1284542 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 發明領域 本發明係提供一種含水溶性樹脂之控時緩釋（Time controlled sustained release)藥劑組成物。更精確地說，本發 明係關於一種在特定時間開始釋放且能維持一定的藥物釋 放速率之含水溶性樹脂之控時緩釋藥劑組成物。 發明背景 有許多醫藥活性成分因具有較短的生物半衰期，於臨床 應用上需要一天施予數次劑量以達到治療的效果。因此，爲 解決此問題，有需要發展能維持一定的藥物釋放速率之緩釋 醫藥組成物。而控制釋放醫藥組成物之優點爲醫藥技藝中所 習知。 我國專利申請案第82107572號（公告第393320號）係關 於一種口服用水膠體徐放性醫藥錠劑，其包括（1)至少一種 以上藥物，（2)使水浸>錠劑內部之添加劑，及(3)形成水膠 體之高分子物質，具有滯留消化管上部之胃及小腸當中製劑 幾乎完全凝膠化能力，且在消化管下部之結腸放出藥物之能 力。該專利倂於此處作爲參考文獻。該專利之口服用水膠體 徐放性醫藥錠劑的主要吸收位置係主要位於消化管下^ ° 美國專利案第5024843號揭示一種口服降血糖藥卩比礦 環己脲(glipizide)顆粒。美國專利案第5〇9119〇號揭示一種施 予降血糖藥之傳送系統。美國專利案第5545413號揭示 3 冢紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐' ~裝------ (請先閱讀背面之注意事項寫本頁) 訂--------- 1284542 A7 B7 五、發明說明（） 口服施用之降血糖藥吡磺環己脲之劑量形式以及一種控制 高血糖症的方法。該等專利倂於此處作爲參考文獻。該等三 件美國專利案係關於提供一種以控制速率釋放吡磺環己脲 之劑量形式且同時提供降血糖治療。 美國專利案第5273758號揭示一種製備錠劑之藥學劑 型的直接壓製方法，其包括下列步驟：a)在不需添加溶劑或 熱量的條件下，混合結晶的醫療藥物與一包含聚氧化乙烯的 直接壓製用載體，以形成一組成物，其中藥物係分散在其 中；及b)以足夠的壓力壓製此生成組成物以形成一錠劑。該 專利倂於此處作爲參考文獻。該專利所製成之錠劑係藉由聚 氧化乙烯控制藥物的釋放速率。 美國專利案第5593694號揭示一種零級溶離的緩釋錠 劑，其包括一水膨潤膠化劑及均勻分散於該膠化劑之藥學上 活性成分，該錠劑被包覆一藉由溶解一或兩個選自乙基纖維 素及乙醯基纖維素所組成之族群中之成分於有機溶劑中所 製備的膜衣組成物。該專利倂於此處作爲參考文獻。該專利 並未使用聚氧化乙烯： 美國專利案第5783212號揭示一種控制釋放醫藥錠 劑，其包括一個含第一膨潤可溶蝕聚合物之第一障蔽層，一 個含第二膨潤可溶蝕聚合物之藥物層，一個含第三膨潤可溶 蝕聚合物之第二障蔽層，其中該第一及第二障蔽層之膨潤及 溶蝕比該藥物層快且該第一及第三層較快的膨潤及溶蝕用 以增加從溶離開始之藥物傳送。該專利併於此處作爲參考文 獻。該專利所使用之聚氧化乙烯的平均分子量爲lxlO6至 4 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------ (請先閱讀背面之注意事項本頁) 訂---------·- 經濟部智慧財產局員工消費合作社印製 1284542 A7 ____B7 _ 五、發明說明（） 2xl〇6〇 美國專利案第6056977號揭示一種固體基質控制釋 放，口服劑量形式，其中該劑量形式包含一治療有效量之磺 醯脲（sulfonyhirea)或其鹽或其衍生物於基質中。此外， 使用水性鹼化介質提供來自錠劑之基質中之藥物之實質上 的完整生物可利用性。該核心錠可選擇地以2°/。至10°/。腸衣 物質或水不溶性物質如乙基纖維素之塗覆物質塗覆。該專利 倂於此處作爲參考文獻。該專利並未使用聚氧化乙烯。 美國專利案第6090411號揭示一種能在一持續時間增 進藥物的直線釋放之包含吸水性膨脹之聚合物基體的控制 釋放錠劑。更精確地說，該藥物係在鹽類的存在下，置於羥 丙基甲基纖維素（HPMC)或聚氧化乙烯所組成之基質中， 該鹽類可爲鹽類之組合。該專利倂於此處作爲參考文獻。該 專利中所使用之鹽類於活性物質之控制釋放中，扮演重要的 角色。 WO 96/26718揭示一種包括一藥劑及一賦形劑之控制 釋放錠劑，其中該賦取劑包括一種至少約50%之水膨脹性聚 合物及一潤滑劑，該聚合物之膨脹速率等於其膨脹後的溶解 速率。該專利倂於此處作爲參考文獻。該專利使用具有平均 分子量900,000至4,000,000之聚氧化乙烯。 WO 97/18814揭示一種口服之控制釋放藥學組成物，其 主要包括一活性藥物化合物，低分子量聚氧化乙烯，羥丙基 甲基纖維素，打錠的賦形劑及可選擇地一或數種腸衣聚合 物。該專利倂於此處作爲參考文獻。該專利使用HPMC爲基 5 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------·裝 (請先閱讀背面之注意事項寫本頁) 訂--------- 經濟部智慧財產局員工消費合作社印製 1284542 A7 B7 五、發明說明（） 劑及具有數量平均分子量20,000至500,000之聚氧化乙烯。 茲目前已發現一種含水溶性樹脂之控時緩釋藥劑組成 物，其主要選擇吡磺環己脲作爲標的藥物；吡磺環己脲爲屬 於磺醯脲類之口服降血糖藥物，主要用來治療非胰島素依賴 型糖尿病(non-insulin-dependent diabetes)，或稱爲成人型糖 尿病(maturity_onset diabetes)。其作用機轉是藉由刺激胰臟 之胰島素分泌使血糖降低，而胰臟外的作用包括增加胰島素 之靈敏度及降低肝糖之製造，同樣對吡磺環己脲之降血糖效 果有重要影響。 磺醯脲類藥物之持續性釋放錠劑，在國外已商品化者主 要是Pfizer公司所開發的Glucotrol XL Tab.(Glipizide 2.5毫 克，5毫克，10毫克），爲屬於口服滲透性幫浦系統(OROS) 之控制劑型，其包括一含藥層與不含藥層之雙層錠核心，外 覆一半透膜，並以雷射光在此半透膜上打洞，其釋放機轉乃 是藉由在體液中錠劑內外滲透壓的差及不含藥層吸溼後膨 脹推擠含藥層之藥物自小洞釋出，而達到零次釋放的效果。 惟此類OROS控釋製劑.，不僅製程繁複，且需以雷射光或其 他機械方式打洞，難以保證每一顆錠劑之洞均在同一位置 (含藥層之那一面)及一定之孔徑大小與深淺，因此亦難以保 證每一顆錠劑的溶離曲線一致。而本發明之控時緩釋藥劑組 成物，係以水溶性樹脂混以適當的賦形劑處方，可以直接打 錠的方式，或加入適當的煉合液煉合製粒，乾燥後再打錠而 成。此裸錠在體外的溶離試驗中具有近似零次釋放的溶離曲 線，而在此裸錠上再被覆一層或多層由水溶性與水不溶性高 6 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項寫本頁) -裝--------訂--------- 經濟部智慧財產局員工消費合作社印製 1284542 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（ 分子聚合物摻合而成的膜衣，依組成的不同而有不同的崩解 與脫落時間，藉以延遲核心錠劑的釋放時間。本發明具有製 程簡單，不需特殊機器，以現今一般GMP藥廠所具有的生產 設備即可生產，是爲最大優點。 本發明之新穎含水溶性樹脂之控時緩釋藥劑組成物， 其能維持一定的藥物釋放速率。此外，本發明對於某些需要 在體內特定部位吸收之活性藥物成份或使活性藥物成份在 一段延遲時間後達到釋放之目的，具有良好的效果。 發明摘述 本發明的目的係提供一種含水溶性樹脂之控時緩釋 (Time controlled sustained release)藥劑組成物，以期能維持 一定的藥物釋放速率，且更精準的控制藥物在胃腸道中持續 的緩釋。 本發明的另一目的係提供一種含磺醯腺類作爲活性成 分之控時緩釋藥劑組成物，其適於每天施用一次，該藥劑組 成物具有生物可利用性。 本發明的進一步目的係提供一種含吡磺環己脲作爲活 性成分之控時緩釋藥劑組成物，其適於每天施用一次，該藥 劑組成物具有生物可利用性。 圖式簡單說明 ‘紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）1284542 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. INSTRUCTION DESCRIPTION () Field of the Invention The present invention provides a time controlled sustained release pharmaceutical composition containing a water-soluble resin. More specifically, the present invention relates to a controlled release sustained-release pharmaceutical composition comprising a water-soluble resin which is released at a specific time and which maintains a certain drug release rate. BACKGROUND OF THE INVENTION There are many pharmaceutically active ingredients that have a short biological half-life and require several doses per day for clinical use to achieve therapeutic effects. Therefore, in order to solve this problem, there is a need to develop a sustained-release pharmaceutical composition capable of maintaining a certain drug release rate. The advantages of controlled release pharmaceutical compositions are well known in the art of medicinal techniques. Chinese Patent Application No. 82107572 (Announcement No. 393320) relates to an oral hydrocolloid drug tablet comprising (1) at least one drug, (2) water immersion > an additive inside a tablet, And (3) forming a high-molecular substance of a hydrocolloid, which has the ability to almost completely gelatinize the preparation in the stomach and small intestine of the upper part of the digestive tract, and to release the drug in the colon of the lower part of the digestive tract. This patent is hereby incorporated by reference. The oral absorption gel of the patent is mainly located under the digestive tract. The US Patent No. 5024843 discloses an oral hypoglycemic agent, glipizide granules. U.S. Patent No. 5,9,119 discloses a delivery system for administering a hypoglycemic agent. U.S. Patent No. 5,554,413 discloses that 3 冢 paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm ' ~ ------ (Please read the back note first to write this page) ------- 1284542 A7 B7 V. INSTRUCTIONS () Dosage form of the orally administered hypoglycemic agent, glipizide, and a method of controlling hyperglycemia. These patents are hereby incorporated by reference. The three U.S. patents are directed to providing a dosage form for the release of glipizide at a controlled rate while providing a hypoglycemic treatment. U.S. Patent No. 5,273, 758 discloses a direct compression method for preparing a pharmaceutical dosage form of a tablet. The method comprises the steps of: a) mixing a crystalline medical drug with a direct compression carrier comprising polyethylene oxide without adding a solvent or heat to form a composition in which the drug is dispersed; and b) The resulting composition is pressed at a sufficient pressure to form a tablet. This patent is hereby incorporated by reference. The tablet made by this patent controls the release rate of the drug by polyethylene oxide. U.S. Patent No. 5,593,694 discloses a zero-order dissolving sustained-release tablet comprising a water-swelling gelling agent and a pharmaceutically active ingredient uniformly dispersed in the gelling agent, the tablet being coated by dissolving Or a film coating composition prepared from an organic solvent in a component selected from the group consisting of ethyl cellulose and ethyl ketone cellulose. This patent is hereby incorporated by reference. This patent does not use polyethylene oxide: U.S. Patent No. 5,718,212 discloses a controlled release pharmaceutical lozenge comprising a first barrier layer comprising a first swellable erodible polymer and a second swellable erodable polymer a drug layer, a second barrier layer comprising a third swelling and erosive polymer, wherein the first and second barrier layers are swollen and eroded faster than the drug layer and the first and third layers are swollen and eroded faster Used to increase drug delivery from dissolution. This patent is incorporated herein by reference. The average molecular weight of the polyethylene oxide used in this patent is lxlO6 to 4. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------ (Read first Note on the back page)---------------- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1284542 A7 ____B7 _ V. Invention Description (2xl〇6〇 US Patent No. 6056977 Revealed A controlled release, solid dosage form of a solid form, wherein the dosage form comprises a therapeutically effective amount of sulfonyhirea or a salt thereof or a derivative thereof in a matrix. In addition, the use of an aqueous alkalizing medium provides substantially complete bioavailability of the drug from the matrix of the tablet. The core ingot is optionally 2°/. Up to 10°/. The casing material or a water-insoluble substance such as a coating material of ethyl cellulose is coated. This patent is hereby incorporated by reference. This patent does not use polyethylene oxide. U.S. Patent No. 6,090,411 discloses a controlled release lozenge comprising a water-swellable polymeric matrix which is capable of increasing the linear release of the drug over a sustained period of time. More specifically, the drug is placed in a matrix composed of hydroxypropylmethylcellulose (HPMC) or polyethylene oxide in the presence of a salt, which may be a combination of salts. This patent is hereby incorporated by reference. The salts used in this patent play an important role in the controlled release of active substances. WO 96/26718 discloses a controlled release lozenge comprising a medicament and an excipient, wherein the repellent comprises at least about 50% of a water-swellable polymer and a lubricant having a rate of expansion equal to Dissolution rate after expansion. This patent is hereby incorporated by reference. This patent uses polyethylene oxide having an average molecular weight of 900,000 to 4,000,000. WO 97/18814 discloses an orally controlled release pharmaceutical composition comprising primarily an active pharmaceutical compound, a low molecular weight polyethylene oxide, hydroxypropyl methylcellulose, an excipient for tableting and optionally one or more Casing polymer. This patent is hereby incorporated by reference. This patent uses HPMC as the basis of 5 paper scales applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) ------------·Installation (please read the note on the back first) Page) Order --------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1284542 A7 B7 V. Invention Description () Agent and polyethylene oxide with a number average molecular weight of 20,000 to 500,000. At present, a controlled release sustained-release pharmaceutical composition containing a water-soluble resin has been found, which mainly selects glipizide as the standard drug; glipizide is an oral hypoglycemic agent belonging to the class of sulfonylureas, mainly used for treatment. Non-insulin-dependent diabetes, or maturity_onset diabetes. Its action is to reduce blood sugar by stimulating insulin secretion from the pancreas, and the effects outside the pancreas include increasing the sensitivity of insulin and reducing the production of glycogen, which also has an important effect on the hypoglycemic effect of glipizide. Sustained release lozenges of sulfonylureas, which have been commercialized abroad, mainly Glucotrol XL Tab. (Glipizide 2.5 mg, 5 mg, 10 mg) developed by Pfizer, belonging to the oral osmotic pump system. (OROS) controlled dosage form comprising a drug-containing layer and a double-layer ingot core without a drug layer, which is covered with a half-transparent film, and holes are made on the semi-permeable film by laser light, and the release mechanism is borrowed. The effect of zero-release is achieved by the difference between the osmotic pressure inside and outside the tablet in the body fluid and the drug which does not contain the drug layer and swells and pushes the drug-containing layer from the small hole. However, such OROS controlled release preparations are not only complicated in process, but also need to be drilled by laser light or other mechanical means. It is difficult to ensure that each of the tablets is in the same position (the side containing the drug layer) and a certain aperture. The size and depth are also difficult to ensure that the dissolution curve of each tablet is consistent. The controlled-time sustained-release pharmaceutical composition of the present invention is prepared by mixing a water-soluble resin with a suitable excipient, and can be directly ingot or added to a suitable refining liquid for refining and granulation, and then dried and then ingot. Made. The bare ingot has an approximately zero-release dissolution curve in the in vitro dissolution test, and one or more layers are coated on the bare ingot by a water-soluble and water-insoluble standard. The paper is applicable to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) (Please read the note on the back to write this page) - Packing -------- Order --------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1284542 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed A7 V. Invention Description (Molecular polymer blended film coat, depending on the composition, there are different disintegration and shedding time, in order to delay the release time of the core tablet. The invention has the advantages of simple process, no special machine, and can be produced by the production equipment of the general GMP pharmaceutical factory, which is the biggest advantage. The novel water-containing resin controlled release sustained-release pharmaceutical composition of the invention can maintain a certain The rate of drug release. In addition, the present invention has good effects for certain active pharmaceutical ingredients that need to be absorbed in specific parts of the body or for the release of the active pharmaceutical ingredient after a delay time. SUMMARY OF THE INVENTION The object of the present invention is to provide a time-controlled sustained release pharmaceutical composition containing a water-soluble resin in order to maintain a certain drug release rate and to more accurately control the sustained duration of the drug in the gastrointestinal tract. Sustained release. Another object of the present invention is to provide a controlled release sustained-release pharmaceutical composition containing a sulfonium gland as an active ingredient, which is suitable for once daily administration, and which has bioavailability. Further of the present invention The object of the invention is to provide a controlled release sustained-release pharmaceutical composition containing glipizide as an active ingredient, which is suitable for daily application, and the composition of the medicament is bioavailable. The drawing simply states that the paper scale is applicable to the Chinese national standard. (CNS) A4 size (210 X 297 mm)
·裝--------訂--------- (請先閱讀背面之注意事項本頁) H 經濟部智慧財產局員工消費合作社印製 1284542 A7 ___B7_ 五、發明說明（） 第1圖係顯示本發明之控時緩釋藥劑組成物與習知醫 藥組成物在ρΗ7·5緩衝溶液中之溶離率(％)之比較。 第2圖係顯示本發明之控時緩釋藥劑組成物與習知醫 藥組成物在血中濃度與時間的關係之比較。 第3圖係顯示迪爾泰健鹽酸鹽自包覆不同量之 Aqixacoat ECD-30的錠劑中釋放的部分相對於時間之迴歸結 果。 發明詳述 "緩釋”一辭係指在一種速率下釋出活性成分，使其在 1液中濃度維持於治療範圍內但低於中毒程度之期間持續 一段時間，例如，12至24小時或更久。 "控時緩釋"一辭係指所給特定藥物成分在生體內藉由 某種技術控制一段時間後達到緩慢釋放之目的。 "生物可利用性"一辭係指所給特定藥物量之生理可利 用性。即該活性成分自耀釋劑型中釋出並在藥物作用位置成 爲可利用的。 本發明提供一種含水溶性樹脂之控時緩釋藥劑組成 物，其能維持一定的藥物釋放速率。本發明對於某些需要在 體內特定部位吸收之活性藥物成份或使活性藥物成份在一 段延遲時間後達到釋放之目的，具有良好之效果。 本發明之控時緩釋藥劑組成物包括核心及膜衣，其核 心可爲錠劑(Tablet)、微錠劑(Minitab·)、圓粒(Pellet)。該核 8 (請先閱讀背面之注意事項寫本頁) -------丨訂-------- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1284542 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 心之組成包含(w/w): 1〜10%活性成分，0〜80%稀釋劑，1〜50% 水溶性樹脂，5〜30%可塑劑，0-50%黏合劑及0.5〜5%潤滑 劑；且其膜衣之組成包含(W/W) : 0.5〜80%膜衣形成劑， 0.5〜30%可塑劑及0.5〜20%抗黏劑或其他稀釋劑。 適用於本發明活性成分之較佳具體實施例爲可選自磺 醯腺類藥物、潘丁生（dipyridamole)、二氯苯胺苯乙酸鈉 (dichlofenac sodium)及迪爾泰健鹽酸鹽（diltiazem hydrochloride)所組成之族群中。擴醯腺類藥物之較佳實例 爲吡磺環己脲。 本發明之控時緩釋藥劑組成物之核心製法可爲乾式混 合、濕式造粒、流化床製粒或擠壓製粒形成顆粒後，加入潤 滑劑後可壓製成錠劑、或經圓粒化製成圓粒，或製成圓粒後 供打錠。其形成顆粒使用之溶液可加入水溶性樹脂、可塑劑 及粘合劑或部份水溶液及/或適當之有機溶劑或其混合性溶 劑或該聚合物之乳狀或非乳狀懸浮液。 於核心表面可包覆一層或多層延遲釋放之膜衣。該膜衣 製法可爲習知加衣法，.如鍋加衣法或流化床加衣法，將聚合 物於水溶液及/或適當之有機溶劑或其混合性溶劑或該聚合 物之乳狀或非乳狀懸浮液加在核心表面，使形成含一層或多 層之膜衣核心。 其中核心部份所用之稀釋劑可選自此技藝中所習用 者。較佳的實例爲選自糖類、澱粉類、纖維素鈉、鹼金屬或 鹼土金屬鹽類。 核心部份所用之水溶性樹脂可選自此技藝中所習用 9 本€尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----- ------------t--------tr--------- (請先閱讀背面之注意事項本頁) 0 1284542 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 者。較佳的實例爲聚氧化乙烯。該聚氧化乙烯之分子量範圍 在 100,000〜7,000,000 之間，較佳者爲 300,000〜1，000,000 之 間，最佳者爲900,000。 核心部份所用之黏合劑可選自此技藝中所習用者。較佳 的實例爲選自乙烯四氫K咯酮(pvp)、明膠、羥乙基纖維素 (HEC)、羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、 乙烯乙酸鹽(VA)、聚乙烯醇(PVA)、甲基纖維素(MC)、乙基 纖維素(EC)、羥丙基甲基纖維苯二甲酸鹽(HPMCP)、乙酸苯 二甲基纖維素(CAP)、三仙膠(xanthan gum)、海藻酸、海藻 酸鹽、甲基丙烯酸甲基丙烯酸酯共聚物（商品名： Eudragit，、共聚之甲基丙烯酸/甲基丙烯酸甲酯及聚乙烯乙 酸苯二甲酸(PVAP)所組成之族群中。 核心部份所用之潤滑劑可選自此技藝中所習用者。較佳 之實例爲選自滑石粉、硬脂酸、硬脂酸鹽、延胡索硬脂酸鈉 (sodium stearyl fumarate)、二十二酸甘油酯（glyceryl behenate)、高嶺土(kaolin)及膠體二氧化砂(aerosil)所組成之 族群中。 . 本發明之控時緩釋藥劑組成物之膜衣部份所用之膜衣 形成劑可選自此技藝中所習用者。較佳的實例爲選自共聚之 甲基丙烯酸/甲基丙烯酸甲酯如商品名爲Eudragit® RL/RS(Rohm藥廠）之化合物、Aquacoat®(美國 FMC)、 Kollicoat®、乙烯四氫吡咯酮(PVP)、明膠、羥乙基纖維素 (HEC)、羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、 乙烯乙酸鹽(VA)、聚乙烯醇(PVA)、甲基纖維素(MC)、乙基 10 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------丨丨訂·！------— (請先閱讀背面之注拳項賣) β 1284542 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 纖維素(EC)、羥丙基甲基纖維苯二甲酸鹽(HPMCP)、乙酸苯 二甲基纖維素(CAP)、海藻酸、海藻酸鹽、聚乙烯乙酸苯二 甲酸(PVAP)或聚乙酸乙烯酯(PVAc)。 本發明之控時緩釋藥劑組成物所用之可塑劑可選自此 技藝中所習知者。較佳的實例爲選自丙三醇、聚乙二醇、檸 檬酸三乙酯、檸檬酸三丁酯、三乙酸丙酯及蓖麻油所組成之 族群中。 本發明之控時緩釋藥劑組成物之膜衣部份所用之其他 稀釋劑可選自此技藝中所習用者。較佳的實例爲選自乳糖、 澱粉、甘露醇、羧甲基纖維素鈉、澱粉鈉、微結晶纖維素及 色素所組成之族群中。 本發明之控時緩釋藥劑組成物之膜衣部份所用之抗黏 劑可選自此技藝中所習用者。較佳的實例爲選自滑石粉、硬 酯酸、硬酯酸鹽、延胡索硬酯酸鈉(sodiumstearylfumarate) 及二十二酸甘油酯(glyceryl behenate)所組成之族群中。 本發明所使用之溶劑可爲此技藝中所習用者。較佳的實 例爲選自水、乙醇、丙酮、異丙醇、二氯甲烷或其混合溶媒。 本發明的進一步細節在以下實施例中加以說明。然而， 絕不因此而限制本發明的範圍。 實施例一： 配方組成： (1)核心錠劑： 製造過程： 50克之潘丁生(dipyridamole)、210克之乳糖、80克之聚 11 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------—I—^--------- (請先閱讀背面5意事項本頁) 0 1284542 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 乙二醇6000、280克之聚氧化乙烯(M.W.=600,000)與320克 之羥丙基甲基纖維素（M.W.=20,000)分別通過適當之篩網 後，合倂在造粒機造粒後 ，再以搓圓機作成圓粒核心 (2)膜衣組成： Aquacoat ECD-30 132克 檸檬酸三乙酯 24.8 克 滑石粉 18克 溶劑 200毫升 製造過程： 將132克之AquacoatECD-30、24.8克之檸檬酸三乙酯及 18克之滑石粉配製在200毫升溶劑中，將此組合液噴到含藥 之圓粒作爲膜衣包覆。 實施例二： 配方組成： ⑴核心錠劑： 製造過程： 100克之二氯苯胺苯乙酸鈉(dichlofenac sodium)、200 克之乳糖、80克之聚乙二醇6000、240克之聚氧化乙烯 (M.W.=600,000)與310克之羥丙基甲基纖維素(M.W.=20,000) 分別通過適當的篩網後，合倂在混合機中混合均勻，之後再 加入18克之硬脂酸鎂，混合均勻。取出最終混合物，於打錠 機壓製成重量爲190毫克、片徑爲8mm之圓形錠。 (2)膜衣組成：·装--------book--------- (please read the note on the back page first) H Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1284542 A7 ___B7_ V. Invention description ( Fig. 1 is a graph showing the comparison of the dissolution rate (%) of the controlled-time sustained-release pharmaceutical composition of the present invention with a conventional pharmaceutical composition in a pH 7.5 buffer solution. Fig. 2 is a graph showing the relationship between the concentration of the controlled release sustained-release pharmaceutical composition of the present invention and the conventional pharmaceutical composition in blood and time. Figure 3 is a graph showing the relative regression of the release of Diltech's hydrochloride from tablets coated with varying amounts of Aqixacoat ECD-30. DETAILED DESCRIPTION OF THE INVENTION "Slow release" refers to the release of an active ingredient at a rate such that it remains in the therapeutic range for a period of time but below the level of poisoning for a period of time, for example, 12 to 24 hours. Or longer. The term "controlled release" refers to the purpose of slow release of a given drug component in a living body for a period of time after being controlled by a certain technique. "Bioavailability" Refers to the physiological availability of a given amount of a drug. That is, the active ingredient is released from the stimulating dosage form and is available at the site of action of the drug. The present invention provides a controlled release sustained-release pharmaceutical composition containing a water-soluble resin. It can maintain a certain rate of drug release. The present invention has a good effect for certain active pharmaceutical ingredients that need to be absorbed in specific parts of the body or to release the active pharmaceutical ingredient after a delay time. The controlled release of the present invention The pharmaceutical composition includes a core and a film coat, and the core thereof may be a tablet, a micro tablet (Minitab), a pellet (Pellet). The core 8 (please read the back note first) Write this page) -------丨-------- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1284542 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System A7 B7 V. Description of invention () The composition of the heart contains (w/w): 1~10% active ingredient, 0~80% diluent, 1~50% water-soluble resin, 5~30% plasticizer, 0- 50% binder and 0.5~5% lubricant; and the composition of the film coat comprises (W/W): 0.5~80% film forming agent, 0.5~30% plasticizer and 0.5~20% anti-adhesive agent or other Preferred embodiments of the active ingredient suitable for use in the present invention are selected from the group consisting of sulfonamides, dipyridamole, dichlofenac sodium and diltiazem hydrochloride (diltiazem). A preferred example of a sputum-promoting drug is pyridoxine. The core method of the controlled-time sustained-release pharmaceutical composition of the present invention may be dry mixing, wet granulation, fluidized bed. After granulation or extrusion granulation to form granules, after adding a lubricant, it can be compressed into tablets, or rounded to make round granules, or made into round granules for use. The ingot may be added to the solution for forming the granules by adding a water-soluble resin, a plasticizer and a binder or a part of an aqueous solution and/or a suitable organic solvent or a mixed solvent thereof or a milky or non-emulsion suspension of the polymer. The core surface may be coated with one or more layers of delayed release film coating. The film coating method may be a conventional coating method, such as a panning method or a fluidized bed coating method, the polymer is in an aqueous solution and/or appropriate The organic solvent or a mixed solvent thereof or a milky or non-emulsion suspension of the polymer is applied to the core surface to form a film coat core containing one or more layers. The diluent used in the core portion can be selected from those skilled in the art. Preferred examples are selected from the group consisting of sugars, starches, cellulose sodium, alkali metal or alkaline earth metal salts. The water-soluble resin used in the core part can be selected from the following in this technique. 9 The scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----- --------- ---t--------tr--------- (Please read the note on the back page first) 0 1284542 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (). A preferred example is polyethylene oxide. The polyethylene oxide has a molecular weight in the range of from 100,000 to 7,000,000, preferably from 300,000 to 1,000,000, and most preferably from 900,000. The binder used in the core portion can be selected from those skilled in the art. Preferred examples are selected from the group consisting of ethylene tetrahydrofuranone (pvp), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), ethylene acetate. Salt (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl fiber phthalate (HPMCP), phenyl dimethyl cellulose acetate (CAP), xanthan gum, alginic acid, alginate, methacrylic acid methacrylate copolymer (trade name: Eudragit, copolymerized methacrylic acid/methyl methacrylate and polyvinyl acetate) The group consisting of phthalic acid (PVAP). The lubricant used in the core portion can be selected from those skilled in the art. Preferred examples are selected from the group consisting of talc, stearic acid, stearate, and fumarate. a group consisting of sodium stearyl fumarate, glyceryl behenate, kaolin, and colloidal silica (aerosil). The membrane of the controlled release sustained-release pharmaceutical composition of the present invention The film forming agent used in the coating portion may be selected from those skilled in the art. A preferred example is selected from the group consisting of copolymerization. Acrylic acid/methyl methacrylate such as the compound of Eudragit® RL/RS (Rohm Pharmaceuticals), Aquacoat® (American FMC), Kollicoat®, ethylene tetrahydropyrrolidone (PVP), gelatin, hydroxyethyl fiber (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), ethylene acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl 10 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------ · · ! ! ! β β β β β β β β β β β 845 845 845 845 845 845 845 845 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed A7 B7 V. Description of Invention () Cellulose (EC), Hydroxypropyl Methyl Phosphate (HPMCP), Benzyl Cellulose Acetate (CAP), Alginic acid, alginate, polyvinyl acetate phthalate (PVAP) or polyvinyl acetate (PVAc). The plasticizer used in the controlled release sustained-release pharmaceutical composition of the present invention may be selected from those skilled in the art. Preferred examples are selected from the group consisting of glycerol, polyethylene glycol, triethyl citrate, tributyl citrate, propyl triacetate and castor oil. Other diluents for use in the film coating portion of the controlled release sustained-release pharmaceutical composition of the present invention may be selected from those skilled in the art. Preferred examples are selected from the group consisting of lactose, starch, mannitol, sodium carboxymethylcellulose. In the group consisting of sodium starch, microcrystalline cellulose and pigments, the anti-adhesive agent used in the film coating portion of the controlled release sustained-release pharmaceutical composition of the present invention may be selected from those skilled in the art. A preferred embodiment is selected from the group consisting of talc, stearic acid, stearate, sodiumstearylfumarate, and glyceryl behenate. The solvent used in the present invention can be used by those skilled in the art. Preferred examples are selected from the group consisting of water, ethanol, acetone, isopropanol, dichloromethane or a mixed solvent thereof. Further details of the invention are illustrated in the following examples. However, the scope of the invention is not limited thereby. Example 1: Formulation composition: (1) Core lozenge: Manufacturing process: 50 g of dipyridamole, 210 g of lactose, 80 g of poly 11 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ) ------------—I—^--------- (Please read the back of this page on page 5) 0 1284542 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. INSTRUCTIONS () Ethylene glycol 6000, 280 g of polyethylene oxide (MW = 600,000) and 320 g of hydroxypropyl methylcellulose (MW = 20,000) are respectively passed through a suitable sieve and combined in granulation. After granulation, the round core is made into a round core (2) film coat composition: Aquacoat ECD-30 132 g triethyl citrate 24.8 g talc 18 g solvent 200 ml Manufacturing process: 132 g of Aquacoat ECD-30 24.8 g of triethyl citrate and 18 g of talc powder were prepared in 200 ml of a solvent, and the mixture was sprayed onto the medicated round pellets as a film coat. Example 2: Formulation composition: (1) Core lozenge: Manufacturing process: 100 g of dichlofenac sodium, 200 g of lactose, 80 g of polyethylene glycol 6000, 240 g of polyethylene oxide (MW=600,000) After passing through a suitable sieve with 310 g of hydroxypropylmethylcellulose (MW = 20,000), the mixture was uniformly mixed in a mixer, and then 18 g of magnesium stearate was added thereto, and the mixture was uniformly mixed. The final mixture was taken out and pressed into a circular ingot having a weight of 190 mg and a diameter of 8 mm by an ingot machine. (2) Membrane composition:
Eudragit® RS30D 140克 12 未紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱1 I--I------· I I I----訂 -------- (請先閱讀背面S.項本頁) 0 1284542 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 羥丙基甲基纖維素 12克 檸檬酸三乙酯 8.4克 滑石粉 16克 溶劑 250毫升 製造過程： 先將12克之羥丙基甲基纖維素以250毫升溶劑溶解，再 將140克之EudragifRSSODU克之檸檬酸三乙酯及16克之 滑石粉配製在溶劑中，將此組合液噴到含藥之錠劑作爲膜衣 包覆。 實施例三： 配方組成： ⑴核心錠劑： 製造過程： 25克之吡磺環己脲、223克之乳糖、9〇克之聚乙二醇 6000、270克之聚氧化乙烯(]\^.=600,000)與315克之羥丙基 甲基纖維素(M.W.=20,000)分別通過適當的篩網後，合倂在 混合機中混合均勻，之後再加入18克之硬脂酸鎂，混合均 勻。取出最終混合物，於打錠機壓製成重量爲190毫克、片 徑爲8mm之圓形鏡。 (2)膜衣組成： Aquacoat ECD-30 140克 羥丙基甲基纖維素 32克 檸檬酸三乙酯 16克 滑石粉 16克 13 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----1 I I I I I I ---I----訂--------- (請先閱讀背面S意事項本頁) 0 經濟部智慧財產局員工消費合作社印製 1284542 ΚΙ ____Β7_ 五、發明說明（） 溶劑 200毫升 製造過程： 先將32克之羥丙基甲基纖維素以200毫升溶劑溶解，再 將140克之AquacoatECD-30、16克之檸檬酸三乙酯及16克之 滑石粉配製在溶劑中，將此組合液噴至含藥之錠劑作爲膜衣 包覆。 實施例四： 配方組成： ⑴核心錠劑： 製造過程： 25克之K磺環己脲、223克之乳糖、90克之聚乙二醇 6000、270克之聚氧化乙烯(]\4.界.=600,000)與315克之羥丙基 甲基纖維素(M.W.=20,000)分別通過適當的篩網後，合倂在 混合機中混合均勻，之後再加入18克之硬脂酸鎂，混合均 勻。取出最終混合物，於打錠機壓製成重量爲190毫克、片 徑爲8mm之圓形銘。 (2)膜衣組成：k Kollicoat® SR 30D 132克 檸檬酸三乙酯 24.8 克 滑石粉 18克 溶劑 200毫升 製造過程： 將132克之Kollicoat® SR 30D、24.8克之檸檬酸三乙酯 及18克之滑石粉配製在200毫升溶劑中，將此組合液噴至含 14 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）Eudragit® RS30D 140g 12 Uncoated paper size for China National Standard (CNS) A4 specification (210 X 297 public 1 I--I------· II I------- - (Please read the back page S.) 0 1284542 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description () Hydroxypropyl Methyl Cellulose 12g Triethyl Citrate 8.4g Talc 16 g solvent 250 ml manufacturing process: firstly dissolve 12 g of hydroxypropyl methylcellulose in 250 ml of solvent, then prepare 140 g of EudrafifRSSODU gram of triethyl citrate and 16 g of talc in a solvent. Sprayed into the drug-containing lozenge as a film coat. Example 3: Formulation composition: (1) Core lozenge: Manufacturing process: 25 g of glipizide, 223 g of lactose, 9 g of polyethylene glycol 6000, 270克克聚氧化乙烯(]\^.=600,000) and 315 grams of hydroxypropyl methylcellulose (MW=20,000) are respectively passed through a suitable sieve, and the mixture is uniformly mixed in a mixer, and then 18 grams of hard is added. Magnesium oleate, mixed evenly. Take out the final mixture and press it into a weight of 190. (2) Membrane composition: Aquacoat ECD-30 140 g hydroxypropyl methylcellulose 32 g triethyl citrate 16 g talc 16 g 13 paper scale for China National Standard (CNS) A4 Specification (210 X 297 mm) ----1 IIIIII ---I----Book--------- (Please read the back S meanings on this page first) 0 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1284542 ΚΙ ____Β7_ V. Invention Description () Solvent 200 ml Manufacturing process: Firstly dissolve 32 grams of hydroxypropyl methylcellulose in 200 ml of solvent, then 140 g of Aquacoat ECD-30, 16 g of triethyl citrate and 16 g of talc powder were prepared in a solvent, and the composition was sprayed to the medicated lozenge as a film coat. Example 4: Formulation composition: (1) Core lozenge: Manufacturing process: 25 Kg sulfacyclohexylurea, 223 grams of lactose, 90 grams of polyethylene glycol 6000, 270 grams of polyethylene oxide (]\4. boundary. = 600,000) and 315 grams of hydroxypropyl methylcellulose (MW = 20,000) respectively After passing through a suitable screen, the mixture is evenly mixed in the mixer, and then 18 grams of hard fat is added. Magnesium, evenly mixed. The final mixture was taken out and pressed into a round punch with a weight of 190 mg and a diameter of 8 mm on a tableting machine. (2) Membrane composition: k Kollicoat® SR 30D 132 g Triethyl citrate 24.8 g Talc 18 grams of solvent 200 ml Manufacturing process: 132 grams of Kollicoat® SR 30D, 24.8 grams of triethyl citrate and 18 grams of talc in 200 ml of solvent, spray this composition onto 14 paper scales for China National Standard (CNS) A4 specification (210 X 297 mm)
---I I--丨訂-------- (請先閱讀H素事項本頁) A 經濟部智慧財產局員工消費合作社印製 1284542 A7 __B7 五、發明說明（） 藥之錠劑作爲膜衣包覆。 實施例五： 配方組成： (1)核心錠劑： 製造過程： 25克之吡磺環己脲、223克之乳糖、90克之聚乙二醇 6000、270克之聚氧化乙烯(1\4^.=600,000)與315克之羥丙基 甲基纖維素(M.W.=20,000)分別通過適當的篩網後，合倂在 混合機中混合均勻，之後再加入18克之硬脂酸鎂，混合均 勻。取出最終混合物，於打錠機壓製成重量爲190毫克、片 徑爲8mm之圓形錠。 (2)膜衣組成： Eudragit® RS 30D 140克 羥丙基甲基纖維素 12克 檸檬酸三乙酯 8.4克 滑石粉 16克 溶劑 | 250毫升 製造過程： 先將12克之羥丙基甲基纖維素以250毫升溶劑溶解，再 將140克之Eudragit® RS 30D、8.4克之檸檬酸三乙酯及16克 之滑石粉配製在溶劑中，將此組合液噴至含藥之錠劑作爲膜 衣包覆。 實施例六： 溶離試驗： 15 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------訂--------- (請先閱讀背面之注意事項wiHar本頁) 0 1284542 A7 五、發明說明（） 將實施例三、四及五所製得之控時緩釋藥劑組成物與 習知醫藥組成物（Glucotrol XL Tab· (Glipizide 5毫克）， 獲自Pfizer公司），用符合美國藥典規範24版之溶離試驗方 、法’在PH7.5緩衝溶液中測其溶離率對時間之曲線圖。其結 果列於表1及第1圖。 、 時間 習知醫藥組成物 實施例三 實施例四 實施例五 一(小時） 平均 標準偏差 平均 標準偏差 平均 標準偏差 平均 標準偏差 0 0.06 0.12 0.07 0.20 0.46 0.49 0.00 0.09 0.5 0.14 0.01 1.59 0.01 0.10 0.34 0.77 0.14 1 0.39 0.03 4.23 0.37 0.81 0.10 2.10 0.30 1.5 0.93 0.25 8.12 0.64 2.35 0.51 3.74 0.47 2 3.93 0.98 12.26 0.81 4.41 0.63 6.09 0.67 2.5 8.00 0.99 16.22 0.81 7.33 1.59 9.19 1.07 3 12.43 1.06 20.45 0.46 11.23 1.73 13.26 1.40 4 21.70 1.01 28.25 1.58 20.12 0.87 22.35 1.36 5 31.43 1.58 44.00 4.30 29.79 1.30 31.64 1.48 6 41.62 1.79 56.98 5.48 38.27 0.24 40.34 1.64 7 51.66 2.29 68.90 8.03 52.48 2.01 51.55 2.65 8 61.91 3.41 77.27 8.27 62.84 3.99 65.00 4.71 9 71.42 3.95 84.25 8.20 71.62 3.61 75.81 5.24 10 79.95 3.70 90.51 9.34 78.93 4.33 85.60 3.96 11 88.38 4.09 96.38 10.22 84.83 4.97 94.63 2.18 16 表1:本發明之控時緩釋藥劑組成物與習知醫藥組成 物在pH7·5緩衝溶液中溶離率(％) (n=6)。 (請先閱讀背面之注意事項HUPk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（210 X 297公釐） 1284542 A7 B7 表2:本發明之控時緩釋藥劑組成物與習知醫藥組成 物在人體血液中吡磺環己脲濃度(Ug/ml) (n=4)。 五、發明說明（） 12 95.49 4.09 101.82 I . 11.32 .........'........ ί 90.25 ί 11 ‘102.38 1.24 14 105.08 2.57 108.05 10.81 101.89 7 0〇 111.59 1.66 16 109.28 0.91 108.73 10.08 105.30 _6^58 110 Π7 1 00 18 107.94 4.51 108.98 10.25 105.64 A X *3 # \y / 113.48 1 .yy 1.81 實施例七： 由受試者服下含10毫克毗磺環己脲之本發明實施例五 所製得之控時緩釋藥劑組成物及習知醫藥mumkd XL Tab· ( Glipizide 5毫克），獲自Pfizer公司）後，於服藥 24小時內密集採血，測試吡磺環己脲在人體內血中濃度之變 化，其結果列於表2及第2圖。 時間 習知醫藥組成物 本發明之控時擦 |釋藥劑組成物 (小時） 平均濃度 標準偏差 平均濃度. 標準偏差 0 0.00 0.00 0.00 0.00 0.5 11.15 0.00 31.06 0.00 1 13.00 . 0.99 23.97 14.38 1.5 13.43 4.63 26.19 14.30 2 36.44 13.45 38.36 21.30 2.5 92.47 22.63 68.86 24.95 3 154.23 24.00 143.40 29.88 3.5 200.92 22.70 197.59 37.05 4 249.56 7.50 293.99 98.41 5 210.09 26.43 230.69 81.10 17 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 裝--------訂--------- §. (請先閱讀背面之注_項\4|^賣) 0 經濟部智慧財產局員工消費合作社印製---I I--丨定-------- (please read the H-item page first) A Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1284542 A7 __B7 V. Invention Description () Ingot of Medicine The agent is coated as a film coat. Example 5: Formulation composition: (1) Core lozenge: Manufacturing process: 25 g of pyrithione, 223 g of lactose, 90 g of polyethylene glycol 6000, 270 g of polyethylene oxide (1\4^.=600,000 After passing through a suitable sieve with 315 g of hydroxypropylmethylcellulose (MW = 20,000), the mixture was uniformly mixed in a mixer, and then 18 g of magnesium stearate was added thereto, and the mixture was uniformly mixed. The final mixture was taken out and pressed into a circular ingot having a weight of 190 mg and a diameter of 8 mm by a tableting machine. (2) Membrane composition: Eudragit® RS 30D 140 g hydroxypropyl methylcellulose 12 g triethyl citrate 8.4 g talc 16 g solvent | 250 ml manufacturing process: first 12 g of hydroxypropyl methyl fiber The solution was dissolved in 250 ml of solvent, and 140 g of Eudragit® RS 30D, 8.4 g of triethyl citrate and 16 g of talc powder were prepared in a solvent, and the composition was sprayed to the drug-containing lozenge as a film coat. Example 6: Dissolution test: 15 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order--------- (please read the back first) Precautions wiHar page) 0 1284542 A7 V. INSTRUCTIONS () The controlled-time sustained-release pharmaceutical composition prepared in Examples 3, 4 and 5 and the conventional pharmaceutical composition (Glucotrol XL Tab· (Glipizide 5 mg) , obtained from Pfizer, using a dissolution test according to the USP Pharmacopoeia, version 24, and measuring the dissolution rate versus time in a pH 7.5 buffer solution. The results are shown in Table 1 and Figure 1. Time-practical pharmaceutical composition Example 3 Example 4 Example 51 (hour) Mean standard deviation mean standard deviation mean standard deviation mean standard deviation 0 0.06 0.12 0.07 0.20 0.46 0.49 0.00 0.09 0.5 0.14 0.01 1.59 0.01 0.10 0.34 0.77 0.14 1 0.39 0.03 4.23 0.37 0.81 0.10 2.10 0.30 1.5 0.93 0.25 8.12 0.64 2.35 0.51 3.74 0.47 2 3.93 0.98 12.26 0.81 4.41 0.63 6.09 0.67 2.5 8.00 0.99 16.22 0.81 7.33 1.59 9.19 1.07 3 12.43 1.06 20.45 0.46 11.23 1.73 13.26 1.40 4 21.70 1.01 28.25 1.58 20.12 0.87 22.35 1.36 5 31.43 1.58 44.00 4.30 29.79 1.30 31.64 1.48 6 41.62 1.79 56.98 5.48 38.27 0.24 40.34 1.64 7 51.66 2.29 68.90 8.03 52.48 2.01 51.55 2.65 8 61.91 3.41 77.27 8.27 62.84 3.99 65.00 4.71 9 71.42 3.95 84.25 8.20 71.62 3.61 75.81 5.24 10 79.95 3.70 90.51 9.34 78.93 4.33 85.60 3.96 11 88.38 4.09 96.38 10.22 84.83 4.97 94.63 2.18 16 Table 1: Dissolution rate (%) of the composition of the controlled release sustained-release pharmaceutical composition of the present invention and the conventional pharmaceutical composition in a pH 7. 5 buffer solution ( n=6). (Please read the following notes on the back of the page.) The Ministry of Economic Affairs, Intellectual Property Office, Employees, Consumer Cooperatives, Printed Paper Size Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 1284542 A7 B7 Table 2: The present invention The concentration of the glipizide (Ug/ml) (n=4) in the human blood of the controlled-time sustained-release pharmaceutical composition and the conventional pharmaceutical composition. V. INSTRUCTIONS () 12 95.49 4.09 101.82 I . 11.32 .........'........ ί 90.25 ί 11 '102.38 1.24 14 105.08 2.57 108.05 10.81 101.89 7 0〇111.59 1.66 16 109.28 0.91 108.73 10.08 105.30 _6^58 110 Π7 1 00 18 107.94 4.51 108.98 10.25 105.64 AX *3 # \y / 113.48 1 .yy 1.81 Example 7: The subject received 10 mg of sulfocyclohexylurea In the fifth embodiment of the invention, the controlled time release sustained-release pharmaceutical composition and the conventional medicine mumkd XL Tab· (Glipizide 5 mg), obtained from Pfizer, were intensively collected within 24 hours of taking the drug, and the pyridoxal was tested. The changes in blood concentration in the human body are shown in Table 2 and Figure 2. Time-practical pharmaceutical composition The controlled time of the present invention wipes the release agent composition (hours) average concentration standard deviation average concentration. standard deviation 0 0.00 0.00 0.00 0.00 0.5 11.15 0.00 31.06 0.00 1 13.00 . 0.99 23.97 14.38 1.5 13.43 4.63 26.19 14.30 2 36.44 13.45 38.36 21.30 2.5 92.47 22.63 68.86 24.95 3 154.23 24.00 143.40 29.88 3.5 200.92 22.70 197.59 37.05 4 249.56 7.50 293.99 98.41 5 210.09 26.43 230.69 81.10 17 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)装--------Book--------- §. (Please read the note on the back_items\4|^sell) 0 Printed by the Intellectual Property Office of the Ministry of Economic Affairs