1232760 九、發明說明： 【發明所屬之技術領域】 本發明係有關一種含三木曱胺克妥洛（Ketorolac Tromethamine)之非麻醉性陣痛消炎之口服腸溶製劑。 【發明背景】 按’手術後疼痛是醫藥界所面臨最棘手的問題，而目 前臨床最常用的止痛劑，大致可分為麻醉性鎮痛劑（鴉片 類製劑）及非類固醇性消炎劑（Nonsteroid antiinflammatory drug; NS AIDS) ’前者可用於中樞神經系統而發揮中度至重 度疼痛之緩解效果，但也容易誘發如鎮靜、欣快感或身體 依賴性等不良反應，而後者為非類固醇性消炎劑 (Nonsteroid antiinflammatory drug; NSAIDS)，其對於人體 之胃黏膜傷害大。 再者’礙於目前相關法令對於麻醉性鎮痛劑（鵪片類 製劑）該等藥物的管制與約束，則更加突顯醫療界對控制 緊急與嚴重性疼痛的無力感與無助感。 爰是，本發明之主要目的，在於解決上述之問題，係 提供一種含二木甲胺克妥洛(Ketorolac Tromethamine)之非 麻醉性陣痛消炎之口服腸溶製劑，鎮痛效能優於傳統非類 固醇性消炎劑（Nonsteroid antiinflammatory drug; NSAIDS)，且活性至少與麻醉性鎮痛劑相當，其臨床應用 不受繁鎖的法令限制，可取代目前麻醉性鎮痛劑之使用， 使醫事人員在處理緊急與嚴重性疼痛病例時，更加得心應 手0 1232760 為達到上述目的，本發明提供一種含三木甲胺克妥洛 (Ketorolac Tromethamine)之口服腸溶製劑，其包括有：一 中性核心25〜85wt% ; —藥物層，係包覆於該中性核心外， 含有三木甲胺克妥洛3〜7wt%、黏合劑〇·3〜7wt%及崩散劑 3〜15wt% ; —保護層5〜16wt%，係包覆於該藥物層外；以 及一腸衣層10〜35wt%，係包覆於該保護層外，俾藉以形成 一含二木曱胺克妥洛(Ketorolac Tromethamine)之非麻醉性 陣痛消炎之口服腸溶製劑，而能減少胃黏膜損害，以使得 該含腸衣層之中性核心到達小腸後即發揮療效。 【詳細說明】 三木曱胺克妥洛為R-(+)及S-㈠之消旋性混合物，化學 全名為（RS)-5-Benzoyl_1.2-dihydro-3H_pyrrolo[l，2] pyrrole-1 -carboxylic acid 2_amino-2-hydroxymethyl -l，3-propanediol，對水溶解度極佳，易溶於曱醇，微溶於 乙醇、無水乙醇及四氫呋喃，不溶於丙酮、二氯曱烷、曱 苯、醋酸乙酯、二氧六環、己烷、丁醇及乙腈，約於162 °(：熔融並立即分解，易受濕氣及光線破壞而變色。 三木曱胺克妥洛(Ketorolac Tromethamine)之化學結構 如下式所示：1232760 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a non-narcotic paroxysmal anti-inflammatory oral enteric preparation containing Ketorolac Tromethamine. [Background of the Invention] According to the post-operative pain is the most difficult problem facing the medical profession, and the most commonly used analgesics in clinical practice can be roughly divided into narcotic analgesics (opiates) and nonsteroidal anti-inflammatory agents (Nonsteroid antiinflammatory drug; NS AIDS) 'The former can be used in the central nervous system to exert moderate to severe pain relief effects, but it can also easily induce adverse reactions such as sedation, euphoria or physical dependence, while the latter is a nonsteroidal anti-inflammatory agent (Nonsteroid antiinflammatory drug; NSAIDS), which causes great damage to human gastric mucosa. Furthermore, the current laws and regulations on the control and restriction of narcotic analgesics (quail preparations) and other drugs have further highlighted the sense of weakness and helplessness in the medical community in controlling emergency and severe pain. That is, the main object of the present invention is to solve the above problems, and to provide a non-narcotic paroxysmal anti-inflammatory oral enteric preparation containing Ketorolac Tromethamine, which has better analgesic efficacy than traditional non-steroidal drugs. Nonsteroid antiinflammatory drug (NSAIDS), and its activity is at least equivalent to that of narcotic analgesics. Its clinical application is not restricted by confusing laws and regulations. It can replace the current use of narcotic analgesics, allowing medical personnel to deal with emergency and severity In case of pain, it is more handy. 0 1232760 In order to achieve the above purpose, the present invention provides an oral enteric preparation containing Ketorolac Tromethamine, which includes: a neutral core 25 ~ 85wt%;-drug layer It is coated on the neutral core and contains 3 ~ 7wt% of ketorolac tromethamine, 0.3 ~ 7wt% of binder and 3 ~ 15wt% of dispersant;-5 ~ 16wt% of protective layer, coated Outside the drug layer; and an enteric coating layer of 10 to 35 wt%, which is coated on the protective layer to form a non-narcotic drug containing Ketorolac Tromethamine Enteric formulations for oral anti-inflammatory pain, and reduce gastric mucosal damage, such that the enteric layer containing in the core reaches the small intestine after play of efficacy. [Detailed description] Mitridamine ketorolac is a racemic mixture of R-(+) and S-fluorene. The full chemical name is (RS) -5-Benzoyl_1.2-dihydro-3H_pyrrolo [l, 2] pyrrole- 1 -carboxylic acid 2_amino-2-hydroxymethyl -l, 3-propanediol, excellent solubility in water, easily soluble in methanol, slightly soluble in ethanol, anhydrous ethanol and tetrahydrofuran, insoluble in acetone, dichloromethane, toluene, Ethyl acetate, dioxane, hexane, butanol, and acetonitrile, about 162 ° (melting and immediate decomposition, easy to be damaged by moisture and light and change color. Chemicals of Ketorolac Tromethamine The structure is shown below:
為非類固醇消炎鎮痛劑（Nonsteroid antiinflammatory drug; NSAIDS)，其可選擇性阻斷致發炎因子、前列腺素 1232760 (prostaglandins)之生成而發揮優異的鎮痛、消炎及退熱效 能，資料顯示三木曱胺克妥洛（Ketorolac Tromethamine)之 藥效強度優於其他同類藥物的主因可能與其導致内生性 嗎啡（Endogenous opioids)之釋放、干擾NMDA receptor activity或與GAB A interneuron等有關，其不與Μ ·Κ及占 opioid receptor結合，更不具麻醉性鎮痛劑那樣不良反應 (Narcotic-like action)，可選擇性抑制環氧酶 (cyclooxygenase)之活性而阻斷致發炎疼痛因子之合成。 三木曱胺克妥洛(Ketorolac Tromethamine)經空腹口服 投與吸收後，三木甲胺克妥洛於生理pH值環境下可解離成 陰離子型態，而其血中濃度之衰退情形可由中央室排泄之 二室或三室性模式加以描述。投與劑量之三木曱胺克妥 洛，其中約有91%可於48小時後由尿液中排除，其中75% 在最初7小時内排除；而有6%由糞便中排除，肝臟為其主 要的代謝部位。 三木甲胺克妥洛與酸醣酸結合成不活性物為其主要 之代謝途徑，代謝方式除了以克妥洛(Ket〇r〇lac)出現於尿 液之外；另一代謝方式為經對位之羥化形成對_經基克妥洛 (p-Hydroxy Ketorolac)，但此代謝物並不具有顯著之藥理活 性，且由資料顯示，其鎮痛活性低於克妥洛的1/1〇〇，消炎 活性低於克妥洛的1/5，而由體外血小板凝集試驗結果顯 示，其抗血小板凝集活性為克妥洛的1/25。經由不同年齡 層與肝或腎功能受損者之投與三木曱胺克妥洛(Ketorolac Tromethamine)之試驗，由排泄情形可知，老年人及腎功能 1232760 受損者投與後之血中半衰期明顯延長，而血中總清除率也 有降低的趨勢，但對肝功能受損者之影響則較不明顯。 三木曱胺克妥洛（Ketorolac Tromethamine)經空腹口服 投與後（10mg)，吸收完全（吸收率大於95%)且不受併服制酸 劑之影響，平均最高血中濃度約於30〜60分鐘之間到達。 其蛋白質結合率為99%，平均穩定血中濃度狀態之分佈容 積為0.11 L/kg，於排泄相（Elimination phase)之分佈容積 〇·17〜〇.25L/kg，平均排泄半衰期約為5.3小時。 服腸溶製劍之結楫 請審查委員參閱第1圖，係本發明之含三木甲胺克妥 洛(Ketorolac Tromethamine)之口服腸溶製劑結構示意圖 ，如第1圖所示：係由一中性核心1、一藥物層2、一保護 層3與一腸衣層4所構成。 中性核心1主要係由蔗糖、澱粉、滑石粉、微晶纖維 素與磷酸氫二鈣等成分單獨使用或以任意比例混和任兩 者以上所組成，其可自行藉由流動層遠心式造粒機(Glatt) 或流動層噴霧造粒機(Huttlin)造粒製備；抑或可自原料商 購得其可為：（1)蔗糖100%之中性核心；（2)蔗糖及殺粉之 中性核心，或（3)微晶纖維素之中性核心。 藥物層2主要係由三木曱胺克妥洛(Ketorolac Tromethamine)、黏合劑與崩散劑所組成，其中，黏合劑係 可由聚乙烯吼咯烷酮、羥丙基纖維素、羥丙基甲基纖維素 等成分單獨使用或以任意比例混和任兩者以上所組成；崩 1232760 散劑係可由澱粉、乳糖、蔗糖與甘露糖等成分單獨使用或 以任意比例混和任兩者以上所組成。而用以製備黏合劑所 使用之溶劑係可由乙醇與蒸餾水單獨使用或以其比例 1:1〜1··4之組成溶劑所組成。 保護層3主要係由羥丙基曱基纖維素、羥丙基纖維素 、羥甲基纖維素等成分單獨使用或以任意比例混和任兩者 以上所組成。另外，保護層必要時可再包含有可塑劑與遮 光劑，其中，可塑劑係可由苯二曱酸二乙酯、甘油三醋酸 酯、擰檬酸三乙酯、聚乙二醇等成分單獨使用或以任意比 例混和任兩者以上所組成；遮光劑可為二氧化鈦。 腸衣層4主要係由曱基丙烯酸一甲基丙烯酸曱酯共聚 物L、曱基丙烯酸一曱基丙烯酸曱酯共聚物S、苯二甲酸羥 丙基曱基纖維素與苯二甲酸醋酸纖維素等成分單獨使用 或以任意比例混和任兩者以上所組成。 根據本發明所形成之含三木曱胺克妥洛(Ketorolac Tromethamine)之非麻醉性陣痛消炎之口服腸溶製劑，其組 成較佳比例為：中性核心25〜85wt%、藥物層由三木曱胺克 妥洛3〜7wt%、黏合劑0.3〜7wt%、崩散劑3〜15wt%組成、保 護層5〜16wt%、腸衣層10〜35wt%。 口服腸溶製劑之製備方法 請審查委員參閱第2圖，係本發明之製備含三木曱胺 克妥洛(Ketorolac Tromethamine)之口服腸溶製劑流程示意 圖，其製備方法依各組成成分適當比例操作如下： 1232760 (步驟1 )製備黏合劑液21 ··取聚乙烯吡咯烷酮、羥丙基 纖維素、羥丙基曱基纖維素等成分單獨使用或 以任意比例混和任兩者以上加入蒸德水中擾拌 至溶解，同時再加入乙醇混合均勻。 (步驟2)製備藥物層之混合粉末22 :取三木曱胺克妥洛 (Ketorolac Tromethamine)與崩散劑（係可由 澱粉、乳糖、蔗糖與甘露糖等成分單獨使用或 以任意比例混和任兩者以上所組成）混合均勻 ，通過150 mesh目篩一次，40 mesh目篩二次。 (步驟3)製備保護層液23 :取羥丙基曱基纖維素、羥丙 基纖維素與羥曱基纖維素等成分單獨使用或以 任意比例混和任兩者以上加入蒸餾水中攪拌至 溶解，同時再加入聚乙二醇攪拌至溶解，再加 入已通過150 mesh目篩一次之遮光劑（可為二 氧化鈦）混合均勻。 (步驟4)製備腸衣層液24 :取曱基丙烯酸一曱基丙烯酸 甲酯共聚物L、甲基丙烯酸一曱基丙烯酸曱酯共 聚物S、苯二甲酸羥丙基曱基纖維素與苯二曱酸 醋酸纖維素等成分單獨使用或以任意比例混和 任兩者以上與可塑劑其可為由苯二曱酸二乙 酯、甘油三醋酸酯、檸檬酸三乙酯、聚乙二醇等 成分單獨使用或以任意比例混和任兩者以上所 組成混合均勻。 (步驟5)取中性核心，置入造粒機内，再將（步驟1)製 1232760 備之黏合劑液自喷鎗中喷出霧化之黏合劑，同 時再加入（步驟2)之混合粉末，如此操作並乾 燥之，即可得含藥物層之球型顆粒25。 (步驟6)取含有效成份之球型顆粒，置入造粒機中，再 將（步驟3)製備之保護層液自喷鎗中喷出霧化 之保護層液，如此操作並乾燥之，即可得含保 護層與含有效成份之球型顆粒；同時再將（步 驟4)製備之腸衣層液自喷鎗中喷出霧化之腸衣 層液，如此操作並乾燥之，即可得含腸衣層、 保護層與藥物層之球型顆粒26。 【實施例一】 1.中性核心：1070.4g 中性核心之製備： 聚乙烯吡咯烷酮（PVP K_30) 40g 異丙醇（Isopropyl Alcohol) 300ml 蒸顧水（Purified water) 200ml 蔗糖（Sucrose) 400g 殿粉（Starch) 800g 滑石粉(Talc) 900g 製備之步驟： (1) 取聚乙烯吡咯烷酮加入異丙醇中，攪拌至溶解，再 加入蒸德水混合均勻。 (2) 取澱粉與滑石粉混合均勻。 11 1232760 (3)取蔗糖置入流動層遠心式造粒機（Glatt)中，再將第 (1)項自喷鎗中喷出霧化之黏合劑，同時再加入第（2 )項，如此操作並乾燥之，即形成為中性核心。 2·藥物層： 三木甲胺克妥洛（Ketorolac Tromethamine) 129.6g 乳糖(Lactose) 115.2g 聚乙烯溁咯烷酮（PVP K_30) 9.6g 乙醇 96ml 蒸餾水 96ml 製備之步驟： (1) 取聚乙烯吡咯烷酮加入蒸餾水中攪拌至溶解，同時 再加入乙醇混合均勻。 (2) 取三木曱胺克妥洛與乳糖混合通過150 mesh目篩一 次，40 mesh目篩二次。 (3) 取中性核心置入微粒造粒機内，再將第（1)項自喷餘 中喷出霧化之黏合劑，同時再加入第（2)項粉末，如 此操作並乾燥之，即可得含有效成份之球型顆粒。 3·保護層： 羥丙基曱基纖維素(H.P.M.C.) 96g 聚乙二醇（P.E.G. 6000) 19.2g 二氧化鈦（Titanium Dioxide) 19.2g 蒸鶴水(Purified water) 1368ml 製備之步驟： (1)取羥丙基曱基纖維素加入蒸餾水中攪拌至溶解，同 12 1232760 時再加入聚乙二醇，攪拌至溶解。 (2) 取二氧化鈦通過150 mesh目篩一次。 (3) 取第（1)項與第項混合均勻。 (4) 取含有效成份之球型顆粒置入流動層遠心式造粒機 (Glatt)中，再將第（3)項自喷鎗中噴出霧化之保護 層溶液，如此操作並乾燥之，即可得含保護層之球 形顆粒。 其中該霧化條件係為入風口溫度為45°C，出風口溫度 為3〇°C，霧化壓力為2.8kg/cm2，轉盤轉速為34rpm。 4·腸衣層： 甲基丙烯酸—甲基丙烯酸曱酯共聚物（Eudragit L30D) 1280g 76.8g 才宁樣酸二乙醋（Triethyl citrate) 製備之步驟： (1)取甲基丙烯酸一曱基丙烯酸曱酯與擰檬酸三乙酯混 合均勻。 ()取s保遵層之球型顆粒置入流動層遠心式造粒機 (G1:U)中’再將第⑴項自喷餘中噴出霧化之腸衣 層溶液，如此操作並乾燥之’即可得含腸衣層、保 護層、藥物層之球形顆粒。 溫 其中該霧化條件係為入風口溫度為45。(：，出風口 為3〇°C ’霧化壓力為2.琴m2 ’轉盤轉速為μ啊。 【實施例二】 13 1232760 1.中性核心：1043.52g 2·藥物層： 三木曱胺克妥洛(Ketorolac Tromethamine) 129 6g 殿粉（Starch) 132.48g 聚乙烯吡咯烷酮（PVP Κ·30) 9.6g 乙醇（Ethanol) 96ml 蒸餾水（Purified water) 96ml 中性核心與藥物層之製備及操作依實施例一操作之。 3. 保護層： 羥丙基甲基纖維素(H.P.M.C·) li5.2g 聚乙二醇（P.E.G· 6000) 23.04g 二氧化鈦(Titanium Dioxide) 23.04g 蒸德水（Purified water) 1368ml 保護層之製備及操作依實施例一操作之。 4. 腸衣層： 曱基丙烯酸一曱基丙稀酸甲醋共聚物(Eudragit L30D) 1280g 檸檬酸三乙酯（Triethyl citrate) 76.8g 腸衣層之製備及操作依實施例一操作之。 【實施例三】 1. 中性核心：939.6g 2. 藥物層： 三木甲胺克妥洛（Ketorolac Tromethamine) 126g 14 1232760 澱粉（Starch) 132.48g 聚乙烯吡咯烷酮（PVP K-30) 9.6g 乙醇（Ethanol) 96ml 蒸顧水（Purified water) 96ml 中性核心與藥物層之製備及操作依實施例 一操作之。 3 ·保護層： 羥丙基曱基纖維素(H.P.M.C.) 192g 聚乙二醇（P.E.G· 6000) 38.4g 二氧化鈦（Titanium Dioxide) 38.4g 蒸餾水(Purified water) 1920ml 保護層之製備及操作依實施例一操作之。 4·腸衣層： 曱基丙烯酸一曱基丙烯酸曱酯共聚物（Eudragit L30D) 1280g 檸檬酸三乙醋（Triethyl citrate) 76.8g 腸衣層之製備及操作依實施例一操作之。 【貫施例四】 1·中性核心：1090.5g 2·藥物層： 三木甲胺克妥洛(Ketorolac Tromethamine) 157.5g 澱粉(Starch) 165.6g 聚乙烯吡咯烷酮（PVP K-30) 12g 乙醇（Ethanol) 120ml 15 1232760 蒸鶴水（Purified water) 120ml 中性核心與藥物層之製備及操作依實施例一操作之。 3·保護層： 羥丙基甲基纖維素(H.P.M.C.) 240g 聚乙二醇（P.E.G· 6000) 48g 二氧化鈦（Titanium Dioxide) 48g 蒸鶴水（Purified water) 2400ml 保護層之製備及操作依實施例一操作之。 4·腸衣層： 甲基丙烯酸一甲基丙烯酸曱酯共聚物(Eudragit L30D) 2〇〇〇g 檸檬酸三乙醋（Triethyl citrate) 60g 腸衣層之製備及操作依實施例一操作之。 【實施例五】 1·中性核心：1217.7g 2. 藥物層： 三木曱胺克妥洛（Ketorolac Tromethamine) 157.5g 澱粉（Starch) 165.6g 聚乙烯吡咯烷酮（PVP K-30) 12g 乙醇（Ethanol) 120ml 蒸顧水（Purified water) 12〇ml 中性核心與藥物層之製備及操作依實施例一操作之。 3. 保護層： 16 1232760 羥丙基曱基纖維素（H.P.M.C.) 288g 聚乙二醇（P.E.G· 6000) 57.6g 二氧化鈦（Titanium Dioxide) 48g 蒸館水（Purified water) 3201ml 保護層之製備及操作依實施例一操作之。 4·腸衣層： 甲基丙烯酸一甲基丙烯酸甲酯共聚物（Eudragit L30D) 1440g 檸檬酸三乙醋（Triethyl citrate) 43.2g 腸衣層之製備及操作依實施例一操作之。 【實施例六】 1·中性核心：1212.9g 2·藥物層： 三木甲胺克妥洛(Ketorolac Tromethamine) 157.5g 澱粉（Starch) 165.6g 聚乙烯吡咯烷酮（PVP K-30) 12g 乙醇（Ethanol) 12〇ml 蒸顧水(Purified water) 12〇ml 中性核心與藥物層之製備及操作依實施例 一操作之。 3 ·保護層： 羥丙基曱基纖維素(H.P.M.C.) 336g 聚乙二醇（P.E.G. 6000) 67.2g 二氧化鈦（Titanium Dioxide) 48g 17 1232760 蒸I留水（Purified water) 3750ml 保護層之製備及操作依實施例一操作之。 4·腸衣層： 甲基丙烯酸一甲基丙烯酸曱酯共聚物（Eudragit L30D) I280g 檸檬酸三乙酯（Triethyl citrate) 38.4g 腸衣層之製備及操作依實施例一操作之。 【實施例七】 1·中性核心：1196.1g 2·藥物層： 三木曱胺克妥洛（Ketorolac Tromethamine) 157.5g 澱粉（Starch) 165.6g 聚乙烯吡咯烷酮（PVP K-30) I2g 乙醇（Ethanol) 12〇ml 蒸餾水（Purified water) 12〇ml 中性核心與藥物層之製備及操作依實施例一操作之。 3·保護層： 24〇g 48g 48g 24〇〇ml 羥丙基曱基纖維素(H.P.M.C.) 聚乙二醇（P.E.G· 6000) 二氧化鈦（Titanium Dioxide) 蒸德水（Purified water) 保護層之製備及操作依實施例一操作之。 4·腸衣層： 18 1232760 曱基丙烯酸一甲基丙烯酸曱酯共聚物（Eudragit L3〇d) 1680g 檸檬酸二乙 1旨（Triethyl citrate) 50.4g 腸衣層之製備及彳呆作依實施例^-操作之。 【試驗結果】 請參閱表一與表二，其係分別為實施例一〜七製劑依 1990年美國藥典（第22版)規定標準所檢測之溶離率、實施 例七製劑依1990年美國藥典（第22版）規定標準並改變溶 媒與轉速所檢測之溶離率，顯示依本發明製備方法製得之 製劑可以得到良好的溶離率。 請參閱表三與表四，其係分別為實施例七之參中滚度 變化（Treatment B)、市售品（Treatment A)之血中滚度 變化，數據經製圖後則如第3圖所示。 本發明利用粉末包覆原理，增加保護層以減少受光、線 、濕氣影響而變色，又增加腸衣層以減少胃黏膜損害’以 使得該含腸衣層、保護層及含有效成份之顆粒核心列遠+ 腸後即發揮療效。表三證明本發明口服腸溶製劑如中/麻& 上升較傳統非類固醇性消炎劑(Nonsteroid 〆 mtiinflammatory drug; NSAIDS)緩慢，因此，本發明大中〆 改善一般非類固醇消炎止痛劑(NSAIDS)所造成之胃黏媒 損害。另外，本發明方法所製得之三木曱胺克妥洛勝农^ 之中性核心符合美國藥典規定之溶離率，可保留固艘^ 而機 之優點，且本發明並無嗎啡樣之成癮性及禁斷症狀’ 19 1232760 器則可以使用一般之流動層遠心式造粒機（Glatt)或流動層 喷霧造粒機（Huttlin)，不受機型限制，對於製藥界為最好 的方法。 【圖式簡單說明】 有關本發明之詳細說明及技術内容，現就配合圖式說 明如下： 第1圖，係本發明之含三木曱胺克妥洛之口服腸溶製劑結 構示意圖。 第2圖，係本發明之製備含三木曱胺克妥洛之口服腸溶製 劑流程示意圖。 第3圖，係本發明實施例七與市售品之血中濃度變化圖。 表一：係本發明實施例----1製劑之溶離率。 表二：係本發明實施例七製劑之溶離率。 表三：係本發明實施例七製劑之血中濃度變化（Treatment B)。 表四：係市售品之血中濃度變化（Treatment A)。 【主要元件符號說明】 第1圖： 中性核心......1 藥物層.......2 保護層.......3 腸衣層.......4 1232760 第2圖： 製備黏合劑液.......21 製備藥物層之混和粉末··· 22 製備保護層液.......23 製備腸衣層液.......24 含藥物層之球型顆粒· · · · 25 含腸衣層、保護層與藥物層之球型顆粒·· ·26Nonsteroid anti-inflammatory drug (NSAIDS), which can selectively block the production of inflammatory factors, prostaglandins 1232760 (prostaglandins) and exert excellent analgesic, anti-inflammatory and antipyretic effects. The main reason why Ketorolac Tromethamine is superior to other similar drugs may be its endogenous morphine (Endogenous opioids) release, interference with NMDA receptor activity or GAB A interneuron, etc., which is not related to Μ · Κ and accounted for Opioid receptor binding, not to mention Narcotic-like action, can selectively inhibit the activity of cyclooxygenase and block the synthesis of inflammatory pain factors. Ketorolac Tromethamine can be dissociated into anionic form under physiological pH environment after oral administration and absorption by Ketorolac Tromethamine on an empty stomach, and its decline in blood concentration can be excreted by the central chamber. Two- or three-compartment models are described. About 91% of the administered dose of ketorolac mitoxamine can be eliminated from the urine after 48 hours, 75% of which is eliminated within the first 7 hours; and 6% is excreted from the feces, with the liver as the main Site of metabolism. The main metabolic pathway is the inactivation of ketorolac and saccharoic acid, which is the main metabolic pathway. In addition to the emergence of ketolac in the urine, another metabolic mode is through The hydroxylation of the position formed p-Hydroxy Ketorolac, but this metabolite does not have significant pharmacological activity, and the data show that its analgesic activity is less than 1/1/10 of Ketorola. The anti-inflammatory activity is lower than 1/5 of ketorola, and the results of in vitro platelet aggregation test show that its antiplatelet agglutination activity is 1/25 of ketorola. Through the test of Ketorolac Tromethamine administered to people of different ages and with impaired liver or kidney function, it can be known from the excretion situation that the elderly and those with impaired renal function have a significant half-life in blood after administration. It is prolonged, and the total blood clearance is also decreasing, but the effect on liver function is less obvious. Ketorolac Tromethamine is administered orally on an empty stomach (10mg), completely absorbed (absorption rate is greater than 95%) and not affected by the concurrent use of antacids, and the average maximum blood concentration is about 30 ~ 60 Arrive in minutes. Its protein binding rate is 99%, the average volume of distribution in stable blood concentration state is 0.11 L / kg, and the volume of distribution in the Elimination phase is 0.15 to 0.25 L / kg, and the average excretion half-life is about 5.3 hours. . The results of taking enteric-coated swords please refer to Figure 1. This is a schematic diagram of the structure of an oral enteric preparation containing Ketorolac Tromethamine according to the present invention, as shown in Figure 1: The sexual core 1, a drug layer 2, a protective layer 3 and an enteric coating layer 4. Neutral core 1 is mainly composed of sucrose, starch, talc, microcrystalline cellulose and dicalcium phosphate alone or by mixing any two or more at any ratio. (Glatt) or fluidized-layer spray granulator (Huttlin) for granulation; or it can be purchased from raw materials: (1) 100% neutral core of sucrose; (2) neutral of sucrose and powder-killing Core, or (3) neutral core of microcrystalline cellulose. The drug layer 2 is mainly composed of Ketorolac Tromethamine, a binder and a disintegrating agent. Among them, the binder is made of polyvinyl rolidone, hydroxypropyl cellulose, and hydroxypropyl methyl fiber. Ingredients such as pigments are used singly or mixed with any two or more at any ratio; Beng 1232760 powder can be composed of ingredients such as starch, lactose, sucrose, and mannose alone or mixed with any two or more at any ratio. The solvent used to prepare the adhesive can be composed of ethanol and distilled water alone or in a composition ratio of 1: 1 to 1 · 4. The protective layer 3 is mainly composed of components such as hydroxypropylfluorenyl cellulose, hydroxypropyl cellulose, and hydroxymethyl cellulose, alone or in combination of any two or more of them in an arbitrary ratio. In addition, the protective layer may further include a plasticizer and a light-shielding agent when necessary. Among them, the plasticizer may be independently used by components such as diethyl phthalate, triacetin, triethyl citrate, and polyethylene glycol. Or any two or more of them are mixed in any ratio; the light-shielding agent may be titanium dioxide. The casing layer 4 is mainly composed of fluorenyl acrylic acid methacrylic acid methacrylate copolymer L, fluorenyl acrylic acid methacrylic acid methacrylate copolymer S, hydroxypropyl fluorenyl cellulose phthalate and cellulose acetate phthalate, etc. The ingredients are used singly or in combination of any two or more at any ratio. The non-narcotic paroxysmal anti-inflammatory oral enteric preparation containing Ketorolac Tromethamine formed according to the present invention has a preferable composition ratio of 25 to 85% by weight of a neutral core, and the drug layer is composed of mitamine The composition of Ketoluo is 3 to 7 wt%, the binder is 0.3 to 7 wt%, the dispersant is 3 to 15 wt%, the protective layer is 5 to 16 wt%, and the casing layer is 10 to 35 wt%. The method for preparing oral enteric preparations please refer to Figure 2. It is a schematic diagram of the process of preparing an oral enteric preparation containing Ketorolac Tromethamine according to the present invention. The preparation method is as follows according to the appropriate proportion of each component: : 1232760 (Step 1) Preparation of binder solution 21 ·· Take polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl fluorenyl cellulose and other components alone or mix any two or more at any ratio and add to distilled water to stir Until dissolved, add ethanol and mix well. (Step 2) Preparation of the mixed powder of the drug layer 22: Take Ketorolac Tromethamine and disintegrant (which can be used separately from starch, lactose, sucrose, and mannose, etc., or mix any two or more of them in any ratio Composition) Mix well, pass once through a 150 mesh sieve and twice through a 40 mesh sieve. (Step 3) Preparation of the protective layer solution 23: Take the components such as hydroxypropyl cellulose, hydroxypropyl cellulose and hydroxymethyl cellulose alone or mix any two or more at any ratio and add them to distilled water and stir until dissolved. At the same time, add polyethylene glycol and stir until dissolved, and then add a sunscreen (which can be titanium dioxide) that has passed through a 150 mesh screen once and mix well. (Step 4) Preparation of casing liquid 24: Take methacrylic acid monomethyl methacrylate copolymer L, methacrylic acid monomethyl methacrylate copolymer S, hydroxypropyl fluorenyl cellulose phthalate and benzene Ingredients such as cellulose acetate and the like are used alone or mixed at any ratio of any two or more with plasticizers. They may be composed of diethyl phthalate, triacetin, triethyl citrate, polyethylene glycol and the like. It can be used singly or in a mixture of any two or more at any ratio to form a uniform mixture. (Step 5) Take the neutral core, put it into the granulator, and spray the adhesive solution prepared by (Step 1) 1232760 from the spray gun, and then add the mixed powder (Step 2) By doing so and drying, spherical particles 25 containing a drug layer can be obtained. (Step 6) Take the spherical particles containing effective ingredients, put them into a granulator, and spray the protective layer liquid prepared in (Step 3) from the spray gun into the atomized protective layer liquid. A spherical particle containing a protective layer and an active ingredient can be obtained; at the same time, the casing liquid layer prepared in (step 4) is sprayed with an atomized casing liquid layer from a spray gun. After this operation and drying, the obtained Spherical particles 26 of the casing, protective and drug layers. [Example 1] 1. Neutral core: 1070.4g Preparation of neutral core: Polyvinylpyrrolidone (PVP K_30) 40g Isopropyl Alcohol 300ml Purified water 200ml Sucrose 400g (Starch) 800g Talc 900g Preparation steps: (1) Take polyvinylpyrrolidone into isopropanol, stir until dissolved, then add distilled German water and mix well. (2) Take starch and mix it with talc. 11 1232760 (3) Take the sucrose and place it in the fluid layer telecentric granulator (Glatt), and then spray the atomized adhesive from the spray gun (1), and then add the item (2), so Handle and dry to form a neutral core. 2. Drug layer: Ketorolac Tromethamine 129.6g Lactose 115.2g Polyvinylpyrrolidone (PVP K_30) 9.6g ethanol 96ml distilled water 96ml Preparation steps: (1) Take polyvinylpyrrolidone Add distilled water and stir until dissolved. Add ethanol and mix well. (2) Take mitamine ketorolac and lactose and pass through a 150 mesh sieve once and a 40 mesh sieve twice. (3) Take the neutral core and place it in the granulator, and then spray the atomized adhesive from (1) from the spray residue, and add the powder (2) at the same time. Spherical particles containing active ingredients can be obtained. 3. Protective layer: HPMC 96g Polyethylene glycol (PEG 6000) 19.2g Titanium Dioxide 19.2g Purified water 1368ml Preparation steps: (1) Take hydroxypropyl Dimethyl cellulose is added to distilled water and stirred to dissolve. At 12 1232760, polyethylene glycol is added and stirred until dissolved. (2) Take titanium dioxide through a 150 mesh sieve once. (3) Take item (1) and mix well. (4) Take the spherical particles containing active ingredients and place them in a fluid layer telecentric granulator (Glatt), and then spray the atomized protective layer solution from the spray gun (3), and then operate and dry it. The spherical particles containing the protective layer can be obtained. The atomization condition is that the temperature of the air inlet is 45 ° C, the temperature of the air outlet is 30 ° C, the atomization pressure is 2.8kg / cm2, and the speed of the turntable is 34rpm. 4. Casing layer: methacrylic acid-methyl methacrylate copolymer (Eudragit L30D) 1280g 76.8g Triethyl citrate Preparation steps: (1) Take methacrylic acid monomethyl acrylate The ester is mixed well with triethyl citrate. () Take the spheroidal particles of the compliant layer and place them in the fluid layer telecentric granulator (G1: U). 'Then spray the atomized casing coating solution from the spray residue, and then operate and dry it.' The spherical particles containing the casing layer, the protective layer and the drug layer can be obtained. Temperature The atomization condition is that the temperature of the air inlet is 45. (:, The air outlet is 30 ° C, the atomizing pressure is 2. piano m2, and the rotating speed of the turntable is μ. [Example 2] 13 1232760 1. Neutral core: 1043.52g 2. Drug layer: Mikiamine g Ketorolac Tromethamine 129 6g Starch 132.48g Polyvinylpyrrolidone (PVP K · 30) 9.6g Ethanol 96ml Purified water 96ml The preparation and operation of the neutral core and drug layer according to the examples One operation. 3. Protective layer: hydroxypropyl methyl cellulose (HPMC ·) li5.2g polyethylene glycol (PEG · 6000) 23.04g titanium dioxide (Titanium Dioxide) 23.04g Purified water 1368ml protection The preparation and operation of the layer were carried out according to Example 1. 4. Casing coating layer: 1280 g of acrylic acid monomethyl acrylic copolymer (Eudragit L30D) 1280 g of triethyl citrate 76.8 g of casing layer The operation and operation are as in Example 1. [Example 3] 1. Neutral core: 939.6g 2. Drug layer: Ketorolac Tromethamine 126g 14 1232760 Starch 132.48g polyvinylpyrrolidone ( PVP K-30) 9.6g B Ethanol 96ml Purified water 96ml Neutral core and drug layer were prepared and operated as in Example 1. 3 · Protective layer: hydroxypropyl fluorenyl cellulose (HPMC) 192g polyethylene glycol (PEG · 6000) 38.4 g of titanium dioxide (Titanium Dioxide) 38.4 g of purified water (1920 ml) The protective layer was prepared and operated as in Example 1. 4. Casing layer: fluorenyl acrylic acid fluorenyl acrylic acid acrylate copolymer ( Eudragit L30D) 1280g Triethyl citrate 76.8g The preparation and operation of the casing layer were carried out according to Example 1. [Example 4] 1. Neutral core: 1090.5g 2. Drug layer: succinyl methylamine Ketorolac Tromethamine 157.5g Starch 165.6g Polyvinylpyrrolidone (PVP K-30) 12g Ethanol 120ml 15 1232760 Purified water 120ml Neutral core and drug layer Preparation and operation The first embodiment is operated. 3. Protective layer: Hydroxypropyl methylcellulose (HPMC) 240g Polyethylene glycol (PEG · 6000) 48g Titanium Dioxide 48g Purified water 2400ml The protective layer is prepared and operated according to the first embodiment Of it. 4. Casing layer: 2,000 g of Triethyl citrate (Eudragit L30D) copolymer (60 g) Triethyl citrate The preparation and operation of the casing layer were carried out according to Example 1. [Example 5] 1. Neutral core: 1217.7g 2. Drug layer: Ketorolac Tromethamine 157.5g Starch 165.6g Polyvinylpyrrolidone (PVP K-30) 12g Ethanol The preparation and operation of 120 ml of Purified water and 120 ml of neutral core and drug layer were performed according to the first embodiment. 3. Protective layer: 16 1232760 HPMC 288g Polyethylene glycol (PEG · 6000) 57.6g Titanium Dioxide 48g Purified water 3201ml The protective layer is prepared and operated according to The first embodiment is operated. 4. Casing layer: 1440 g of Eudragit L30D copolymer (Eudragit L30D) Triethyl citrate (43.2 g) The preparation and operation of the casing layer were carried out according to Example 1. [Example 6] 1. Neutral core: 1212.9g 2. Drug layer: Ketorolac Tromethamine 157.5g Starch 165.6g Polyvinylpyrrolidone (PVP K-30) 12g Ethanol 120ml Purified water The preparation and operation of 120ml neutral core and drug layer were performed according to the first embodiment. 3 · Protective layer: 336g of hydroxypropyl fluorenyl cellulose (HPMC), polyethylene glycol (PEG 6000), 67.2g of titanium dioxide (Titanium Dioxide), 48g, 17 1232760, Purified water, 3750ml The first embodiment is operated. 4. Casing layer: Eudragit L30D (Iudragit L30D) I280g Triethyl citrate 38.4g The preparation and operation of the casing layer were carried out according to Example 1. [Example 7] 1. Neutral core: 1196.1g 2. Drug layer: Ketorolac Tromethamine 157.5g Starch 165.6g Polyvinylpyrrolidone (PVP K-30) I2g Ethanol 120ml of purified water (Purified water) The preparation and operation of 120ml of neutral core and drug layer were performed according to the first embodiment. 3. · Protective layer: 2480g 48g 48g 2400ml Hydroxypropyl fluorenyl cellulose (HPMC) Polyethylene glycol (PEG · 6000) Titanium Dioxide Purified water protective layer preparation and The operation is performed according to the first embodiment. 4. Casing layer: 18 1232760 Eudragit L3Od copolymer (Eudragit L30d) 1680 g Triethyl citrate 50.4 g The preparation and dullness of the casing layer are based on the examples ^- Operate it. [Test results] Please refer to Tables 1 and 2 for the dissolution rates of the preparations of Examples 1 to 7 according to the 1990 USP (22nd Edition), and the preparations of Example 7 to the 1990 USP ( The 22nd edition) specifies the standard and changes the dissolution rate detected by the solvent and the rotation speed, showing that the preparation prepared according to the preparation method of the present invention can obtain a good dissolution rate. Please refer to Tables 3 and 4, which are the changes in rolls in blood of the ginseng in Example 7 (Treatment B) and commercially available products (Treatment A). The data are plotted as shown in Figure 3 Show. The invention uses the principle of powder coating to increase the protective layer to reduce the discoloration due to the effects of light, lines and moisture, and to increase the casing layer to reduce gastric mucosal damage 'so that the core layer containing the casing layer, the protective layer and the active ingredient is included. After far + intestine is effective. Table 3 proves that the oral enteric preparations of the present invention, such as Zhong / Ma & Gastric mucosal damage caused. In addition, the mitochondriol ketoroxantrin ^ neutral core prepared by the method of the present invention meets the dissolution rate prescribed by the United States Pharmacopoeia, which can retain the advantages of solid ship ^ and machine, and the present invention does not have morphine-like addiction Sex and forbidden symptoms' 19 1232760 device can use the general fluid layer telecentric granulator (Glatt) or fluid layer spray granulator (Huttlin), not limited by model, the best method for the pharmaceutical industry . [Brief Description of the Drawings] The detailed description and technical contents of the present invention will be described with reference to the drawings as follows: Figure 1 is a schematic diagram showing the structure of an oral enteric preparation containing mitropamine and ketorol according to the present invention. Fig. 2 is a schematic diagram showing a process for preparing an oral enteric preparation containing mitamine ketorolab according to the present invention. FIG. 3 is a graph showing changes in blood concentration in Example 7 of the present invention and commercially available products. Table 1: The dissolution rate of the formulation of Example 1 of the present invention. Table 2: Dissolution rate of the preparation of Example 7 of the present invention. Table III: Changes in blood concentration (Treatment B) of the preparation of Example 7 of the present invention. Table 4: Changes in blood concentration of commercial products (Treatment A). [Description of main component symbols] Figure 1: Neutral core ... 1 Drug layer ... 2 Protective layer ... 3 Casing layer ... 4 1232760 Figure 2: Preparation of adhesive solution ... 21 Preparation of mixed powder for drug layer ... 22 Preparation of protective layer liquid ... 23 Preparation of casing liquid ... 24 Spherical particles with drug layer ... 25 Spherical particles with casing, protective layer and drug layer ... 26
21 1232760 o o 气 B cn B cn o B 溶離率時間 0.86% 1.14% 0.62% 0·1Ν HCI(120分鐘） 4.28% 4.56% 3.87% ρΗ4·5 (120分鐘） 107.26% 105.93% 103.11% ρΗ6·8 (120分鐘） 体丨 cV s HI n l 溶離率轉速 0.86% ο o 0.25% o 5.3% 8.5% 0.1N HCI(120分鐘）lOOrpm 107.26% 100.5% 95.7% 90.95% 99.6% 93.3% 86.7% pH6.8 (30分鐘）lOOrpm 29 123276021 1232760 oo Gas B cn B cn o B Dissolution rate time 0.86% 1.14% 0.62% 0 · 1Ν HCI (120 minutes) 4.28% 4.56% 3.87% ρΗ4.5 (120 minutes) 107.26% 105.93% 103.11% ρΗ6 · 8 ( 120 minutes) volume 丨 cV s HI nl Dissolution rate 0.86% ο o 0.25% o 5.3% 8.5% 0.1N HCI (120 minutes) 100rpm 107.26% 100.5% 95.7% 90.95% 99.6% 93.3% 86.7% pH6.8 (30 Minutes) lOOrpm 29 1232760
unit : ng/ml ..below sensitivity iO iNJ 00 〇) 3.5 CO I 2.671 1 2.33| 1 1.671 1 1.331 1 0.831 1 0.671 …〇·5 1 0.331 10.1671 ο Time (hr) 1 20.4 1 78.0 109 172 272 727 270 I 38.0 I I 24.5 I I 29.3j I 37.31 1 20.6 1 * * * * * * * ο 1 ω 41.7 126 152 277 I 390 I 667 303 I 189 I I 205 I 32.1 * * * * * * * * * ο 2-Β _I 28.7 108 128 209 331 657 890 879 193 * * * * * * 卄 * * * ο 3-Β 33.1 97.2 127 203 I 272 I 448 514 I 584 1 I 671 I 1 781 I 831 1 811 I 501 1 1 61.2 1 1 17.2 1 * * * * ο 4-Β 39.7 110 125 197 322 532 631 838 I 874 363 67.5 * * * * * * * * ο 5~Β 25.0 ! 82.2 105 179 259 429 I 464 I 541 I 658 I 1 727 1 L918 1 960 1 1 252 1 1 11.3 1 * * * * * ο 6-Β 32.5 103 128 207 265 434 475 553 594 1 675 I 1 766 1 1 967 1 11045 1 I 63.1 I * * * * * ο 7-Β 25.5 73.0 100 162 251 488 527 603 656 773 832 1 572 | 1 99.5 1 * * * * * * ο 00 1 tfl 16.5 69.4 92.3 151 266 478 557 618 I 718 ! 1 753.1 11015 I 1 552 I L105J I 27.5 I 15.1 * * * * ο CO 1 ω 28.7 98.8 130 240 322 698 799 769 369 155 1 52.01 [24.3 1 30.4 1 15.6 1 13.9 12.5 10.8 * * ο Ο 1 td 32.8 96.8 121 237 409 913 260 27.0 * * * * * * * * * * * ο 1 td 36.0 93.9 109 171 218 338 357 411 449 518 584 1 308 1 11641 1 79.7 1 i 38.6 1 * * * * ο h·^ ΓΟ 1 td 30.1 94.7 119 200 298 567 504 504 492 481 56?—J 527—J [314 1 1 43.1 1 21.2 12.5 10.8 ο ο ο Mean Value I 7.5 1 16.6 CO cn CD L副 I 199 1 1 287 1 1 265 1 1 312 1 1 403 1 1 382 1 ! 357 1 28.61 11.7 0.0 0.0 ο ο ο Ul 〇 30 1232760unit: ng / ml ..below sensitivity iO iNJ 00 〇) 3.5 CO I 2.671 1 2.33 | 1 1.671 1 1.331 1 0.831 1 0.671… 〇 · 5 1 0.331 10.1671 ο Time (hr) 1 20.4 1 78.0 109 172 272 727 270 I 38.0 II 24.5 II 29.3j I 37.31 1 20.6 1 * * * * * * * ο 1 ω 41.7 126 152 277 I 390 I 667 303 I 189 II 205 I 32.1 * * * * * * * * * ο 2-Β _I 28.7 108 128 209 331 657 890 879 193 * * * * * * 卄 * * * ο 3-Β 33.1 97.2 127 203 I 272 I 448 514 I 584 1 I 671 I 1 781 I 831 1 811 I 501 1 1 61.2 1 1 17.2 1 * * * * ο 4-Β 39.7 110 125 197 322 532 631 838 I 874 363 67.5 * * * * * * * * ο 5 ~ Β 25.0! 82.2 105 179 259 429 I 464 I 541 I 658 I 1 727 1 L918 1 960 1 1 252 1 1 11.3 1 * * * * * ο 6-Β 32.5 103 128 207 265 434 475 553 594 1 675 I 1 766 1 1 967 1 11045 1 I 63.1 I * * * * * ο 7-Β 25.5 73.0 100 162 251 488 527 603 656 773 832 1 572 | 1 99.5 1 * * * * * * ο 00 1 tfl 16.5 69.4 92.3 151 266 478 557 618 I 718! 1 753.1 11015 I 1 552 I L105J I 27.5 I 15.1 * * * * ο CO 1 ω 28.7 98.8 130 240 32 2 698 799 769 369 155 1 52.01 [24.3 1 30.4 1 15.6 1 13.9 12.5 10.8 * * ο Ο 1 td 32.8 96.8 121 237 409 913 260 27.0 * * * * * * * * * * * ο 1 td 36.0 93.9 109 171 218 338 357 411 449 518 584 1 308 1 11641 1 79.7 1 i 38.6 1 * * * * ο h · ^ ΓΟ 1 td 30.1 94.7 119 200 298 567 504 504 492 481 56? —J 527—J [314 1 1 43.1 1 21.2 12.5 10.8 ο ο ο Mean Value I 7.5 1 16.6 CO cn CD L Vice I 199 1 1 287 1 1 265 1 1 312 1 1 403 1 1 382 1! 357 1 28.61 11.7 0.0 0.0 ο ο Ul 〇30 1232760
unit : ng/ml * : below sensitivity >s CO CO CO 2.67 I 2.331 〇) CO CO 1 0.831 1 0.67! L〇^J 1 0.331 10.1671 o Time (hr) 1 23.3 1 62.4 72.4 123 179 244 281 I 327 I 333 381 I 423 I 1 484 1 1 545 1 | 646」 1 701 1 1 784 1 1 934 I 111351 1 11011 o 1 一A 33.2 91.5 107 1 169 208 325 429 397 346 493 I 526 I 584 1593 I 1637 I L614J [482 1 1 252 1 1 61.3 1 * o i\D 1 31.7 91.0 103 159 222 335 372 399 ! 438 1 480 I 550 600 699 I 810 921 996 110731 1 10611 L3_47 1 o CO 1 > 32.2 94.6 106 163 275 ! 433 480 560 ! 608 676 760 835 965 916 1032 964 881」 1 662 I 227 o 1 > 1 28.8 1 77.6 82.5 144 186 269 | 299 329 349 377 428 46jJ I 544 I I 665 I I 706 I I 739 I 1 883 1 11048 1 1 969 1 o CJ1 1 > 25.3 79.4 95.3 148 214 346 362 427 436 489 I 559 ! 1 640 1 ! 719 I 841 951 ! 1009 I 11112] Illl6l 452 1 o 〇) 1 > 33.5 89.6 123 194 255 395 i 418 I 478 I 505 570 I 669 I 5761 I 373 I 1 247 I 198 L174 —155 — L122J 137.1 I o 7-A 24.2 82.9 99.4 159 251 393 435 418 | 483」 I 494 I 517 527 '590 592 594 591 521 334 86.1 o CO 1 > 26.3 82.8 110 1 189 265 457 468 525 555 582 I 636 1 ί 711 1 809 875 949 1013 1008 811 26.4 o CO 1 i> 21.0 66.9 83.6 155 228 322 366 413 1 429 丨 473 545 1 598 1 1 662 I I 784 I 1 847 1 981 1 ! 1043 1 11177 411 o 0 1 28.9 74.3 92.0 151 224 396 384 460 466 471 541 1 610 1 1 697 1 i 781 1 816 916 990 1097 1 561 o — 1 ί> 23.9 65.4 81.8 117 174 242 261 301 316 343 392 1 448 1 1 521 1 1 463 1 1 365 182 93.6 49.6 * o 1 > 27.7 79.9 96.3 156 223 346 380 420 439 486 546 1 1 590 1 643 1 1 688 1 725 736 745 723 422 o Mean Value | 4.3 1 10.9 1-副 i\D CO CO CO iO <1 CD ΓΟ CO 1 106 1 109. .....1531 19JLJ 251 312 381 458 371 o cn a 31unit: ng / ml *: below sensitivity > s CO CO CO 2.67 I 2.331 〇) CO CO 1 0.831 1 0.67! L〇 ^ J 1 0.331 10.1671 o Time (hr) 1 23.3 1 62.4 72.4 123 179 244 281 I 327 I 333 381 I 423 I 1 484 1 1 545 1 | 646 '' 1 701 1 1 784 1 1 934 I 111351 1 11011 o 1 A A 33.2 91.5 107 1 169 208 325 429 397 346 493 I 526 I 584 1593 I 1637 I L614J [482 1 1 252 1 1 61.3 1 * oi \ D 1 31.7 91.0 103 159 222 335 372 399! 438 1 480 I 550 600 699 I 810 921 996 110731 1 10611 L3_47 1 o CO 1 > 32.2 94.6 106 163 275 ! 433 480 560! 608 676 760 835 965 916 1032 964 881 '' 1 662 I 227 o 1 > 1 28.8 1 77.6 82.5 144 186 269 | 299 329 349 377 428 46jJ I 544 II 665 II 706 II 739 I 1 883 1 11048 1 1 969 1 o CJ1 1 > 25.3 79.4 95.3 148 214 346 362 427 436 489 I 559! 1 640 1! 719 I 841 951! 1009 I 11112] Illl6l 452 1 o 〇) 1 > 33.5 89.6 123 194 255 395 i 418 I 478 I 505 570 I 669 I 5761 I 373 I 1 247 I 198 L174 —155 — L122J 137.1 I o 7-A 24.2 82.9 99.4 159 251 393 435 418 | 483 ″ I 494 I 517 527 '590 592 594 591 521 334 86.1 o CO 1 > 26.3 82.8 110 1 189 265 457 468 525 555 582 I 636 1 ί 711 1 809 875 949 1013 1008 811 26.4 o CO 1 i > 21.0 66.9 83.6 155 228 322 366 413 1 429 丨 473 545 1 598 1 1 662 II 784 I 1 847 1 981 1! 1043 1 11177 411 o 0 1 28.9 74.3 92.0 151 224 396 384 460 466 471 541 1 610 1 1 697 1 i 781 1 816 916 990 1097 1 561 o — 1 ί > 23.9 65.4 81.8 117 174 242 261 301 316 343 392 1 448 1 1 521 1 1 463 1 1 365 182 93.6 49.6 * o 1 > 27.7 79.9 96.3 156 223 346 380 420 439 486 546 1 1 590 1 643 1 1 688 1 725 736 745 723 422 o Mean Value | 4.3 1 10.9 1- vice i \ D CO CO CO iO < 1 CD ΓΟ CO 1 106 1 109. ..... 1531 19JLJ 251 312 381 458 371 o en a 31