TW577754B - Method for the preparation of a pharmaceutical composition comprising 5-aminosalicylic acid for use in treatment of ulcerative colitis and Crohn's disease - Google Patents

Method for the preparation of a pharmaceutical composition comprising 5-aminosalicylic acid for use in treatment of ulcerative colitis and Crohn's disease Download PDF

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TW577754B
TW577754B TW091120757A TW91120757A TW577754B TW 577754 B TW577754 B TW 577754B TW 091120757 A TW091120757 A TW 091120757A TW 91120757 A TW91120757 A TW 91120757A TW 577754 B TW577754 B TW 577754B
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particles
granules
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TW091120757A
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Chinese (zh)
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Jepsen Svenn Kluver
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Ferring Bv
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Priority claimed from PCT/DK2001/000677 external-priority patent/WO2003032952A1/en
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Abstract

The present invention concerns a new method of preparing granules comprising 5-aminosalicylic acid and a new method of preparing a pharmaceutical composition for the treatment of ulcerative colitis or Crohn's disease by oral administration comprising as active ingredient 5-aminosalicylic acid.

Description

577754 A7 B7 五、發明説明（1 ) 本發明關於製備用於治療潰瘍性結腸炎與克隆氏症（ Crohn’s disease )(目前命名爲、發炎性腸症〃 （I B D ) (請先閱讀背面之注意事項再填寫本頁) )之藥學組合物的方法。更特別的是，本發明關於新穎之 含5 -胺基柳酸（5 - ASA)之顆粒的製備方法，該種 顆粒可用於固體口服劑型的製備方法中。 潰瘍性結腸炎係一種未知病原之結腸發炎疾病。在其 急性期待很類似於感染症，但並未確立出其致病微生物。 此疾病會造成結腸黏膜發炎，在嚴重的病例中，甚至會蔓 延至黏膜下層。通常，除了結腸外，亦有可能侵襲到直腸 ，但侵襲到迴腸的情況就很少了。形成潰瘍及其嚴重程度 會因疾病發展的階段而有不同，但這通常可利用顯微鏡檢 查來決定（乙狀結腸鏡檢查及結腸鏡檢查）。 經濟部智慧財產局員工消費合作社印製 相關疾病一克隆氏症（亦稱爲局部腸炎或結腸炎肉芽 腫）最常發生在小腸，尤其是在迴腸中，但也可能影響空 腸及任何部分之結腸，包括直腸。在後項情況中，欲區分 克隆氏症及潰瘍性結腸炎會有很多診斷上的問題。一般而 言，克隆氏症之發炎情況與潰瘍性結腸炎之不同處在於其 發炎情況會進展至較黏膜更深的部位，且其影響表皮的程 度較輕微。 目前，此二種疾病之發生情況愈來愈頻繁，尤其是在 已開發之國家中。在美國，潰瘍性結腸炎之發病率每 100， 000個居民中有5-15個病例，然而，克隆 氏症之發病率爲每100， 000個居民中有約5個病例 ，且其比率仍持續增加中。因此，治療Γ B D已成爲現代 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -4 - 577754 A7 B7 五、發明説明（2 ) 醫學的重要課題。 W 0 8 1/026 7 1中揭示經由口服途徑投遞藥 (請先閲讀背面之注意事項再填寫本頁) 學組合物以治療I B D。此發明係根據發現將游離酸型式 之5 - A S A或其鹽或酯經口服途徑投遞給個體時，可有 效治療潰瘍性結腸炎，尤其是當投予個體的爲持續釋出之 錠片劑型時。WO 8 1/0 2 6 7 1還揭示一種製備持 續釋出之錠劑的方法，其包含下列步驟：從5 - A S A及 在異丙醇中之聚乙烯吡咯啶酮溶液製備顆粒，將溶劑蒸發 掉’以乙基纖維素將顆粒包衣，並將該包衣顆粒製成錠劑 〇 U S 4，632，921還揭示一種製備即溶之5 - A S A製劑的方法，其係經由下列步驟進行：將5 - 經濟部智慧財產局員工消費合作社印製 A S A與生理學上及毒物學上可接受上之佐劑及/或緩衝 混合物（其在1%水溶液中所產生之pH値係在8至1 2 間）混合在一起，並將所得之混合物以已知方式形成錠劑 、薄膜錠劑、糖衣錠、膠束或栓劑，也就是：以5 -A S A爲基礎，用於I B D治療中的穩定，且即溶之口服 用或直腸用藥學製劑。 美國4， 880，794中揭示治療IBD之方法， 其包含經口投予個體一有效量之組合物，此組合物主要係 由游離5 - A S A之藥學上可接受的鹽類與藥學上可接受 之載體所混合組成，此藥學上之載體可控制該欲投遞之5 - A S A的鹽，使其根據該疾病之確實位置來釋出該有效 量。 本紙張尺度適用中國國家榡準（CNS ) A4規格（210X 297公釐） -5 - 577754 A7 B7__ 五、發明説明（3 ) (請先閱讀背面之注意事項再填寫本頁) 美國4，960，765還揭示一種用於治療IBD 的方法，其包含經口服投遞一有效量之組合物，此組合物 主要係由游離5 - A S A之酯與藥學上可接受之載體所混 合組成，該載體可使5 - A S A大體上從該組成物中延遲 釋出直到其已抵達患者之結腸。經由使用可令5 - A S A 逐漸釋出的包衣，可達到該組成物根據結腸中之P H値來 釋出的需求。該顆粒係以乙基纖維素來包衣。 美國4， 980， 173中揭示一種製備用於治療 I B D之持續釋出錠劑的方法，其係藉由使用有機溶劑製 備含5 - A S Α和Ρ V Ρ的顆粒來進行。以ρ Η敏感性包 衣（纖維素衍生物）將顆粒包衣。製備第二種未包衣之顆 粒，並將其與已包衣之顆粒及潤滑劑混合。 美國5，013，727中揭示一種含有5— ASA 或其藥學上可接受之鹽或酯以做爲其活性成分的藥學組合 物，其可經口服投遞來治療I B D。文中並揭示了特殊之 緩慢釋出的錠劑配方及其製劑。 美國5， 5 4 1， 1 7 0還揭示一種用於經口服投遞 經濟部智慧財產局員工消費合作社印製 ，以治療I B D的藥學組合物及方法。本發明可爲固體劑 型，如：膠束或錠劑，且其中含有足夠量之以陰離子性聚 合物包衣的藥學上活性劑。此包衣用之陰離子性聚合物在 Ρ Η値低於7的胃液及小腸液中不可溶，但可在結腸小腸 液中溶解，因此，該口服劑型可維持完整，直到其抵達結 腸。較佳之陰離子性聚合物係一種經部分甲酯化的甲基丙 烯酸聚合物，其中該游離羧基團對酯基團之比例爲約1 : 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -6 - 577754 A7 __ B7 五、發明説明（4 ) (請先閲讀背面之注意事項再填寫本頁) 2。本發明特別適用於腎上腺皮質酮及其鹽類，吲哚美沙 辛（indomethacin)，伊布普吩（ibuproten)，尤其是 5 — 胺基柳酸。 5 - A S A已經證實對治療潰瘍性結腸炎和克隆氏症 非常有用。不同之5 - A SA延長釋出型2 5 0毫克錠劑 及稍後之5 0 0毫克錠劑，如：潘朵沙® ( Pentasa® ))已 在不同國家註冊許多年。 所有關於5 - A S A錠劑配方之習知技藝均揭示：以 異丙醇來做爲5 - A S A顆粒之製備方法中，連接劑的主 要溶劑。並無任何地方曾提出可使用其它溶劑，如水來取 代有機溶劑，以用來製備錠劑。577754 A7 B7 V. Description of the invention (1) The invention relates to preparation for the treatment of ulcerative colitis and Crohn's disease (currently named, inflammatory bowel disease (IBD)) (Please read the precautions on the back first) Then fill in this page))) method of pharmaceutical composition. More specifically, the present invention relates to a method for preparing novel 5-aminosalicylic acid (5-ASA) -containing particles, which can be used in a method for preparing solid oral dosage forms. Ulcerative colitis is an inflammatory disease of the colon of unknown etiology. In its acute expectation is very similar to infectious disease, but its pathogenic microorganisms have not been established. The disease can cause inflammation of the colonic mucosa, and in severe cases can spread to the submucosa. Usually, in addition to the colon, it may also invade the rectum, but it rarely affects the ileum. The formation of ulcers and their severity will vary depending on the stage of the disease, but this is usually determined by microscopy (sigmoidoscopy and colonoscopy). Employees ’cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs print related diseases-Crohn's disease (also known as local enteritis or colitis granulomatosis) most often occurs in the small intestine, especially in the ileum, but may also affect the jejunum and any part of the colon Including the rectum. In the latter case, there are many diagnostic problems to distinguish Crohn's disease from ulcerative colitis. In general, Crohn's inflammation differs from ulcerative colitis in that it progresses deeper than the mucosa and affects the epidermis to a lesser extent. These two diseases are occurring more and more frequently, especially in developed countries. In the United States, the incidence of ulcerative colitis is 5-15 cases per 100,000 inhabitants, however, the incidence of Crohn's disease is approximately 5 cases per 100,000 inhabitants, and the rate remains Continue to increase. Therefore, the treatment of Γ B D has become modern. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -4-577754 A7 B7 V. Description of invention (2) An important subject of medicine. W 0 8 1/026 7 1 discloses the delivery of drugs by oral route (please read the precautions on the back before filling this page) to study the composition to treat I B D. This invention is based on the finding that when free acid form 5-ASA or its salt or ester is delivered to an individual via an oral route, it can effectively treat ulcerative colitis, especially when the sustained-release tablet form is administered to an individual . WO 8 1/0 2 6 7 1 also discloses a method for preparing sustained-release lozenges, which comprises the following steps: preparing granules from 5-ASA and a polyvinylpyrrolidone solution in isopropanol, and evaporating the solvent The granules were coated with ethyl cellulose, and the coated granules were made into lozenges. US 4,632,921 also discloses a method for preparing an instant 5-ASA preparation by the following steps: 5-ASA printed with ASA and physiologically and toxicologically acceptable adjuvants and / or buffer mixtures (the pH produced by it in a 1% aqueous solution is between 8 and 1) 2) mixed together, and the resulting mixture is formed into lozenges, film lozenges, dragees, micelles or suppositories in a known manner, that is, based on 5-ASA for stabilization in IBD treatment, and Instant pharmaceutical preparation for oral or rectal use. A method for treating IBD is disclosed in U.S. 4,880,794, which comprises orally administering to an individual an effective amount of a composition, the composition is mainly composed of pharmaceutically acceptable salts of free 5-ASA and pharmaceutically acceptable The carrier is mixed and the pharmacological carrier can control the 5-ASA salt to be delivered, so that it can release the effective amount according to the exact location of the disease. This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) -5-577754 A7 B7__ V. Description of the invention (3) (Please read the notes on the back before filling this page) US 4,960, 765 also discloses a method for treating IBD, which comprises orally delivering an effective amount of a composition, which composition is mainly composed of a mixture of free 5-ASA esters and a pharmaceutically acceptable carrier. 5-The release of ASA from this composition is generally delayed until it has reached the patient's colon. By using a coating that allows 5-A S A to be gradually released, the composition can be released according to the pH of the colon. The granules were coated with ethyl cellulose. U.S. Patent No. 4,980,173 discloses a method for preparing a sustained release lozenge for treating I B D by preparing particles containing 5-AS and P V P using an organic solvent. The particles were coated with a ρ Η sensitive coating (cellulose derivative). A second uncoated pellet was prepared and mixed with the coated pellet and lubricant. U.S. Patent No. 5,013,727 discloses a pharmaceutical composition containing 5-ASA, or a pharmaceutically acceptable salt or ester thereof as an active ingredient, which can be administered orally to treat IB D. The article also reveals special slow-release lozenge formulations and their formulations. The United States 5, 5 41, 1 70 also discloses a pharmaceutical composition and method for oral delivery, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs for the treatment of I B D. The present invention can be a solid dosage form, such as a micelle or a lozenge, and contains a sufficient amount of a pharmaceutically active agent coated with an anionic polymer. The coating's anionic polymer is insoluble in gastric and small intestinal fluids with a PΗ 値 of less than 7, but can be dissolved in colonic small intestinal fluids. Therefore, the oral dosage form can remain intact until it reaches the intestines. A preferred anionic polymer is a partially methylated methacrylic polymer, wherein the ratio of the free carboxyl group to the ester group is about 1: This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297) (Centi) -6-577754 A7 __ B7 V. Description of Invention (4) (Please read the precautions on the back before filling this page) 2. The present invention is particularly suitable for adrenocorticone and its salts, indomethacin, ibuproten, and especially 5-aminosalicylic acid. 5-A S A has proven to be very useful for the treatment of ulcerative colitis and Crohn's disease. Different 5-A SA extended release 250 mg tablets and later 500 mg tablets, such as Pentasa®, have been registered in different countries for many years. All the know-how of formulating 5-A S A lozenges revealed that isopropyl alcohol was used as the main solvent of the linker in the method of preparing 5-A S A granules. Nowhere has it been proposed that other solvents, such as water, be used in place of organic solvents for the preparation of lozenges.

W 0 97 / 2 3 1 9 9中揭示一種用於治療I BD 之包含球形顆粒的改良型釋出組合物，這些球形顆粒中包 含5 - A S A核心，及一球化輔助劑（其係以水做爲溶劑 )，並以限制速率的屏障材料包衣。此種組合物可在胃中 小量釋出5 - A SA，且該顆粒可包裏在小藥束中。這些 顆粒並不適合用於錠劑中。 經濟部智慧財產局員工消費合作社印製 由於市場對含5 - A S A之藥物的需求持續增加，因 此，需要改良製備含5 - A S A之錠劑的方法。 發明槪述 由於各包含5 - A S A之錠劑或劑量中，含有相當大 量之活性成分來使治療效果最優化，因此在製造設備中需 處理大量的物質。 本紙張尺度適用中國國家標準（CNS ) A4規格（210'〆297公釐） 577754 A7 B7 五、發明説明（5 ) (請先閲讀背面之注意事項再填寫本頁) 由於含5 — A SA之藥物的市場持續成長’因此’目 前用來製備含5 - A S A之錠劑的方法有改良的必要。在 本發明中，改良部分提供該製備含5 - A SA錠劑之方法 一種更好、更快速、花費較少’且不會損失5 — A S A之 品質和生物有效性的方法。 本發明的目的係取得可用於潘朵沙®或類似之錠劑中的 擠出顆粒的改良組合物。這些顆粒必須要牢固且平滑’於 製造過程期間可忍受不同的處理步驟，且具有狹窄並可複 製之顆粒大小分佈。 令人驚訝地，本方法不必改變現有製備方法的主要原 則即可將其改良。 經濟部智慧財產局員工消費合作社印製 根據本發明所製備之含5 - A S A的錠劑仍舊是先將 活性成分，5 -胺基柳酸，與在溶劑中之藥學上可接受的 連接劑（如：聚乙烯吡咯啶酮（P V P ))的溶液混合。 將此混合物擠成顆粒，並將其在流體床中加以乾燥。乾燥 後，硏磨顆粒，並在包衣前先將其過篩，如：可在流體床 中進行。在包衣過程中，需將一聚合物包覆在顆粒上，直 到取得所需之溶解速率略圖。然後，將包衣顆粒與錠劑賦 形劑混合，並壓成錠劑。 本發明的觀點之一係驚奇發現：現有方法中所使用之 有機溶劑，若以水來部分或全部取代較爲有利。 美國專利Re 33， 239中教示：由於5— A S A對濕度及光敏感，因此其穩定性不佳。該專利中揭 示一種藥學組合物，其含有在溶液中之5 - A S A，或者 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) :8 - 577754 A7 B7 五、發明説明（6 ) ，5 - A S A係與添加劑一起爲懸浮液型式，此添加劑可 穩定5 - A S A。再者，該組合物係在惰性氣體下，包裝 於密不滲漏，且不透光的包裝中。 (請先閲讀背面之注意事項再填寫本頁) 因此，使用水來做爲主要溶劑將與關於5 - A S A錠 劑之配方的教示內容相反。在現有方法中，係經由使用有 機溶劑做爲主要溶劑來避免濕度相關之穩定度方面的問題 。令人驚訝地，現已發現水真的可在製備含5 - A S A之 顆粒的方法中做爲主要溶劑，且其大體上不會影響5 -A S A之穩定度，而這些含5 - A SA之顆粒可用於錠劑 配方中。一般相信：在，如：流體床中進行之連續乾燥過 程對於取得能忍受快速且溫和之乾燥過程的穩定產物，並 保護產品不受光害而言是有利的。 W〇 9 7 / 2 3 1 9 9中以水做爲球形顆粒之製備 方法中的溶劑，然而，這些顆粒中含有不同的連接劑，且 在球化及乾燥過程中係經直接處理。該球形顆粒由於會離 散，所以若將其用於錠劑中，並非最理想。 經濟部智慧財產局員工消費合作社印製 令人驚訝地，現已發現以水來部分或全部取代有機溶 劑時，可製出具狹窄顆粒大小分佈之顆粒，且所產生之顆 粒較堅固並有較平滑之表面。這些改良可增加由此方法所 製出之錠劑的產量。再者，該顆粒之平滑表面可令包衣過 程更容易複製，並可減少用於此方法中之包衣物質的量。 除了上述之產品的改良處外，亦可減少使用有機溶劑 ，這使得在製造設備中之操作者，及環境中所面臨的危險 減少，並可減少最終產品中之有機溶劑的全部含量。另外 -9 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 577754 A7 B7_ 五、發明説明（7 ) ’可大爲降低有機溶劑的花費。 (請先閱讀背面之注意事項再填寫本頁) 本發明的第二種觀點中，從5 - A S A之濕團塊及連 接劑製備顆粒，形成製造5 - A S A顆粒之連續生產線的 一部分。 本發明的第三觀點中，製備顆粒的方法形成製備5 -A S A錠劑之方法的一部分。 如上述所討論，在生產線中可能需處理大量之材料。 因此，該生產線最好能設計爲連續生產線，其中5 -A S A係在擠出器之前或在擠出器中與水性P V P溶液相 混合，再讓所產生之顆粒於一連續過程中乾燥、硏磨及過 篩。個別成分之進料係持續受到調整，如：經由測量不同 進料的重量來進行（此爲生產線之一部分）。 圖示簡單說明 第1 A圖示爲根據現有方法製也之顆粒過篩後的放大 圖（批號：KGGU 405R)。 第1 B圖示爲根據現有方法製出之顆粒過篩後的顆粒 大小分佈（篩析）（批號：K G G U 4 0 5 R )。 經濟部智慧財產局員工消費合作社印製 第2 A圖示爲根據現有方法製出之顆粒過篩後的放大 圖（批號：KGGU 406Q)。 第2 B圖示爲根據現有方法製出之顆粒過篩後的顆粒 大小分佈（篩析）（批號：K G G U 4 0 6 Q )。 第3 A圖示爲根據現有方法製出之顆粒過篩後的放大 圖（批號：KGGU 406T)。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -10- 577754 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明（8 ) 第3 B圖示爲根據現有方法製出之顆粒過篩後的顆粒 大小分佈（篩析）（批號：K G G U 4 0 6 T )。 第4圖示爲潘朵沙⑧或類似錠劑之新製備方法的流程圖 〇 第5 A圖示爲根據新方法製出之顆粒在硏磨及過篩後 的放大圖。（批號：HLGU 311)。 第5 B圖示爲根據新方法製出之顆粒在硏磨及過篩後 的顆粒大小分佈（篩析）（批號：H L G U 311)。 第6 Α圖示爲根據新方法製出之顆粒在硏磨及過篩後 的放大圖。（批號：H L G U 315)。 第6 Β圖示爲根據新方法製出之顆粒在硏磨及過篩後 的顆粒大小分佈（篩析）（批號·· H L G U 315)。 第7 Α圖示爲根據新方法製出之顆粒在硏磨及過篩後 的放大圖。（批號：H L G U 319)。 第7 Β圖示爲根據新方法製出之顆粒在硏磨及過篩後 的顆粒大小分佈（篩析）（批號·· H L G U 319)。 第8圖示爲根據本發明製備之潘朵沙⑧錠劑的溶解速率 略圖。該圖形顯示出本申請者爲該產品所建立之釋出明細 表，以用來獲得出售許可。 第9圖示爲從摻合器中取出，以證明摻合物之同質性 的樣本。 本發明的詳細說明 本發明關於製備5 - A S Α顆粒的新穎方法及製備含 (請先閱讀背面之注意事項再填寫本頁) 訂 ίφ. 本紙張尺度適用中國國家標準（CNS ) Α4規格（21〇χ297公釐） -11 - 577754 A7 _____B7_ 五、發明説明（9 ) 5 - A S A錠劑的新穎方法。 (請先閱讀背面之注意事項再填寫本頁) 本發明已改良總體之錠劑製造方法，也同時改良含5 - A S A顆粒之製造方法，這些改良爲本發明目的之需求 ，但這也意味此部分的成功並非預期中的，也非可預知的 。在習知技藝中並未指出以水取代有機溶劑可實現本發明 的目的，且可藉此得到所需之改良。習知技藝之方法係教 示使用含有約9 0% w/w異丙醇及1 〇% w/w水 的溶劑。 經濟部智慧財產局員工消費合作社印製 根據本發明，適合用於溶解連接劑的溶劑係以水爲基 礎，此溶劑含有至少5 0 % w/w水，宜爲至少含8 5 % w/w水，以至少含95% w/w水更佳，而以含 10 0% w/ w水爲最佳。溶劑之剩餘部分可爲任何適 合的液體，如：有機溶劑。該溶劑也可包含該方法或最終 產物中重要的添加劑。這類添加劑係在技術熟習人士的知 識範圍內。這些實例有：螯合劑、抗氧化劑、還原劑、緩 衝劑、p Η値調整劑、共溶劑或任何其它相關賦形劑。有 機溶劑可做爲，添加劑之溶解劑，少量的存在於其中。較 合適的爲，溶劑中不含有機溶劑。 由於各錠劑含有高劑量之活性成分，5 -胺基柳酸， 因此，在製造設備中需要處理大量物質。因此，本發明的 目的係改良現有的方法，以藉此以較低花費來製備更多錠 劑，並且不會損害到產物品質。 本發明的主要重點爲尋找一種可藉其取得具下列優點 之顆粒的方法：該顆粒較根據習知方法所取得之顆粒來得 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -12 - 577754 A7 _B7____ 五、發明説明（10 ) 堅固表面較平滑，並具較狹窄之顆粒大小分佈。 (請先閱讀背面之注意事項再填寫本頁) 較堅固之顆粒在接下去之製備步驟中非常重要’這些 顆粒若能抵擋壓力，則可減少磨損。磨損會產生細粒’由 於這使得表面區域易發生變化，因此不利於包衣過程。細 粒亦會減少總產量。 爲了能正確測量顆粒之表面積，且藉此方法提供正確 之鋪置在顆粒上之聚合物的量來取得正確之分解速率略圖 ，顆粒的表面平滑與否是很重要的。另外，根據本發明所 製造之顆粒表面積減少會使得包衣物質的量大量減少。 經濟部智慧財產局員工消費合作社印製 在包衣過程的管控中，可複製之顆粒大小分佈對顆粒 而言，與前二項參數一樣重要。顆粒大小分佈可藉由執行 篩析的分法來界定。在此分析中，可使用之設備爲許多互 相置放在彼此頂端，具不同隔板篩之篩子。第一個隔板篩 之網孔較第二個隔板篩之網孔大，而第二個隔板篩所具之 網孔較第三個隔板篩所具者大，依此類推。可一起使用之 網孔的實例爲1400微米，1250微米，1180微 米，1000微米，850微米，710微米，600微 米和500微米大之網孔。因此，850 - 1〇〇〇微米 之部分爲可通過1 0 0 0微米網孔，但不可通過8 5 0微 米網孔的顆粒部分。 硏發工作的結果顯示出確實可能取得具所需性質的顆 粒。令人驚訴地，與現有方法相較下，爲了取得所需性質 ，唯一的改變爲將現有方法中用於溶解P V p之里丙醇對 水的比例從9 : 1改變成使用較多的水。根據本發明，其 本紙張尺度適用中國國家標準（CNS〉A4規格（210X297公釐） :13- 577754 A7 B7 五、發明説明（1彳） (請先閱讀背面之注意事項再填寫本頁) 比例爲1 : 1或更小。在表2中所列出之最初結果顯示出 :產量與異丙醇之含量成反比。不欲受限於任何理論，一 般相信，現有方法所製出之顆粒具粗糙表面且不同大小係 由於在乾燥步驟中，異丙醇所產生之像爆發的蒸氣會從顆 粒分裂出大和小碎片。粗糙表面亦可能係由於較不堅固的 顆粒在乾燥過程中受損所造成。使用根據本發明之水性顆 粒化作用，加上連續乾燥處理被認爲可使顆粒之乾燥過程 較溫和，因而產生具平滑表面之較堅固的顆粒。 改良顆粒強度亦被認爲可取得預先界定之可複製的顆 粒大小分佈。 除了可取得具如上述所需性質的顆粒外，結果亦顯示 新製備方法還有些其它優點，也就是·_ -更可爲環境上所接受。 -製造區中的環境對操作者而言較安全。 -較低之製造花費。 經濟部智慧財產局員工消費合作社印製 避免或減少使用有機溶劑異丙醇對處理過程及環境而 言都有很大的利益，在處理過程方面，操作者可避免與製 造區中使用異丙醇有關的風險或將其降至最低，在環境方 面，可減少在顆粒乾燥期間或乾燥之後，與收集和拋棄異 丙醇相關的問題。再者，購買及處理異丙醇的花費亦減少 。然而，若合適時，可加入至多爲溶劑之5 0%w/w的 有機溶劑，而宜爲低於1 5 % w /w ’以低於5 % w /w 更佳。最合適的爲不使用有機溶劑。 因此，當與現有方法比較時，本發明之製造方法的主 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -14 - 577754 A7 B7 五、發明説明（12 ) (請先閱讀背面之注意事項再填寫本頁) 要原則並未改變。5 - A S A錠劑之製備方法係先將活性 成分，5 -胺基柳酸，與連接劑溶液，如：在溶劑中之聚 烯吡咯啶酮（本發明中此溶劑係至少由5 0 % w / w 7jC 所組成）相混合。較合適的爲，該溶劑不含有機溶劑。將 此濕團塊擠成顆粒，再將顆粒置於連續流體床中乾燥。乾 燥後，於顆粒包衣（如：在流體床中進行）前，先將其硏 磨並過篩。在包衣過程中係將一聚合物包衣在顆粒上，直 到取得所需之分解速率略圖。然後，將已包衣之顆粒與錠 劑賦形劑混合，再壓成錠劑。 因此，本發明係關於第一個基礎觀點，用來製備含5 -胺基柳酸（5 - ASA)或其藥學上可接受之鹽或酯， 及藥學上可接受之連接劑之顆粒的方法，其包含下述步驟 (a )將藥學上可接受的連接劑溶解在溶劑中， (b )將已溶解之連接劑與5 - A S A混合，以形成 濕團塊， (c )將濕團塊擠成顆粒，及 經濟部智慧財產局員工消費合作杜印製 (d )在溶劑蒸發時乾燥該顆粒， 其中之新穎，令人驚訝且有利的特佳爲該溶劑係由至 少5 0 % w/w水所組成。 接著，將顆粒硏磨及過篩。 在本發明之較佳實施例中，溶劑中含有超過8 5 % w/w水。在另一較佳實施例中，溶劑爲含有超過9 5 % w/w水。更合適的爲，溶劑中不含有機溶劑。該溶劑中 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -15 - 577754 A7 B7 五、發明説明（13 ) 可任意含有一或多種添加劑。 (請先閱讀背面之注意事項再填寫本頁) 在另一種較佳實施例中，硏磨後，所產生的顆粒所具 有之顆粒大小分佈（此係藉由篩析來測量），主要係在 8 5 0微米至1 0 0 0微米之間。變更擠出器中的洞可取 得所需之顆粒大小。在全部顆粒中，顆粒大小在8 5 0微 米至1 0 0 0微米間的超過7 5%，宜爲超過8 5%，且 以超過9 0 %最佳。 在所產生之顆粒中，連接劑（如：聚乙烯吡咯啶酮） 對活性成分（5 - A S A )的比例宜至多爲8 : 1 0 0， 以至多爲6 · 5 : 100較佳，而以至多爲5 : 100最 佳。若需要時，可以其它連接劑取代聚乙烯吡咯啶酮。製 備顆粒時可考慮使用的連接劑係選自如下群體：纖維素之 衍生物，聚乙烯吡咯啶酮，預先膠化之玉米澱粉，或任何 其它合適的連接劑。這類連接劑之使用量可爲不同之5 -A S A相對量。 本發明另一觀點係利用第一個基礎觀點來製備可用於 治療潰瘍性大腸炎或克隆氏症之延長釋出錠劑的方法，其 包含下列步驟： 經濟部智慧財產局員工消費合作杜印製 (a )從5 -胺基柳酸或其藥學上可接受的鹽或酯， 及至多爲8重量％ (固體含量，以5 -胺基柳酸計）在溶 劑中的連接劑（該溶劑中含有至少5 0 % w / w水）製 備顆粒。 (b )將一聚合體組合物鋪放至該顆粒上，此聚合體 組合物含有一在有機溶劑中之藥學上可接受之聚合體物質 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -16 - 577754 A7 B7 五、發明説明（14 ) 的溶液，以在溶劑蒸發時，將顆粒包衣。 (請先閱讀背面之注意事項再填寫本頁) (C )將包衣之顆粒與藥學上可接受的錠劑賦形劑混 合，及 (d )從所產生之混合物形成錠劑。 較合適的爲，根據本發明第一觀點來製備顆粒，也就 是，將顆粒以連續程序進行擠出、乾燥、硏磨並過篩。 在本方法的一種實施例中，顆粒係在流體床中乾燥。 在另一種實施例中，包衣物質爲纖維素衍生物，如： 乙基纖維素。 在另一種實施例中，錠劑賦形劑係包含錠劑載體，如 :微晶型纖維素、潤滑劑，如：硬脂酸鎂，且還可任意地 包含如：滑石粉之類的賦形劑。 工業方面的適用性 1 · 一般考暈 經濟部智慧財產局員工消費合作社印製 由於各錠劑或劑量中含有相當大量的物質，因此生產 線中必須處理大量物質。該顆粒可分批製造或以連續程序 製造，也就是，顆粒可以連續程序擠出、乾燥、硏磨和過 篩。以連續程序製造顆粒的生產線應該要能處理下列製造 步驟（亦見第4圖）。 1 _將5 - A S A與連接劑之溶液，如：在水（5 0 %w/w或更多）中之聚乙烯吡咯啶酮（普維酮（Povidone ))濕性混合 2 .擠出 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -17 - 577754 Α7 Β7 五、發明説明（15) 3 .乾燥 4 .硏磨 (請先閱讀背面之注意事項再填寫本頁) 5 .過篩 由於其爲連續程序，因此需將設備建造成可控制不同 的成分流進入加工處理。經由控制成分流，可在整體程序 中取得成分間之正確比例。 2 ·含P V P顆粒之製備方法 將聚乙烯吡咯啶酮（P V P )溶於溶劑（如：1 0 0 % w / W水）中。將5 — A S A和P V P之水溶液混合 並加至擠出器中。或者，可將5 - A SA和PVP之水溶 液在擠出器中混合。將由5 - A S A和P V P所組成的濕 團塊通過篩子擠出，並使其落入用於乾燥濕顆粒的裝置中 〇 水性溶劑宜爲具合適品質的水，但可含有添加劑，如 :螯合劑、抗氧化劑、還原劑、緩衝劑及p Η調節劑。 經濟部智慧財產局員工消費合作社印製 較有利的爲，擠出器含有篩子，其上有許多直徑在 0 · 5和1 . 3毫米間（宜爲0 _ 9毫米）的圓孔。此飾 子的厚度介於0 _ 9和2 . 0毫米間。這些圓孔穿過篩子 時可具相同的橫截面，或者是在任一方向變得尖細。較合 適的爲，圓孔形狀爲一端尖細，各圓孔在薄板之入口端的 橫截面比篩子出口端的橫截面大，較佳之出口直徑爲 0 · 9毫米，而較佳之入口直徑爲〇 . 95毫米。 較有利的爲，該乾燥裝置宜爲流體床。然而，亦可使 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X297公釐） -18 - 577754 A7 B7 五、發明説明（16) 用技術熟習人士所已知之其它可用裝置。 (請先閱讀背面之注意事項再填寫本頁) 若使用流體床，則可設計成在流體床中的停留時間約 爲2 %小時。然而，較短或較長的時間亦在本發明的範圍 內。流體床最好分成二部分，在第一部分中’該顆粒係表 面上乾燥，以避免其黏在一起。在此部分中’顆粒發生任 意混合。在流體床的第二部分中，進行顆粒之最後乾燥， 且顆粒係透過底板的圓孔樣式，而被引導通過流體床。 當顆粒乾燥後，其從流體床釋出，並轉移入硏磨機中 ，以減小顆粒長度。硏磨過程會產生小量的細粒，在將顆 粒包衣前，必須經由過篩來先將這些細粒移除。此時，可 進行如先前所描述之篩析。 3 ·包衣 將所產生的顆粒包衣。顆粒可在任何適用於本方法的 包衣裝置上進行包衣。 經濟部智慧財產局員工消費合作社印製 技術熟習人士可以很容易地知道何種裝置可適合本方 法，如：流體床系統（如：庫吉包衣器（Kugelcoatei:)。 顆粒宜以溶在適合該聚合物之溶劑中的聚合物來包衣，而 溶劑宜爲有機溶劑，如：丙酮。 爲了決定必須鋪放在顆粒上的聚合物量，需測量顆粒 表面積。根據每表面積之聚合物量與，分解速率略圖間的 相關性，可從所測得之顆粒表面積預測出所需之聚合物量 。顆粒之表面愈平滑，則所需之聚合物量愈少。在包衣步 驟期間所形成的任何集結物均可藉由過篩來移除。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -19 - 577754 A7 B7 五、發明説明（17 ) (請先閲讀背面之注意事項再填寫本頁) 所選擇之包衣聚合物主要係取決於所需之釋出型式。 其可選自速率-限制屏障物質，如：腸包衣物質或延遲性 包衣物質，如··聚甲丙烯酸酯，可購得之型式各爲優多吉 ™ s ( Eudragit™ S)，優多吉^ RL 和優多吉^113。 當使用半滲透性之聚合物時，乙基纖維素爲最佳聚合物。 4 .混合 將已包衣之顆粒以傳統乾燥混合方法與剩餘的錠劑賦 形劑混合。 錠劑賦形劑可包括任何本領域技術熟習人士熟知之合 適的藥學上可接受的載體，如：乳糖、玉蜀黍澱粉、馬鈴 薯澱粉及潤滑劑，如：硬脂酸鎂及滑石粉。 較佳之載體構成物爲微晶型纖維素。 根據習知方法所製出之潘朵沙@錠劑含有做爲錠劑賦形 劑之微晶型纖維素、硬脂酸鎂及滑石粉。根據本發明之錠 劑適合含有相同之賦形劑。 經濟部智慧財產局員工消費合作社印製 -20- 577754 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明（18 ) 5 -胺基柳酸或任何其鹽或酯爲顆粒中的活性成分。 5 - A S A之鹽類可爲酸加成鹽類，尤其是氫氯酸鹽，但 也可使用任何藥學上可接受的，非毒性的有機或無機酸。 亦可使用以羧酸基團生成之鹽類。可提出之實例有： 鹼金屬鹽類（K，Na)、鹼土金屬鹽類（Ca，Mg) ，但也可使用任何藥學上可接受的，非毒性的鹽。以N a 鹽和Ca鹽爲較佳者。 在DE專利申請案271 2 394號（AU申請案 7723548號）（此篇倂爲本文之參考資料）中揭示 許多鄰-、間一和對-柳酸之酯類。所揭示之間一（或5 -）胺基柳酸酯類及許多相關酯類亦可做爲根據本發明所 製出之組合物中的活性成分。 可適用之酯類，如：直鏈型或側鏈型C i - C i 8烷基 酯類，如：甲基、乙基、丙基、異丙基、丁基、異丁基、 戊基、己基、庚基、辛基、壬基、癸基、月桂基、肉豆蔻 基、鯨蠛基、及硬脂醯基，等，直鏈型或側鏈型C 2 -C18烯基酯類，如：乙烯基、丙烯基、十一烯基、油基、 亞麻基、等，C3 - C8環烷基酯類，如：環丙基、環丁基 、環戊基、環己基、環庚基和環辛基、等，芳基酯類，如 :苯基、甲苯甲醯基、二甲苯基、萘基，等，脂環族酯類 ，如··盖基，等，或芳烷基酯類，如··苄基、苯乙基，等 。一般而言，活性成分係根據所選擇之配方型式，疾病典 型，尤其是疾病之位置和形態，以及所需釋出之活性成分 來做正確的選擇。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -21 - — 批衣 _ 訂 . . - - (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 577754 A7 -_____ B7 五、發明説明（19 ) 當選擇適合5 - A S A衍生物之載體組合物時，必須 考慮該成分之物理狀態及溶解度特性。 目前較佳之活性成分爲該游離酸，5 -胺基柳酸。 有效之口服劑量係根據疾病的程度而定，在成人方面 ’此劑量通常爲0·5-1·0克，每日四次。一般所建 議之起始每日劑量爲每公斤體重服用約2 0毫克5 -A S A或其鹽或酯（計算法如同5 - A S A )，再接著根 據所觀察到的治療結果來調整。 雖然較佳之包衣劑爲乙基纖維素，但只要能保護所需 之釋出典型的安全，亦可使用其它包衣劑。尤其是，必須 確定多種其它纖維素衍生物爲可適用者。目前，較佳之釋 出典型爲在抵達小腸後，以連續方式釋出。此種釋出典型 最初係設計爲讓錠劑，如：潘朵沙@能同時有效對抗克隆氏 症及潰瘍性結腸炎。 然而，當需確保能在小腸中早期釋出（在克隆氏症的 情況中），或直到抵達結腸時才延遲釋出（在潰瘍性結腸 炎的情況中）時，藉由改變如W〇 8 1 / 0 2 6 7 1中 所討論的不同錠劑參數，可控制錠劑之釋出典型，該篇文 章在此倂爲參考資料。 實施例1 潘朵沙錠劑之製備方法（現有之以異丙醇爲基礎的粒 化方法） 潘朵沙@緩慢-釋出錠劑5 0 0毫克 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -22 - 裝 ^ 訂 義 - _ . (請先閱讀背面之注意事項再填寫本頁) 577754 A7 B7 五、發明説明（20 ) 構成物名稱 每批之量（155000個錠劑） 規格說明 活性成分 77.5公斤 (菲林藥廠） 5-胺基柳酸 其它成分 普維酮 3875 克土 10% 歐洲藥典 異丙醇 17.3公斤 歐洲藥典 純水 1 550 克 歐洲藥典 乙基纖維素 q. s 歐洲藥典 丙酮 q.s. 歐洲藥典 硬脂酸鎂 155克 歐洲藥典 滑石粉 1 395 克 歐洲藥典 微晶型纖維 ad 116250克 歐洲藥典 素 I ^^裝 ^ 訂 . I · ' (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -23 - 577754 五、發明説明（21 ) 製造設備： 設備 功能 NICA混合器M6L 顆粒化 NICA擠出器E 220 擠出 AEROMATIC流體床乾燥器 乾燥 FREWITT MG 8振動器 振動 MOGENSEN Typ 0254篩選器 過篩 HUTTLIN庫吉包衣器HKC200或 包衣 HUTTLIN庫吉包衣器HKC400 PRODIMA 混合器 AC-HLR 500 混合 KILIAN T 300或 製成錠劑 KORSCH藥物壓製250 (請先閱讀背面之注意事項再填寫本頁)W 0 97/2 3 1 9 9 discloses an improved release composition comprising spherical particles for treating I BD. These spherical particles include a 5-ASA core, and a nodulizing adjuvant (which is based on water As a solvent) and coated with a rate-limiting barrier material. Such a composition can release 5-A SA in a small amount in the stomach, and the particles can be enclosed in a small drug bundle. These granules are not suitable for use in tablets. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. As the market demand for drugs containing 5-A S A continues to increase, it is necessary to improve the method for preparing tablets containing 5-A S A. Summary of the Invention Since each tablet or dose containing 5-A S A contains a relatively large amount of active ingredient to optimize the therapeutic effect, a large amount of substance needs to be processed in the manufacturing equipment. This paper size applies the Chinese National Standard (CNS) A4 specification (210'〆297 mm) 577754 A7 B7 V. Description of the invention (5) (Please read the precautions on the back before filling this page) As it contains 5 — A SA The drug market continues to grow 'so' the methods currently used to make 5-ASA lozenges need to be improved. In the present invention, the improved part provides the method for preparing a 5-A SA-containing lozenge, which is a better, faster, less expensive 'method without losing the quality and bioavailability of 5-A SA. The object of the present invention is to obtain an improved composition for extruded granules that can be used in Pandosa® or similar lozenges. These particles must be strong and smooth, tolerate different processing steps during the manufacturing process, and have a narrow and reproducible particle size distribution. Surprisingly, this method can be modified without changing the main principles of existing preparation methods. The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed the 5-ASA-containing lozenge prepared according to the present invention. The active ingredient, 5-aminosalicylic acid, and a pharmaceutically acceptable linker in a solvent ( For example: polyvinylpyrrolidone (PVP)) solution is mixed. This mixture was extruded into granules and dried in a fluid bed. After drying, the particles are honed and sieved before coating, for example in a fluid bed. During the coating process, a polymer needs to be coated on the particles until the desired dissolution rate is obtained. The coated granules are then mixed with lozenge excipients and compressed into lozenges. One of the viewpoints of the present invention is that it is surprisingly found that it is advantageous to partially or completely replace the organic solvent used in the conventional method with water. U.S. Patent Re 33,239 teaches that since 5-A S A is sensitive to humidity and light, its stability is not good. The patent discloses a pharmaceutical composition containing 5-ASA in solution, or this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm): 8-577754 A7 B7 V. Description of the invention (6) , 5-ASA is a suspension type together with additives, this additive can stabilize 5-ASA. Furthermore, the composition is packaged in an inert gas in a tight, leak-proof and light-tight package. (Please read the notes on the back before filling out this page.) Therefore, the use of water as the main solvent will be contrary to the teaching about the formulation of 5-A S A tablets. In the existing methods, the problem of humidity-related stability is avoided by using an organic solvent as the main solvent. Surprisingly, it has been found that water can indeed be used as the main solvent in the process for preparing 5-ASA containing particles, and it does not substantially affect the stability of 5-ASA, and these 5-A SA containing Granules can be used in lozenge formulations. It is generally believed that a continuous drying process in, for example, a fluid bed is advantageous for obtaining a stable product that can tolerate a fast and gentle drying process and protect the product from light damage. W09 7/2 3 1 99 uses water as a solvent in the preparation of spherical particles. However, these particles contain different linking agents and are directly treated during spheroidization and drying. Since the spherical particles are scattered, it is not optimal to use them in a tablet. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, surprisingly, it has been found that when water is used to partially or completely replace organic solvents, particles with a narrow particle size distribution can be produced, and the particles produced are stronger and smoother. The surface. These improvements can increase the yield of lozenges made by this method. Furthermore, the smooth surface of the particles makes the coating process easier to reproduce and reduces the amount of coating material used in this method. In addition to the improvement of the above products, the use of organic solvents can be reduced, which reduces the risks to operators and manufacturing environments in manufacturing equipment, and reduces the total content of organic solvents in the final product. In addition -9-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 577754 A7 B7_ 5. Description of the invention (7) ′ can greatly reduce the cost of organic solvents. (Please read the notes on the back before filling this page) In the second aspect of the present invention, granules are prepared from 5-A S A wet agglomerates and a linker to form part of a continuous production line for manufacturing 5-A S A pellets. In a third aspect of the present invention, the method for preparing granules forms part of the method for preparing 5-A S A lozenges. As discussed above, a large amount of material may need to be processed in a production line. Therefore, the production line can be designed as a continuous production line, in which 5-ASA is mixed with an aqueous PVP solution before or in the extruder, and the resulting particles are dried and honed in a continuous process. And sieved. The feed of individual ingredients is continuously adjusted, such as by measuring the weight of different feeds (this is part of the production line). Brief description of the diagram The 1A diagram is an enlarged view of the granules produced by the existing method after sieving (batch number: KGGU 405R). Figure 1B shows the particle size distribution (sieve analysis) of the particles prepared according to the conventional method after sieving (batch number: K G G U 4 0 5 R). Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Figure 2A is an enlarged view of the particles produced by the existing method after sieving (batch number: KGGU 406Q). Figure 2B shows the particle size distribution (sieve analysis) of the particles prepared by the conventional method after sieving (batch number: K G G U 4 0 6 Q). Figure 3A is an enlarged view of the granules produced according to the existing method after sieving (batch number: KGGU 406T). This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -10- 577754 A7 B7 Printed by the Consumer Consumption Cooperative of Intellectual Property Bureau of the Ministry of Economy The particle size distribution (sieve analysis) of the obtained particles after sieving (batch number: KGGU 4 0 6 T). Figure 4 shows a flowchart of a new method for preparing pandoxacin or similar lozenges. Figure 5A shows an enlarged view of the granules produced according to the new method after honing and sieving. (Lot number: HLGU 311). Figure 5B shows the particle size distribution (sieve analysis) of the particles produced by the new method after honing and sieving (batch number: H L G U 311). Figure 6A is an enlarged view of the particles made according to the new method after honing and sieving. (Lot number: H L G U 315). Figure 6B shows the particle size distribution (sieve analysis) of the particles prepared according to the new method after honing and sieving (batch number · H L G U 315). Figure 7A shows an enlarged view of the particles produced by the new method after honing and sieving. (Lot number: H L G U 319). Figure 7B shows the particle size distribution (sieve analysis) of the particles produced by the new method after honing and sieving (batch number · H L G U 319). Figure 8 is a schematic diagram of the dissolution rate of the pandoxacin tablets prepared according to the present invention. The graphic shows a release schedule created by the applicant for the product to be used to obtain permission to sell. Figure 9 shows a sample taken from the blender to demonstrate the homogeneity of the blend. Detailed description of the invention The novel method and preparation method for preparing 5-AS Α particles according to the present invention (please read the precautions on the back before filling this page) Order. Φ This paper size applies Chinese National Standard (CNS) Α4 size (21 〇χ297mm) -11-577754 A7 _____B7_ 5. Description of the invention (9) 5-A novel method of ASA tablets. (Please read the precautions on the back before filling this page) The present invention has improved the overall method for manufacturing lozenges, as well as the method for manufacturing 5-ASA particles. These improvements are required for the purpose of the present invention, but this also means Part of the success was not expected or predictable. It is not pointed out in the conventional art that replacing the organic solvent with water can achieve the object of the present invention, and the desired improvement can be obtained therefrom. The conventional method teaches the use of a solvent containing about 90% w / w isopropanol and 10% w / w water. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs According to the present invention, the solvent suitable for dissolving the linking agent is based on water. This solvent contains at least 50% w / w water, preferably at least 85% w / w Water is more preferably at least 95% w / w water, and more preferably 100% w / w water. The remainder of the solvent can be any suitable liquid, such as organic solvents. The solvent may also contain important additives in the process or end product. Such additives are within the knowledge of those skilled in the art. These examples are: chelating agents, antioxidants, reducing agents, buffers, pH modifiers, co-solvents or any other related excipients. An organic solvent can be used as a dissolving agent for the additive in a small amount. It is more suitable that the solvent does not contain an organic solvent. Since each lozenge contains a high dose of the active ingredient, 5-aminosalicylic acid, a large amount of substance needs to be processed in the manufacturing equipment. Therefore, the object of the present invention is to improve the existing method so as to prepare more lozenges at a lower cost without compromising the product quality. The main focus of the present invention is to find a method by which particles with the following advantages can be obtained: the particles are obtained from the particles obtained according to the conventional method. 12-577754 A7 _B7____ 5. Description of the invention (10) The solid surface is smoother and has a narrower particle size distribution. (Please read the precautions on the back before filling out this page.) Stronger particles are very important in the next preparation steps ’These particles can reduce wear if they can withstand pressure. Abrasion produces fine particles', which is not conducive to the coating process because it makes the surface area susceptible to change. Fines also reduce overall yield. In order to accurately measure the surface area of the particles, and to provide the correct amount of polymer deposited on the particles to obtain the correct sketch of the decomposition rate, it is important to smooth the surface of the particles. In addition, a reduction in the surface area of the particles produced according to the present invention results in a substantial reduction in the amount of coating material. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs In the control of the coating process, the reproducible particle size distribution is as important to the particles as the first two parameters. The particle size distribution can be defined by performing a sieving method. The equipment that can be used in this analysis is a number of sieves with different baffles placed on top of each other. The first baffle screen has a larger mesh than the second baffle screen, the second baffle screen has a larger mesh than the third baffle screen, and so on. Examples of meshes that can be used together are 1400 micron, 1250 micron, 1180 micron, 1000 micron, 850 micron, 710 micron, 600 micron, and 500 micron large meshes. Therefore, the part of 850-10000 microns is the part of particles that can pass through the 1000 micron mesh, but cannot pass through the 850 micron mesh. The results of the bursting work show that it is indeed possible to obtain particles with the required properties. Surprisingly, in order to obtain the required properties compared to the existing methods, the only change is to change the ratio of propanol to water used to dissolve PV p in the existing methods from 9: 1 to more used water. According to the present invention, the paper size of this paper applies the Chinese national standard (CNS> A4 specification (210X297 mm): 13-577754 A7 B7 V. Description of the invention (1 彳) (Please read the notes on the back before filling this page) Proportion It is 1: 1 or less. The initial results listed in Table 2 show that the yield is inversely proportional to the content of isopropanol. Without wishing to be bound by any theory, it is generally believed that the granules produced by existing methods have Rough surfaces and different sizes are due to the explosive explosion of isopropyl alcohol during the drying step which will break up large and small fragments from the particles. Rough surfaces may also be caused by the less robust particles being damaged during the drying process The use of the aqueous granulation according to the present invention, coupled with continuous drying treatment, is considered to make the drying process of the granules gentler, thus producing stronger granules with smooth surfaces. Improved granule strength is also considered to obtain pre-defined Reproducible particle size distribution. In addition to obtaining particles with the desired properties as described above, the results also show that the new preparation method has some other advantages, that is, Accepted by the environment. -The environment in the manufacturing area is safer for the operator. -Lower manufacturing costs. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs to avoid or reduce the use of organic solvent isopropyl alcohol on the process and There are great benefits in terms of the environment. In terms of processing, the operator can avoid or minimize the risks associated with the use of isopropyl alcohol in the manufacturing area. In terms of the environment, it can reduce the particle drying period or after drying. Problems related to the collection and disposal of isopropanol. Furthermore, the cost of purchasing and disposing of isopropanol is also reduced. However, if appropriate, up to 50% w / w of organic solvents can be added, which is appropriate It is preferably less than 15% w / w 'and more preferably less than 5% w / w. The most suitable is not to use an organic solvent. Therefore, when compared with the existing method, the main paper size of the manufacturing method of the present invention is applicable. China National Standard (CNS) A4 Specification (210X297 mm) -14-577754 A7 B7 V. Description of Invention (12) (Please read the notes on the back before filling this page) The principle has not changed. 5-ASA tablets Preparation The method is to first combine the active ingredient, 5-aminosalicylic acid, with a linker solution, such as polypyrrolidone in a solvent (the solvent in the present invention is composed of at least 50% w / w 7jC). Mixing. It is more suitable that the solvent does not contain organic solvents. This wet mass is extruded into granules, and then the granules are dried in a continuous fluid bed. After drying, the granules are coated (eg, in a fluid bed) Before, it is honed and sieved. During the coating process, a polymer is coated on the granules until a sketch of the desired decomposition rate is obtained. Then, the coated granules and lozenge excipients are used. Therefore, the present invention relates to the first basic point for preparing 5-aminosalicylic acid (5-ASA) or a pharmaceutically acceptable salt or ester thereof, and pharmaceutically acceptable A method of accepting a particle of a linker comprising the steps of (a) dissolving a pharmaceutically acceptable linker in a solvent, and (b) mixing the dissolved linker with 5-ASA to form a wet mass (C) Squeeze the wet mass into pellets, and cooperate with the staff of the Intellectual Property Bureau of the Ministry of Economic Affairs Ltd. and (d) drying the granules upon evaporation of the solvent, wherein the new, surprising and advantageous for the particularly preferred solvent system consisting of at least 5 0% w / w water. The particles are then honed and sieved. In a preferred embodiment of the invention, the solvent contains more than 85% w / w water. In another preferred embodiment, the solvent contains more than 95% w / w water. More suitably, the solvent does not contain an organic solvent. In this solvent, the paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) -15-577754 A7 B7 V. Description of the invention (13) It may contain one or more additives arbitrarily. (Please read the notes on the back before filling this page) In another preferred embodiment, the particle size distribution of the particles produced after honing (this is measured by sieve analysis) is mainly based on 850 microns to 1000 microns. Changing the holes in the extruder can achieve the desired particle size. In all particles, the particle size is more than 75% between 850 microns and 1000 microns, preferably more than 85%, and most preferably more than 90%. In the granules produced, the ratio of linker (such as polyvinylpyrrolidone) to the active ingredient (5-ASA) should preferably be at most 8: 1 0 0, at most 6 · 5: 100, and even 5: 100 is the best. If desired, polyvinylpyrrolidone may be replaced by other linking agents. The linker to be considered for preparing the granules is selected from the group consisting of cellulose derivatives, polyvinylpyrrolidone, pregelatinized corn starch, or any other suitable linker. The amount of such linking agents can be different relative amounts of 5-A S A. Another aspect of the present invention is to use the first basic aspect to prepare a method for prolonged release tablets that can be used to treat ulcerative colitis or Crohn's disease, which includes the following steps: Consumption cooperation by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs (a) from 5-aminosalicylic acid or a pharmaceutically acceptable salt or ester thereof, and up to 8% by weight (solid content, based on 5-aminosalicylic acid) in a solvent (in the solvent Contain at least 50% w / w water) to prepare granules. (b) Placing a polymer composition on the particles, the polymer composition containing a pharmaceutically acceptable polymer substance in an organic solvent. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297). (Mm) -16-577754 A7 B7 V. Solution of the invention (14), to coat the particles when the solvent evaporates. (Please read the notes on the back before filling out this page) (C) Mix the coated granules with a pharmaceutically acceptable lozenge excipient, and (d) Form a lozenge from the resulting mixture. It is more appropriate to prepare the granules according to the first aspect of the present invention, that is, the granules are extruded, dried, honed and sieved in a continuous process. In one embodiment of the method, the particles are dried in a fluid bed. In another embodiment, the coating material is a cellulose derivative, such as ethyl cellulose. In another embodiment, the lozenge excipients include lozenge carriers, such as microcrystalline cellulose, lubricants, such as magnesium stearate, and may optionally include excipients such as talc.形 剂。 Shape agent. Industrial applicability 1 · General test print Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Because each tablet or dose contains a considerable amount of substance, a large amount of substance must be processed in the production line. The granules can be manufactured in batches or in a continuous process, that is, the granules can be extruded, dried, honed, and sieved in a continuous process. A line that produces pellets in a continuous process should be able to handle the following manufacturing steps (see also Figure 4). 1 _ Wet mixing 5-ASA with a solution of a linking agent, such as polyvinylpyrrolidone (Povidone) in water (50% w / w or more) 2. Extruded Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -17-577754 Α7 Β7 V. Description of invention (15) 3. Drying 4. Honing (please read the precautions on the back before filling this page) 5 .Since the sieving is a continuous process, the equipment needs to be built to control different component flows into the processing. By controlling the component flow, the correct ratio between components can be obtained in the overall process. 2 · Preparation method of P V P particles Dissolve polyvinyl pyrrolidone (P V P) in a solvent (such as 100% w / W water). An aqueous solution of 5-A S A and P V P was mixed and added to the extruder. Alternatively, an aqueous solution of 5-A SA and PVP can be mixed in an extruder. Squeeze the wet mass consisting of 5-ASA and PVP through a sieve and drop it into the device for drying wet granules. The aqueous solvent should be water of suitable quality, but it can contain additives such as chelating agents. , Antioxidants, reducing agents, buffers and p p regulators. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. It is advantageous that the extruder contains a sieve with many circular holes with a diameter between 0.5 and 1.3 mm (preferably 0 -9 mm). The thickness of this decoration is between 0 _ 9 and 2.0 mm. These round holes can have the same cross-section as they pass through the screen, or they can be tapered in either direction. More preferably, the shape of the round hole is tapered at one end, and the cross-section of each round hole at the entrance end of the thin plate is larger than the cross-section of the exit end of the sieve. The preferred exit diameter is 0.9 mm, and the preferred entrance diameter is 0.95. Mm. Advantageously, the drying device is preferably a fluid bed. However, this paper size can also be adapted to the Chinese National Standard (CNS) A4 (210 X297 mm) -18-577754 A7 B7 V. Description of the invention (16) Use other available devices known to those skilled in the art. (Please read the notes on the back before filling out this page.) If a fluid bed is used, the residence time in the fluid bed can be designed to be about 2% hours. However, shorter or longer times are also within the scope of the present invention. The fluid bed is preferably divided into two parts. In the first part, the particles are dried on the surface to prevent them from sticking together. In this section, the 'particles are arbitrarily mixed. In the second part of the fluid bed, the particles are finally dried, and the particles are guided through the fluid bed through the circular hole pattern of the bottom plate. When the granules are dried, they are released from the fluid bed and transferred to a honing machine to reduce the length of the granules. The honing process produces a small amount of fine particles, which must be removed by sieving before coating the particles. At this point, sieving can be performed as previously described. 3. Coating The resulting particles are coated. The granules can be coated on any coating device suitable for the method. Those familiar with the printing technology of the Intellectual Property Bureau of the Ministry of Economic Affairs and the Consumer Cooperative Printing Technique can easily know which devices are suitable for this method, such as: fluid bed systems (such as: Kugelcoatei :). The particles should be dissolved in The polymer is coated in a polymer solvent, and the solvent is preferably an organic solvent, such as acetone. In order to determine the amount of polymer that must be laid on the particles, the surface area of the particles needs to be measured. According to the amount of polymer per surface area and the decomposition rate The correlation between the sketches can predict the amount of polymer required from the measured particle surface area. The smoother the surface of the particles, the less polymer is required. Any aggregates formed during the coating step can be Removed by sieving. This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) -19-577754 A7 B7 V. Description of invention (17) (Please read the precautions on the back before filling this page The coating polymer chosen depends mainly on the desired release pattern. It can be selected from rate-limiting barrier substances such as enteric coating substances or delayed coatings Materials, such as polymethacrylate, are available in Eudragit ™ s (Eudragit ™ S), Eudogit ^ RL, and Eudogit ^ 113. When using semi-permeable polymers, ethyl fibers Is the best polymer. 4. Mixing The coated granules are mixed with the remaining lozenge excipients by conventional dry blending methods. Lozenge excipients may include any suitable pharmacy known to those skilled in the art. Acceptable carriers, such as: lactose, maize starch, potato starch, and lubricants, such as: magnesium stearate and talc. The preferred carrier composition is microcrystalline cellulose. Panduo produced according to conventional methods Sha @ Lozenge contains microcrystalline cellulose, magnesium stearate, and talc as lozenge excipients. Lozenges according to the present invention are suitable to contain the same excipients. Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs -20- 577754 A7 B7 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (18) 5-aminosalicylic acid or any salt or ester thereof is the active ingredient in the granules. 5-ASA salts may For acid addition salts, especially It is hydrochloride, but any pharmaceutically acceptable, non-toxic organic or inorganic acid can also be used. Salts generated by carboxylic acid groups can also be used. Examples that can be mentioned are: alkali metal salts (K , Na), alkaline earth metal salts (Ca, Mg), but any pharmaceutically acceptable, non-toxic salt can also be used. Na salts and Ca salts are preferred. In DE patent application 271 2 394 No. (AU Application No. 7723548) (this article is a reference for this article) discloses many ortho-, meta- and p-salicylic acid esters. The mono- (or 5--) aminosalicylates disclosed And many related esters can also be used as the active ingredient in the composition prepared according to the present invention. Applicable esters, such as: linear or side chain C i-C i 8 alkyl esters, such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl , Hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl, etc., linear or side chain C 2 -C18 alkenyl esters, Such as: vinyl, propenyl, undecenyl, oleyl, flaxyl, etc., C3-C8 cycloalkyl esters, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl And cyclooctyl, etc., aryl esters, such as: phenyl, tolyl, xylyl, naphthyl, etc., cycloaliphatic esters, such as ... Classes, such as benzyl, phenethyl, etc. Generally speaking, the active ingredient is selected correctly based on the selected formula, disease type, especially the location and shape of the disease, and the active ingredient to be released. This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) -21-— Approval _ Order..--(Please read the precautions on the back before filling this page) Employee Cooperatives of Intellectual Property Bureau, Ministry of Economic Affairs Printing 577754 A7 -_____ B7 V. Description of the invention (19) When selecting a carrier composition suitable for a 5-ASA derivative, the physical state and solubility characteristics of the component must be considered. The currently preferred active ingredient is the free acid, 5-aminosalicylic acid. The effective oral dose depends on the severity of the disease. In adults, this dose is usually 0.5-1.0 g, four times a day. The recommended daily starting dose is about 20 mg 5 -A S A or its salt or ester per kilogram of body weight (calculated like 5-A S A), and then adjusted based on the observed treatment results. Although the preferred coating agent is ethylcellulose, other coating agents may be used as long as they protect the desired release typical safety. In particular, a variety of other cellulose derivatives must be identified as applicable. Currently, the preferred release is typically continuous after reaching the small intestine. This release is typically designed as a lozenge, such as Pandora @, which is effective against both Crohn's disease and ulcerative colitis. However, when it is necessary to ensure early release in the small intestine (in the case of Crohn's disease) or delayed release until the colon is reached (in the case of ulcerative colitis), change such as W08 The different tablet parameters discussed in 1/0 2 6 7 1 can control the typical release of tablets. This article is here for reference. Example 1 Preparation method of panduosha tablets (existing granulation method based on isopropanol) Panduosha @ Slow-Release Tablets 500 mg This paper is applicable to Chinese National Standard (CNS) A4 Specifications (210X297 mm) -22-Packing ^ Definition-_. (Please read the notes on the back before filling out this page) 577754 A7 B7 V. Description of the invention (20) The name of the component (155000 ingots) Agent) Specification Description Active ingredient 77.5 kg (Filin Pharmaceutical) 5-aminosalicylic acid other ingredients Prevazone 3875 g 10% European Pharmacopoeia isopropanol 17.3 kg European Pharmacopoeia pure water 1 550 g European Pharmacopoeia ethyl cellulose q s European Pharmacopoeia acetone qs European Pharmacopoeia magnesium stearate 155 g European Pharmacopoeia talcum powder 1 395 g European Pharmacopoeia microcrystalline fiber ad 116250 g European Pharmacopoeia I I ^^ Pack ^ Order. I · '(Please read the note on the back first Please fill in this page for further information) Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is printed in accordance with Chinese National Standard (CNS) A4 (210X297 mm) -23-577754 V. Description of Invention (21) Manufacturing Equipment : Equipment Features NICA Mixer M6L Granulated NICA Extruder E 220 Extrusion AEROMATIC Fluid Bed Dryer Drying FREWITT MG 8 Vibrator Vibration MOGENSEN Typ 0254 Screener HUTTLIN Cowicher HKC200 or Coat HUTTLIN HKC400 PRODIMA mixer AC-HLR 500 mixed with KILIAN T 300 or made into tablets KORSCH drug compression 250 (Please read the precautions on the back before filling this page)

k」L 製造步驟 -Li 潘朵沙@緩慢-釋出錠劑之製造係分成1 0個步驟進行 0 步驟0 :設備及成分之開始例行程序 經濟部智慧財產局員工消費合作社印製 開始使用前，先檢查所有設備是否淸潔。 步驟1:稱重 稱量5 -胺基柳酸之重，並將其送進混合器中。 步驟2 :粒化作用 製備粒化液體（溶於純水與2 -丙醇之混合物中的普 維酮）並在混合期間加入。在加入粒化液體後，持續混合 一段固定時間。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -24 - 577754 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明（22 ) 步驟3 :擠出作闲 將粒化團塊以相同步驟擠成小九（篩子i . 〇 x 1 · Ο (篩子之直徑x厚度））。 步驟4 :乾燥作用 將顆粒轉移入流體床乾燥器中並乾燥之。 步驟5 =過篩 將乾燥的小九撒在莫金森（Mogensen )篩子（偏斜的 篩子）上。將能通過大小爲〇 · 8毫米之隔板篩的顆粒丟 棄，或將其收集起來貯存在密封，有標示之容器內，以供 再處理。不能通過大小爲1 · 8毫米之隔板篩的顆粒亦丟 棄。 步驟6 :包衣 將顆粒在庫吉包衣器（流體床系統）中，以由乙基纖 維素在丙酮中所組成的液體來包衣。若有任何隆起形成， 則將顆粒撒在莫金森篩子上（偏斜的篩子）過篩。 步驟7 :混合 將包衣之顆粒，塡充劑/連接劑（微晶型纖維素）及 潤滑劑（硬脂酸鎂和滑石粉）轉移至混合器中並完全混合 〇 步驟8 :壓製 將包衣顆粒和潤滑劑之最終摻合物在旋轉製錠機上壓 成錠劑。 步驟9 :除塵 將錠劑除塵。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 「25- 裝 „ 訂 滅 - · · (請先閲讀背面之注意事項再填寫本頁) 577754 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明（23 ) 步驟1〇:包裝 將緩慢-釋出錠劑置於已標示之散裝容器中’並貯存 於隔離處所，直到品管部門放行。 第1 A - 3 A圖示爲從現有方法所製得之三批不同產 品取得之顆粒的放大照片。 實施例2 製備渦程中，不同參數變化的效果 本實施例中，乾及濕物質係在爾維卡（Erweka ) A R 4 Ο Ο E強力混合器中混合。擠出作用則是在尼諾•費爾 德（Niro Fielder )擠出器E 1 4 0中進行。除非另外指出 ，在擠出器中所使用之篩子所含有的圓孔大小係在0 . 9 X 0 · 9毫米的範圍內（篩子之直徑X厚度）。使用瑞奇· 維布洛（Retch Vibro )篩來進行篩析。 首先，在2 3因數分析中檢查本方法的3種關鍵參數： PVP含量，水含量及混合器之速度： 低級位 高級位 因子a PVP 3% w/w 8% w/w 因子b 水 0% w/w 6% w/w 因子c 葉輪 33rpm 66rpm 對所產生之顆粒進行評估，以做爲在0 . 8 5 0 -1 · 0毫米之範圍內過節後的產量。重複此測試5次，結 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 「26 - I 裝 „ 訂 - -(請先閱讀背面之注意事項再填寫本頁) 577754 A7 B7 五、發明説明（24 ) 果顯示出水和PVP二者之含量對於在0.850-1 . 0毫米之範圍間的產量的影響。如表1所示，葉輪的 速度對在所指定之範圍內的產量並無影響： 試驗 平均値 SD ⑴ 63.40 3.62 a 60.48 2.22 b 70.22 2.12 ab 80.66 3.74 c 60.68 3.59 ac 66.38 4.52 be 70.44 2.21 abc 80.22 3.00 (請先閲讀背面之注意事項再填寫本頁) 表1係從2 3因數實驗所得之結果，其顯示在0 . 8 5 0 -1 . 0毫米之範圍內過篩後的％產量。 經濟部智慧財產局員工消費合作社印製 爲了讓擠出之顆粒中的水和P V P含量最優化，重複 進行二次一個新試驗。水加異丙醇（I P A )維持固定在 3 5 % w/w，而水之含量則在6，12和18% w /w間變化。PVP之含量在5，6 · 5和8% w / w 間變化。 結果顯示於表2中，且其顯示出水的含量較高時，可 取得較高產量。若將PVP之含量增加至8% w/w， 則產量將因集結物產生而減少。 受到上述結果之鼓舞後，再設立另一試驗來檢查當水 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） _ 27 - 577754 A7 B7 五、發明説明（25 ) (請先閱讀背面之注意事項再填寫本頁) 的含量繼續增加並省略掉I Ρ Α時，會產生什麼樣的結果 。將溶劑（水+ I P A )含量仍固定爲3 5 % w/w， 而水含量則在2 4，3 0和3 5 % w /w間變化。另外 ，在試驗中使用3 0和3 3 % w/w之溶劑含量，不含 I PA。pvp含量在5和6 . 5% w/w間變化。 如表2中所顯示，若水之含量增加至3 % w/w， 且省略I Ρ A時，可取得較高之顆粒產量。_, % w/w PVP 5 6.5 8 % w/w Water 6 72.8 78.1 82.9 12 78.0 82.7 48.3 18 80.3 82.7 42.9 24 80.0 85.5 30 84.8 89.6 30 no IPA 93.7 94.2 33 no IPA 94.9 Too wet 35 no IPA Too wet 經濟部智慧財產局員工消費合作社印製 表2:%產量爲水之含量及PVP之量的函數。 篩子對所產牛之顆粒的效果 爲了將擠出器中之圓孔最優化，對不同的篩子進行測 試。結果顯示於表3中，其指出：對所選擇之濕團塊而言 ，Ο · 9χ 0 . 9毫米（篩子之直徑X厚度）爲取得大小爲 8 5 0 - 1 0 0 0微米之顆粒的最佳選擇。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -28 - 577754 Β7 五、發明説明（26 ) 洞孔尺寸 毫米 1.0x1.2 1.0x1.0 0.9x1.0 0.9x0.9 顆粒大小 微米 >1180 2.0% 1.7% 1.0% 0.7% 1000-1180 78.2% 57.0% 4.5% 1.4% 850-1000 17.1% 39.2% 58.6% 92.8% <850 2.7% 2.2% 35.9% 5.2% (請先閱讀背面之注意事項再填寫本頁) 表3 顆粒大小分佈爲篩子中之圓孔尺寸的函數 在重複試驗中，檢查根據本發明之較佳方法所製備之 顆粒的狹窄及可複製的顆粒大小分佈，結果顯示於表4中 批號： >1 180微米 850微米<χ<1 180微米 <850微米 % (w / w) 濕度 732902 2.2 92.8 4,7 0.56 733101 1.1 94.2 5,7 1.14 733102 0.9 94.2 5,2 0.99 733103 0.8 94.1 5,4 0.53 733104 1.0 94.2 5,3 0.46 733107 2.2 94.5 4,6 0.50 平均値 1.4 94.0 5,2 0.5 1 SD 0.65 0,60 0.42 0.04 RDS 48 0.64 8.1 8.3 經濟部智慧財產局員工消費合作社印製 表4 根據本發明之較佳方法所製備之各批顆粒的顆粒大 本紙張尺度適用中國國家標準（CNS ) A4規格（21 OX 297公釐） -29 - 577754k ″ L Manufacturing steps-Li Panduosha @ Slow-Releasing Lozenges is divided into 10 steps and 0 steps 0: Routine procedures for the start of equipment and ingredients Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy Before checking all equipment for cleanliness. Step 1: Weighing the weight of 5-aminosalicylic acid and feeding it into the mixer. Step 2: Granulation Preparation of a granulated liquid (prednisolone dissolved in a mixture of pure water and 2-propanol) and addition during mixing. After adding the granulated liquid, continue mixing for a fixed time. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -24-577754 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (22) Step 3: Extrude and granulate The agglomerates were squeezed into small nines (sieve i. 〇x 1 · 〇 (sieve diameter x thickness)) in the same steps. Step 4: Drying The particles are transferred into a fluid bed dryer and dried. Step 5 = Sieving Sprinkle the dried small nine on a Mogensen sieve (deflected sieve). Discard particles that can pass through a baffle sieve with a size of 0.8 mm or collect them in a sealed, labeled container for reprocessing. Particles that cannot pass through a baffle screen of size 1.8 mm are also discarded. Step 6: Coating The particles were coated in a Coogee coater (fluid bed system) with a liquid consisting of ethyl cellulose in acetone. If any bulges are formed, sprinkle the particles on a Mokinson sieve (deflected sieve) and sieve. Step 7: Mix and transfer the coated granules, fillers / linkers (microcrystalline cellulose) and lubricants (magnesium stearate and talc) to the mixer and mix thoroughly. Step 8: Compress the coating The final blend of coating particles and lubricant is compressed into a tablet on a rotary tableting machine. Step 9: Dedusting Dust off the tablets. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) "25-pack" 灭-· (Please read the precautions on the back before filling this page) Preparation A7 B7 V. Description of the invention (23) Step 10: Packaging: Put the slow-release tablets in labeled bulk containers' and store them in an isolated space until the quality control department releases them. Figures 1 A-3 A are enlarged photographs of particles obtained from three different batches of products made by existing methods. Example 2 Effect of different parameter changes during the preparation of the vortex path In this example, dry and wet materials were mixed in an Erweka A R 4 〇 〇 E powerful mixer. Extrusion is performed in a Niro Fielder extruder E 1 40. Unless otherwise stated, the size of the round holes contained in the sieve used in the extruder is in the range of 0.9 x 0.9 mm (diameter x thickness of the sieve). A Retch Vibro sieve was used for sieve analysis. First, check the 3 key parameters of the method in a factor analysis of 2 and 3: PVP content, water content, and speed of the mixer: low order high order factor a PVP 3% w / w 8% w / w factor b water 0% w / w 6% w / w factor c Impeller 33rpm 66rpm The produced particles are evaluated as the output after the knot in the range of 0.850 to -1 · 0 mm. Repeat this test 5 times. The final paper size is in accordance with China National Standard (CNS) A4 (210X297 mm). "26-I Pack"--(Please read the precautions on the back before filling this page) 577754 A7 B7 5 2. Description of the invention (24) The results show that the content of both water and PVP has an effect on the yield in the range of 0.850-1. 0 mm. As shown in Table 1, the speed of the impeller has no effect on the output within the specified range: test average 试验 SD ⑴ 63.40 3.62 a 60.48 2.22 b 70.22 2.12 ab 80.66 3.74 c 60.68 3.59 ac 66.38 4.52 be 70.44 2.21 abc 80.22 3.00 (Please read the notes on the back before filling this page) Table 1 is the result obtained from the experiment of factor 2 3, which shows the% output after sieving in the range of 0.850 to 1.0 mm. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs To optimize the water and P V P content in the extruded pellets, a new test was repeated twice. Water plus isopropyl alcohol (IPA) remained fixed at 35% w / w, while the water content varied between 6, 12 and 18% w / w. The content of PVP varies between 5, 6 · 5 and 8% w / w. The results are shown in Table 2, and it is shown that when the water content is higher, a higher yield can be obtained. If the content of PVP is increased to 8% w / w, the yield will be reduced due to the generation of aggregates. Encouraged by the above results, another test was set up to check when the paper size of the paper was applicable to the Chinese National Standard (CNS) A4 (210X297 mm) _ 27-577754 A7 B7 V. Description of the Invention (25) (Please read first (Notes on the back, please fill in this page again) What kind of results will be produced when the content of I Α is continuously increased and I P Α is omitted. The solvent (water + IPA) content was still fixed at 35% w / w, while the water content varied between 24, 30 and 35% w / w. In addition, a solvent content of 30 and 33% w / w was used in the test, without I PA. The pvp content varies between 5 and 6.5% w / w. As shown in Table 2, if the water content is increased to 3% w / w and IPA is omitted, a higher pellet yield can be obtained. _,% w / w PVP 5 6.5 8% w / w Water 6 72.8 78.1 82.9 12 78.0 82.7 48.3 18 80.3 82.7 42.9 24 80.0 85.5 30 84.8 89.6 30 no IPA 93.7 94.2 33 no IPA 94.9 Too wet 35 no IPA Too wet Economy Printed by the Ministry of Intellectual Property Bureau's Consumer Cooperatives Table 2:% Production is a function of the water content and the amount of PVP. Effect of the sieve on the granules of the cattle produced. To optimize the round holes in the extruder, different sieves were tested. The results are shown in Table 3, which states that, for the selected wet mass, 0 · 9x0.9 mm (diameter x thickness of the sieve) is used to obtain particles with a size of 8 500-100 micron. best choice. This paper size applies Chinese National Standard (CNS) A4 (210X297mm) -28-577754 Β7 V. Description of the invention (26) Hole size mm 1.0x1.2 1.0x1.0 0.9x1.0 0.9x0.9 particles Size Micron > 1180 2.0% 1.7% 1.0% 0.7% 1000-1180 78.2% 57.0% 4.5% 1.4% 850-1000 17.1% 39.2% 58.6% 92.8% < 850 2.7% 2.2% 35.9% 5.2% (Please read first Note on the back, please fill out this page again) Table 3 Particle size distribution as a function of the size of the round holes in the sieve The results are shown in Table 4. Lot numbers: > 1 180 microns 850 microns < χ < 1 180 microns < 850 microns% (w / w) Humidity 732902 2.2 92.8 4,7 0.56 733101 1.1 94.2 5,7 1.14 733102 0.9 94.2 5,2 0.99 733103 0.8 94.1 5,4 0.53 733104 1.0 94.2 5,3 0.46 733107 2.2 94.5 4,6 0.50 Average 値 1.4 94.0 5,2 0.5 1 SD 0.65 0,60 0.42 0.04 RDS 48 0.64 8.1 8.3 Intellectual property of the Ministry of Economic Affairs Table 4 printed by the Bureau's Consumer Cooperatives Batches prepared according to the preferred method of the present invention This paper grain particles large scale suitable for China National Standard (CNS) A4 Size (21 OX 297 mm) -29--577754

A B 五、發明説明（27 ) 小分佈。 (請先閲讀背面之注意事項再填寫本頁) 其濕度含量亦爲可接受之程度。 對製造設備中之篩子的實用性而言，篩子之厚度以 1 · 5 _；米較佳。 批號： 在Strea處理前 在Strea處理後 差値 本發明 733102 94.2 95.2 -1.0 733103 93.9 94.1 -0.2 733104 93.9 94,6 -0,7 733107 94.8 93.9 0.9 現有方法 EJGU83 8C 57.5 54,9 2.6 EJGU83 8D 63.5 60.9 2.6 EJGU837G 68.5 61.9 6.6 EJGU838H 53.3 44.6 8.7 表5顯示出在實驗室流體床中處理1小時之前和之後 顆粒力量之評估係經由將顆粒在實驗室之流體床（ STREA )中處理1小時來進行。將其力量與那些根據現有之 用於製備潘朵沙®的製造設備所製出的顆粒相比較。如表5 ^1^示，根據本發明所製出之顆粒的力量較強: 經濟部智慧財產局員工消費合作杜印製 ’顆粒大小在8 5 0微米—1 0 0 0微米間的％顆粒。 實施例3 S A之錠劑的製備方法（以7k爲某礎之粒化方法 1_ -30 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 577754 A7 B7 五、發明説明（28 ) 新穎之5-ASA錠劑的製備方法可分成11個步驟 (第4圖）： 1.製備粒化液體 2 .將5 - A S A與水和P V P粒化 3 .擠出 4.流體床乾燥 5 ·硏磨 6 .過篩 7 .包衣 8 ·過篩 9 ·以空氣淸淨 1 0 ·與賦形劑進行乾性摻合 1 1 .壓製成錠劑 製造設備_ (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 NICA擠出器E220 擠 出 Rotostat T05 摻 合 NIRO流體床乾燥器 乾 燥 Quadro Comil U10 硏 磨 莫金森篩 m 篩 Huttling庫吉包衣器HKC400 包衣 普洛廸馬（Prodima)旋轉篩 Μ 篩 淸淨組件 氣 淸 除 普洛廸馬混合器AC-HLR 1200 乾 性 混 合 Kilian T300-32 製 成 錠 劑 本纸張尺度適用中國國家襟準（CNS ) A4規格（210X297公釐） -31 - 577754 A7 B7 五、發明説明（29 ) 步驟1 (請先閱讀背面之注意事項再填寫本頁) 將1 1 8 . 4公斤水塡入慕勒滾筒（Muller Drum )中 以供製備一批粒化液體。將混合器就位後啓動。將3 2公 斤聚乙烯吡咯啶酮（P V P )慢慢地灑至水上，並讓混合 器運轉一段固定時間，直到所有P V P均已溶解。 步驟2和3 將5 - A S A置於一振動的普洛廸馬加料漏斗中，並 利用連續搬運裝置，將5 - A S A送上重量帶飼機，以將 5 - A S A加藥入連續的尼諾（Niro )線。在尼諾線的第一 部分中，5 - ASA和PVP之水溶液在輸送入擠出器前 ，先混合成濕團塊。將由5 - A S A和P V P /水所組成 的濕團塊通過一 0 . 9毫米的網篩擠出後，顆粒便直接掉 入流體床乾燥器中。 步驟4 經濟部智慧財產局員工消費合作社印製 將流體床乾燥器分成二個主要部分。在第一部分中， 將顆粒表面乾燥，以預防它們黏在一起。在流體床中此部 分中，顆粒會任意混合。在停留一段時間後，將顆粒移入 乾燥器的第二部分，此爲實際進行乾燥的部分。在乾燥器 的第二部分中，顆粒係利用通過乾燥器的乾燥空氣來引導 (在腮板中有特殊樣本的洞）。當將顆粒乾燥後，讓顆粒 落入置於流體床下的滾筒中。流體床之構造需讓顆粒在流 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -32 - 577754A B V. Description of the invention (27) Small distribution. (Please read the notes on the back before filling out this page) The humidity content is also acceptable. For the practicality of the sieve in the manufacturing equipment, the thickness of the sieve is 1 · 5 _; rice is preferred. Batch number: Before Strea treatment, after Strea treatment, the invention 733102 94.2 95.2 -1.0 733103 93.9 94.1 -0.2 733104 93.9 94,6 -0,7 733107 94.8 93.9 0.9 Existing method EJGU83 8C 57.5 54, 2.6 EJGU83 8D 63.5 60.9 2.6 EJGU837G 68.5 61.9 6.6 EJGU838H 53.3 44.6 8.7 Table 5 shows that the evaluation of particle strength before and after treatment in the laboratory fluid bed for 1 hour was performed by treating the particles in the laboratory fluid bed (STREA) for 1 hour. Compare its power with those made with existing manufacturing equipment used to make Pandosa®. As shown in Table 5 ^ 1 ^, the strength of the particles produced according to the present invention is strong: The consumer cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs Du printed '% particles between 850 microns and 100 microns . Example 3 Preparation method of SA tablets (granulation method based on 7k 1_ -30-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 577754 A7 B7 V. Description of the invention (28 ) The novel method for preparing 5-ASA tablets can be divided into 11 steps (Figure 4): 1. Preparation of granulated liquid 2. Granulation of 5-ASA with water and PVP 3. Extrusion 4. Fluid bed drying 5 · Honing 6. Screening 7. Coating 8 · Screening 9 · Purging with air 1 0 · Dry blending with excipients 1 1. Pressing into tablets manufacturing equipment _ (Please read the precautions on the back first Refill this page) Printed by NICA Extruder E220 Extruder Rotostat T05 Blended with NIRO Fluid Bed Dryer Drying Quadro Comil U10 Honed Mulkinson Sieve m Sieve Huttling Coji Coater HKC400 Coating Prodima rotary sieve M sieve net assembly air purifier Pro-Dima mixer AC-HLR 1200 dry mixing Kilian T300-32 made into tablets This paper size is applicable to China National Standard (CNS) A4 Specifications (210X297 mm) -31-5 77754 A7 B7 V. Description of the invention (29) Step 1 (Please read the notes on the back before filling this page) Put 1 18.4 kg of water into the Muller Drum for preparing a batch of granulation Liquid. Put the mixer in place and start. Spread 32 kg of polyvinylpyrrolidone (PVP) slowly onto the water and let the mixer run for a fixed time until all PVP has dissolved. Steps 2 and 3 will The 5-ASA is placed in a vibrating Prodima feeding funnel and the 5-ASA is fed to a weight belt feeder using a continuous handling device to dose the 5-ASA into a continuous Niro line. In the first part of the Nino line, the 5-ASA and PVP aqueous solution is mixed into wet agglomerates before being conveyed into the extruder. The wet agglomerate consisting of 5-ASA and PVP / water is passed through a 0.9 After the millimeter mesh screen is extruded, the granules fall directly into the fluid bed dryer. Step 4 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the fluid bed dryer is divided into two main parts. In the first part, the granule surface is Dry to prevent them from sticking together. In the fluid In this part of the bed, the granules are mixed arbitrarily. After a certain period of time, the granules are moved into the second part of the dryer, which is the part where the actual drying takes place. In the second part of the dryer, the particles are guided using dry air passing through the dryer (there are holes in the cheeks for special samples). When the granules are dried, the granules are allowed to fall into a drum placed under the fluid bed. The structure of the fluid bed needs to allow the particles to flow. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -32-577754

7 7 A B 五、發明説明（30 ) 體床中的全部停留時間約爲2 %小時。 (請先閱讀背面之注意事項再填寫本頁) 由於連續方法的性質，因此每批的大小係由設備的操 作時間來界定。因此，所設立之設備需可控制不同成分的 物流進入製程中。爲了提供此乾燥方法的文件證明，表6 中顯示出乾燥時之損失的結果。 慕勒滾筒 AAA137 AAAI 38 AAA139 AAA140 1 0.40 0.34 0.37 0.37 2 0.37 0.30 0.40 0.40 3 0.46 0.29 0.37 0.37 4 0.33 0.40 0.40 0.33 5 0.37 0.39 n. a. 0.37 6 n. a. 0.29 n. a. 0.33 7 n. a. 0.34 n. a. 0.33 8 η. a. 0.37 n. a. 0.39 Mean 0.37 0.39 0.39 0.36 經濟部智慧財產局員工消費合作社印製 表6 乾燥時之損失（乾燥後，顆粒中之％濕度）（n.a.= 無法取得） 步驟5 將含乾燥顆粒之滾筒上下顛倒置於硏磨機頂端，並利 用篩子將顆粒緩緩地硏磨，此篩子僅會將太長的顆粒打破 。通過硏磨機後，讓顆粒落入滾筒中。第5 A - 7A圖示 爲根據本發明所製出之三批不同批顆粒的放大圖。當將其 -33- 本紙張尺度適用中國國家襟準（CNS ) A4規格（210Χ：297公釐） 577754 A7 __ B7 五、發明説明（31 ) 與根據現有方法製出之顆粒（第1 A - 3 A圖）相比較時 ’可淸楚地看出它們在形狀、一致性和均勻度上的差異。 (請先閲讀背面之注意事項再填寫本頁) 步驟6 由於硏磨過程中會產生少量較一般小的顆粒，因此， 需利用旲金森振動tfp將其過筛。將可通過0 - 8毫米過爐 篩的顆粒丟棄或收集起來，貯存在密封，有標籤之容器中 ，以供再處理用。硏磨及過篩過之顆粒的過篩分析結果顯 示於第5B — 7B圖中。 步驟7 將2 0 0公斤過篩好的顆粒在庫吉包衣器（流體床系 統）中，以由溶在丙酮中之乙基纖維素所組成的液體將其 包衣。 爲了能決定出施放在顆粒上之正確聚合體量，以取得 具所需之溶解速率略圖的顆粒，在包衣過程開始前，必須 先測量顆粒之表面積。 經濟部智慧財產局員工消費合作社印製 根據每表面積之聚合物量與顆粒之溶解速率間的相關 性，可預測出需要施放在顆粒上的聚合物量。完成包衣過 程後，將已包衣之顆粒塡裝入滾筒中，以供進一步處理。 步驟8 包衣過程完成後，將已包衣之顆粒在普洛狄馬旋轉飾 中過篩。丟棄大團塊。 -34- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 5777547 7 A B V. Description of the invention (30) The total residence time in the body bed is about 2% hours. (Please read the notes on the back before filling this page.) Due to the nature of the continuous method, the size of each batch is defined by the operating time of the equipment. Therefore, the equipment set up must be able to control the logistics of different components into the process. In order to provide documentation of this drying method, the results of the loss on drying are shown in Table 6. Muller drum AAA137 AAAI 38 AAA139 AAA140 1 0.40 0.34 0.37 0.37 2 0.37 0.30 0.40 0.40 3 0.46 0.29 0.37 0.37 4 0.33 0.40 0.40 0.33 5 0.37 0.39 na 0.37 6 na 0.29 na 0.33 7 na 0.34 na 0.33 8 η. A. 0.37 na 0.39 Mean 0.37 0.39 0.39 0.36 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6 Loss on drying (% humidity in granules after drying) (na = not available) Step 5 Place the roller containing the dried granules upside down The top of the honing machine, and slowly honing the particles with a sieve, this sieve will only break too long particles. After passing through the honing machine, let the particles fall into the drum. Figures 5A-7A are enlarged views of three different batches of particles made according to the present invention. When it is -33- This paper size is applicable to China National Standard (CNS) A4 specification (210 ×: 297 mm) 577754 A7 __ B7 V. Description of the invention (31) and the particles produced according to existing methods (Part 1 A- (Figure 3 A) When comparing, you can clearly see the difference in shape, consistency and uniformity. (Please read the precautions on the back before filling this page.) Step 6 As the honing process will generate a small amount of relatively small particles, it needs to be sieved by using Hodgkinson vibration tfp. Discard or collect the particles that can pass through the 0-8mm sieving sieve and store them in sealed, labeled containers for reprocessing. The sieving analysis results of the honing and sieving particles are shown in Figures 5B-7B. Step 7: 200 kg of sieved granules are coated in a Coogee coater (fluid bed system) with a liquid consisting of ethyl cellulose dissolved in acetone. In order to determine the correct amount of polymer to be applied to the granules to obtain granules with the desired dissolution rate profile, the surface area of the granules must be measured before the coating process begins. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Based on the correlation between the amount of polymer per surface area and the dissolution rate of the particles, the amount of polymer to be applied to the particles can be predicted. After the coating process is complete, the coated granules are loaded into a drum for further processing. Step 8 After the coating process is complete, the coated granules are sieved in a Prodimar spinner. Discard large clumps. -34- This paper size is applicable to China National Standard (CNS) A4 (210X297mm) 577754

現有方法潘朵沙@顆 以空氣/氮氣滌洗前 以空氣/氮氣滌洗後 粒批號. 之丙酮量（ppm) 之丙酮量（ppm) GIGC 905 5277 2607 GIGC 906 5556 1870 GIGC 907 4310 1798 五、發明説明（32 ) 步驟9 將包衣顆粒批過篩後，將其分裝入二個滾筒中，以壓 縮空氣或氮氣淸淨之。將顆粒淸淨6 - 1 4小時。此淸淨 過程對減少包衣好之顆粒中的殘餘溶劑（丙酮）量而言是 有必要的。 表7中所示的爲以現有方法及新方法製得之顆粒中所 殘存之溶劑量的測試結果。從表7中可看出，根據新方法 所製出之顆粒中所殘存的溶劑量已大量減少。這可能是由 於這些顆粒之表面較那些以現有方法製出者來得平滑，這 暗示所需之包衣物質量減少。 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 新方法潘朵沙®顆粒 以空氣/氮氣滌洗前 以空氣/氮氣滌洗後 批號. 之丙酮量（ppm) 之丙酮量（ppm) AAF 333 965 331 AAF 322 1125 402 AAF 327 1020 492 表7 在已包衣之潘朵沙⑧顆粒中之剩餘溶劑量。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -35 - 577754 A7 B7 五、發明説明（33 ) 步驟1 Π (請先閲讀背面之注意事項再填寫本頁) 稱出1 7 8 · 5 6公斤之已包衣的潘朵沙顆粒，並將 其與6 9 . 3 4公斤之微晶型纖維素一起塡入普洛廸馬摻 合器中。混合2 1 0秒後，終止摻合器。將0 · 3 3 5公 斤硬脂酸鎂和3 . 0 2公斤滑石粉加入摻合器中，並將成 分混合9 0秒。此摻合物可產生3 3 5，0 0 0個錠劑。 混合後，將摻合物置入慕勒滾筒中以進行壓製。 步驟1 1 將包衣顆粒及賦形劑之最終摻合物在旋轉製錠機上壓 製。錠劑之重量爲：7 5 0毫克。錠劑之除塵係同時在製 錠機上進行。錠劑除塵後，將其塡入散裝容器中，各容器 可塡裝約3 0，0 0 0個錠劑。 本發明之方法可使5 - A S A錠劑之全部產量較利用 現有方法，以相同量之成分所製得者來得多。表8中所示 者爲來自1 0批根據本發明方法所製得之錠劑的性質。 經濟部智慧財產局員工消費合作社印製 從這些表中可看出，根據本發明所製備之錠劑符合錠 劑之認可標準，且其全部產量與現有方法之6 9 . 2 %相 較下爲約8 5 . 5 %。第8圖示中爲潘朵沙®錠劑之溶解速 率略圖。 第9圖示爲從摻合器中取出，欲證明摻和物之同質性 的樣本之結果。 本紙張尺度適用中國國家標準（CNS ) A4規格（2〗0Χ297公釐） -36 - 577754 A7 B7 五、發明説明（34 ) 經濟部智慧財產局員工消費合作社印製 易碎性％ S s o' g o' s o' g o' g o' s ο" 〇" o' 分析 毫克/錠劑 〇 § 503,8 492,4 489,3 497,1 502,2 495,9 504,4 vn On 寸 491,8 重量變化 毫克 515.8 498.9 509,2 498,4 495.7 487.8 〇〇 σ\ 〇〇 寸寸 495.1 487.2 On 〇0 OO v〇 ο σ\ υο寸 499,9 492,6 寸办◦办 M3 On O On 寸 500,9 488,4 OO CN co vn On oo 寸寸 含量一致性 毫克 520,0 491,4 On cxd cn CN G\ 寸 co ci t-H 〇〇 寸 寸CO 〇〇 寸 i-i ^«〇 r-H 〇〇 509,9 481,4 507,3 485,9 CO < On 寸 513,6 467,3 1~ i-π m oo 寸 崩解 秒 〇 1.......Η r 4 vn oo oo 〇\ t i Os 高度 毫米 〇 1—Η g ON CO g 寸6 o oo CO cn CN o g 重量 毫克 1 i ON r- 751,5 〇〇 751,4 1—H oo 芝 σ\ 751,6 753,1 749,1 oo aC 硬度 Ν 〇〇 ON 〇 ! λ g CN S r- i 錠劑批 AAH025 AAH026 AAH027 AAH028 AAH030 ΑΑΗ031 AAH032 AAH033 AAH034 AAH035 ^0,8% average of 10 符合 450-550 average of 20 符合 425-575 各錠劑 符合 425-575 各錠劑 符合 ^5min average of 6 符合 3,80-4,20 average of 10 符合 735-765 average of 10 符合 84-112 average of 10 符合 認可標準 結果 ii 05- ϊ -----衣-- (請先閱讀背面之注意事項再填寫本頁) 、1Τ 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） -37-Existing method Pan Duosha @ Pellets with air / nitrogen before washing with air / nitrogen. The batch number of acetone (ppm) and acetone (ppm) GIGC 905 5277 2607 GIGC 906 5556 1870 GIGC 907 4310 1798 5. Description of the invention (32) Step 9 After the coated granules are sieved, they are divided into two rollers and cleaned with compressed air or nitrogen. Let the granules clean for 6-14 hours. This cleaning process is necessary to reduce the amount of residual solvent (acetone) in the coated particles. Table 7 shows the test results of the amount of solvent remaining in the granules prepared by the existing method and the new method. As can be seen from Table 7, the amount of residual solvent in the granules produced according to the new method has been greatly reduced. This may be because the surface of these particles is smoother than those produced by existing methods, which implies that the required quality of the laundry is reduced. (Please read the precautions on the back before filling this page) A new method for printing by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Pandosa® granules before washing with air / nitrogen and washing with air / nitrogen. Batch number. Acetone amount ( Acetone content (ppm) AAF 333 965 331 AAF 322 1125 402 AAF 327 1020 492 Table 7 Amount of solvent remaining in the coated Pandora sand granules. This paper size applies to China National Standard (CNS) A4 (210X297 mm) -35-577754 A7 B7 V. Description of Invention (33) Step 1 Π (Please read the precautions on the back before filling this page) Weigh out 1 7 8.56 kg of coated Pandosa granules were mixed into a Prodimar blender together with 69.34 kg of microcrystalline cellulose. After mixing for 210 seconds, the blender was terminated. 0.35 kg of magnesium stearate and 3.02 kg of talc were added to the blender and the ingredients were mixed for 90 seconds. This blend can produce 3,35,000,000 lozenges. After mixing, the blend was placed in a Muller drum for compression. Step 11 1 The final blend of coated particles and excipients is compressed on a rotary tablet mill. The weight of the tablets is: 750 mg. Dust removal of the tablets is performed simultaneously on the tablet mill. After dusting the lozenges, they are scooped into bulk containers, each container can contain about 30,000 lozenges. The method of the present invention enables the entire yield of 5-A S A lozenges to be much greater than those produced with the same amount of ingredients using existing methods. Shown in Table 8 are properties from 10 batches made according to the method of the present invention. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs From these tables, it can be seen that the tablets prepared according to the present invention meet the standards for the approval of tablets, and their total output is 69.2% compared to the existing method About 8 5. 5%. Figure 8 shows a sketch of the dissolution rate of Pandora® tablets. Figure 9 shows the results of samples taken from the blender to demonstrate the homogeneity of the blend. This paper size applies to China National Standard (CNS) A4 specifications (2〗 0 × 297 mm) -36-577754 A7 B7 V. Description of invention (34) Fragility printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy% S so 'go 'so' go 'go' ο " 〇 " o 'Analytical mg / tablet 〇§ 503,8 492,4 489,3 497,1 502,2 495,9 504,4 vn On Inch 491,8 Weight Change mg 515.8 498.9 509, 2 498, 4 495.7 487.8 〇〇σ \ 〇〇 inch 495.1 487.2 On 〇0 OO v〇 σ \ υο inch 499,9 492,6 inch Office ◦ M3 On O On inch 500,9 488,4 OO CN co vn On oo inch content consistency mg 520,0 491,4 On cxd cn CN G \ inch co ci tH 〇inch inch CO 〇〇inchii ^ «〇rH 〇〇509,9 481,4 507,3 485,9 CO < On inch 513,6 467,3 1 ~ i-π m oo inch disintegration second 〇1 ....... Η r 4 vn oo oo 〇 \ ti Os height mm 〇 1—Η g ON CO g inch 6 o oo CO cn CN og Weight mg 1 i ON r- 751,5 〇〇751,4 1—H oo σσ \ 751,6 753,1 749,1 oo aC hardness N 〇〇ON 〇! Λ g CN S r- i Lozenge batch AAH025 AAH026 AAH027 AAH028 AAH 030 ΑΑΗ031 AAH032 AAH033 AAH034 AAH035 ^ 0,8% average of 10 conforming to 450-550 average of 20 conforming to 425-575 each tablet conforming to 425-575 each tablet conforming to ^ 5min average of 6 conforming to 3,80-4,20 average of 10 in accordance with 735-765 average of 10 in accordance with 84-112 average of 10 in accordance with the results of recognized standards ii 05- ϊ ----- clothing-(Please read the precautions on the back before filling this page), 1T This paper size Applicable to China National Standard (CNS) Α4 specification (210X 297 mm) -37-

Claims (1)

577754577754 贬 12. - 4 附件二··第91120757號專利申請案 修正後無劃線之中文申請專利範圍替換本 民國92年12月4日呈 六、申請專利範圍 1·一種含有5-胺基柳酸（5-ASA)或其藥學 上可接受之鹽或酯及藥學上可接受之連接劑之顆粒的製備 方法，其包含 (a )將藥學上可接受之連接劑溶於溶劑中， (b )將溶解的連接劑與5 一 a S a混合以形成濕團 (C )將濕團塊擠成顆粒，及 (d )在溶劑蒸發時，將顆粒乾燥， w / w 水。 其中該溶劑含有 其特徵在於該溶劑含有5 0 %至1 0 0 % 2 ·如申請專利範圍第1項之方法 至少85%w/w水。 3 ·如申請專利範圍第1項之方法，其中該溶劑含有 至少9 5% w/w水。 其中該溶劑不含 經濟部智慧財產局員工消費合作社印製 (請先閲囀背面之注意事項再填寫本頁) 4 .如申請專利範圍第1項之方法 有機溶劑。 5 _如申請專利範圍第1 一 4項中任一項之方法，其 中該溶劑含有一或多種添加劑，如一或多種螯合劑、抗氧 化劑、還原劑、緩衝劑、P Η調節劑、共溶劑或任何其它 相關之賦形劑。 6 ·如申請專利範圍第1項之方法，其中該濕團塊係 通過一具有錐形洞孔之篩子擠出，各洞孔在篩子之入口側 本紙乐尺度適用中國國家標準（CNS ) Α4規格（21〇Χ 297公釐） 577754 ABCD 穴、申請專利範圍 的橫截面大於篩子出口側之橫截面。 (請先閲脅背面之注意事項再填寫本頁) 7 .如申請專利範圍第6項之方法，其中該出口直徑 爲0.9毫米，入口直徑爲0.95毫米。 8 .如申請專利範圍第1項之方法，其中超過7 5 % 之顆粒其顆粒大小爲從8 5 0微米至 1 0 0 0微米。 9 .如申請專利範圍第1項之方法，其中超過8 5 % 之顆粒其顆粒大小爲從8 5 0微米至 1 0 0 0微米。 1 〇 .如申請專利範圍第1項之方法，其中超過9 0 %之顆粒其顆粒大小爲從8 5 0微米至 1 0 0 0微米。 1 1 .如申請專利範圍第1項之方法，其中該乾燥顆 粒含有至多8重量％之該連接劑（固體含量，以5 -胺基 柳酸計）。 1 2 .如申請專利範圍第1項之方法，其中該乾燥顆 經濟部智慧財產局員工消費合作社印製 粒含有至多6 · 5重量％之連接劑（固體含量，以5 -胺 基柳酸計）。 1 3 .如申請專利範圍第1項之方法，其中該乾燥顆 粒含有至多5重量％之連接劑（固體含量，以5 -胺基柳 酸計）。 1 4 .如申請專利範圍第1項之方法，其中該連接劑 爲聚乙烯吡咯啶酮。 1 5 .如申請專利範圍第1項之方法，其中該乾燥步 本纸張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） · 2 - 577754 ABCD 六、申請專利範圍 驟係在流體床中進行。 1 6 ·如申請專利範圍第1項之方法，其還包含將顆 粒硏磨和過筛的步驟。 (請先閲讀背面之注意事項再填寫本頁) 1 7 ·如申請專利範圍第1項之方法，其中該等步驟 爲連續方法的部分。 1 8 · —種用來製備可治療潰瘍性結腸炎或克隆氏症 之延長釋出型錠劑的方法，其包含下述步驟： (a )在含有5 〇%至1 〇〇% w/w水之溶劑中 使5 -胺基柳酸或其藥學上可接受之鹽或酯與藥學上可接 受的連接劑混合，然後擠出混合物，藉此在將溶劑蒸發後 得到顆粒， (b )將包衣組合物施於該顆粒上（該包衣組合物包 含藥學上可接受的包衣物質之有機溶劑溶液），藉此在溶 劑蒸發後，得到包衣過之顆粒， (c )將包衣過的顆粒與一或多種藥學上可接受之錠 劑賦形劑混合，及 (d )從所得混合物形成錠劑。‘ 經濟部智慧財產局員工消費合作社印製 1 9 .如申請專利範圍第1 8項之方法，其中該來自 步驟（a )之顆粒係根據申請專利範圍第1至1 7項中任 一項之方法製造。 2 〇 ·如申請專利範圍第1 8或1 9項之方法，其中 選擇包衣物質以在顆粒上提供速率-限制屏障，以半-滲 透性屏障較佳。 2 1 .如申請專利範圍第2 0項之方法，其中該包衣 本紙法尺度適用中國國家梂準（CNS ) A4規格（210X 297公釐） 577754 ABCD 六、申請專利範圍 物質爲纖維素衍生物。 2 2 .如申請專利範圍第2 1項之方法，其中該包衣 物質爲乙基纖維素。 2 3 .如申請專利範圍第Ί 8項之方法，其中該錠劑 賦形劑包含微晶型纖維素。 2 4 .如申請專利範圍第1 8項之方法，其中該錠劑 賦形劑包含硬脂酸鎂。 2 5 .如申請專利範圍第1 8項之方法，其中該錠劑 賦形劑包含硬脂酸鎂和滑石。_ 2 6 . —種藥學顆粒，其係以申請專利範圍第1 一 1 7項中任一項之方法製得。 2 7 . —種藥學錠劑，其係以申請專利範圍第1 8 -2 5項中任一項之方法製得。 (請先閲令背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（〇奶）六4故^(210父297公釐） -4 -Depreciation 12.-4 Attachment II ·· The amended Chinese patent application with no underline after the amendment of Patent Application No. 91120757 was replaced on December 4, 1992. The scope of the applied patent was 1. One containing 5-aminosalicylic acid (5-ASA) or a pharmaceutically acceptable salt or ester thereof and a method for preparing granules of a pharmaceutically acceptable linker, comprising (a) dissolving a pharmaceutically acceptable linker in a solvent, (b) The dissolved linking agent is mixed with 5-asa to form a wet mass (C) to squeeze the wet mass into granules, and (d) when the solvent evaporates, the granules are dried, w / w water. The solvent contained therein is characterized in that the solvent contains 50% to 100% 2 · The method according to item 1 of the patent application scope is at least 85% w / w water. 3. The method of claim 1 in which the solvent contains at least 95% w / w water. The solvent does not include the printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (please read the precautions on the back of the page before filling out this page) 4. If the method of applying for the scope of the patent No. 1 organic solvents. 5 _ The method according to any one of claims 1 to 4 of the scope of patent application, wherein the solvent contains one or more additives, such as one or more chelating agents, antioxidants, reducing agents, buffering agents, P Η regulators, co-solvents or Any other related excipients. 6. The method according to item 1 of the scope of patent application, wherein the wet mass is extruded through a sieve with a conical hole, and each hole is on the entrance side of the sieve. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification. (21〇 × 297 mm) 577754 The cross section of the ABCD cavity and the scope of patent application is larger than the cross section of the outlet side of the sieve. (Please read the precautions on the back of the threat before filling out this page.) 7. If the method of the 6th scope of the patent application, the diameter of the outlet is 0.9mm, and the diameter of the inlet is 0.95mm. 8. The method according to item 1 of the patent application range, wherein more than 75% of the particles have a particle size of from 850 microns to 1000 microns. 9. The method according to item 1 of the patent application range, wherein more than 85% of the particles have a particle size from 850 microns to 1000 microns. 10. The method according to item 1 of the scope of patent application, wherein more than 90% of the particles have a particle size of from 850 microns to 1000 microns. 1 1. The method according to item 1 of the scope of patent application, wherein the dry particles contain up to 8% by weight of the linking agent (solid content, based on 5-aminosalicylic acid). 12. The method according to item 1 of the scope of patent application, wherein the dried granules of the Intellectual Property Bureau of the Ministry of Economic Affairs' employee consumer cooperative printed granules contain up to 6.5 wt% of a linking agent (solid content, based on 5-aminosalicylic acid) ). 13. The method according to item 1 of the patent application range, wherein the dry granules contain up to 5% by weight of a linking agent (solid content, based on 5-aminosalicylic acid). 14. The method according to item 1 of the scope of patent application, wherein the linker is polyvinylpyrrolidone. 1 5. The method of item 1 in the scope of patent application, in which the paper size of the drying step applies Chinese National Standard (CNS) A4 (210X 297 mm) · 2-577754 ABCD 6. The scope of patent application is in fluid Performed in bed. 16 · The method according to item 1 of the patent application scope further comprising the steps of honing and sieving the particles. (Please read the notes on the back before filling out this page) 1 7 · If the method of the scope of patent application No. 1, these steps are part of the continuous method. 18. A method for preparing an extended release lozenge for treating ulcerative colitis or Crohn's disease, comprising the steps of: (a) containing 50% to 100% w / w In a solvent of water, 5-aminosalicylic acid or a pharmaceutically acceptable salt or ester thereof is mixed with a pharmaceutically acceptable linker, and then the mixture is extruded, whereby particles are obtained after the solvent is evaporated, (b) the A coating composition is applied to the granules (the coating composition comprises an organic solvent solution of a pharmaceutically acceptable coating substance), whereby the coated granules are obtained after the solvent is evaporated, and (c) the coating is applied The granulated particles are mixed with one or more pharmaceutically acceptable lozenge excipients, and (d) a lozenge is formed from the resulting mixture. '' Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 19. For the method of applying for the scope of patent No. 18, wherein the particles from step (a) are based on any one of the scope of applying for patent No. 1 to 17 Method manufacturing. 20. The method of claim 18 or 19, wherein the coating material is selected to provide a rate-limiting barrier on the particles, preferably a semi-permeable barrier. 2 1. The method of item 20 in the scope of patent application, in which the coated paper method is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 577754 ABCD 6. The substance in the scope of patent application is cellulose derivative . 2 2. The method according to item 21 of the scope of patent application, wherein the coating substance is ethyl cellulose. 2 3. The method according to item 28 of the scope of patent application, wherein the lozenge excipient comprises microcrystalline cellulose. 24. The method of claim 18, wherein the lozenge excipient comprises magnesium stearate. 25. The method of claim 18, wherein the lozenge excipient comprises magnesium stearate and talc. _ 2 6. — A kind of pharmaceutical granule, which is prepared by the method of any one of the items 11 to 17 in the scope of patent application. 27. A pharmaceutical lozenge, which is prepared by a method according to any one of claims 18 to 25 of the scope of patent application. (Please read the notes on the back of the order first and then fill out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs
TW091120757A 2001-10-15 2002-09-11 Method for the preparation of a pharmaceutical composition comprising 5-aminosalicylic acid for use in treatment of ulcerative colitis and Crohn's disease TW577754B (en)

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US32883101P 2001-10-15 2001-10-15
PCT/DK2001/000677 WO2003032952A1 (en) 2001-10-15 2001-10-15 Method for the preparation of a pharmaceutical composition comprising 5-aminosalicyclic acid for use in treatment of ulcerative colitis and crohn's disease

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