200824710 九、發明說明： 【發明所屬之技術領域】 本發明係關於-種減少對消化管具有刺激性之藥物的刺 激性之經口固形組合物。 【先前技術】 並不限於非類固醇抗炎藥、抗生素、氯化鉀等醫療用醫 藥品’於精神神經用藥、消化器官用藥、循環器官/灰Z 用藥、呼吸器官用藥、泌尿生殖器官及肛門用藥、滋養強 壯保健藥、女性用藥、過敏用藥、禁煙辅助劑、中藥/生 藥製劑等之普通用醫藥品中，多少具有對消化管之刺激 性。由於其刺激性，若服用醫藥品，則經常會出現胃部不 適感、噁心/嘔吐、食慾不振等消化器官症狀之副作用。 進而，於非類固醇消炎藥等對消化管的刺激性為特別強之 藥物中，有時亦會產生胃黏膜出血或形成潰瘍等嚴重的消 化器官症狀之副作用。因此，難以繼續服用醫藥品，有時 亦會造成無法進行疾病治療。 為了減少醫藥品對消化管之刺激性，而採取飯後服用等 措施，但僅藉由上述措施經常效果並不理想，因而業者提 出有於同一製劑中同時調配入碳酸鎂（專利文獻1}、氫氧化 鎂（專利文獻2)、胺基乙酸（專利文獻3)等制酸劑；或者同 時調配入Hz阻斷劑（專利文獻4)或質子泵抑制劑（專利文獻 5) ;或者調配入 tiquizilim bromide 或 butylsc〇p〇lamine bromide等具有消化管活動亢進作用之抑制劑（專利文獻 6) ;或者調配入柴胡桂枝湯萃取物（專利文獻7)之方法。 125849.doc 200824710 又，作為減輕對消化管的刺激性之製劑性方法，係藉由施 加腸溶性被膜（專利文獻8、9)而防止對胃的刺激性。 [專利文獻1]日本專利特開昭63-198620號公報 [專利文獻2]日本專利特開2〇〇2_2558〇2號公報 • [專利文獻3]日本專利特開2004-123712號公報 、 [專利文獻4]曰本專利特開平5-246853號公報 [專利文獻5]日本專利特開2〇〇5_145894號公報 [專利文獻6]曰本專利特開2〇〇4_2454號公報 _ [專利文獻7]曰本專利特開平8-208465號公報 [專利文獻8]日本專利特開平6_293635號公報 [專利文獻9]曰本專利特開平8_1〇9126號公報 【發明内容】 [發明所欲解決之問題] 然而，同時調配入制酸劑等其他醫藥成分之方法，則有 產生調配變化、效果不理想之情形，存在成本提高、製劑 φ 本身變大而難以服用等缺點，並非具有可適應各種藥物的 通用性者。又，腸溶性製劑，雖然可減少對胃的刺激性， 但亦存在腸溶性被膜材料的自身價袼較高、包覆皮膜之製 . 造步驟自身的成本較高等缺點，進而，直至醫藥品溶解被 • 吸收而發揮效果之延遲時間變長，無法製成如服用後立即 表現效果之速釋性製劑。就該等方面而言，難以將為了減 少對月的刺激性而施加腸溶性被膜而製成腸溶性製劑之方 法，應用於大部分的一般的普通速釋性醫藥品。 因此’本發明之目的在於提供—種可適⑽各種藥物的 125849.doc 200824710 '、 製七丨可猎由簡單的製造方法而廉價地製造且減少 對/肖化官的刺激性之經口固形製劑。 [解決問題之技術手段] 本發明者們研究了各種防止具有對消化管的刺激性之藥 人的肖化吕刺激之方法，結果發現，若經口投與利用水或 3水醇將具有對消化管的刺激性之藥物與水膨潤性高分子 ' 〆'、、、弋迈粒而獲得之經口固形組合物，則出乎意料地抑[Technical Field] The present invention relates to an oral solid composition which is irritating to a drug which is irritating to a digestive tract. [Prior Art] It is not limited to medical drugs such as non-steroidal anti-inflammatory drugs, antibiotics, and potassium chloride. It is used in psychotropic drugs, digestive organs, circulatory organs/grey Z drugs, respiratory organs, genitourinary organs, and anal drugs. How many of the common pharmaceutical products such as nourishing strong health medicine, female medicine, allergy medicine, no smoking adjuvant, Chinese medicine/green medicine preparation have irritating to the digestive tract. Due to its irritating properties, if you take medicines, you will often have side effects such as stomach discomfort, nausea/vomiting, and loss of appetite. Further, among drugs which are particularly irritating to the digestive tract such as non-steroidal anti-inflammatory drugs, there are cases in which gastric mucosal hemorrhage or ulceration causes serious symptoms of digestive organs such as ulcers. Therefore, it is difficult to continue taking medicines, and sometimes it is impossible to treat diseases. In order to reduce the irritating effect of the drug on the digestive tract, and taking measures such as taking it after meals, but the above measures are often not effective, the manufacturer proposes to simultaneously mix magnesium carbonate into the same preparation (Patent Document 1), An antacid such as magnesium hydroxide (Patent Document 2) or aminoacetic acid (Patent Document 3); or a Hz blocker (Patent Document 4) or a proton pump inhibitor (Patent Document 5); or a tiquizilim An inhibitor of mitochondrial hyperactivity such as bromide or butylsc〇p〇lamine bromide (Patent Document 6); or a method of blending into Chaihu Guizhi Decoction (Patent Document 7) 125849.doc 200824710 The irritating method of the tube is to prevent irritation to the stomach by applying an enteric film (Patent Documents 8 and 9). [Patent Document 1] Japanese Patent Laid-Open Publication No. SHO63-198620 [Patent Document 2] [Patent Document 3] Japanese Patent Laid-Open Publication No. 2004-123712, [Patent Document 4] Japanese Patent Laid-Open No. Hei 5-246853 (Patent Literature) Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. [Patent Document 9] Japanese Laid-Open Patent Publication No. Hei 8 No. Hei 9 126 [Invention] [Problems to be Solved by the Invention] However, a method of simultaneously blending other pharmaceutical ingredients such as an antacid is In the case of a change in the formulation and an unsatisfactory effect, there is a disadvantage that the cost is increased, the preparation φ itself becomes large and difficult to take, and the like, and it is not suitable for the versatility of various drugs. Further, the enteric preparation can reduce the irritation to the stomach. However, there are also disadvantages such as a high price of the enteric film material, a coating film, a high cost of the process itself, and a delay in the effect of the drug being dissolved and absorbed. It is an immediate release preparation which exhibits an effect immediately after administration. In these respects, it is difficult to apply an enteric coating to reduce the irritation to the moon to prepare an enteric preparation. The method is applied to most common general-purpose immediate-release medicines. Therefore, the object of the present invention is to provide a suitable and suitable (10) various drugs for 125849.doc 200824710 ', and the system can be hunted by a simple manufacturing method and is inexpensive. The present invention has been developed to improve the irritating effect of the stimuli of the gastrointestinal tract. As a result, it was found that if the oral solid composition obtained by using a drug which is irritating to the digestive tract and a water-swelling polymer '〆', 弋, 弋 粒 granules using water or 1,3-alcohol is used orally, Unexpectedly
制對口腔及咽喉或食道、胃等上部消化管的刺激性，從而 完成本發明。 ,二本發明係關於一種包含消化管刺激性藥物及水膨潤 I·生间分子，且利用水或含水醇進行濕式造粒而獲得之經口 固形組合物。 、工 [發明之效果] 可防止具有消化管刺激性之 本發明之經口固形組合物 藥物對消化管之刺激。 【實施方式】 以下，就本發明加以詳細說明。 本發明中所使用之所謂消化管刺激性藥物，係指如經口 服用後出現胃冑、胃部不適感、胃脹感、腹痛、腹脹感、 °惡心"區吐、食懲不振等消化器官症狀之副作用之荜物 至於消化管刺激性藥物，例如於普通用醫藥品中:、 出：感冒藥（内服）、解熱鎮痛藥、催眠鎮靜藥、睡音防: 樂、以及含有大黃之小兒鎮靜藥等被分類為精神神經用荜 之藥物；驅蟲劑等被分類為消化器官用藥之藥物，= 125849.doc 200824710 劑 劑 藥 '動，硬化用藥、以及貧血用藥等之被分類為循環器官， 液用藥之藥物；鎮咳去痰藥等被分類為呼吸器官用藥 藥物，内用痺瘡用藥等被分類為泌尿生殖器管及肛門 之藥物；以維生素A為主藥之製劑、以維生素D為主藥： 製劑、以維生素E為主藥之製劑、以維生素仏為主藥之 劑 '以維生素B2為主藥之製劑、以維生素&為主藥 剑、以維生素c為主藥之製劑、以維生素AD為主藥之掣 以維生素B2B6為主藥之製劑、以維生素叫主藥之: 以維生素BlB6B12為主藥之製劑、含維生素之保储 以蛋白質/胺基酸為主藥之製劑、以及以生藥為主率 之製劑等被分類為滋養強壯保健藥之藥物；婦科藥八 類為女性用藥之藥物；以抗組織胺藥為主藥之製劑二 類為過敏用藥之藥物、鼻炎用内服藥等被分類為耳魯科； 藥之藥物、禁煙輔助劑等被分類為禁煙輔助劑之藥物’一 陳蒿湯、溫清飲、溫膽湯、應鐘散、乙字湯、葛根紅： 湯、葛根湯、葛根湯加；丨丨弓辛夷、加味溫膽湯、加味逍2 散、档梗湯、弓歸膠艾湯、弓歸調血飲、弓歸調血飲第^ 加減、響聲破笛丸、驅風解毒散、料独湯、桂枝 藥大黃湯、桂枝获茶丸、桂枝茯荟丸料加意孩仁、^敗 毒散、甲字湯、五虎湯、牛車腎氣丸、五物解毒散、 散、柴胡加龍骨牡料、㈣桂枝乾姜湯、柴胡清肝湯、 三黃寫心湯、三棗仁湯、三物黃答湯、滋陰降火湯、:降 至寶湯、七物降下湯、四物湯、炙甘草湯、鶴鴻菜湯^ 全大補湯、潤腸湯、小承氣湯、小青龍湯、小青龍湯加石 125849.doc 200824710 膏、小青龍湯合麻杏甘石湯、消風散、辛夷清風湯、秦幾 防風湯、神秘湯、清上防風湯、折沖飲、川弓茶調散、千 金雞鳴散、疏經活血散、大黃甘草湯、大黃牡丹皮湯、大 柴胡湯、治頭瘡-方、調胃承氣湯、釣藤散、猪茶湯合四 «、通導散、桃核承氣湯、當歸飲子、#歸散、當歸苟 藥散、獨活葛根湯、獨活湯、女神散、人寨養榮湯、排腹 散、排膿湯、麥門冬湯、八味地黃丸、白虎加桂枝湯、白 虎力:人蔘湯、白虎湯、防己黃耆場、防風通聖散、麻杏甘 石湯、麻杏意甘湯、麻子仁丸、意孩仁湯、龍膽濱肝湯、 六味丸等被分類為中藥/生藥製劑之藥物。已知有該等藥 物於服用後會出現消化器官症狀的副作用，因此係消化管 刺激性藥物，對於適用於本發明而言係較好的藥物。 “醫：用醫樂品中’於内服藥中，已知有中樞神經系統用 二梢神經用藥、感覺器官用藥等被分類為神經系統及 感見盗官用藥之藥物；循環器官用藥、Μ器 :器官用藥、激素劑、泌尿生殖器及肛門用藥等被㈣： 各器官系統用醫藥品之犖铷·嫉α * 汉刀頭馬 分類為抑 Μ ::'、，、”生素劑、滋養強壯藥等被 =為代谢性醫樂品之藥物；細胞賦活㈣、腫瘤 ㈣用藥等被分類為組織細胞機能用醫藥品之藥物生 枭、中樂製劑等被分類為基於生 ’、 荜物玍杀及中樂處方之醫藥品之 .:物，抗生素製劑、化學療法劑、寄生動物用藥 為針對病原生物之醫藥品之藥物中^被 的副作用，因此被分類為該等之藥物係消見二:吕症狀 物，對於適用於本發明而言係較好的藥物。吕刺激性藥 125849.doc 200824710The present invention is accomplished by making irritation to the upper digestive tract of the mouth and throat or the esophagus, stomach, and the like. The present invention relates to a transdermal composition comprising a digestive tract irritant drug and a water swell I. interstitial molecule and wet granulation using water or an aqueous alcohol. [Effects of the Invention] The oral solid composition of the present invention having gastrointestinal irritation can be prevented from stimulating the digestive tract. [Embodiment] Hereinafter, the present invention will be described in detail. The so-called digestive tract irritating drug used in the present invention refers to a stomach sputum, a stomach discomfort, a feeling of bloating, abdominal pain, a feeling of bloating, a nausea, a vomiting, a vomiting, and the like. The side effects of digestive organ symptoms are gastrointestinal irritant drugs, for example, in general medicines: out: cold medicine (internal administration), antipyretic analgesics, hypnotic sedatives, sleep sound prevention: music, and rhubarb Pediatric sedatives are classified as drugs for mental nerves; insect repellents are classified as drugs for digestive organs, = 125849.doc 200824710 Agents for drugs, sclerotherapy, anemia, etc. are classified as Circulatory organs, drugs for liquid medication; antitussive and antispasmodic drugs classified as respiratory medicines, internal acne medications, etc. classified as urogenital tubes and anal drugs; vitamin A as the main drug preparation, with vitamin D Main drugs: preparations, preparations containing vitamin E as the main medicine, and agents based on vitamin ' as the main preparation of vitamin B2, vitamins and amp; main medicine sword, vitamin C The preparation, the vitamin AD as the main medicine, the preparation of vitamin B2B6 as the main medicine, and the vitamin as the main medicine: the preparation of vitamin B1B6B12 as the main medicine, and the preservation of vitamins with protein/amino acid as the main medicine The preparations and the preparations based on the crude drug are classified as medicines for nourishing strong health care medicines; the eight types of gynecological medicines are medicines for women; the preparations based on anti-histamine medicines are medicines for allergy medicine, Rhinitis is classified into earlure by internal medicine, medicines such as medicines, smoking-free adjuvants, etc., which are classified as non-smoking adjuvants, 'Yi Chen Hao Tang, Wen Qing Yin, Wen Dan Tang, Ying Zhong San, Yi Zi Tang, Pueraria Red: soup, puergan soup, gegen tongjia; 丨丨 bow Xinyi, Jiawei Wendan soup, Jiawei 逍2 scattered, stalk soup, bow to Jiao Ai Tang, bow to blood, drink, bow to adjust blood drink ^ increase, subtract, Sounds broken flute pill, drive wind detoxification powder, material alone soup, Guizhi medicine rhubarb soup, Guizhi won tea pills, Guizhi glutinous rice balls, add intentional child, ^ defeat poison powder, A word soup, Wuhu soup, cattle cart Kidney gas pill, Wuwu Jiedu San, San, Chaihu plus keel, (4) Guizhi Ginger Soup, Chaihu Qing Live Decoction, Sanhuang Written Decoction, Sanzao Ren Tang, Sanwu Huang Dian Decoction, Ziyin Jianghuo Decoction,: Down to Bao Tang, Qiwu Decoction, Siwu Decoction, Zhigancao Decoction, Hehong Vegetable Soup ^ Quandabu Soup, Runchang Decoction, Xiaochengqi Decoction, Xiaoqinglong Decoction, Xiaoqinglong Decoction and Stone 125849.doc 200824710 Ointment, Xiaoqinglong Decoction and Ma Xing Ganshi Decoction, Xiaofeng San, Xinyi Qingfeng Decoction, Qin Several wind-proof soup, mysterious soup, Qingshang wind-proof soup, broken red drink, Chuan bow tea, scattered, Qianjinjiming powder, Shujing Huoxue San, Dahuang licorice soup, rhubarb peony soup, Dachaihu soup, treatment of head sores - Fang, Tiaowei Chengqi Decoction, Yuteng Powder, Pork Tea Soup, Four «, Tongdaosan, Taohe Chengqi Decoction, Danggui Yinzi, #归散, Danggui Shaoyao San, Duhuo Gegen Decoction, Duhuo Tang, Female goddess, Renzhai Yangrong soup, Pai belly powder, drainage pus soup, Maimendong soup, Bawei Dihuang Wan, Baihu plus Guizhi soup, Bai Huli: human soup, white tiger soup, anti-Huang Huang Yu field, wind-proof St. San, Ma Xing Gan Shi Tang, Ma Xing Yi Gan Tang, Ma Zi Ren Wan, Yi Ni Ren Tang, Longdan Bingan Tang, Liuwei Pill, etc. are classified as traditional Chinese medicine / raw medicine preparations . These drugs are known to have side effects of digestive organ symptoms after administration, and therefore are gastrointestinal tube stimulating drugs, and are preferred drugs for use in the present invention. "Medical: in the use of medical music in the internal medicine, known as the central nervous system with the use of the two nerves, sensory organs and other drugs classified as the nervous system and drugs that sense the use of drugs; circulatory organs medication, sputum : Organ medicines, hormonal agents, genitourinary organs and anal medications (4): 器官·嫉α* for various organ systems. Han knife head horse is classified as sputum: ::,,,,,,,,,,,,,,,,, Drugs such as drugs that are classified as metabolic drugs; cells (4), tumors (4), drugs, etc., which are classified as tissue cell function drugs, are classified as raw, and stolen. The drug of the Chinese music prescription: the substance, the antibiotic preparation, the chemotherapeutic agent, and the parasitic animal drug are the side effects of the drug for the drug of the pathogenic organism, and therefore are classified as the drug system of the drug. Symptoms are preferred drugs for use in the present invention. Lu irritant medicine 125849.doc 200824710
該等之中，非類固醇消炎藥，就係除由於前列腺素合成 抑制作用之消炎作用之作用機制而導致消化管障礙以外， 直接的消化管黏膜刺激作用較強，因此特別是消化管刺激 性非常強，多數患者可獲得本發明效果之藥物之方面而 言，對於本發明係較好的藥物。至於此種非類固醇消炎藥 之具體藥物名，可舉出：乙醯氨酚、非那西汀、aluminum flufenamate、mefenamic acid、阿司匹靈、ethenzamide、 水揚酸醯胺、水揚酸鈉、異丙基安替比林、斯爾比林 (sulpyrine) 、 migrenin 、 acemetacin 、 indomethacin 、 indomethacin farnesil、馬來酸 proglumetacin、amfenac sodium、diclofenac sodium、actarit、胺普芬（alminoprofen)、 ampiroxicam、異丁 苯丙酸（ibuprofen)、etodolac、鹽酸鎮 痛新（pentazocine)、oxaprozin、可多普洛菲（ketoprofen)、 zaltoprofen、sulindac、tiaprofen、tenoxicam、nabumetone、 naproxen、piroxicam、bucolome、pranoprofen、夫比普洛 芬（flurbiprofen)、dimetotiazine mesilate、meloxicam、 mofezolac、loxoprofen Sodium、lobenzarit disodium、 lornoxicam等 0 又，強心劑、支氣管擴張劑、作為睡意防止劑之咖啡因 系藥物、以及黃嘌呤系藥物，就係直接的消化管黏膜刺激 作用較強，該等藥物以強心劑、支氣管擴張劑、睡意防止 劑為代表，被調配於解熱鎮痛劑、鼻炎用劑、複合感冒 劑、鎮咳去痰劑、鎮暈劑、強心劑、複合維生素劑、滋養 強壯劑等各種治療領域之藥劑中，服用頻率非常高，多數 125849.doc -11- 200824710 患者可獲得本發明效果之藥物之方面而言，對於本發明係 較好的藥物。至於此種咖啡因系藥物、以及黃嘌呤系藥 物，可舉出：咖#因、無水咖啡因、苯甲酸納咖啡因、胺 基菲林（aminophylline)、膽驗-茶驗、茶驗、經丙基茶鹼 等。 進而，抗組織胺藥，就係廣泛應用於鎮咳去痰劑、複合 感冒劑、鎮暈劑、催眠鎮靜藥、過敏用藥、鼻炎用劑等 中，服用頻率較高，但局部麻醉作用或黏膜刺激作用較 強，直接的消化管刺激性非常強，且調配抗組織胺藥之頻 率非常高，多數患者易於獲得本發明效果之藥物之方面而 言，對於本發明係較好的藥物。此種抗組織胺藥中，至於 消化管刺激性非常強者，可舉出：鹽酸苯海拉明、鞣酸苯 海拉明、琥拍酸杜西拉明（doxylamine succinate)、 clemastine fumarate、酒石酸 alimemazine、鹽酸普敏太定 (promethazine)、海苯酸普敏太定（promethazine hibenzate)、 mequitazine、promethazine methylenedisalicylate等。 作為本發明所使用之消化管刺激性藥物，尤其好的是異 丁苯丙酸（ibuprofen)、阿司匹靈、乙醯氨酚、乙水揚胺 (ethenzamide)、水楊酸龜胺、鹽酸苯海拉明、苯甲酸納咖 _因、無水咖啡因、咖啡因。 於本發明之固形組合物中，消化管刺激性藥物之含量， 較好的是80質量％以下，更好的是70質量％以下，尤其好 的是0.01〜60質量％。 於本發明中所謂水膨潤性高分子，係指於添加水或含水 125849.doc -12- 200824710 醇時發生膨潤且可保持大量的水或含水醇而Among these, non-steroidal anti-inflammatory drugs, in addition to the action mechanism of anti-inflammatory effects of prostaglandin synthesis inhibition, lead to gastrointestinal tract dysfunction, direct gastrointestinal tract mucosal stimulation is strong, so especially the digestive tract is very irritating It is a good drug for the present invention in terms of a drug which is most effective in obtaining the effects of the present invention. As the specific drug name of such a non-steroidal anti-inflammatory drug, acetaminophen, phenacetin, aluminum flufenamate, mefenamic acid, aspirin, ethenzamide, salicylic acid, sodium salicylate, Isopropyl antipyrine, sulpyrine, migrenin, acemetacin, indomethacin, indomethacin farnesil, maleic acid proglumetacin, amfenac sodium, diclofenac sodium, actarit, alfeneprofen, ampiroxicam, ibuprofen Acid (ibuprofen), etodolac, pentazocine hydrochloride, oxaprozin, ketoprofen, zaltoprofen, sulindac, tiaprofen, tenoxicam, nabumetone, naproxen, piroxicam, bucolome, pranoprofen, flurbiprofen ), dimetotiazine mesilate, meloxicam, mofezolac, loxoprofen Sodium, lobenzarit disodium, lornoxicam, etc. 0, cardiotonic, bronchodilator, caffeine as a sleepiness preventive, and jaundice, direct gastrointestinal mucosal irritation Strong effect, these drugs are strong Agent, bronchodilator, and drowsing preventive agent are representative, and are formulated in various therapeutic fields such as antipyretic analgesics, rhinitis agents, compound cold agents, antitussive expectorants, antifocal agents, cardiotonic agents, multivitamins, nourishing and strongening agents. The frequency of administration is very high, and most of the drugs which are useful for the present invention are in the aspect of the drug of the invention of 125849.doc -11-200824710. As for such caffeine-based drugs, as well as jaundice drugs, it can be exemplified by: ca#, anhydrous caffeine, sodium caffeine benzoate, aminophylline, biliary-tea test, tea test, and propylene Ketoline and the like. Furthermore, antihistamines are widely used in antitussive and expectorant, compound cold, antiperspirant, hypnotic sedative, allergy, rhinitis, etc., and the frequency of administration is higher, but local anesthetic or mucosal stimulation is more effective. The strong, direct digestive tract is very irritating, and the frequency of formulating antihistamines is very high, and most of the patients are apt to obtain the effects of the present invention, and are preferred drugs for the present invention. Among such antihistamines, as for the irritating tube, the digestive tract is very strong, and examples thereof include diphenhydramine hydrochloride, diphenhydramine citrate, doxylamine succinate, clemastine fumarate, and tartaric acid alimemazine. , promethazine hydrochloride, promethazine hibenzate, mequitazine, promethazine methylenedisalicylate, and the like. As the digestive tract stimulating drug used in the present invention, ibuprofen, aspirin, acetaminophen, ethenzamide, salicylic acid, hydrochloric acid, and particularly preferred are particularly preferred. Diphenhydramine, benzoate benzoate, anhydrous caffeine, caffeine. In the solid composition of the present invention, the content of the gastrointestinal irritant drug is preferably 80% by mass or less, more preferably 70% by mass or less, and particularly preferably 0.01% to 60% by mass. The term "water-swellable polymer" as used in the present invention means that it swells when water or water-containing 125849.doc -12-200824710 alcohol is added and can retain a large amount of water or aqueous alcohol.
高分子’較好的是對黏膜等不具有附著性者 醇而膨潤，且不溶 本發明之水膨潤性 性者。至於本發明 所使用之水膨潤性高分子，例如可舉出：低取代度羥丙基 纖維素、結晶纖維素、交聯羧甲基纖維素鈉、交聯聚乙稀 ㈣㈣、緩甲基纖維制、緩甲基纖維素納、緩甲基纖 維素等，該等可使用丨種或者將2種以上混合使用。至於本 發明中較好的水膨潤性高分子，可舉出自低取代度羥丙基 纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、交聯羧曱基 纖維素鈉、結晶纖維素中選擇之丨種或2種以上。至於更好 的水膨、;《性高分子，可舉出低取代度經丙基纖維素，較好 的是使用水膨潤性高分子整體的4〇質量％以上之低取代度 羥丙基纖維素，尤其好的是使用6〇質量％以上。 於使用低取代度羥丙基纖維素作為水膨潤性高分子之情 形時，就消化管#激性藥物之刺激抑制效果以及易加工成 經口固形組合物之製造性方面而言，較好的是羥丙氧基為 5·0〜16.G質量％者，更好的是6G〜14()f量％者，尤其好的 是7.0〜13』質量％者。至於此種低取代度經丙基纖維素， 可舉出信越化學股份有限公司製造iLH-31(羥丙氧基為 10.0〜12.9質量％)、LH-32(羥丙氧基為70〜9·9質量％)。進 而，低取代度羥丙基纖維素之平均粒徑較好的是約為6〇 μπι以下，更好的是45μηι以下，更好的是4〜25μιη。 於本發明之經口固形組合物中，就消化管刺激性藥物之 刺激抑制效果以及藥物之溶解性方面而言，水膨潤性高分 125849.doc -13· 200824710 子之含量，較好的是20質量％以上，更好的是3〇質量％以 上，尤其好的是40〜99·99質量％。 於本發明之經口固形組合物中，就消化管刺激性藥物之 刺激抑制效果之方面而言，水膨潤性高分子之調配量，相 對於消化管刺激性藥物！質量份，較好的是〇.2質量份以 上，更好的是0.4質量份以上，尤其好的是〇8〜1〇〇⑽質量 份。 於本發明之經口固形組合物中，除消化管刺激性藥物及 水膨潤性高分子以外，亦可視其目的適當調配入其他藥理 活性成分或通常於醫藥品或食品中所使用之成分。例如， 至於其他藥理活性成分，可舉出於健胃藥、制酸藥、消化 藥、抗潰瘍藥、整腸藥等中所使用之藥理活性成分。又， 至於醫藥品或食品中所使用之成分，可舉出：賦形劑（稀 釋劑）、黏合劑、崩解劑、甜味劑、著色劑、香料等。例 如’至於賦形劑’可舉出：乳糖、精製白糖、葡萄糖、海 藻糖等糖類；D·甘露醇 '山梨糖醇、木糖醇、赤蘚糖醇等 糖醇等。至於黏合劑，可舉出：_基纖維素、㈣基曱 基纖、准素、甲基纖維素、聚乙稀吼嘻烧嗣、糊精、α化殿 粉等。至於崩解劑’可舉出：玉米澱粉、馬鈐薯澱粉、米 澱粉、小麵粉等澱粉類等。至於甜味料，可舉出：糖精 鈉阿斯巴甜、乙醯磺胺酸鉀（acesulfame_K)、蔗糖素、 甘草萃取物、甜菊萃取物、羅漢果萃取物。至於著色劑， 可舉出：二氧化鈦、天然食用色素、適用於食品及藥品用 途之染料等。 125849.doc -14- 200824710 本發明之經口固形組合物，藉由將消化管刺激性藥物與 水膨潤性高分子加以混合，再以混練液將所獲得之混合粉 末進行濕式造粒，而發揮抑制消化管刺激性藥物的刺激之 效果。因此，於將簡單地將消化管刺激性藥物與水膨潤性 … 高分子混合而成之組合物或消化管刺激性藥物與水膨潤性 . 高分子進行乾式造粒之情形時，無法獲得抑制藥物對消化 管的刺激性之理想效果。作為本發明中所使用之混練液， 係水或含水醇；於製造本發明之組合物時，較好的是使用 水或者50質量❶/。以下之含水醇，更好的是使用水或者乃質 量％以下之含水醇，更好的是使用水或者15質量％以下之 含水醇。又，至於本發明中所使用之含水醇中之醇，可舉 出乙醇、甲醇、異丙醇等於醫藥品或其製造中可使用之 ^於製成經π投與製劑之情形時，較好的是使用乙醇。 混練液之添加量，相對於水膨潤性高分子，較好的是1〜10 質量倍，尤其好的是2〜5質量倍。 # 作為製仏本發明之經口固形組合物時之濕式造粒，若係 攪拌造粒、流動層造粒、押出造粒等通常於醫藥品或食品 等肩域所使用之濕式造粒法，則無特別限定，但較好的是 * 攪拌造粒法及押出造粒法。 • 、，本發明之經口固形組合物，例如可以如下之方式製造。 : f先添加，肖化官刺激性藥物及水膨_性高分子，視需要 添加其他添加物’以攪拌型混合機例如立式造粒機 (:〇WR:X股份有限公司製造)等混合機加以混合後，以水 門丨生回刀子的1倍至5倍左右量緩慢加入純化水或者50重 125849.doc -15- 200824710 量％以下之含水醇再進行混練，使水膨潤性高分子成為膨 潤狀態。押出該混練物，以造粒機例如打加 TmU_(Fujipaudal股份有限公司製造）押出造粒機進行 ^粒’製造濕潤顆粒狀組合物，以箱形乾燥機或者流動層 - 隸乾燥機進行乾燥。又，亦可利用篩製成具有目的粒^ . 、彳$而進灯押出造粒後’以球形整粒機（Fujipaudal 股份有限公司製造）施行球形處理後，以箱形乾燥機或者 # '流動層乾燥機進行乾燥，最後利用筛亦可製造具有目的粒 度之球形顆粒。 立即以粕形乾燥機或者流動層造粒乾燥機將上述混 練物進行乾燥，最制用篩亦可製成具有目的粒度之顆 粒。顆粒之粒度調節，係可藉由調節水或者含水醇之量， 或者於0H2 mm範圍内改變押出造粒時之篩孔徑，而獲 得=或細粒劑繼而獲得顆粒劑。進而考慮服用感或藥： 的穩疋f生等，亦可藉由糖類或高分子等對所獲得之顆粒劑 φ 進行包覆。 :本發月中，進行濕式造粒所獲得顆粒之平均粒徑，於 以師分法來測定粒子徑之情形時，較好的是h 以上， 更好的疋50〜1500 μιη，更好的是1〇〇〜1〇〇〇μιη。 ' 如此製造之經口固形組合物，具有顆粒狀之形狀，且抑 制消化管刺激性藥物對消化管之直接的刺激性，進而流動 险良好，因此可將經口固形組合物之顆粒直接作為散劑、 細粒劑、顆粒劑等使用，但亦可填充於硬膠囊或軟膠囊中 而作為膠囊劑使用，亦可將固形組合物之顆粒打錠而作為 125849.doc -16- 200824710 錠劑使用。進而，亦可藉由 或片劑進行包覆。於Μ借姑& 阿刀千等將該等膠囊劑 或艮口口中所使用之製劑添加物 將通樂品 面活性劑、塑化劑 乂劑、穩定化劑、界 潤滑化劑、潤滑劑、還盾^ 劑、稀釋劑、吸附劑、矯味劑、黏 、原划、甜味 化劑、包覆劑、香料、包 口 "抗#1化劑、光澤 劑、呕嚼劑、著色劑、著香劑真=軋包劑、清涼化The polymer ' is preferably swellable to an alcohol having no adhesion to a mucous membrane or the like, and is insoluble in the water swelling property of the present invention. The water-swellable polymer used in the present invention may, for example, be a low-substituted hydroxypropylcellulose, a crystalline cellulose, a croscarmellose sodium, a cross-linked polyethylene (tetra) (four), or a slow methyl fiber. For the production, the slow-acting methyl cellulose, the slow-methyl cellulose, and the like, these may be used in combination or in combination of two or more. The water-swellable polymer which is preferable in the present invention may, for example, be a hydroxypropylcellulose, a carboxymethylcellulose calcium, a sodium carboxymethylcellulose, a croscarmellose sodium, or a crystallization of a low degree of substitution. Two or more species selected from cellulose. As for the better water swelling, "the low molecular weight of the polymer is propyl cellulose, and it is preferred to use a low-substituted hydroxypropyl fiber of 4% by mass or more of the water-swellable polymer as a whole. It is particularly preferable to use 6% by mass or more. When a low-substituted hydroxypropylcellulose is used as the water-swellable polymer, it is preferable in terms of the stimulating inhibitory effect of the digestive tract drug and the ease of processing into the manufacturability of the oral solid composition. It is a hydroxypropoxy group of 5·0~16.G mass%, more preferably a 6G~14()f amount%, and particularly preferably 7.0 to 13" mass%. As for the low-substituted propylcellulose, it is possible to manufacture iLH-31 (hydroxypropoxy group of 10.0 to 12.9% by mass) and LH-32 (hydroxypropoxy group of 70 to 9·). 9% by mass). Further, the average particle diameter of the low-substituted hydroxypropylcellulose is preferably about 6 〇 μπ or less, more preferably 45 μηι or less, still more preferably 4 to 25 μm. In the oral solid composition of the present invention, the water swelling high score of 125,849.doc -13 · 200824710 is preferably in terms of the stimulating effect of the gastrointestinal irritant drug and the solubility of the drug. 20% by mass or more, more preferably 3% by mass or more, particularly preferably 40 to 99.9% by mass. In the oral solid composition of the present invention, the amount of the water-swellable polymer is proportional to the gastrointestinal irritant drug in terms of the stimulating effect of the gastrointestinal irritant drug! The mass part is preferably 〇. 2 parts by mass or more, more preferably 0.4 parts by mass or more, and particularly preferably 〇8 to 1 〇〇 (10) parts by mass. In addition to the digestive tract irritant and the water-swellable polymer, the oral solid composition of the present invention may be appropriately formulated into other pharmacologically active ingredients or components which are usually used in medicines or foods, depending on the purpose. For example, as other pharmacologically active ingredients, pharmacologically active ingredients used in stomach medicines, antacids, digestive medicines, antiulcer drugs, and colon preparations can be cited. Further, examples of the components used in the pharmaceutical or food include excipients (dilution agents), binders, disintegrators, sweeteners, coloring agents, and perfumes. For example, 'the excipients' include sugars such as lactose, refined white sugar, glucose, and trehalose; and D-mannitol such as sorbitol, xylitol, and erythritol. Examples of the binder include _based cellulose, (iv) fluorenyl ketone, quasi-protein, methyl cellulose, polyethylene sputum, dextrin, and gelatinized powder. As the disintegrator, corn starch such as corn starch, horse starch starch, rice starch, and small flour may be mentioned. As the sweetener, sodium saccharin, aspartame, acesulfame-K, sucralose, licorice extract, stevia extract, and mangosteen extract can be mentioned. Examples of the coloring agent include titanium dioxide, natural food coloring matter, and dyes suitable for use in foods and pharmaceuticals. 125849.doc -14- 200824710 The oral solid composition of the present invention is obtained by mixing a digestive tract stimulating drug and a water-swellable polymer, and then wet-granulating the obtained mixed powder with a kneading liquid. It exerts the effect of suppressing the stimulation of gastrointestinal irritating drugs. Therefore, a composition in which a digestive tract irritating drug and a water swellable polymer are simply mixed or a gastrointestinal stimulating drug and water swellability are used. When the polymer is subjected to dry granulation, an inhibitory drug cannot be obtained. The ideal effect on the irritation of the digestive tract. As the kneading liquid used in the present invention, it is water or an aqueous alcohol; in the production of the composition of the present invention, it is preferred to use water or 50 mass%. The following aqueous alcohols are more preferably water or an aqueous alcohol having a mass % or less, more preferably water or 15% by mass or less of an aqueous alcohol. Further, as for the alcohol in the aqueous alcohol used in the present invention, ethanol, methanol, and isopropanol are equivalent to those which can be used in the production of the π-administered preparation. It is the use of ethanol. The amount of the kneading liquid to be added is preferably from 1 to 10 times by mass, particularly preferably from 2 to 5 times by mass, based on the water-swellable polymer. # Wet granulation in the case of the oral solid composition of the present invention, if it is agitating granulation, flowing layer granulation, extrusion granulation, etc., wet granulation usually used in shoulders such as pharmaceuticals or foods The method is not particularly limited, but is preferably a stirring granulation method and an extrusion granulation method. The oral solid composition of the present invention can be produced, for example, in the following manner. : f first added, Xiao Huaguan stimulating drugs and water-expanded polymers, if necessary, add other additives' mixed with a blending mixer such as vertical granulator (: 〇 WR: X Co., Ltd.) After mixing the machine, slowly add purified water or 50 parts of water alcohol with a weight of 125 mil. or less of 125 849.doc -15-200824710, and then mix the water to make the water swellable polymer become 1 to 5 times. Swelling state. The kneaded product is extruded, and the granulator is used, for example, by adding TmU_ (manufactured by Fujipaudal Co., Ltd.) to a pelletizer to produce a wet granular composition, which is dried in a box dryer or a fluidized bed-dryer. In addition, it is also possible to use a sieve to form a target granule, and to smash it into a granule, and then perform a spherical treatment by a spherical granulator (manufactured by Fujipaudal Co., Ltd.), and then flow in a box-shaped dryer or # ' The layer dryer is dried, and finally a spherical particle having a target particle size can be produced by using a sieve. The above kneaded product is immediately dried by a kneading dryer or a fluidized bed granulating dryer, and the most suitable sieve can also be used to form granules having a target particle size. The particle size adjustment of the particles can be achieved by adjusting the amount of water or aqueous alcohol, or by changing the sieve pore size at the time of granulation in the range of 0H2 mm, to obtain = or fine granules and then obtaining granules. Further, it is also possible to coat the obtained granule φ by a saccharide or a polymer, etc., in consideration of the feeling of taking the medicine or the medicine. : In the present month, the average particle size of the particles obtained by wet granulation is preferably h or more, more preferably 〜50 to 1500 μmη, in the case of measuring the particle diameter by the division method. It is 1〇〇~1〇〇〇μιη. The orally-formed composition thus produced has a granular shape and inhibits direct irritation of the digestive tract irritating drug to the digestive tract, and thus has a good flow risk, so that the granules of the oral solid composition can be directly used as a powder. The granules, granules, and the like may be used, but may be used as a capsule in a hard or soft capsule, or the granules of the solid composition may be used as a tablet of 125849.doc -16-200824710. Further, it may be coated by a tablet or a tablet. Μ Μ & && A knife thousand etc. These capsules or preparations used in the mouth and mouth will be used in the Tongle surfactant, plasticizer tincture, stabilizer, boundary lubricant, lubricant , Shielding agent, thinner, adsorbent, flavoring agent, viscosity, original, sweetener, coating agent, perfume, Baokou"anti-chemical agent, glossing agent, chewable agent, coloring agent , the fragrance is true = rolling agent, cooling
劑、防腐劑、保存劑、产香4、防濕 机動化劑、抗靜電劑、 味料、酸味料、甜味料、著 調 者色枓/發色劑、著香料、強 劑、膨脹劑、防腐劑、俘在 55 保存枓/防檄劑、抗氧化劑/漂白 別、增黏敎劑、苦味料、_、光㈣、製造用㈣，而 進打適時調配。又，如此製造之本發明之經口固形組合物 3有/、之製背丨，可防止消化管刺激性，從而可提供安全 性提昇之製劑。 、1 [實施例] 其次，舉出實施例及試驗例來更具體地說明本發明，但 本發明並不限定於該等例。 實施例1 以立式造粒機VG_25(P0WREX股份有限公司）將作為消 化管刺激性藥物之異丁苯丙酸（BASF曰本股份有限公司製 造）900 g與作為水膨潤性高分子之低取代度羥丙基纖維素 (LHPC · LH-31(經丙氧基為1〇 〇〜ΐ2·9質量％) ··信越化學股 份有限公司製造）1500 g混合後，添加純化水4537 g且進行 125849.doc -17- 200824710 混練後’利用濕式押出造粒機TDG-80(Fujipaudal股份有限 公司製造）0.6 mm篩進行押出造粒，以球形整粒機 Q400(FnjiPaudal股份有限公司製造）施行球形化處理後， 以流動層乾燥裝置FLO_5A/2(Freund產業股份有限公司製 造）進行乾燥，獲得作為平均粒徑約為5 〇〇 μιη的顆粒劑之 實施例1之製劑。 比較例1 將異丁苯丙酸（BASF日本股份有限公司製造）45 g與低取 代度羥丙基纖維素（LHPC : LH_3 1 ··信越化學股份有限公 司製造）75 g均勻混合，獲得比較例1之製劑。 試驗例1 依據日本藥局方第15次改正·溶解試驗法，進行實施例1 之本發明之製劑與比較例1之比較製劑的溶出試驗。試驗 液係使用弟一液（pΗ 6 · 8緩衝液），以槳法以5 〇 r·p ·m的轉速 進行溶出試驗，以高速液體層析儀測定溶出液中之布洛芬 ί辰度’异出溶出速度，將其結果示於圖1。 可知本發明之製劑，在將原粉分散之比較例1之製劑的 八丁笨丙8文之溶出幾乎未變化的情況下，異丁苯丙酸被快 速溶出，顯示速釋性製劑之溶出特性。 試驗例2 使用大白鼠之胃黏膜刺激性試驗： 武驗方法·將SD系雄性大鼠（購自日本CHARLES RIVER 版伤有限公司）預飼養1週。給一群10隻之於投與試驗藥劑 月）、、二24小時絕食的動物（210〜230 g)經口投與1〇 mg/kg之異 125849.doc -18- 200824710 丁苯丙酸。4小時後’藉由頭部擊打異及頸動脈放血而使 動物死亡，摘出胃。將1〇/〇福馬林液10 mL注入胃内，於相 同液中進行輕度固定。沿大彎將胃切開，於實體顯微鏡下 (10倍）觀察有無潰瘍且求出潰瘍發現率，測定且累計所產 生潰瘍的長度（mm)，作為每1隻之潰瘍係數。 結果：如表1所示，本發明之實施例1之製劑中未發現潰 瘍，相對於此，比較例1之製劑中，40%的各藥劑中有潰 瘍發現率，潰瘍係數亦為〇·9土0.4 mm(平均值士標準偏差）。 由此說明，發明之製劑減低異丁苯丙酸對消化管的刺激 性，且抑制潰瘍的發生。 [表1] 試驗結果 試驗藥劑 潰瘍之發現 μ (隻/售） 潰瘍係數 (mm) 實施例1製劑 0/10 0·0 士 0.0 比較例1製劑 4/10 0.9 士 0.4 實施例2 以立式造粒機VG-10(P〇WREX股份有限公司）將作為消 化管刺激性藥物之鹽酸苯海拉明（金剛化學股份有限公司 製造）80 g與作為水膨潤性高分子之低取代羥丙基纖維素 (LHPC : LH-31 :信越化學股份有限公司製造）720 g混合 後，添加15%乙酵/純化水2026 g且加以混練後，以濕式整 粒機TDG-80(Fujipaiidal股份有限公司製造）0.6 mm篩進行 押出造粒，以流動層乾燥裝置FLO-5A/2(Freund產業股份 125849.doc •19- 200824710 有限公司製造）進行乾燥，獲得平均粒徑約為5〇〇 μιη之顆 粒劑。 實施例3 以立式造粒機VG-10(POWREX股份有限公司）將作為消 化管刺激性藥物之咖啡因（靜岡咖啡因工業股份有限公司 製造）400 g、硝酸噻胺（Basf曰本股份有限公司製造）2〇 g、 及作為水膨潤性高分子之低取代度羥丙基纖維素（LHpc : LH-3 1 :信越化學股份有限公司製造）38〇 g混合後，添加 純化水1053 g且加以混練後，以濕式造粒機丁〇〇_ 80(卩1^卩311(^1股份有限公司製造）1〇111111篩進行押出造粒， 以球形整粒機Q400(Fujipaudal股份有限公司製造）施行球 形化處理後’以流動層乾燥裝置FL〇-5A/2(Freund產業股 份有限公司製造）進行乾燥，製備平均粒徑約為800 ^❿之 球形顆粒，以每個膠囊為200 mg之方式將該顆粒填充於硬 膠囊中，而獲得膠囊劑。 [產業上之可利用性] 包合消化官刺激性藥物之本發明之經口固形組合物，可 防止具有消化管刺激性之藥物對消化管的刺激，進而可適 應於各種消化管刺激性藥物。進而，本發明之經口固形組 合物亚不會如腸溶性製劑般使溶出延遲，因此可適用於各 種藥物之速釋性製劑。又，該經口固形組合物，具有顆粒 狀之形狀且流動性I好，因此不僅可將經口固形組合物的 顆粒直接製成散劑、細粒劑、顆粒劑等，而且亦易於加工 成膠囊劑或片齊卜係可廣泛適用於醫藥品、食品等者。此 125849.doc -20- 200824710 外，本發明之經口固形組合物，不僅可藉由簡單的製造方 法而廉價地製造，而且減少對消化管的刺激性，因此可進 一步減少多數患者的胃部不適感、噁心/嘔吐、食轉 ::化器官症狀的副作用’係多數患者可受 ：:: 治療效果的好處之製劑。 摩凌之 【圖式簡單說明】 圖1係表示本發明品與 ，、比季父品之溶出率 平之圖式。Agent, preservative, preservative, aroma 4, moisture-proof motorizing agent, antistatic agent, flavoring material, sour material, sweetener, coloring agent/coloring agent, flavoring agent, strong agent, expansion agent Preservatives, captives in 55 preserved cockroaches / anti-caries agents, antioxidants / bleaching, thickening bismuth, bitter, _, light (four), manufacturing (four), and timely blending. Further, the orally-sealed composition 3 of the present invention thus produced has a backing which can prevent the gastrointestinal tube from being irritating, thereby providing a safely improving preparation. [Embodiment] Next, the present invention will be more specifically described by way of examples and test examples, but the present invention is not limited to the examples. Example 1 900 g of ibuprofen (manufactured by BASF Co., Ltd.) as a digestive tract stimulant and low substitution as a water-swelling polymer by a vertical granulator VG_25 (P0WREX Co., Ltd.) Degree hydroxypropyl cellulose (LHPC · LH-31 (1 〇〇~ΐ2·9 mass% by propoxy group) ··Shin-Etsu Chemical Co., Ltd.) 1500 g After mixing, 4537 g of purified water was added and 125849 was added. .doc -17- 200824710 After the kneading, the granulation was carried out by a wet extrusion granulator TDG-80 (manufactured by Fujipaudal Co., Ltd.) 0.6 mm sieve, and spheroidized by a spherical granulator Q400 (manufactured by Fnji Paudal Co., Ltd.). After the treatment, the mixture was dried by a fluidized bed drying apparatus FLO_5A/2 (manufactured by Freund Industries Co., Ltd.) to obtain a preparation of Example 1 as a granule having an average particle diameter of about 5 μm. Comparative Example 1 45 g of ibuprofen (manufactured by BASF Japan Co., Ltd.) and 75 g of low-substituted hydroxypropylcellulose (LHPC: LH_3 1 · Shin-Etsu Chemical Co., Ltd.) were uniformly mixed to obtain a comparative example. Formulation of 1. Test Example 1 The dissolution test of the comparative preparation of the preparation of the present invention of Example 1 and Comparative Example 1 was carried out in accordance with the 15th correction and dissolution test method of the Japanese Pharmacopoeia. The test solution was prepared by using the first solution (pΗ 6 · 8 buffer), and the dissolution test was performed at a rotation speed of 5 〇r·p ·m by a paddle method, and the ibuprofen in the eluate was measured by a high-speed liquid chromatograph. 'Different dissolution rate, the result is shown in Fig. 1. It was found that the preparation of the present invention showed that ibuprofen was rapidly eluted in the case where the dissolution of the preparation of Comparative Example 1 in which the original powder was dispersed was almost unchanged, and the dissolution characteristics of the immediate release preparation were exhibited. Test Example 2 Gastric Mucosal Irritation Test Using Rats: Test Method: SD male rats (purchased from CHARLES RIVER, Japan) were pre-fed for 1 week. A group of 10 animals (210~230 g) who were on a hunger strike for 24 hours, and 24 hours of hunger strike were orally administered with 1 〇 mg/kg. 125849.doc -18- 200824710 phenylpropanoid. After 4 hours, the animal was killed by a blood clot from the head and the carotid artery was excreted, and the stomach was removed. 10 mL of 1 〇/〇福马林液 was injected into the stomach and gently fixed in the same solution. The stomach was incised along a large curve, and the presence or absence of an ulcer was observed under a stereoscopic microscope (10 times), and the ulceration rate was determined. The length (mm) of the ulcer produced was measured and accumulated as the ulcer coefficient per one. Results: As shown in Table 1, no ulcer was found in the preparation of Example 1 of the present invention. In contrast, in the preparation of Comparative Example 1, 40% of each of the preparations had an ulcer discovery rate, and the ulcer coefficient was also 〇·9. Soil 0.4 mm (mean standard deviation). Thus, the preparation of the invention reduces the irritation of ibuprofen to the digestive tract and inhibits the occurrence of ulcers. [Table 1] Test results Test agent ulcer findings μ (only/sold) Ulcer coefficient (mm) Example 1 Formulation 0/10 0·0 ± 0.0 Comparative Example 1 Preparation 4/10 0.9 ± 0.4 Example 2 Granulator VG-10 (P〇WREX Co., Ltd.) will be used as a digestive tract stimulant drug, diphenhydramine hydrochloride (manufactured by King Kong Chemical Co., Ltd.) 80 g and a low-substituted hydroxypropyl group as a water-swellable polymer. After 720 g of cellulose (LHPC: LH-31: manufactured by Shin-Etsu Chemical Co., Ltd.) was mixed, 2026 g of 15% ethanol/purified water was added and kneaded, and then wet-type granulator TDG-80 (Fujipaiidal Co., Ltd.) Manufactured) 0.6 mm sieve was extruded and granulated, and dried by a fluidized bed drying device FLO-5A/2 (Freund Industries, 125849.doc • 19-200824710 Co., Ltd.) to obtain granules having an average particle diameter of about 5 μm Agent. Example 3 As a digester stimulating drug, caffeine (manufactured by Shizuoka Caffeine Industry Co., Ltd.), 400 g, tidy nitrate (Basf 曰 曰 shares), a vertical granulator VG-10 (POWREX Co., Ltd.) 2制造g, and low-substituted hydroxypropylcellulose (LHpc: LH-3 1 : manufactured by Shin-Etsu Chemical Co., Ltd.), which is a water-swellable polymer, is mixed with 38〇g, and purified water is added to 1053 g. After being kneaded, the granulation machine Ding _ 80 (卩1^卩311 (manufactured by Co., Ltd.) 1〇111111 sieve was used for granulation, and the spherical granulator Q400 (Fujipaudal Co., Ltd.) After the spheroidization treatment, it is dried by a fluidized bed drying device FL〇-5A/2 (manufactured by Freund Industries Co., Ltd.) to prepare spherical particles having an average particle diameter of about 800 μM, which is 200 mg per capsule. In this way, the granules are filled in a hard capsule to obtain a capsule. [Industrial Applicability] The oral solid composition of the present invention comprising a digestive stimulating drug can prevent a drug having gastrointestinal irritant Thorn to the digestive tract Further, the oral solid composition of the present invention does not delay dissolution as an enteric preparation, and thus can be applied to various drug immediate release preparations. The oral solid composition has a granular shape and good fluidity I, so that not only the granules of the oral solid composition can be directly formed into powders, fine granules, granules, etc., but also easily processed into capsules or tablets. The invention is widely applicable to pharmaceuticals, foods, etc. In addition, the oral solid composition of the present invention can be inexpensively manufactured not only by a simple manufacturing method but also by reducing the digestive tract. It is irritating, so it can further reduce the stomach discomfort, nausea/vomiting, and food transfusion in most patients: The side effects of the symptoms of the organ are 'the majority of patients can be treated with::: The benefits of the therapeutic effect. Moline's [Figure BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagram showing the dissolution rate of the product of the present invention and the ratio of the parent product.
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