TW200904415A - Improved bioavailability of antibiotics - Google Patents

Abstract

The object of the invention consists on the preparation of pharmaceutical formulations containing rifaximin in the shape of microgranules made gastroresistant by an insoluble polymer at pH values between 1.5 and 4.0 and soluble at pH values between 5.0 and 7.5, having the characteristic to be a higher bioavailability in comparison to other formulations, by their preparation and by their use in the manufacture of medicinal preparations useful in the treatment of inflammatory bowel diseases (IBD) and mainly Crohn's disease.

Description

200904415 九、發明說明： 【杳明所屬之技術領域】 本發明之目的係由下列各項所組成：含有呈微顆粒形狀 之利福昔明（rifaximin)之醫藥配方，其經由共同包含在 如值丨.5與4.0間不溶解且在pH值5.0與7.5間可溶解 的聚δ物而具有耐胃性（gastr〇resistant);其之製備； /、於‘ k有用於治療腸道感染及發炎性腸道疾病 :諸如克隆氏（Crohn，s)疾病之藥物製劑的用途， 該藥物製劑與未經塗覆的製劑相比具有改良生體 的性質。 干 【先前技術】 :道器官會受許多總稱為發炎性腸道疾病的發炎性疾 之i Γ、特疋而e ’克隆氏疾病係一種感染從口腔至肛門 牒道之各個範圍的嚴重慢性發炎性疾病 :::最後部分(迴腸、結腸或兩者)且有時亦在結腸二 腸辟t肛門區域中觀察得。在相關的腸道部分令’在整個 疼痛，而未受感染的Μ織: = 性潰癌及 現諸如下列症狀之不同嚴二 克隆氏疾病展 期：腹瀉、腹痛、體重減輕 狀的父替週 直腸周圍凄管。有三分之二s、+ ^被襄（rhagade)或 病患在其-生中的某時刻：需三：有克隆氏疾病的 膿瘡、或出血的併發症。°療諸如％道尹阻塞、穿孔、 3】2XP/發明說明書(補件)/96-腑61277】2 6 200904415 腸道菌叢於腸道發炎性疾病及尤其係克隆氏疾病之病 因中所扮演的角色係由例如集中於高細菌濃度區域的頻 率獲得證實，參見 Jann〇witz，H. D.，Inflamm200904415 IX. Description of the invention: [Technical field to which the invention belongs] The object of the present invention is composed of a pharmaceutical formulation containing rifaximin in the form of microparticles, which are collectively included in the value聚.5 and 4.0 polyδ substances which are insoluble in pH and soluble between pH 5.0 and 7.5 and have gastric resistance (gastr〇resistant); preparation thereof; /, used in the treatment of intestinal infections and inflammation Sexual enteric disease: The use of a pharmaceutical preparation such as Crohn's disease, which has improved biologic properties compared to an uncoated preparation. Dry [Prior Art]: The organ is subject to many inflammatory diseases commonly referred to as inflammatory bowel diseases, and e 'Clone' disease is a serious chronic inflammation of the infection from the oral cavity to the anal fistula. Sexual disease::: The last part (ileum, colon or both) and sometimes also observed in the colonic anal area. In the relevant part of the intestines, 'the whole pain, but the uninfected woven:= Sexual ulceration and now different symptoms such as the following: The diarrhea, abdominal pain, weight loss of the father for the rectum Surrounded by a fistula. Two-thirds of s, + ^ rhagade, or at some point in the patient's life: need three: abscesses with Crohn's disease, or complications of bleeding. °Treatment such as % Dao Yin obstruction, perforation, 3] 2XP / invention instructions (supplement) / 96-腑61277] 2 6 200904415 Intestinal flora plays a role in the intestinal inflammatory diseases and especially the cause of Crohn's disease The role is confirmed by, for example, the frequency concentrated in areas of high bacterial concentration, see Jann〇witz, HD, Inflamm

Dis.，1 998，4生，29-39 ;以糞便流動的偏差測出管道形 成（canal isation)復原時可減輕再次内視鏡檢查之受 損，參見 Rutgeerts，P.，Lancet，1991，338，77卜774 ; 實驗模型（例如，關於IL_1Q基因或其他基因剔除小鼠 (knock-out mouse))顯示若維持「無菌」條件，則不會發 展出自發性結腸炎，參見Blumberg R s.，Dis., 1 998, 4 students, 29-39; can reduce the damage of re-endoscopic examination when the canal isation is detected by the deviation of fecal flow, see Rutgeerts, P., Lancet, 1991, 338 , 77 774 ; experimental models (for example, regarding the IL_1Q gene or other knock-out mice) show that spontaneous colitis is not developed if "sterile" conditions are maintained, see Blumberg R s.,

Immunol.，1 999’ 11(6)’648_56;在與糞便接觸後會發 展成腸黏膜發炎，參見Harper p. η. , Gut，1985，π， 279-84;在由迴結腸吻合術所組成的手術「治癒性」療法 中’抗生素治療可延緩内視鏡檢查及臨床復發兩者的發 展，參見 Cameron J.L.，Ann.Surg，1 992,215 546 52 且療管或膿腫囊的存在進—步指出細㈣疾㈣貢 者上Λ ν只 、克隆氏疾病先前係、利用可減低或控制發炎的藥物治 f /列如·’可的松（⑶rtisQnes)、水揚酸偶氮續胺口比咬Immunol., 1 999' 11(6) '648_56; develops intestinal mucosal inflammation after contact with feces, see Harper p. η., Gut, 1985, π, 279-84; composed of ileocecal anastomosis 'Antibiotic treatment in the "cure" therapy can delay the development of both endoscopy and clinical recurrence, see Cameron JL, Ann. Surg, 992, 215 546 52 and the presence of a treatment tube or abscess sac (4) Disease (4) tribute to the sputum ν, the previous line of Crohn's disease, the use of drugs that can reduce or control inflammation, f / column such as 'cortisone ((3) rtisQnes), salicyl azo hydrazine mouth bite than bite

:二Zopirine)、美沙拉嗪免疫抑制劑、 寸疋的化學治療劑、抗生素及腫瘤壞死因子(W: 2 Zopirine), mesalazine immunosuppressive agents, chemotherapeutic agents, antibiotics and tumor necrosis factor (W)

Necrosis Factor，TNF)之你爾沾疋厶讲』 枓賜_、音、广 的蛋白貝抑制劑。於發炎 f生腸道疾病之急性期的、、Λ、波如叫 期間，通常需要較強烈的治療 以確保利用非經腸道的供认 陳 耗，以使腸道休息而利於潰疬 才貝 J瓦/貝灰的癒合。治療的目的係要減 312XP/發明說明書(補件)/96-】〇/961277〗2 7 200904415 低症狀的再現頻率及降低當症狀出現時的嚴重急性事 件。然而，利用目前的療法，急性事件佔約5 〇 _ 7⑽的病 例，但有80%的病患會發生復發。 通常使用抗生素於減低腔道細菌的生長；減低由於細菌 生長而持續存在的發炎狀態；減輕疾病急性期的症狀，例 如，腹瀉、腸道疼痛及鼓脹；及預防及治癒敗血性併發症， 例如，膿腫、瘻管及毒性狀態。 ί 最常使用的抗生素為全身吸收性，例如，滅滴靈 (metronidazole)(具有對抗某些寄生蟲以及許多厭氧菌Necrosis Factor, TNF), you can talk about it, 枓, 音, 广, protein shell inhibitor. During the acute phase of inflammatory disease, sputum, and wave, it is usually necessary to have a stronger treatment to ensure the use of parenteral confession, so that the bowel rests and is good for collapse. The healing of the tile/shellfish. The purpose of treatment is to reduce 312XP / invention manual (supplement) / 96-] 〇 / 961277〗 2 7 200904415 The frequency of low symptom reproduction and reduce the serious acute events when symptoms appear. However, with current therapies, acute events account for approximately 5 〇 _ 7 (10) of the cases, but 80% of patients will relapse. Antibiotics are commonly used to reduce the growth of bacteria in the lumen; to reduce the inflammatory state that persists due to bacterial growth; to alleviate symptoms in the acute phase of the disease, such as diarrhea, intestinal pain and bloating; and to prevent and cure septic complications, for example, Abscess, fistula and toxic state. ί The most commonly used antibiotic is systemic absorption, for example, metronidazole (with against certain parasites and many anaerobic bacteria)

=性）及環丙沙星（ciprofl〇xacin)(具有對抗諸如大腸 桿囷(昃⑽)及好氧腸桿菌之細菌的活性）。滅滴靈係以 10-20毫克/公斤八之劑量使用4個月（Sunteriand L= sex) and ciprofl〇xacin (having activity against bacteria such as the large intestine (囷(10)) and Enterobacter aerogenes). Metronidazole is used for 10 months at a dose of 10-20 mg/kg (Sunteriand L)

Gut’ 1991 32’ 1071_5)’而環丙沙星係以测毫克/天 之劑量使用6星期（Col⑽bel】F ，Am ;Gut' 1991 32' 1071_5)' and ciprofloxacin was used at a dose of mg/day for 6 weeks (Col(10)bel)F, Am;

Gastoenteroi.，1 999,94’674_8)，同時卜如⑽於Gastoenteroi., 1 999, 94’674_8), at the same time Bu Ru (10)

Am. J. Gast〇enterol•’ 1996,9卜 328,中採用兩種 抗生素之組合，使用1 〇〇〇蒼券/ > 士 笔兄/天劑1之滅滴靈及1000 宅克/天劑量之環丙沙星達〗？窟甘 „ LL 運U星期。此等抗生素的高全 身性生體利用率係其於長期心 L , 、负期/口療中所顯示之高副作用發 生率的根源，而對其之#用古$工…_ 一，/、之使用有負面影響。使用滅滴靈時之 田1J作用的發生率視劑量及治瘆 口蜃期間而在自10%至20%之範 圍内。敢常見的副作用包括奋厘。土 田 P叫匕祜金屬味、胃不耐受、噁心、舌 k、碩痛、眩暈、運動奂★固、4上4亡Λ、丄_ ^ Ε 夫调抽搐及神經毒性。在50-85% 接文長期治療的病患中記錚到 τ心π判周圍神經病變，其只有在中 312ΧΡ/發明說明書(補件)/96_ ί ο/% 127712 8 200904415 斷治療數個月後才可復 用的百分比分歧，且二::丙沙星研究中所述之副作 見的副作用係源自胃腸]量及治療期間而定。最常 膚反應。因此：:二:道：辑提及轉 如，胃腸病症）的長期治療選擇。 疾病（例 乂抗生素為主之用於治療發炎性腸道疾病（例如 醫藥製劑最好具有一或多個下述特性：腸部位之 七’牒吸收-、於腸腔中之細菌含量控制、對抗微生物(例 二作Γ?:陽性、格蘭氏陰性、好氧及厭氧成分)的 廣=用、長期治療而無副作用的可能性、即使係可能有 南心需求（例如，長期給藥及/或每天多次給藥）亦可容 易給藥而有利於依從性。 一種具有數項此等特性的抗生素為利福昔明（H史見 TheMerck Index，XIH版，δ3⑷，其之特徵在於對抗 终多格蘭氏陽性及格蘭氏陰性細菌，包括好氧及厭氧細菌 G的廣效作用。於健康自願者中所作的生體利用率研究顯示 备口服投藥時，有低於1 %的利福昔明被吸收，且其集中 於腸腔及文中所述的糞便中（加此⑽如乂乂事_乂，淤在鎗 康自願者中口服給藥後之利福昔明的藥物動力研究， J Clin Phaimacol Res，u(2)，51-56 ’（1994乃。於 t 慢性腸道疾病感染的病患中確認不存在利福昔明的吸收 (參見 Rizzello ’ Eur. J. Clin. Pharmacol. (1 998) 54， 91-93)。此外，利福昔明的低吸收分佈使副作用之發生率 及不期望之藥理交互作用的風險降低。因此，利福昔明可 312XP/發明說明書(補件)/96-10/96127712 9 200904415 被視為有用於治療發炎性慢性腸道疾病及尤其是克隆氏 疾病。利福昔明於慢性發炎性腸道疾病中的可能效力已經 證實，參見 Gionchetti，P.，Dig. Dis Sci ，1 999， 44 1220 1 ’其假疋於患有對類固醇治療具頑抗性之中或 重度潰瘍性結腸炎的病患中使用利福昔明。 利福昔明已於義大利專利Ιτ 1 154655 (198〇)及卯 .01 61534 (1 985)中作說明，將兩篇專利之全體併入本文為 「參考資料供所有用途用。Ep隨53揭示—種使用利福徵 素（ri famycirOO作為原料之利福昔明的製造方法（TheAm. J. Gast〇enterol•' 1996, 9 328, using a combination of two antibiotics, using 1 券 券 / > 士笔兄 / 天剂1 of metronidazole and 1000 housew / day Dosage of ciprofloxacin 〗?甘甘„ LL U Week. The high systemic bioavailability of these antibiotics is the root cause of the high side effects found in long-term heart L, and negative/oral therapy. $工..._ The use of I, /, has a negative effect. The incidence of the action of 1J in the use of metronidazole is in the range of 10% to 20% depending on the dose and the period of treatment. Including Fenyi. Tutian P is called metal taste, stomach intolerance, nausea, tongue k, sore pain, dizziness, exercise 奂 ★ solid, 4 on 4 dead, 丄 _ ^ 夫 搐 twitching and neurotoxicity. 50-85% of the patients who received long-term treatment, recorded τ heart π judgment of peripheral neuropathy, which only after 312 ΧΡ / invention manual (supplement) / 96_ ί ο /% 127712 8 200904415 after treatment for several months The percentage difference that can be reused, and the second side: the side effects of the side effects described in the study of propylfloxacin are derived from the amount of gastrointestinal tract and the duration of treatment. The most common skin reaction. Therefore:: 2: Dao: Reference to long-term treatment options such as gastrointestinal disorders. Diseases (eg antibiotics are mainly used to treat inflammatory bowel disease) The disease (for example, the pharmaceutical preparation preferably has one or more of the following characteristics: absorption of the seven parts of the intestinal tract - control of the bacterial content in the intestinal lumen, and resistance to microorganisms (eg, Γ?: positive, gram negative, A wide range of aerobic and anaerobic ingredients, long-term treatment without side effects, even if there may be a need for South Heart (for example, long-term administration and / or multiple daily administration) can be easily administered Compliance. An antibiotic with several of these properties is rifaximin (H history see The Merck Index, XH version, δ 3 (4), which is characterized by resistance to terminal gram-positive and gram-negative bacteria, including aerobic And the broad-spectrum effect of anaerobic bacteria G. The bioavailability study conducted in healthy volunteers showed that less than 1% of rifaximin was absorbed when administered orally, and it was concentrated in the intestinal cavity and in the text. In the feces (additional (10), such as anecdotal _ 乂, the drug kinetic study of rifaximin after oral administration in gun volunteers, J Clin Phaimacol Res, u (2), 51-56 ' (1994 is. Confirmed in patients with chronic intestinal infections Absorption in rifaximin (see Rizzello ' Eur. J. Clin. Pharmacol. (1 998) 54, 91-93). In addition, the low absorption profile of rifaximin causes the incidence of side effects and undesired pharmacology The risk of interaction is reduced. Therefore, rifaximin 312XP/invention specification (supplement)/96-10/96127712 9 200904415 is considered to be useful in the treatment of inflammatory chronic intestinal diseases and especially Crohn's disease. The possible efficacy of serotonin in chronic inflammatory bowel disease has been confirmed, see Gionchetti, P., Dig. Dis Sci, 1 999, 44 1220 1 'The false sputum is resistant to steroid therapy or severe Rifaximin is used in patients with ulcerative colitis. Rifaximin has been described in the Italian patents Ιτ 1 154655 (198〇) and 卯.01 61534 (1 985), and the entire contents of both patents are incorporated herein by reference as "references for all purposes. Ep with 53 Revealing a method for producing rifaximin using rifamycin (ri famycirOO as a raw material)

Merck Index ， XIII 版，8301)。 關於利福昔明結晶及乾燥的指導說明於義大利專利申 請案第MI2003A002144號（2003)、歐洲專利申請案第Ep 1557421號（2003)、美國專利申請案第1〇/728, 〇9〇號 (2003)、PCT專利申請案第w〇2〇〇5/〇44823號中；’將全體° 專利之全體内容併入本文為參考資料供所有用途用。於此 I,等專利中所述之實驗條件可產生分別稱為α式、p式、丫式、 δ式及ε式之利福昔明的多形體形式。 利福昔明於某些國家中被認可用於治療其病因係部分 或完全歸因於由格蘭氏陽性及格蘭氏陰性細菌之腸道急 性及慢性感染的病症，包括腹瀉症候群、經改變的腸道菌 叢、似夏日腹瀉（summer diarrh〇ea)事件、旅行者腹瀉及 腸結腸炎；於手術前後預防胃腸手術中的感染併發症；及 作為輔助的高氨血症治療。利福昔明目前係以ι〇〇毫克及 2〇〇毫克劑量的旋劑或膠囊、以供孩童用之立即可用製 312XP/發明說明書(補件)/96-1〇/96127712 200904415 劑、或作為用於治療局部感染的軟膏銷售。 此==品’尤其係2〇0毫克旋劑所作的研究顯示利福 ^ 月對於預防在内視鏡切除術後之克隆氏疾病復^ 效用。然而’於臨床試驗t不存在 日’曰 確信的結論，參見Rlzzello，Gut.，2〇〇〇,47=法传到 A12。然而’所建議之使用利福昔明⑽毫克Merck Index, XIII Edition, 8301). Guidance notes on crystallization and drying of rifaximin in Italian Patent Application No. MI2003A002144 (2003), European Patent Application No. Ep 1557421 (2003), U.S. Patent Application Serial No. 1/728, No. 9 (2003), PCT Patent Application No. WO 〇 〇〇 〇 〇 〇 〇 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The experimental conditions described in the I, et al. patents can result in polymorphic forms of rifaximin, respectively referred to as alpha, p, oxime, delta, and epsilon. Rifaximin is approved in certain countries for the treatment of conditions whose stage is partially or completely attributed to acute and chronic infections of the gut by Gram-positive and Gram-negative bacteria, including diarrheal syndrome, altered Intestinal flora, summer diarrh〇ea events, traveller's diarrhea and enterocolitis; prevention of infection complications during gastrointestinal surgery before and after surgery; and as an adjuvant treatment for hyperammonemia. Rifaximin is currently available in children's 312XP/invention manual (supplement)/96-1〇/96127712 200904415 in doses of ι〇〇mg and 2〇〇mg of a saponin or capsule for children, or As an ointment for the treatment of local infections. This == product' especially the study of 2〇0 mg of spirulina showed that rifampicin was effective in preventing Crohn's disease after endoscopic resection. However, in the absence of a clinical trial t, the conclusion is convinced, see Rlzzello, Gut., 2〇〇〇, 47 = Pass to A12. However, the recommended use of rifaximin (10) mg

由於需要高達每天六錠長達三個月，會 1的糸I 從性，而被認為未達最佳值。2〇〇 “之利_ 被用於以600毫克/天之劑量經16星期 = 病，如处价叫 L，Am. J. GastnDenter^'、= = (suppl.) S-25G 所述。 ·，2003, 98 【發明内容】 =技藝中有需要一種用於治療特定位於腸道之残毕 曰明醫樂配方。先前的配方於給藥後經釋放且散佈 U之間。因此’當利福昔明最終到達腸道時，濃产 …增加劑量。為使利福昔明對於治療腸道2 病的療效最大化，此處提供新穎的醫藥配方，苴包括 如^經塗覆僅於腸道中溶解釋放抗生素之耐胃㈣膜的利 :曰明微顆粒。此新穎配方部分由於微顆粒的高表面積而 ^舌性，分與腸黏液間的接觸最大化。此新穎配方亦可容 易地以南及低劑量給藥，例如，用於小兒科用余中 此新:員的对胃性利福昔明配方善加利用在；環境(例 如，其PH值視禁食或存在食物的狀態而自約ι·5至約4㈧ 與腸腔（例如’其pH值視所考慮之腔道而自5 〇至約？· 5) 312XP/發明說明書(補件)/96-10/96127712 11 200904415 之間的pH差。 此新穎形式亦利用利福昔明的多形體形式。 Ϊ醫樂微難塗覆耐胃性薄膜係醫藥領域巾已知多年 的技術。其一般将八a此峨、a y 千 糸刀兩步驟進行：製粒及塗覆。然而，包 粒产褐:丨：在内之許多活性物質的特徵在於相當微細的 1 口’在利福昔明的情況中’大約50%的顆粒粒徑 ^ ^微米與4G«之間。在此種條件下，很難使用 白知之糸統像是流體床塗覆或鋼盤技術。經常會發生 或:會得到經塗覆與未經塗覆職的無規摻混物。’ :=發現可㈣應用流體床技術而獲得包有腸溶衣的 褐曰明微顆粒（且此係本發明之目的），其驚人地可於一 :::::: 夺地進行粉末的濕式製粒及將形成之微顆粒 塗覆可抵抗胃環境的聚合物（一般稱為腸溶包衣）。藉此方 可使在個別步驟中實施之濕式製粒及微顆粒塗覆的主 要不便以及實施整個程序所需之時間及 :規職至最小。此結果係來自在利福昔明之性質二 褐昔明、腸衣聚合物、增塑劑之量及製程參數之適當㈣ =間的組合。此外，且在意料之外地，吾人發現藉由此製 ，吾人獲得具有較各別之未經塗覆配方具更高生體利用 率之特性的抗生素。 此技術對於在利福昔明周圍提供完整塗層的效率由SEM 顯微術獲得證實，如記述於圖la(利福昔明耐胃性微顆粒 之掃描電子顯微照片）及lb(利福昔明耐胃性微顆粒之單 —顆粒的掃描電子顯微照片）令，其中清楚顯示利福昔明 312XP/發明說明書(補件)/96-10/96127712 12 200904415 經腸衣聚合物完全塗覆。粒度相當均勻，而無 當微細的粉末。若存在此等態樣的—或兩者，將會對= 目 進一步的醫藥製劑具有負面影響Q e 可 作為塗覆完整度的證實’利福昔明之财胃性微顆 解分佈顯示利福昔明在低pH值下完全保留且在高於 之pH值下釋放，如圖2(溶解分佈）中所記述。 · 為使活性成分在接近腸黏膜處的釋放最大化，經 胃環境（其pH值視禁食或存在食物的狀態而自工5至4 。PH差。為此，使用具有在5.〇與75間之pH值下溶 衣聚合材料，其包括··具有丙稀酸或甲基丙烯 曰之甲基丙㈣共聚物像是甲基丙烯酸丙㈣乙醋共 聚物（1:1)及甲基丙烯酸甲基丙婦酸甲酉旨共聚物（12)，ς ^酸酉太酸乙職’乙酸㈣經丙基纖維素及乙酸駄酸纖維 =，可於市面購得之產物例如註冊商標K0LLIC0AT⑧、 EUDRAGIT® > AQUATERIC® > AQ0AT® 〇 ^等耐胃性薄膜施用至利福昔明粉末或顆粒係利用 右嫩二體床塗覆技術的習知裝置進行。藉由喷霧將溶解於 ㈣ί劑中或懸浮於水中之薄膜塗料施用於在流體床系 劑氣错由ί氣保持懸浮的粉末或顆粒上。最常用的有機溶 ;台:、’氯甲烧、甲醇丙醇、丙酉同、乙酸三乙g旨及乙 =、或者♦ δ耐月性材料可懸浮於水中而施用。此技術 :其不需要使用溶劑且因此可避免毒物及與安全相關 的問題而為較佳。 127712 512»/發明說明書(補件)_㈣ 13 200904415 可與水合材料-起添加其他具有抗凝聚性質的賦形 劑，像是滑石；具有增塑性質的賦形劑，像是乙酿化甘油 酉曰酞酉义一乙酉曰、丙一醇及聚乙二醇；表面活性劑，像是 縮聚山梨醇油酸酉旨及聚氧伸乙基酉旨；消泡劑以及防黏劑。 、2前述技術成功應用㈣覆利福昔明#末係相當值得 注意，因其並非將腸衣聚合物直接喷塗於活性成分上，而 沒有任何像是製粒或將活性成分鋪設於惰性顆粒上之初 f處理之最新型的流體床技術。事實上，若沒有任何粉末 刖處理將會發生數項缺失，諸如形成大團塊、顆粒直捏變 化巾田度大、不均勻的微顆粒組成物、不均句的塗層。利福 昔明常會發生-些此等缺失，其之粉末係由微細顆粒所構 成，且極度疏水、帶靜電、吸濕且很難與粉末中之常用賦 形劑混合。此外，其有分離而無法形成均勾混合物的傾 向。在存在此等不利㈣*使得經塗覆之利福昔明需要使 用超過-步驟及大量賦形劑時，將會限制人類 濃度。 — 本發明之再-優點為可直接使用基於本發明所述之技 術而製備之利福昔明的耐胃性微顆粒於填裳膠囊，或 其與賦形劑及甜味增強劑混合，而得以水性懸浮液 可能性。 vs =此之外且更值得注意地’利福昔明之耐胃性微顆粒亦 可透過直接I縮技術經由添加習知之媒劑或載劑而直接 用於錠劑製備。另一優點為可劃分錠劑以調整劑量濃度或 將其麼碎以利於服用，而不會喪失微顆㈣耐胃^〇 312XP/發明說明書(補件)/96-10/96127712 14 200904415 所有此等機會賦予本發明中所述用於製備利福昔明之Due to the need for up to six ingots per day for up to three months, it will be considered to be less than optimal. 2〇〇 “The profit _ is used for a dose of 600 mg/day for 16 weeks = sick, as the price is L, Am. J. GastnDenter^', = = (suppl.) S-25G. , 2003, 98 [Summary] = There is a need in the art for the treatment of a specific formula in the intestines. The previous formula is released and spread between U after administration. Therefore, 'When Leefu When the sun finally reaches the intestine, it is concentrated... increasing the dose. In order to maximize the therapeutic effect of rifaximin on the treatment of intestinal disease, a novel pharmaceutical formula is provided here, including, for example, coating only in the intestine. Dissolving the release of antibiotics against the stomach (4) membrane: 曰明微粒. This novel formulation is partially due to the high surface area of the microparticles, and the contact between the intestinal mucus is maximized. This novel formula can also be easily south. And low-dose administration, for example, for pediatric use, this new: the use of the stomach rifaximin formula; the environment (for example, its PH value is dependent on the state of fasting or food) ι·5 to about 4 (eight) with the intestinal lumen (eg 'the pH depends on the lumen considered from 5 〇 to about?· 5) pH difference between 312XP/invention specification (supplement)/96-10/96127712 11 200904415. This novel form also utilizes the polymorphic form of rifaximin. The towel is known for many years. It is generally carried out in two steps: a 峨, ay 糸 糸 knife: granulation and coating. However, the browning of the granules: 丨: many active substances are characterized by a rather fine 1 'in the case of rifaximin' between about 50% of the particle size ^ ^ micron and 4G «. Under such conditions, it is difficult to use a white bed like a fluid bed coating or steel plate Technology. Often occurs or: a random blend of coated and uncoated jobs is obtained. ' := It is found that (4) application of fluid bed technology to obtain enteric coated brown peony microparticles (and It is an object of the present invention) that it is surprisingly capable of wet granulation of a powder and coating of the formed microparticles with a polymer resistant to the stomach environment (generally referred to as enteric solution) on a :::::: Coating). The main inconvenience of wet granulation and microparticle coating which can be carried out in individual steps The time required to implement the entire procedure and: minimum to the standard. This result is derived from the combination of the amount of cifuximin in the rifaximin, the amount of the casing polymer, the amount of plasticizer and the appropriate (four) = process parameters. And unexpectedly, we have found that by this method, we have obtained antibiotics with higher bioavailability characteristics than the different uncoated formulations. This technique provides a complete coating around rifaximin. The efficiency was confirmed by SEM microscopy, as described in Figure la (scanning electron micrograph of rifaximin-resistant gastric microparticles) and lb (scanning of rifaximin-resistant gastric microparticles - single-particles) Electron micrograph), which clearly shows rifaximin 312XP / invention specification (supplement) / 96-10/96127712 12 200904415 completely coated with the casing polymer. The particle size is fairly uniform without the fine powder. If there is such an aspect - or both, it will have a negative impact on further pharmaceutical preparations. Q e can be used as a confirmation of the integrity of the coating. The rifaximin's gastric micro-dissolution distribution shows rifaxi It is completely retained at low pH and released above pH, as depicted in Figure 2 (dissolution profile). · In order to maximize the release of the active ingredient near the intestinal mucosa, the stomach environment (the pH value is self-working 5 to 4 depending on the state of fasting or food presence. PH difference. For this purpose, use has a a coating polymer material at a pH of 75, comprising: a methyl propyl (tetra) copolymer having acrylic acid or methacryl oxime, such as propylene (tetra) methacrylate copolymer (1:1) and methyl Methyl propyl acrylate methyl methacrylate copolymer (12), ς 酸 酸 酸 酸 酸 酸 ' acetic acid (four) propyl cellulose and acetic acid phthalic acid fiber =, commercially available products such as registered trademark K0LLIC0AT8, EUDRAGIT ® > AQUATERIC® > AQ0AT® 等^ is applied to the rifaximin powder or granules using a conventional device using the right tender body bed coating technique. It is dissolved by the spray (4) The film coating in medium or suspended in water is applied to the powder or granules in which the fluid bed is kept in suspension by the gas. The most commonly used organic solvent; Taiwan: 'chloroform, methanol, propanol, The triethyl g acetate and the B=, or ♦ δ-resistant lunar material can be suspended in water for application. This technique: it does not require the use of solvents and thus avoids poisons and safety-related problems. 127712 512»/Invention Manual (Supplement)_(4) 13 200904415 Can be combined with hydrated materials to add other anti-agglomerating properties Excipients, such as talc; excipients with plasticizing properties, such as glycerin, glycerol, propanol, and polyethylene glycol; surfactants, such as polysorbitol Oleic acid and polyoxyethylene ethyl ester; defoamer and anti-adhesive agent. 2 Successful application of the above technology (4) rifaximin # is very noteworthy because it is not directly spraying the casing polymer On the active ingredient, without any of the latest fluid bed technologies like granulation or the initial treatment of the active ingredient on inert particles. In fact, if there is no powder 刖 treatment, several defects will occur, such as Forming large agglomerates, granules, straight-kneading, large-scale, uneven micro-particle composition, uneven coating, rifaximin often occurs - some of these defects, the powder is composed of fine particles Extremely sparse It is electrostatically charged, hygroscopic and difficult to mix with the usual excipients in the powder. In addition, it has a tendency to separate and fail to form a homogenous mixture. In the presence of such disadvantages (4)*, the coated rifaximin needs When more than the steps and a large number of excipients are used, the human concentration will be limited. - A further advantage of the present invention is the direct use of gastric resistant microparticles of rifaximin prepared according to the techniques described herein. Capsules, or their combination with excipients and sweetness enhancers, make it possible to obtain an aqueous suspension. vs = this and more notably the 'living-resistant microparticles of rifaximin can also be directly condensed The technique is directly used for tablet preparation by adding a conventional vehicle or carrier. Another advantage is that the tablet can be divided to adjust the dosage concentration or to break it to facilitate the administration without losing the microparticles. 312XP/Invention Manual (Supplement)/96-10/96127712 14 200904415 All such opportunities are given to the preparation of rifaximin as described in the present invention

耐胃性微顆粒之技術重要價值，而使其適用於寬廣地調整 劑量及醫藥形式。 ° I 總而言之，本發明相對於其他市售利福昔明製劑展現可 概述於下的顯著改良：僅以一步驟製造利福昔明之^胃性 微顆粒的可能性，該微顆粒於胃中（例如，pH值於約^ 5 與約4.0之間的範圍内）保持不溶解及於腸中（例如，於較 高PH值下，例如在約5.5與約75之間）可溶解，以投: 高㈣’使活性成分於腸中有最大釋放且㈣由於微顆^ 之面表面積而使其與腸黏膜的接觸最大化。 【實施方式】 本發明之目的係由以下各項所組成：含有經塗覆在^ 5 與4.0間之pH值範圍内不溶解且在5. 〇與7 5間之邱值 範圍内可溶解之财胃性聚合物之利福昔明之微顆粒的醫 藥配方；其之製備；及其於腸發炎性腸道疾病，及尤其係 於克隆氏疾病中之用途。 微顆粒之直徑可在約"敞米至約9〇〇微米之間，或更佳 為直徑在約1 0微米至約5〇〇微米之間。 财胃性可使用任何PH值範圍在約i至約4 9 至約4.2、或約L5與約4·〇間不溶解的材料而 · 當的聚合物亦可在pH值範圍約5. 〇至 又 、 7.5、或5.0與約7.7及以上間溶解。'、、.、5.〇至約 利用於耐胃性利福昔明配方中之人 與腸腔-致的pH值(例如’在約4.9 如刚所述在 一幻7. 7之間）下溶 312XP/發明說明書(補件)/96· 10/96127712 15 200904415 解，且可使用作為當需要時於腸中釋放藥物的耐胃性、腸 溶解塗層。適當聚合材料的實例包括，例如，丙烯酸系聚 合物，具有丙烯酸或曱基丙烯酸酯之甲基丙烯酸共聚物 (例如，曱基丙烯酸丙烯酸乙酯共聚物（1:1)及曱基丙烯酸 甲基丙烯酸曱酯共聚物（1: 2 )、聚乙酸酞酸乙烯酯、乙酸 酞酸羥丙基纖維素及乙酸酞酸纖維素），以及乙酸酞酸纖 維素，酞酸經丙基曱基纖維素，聚乙酸駄酸乙稀s旨。市售 產品包括，例如，K0LLIK0AT®、EDRAGIT®(例如，EUDRAGIT (40)、AQUATERIC®、AQ0AT®。 經常將可在較高pH值下溶解的腸衣材料使用於對結腸 特異的傳遞系統中，且其可使用於此處所述的耐胃性利福 昔明配方中。所使用之腸衣聚合物亦可經由與其他不為 pH敏感性的塗覆產品混合而改質。此等塗覆產品的實例 包括，例如，目前以商品名EUDRAGIT®及EUDRAGIT® RL 銷售之具有小部分氣化甲基丙烯酸三曱基胺乙酯之中性 y 甲基丙烯酸酯；以商品名EUDRAGIT® NE30D及EUDRAGIT® NE30、EUDRAGIT® 40銷售之沒有任何官能基的中性酯分 散物；多醣，像是直鏈澱粉、聚葡萄胺糖、軟骨素硫酸鹽、 聚葡萄糖、瓜爾膠（guar gum)、菊糖及果膠；及其他與 pH無關之塗覆產品。 聚合物佔微顆粒重量之約5%與約75%之間。在其他具體 例中，聚合物佔微顆粒重量之約10%與約60%、20%與約 55%、約30%至約80%、或25%與約50%之間。聚合物對微 顆粒重量之重量百分比可部分視所使用之聚合物、聚合物 312XP/發明說明補件)/96-10/96127712 16 200904415 之溫度、配方（例如，袋、丸劑、膠囊等等）、及聚合物可 溶解的pH而定。 耐胃性利福昔明微顆粒可進一步包含稀釋劑、增塑劑、 抗凝聚劑、防黏劑、滑動劑、消泡表面活性劑、或著色物 質中之一或多者。將此等以及其他的聚合物及塗層（例 如’保護性塗層、面塗層、及薄膜）說明於下。 可將適當的成分併入至塗覆配方中，諸如增塑劑，其包 括’例如’己二酸酯、壬二酸酯、苯曱酸酯、擰檬酸鹽、 ' 異依布酸酯（is〇ebucates)、酞酸酯、癸二酸酯、硬脂酸 醋及二醇類。代表性的增塑劑包括乙醯基化單甘油酯、丁 基駄醯基丁基羥乙酸酯、酒石酸二丁酯、酞酸二乙酯、酞 酸二曱酯、乙基酞醯基乙基羥乙酸酯、甘油、乙二醇、丙 二醇、三乙醯甘油檸檬酸酯、三乙醯甘油、三丙姻 (tripropinoin)、二乙醯甘油、酞酸二丁酯、乙醯基單甘 油酯、聚乙二醇、蓖麻油、擰檬酸三乙酯、多羥醇、乙酸 酯、甘油三乙酸酯、乙醯基三乙基檸檬酸酯、酞酸二苄酯、 酞酸二己酯、丁基辛基酜酸酯、酜酸二異壬酯、丁基辛基 酞酸酯、壬二酸二辛酯、環氧化妥爾油酸酯（tallate)、 1，2,4-苯三曱酸三異辛酯、酞酸二乙基己酯、酞酸二正辛 酯、酞酸二-1-辛酯、酞酸二-1-癸酯、酞酸二-正十一烧 酯、酞酸二-正十三烷酯、1，2, 4-苯三曱酸三-2-乙基己 酯、己二酸二-2-乙基己酯、癸二酸二-2-乙基己酯、壬二 酸二-2 -乙基己酯、癸二酸二丁酯、單辛酸甘油酯、及單 癸酸甘油酯。亦可設想熟悉技藝人士所知曉之其他各種 312XP/發明說明書(補件)/96-10/96127712 17 200904415 層。以乾燥聚合物之重量計，增塑劑於聚合材料中之使用 量典型上係在約10%至約50%之範圍内，例如，約10、20、 30、40、或 50%。 可於腸溶包衣或其他塗層上方使用之保護層之視需要 的改質成分包括水分滲透障壁層（半滲透性聚合物），其可 於腸溶包衣或其他塗層之後相繼塗覆，以降低通過腸溶包 衣層的水分滲透速率且因此提高藥物釋放的延遲時間。可 利用諸如流體床塗覆之塗覆技術使用聚合物於水或適當 1 有機溶劑中之溶液或經由使用水性聚合物分散液將熟悉 技藝人士一般知曉的塗層使用於此目的。舉例來說，有用 的材料包括乙酸纖維素、乙酸丁酸纖維素、乙酸丙酸纖維 素、乙基纖維素、脂肪酸及其之酯、蠟、玉米蛋白、及水 性聚合物分散液諸如EUDRAGIT® RS及RL 30D、EUDRAGIT® NE 30D、EUDRAGIT® 40、AQUACOAT®、SURELEASE®、乙酸 纖維素乳膠。亦可使用聚合物之組合及親水性聚合物諸如 ， 經乙基纖維素、經丙基纖維素（KLUCEL®，Hercules Corp.)、經丙基甲基纖維素（METHOCEL®，Dow Chemical Corp.)、聚乙烯基吼p各咬酮。 亦可將消泡劑包含於耐胃性利福昔明配方中。在一具體 例中，消泡劑為二曱石夕油（simethicone)。消泡劑之使用 量典型上佔最終配方的0%至0. 5%。可添加其他試劑以改 良密封劑或障壁層的加工性。此等試劑包括，例如，滑石、 膠態矽石、聚乙烯醇、二氧化鈦、微粒化矽石、煅製矽石、 甘油單硬脂酸酯、三矽酸鎂、及硬脂酸鎂、或其混合物。 312XP/發明說明書(補件)/96-10/96127712 18 200904415 典型上調整耐胃性配方 望的華物禮、庚u 合物的使用量’以獲致期 物 質，包括藥物之傳遞量、藥物傳遞之速车 聚合材料之所有固體成八上及配方中之多顆粒大小。 及視-要夕糾括共聚物、填料、增塑劑、 及視而要之賦形劑及加工助 日土w 1重量％至約50重量％。 fa典型上佔核心的約 形式明微顆粒包含呈多形體形式及/或原料 式、職形ίΓ分视‘經塗覆之利福昔明之形 钿曰明多形體形式係選自以上 勺 式丄或ε式之利福昔明。上所叙4、β式、γ式、δ 水；有：:：材料之混合物係經由使成分懸浮於去礦質 二速混合系統(較佳為U1™均質機） 均質化，以獲得含有介於15%與綱間 粒的均勾懸浮液而製備得。含有 衣有付3有耐月性材料之均勻懸浮液 和用主覆糸統或流體床裝置施用。 ^發明係使用流體床技術。藉由暖空氣之流出使含有 1/喷.=之混合物保持懸浮，同時利用於裝置之頂部(頂 或於下部（底部喷霧—Wurster系統）施加之喷射喷The technically important value of gastric-resistant microparticles makes them suitable for a wide range of dosages and pharmaceutical forms. In summary, the present invention exhibits a significant improvement outlined below with respect to other commercially available rifaximin formulations: the possibility of making sulphate microparticles of rifaximin in only one step, the microparticles in the stomach ( For example, a pH in the range between about 5 and about 4.0 remains insoluble and soluble in the intestine (eg, at a higher pH, such as between about 5.5 and about 75) to administer: High (four) 'allows the active ingredient to have maximum release in the intestine and (iv) maximizes contact with the intestinal mucosa due to the surface area of the micro-particles. [Embodiment] The object of the present invention consists of containing a solution which is insoluble in a pH range between 5 and 4.0 and soluble in a range of values between 5. 〇 and 75. Pharmaceutical formula of rifaximin microparticles of a curative polymer; preparation thereof; and its use in intestinal inflammatory bowel diseases, and especially in Crohn's disease. The diameter of the microparticles may range from about "open meters to about 9 microns, or more preferably between about 10 microns and about 5 microns. The pH can range from about i to about 4 9 to about 4.2, or about between about L5 and about 4, and the polymer can also be used in the pH range of about 5. Further, 7.5, or 5.0 is dissolved between about 7.7 and above. ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The solution is 312XP/invention specification (supplement)/96·10/96127712 15 200904415, and can be used as a gastric-resistant, enteric coating which releases the drug in the intestine when needed. Examples of suitable polymeric materials include, for example, acrylic polymers, methacrylic acid copolymers having acrylic acid or mercapto acrylate (for example, methacrylic acid ethyl acrylate copolymer (1:1) and methacrylic acid methacrylic acid) An oxime ester copolymer (1: 2), polyvinyl acetate phthalate, hydroxypropyl cellulose acetate and cellulose acetate phthalate, and cellulose acetate phthalate, decanoic acid via propyl fluorenyl cellulose, Polyacetate bismuth sulphate. Commercially available products include, for example, K0LLIK0AT®, EDRAGIT® (eg, EUDRAGIT (40), AQUATERIC®, AQ0AT®. Casing materials that can be dissolved at higher pH values are often used in colon-specific delivery systems, and It can be used in the gastric resistant rifaximin formulations described herein. The casing polymers used can also be modified by mixing with other non-pH sensitive coated products. Examples include, for example, a small portion of gasified tridecylamine ethyl methacrylate neutral y methacrylate sold under the trade names EUDRAGIT® and EUDRAGIT® RL; under the trade names EUDRAGIT® NE30D and EUDRAGIT® NE30 , EUDRAGIT® 40 sells neutral ester dispersions without any functional groups; polysaccharides such as amylose, polyglucamine, chondroitin sulfate, polydextrose, guar gum, inulin and fruit Glue; and other pH-independent coated products. The polymer is between about 5% and about 75% by weight of the microparticles. In other embodiments, the polymer comprises about 10% and about 60% by weight of the microparticles, 20% and about 55%, about 30% to about 80%, Between 25% and about 50%. The weight percent of the polymer to the weight of the microparticles may depend, in part, on the temperature of the polymer used, polymer 312XP/invention instructions)/96-10/96127712 16 200904415 (eg , bags, pills, capsules, etc.), and the pH at which the polymer can dissolve. The gastric-resistant rifaximin microparticles may further comprise one or more of a diluent, a plasticizer, an anti-agglomerating agent, an anti-sticking agent, a slip agent, a defoaming surfactant, or a coloring matter. These and other polymers and coatings (e.g., 'protective coatings, topcoats, and films') are described below. Suitable ingredients can be incorporated into the coating formulation, such as plasticizers, including, for example, 'adipate, sebacate, benzoate, citric acid, 'isophthalate ( Is〇ebucates), phthalic acid esters, sebacates, stearic acid vinegars and glycols. Representative plasticizers include ethoxylated monoglycerides, butyl decyl butyl hydroxyacetate, dibutyl tartrate, diethyl decanoate, dinonyl decanoate, ethyl decyl ethene Glycolate, glycerol, ethylene glycol, propylene glycol, triethylene glycol glyceride, triethylene glycol glycerin, tripropinoin, diacetyl glycerol, dibutyl phthalate, acetyl glycerol Ester, polyethylene glycol, castor oil, triethyl citrate, polyhydric alcohol, acetate, triacetin, acetyl triethyl citrate, dibenzyl citrate, citric acid Hexyl ester, butyl octyl decanoate, diisononyl phthalate, butyl octyl phthalate, dioctyl sebacate, oxidized tallate, 1,2,4- Triisooctyl phthalate, diethylhexyl phthalate, di-n-octyl phthalate, di-1-octyl phthalate, di-1-decyl phthalate, di-n-decyl citrate Ester, di-n-tridecyl phthalate, tris-2-ethylhexyl 1,2,4-benzenetridecanoate, di-2-ethylhexyl adipate, di-2-sebacate Ethylhexyl ester, di-2-ethylhexyl sebacate, dibutyl sebacate, monocaprylic glycerol Ester, and glycerol monocaprate. Other various 312XP/invention manuals (supplements)/96-10/96127712 17 200904415 layers known to those skilled in the art are also contemplated. The amount of plasticizer used in the polymeric material is typically in the range of from about 10% to about 50% by weight of the dry polymer, for example, about 10, 20, 30, 40, or 50%. The optional modifying component of the protective layer that can be applied over the enteric coating or other coating comprises a moisture permeable barrier layer (semi-permeable polymer) which can be applied sequentially after the enteric coating or other coating. To reduce the rate of moisture permeation through the enteric coating layer and thus increase the delay in drug release. Coatings generally known to those skilled in the art can be used for this purpose using a coating technique such as fluid bed coating using a solution of the polymer in water or a suitable organic solvent or via the use of an aqueous polymer dispersion. Useful materials include, for example, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and esters thereof, waxes, zein, and aqueous polymer dispersions such as EUDRAGIT® RS. And RL 30D, EUDRAGIT® NE 30D, EUDRAGIT® 40, AQUACOAT®, SURELEASE®, cellulose acetate latex. Combinations of polymers and hydrophilic polymers such as ethylcellulose, propylcellulose (KLUCEL®, Hercules Corp.), propylmethylcellulose (METHOCEL®, Dow Chemical Corp.) may also be used. , polyvinyl 吼p each biting ketone. Antifoaming agents can also be included in the gastric resistant rifaximin formulation. In one embodiment, the antifoaming agent is simethicone. 5%。 The amount of defoaming agent is typically 0% to 0.5% of the final formulation. Other reagents may be added to improve the processability of the sealant or barrier layer. Such agents include, for example, talc, colloidal vermiculite, polyvinyl alcohol, titanium dioxide, micronized vermiculite, fumed vermiculite, glyceryl monostearate, magnesium tristearate, and magnesium stearate, or mixture. 312XP/Inventive Manual (Supplement)/96-10/96127712 18 200904415 Typically, the amount of Huali et al. used to adjust the stomach resistance formula is used to obtain the substance, including the drug delivery amount and drug delivery. All of the solids of the speeding vehicle polymeric material are in the form of a plurality of particles and a plurality of particles in the formulation. It is also important to rectify the copolymer, the filler, the plasticizer, and the excipients and processing aids, from 1% by weight to about 50% by weight. Fa typically occupies the core form of the microparticles in the form of polymorphs and/or raw materials, and the shape of the lyophilized form of the coated rifaximin is selected from the above spoons. Or ε-type rifaximin. 4, β, γ, δ water; there is:: mixture of materials is homogenized by suspending the components in a demineralized two-speed mixing system (preferably U1TM homogenizer) to obtain Prepared by 15% suspension with the inter-column. A uniform suspension containing a durable material having a durability of 3 is applied and applied by a main cover or fluid bed device. ^Inventives use fluid bed technology. The mixture containing 1/spray is suspended by the outflow of warm air while being applied to the top of the apparatus (top or to the lower part (bottom spray - Wurster system))

^而、/性懸浮液。舉例來說’使用流體床裝置Glatt GPG t变'，利用具有K8毫米噴霧噴射之18英吋的Wurster 糸統。 月確地控帝j包括空氣進入溫度、產物溢度及薄膜施用速 312XP/__®(_)/%_ 10/% 112 19 200904415 度的製程參數。使薄膜施用速度及空氣溫度平衡，以避免 產物過熱而導致不均勻的耐胃性微顆粒形成（產物過快乾 舞）’或待塗覆之混合物滅聚而減緩產物之乾燥。 在調配時’例如’可使用25公斤批量之耐胃性利福昔 明，介於150與300克/分鐘之間的喷射噴霧。亦可使用 150與250克/分鐘之喷射噴霧，及介於1〇與15巴（1^4 之間的壓力。速度及壓力可獨立地操控。將噴霧期間的Z 厂物溫度維持在介於約20°C與約4(TC之間的恆溫下。亦可 f 將入口中的空氣溫度調整在介於約4〇t與約75。〇之間， 較佳介於約60°C與約70。(：之間。 將獲得的耐胃性微顆粒調配供醫藥製劑用，以於添加水 之後獲得具有供病患用之悅人味道的懸浮液。為此可將甜 味劑像是蔬糖、山梨糖醇、甘露糖醇、糖精、醋磺内醋 (aceSulfame)、新橘皮甙（ne〇hesperidin);懸浮劑像是 聚乙烯基吼咯啶酮（PVP)、羧甲基纖維素鈉、果膠、三仙 g膠、瓊脂；及滑動劑像是矽膠添加至耐胃 田於適當的裝置像是雙錐形混合機或中將耐 月性微顆粒與前述賦形劑混合可於混合物内得到耐胃性 微顆粒之均勻度所需的時間。而才胃性微顆粒與賦形 的比係在1 . 〇 1盘卜1 η令p目知· /+ + , 〜牡1.U.1興1.10之間，較佳在1:〇 5與1:5之 可將獲得之混合物分配於含有介於i亳克與300 間:較佳介於50毫克與_毫克之間之利福昔明量的袋 内 所獲得之利福昔明之耐胃性微顆粒可在與諸如下列之 312XP/翻義書(補件)/96.1G/96127712 200904415 二 適當賦㈣混合後直接㈣成㈣m諸如罐酸一 鈣、硫酸鈣、纖維素、微晶纖維素u 基，維素:玉米殺粉、乳糖、高屬土、甘露糖醇、=甲 乾m #占合劑，諸如殿粉、明膠、糖如 鳩、乳糖、合成膠、海草酸納、綾甲基纖維：萄:基 :雉：:聚上烯基°比咯啶酮、聚乙二醇、乙基纖維素、水、 各⑺劑，諸如滑石、硬脂酸鎂、硬脂酸鈣、硬脂 二風：：：油:聚乙二醇;滑動劑’諸如膠態二氧化矽、 朋—諸如玉米及馬鈴薯澱粉、交聯羧甲基纖维 =二=乙埽…酮(crospovi done)、殿粉經基乙酸 :二=甜味劑，諸如嚴糖、山梨糖醇、甘露糖醇、 糖精、醋％内酯、新橘皮甙。 技藝專家已知之習知的技術及裝置。於 =w、: \疋雙錐形混合機或v型混合機中將耐胃性 微顆粒與前述賦形劑入 粒之均勻度所需的二 Γ 合物内得到耐胃性微顆 方=Γ耐胃性顆粒在自由流動能力、内聚力及潤滑 係介朴質，因此耐胃性微顆粒與賦形劑之間的比 ' ./ ，、1:〇. 05 之間，較佳介於 1··0. 15 與 1:〇 Ί :二。所獲得之混合物可使用適當的衝頭加壓得人 =於？毫克與_毫克之間，較佳介於i。。毫克二 笔克之間之利福昔明量的錠劑。 、 性微顆粒之有利性質容呼獲致用“所述，利褐昔明耐胃 ^令扪性貝谷°午獲致用於藉由添加最少量之神 而直接壓縮的適當摻混物。使用含有高達咖之耐胃 Μ2ΧΡ/發明說明書⑽件y96_1〇/%1277i2 21 200904415 性微顆粒之摻混物製得錠劑之可能性呈現進一步 點：其可使400亳克之劑量保持適當的尺寸 ( 的良好依從性。 再符届患 可接著將錠劑塗覆習知之親水性薄膜，以獲致味道掩飾 性質及改善外觀。適當的材料可為：經乙基纖維素、 基纖維素（KLUCEL®，Hercules C(Drp.)、㈣基甲基^ 素⑽職⑽，_c：hemieal _.)、聚乙 w 酮。 心 含有利福昔明耐胃性微顆粒之錠劑可依據孰朵技蓺人 士已知之習知程序選擇-或多種纖維素及其^物:如 2基纖維素、經甲基纖維素、經丙基甲基纖維素作為聚 二士而進打薄膜塗覆。纖維素醚之替代選擇為某些丙烯酸 系樹脂’諸如甲基丙烯酸醋及甲基丙烯酸甲酿共聚物。聚 合物可以水性或基於有機溶劑之系統的溶液使用。併入增 改良塗膜的可撓性；藉由添加增塑劑，可降低薄膜 風險’且可改良薄膜對基質之黏著。典型增塑劑的 只例包括甘油、丙二醇、聚乙二醇、三乙酿甘油、乙献 =早甘油酯、檸檬酸酉旨及酉太酸酉旨。通常使用著色劑以改良 =外觀。可使用水溶性及/或有機溶劑可溶解的染料， ^白蛋白湖（albumin lake)、二氧化鈦、氧化鐵。最後， J將諸如EDTA之穩定劑添加至塗層。 圖3中所示之圖(壓縮成錠劑之利福昔明耐胃性微顆粒 =描電子顯微照片）及圖2之數據顯示壓縮不會改變壓 縮錠劑之耐胃性微顆粒層的整體性。 312XP/發明說明書(補件)/%-10/96127712 22 200904415 於:Ϊ膠所:Λ之利福昔明之对胃性微顆粒藉由添加填裝 及自由、、^囊之惰性稀釋劑及滑動劑而具有關於粒度 實例包能力的有利性質。典型稀釋劑的 基甲基纖維素:王二維^微 μ r 殿粉、乳糖、高嶺土、甘露糖醇、氮 ’乙燥澱粉，其係介於約1至約225毫克之門t ' 情況’根據耐胃性微顆粒中之利福昔明含量克之介 ί '·笔克/耄升之間之耐胃性微顆粒之密度容許於習 ::〇〇〇物膠嚢中填裝約140_250毫克之利福昔明。 、所有的藥物製劑，即熱熔袋、錠劑及膠囊， 治療包括克隆氏疾病的發炎性腸道疾病中。 、 利祸昔明的生體利用率研究係以交叉(cross—―嘹 =於母的小獵犬上進行。經由σ服途徑以存於湘耐^ 从顆粒製備得之膠囊中之⑽毫克/天劑量治療動物，且 於至少7天的藥物排除時間（wash_〇ut peri〇d)後，利用 C存於膠囊十之100 «克/天利福昔明對其進行治療。於各 次給藥前及各次給藥後的卜2、4、6、8及24小時自各^ and / / sexual suspension. For example, 'the fluid bed device Glatt GPG t' was used, using an 18-inch Wurster system with a K8 mm spray jet. The monthly control parameters include air inlet temperature, product overflow and film application speed 312XP/__®(_)/%_ 10/% 112 19 200904415 degrees. The film application speed and air temperature are balanced to avoid overheating of the product resulting in uneven gastric microparticle formation (products are too fast to dry) or the mixture to be coated is depolymerized to slow the drying of the product. A spray spray of between 150 and 300 g/min can be used, for example, in a 25 kg batch of gastric resistant rifaximin at the time of formulation. Spray sprays of 150 and 250 g/min can also be used, and pressures between 1 and 15 bar (1^4). Speed and pressure can be independently controlled. Maintain the temperature of the Z plant during the spray. At a constant temperature between about 20 ° C and about 4 (TC), the air temperature in the inlet can also be adjusted to be between about 4 〇t and about 75 〇, preferably between about 60 ° C and about 70. (: between. The obtained gastric microparticles are formulated for use in pharmaceutical preparations to obtain a suspension having a pleasant taste for the patient after adding water. For this purpose, the sweetener can be like a vegetable candy. , sorbitol, mannitol, saccharin, aceSulfame, neo〇hesperidin; suspensions like polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose , pectin, sanxian g gel, agar; and slip agent such as silicone added to the stomach resistant in a suitable device such as a double cone mixer or medium-to-month microparticles mixed with the aforementioned excipients can be mixed The time required to obtain the uniformity of the gastric microparticles is obtained, and the ratio of the gastric microparticles to the shaping is 1. 1 盘1盘卜1 η令普目Know that / / + + , ~ between 1.U.1 Xing 1.10, preferably at 1: 〇 5 and 1: 5 can be obtained by distributing the mixture between i gram and 300: preferably between The gastric-resistant microparticles of rifaximin obtained in a bag of rifaximin between 50 mg and _mg can be used in conjunction with 312XP/Findbacks (supplement)/96.1G/96127712 200904415 Appropriately (4) mixed directly (four) into (four) m such as candonic acid calcium, calcium sulfate, cellulose, microcrystalline cellulose u base, vitamins: corn powder, lactose, high genus, mannitol, = jiagan m # Occupation agent, such as temple powder, gelatin, sugar such as sputum, lactose, synthetic rubber, sodium oxalate, strontium methyl fiber: :: base: 雉:: poly(alkenyl), pyridone, polyethylene glycol, B Cellulose, water, each (7) agent, such as talc, magnesium stearate, calcium stearate, stearic acid:::oil: polyethylene glycol; slip agent 'such as colloidal cerium oxide, penta- such as Corn and potato starch, cross-linked carboxymethyl fiber = crospovi done, phylum powder, acetic acid: two = sweetener, such as Yan sugar, sorbitol, mannitol, saccharin , vinegar % lactone, new cellulite. Known techniques and devices known to the skilled artisan. In the =w,: \疋 double conical mixer or v-type mixer, the gastric-resistant micro-particles and the aforementioned shaping The bismuth compound required for the uniformity of the granules is obtained into the stomach-resistant micro-particles. The sputum-resistant granules are free-flowing, cohesive and lubricating, so the gastric micro-particles and excipients are resistant. Between the ratios of . . . , , 1: between 05. 05, preferably between 1··0. 15 and 1: 〇Ί: two. The obtained mixture can be pressurized with a suitable punch = ? Between milligrams and _ milligrams, preferably between i. . A dose of rifaximin between two grams of gram. The advantageous properties of the micro-particles are obtained by the use of "the above-mentioned, the sirloin is resistant to the stomach and the sputum is used to obtain a suitable blend for direct compression by adding a minimum amount of god.咖耐胃Μ2ΧΡ/Invention Manual (10) y96_1〇/%1277i2 21 200904415 The possibility of making a tablet with a blend of micro-particles presents a further point: it can maintain a proper size of 400 gram dose (good compliance) Further, the tablet may be coated with a conventional hydrophilic film to obtain a taste-masking property and an improved appearance. Suitable materials may be: ethyl cellulose, cellulose (KLUCEL®, Hercules C ( Drp.), (iv) ketomethyl (10) (10), _c:hemieal _.), polyethylidene ketone. The heart contains rifaximin-resistant gastric microparticle tablets can be based on the knowledge known to the skilled person Know the program choice - or a variety of cellulose and its contents: such as 2-based cellulose, methyl cellulose, propyl methyl cellulose as a poly-dioxide film coating. The alternative to cellulose ether is Certain acrylic resins such as methacrylic acid vinegar and nail Acrylic styrene copolymer. The polymer can be used in aqueous or organic solvent based systems. Incorporating flexibility to improve the coating film; by adding a plasticizer, the film risk can be reduced' and the film can be modified Adhesive. Typical examples of typical plasticizers include glycerin, propylene glycol, polyethylene glycol, triethyl glycerol, ethyl glycerol, glyceryl citrate, and citrate. Colorants are commonly used to improve = appearance. Water-soluble and/or organic solvent-soluble dyes, ^ albumin lake, titanium dioxide, iron oxide can be used. Finally, J adds a stabilizer such as EDTA to the coating. The rifaximin-resistant microparticles compressed into tablets were shown in the electron micrographs and the data in Figure 2 showed that compression did not change the integrity of the gastric-resistant microparticle layer of the compressed tablet. 312XP/Invention Manual ( Supplement) /%-10/96127712 22 200904415 In: Ϊ胶所: 利 rifaximin on the stomach microparticles by adding filler and free, sac inert diluent and slip agent with respect to particle size The advantageous nature of the instance package capability. The typical diluent of methylcellulose: Wang two-dimensional ^ micro μ r palace powder, lactose, kaolin, mannitol, nitrogen 'ethyl dry starch, which is between about 1 to about 225 mg of the door 't case' The rifaximin content in the gastric microparticles is based on the density of the gastric microparticles between the pens and the sputum. The density of the gastric microparticles is allowed to be applied to the habit:: 〇〇〇 嚢 140 140 140 140 140 140 140 Fuximin. All pharmaceutical preparations, namely hot-melt bags, lozenges and capsules, are used to treat inflammatory bowel diseases including Crohn's disease. The study on the bioavailability of the past is cross-cross (cross-嘹 = on the mother's beagle. The animals were treated with the (10) mg/day dose in the capsule prepared from the granules via the σ service route, and after at least 7 days of drug exclusion time (wash_〇ut peri〇d), Capsule Ten of 100 «g/day rifaximin treats it. 2, 4, 6, 8 and 24 hours before each administration and after each administration

動物之頸靜脈收集血液樣本，將樣本轉移至含有肝素的管 中’且藉由離心分離血漿。 B 利用有效的LC-MS/MS方法檢定血漿中的利福昔明，且 計算最大觀察得的血漿濃度（Craax)、達到Cmax之時間 (Traax)、及濃度—時間曲線下之面積（Auc)。 以下實施例係應視為本發明目的之進一步說明，而 為限制用。 312XP/發明說明書(補件y96-〗 0/96127712 23 200904415 [實施例1] (耐胃性微顆粒中之利福昔明製備） 將25000克之利福昔明粉末及125克作為流化劑之 Aerosil装填入具有18英吋之Wurs1：er系統與毫米 噴霧喷射的流體床裝置GlattGPC3〇中。同時使用48ι〇7 克之去礦質水' 9281克之以註冊商標KOLLICOAT® MAE 100 p銷售之曱基丙烯酸丙烯酸乙酯共聚物、1392克之丙二 醇、2475克之滑石、557克之二氧化鈦FU及62克之氧化 鐵E 172於混合機中在攪拌下製備懸浮液。利用高速均質 機（Ultra Turrax)使懸浮液之固體成分均勻混合於去礦 貝水中。將製備得之懸浮液供給至流體床裝置之喷霧系 統，且在介於1. 0與1 · 5巴間之壓力下經由1 · 8毫米噴嘴 喷霧於藉由暖空氣流動而於流體床中保持懸浮之利福昔 明粉末與Aerosil 200的混合物上。 所用的條件說明於表i : [表1] 製程參數 預熱期 施用塗覆溶液 乾燥 入口中之空氣流量（m3/小時） 400±100 550±100 350150 入口中之空氣溫度（) 60±2 60°C +10 50 + 2 產物溫度（°c ) 32 25-27 30 + 2 喷射壓力（巴）（起始期） 1-1.5±0.1 喷射速度（g/min) 150-200 使用Malvern Mastersizer 2000裝置利用光散射技術 使所獲得之微顆粒進行粒度測量分析，而得以下結果： 100% < 200 微米 99· 17% < 15〇 微米 312XP/發明說明書(補件)/96-10/96127712 200904415 9〇. 03% < loo 微米 48· 37% < 50 微米 6. 20% < 1〇 微米 當於總顆粒重量之 耐月性微顆粒製劑中之利福昔明相 61.4%。 [實施例2] (利福昔明之耐胃性微顆粒的S Ε Μ顯微分析） 使用SEM Philips 515儀器進行觀察。 利用3 0耄安培之電流將利福昔田 金，而得約100奈米之金層。施加性微顆粒減鑛 利用⑽相機以數位方式記錄影像。伏特之加速電麼。 將，=明之微顆粒的影像示於圖1A，同時於圖财 良、貝不单 Μ顆粒的細部。 [實施例3 ] (製備於熱熔袋中之利福昔明的耐胃性微顆粒） 將9.12公斤之根據實施例j製備得之 微顆粒、㈣公斤之山梨糖醇 ==曰月 ⑽公斤之阿斯巴甜 卿artame)、0.21公斤之無水檸檬酸、 膠:2.10公斤之甘露糖醇、…斤之新橘皮錢ΓΓ2 2之櫻桃香料及〇.〇7公斤之卿於具有G 5毫米網目 =上過筛’然後於V型混合機中混合2〇分鐘。將所得 ^物分配成含有5克產品（相當於_毫克利福昔明） 的熱炫袋。下表2中記述藥用熱溶袋之組成物： [表2] 312XP/發明說明書(補件)/96_ 1 ο/% 127712 25 200904415 成分 _____ 量一 (mg) 耐胃性利福昔明微顆粒（相當於8 〇 〇毫克利福昔明） 1303 26 阿斯巴甜 70 無水檸檬酸 30 _0^6〇_ 果膠 300 6. 〇X- 甘露糖醇 300 新橘皮武DC 30 山梨糖醇 2797 55.^9^ 櫻桃香料 160 3. 2〇_ 矽膠 10 [實施例4] 《（製備於壓縮錠劑中之利福昔明的耐胃性微顆粒） 將9. 3公斤之根據實施例i製備得之耐胃性利福昔明微 顆粒、593克之澱粉羥基乙酸鈉、1〇()克之硬脂酸鎂於具 有0.5毫米網目的篩上過篩，然後於v型混合機中混合 20分鐘。使用設有橢圓形、刻痕19χ9毫米衝頭之 ； 錠機（Fette 1200)將所得混合物壓縮成718亳克之終二 (相當於400毫克之利福昔明含量）。 、'’；里 將键劑組成物記述於表3。 [表3 ]A blood sample is collected from the jugular vein of the animal, and the sample is transferred to a tube containing heparin' and the plasma is separated by centrifugation. B Determination of rifaximin in plasma using an effective LC-MS/MS method and calculation of the maximum observed plasma concentration (Craax), time to Cmax (Traax), and area under the concentration-time curve (Auc) . The following examples are intended to be further illustrative of the objects of the invention and are intended to be limiting. 312XP/Invention Manual (Supplement y96-〗 0/96127712 23 200904415 [Example 1] (Preparation of rifaximin in gastric-resistant microparticles) 25,000 g of rifaximin powder and 125 g were used as a fluidizer Aerosil is filled in a Glab1:er system with a millimeter spray-jet fluid bed unit GlattGPC3®. Also used is 48 〇 7 grams of demineralized water '9281 grams of thiol acrylic acid sold under the registered trademark KOLLICOAT® MAE 100 p Ethyl acrylate copolymer, 1392 g of propylene glycol, 2475 g of talc, 557 g of titanium dioxide FU and 62 g of iron oxide E 172 were prepared in a mixer under stirring. The solid content of the suspension was made using a high speed homogenizer (Ultra Turrax). The mixture is uniformly mixed in the demineralized water. The prepared suspension is supplied to the spray system of the fluid bed device, and is sprayed through a 1·8 mm nozzle under a pressure of between 1.0 and 1.9 bar. The mixture of rifaximin powder and Aerosil 200 kept in a fluid bed by warm air flow. The conditions used are shown in Table i: [Table 1] Process parameters Preheating period Application coating solution drying Air flow in the mouth (m3/hour) 400±100 550±100 350150 Air temperature in the inlet () 60±2 60°C +10 50 + 2 Product temperature (°c) 32 25-27 30 + 2 Injection pressure ( Bar) (initial period) 1-1.5±0.1 Jet velocity (g/min) 150-200 Using the Malvern Mastersizer 2000 device, the obtained microparticles were subjected to particle size measurement analysis by light scattering technique, and the following results were obtained: 100% < 200 micron 99· 17% < 15 inch micron 312XP / invention specification (supplement) / 96-10 / 96127712 200904415 9〇. 03% < loo micron 48 · 37% < 50 micron 6. 20% < 1 〇Micron is 61.4% of the rifaximin phase in the total particle weight of the moon-resistant microparticle preparation. [Example 2] (S Ε Μ microscopic analysis of gastric resistant microparticles of rifaximin) Using SEM Philips The instrument was observed with 515. The gold was used to make rifaxixi gold with a current of 30 amps, and a gold layer of about 100 nm was used. The application of microparticles was reduced. (10) The camera recorded the image digitally. The image of the microparticles of =, Ming is shown in Fig. 1A, and at the same time, in Fig. [Example 3] (Stomach-resistant microparticles of rifaximin prepared in a hot-melt bag) 9.12 kg of the microparticles prepared according to Example j, (four) kilograms of sorbitol ==曰月(10) kilograms of aspartame artate), 0.21 kilograms of anhydrous citric acid, gum: 2.10 kilograms of mannitol, ... pounds of new orange peel money ΓΓ 2 2 cherry spice and 〇. 〇 7 kg of Qing in the G 5 mm mesh = upper sieved' then mixed in a V-blender for 2 minutes. The resulting material was dispensed into a blister bag containing 5 grams of product (equivalent to _mg rifaximin). The composition of the medicinal hot-melt bag is described in Table 2 below: [Table 2] 312XP/Invention Manual (supplement)/96_ 1 ο/% 127712 25 200904415 Ingredients _____ Quantity one (mg) Stomach-resistant rifaximin Microparticles (equivalent to 8 mg of rifaximin) 1303 26 Aspartame 70 Anhydrous Citric Acid 30 _0^6〇_ Pectin 300 6. 〇X- Mannitol 300 New Orange Peel DC 30 Yam The alcohol is exemplified by the implementation of the medicinal microparticles of rifaximin in the compressed tablet. The gastric-resistant rifaximin microparticles prepared in Example i, 593 g of sodium starch glycolate, and 1 g of magnesium stearate were sieved on a sieve having a mesh of 0.5 mm, and then mixed in a v-type mixer. 20 minutes. The resulting mixture was compressed to a final of 718 grams (equivalent to a rifaximin content of 400 mg) using an elliptical, scored 19 χ 9 mm punch; ingot machine (Fette 1200). , ''; The composition of the key agent is described in Table 3. [table 3 ]

利福昔明耐胃性微顆粒（相 4 0 0毫克利福昔明） 羧曱基纖維i鋼 ~ Avicel PH IQ] 硬脂酸鎮 ~ ' ~~___ (mg) 當於65(K00 %__ 9〇Τ?Γ~ 34. 95 4. 8 7 24.31 ~m 718. 00Rifaximin-resistant gastric microparticles (phase 400 mg rifaximin) carboxymethyl-based fiber i steel ~ Avicel PH IQ] stearic acid town ~ ' ~~___ (mg) at 65 (K00 %__ 9〇Τ?Γ~ 34. 95 4. 8 7 24.31 ~m 718. 00

缺铋/* 宙羽上 -~——LLi〇· υυ 100. QQ 然後使用“ 維 組 素薄膜’以改良外觀及獲致味道掩飾性質。將i元; 312XP/發明說明書(補件)/96-10/96127712 26 200904415 成物記述於表4 : [表4] 塗覆組成物 量 (mg) HPMC 14. 07 二氣化鈦 4. 10 Na-EDTA 0. 05 丙二醇 1. 37 紅色氣化鐵E 1 7 2 __ 0.41 [實施例5 ] ((製備於硬膠囊中之利福昔明的耐胃性微顆粒） 將9.0公斤之根據實施例丨製備得之耐胃性利福昔明微 顆粒與110克之滑石及1. 1公斤之乳糖摻混且於〇. 5毫米 上過篩。使用習知之設備像是Zanasi LZ64將所得混合j勿 以461. 00毫克之終重量（相當於約27〇毫克之利福昔明含 量）引入至硬明膠膠囊000型中。將膠囊組成物記述於表 5 ° 5] 膠囊組成物 量 mg % 利福昔明耐胃性顆粒（相當 於2 7 0毫克利福昔明、 406.00 88. 01 滑石 5. 00 ^IToi 乳糖 50. 00 10. 8 施例6 ] [表 [實 (利福昔明醫藥製劑之耐胃性微顆粒的溶解性能） 根據美國樂典（USP)，第283版，第247頁中戶斤述，評估 醫藥製劑之耐胃性。 經由使用以下條件評估分別含有於實施例丨、3及4中 312XP/發明說明書(補件)/96-10/96127712 27 200904415 所述之利福曰明之耐胃性微顆粒，且由利福昔明耐胃性微 顆粒、含有利福昔明耐胃性微顆粒之熱熔袋、及含有利福 昔明耐胃性微顆粒之錠劑所組成之醫藥製劑的溶解試驗： 設備：SOTAX AT7 SmartLack of 铋/* 宙羽上-~——LLi〇· υυ 100. QQ Then use “vitamin film” to improve the appearance and taste-masking properties. I yuan; 312XP/invention manual (supplement)/96- 10/96127712 26 200904415 The contents are described in Table 4: [Table 4] Coating composition amount (mg) HPMC 14. 07 Di-titanium oxide 4. 10 Na-EDTA 0. 05 Propylene glycol 1. 37 Red gasified iron E 1 7 2 __ 0.41 [Example 5] ((Stomach-resistant microparticles of rifaximin prepared in hard capsules) 9.0 kg of gastric-resistant rifaximin microparticles prepared according to Example 与 and 110 Kg's talc and 1.1 kg of lactose are blended and sieved on a 5 mm. Use a conventional device like Zanasi LZ64 to mix the resulting j to a final weight of 46. 00 mg (equivalent to about 27 mg) The rifaximin content is introduced into the hard gelatin capsule type 000. The capsule composition is described in Table 5 ° 5] Capsule composition amount mg % rifaximin resistant stomach granules (equivalent to 270 mg rifaximin) , 406.00 88. 01 Talc 5. 00 ^IToi Lactose 50. 00 10. 8 Example 6 ] [Table [Real (Rifampicin Pharmaceutical Preparation) Solubility of Microparticles) According to American Music (USP), 283th edition, page 247, the stomach resistance of pharmaceutical preparations was evaluated. The evaluations were carried out in Examples 3, 3 and 4 by using the following conditions. 312XP/Invention Manual (Supplement)/96-10/96127712 27 200904415 The rifampicin-resistant gastric microparticles, and the rifaximin-resistant gastric microparticles containing rifaximin-resistant gastric microparticles Dissolution test of a hot melt bag and a pharmaceutical preparation containing a flavonoid-resistant gastric microparticle tablet: Equipment: SOTAX AT7 Smart

介質：HC1 0. 1 N，PH 1 ;於2小時後添加具有2%月桂 石”l酸納之碟酸鹽緩衝液，且使pH提升至6. 8 攪拌速度：100 rpm 溫度：37°C 取樣時間：120、135、150、及180分鐘。 利用HPLC方法測量經溶解利福昔明之含量。 記述於表6之結果係六次測量的平均，且經表示為相對 於利福昔明總量的溶解百分比。 [表6 ] 介質及pH 時間 溶解（％) (分鐘） 微顆粒1 鍵劑 袋 HC1 0. 1 N, pH 1 120 2.41 1. 07 2. 57 鱗酸鹽緩衝液，pH 6.8 135 93. 8 67. 9 90. 3 磷酸鹽緩衝液，pH 6. 8 150 95. 4 81. 6 95. 1 磷酸鹽緩衝液，pH 6. 8 165 97. 2 88. 1 96. 4 鱗酸鹽緩衝液，pH 6.8 180 97. 4 93. 1 96. 2 於在25°C下儲存12個月後，如於實施例1中製備得之 微顆粒顯現類似的溶解分佈，確切而言於〇. 1 N鹽酸中在 pH 1下120分鐘後溶解2. 2%，及於磷酸鹽緩衝液中在pH 6. 8下60分鐘後溶解91. 1%。 [實施例7] (經由口服途徑投與利福昔明β於狗的生體利用率） 312ΧΡ/發明說明書(補件)/96-10/96127712 28 200904415 根據以下程序以交又設計治療四隻重量介於5. 0與7 5 公斤間的純種母小獵犬。 /吏其中每隻狗口服100 «克/公斤之經製備成存於明 膠膠囊中之耐胃性微顆粒的利福昔明多形體0，並間隔至 少7天的藥物排除時間。 使相同的動物接受100毫克/公斤之存於明膠膠囊中 的利福昔明多形體β。 、 f各次給藥前及於給藥後的1、2、3、4、6、8、及24 ::!自屬於各組之每隻動物的頸靜脈收集由2毫升血液 所構成的樣本。 2樣本轉移至經肝素化的管中且將其H灰裝分 成500微升等份且冷凍於_2〇t：下。 利用有效的IX-MS/MS方法檢定血漿 明’且根據標準的非隔 3 J^ 9 以下參數： 隔至（non compartmental)分析計算 n:”觀察得之利福昔明的最大血裝濃度； Ι-ax =達到之時間； 之rt透過線性梯形法則計算得之在濃度—時間曲線下 己迟於下表7中之結果清楚顯示以 传之利福昔明之多形_ h 政顆粒I備 生體利用率。 7相钹於其他配方具有較大的 [表7 ] 以耐胃性微顆粒製備Medium: HC1 0. 1 N, PH 1 ; After 2 hours, a buffer containing 2% laurel "sodium citrate" was added, and the pH was raised to 6.8. Stirring speed: 100 rpm Temperature: 37 ° C Sampling time: 120, 135, 150, and 180 minutes. The content of dissolved rifaximin was measured by HPLC method. The results described in Table 6 are the average of six measurements and are expressed as relative to the total amount of rifaximin. Percent of dissolution. [Table 6] Medium and pH time solution (%) (minutes) Microparticle 1 bond bag HC1 0. 1 N, pH 1 120 2.41 1. 07 2. 57 sulphate buffer, pH 6.8 135 93. 8 67. 9 90. 3 Phosphate buffer, pH 6. 8 150 95. 4 81. 6 95. 1 phosphate buffer, pH 6. 8 165 97. 2 88. 1 96. 4 sulphate Buffer, pH 6.8 180 97. 4 93. 1 96. 2 After storage at 25 ° C for 12 months, the microparticles prepared as in Example 1 exhibited a similar dissolution profile, specifically 〇. 1%。 [1] The solution was dissolved in the phosphate solution at pH 1 for 120 minutes, and then dissolved in phosphate buffer solution at pH 6. 8 for 60 minutes after dissolution of 91.1%. [Example 7] (administered via oral route) Rifaximin beta in dogs Bioavailability) 312ΧΡ/Invention Manual (supplement)/96-10/96127712 28 200904415 According to the following procedure, we will treat four purebred female beagles weighing between 5.0 and 7 5 kg.吏 Each of the dogs was orally administered 100 « g / kg of rifaximin polymorph 0 prepared as gastric-resistant microparticles in gelatin capsules, and at least 7 days of drug exclusion time. 100 mg/kg of rifaximin polymorphism in gelatin capsules, before and after each dose, 1, 2, 3, 4, 6, 8, and 24 after administration: ::! The jugular vein of each animal belonging to each group collected a sample consisting of 2 ml of blood. 2 The sample was transferred to a heparinized tube and the H gray was divided into 500 μl aliquots and frozen at _2 〇t: Use the effective IX-MS/MS method to characterize plasma phlegm and according to the standard non-separated 3 J^ 9 following parameters: Calculated by non compartmental analysis n: "The maximum blood volume of rifaximin observed" Concentration; Ι-ax = time reached; rt is calculated by the linear trapezoidal rule under the concentration-time curve In the results in Table 7 clearly shows that rifaximin to pass on much shaped particles governance _ H I Preparation bioavailability. 7 phase is superior to other formulations [Table 7] for the preparation of gastric microparticles

、之利褐昔明β相較於利福昔明P 312ΧΡ/發明說明書(補件)/96· 10/96127712 29 200904415 的藥物動力參數 製劑^ 利福昔明β 呈_微顆粒之利明Pharmacological parameters of lyfoxantine β compared to rifaximin P 312 ΧΡ / invention specification (supplement) / 96· 10/96127712 29 200904415 Preparation ^ rifaximin β is a _ microparticle of Liming

C m a X (ng/ml) T»ax (h) AUC〇~tlast AUCo-inf 2. 07 5 NC NC 32. 31 1.5 53 NCC m a X (ng/ml) T»ax (h) AUC〇~tlast AUCo-inf 2. 07 5 NC NC 32. 31 1.5 53 NC

[實施例8 ] (經由口服途徑投與利福昔明δ於狗的生體利用率） 根據以下程序以交又設計治療四隻重量介於5. 0與7. 5 公斤間的純種母小獵犬。 Γ g =其中每隻狗口服1〇〇毫克/公斤之經製備成存於明 膠膠囊中之耐胃性微顆粒的利福昔明多形體δ，並間隔至 少7天的藥物排除時間。 仏至 使相同的動物接受1〇〇毫克/公斤之存於明膠膠 的利福昔明多形體δ。 f各次給藥前及於給藥後的卜2、3、4、6、8、及 各組之每隻動物的頸靜脈收集由2毫升血液 所構成的樣本。 2樣本轉移至經肝素化的管中且將其離心；將血聚八 成500倣升等份且冷凍於_2〇〇c下。 刀 利用有效的LC-MS/MS方法檢定血聚中所含之 明，且根據標準的非隔室 曰 _ f丨同至刀析计异以下參數： 匕利福昔明的最大血漿濃度； 之Π透過線㈣料則計算得之在濃度-時間曲線下 312XP/發明說明書(補件)/96-1 〇/96127712 30 200904415 記述於下表8中之姓果、、主絲 件之利福昔明之多形體 令月性微顆粒製備 的生體利用Ψ。如何相較於其他配方具有較大 [表8] :::::::粒製備得之利福昔_較於利福昔明δ[Example 8] (The bioavailability of rifaximin δ in the oral administration via the oral route) The purebred mothers having a weight between 5.0 and 7.5 kg were treated according to the following procedure. Beagle. Γ g = rifaximin polymorph δ prepared as a gastric-resistant microparticle in a gelatin capsule per oral administration of 1 mg/kg per dog, with a drug exclusion time of at least 7 days. The same animals received 1 mg/kg of rifaximin polymorph δ in gelatin. f A sample consisting of 2 ml of blood was collected from the jugular vein of each of the animals 2, 3, 4, 6, 8, and each of the groups before and after the administration. 2 The sample was transferred to a heparinized tube and centrifuged; the blood was condensed into 500 aliquots and frozen under _2 〇〇c. The knife uses an effective LC-MS/MS method to determine the evidence contained in the blood pool, and according to the standard non-compartment 曰 丨 f 丨 丨 刀 异 异 以下 以下 : : : : : : : : : : : 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大Π Through the line (4) material, calculated under the concentration-time curve 312XP / invention manual (supplement) / 96-1 〇 /96127712 30 200904415 The morphological body of the Ming makes the living body prepared by the monthly microparticles use sputum. How to compare with other formulas [Table 8] ::::::: Granules prepared from rifaxi _ compared to rifaximin δ

801 830 1227 308. 31 V 11夕 2 567. 56 ---- ί 2 1326 利福昔^ 1._声 <顆粒之利适j明g [實施例9] (克隆氏疾病之治療） 醫==施例3中所述之耐f性微顆粒之利福昔明 :”感染克隆氏疾病之病患中使用於相對於安 慰劑的臨床多’心隨機試驗。徵得55位罹患重度、輕缓 至中等等級、時期’具有介於2〇〇與3〇〇間之cmi(克隆 氏疾病活性指數；CnDhn Disease Active卜㈣值的克 隆氏疾病病患。由經定義為在研究結束時低於丨5〇點之 CDAI之臨床緩解的病患百分比呈現主要終點。根據以下 的治療時程將經隨機分成兩組之病患（組A : 27位病患， 及組B : 28位病患）治療12星期： 組A :利福昔明8 〇 〇毫克，每天投與兩次，總劑量等於 1600亳克/天； 組B :安慰劑’每天投與兩次，此一量相當於活性成分 之劑量含量。 312XP/發明說明書(補件)/96-10/96127712 31 200904415 於治療12星期後之臨床緩解的主要終點由η 9%經耐 胃性配方治療之病患及32•難安慰劑治療之病患所達 成。此外，在接受利福昔明治療之組中僅有—位病患因治 療失敗而被迫提早離開臨床試驗 療的病患中斷治療。 結果概述於表9。 而有九位接受安慰劑治 f [表9] 組 [實施例10] A(利福昔明）27位病患 B (安慰劑）2 8位病患801 830 1227 308. 31 V 11 eve 2 567. 56 ---- ί 2 1326 rifampicin ^ 1. _ sound & granules of granules g [Example 9] (treatment of Crohn's disease) == rifaximin resistant to f-resistant microparticles as described in Example 3: "Clinical multi-heart randomized trials relative to placebo in patients infected with Crohn's disease. 55 severely affected, Mild to moderate, period 'clon's disease patient with a CMI (Clone's Disease Activity Index; CnDhn Disease Active Bu (4) value between 2〇〇 and 3〇〇. Defined as low at the end of the study The percentage of patients with clinical remission of CDAI at 5 呈现 showed the primary endpoint. Patients who were randomized into two groups according to the following treatment schedule (Group A: 27 patients, and Group B: 28 patients) Treatment for 12 weeks: Group A: rifaximin 8 mg, administered twice daily for a total dose equal to 1600 g/day; Group B: placebo 'administered twice daily, this amount corresponds to activity Dosage content of ingredients. 312XP/Invention Manual (supplement)/96-10/96127712 31 200904415 Master of clinical remission after 12 weeks of treatment The endpoint was achieved by η 9% of patients treated with a gastric-resistant formula and 32 patients treated with a difficult placebo. In addition, only the patients in the group receiving rifaximin had failed treatment. Patients who were forced to leave clinical trials early discontinued treatment. The results are summarized in Table 9. Nine patients received placebo treatment [Table 9] Group [Example 10] A (rifaximin) 27 patients B (placebo) 2 8 patients

(32.1%) 鱼療失敗之數目 (3.4%) (治療特徵在於蛋白質 病患） 反應性值超出正常的克隆氏疾病 在治療開始時，31位病患具有超出 應性值（過程中之發炎指數）。如鲁/吊的蛋白質C反 分成兩組：-纟且16位接、◊ 施例3中所述，將病患 受安慰劑治療、、。接以福昔明治療，及其餘病患接 經及僅㈣ 在接受利福昔明治療的小組中主要終點。此外， 開研究，但在接受安慰劑治療的^組丙^貝因治療失敗而離 表10顯示所得結果。 、 '有6位病患。 咖魏明書(補件)/96，10/961雇 200904415 [表 ίο] 具有超出正常值之蛋白質C值 臨床緩解之數目 _的小組 1 6位病患接受利福昔明治療 10 (62.5¾) 」5位病患接受安慰劑治療 3 (20%) 〉台療失敗之數目 0(0%) (40¾) 一…叼曰％配万於連 、，貝及長期使用中的優良对受性。 【圖式簡單說明】 條件得出 圖1A:利福昔明耐胃性微顆粒之掃描電子顯微照片， 利用SEM Philips 515儀器’以實施例2中所記述：實驗 圖1B:利福昔明耐胃性微顆粒之單一顆粒的掃描電子 顯微照片，利肖SEMPhilips515儀器，以實施例 記述之實驗條件得出。 圖2 :呈微顆粒、錠劑及袋之醫藥製劑中之耐胃性利福 昔明的溶解分佈，利用溶解儀器s〇TAX AT 7 s贴忖得出。 貫驗條件記述於實施例6。 圖3 :壓縮成錠劑之利福昔明耐胃性微顆粒之掃描電 顯微照片’利用SEM Philips 515儀器，以實施例2 = 吕己述之貫驗條件得出。 312ΧΡ/發明說明書(補件)/9卜1〇/96127712 33(32.1%) Number of fish treatment failures (3.4%) (Treatment characterized by protein patients) Reactivity values exceeded normal Crohn's disease At the beginning of treatment, 31 patients had exceeded the value (inflammation index in the process) ). For example, the protein C of Lu/Hang is divided into two groups: -纟 and 16-bit, 所述, as described in Example 3, the patient is treated with placebo. The main endpoint was in the group receiving rifaximin and the remaining patients and only (iv) in the group receiving rifaximin. In addition, the study was conducted, but the results of the treatment of the placebo group treated with the placebo were shown in Table 10. , 'There are 6 patients.咖魏明书(补件)/96,10/961在200904415 [表ίο] The number of clinical remissions with protein C values exceeding the normal value _ group of 16 patients receiving rifaximin treatment 10 (62.53⁄4) 5 patients received placebo treatment 3 (20%) 〉 Number of treatment failures 0 (0%) (403⁄4) One...叼曰% with excellent compatibility with Wan Yulian, Beibei and long-term use. BRIEF DESCRIPTION OF THE DRAWINGS Conditions are shown in Figure 1A: Scanning electron micrograph of rifaximin-resistant gastric microparticles, as described in Example 2 using SEM Philips 515 instrument: Experimental Figure 1B: rifaximin Scanning electron micrographs of single particles of gastric resistant microparticles, Lishaw SEM Philips 515 instrument, were obtained under the experimental conditions described in the examples. Figure 2: Dissolution distribution of gastric-resistant rifaximin in pharmaceutical preparations of microparticles, tablets and sachets, obtained by dissolving the apparatus s〇TAX AT 7 s. The test conditions are described in Example 6. Figure 3: Scanning micrograph of rifaximin-resistant gastric microparticles compressed into tablets was made using the SEM Philips 515 instrument and the experimental conditions of Example 2 = Lü Jishu. 312ΧΡ/Invention Manual (supplement)/9卜1〇/96127712 33

Claims (1)

200904415 十、申請專利範圍： 1. 種w藥組成物，其包含可改良生體利用率之抗生 素。 2. 如申明專利範圍第1項之醫藥組成物，其中抗生素之 改良生體利用率係歸因於耐胃性微顆粒。 3 · 士申明專利範圍第2項之醫藥組成物，其中該組成物 中所含之抗生素係利福昔明（rifaximin)。 4:如申請專利範圍第3項之醫藥組成物，其中該耐胃性 利祸曰明微顆粒包含一或多種利福昔明之多形體形式 原始形式。 一 5 _如申明專利範圍第3項之醫藥組成物，其中該利福昔 明多形體形式係選自α式、β式、γ式、3式、或ε式。 如申請專利範圍第1項之醫藥組成物，其中該耐胃性 利福昔明微顆粒之直徑係介於約〗微米至約9〇〇微 間。 〃 7. 如申請專利範圍第2項之醫藥組成物，其中該耐胃性 利福昔明微顆粒之直徑係介於約10微米至約500微米之 間。 8. 如申請專利範圍第u 3項中任—項之醫藥組成物， 其中該耐胃性係經由使用PH值在1.5與4. G間不溶解且 pH值在5. 0與7. 7間可溶解的聚合物而獲得。 乂如申請專利範圍第4項之醫藥組成物，其中該聚合物 係選自乙酸酞酸纖維素、乙酸酞酸羥丙基纖維素、聚乙酸 酞酸乙烯酯及甲基丙烯酸之共聚物。 312XP/發明說明書(補件)/96-1 〇/96127712 34 200904415 1 〇.如申睛專利範圍第4或5項之醫藥組成物，其中該 耐胃性聚合物相對於微顆粒總量的量係介於5重量％與75 重量％之間。 ~ 11. 如申請專利範圍第4至6項中任一項之醫藥組成 物，其中3亥耐月性混合物亦包含稀釋劑、增塑劑、抗凝聚 劑、防黏劑、滑動劑、消泡劑及著色物質。 12. —種醫藥組成物，其包含： 存於熱熔袋中之介於約〗至約3〇〇〇毫克間之耐胃性利 福昔明微顆粒；介於〇至約45〇毫克間之甜味劑，其選自 阿斯巴甜（aspartame)、糖、木糖醇、乳糖醇、SPLENDA⑧、 %己基磺醯胺酸鈉（s〇dium cyclamate)、右旋糖、果糖、 葡萄糖、乳糖、及蔗糖、或新橘皮甙（ne〇hesperidin)队 :之-或多者；介於〇至約50毫克間之有機酸，其選自 檸檬酸、乙酸、己二酸、檸檬酸、反丁烯二酸、戊二酸、 蘋果酸、琥㈣、或酒石酸中之一或多者；介於約i至約 5〇〇宅克間之懸浮劑，其選自聚乙烯基吼咯啶酮、 羧甲基纖維素鈉、果膠、三仙膠、或瓊脂中之一或多者； 介於〇至約500毫克間之甘露糖醇；介於〇至約4〇〇〇毫 克間之糖醇，其選自諸如乳糖醇、麥芽糖醇、甘露糖醇、 山梨糖醇、及木糖醇之糖醇、三仙膠、糊精、或麥芽糊精 中之-或多者；介於〇至約300毫克間之芳香劑，豆選自 水果或植物香料中之-或多者；及介於至約_毫 之滑動劑，其選自矽膠、硬脂酸鎂、或滑石中之一或多者日。 13. —種醫藥組成物，其包含： 312XP/發明說明書(補件)/96· 10/96127712 35 200904415 存於壓縮錠劑中之介於約50至約1000毫克間之耐胃性 利福昔明微顆粒；介於約i至約500毫克間之稀釋劑，其 選自磷酸二鈣、硫酸鈣、纖維素、微晶纖維素（Avicel®)、 羥丙基甲基纖維素、玉米澱粉、乳糖、高嶺土、甘露糖醇、 氯化納、乾燥殿粉中之一或多者；介於約1至約5⑽毫克 間之黏合劑，其選自澱粉、明膠、糖如蔗糖、葡萄糖、右 旋糖、乳糖、合成膠、海草酸鈉、羧甲基纖維素、甲基纖 維素、聚乙烯基吡咯啶酮、聚乙二醇、乙基纖維素、水、 蠟、醇中之一或多者；介於約〇至約2〇毫克間之潤滑劑， 其選自滑石、硬脂酸鎂、硬脂酸鈣、硬脂酸、氫化植物油、 聚乙二醇中之一或多者；介於約〇至約2〇毫克間之滑動 劑，其選自膠態二氧化矽、滑石中之一或多者；介於約〇 至約200毫克間之崩解齊！，其選自繞甲基纖維素納、玉米 及馬鈴薯殿粉、交聯羧甲基纖維素、交聯聚乙稀料唆酮 (crospovidone)、澱粉羥基乙酸鈉+之一或多者；介於約 0至約10毫克間之著色劑，其選自二氧化鈦、氧化鐵中 之一或多者；介於約〇至約500毫克間之甜味劑，其選自 蔗糖、山梨糖醇、甘露糖醇、糖精、醋磺内酯 (acesulfame)、新橘皮甙中之一或多者。 14. 一種錠劑之膜衣組成物，其包含： 介於約0至約5〇毫克間之聚合物，其選自纖維素及其 取代物諸㈣丙基纖維素、W基纖維素、經丙基—曱基 纖維素’特定的丙烯酸系樹脂，語如 mm遺如甲基丙稀酸酯及曱基 丙刘j酸曱@旨共聚物中之一成多者·八& Λ 及夕首，介於約〇至約5毫克間 312ΧΡ/發明說明書(補件)/96-10/96127712 36 200904415 之增塑劑，其選自甘油、丙二醇、聚乙二醇、三乙醯甘油、 乙醯基化單甘油酯、檸檬酸酯及酞酸酯中之一或多者的； 介於約〇至約1毫克間之穩定劑，諸如EDTA ;介於約〇 至約ίο耄克間之著色劑，其選自白蛋白湖（alb⑽h lake)、二氧化鈦、氧化鐵中之一或多者。 15. —種醫藥組成物，其包含： r200904415 X. Patent application scope: 1. A composition of w medicine containing antibiotics which can improve the utilization rate of the living body. 2. For the pharmaceutical composition of claim 1 of the patent scope, the improved bioavailability of antibiotics is attributed to gastric resistant microparticles. 3. The pharmaceutical composition of claim 2, wherein the antibiotic contained in the composition is rifaximin. 4: The pharmaceutical composition of claim 3, wherein the gastric resistance comprises the microscopic form comprising one or more polymorphic forms of rifaximin. A pharmaceutical composition according to claim 3, wherein the rifaximin polymorph form is selected from the group consisting of α, β, γ, 3, or ε. The pharmaceutical composition of claim 1, wherein the gastric-resistant rifaximin microparticles have a diameter of from about 微米 to about 9 Å. 7. The pharmaceutical composition of claim 2, wherein the gastric resistant rifaximin microparticles have a diameter of between about 10 microns and about 500 microns. 0之间。 7. The ratio of the pH of the drug is between 0.5 and 4. G and the pH is between 5.0 and 7. 7 Obtained from a soluble polymer. For example, the pharmaceutical composition of claim 4, wherein the polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl cellulose acetate, polyvinyl acetate and methacrylic acid. 312XP/Inventive Manual (Supplement)/96-1 〇/96127712 34 200904415 1 医药. The pharmaceutical composition of claim 4 or 5, wherein the amount of the gastric resistant polymer relative to the total amount of the microparticles The system is between 5% by weight and 75% by weight. ~ 11. The pharmaceutical composition according to any one of claims 4 to 6, wherein the 3H aging monthly mixture also contains a diluent, a plasticizer, an anti-agglomerating agent, an anti-adhesive agent, a slip agent, and a defoaming agent. Agent and coloring matter. 12. A pharmaceutical composition comprising: gastric-resistant rifaximin microparticles in a hot-melt bag between about 至 and about 3 〇〇〇 milligrams; between 〇 and about 45 〇 milligrams a sweetener selected from the group consisting of aspartame, sugar, xylitol, lactitol, SPLENDA8, sodium cyclamate, dextrose, fructose, glucose, lactose, And sucrose, or neo-hesperidin team: - or more; between about 50 mg of organic acid selected from the group consisting of citric acid, acetic acid, adipic acid, citric acid, and anti-butyl One or more of adipic acid, glutaric acid, malic acid, succinic acid (tetra), or tartaric acid; a suspending agent between about i and about 5 mils, selected from polyvinylpyrrolidone, One or more of sodium carboxymethylcellulose, pectin, sinosaur, or agar; mannitol ranging from 〇 to about 500 mg; sugar alcohol ranging from 〇 to about 4 〇〇〇 , which is selected from the group consisting of sugar alcohols such as lactitol, maltitol, mannitol, sorbitol, and xylitol, triterpene, dextrin, or maltodextrin - or a plurality of fragrances ranging from about 300 to about 300 mg, beans selected from the group consisting of fruit or botanical flavors; and a slipping agent ranging from about _ to 毫, which is selected from the group consisting of silicones, magnesium stearate, Or one or more of the talc days. 13. A pharmaceutical composition comprising: 312XP/invention specification (supplement)/96·10/96127712 35 200904415 a gastric-resistant rifampicin between about 50 and about 1000 mg in a compressed tablet a microparticle; between about i and about 500 mg, selected from the group consisting of dicalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose (Avicel®), hydroxypropyl methylcellulose, corn starch, One or more of lactose, kaolin, mannitol, sodium chloride, dry powder; between about 1 and about 5 (10) milligrams of binder selected from starch, gelatin, sugars such as sucrose, glucose, right-handed One or more of sugar, lactose, synthetic gum, sodium sea oxalate, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, ethyl cellulose, water, wax, alcohol a lubricant between about 〇 and about 2 〇, selected from one or more of talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol; a slip agent of about 2 〇 milligrams, selected from one or more of colloidal cerium oxide and talc; To about 200 mg of disintegrant between Qi! , selected from the group consisting of methylcellulose nano, corn and potato powder, croscarmellose, crospovidone, sodium starch glycolate + one or more; a coloring agent between 0 and about 10 mg, selected from one or more of titanium dioxide and iron oxide; a sweetener between about 〇 and about 500 mg, selected from the group consisting of sucrose, sorbitol, and mannitol One or more of saccharin, acesulfame, and new cellulite. 14. A film coating composition for a tablet comprising: a polymer between about 0 and about 5 milligrams selected from the group consisting of cellulose and its substitutes (tetra)propylcellulose, W-based cellulose, Propyl-mercapto cellulose 'specific acrylic resin, such as mm such as methyl acrylate and thiol propylene j 曱 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨First, between about 〇 to about 5 mg, 312 ΧΡ / invention specification (supplement) / 96-10/96127712 36 200904415 plasticizer selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, triethylene glycol glycerol, B One or more of a thiolated monoglyceride, a citrate, and a phthalate; a stabilizer between about 〇 and about 1 mg, such as EDTA; a color between about 〇 and about ίο耄An agent selected from one or more of albumin lake (alb(10)h lake), titanium dioxide, iron oxide. 15. A pharmaceutical composition comprising: r 存於硬明膠膠囊中之介於約50至約450毫克間之耐胃 性巧福昔明微顆粒；介於約〇至約25毫克間之潤滑劑， 其選自滑石、硬脂酸鎂、硬脂酸舞、硬脂酸、氫化植物油、 聚乙一醇中之一或多者；介於約i至約225亳克間之稀釋 劑，其選自磷酸二與、硫酸約、纖維素、微晶纖維素、經 丙基曱基纖維素、玉米殿粉、乳糖、高崩土、甘露糖醇、 氣化鈉、乾燥澱粉中之一或多者。 、'J6. 一種利用含有利福昔明之耐胃性微顆粒於製造用於 /口療發炎性腸道疾病之醫藥製劑的用途。 广利範圍第16項之用途:其中該發炎性腸道 疾病係為克隆氏（Crohn，s)疾病。 、 二如㈣利範圍第17項之用途，其中該羅患 疾病病患之C -反應性蛋白質的值係高於標準。 19. 一種製造含有尺寸介 财胃性微顆粒形狀之利福昔明至約9〇°微米間之 由下列步驟所組成：將含有耐胃性取：，邊方法係 釋劑、防黏劑、抗凝聚劑、滑動物，'增塑劑二稀 水性懸浮液在壓力介於1Q //包劑及著色物質之 、* 5巴間及流速介於15 〇與 312XP/發明說明書(補件)/96· 1 〇/96127712 37 200904415 300克/分鐘間透過喷嘴喷霧至流體床裝置中，於該流體 床裝置中經加溫在溫度介於50°C與75°C間且以450至650 立方米/小時輸出之空氣流使與流度增進劑混合之活性 成分利福昔明保持懸浮。 20. —種申請專利範圍第3項之醫藥組成物之用途，其 具有較高的利福昔明生體利用率。 312XP/發明說明書(補件)/96-10/96127712 38 200904415 七、指定代表圖： (一） 本案指定代表圖為：第（1A )圖。 (二) 本代表圖之元件符號簡單說明： 益 C 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式： 益a gastric-resistant coufoximin microparticle of between about 50 and about 450 mg in a hard gelatin capsule; a lubricant between about 〇 and about 25 mg, selected from the group consisting of talc, magnesium stearate, One or more of stearic acid dance, stearic acid, hydrogenated vegetable oil, polyethyl alcohol; a diluent between about i and about 225 gram, selected from the group consisting of phosphoric acid, sulfuric acid, cellulose, micro One or more of crystalline cellulose, propyl decyl cellulose, corn house powder, lactose, high collapse soil, mannitol, sodium vaporized, dried starch. , 'J6. Use of a gastric-resistant microparticle containing rifaximin for the manufacture of a pharmaceutical preparation for inflammatory bowel disease for / oral therapy. Use of the 16th item of the wide range: wherein the inflammatory bowel disease is Crohn's disease. 2. The use of the fourth item of the fourth paragraph, in which the value of the C-reactive protein of the diseased patient is higher than the standard. 19. A method for producing rifaximin containing a size of a stomach-like microparticle having a size of about 9 Å micrometers consisting of the following steps: containing gastric resistance: a method of releasing a release agent, an anti-adhesive agent, Anti-agglomerating agent, sliding material, 'plasticizer dilute aqueous suspension at pressure between 1Q // bag and coloring matter, * 5 bar and flow rate between 15 〇 and 312XP / invention manual (supplement) / 96· 1 〇/96127712 37 200904415 300 g / min sprayed through a nozzle into a fluid bed device, heated in the fluid bed device at a temperature between 50 ° C and 75 ° C and 450 to 650 cubic meters The air flow output in meters per hour keeps the active ingredient rifaximin mixed with the fluidity enhancer in suspension. 20. Use of a pharmaceutical composition according to item 3 of the patent application, which has a high utilization rate of rifaximin. 312XP/Invention Manual (supplement)/96-10/96127712 38 200904415 VII. Designated representative map: (1) The representative representative of the case is: (1A). (2) A brief description of the symbol of the representative figure: Benefit C 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 312XP/發明說明書(補件)/96-10/96127712 5312XP/Invention Manual (supplement)/96-10/96127712 5 200904415 姓名或名稱：（中文/英文） 阿爾法韋士曼公司 / ALFA WASSERMANN S.p.A. 代表人：（中文/英文） 〇女帕各吉羅堤/ Giampaolo Girotti 住居所或營業所地址：（中文/英文） 義大利阿蘭諾市艾里哥佛米路1號 1, Via Enrico Fermi, 65020 Alanno (PE), Italy 國籍：（中文/英文） 義大利/ Italian 三、發明人：（共4人） 姓名：（中文/英文） (1) 吉賽普克勞迪歐維斯柯米/ Giuseppe Claudio Viscomi (2) 厄内斯托帕拉齊尼/ Ernesto Palazzini (3) 維廉薩波尼 / Villiam Zamboni (4) 瑪麗亞羅薩里亞朋塔烈歐/ Maria Rosaria Pantaleo 國籍·(中文/英文） (1)〜（4)義大利 / Italian 312XP/發明說明書(補件)/96-10/96127712 1200904415 Name: (Chinese/English) Alpha Weissman Company / ALFA WASSERMANN SpA Representative: (Chinese / English) Prostitute Paggio Giorgio / Giampaolo Girotti Residence or establishment Address: (Chinese / English) Yida Via Enrico Fermi, 65020 Alanno (PE), Italy Nationality: (Chinese / English) Italian / Italian III. Inventor: (Total 4 persons) Name: (Chinese) /English) (1) Giuseppe Claudio Viscomi (2) Ernesto Palazzini / Ernesto Palazzini (3) Virgin Saboni / Villiam Zamboni (4) Maria Rosario Pantaleo Nationality (Chinese / English) (1) ~ (4) Italy / Italian 312XP / invention manual (supplement) / 96-10/96127712 1