TW201004625A - A fine grain agent having improved water-suspensibility - Google Patents
A fine grain agent having improved water-suspensibility Download PDFInfo
- Publication number
- TW201004625A TW201004625A TW098110613A TW98110613A TW201004625A TW 201004625 A TW201004625 A TW 201004625A TW 098110613 A TW098110613 A TW 098110613A TW 98110613 A TW98110613 A TW 98110613A TW 201004625 A TW201004625 A TW 201004625A
- Authority
- TW
- Taiwan
- Prior art keywords
- surfactant
- fine
- weight
- polyoxyethylene
- fine granule
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Description
201004625 六、發明說明： 【明 /^屬 3 發明領域 本發明係關於改善醫藥細粒劑對水之懸浮性的方法’ 以及藉由該方法製造之新穎細粒劑。尤其，本發明係關於 改良以鹽酸頭孢卡品酯（cefcapene pivoxil hydrochloride)作 為有效成分之細粒劑對水的懸浮性之方法’以及藉由該方 法製造之新穎細粒劑。 【先前技術3 發明背景 關於經口投藥之醫藥品，散劑是可期待比錠劑及膠囊 劑更快吸收的有用劑形。尤其因為細粒劑比粉末狀的散劑 更容易服用，故利用的範圍廣。然而，在醫藥品有苦味等 令人不悅的味道時，因為投藥細粒劑常常伴隨困難，已開 發藉由披覆細粒劑表面來克服此等令人不悦味道的技術 (舉例而言，參照下文中的發明專利文獻1)。 鹽酸頭孢卡品酯（cefcapene pivoxil hydrochloride)為頭 孢卡品（cefcapene)經新戊醯氧甲酯化之經口吸收性高的前 藥。具有自革蘭氏陽性菌至革蘭氏陰性菌之廣效抗菌性， 但以細粒劑服用時產生苦味的問題。因此，已公開在該等 基本粒劑表面上藉由熱熔融塗覆法施予硬化蓖麻油以改善 令人不悅的味道（參考下文中專利文獻2)。 【發明專利文獻1】特開平04-300821號公報 【發明專利文獻2】國際公開案第2005/039538號小冊 3 201004625 t發明内容】 發明概要 發明欲解決的課題 在病患為老人及小孩的例子中，一般係使細粒劑懸浮 於少量的熱水或水來進行服用。然而，為了改善令人不悅 的味道而在細粒劑之表面披覆硬化蓖麻油等疏水性物質， 在加水的例子下，大多數此等粒子係浮在水面上，因靜電 的緣故，增加與容器的靜電附著性，而使一部的的粒子附 著於容器内壁表面。因此，對於藉由吸管等平滑地定量的 懸浮液，服用上有困難。 又，特定醫藥在與添加劑混合進行製劑時產生副反 應，生成類似物是已知的。本發明的目的為在抑制進行製 劑化時的副反應，且不損及改善令人不悅之味道的效果之 下，提供提昇細粒劑之濕潤性的改良懸浮性之方法。 解決課題之手段 鹽酸頭孢卡品酯（cefcapene pivoxil hydrochloride)在市 面上是以已披覆硬化蓖麻油之細粒劑，「頭孢嗟將納 (Flomox® (登録商標））幼兒用細粒」販售。本案發明人 等對懸浮劑及界面活性劑進行各種檢討的結果，發現藉由 僅新添加二氧化石夕及界面活性劑，能改良對水的懸浮性。 本案發明人等更進一步確認此方法可廣泛地適用於一般懸 浮性不足的細粒劑，而完成下述之本發明。亦即有關於： (1 ) 一種細粒劑，其特徵在於：有效成分的粒子含有已 被疏水性物質彼覆之主藥細粒、二氧化矽及界面活性劑； 201004625 (2 )上述（1 )記載的細粒劑，該有效成分為鹽酸頭孢 卡品酯（cefcapene pivoxil hydrochloride); ' (3)上述（1)或（2)記載的細粒劑，二氧化碎為親 水性二氧化矽； (4) 上述（3)記載的細粒劑，二氧化矽為含水二氧化 石夕； (5) 上述（1)至（4)中任一者記載的細粒劑，二氧 ^ 化矽的含量相對於製劑總量為0.1-5重量％ ; (6) 上述（1 )至（5)中任一者記載的細粒劑，該界 面活性劑的融點為3(Tc以上； (7) 上述（1 )至（6)中任一者記載的細粒劑，該界 面活性劑為非離子性界面活性劑； (8) 上述（1)至（7)中任一者記載的細粒劑，該界 • 面活性劑為含有聚氧乙烯鏈之界面活性劑； (9) 上述（8)記載的細粒劑，該界面活性劑為丨種或2 Θ 種以上選自於由聚氧乙稀（40)單硬脂酸醋、聚氧乙稀硬 化ϋ麻油(60)及聚氧乙稀（16〇)聚氧丙稀（3〇)二醇等所 組成之組群者； (10) 上述（9)記載的細粒劑，該界面活性劑為聚氧 乙烯（160)聚氧丙烯（3〇)二醇； (1 1)上述⑴至（丄〇)中任一者記載的細粒劑， 該界面活性劑的含量相對於製劑總量為0.025-2重量％ ; 迷（1)至（11)中任—者記載的細粒劑， 該疏水性物質為硬化油； 5 201004625 (1 3) —種細粒劑’其特徵在於：含有鹽酸頭孢卡品酯 (cefcapene pivoxil hydrochloride)之粒子係含有已被疏水性 物質披覆之主藥細粒、二氧化矽及融點30°C以上的界面活 性劑； (1 4) 一種細粒劑，其特徵在於：含有鹽酸頭孢卡品酯 (cefcapene pivoxil hydrochloride)之粒子含有已被硬化油彼 覆之主藥細粒、含水二氧化矽及含有融點3〇°c以上的聚氧 乙烯鏈之界面活性劑； (1 5 )上述（1 4)或（1 5 )記載的細粒劑，其係在 製劑中含有1 -20重量％之鹽酸頭孢卡品醋（cefcapene pivoxil hydrochloride)、1-50 重量％之硬化油、0.1-5 重量％ 之含水二氧化矽、0.025-2重量％之含有融點3(TC以上的聚 氧乙烯鏈之界面活性劑； (1 6)上述（1)至（1 5)中任一者記載的細粒劑， 主藥細粒更進一步包含崩解劑及/或賦形劑； (1 7)—種懸浮劑，其包含上述（1 )至（1 6)中任 一者記載的細粒劑； (1 8)—種提昇細粒劑之水懸浮性的方法，其特徵在於： 在有效成分已被疏水性物質彼覆之主藥細粒中，添加二氧 化碎及界面活性劑。 發明的效果 根據本發明，能提昇彼覆疏水性包衣膜的細粒劑之對 水的懸浮性，結果提供容易懸浮於水中的可服用細粒劑。 再者，因藉由該包衣膜亦未損及有效成分之令人不悅的味 201004625 道之遮掩效果，特別適用於作為幼兒用製劑。又更佳地， 可抑制因主藥分解伴隨生成之類似物的發生。 圖式簡單說明 第1圖為含有鹽酸頭抱卡品酿（cefcapene pivoxil hydrochloride)之主藥細粒製劑的製造步驟（1 ); 第2圖為含有鹽酸頭抱卡品醋（cefcapene pivoxil hydrochloride)之主藥細粒製劑的製造步驟（2 ); 第3圖為懸浮劑杯散的製造步驟； 第4圖為懸浮劑杯散及細粒劑的混合步驟； 第5圖為在温度40°C/濕度75%之環境下2週後生成 的類似物之總量。 L實施方式j 實施本發明之最佳態樣 本發明中所使用之有效成分為供廣範圍使用之作為細 粒劑的醫藥化合物，舉例而言，國際公開案第2005/039538 號中所例示的醫藥化合物。較佳為具有苦味等令人不悅的 味道之成分。再者，也可使用水難溶性成分。更佳地為頭 芽孢菌素（Cephalosporin)系抗菌劑，例如盤尼西林 (Penicillin)系的氟氣西林(Flucloxacillin)、鹽酸泰安比西林 (Talampicillin hydrochloride )、曱苯績酸舒他西林片 (Sultamicillin Tosilate)，及鹽酸巴坎西林（Bacampicillin Hydrochloride)、頭孢烯(Cephem)系的頭孢克落(Cefaclor)、 頭孢泊两醋（Cefpodoxime Proxetil)、頭孢替安醋（Cefotiam Hexetil)、頭孢吱將酯（CefuroximeAaxetil)、鹽酸頭抱卡品 201004625 酯（cefcapene pivoxil hydrochloride)及頭孢特輪新戊酯 (Cefteram Pivoxil)、或大環内酯（Macrolide)系的紅黴素 (Erythromycin)等抗生素；洛美沙星（Lomefloxacin)、氟諾 沙星（Norfloxacin)、氧氟沙星（Ofloxacin)、依諾沙星 (Enoxacin)、吡哌酸等之喹諾酮系抗菌劑；氫溴酸右美沙芬 (Dextromethorphan Hydrobromide)、檸檬酸異米尼爾 (Isoaminile Citrate)，及填酸二甲_烧（Dimemorfan Phosphate)等之鎮咳去痰藥；乙醯胺盼（Acetaminophen)、 酮基布洛芬（Ketoprofen)，及托芬那酸（Tolfenamic Acid) 等之退燒鎮痛消炎藥；鹽酸苯拉海明（Diphenhydramine Hydrochloride )及鹽酸異丙嗪(Promethazine Hydrochloride) 等之抗組織胺劑；例如其他的鹽酸夕七千7 S y也可使 用。尤其，在使用溶解性低的醫藥化合物之例子下，對於 一方面確保溶出性，一方面抑制令人不悅的味道，可得到 優異的效果。因此，特佳為鹽酸頭孢卡品醋（cefcapene pivoxil hydrochloride)(化學命名：（+)-(6R，7R)-7-[(Z)-2-(2-胺基-4-噻唑基)-2-戊烯酿胺基]-3-胺基甲醯氧基曱基-8-氧 代-5-噻-1·二氮雜二環[4,2,0]八-2-烯-2-羧酸新戊醯氧基甲 基醋鹽酸鹽.1水和物）。 有效成分的含量相對於製劑總量約為1-20重量％，較 佳為約2.5-17.5重量％，更佳為約5-15重量％。 作為疏水性物質，舉例而言，例如國際公開案第 2005/039538號中記載的臘狀物質。在下文中，稱為疏水性 物質或蠟狀物質。具體地，作為疏水性物質，可使用在室 201004625 温上下的溫度下為固體狀，藉由加熱容易軟化及熔融之廣 泛使用的製藥上各許的物質。舉例而言，例如硬化油（硬 化蓖麻油、硬化大豆油、硬化油菜籽油等）、高級醇（十八 烧醇、十六院醇等）'高級脂肪酸（硬脂酸酸、棕棚酸酸等）、 植物性或動物性脂肪（牛脂、巴西棕櫊蠟）、蜜蠟、聚乙二 醇（PEG :聚乙二醇（Macrog〇1) 4〇〇〇、聚乙二醇（Macr〇g⑷ 6000等）。由工業實施的層面來看較佳地，其融點在約 Q 4〇C_約l〇〇t>C2範圍内。特佳為硬化油，更佳為硬化蓖麻 油。 疏水性物質的含量相對於主藥為約50_200重量％，較 佳為約75-175重量％ ’更佳為約100·150重量％。相對於 主藥細粒為約丨·50重量％、較佳為約5-40重量％，更佳為 約10-30重量％。再者，相對於製劑總量為約1-50重量％， 較佳為約2.5-25重量％，更佳為約5_2()重量％。當疏水性 物質為具有令人不悅的味道之有效成分時，具有遮掩效 © 果。疏水性物質高於上述量，有體内顆粒崩壞所致之内包 成分之溶出性降低的可能性θ相反地，少於上述量恐怕無 法充分地抑制在口腔内漏出。 一氧化矽較佳為親水性二氧化矽。於親水性二氧化矽 中’可使用藉由濕式法製造之含水二氧化梦（例如卡普勒 克斯（CARPLKC®)(登録商標，酿.日本股份有限公司）） 或藉由乾式法製造之輕質無水矽酸無水矽酸（例如愛羅西 爾（AEROSIL®)(登録商標，飢.日本股份有限公司）） 中任一者，較佳為親水性含水二氧化矽（例如卡普勒克斯 9 201004625 (CARPLEX®)(聲錄商標））。對於親水性含水二氧化石夕， 具體而言，可為卡普勒克斯（CARPLEX) #67 (比表面積： 約429 m2/g，平均粒徑：約6.4 μιη )、卡普勒克斯 (CARPLEX) #80 (比表面積：約193 m2/g ’平均粒徑： 約8.1 μιη)、卡普勒克斯（CARPLEX) #1120 (比表面積： 約109 m2 / g，平均粒徑：約8.1 μιη )、卡普勒克斯 (CARPLEX)FPS-1(比表面積：約I99m2/g，平均粒徑： 約2.11 μιη)、卡普勒克斯（CARPLEX) FPS-2(比表面積： 約242 m2/ g，平均粒徑：約1.8 μιη )、卡普勒克斯 © (CARPLEX) CS·5 (比表面積：約⑼瓜2/^平均粒徑： 約2.3 μπι)(皆為DSL.曰本股份有限公司）等，較佳為卡 普勒克斯（CARPLEX) #67。 二氧化矽的含量，相對於主藥為約重量％，較佳 _ 為約2.5-17.5重量％，更佳為約5_15重量％。再者，相對 於製劑總量為約G.1-5重量％，較佳為約〇 25_4 75重量％， ^佳為約0.3-4.5重量％。若高於此等含量，製劑投藥時可 能維持粉體，若低於此等含量，恐怕細粒劑在水中無料 © 分懸浮。 界面活|·生劑係使用月桂基硫酸納及非離子性界面活性 劑。作為非離子性界面活性劑，較佳為含有聚氧乙烯鏈之 =面活性劑’具體而言為單油酸聚氧乙稀脫水山梨糖醇 -曰聚氧乙稀脫水山梨糖醇單硬脂酸醋、聚氧乙稀（4〇) 單，月曰酸^、聚氧乙稀硬化t麻油6G及聚氧乙稀（160) 聚氧丙稀⑼）二醇。更佳為融點3G°C以上的界面活性劑， 10 201004625 又更佳為融點3(TC以上之含有聚氧乙烯鏈的界面活性劑 (例如聚氧乙烯（4〇)單硬脂酸酯、聚氧乙烯硬化蓖麻油 60及聚氧乙烯（160)聚氧丙烯（30)二醇）。尤其較佳為 聚氧乙烯（160)聚氧丙烯（30)二酵。主藥為鹽酸頭跑卡 品酯（cefcapene pivoxil hydrochloride)的情況中，自有欵成 分之安定性的觀點’最適為聚氧乙烯（160)聚氧丙歸（3〇) 二醇。關於界面活性劑的種類，恐怕會引起有效成分之類 ❹ 似物的發生，有效成分的安定性可藉由類似物之發生來判 斷。 界面活性劑的含量，相對於主藥為約0.1-20重量％， 較佳為約0.25-15重量％，更佳為約0.5-10重量％。相對於 製劑總量為約0.025-2重量％，較佳為約0.05-1.75重量％， 更佳為約0.1-1.5重量％。若高於此等含量，有類似物增加 的可能性，若低於此等含量，恐怕細粒劑在水中無法充分 懸浮。 Q 按照上述，為了細粒劑之懸浮化，作為特別有用的添 加物為二氧化石夕及界面活性劑的混合物（在下文中稱為「懸 浮劑卡普（CARP)散」的例子）。若將其等之混合物披覆在細 粒劑及細粒劑的表面，可使細粒劑容易懸浮於水中。尤其， 在披覆有疏水性物質之細粒劑的例子中’疏水性物質的表 面披覆有懸浮劑卡普（CARP)散，該細粒劑容易在水中懸 浮。再者，對於二氧化矽與界面活性劑的混合比例，以二 氧化矽為卜界面活性劑為約〇1_2、較佳為約〇 5_2。對於 其等之混合比，若二氧化矽的比例高，有製劑維持粉體的 11 201004625 可能性，若低的話，細粒劑等的黏著性増加，細粒劑等恐 怕會產生凝集。 ~ 再者，對於二氧化矽及界面活性劑之混合物亦即懸 序劑卡普(CARP)散的含有量’相對於製劑總量為my 重量％，較佳為0.3-6.5重量％，更佳為〇·4_6重量％。若 咼於此等量，因二氧化矽而有維持粉體的可能性若低於 此等量，恐怕無法獲得充分的懸浮性。 本發明製劑更可含有一述的製藥上容許的添加物。 作為朋解劑，舉例而言，例如國際公開案第2005/ ® 039538號中記載之水膨潤性物質。在下文中，稱為崩解劑 或水膨潤性物質。該等物質一面在水中幾乎不溶解而保持 製劑形，一面在吸水時形成膨張基質的構造。可作為水膨 潤性物質的例子，例如羧甲基纖維素鈣、羧曱基纖維素鈉 (CMC-Na )、交聯羥曱基纖維素鈉（cr〇scarmell〇se „ sodium)、低取代性羥丙基纖維素（L_Hpc)等的纖維素衍 生物；部分α化的澱粉（PCS)、羧甲基澱粉鈉（CMS_Na) 等的澱粉類。 ® 崩解劑的含量，相對於主藥為約5〇_25〇重量％，較佳 為約75-200重量％，更佳為約100_175重量％。相對於主 藥細粒約1-50重量％，較佳為約2 5_4〇重量％，更佳為約 5-30重量％。再者，相對於製劑總量為約uo重量％，較 佳為約2.5-25重’更佳為約5-20重量％。崩解劑的量 少於上述量，具有在體内顆粒很難崩解且内包成分的溶出 性低的可能性。相反地，若崩解劑的量高於上述記量，恐 12 201004625 怕無法充分地抑制在口腔内漏出。 對於甜味劑，舉例而言，可使用國際公開案第2005/ 039358號中記載使用的甜味劑。具體而言係使用乳糖、白 糠、粉末還原麥芽糖水飴、葡萄糖、木糖醇、D_甘露糖醇、 甘露糖醇、山梨糖醇、麥芽糖、赤蘚醇、阿斯巴甜、糖精、 糖精鈉、醋續内醋卸（Acesulfame-K)或甘草酸二却 (Dipotassium Glycyrrhizinate)等，較佳為粉末還原麥芽糖水 始、D-甘露糖醇、木糖醇及阿斯巴甜。 甜咮劑之含量相對於主藥約100-800重量％，較佳為 約200-750重量％ ’更佳為約300—700重量％。再者，相對 於製劑總量為約10-80重量％，較佳為約20-75重量％，更 佳為約30-70重量％。 作為結合劑’舉例而言，可使用國際公開案第2005/ 039358號中記載之水溶性結合劑。尤其時，持有界面活性 作用的結合劑，舉例而言，較佳為羥丙基纖維素（HPC)、 羥丙基曱基纖維素（HPMC)、聚乙烯吡咯烷酮（PVP)等， 更佳為羥丙基纖維素（HPC)。 結合劑之含量，相對於主藥約5-40重量％，較佳為約 7.5-35重量％，更佳為約10-30重量％。相對於甜味細粒約 0.1-10重量％，較佳為約〇_5-8重量％，更佳為約1-7.5重 量％。再者，相對於製劑總量為約0.1-5重量％，較佳為約 0.5-4.5重量％，更佳為約1-4重量％。 對於其他的添加劑，例示如香料（例如草莓香精）、潤 滑劑（例如硬脂酸鎂）、赋形劑（例如滑石）。 13 201004625 此等製藥上容許的添加物可存在於主藥細粒的内部及 /或外部。舉例而言’此等製藥上容許之添加物的一部分 也可在主藥細粒與其他細粒一起配製之後，再與主藥細粒 混合。在主藥具有令人不悅的味道的例子中，在主藥細粒 中也可存在甜味劑（例如糖類等 > 再者，也可將主藥細粒 與含有其他甜味劑之甜味細粒一起配製。 主藥為鹽酸頭抱卡品醋（cefcapene pivoxil hydrochloride)之例子的本發明較佳態樣如下文中所示。再 者，任一者的含量為相對於製劑總量的量。亦即，鹽酸頭 ® 抱卡品SI(cefcapene pivoxil hydrochloride)為約 1-20 重量 %，疏水性物質為約1-50重量％，二氧化矽為約0.1-5重 量％，界面活性劑為約0,025-2重量％ (尤其，對懸浮劑卡 普（CARP)散而言約0.125-7重量％)，崩解劑為約1-5〇重量 % ’甜味劑為約10-80重量％。較佳為鹽酸頭孢卡品醋 (cefcapene pivoxil hydrochloride)為約 2.5-17.5 重量％，疏 水性物質為約2.5-25重量％，二氧化矽為約0.25-4.75重量 %，界面活性劑為約0.05-1.75重量％ (尤其，對懸浮劑卡 ® 普（CARP)散而言為0.3-6.5重量％)，崩解劑為約5·30重量 %，甜味劑為約20-75重量％。更佳為鹽酸頭孢卡品醋 (cefcapene pivoxil hydrochloride)為約 5-15 重量％，疏水性 物質為約5-25重量％，二氧化矽為約0.3-4.5重量％，界面 活性劑為約0.1-1.5重量％ (尤其，對懸浮劑卡普(Carp) 散而言為0.4-6重量％ )，崩解劑為約5-20重量％，甜味劑 為約30-70重量％。 14 201004625 主藥為鹽酸頭抱卡品醋（cefcapene pivoxil hydrochloride)之例子的本發明較佳態樣如下文中所示。再 者，任一者之量亦為相對於製劑總量的量《亦即，鹽酸頭 孢卡品酯（cefcapene pivoxil hydrochloride)為約 1-20 重量 %，硬化油為約1-50重量％，含水二氧化石夕為約〇.ι_5重 量％ ’聚氧乙烯（160)聚氧丙烯（30)二醇為約0.025-2 重量％ (尤其，對懸浮劑卡普（CARP)散而言為約0.125-7 重量％)、低取代性羥丙基纖維素為約1-50重量％、粉末 還原麥芽糖水飴、D-甘露糖醇、木糖醇及阿斯巴甜為約 10-80重量％。較佳地，鹽酸頭孢卡品醋（cefcapene pivoxil hydrochloride)為約2.5-17.5重量％，硬化油為約2.5-25重 量％’含水二氧化矽為約0.25-4.75重量％，聚氧乙烯（160) 聚氧丙烯（30)二醇硬脂酸鎂為約0.05-1.35重量％ (尤其， 對懸浮劑卡普(CARP)散而言為約0.3-6.5重量％)，低取代 性羥丙基纖維素為約5-30重量％、粉末還原麥芽糖水飴、 D-甘露糖醇、木糖醇及阿斯巴甜為約20-75重量％。更佳 地，鹽酸頭孢卡品酯（cefcapene pivoxil hydrochloride)為約 5-15重量％，硬化油為約5-20重量％，含水二氧化石夕為約 0.3-4.5重量％，聚氧乙稀（160)聚氧丙烯（30)二醇為約 0.1-1.5重量％ (尤其，對懸浮劑卡普（CARP)散而言為約 0.4-6重量％ )，低取代性羥丙基纖維素為約5-20重量％， 粉末還原麥芽糖水飴、D-甘露糖醇、木糖酵及阿斯巴甜為 約30-70重量％。 本發明製劑為細粒劑，粒徑75 μιη-500 μιη之細粒劑佔 15 201004625 85%以上。 在服用本發明製劑的例子中，當該製劑照原樣口脉 時，可藉由水等服用，也可將本發明製劑懸浮於水、牛乳， 果汁等，服用該懸浮液。本發明製劑在水性液體中的懸淨 性良好’能在液體中充分懸浮。 細粒劑的代表性製法將於下文中說明。 混合有效成分，依所欲之前述製藥上容許之添加物， 及疏水性物質，於配製含有其等之基本粒劑之後，經過妒 Φ 熱處理，得到經疏水性物質彼覆的有效成分粒子之主藥.細 粒。該加熱處理係例如依照特開平4_3〇〇821號的方法進 行。亦即，本發明之彼覆製劑可經由具有下述特徵的製造 方法容易地製造而得：將由醫藥化合物，尤其是具有令人 不悦的味道或/及在溶劑中容易分解之性質的醫藥化合 物、蠟狀物質、水膨潤性物質、二氧化矽及界面活性劑， ， 及視需要之結合劑、潤滑劑、甜味劑、著色劑等其他添加 劑所形成的混合粉末，予以乾式造粒，例如壓縮成形後破 砕，調整成任意的粒徑，接著進行加熱處理使蠟狀物質至 © 少披覆在表面上。 各粉末成分的混合、壓縮、整粒可依據常用的方法進 行。舉例而言’粉末的壓縮係利用打錠機、輥壓縮機等壓 制機，以500-1000 kg/cm2的壓力，成形為小丸狀、薄片狀， 接著藉由架碎方式的調整機調整成任意的粒度。由本製法 獲得的基本粒劑（稱為加熱處理前粒劑。在下文中同），推 定為構成成分的蝶狀物質’水膨潤性物質係均—分散，同 16 201004625 時經由壓縮使一部分的蠟狀物質展延的物質。接下來’對 此基本粒劑施與加熱處理，配製成熱溶融粒劑（稱為加熱 處理後粒劑。在下文中同）。 加熱處理步驟係在至少使蠟狀物質軟化之充分溫度及 充分時間下進行。此等温度及時間通常為在約40°C以上約 10-約90分鐘，較佳為約20-約60分鐘《亦即，加熱温度 較佳為在該溫度至少使蠟狀物質的表面濕潤之温度以上 者。棚架乾燥也可進行加熱，較佳為藉由流動層乾燥裝置 的方式。藉由此處理，使分散於基質中的蠟狀物質熔融， 在均一且大致連續狀態下，彼覆具有令人不悅之味道的粉 末狀物質。因此，加熱温度係因蠟狀物質的融點而變動。 好的蠟狀物質較佳為在約40-約90°C下熔融的物質，更佳 為在約50-約85°C下熔融的物質。 又’也可依據WO 2005/039538號中記載的方法進 行。亦即，疏水性物質的添加及繼續加熱處理的操作也可 反覆進行2次。本發明之彼覆製劑係例如藉由下述的方法 容易地製得：將由醫藥化合物，尤其是具有令人不悦的味 道之醫藥化合物、壤狀物質、水膨潤性物質、二氧化梦及 界面活性劑、視需要之結合劑、潤滑劑、矯味劑、著色劑 等其他添加劑所組成的混合粉末，經由濕式法或乾式法造 粒，整粒，調整成任意的粒徑，接著以蠟狀物質當作結合 劑地加熱處理，進一步加入約5-約25重量％之粉末狀蠟狀 物質，進行熱熔融塗覆。 各粉末成分的混合、造粒、整粒可利用一般常用的方 17 201004625 法進行。舉例而言，在利用乾式法的例子中’粉末的造粒 係利用打錠機、輥壓縮機等的壓制機，在50-100 MPa的壓 力下’壓縮成形為小丸狀、薄片狀，接著利用架碎方式的 整粒機調整成任意的粒度。利用本製法所得到的基本粒劑 (稱為加熱處理前的粒劑。在下文中同。）為構成成分的 蠟狀物質，推定為水膨潤性物質均一地分散，且經由壓縮 使增<狀物質的一部分展延的物質。 接下來，於加熱處理此基本粒劑之後，經由添加粉末 狀蝶狀物質，配製熱溶融塗覆粒劑（稱為一面加熱一面塗 覆處理後的粒劑。在下文中同）。 關於熱熔融塗覆步驟，粉末狀蠟狀物質之添加前及添 加時的加熱’係在使内添加之蠟狀物質軟化之充分溫度及 充分時間下進行。加熱温度通常約4〇。(：以上，較佳為内添 加蠟狀物質的融點以下。亦即，加熱温度係在該步驟中， 使内添加蠟狀物質得以濕潤基本粒劑表面的溫度以上即 可。經由此處理，熔融之内添加蠟狀物質的作用為，在基 本粒劑表面作為外添加蠟狀物質的結合劑。因此，加熱溫 度係依據内添加蠛狀物質的融點而變動。内添加纖狀物質 可為在較佳為約40-約9(TC下軟化的物質，特佳為在約5〇_ 約85°C下軟化的物質。 對於粉末狀蠛狀物質之添加後的加熱，係在使外添加 «物質軟化之充分溫度及充分時間下進行。加熱温度通 常約40。(：以上，較佳為外添加蠟狀物質之融點以下。因此， 加熱恤度係依據外添加缫狀㈣的㈣而變動。外添 201004625 狀物質可為在較佳為約40_約9〇。(：下軟化的物質，特佳為 在約50-約85°C下軟化的物質。 對於熱溶融塗覆步驟，在提高加熱温度的情況中，内 添加螺•狀物質及外添加蠟狀物質係完全融解，由於蠟狀物 質使顆粒完全被披覆，在體内顆粒難以崩解，内包成分的 溶出性低。相反地’在降低加熱温度的情況中，内添加蠟 狀物質係作為外添加蠟狀物201004625 VI. Description of the invention: [Ming/^ genus 3 Field of the invention The present invention relates to a method for improving the suspensibility of a medicinal fine granule to water' and a novel granule manufactured by the method. In particular, the present invention relates to a method for improving the suspensibility of water by a fine granule having cefcapene pivoxil hydrochloride as an active ingredient, and a novel fine granule produced by the method. [Prior Art 3] BACKGROUND OF THE INVENTION With regard to oral pharmaceuticals, powders are useful dosage forms that can be expected to absorb faster than tablets and capsules. In particular, since fine granules are easier to take than powdered granules, they are used in a wide range. However, when pharmaceuticals have an unpleasant taste such as bitterness, since the administration of fine granules is often accompanied by difficulties, techniques for overcoming such unpleasant tastes by coating the surface of fine granules have been developed (for example, Reference is made to the invention patent document 1) below. Cefcapene pivoxil hydrochloride is a highly orally absorbable prodrug of cefcapene via methyl iodide. It has a broad-acting antibacterial property from Gram-positive bacteria to Gram-negative bacteria, but has a problem of bitterness when taken with a fine granule. Therefore, it has been disclosed that hardened castor oil is applied by hot melt coating on the surface of the basic granules to improve an unpleasant taste (refer to Patent Document 2 below). [Patent Document 1] JP-A-2004-300821 (Patent Document 2) International Publication No. 2005/039538 Booklet 3 201004625 t Summary of the Invention Summary of the Invention The problem to be solved by the invention is that the patient is an elderly person and a child. In the examples, the fine granules are generally suspended in a small amount of hot water or water for administration. However, in order to improve the unpleasant taste, a hydrophobic substance such as hardened castor oil is coated on the surface of the fine granule. In the case of adding water, most of these particles float on the water surface, and are increased due to static electricity. The electrostatic adhesion to the container causes one of the particles to adhere to the inner wall surface of the container. Therefore, it is difficult to take a suspension which is smoothly quantified by a pipette or the like. Further, a specific medicine produces a side reaction when it is mixed with an additive, and it is known to produce an analog. SUMMARY OF THE INVENTION An object of the present invention is to provide a method for improving the suspensibility of improving the wettability of a fine granule while suppressing side reactions during formulation and without impairing the effect of improving unpleasant taste. Solution to the problem Cefcapene pivoxil hydrochloride is sold on the market as a fine granule of hardened castor oil, "Flomox® (registered trademark)) for children" . As a result of various reviews of the suspending agent and the surfactant, the inventors of the present invention found that the suspensibility to water can be improved by newly adding only the cerium oxide and the surfactant. The inventors of the present invention have further confirmed that the method can be widely applied to fine granules which are generally insufficient in suspension, and the present invention described below is completed. That is to say: (1) A fine granule characterized in that: the particles of the active ingredient contain the main drug fine particles, the cerium oxide and the surfactant which have been coated with the hydrophobic substance; 201004625 (2) above (1) The fine granule according to the above description, wherein the active ingredient is cefcapene pivoxil hydrochloride; (3) the fine granule according to the above (1) or (2), which is oxidized to hydrophilic cerium oxide; (4) The fine granule according to the above (3), wherein the cerium oxide is an aqueous cerium oxide, and the granules according to any one of the above (1) to (4), (6) The fine granule according to any one of the above (1) to (5), wherein the melting point of the surfactant is 3 (Tc or more; (7) The fine granule according to any one of the above aspects (1) to (6), wherein the surfactant is a nonionic surfactant; (8) The fine granule according to any one of the above (1) to (7) The surfactant is a surfactant containing a polyoxyethylene chain; (9) The fine granule according to the above (8), wherein the surfactant is ruthenium or 2 Θ or more selected from the group consisting of A group consisting of polyoxyethylene (40) monostearate, polyoxyethylene hardened castor oil (60), and polyoxyethylene (16 〇) polyoxypropylene (3 〇) diol. (10) The fine granule according to the above (9), wherein the surfactant is polyoxyethylene (160) polyoxypropylene (3 fluorene) diol; (1) any one of the above (1) to (丄〇) In the fine granules, the content of the surfactant is from 0.025 to 2% by weight based on the total amount of the preparation; the fine granule according to any one of (1) to (11), wherein the hydrophobic substance is a hardened oil; 5 201004625 (1 3) - a fine granule' characterized in that the particles containing cefcapene pivoxil hydrochloride contain main drug fine particles, cerium oxide and melting point which have been coated with a hydrophobic substance. a surfactant of 30 ° C or higher; (1 4) a fine granule characterized in that: the particles containing cefcapene pivoxil hydrochloride contain the main drug fine particles which have been hardened by oil, and the water contains two a cerium oxide and a surfactant having a polyoxyethylene chain having a melting point of 3 〇 or more; (15) the fine particles described in the above (1 4) or (1 5) It contains 1-20% by weight of cefcapene pivoxil hydrochloride, 1-50% by weight of hardened oil, 0.1-5 wt% of aqueous ceria, and 0.025-2% by weight in the preparation. The fine granules according to any one of the above (1) to (1), wherein the main granule further contains a disintegrating agent. And/or an excipient; (1) a suspending agent comprising the fine granule according to any one of the above (1) to (6); (18) a water suspension for lifting the fine granule The method is characterized in that: the oxidized granules and the surfactant are added to the main drug fine particles in which the active ingredient has been coated with the hydrophobic substance. EFFECTS OF THE INVENTION According to the present invention, the water suspensibility of the fine granules of the hydrophobic coating film can be improved, and as a result, a fine granule which can be easily suspended in water can be provided. Furthermore, since the coating film does not impair the unpleasant taste of the active ingredient, the masking effect of the 201004625 channel is particularly suitable for use as a preparation for infants. Still more preferably, the occurrence of an analog which is accompanied by the decomposition of the main drug can be suppressed. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a manufacturing step (1) of a main drug fine particle preparation containing cefcapene pivoxil hydrochloride; Fig. 2 is a view showing a cefcapene pivoxil hydrochloride containing hydrochloric acid. The manufacturing step of the main drug fine particle preparation (2); the third drawing is the manufacturing step of the suspension agent cup dispersion; the fourth drawing is the mixing step of the suspension agent cup powder and the fine particle agent; the fifth figure is the temperature at 40 ° C / The total amount of analogs produced after 2 weeks in an environment with a humidity of 75%. L. Embodiment j The embodiment of the present invention is to use a pharmaceutical compound as a fine granule for a wide range of uses. For example, the medicine exemplified in International Publication No. 2005/039538 Compound. It is preferably an ingredient having an unpleasant taste such as bitterness. Further, a poorly water-soluble component can also be used. More preferably, it is a Cephalosporin-based antibacterial agent, such as Penicillin-based Flulucoxacillin, Talampicillin hydrochloride, and Sultancilin Tosilate. , and Bacampicillin Hydrochloride, Cefaclor, Cefpodoxime Proxetil, Cefotiam Hexetil, Cefuroxime Aaxetil , antibiotics such as cefcapene pivoxil hydrochloride and cefteram Pivoxil, or macrolide erythromycin (Erythromycin); lomefloxacin , quinolone-based antibacterial agents such as Norfloxacin, Ofloxacin, Enoxacin, Pipermic Acid; Dextromethorphan Hydrobromide; Isoaminile Citrate, and antitussive and expectorant such as Dimmorfan Phosphate; Acetaminophen Ketoprofen, and Tolfenamic Acid and other antipyretic analgesic and anti-inflammatory drugs; Diphenhydramine Hydrochloride and Promethazine Hydrochloride and other antihistamines; For example, other hydrochloric acid eve 7 7 S y can also be used. In particular, in the case of using a pharmaceutical compound having a low solubility, it is possible to obtain an excellent effect by ensuring the elution property while suppressing an unpleasant taste. Therefore, it is particularly preferred to be cefcapene pivoxil hydrochloride (chemical name: (+)-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)- 2-pentene arylamino]-3-aminomethyl methoxy fluorenyl-8-oxo-5-thia-1·diazabicyclo[4,2,0]octa-2-ene-2 - carboxylic acid neopentyloxymethyl vine hydrochloride. 1 water and). The content of the active ingredient is from about 1 to 20% by weight, preferably from about 2.5 to 17.5% by weight, more preferably from about 5 to 15% by weight, based on the total amount of the preparation. As the hydrophobic substance, for example, a waxy substance described in International Publication No. 2005/039538 is exemplified. Hereinafter, it is called a hydrophobic substance or a waxy substance. Specifically, as the hydrophobic substance, a pharmaceutically acceptable substance which is solid at a temperature above and below the temperature of the room 201004625 and which is easily softened and melted by heating can be used. For example, such as hardened oil (hardened castor oil, hardened soybean oil, hardened rapeseed oil, etc.), higher alcohol (octadecanol, hexadecanol, etc.) 'higher fatty acid (stearic acid, palm succinic acid) Etc.), vegetable or animal fat (tallow, Brazilian brown wax), beeswax, polyethylene glycol (PEG: polyethylene glycol (Macrog〇1) 4〇〇〇, polyethylene glycol (Macr〇g (4) 6000, etc.) From the viewpoint of industrial implementation, it is preferable that the melting point is in the range of about Q 4 〇 C_about l〇〇t > C2. Particularly preferred is a hardened oil, more preferably hardened castor oil. The content of the substance is about 50 to 200% by weight, preferably about 75 to 175 % by weight, more preferably about 100 to 150% by weight, based on the main drug, and about 50% by weight based on the main drug fine particles, preferably About 5 to 40% by weight, more preferably about 10 to 30% by weight. Further, it is about 1 to 50% by weight, preferably about 2.5 to 25% by weight, more preferably about 5 to 2% by weight based on the total amount of the preparation. % by weight. When the hydrophobic substance is an active ingredient having an unpleasant taste, it has a masking effect. The hydrophobic substance is higher than the above amount, and has a body weight. The possibility of a decrease in the elution property of the inner component due to collapse is θ. Conversely, less than the above amount may not sufficiently suppress leakage in the oral cavity. Monosaccharide is preferably hydrophilic cerium oxide. Hydrophilic cerium oxide is used. Medium's use of a water-based dioxide dream made by a wet process (for example, CARPLKC® (registered trademark, brewing. Japan Co., Ltd.)) or light anhydrous anhydrous citric acid anhydrous yttrium produced by dry method Acid (for example, AEROSIL® (registered trademark, Hungry. Japan Co., Ltd.)), preferably hydrophilic aqueous cerium oxide (for example, Capulax 9 201004625 (CARPLEX®) (sound) Recorded trademark)). For hydrophilic hydrous dioxide, specifically, it can be CARPLEX #67 (specific surface area: about 429 m2/g, average particle size: about 6.4 μηη), Caplux (CARPLEX) #80 (specific surface area: approx. 193 m2/g 'average particle size: approx. 8.1 μηη), CARPLEX #1120 (specific surface area: approx. 109 m2 / g, average particle size: approx. 8.1 μιη) , CARPLEX FPS-1 ( Surface area: about I99m2/g, average particle size: about 2.11 μηη), CARPLEX FPS-2 (specific surface area: about 242 m2/g, average particle size: about 1.8 μιη), Caplux © (CARPLEX CS·5 (specific surface area: about (9) melon 2/^ average particle size: about 2.3 μπι) (all are DSL. 曰本股份有限公司), etc., preferably CARPLEX #67. The content of cerium oxide is about 5% by weight based on the main drug, preferably _2.5-1.5% by weight, more preferably about 5-15% by weight. Further, it is about G.1-5.5% by weight, preferably about 25_475 wt%, and preferably about 0.3-4.5 wt%, based on the total amount of the preparation. If it is higher than this content, the powder may be maintained during the administration of the preparation. If it is lower than this content, the fine granule may be suspended in the water. Interface activity|·The biocide uses sodium lauryl sulfate and a nonionic surfactant. As the nonionic surfactant, it is preferably a polyoxyethylene chain-containing surfactant*, specifically, polyoletoic acid polyoxyethylene sorbitan-indene polyoxyethylene sorbitan monostearate Sour vinegar, polyoxyethylene (4 〇) single, lunar acid ^, polyoxyethylene hardened t sesame oil 6G and polyoxyethylene (160) polyoxypropylene (9)) diol. More preferably, it is a surfactant above 3G °C, 10 201004625 and more preferably a melting point 3 (more than TC surfactant containing polyoxyethylene chain (such as polyoxyethylene (4〇) monostearate) , polyoxyethylene hardened castor oil 60 and polyoxyethylene (160) polyoxypropylene (30) diol). Particularly preferred is polyoxyethylene (160) polyoxypropylene (30) di leaven. The main drug is hydrochloric acid head running In the case of cefcapene pivoxil hydrochloride, from the viewpoint of the stability of the bismuth component, it is most suitable for polyoxyethylene (160) polyoxypropylene (3 〇) diol. Regarding the type of surfactant, I am afraid The occurrence of an analogous substance such as an active ingredient causes the stability of the active ingredient to be judged by the occurrence of the analog. The content of the surfactant is from about 0.1 to 20% by weight, preferably about 0.25, based on the main drug. 15% by weight, more preferably from about 0.5 to 10% by weight, based on the total amount of the preparation, from about 0.025 to 2% by weight, preferably from about 0.05 to 1.75% by weight, more preferably from about 0.1 to 1.5% by weight. These contents have the possibility of increasing the analogue. If it is lower than this content, the fine granules may be in the water. It is not possible to fully suspend. Q According to the above, as a particularly useful additive for the suspension of fine granules, it is a mixture of sulphur dioxide and a surfactant (hereinafter referred to as "suspending agent" (CARP). If a mixture of these is coated on the surface of the fine granules and the fine granules, the fine granules can be easily suspended in water. In particular, in the case of a fine granule coated with a hydrophobic substance, 'hydrophobicity The surface of the substance is coated with a suspension agent, CARP, which is easily suspended in water. Further, for the mixing ratio of cerium oxide and surfactant, cerium oxide is used as a surfactant. 〇1_2, preferably about _25_2. If the ratio of the cerium oxide is high, there is a possibility that the preparation maintains the powder 11 201004625, and if it is low, the adhesion of the fine granules and the like is increased. There may be agglomeration of granules, etc. ~ Further, the mixture of cerium oxide and a surfactant, that is, the content of the suspension agent (CARP) is '% by weight relative to the total amount of the preparation, preferably 0.3-6.5 wt%, more preferably 〇·4_6% by weight. If the amount is less than this amount due to cerium oxide, sufficient suspensibility may not be obtained. The preparation of the present invention may further contain a pharmaceutical preparation. The water-swellable substance described in, for example, International Publication No. 2005/039039, hereinafter, is referred to as a disintegrating agent or a water-swellable substance. A structure in which a form of a swelling matrix is formed while being insoluble in water while maintaining a formulation shape, and can be used as an example of a water-swellable substance such as calcium carboxymethylcellulose or sodium carboxymethylcellulose (CMC-Na). Cellulose derivatives such as cross-linked hydroxymethyl cellulose sodium (cr〇scarmell〇se „ sodium), low-substituted hydroxypropyl cellulose (L_Hpc); partially gelatinized starch (PCS), sodium carboxymethyl starch Starch (CMS_Na). The content of the disintegrant is about 5 〇 25 5% by weight, preferably about 75 to 200% by weight, more preferably about 100 175 % by weight based on the main drug. It is about 1 to 50% by weight, preferably about 25% to 4% by weight, more preferably about 5 to 30% by weight, based on the main drug fine particles. Further, it is preferably about uo% by weight, more preferably about 2.5 to 25 Å, more preferably about 5 to 20% by weight, based on the total amount of the preparation. When the amount of the disintegrant is less than the above amount, the particles are hard to disintegrate in the body and the elution property of the inner component is low. On the other hand, if the amount of the disintegrant is higher than the above-mentioned amount, it is feared that the leakage in the oral cavity cannot be sufficiently suppressed. As the sweetener, for example, a sweetener described in International Publication No. 2005/039358 can be used. Specifically, it uses lactose, white peony, powder reduction maltose leeches, glucose, xylitol, D_mannitol, mannitol, sorbitol, maltose, erythritol, aspartame, saccharin, sodium saccharin, Acesulfame-K or Dipotassium Glycyrrhizinate, etc., preferably powder-reduced maltose start, D-mannitol, xylitol and aspartame. The content of the sweetener is from about 100 to 800% by weight, preferably from about 200 to 750% by weight, more preferably from about 300 to 700% by weight, based on the main drug. Further, it is from about 10 to 80% by weight, preferably from about 20 to 75% by weight, more preferably from about 30 to 70% by weight, based on the total amount of the preparation. As the binder, for example, a water-soluble binder described in International Publication No. 2005/039358 can be used. In particular, the binding agent having an interfacial activity is preferably, for example, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), or the like, more preferably Hydroxypropyl cellulose (HPC). The content of the binder is from about 5 to 40% by weight, preferably from about 7.5 to 35% by weight, more preferably from about 10 to 30% by weight, based on the main drug. It is preferably from 0.1 to 10% by weight, preferably from about 5% to about 5% by weight, more preferably from about 1 to 7.5 % by weight, based on the sweet fine particles. Further, it is from about 0.1 to 5% by weight, preferably from about 0.5 to 4.5% by weight, more preferably from about 1 to 4% by weight, based on the total amount of the preparation. For other additives, examples are perfumes (e.g., strawberry flavors), lubricants (e.g., magnesium stearate), and excipients (e.g., talc). 13 201004625 These pharmaceutically acceptable additives may be present inside and/or outside the main drug granules. For example, a portion of such pharmaceutically acceptable additives may also be mixed with the main drug fine particles after the main drug fine particles are formulated together with other fine particles. In the case where the main drug has an unpleasant taste, a sweetener (for example, a saccharide or the like) may be present in the main drug granules. Further, the main drug granule may be sweetened with other sweeteners. The fine particles are prepared together. The preferred embodiment of the present invention in which the main drug is cefcapene pivoxil hydrochloride is as follows. Further, the content of any one is relative to the total amount of the preparation. That is, the cefcapene pivoxil hydrochloride is about 1-20% by weight, the hydrophobic substance is about 1-50% by weight, the cerium oxide is about 0.1-5% by weight, and the surfactant is About 0,025-2% by weight (especially about 0.125-7% by weight for the suspension agent (CARP) dispersion), about 1-5% by weight for the disintegrant, and about 10-80% by weight of the sweetener. Preferably, cefcapene pivoxil hydrochloride is about 2.5-17.5 wt%, the hydrophobic material is about 2.5-25 wt%, the ceria is about 0.25-4.75 wt%, and the surfactant is about 0.05. -1.75 wt% (especially, 0.3-6.5 wt% for the Suspended Card® (CARP) dispersion), collapse The decomposing agent is about 5.30% by weight, the sweetener is about 20-75% by weight, more preferably about 5-15% by weight of cefcapene pivoxil hydrochloride, and about 5-25 for hydrophobic substances. % by weight, cerium oxide is about 0.3-4.5% by weight, surfactant is about 0.1-1.5% by weight (especially 0.4-6% by weight for the suspension agent Carp), and the disintegrant is About 5-20% by weight, the sweetener is about 30-70% by weight. 14 201004625 The preferred embodiment of the present invention is exemplified by cefcapene pivoxil hydrochloride, as shown in the following. The amount of either is also relative to the total amount of the preparation "that is, cefcapene pivoxil hydrochloride is about 1 to 20% by weight, and the hardened oil is about 1 to 50% by weight. Shi Xi is about 〇.ι_5 wt% 'polyoxyethylene (160) polyoxypropylene (30) diol is about 0.025-2% by weight (especially, about 0.125-7 for the suspension agent (CARP) dispersion % by weight, low-substituted hydroxypropyl cellulose is about 1-50% by weight, powder-reduced maltose leeches, D-mannitol, xylose The alcohol and aspartame are about 10-80% by weight. Preferably, cefcapene pivoxil hydrochloride is about 2.5-17.5 wt%, and the hardened oil is about 2.5-25 wt% 'aqueous ceria. From about 0.25 to about 4.75 weight percent, the polyoxyethylene (160) polyoxypropylene (30) glycol magnesium stearate is from about 0.05 to about 1.35 weight percent (especially, about 0.3 for the suspension agent (CARP) dispersion. -6.5% by weight), low-substituted hydroxypropylcellulose is about 5-30% by weight, powder-reduced maltose mash, D-mannitol, xylitol and aspartame are about 20-75% by weight. More preferably, cefcapene pivoxil hydrochloride is from about 5 to 15% by weight, the hardened oil is from about 5 to 20% by weight, and the aqueous sulfur dioxide is from about 0.3 to 4.5% by weight, polyoxyethylene ( 160) The polyoxypropylene (30) diol is from about 0.1 to 1.5% by weight (especially from about 0.4 to 6% by weight for the suspension agent (CARP) dispersion), and the low-substituted hydroxypropyl cellulose is about 5-20% by weight, powder-reduced maltose leeches, D-mannitol, xylose and aspartame are about 30-70% by weight. The preparation of the invention is a fine granule, and the fine granules having a particle diameter of 75 μηη - 500 μηη account for more than 85% of 15 201004625. In the case of administering the preparation of the present invention, when the preparation is as it is, it can be administered by water or the like, and the preparation of the present invention can be suspended in water, milk, fruit juice or the like, and the suspension can be administered. The formulation of the present invention has a good suspension in an aqueous liquid and can be sufficiently suspended in a liquid. A representative method of preparing a fine granule will be described below. Mixing the active ingredient, the above-mentioned pharmaceutically acceptable additive, and the hydrophobic substance, after formulating the basic granules containing the same, and then heat-treating by 妒Φ to obtain the active ingredient particles which are coated with the hydrophobic substance. Medicine. Fine particles. This heat treatment is carried out, for example, in accordance with the method of JP-A-4-367. That is, the coating formulation of the present invention can be easily produced by a manufacturing method having the following characteristics: a pharmaceutical compound which is a pharmaceutical compound, particularly a property having an unpleasant taste or/and easily decomposed in a solvent. a mixed powder of a waxy substance, a water-swellable substance, cerium oxide and a surfactant, and other additives such as a binder, a lubricant, a sweetener, a coloring agent, etc., for dry granulation, for example After compression molding, it is broken, adjusted to an arbitrary particle diameter, and then heat-treated to make the waxy substance adhere to the surface less. The mixing, compression, and granulation of the respective powder components can be carried out according to a usual method. For example, 'the compression of the powder is formed into a pellet shape or a flake shape by a press such as a tableting machine or a roll compressor at a pressure of 500 to 1000 kg/cm 2 , and then adjusted to an arbitrary shape by a frame crushing machine. Granularity. The basic granules obtained by the present process (referred to as pre-heat treatment granules. Hereinafter), the butterfly-like water-swelling substance which is presumed to be a constituent is uniformly dispersed, and a part of the wax is formed by compression at the same time as 16 201004625 Substance extended material. Next, this basic granule is subjected to heat treatment to prepare a hot solute granule (referred to as granule after heat treatment. Hereinafter). The heat treatment step is carried out at a sufficient temperature for at least softening the waxy substance and for a sufficient period of time. The temperature and time are usually from about 10 ° C to about 90 minutes, preferably from about 20 to about 60 minutes. That is, the heating temperature is preferably such that at least the surface of the waxy substance is wetted at the temperature. Above the temperature. The drying of the scaffolding can also be carried out, preferably by means of a fluidized bed drying device. By this treatment, the waxy substance dispersed in the matrix is melted, and in a uniform and substantially continuous state, a powdery substance having an unpleasant taste is coated. Therefore, the heating temperature fluctuates due to the melting point of the waxy substance. The waxy substance is preferably a substance which melts at about 40 to about 90 ° C, more preferably a substance which melts at about 50 to about 85 ° C. Further, it can also be carried out in accordance with the method described in WO 2005/039538. That is, the addition of the hydrophobic substance and the operation of continuing the heat treatment can be repeated twice. The coating formulation of the present invention is easily obtained, for example, by a pharmaceutical compound, particularly a pharmaceutical compound having an unpleasant taste, a loamy substance, a water-swelling substance, a dioxide dream, and an interface. a mixed powder composed of an active agent, an optional binder, a lubricant, a flavoring agent, a coloring agent, and the like, granulated by a wet method or a dry method, sized, adjusted to an arbitrary particle diameter, and then waxed The substance is heat treated as a binder, and further about 5 to about 25% by weight of a powdery waxy substance is added for hot melt coating. The mixing, granulation, and granulation of each of the powder components can be carried out by a commonly used method. For example, in the example using the dry method, the granulation system of the powder is 'compressed into a pellet shape or a flake shape by a press such as a tableting machine or a roll compressor at a pressure of 50 to 100 MPa, and then used. The granulator of the crushing method is adjusted to an arbitrary particle size. The basic granules obtained by the present process (referred to as granules before heat treatment, hereinafter the same) are waxy substances constituting the components, and it is presumed that the water swellable substances are uniformly dispersed, and are increased by compression. A substance that is part of a substance that is extended. Next, after heat-treating the base granules, a hot melt-coated granule is prepared by adding a powdery pterygium (referred to as granules which are heated on one side and coated on one side. Hereinafter). In the hot melt coating step, the heating before and during the addition of the powdery waxy substance is carried out at a sufficient temperature for softening the internally added waxy substance and for a sufficient period of time. The heating temperature is usually about 4 Torr. (The above is preferably below the melting point of the waxy substance added thereto. That is, the heating temperature is in this step, so that the internal waxy substance is allowed to wet above the temperature of the surface of the basic granule. The action of adding a waxy substance in the melt is to add a wax-like substance to the surface of the basic granule. Therefore, the heating temperature varies depending on the melting point of the internally added enamel substance. Preferably, it is a softening material at a temperature of about 40 to about 9 (TC), particularly preferably a material which softens at about 5 Torr to about 85 ° C. The heating after the addition of the powdery enamel substance is added externally. «The temperature is softened at a sufficient temperature and sufficient time. The heating temperature is usually about 40. (: Above, it is preferably below the melting point of the externally added waxy substance. Therefore, the heating degree is based on the external addition of the 缫 (4) (4) The externally added 201004625-like substance may be a substance which is preferably about 40 to about 9 Å. (: a softening substance, particularly preferably a softening at about 50 to about 85 ° C. For the hot melt coating step, In the case of increasing the heating temperature, add internally The snail-like substance and the externally added waxy substance are completely melted, and the granules are completely covered by the waxy substance, and the particles are hardly disintegrated in the body, and the elution property of the inner component is low. Conversely, in the case of lowering the heating temperature , adding a waxy substance as an externally added wax
質的結合劑，且外添加蠟狀物 質在基本粒劑表面充分地展延，顆粒的披覆過少使得口 腔内的漏出抑制不充分。 在加熱温度逹到適當温度的時間點之 下，添加粉末狀The quality of the bonding agent and the externally added waxy substance are sufficiently extended on the surface of the basic granule, and the excessive coating of the granules causes insufficient leakage in the oral cavity. Add powder when the heating temperature is raised to the appropriate temperature
斗勿質9 jh直 I 伯·&本粗劑表面施與熱熔融塗層。塗覆時間較 佳為約1〇'約90分鐘，特佳為約20-約60分鐘。作為熱熔 融塗覆之適當|置，例如為流動層乾燥裝置。 L常在藉由流動層進行粉末塗覆的例子中，均一地 塗覆^常困難。然而，在添加粉末狀蠛狀物質時即使不均 u1由流動層乾燥装置（流動型塗覆機（flow coter-FLO-5 大/可原製作所），經由一邊加熱-邊流動使蠛狀物質軟 在基本粒劑表面展延，可以使之均一化。由此，本法 係提供非常簡易的外部塗覆方法。 ’將詳細說明有關本發明之披覆製劑的製造 在下文中 示，係採用此技術 方法。於本發明說明書中，除非特別指 領域中公_製劑步驟。 (1)主藥細粒的製造 先將約40重量％以下之醫藥化合物，尤其是具有 19 201004625 令人不悅的味道之醫藥化合物，約5_約25重量％之鱲狀物 質及約5-約35重量％之水膨潤性物質，視需要之結合劑、 潤滑劑、甜味劑、著色劑等其他的添加劑混合。將此混合 粉末在壓縮成薄片狀地成形後、破碎。之後，藉由分子篩 機分級，經由調整成任意的粒徑，得到基本粒劑。（造粒步 驟） 又在此使用之原料亦為下述添加劑的全部’依其性 質實施下表中所示的處理之混合用細粒，有可能得到效率 良好之混合作業。 ϋ 【表1】 原料的性質 細粒的製造 粉末 粉碎以使50%之平均粒徑為5〇 μπι以下的 製造。 液狀 將香油卡普（CARP)_散及液體原料置於袋 中，於袋内混合1分鐘之後，藉由標準篩 100號過篩的製造。 蠟狀 將蝶狀原科遇熱溶解。將香油卡普（CARP) 散或二氧化矽置於研缽中，添加溶解的原料 混練’藉由標準篩100號過篩的製造。 接下來，加熱藉由蝶狀物質濕潤表面之基本粒劑，在 此狀態下添加粉末狀蠟狀物質（約5_約25重量％)。之後， 在加熱狀態下，經由一定時間的流動，得到熱溶融塗覆粒 劑（熱炫融塗覆步驟）。 (2)甜味細粒的製造 再者，為了改善在口腔内之令人不悅的味道，可進行 含有甜味劑之該被覆製劑的造粒。或者，可將經造粒之甜 20 201004625 味細粒與該披覆製劑混合。作為甜味劑，舉例而言係使用 乳糖、白糖、粉末還原麥芽糖水飴、葡萄糖、木糖醇、甘 露糖醇、λ梨糖醇、麥芽糖、赤蘚醇、阿斯巴甜、糖精、 糖精鈉、醋磺内酯鉀（Acesulfame_K)或甘草酸二鉀 (Dipotassium Glycyrrhizinate)等。 在甜味細粒與該被覆製劑混合的情況中，可使用藉由 一般方法製造之甜味細粒。舉例而言，混合甜味劑，添加 適量的水混練，經由擠壓造粒來製造、乾燥而得到混練物。 相較於上述的甜味細粒，本發明提供甜味增加的甜味 細粒。亦即，在本發明中的甜味細粒，為了改善甜味劑的 溶出性，可藉由在將甜味劑造粒時，將一部的甜味劑與具 有可溶化作用之結合劑一起溶解或分散於水中的物質作為 結合液，添加剩餘的甜味劑，混練，將混練物造粒，乾燦 而獲得。 經由將此甜味細粒與上述的坡覆製劑混合服用，可更 一步改善更令人不悅的味道。 本發明中的甜味細粒係使用甜味劑、甜味劑與結合劑 共同溶解或分散於水中的結合液，藉由濕式法造粒。作為 甜味劑，可使用上述的甜味劑。作為結合劑，可使用上述 記載之水溶性結合劑。尤其，持有界面活性作用的結合劑， 較佳為例如羥丙基纖維素（HPC)、羥丙基甲基纖維素 (HPMC)、聚乙烯。比咯烷酮(PVP)。 (3)界面活性劑及二氧化石夕混合物之製造方法 將界面活性劑粉碎之後，藉由倍散過篩機（Shion〇gi 21 201004625Do not quality 9 jh straight I Bo · & this crude agent surface is applied with a hot melt coating. The coating time is preferably from about 1 Torr to about 90 minutes, particularly preferably from about 20 to about 60 minutes. As a suitable heat-sealing coating, for example, a fluidized bed drying device. L is often difficult to apply uniformly in the case of powder coating by a fluidized layer. However, even when the powdery enamel-like substance is added, even if it is not uniform, the fluidized layer drying device (flow type coating machine (flow coter-FLO-5 large/reproduced)) is heated by the side while flowing to make the enamel substance soft. It can be made uniform on the surface of the basic granules. Thus, the present method provides a very simple external coating method. 'The manufacture of the coating formulation relating to the present invention will be described in detail below, using this technique. In the specification of the present invention, unless otherwise specified in the field, the preparation step of the main drug fine particles is about 40% by weight or less of a pharmaceutical compound, especially a medicine having an unpleasant taste of 19 201004625. a compound, about 5 to about 25% by weight of a waxy substance and from about 5 to about 35% by weight of a water-swellable substance, optionally mixed with other additives such as a binder, a lubricant, a sweetener, a coloring agent, etc. The mixed powder is molded into a sheet and then crushed. After that, it is classified by a molecular sieve machine and adjusted to an arbitrary particle diameter to obtain a basic granule. (granulation step) The raw material used here. It is possible to obtain an efficient mixing operation by performing the mixing fine particles of the following additives according to the properties shown in the following table. ϋ [Table 1] Properties of raw materials Production of fine particles Powder pulverization so that 50 The average particle size of % is 5 〇μπι or less. The scented oil carb (CARP) _ powder and liquid raw materials are placed in a bag, mixed in a bag for 1 minute, and then sifted by a standard sieve No. 100. The waxy form dissolves the butterfly genus. The eucalyptus oil (CARP) powder or cerium oxide is placed in a mortar, and the dissolved raw material is mixed and sifted by the standard sieve No. 100. Next, Heating the basic granules of the surface by the butterfly-like substance, and adding a powdery waxy substance (about 5 to about 25% by weight) in this state. Thereafter, in a heated state, a hot melt coating is obtained through a certain period of flow. A granulating agent (hot smelting and coating step). (2) Manufacture of sweet granules Further, in order to improve an unpleasant taste in the oral cavity, granulation of the coated preparation containing a sweetener may be carried out. Or, the granulated sweet 20 201004625 A fine granule is mixed with the coating preparation. As a sweetener, for example, lactose, white sugar, powder-reduced maltose mash, glucose, xylitol, mannitol, λ-sorbitol, maltose, erythritol are used. , aspartame, saccharin, sodium saccharin, potassium acesulfate (Acesulfame_K) or dipotassium Glycyrrhizinate, etc. In the case where the sweet granules are mixed with the coated preparation, a general method can be used. The sweet taste granules are produced, for example, by mixing a sweetener, adding an appropriate amount of water, and culturing and drying by extrusion granulation to obtain a kneaded product. The present invention provides sweetness compared to the above-mentioned sweet granules. Sweet flavours with increased flavor. That is, in the sweet taste granules of the present invention, in order to improve the dissolution property of the sweetener, a sweetener and a solubilizing binder may be combined by granulating the sweetener. The substance dissolved or dispersed in water is used as a binding liquid, and the remaining sweetener is added, kneaded, and the kneaded material is granulated and dried. By mixing this sweet granule with the above-mentioned sloping preparation, it is possible to further improve the more unpleasant taste. The sweet fine granules of the present invention are granulated by a wet method using a sweetener, a binding agent in which a sweetener and a binder are dissolved or dispersed in water. As the sweetener, the above sweetener can be used. As the binder, the water-soluble binder described above can be used. In particular, a binding agent having an interface activity is preferably, for example, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), or polyethylene. Pyrrolidone (PVP). (3) Method for producing surfactant and cerium oxide mixture After pulverizing the surfactant, by doubling the sieve machine (Shion〇gi 21 201004625
Engineering Service Co.，Ltd.製造）過篩。之後，將過筛的 界面活性劑與二氧化矽混合，在攪拌造粒機（高速混合機， Fukae P〇wtec公司製造）内熔融後，再度藉由倍散過篩機 過篩。在下文中，該混合物也稱為「懸浮劑卡普（CARp)散。」 (4 )懸浮劑卡普（CARP)散及香油卡普(CARp)散的添加 在如上文所述般製造主藥細粒之後，添加前述的懸浮 劑卡普(CARP)^。^㈣卡f (GARp)散也可姉於主藥細 粒分批多次添加。舉例而言，在頭抱卡品鹽酸鹽㈣哪⑽Screened by Engineering Service Co., Ltd.). Thereafter, the sieved surfactant was mixed with cerium oxide, melted in a stirring granulator (high speed mixer, manufactured by Fukae P〇wtec Co., Ltd.), and sieved again by a double sifting sieve. Hereinafter, the mixture is also referred to as "suspension agent (CARp) dispersion." (4) The addition of the suspension agent CARP (CARP) and the eucalyptus oil (CARp) dispersion is as described above. After the granules, the aforementioned suspending agent Karp (CARP)^ was added. ^ (4) Card f (GARp) can also be added to the main drug fines in batches. For example, in the head holding the card product hydrochloride (four) which (10)
hydr〇Chl〇ride)的情況中，較佳為分2次添加。更佳地，香 料及二氧化㈣混合物（稱為「香油卡普(CARp)散」的情 況下）添加之後，添加前述的懸浮劑卡普（CARP)散。再者， 也可事先將主藥細粒與甜味細粒等其他的細粒混合之後， 再添加前㈣料劑卡普(CARpM。χ，上㈣劑的製造 反應圖，如第1-4圖所示。 【實施例】 實施例1In the case of hydr〇Chl〇ride), it is preferred to add it in two portions. More preferably, after the addition of the mixture of the fragrance and the (4) mixture (referred to as "CARP"), the aforementioned suspension agent CARP is added. Furthermore, it is also possible to mix the main drug fine particles with other fine particles such as sweet fine particles in advance, and then add the production reaction chart of the former (four) agent Kappa (CARpM. χ, the upper (four) agent, such as the first 1-4 Figure 1. Example 1
(1)主藥細粒及甜味細粒的製造 主藥細粒係將如下* 所示的成分，以發明專利文獻 (W02005/039538)記載的太、土 赞月哥 ϋ 方法，亦即依據第1及2圖的反 應圖來製造。再者’甜味 載的方法製造。 …、健自上述制專利文獻記 22 201004625(1) Manufacture of main drug fine granules and sweet granules The main granules of the main drug are as follows, and the ingredients shown in the following patents are described in the patent document (W02005/039538). The reaction diagrams of Figures 1 and 2 are manufactured. Furthermore, it is manufactured by the method of sweetness. ..., from the above-mentioned patent documents 22 201004625
【表2】 中間製品及其原料 組成(mg) 鹽酸頭孢卡品醋（cefcapene 100.0 pivoxil hydrochloride) 低取代性羥丙基纖維素 (L-HPC) 115.0 硬化油 140.0 還原麥芽糖水飴（阿瑪路德 132.0 (巧时代商標名）)MR100) D-甘露糖醇 55.0 硬脂酸鎂 18.0 總計 560.0 mg 甜味細粒 阿斯巴甜 13.4 D-甘露糖醇 182.9 木糖醇 194.9 經丙基纖維素 19.5 CZ -化殿粉 7.8 總計418.5 mg 香油卡普(CARP)散 香料 1.0 含水二氧化矽 6.0 總計7.0 mg 三氧化二鐵五倍散 三氧化二鐵 0.7 玉米澱粉 2.8 總計3.5 mg (2)添加含水二氧化矽或月桂基硫酸鈉之細粒劑的製造 23 201004625 預先根據前述的表1處理性狀為粉體的月桂基硫酸 鈉。具體而言，使用ZM 200型超離心粉碎機，將月桂基硫 酸鈉粉碎成50%平均粒徑為50 μιη以下（篩目：1 mm，旋 轉數：低速）之混合用細粒。接下來如表3所示，利用月 桂基硫酸鈉之該混合用細粒與含水二氧化矽製造懸浮劑卡 普（CARP)散，與將經秤重之定量懸浮劑卡普（CARP)散之主 藥細粒進行袋混合之後，製造為了與甜味細粒、香油卡普 (CARP)散及三氧化二鐵五倍散及其他進行袋混合的細粒。 【表3】 中間製品或原料 組成量(mg) 實施例1 比較例1 比較例2 主藥細粒 560.0 560.0 560.0 甜味細粒 418.5 429.5 424.5 香油卡普(CARP)散 7.0 7.0 7.0 三氧化二鐵五倍散 3.5 3.5 3.5 含水二氧化矽 5.0 - 5.0 月桂基硫酸鈉 5.0 - - 天然草莓 1.0 - - 合計 1000.0 1000.0 1000.0 又，在表3的記載中，另外配製無天然草莓及懸浮劑 卡普(CARP)散及無天然草莓及月桂基硫酸鈉的物質，分別 為比較例1及2。 實施例4-6及參考例2-3 性狀為液體或蠟狀。預先根據表1之記載處理界面活 24 201004625 性劑作為界面活性劑混合用細粒。接下來根據下文中的表 4，將其與疋量之主藥細粒進行袋混合之後，製造為了與甜 味細粒、香油卡普（CARP)散及三氧化二鐵五倍散及其他進 行袋混合的細粒。 【表4】 中間製品或原料 組成量(mg) 參考例編號 實施例編號 2 3 4 5 6 主藥細粒 —------------------------.···.· ............ 560.0 560.0 560.0 560.0 560.0 甜味細粒 424.5 423.5 419.5 419.5 419.5 香油卡普(CA:K^^ 7.0 7.0 7.0 7.0 7.0 二氧化二鐵五倍散 .......................... 3.5 3.5 3.5 3.5 3.5 界面劑混合用細粒 Ϊ乙氧 ............ 5.0 多乙氧基醚60 5.0 聚氧乙烯40單硬脂酸酯 5.0 系氧乙烯硬化蓖麻油而 5.0 聚氡乙嬅嬅 (30)二醇 5.0 含水二氧化石夕 5.0 5.0 5.0 5.0 5.0 天然草莓 1.0 1.0 1.0 1.0 1.0 合計 匕 1000.0 1000.0 1000.0 1000.0 1000.0 試驗例1 水懸浮性的評估 關於本發明之細粒劑，製造後立即於水中進行懸浮性 25 201004625 試驗。試驗為在50 mL的燒杯中置入3〇 mL之純水，於其 中投入約0.5 g之實施例細粒劑，藉由目視確認該該細粒劑 的沈降性。結果顯示於表5 (緊接著）。 實驗例2水懸浮性的安定性評估 關於本發明之細粒劑，置於温度4〇t/濕度75%之環 境下實施歷時安定性評估。於2週後藉由與上述試驗例相 同的方法進行水中的懸浮性試験，結果顯示於表5中。[Table 2] Intermediate product and its raw material composition (mg) Cefcapene hydrochloride vinegar (cefcapene 100.0 pivoxil hydrochloride) Low-substituted hydroxypropyl cellulose (L-HPC) 115.0 Hardened oil 140.0 Reduced maltose leeches (Amar Luther 132.0 (Qiao Times brand name)) MR100) D-mannitol 55.0 Magnesium stearate 18.0 Total 560.0 mg Sweet fine grain Aspartame 13.4 D-mannitol 182.9 Xylitol 194.9 Propyl cellulose 19.5 CZ - Huadian powder 7.8 Total 418.5 mg sesame oil cappuccino (CARP) loose spice 1.0 aqueous cerium oxide 6.0 total 7.0 mg ferric oxide five times scattered ferric oxide 0.7 corn starch 2.8 total 3.5 mg (2) adding aqueous cerium oxide Or the production of fine granules of sodium lauryl sulfate 23 201004625 The sodium lauryl sulfate which is a powder is treated in advance according to the above Table 1. Specifically, sodium lauryl sulfate was pulverized into a mixed fine particle having a 50% average particle diameter of 50 μm or less (mesh: 1 mm, number of revolutions: low speed) using a ZM 200 ultracentrifugation pulverizer. Next, as shown in Table 3, the mixed fine particles of sodium lauryl sulfate and the aqueous cerium oxide are used to prepare a suspension agent (CARP) dispersion, and the weighed quantitative suspension agent (CARP) is dispersed. After the main drug fine particles are mixed in a bag, fine particles are prepared for mixing with sweet fine particles, sesame oil (CARP) powder, and ferric oxide five times and other bags. [Table 3] Intermediate product or raw material composition amount (mg) Example 1 Comparative Example 1 Comparative Example 2 Main drug fine particles 560.0 560.0 560.0 Sweet fine particles 418.5 429.5 424.5 Sweet oil cappuccino (CARP) dispersion 7.0 7.0 7.0 Ferric oxide Five times the dispersion 3.5 3.5 3.5 Aqueous cerium oxide 5.0 - 5.0 Sodium lauryl sulfate 5.0 - - Natural strawberry 1.0 - - Total 1000.0 1000.0 1000.0 Also, in the description of Table 3, there is no additional natural strawberry and suspension agent (CARP) The materials which were scattered and free of natural strawberry and sodium lauryl sulfate were Comparative Examples 1 and 2, respectively. The properties of Examples 4-6 and Reference Examples 2-3 were liquid or waxy. The interface was treated in advance according to the description in Table 1. 24 201004625 The agent was used as a surfactant-mixing fine particle. Next, according to Table 4 below, it is mixed with the amount of the main drug fine particles, and then made to be mixed with sweet fine particles, sesame oil (CARP) and ferric oxide five times and others. The bag is mixed with fine particles. [Table 4] Intermediate product or raw material composition amount (mg) Reference example No. Example No. 2 3 4 5 6 Main drug fine particles ----------------------- ---.···.· ............ 560.0 560.0 560.0 560.0 560.0 Sweet granules 424.5 423.5 419.5 419.5 419.5 香油卡普 (CA:K^^ 7.0 7.0 7.0 7.0 7.0 II Five times the oxidation of iron oxide.................... 3.5 3.5 3.5 3.5 3.5 Interfacial agent mixing with fine particles Ϊ ethoxy... ........ 5.0 Polysorbate 60 5.0 Polyoxyethylene 40 Monostearate 5.0 Oxygen Ethylene Hardened Castor Oil 5.0 Polyethylene Ethylene (30) Glycol 5.0 Aqueous Oxygen Dioxide 5.0 5.0 5.0 5.0 5.0 Natural Strawberry 1.0 1.0 1.0 1.0 1.0 Total 匕1000.0 1000.0 1000.0 1000.0 1000.0 Test Example 1 Evaluation of water suspensibility The fine granules of the present invention are suspended in water immediately after manufacture. 25 201004625 Test. 3 mL of pure water was placed in a 50 mL beaker, and about 0.5 g of the example fine granules were placed therein, and the sedimentation property of the fine granules was visually confirmed. The results are shown in Table 5 (immediately). Experimental example 2 water Evaluation of Suspension Stability The fine granules of the present invention were subjected to a diachronic stability evaluation in an environment of a temperature of 4 〇t / humidity of 75%. After 2 weeks, suspension in water was carried out by the same method as the above test example. The test results are shown in Table 5.
【表5】【table 5】
本發明的細粒劑：添加劑 水中的懸浮性 立即 2週後 比較例1.無界面活性劑及含水二 氧化矽（無懸浮劑卡普(CARP)散） X X 比較例2 .僅有含水二氧化石夕 〇 △ 實施例1 .月桂基硫酸鈉 〇 〇 參考例2 ·多乙氧基醚§ 〇 〇 〇 參考例3 ·多乙氧基醚6〇 〇 〇 實施例4 .聚氧乙稀4〇單硬脂酸酯 〇 〇 貫施例5 · 1乳乙稀硬化乾麻油6〇 〇 〇 實施例6 ·聚氡乙烯（16〇)聚氧丙烯 (30)二酵 〇 〇 〇：快速沈降 △:雖然有沈，但水面上殘留粒子 X :未沈降 在未含有懸浮劑卡普（CARP)散之細粒劑置於水中的 26 201004625 情況下’無法在水中懸浮’未沈降。然而，其他的細粒劍 在製造直後立即置於水中，皆被判斷為快速地沈降。再者， 在置於温度40°C/相對濕度75%的環境下評估歷時安定性 的之情況下，僅有含水二氧化石夕的細粒劑被判斷為整時懸 浮性不良’其他的細粒劑則未被判斷出特別的懸浮性變化。 試驗例3 有效成分的安定性評估 鹽酸頭孢卡品酯（cefcapene pivoxil hydrochloride)的情 況下，已有報告提及經由聚乙二醇類之添加，促進朝向反 式異構物、類似物的分解。因此’藉由上述的試驗例2，進 行反式異構物、類似物之產生量的追蹤。 在温度40°C、相對濕度75%的環境下經過2週之後， 添加相當於10 mg之鹽酸頭抱卡品醋（cefcapene pivoxil hydrochloride)(力價）之量的甲醇lmL振盪混合之後，添 加約25 mL之水/曱醇混合液（1 : 1)進行1〇分鐘的激烈 浸透，再添加水/甲醇之混合液（1 : 1 )，取精埃量50 mL， 使讓液經過孔徑0.45 μιη之膜過濾器過濾。去除5 mL以上 之初始流出物，以後來的流出物作為試料溶液。 HPLC的條件如下文所述。 •檢測器：紫外光吸光光度計（測定波長：265 nm)。 •管柱：内徑4.6 mm、長度15 cm之不銹鋼管中充填5 μπι 之液相層析用十八烷基甲矽烷基化矽膠。 •管柱：約20°C之一定温度。 •移動相A :將5.99 g之磷酸二氫鉀溶於水至11〇〇 mL。 於該溶液中，添加1.89 g之四正戊基溴化銨溶於曱醇之 27 201004625 1000 mL 溶液。 •移動相B :甲醇/水之溶液（22 : 3)。 •移動相之送液：在注入試料後20分鐘，進行移動相A/ 移動相B之混合液（49 : 11)送液，接下來20分鐘的送液 係增加移動相B之比例，直至移動相A與移動相B的混合 比為1 : 1為止。再者，接下來的10分鐘係進行移動相A /移動相B之混合液（1 : 1)的送液。 •流量：每分鐘0.8 mL。 •面積測定範囲：頭孢卡品新戊醯氧甲酯之滯留時間的約 2.5倍之範圍。 •注入量：30 μίν。 經過2週後之類似物的總量值顯示於圖5中。在使用 聚氧乙烯40單硬脂酸酯、聚氧乙烯硬化蓖麻油60及聚氧 乙烯（160)聚氧丙烯(30)二醇等熔點為30°C以上的界面活性 劑之情況下，與對照組相較，確認安定性並不遜色。 使用熔點為30°C以上之界面活性劑，經由將香油卡普 (CARP)散與界面活性劑之混合物，與鹽酸頭孢卡品酯 (cefcapenepivoxil hydrochloride)細粒混合，製造實施例 7-9 之製劑。又，比較例3為未添加界面活性劑之製劑，比較 例4及5為使用熔點未達30°C之界面活性劑的製劑。 28 201004625 【表6】 原料 組成量（mg) 比較例 5 實施例 7 實施例 8 實施例 9 比較例 3 比較例 4 主藥細粒13 560.0 560.0 560.0 560.0 560.0 560.0 香油卡普 (CARP)散 7.0 7.0 7.0 7.0 7.0 7.0 聚乙二醇 (Macrogol) 400” 5.0 聚山梨糖醇酯 8011 5.0 聚氧乙烯(40) 單硬脂酸酯#2 5.0 聚氧乙烯硬化 蓖麻油60#2 5.0 聚氧乙烯 (160)聚氧丙 烯(30)二醇u 5.0 合計（mg) 567.0 572.0 572.0 572.0 572.0 572.0 * 1 :熔點未達30°C之界面活性劑（在室温下為液體） *2 :熔點為30°C以上之界面活性劑 29 1 3 ··鹽酸頭孢卡品醋（cefcapene pivoxil hydrochloride)細粒 使該製劑經過歷時保存之後（40°C、相對濕度75%、 2週），經由上述方法測定鹽酸頭抱卡品醋（cefcapene pivoxil 201004625 hydrochloride)的類似物，其結果顯示於表7中。又，實驗 開始之最初類似物質量為總共1.97%。 【表7】 細粒劑 (製劑編號：使用之界面活性劑） 類似物量 保存期甸 0週 2週 比較例3 :無界面活性劑 1.97 比較例4 :聚乙二醇(Macrogol) 400 (在室温下為液體） 1.97 4矿 比較例5 :多乙氧基醚80 (在室温下為液體） 1.97 實施例7 :聚氧乙烯（40)單硬脂酸酯 (熔點 30-34°C ) 1.97 實施例8 :聚氧乙烯硬化蓖麻油60 (熔點 39-44°C ) 1.97 2.23~ 實施例9 :聚氧乙烯（160)聚氧丙烯（30) 二醇（熔點 46-56°C ) 1.97 2.20_ 由表7的結果，熔點未達30°C之界面活性劑（聚乙二 醇(Macrogol) 400，聚山梨糖醇酯80)係在2週以後產生3 %以上的類似物，而熔點為30°C以上之界面活性劑係分別 未達3%，類似物的產生量較少。因此，在使用熔點30°C 以上之界面活性劑與二氧化矽的情況下，明確地可抑制保 存期間中的鹽酸頭孢卡品醋（cefcapene pivoxil hydrochloride)之類似物的產生，且可改善水分散性。 再者，接下來，使用月桂基硫酸鈉（熔點30°C以上） 30 201004625 作為界面活性_結果顯示於表8。 【表8】 細粒劑Fine granule of the present invention: Suspension of additive in water immediately after 2 weeks Comparative Example 1. No surfactant and aqueous cerium oxide (no suspension agent (CARP) dispersion) XX Comparative Example 2: only aqueous oxidizing Shi Xiyu △ Example 1. Sodium lauryl sulfate 〇〇 Reference Example 2 · Polysorbate § 〇〇〇 Reference Example 3 · Polysorbate 6 〇〇〇 Example 4. Polyoxyethylene 4 〇 Monostearate 施 施 5 5 · · 乳 乳 乳 乳 乳 乳 〇〇〇 〇〇〇 〇〇〇 · · · · · · · · · · · · · · · · · · · · · · · · · · · · Although there is sedimentation, the residual particles on the water surface X: not settled in the case of 26 201004625, which does not contain the suspension agent (CARP) scattered fine granules placed in water, 'cannot be suspended in water' does not settle. However, other fine-grained swords were placed in the water immediately after being manufactured, and were judged to settle quickly. Further, in the case where the stability was evaluated in an environment of a temperature of 40 ° C / a relative humidity of 75%, only the fine granules containing the aqueous hydrated oxidized stone were judged to be poor in suspension at all times. The granules were not judged to have a particular suspension change. Test Example 3 Evaluation of the stability of the active ingredient In the case of cefcapene pivoxil hydrochloride, it has been reported that the addition of polyethylene glycols promotes the decomposition toward the trans isomers and the like. Therefore, the amount of production of the trans isomer and the analog was traced by the above Test Example 2. After 2 weeks in an environment of a temperature of 40 ° C and a relative humidity of 75%, 1 mL of methanol equivalent to 10 mg of cefcapene pivoxil hydrochloride was added and shaken, and then added. 25 mL of water/sterol mixture (1:1) for 1 minute of intense soaking, add water/methanol mixture (1:1), take a volume of 50 mL, and let the solution pass through a pore size of 0.45 μm. The membrane filter is filtered. More than 5 mL of the initial effluent was removed, and the subsequent effluent was used as a sample solution. The conditions of the HPLC are as follows. • Detector: UV spectrophotometer (measuring wavelength: 265 nm). • Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is filled with 5 μπι of liquid chromatography using octadecylformamidine alkylate. • Column: a certain temperature of about 20 °C. • Mobile phase A: Dissolve 5.99 g of potassium dihydrogen phosphate in water to 11 〇〇 mL. To this solution, 1.89 g of tetra-n-pentylammonium bromide was dissolved in sterol 27 201004625 1000 mL solution. • Mobile phase B: methanol/water solution (22: 3). • Liquid phase feeding: 20 minutes after the sample is injected, the mobile phase A/mobile phase B mixture (49:11) is fed, and the next 20 minutes is added to the mobile phase B until the movement The mixing ratio of phase A to mobile phase B is 1:1. Further, the liquid supply of the mixed liquid (1:1) of the mobile phase A/mobile phase B was carried out for the next 10 minutes. • Flow: 0.8 mL per minute. • Area measurement: A range of about 2.5 times the residence time of cefacazole neopentyloxymethyl ester. • Injection volume: 30 μίν. The total amount of the analog after 2 weeks was shown in Fig. 5. In the case of using a surfactant having a melting point of 30 ° C or higher, such as polyoxyethylene 40 monostearate, polyoxyethylene hardened castor oil 60, and polyoxyethylene (160) polyoxypropylene (30) diol, Compared with the control group, it was confirmed that the stability was not inferior. The preparation of Examples 7-9 was prepared by using a surfactant having a melting point of 30 ° C or higher, by mixing a mixture of sesame oil (CARP) and a surfactant, with fine particles of cefcapenepivoxil hydrochloride. . Further, Comparative Example 3 is a preparation in which no surfactant is added, and Comparative Examples 4 and 5 are preparations using a surfactant having a melting point of less than 30 °C. 28 201004625 [Table 6] Raw material composition amount (mg) Comparative Example 5 Example 7 Example 8 Example 9 Comparative Example 3 Comparative Example 4 Main drug fine particles 13 560.0 560.0 560.0 560.0 560.0 560.0 香油卡普(CARP)散7.0 7.0 7.0 7.0 7.0 7.0 Polyethylene glycol (Macrogol) 400" 5.0 Polysorbate 8011 5.0 Polyoxyethylene (40) Monostearate #2 5.0 Polyoxyethylene hardened castor oil 60#2 5.0 Polyoxyethylene (160 Polyoxypropylene (30) diol u 5.0 Total (mg) 567.0 572.0 572.0 572.0 572.0 572.0 * 1 : Surfactant having a melting point of less than 30 ° C (liquid at room temperature) *2 : Melting point of 30 ° C or higher Surfactant 29 1 3 ··cefcapene pivoxil hydrochloride fine granules After the preparation has been preserved for a while (40 ° C, relative humidity 75%, 2 weeks), the hydrochloric acid head holding card is determined by the above method The analog of vinegar (cefcapene pivoxil 201004625 hydrochloride), the results are shown in Table 7. In addition, the initial analog mass at the beginning of the experiment was 1.97% in total. [Table 7] Fine granules (formulation number: interface used) The amount of the analog was preserved during the period of 0 weeks and 2 weeks. Comparative Example 3: No surfactant 1.97 Comparative Example 4: Polyglycol (Macrogol) 400 (Liquid at room temperature) 1.97 4 Mine Comparative Example 5: Polyethoxylate Ether 80 (liquid at room temperature) 1.97 Example 7: Polyoxyethylene (40) monostearate (melting point 30-34 ° C) 1.97 Example 8: Polyoxyethylene hardened castor oil 60 (melting point 39- 44 ° C) 1.97 2.23~ Example 9: Polyoxyethylene (160) polyoxypropylene (30) diol (melting point 46-56 ° C) 1.97 2.20_ From the results of Table 7, the melting point is less than 30 ° C interface The active agent (Macrogol 400, polysorbate 80) produced more than 3% of the analog after 2 weeks, and the surfactants having a melting point of 30 ° C or higher were less than 3%, respectively. The amount of the analog produced is small. Therefore, in the case of using a surfactant having a melting point of 30 ° C or more and ceria, the analog of cefcapene pivoxil hydrochloride in the storage period can be suppressed remarkably. Produced and improved water dispersibility. Further, next, sodium lauryl sulfate (melting point: 30 ° C or more) 30 201004625 was used as the interface activity. The results are shown in Table 8. [Table 8] Fine granules
乳化石夕及界面活性劑之添力口 皆未添加Emulsified Shixia and the addition of surfactants are not added
僅添加二氧化碎 實施例1 添加二氧化矽及月桂基硫酸鈉 保存期間 0週 L55 1.57 1.51 2週 L72 1.73 1.75 對於上述的比較例1及2及實施例1之細粒劑，進行 與上述相同的試驗。製劑化後立即進行試驗（0週）的類似 物量係在1.51-1.57%的範圍内，在溫度4〇°C、相對濕度75 %之條件下保存2週間’個別的製劑中之類似物的生成極Only the oxidized granules were added. Example 1 The addition of cerium oxide and sodium lauryl sulfate was carried out for 0 weeks. L55 1.57 1.51 2 weeks L72 1.73 1.75 The fine granules of the above Comparative Examples 1 and 2 and Example 1 were subjected to the same as above. Test. Immediately after the formulation, the amount of the analog (0 week) was in the range of 1.51 to 1.57%, and the preparation of the analog in the individual preparation was carried out for 2 weeks at a temperature of 4 ° C and a relative humidity of 75%. pole
少。 再者’本發明之製劑與比較例1相較，亦減輕由於靜 電產生之對容器的靜電附着性。 【產業上的利用可能性】 根攄本發明，提供可容易地懸浮於水中地服用之細粒 劑。因亦未破壞經由疏水性包衣膜遮掩有效成分之令人不 悅的味道之效果下，本發明之細粒劑係特别適用於幼兒用 製劑。 【圖武簡草說明】 31 201004625 第1圖為含有鹽酸頭孢卡品酯（cefcapene pivoxil hydrochloride)之主藥細粒製劑的製造步驟（1); 第2圖為含有鹽酸頭孢卡品S旨（cefcapene pivoxil hydrochloride)之主藥細粒製劑的製造步驟（2); 第3圖為懸浮劑杯散的製造步驟； 第4圖為懸浮劑杯散及細粒劑的混合步驟； 第5圖為在温度40°C/濕度75%之環境下2週後生成 的類似物之總量。 【主要元件符號說明】 ® 無less. Further, the preparation of the present invention also reduced the electrostatic adhesion to the container due to static electricity as compared with Comparative Example 1. [Industrial Applicability] According to the present invention, a fine granule which can be easily suspended in water is provided. The fine granules of the present invention are particularly suitable for use in infant preparations because they do not impair the unpleasant taste of the active ingredient by the hydrophobic coating film. [Description of the martial arts] 31 201004625 The first picture shows the manufacturing steps (1) of the main drug fine granule preparation containing cefcapene pivoxil hydrochloride; the second picture shows the cefcapene containing cefcarpine hydrochloride Pivoxil hydrochloride) manufacturing step of the main drug fine particle preparation (2); Fig. 3 is a manufacturing step of the suspension agent cup dispersion; Fig. 4 is a mixing step of the suspension agent cup powder and the fine particle agent; Fig. 5 is a temperature mixing step; The total amount of analogs formed after 2 weeks in an environment of 40 ° C / humidity 75%. [Main component symbol description] ® None
3232
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008098204A JP2011153075A (en) | 2008-04-04 | 2008-04-04 | Fine granule having improved suspension performance in water |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201004625A true TW201004625A (en) | 2010-02-01 |
| TWI426913B TWI426913B (en) | 2014-02-21 |
Family
ID=41135667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW098110613A TWI426913B (en) | 2008-04-04 | 2009-03-31 | A fine grain agent having improved water-suspensibility |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2011153075A (en) |
| KR (1) | KR101343283B1 (en) |
| CN (1) | CN102056610B (en) |
| RU (1) | RU2488396C2 (en) |
| TW (1) | TWI426913B (en) |
| WO (1) | WO2009123304A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756906B (en) * | 2009-11-02 | 2011-11-16 | 严洁 | Pharmaceutical composition of cefcapene pivoxil hydrochloride granules and preparation method thereof |
| JP6192919B2 (en) * | 2012-11-02 | 2017-09-06 | Ntn株式会社 | In-wheel motor drive device |
| JP6196730B2 (en) * | 2014-03-31 | 2017-09-13 | 富山化学工業株式会社 | Granular solid preparation containing cephalosporin ester and method for producing the same |
| CN113423570A (en) * | 2019-02-22 | 2021-09-21 | 大金工业株式会社 | Laminated body |
| CN110974803B (en) * | 2019-12-31 | 2022-03-11 | 山东罗欣药业集团股份有限公司 | Cefcapene pivoxil hydrochloride granules and preparation method thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07242568A (en) * | 1994-03-04 | 1995-09-19 | Eisai Co Ltd | Pharmaceutical preparation for masking bitterness |
| AU2001290239A1 (en) * | 2000-09-19 | 2002-04-02 | Daiichi Pharmaceutical Co., Ltd. | Medicinal composition |
| JP3981134B2 (en) * | 2003-10-29 | 2007-09-26 | 塩野義製薬株式会社 | Method for producing coated preparation with improved unpleasant taste |
| JP4945108B2 (en) * | 2004-09-24 | 2012-06-06 | 興和株式会社 | Isosorbide preparation |
| JP2007211006A (en) * | 2006-01-16 | 2007-08-23 | Ono Pharmaceut Co Ltd | Coated solid preparation having elution stability |
| JP2007197375A (en) * | 2006-01-27 | 2007-08-09 | Pfizer Japan Inc | Composition comprising azithromycins as active ingredient and having antistatic action |
-
2008
- 2008-04-04 JP JP2008098204A patent/JP2011153075A/en active Pending
-
2009
- 2009-03-31 TW TW098110613A patent/TWI426913B/en not_active IP Right Cessation
- 2009-04-03 CN CN2009801207603A patent/CN102056610B/en active Active
- 2009-04-03 KR KR1020107024757A patent/KR101343283B1/en active IP Right Grant
- 2009-04-03 WO PCT/JP2009/056942 patent/WO2009123304A1/en active Application Filing
- 2009-04-03 RU RU2010145148/15A patent/RU2488396C2/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN102056610B (en) | 2013-07-17 |
| CN102056610A (en) | 2011-05-11 |
| RU2488396C2 (en) | 2013-07-27 |
| TWI426913B (en) | 2014-02-21 |
| KR20110003357A (en) | 2011-01-11 |
| WO2009123304A1 (en) | 2009-10-08 |
| KR101343283B1 (en) | 2013-12-18 |
| JP2011153075A (en) | 2011-08-11 |
| RU2010145148A (en) | 2012-05-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5315056B2 (en) | Anti-caking granular formulation | |
| JP5202856B2 (en) | Granular solid formulation containing tosfloxacin tosylate | |
| KR101551506B1 (en) | Medical composition containing rebamipide | |
| WO2011110939A2 (en) | Pharmaceutical compositions of substituted benzhydrylpiperazines | |
| EP3862318A1 (en) | Porous silica particle composition | |
| WO2007011018A1 (en) | Rapidly disintegratable oral tablet | |
| TW201004625A (en) | A fine grain agent having improved water-suspensibility | |
| JPH0717866A (en) | Medicinal composition | |
| MXPA06001481A (en) | Dry syrup containing loratadine. | |
| JP4853818B2 (en) | Solid formulation containing ibuprofen and ambroxol hydrochloride | |
| JP2005132801A (en) | Orally disintegrable tablet | |
| JP4131747B2 (en) | Manistol-containing cilostazol orally disintegrating powder | |
| EP2046337B1 (en) | Solid forms containing meloxicam with improved buccal taste and process for their preparation | |
| JP3981134B2 (en) | Method for producing coated preparation with improved unpleasant taste | |
| JP4336380B1 (en) | Fine granules with improved water suspension | |
| CN107625734B (en) | Water-free swallow taste masking preparation and preparation method thereof | |
| CN1311831C (en) | Antibacterial medicinal composition of enhanced oral absorptivity | |
| JP4731941B2 (en) | Oral formulation particles | |
| KR20140076998A (en) | Bitter taste masked pharmaceutical formulation comprising esomeprazole free base or alkali salt thereof and preparation method thereof | |
| KR102149080B1 (en) | Orally Disintegrating Tablet comprising sugar or sugar alcohol granules reformed with ethyl cellulose | |
| KR101501889B1 (en) | Orally disintegrating tablet containing low-dose ramosetron | |
| JP3995202B2 (en) | Turmeric composition for oral use | |
| JP2005053792A (en) | Compression-molded preparation and method for producing the same | |
| JP2005139086A (en) | Quick-disintegration preparation | |
| JP5186159B2 (en) | Fenofibrate-containing composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |