200950818 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種半胱胺酸臭味減低後之固形製劑。更 詳細而δ，本發明係關於一種半胱胺酸臭味減低後之包膜 製劑。 、 【先前技術】 ❹ 調配有L-半胱胺酸之固形製劑中，L-半胱胺酸自身之令 人不舒服之臭味較為強烈，因而無法直接服用。作為遮蔽 *亥令人不舒服之臭味的最普通之方法，有使用經丙基纖維 素經丙基曱基纖維素、聚乙婦π比口各烧嗣等水溶性高分子 作為基材㈣固形製劑實施包膜之方法，然、而於該等包膜 下’並無法阻止半胱胺酸臭味，因此進一步包上糖衣，藉 此形成非常緻密之衣膜，來阻止半耽胺酸臭味。但是，糖 衣步驟不僅;fb費較長之製造時間、製劑變大變重，而且， 由於糖衣步驟期間係處於高溫多濕之狀態下，因此有時亦 會由於製造步驟期間之水分或溫度管理之不善等，而影響 所共存之其他活性成分之穩定性或外觀等。 因此& 了減低固形製劑之L_半胱胺酸的令人不舒服之 臭味，而提出了如下方沐.制 .製成溥層糖衣銳之方法（專利 文獻1);乾相㈣定粒徑仏半㈣酸之方法（專利文獻 2广調配酸味駭甜味敎㈣（專敎獻3): ^基纖維 素包覆固形製劑，並調配酸味 文木剛及甜味劑之方法（專利文 獻4);調配羧曱基纖維素或 4八盟之方法（專利文獻5);以及 調配水膨潤性物質之方法彳皇各丨+ & 方法（專利文獻6)等。然而，製成薄層 132032.doc 200950818 糖衣錠之方法雖可阻止半胱胺酸臭味，但亦存在仍然遺留 有糖衣步驟之問題，其他方法則存在阻臭效果不充分之問 題。200950818 IX. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention relates to a solid preparation having a reduced odor of cysteamine. More specifically, δ, the present invention relates to a coated preparation having a reduced cysteic acid odor. [Prior Art] L In the solid preparation formulated with L-cysteine, L-cysteine itself has a strong unpleasant odor and cannot be taken directly. As the most common method for masking the unpleasant odor of *H, there are water-soluble polymers such as propyl cellulose, propyl sulfonate, and siloxane, which are used as substrates (4). The method of applying the coating to the solid preparation, however, does not prevent the cysteine odor under the envelopes, so the sugar coating is further coated, thereby forming a very dense coating film to prevent the semi-proline odor. taste. However, the sugar coating step is not only expensive; the manufacturing time is longer, the preparation becomes larger and heavier, and since the sugar coating step is in a state of high temperature and high humidity, it is sometimes managed due to moisture or temperature during the manufacturing step. Inappropriate, etc., affecting the stability or appearance of other active ingredients that coexist. Therefore, the method of reducing the unpleasant odor of L-cysteine in the solid preparation is proposed, and the method of making the layer of sugar coating is proposed (Patent Document 1); dry phase (4) Method for particle size bismuth (tetra) acid (Patent Document 2 Widely formulated with sour glutinous rice glutinous rice glutinous rice glutinous rice) (IV) (Special 敎 3 3): ^Base cellulose coated solid preparation, and method of mixing sour wenmugang and sweetener (patent Document 4); a method of formulating carboxymethyl cellulose or 4 octopus (Patent Document 5); and a method of formulating a water swellable substance 彳 丨 丨 + & method (Patent Document 6), etc. Layer 132032.doc 200950818 Although the method of sugar-coated ingot can prevent the smell of cysteine, there is also a problem that the step of icing is still left, and other methods have the problem that the odor-reducing effect is insufficient.
❷ [專利文獻1]日本專利特開2002-179559號公報 [專利文獻2]日本專利特開20034 55232號公報 [專利文獻3]日本專利特開2〇〇4_1617〇〇號公報 [專利文獻4]日本專利特開20044 617〇1號公報 [專利文獻5]日本專利特開20054 6261 9號公報 [專利文獻6]日本專利特開2〇〇5_298528號公報 【發明内容】 [發明所欲解決之問題] 本發明之目的在於提供一種含有L-半胱胺酸之固形製 劑，其製造時間短，製劑可實現小型化，並減低令人不舒 服之臭味。 [解決問題之技術手段] 為了達成上述目的，本發明者等人進行了潛心研究，妗 果意外地發現’若對含有L·半胱胺酸之固形製劑包上含有 聚乙烯酵之部分皂化物的包衣膜，則即使不進一步包上糖 衣’亦可減低L-半胱胺酸的令人不舒服之臭味，從而 了本發明。 亦即’本發明提供—㈣含有L4胱胺酸或其鹽之固形 製劑，包上含有聚乙烯醇之部分皂化物之包衣膜的包覆固 形製劑。 [發明之效果] 132032.doc 200950818 根據本發明，可獲得一種即使不包上糖衣，令人不舒服 之臭味亦減低了的含有L-半胱胺酸之固形製劑。又，本發 明之製劑由於可實現製劑之小型化，因此容易吞嚥，且製 造時間亦短。 【實施方式】 本發明中所使用之L-半胱胺酸（化學名：2_Amin〇_3_ ❹ ❹ mercapt〇propionic acid，2_胺基_3_巯基丙酸），係以分子 式：c3h7no2s、分子量：121.16表示，於生物體内之代謝 系統中，發揮SH供體之作用’且發揮SH酶之活化劑 (aCtiVat〇r)之作用。作為醫療用醫藥品，利用L-半胱胺酸 之可使皮膚代謝正常、抗過敏、解毒等作用，而將其用於 濕療、蓴麻療、藥物療、毒療、尋常性痤瘡、滲出性多形 紅斑等各種皮膚病之治療，或用於由轄射損傷所引起的白 血球減夕症之冶療。作為常用醫藥品，係調配於主藥為維 生素之製劑、主藥為鈣之製劑、含維生素之保健劑等中， :廣泛地驗斑點.雀斑曬斑等色素沈積症、全身倦急、 宿醉、粉刺、濕疹、蓴麻疹、斑疹、藥物I、皮膚皲裂、 粉刺、口炎、口角炎、辰 月人。炎、舌炎、濕疹、皮膚炎、斑 療、潰爛之治療，以及營養強 I 5$化（虛弱體質、肉體疲勞.病 中病後、食慾不振.營養不良· 赞‘、、、性沩耗性病症.產前產 後等之f月形之營養補充）、屮&箱仏， 4血預防（牙齦出血、鼻出血）等 其他各種治療。 作為本發明中所使用之^ r τ屯心…* 牛脱胺酸或其鹽（以下稱為 L-+胱胺馱類」），除上 干耽胺酸自身以外，可列 132032.doc 200950818 舉L-鹽鲅半胱胺酸等L_半胱胺酸之酸加成鹽等。本發明 中，該等均可使用，較好的是L-半胱胺酸。 固形製劑中之L -半胱胺酸類之含量根據有無共存之其他 F成刀及八他/舌性成分之調配量、劑形的不同而不同， 例如，製成錠劑時，L_半胱胺酸類之含量較好的是丨〜肋質 里/。，製成顆粒劑及細粒劑時，較好的是卜丨〇〇質量％。 本發月之製別中’除L—半胱胺酸類以外亦可適當地調配 #他藥效成分。作為其他藥效成分之具體例，例如可列 舉·抗壞血酸、抗壞血酸鈣、抗壞血酸鈉等維生素c類； 硝酸硫胺、鹽酸硫胺、核黃素、核黃素丁酸醋、核黃素填 酸鈉、鹽酸吡哆醇、磷酸吡哆醛、泛酸鈣、菸鹼醯胺、生 物素、葉酸等維生素B類；硫辛醯胺、乳清酸等類維生素 活性物質；乙酸d-α-生育醇酯、琥珀酸d_a_生育醇酯等維 生素E;麥角鈣化固醇、膽鈣化醇等維生素D;磷酸氫 鈣乳酸舞等碌物質；甲硫胺酸、甘胺酸、鹽酸精胺酸等 ❹胺基酸；胺乙基磺酸、葡萄糖醛酸内酯、甘草酸、熊去氧 膽酸等肝臟疾病用藥；何首烏萃取物、歐洲山楂萃取物、 刺五加乾燥萃取物、淫羊霍萃取物、薏仁萃取物、肝臟水 解物、膽汁萃取粉末、柴胡乾燥萃取物、川琴乾燥萃取 物、山揸乾燥萃取物、茯苓乾燥萃取物等天然藥材等。 作為本發明中所使用之聚乙烯醇之部分皂化物，除將聚 乙酸乙烯酯水解而獲得之聚乙稀醇部分皂化物以外，還可 歹J舉.以叛基、石黃醯基等將聚乙婦醇之一部分加以修飾所 得的改性陰離子化聚乙烯醇之部分皂化物等。 132032.doc 200950818 自半胱胺酸臭味之減低效果之觀點考慮，聚乙烯醇部分 皂化物之皂化度較好的是70〜97 mol%，尤其好的是78〜96 mol%。又’平均聚合度較好的是2〇〇〜3,3〇〇，尤其好的是 300〜1，500。其中，皂化度可依據113 K6726(聚乙烯醇試驗 方法）來測定。 作為該等之聚乙烯醇市售品，例如可列舉： Gohsenol(曰本合成化學工業（股、j p〇val(JApAN VAM & POVAL(股））、Kuraray Poval(KURARAY(股））、Denka P〇val(電氣化學工業（股））等。又，亦可使用含有聚乙烯醇 作為主成分之預混料，例如，可在曰本國内獲得〇pad7 AMB(曰本C0L0RC0N(股））β該等可單獨使用或將兩種以 上混合使用。 自阻臭效果、衣膜強度以及包衣之容易性的觀點考慮， 包衣膜中之聚乙烯醇之含量較好的是3〇〜1〇〇質量％，尤其 好的是40〜95質量。/〇。 包衣膜中，除聚乙烯醇部分皂化物以外，例如，可視需 要添加塑化劑、包衣劑、分散劑、著色劑、消泡劑等通常 使用在經口投予醫藥品之包衣膜中的醫藥品添加物。 作為塑化劑之具體例，可列舉：karion 83、檸檬酸三乙 酿、甘油、甘油脂肪酸酯、芝麻油、二甲基聚矽氧燒.二 氧化矽混合物、D-山梨糖醇、中長鏈三酸甘油酯、源自玉 米澱粉之糖醇液、甘油三乙酸酯、濃甘油、蓖麻油、鄰笨 一甲酸二乙酯、鄰苯二曱酸二丁酯、乙醇酸丁酯丁醇鄰苯 一甲酸酯、聚氧乙烯（105)聚氧丙烯（5)二醇、丙二醇、聚 132032.doc 200950818 山梨醇酯80、聚乙二醇400、聚乙二醇600、聚乙二* 1500、聚乙二醇4000、聚乙二醇600〇、棉籽油.大豆油現 合物、單硬脂酸甘油酯等，該等可單獨使用或將兩種以上 混合使用。包衣膜中之塑化劑之含量較好的是3〇質量％以 下’尤其好的是25質量％以下。 作為包衣劑之具體例’除聚乙烯醇部分皂化物以外，例 如可列舉：丙烯酸乙酯.甲基丙稀酸甲酯共聚物分散液、 乙醯甘油脂肪酸酯、甲基丙烯酸胺基炫基酯共聚物E、甲 基丙烯酸胺基烷基酯共聚物RS、阿拉伯膠、阿拉伯膠粉、 乙基纖維素、乙基纖維素水分散液、辛基癸基三酸甘油 脂、Opadry OY-6950、Opadry OY-S-7135、〇padry 〇Y_s_ 8471、〇padry OY-S-9607、Opadry OY-S-22829、〇padry OY-S-22835、Opadry OY-S-22961、橄欖油、高嶺土、可 可脂、夏枯草、蓖麻蠟、焦糖、巴西棕櫚蠟、羧乙烯聚合 物、羧甲基乙基纖維素、羧曱基澱粉鈉、羧甲基纖維素 妈缓甲基纖維素納、水合二氧化石夕、乾燥氫氧化銘凝 膠、乾燥乳狀白蟲膠、乾燥甲基丙烯酸共聚物Ld、寒梅 板、魚鱗、冶、金箔、銀箔、檸檬酸三乙醋、甘油、甘油脂 肪酸酯、矽酸鎂、輕質無水矽酸、含輕質無水矽酸之羥丙 基纖維素、輕質液態石蠟、鯨蠟、結晶纖維素、硬化油、 合成矽酸鋁、合成蠟、高葡萄糖水飴、硬蠟、琥珀醢明 膠、小麥粉、小麥澱粉、大米澱粉、乙酸纖維素、乙酸乙 烯酯樹脂、乙酸鄰苯二曱酸纖維素、白蜂蠟、氧化欽、氧 化鎂、曱基丙烯酸二甲胺乙酯.曱基丙烯酸甲酯共聚物、 132032.doc 11 200950818 二甲基聚矽氧烷（内服用）、二 物、燒石膏、薦糖脂肪酸醋、沉土香粉、二氧化梦混合 化松香甘油醋、硬脂醇、硬脂酸、硬脂酸：化：凝膠、氫 J-* Ot JSA ϊ» ,-- 私銘、硬塘酸在丐、 硬月曰馱聚烴氧酯40、硬脂酸鎂电 电化明膠、純化Α踉 ,, 化白糖、玉米蛋白、倍半異硬 ’、、 ^ ^ 米糖和酐、鯨蠟醇、 石：：膠、蟲膠、山梨糖醇軒脂肪酸… 、 D·山梨糖醇液、磷酸三舞、滑石、碳酸約、碳酸鎂、單糖 ❹ ❹ 漿、中金箱、沈殿碳酸約、低取代經丙基纖維素、莊稀樹 脂、殿粉（溶性）、玉米糖聚、玉米油、甘油三乙酸醋、乳 酸約、乳糖、濃甘油、白蟲膠、白糖、蜂蜜、石壤、珍珠 粉、馬鈴薯殿粉、經丙基纖維素、經丙基子基纖維素 2208、羥丙基甲基纖維素29〇6、羥丙基甲基纖維素“ίο、 羥丙基甲基纖維素乙酸琥珀酸酯、羥丙基甲基纖維素 2910氧化鈦·聚乙二醇4〇〇混合物、羥丙基甲基纖維素鄰 苯二曱酸酯、胡椒基丁醚、蓖麻油、鄰苯二甲酸二乙酯、 鄰苯二曱酸二丁酯、乙醇酸丁酯丁醇鄰苯二甲酸酯、葡萄 糖、反丁婦二酸.硬脂酸.聚乙婦縮酸:二乙胺基乙酸酯經 丙基曱基纖維素2910混合物、聚三葡萄糖、丙二醇、膨 土、聚維酮、聚氧乙烯硬化蓖麻油4〇、聚氧乙烯硬化蓖麻 油60、聚氧乙烯（1〇5)聚氧丙烯（5)二醇、聚氧乙烯（16〇)聚 氧丙烯（30)二醇、聚山梨醇酯80、聚乙烯縮醛二乙胺基乙 酸酯、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙 二醇1500、聚乙二醇154〇、聚乙二醇4000、聚乙二醇 6000、聚乙二醇20000、聚乙二醇35000、D-甘露糖醇、水 132032.doc 200950818 始、蜂蠟、肉豆蔻酵、無水矽酸水合物、鄰苯二甲酸針、 無水破酸氣妈、甲基丙烯酸共聚物L、甲基丙烯酸共聚物 LD、甲基丙烯酸共聚物S、偏矽酸鋁酸鎂、甲基纖維素、 丙烯酸2-曱基-5-乙烯基吡啶基曱酿.甲基丙浠^共聚物、 • 漆樹蠟、單硬脂酸鋁、單硬脂酸甘油酯、山梨糖醇酐單月 . 桂酸醋、褐煤酸醋蠟、藥用碳、聚桂醇、硫酸鈣、液態石 蠟、DL-蘋果酸、正磷酸氫鈣、磷酸氫鈣、磷酸氫鈉、磷 & -氫鈣、松香等’該等可單獨添加或將兩種以上混合添 力σ〗等包衣劑中’自抗附著效果之觀點考慮，較好的是 添加滑石。包衣膜中之包衣劑之含量較好的是卜5〇質量 % ’尤其好的是5〜40質量％。 作為分散劑之具體例，可列舉：甲基丙稀酸胺基烧基醋 共聚物RS、阿拉伯膠、阿拉伯膠粉、褐藻酸丙二醇酉旨、乙 醇、油酸、竣乙稀聚合物、缓甲基纖維素納、遭脂粉、棒 檬酸#檬鈉、甘油、甘油脂肪酸g旨、#酸鎮、輕胃& ❹ 水:酸、結晶纖維素、硬化油、合成石夕酸銘、填酸膽驗、 、才匕子'由自蜂樣、氧化鈦、續號ί白酸鈉二辛酉旨、蔗糖脂 肺酸酉曰、氫氧化納、硬脂酸、硬脂酸鎮、純化油酸、純化 大丑印磷月曰、倍半異硬脂酸山梨糖醇肝、山梨糖醇肝脂肪 - 、日^山梨糖醇、大丑油、大豆印磷脂、低取代經丙基 ':隹素糊精、玉米澱粉、黃蓍膠粉、山梨糖醇酐三油酸 乳糖/農甘油、馬鈐薯殿粉、經乙基纖維素、經丙基 、•刀功羥丙基纖維素、羥丙基甲基纖維素2910、丙二醇、 丙醇月曰肪酸酿、膨土、聚維剩、聚氧乙稀硬化萬麻油、 132032.doc -13- 200950818 聚氧乙烯硬化蓖麻油40、聚氧乙烯硬化蓖麻油6〇、聚氧乙 烯（1〇5)聚氧丙烯（5)二醇、聚氧乙烯（16〇)聚氧丙烯（3〇)二 醇聚山梨醇酯2〇、聚山梨醇酯60、聚山梨醇酯80、聚磷 酸鈉、聚乙二醇300、聚乙二醇4〇〇〇、聚乙二醇6〇〇〇、無 水檸檬酸鈉、無水焦磷酸鈉、偏矽酸鋁酸鎂、偏磷酸鈉、 甲基纖維素、漆樹蠟、山梨糖醇肝單油酸醋、單硬脂酸 鋁、單硬脂酸甘㈣、&梨糖醇酐單標櫚酸酉旨、山梨糖醇[Patent Document 1] Japanese Patent Laid-Open Publication No. JP-A-2002-179559 [Patent Document 2] Japanese Patent Laid-Open Publication No. Hei. No. Hei. [Patent Document 5] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. An object of the present invention is to provide a solid preparation containing L-cysteine, which has a short manufacturing time, can be miniaturized, and reduces an unpleasant odor. [Means for Solving the Problems] In order to achieve the above object, the inventors of the present invention conducted intensive studies, and unexpectedly found that "if a solid preparation containing L-cysteine contains a partially saponified product of polyethylene yeast. The coating film, if not further coated with a sugar coating, can also reduce the unpleasant odor of L-cysteine, and thus the present invention. That is, the present invention provides - (iv) a solid preparation containing L4 cystic acid or a salt thereof, and a coated solid preparation containing a coating film of a partial saponified product of polyvinyl alcohol. [Effects of the Invention] 132032.doc 200950818 According to the present invention, it is possible to obtain a solid preparation containing L-cysteine which is unpleasant and has an unpleasant odor even if it is not coated with a sugar coating. Further, since the preparation of the present invention can achieve miniaturization of the preparation, it is easy to swallow and the preparation time is also short. [Embodiment] L-cysteine (chemical name: 2_Amin〇_3_ ❹ ❹ mercapt〇propionic acid, 2_amino _3_mercaptopropionic acid) used in the present invention is a molecular formula: c3h7no2s, molecular weight 121.16 indicates that the role of the SH donor is exerted in the metabolic system of the living body, and the action of the SH enzyme activator (aCtiVat〇r) is exerted. As a medical pharmaceutical, L-cysteine can be used for moisturizing, anti-allergic, detoxification, etc., and it can be used for moist therapy, ramie therapy, drug therapy, poison therapy, acne vulgaris, exudation The treatment of various skin diseases such as polymorphous erythema, or the treatment of white blood cell ecstasy caused by damage caused by the damage. As a commonly used pharmaceutical product, it is formulated in the main drug as a vitamin preparation, the main drug is a calcium preparation, a vitamin-containing health care agent, etc., and is widely used for detecting spots, freckles, sunburns and other pigmentation diseases, general fatigue, hangovers. , acne, eczema, urticaria, rash, drug I, skin cleft palate, acne, stomatitis, angular cheilitis, Chen Yueren. Inflammation, glossitis, eczema, dermatitis, plaque therapy, ulceration treatment, and strong nutrition I 5$ (weak body, physical fatigue, sickness after illness, loss of appetite, malnutrition, praise, and sexual abuse) Sexual illness. Pre- and post-natal and other f-shaped nutritional supplements), 屮 & box 仏, 4 blood prevention (gum bleeding, nosebleeds) and other various treatments. As the r ^ τ 屯 heart used in the present invention * * bovine deaminic acid or its salt (hereinafter referred to as L - + cystamine steroids), in addition to the dry lysine itself, can be listed 132032.doc 200950818 An acid addition salt of L-cysteine such as L-salt cysteine. In the present invention, these may be used, and L-cysteine is preferred. The content of the L-cysteine in the solid preparation differs depending on the presence or absence of coexistence of other F-forming knives and the amount of the octahedron/tongue component, and the dosage form, for example, L-cysteine when used as a tablet. The content of the amino acid is preferably 丨~ ribs/. When the granules and the fine granules are prepared, it is preferably a dip quality%. In the preparation of this month's month, 'the other medicinal ingredients may be appropriately formulated in addition to L-cysteine. Specific examples of the other medicinal component include vitamin C such as ascorbic acid, calcium ascorbate, and sodium ascorbate; thiamine nitrate, thiamine hydrochloride, riboflavin, riboflavin butyrate, riboflavin sodium, and hydrochloric acid. Pyridoxine, pyridoxal phosphate, calcium pantothenate, nicotinamide, biotin, folic acid and other vitamin B; siminamide, orotic acid and other vitamin active substances; acetic acid d-α-tocopherol ester, amber Acid d_a_tocopherol ester and other vitamin E; ergot calcification sterol, cholecalciferol and other vitamin D; calcium hydrogen phosphate lactic acid dance and other substances; methionine, glycine, arginine hydrochloride and other lysine ; Aminoethyl sulfonic acid, glucuronolactone, glycyrrhizic acid, ursodeoxycholic acid and other liver diseases; Polygonum multiflorum extract, European hawthorn extract, Acanthopanax dry extract, Epimedium extract, Coix seed extract Natural medicinal materials such as liver, liver hydrolysate, bile extract powder, Bupleurum extract, Chuanqin dry extract, hawthorn dry extract, and dried extract. As a part of the saponified product of the polyvinyl alcohol used in the present invention, in addition to the polyethylene saponified partial saponified product obtained by hydrolyzing polyvinyl acetate, it is also possible to use a retort, a ruthenium group, etc. A part of the saponified product of the modified anionized polyvinyl alcohol obtained by modifying one part of the mother alcohol. 132032.doc 200950818 From the viewpoint of the effect of reducing the odor of cysteine, the degree of saponification of the partially saponified polyvinyl alcohol is preferably 70 to 97 mol%, particularly preferably 78 to 96 mol%. Further, the average degree of polymerization is preferably 2 〇〇 to 3, 3 Å, and particularly preferably 300 to 1,500. Among them, the degree of saponification can be measured in accordance with 113 K6726 (polyvinyl alcohol test method). As such a polyvinyl alcohol commercial product, for example, Gohsenol (Sakamoto Synthetic Chemical Industry Co., Ltd., Jp〇val (JApAN VAM & POVAL), Kuraray Poval (KURARAY), Denka P 〇val (Electrical Chemical Industry Co., Ltd.), etc. Alternatively, a premix containing polyvinyl alcohol as a main component may be used. For example, 〇pad7 AMB (曰本C0L0RC0N(股)) β can be obtained in Sakamoto. The mixture may be used singly or in combination of two or more. From the viewpoints of the odor-reducing effect, the film strength, and the ease of coating, the content of the polyvinyl alcohol in the coating film is preferably 3 〇 1 〇〇 1 〇〇. % by mass, particularly preferably 40 to 95 mass%. / 〇. In the coating film, in addition to the polyvinyl alcohol partial saponified product, for example, a plasticizer, a coating agent, a dispersing agent, a coloring agent, and a defoaming may be added as needed. A pharmaceutical additive such as a drug for oral administration into a coating film of a pharmaceutical product is usually used. Specific examples of the plasticizer include karion 83, triethyl citrate, glycerin, glycerin fatty acid ester, and sesame oil. , dimethyl polyfluorene oxide, cerium oxide mixture, D-mountain Sugar alcohol, medium long chain triglyceride, sugar alcohol liquid derived from corn starch, triacetin, concentrated glycerin, castor oil, diethyl phthalate, dibutyl phthalate, ethanol Butyrate butanol phthalate, polyoxyethylene (105) polyoxypropylene (5) diol, propylene glycol, poly 132032.doc 200950818 sorbitol 80, polyethylene glycol 400, polyethylene glycol 600 , polyethylene-2*1500, polyethylene glycol 4000, polyethylene glycol 600〇, cottonseed oil, soybean oil, glyceryl monostearate, etc., which may be used alone or in combination of two or more. The content of the plasticizer in the coating film is preferably 3% by mass or less, and particularly preferably 25% by mass or less. Specific examples of the coating agent 'In addition to the polyvinyl alcohol partial saponified product, for example, Ethyl acrylate. Methyl methacrylate copolymer dispersion, acetyl glycerin fatty acid ester, amino methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, Acacia powder, ethyl cellulose, ethyl cellulose aqueous dispersion, octyl decyl triglyceride, Opadry OY-6950, Opadry OY-S-7135, 〇padry 〇Y_s_ 8471, 〇padry OY-S-9607, Opadry OY-S-22829, 〇padry OY-S-22835, Opadry OY-S-22961, olive oil , kaolin, cocoa butter, prunella, castor wax, caramel, carnauba wax, carboxyvinyl polymer, carboxymethyl ethyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose Nano, hydrated sulphur dioxide, dry oxidized gelatin, dried milky white shellac, dry methacrylic acid copolymer Ld, cold plum board, fish scale, metallurgy, gold foil, silver foil, citric acid triacetate, glycerin, glycerin Fatty acid ester, magnesium citrate, light anhydrous citric acid, hydroxypropyl cellulose containing light anhydrous citric acid, light liquid paraffin, cetyl wax, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic wax, High glucose leeches, hard wax, amber gelatin, wheat flour, wheat starch, rice starch, cellulose acetate, vinyl acetate resin, cellulose acetate phthalate, white beeswax, oxidized chin, magnesium oxide, methacrylic acid Dimethylamine ethyl ester. Methyl methacrylate copolymer, 13203 2.doc 11 200950818 Dimethyl polyoxane (intake), two substances, calcined gypsum, sucrose fatty acid vinegar, earthworm powder, oxidized dream mixed rosin glycerin, stearyl alcohol, stearic acid, Stearic acid: gelatin, hydrogen J-* Ot JSA ϊ» , --- 私, hard tang acid in 丐, hard moon 曰驮 polyoxyl ester 40, magnesium stearate electro-chemical gelatin, purified Α踉,, white sugar, zein, sesqui-iso-hard, ' ^ rice sugar and anhydride, cetyl alcohol, stone:: gum, shellac, sorbitol Xuan fatty acid..., D · sorbitol liquid, phosphoric acid three Dance, talc, carbonic acid, magnesium carbonate, monosaccharide ❹ 浆 pulp, medium gold box, shoal carbonate, low-substituted propyl cellulose, thin resin, temple powder (soluble), corn sugar, corn oil, glycerin Triacetate, lactic acid, lactose, concentrated glycerin, white shellac, sugar, honey, stone soil, pearl powder, potato powder, propyl cellulose, propyl cellulose 2208, hydroxypropyl methyl fiber 〇29〇6, hydroxypropyl methylcellulose "ίο, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 titanium oxide·polyethylene glycol 4〇〇 mixture, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, castor oil, diethyl phthalate, dibutyl phthalate Ester, butyl butyrate butyl phthalate phthalate, glucose, thiobutanic acid, stearic acid, polyacetate: diethylaminoacetate, propyl fluorenyl cellulose 2910 mixture, Polytriglucose, propylene glycol, bentonite, povidone, polyoxyethylene hardened castor oil 4, polyoxyethylene hardened castor oil 60, polyoxyethylene (1〇5) polyoxypropylene (5) diol, polyoxyethylene (16〇) polyoxypropylene (30) diol, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, poly Ethylene glycol 1500, polyethylene glycol 154 〇, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, polyethylene glycol 35000, D-mannitol, water 132032.doc 200950818, beeswax , nutmeg fermentation, anhydrous citric acid hydrate, phthalic acid needle, anhydrous acid-breaking gas, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid Polymer S, magnesium metasilicate magnesium silicate, methyl cellulose, 2-mercapto-5-vinylpyridyl acrylate brewing. Methyl propyl hydrazine copolymer, • lacquer wax, aluminum monostearate, single Stearic acid glyceride, sorbitan single month. lauric acid vinegar, montanic acid vinegar wax, medicinal carbon, polyglycerol, calcium sulfate, liquid paraffin, DL-malic acid, calcium orthophosphate, calcium hydrogen phosphate, Sodium hydrogen phosphate, phosphorus &-hydrogen calcium, rosin, etc. can be added alone or in a coating agent such as a mixture of two or more kinds of addition force σ, and it is preferable to add talc from the viewpoint of the self-adhesion effect. The content of the coating agent in the coating film is preferably from 5 to 40% by mass, particularly preferably from 5 to 40% by mass. Specific examples of the dispersing agent include methacrylic acid amine ketone vinegar copolymer RS, gum arabic, gum arabic powder, alginate propylene glycol, ethanol, oleic acid, bismuth ethylene polymer, and slow armor. Cellulose sodium, fat powder, citric acid # Sodium, glycerin, glycerin fatty acid g, #酸镇, light stomach & ❹ water: acid, crystalline cellulose, hardened oil, synthetic stone acid, acid The biliary test, the scorpion's from the bee sample, titanium oxide, the continuation of sodium citrate, the sucrose, the sucrose, the sodium hydroxide, the stearic acid, the stearic acid, the purified oleic acid , Purification of big ugly phoenix, sesquiterpene sorbitol liver, sorbitol liver fat -, ri sorbitol, big ugly oil, soybean imprinted phospholipid, low substitution propyl ': alizarin Dextrin, corn starch, gum tragacanth powder, sorbitan trioleate lactose/agricultural glycerin, horse mash potato powder, ethyl cellulose, propyl, • knife hydroxypropyl cellulose, hydroxypropyl Methylcellulose 2910, propylene glycol, propanol, fatty acid brewing, bentonite, polyvitre, polyoxyethylene hardened, kennel oil, 132032.doc -13-2 00950818 Polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 6〇, polyoxyethylene (1〇5) polyoxypropylene (5) glycol, polyoxyethylene (16〇) polyoxypropylene (3〇) II Alcohol polysorbate 2〇, polysorbate 60, polysorbate 80, sodium polyphosphate, polyethylene glycol 300, polyethylene glycol 4〇〇〇, polyethylene glycol 6〇〇〇, anhydrous lemon Sodium, anhydrous sodium pyrophosphate, magnesium metasilicate aluminate, sodium metaphosphate, methylcellulose, lacquer wax, sorbitol liver oleic acid vinegar, aluminum monostearate, succinate (IV), &; sorbitol anhydride single-label palmitic acid, sorbitol
肝單月桂酸S旨、月桂基硫酸納、聚桂醇、&態石堪、麟酸 氫鈣等，肖等可單獨添加或將兩種以上混合添加。包衣膜 中之分散劑之含#較好的是25質量％以下，尤其好的是15 質量％以下。 作為著色劑之具㈣，可列舉：料茶單寧粉、墓黃萃 取液、頁色三氧化二鐵、0paspray κ小249〇4、橘子香 精、褐色氧化鐵、碳黑、焦糖、洋紅、胡蘿萄素液、β·胡 禮萄素、甘草萃取物、金荡、黑氧化鐵、輕質無水石夕酸、 乳化鈦、三氧化二鐵、食用藍色旧、食用黃色4號、食用 二色4號銘色厥、食用黃色5號、食用紅色2號、食用紅色3 2食用紅化鈉、滑石、葉綠素銅納、葉 、，亲素銅、裸麥綠葉萃取物、d_龍腦、肉豆㈣ 基酯、藥用碳、核黃素丁酸醋、 沐缺方 素、綠茶粉、核黃素 %酸納、玫瑰油等，該等可單獨 .^ 早獨添加或將兩種以上混合添 二！：？膜中之著色劑之含量較好的是35質量％以下，尤 /、好的是25質量％以下。 作為消泡劑之具體例，可列舉：乙醇、甘油脂肪酸§旨、 132032.doc 200950818 二曱基聚矽氧烷（内服用）、二甲基聚矽氧烷.二氧化矽混合 物、嚴糖脂肪酸醋、發樹脂乳液、石夕消泡劑、硬脂酸聚烴 氧酯40、山梨糖酵酐脂肪酸酯、山梨糖醇酐三油酸酯、聚 山梨醇酯80等，該等可單獨添加或將兩種以上混合添加。 包衣膜中之消泡劑之含量較好的是1〇質量％以下’尤其好 的是2質量％以下。 本發明之製劑，係對含有L_半胱胺酸類之製劑，包上含 有聚乙烯醇之部分皂化物的包衣膜所得之包覆固形製劑。 作為固形製劑之劑形，例如可列舉㈣、顆粒劑、細粒劑 等，尤其好的是鍵劑。X，亦可對該等錠劑、顆粒劑、細 粒劑包上含有聚乙烯醇之部分息化物的包衣膜並填充至硬 膠囊或軟膠囊中，製成膠囊劑。 :對含有L-半胱胺酸類Liver monolaurate S, sodium lauryl sulfate, polyglycerol, & state stone, calcium phytate, etc., may be added separately or in combination of two or more. The content of the dispersing agent in the coating film is preferably 25% by mass or less, particularly preferably 15% by mass or less. As a coloring agent (four), there may be mentioned: tea tannin powder, tomb yellow extract, page color ferric oxide, 0 paspray κ small 249 〇 4, orange flavor, brown iron oxide, carbon black, caramel, magenta, Caraway solution, β·hushuisu, licorice extract, Jindang, black iron oxide, light anhydrous aristolochic acid, emulsified titanium, ferric oxide, edible blue old, edible yellow No. 4, edible Two-color No. 4, color 厥, edible yellow No. 5, edible red No. 2, edible red 3 2 edible sodium sulphate, talc, chlorophyll copper, leaf, pro-copper, naked green leaf extract, d_ borneol , peas (4) base ester, medicinal carbon, riboflavin butyric acid vinegar, MU deficiency, green tea powder, riboflavin% sour, rose oil, etc., these can be alone. ^ Add alone or mix two or more Tim two! :? The content of the coloring agent in the film is preferably 35% by mass or less, more preferably 25% by mass or less. Specific examples of the antifoaming agent include ethanol, glycerin fatty acid §, 132032.doc 200950818 dimercapto polyoxyalkylene (internal administration), dimethyl polyoxane, cerium oxide mixture, and sucrose fatty acid. Vinegar, hair resin emulsion, Shixi defoamer, polyoxyl stearate 40, sorbitan fatty acid ester, sorbitan trioleate, polysorbate 80, etc., can be added separately Or add more than two types. The content of the antifoaming agent in the coating film is preferably at most 1% by mass, and particularly preferably at most 2% by mass. The preparation of the present invention is a coated solid preparation obtained by coating a coating containing L-cysteine with a coating film containing a partial saponified product of polyvinyl alcohol. As the dosage form of the solid preparation, for example, (4), granules, fine granules and the like can be mentioned, and a key agent is particularly preferable. X. The tablets, granules, and fine granules may be coated with a coating film containing a partial polysaccharide of polyvinyl alcohol and filled into a hard capsule or a soft capsule to prepare a capsule. : For L-cysteine
本發明之製劑係以如下方式製造： 之製劑或L-半胱胺酸類之結晶，包上 4化物的包衣膜。對製造固形劁添，丨^The preparation of the present invention is produced in the following manner: a preparation or a crystal of L-cysteine, coated with a coating film of a compound. For the manufacture of solid shape, 丨^
132032.doc 200950818 Ο 作為製劑添加劑之具體例，可在上述目的下使用如下所 述之先前公知的可用於固形製劑之製劑添加劑：乳糖'白 糖、甘露糖醇、木糖醇、糊精、山梨糖醇、赤藻糖醇、還 原麥芽糖水始、聚三葡萄糖、聚維綱、纖維素、結晶纖維 素、低取代經丙基纖維素、甲基纖維素、經丙基甲基纖維 素經丙基纖維素、聚乙二醇、丙二醇、聚氧乙稀聚氧丙 稀二醇、交聯叛甲基纖維素納、交聯聚維_、澱粉、預糊 化殺粉、叛甲基纖維素妈、乙基纖維素、缓甲基殿粉、反 丁烯二酸、檸檬酸、硬脂酸、硬脂酸鎂、硬脂酸鈣、滑 石、輕質無水石夕酸、二氧化石夕、滑石、薦糖脂肪酸酿、聚 氧乙稀（1G5)聚氧丙稀（5):醇、氧化鈦、依地酸納、沒食 子酸丙酯、乳酸鈣、碳酸鈣、沈澱碳酸鈣、矽酸鈣、磷酸 氮鈣、偏矽酸鋁酸鎂、明膠、阿拉伯膠、巴西棕櫚蠟、白 蜂蠟、甲基丙烯酸胺基烷基醋共聚物Ε、聚乙烯縮醛二乙 胺基乙酸醋、聚氧乙稀聚氧丙稀二醇、二甲基聚石夕氧烧、 甘油脂肪酸酯、中長鏈三酸甘油酯、琥站醯明膠、甘油、 硬化油、焦糖、核黃素磷酸納、三氧化二鐵、紅色⑽ 號、黃色5號等。 在製造錠劑、顆粒劑、散劑等時，若需要製備造粒粉 末，則係藉由通常所採用之造粒法來製造，例如，使用含 有水或有機溶劑之溶液或分散液的喷霧造粒法、 法'、流化造粒法、旋轉造粒法、旋轉流化造粒法等濕式造 粒法’使用粉粒狀#合劑的麼密造粒法等乾式造粒法等。 錠劑可藉由如下方式來製備：將原粉、粉末劑、細粒劑， 132032.doc 200950818 顆製劑添加物相混合，並進行壓縮成型。 勺二 ^劑包上含有聚乙烯醇之部分息化物的衣膜 展二Γ並無特別限ι例如可列舉：純衣法、流化 二 旋轉包衣法、乾式包衣法、或將其等加以組合 要f趟彳h制幻如，將添加有聚乙烯醇之部分皂化物及視需 1、包衣劑、分散劑、著色劑、消泡劑等之包膜 σ物'合解.懸浮於視需要已加溫之純化水中，製備 Ο132032.doc 200950818 Ο As a specific example of a formulation additive, a previously known formulation additive which can be used for a solid preparation as described below can be used for the above purpose: lactose 'white sugar, mannitol, xylitol, dextrin, sorbose Alcohol, erythritol, reduced maltose water, polytriglucose, polyvitidine, cellulose, crystalline cellulose, low substituted propyl cellulose, methyl cellulose, propyl methyl cellulose by propyl Cellulose, polyethylene glycol, propylene glycol, polyoxyethylene polyoxypropylene glycol, cross-linked methyl cellulose nano, cross-linked poly-dimensional, starch, pre-gelatinized powder, methylene cellulose , ethyl cellulose, slow methyl temple powder, fumaric acid, citric acid, stearic acid, magnesium stearate, calcium stearate, talc, light anhydrous stone acid, dioxide dioxide, talc , recommended sugar fatty acid brewing, polyoxyethylene (1G5) polyoxypropylene (5): alcohol, titanium oxide, sodium edetate, propyl gallate, calcium lactate, calcium carbonate, precipitated calcium carbonate, tannic acid Calcium, calcium phosphate, magnesium metasilicate aluminate, gelatin, gum arabic, carnauba wax, Beeswax, aminoalkyl methacrylate copolymer oxime, polyvinyl acetal diethylaminoacetate vinegar, polyoxyethylene polyoxypropylene diol, dimethyl polyoxan, glycerol fatty acid ester, Medium long chain triglyceride, sulphate gelatin, glycerin, hardened oil, caramel, riboflavin sodium phosphate, ferric oxide, red (10), yellow 5, and the like. In the preparation of tablets, granules, powders, and the like, if it is necessary to prepare a granulated powder, it is produced by a granulation method generally employed, for example, by spraying with a solution or dispersion containing water or an organic solvent. The wet granulation method such as the granulation method, the method ′, the fluidized granulation method, the rotary granulation method, and the rotary fluidized granulation method is a dry granulation method such as a granulation method using a powder granule mixture. Tablets can be prepared by mixing raw powder, powder, fine granules, 132032.doc 200950818 formulation additives, and compression molding. The coating film containing the partial polysaccharide of polyvinyl alcohol on the scooping agent package is not particularly limited to, for example, a pure clothing method, a fluidized two-rotation coating method, a dry coating method, or the like. In combination, it is necessary to combine the saponification of the polyvinyl alcohol with the slag of the polyvinyl alcohol, and the coating σ of the coating 1, the dispersing agent, the coloring agent, the defoaming agent, etc. Prepare hydrazine in purified water that has been heated as needed
匕衣τ I用包臈所慣用之方法來對製劑包衣。包衣液較 ㈣疋成111形分通常為1〜50質量％ ’尤其好的是調整 成固形分為2〜3〇質量％。 本發明中，形成於固形製劑上之包衣膜層之厚度，係根 據固形製劑之劑形或其質量、形狀以及包衣量之不同而不 同，較好的是5 μιη以上，更好的是1〇 μηι〜2 〇〇〇 μηι，尤其 好的是2G μιη〜ι，_ μιη，更好的是2G叫〜则_。例如， 若為直徑約為9 mm、質量約為2〇〇 mg左右之錠劑，則用 以獲得上述衣臈層之厚度所必需的包衣量如下：當衣臈層 之厚度為5 μηι時約為M mg/錠，當衣膜層之厚度為1〇 時約為2.3 mg/錠，當衣膜層之厚度為20 μπι時約為4 6 mg/ 錠。 本發明之製劑之投予量係根據患者之體重、年齡、性 別、疾病種類及症狀而適當選擇，以L-半胱胺酸計，對成 人之投予量如下：用作醫療用醫藥品時，較好的是每天投 予160〜480 mg，用作常用醫藥品時，較好的是每天投予 30〜240 mg。投予次數較好的是每天1~3次。 132032.doc -17- 200950818The coat τ I is coated with the formulation by the method conventionally used for packaging. The coating liquid is usually 1 to 50% by mass in the case of the (4) bismuth 111. It is particularly preferable to adjust the solid content into 2 to 3 〇 mass%. In the present invention, the thickness of the coating film layer formed on the solid preparation varies depending on the dosage form of the solid preparation or its mass, shape and coating amount, and is preferably 5 μm or more, more preferably 1〇μηι~2 〇〇〇μηι, especially good is 2G μιη~ι, _ μιη, and more preferably 2G is called ~ then _. For example, in the case of a tablet having a diameter of about 9 mm and a mass of about 2 〇〇mg, the amount of coating necessary to obtain the thickness of the above-mentioned layer of the enamel layer is as follows: when the thickness of the enamel layer is 5 μηι It is about M mg/ingot. When the thickness of the coating layer is 1 〇, it is about 2.3 mg/ingot. When the thickness of the coating layer is 20 μm, it is about 46 mg/ingot. The dosage of the preparation of the present invention is appropriately selected depending on the body weight, age, sex, type of disease, and symptoms of the patient, and the dose administered to an adult is as follows for L-cysteine: when used as a medical drug Preferably, 160 to 480 mg is administered per day. When used as a common pharmaceutical, it is preferred to administer 30 to 240 mg per day. The number of times of administration is preferably 1 to 3 times a day. 132032.doc -17- 200950818
態下之時間亦較少， V衣劑黑冩糖衣步驟，故可實現製劑 較低’又’製劑曝露於高溫多濕之狀 故可維持醫藥成分之穩定性，並且亦 可防止製劑變色。 [實施例] 以下，列舉實施例對本發明加以具體說明，但本發明並 不受该專實施例之任何限定。 實施例1 [素錠之製造] .使用L-半胱胺酸（協和酸酵（股）製造）16〇() g、乳糖328〇 g、結晶纖維素2400 g、低取代羥丙基纖維素丨〇〇〇 g、輕質 無水矽酸40 g、硬脂酸鎂4〇 g及滑石40 g，利用常法製作 打錠用粉末，於旋轉式打錠機（virg〇-〇512型打錠機；菊 水製作所股份有限公司製造）中，用9 mmφ之研绰棒將所獲 得之混合粉末打錠’使每1錠之質量為21〇 mg、厚度為4 mm ’藉此獲得素錠約8 kg。 [包膜錠之製造] 使用將聚乙烯醇部分皂化物（G型Gohsenol GL-05 :皂化 度為86.5〜89.0，曰本合成（股）製造）160 g、滑石40 g溶解. 懸浮於純化水1 800 g中所得的包膜液’利用包衣機（m· 132032.doc •18- 200950818 coater HCT-30N，FREUND INDUSTRIAL)，對上述素錠 1 kg進行包衣’直至每1鍵素鍵之質量增加量達到5 mg為 止’獲得本發明之包膜錠。此時之衣膜層之厚度為21.3 μηι(由圖像分析法所得之n=20之平均值）。 將所獲得之包膜錠30錠放入至玻璃5號規格瓶中，並蓋 緊瓶塞而加以密閉，對臭味進行測試，結果，於室溫下保 存12個月及於40°C下保存6個月之後均未聞到令人不舒服 之臭味。另一方面’將上述素錠30錠放入至玻璃5號規格 ® 瓶中並蓋緊瓶塞而加以密閉，對臭味進行測試，結果，於 至溫下保存12個月及於4 0 C下保存6個月後均聞到令人不 舒服之臭味。 比較例1 :普通包膜錠之製造 使用將羥丙基曱基纖維素2910(TC-5RW :信越化學工業 (股）製造）150 g、聚乙二醇6000(曰本油脂（股）製造）i〇 g、 滑石40 g溶解.懸浮於溶劑（乙醇：純化水=3:7)18〇〇 g中所得 ❹之包膜液’利用包衣機（Hi-coater HCT-30N，FREUND INDUSTRIAL)對實施例1中所獲得之素錠1 kg進行包衣， 直至母1錠素旋之質量增加量達到5mg為止，獲得本發明之 •包膜錢；。此時之衣膜層之厚度為3 9 · 7 μηι(由圖像分析法所 得之η=20之平均值）。 將該包衣錠放入至玻璃5號規格瓶中，並蓋緊瓶塞而加 以被閉’對臭味進行測試，結果，於室溫下保存丨2個月及 於4〇 C下保存6個月後均聞到令人不舒服之臭味。 實施例2 :包膜錠之製造 132032.doc •19· 200950818 以與實施例1相同之方式，對實施例丨中所獲得之素錠1 kg進行包衣，直至每1錠素錠之質量增加量達到2 $⑺呂為 止，獲得本發明之包膜錠。此時之衣膜層之厚度為1〇2 μιη(由圖像分析法所得之n=2〇之平均值）。 將該包膜錠30錠放入至玻璃5號規格瓶中，並蓋緊瓶塞 而加以密閉，冑臭味進行測試，結果，於室溫下保存⑵固 ❹ 月及於40 C下保存6個月後均未聞到令人不舒服之臭味。 實施例3 :包臈錠之製造 、 以與實施例1相同之方式’對實施你"中所獲得之素錠【 kg進行包衣’直至每!錠素錠之質量增加量達到】3叫為 止，獲侍本發明之包膜錠。此時之衣膜層之厚度為51 μ«ι(由圖像分析法所得之^⑽之平均值）。 又. 將該包膜錠30錠放入至玻璃5號規格瓶中，並蓋 而加以錢’對臭味進行測試，結果，於室溫下保存⑵固 月及於40C下保存6個月後均未聞到令人*舒服之臭味。 實施例4 :包膜錠之製造 、 與：施例1相同之方式’對實施例1中所獲得之素鍵1 g仃匕衣，直至每1鍵素鍵之質量增加量達到75叫為 止，獲得本發明之句暄铉+ §為 哗（由圖像分析法所得之㈣之平均值）。厚度為31.3 將該包臈錠30錠放入 而加以玄„ 埤5唬規格瓶中，並蓋緊瓶塞 月及ΜοΓ1"臭味進行測試，結果，於室溫下保存12個 =7保存6個月後均未聞到令人不舒服之臭味。 實例5.包膜錠之製造 132032.doc -20- 200950818 以與實施例1相同之方式，對實施例1中所獲得之辛w kg進行包衣，直至每丨錠素錠之質 =素紅 月里增加量達到10 mg為 止，獲知本發明之包膜鍵。此時之衣媒層之厚度為4〇9 μηι(由圖像分析法所得之n=2〇之平均值）。 將該包膜錠30鍵放入至玻璃5號規格瓶中， 而加以密閉臭味進行測試，結果，於室溫下保存⑽ 月及於4G°C下保存6個月後均未聞到令人不舒服之臭味。 實施例6The time under the state is also small, and the V-coating agent is a black sugar coating step, so that the preparation can be kept at a lower temperature and the composition is exposed to high temperature and humidity, thereby maintaining the stability of the pharmaceutical ingredient and preventing discoloration of the preparation. [Examples] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited by the specific examples. Example 1 [Production of a plain ingot]. Using L-cysteine (manufactured by Kyowa Kevyo Co., Ltd.) 16 〇 () g, lactose 328 〇 g, crystalline cellulose 2400 g, low-substituted hydroxypropyl cellulose丨〇〇〇g, light anhydrous decanoic acid 40 g, magnesium stearate 4 〇g and talc 40 g, using the usual method to make powder for ingot, in rotary type ingot machine (virg〇-〇512 type ingot In the machine, manufactured by Kikusui Co., Ltd., the obtained mixed powder was ingots with a 9 mmφ mortar bar to make the mass of each ingot 21 μm and the thickness 4 mm. Kg. [Production of coated ingots] 160 g of polyvinyl alcohol partial saponified material (G-type Gohsenol GL-05: saponification degree: 86.5 to 89.0, manufactured by Sakamoto Co., Ltd.), 40 g of talc, and suspended in purified water. The coating liquid obtained in 1 800 g was coated with 1 kg of the above-mentioned prime ingot by a coating machine (m·132032.doc •18-200950818 coater HCT-30N,FREUND INDUSTRIAL) until it was bonded to each 1 bond. The coated ingot of the present invention was obtained until the mass increase amount reached 5 mg. The thickness of the coating layer at this time was 21.3 μη (the average value of n = 20 obtained by image analysis). The obtained ingot 30 pieces were placed in a glass No. 5 size bottle, and the bottle stopper was tightly closed to test the odor. As a result, it was stored at room temperature for 12 months and at 40 ° C. After 6 months of storage, no unpleasant smell was heard. On the other hand, '30 ingots of the above-mentioned plain ingots were placed in a glass No. 5 gauge® bottle and tightly closed, and the odor was tested. As a result, it was stored at a temperature of 12 months and at 40 C. After 6 months of storage, it smelled unpleasant smell. Comparative Example 1: Production of a conventional coated ingot 150 g of hydroxypropyl fluorenylcellulose 2910 (TC-5RW: manufactured by Shin-Etsu Chemical Co., Ltd.), polyethylene glycol 6000 (manufactured by Sakamoto Oil Co., Ltd.) I〇g, talc 40 g dissolved. Suspended in a solvent (ethanol: purified water = 3:7) 18 〇〇g obtained in a coating solution of '❹- using a coating machine (Hi-coater HCT-30N, FREUND INDUSTRIAL) 1 kg of the ingot obtained in Example 1 was coated until the mass increase of the mother 1 tablet was 5 mg, and the envelope of the present invention was obtained. The thickness of the coating layer at this time was 3 9 · 7 μη (the average value of η = 20 obtained by image analysis). The coated ingot was placed in a glass No. 5 size bottle, and the stopper was tightly closed to test the odor. As a result, it was stored at room temperature for 2 months and stored at 4 ° C. After a month, I smelled an unpleasant smell. Example 2: Production of Coated Ingot 132032.doc • 19· 200950818 In the same manner as in Example 1, 1 kg of the ingot obtained in Example 进行 was coated until the mass of each ingot was increased. The amount of the coated ingot of the present invention is obtained when the amount reaches 2 $(7). The thickness of the coating layer at this time was 1 〇 2 μm (the average value of n = 2 所得 obtained by image analysis). The ingot 30 pieces were placed in a glass No. 5 size bottle, and the bottle stopper was tightly closed, and the odor was tested. As a result, it was stored at room temperature (2) and it was stored at 40 C. No unpleasant smell was heard after a month. Example 3: Manufacture of a coated ingot, in the same manner as in Example 1, 'coating the primed ingot obtained in the implementation of [the kg] until the mass increase per ingot of the ingot is reached] 3 So far, the coated ingot of the present invention has been obtained. The thickness of the coating layer at this time was 51 μΩ (the average of ^(10) obtained by image analysis). In addition, 30 ingots of the coated ingot were placed in a glass No. 5 size bottle, and covered with a money to test the odor. As a result, it was stored at room temperature (2) solid month and stored at 40 C for 6 months. Did not smell the smell of comfort. Example 4: Manufacture of a coated ingot, in the same manner as in Example 1, '1 g of the prime bond obtained in Example 1 until the mass increase per 1 bond of the bond reached 75. The sentence 暄铉 + § of the present invention is obtained (the average value of (4) obtained by image analysis). The thickness is 31.3. Put 30 ingots into the bottle and add it to the bottle of 玄 埤 唬5唬, and cover the bottle stopper and ΜοΓ1" odor test. As a result, save 12 at room temperature = 7 save 6 No unpleasant odor was observed after one month. Example 5. Production of Coated Ingot 132032.doc -20- 200950818 In the same manner as in Example 1, the sim w kg obtained in Example 1 was obtained. The coating is carried out until the amount of increase in the quality of each of the ingots is 10 mg, and the envelope bond of the present invention is known. The thickness of the coating layer at this time is 4〇9 μηι (by image analysis) The average value of n=2〇 obtained by the method.) The 30-injected ingot was placed in a glass No. 5 bottle, and the sealed odor was tested. As a result, it was stored at room temperature for (10) months and at 4G°. No unpleasant odor was observed after 6 months of storage under C. Example 6
[素錠之製造] 使用L-半胱胺酸（協和醱酵（股）製造H〇〇g、抗壞血酸Mo 8、鹽酸Μ醇250 g、㈣醢胺· g、核黃素磷酸納19〇 g、硝酸硫胺50 g、±物素0.5 g、_殿粉5 §、結晶纖維 素424.5 g、羥丙基纖維素2〇〇 g、低取代羥丙基纖維素ιι〇 g、硬脂酸鎂10 g及滑石10g，使用常法製作打錠用粉末， 於旋轉式打錠機（VIRGO_0512型打錠機；菊水製作所股份 有限公司製造）中，利用9 ιηηιφ之研缽棒將所獲得之混合粉 末打錠，使每1錠之質量為210 mg、厚度為4 mm，藉此獲 得素鍵約1.9 kg。 [包臈錠之製造] 使用將 Opadry AMB White(日本 COLORCON(股））4〇〇 g溶 解.懸浮於純化水1 600 g中所得之包膜液，利用包衣機（出_ coater HCT-30N’ FREUND INDUSTRIAL)對上述素鍵 i kg 進行包衣，直至每1錠素錠之質量增加量達到7 mg為止， 獲得本發明之包膜錠。此時之衣膜層之厚度為3〇.8 μηι(由 I32032.doc •21 · 200950818 圖像分析法所得之n=20之平均值）。 將該包膜錠30錠放入至玻璃5號規格瓶中，並蓋緊瓶塞 而加以密閉，對臭味進行測試，結果，於室溫下保存12個 月及於40°C下保存6個月後均未聞到令人不舒服之臭味。[Production of plain ingot] Using L-cysteine (Xiehe Yeast), H〇〇g, ascorbic acid Mo 8 , sterol hydrochloride 250 g, (iv) guanamine·g, riboflavin phosphate 19〇g , thiamine nitrate 50 g, ± substance 0.5 g, _Dian powder 5 §, crystalline cellulose 424.5 g, hydroxypropyl cellulose 2 〇〇 g, low-substituted hydroxypropyl cellulose ιι〇g, magnesium stearate 10 g and talc 10 g, using a conventional method to make a powder for ingots, and using a rotary tableting machine (VIRGO_0512 type ingot machine; manufactured by Kikusui Co., Ltd.), the mixed powder obtained by using a mortar stick of 9 ιηηιφ The ingot is made so that the mass per one ingot is 210 mg and the thickness is 4 mm, thereby obtaining a prime bond of about 1.9 kg. [Manufacture of the ingots] Using Opadry AMB White (Japan COLORCON) 4〇〇g The coating liquid obtained by suspending in 1 600 g of purified water was coated, and the above-mentioned prime bond i kg was coated by a coater (manufactured by _ coater HCT-30N'FREUND INDUSTRIAL) until the mass of each ingot was increased. When the amount reaches 7 mg, the coated ingot of the present invention is obtained, and the thickness of the coating layer at this time is 3 〇.8 μηι (by I32032.doc • 21 · 200950818 The average value of n=20 obtained by image analysis method. The 30 ingots were placed in a glass No. 5 bottle, and the stopper was tightly closed to test the odor. After storage for 12 months at room temperature and 6 months at 40 ° C, no unpleasant odor was observed.
132032.doc -22-132032.doc -22-