TW215057B

TW215057B -

Info

Publication number: TW215057B
Application number: TW080109239A
Authority: TW
Original assignee: Astra Ab
Priority date: 1990-12-07
Filing date: 1991-11-25
Publication date: 1993-10-21
Also published as: FI932554A; MY106776A; NZ240731A; EP0560821A1; ZA919264B; PT99719A; MX9102325A; HU9301670D0; SE9003902D0; SK55693A3; LTIP1717A; CN1063039A; TNSN91117A1; JPH06503312A; HUT64217A; AP258A; YU186891A; MA22355A1; AP9100338A0; WO1992010172A1

Description

Λ 6 Π 6 21505*7 五、發明説明（1 ) 發明領域 (請先閱讀背而之注意事項孙蜞寫本玎) 本發明關於抗心律失常藥愛默克梗（Ρ -INN )之固態劑型，調配成立即釋放（IR)藥片及延伸釋放（·ΕΚ )藥片，及其製法。本發明特別關於愛默克梗之聚苯乙烯磺酸塩複合物固態劑型之使用。發明之背景過去從未報告含愛默克梗之聚苯乙烯磺酸塩複合物之固態劑型。愛默克梗之聚苯乙烯磺酸塩複合物敍述於歐洲專利申請案ΕΡ 908502420 ，其在瑞典申請基本案時尙未公開可得，但以後很快即將如此。愛默克梗（Ρ-INN) ，4 一〔3 —〔乙基〔3—(丙基亞磺醯基）一丙基〕胺基〕一 2 —羥丙氧基〕一苯甲腈自由鹸爲黏性、黏著物質，在固態劑型之製造時處理成問題。已有得到聞起來像老E之討厭臭味降解產物之顯著趨勢。已試驗許多不間方法以製備愛默克梗之固態劑型。通常所用方法具有以下缺點。經濟部+央標準’々A工消作合作社印5i 由於鹸之不安定性及其惡化藥片結合性質之趨勢，自由鹼之固態劑型難以製造。參見進一步參考例ΠΙ。傳統技術製備之具有溶於酸性成粒溶液之愛默克梗藥片具有較差安定係質且發生討厭的似1；臭昧。參見進一步參考例I及ΠΙ。具有離子交換樹脂於藥學配方之藥物質複合物之使用如前所述。得到含甲基嗎啡之對照釋放懸浮液之方法敍述於尺度逍用中SS家棕if(CNS)T规tM210x2町公及）_ 3 - .77Λ 6 Π 6 21505 * 7 5. Description of the invention (1) Field of the invention (please read the precautions written by Sun Yao first) This invention relates to the solid dosage form of the anti-arrhythmic drug Emecker (Ρ-INN), It is formulated into immediate release (IR) tablets and extended release (· EK) tablets, and its preparation method. The present invention is particularly concerned with the use of solid dosage forms of polystyrenesulfonate complexes of Emergent Terrier. BACKGROUND OF THE INVENTION The solid dosage forms of polystyrenesulfonate complexes containing Emergent Terrier have never been reported in the past. The polystyrene sulfonate compound of the Emmerke Terrier is described in the European patent application EP 908502420, which was not publicly available when the basic application was applied in Sweden, but this will soon be the case. Emperor Terrier (Ρ-INN), 4-one [3- [ethyl [3- [propylsulfinyl] -propyl] amino] -2-hydroxypropoxy] -benzonitrile free It is a sticky and sticky substance, which is a problem in the manufacture of solid dosage forms. There has been a significant trend to get the nasty odor degradation products that smell like old E. Many incessant methods have been tested to prepare solid dosage forms of Emmerk Terrier. Generally, the method used has the following disadvantages. Ministry of Economic Affairs + Central Standard ’々A Gongxiaozuo Cooperative Printed 5i Due to the instability of emu and its tendency to deteriorate the binding properties of tablets, it is difficult to manufacture solid dosage forms of free base. See further reference example III. The traditionally prepared Emergentin tablets with an acidic granulation solution have poor stability and are annoying; See further reference examples I and III. The use of the ion-exchange resin in the pharmaceutical composition of the pharmaceutical composition is as described above. The method of obtaining the control release suspension containing methylmorphine is described in the standard Xiaoyong SS home palm if (CNS) T regulation tM210x2 Machiko) _ 3-.77

Hi 五、發明説明（2)Hi 5. Description of the invention (2)

Amsel L.P.等人之 “ Unique Oral Controlled ReleaseAmsel L.P. et al. "Unique Oral Controlled Release

Systems” ： In-Vivo Drug Release Pattern 第 83 — 93 頁，其中甲基嗎啡及離子交換樹脂間之複合物塗有擴散膜然後調配成懸浮液。此外，Pennwal t 公司已公告敍述具有吸收其上藥理學活性物質之離子交換樹脂用於如此或進一步以擴散膜塗覆之對照釋放製劑之使用之一系列專利（美國專利 4,221，778、EP 0171528、EP 0254811 )。離子交換齒脂複合物與藥於藥學配方之其他使用如Raghunathan 等人，Jpharm Sci 1981 . _70_. ( No . 4 )，379 — 384 所歸二納。發明之說明本發明之目標爲提供抗心律失常藥愛默克梗之固態劑型，調配成具有改良安定性及最小臭味之IR藥片及ER藥片。ER藥片可藉一種調配原則，例如親水性凝膠基質藥片、基質華片、膜擴散對照配方、滲透壓對照劑型等而調配。由於在藥片製造中固態物質之使用通常爲有利的且利於製備，故調査製備固態劑'型之方法。由於巳發現愛默克梗於酸性溶液中具有良好安定性，使其可經高溫經濟部屮央榀準：ir A工消fr合作社印3i (請先閉^背而之：>χ*;項再碣'K本頁) 高鬆而無顯著之降解，故試驗酸化合物之加入。雖然對黏性、不安定、藥理活性劑離子交換樹脂之複合物結合以形成藥學處理用安定固態複合物尙未被提出，其以愛默克梗試驗。 : 因此試驗在藥學劑型使用愛默克梗之聚苯乙烯磺酸塩複合物。然後出乎意料在發現聚苯乙烯磺酸塩複合物（A-PSS)" 本从尺度边用中Ha家榀準（CNS)I?M規岱（210x297公及）一 4 經濟部屮央楳準劝员工消赀合作社印製Systems ”: In-Vivo Drug Release Pattern pages 83-93, where the compound between methyl morphine and ion exchange resin is coated with a diffusion membrane and then formulated into a suspension. In addition, Pennwalt has announced that it has absorbed the pharmacology A series of patents for the use of ion-exchange resins with biologically active substances in control release formulations coated with such or further diffusion membranes (US Patent 4,221,778, EP 0171528, EP 0254811). Other uses of pharmaceutical formulations such as Raghunathan et al., Jpharm Sci 1981. _70_. (No. 4), 379-384 are included. Description of the invention The object of the present invention is to provide a solid dosage form of the anti-arrhythmic drug Emecker , Formulated into IR tablets and ER tablets with improved stability and minimum odor. ER tablets can be formulated by a principle of formulation, such as hydrophilic gel matrix tablets, matrix Hua tablets, membrane diffusion control formulations, osmotic pressure control dosage forms, etc. Since the use of solid substances in the manufacture of tablets is generally advantageous and conducive to preparation, the method of preparing solid dosage forms is investigated. Since it has been found that the Emock Terrier has good stability in an acidic solution, it can be approved by the Ministry of High Temperature Economy: ir A Gongxiao fr Cooperative Society Printed 3i (please close ^ back first: > χ *; Xiang Zaijie's' K page) Takamatsu without significant degradation, so the test acid compound was added. Although the combination of viscosity, instability, pharmacologically active agent ion exchange resin combined to form a stable solid compound for pharmaceutical treatment It was not proposed, but it was tested by Emergent Terrier .: Therefore, the polystyrene sulfonate complex of Emergent Terrier was used in the pharmaceutical dosage form. Then unexpectedly, the polystyrene sulfonate complex (A -PSS) " This standard is used in the Ha Family of Standards (CNS) I? M Regulation Dai (210x297 gong and) a 4 printed by the Ministry of Economic Affairs of the People ’s Republic of China, Counselor persuaded the employees to print

AG __H G __ 五、發明説明（3 ) 具有較佳安定性，較小討厭臭昧且在藥片製造非常易於處理0 爲了形成ER藥射，其需混合形成複合物與例如親水性基質。使用羥丙基甲基纖維素作爲凝膠形成物質特佳。使用含低及高分子量HPMC之HPMC混合物更佳。依照已知技術（Journal of Controlled release. S ( 1987) 159 — 172 ) ，HPMC之不同混合物之使用得到不同之活性成份愛默克梗釋放速率。實施例實施例1 混合90份A-PSS、85份乳糖、91份微晶纖維素及27份聚乙烯基吡咯啶酮然後與純水粒化混合物而製備愛默克梗之立即釋放藥片。顆粒乾燥後粉碎，然後與硬脂醯福馬酸鈉混合並壓縮成片。在2 Μ氫氯酸溶液溶解自由鹸並使用此溶液粒化賦形劑而製造參考製劑。 A-PSS藥片實施例1 參考例1 1-對應愛默克梗之A-PSS 50.0 - 愛默克梗 — 50.0 2·乳糖粉末 84.5 — 無水乳糖一 106.8AG __H G __ 5. Description of the invention (3) It has better stability, is less annoying and smelly, and is very easy to handle in the manufacture of tablets. 0 In order to form an ER shot, it needs to be mixed to form a complex with, for example, a hydrophilic matrix. The use of hydroxypropyl methyl cellulose as a gel-forming substance is particularly preferred. It is better to use HPMC mixtures containing low and high molecular weight HPMC. According to the known technology (Journal of Controlled release. S (1987) 159-172), the use of different mixtures of HPMC results in different release rates of the active ingredient Emergent Terrier. Examples Example 1 90 parts of A-PSS, 85 parts of lactose, 91 parts of microcrystalline cellulose, and 27 parts of polyvinylpyrrolidone were mixed and then granulated with pure water to prepare an immediate release tablet of Emperor Terrier. The granules are dried and crushed, then mixed with sodium stearyl fumarate and compressed into tablets. Dissolve the free emu in a 2 M hydrochloric acid solution and use this solution to granulate excipients to make a reference formulation. A-PSS Tablets Example 1 Reference Example 1 1-A-PSS 50.0 corresponding to Emergent Terrier-Emergent Terrier — 50.0 2 · Lactose powder 84.5 — Lactose anhydrous 106.8

Avicel1^ PH 101 91.3 114.0 (請先閲讀背而之注意事項'冉碼寫木页) 裝· 訂- 線· Λ (ί η 6 (請先間讀背而之注总事項·扑艰寫本頁) 經濟部屮央標準灼貝工消许合作社印5i 五、發明説明（4 )Avicel1 ^ PH 101 91.3 114.0 (please read the notes on the back 'ran code to write the wooden page) Pack · Order-Line · Λ (ί η 6 (please read the notes on the back and note the general matters · write hard on this page ) The Ministry of Economic Affairs, the standard of the central government, printed 5i V. Cooperative Society V. Description of the invention (4)

Povidone K-25 交聯聚乙烯基吡咯啶酮 ⑧Povidone K-25 cross-linked polyvinyl pyrrolidone ⑧

Aerosil 3. 純水 2 Μ氫氯酸 (對應HC1 ) 4. 硬脂醯福馬酸鈉硬脂酸鎂滑石粉交聯聚乙烯基吡咯啶酮首先混合成份1及2而製化。乾燥及粉碎後摻合4，實行壓縮藥片。製造成份1及3之粒化溶 )。混合2之粉末，然後與後，摻合4之潤滑劑、助流壓縮。衝床：藥片重量：硬度：崩散： 26.8 — 7.1 — 3.6 105 — — 71.2 — (5.2) 5.8 — — 2.9 — 11.5 — 5.7 備A-PSS藥片。混合物與3粒而在 Korsch Pharmapress 100 液而製備參考藥片（參考例1 製備之溶液粒化。乾燥及粉碎劑及崩散劑且藥片在相同機器 A-PSS藥片考例1 實施例1 9mm 10 mm 298 mg ， 307mg 7.5 kp 6.7 kp 1 -2分鐘 1-.2分鐘本紙張尺度边用中aa家岱（210x297公及）一 6 一 Λ 6 η 6 五、發明説明（5) 實施例1 A-PSS藥片 .參考例1 在玻璃瓶儲存之安定性數據。降解測量爲HPLC系統中副產物之面積總和。 0個月 0.81 2.11 1個月於25 t 0.88 2.83 1個月於50 °C 1.82 3.51 3.5個月於25 °C 0.88 2.87 實施例2 混合90份A-PSS、85份乳糖、91份微晶纖維素及27份聚乙烯基吡咯啶酮然後與純水粒化混合物而製備愛默克梗之立即釋放藥片。顆粒乾燥後粉碎，然後與硬脂醯福馬酸鈉混合並完成壓縮成片。溶解自由鹼於酒石酸水溶液並使用此溶液粒化賦形劑而製造參考製劑（參考例]])。裝* ,ΐτ_ 線· 經沭部屮央桴準·局β工消"合作社印^ A-PSS藥片藥片實施例2 參考例Π 1.對應愛默克梗之A-PSS 50.0 — 愛默克梗 — 50.0 2.乳糖粉末 84.5 — 無水乳糖 — 110.7 Avicel®PH 101 9 1.3 114.3 本紙尺度边用中a a家诈準（CNS) Τ Ί規怙（210 X 297公及) 7 21505^ Λ (ί Π 6 五、發明説明（6) Polyvidone K-25 26.8 — 3.純水 105 57.1 酒石酸 — 21.5 4.硬脂醯福馬酸鈉 5.8 6.0 滑石粉 — 12.0 交聯聚乙烯基吡咯啶酮 — 12.0 首先混合成份1及2而製備A-PSS藥片。混合物與化。乾燥及粉碎後接合4，而在Korsch Pharmapress 100 實行壓縮藥片。製造成份1及3之粒化溶液而製備參考藥片（參考例π ) 。粉末2與溶液混合及粒化。乾燥及粉碎後，摻合4之助流劑及崩散劑且藥片在相同機器壓縮。製造後立刻及在玻璃瓶儲存1個月後強度。臭味強度較二配方之臭昧 (請先閲讀背而之注意事項#艰寫木頁) 裝· 線‘ A-PSS藥片實施例2 一參考例Π 新鮮製備 + 經濟部屮央標準灼β工消货合作杜印¾ 1個月實施例3 有些咮道，但非洋葱） + 有些咏道，但非洋葱） (顯著洋葱昧） (強烈洋葱味）本紙乐尺度边用中SS家樣準([奶）〒4規岱没）一 8 一 Λ fi Π 6 五、發明説明（7 ) 愛默克梗之立即釋放藥片可以適當濃度製備。 (請先間讀背而之注意事項孙艰艿木頁) 實施例1及2敍述50 mg之製劑。以下顯·示70 mg及 1 · 8 mg製劑之實施例。實施例3a 70mg 實施例3b 1.8mg_ 1. A-PSS 127 3.3 Λ ^ Av i cel PH 101 148 29 Polyvidone^ K- 90 35 — 2. Polyvidone^K-90 10 — Polyvidone®K - 25 — 4.7 3.粗級 Avi ce 1® PH 102 — 107 交聯聚乙烯基吡咯啶酮 — 4.3 硬脂醯福馬酸鈉 1.6 1.4 首先混合成份1而製備A-PSS藥片。混合物與成份2製造之溶液粒化。乾燥及粉碎後摻合成份3而在Korsch Pharmapress 100實行壓縮藥片。製造成份1及3之粒化溶液而製備參考藥片（參考例1 )。混合2之粉末，然後與製備之溶液粒化。乾燥及粉碎後，摻合4之潤滑劑、助流劑及崩散劑且藥片在相同機器經濟部中央櫺準^只工消仲合作社印51 壓縮。衝床： 1 0 mm 5.5 X 10.5 m: 藥片重量： 322 mg 150 mg 硬度： 9-10 kp 9-10 kp 崩散（無碟）： 0.6- 1.0 分鐘 0.2-0.4 分鐘實施例4 ^紙张尺度边用中® s家详準（CN5)lfM規格（210x297公及)—Q — Λ Γ> Π 6 21505^ 五、發明説明（8 ) (請先間讀背而之注意事項孙艰寫木π) 混合95份A-PSS、40份羥丙基甲基纖維素（HPMC ) 50cps 、：l 60份HPMC 10000 cps、及50份羥丙基甲基纖維素 (HPC )然後與99.5%乙醇粒化混合物而製備愛默克梗之延伸釋放藥片。顆粒乾燥後粉碎，然後與硬脂醯福馬酸鈉混合並完成壓縮成片。溶解自由鹼於乙醇（99.5 % )並使用此溶液粒化乾燥賦形劑而製造參考製劑（參考例ΙΠ)。實施例4 mg /片參考例I mg/k 1.對應愛默克梗之A-PSS 50.0 — 愛默克粳 — 50.0 (K) 2. HPMCsOcpsCMetolose^eOSHSO) 40.0 40.0 3. HPMClOOOOcps(Methoce^E 10MCR) 160.0 160.0 4. HPC LF ( KluceflE) 50.0 50.0 5. 99.5 % 乙醇 261 235 6.硬脂醯福馬酸鈉（Pruv®) 3.3 3.3 成份1及4混合。混合物與乙醇粒化。乾燥及粉碎後顆粒與6混合。經济部+央標準，^Α工消仲合作社印5i 壓縮藥片在具有11 mm圓形衝床之Korsch Pharmapress 100實行。此製片機器裝有壓縮力量讀數。藥片重量： 348 mg 303 mgAerosil 3. Pure water 2 M hydrochloric acid (corresponding to HC1) 4. Sodium Stearate Fumarate Magnesium Stearate Talc Crosslinked Polyvinylpyrrolidone First mix ingredients 1 and 2 to make it. After drying and crushing, blend 4 to compress the tablets. Manufacture of granulated solution of ingredients 1 and 3). The powder of 2 is mixed, and then mixed with the lubricant of 4 and flow-assisted and compressed. Punch: Tablet weight: Hardness: Disintegration: 26.8 — 7.1 — 3.6 105 — — 71.2 — (5.2) 5.8 — — 2.9 — 11.5 — 5.7 Prepare A-PSS tablets. Mix the mixture with 3 tablets to prepare reference tablets in Korsch Pharmapress 100 solution (Reference Example 1 granulate the solution prepared. Drying and pulverizing agent and disintegrating agent and tablets in the same machine A-PSS Tablets Test Example 1 Example 1 9mm 10 mm 298 mg, 307mg 7.5 kp 6.7 kp 1-2 minutes 1-2 minutes This paper is used for the edge of the paper aa Jiadai (210x297 g) and a 6 a Λ 6 η 6 5. Description of the invention (5) Example 1 A-PSS Tablets. Reference Example 1 Stability data stored in glass bottles. Degradation is measured as the total area of by-products in the HPLC system. 0 months 0.81 2.11 1 month at 25 t 0.88 2.83 1 month at 50 ° C 1.82 3.51 3.5 Monthly at 25 ° C 0.88 2.87 Example 2 Mixing 90 parts of A-PSS, 85 parts of lactose, 91 parts of microcrystalline cellulose and 27 parts of polyvinylpyrrolidone and then granulating the mixture with pure water to prepare an Emergent Terrier Immediately release the tablets. The granules are dried and pulverized, and then mixed with sodium stearyl fumarate and compressed into tablets. Dissolve the free base in the aqueous solution of tartaric acid and use this solution to granulate the excipient to manufacture a reference formulation (Reference Example]]). Outfit *, lτ_ line · warp沭部屮極桴准 · 局 β 工消 " Cooperative cooperative print ^ A-PSS tablet Example 2 Reference example Π 1. A-PSS 50.0 corresponding to the Emergent Terrier — Emergent Terrier — 50.0 2. Lactose powder 84.5 — Anhydrous lactose — 110.7 Avicel® PH 101 9 1.3 114.3 The standard size of the paper is CNA Τ Ί regulations (210 X 297 public) 7 21505 ^ Λ (ί Π 6 V. Description of invention (6 ) Polyvidone K-25 26.8 — 3. Pure water 105 57.1 Tartaric acid — 21.5 4. Sodium stearyl fumarate 5.8 6.0 Talc powder — 12.0 Crosslinked polyvinylpyrrolidone — 12.0 First mix ingredients 1 and 2 to prepare A- PSS tablets. Mixture, chemical, drying and crushing. Join 4, and compress tablets in Korsch Pharmapress 100. Manufacture of granulated solutions of ingredients 1 and 3 to prepare reference tablets (reference example π). Powder 2 mixed with solution and granulated After drying and crushing, the glidant and disintegrant 4 are blended and the tablets are compressed in the same machine. The strength is immediately after manufacturing and after storage in a glass bottle for 1 month. The odor strength is more odorous than the second formula (please read first背而之注问题 # Hard to write wooden pages) 'A-PSS tablet example 2 a reference example Π fresh preparation + the Ministry of Economic Affairs standard burning β industry and consumer goods cooperation Du Yin ¾ 1 month Example 3 Some 咮道, but not onions) + Some chants, but not Onion) (Significant onion ambiguity) (Strong onion flavor) This paper music standard is used in the SS family like standard ([milk) 〒4 regulations Daimo) one 8 one Λ fi Π 6 V. Description of the invention (7) Emock terrier The immediate-release tablets can be prepared in appropriate concentrations. (Please read the notes on the back of the book for a while before. Sun Dangji's page) Examples 1 and 2 describe the 50 mg formulation. Examples of 70 mg and 1.8 mg preparations are shown below. Example 3a 70mg Example 3b 1.8mg_ 1. A-PSS 127 3.3 Λ ^ Av i cel PH 101 148 29 Polyvidone ^ K- 90 35 — 2. Polyvidone ^ K-90 10 — Polyvidone® K-25 — 4.7 3. Coarse Avi ce 1® PH 102 — 107 Crosslinked Polyvinylpyrrolidone — 4.3 Sodium Stearyl Fumarate 1.6 1.4 First mix component 1 to prepare A-PSS tablets. Granulate the solution made with the mixture and ingredient 2. After drying and crushing, the compound 3 is blended and compressed into tablets in Korsch Pharmapress 100. The granulated solutions of ingredients 1 and 3 were prepared to prepare reference tablets (Reference Example 1). Mix powder 2 and granulate with the prepared solution. After drying and crushing, the 4 lubricants, glidants and disintegrants are blended and the tablets are compressed in the same machine of the Ministry of Economic Affairs of the Ministry of Economic Affairs. Punch: 1 0 mm 5.5 X 10.5 m: Tablet weight: 322 mg 150 mg Hardness: 9-10 kp 9-10 kp Disintegration (no disc): 0.6-1.0 minutes 0.2-0.4 minutes Example 4 ^ Paper size edge In use ® s home detailed standard (CN5) lfM specifications (210x297 g) -Q — Λ Γ > Π 6 21505 ^ V. Description of invention (8) (please read the backing notes first and write the wood π) Mix 95 parts A-PSS, 40 parts hydroxypropyl methylcellulose (HPMC) 50cps ,: 60 parts HPMC 10000 cps, and 50 parts hydroxypropyl methylcellulose (HPC) and then granulate the mixture with 99.5% ethanol And the extended release tablets of Emergent Terrier are prepared. The granules are dried and crushed, then mixed with sodium stearyl fumarate and compressed into tablets. Dissolve the free base in ethanol (99.5%) and use this solution to granulate the dry excipient to manufacture a reference formulation (Reference Example Π). Example 4 mg / tablet Reference Example I mg / k 1. A-PSS 50.0 corresponding to Emergent Terrier-Emergent japonica-50.0 (K) 2. HPMCsOcpsCMetolose ^ eOSHSO) 40.0 40.0 3. HPMClOOOOcps (Methoce ^ E 10MCR ) 160.0 160.0 4. HPC LF (KluceflE) 50.0 50.0 5. 99.5% ethanol 261 235 6. Sodium stearyl fumarate (Pruv®) 3.3 3.3 Ingredients 1 and 4 are mixed. Granulate the mixture with ethanol. After drying and crushing, the particles are mixed with 6. Ministry of Economic Affairs + Central Standard, ^ Α 工消仲联合社 Printed 5i compressed tablets are implemented in Korsch Pharmapress 100 with 11 mm round punch. This production machine is equipped with compression force readings. Tablet weight: 348 mg 303 mg

藥片壓縮力量： 8.6kN ， 12.3 kNTablet compression force: 8.6kN, 12.3kN

藥片硬度： 5.5 kP 3.7 kP 使用自由鹼之藥片具有較差結合性質。本紙5良尺度边用中SH家樣孕（(^5)Τ〇βίΜ21〇χ2!Τ/公及）一 10 — 21505? Λ η ___Π_6_ 五、發明説明（9 ) 臭昧強度 A-PSS藥片（參考藥片（實施例4 ) 參考例ΠΙ ) 新鮮製備 + (有些味道，（強烈洋葱昧）但非洋葱）由6個個別藥片使用USP溶解裝置2以輪葉在l〇〇r/min 轉動且藥片置於輪葉上之固定式工作台而測量釋放速率，使用500 ml保持於37 °C之緩衝溶液pH 6.8 作爲溶解介質。 A-PSS藥片（參考藥片（實施例4 ) 參考例ΠΙ ) 小時釋放累積％釋放累積％平均（min- max) 平均（min - max 2 15(14-15) 28(28-29) 4 24(23-25) 43(42-43) 6 34(33-35) 55(54-56) 10 51(48-52) 74(72-75) 24 91(87-93) 102(100-105) 經濟部屮央標準而只工消抨合作杜印奴 (請先間請背u<,之注意事項孙项寫木頁) 實施例5 愛默克粳之延伸釋放藥片可於適當濃度及以不同釋放速率而製備。實施例4敍述50 mg強度之製劑。以下爲10 mg及1〇〇 mg之實施例。本紙张尺度边用中SS家樣iMCNS)>F4WiM2]0x297公及）一 11 一 505 *7 Λ Γ» ΙΪ6 五、#明説明（ΙΟ) 10 mg實施例5a 100 mg實施例5b 成份 mg/片 mg/片 1.對應愛默克梗之A-PSS 10.0 100.0 2.乳糖粉末 100.0 40.0 HPMC 50 cps 27.6 39.2 (Metolose ⑰60SH50 ) HPMC 10000 cps 110.4 146.4 /ty\ · (Methocel E10MCR) dR) HPC LF (KluceP LF) 25.0 一 3.聚乙二醇20M 30.0 — (R) C Carbowax^ 2〇M) 聚乙二醇6000 — 42.0 (Η) (Carbowax 6000 ) 4.純水 70.0 98.1 (S) 5.硬脂醯福馬酸鈉（PrUV~ ) 1.6 2.3 1及2混合。混合物與3及4製造之溶液粒化。乾燥及粉碎後顆粒與5混合。壓縮藥片在Korsch Pharmapress 100實行。此製片機器裝有壓縮力量讀數。衝床直徑： l〇mm 1 1 mm 藥片重量： 3 1 4 mg 459mg 藥片壓縮力量（kN): 11.0 11.4 藥片硬度（kP): 8.2 5.4 經浒部屮央榀準而一^工消^合作社印51 由6個個別藥片使用USP溶解裝置2以輪葉在1()〇r/min 本紙5良尺度边用中SS家榀毕（CNS)T<U:.{1格（210x297公从）一 12 — Λ Γ» Π 6 215057 五、發明説明（11) (請先間讀背而之注意事項祚项寫本頁) 轉動且藥片置於輪葉上之固定式工作台而測量釋放速率。使用500 ml保持於37 °C之緩衝溶液pH 6 . S作爲溶解介質。 10mg ER藥片 100 mg ER 藥片小時釋放累積％釋放累積％平均（min-max) 平均（min-max) 2 27(27-28) 17(17- 18) 4 44(43-45) 28(26-29) 6 — 37(35-39) 8 72(70-75) — 10 — 55(52-60) 12 105(96-109) — 20 . — 91(84-95) 24 — 100(99-101) 實施例6 — 7 粒化54,3份活性物質、30,0份甘露醇、154份HPMC 50 cps、221 份 HPMC 10000 cps、37.5 份 HPC、0.3 份掊經濟部屮央標準而β工消奸合作杜印製酸丙酯與45份PEG 20，000 (實施例6 )或PVP K-25 (實施例7 )溶於105份水之溶液而製備對照釋放藥片。乾燥顆粒以2.7份硬脂醯福馬酸鈉潤滑。實施例6，實施例7 成份 mg/片 mg/片 1.對應愛默克梗之A-PSS 30.0 30.0 2.甘露醇粉末 30.0 3〇.〇本紙5民尺度边用中SS家樣準（CNS)lMWtM2】〇x297公及）_ 13 —- 21505^ Λ Γ) Ιί 6 五'、發明説明（12) 3. HPMC50cps(Metolose®60SH50) 154.0 154.0 4. HPMCl0000cps(Methocel^El0MCR)l 10.4 146.4 5. HPC LF (Kluce® LF) 37.5 37.5 6.掊酸丙酯 0.3 0.3 7. PEG(Carbowax® 2〇M) 45.0 — PVPC Povidone® K-25 ) — 45.0 8.水 105.0 105.0 9.硬脂醢福馬酸鈉（Pruv@ ) 2.7 2.7 成份1至6混合。混合物與7 及8製造之溶液粒化。乾燥及粉碎後與9混合。壓縮藥片在具有11 mm圓形衝床之Korsch Pharmapress 100實行。此製片機器裝有壓縮力量讀數。實施例6 實施例7 藥片重量： 545mg 545 mg 藥片壓縮力量（kN): 20 19 藥片硬度（kP ): 7.7 12.2 (請先閲讀背而之注意事項#艰寫木页) 裝- 線- 經试部屮央桴準而β工消"合作社印3i 釋放速率在輪葉以l〇〇r/min轉動且藥片置於輪葉上之固定式工作台測置。使用500 ml保持37 °C之緩衝溶液PH 6.8作爲溶解介質。釋放累積％平均（min- max ) 實施例6 實施例7 2h 17(17-18) 18(17-18) 4h 28(28-29) 28(28-29) 本紙张尺度边用中困困家樣準（CNS)1^规格（210χ297公及）一 14 一 21505 * Λ 6 η 6 五、發明説明（13) 6h 38(38-39) 38(37-39) 10h 55(54-56) 54(53-56) 16h 74(73-76) 73(71-74) 實施例顯示PEG 20000及PVP Κ-25在過程中均作用。 17 m 由實施例相當明顯地愛默克梗自由鹸於藥學配方之使用，除了處理黏性、黏著物質之不便，生成具有較差安定性及味道且技術性質較差之劑型。愛默克梗聚苯乙烯磺酸塩複合物於藥學配方之使用簡化處理且生成更安定且昧道更佳劑型。目前已知進行本發明之最佳模式爲依照實施例6 — 7製備配方。經濟部屮央榀準枸A工消价合作杜印5i 本紙5良尺度边用中SB家*^Μ〇<5)Ή>ϋ^(2]ΟΧ297公犮）—15 — 92 06/17 17:51 046 31Tablet hardness: 5.5 kP 3.7 kP Tablets using free base have poor binding properties. This paper is 5 good-scale side-use medium SH home-like pregnancy ((^ 5) Τ〇βίΜ21〇χ2! Τ / 公和) 一 10 — 21505? Λ η ___ Π_6_ V. Description of the invention (9) A-PSS tablets of odor strength ( Reference tablet (Example 4) Reference example III) Freshly prepared + (some flavor, (strong onion ambiguity) but not onion) 6 individual tablets using a USP dissolving device 2 rotating with a paddle at 100r / min and tablets The release rate was measured on a fixed bench placed on the impeller, using 500 ml of buffer solution pH 6.8 maintained at 37 ° C as the dissolution medium. A-PSS tablet (reference tablet (Example 4) Reference example III) Hourly release cumulative% Release cumulative% Average (min-max) Average (min-max 2 15 (14-15) 28 (28-29) 4 24 ( 23-25) 43 (42-43) 6 34 (33-35) 55 (54-56) 10 51 (48-52) 74 (72-75) 24 91 (87-93) 102 (100-105) Economy According to the standard of the Ministry of Labor and Development, only the cooperation of Du Yinnu (please note the u <, Sun Xiang writes a wooden page first) Example 5 The extended release tablets of Emergent can be released in appropriate concentrations and in different concentrations Preparation at a rate. Example 4 describes a 50 mg strength formulation. The following is an example of 10 mg and 100 mg. This paper is used in the size of the home SS iMCNS)> F4WiM2] 0x297 Gong)) 11-11 505 * 7 Λ Γ »ΙΪ6 V. #Description (10) 10 mg Example 5a 100 mg Example 5b Ingredient mg / tablet mg / tablet 1. A-PSS 10.0 100.0 corresponding to Emergent Terrier 10.0 lactose powder 100.0 40.0 HPMC 50 cps 27.6 39.2 (Metolose ⑰60SH50) HPMC 10000 cps 110.4 146.4 / ty \ (Methocel E10MCR) dR) HPC LF (KluceP LF) 25.0-3. Polyethylene glycol 20M 30.0 — (R) C Carbowax ^ 2〇M ) PEG 6000 42.0 (Η) (Carbowax 6000) 4. water 70.0 98.1 (S) 5. Sodium stearyl acyl Fuma (PrUV ~) 1.6 2.3 1 and 2 were mixed. The mixture is granulated with the solutions made in 3 and 4. After drying and crushing, the particles are mixed with 5. Compressed tablets are implemented in Korsch Pharmapress 100. This production machine is equipped with a compression force reading. Punch diameter: l〇mm 1 1 mm Tablet weight: 3 1 4 mg 459mg Tablet compression force (kN): 11.0 11.4 Tablet hardness (kP): 8.2 5.4 By the Department of the Ministry of Finance and Economics of the Ministry of Justice ^ 工消 ^ Cooperative print 51 6 individual tablets using USP dissolution device 2 with a paddle at 1 () 〇r / min on paper 5 good-scale side use in the middle of the home SS (CNS) T &U; — Λ Γ »Π 6 215057 V. Description of the invention (11) (Please read the notes on the back and write the page on this page) Rotate and place the tablet on the fixed table of the wheel to measure the release rate. Use 500 ml buffer solution pH 6. S maintained at 37 ° C as the dissolution medium. 10 mg ER tablet 100 mg ER tablet hourly cumulative release% cumulative release% average (min-max) average (min-max) 2 27 (27-28) 17 (17- 18) 4 44 (43-45) 28 (26- 29) 6 — 37 (35-39) 8 72 (70-75) — 10 — 55 (52-60) 12 105 (96-109) — 20. — 91 (84-95) 24 — 100 (99-101 ) Example 6-7 granulated 54,3 parts of active substance, 30,0 parts of mannitol, 154 parts of HPMC 50 cps, 221 parts of HPMC 10000 cps, 37.5 parts of HPC, 0.3 parts of the Ministry of Economic Affairs and the standard of β labor consumption A control release tablet was prepared by dissolving a solution of propyl acid ester with 45 parts of PEG 20,000 (Example 6) or PVP K-25 (Example 7) in 105 parts of water. The dried granules were lubricated with 2.7 parts of sodium stearyl fumarate. Example 6, Example 7 Ingredients mg / tablet mg / tablet 1. A-PSS corresponding to Emock Terrier 30.0 30.0 2. Mannitol powder 30.0 30.0. Local paper 5 civilian scale standard SS home sample standard (CNS ) lMWtM2] 〇x297 public and) _ 13 --- 21505 ^ Λ Γ) Ιί 6 Five ', description of the invention (12) 3. HPMC50cps (Metolose®60SH50) 154.0 154.0 4. HPMCl0000cps (Methocel ^ El0MCR) l 10.4 146.4 5. HPC LF (Kluce® LF) 37.5 37.5 6. Propyl butyrate 0.3 0.3 7. PEG (Carbowax® 2〇M) 45.0 — PVPC Povidone® K-25) — 45.0 8. Water 105.0 105.0 9. Stearyl fumaric acid Sodium (Pruv @) 2.7 2.7 Ingredients 1 to 6 are mixed. The mixture is granulated with solutions made in 7 and 8. Mix with 9 after drying and crushing. Compressed tablets are implemented on Korsch Pharmapress 100 with an 11 mm round punch. This production machine is equipped with compression force readings. Example 6 Example 7 Tablet weight: 545mg 545 mg Tablet compression force (kN): 20 19 Tablet hardness (kP): 7.7 12.2 (please read back to the precautions # Difficult to write wooden pages) Pack-line-test The release rate of the 3G release of the "Cooperative Society" printed by the Cooperative Society is "3". The release rate is measured on a fixed table where the blade is rotated at 100r / min and the tablets are placed on the blade. Use 500 ml of pH 6.8 buffer solution maintained at 37 ° C as the dissolution medium. Cumulative release% average (min-max) Example 6 Example 7 2h 17 (17-18) 18 (17-18) 4h 28 (28-29) 28 (28-29) Sample Standard (CNS) 1 ^ Specifications (210 × 297mm)-14-21505 * Λ 6 η 6 V. Description of the invention (13) 6h 38 (38-39) 38 (37-39) 10h 55 (54-56) 54 (53-56) 16h 74 (73-76) 73 (71-74) The examples show that PEG 20000 and PVP K-25 both play a role in the process. 17 m It is quite obvious from the examples that the use of the Emergent Terrier Free Emu in pharmaceutical formulations, in addition to the inconvenience of handling sticky and sticky substances, produces a dosage form with poor stability and taste and poor technical properties. The use of Emergent polystyrenesulfonate complex in pharmaceutical formulations simplifies handling and produces more stable and better dosage forms. It is currently known that the best mode for carrying out the invention is to prepare a formulation according to Examples 6-7. The Ministry of Economic Affairs, the central government, the quasi-copper A industrial price-cutting cooperation, Duin 5i, the original paper, 5 good-scale side-use SB homes * ^ Μ〇 < 5) Ή > ϋ ^ (2) ΟΧ297 公羮) — 15 — 92 06/17 17:51 046 31

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Enclosure 1 表 6 愛默克梗立印释放錠劑76，8·8及70毫克 (係聚从C蟀碰酸鹽’相當於I 76，8.8及70毫克愛默克梗）配方毫克/鍵劑Enclosure 1 Table 6 Emergent Terrier Liyin Release Lozenges 76, 8.8 and 70 mg (contained from C-cricket acid salt equivalent to I 76, 8.8 and 70 mg Emperor Terrier) Formula mg / bond

ArTab 74 ArTab 71 ArTab 70 工-76毫克 8.8毫克 70毫克愛默克梗pss 3.3 16 127 Avicel® PH 101 29 140 148 Avicel® PH 102 coarse grade 107 一 - Polyvidone®K-25 4.7 23 誉 Polyvidone K-90 - - 45 纯水 19 90 161 交聯態聚C蟀毗咯酮 4.3 5-4 - 硬脂酿及丁坤二酸鈉 1.4 1.8 1 215057ArTab 74 ArTab 71 ArTab 70 g-76 mg 8.8 mg 70 mg Emergent Terrier pss 3.3 16 127 Avicel® PH 101 29 140 148 Avicel® PH 102 coarse grade 107 I-Polyvidone® K-25 4.7 23 Fame Polyvidone K-90 --45 Pure water 19 90 161 Cross-linked poly-C-crickerodone 4.3 5-4-Stearin and sodium succinate 1.4 1.8 1 215057

Enclosure 2 表 7 30毫克愛默克梗延伸釋放錠劑 C係聚東L>稀續酸鹽，相當於30毫克愛默克梗）配方毫克/錠劑愛默克梗PSS，相當於愛默克梗 30.0 甘露糖耠末 30.0 酬。 375.0 HPC (Klucel® LF) 37.5 梧氣酸丙酯〇-3 PEG (Carbowax® 2〇M> 45.0 水 105.0 硬脂Si反丁缔二酸納 (PruvO) 2.7Enclosure 2 Table 7 30 mg Emergent Terrier Extended Release Lozenges C Series Poly East L > dilute acid salt, equivalent to 30 mg Emergent Terrier) Formula mg / lozenge Emergent Terrier PSS, equivalent to Emergent Terrier Terrier 30.0 Mannan sugar 30.0 reward. 375.0 HPC (Klucel® LF) 37.5 propyl oleate 〇-3 PEG (Carbowax® 2〇M> 45.0 water 105.0 sodium stearate fumarate (PruvO) 2.7

[PA1] (ALM0REL) /JO[PA1] (ALM0REL) / JO

Claims

Six 'patent application Β Β · -Αι2β 鬈 D HC Sock Moai contains iE species combination group pharmaceutical form dosage form solid P 2. The affinity of water contains complex salt and acid sulfonate Heene sister B learns benzene medicine poly. Contradiction of sexual terms 1 The encirclement of Kantimer loves the terrier fan in Clymore special application, and the application is based on the increase of the roots of the water. The application of circumvention and learning medicine is based on the basic foundation of propargyl. The Chinese medicine tx, uii's dimensionality's medicine base is the same as the base and the base is the medicine hydroxy. The quantity of the sub-dimension of the third dimension of the fiber is high and the base is low and the base is low. The propylene-containing hydroxy group is required to apply for the quality of the fiber according to the base of the base. (Please read «I read the precautions on the back and then fill in this page ) • Installed • • sf • Armoured 4 (210X297 Koji) printed by the Central Standards Bureau of the Ministry of Economic Affairs