«至少含杨溶縣㈣腸雜基材塗料 而形成。 -腸溶性基材塗佈液_ 該腸溶性紐塗佈液至少含有腸溶性錄，因應必要 而含有其他成分。 --腸溶性基材-_ 該腸/谷性基材係形成於胃及小腸中不溶解，且於大腸 溶解的皮膜的成分。 就該腸办性基材而言，並未特別限定，可因應目的加 以適當選擇’例如’可例舉缓基甲基乙基纖維素（CMEC)、 甲基丙烯酸共聚物、羥丙基曱基纖维素（hypromell〇se)酞 ，酉曰（HPMCP)、醇蟲膠（shellac)、水性蟲膠等。上述此 等中於可最能防止水侵入膠囊内部的觀點，以cmEC、 HPMCP、醇蟲膠或水性蟲膠為較佳。 一其他成分― 就=其他成分而言，只要不損及本發明之效果，並未 】阳疋可因應目的加以適當選擇，但含有該的甘油脂 肪酸醋或水不溶性的添加劑為較佳。 20 201249481 本發明之雙又乳酸桿菌大腸遞送膠囊係於大腸内含有 腸溶性基材之層經溶解後，水分經過含有幾丁聚糖之層而 浸入膠囊内，但含有腸溶性基材之層於溶解前，亦有某程 度的水分會經過含有腸溶性基材之層浸入含有幾丁聚糖之 層。因此，藉由將含有腸溶性基材之層更為疏水化、使含 有谷性成分，可抑制經由通過含有腸溶性基材之層的 h刀里故可抑制經由含有幾丁聚糖之層而入 桿菌大腸遞送膠囊之水。 又又礼酉夂 目之：劑而言，並未特別限定，可因應 以上之有機;=屬土、碳數心 繼容易的觀點，二土為較佳。’於對該塗佈液之 定，可因庵^容性基材之層之厚度而言，並未特別限 ===:。質：〜9·。議的厚度為 於1.1質量％〜3、〇 質里0/〇的厚度為更佳’相當 於0.8質量％的厚度時量^厚度為最佳。該厚度低於相當 性基材之層，於小人㈣具#充分厚度之含有腸溶 雙叉乳酸桿g内包容性基材之層會快速崩壞， 有崩壞的情形，超大腸前，含有幾丁聚糖之層 囊表面形成含有腸的厚料，為了於膠 佈時間會增長。基材之層而進行㈣之際，恐怕塗The V is preferably 0.1% by mass to 20% by mass based on the chitosan concentration of the chitosan coating liquid. The inlet temperature in the formation (coating) of the chitosan-containing layer is not particularly limited and may be appropriately selected depending on the purpose, but 4 〇〇 c to 95 ° C is preferred. When the intake temperature is lower than 40 Ϊ: the organic acid is not sufficiently removed, so that the water resistance of the chitosan film cannot be imparted, and when it exceeds 1 〇〇〇c, coloration, deformation, etc. occur due to the chitosan film. The appearance of the problem, it is not good. Further, under the application of the water system, the intake air temperature exceeding 1 〇〇 ° C is not a general temperature, and the burden on the coating device is also large, which is not feasible. The exhaust gas temperature 19 201249481 in the formation (coating) of the chitin-containing layer is not particularly limited, and may be 30 ° C to 90 depending on the purpose. (: can be appropriately selected. <layer containing enteric-soluble substrate> The layer containing the enteric substrate contains at least an enteric substrate, and further contains other components. The layer of the material is formed by coating the surface containing the chitosan or the coating containing at least the Yangrong County (4) enteric substrate. - The enteric substrate coating solution _ The enteric coating solution contains at least enteric Recorded, if necessary, contains other ingredients. - Enteric Substrate -_ This enteric/gluten substrate is a component of the film that is formed in the stomach and small intestine and is insoluble in the large intestine. It is not particularly limited, and may be appropriately selected depending on the purpose, for example, sulfomethylethylcellulose (CMEC), methacrylic acid copolymer, hydroxypropyl fluorenylcellulose (hypromell〇se) 酞, 酉曰 (HPMCP), shellac (shellac), water-based shellac, etc. These are the best ways to prevent water from invading the inside of the capsule, preferably cmEC, HPMCP, alcoholic shellac or water-based shellac. One other ingredient - in terms of other ingredients, only Without impairing the effects of the present invention, it is not preferable that the impotence can be appropriately selected depending on the purpose, but it is preferable to contain the glycerin fatty acid vinegar or the water-insoluble additive. 20 201249481 The double lactic acid bacteria large intestine delivery capsule of the present invention is After the layer containing the enteric substrate in the large intestine is dissolved, the water is immersed in the capsule through the layer containing the chitosan, but the layer containing the enteric substrate is dissolved to a certain extent before the dissolution. The layer of the base material is immersed in the layer containing the chitosan. Therefore, by further hydrophobizing the layer containing the enteric substrate and containing the gluten component, the h-knife passing through the layer containing the enteric substrate can be suppressed. Therefore, the water can be inhibited from being delivered to the bacillus in the large intestine via the layer containing chitosan. Also, the agent is not particularly limited, and may be organic according to the above; = soil, carbon number In view of the ease of the heart, the two soils are preferred. 'The setting of the coating liquid can be made because of the thickness of the layer of the porous substrate, and is not particularly limited to ===:. Quality: ~9 · The thickness of the discussion is 1.1% by mass to 3 The thickness of 0/〇 in the enamel is better, and the thickness is the best when it is equivalent to 0.8% by mass. The thickness is lower than the layer of the equivalent substrate, and it is contained in the small thickness of the human body. The layer of the inclusive substrate of the bifurcated lactic acid rod g will collapse rapidly and collapse. In the case of the large intestine, the surface of the layer capsule containing chitosan forms a thick material containing the intestine, which will increase in time for the adhesive tape. When the layer of the substrate is carried out (4), I am afraid that it is coated.
-含有腸溶性基材之層H 201249481 該含有腸溶性基材之層係藉由將至少含有腸溶性基材 的腸溶性基材塗佈液塗佈或喷霧於該含有幾丁聚糖之層表 面而形成。 例如’可例舉使用流動層造粒塗佈裝置（Fi〇w coater > FREUND產業股份有限公司製）、離心轉動造粒塗佈裝置 (CF GRANULATOR、GRANUREX ; FREUND 產業股份有 限公司製）、複合型造粒塗佈裝置（Spirafjow，FREUND產 業股份有限公司製）、糖衣薄膜塗佈裝置（Hicoater ，Aqua coater ; FREUND產業股份有限公司製）等之各種塗佈裝 置，使膠囊於裝置内流動，給予乾燥空氣的同時使用喷霧 等，而於含有幾丁聚糖之層表面喷霧或塗佈該腸溶性基材 塗佈液的万法。 就該勝溶性基材塗佈液之黏度、腸溶性基材濃度而 言，只要適用於塗佈裝置者即可，並未特別限定，可因應 目的加以適當選擇。 就該腸溶性基材塗佈液之黏度而言，於溶液溫度23。〇， lOmPa · s~ 1，OOOmPa · s 為較佳。 就該腸溶性基材塗佈液之腸溶性基材濃度而言，〇1質 量％〜20質量％為較佳。 就該含有腸溶性基材之層之形成（塗佈）中的進氣溫 度而言，ϋ未特別限定，可因應目的加以適當選擇，但30 。(：〜95°C為較佳。該進氣溫度低於30°C時，因乾燥效率低， 必須壓制送液速度’有塗佈時間增長的情形。 就該含有腸溶性基材之層之形成（塗佈）中的排氣溫 22 201249481 可因應 度而言，只要為30°C〜901：即可，並未特別限定， 目的加以適當選擇。 <其他層> 本發明之雙叉乳酸桿菌大腸遞送膠囊除了具 、 膠囊、雙叉乳酸桿菌、帶式封合、含有幾丁聚糖之^述石更 含有腸溶性基材之層之外，可進一步具有以蜜蠟、二西^ 橺蠟（carnaubawax)等作為基材的被覆層。 不 該被覆層係藉由例如，將至少含有蜜壤的被覆液 或喷霧於該含有腸溶性基材之層表面而形成。 該被覆液之調製係可例如，將蜜蠟溶解於乙醇 機溶媒來進行。 之有 此外，於該被覆液之塗佈或喷霧，例如，可使用與含 有幾丁聚糖之層或含有腸溶性基材之層之形成可使用的^ 置相同之裝置。 乂 [實施例] 以下以實施例及比較例為例舉來具體說明本發明，但 本發明並未受此等任何實施例的限制。 (實施例1) 〈雙又乳酸桿菌對硬膠囊之填充> 將100g雙又乳酸桿菌之活菌粉末（森永乳業股份有限 公司製’森永雙叉乳酸桿菌末）與i/OOg乾燥馬鈴薯澱粉 混合並稀釋’於溫度25〇c、濕度60%下充分攪拌，作成膠 囊填充用之粉末。該粉末之雙叉乳酸桿菌濃度為 lxl〇1〇cfu/g。 23 201249481 使用羥基丙基甲基纖維素（HPMC)膠囊（Qualicaps 股份有限公司製，QUALI-V( R)_N、3號、膠囊質量：51mg) 作為填充所得粉末的硬膠囊，於膠囊填充機（Qualicaps股 份有限公司製，LIQFIL super 100型），安置該雙叉乳酸桿 菌之粉末及該硬膠囊，於硬膠囊内填充220mg之雙叉乳酸 桿菌粉末。 <經由帶式封合的密封> 作為帶式封合所使用的調製液，將16g羥基丙基曱基 纖維素（HPMC)溶解於水34mL及無水乙醇 50mL之混合 液而調製帶式封合調製液。使用該調製液，藉由帶式封合 機（Qualicaps股份有限公司製，mCApsEAL 1〇〇型），於 所付的雙又乳酸桿菌填充膠囊之嵌合部，施予帶式封合。 此外，作為帶式封合之條件如以下所示。 -帶式封合條件- 塗佈寬：3mm 塗佈次數：2次 3周製液之溫度.2〇。(^至22°C <含有幾丁聚糖之層之形成> 於脱乙醯基化度為8〇莫耳％以上的幾丁聚糖（片倉 Chikk—股份有限公司製），添加相對幾丁聚糖之胺基為 0.9莫耳當量之乙酸’進1溶解於水使幾了雜濃度成為 2質量％，充分㈣作成幾丁聚糖塗佈液。調製的幾丁聚糖 塗佈液使用薄膜塗佈裝f Hic〇ater HC LAB〇 2〇塑盤 (服UND產業股份魏公司製），㈣於經㈣式封合而 201249481 封口之包含雙叉乳酸桿菌的膠囊，獲得相當於幾丁聚糖之 質量相對於膠囊之質量為1.5質量％的厚度之膠囊。 <含有腸溶性基材之層之形成> 其次’將10質量份之脱色蟲膠（Gifu Shellac Manufacturing Co 製，PEARL-N10)、及 0.5 質量份之甘油 脂肪酸醋（Eastman chemical campany 製，Myvacet 9·45) 溶解於8質量％乙醇水溶液54mL，調製腸溶性基材塗钸 液。使用該腸溶性基材塗佈液，塗佈於膠囊使蟲膠之質量 相對於膠囊質量成為1.5質量％。此外，塗佈係使用薄膜塗 佈裝置Hicoater HC-LABO 20型盤（FREUND產業股份有 限公司製）。 再者，將使溶解飽和溶解量之蜜壤（三木化學工業股 份有限公司製）的無水乙醇溶液2g塗佈於膠囊’獲得雙又 乳酸桿菌大腸遞送膠囊。此外，塗佈係使用薄膜塗佈裝置 Hicoater HC-LABO 20型盤（FREUND產業股份有限公 製）。 。 據此，獲得的雙叉乳酸桿菌大腸遞送膠囊於其表面仗 序被覆含有幾丁聚糖之層、及含有腸溶性基材之層。 <評價：崩壞試驗> 於所得之膠囊，使用日本藥典之崩壞試驗裝置及震蘆 器’進行崩壞試驗。就試驗步驟之摘要而言，係將該膠囊 於無辅助盤的條件下浸潰於崩壞試驗第一液中一小時:其 次，於無辅助盤之條件下浸潰於崩壞試驗第二液令兩 時’之後’移到置入50mL之大腸假想液的= 二角 25 201249481 燒瓶中，使其以100次往反/分鐘，往返震盪2小時。該大 腸假想液係使用pH3.5之乙酸緩衝液（Michaelis.之緩衝 液）。然後，該試驗係以六個前述之膠囊作為一組來進行。 以目視觀察於各液處理後之膠囊有無膨潤及變形，以 及内容物有無釋出。結果示於表1。此外，以該第一液及該 第二液處理後之膠囊，依據下述評價基準，以四階段來判 定。 -評價基準- ◎:全部六個皆保持形狀，不被認為有膨潤或變形。 〇：六個中有一個以上被認為有若干膨潤或變形。 △:六個中有一個以上被認為有顯著膨潤或變形，但保持 内容物。 X:六個中有一個以上之内容物被溶出。 (實施例2) 於實施例1，除了將脱色蟲膠之質量相對於膠囊質量由 1.5質量％變更為1.7質量％之外，與實施例1同樣地，獲 得雙叉乳酸桿菌大腸遞送膠囊，並進行評價。評價結果示 於表1。 (實施例3) 於實施例1，除了將硬膠囊由HPMC膠囊變更為明膠 膠囊（Qualicaps股份有限公司製、食品用明膠膠囊、3號、 膠囊質量：48mg)之外，與實施例1同樣地，獲得雙叉乳 酸桿菌大腸遞送膠囊，並進行評價。評價結果示於表1。 (比較例1)- layer containing enteric substrate H 201249481 The layer containing the enteric substrate is coated or sprayed on the layer containing chitosan by coating an enteric substrate coating solution containing at least an enteric substrate Formed on the surface. For example, a fluidized layer granulation coating apparatus (Fi〇w coater > FREUND Industries Co., Ltd.), a centrifugal tumbling granulation coating apparatus (CF GRANULATOR, GRANUREX; manufactured by FREUND Industries Co., Ltd.), and a composite can be used. Various types of coating devices such as a granulation coating device (Spirafjow, manufactured by FREUND Industries Co., Ltd.) and a sugar coating film coating device (Hicoater, Aqua coater; manufactured by FREUND Industries Co., Ltd.), which allow the capsule to flow in the device and give The method of spraying or coating the enteric substrate coating liquid on the surface of the layer containing chitosan is carried out by using a spray or the like while drying the air. The viscosity of the liquid-soluble substrate coating liquid and the concentration of the enteric substrate are not particularly limited as long as they are suitable for the coating apparatus, and may be appropriately selected depending on the purpose. The viscosity of the enteric substrate coating solution was at a solution temperature of 23. 〇, lOmPa · s~ 1, OOOmPa · s is preferred. The concentration of the enteric substrate of the enteric substrate coating liquid is preferably from 〜1 to 20% by mass. The temperature in the formation (coating) of the layer containing the enteric substrate is not particularly limited, and may be appropriately selected depending on the purpose, but 30. (: ~95 ° C is preferred. When the inlet temperature is lower than 30 ° C, the drying efficiency is low, and the liquid feeding speed must be suppressed.] The coating time is increased. The layer containing the enteric substrate is The exhaust gas temperature 22 201249481 in the formation (coating) is not particularly limited as long as it is 30° C. to 901. The purpose is appropriately selected. <Other layers> The bifurcated lactic acid of the present invention The bacillus large intestine delivery capsule may further have a beeswax, a dioxin, in addition to a layer containing a capsule, a bifidobacterium, a band seal, a chitin containing an enteric substrate. A coating layer of a substrate such as a wax (carnaubawax) or the like. The coating layer is formed by, for example, spraying a coating liquid containing at least a honey soil on a surface of the layer containing the enteric substrate. For example, the beeswax may be dissolved in an ethanol-based solvent. Further, in the coating or spraying of the coating liquid, for example, a layer containing chitosan or a layer containing an enteric substrate may be used. The same device can be used to form the device. EXAMPLES Hereinafter, the present invention will be specifically described by way of examples and comparative examples, but the present invention is not limited by any of the examples. (Example 1) <Double Lactobacillus filling of hard capsules> 100 g of live bacteria powder of Lactobacillus brevisii (Mori Mori Co., Ltd. manufactured by Morinaga Dairy Co., Ltd.) and i/OOg dry potato starch were mixed and diluted at a temperature of 25 ° C and a humidity of 60% to be fully stirred. A powder for filling a capsule having a concentration of 1 x 10 〇 1 〇 cfu / g. 23 201249481 Using hydroxypropyl methyl cellulose (HPMC) capsule (QUALI-V (R), manufactured by Qualicaps Co., Ltd. _N, No. 3, capsule quality: 51 mg) As a hard capsule filled with the obtained powder, a capsule filling machine (LIQFIL super 100 type manufactured by Qualicaps Co., Ltd.) was placed, and the powder of the lactic acid bacillus and the hard capsule were placed on the hard The capsule was filled with 220 mg of Lactobacillus bifidum powder. <Sealing by band sealing> As a preparation liquid used for the band sealing, 16 g of hydroxypropyl fluorenylcellulose (HPMC) was dissolved in 34 mL of water and A mixture of 50 mL of anhydrous ethanol was used to prepare a band-sealing preparation liquid. The prepared solution was filled with Lactobacillus by a band sealer (manufactured by Qualicaps Co., Ltd., mCApsEAL 1〇〇 type). The fitting portion of the capsule was subjected to tape sealing. The conditions for the tape sealing were as follows. - Band sealing conditions - Coating width: 3 mm Coating times: 2 times 3 weeks liquid preparation Temperature: 2 〇. (^ to 22 ° C <Formation of a layer containing chitosan > Chitosan with a degree of deacetylation of 8 〇 mol% or more (Pak Cang Chiikk - Co., Ltd. The system was prepared by adding acetic acid having a molar ratio of 0.9 moles to the amine group of chitosan, and dissolving it in water to a concentration of 2% by mass, and sufficiently (iv) forming a chitosan coating liquid. The prepared chitosan coating liquid is coated with f Hic〇ater HC LAB〇2〇 plastic disk (made by UND Industry Co., Ltd.), (4) sealed by (4) and 201249481, and contains bifurcated lactic acid. The capsule of the bacillus obtained a capsule having a thickness equivalent to 1.5 mass% of the mass of the chitosan relative to the mass of the capsule. <Formation of a layer containing an enteric substrate> Next, 10 parts by mass of a dander shellac (made by Gifu Shellac Manufacturing Co., PEARL-N10), and 0.5 part by mass of a glycerin fatty acid vinegar (manufactured by Eastman Chemical Campany, Myvacet) 9·45) Dissolved in 54 mL of an 8 mass% ethanol aqueous solution to prepare an enteric substrate coating solution. The enteric substrate coating liquid was applied to the capsules so that the mass of the shellac was 1.5% by mass based on the mass of the capsule. Further, as the coating, a film coating apparatus Hicoater HC-LABO 20 type disc (manufactured by FREUND Industries Co., Ltd.) was used. Further, 2 g of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a mixture of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of a solution of Further, the coating system was a film coating apparatus Hicoater HC-LABO 20 type disk (FREUND Industries Co., Ltd.). . According to this, the obtained Bifidobacterium breve large intestine delivery capsule is coated on its surface with a layer containing chitosan and a layer containing an enteric substrate. <Evaluation: collapse test> The resulting capsule was subjected to a collapse test using a Japanese Pharmacopoeia collapse test device and a shaker. For the summary of the test procedure, the capsule was immersed in the first liquid of the collapse test for one hour without the auxiliary disk: secondly, the second liquid was immersed in the collapse test without the auxiliary disk. Let the two-time 'after' move to the 50 mL of the large intestine imaginary liquid = 22 494 25 201249481 flask, and make it back and forth for 2 hours in reverse counter/minute. The colonic hypothetical solution was pH 3.5 acetate buffer (Michaelis. buffer). The test was then carried out as a group of six of the aforementioned capsules. The capsules after treatment with each liquid were visually observed for swelling and deformation, and whether or not the contents were released. The results are shown in Table 1. Further, the capsules treated with the first liquid and the second liquid were determined in four stages in accordance with the following evaluation criteria. - Evaluation criteria - ◎: All six are kept in shape and are not considered to be swollen or deformed. 〇: More than one of the six is considered to have some swelling or deformation. △: More than one of the six is considered to have significant swelling or deformation, but the contents are kept. X: One or more of the six contents are dissolved. (Example 2) In the same manner as in Example 1, except that the mass of the decolorized shellac was changed from 1.5% by mass to 1.7% by mass based on the mass of the capsule, the Bifidobacterium breve large intestine delivery capsule was obtained, and Conduct an evaluation. The evaluation results are shown in Table 1. (Example 3) In the same manner as in Example 1, except that the hard capsule was changed from a HPMC capsule to a gelatin capsule (manufactured by Qualicaps Co., Ltd., gelatin capsule for food, No. 3, capsule mass: 48 mg). The Bifidobacterium lactis large intestine delivery capsule was obtained and evaluated. The evaluation results are shown in Table 1. (Comparative Example 1)
26 201249481 於實施例1，除了將硬膠囊由HPMC膠囊變更為幾丁 聚糖膠囊（AICELLO化學股份有限公司製）、將脱色蟲膠 之質量相對於膠囊質量由1.5質量％變更為1.9質量％之 外，與實施例1同樣地，獲得雙叉乳酸桿菌大腸遞送膠囊， 並進行評價。評價結果示於表1。 (比較例2) 於實施例2,除了未進行藉由帶式封合的封口之外，與 實施例2同樣地，獲得雙叉乳酸桿菌大腸遞送膠囊，並進 行評價。評價結果示於表1。 [表1] 膠囊材料 帶式封合 幾丁聚糖相 對於膠囊質 腸溶性基材 相對於膠囊 第一液 第二液 大腸彳段想液 (乙酸緩衝 液） 之種類 之有無 量之質量 (%) 質量之質量 (%) 目視評價 目視評價 實施例1 HPMC 有 1.5 1.5 ◎ ◎ 全部膠曩之 内容物溶出 實施例2 HPMC 有 1.5 1.7 ◎ ◎ 全部膠囊之 内容物溶出 實殚例3 明膠 有 1.5 1.5 ◎ ◎ 全部膠囊之 内容物溶出 比較例1 幾丁聚糖 有 — 1.9 Δ 全部膠囊 膨潤 X 一個膠囊 之内容物 溶出 全部膠囊之 内容物溶出 無 X 全部膠囊 比較例2 HPMC 1.5 1.7 之内容物 一 溶出 [產業上之利用可能性] 本發明之雙叉乳酸桿菌大腸遞送膠囊及其製造方法， 因硬膠囊内包含雙叉乳酸桿菌，故於胃及小腸不會溶出， 於大腸中快速溶出、且於胃及小腸中可抑制水分對硬膠囊 内之侵入、抑制雙叉乳酸桿菌之失活，並具有充分的強度， 不須用以增大強度的塗佈*再者因抑制塗佈I 5可以有利 27 201249481 的製造成本來製造，故可較佳利用於使用雙叉乳酸桿菌的 整腸劑等之醫藥品、保健食品、健康輔助食品、及其類似 者之製造方法等。 【圖式簡單說明】 無。 【主要元件符號說明】 無。 28 326 201249481 In the first embodiment, the hard capsule was changed from a HPMC capsule to a chitosan capsule (manufactured by AICELLO Chemical Co., Ltd.), and the mass of the bleached shellac was changed from 1.5% by mass to 1.9% by mass based on the mass of the capsule. Further, in the same manner as in Example 1, a Bifidobacterium lactis large intestine delivery capsule was obtained and evaluated. The evaluation results are shown in Table 1. (Comparative Example 2) In the same manner as in Example 2 except that the seal by the band seal was not carried out, the Bifidobacterium breve large intestine delivery capsule was obtained and evaluated. The evaluation results are shown in Table 1. [Table 1] The mass of the capsule material band-sealed chitosan relative to the capsule enteric substrate relative to the capsule first liquid second liquid large intestine section (acetic acid buffer) Quality of quality (%) Visual evaluation Visual evaluation Example 1 HPMC 1.5 1.5 ◎ ◎ Dissolution of the contents of all capsules Example 2 HPMC 1.5 1.7 ◎ ◎ The contents of all capsules were dissolved Example 3 Gelatin 1.5 1.5 ◎ ◎ The contents of all the capsules were dissolved. Comparative Example 1 Chitosan had - 1.9 Δ All capsules swelled X The contents of one capsule were dissolved. The contents of all the capsules were dissolved without X. All capsules Comparative Example 2 The contents of HPMC 1.5 1.7 were dissolved. [Industrial Applicability] The Biloba lactobacillus large intestine delivery capsule of the present invention and the method for producing the same are characterized in that the hard capsule contains the bifidobacteria, so that it does not dissolve in the stomach and small intestine, dissolves rapidly in the large intestine, and In the stomach and small intestine, it can inhibit the invasion of water into hard capsules, inhibit the inactivation of Lactobacillus bifidum, and has sufficient strength, so it is not necessary to increase The high-strength coating* can be manufactured by suppressing the application of I 5 to the manufacturing cost of 27,494,941. Therefore, it can be preferably used for pharmaceuticals, health foods, and health supplements such as intestinal tract preparations using Bifidobacterium breve. And the manufacturing methods of similar people, and the like. [Simple description of the diagram] None. [Main component symbol description] None. 28 3