五 0 °τ*> 咿域明？ 發1 關 有 偽 明 發 本 途 用 療 台 XVJ1 是 別 特 '4 1 6 8 5 3 A7 B7 其劑 關閉 有封 及白 粒蛋 撤維 之纖 得血 製種 燥 一 乾關 霧有 噴係 藉明 可發 種本 生之 之口 成 傷 構術 所手 酶科 血 外 凝供 及提 原並 朊合 維癒 纖口 由傷 像助 劑輔 閉 於 封 用 白泛 蛋廣 維 ， 雜劑 血箸 黏 物 責 負 質 白 «6- 5 構 結 之 要 主 中 液 血 為 原 朊 維 繼 ο 合 〇 閉塊 合凝 缝成 無形 雜 原 成 而 合 I 0 血 ， 單 予 凝 } 白 皮毎 賢 莽 Θ S 需白雒 原蛋餓 朊酸血 維胺 。 纖絲體 , 之 簞 言 態白 而性蛋 成活維 形其纖 塊成血 凝化成 對轉化 子轉 因並 X 裂 藉斷 可解 I 白 /|\ 蛋 以 予 子性 因活 II其 XI成 要化 需轉 亦酶 成血 形凝 塊被 凝可 0 下 維在 潘存 之鈣 路在 網為 維子 三 因 成II 形XI 後 C 最 性 , 活 維之 I 轉 _—ί X 拜 (F作 子移 因轉 II基 XI胺 之藉 化鍵 活價 經共 β, ， nv. 著之 接間 〇 體 酶單 Θ S tiinf 5 酸維 胺纖 絲血 之 合 化 使成 (請先閲讀背面之注意事項再填寫本頁) .装. 訂 經濟部中央標準局員工消費合作社印製 溶 。收 白性吸 蛋硬被 維堅再 纖及徑 血度途 受強之 易體用 不整作 較之胞 腠瞟細 凝凝噬 白加呑 蛋增及 雒亦素 纖且酵 血 ，藉 得解易 使分膠 此解凝 如水白 。 白 蛋 I h一天 i s S 鉍 價之 _ 共酶血 封偽 白分 蛋成 維酶 谶血 血凝 ， 且 程 過子 結因 凝II - I 之 X 態有 劑 含 著常 黏通 物分 生成 呈原 ΜΓ9 ΗΗΠ 複維 了纖 為之 劑 閉 部黏 復易 修 劑 至閉 加 封 施白 時蛋 同雒 或纗 序血 依 。 偽法 分方 成霧 兩噴 該藉 〇 或 液筒 溶針 鈣用 化利 氣 般 成 一 備 ， 製位 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） 3 9 1404 經濟部中央標準局員工消費合作社印製 416853 A7 B7五、發明説明（2 ) 附至濕表面，且一旦聚合後，則變成可使組鏃或物質保持 於所需組態之半硬質、止血、緊固流體之鈷著劑。 目前，血纖維蛋白封閉劑産物偽以溶液絶用至受傷部 位，例如使用雙針筒裝置，在壓出之際使潘維朊原及凝血 SS混合。此種輸送裝置之主要缺點為在裝置内會形成凝塊 而阻塞針頭及管體。此種雙針筒条統在填藥及操作上亦嫌 麻煩。再者，若不當地混合纖維朊原及凝血SS溶液，則僅 形成檝弱之凝塊。 許多傷口部位會滲出分泌物且導致在該部位體液之明 顯累積。當血纖維蛋白封閉劑成分之溶液施加至該部位時 ,經常會流失。 US-A-4427651掲示一種含有15-60重量％凝血01、5-80重量％乾燥安定劑（白蛋白，球蛋白及/或纖維朊原）、 及卜10重量％血纖維蛋白溶0S作用抑制劑之粉末混合物之 可噴霧製劑，用於加速止血及使傷口閉合之生化控制最適 化。該粉末混合物懸浮於作為推進劑用之低沸點無水溶劑 中。 W0-A-9213495掲示一種藉沈澱作用不控制粒徑而製備 之凍乾纖雒脘原粉末。該粉末通常在使用前與水結合，具 有上述之缺點。其中亦提及當欲閉合之脈管或傷口小且血 液流失不快時，可直接使用該粉末。此時，度應與内源凝 血酶之存在與否有關。於較大傷口中，較大之血流會洗除 該内源物質而不會發生凝塊。 發明概沭 本紙張尺度適用中國國家標準（CNS )A4規格{ 210X297公釐） 4 91404 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 A7 4 16853 B7五、發明説明（3 ) 頃已理解可使用噴菘乾燥法作為得到含有纖維朊原或 凝血酶之新穎可溶撤粒（包含徹朦囊）之方式。 含纖維朊原及含凝血酶之傾別可溶撤粒可一起調配而 呈安定乾燥態。此調配物隨後可如所需予以活化，得到可 用於傷口治療及外科手術修復之血織維蛋白封閉剤。其可 符合逹成良好流動性質、增強輸送至活化部位之效果，及 僅在該部位溶解而非在輸送条統内溶解等主要目的。 發明钓沭 含有潘維朊原或凝血酶之檝粒可藉W0-A-9218164、 W0-A-9609814及W0-A-9618388所述程序製備。該等噴孩乾 燥法及相關之頼粒操作製程可製得具界定粒徑分佈（如直 徑逹50撤米）之可溶蛋白質撤膠囊。例如，如該等文獻所 述，該撤粒可以再製性地製得例如90¾或更多（質量比）徹 粒具有達20檝米（如1至10撤米）或達5微米之尺寸，或若 需要，可具有次撤米之尺寸。 本發明之撤粒可藉噴蓀乾燥活性成分單獨溶液而製備 。另一種程序為共噴霧乾燥法，其中纖維朊原或凝血_及 其他成壁物質搽一起調配並予以噴霧乾燥，得到其中活性 成分併於顆粒壁中之黴粒。 雜維朊原或凝血酶可為全長或其任何活性片段。片段 為已知；參考柯勒（col ler)等之Clin, ΐ n v s h . 89 : 5 4 6 - 5 5 5 ( 1 9 9 2 )。_維朊原原料可為冷凍溶液，但亦可使用 於噴霧乾燥前需復水之凍乾粉末。 在賦形劑如糖類（如蔗耱、乳糖或甘露糖酵）或其他蛋 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標隼（CNS ) Λ4規格（210:<297公釐） 5 9 1404 '丨 4 ' > 1 w r 、+ B7 經濟部中央標準局員工消費合作.杜印製 五、發明説明（ 4 ) 1 1 白 質 存 在 下 使 蛋 白 質 噴 孩 乾 燥 可 使 參 與 蛋 白 質 安 定 赘 且當 1 I 需 要 低 劑 量 時 亦 確 保 其 有 效 稀 釋 〇 糖 在 傷 P 治 療 中 具 有有 1 1 I 利 效 益 0 一—、 請 先 閱 讀 1 1 I 適 宜 之 其 他 蛋 白 質 可 為 天 然 或 重 組 體 > 其 可 作 為 ”成 1 1 壁 物 質 ，.用， 如WO- A- 9 2 1 8 1 6 4 所述， 其中也載述多種實例 背 意 事 1 1 I 〇 較 佳 之 物 質 為 HS/U 人 類 血 清 白 蛋 白 )。 例如， 纖維朊原 1 1 DD 単 獨 噴 Μ 乾 燥 或 在 不 同 量 賦 形 劑 如 H S A (例 如 潘 雄 9π 原： 項 再 填 1 1 装 I ^六之比例為1 ：1 9 1 ： 3 , 3 ：1 )及耱類（例 如 甘 露 糖 醇 )存在 本 育 下 予 以 噴 孩 乾 燥 〇 '·· 1 1 I 本 發 明 微 粒 可 具 有 上 述 三 個 文 獻 中 所 述 之 物 理 性 質， 1 1 | 如 平 滑 性 及 球 形 9 而 因 吸 收 性 不 列 入 考 慮 所 以 大 小 並 不重 1 i 訂 1 要 〇 可 使 用 已 知 條 件 製 造 例 如 • 直 徑 約 1 . 5撤米或約1 0 撤 米 之 撤 粒 » 其 可 確 使 兩 種 參 與 蛋 白 質 之 一 最 適 地 回 1 1 已 發 現 Μ 噴 m 乾 燥 m 雄 Μ 原 所 製 得 之 撤 粒 思、 外 地 具有 1 | 活 性 且 可 溶 0 因 此 使 用 噴 孩 乾 燥 之 m 雄 itWC； 肢 原 製 劑 對 於 溶解 1 冷 凍 乾 燥 之 m 維 朊 原 需 花 費 1 5分 鐘 以 上 旦 通 常 需 要 加 熱之 Γ | 殺 院 裝 置 恃 別 有 利 0 此 溶 解 為 速 率 決 定 步 驟 i 且 在 對 病患 1 1 作 血 m 維 蛋 白 封 閉 劑 之 投 藥 中 會 引 起 相 當 的 延 誤 〇 I 1 血 雜 維 蛋 白 封 閉 劑 中 凝 血 m 成 分 之 濃 度 相 當 低 (如每 1 1 40毫 克 潘 維 朊 原 為 1 50撤克凝血酶） 〇 因 此 » 凝 血 m 較 好與 1 陚 形 劑 如 HSA, 蔗糖、 乳糖或甘露糖醇以不同比例- -起噴 1 [ 孩 乾 燥 0 如 此 可 提 供 均 勻 之 調 配 物 ， 如 於 申 請 案 PCT/GB97 1 I /00953 中 有 所 詳 述 〇 1 I J 鈣 離 子 (如氯化鈣） 可 併 入 凝 血 梅 原 料 中 t 或 者 1 可在 1 1 本紙悵尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） 6 91404 416853 B7 經濟部中央標準局男工消费合作杜印製 五、發明説明（ 5 ) 1 | 製 程 後 將 氣 化 鈣 加 至 微 粒 中 〇 1 I 若 需 要 9 本 發 明 之 徹 粒 可 予 以 滅 菌 0 滅 菌 製 程 中 1 以 1 1 I 7 -照射及環氣乙烷為適宜之技術宵例^ 請 先 閱 背 τδ 之 1 1 I 雖 然 本 發 明 血 纖 維 蛋 白 封 閉 劑 中 撤 粒 之 成 分 較 好 為 水 1 1 I 溶 性 ί 且 撤 粒 較 好 藉 由 使 適 宜 溶 液 噴 霧 乾 燥 而 得 % 但 可 獲 1 1 1 得 之 撤 粒 可 為 白 由 流 動 且 彼 此 分 開 及 實 質 上 無 水 者 〇 此 意 '/主 意 事 1 i 指 本 發 明 之 血 潘 維 蛋 白 封 閉 劑 之 成 分 在 濕 化 (如在傷口部 項 再 1 I 位 與 體 液 接 觸 )之前並未活化。 因此活性成分可成為乾燥 寫 本 頁 装 ] 混 合 物 輸 送 ， 但 亦 可 分 別 施 用 不 同 徹 粒 0 1 | 乾 燥 粉 末 血 m 維 蛋 白 封 閉 劑 産 物 在 需 要 施 加 至 大 表 面 1 1 1 稹 之 用 途 中 恃 別 有 價 值 0 此 包 含 各 種 器 官 如 旰 及 睥 之 創 傷 1 1 之 手 Alt* 術 及 修 復 〇 進 步 之 有 利 用 途 為 燒 傷 病 患 之 皮 * 移 棺 訂 1 1 特 別 是 在 活 體 外 培 養 皮 m 表 皮 Η 接 著 移 植 至 受 傷 部 位 1 1 之 情 形 下 〇 在 後 一 用 途 中 使 用 血 m 雄 蛋 白 封 閉 劑 已 證 明 對 i | 廣 範 圍 燒 傷 之 病 患 恃 別 有 效 * 為 皮 ft 移 植 片 提 供 生 物 可 相 1 1 容 之 固 定 作 用 0 此 亦 適 用 於 治 療 局 部 潰 瘍 〇 Γ | 本 發 明 産 物 可 為 實 質 上 乾 燥 〇 此 意 指 其 可 與 吸 劑 物 1 1 質 起 調 配 r 尤 其 是 比 液 態 血 m 雒 蛋 白 封 閉 劑 具 有 乾 操 1 1 並 使 産 物 集 中 在 作 用 (例如止血）部 位 之 優 點 〇 適 宜 之 此 等 1 ί 物 質 為 羧 甲 基 織 維 素 〇 1 調 配 物 中 亦 可 包 含 H0清 除 劑 1 或 更 通 常 地 1 促 進 凝 塊 1 凝 集 抑 制 其 分 ύρι m 或 抑 制 血 m 雒 蛋 白 溶 解 之 任 何 物 質 r 此 1 I 物 質 如 白 蛋 白 具 有 SH基 0 該 等 物 質 可 自 凝 集 部 位 移 除 HO > 1 1 ί 因 而 增 進 凝 塊 形 成 0 1 [ 本纸張尺度適用中國國家標準（CNS ) Λ4規格（別X⑽楚）? B7 經濟部t央標準局員工消費合作杜印製 五、發明説明 ( 6 ) 1 I 如 W0 -A -96098 1 4所 詳 述 ， 噴 霧 乾 燥 之 徹 粒 可 保 留 供 與 i [ 治 療 劑 結 合 之 官 能 基 0 本 發 明 中 > 若 需 要 ， 則 可 在 施 用 部 1 I | 位 使 藥 物 與 撤 結 合 〇 例 如 * 在 需 要 治 療 皮 癌 時 1 可 使 1 ί 請 I 用 胞 毒 m 物 0 先 閱 ϊ I 讀 \ [ 可 包 含 於 本 發 明 産 物 (如含繼維朊原者） 中 之 其 他 藥 物 背 1 I 之 1 I 為 凝 集 因 子 如 V I I、 V I I I、 IX、 X及 X I I I 因 子 • 及 V 0 η 注 意 1 1 事 1 W i 11 e b r a n d 1 S 因 子 0 此 可 藉 共 噴 m 乾 燥 法 予 以 併 入 〇 項 1 % 1 装 近 來 已 觀 察 到 變 性 之 白 蛋 白 徹 泡 傾 向 於 黏 附 至 受 損 之 頁 1 内 皮 細 胞 0 此 意 味 本 發 明 産 物 之 凝 聚 在 受 傷 部 位 將 不 僅 '· 1 I 因 為 纖 維 Η元 原 之 活 化 作 用 ， 亦 因 為 微 粒 中 如 果 有 白 蛋 白 成 1 1 I 分 之 故 〇 1 1 訂 1 1 苷 Μ 下 列 實 例 將 用 以 說 明 本 發 明 0 员. JSL 製 備 一 種 血 m m 蛋 白 封 閉 劑 〇 此 包 括 分 別 含 纖 維 肢 原 1 1 1 及 凝 血 酶 之 徹 粒 之 乾 粉 末 摻 合 物 0 1 τ m 雒 朊 原 (SNBTS)與 600 毫 克 m 糖 一 起 調 配 0 使 用 具 有 \ 1 收 集 容 器 之 小 型 噴 乾 燥 機 進 行 噴 霧 乾 燥 0 條 件 如 下 1 1 入 □ 溫 度 ； 100¾ 1 1 出 □ 溫 度 ： 65 TC 1 1 m 化 壓 力 ： 1 . 〇巴 1 霧 化 種 類 ； S C hi i C k 9 70/0 ί I 進 料 速 率 1 克 /分鐘 1 1 I 達 到 20 % 之 最 终 賦 形 劑 加 料 量 〇 使 用 動 力 分 析 偵 測 之 1 1 I 活 性 為 13 .88毫克/100毫克， 理論活性為1 〇毫克/ 100毫克， 1 1 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210 X 297公釐） 8 91404 經濟部中央標準局員工消費合作社印製 a? ' 4 16 8 5 3 B7 五、發明説明（7 ) 此顯示纖Μ朊原生物活性完全保留。 S外，將1克D -甘露糖醇（Roquette, ESEX4)溶於10 毫升4 0 m M C a C 1 2中，使用所得溶液使1小玻瓶之凝血酶（ SHBTS)復水。所用之噴霧乾燥條件如上，但出口溫度約62 t且進料速率降至0.75克/分鐘。 凝血酶凝塊分析顯示凝血酶活性為91.86單位/100毫 克，與93單位/100毫克之理論活性相較下為有利。 含纖維朊原及凝血酶之個別撤粒於玻璃小瓶中予以混 合形成50:50摻合物。將小玻瓶置於棍混合機上20分鐘。 摻合物以各種摻合量於肉黏附分析中予以評估。毎一 分析需要兩段肝片（2.5公分X2.5公分）將一段肝Μ釘於 一張卡紙板上，兩段均包捲於鋁箔紙中並在371培育20分 鐘。 鬆開之肝片以棉線串起，於兩段肝片表面上施加5 % 人類血清白蛋白溶液，接著施加纖維朊原與凝血_之乾粉 末摻合物（血纖維蛋白封閉劑將兩段肝Μ置放在一起並 在37 t培育10分鐘。 然後將肝Μ用夾具懸掛起來，以吊鈞附接於棉線上。 於吊鈞上置放砝碼，使用懸掛之總重計算乾粉末血_維蛋 白封閉劑摻合物之抗拉強度，單位為毫克/平方毫米。結 果示於下表。 ---------病------1Τ (請先聞讀背面之注意事項再填寫本頁) 本纸張尺度適用中國國家標準（CNS ) Λ4規格（2丨0X297公釐） 9 9 1404 A7 416853 B7 五、發明説明（8 ) 摻合物量 缴維朊原 凝血酶 抗拉強度 (毫克/平 (毫克） (毫克） (單位） 方毫米） 0 0 0 0 100 5 45 29.6 200 10 90 23.7 3 00 15 135 36.0 400 20 180 46.4 500 25 225 50.6 ί請先閱讀背面之注意事項再填寫本頁) .裝.Five 0 ° τ * > 咿 域 明? Hair 1 related to fake Mingfa The treatment table XVJ1 used this way is a special '4 1 6 8 5 3 A7 B7 The agent is closed and sealed and the white eggs are removed from the fiber to obtain blood. In the Ming Dynasty, a kind of Bunsen's oral wound formation technique was used to enzymatically provide extracorporeal blood condensate and extract the original and combine the vitamins. The fibrous mouth was supplemented by the wound image assistant in the closed white pan egg, and the blood was mixed.箸 Mucus is responsible for the quality of white «6- 5 The main structure of the main blood is the original blood. 合 〇 closed block and coagulation suture to form intangible impurities and I 0 blood, single coagulation} White skin 毎Hysteria Θ S requires white primordial egg hunger and serotonin. The fibrid body, the verbal expression is white, and the sex egg is alive. Its fibrous blood is coagulated into a pair of transformants, and the X-split borrowing is solvable. I white / | In order to change, the enzyme needs to be converted into a blood clot, which can be coagulated. The next dimension is on the calcium road in Pancun, and it is the most important factor in the three dimensions of the dimensional form of XI in the network, and the most important is the transformation of the living dimension. The transference of the transference bond of II-based XI amine via β,, nv. Is linked to the β-somal enzyme single Θ S tiinf 5 acid retamine fibrillary blood synthesis (please read the note on the back first) Please fill in this page for further information.) Packing. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. White egg suckers are hard-coated with vitamins and fibers.瞟 Fine coagulation and phagocytosis of white eggs, gluten and egg whites, and fermented blood, which can be easily dissolved by dehydration. White eggs I h a day is S bismuth value _ coenzyme blood seal pseudo white Egg Dimensional Enzyme 谶 Hemagglutination, and the X-State Agent of Process Passing Factor II-I Contains Normal Adhesives ΜΓ9 ΗΗΠ restores the fibrous agent to the closed part of the sticky repairing agent until the closed seal and white, the egg is the same or the sequence of blood. The pseudo method is divided into two sprays, which should be borrowed, or the tube dissolves the needle and calcium. Prepared with good luck, the paper size of the paper is in accordance with the Chinese National Standard (CNS) Λ4 specification (210X297 mm) 3 9 1404 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 416853 A7 B7 V. Description of the invention (2) Attach to Wet surface, and once polymerized, it becomes a semi-rigid, hemostatic, fastening fluid cobalt implant that can keep the group or substance in the desired configuration. At present, the fibrin sealant product is used as a solution. Injured parts, such as the use of a double syringe device, mix panavidin and coagulation SS during extrusion. The main disadvantage of this type of delivery device is that clots will form in the device and block the needle and tube. This double syringe The system is also troublesome in filling and handling. In addition, if the fibrinogen and coagulation SS solution are improperly mixed, only weak clots will be formed. Many wound sites will exudate secretions and cause body damage in this area. Significant accumulation of fluid. When a solution of the fibrin sealant component is applied to the site, it is often lost. US-A-4427651 shows a dry stabilizer containing 15-60% by weight of blood coagulation 01 and 5-80% by weight. Protein, globulin and / or fibrinogen), and a sprayable formulation of a powder mixture of 10% by weight fibrinolytic OS inhibitor, used to accelerate hemostasis and optimize biochemical control of wound closure. The powder mixture is suspended in a low-boiling anhydrous solvent used as a propellant. WO-A-9213495 shows a lyophilized fibrinogen powder prepared by precipitation without controlling the particle size. The powder is usually combined with water before use and has the disadvantages described above. It is also mentioned that the powder can be used directly when the vessel or wound to be closed is small and blood loss is not fast. At this time, the degree should be related to the presence or absence of endogenous thrombin. In larger wounds, larger bloodstreams wash away the endogenous material without clotting. Summary of invention: This paper size applies the Chinese National Standard (CNS) A4 specification {210X297 mm) 4 91404 (Please read the notes on the back before filling this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, A7 4 16853 B7 5. Description of the invention (3) It has been understood that the spray drying method can be used as a way to obtain novel soluble withdrawal granules (including complete capsules) containing fibrinogen or thrombin. The fibrinogen-containing and thrombin-containing decanted soluble granules can be formulated together to be stable and dry. This formulation can then be activated as needed to obtain a hemoglobin-blocked puppet that can be used for wound treatment and surgical repair. It can meet the main purposes of forming good flow properties, enhancing the effect of delivery to the activated site, and dissolving only in that site rather than within the transport system. Invention fishing maggots. Panicles containing panavirin or thrombin can be prepared by the procedures described in WO-A-9218164, WO-A-9609814 and WO-A-9618388. These spray-drying methods and related granule operation processes can produce soluble protein withdrawal capsules with a defined particle size distribution (eg, diameter 50 mm). For example, as described in these documents, the withdrawal can be reconstituted to produce, for example, 90¾ or more (mass ratio) cut grains having a size of up to 20 mm (eg, 1 to 10 mm) or up to 5 microns, If necessary, it can have the size of sub-meter. The granular removal of the present invention can be prepared by spray drying a separate solution of the active ingredient. Another procedure is a co-spray drying method in which fibrinogen or coagulation and other wall-forming substances are formulated together and spray-dried to obtain mold particles in which the active ingredient is contained in the particle wall. The provitamin or thrombin may be full length or any active fragment thereof. Fragments are known; see Clin, ΐ n v s h., Col ler et al. 89: 5 4 6-5 5 5 (1 9 9 2). _Vitamin raw materials can be frozen solutions, but can also be used in lyophilized powders that need to be rehydrated before spray drying. In excipients such as sugar (such as sugar cane, lactose or mannose) or other eggs (please read the precautions on the back before filling out this page) This paper size applies to China National Standard (CNS) Λ4 specification (210: < 297 mm) 5 9 1404 '丨 4' > 1 wr, + B7 Consumption cooperation between employees of the Central Standards Bureau of the Ministry of Economic Affairs. Du Yin 5. Description of the invention (4) 1 1 Drying the protein spray in the presence of white matter allows Participate in protein stabilization and also ensure effective dilution when 1 I requires low doses. 0 Sugar has 1 1 I benefits in wound P treatment. 0-Please read 1 1 I. Other suitable proteins can be natural or recombinant The body > It can be used as "1 1 wall material", as described in WO-A-9 2 1 8 1 6 4, which also contains a variety of examples to contradict the matter 1 1 I 〇 The preferred substance is HS / U human serum albumin). For example, fibrinogen 1 1 DD is sprayed alone or dried in different amounts of excipients such as HSA (eg pan Male 9π Original: Fill in the item 1 1 again. The ratio of 1 to 6 is 1: 1 9 1: 3, 3: 1) and tadpoles (such as mannitol) are spray-dried in the presence of this child. 0 ′ · 1 1 I The microparticles of the present invention may have the physical properties described in the above three documents, 1 1 | such as smoothness and spherical 9 but the size is not heavy because the absorbency is not taken into account 1 i order 1 if 0 can be used known Conditional manufacturing, for example, • grain removal of about 1.5 dm or about 10 dm »it can surely make one of the two participating proteins optimally return to 1 1 has been found Μ spray m dry m male M original Withdrawal thinking, field has 1 | active and soluble 0 so use spray male dried m male itWC; limb original preparation for dissolving 1 freeze-dried m dimensional primordia takes more than 15 minutes, usually requires heating Γ | kill The hospital device is not favorable. This dissolution is the rate-determining step i. Administration as a blood m-dimensional protein blocker can cause considerable delays. The concentration of the coagulation m component in the blood heterovitamin blocker is quite low (e.g., 150 mg of thrombin per 40 mg of panvidin). Therefore »Coagulation m is better than 1 tincture such as HSA, sucrose, lactose or mannitol in different ratios--spray 1 [Child dry 0 so it can provide a uniform formulation, as in the application PCT / GB97 1 I / 00953 is detailed in detail. 0 IJ calcium ion (such as calcium chloride) can be incorporated into the raw materials of clotting plum t or 1 can be used in 1 1 paper size applicable to the Chinese National Standard (CNS) Λ4 specifications (210X297 mm) 6 91404 416853 B7 Printed by the male laborer of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China. 5. Printed description of the invention (5) 1 | Add the vaporized calcium to the microparticles after the process. In the manufacturing process, 1 1 I 7-irradiation and cyclogas ethane are Examples of suitable techniques ^ Please read back 1 1 I of τδ. Although the component of particle removal in the fibrin sealant of the present invention is preferably water 1 1 I soluble, and the particle removal is preferably carried out by spray drying a suitable solution. Obtained% but obtainable 1 1 1 The obtained pellets can be free flowing and separated from each other and substantially anhydrous. This means' / idea matter 1 i means that the components of the blood pavidin blocker of the present invention are wet ( Such as contact with body fluids before the wound site (position 1 I) is not activated. Therefore, the active ingredient can be delivered as a dry sheet.] Mixtures can also be delivered separately, but can also be applied separately. 0 1 | Dry powder blood m-dimensional protein blocker products are used in applications that need to be applied to large surfaces 1 1 1 稹Value 0 This contains various organs such as trauma and sacral wounds 1 1 Hand Alt * surgery and repair 0 beneficial use of progress is the skin of burn patients * transfer coffin 1 1 especially in vitro culture of skin m epidermis Η then transplant In the case of injury to the wound site 1 〇 The use of blood m androgen blocking agent in the latter application has proven to be effective for patients with a wide range of burns * Provide biocompatible phase 1 1 volume fixation for skin ft grafts Action 0 This is also suitable for the treatment of local ulcers. Γ | The product of the present invention may be substantially dry. This means that it can be formulated with the inhalant 1 1 quality r, especially compared to liquid blood m 雒 protein Closing agents have the advantage of drying 1 1 and allowing the product to focus on the site of action (such as hemostasis). 0 These are suitable 1 ί The substance is carboxymethyl oryzanol 0 1 The formulation may also contain H 0 scavenger 1 or more commonly Ground 1 Promotes clotting 1 Any substance that inhibits its fragmentation m or blood m 雒 protein dissolution r This 1 I substance such as albumin has SH group 0 These substances can be removed from the agglutination site HO > 1 1 ί Therefore Promote the formation of clot 0 1 [This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (don't X⑽chu)? B7 Printed by the staff of the Ministry of Economic Affairs and the Central Standards Bureau. 5. Production description (6) 1 I such as W0 -A -96098 1 4 As detailed, the spray-dried cut granules can retain functional groups for binding to i [therapeutic agent 0 In the present invention> If necessary, the drug can be combined with the drug at the 1 | 〇 For example * Time 1 can make 1 Please use cytotoxic m substance 0 Read it first I read \ [Other drugs that can be included in the product of the present invention (such as those containing the following vitamins) 1 I 1 I is an agglutination factor such as Factors VII, VIII, IX, X and XIII • and V 0 η Note 1 1 Matter 1 W i 11 ebrand 1 S Factor 0 This can be incorporated by co-spray drying method 0 item 1% 1 Packing Denaturation has been observed recently The albumin through the foam tends to adhere to the damaged page 1 Endothelial cells 0 This means that the aggregation of the product of the present invention at the injured site will not only be due to the activation of fibrinogen, but also if there is albumin in the microparticles The reason is 1 1 I. 0 1 1 Order 1 1 glycoside M The following examples will be used to illustrate the present invention. JSL prepares a blood mm protein blocker. This includes a fibrinogen 1 1 1 and a thrombin-containing dry powder blend of 0 1 τ m Kryogen (SNBTS) and 600 mg m sugar. 0 Use a small spray dryer with a \ 1 collection container for spray drying. The conditions are as follows: 1 1 □ temperature; 100 ¾ 1 1 outlet □ temperature: 65 TC 1 1 m pressure: 1. 〇bar 1 atomization type; SC hi i C k 9 70/0 ί I feed rate 1 g / min 1 1 I reached the final excipient charge of 20%. 1 1 I activity detected using dynamic analysis 1 13.88 mg / 100 mg, theoretical activity 10 mg / 100 mg, 1 1 This paper size applies Chinese National Standard (CNS) Λ4 specification (210 X 297 mm) 8 91404 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs a? '4 16 8 5 3 B7 V. Description of the invention (7) This display fiber M Liaoyuan biological activity is completely retained. In addition, 1 g of D-mannitol (Roquette, ESEX4) was dissolved in 10 ml of 40 m M C a C 12 and the obtained solution was used to reconstitute 1 vial of thrombin (SHBTS). The spray drying conditions used were the same as above, but the outlet temperature was about 62 t and the feed rate was reduced to 0.75 g / min. Thrombin clot analysis showed that the thrombin activity was 91.86 units / 100 mg, which is advantageous compared to the theoretical activity of 93 units / 100 mg. Individual pellets containing fibrinogen and thrombin were mixed in glass vials to form a 50:50 blend. Place the vial on the stick mixer for 20 minutes. The blends were evaluated at various blending amounts in a meat adhesion analysis. The first analysis required two sections of liver slices (2.5 cm x 2.5 cm) to nail one section of liver M to a piece of cardboard. Both sections were wrapped in aluminum foil and incubated at 371 for 20 minutes. The loosened liver pieces were strung with cotton thread, and a 5% human serum albumin solution was applied to the surface of the two pieces of liver pieces, followed by a dry powder blend of fibrinogen and coagulation. Μ was put together and incubated for 10 minutes at 37 t. Then the liver was suspended with a clamp and attached to a cotton thread with a crane. Place a weight on Crane and calculate the dry powder blood using the total weight of the suspension_ Tensile strength of vitamin blocker blends in milligrams per square millimeter. The results are shown in the table below. --------- Disease--1T (Please read the note on the back first Please fill in this page again for this matter) This paper size applies to Chinese National Standard (CNS) Λ4 specification (2 丨 0X297 mm) 9 9 1404 A7 416853 B7 V. Description of the invention (8) Blend amount Miscellaneous protamine Strength (mg / flat (mg) (mg) (millimeters) (mm) 0 0 0 0 100 5 45 29.6 200 10 90 23.7 3 00 15 135 36.0 400 20 180 46.4 500 25 225 50.6 Please read the precautions on the back first Fill out this page again).
、1T 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家樓準（CNS ) Λ4規格（210X297公釐） 10 9 1404、 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This paper size applies to China National Building Standard (CNS) Λ4 specification (210X297 mm) 10 9 1404