TWI324524B - Carrier with solid fibrinogen and solid thrombin - Google Patents

Description

Translated fromChinese

五、發明説明（i ) 發明範圍V. Description of invention (i) Scope of invention

本發明係關於一種準備好可使用之可吸收的組成 物，其可用於組織膠合、組織封口及止血，其基本上由一 種塗佈著固態已固定的人類纖維蛋白膠組分（人類纖維蛋 白原及人類凝血酶）之載劑組成。此固定的組合可例如直接 地塗敷至一創傷表面。在與血液、體液或生理鹽液接觸之 後，此系統的機制會模仿凝血連鎖反應的最後階段，其中 凝血酶會催化纖維蛋白原轉換成纖維蛋白及活化因子XIII 以提供xnla。因子XIIIa-旦形成則可藉由共價交聯而穩定 纖維蛋白凝塊。 類似二組分黏著劑，創傷表面及載劑可藉由聚合反應 而膠合在一起。在此方法期間（其持續約3至5分鐘），較佳 地將本發明之組成物壓到創傷區域上。本發明之組成物組 分會在敷貼約4-6個月之後酵素地降解。 先述技藝 模仿凝血連鎖反應的最後步驟之商業上的纖維蛋白 膠類由一種高濃縮的纖維蛋白原溶液組成，其在敷貼至存 在的外科創傷之前與一凝血酶溶液混合。這些混合物包括 纖維蛋白溶解抑制劑（例如抗蛋白酶肽或ε-胺基己酸）， 以防止纖維蛋白凝塊過早由Α解纖維蛋㈣酵素纖維蛋白 溶酶溶解。這些二組分纖維蛋自義在不同的外科程序中 很有用’但是若大量出血時其會在止血完成前被沖走。再 者’二組分纖維蛋白膠類需要某些預備㈣，包括融化或 溶解。因此，它們在操作上相當不切實際且不方便而需要 1324524 五、發明説明（2 ) 經驗才可成功地使用這些纖維蛋白膠。 近十年間，許多纖維蛋白密封膠類 適應證上所方法的選擇。但是， —卜科 驗中比由田任 在夕數的纖維蛋白膠類試 驗中白額外地使用一種膠原質纖維網來改善止錢 徵，此點出其缺點及外科醫生在❹上的限制。 膠原質從六十年代晚期已使用做為-種止企藥劑。勝 原質為所有㈣乳祕類巾最常發生的結構蛋白質。的 3〇動a(膠原單位）的單體蛋白質在料的場址共價地交 聯。因此成熟的蛋白質為不溶且會形成具高抗張強度之特 1的細纖維類。已描述許多次級膠原質，最普通的為勝原 為型式I，其為皮膚、腱、骨頭及角膜中主要的膠原質型式。 膠原質為-種由長度約290奈米的三螺旋結構組成之纖維 狀蛋白質。五個這些三螺旋結構（膠原單位分子）互相交錯 以形成-種直徑約3.6奈米的微細纖維。這些微細纖維具^ 極性及非極性部分而容易獲得特定的微纖維間_及内交互 作用。這些微細纖維類會填充至一四方晶格而形成直徑約 3〇奈米的亞原纖維。然後，這些亞原纖維再組合成直徑為 數百奈米的膠原質細纖維（結蒂組織的基本單位），因此其 了在光學顯微鏡看見而為一細線。 膠原質其大概以包含纖維蛋白膠的被覆形式而使用 來做為封住創傷的材料。纖維蛋白膠類（即纖維蛋白原、凝 血酶及抗蛋白酶肽之組合）已成功地使用在治療上許多 年’其用於膠合組織及神經、封住小量出血時的表面。此 類纖維蛋白膠的一個缺點為如果發生大量出血時，則該膠 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐）The present invention relates to an absorbable composition ready for use, which can be used for tissue gluing, tissue sealing and hemostasis, which consists essentially of a human fibrin glue component (human fibrinogen) that has been immobilized in a solid state. And the carrier composition of human thrombin). This fixed combination can for example be applied directly to a wound surface. After contact with blood, body fluids or physiological saline, the mechanism of this system mimics the final stage of the coagulation cascade, in which thrombin catalyzes the conversion of fibrinogen to fibrin and activator factor XIII to provide xnla. Factor XIIIa-denier can stabilize fibrin clots by covalent cross-linking. Similar to the two-component adhesive, the wound surface and the carrier can be glued together by polymerization. During this method, which lasts about 3 to 5 minutes, the composition of the present invention is preferably pressed onto the wound area. The composition component of the present invention degrades enzymatically after about 4-6 months of application. The prior art commercial fibrin glue that mimics the final step of the coagulation chain reaction consists of a highly concentrated fibrinogen solution that is mixed with a thrombin solution prior to application to the existing surgical wound. These mixtures include fibrinolytic inhibitors (e.g., anti-protease or ε-aminocaproic acid) to prevent fibrin clots from prematurely lysing by the lytic fibrin egg (four) enzyme plasmin. These two-component fiber egg self-sense is useful in different surgical procedures' but if there is a large amount of bleeding it will be washed away before the hemostasis is completed. Furthermore, the two-component fibrin glue requires some preparation (four), including melting or dissolution. Therefore, they are quite impractical and inconvenient to operate and require 1324524 V. Inventive Notes (2) Experience to successfully use these fibrin glues. In the last decade, many fibrin sealants have been adapted to the choice of methods. However, in the Bu Ke test, a collagen fiber web was additionally used to improve the stop money in the fibrin glue test by Tian Ren, which points out its shortcomings and limitations on the surgeon. Collagen has been used as a stop-killing agent since the late 1960s. The original quality is the most commonly occurring structural protein of all (iv) milky towels. The 3 〇 a (collagen unit) monomeric proteins are covalently cross-linked at the site of the material. Therefore, the mature protein is insoluble and forms fine fibers having a high tensile strength. A number of secondary collagens have been described, the most common being Type I, which is the predominant collagen type in the skin, tendons, bones and cornea. Collagen is a fibrous protein composed of a triple helix structure of about 290 nm in length. Five of these triple helix structures (collagen unit molecules) are interdigitated to form microfibers having a diameter of about 3.6 nm. These fine fibers have a polar and non-polar portion to easily obtain specific interfiber-to-inner interactions. These fine fibers are filled into a tetragonal lattice to form sub-fibrils having a diameter of about 3 nanometers. Then, these subfibrils are further combined into collagen fine fibers (basic units of the knotted tissue) having a diameter of several hundred nanometers, and thus they are seen as a thin line in an optical microscope. Collagen is used in a coated form containing fibrin glue as a material for sealing wounds. Fibrin glues (i.e., combinations of fibrinogen, thrombin, and anti-protease peptides) have been successfully used for many years in the treatment of their surfaces for cementing tissues and nerves, and sealing small amounts of bleeding. One disadvantage of such fibrin glue is that if a large amount of bleeding occurs, the size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm).

......................變---- (請先閲讀背面之注意事項再場窝本頁) •訂· Φ: 1324524 A7 _B7_ 五、發明説明（3 ) 劑通常會在纖維蛋白發生足夠的聚合反應前被沖走。為了 克服此問題，外科醫生已開始手動地將液體纖維蛋白膠塗 .敷至可吸收的載劑諸如膠原質纖維網。 雖然這些結合的塗敷法已令人印象深刻地成功，但是 此方法由於某些缺點而無法大規模地應用。因其製備相當 不方便故該方法需要有經驗及熟練的人員，且該方法在急 救下無法容易地配製而獲得，因其配製的時間範圍為1〇至 15分鐘。這些因素刺激了發展改善的產物，結果為已發展 出一種固定覆蓋著一層固態纖維蛋白原、固態凝血酶及固 態抗蛋白酶肽被覆之膠原質載劑組合，如揭示在EP 〇 〇59 265。 此揭示在EP 〇 059 265中的膠原質載劑之功能主要地 為該載劑能吸附和授予塗敷的凝血製劑之機械穩定性。 已發展出一種結合纖維蛋白膠之止血特徵與做為載 劑帛的膠原質材才斗之產品，且已在泰可康柏（Tach〇c⑽ 商‘下製造。泰可康柏®為一種準備好可使用且容易塗敷之 ®定組合的膠原質貼片，其塗敷著下列的纖維蛋白膠活性 •组分：人類纖維蛋白原、牛的凝血酶及牛的抗蛋白酶肽。 從1990年代早期泰可康柏®已由尼康梅得製藥 (Nyeomed Pha刪）出f，且已使用在歐洲的臨床試驗中而 ❹於25_患者。該產品已再使用於日本臨床計劃中多 於7 0 0個患者上，而用力士曰丁门：立# u @用在大1不㈣應證m肝及肺切 除、膽道外科、脾臟 '腎臟及騰臟外科、ΕΝΤ外科、 外科及血管外科。已發現泰可康柏®為有效且具安全性。 本紙張尺度國國家標^) -----......................Change---- (Please read the notes on the back first and then on the page) • Order· Φ: 1324524 A7 _B7_ V DESCRIPTION OF THE INVENTION (3) Agents are usually washed away before sufficient polymerization of fibrin occurs. To overcome this problem, surgeons have begun to manually apply liquid fibrin glue to an absorbable carrier such as a collagen fiber web. Although these combined coating methods have been impressively successful, this method cannot be applied on a large scale due to certain disadvantages. This method requires experienced and skilled personnel because of its inconvenience in preparation, and the method cannot be easily prepared by emergency treatment because it is formulated for a time ranging from 1 to 15 minutes. These factors stimulate the development of improved products, resulting in the development of a combination of collagen carriers that are fixedly covered with a layer of solid fibrinogen, solid thrombin and solid anti-protease peptides as disclosed in EP 〇 59 265. The function of the collagen carrier disclosed in EP 059 059 265 is primarily that the carrier is capable of adsorbing and imparting mechanical stability to the coated coagulant formulation. A product that combines the hemostatic properties of fibrin glue with the collagen material as a carrier, has been developed and manufactured under the Tach〇c(10) business. Tektronix® is a preparation A collagen patch that is easy to apply and easy to apply. It is coated with the following fibrin glue activity components: human fibrinogen, bovine thrombin and bovine antiprotease. From the 1990s Early Tycoon Compaq® has been removed from Nikonmed Pha (Nyeomed Pha) and has been used in clinical trials in Europe for 25 patients. This product has been reused in Japanese clinical programs more than 70 0 patients, and the use of Luxi Dingmen: Li # u @ used in the big 1 no (four) should be proven m liver and lung resection, biliary surgery, spleen 'kidney and spleen surgery, sputum surgery, surgery and vascular surgery. It has been found that Tecco Compaq® is effective and safe. The national standard for this paper scale is ^) -----

(請先閲讀背面之注意事項再填寫本頁) .、tr— Φ... 1324524 五、發明說明（ 腔室直徑大於0.75 mm且小於4mm，和/或平均腔室直 徑小於3mm ; 及均勻分佈且固定在該載劑上之： b) 固態纖維蛋白原，及 c) 固態凝金酶。 該組成物可具有二種、三種或全部上述所提及之物理性(Please read the precautions on the back and fill out this page) ., tr— Φ... 1324524 V. INSTRUCTIONS (The chamber diameter is greater than 0.75 mm and less than 4 mm, and/or the average chamber diameter is less than 3 mm; and evenly distributed And immobilized on the carrier: b) solid fibrinogen, and c) solid condensate. The composition may have two, three or all of the aforementioned physical properties

質。在目前的較佳具體實施例中，該載劑材料以如在DKPA 2001 0〇135中所描述而製造，而該申請案為由尼康梅得製藥 在2002年！月25日主張其優先權的申請案，該申請宰的發 表名稱為“膠原質海綿之製備方法，及用來分轉原質泡泳部 分和延長的膠原質海綿之設傷，，。在本上下文中，名稱“腔室 直徑，，應該了料在腔室巾壁與壁㈣大直線㈣，即腔室的 最大對角直線距離。該腔室可為多角形，諸如八角形。因此， 當該載劑被切割時，該些腔室會被分開而切割成_些腔洞。 該固態纖維蛋白原及該固態凝血酶則固定在該載劑中，且大 部分存在於該些腔洞中，因此可提供__種實質上均勻的固離 凝血酶及固態纖維蛋白原分佈。比較至將凝血酶及纖維蛋白 原的液體組錢例如滴人或㈣到材料上之狀況由於此及 固定而可在載劑上導入實質量的纖維蛋白原及凝血酶。 塗敷的載劑之製備： -種塗敷的載劑之製傷’其基本上的組成為：· -製備一活性成份的懸浮液， •將該懸浮液均勾分佈至該載劑， 9 1324524 五、發明說明（7) 在目前較佳的具體實施例中，該膠原質載劑以如在DK PA 2001 00135中所描述而製造。三個膠原質載劑實例之物理 性質則提供在下列表中： 實例 I II III pH值 5.3 5.1 5.4 乳酸含量 2.3% 2.8% 2% 敍含量 0.1% 0.2% 0.1% 可溶的蛋白質含量 0.04% 0.05% 0.08% 硫酸鹽灰燼含量 0.3% 0.3% 0.3% 微生物純度(CFU/克） <12-345 <18-124 <11-33 與乾燥質量相關的 膠原質含量 95% 95% 98% 水含量 14% 15% 16% 彈性模數 10.4-42.1 N/cm2 15-50 N/cm2 12.3-41.0 N/cm2 孔洞尺寸 (直徑，平均值） 2.9 mm 2.1 mm 2.9 mm 密度 2.9-5.3 mg/cm3 2.9-5.9 mg/cm3 2.4-5.0 mg/cm3 3quality. In the presently preferred embodiment, the carrier material is manufactured as described in DKPA 2001 0 135, and the application is made by Nikon Med Pharmaceuticals in 2002! The application for claiming priority on the 25th of the month, the publication name of the application is "the preparation method of collagen sponge, and the use of the separation of the original bubble and the extended collagen sponge." In the context, the name "cavity diameter," should be the material in the chamber wall and the wall (four) large straight line (four), that is, the maximum diagonal straight distance of the chamber. The chamber can be polygonal, such as an octagonal shape. Therefore, when the carrier is cut, the chambers are separated and cut into cavities. The solid fibrinogen and the solid thrombin are immobilized in the carrier and are mostly present in the cavities, thereby providing a substantially uniform distribution of solid thrombin and solid fibrinogen. In comparison to the condition in which the liquid of thrombin and fibrinogen, for example, drops or (iv) onto the material, a fixed amount of fibrinogen and thrombin can be introduced onto the carrier. Preparation of coated carrier: - Injuring of a coated carrier 'The basic composition is: - preparing a suspension of the active ingredient, • Hooking the suspension to the carrier, 9 1324524 V. INSTRUCTION DESCRIPTION (7) In a presently preferred embodiment, the collagen carrier is manufactured as described in DK PA 2001 00135. The physical properties of the three collagen carriers are provided in the following table: Example I II III pH 5.3 5.1 5.4 Lactate content 2.3% 2.8% 2% Content 0.1% 0.2% 0.1% Soluble protein content 0.04% 0.05% 0.08% Sulfate ash content 0.3% 0.3% 0.3% Microbial purity (CFU/g) <12-345 <18-124 <11-33 Collagen content related to dryness quality 95% 95% 98% Water content 14% 15% 16% Elastic modulus 10.4-42.1 N/cm2 15-50 N/cm2 12.3-41.0 N/cm2 Hole size (diameter, average) 2.9 mm 2.1 mm 2.9 mm Density 2.9-5.3 mg/cm3 2.9- 5.9 mg/cm3 2.4-5.0 mg/cm3 3

可使用如揭示在美國專利案號5,942,278及6,177,126中 的滴注設備（drip-on-device)來進行均勻地分佈懸浮液或可 使用至少包含一個喷嘴的塗抹器來將懸浮液塗佈至載劑。 該喷射塗抹器為將該懸浮液用力推進噴嘴，同時互相相對 地移動載劑及噴嘴。該塗抹器可包括或安排在靠近一運送 帶、一授拌單位（其與一個泵或一組泵系統連接）或另一種 提供設備、及一個噴嘴或一組可橫向移動的喷嘴系統， 例如可在與運送帶正確的角度處移動。依介質的特定特 徵而定，該喷嘴或該喷嘴系統可具有不同的形狀及尺寸 。該噴嘴或噴嘴系統可經由管子連接至提供設備。該提供 設備可^將被覆介質從攪拌單位提供至喷嘴系統。在被覆 11 丄J五、發明說明（ 製程期間’該噴嘴系統可橫越載劑而移動。在其等待位置 時可將其保持在運送帶的-邊上。該被覆製程可利用光柵 來檢測於運送帶上之_的存在而開始，同樣地可利用光 柵Λ號來停止。此_塗抹器可提供一相當小的死體積且容 、地(^栝合易清潔）。再者，其具有可在任何時間中斷 被覆製的可能性，且其可在相當寬廣的黏度範圍下塗敷 且提供同質被覆。 一系統可於每平方公分的載劑上塗佈0.08毫升-0.12毫 升體積的懸浮液。 個重要的步驟為乾燥塗敷在載劑表面的被覆，該被 覆為漫式被覆之纖維蛋白原、凝錢及醇的懸浮液。該 法之實例包括之步驟有將塗敷的載劑提交至低於咖毫。 的C力T，以便獲得在載劑纟面上乾燥的被覆且可使該乾 燥的被覆物固定至該被覆表面。藉由施加—真空且在乾 製私中使用真空可保持低溫（2-10 t )及高相對濕a (8〇-95%) ’藉此可維持載劑、纖維蛋白原和凝血酶的結： 及物理性質’特別是以膠原質形式的載劑，諸如膠原質海 綿。 名稱“基本上的組成為，，意謂著三種組分對本發明來說 全：為基本且需要的。但是，非基本的添加劑諸如鈣離 及著色劑（諸如核黃素）亦可存在於組成物_。該組成物」 進-步包括其它有㈣成份，諸如—種或多種醫藥活性材 料’例如其可選自抗生素，諸如抗菌或抗黴菌及防止惡性 腫瘤發生的藥劑。 方 巴 燥 度 子可The drip-on-device as disclosed in U.S. Patent Nos. 5,942,278 and 6,177,126 may be used to uniformly distribute the suspension or the applicator comprising at least one nozzle may be used to apply the suspension to the carrier. . The jet applicator pushes the suspension vigorously to move the nozzle while moving the carrier and the nozzle relative to each other. The applicator may comprise or be arranged adjacent to a conveyor belt, a mixing unit (which is coupled to a pump or a group of pump systems) or another providing device, and a nozzle or a set of laterally movable nozzle systems, for example Move at the correct angle to the conveyor belt. The nozzle or the nozzle system can have different shapes and sizes depending on the particular characteristics of the media. The nozzle or nozzle system can be connected to the supply device via a tube. The providing device can supply the coated medium from the agitation unit to the nozzle system. In the coating 11 丄 J, invention description (during the process 'the nozzle system can move across the carrier. It can be held on the side of the conveyor belt when it is in the waiting position. The coating process can be detected by the grating Starting with the presence of the _ on the conveyor belt, the grating nickname can also be used to stop. This _applicator can provide a relatively small dead volume and can be easily and cleanly cleaned. The possibility of coating is interrupted at any time, and it can be applied over a relatively wide range of viscosities and provides a homogeneous coating. A system can apply a volume of 0.08 ml to 0.12 ml of suspension per square centimeter of carrier. An important step is to dry the coating applied to the surface of the carrier, which is a suspension of diffusely coated fibrinogen, coagulation and alcohol. Examples of the method include the step of submitting the coated carrier to a low level. C force T to obtain a coating that is dry on the surface of the carrier and to fix the dried coating to the coated surface. The vacuum can be maintained by applying a vacuum and using a vacuum in the dry process. (2-10 t ) and High relative wet a (8〇-95%) 'This maintains the carrier, fibrinogen and thrombin knots: and physical properties', especially in the form of collagen, such as collagen sponges. The composition above means that the three components are all: essential and necessary for the present invention. However, non-essential additives such as calcium and coloring agents such as riboflavin may also be present in the composition. The composition includes other components having a (four) component, such as one or more pharmaceutically active materials, for example, which may be selected from antibiotics, such as antibacterial or anti-fungal agents and prevention of malignant tumors.

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back and fill out this page)

12 A7 ' ---------B7_ 五、發明制（9 ) — 。雖然該載劑材料較佳地為一種膠原質海綿（其包括從 二=動物、轉殖基因或重組來源來的膠原質型式I材料）， 亦可利用其它型式的膠原質來製造，即膠原質型式卜Π、 /、IV、VII及但是，亦熟視的是該載劑可為一種生物 I降解的聚合物，諸如聚琉璃醣酸酸；多經基酸，例如乳 馱、glucolic酸、羥基丁酸；纖維素或凝膠。 且在本發明的一個較佳具體實施例中，該組成物包括一 具有-個或多個活性邊的載劑，其中纖維蛋白原的存在量 ^ 毫克/平方公分，諸如（3-6.7毫克/平方公分，較佳地 毛克/平方公分，及凝血酶的存在量為1 〇·5 5 IU/平方 公分，較佳地約2 · 〇 ί U/平方公分。該纖維蛋白原及/或凝血 酶較佳地為人類的，例如其可利用由熟知此技藝之人士所 热知的方法純化自天然來源、，或可利用由熟知此技藝之人 士所熟知的方法而製造之轉殖基因或重組的人類纖維蛋白 原及/或凝血酶。 先述技藝產品，諸如泰可康柏®、巴利布拉斯特 (BeripUst)®及蒂休斯爾（TissueSeal)@全部包含抗蛋白酶肽 «員似的抗分解纖維蛋白的藥劑。抗蛋白酶肽的來源僅可 來自牛本發明豕之目標為發展一種組成物，其具有改善 的載劑材料且僅含人類的、重組或轉殖基因起源的組分。 因此已製彳于與載劑材料相關的發展，且已研究出可以人 類凝血酶代替牛的凝血酶並避開抗蛋白酶肽。本發明家已 透過一步驟的方法朝向此目標工作。 百先，已發展出的泰可康柏Η(其為泰可康柏®的下一 本纸張尺度適用中國國豕標準（CNs) Α4規格（210X297公爱）12 A7 ' ---------B7_ V. Invention system (9) — . Although the carrier material is preferably a collagen sponge (which includes a collagen type I material from two animals, a transgenic gene or a recombinant source), it can also be produced using other types of collagen, namely collagen. Types of dip, /, IV, VII and, however, it is also apparent that the carrier can be a bio-degradable polymer, such as poly-glucaric acid; poly-basic acid, such as chylomicron, glucolic acid, hydroxyl Butyric acid; cellulose or gel. And in a preferred embodiment of the invention, the composition comprises a carrier having one or more active edges, wherein fibrinogen is present in an amount of ^mg/cm2, such as (3-6.7 mg/ The square centimeter, preferably the gross/square centimeter, and the thrombin are present in an amount of 1 〇 5 5 IU/cm 2 , preferably about 2 · 〇ί U/cm 2 . The fibrinogen and/or coagulation The enzyme is preferably human, for example, it can be purified from a natural source by methods well known to those skilled in the art, or can be produced using recombinant methods or methods produced by methods well known to those skilled in the art. Human fibrinogen and/or thrombin. The above-mentioned technical products, such as Tecco Compaq®, BeripUst® and TissueSeal@ all contain anti-protease peptides. An agent against fibrinolytics. The source of the anti-protease peptide can only be derived from the bovine invention. The object of the invention is to develop a composition having an improved carrier material and containing only human, recombinant or transgenic gene-derived components. So it’s already The development of carrier materials has led to the development of human thrombin instead of bovine thrombin and avoiding protease peptides. The inventors have worked towards this goal through a one-step approach. Compaq (this is the next paper scale for Tecco Compaq® for China National Standard (CNs) Α 4 specifications (210X297 public)

訂— (請先閱讀背面之注意事項再填寫本頁) Φ: 13 丄 A7 -------------B7__ 五、發明説明（1〇 ) " 個產扣）其中的牛凝血酶已由人類凝血酶取代。已進行泰可 康柏Η的臨床試驗，此試驗乃關於一些在止血、組織膠合 及組織封口的適應証中之處理證實的(階段Ilia)臨床試 驗在這些研究中所獲得但尚未公告之結果已証實泰可康 柏Η在血液及漏氣控制上的有效性及安全性，因此可提供 做為佐藥治療以在外科期間縫合止血組織膠合及組織封 特別地，泰可康柏Η在局部止血上的功效（與對照組比 車父，其可顯示出明顯地降低止血時間）已在類似的血管及肝 外科上有說服力地顯示。 同樣地，經發現泰可康柏Η能夠減低肺在尺寸上的缺 陷，而使得漏氣可更快速地消退且可有用地封住嚴重的肺 漏氣及肺氣腫。 但是，泰可康柏®及泰可康柏Η二者皆包含抗蛋白酶肽 做為產品的完整部分。抗蛋白酶肽已視為抑制纖維蛋白原 組i中的小量纖維蛋白溶酶原轉換至纖維蛋白溶酶及防止 纖維蛋白凝塊過早溶解（特別是在過度纖維素溶解的狀況 下）所需。 本發明家設計出新的實驗以測試抗蛋白酶肽為必需 的此假設。試管内實驗顯示出在凝塊中抗蛋白酶肽的抗纖 維素溶解保護及沒有抗蛋白酶肽的泰可康柏®(泰可康柏s) 不會在非常短的時間内溶解。因此設計出緊張的動物模 型’且比較泰可康柏S與泰可康柏Η以註明其有類似的功 效°在全部的模型中，各別地使用泰可康柏Η或S做為唯一 的止血方法。 本紙張尺度適用中國國家標準（CNS) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)Order — (Please read the notes on the back and fill out this page) Φ: 13 丄A7 -------------B7__ V. Invention description (1〇) " Production buckle) Bovine thrombin has been replaced by human thrombin. A clinical trial of Tekcombe has been conducted for the treatment of some of the indications in the indications for hemostasis, tissue gluing and tissue sealing (stage Ilia) clinical trials in these studies but not yet announced Confirmation of the effectiveness and safety of Tecco cypress in blood and air leakage control, so it can be used as an adjuvant treatment to suture hemostatic tissue gel and tissue seal during surgery, in particular, Tektronix cypress in local hemostasis The efficacy (in contrast to the control group, which can show a significant reduction in hemostasis time) has been convincingly demonstrated in similar vascular and hepatic surgery. Similarly, it has been found that Tecco cypress can reduce the size defects of the lungs, allowing the air leak to resolve more quickly and usefully to seal severe lung leaks and emphysema. However, both Coco Compo® and Tecco Companion contain anti-protease peptides as an integral part of the product. Anti-protease peptides have been considered to inhibit the conversion of small amounts of plasminogen to fibrinolytic enzymes in fibrinogen group i and to prevent premature dissolution of fibrin clots (especially in the case of excessive cellulose solubilization) . The inventors have devised a new experiment to test this hypothesis that anti-protease peptides are necessary. In vitro experiments showed that the anti-cellulolytic treatment of the anti-protease in the clot and the Tekcomb® without the anti-protease peptide did not dissolve in a very short time. Therefore, a tense animal model was designed' and the Tecco Compaq S and Tekcombe cypress were compared to indicate that they have similar efficacy. In all models, Tektronix or S is used as the sole Hemostasis method. This paper size applies to the Chinese National Standard (CNS) Α4 specification (210X297 mm) (please read the notes on the back and fill out this page)

14 U24!)24 A7 " B7 五、發明説明（11 ) 已進仃四組大量的實驗系列來研究本發明目前較佳 的具體實施例（泰可康柏s)與泰可康柏Η在功效及組織病理 乾型上的比較。將泰可康柏s或泰可康柏Η應用在狗、豬或 兔的肝臟、脾臟、胰臟器官或腦/腦膜上。該些實驗設計成 類似於正常的外科條件，即嚴重的緊張狀況及過度纖維素 溶解的症狀。 在這四..·且研九中所獲得的結果並無顯示出在泰可康 柏S及泰可康柏η間有任何有關聯的差異。二產品表現出類 似的止血及創傷封口功效，包括在嚴重的緊張狀況下會增 加器g内的壓力或藉由局部施加r_tPA而引起之過度纖維 素溶解。 因此可推斷，設計來評估抗蛋白酶肽（為泰可康柏Η的 一種組分）的整體必要性之臨床前的計劃已証明泰可康柏 Η及泰可康柏S具有類似的功效。二產品已成功地在所有的 貫驗條件下使用做為唯一的止血、組織膠合及组織封口方 法。在動物貫驗期間’並無不想要的組織反應。因此，抗 蛋白酶狀已從本發明之組成物中消除。 本發明之組成物已預計可如其前期材料般臨床地發 揮相同的止血、組織膠合及組織封口性質，且具有相同或 甚至更令人滿意的安全狀態。缺乏抗蛋白酶版（其目前僅可 來自於牛）可增加抗過敏性反應的安全性。就這一點而言， 應注意的是抗抗蛋白酶肽的抗體有在三個日本研究中發 生。在沒有抗蛋白酶肽的組成物上並無觀察到此類的免疫 反應。 本纸張尺度適用中國國家標準（CNS) Α4規格（210X 297公釐） (請先閲讀背面之注意事項再塡寫本頁)14 U24!) 24 A7 " B7 V. INSTRUCTIONS (11) Four sets of experimental series have been studied to study the presently preferred embodiments of the present invention (Tecco Compaq) and Tektronix Comparison of efficacy and histopathological dryness. Apply Tecco Compaq or Tecco cypress to the liver, spleen, pancreas or brain/mening of dogs, pigs or rabbits. These experiments were designed to resemble normal surgical conditions, namely severe stress conditions and symptoms of excessive cellulose dissolution. The results obtained in these four.. and the results of the study did not show any correlation between Tektronix S and Tektronix η. The second product exhibits similar hemostasis and wound sealing effects, including increased stress in the g or severe fibrin dissolution caused by local application of r_tPA under severe stress conditions. Therefore, it can be inferred that a preclinical plan designed to evaluate the overall necessity of the anti-protease peptide (a component of taikeke cypress) has demonstrated that Tekcombe and Tektronix S have similar efficacy. The two products have been successfully used under all the conditions of continuity as the sole hemostasis, tissue gluing and tissue sealing methods. There was no unwanted tissue response during the animal's examination. Therefore, the anti-protease form has been eliminated from the composition of the present invention. The compositions of the present invention have been expected to perform the same hemostasis, tissue gluing and tissue sealing properties clinically as their pre-materials, and have the same or even more satisfactory safety conditions. The lack of an anti-protease plate (which is currently only available from cattle) increases the safety of anti-allergic reactions. In this regard, it should be noted that antibodies against protease peptides have occurred in three Japanese studies. No such immune response was observed on the composition without the anti-protease peptide. This paper size applies to the Chinese National Standard (CNS) Α4 specification (210X 297 mm) (please read the notes on the back and write this page first)

1324524 五、發明説明（1S ) 時在礼膠薄片膨脹的最高點處測量經塗敷的載劑之面積， 比卓乂經塗数的載劑之膨張面積與經塗敷的載劑之起始 而擭得.。 ^本岛明之杈佳組成物為唯一的非牛的纖維蛋白密封 膠其令的纖維蛋白原及凝血酶為人類的，例如其可純化 自天然來源、或轉殖基因或重組的人類纖維蛋白原及凝血 酶’且可以-種將活性組分塗敷在具彈性的載劑之固定組 合方式而獲得，其具有數個優點： 其為準備好可使用的，並不需要耗費時間在融化或製 備程序： 其可容易直接地敷貼到大部分的組織及器官表面上； 可做内視鏡敷貼： 且無使止血再流出或被從目標區域沖掉的問題； 具有哉难蛋白，疑結成塊的膠合效應及具彈性的載劑 之機械支持的組合： 具有南彈性且能抵撞沉重的拉伸及壓缩； 可在3 〇分鐘内有效地止血及組織封口； 有利的安全狀態，即無牛的組分； 生物可降解的’僅會遺留小的組織疤； 可杆存在+2C至+ 8C下’且具有36個月的預計閑置壽 佘： 或在室溫最高至少2年的時期3 發展本發明之較佳·祖成物的理由源自於想要擺脫最 凌的丰組分’以防止任何（甚至是理論上的）將牛的疾病傳 二或土又 S 3 孓漂CNS ) Μ規格（210 X 297公釐） 17 1324524 A7 、發明説明（14 ) ~ 染至人類的風險，包括會傳染的海綿狀腦病類（TSEs)。該 活性組分（纖維蛋白原及凝血酶）因此源自於人類，而已移 除牛的抗蛋白酶肽（分解纖維蛋白的酵素纖維蛋白溶酶之 抑制劑）。因此’不包含牛的組分之本發明的較佳組成物之 I點為已消除會經由牛的材料傳染疾病（包括牛的海綿狀 腦病（BSE))之風險。 類似於其它纖維蛋白膠，本發明之組成物藉由再現血 液凝血連鎖反應的最後步驟而作用。一纖維蛋白原及凝血 酶混合物在具彈性的載劑表面上形成一固定的固態層。在 與流體（例如出血表面、體液或生理鹽液）接觸之後，該層 的組分會溶解並擴散至創傷的腔中而開始反應。 聚合反應會在創傷表面及載劑貼片間產生一強有力 的附著。在所需的膠合時間（即3至5分鐘）期間’應該較佳 地將本發明之組成物溫和地加壓至創傷表面上。該載劑貼 片提供了機械支持而允許創傷填塞。當創傷大量出血時該 貼片可適當地保持凝結組分且防止可能的再出血。作用機 制包括藉由凝血酶裂解胜肽而將纖維蛋白原轉換成纖維蛋 白。纖維蛋白單體自然地聚合成會形成黏的及具彈性的凝 I 塊之纖維蛋白索，而將載劑貼片膠合至創傷表面。該纖維 蛋白基質隨後提供做為纖維蛋白芽（fibrinoblast)漂移的支 架（第8圖）。 如二組分黏著劑，創傷表面及載劑藉由聚合反應而黏 著在一起。載劑貼片的機械穩定性可對纖維蛋白凝結成塊 之止血效應加入一填塞效應。再者，活性物質僅存在面對 國國家標準(_規格⑵οχ騰幻 —1324524 V. Inventive Note (1S) Measure the area of the coated carrier at the highest point of expansion of the sapphire sheet, the area of the swell of the carrier and the start of the coated carrier And Chad. ^本岛明之杈 composition is the only non-bovine fibrin sealant which makes fibrinogen and thrombin human, for example, it can be purified from natural sources, or transgenic genes or recombinant human fibrinogen and Thrombin's can be obtained by applying the active component to a fixed combination of elastic carriers, which has several advantages: it is ready for use and does not require time in the melting or preparation process. : It can be easily applied directly to the surface of most tissues and organs; it can be applied as an endoscope: there is no problem of stopping bleeding or being washed away from the target area; Combination of gluing effect and mechanical support of elastic carrier: It has south elasticity and can withstand heavy stretching and compression; it can effectively stop bleeding and tissue sealing within 3 ; minutes; favorable safety status, ie no cattle The components; biodegradable 'only left small tissue 疤; can exist under +2C to + 8C' and have 36 months of estimated idle life: or at room temperature for at least 2 years 3 development The reason for the preferred ancestral object of the present invention stems from the desire to get rid of the most abundant abundance component' to prevent any (or even theoretical) spread of the disease of the cattle or the soil and the S 3 孓 drift CNS) Specifications (210 X 297 mm) 17 1324524 A7, invention description (14) ~ Risk of infection to humans, including sporadic encephalopathies (TSEs) that can be transmitted. The active component (fibrinogen and thrombin) is thus derived from humans, and the bovine anti-protease peptide (an inhibitor of fibrinolytic enzyme plasmin) has been removed. Thus, the point I of the preferred composition of the present invention which does not contain bovine components is the risk of eliminating diseases that may be transmitted through bovine materials, including bovine spongiform encephalopathy (BSE). Similar to other fibrin glues, the compositions of the present invention act by reproducing the final step of the blood coagulation cascade reaction. A fibrinogen and thrombin mixture forms a fixed solid layer on the surface of the elastomeric carrier. After contact with a fluid (such as a bleeding surface, body fluids, or physiological saline), the components of the layer dissolve and diffuse into the cavity of the wound to initiate the reaction. The polymerization produces a strong adhesion between the wound surface and the carrier patch. The composition of the present invention should preferably be gently pressurized onto the wound surface during the desired bonding time (i.e., 3 to 5 minutes). The carrier patch provides mechanical support to allow for wound filling. The patch suitably maintains the coagulation component and prevents possible rebleeding when the wound is heavily bleeding. The mechanism of action involves the conversion of fibrinogen to fibrillar by thrombin cleavage of the peptide. The fibrin monomer naturally polymerizes into a fibrin strand that will form a viscous and elastic gel, while the carrier patch is glued to the wound surface. The fibrin matrix is then provided as a scaffold for fibrinoblast drift (Fig. 8). For example, a two-component adhesive, the wound surface and the carrier are adhered together by polymerization. The mechanical stability of the carrier patch adds a packing effect to the hemostatic effect of fibrin coagulation. Furthermore, the active substances only exist in the face of national standards (_Specifications (2) οχ 幻 — —

..................----- (請先閲讀背面之注意事項再填窝本頁) -一° 五、發明説明（15 ) 受傷區域的載劑表面上’且它們不會藉由填塞效應及溫和 —壓力而擴散通過載劑。因此，比較至使用大部分纖 維蛋白膠類的狀況’當已使用本發明之組成物時，在覆蓋 著本發明之組成物的受傷區域及其它器官或部分間並無附 著。 不像氰基丙烯酸酯及凝膠_雷瑣辛-甲醛（grf)膠合類 (其對實質組織具高度組織毒害），本發明之固態組成物可 生理地降解且在塗佈後數週或月内會由組織取代，其主要 地經由二個機制： 1·該纖維蛋白凝塊部分由於纖維蛋白溶解而降解及部分由 細胞吞喔作用而降解。 2.該載劑逐層由可吸附的肉芽組織降解而轉換成一種由内 生性結蒂組織組成的假囊膜。 本發明之組成物可有用地用於止血、組織膠合及組織 封口 1別是在外科干預（interventi〇n)上，在胃與腸系統 中諸如食道、3、小腸、大腸、直腸；在實質器官中， 諸如肝臟、脾臟、胰臟、腎臟、肺臟、腎上腺、甲狀腺及 淋巴結；心企管外科；料科’包括氣管、支氣管或肺.上 的外科；在耳、鼻及咽喉（ENT)區域中的外科干預，包括 科卜科’婦科、泌尿科、骨頭（例如骨鬆質切除）及急救 外科’神經外科 '淋巴 '膽及腦脊髓（csf)療管；及在胸及 肺外科期間的漏氣。心b，本發明亦關於將所描述的組成 物使用在上述的用途中。 應該強調的是本發明之組成物實質上為空氣緊密及 本紙張尺度適财S國家標準⑽）A娜⑵GX297公复) 1324524 A7 B7 五、發明説明（l6 ) 液體緊密的，此為該產品可特別用來處理淋巴、膽及腦脊 髓的（CSF)瘻管及在肺病及胸外科期間漏氣的理由。再者， 由於該產品實質上為液體緊密的，其可高度地使用在會高 度出血的器官（諸如肝臟及脾臟）外科上，及例如在胃與腸 道中的外科上。 當出血或淋巴、膽、空氣或CSF漏氣而無法以傳統的 方法控制時，或這些方法會產生不利的結果時可塗敷本發 明之產品。 該載劑較佳地為一種膠原質海綿、纖維網或貼片，此 些名稱與在本專利說明書及申請專利範圍中所使用的同 義。該些組分（膠原質、纖維蛋白原及凝血酶）較佳地為哺 乳動物起源。較佳地，該些固態組分為人類起源。該膠原 質、纖維蛋白原及凝血酶可純化自天然來源，或重組或轉 殖基因的人類纖維蛋白原及/或凝血酶。 目前較佳的膠原質來源為馬。為了防止由於受病毒污 染而藉由膠原質貼片將會引起疾病的馬病毒傳染至人類， 適當地選擇來源材料及藉由製造方法對會潛在地引起疾病 的藥劑減能為重要的預防措施。 圖形之符號表 第1圖 1.1歐普拉斯金(Opraskin)® :無塗敷/已塗敷 1.2已塗敷的歐普拉斯金® :塞入内視鏡設備 1.3已塗敷的歐普拉斯金：在塞入内視鏡設備後無摺疊 第2圖 2.1威羅斯潘(Willospon)®專長(forte):無塗敷/已塗敷 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 20 Ί. 1. Φ (請先閲讀背面之注意事項再填寫本頁) .、tT— t 1324524 A7 B7五、發明説明（17 ) 2.2已塗敷的咸羅斯潘®專長:塞入内視鏡設備 2.3已塗敷的威羅斯潘®專長：在塞入内視鏡設備後無摺疊 第3圖‘ 3.1威羅斯潘⑯斯佩滋而(Spezial):無塗敷/已塗敷 3.2已塗敷的威羅斯潘@斯佩滋而:塞入内視鏡設備 3.3已塗敷的威羅斯潘@斯佩滋而：在塞入内視鏡設備後無摺疊 第4圖 4·1愛斯吸(Ethisorb)®貼片:無塗敷/已塗敷 4.2已塗敷的愛斯吸@貼片：塞入内視鏡設備 4.3已塗敷的愛斯吸®貼片：在塞入内視鏡設備後無摺疊 第5圖 5.1泰普坦柏(Tabotamp)®NU尼特(Knit):無塗敷/已塗敷 5.2已塗敷的泰普坦柏®NU尼特：塞入内視鏡設備 ϋ塗敷泰普坦柏®NU尼特：在塞入内視鏡設備後無摺疊 第6圖 6.1海綿尼康梅得:無塗敷/已塗敷[實驗樣品] 6.2已塗敷的海綿尼康梅得[實驗樣品]:塞入内視鏡設備 6·3已塗敷的膠原質海綿尼康梅得[實驗樣品]:在塞入内視鏡設備後無摺疊 原質海綿尼康梅得[製造樣 %m ^ - 内視鏡工具：安德達克(Endodock)® 内視鏡f具:安德達克® 内視鏡^#:安德達克® " -- 載劑貼片的降解。且分以暗灰 實例 下列實例I-IV闡明以不同的纖維蛋白原及凝血酶原始 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)..................----- (Please read the note on the back and fill in the page) -1° 5, invention description (15) On the surface of the carrier 'and they do not diffuse through the carrier by the packing effect and the mild-pressure. Therefore, it is compared to the case where most of the fibrin glue is used. When the composition of the present invention has been used, there is no attachment between the wounded area covering the composition of the present invention and other organs or parts. Unlike cyanoacrylates and gels - resorcinol-formaldehyde (grf) gluing, which are highly tissue toxic to parenchymal tissue, the solid compositions of the present invention are physiologically degradable and are weeks or months after coating. The inside is replaced by tissue, which is mainly via two mechanisms: 1. The fibrin clot is partially degraded by fibrinolysis and partially degraded by cell swallowing. 2. The carrier is converted layer by layer from the adsorbable granulation tissue to a pseudocapsule composed of endogenous pedicle tissue. The compositions of the present invention are useful for use in hemostasis, tissue gluing, and tissue sealing 1 in surgical interventions such as the esophagus, the small intestine, the large intestine, the rectum, and the parenchyma in the stomach and intestine systems; Medium, such as liver, spleen, pancreas, kidney, lung, adrenal gland, thyroid gland and lymph nodes; cardiac surgery; materials 'including surgery on the trachea, bronchus or lungs; in the ear, nose and throat (ENT) area Surgical interventions, including Cobco's gynecology, urology, bones (eg, cancellous bone resection), and emergency surgery 'neurosurgery' lymphatic bile and cerebrospinal (csf) treatments; and leaks during thoracic and pulmonary surgery . Heart b, the invention also relates to the use of the described compositions in the above-mentioned uses. It should be emphasized that the composition of the present invention is substantially air tight and the paper scale is suitable for S national standards (10)) A Na (2) GX297 public recovery) 1324524 A7 B7 V. Invention description (l6) Liquid is tight, this is the product It is especially used to treat lymphatic, biliary and cerebrospinal (CSF) fistulas and the reasons for leaks during lung and thoracic surgery. Furthermore, since the product is substantially liquid tight, it can be highly used in the surgical treatment of organs which are highly bleeding, such as the liver and spleen, and in surgery such as in the stomach and intestines. The product of the present invention can be applied when bleeding or lymph, gall, air or CSF leaks and cannot be controlled by conventional methods, or when these methods produce unfavorable results. The carrier is preferably a collagen sponge, fiber web or patch, and these names are synonymous with those used in the scope of this patent specification and the patent application. These components (collagen, fibrinogen and thrombin) are preferably of mammalian origin. Preferably, the solid components are of human origin. The collagen, fibrinogen and thrombin can be purified from natural sources, or human fibrinogen and/or thrombin recombinant or transgenic. The current preferred source of collagen is horse. In order to prevent the infection of the horse virus which causes disease by the collagen patch due to virus contamination to humans, it is an important preventive measure to appropriately select the source material and to reduce the potential of the agent which may cause the disease by the manufacturing method. Symbolic Chart of the Figure 1 Figure 1.1 Opraskin®: Uncoated/coated 1.2 Applied Oprahkin®: Inserted into the endoscope device 1.3 Coated Oprahkin: No folding after insertion into the endoscope device Figure 2 2.1 Willospon® specialty (forte): uncoated/coated paper size applicable to Chinese National Standard (CNS) A4 size (210X297 mm) 20 Ί. 1. Φ (please read the precautions on the back and fill out this page) .,tT— t 1324524 A7 B7 V. Description of invention (17) 2.2 Salted Rosepan® specialty: Inserted into endoscope equipment 2.3 Coated Verospan® Specialty: No Folding After Inserting Endoscopic Equipment Figure 3 3.1 Spezial: No-coated/coated 3.2 coated Willis Pan @Spezi and: Inserted into the endoscope equipment 3.3 has been coated with Willospan @斯佩滋: without folding after inserting the endoscope device 4th Figure 4·1 Ethisorb® patch : No coating / Applied 4.2 Applied Ace Suction @ Patch: Tucked into the endoscope device 4.3 Coated Ace® patch: no folding after insertion into the endoscope device Figure 5 5.1 Tabotamp® NU Knit: No coating/coated 5.2 coated Tuptan® NU Nit: Inserted into the endoscope device ϋ coated Taipu Tambo® NU Nit: No folding after insertion into the endoscope device Figure 6 6.1 Sponge Nikonme: No coating/coated [Experimental sample] 6.2 Coated sponge Nikonme [Experimental sample]: Inserted into the endoscope device 6.3 coated collagen sponge Nikonme [Experimental sample]: Unfolded original sponge Nikonme after insertion into the endoscope device [Make Sample %m ^ - Endoscope Tool: Endodock® Endoscopes: Andertec® Endoscopes ^#: Andertec® " -- Degradation of carrier patches. And the dark ash example The following examples I-IV clarify that the Chinese National Standard (CNS) A4 specification (210X297 mm) is applied to different fibrinogen and thrombin original paper scales (please read the notes on the back and fill in the form) page)

21 1324524 A7 B7 五、發明説明（丨8) 材料來製備經塗敷的膠原質海綿之不同程序。 纖維蛋白原的原始材料 組分 總材料的％ 配方A 配方B 配方C 人類纖維蛋白原 36-52 42-47 36-52 人類白蛋自 16-24 20-24 16-24 總蛋白質 52-76 62-71 52-76 氣化納 8-14 0 8-14 檸檬酸三鈉 2-4 1-3 2-4 精胺酸(鹽酸） 15-26 15-21 15-26 甘胺酸 0 6-9 1-2 組胺酸 0 3-5 0 蔗糖 0 0 1-2 剩餘的水分 <=2 2-4 <=1.5 (請先閲讀背面之注意事項再填寫本頁) 凝血酶的原始材料 配方 活性(I.U/毫克） 物質 剩餘的水分 額外的物質添加劑 人類凝血酶A 360-540 <=3% 人類白蛋白、氣化 鈉、檸檬酸鈉 人類凝血酶B 7-10 <=3% 人類白蛋白、氣化 鈉、檸檬酸鈉 人類凝血酶C 35-60 <=3% 人類白蛋白、氣化 鈉、醋酸納、孙胺酸21 1324524 A7 B7 V. INSTRUCTIONS (丨8) Materials to prepare different procedures for coated collagen sponges. Fibrinogen Raw Material Components % of Total Materials Formulation A Formulation B Formulation C Human Fibrinogen 36-52 42-47 36-52 Human White Eggs from 16-24 20-24 16-24 Total Protein 52-76 62 -71 52-76 gasification nano 8-14 0 8-14 trisodium citrate 2-4 1-3 2-4 arginine (hydrochloric acid) 15-26 15-21 15-26 glycine 0 6-9 1-2 Histamine 0 3-5 0 Sucrose 0 0 1-2 Remaining moisture <=2 2-4 <=1.5 (Please read the note on the back and fill out this page) Thrombin Original Material Formulation Activity (IU/mg) Substance Residual Moisture Additional Substance Additive Human Thrombin A 360-540 <=3% Human Albumin, Sodium Sulfate, Sodium Citrate Human Thrombin B 7-10 <=3% Human Albumin, sodium vaporification, sodium citrate, human thrombin C 35-60 <=3% human albumin, sodium gasification, sodium acetate, betaine

實例I 在本實例中，該懸浮液包括人類纖維蛋白原配方B及 人類凝血酶配方B。 藉由施加下列的量及參數而獲得最後為3500毫升的 懸浮液體積： 22 本紙張尺度適用中國國家標準（CNS) A4規格（210 X 297公釐） 1324524 A7 _________ 五、發明説明（w ) 纖維蛋白原混合物： -2800毫升.的乙醇（94%，於2X： -8°C下）， '._492.5克的人類纖維蛋白原配方B， -493.5毫克的核黃素， 將該纖_蛋白原混合物在授拌下貯存於2_8 °C中8-16小 時。 凝血酶混合物： -100毫升的乙醇（100%，於_3〇。〇下）， -12.27克的人類凝血酶配方b， 將該凝血酶混合物貯存在_3〇。(：下8-16小時。 懸浮液： -將1 57毫升的凝血酶混合物加入至該纖維蛋白原混合 物， -充入94%於2-8°C的乙醇至最後為3500毫升的懸浮液體 積。 懸浮液特徵： 1.乙醇濃度：94.3% 2·沉降行為： a) 在起始後5分鐘之沉降體積：測試體積的98〇/〇， b) 在起始後24小時之沉降體積：測試體積的64〇/〇。 3.粒子尺寸（福克瓦德平均直徑）：56.4+/-1.3微米Example I In this example, the suspension comprises human fibrinogen formulation B and human thrombin formulation B. The final volume of 3500 ml is obtained by applying the following amounts and parameters: 22 This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1324524 A7 _________ V. Description of invention (w) Fiber Proprotein mixture: -2800 ml. of ethanol (94% at 2X: -8 ° C), '._492.5 g of human fibrinogen formula B, -493.5 mg of riboflavin, the fiber _ The proprotein mixture was stored at 2_8 °C for 8-16 hours under agarose. Thrombin mixture: -100 ml of ethanol (100% in _3 〇. underarm), -12.27 g of human thrombin formulation b, the thrombin mixture was stored at _3 〇. (: 8-16 hours. Suspension: - Add 1 57 ml of thrombin mixture to the fibrinogen mixture, - Fill with 94% ethanol at 2-8 °C to a final volume of 3500 ml suspension Suspension characteristics: 1. Ethanol concentration: 94.3% 2. Settling behavior: a) Settling volume 5 minutes after start: 98 〇 / 测试 of the test volume, b) Settling volume 24 hours after the start: Test The volume is 64 〇 / 〇. 3. Particle size (Fuckwald average diameter): 56.4 +/- 1.3 microns

將膠原質條形式之載劑塗敷上懸浮液。首先，將Μ條 膠原質海綿條預先培養在一冷卻的腔室中，其條件如下” -溫度：5.2°C 本紙張尺度適用中國國家標準（CNS) A4規格（210X 297公釐） (請先閱讀背面之注意事項再填窝本頁) 23 1324524 A7 B7 五、發明説明（20 ) -絕對濕度：每公斤空氣4.8克的水 -培養時間：18.5小時 如下乾燥已塗敷的膠原質海绵條： 將已塗敷的長條培養在溫度5 2艽、每公斤空氣4 8克水之 絕對濕度下15分鐘。 然後將已塗敷的長條在真空乾燥室中以下列乾燥條 件乾燥： -空氣狀悲：溫度5.2。(：，絕對濕度每公斤空氣4.8克的水 -流經吸氣閥的空氣：每小時23立方公尺 -真空：59毫巴 -乾燥時間：4小時 當在威伯菲克斯攪拌器上以⑽卜丨2〇〇rpm的頻率搖晃2 分鐘時’在膠原質海綿條上獲得的被覆之剝落約略為〇2 毫克/平方公分。The carrier in the form of a collagen strip is applied to the suspension. First, the strip of collagen sponge is pre-cultured in a cooled chamber under the following conditions: - Temperature: 5.2 °C This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (please first Read the notes on the back and fill in this page) 23 1324524 A7 B7 V. INSTRUCTIONS (20) - Absolute humidity: 4.8 grams of water per kilogram of air - Incubation time: 18.5 hours Dry the coated collagen sponge strip as follows: The coated strips were incubated at a temperature of 5 2 Torr for 15 minutes at an absolute humidity of 48 grams of water per kg of air. The coated strips were then dried in a vacuum drying chamber under the following drying conditions: - air Sadness: Temperature 5.2. (:, absolute humidity 4.8 grams of water per kilogram of air - air flowing through the suction valve: 23 cubic meters per hour - vacuum: 59 mbar - drying time: 4 hours when in Wilburfink When the shaker was shaken at a frequency of (10) dip 2 rpm for 2 minutes, the peeling of the coating obtained on the collagen sponge strip was approximately 〇2 mg/cm 2 .

實例II 在本實例中’該懸浮液包括人類纖維蛋白原配方C及 人類凝血酶配方c。 可藉由施加下列的量及參數而獲得最後3500毫升的 懸浮液體積： 纖維蛋白原混合物： -2252毫升的乙醇（94〇/。，在2°c -8〇c下）， -370.7克的人類纖維蛋白原配方c， •493.5毫克的核黃素， 將纖維蛋白原混合物在攪拌下貯存於2-8X：中8-16小時。 本纸張尺度適用中國國家標準（CNS) A4規格（210 X 297公爱） 24 (請先閱讀背面之注意事項再填寫本頁) -訂— f 1324524 五、發明説明（21 本紙張尺度適用中國國家標準（CNS) A4規格（21〇><297公楚） A7 B7 凝血酶混合物： -188毫升的乙醇（100%，在-川它下） -12小瓶的人類凝血酶配方c(i〇650 I.U./小瓶）/12毫升的 注射用水 將該凝血酶混合物貯存在_3〇°c下8-16小時。 懸浮液：_ -將164.5毫升的凝血酶混合物加入至該纖維蛋白原混合 物， -充入94%在2-8。(：的乙醇至最後3500毫升的懸浮液體積。 懸浮液特徵： 1.乙醇濃度：94.1% 2-沉降行為： a) 在起始5分鐘後之沉降體積：測試體積的94%， b) 在起始24小時後之沉降體積：測試體積的71〇/〇。 3.粒子尺寸（福克瓦德平均直徑）：49.2+/-0.93微米 將膠原質條形式之載劑塗敷懸浮液。首先，將48條膠 原質海綿條預先培養在一冷卻的腔室中，其條件如下： -溫度：4.8°C -相對濕度：90.3% -培養時間：22.25小時 如下乾燥已塗敷的膠原質海綿條： 將已塗敷的長條培養在溫度4.9。〇、每公斤空氣4.8克水的 絕對濕度下i 3分鐘。 然後’已塗敷的長條在真空乾燥室中以下列乾燥條件 25 (諳先閲讀背面之注意事項再填寫本頁)Example II In this example, the suspension included human fibrinogen formulation C and human thrombin formulation c. The final 3500 ml suspension volume can be obtained by applying the following amounts and parameters: Fibrinogen mixture: -2252 ml of ethanol (94 〇 /., at 2 ° c -8 ° c), -370.7 g Human fibrinogen formulation c, • 493.5 mg of riboflavin, stored in 2-8X: 8-16 hours with stirring. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 24 (Please read the note on the back and fill out this page) - set - f 1324524 V. Invention description (21 paper scale applies to China) National Standard (CNS) A4 Specification (21〇><297 public Chu) A7 B7 Thrombin Mixture: -188ml of ethanol (100%, under -chuan) -12 vials of human thrombin formula c(i 〇650 IU/vial)/12 ml of water for injection The thrombin mixture was stored at _3 ° C for 8-16 hours. Suspension: _ - 164.5 ml of thrombin mixture was added to the fibrinogen mixture, - Fill 94% in 2-8. (: ethanol to the final 3500 ml suspension volume. Suspension characteristics: 1. Ethanol concentration: 94.1% 2-Settling behavior: a) Settling volume after 5 minutes from the start : 94% of the test volume, b) Settling volume after the first 24 hours: 71 〇/〇 of the test volume. 3. Particle size (Fickwald average diameter): 49.2 +/- 0.93 microns The carrier in the form of a collagen strip was coated with a suspension. First, 48 collagen sponge strips were pre-cultured in a cooled chamber under the following conditions: - Temperature: 4.8 ° C - Relative humidity: 90.3% - Culture time: 22.25 hours Drying the coated collagen sponge as follows Strip: The coated strip was incubated at a temperature of 4.9. 〇, 4.8 grams of water per kilogram of water at absolute humidity for 3 minutes. Then the 'coated strips are in the vacuum drying chamber with the following drying conditions 25 (please read the back of the back sheet and fill out this page)

1324524 A7 ~_ B7__— 五、發明説明（22 ) " 乾燥： -空氣狀態· μ度5.2 C，絕對濕度每公斤空氣4.9克的水 -流經吸氣閥的空氣：每小時25立方公尺 -真空：60毫巴 -乾燥時間：4小時 S在威伯菲克斯搜拌器中以800-12〇〇rpm的頻率搖晃2 分鐘時，在膠原質海绵條上獲得的被覆之剝落約為〇 3毫克 /平方公分。1324524 A7 ~_ B7__- V. Invention description (22) " Drying: - Air condition · μ degree 5.2 C, absolute humidity 4.9 g of water per kg of air - Air flowing through the suction valve: 25 m ^ 3 per hour - Vacuum: 60 mbar - Drying time: 4 hours S. When shaking at a frequency of 800-12 rpm for 2 minutes in a Wilburks sifter, the peeling of the coating obtained on the collagen sponge strip is about 〇 3 mg / cm ^ 2 .

實例III 在本實例中’該懸浮液包括人類纖維蛋白原配方c及 人類凝血酶配方C。 藉由施加下列的量及參數而獲得最後780毫升的懸浮 液體積： 纖維蛋白原混合物： -700毫升的乙醇（94%，在2°〇-8。〇下）， -84.42克的人類纖維蛋白原配方c， -110毫克的核黃素， 將該纖維蛋白原混合物在攪拌下貯存於2_8。(：中8-16小 時。 凝血酶混合物： •35毫升的乙醇（100%，在-3〇°c下）， -0.54克的人類凝血酶配方C， 將凝血酶混合物貯存在-3(TC下8-16小時。 懸浮液： 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)Example III In this example, the suspension included human fibrinogen formulation c and human thrombin formulation C. The final 780 ml suspension volume was obtained by applying the following amounts and parameters: Fibrinogen mixture: -700 ml of ethanol (94% at 2 ° 〇-8. underarm), -84.42 g of human fibrin Original formulation c, -110 mg of riboflavin, the fibrinogen mixture was stored at 2-8 with stirring. (: 8-16 hours. Thrombin mixture: • 35 ml of ethanol (100% at -3 ° C), -0.54 g of human thrombin formulation C, storing thrombin mixture at -3 (TC 8-16 hours. Suspension: This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

26 五 23 、發明説明 -將23.0毫升的凝企酶混合物加入至該纖維蛋白原混合 物， -充入H)0%2-n；的乙醇至最後780毫升的懸浮液體積。 懸浮液特徵： L乙醇濃度：94% 2.沉降行為： a)在起始5分鐘後之沉降體積：測試體積的92%， )在起始24小時後之沉降體積：測試體積的72%。 淖子尺寸（福克瓦德平均直控）：60.5+/-0.5微米 將膠原質條形式之載劑塗敷懸浮液。首先，將8條膠 原質海錦條預先培養在__冷卻的腔室中，條件如下列： -溫度：6.0。〇 相對濕度：85% -培養時間：丨8_5小時 如下乾燥已塗敷的膠原質海綿條： 將已塗敷的長條培養在溫度51及8 5 %的相對濕度下4 5分 鐘0 然後，將已塗敷的長條在真空乾燥室中以下列乾燥條 件乾燥： u -空氣狀態：溫度5。〇，相對濕度85% -流經吸氣閥的空氣：每小時1.2立方公尺 -真空：35毫巴 -乾燥時間.：4小時 备在威伯菲克斯攪拌器上以800-1200rpm的頻率搖晃2 本紙張尺度適用中國國家標準（CNS) M規格（21〇χ297公楚）26 V. 23, INSTRUCTION DESCRIPTION - 23.0 ml of the coagulating enzyme mixture was added to the fibrinogen mixture, -H) 0%2-n; ethanol was charged to the final 780 ml suspension volume. Suspension characteristics: L ethanol concentration: 94% 2. Settling behavior: a) Settling volume after the first 5 minutes: 92% of the test volume, ) Settling volume after the first 24 hours: 72% of the test volume. Gardenia size (Fuckerwald average direct control): 60.5 +/- 0.5 micron A carrier in the form of a collagen strip is coated with a suspension. First, 8 gelatin jellyfish were pre-cultured in a __cooled chamber under the following conditions: - Temperature: 6.0. 〇 Relative humidity: 85% - Culture time: 丨 8_5 hours Dry the coated collagen sponge strip as follows: The coated strips are incubated at a temperature of 51 and 85 % relative humidity for 45 minutes 0 Then, The coated strips were dried in a vacuum drying chamber under the following drying conditions: u - air state: temperature 5. 〇, relative humidity 85% - air flowing through the suction valve: 1.2 cubic meters per hour - vacuum: 35 mbar - drying time.: 4 hours on the Wilburks mixer at 800-1200 rpm Shake 2 This paper scale applies to China National Standard (CNS) M specification (21〇χ297 public Chu)

_、1Γ· Α讀先閱讀背面之注意事喟再填寫本頁j 27 - 0.3毫克 1324524 五、發明説明（24 ) 分鐘時，在膠原質海绵條上獲得的被覆之剝落 /平方公分。_, 1Γ· Read the first note on the back and then fill out this page j 27 - 0.3 mg 1324524 V. Inventive Note (24) Minutes, peeling/square centimeter of the coating obtained on the collagen sponge strip.

實例IV 在本實例中，該懸浮液包括人類纖維蛋白原配方A及 人類凝血醇配方A。 可藉由施加下列的量及參數獲得最後312〇毫升的驂浮 液體積： ^ 纖維蛋白原混合物： ·2540毫升的乙醇（100〇/〇，在2。(：-8。(：下）， -311.6克的人類纖維蛋白原配方a， -440毫克的核黃素， 將該纖維蛋白原混合物在攪拌下貯存於2 8t：中8_16小 時。 凝jk酶混合物： -210毫升的乙醇（ι〇〇〇/〇，在_3〇。匸中）， -229克的人類凝血酶配方a 懸浮液： -將87.3毫升注射用水加入至該纖維蛋白原混合物。 將該凝血酶混合物加入至該纖維蛋白原混合物。 充入100%2-8。(：的乙醇至最後的懸浮液體積。 懸浮液特徵： L乙醇濃度：97% 2·沉降行為： a)在起始5分鐘後之沉降體積：測試體積的95.6%， 本紙張尺度適用中國國家標準（cns) A4規格（21〇><297公爱）Example IV In this example, the suspension comprised Human Fibrinogen Formula A and Human Thrombin Formula A. The final 312 ml of the float volume can be obtained by applying the following amounts and parameters: ^ Fibrinogen mixture: · 2540 ml of ethanol (100 〇 / 〇, at 2. (: -8. (:)), - 311.6 g of human fibrinogen formula a, -440 mg of riboflavin, the fibrinogen mixture was stored under stirring at 28 °C for 8-16 hours. Condensed jk enzyme mixture: -210 ml of ethanol (ι〇) 〇〇/〇, in _3〇.匸), -229 grams of human thrombin formulation a suspension: - 87.3 ml of water for injection is added to the fibrinogen mixture. The thrombin mixture is added to the fibrin Original mixture. Filled with 100% 2-8. (: ethanol to the final suspension volume. Suspension characteristics: L ethanol concentration: 97% 2. Settling behavior: a) Settling volume after the first 5 minutes: test 95.6% of the volume, this paper scale applies to the Chinese National Standard (cns) A4 specification (21〇><297 public)

(請先閲讀背面之注意事項再填寫本頁) 28 五、發明説明（25 b)在起始24小時後之沉降體積：測試體積的63.5%。 3·粒子尺-寸（福克瓦德平均直徑）：51.8+/-0.8微米 將膠原質條形式的載劑塗敷懸浮液。首先，將48條膠 原貧海’4條預先培養在冷卻的腔室中，條件如下列： -溫度：6.. 5 -相對濕度：90% -培養時間：22.5小時 如下乾燥已塗敷的膠原質海綿條： 10 將已塗敷的長條培養在溫度6 5及9〇%的相對濕度下 分鐘。 然後將已塗敷的長條於真空乾燥室中在下列乾燥條 件下乾燥： 二氣狀態·溫度6.5°C ,相對濕度9〇〇/0 •流經吸氣閥的空氣：每小時21立方公尺 -真空：58毫巴 -乾燥時間：4小時 虽在威伯菲克斯攪拌器上以800-1200rpm的頻率搖晃2 刀知日寺’在膠原質海綿條上獲得的被覆剝落少於〇 ι毫 平方公分。 實例1 抗蛋白酶肽為泰可康柏®的組分 類似於活體内狀況在沖出條件下，試管内研究抗分解纖 蛋白的活性 白 (請先閲讀背面之注意事項再填寫本頁) 本研九之目標為藉由試管内測試模型顯示出抗蛋 29 2.1毫克 5.5毫克 2.0I.U. 16.5微克 五、發明説明（ 崎肽（為泰可康柏Η之組分）在過度纖維素溶解的條件下之 功效。 .泰可康柏S為-種灰白色、已塗敷海綿似的貼片。 使用該發泡的乾膠原質貼片做為該活性'固態組分的載 劑。該貼片的尺寸為9.5χ4胸.5公分^活性邊著成黃色。 1平方公分的泰可康柏S貼片（厚度G5公分）之組成為： 馬起源的膠原質， 其塗敷著： 人類纖維蛋白原 人類凝血酶 核黃素(在塗敷區域產生黃顏色） 活體内的實驗劑量研究測試已確定上述濃度的凝』 酶及纖維蛋白原可產生最大膠合強度（參見實例3)。 將包含人類凝血酶、人類纖維蛋白原及抗蛋白酶版3 泰可康柏Η與僅含人類凝血酶及人類纖維蛋白原做為活士 組分的泰可康柏S做比較。 發展二種測試模型用以定量地測量在過度纖維素2 解的狀況下之功效，而此狀況可視為與外科狀況相關且3 許進行一數量所需的測試以說明一明顯的效應。 在測試模型1中，將測試樣品塗敷至一做為附著表t 的合成織品上。在該織品中切出一明確的孔洞以模擬例y 血官的穿孔.。該封口經由該孔洞曝露至二種不同分解纖《 蛋白的溶液（培育溶液）。這些溶液之一額外地包括抗纖< 本紙張尺度適用中國國家標準（CNS) M規格（210X 297公楚） (請先閲讀背面之注意事再填寫本頁)(Please read the notes on the back and fill out this page) 28 V. INSTRUCTIONS (25 b) Settling volume after the first 24 hours: 63.5% of the test volume. 3. Particle size - inch (Fuckwald average diameter): 51.8 +/- 0.8 microns A carrier in the form of a collagen strip is coated with a suspension. First, 48 strips of collagen-poor seas were pre-cultured in a cooled chamber under the following conditions: - Temperature: 6. 5 - Relative humidity: 90% - Culture time: 22.5 hours Dry coated collagen as follows Sponge strips: 10 The coated strips were incubated at a relative humidity of 6 5 and 9 % for a minute. The coated strips are then dried in a vacuum drying chamber under the following drying conditions: two gas state, temperature 6.5 ° C, relative humidity 9 〇〇 / 0 • air flowing through the suction valve: 21 cubic meters per hour Ruler-vacuum: 58 mbar-drying time: 4 hours while shaking at 800-1200 rpm on the Wilburks mixer 2 Knife-ji Temple's peeling on the collagen sponge strip is less than 〇ι Millimeter centimeters. Example 1 The anti-protease peptide is a component of Tecco Compo® similar to the in vivo condition. In the test tube, the activity of anti-degrading fibrin is studied in vitro (please read the note on the back and fill out this page). The goal of Nine is to show anti-egg 29 2.1 mg 5.5 mg 2.0 IU 16.5 μg by in-vitro test model. 5. Description of the invention (Sagodapeptide (a component of taikekang cymbal) in the condition of excessive cellulose dissolution Efficacy. Tekcombe S is an off-white, sponge-coated patch. The foamed dry collagen patch is used as a carrier for the active 'solid component. The size of the patch is 9.5 χ 4 chest. 5 cm ^ active edge into yellow. 1 square centimeter of Tektronix S patch (thickness G5 cm) is composed of: horse origin of collagen, coated with: human fibrinogen human coagulation Enzyme riboflavin (yellow color in the coated area) In vivo experimental dose studies have determined that the above concentrations of clotting enzyme and fibrinogen produce maximum binding strength (see Example 3). Will contain human thrombin, human Fibrinogen and anti-fibrinogen The white enzyme version 3 Tecco cypress is compared with the Tektronix S which contains only human thrombin and human fibrinogen as the active component. Two test models were developed to quantitatively measure the excess cellulose 2 The effect of the condition, which can be considered to be related to the surgical condition and to perform a required number of tests to account for a significant effect. In Test Model 1, the test sample is applied to an attached table. On the synthetic fabric of t. A clear hole is cut in the fabric to simulate the perforation of the blood of the patient. The seal is exposed through the hole to a solution of two different decomposition fibers (culture solution). One additional includes anti-fibrous < This paper scale applies to China National Standard (CNS) M specification (210X 297 public Chu) (please read the note on the back and fill out this page)

30 1324524 A7 B7 五、發明説明（27 ) 素溶解的組分，α2-抗纖維蛋白溶酶。 培育溶液之組成物： (請先閲讀背面之注意事項再填寫本頁) 全部的材料稀釋在緩衝劑1中（50mM的缓血胺、lOOmM 的NaCl、2_5mM的CaCl2、2毫克/毫升的BSA(無蛋白酶）、 0.5毫克/毫升的Na-三氮化物/毫升）； 培育溶液1(1微莫耳濃度的纖維蛋白溶酶原、1毫微莫 耳濃度的組織纖維蛋白溶酶原活化劑（tPA)、1微莫耳濃度 的α2-抗纖維蛋白溶酶）； 49微升的缓衝劑1，ρΗ7.4 ; 5 1微升的纖維蛋白溶酶原溶液（濃度為4.9微莫耳濃度 的克客隆（Coachrom)人類纖維蛋白溶酶原活性）； 50微升的tPA溶液（50毫微莫耳濃度）； 100微升的α2-抗纖維蛋白溶酶溶液（2.5微莫耳濃度）； 培育溶液11(1微莫耳濃度的纖維蛋白溶酶原、1毫微莫 耳濃度的組織纖維蛋白溶酶原活化劑）； 149微升的缓衝劑1，ρΗ7.4 ; 5 1微升的纖維蛋白溶酶原溶液（濃度為4.9微莫耳濃度 的克客隆人類纖維蛋白溶酶原活性）； 50微升的tPA溶液（50毫微莫耳濃度）； 將培育溶液再放置2小時以模擬沖出效應。在此場合 下可控制附著力。在樣品上施加50毫巴的壓力。當壓力$50 毫巴而樣品分離時登記該時間。 測試模型2則說明損傷的腸組織之分解纖維蛋白效 應。將該測試樣品塗敷至豬腸（例如在活體中）做為附著表 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1324524 A730 1324524 A7 B7 V. INSTRUCTIONS (27) A soluble component, α2-antiplasmin. Composition of the incubation solution: (Please read the notes on the back and fill out this page.) All materials are diluted in buffer 1 (50 mM tromethamine, 100 mM NaCl, 2_5 mM CaCl2, 2 mg/ml BSA ( No protease), 0.5 mg/ml Na-trinitride/ml); incubation solution 1 (1 micromolar plasminogen, 1 nanomolar tissue plasminogen activator ( tPA), 1 micromolar concentration of α2-antiplasmin); 49 μl of buffer 1, ρ 7.4; 5 1 μl of plasminogen solution (concentration of 4.9 micromolar) Coachrom human plasminogen activity; 50 microliters of tPA solution (50 nanomolar concentration); 100 microliters of alpha2-antiplasmin solution (2.5 micromolar concentration) Incubation solution 11 (1 micromolar concentration of plasminogen, 1 nanomolar concentration of tissue plasminogen activator); 149 microliters of buffer 1, ρ 7.4; 5 1 micro Liter plasminogen solution (Kelon's human plasminogen activity at a concentration of 4.9 micromolar) ; Of 50 [mu] l tPA solution (50 ng molarity); the solution was incubated for 2 hours to simulate the effect out. In this case, the adhesion can be controlled. A pressure of 50 mbar was applied to the sample. This time is registered when the pressure is $50 mbar and the sample is separated. Test Model 2 illustrates the decomposed fibrin effect of damaged intestinal tissue. Apply the test sample to the pig intestine (for example, in a living body) as an attached sheet. The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1324524 A7

本紙張尺度適用令國國家標準 (CNS) A4規格（210X297公釐） 1324524 五、發明説明（29 A7 B7 測试模型1亦顯示出心-抗纖維蛋白溶酶額外的抗纖維 素溶解效應’其對泰可康柏Η來說將纖維蛋白溶解時間從 31.6延長至41_2小時（130%)，及對泰可康柏s來說則從8.3 延長至12.8小時（154%)。 實例2 已k敷的尼康梅得海绵（泰可康柏s)與其它如泰可康 柏S般相同地塗敷的載劑產品之比較。 該層之附著性 程序 1.不同載劑之被覆This paper scale applies to the national standard (CNS) A4 specification (210X297 mm) 1324524 V. Description of the invention (29 A7 B7 Test Model 1 also shows the additional anti-cellulolytic effect of heart-anti-plasmin) For the tecoco cypress, the fibrinolytic time was extended from 31.6 to 41_2 hours (130%), and for the tecocon s, it was extended from 8.3 to 12.8 hours (154%). Comparison of Nikonmede Sponge (Tecco Compaq) with other carrier products coated in the same manner as Taike Compaq S. Adhesion procedure for this layer 1. Coverage of different carriers

商標名稱 材料 製造/分發 歐普拉斯金 膠原質海綿 羅曼(Lohmann)、保斯特費許(postfach) 2343、D-56513 紐維德(Neuwied) 威羅斯潘專長 膠原質海綿(牛類） 威爾製藥(Will-Pharma)、保斯特巴士 (Postbus)30 、NL1160 AA 文堡 (Zwenburg) 威羅斯潘斯佩;兹而 凝膠海綿 威爾製藥，保斯特巴士30，NL ]160 AA 文堡 愛斯吸貼片 聚葛來克丁(P〇lyglactin)910/ 聚戴可珊嗣(Polydioxanon) 強生/強生(Johnson/Johnson)(製造商） 愛斯康(Ethicon)、羅柏-卡許-Str. 1 (Robert-Koch-Str. 1) D-22851 諾得斯泰 德(Norderstedt) 泰普坦柏®NU尼特 氧化的再生纖維素 強生/強生(製造商） 一~~ 愛斯康、羅柏-卡許-Str.丨D-2285l諾得 斯泰德 膠原質海綿尼康梅得 馬的膠原質海綿 尼康梅得奥地利 '' 山克-彼得-Str. 25(Sankt-Peter-Str. 25) A-4021 LINZ 每個面積為2x4.5平方公分之載劑以泰可康柏S被覆懸 浮液來塗敷。被覆懸浮液的量符合泰可康柏規格（5.5毫克 纖維蛋白原/平方公分）。乾燥該樣品。 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁)Trademark name material manufacturing / distribution of Oprahmann collagen sponge Lohmann, postfach 2343, D-56513 Neuwied Weisspan specialty collagen sponge (cattle) Weir Pharmaceutical (Will-Pharma), Postbus 30, NL1160 AA Zwenburg Wiros Penspe; Gel Sponge Weil Pharmaceuticals, Pau Bus 30, NL] 160 AA Fort Worth Adhesive patch P〇lyglactin 910/ Polydioxanon Johnson/Johnson (manufacturer) Ethicon, Rob-Kax-Str. 1 (Robert-Koch-Str. 1) D-22851 Norderstedt Reuterate Regeneration Cellulose Johnson/Johnson (manufacturer) One~~ Aiskan, Robb -Kash-Str.丨D-2285l Nordsted Collagen Sponge Nikon Medal's Collagen Sponge Nikonme De Austria'' Shank-Peter-Str. 25 (Sankt-Peter-Str. 25) A -4021 LINZ Each carrier of 2x4.5 cm2 is coated with a Tektronix S coating suspension. The amount of the coated suspension is in accordance with the Taike Compaq specification (5.5 mg fibrinogen/cm 2 ). The sample was dried. This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

1324524 A7B7 五、發明説明（30 2. 將每個已塗敷的載劑製備成1x4平方公分的樣品。 3. 如下測試該層的附著性。 方法說明 設備 分析天秤（測量精確度±0.5毫克）； 與固定裝置結合的威伯菲克斯攪拌器； 具毫米刻度的尺； 計時錶、解剖刀、内徑2公分含塞子的管子。 程序 使用解剖刀將已塗敷的載劑切出4x1平方公分的塗敷 面積。 將該樣品放置在一含塞子的衡量管中。然後，將其在 威伯菲克斯攪拌器（頻率約lOOOrpm)中搖晃2分鐘。 移開薄片及再稱重剩餘的被覆材料量（剝落：毫克/平方 公分）。 計算： 剝落(毫克/平方公分） 剩餘的重量(毫克)-容器重量(毫克） 4平方公分 結果 載劑 物質 剝落(毫克/平方公分） 歐普拉斯金® Lyoph.膠原質 2.1 威羅斯潘®專長(3毫米） Lyoph.膠原質 1.2 威羅斯潘@斯佩滋而（丨毫米） 凝膠 2.1 愛斯吸®貼片（ZVP609) 聚葛萊克丁 /聚戴可珊酮 14.3 泰普坦柏®NU尼特 氧化的纖維素 9.2 膠原質海綿尼康梅得 膠原質，發泡型 0.15 34 (請先閲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準（CNS) A4規格（210X297公釐） 五、發明説明（31 ) 評論 除了尼·康梅得膠原質海綿外，全部的載劑在被覆後皆 不具彈性。 S亥樣品必需非常小心地切斷。若使用剪刀切斷則多數 的被覆材料將會剝落，因為該層其自身為堅硬的。愛斯吸(§) 貼月顯示出與被覆材料幾乎不連接。當搖晃一小段時間 後’全部的被覆會剝落掉（像“地毯，’）。 在尼康梅得膠原質海綿及其它載劑材料間則顯示出 相當明顯的差異。 弄溼的塗敷載劑之彈性 程序 1 不同載劑的被覆 將每個面積2X4.5平方公分的載劑以泰可康柏8被覆懸浮 液塗敷。被覆懸浮液的量符合至泰可康柏規格（5 5毫克 纖維蛋白原/平方公分）。乾燥該樣品。 2. 將每個已塗敷的載劑製備成約5_7平方公分的樣品。測量 乾燥樣品的精確起始面積。 3. 將樣品弄溼且將其放在已固定至特別設備的彈性乳膠薄 片上如在私題私序下之詳細描述。然後在乳膠薄片 j施加壓力使其膨脹。在2次膨服及鬆他之後，再膨服該 薄片第三次。測量於最高的膨脹點處之載劑面積。 方法說明 設備/化學品· 蠕動泵（IKA PA-SF); 1324524 五、發明説明（32) 壓力緩衝瓶（3個排出口）； \^0壓力計（〇-250毫巴）；玻璃漏斗(0開口 1 ·· 30亳米，開口2 : 15毫米）； 矽酮管子及夾鉗、乳膠手套（Semper med)、解剖刀 米刻度的尺、剪刀； 生理鹽液。 程序 將下列設備經由矽酮管子空氣緊密地連接至 出口的壓力缓衝瓶： a) 蠕動泵 b) 壓力計 c) 玻璃漏斗/開口 2 從乳膠手套切出-約8x8平方公分的雙薄片。將此薄 片空氣密封地固定在玻璃漏斗/開口 1。 使料剖刀切出塗敷面積約5_7平方公分的塗敷載劑。 測量該樣品面積（起始面積）。以鹽液弄澄該樣品的被 覆且將其放置在乳膠薄片上。然後手動地加壓該乳膠薄 約1分鐘。 使用蠕動泵施加约70毫巴的壓力膨脹該乳膠薄片％ 鬆弛乳膠薄片後重覆此兩次。在第三次膨脹時，在膨脹的 乳膠薄片之最高點處測量該塗敷載劑的面積（長度及 度）。 計算： 具毫 個排 片 在 見 本紙張尺度適财關家標準（QJS) A4規格（21()χ297公复）1324524 A7B7 V. INSTRUCTIONS (30 2. Prepare each coated carrier as a 1x4 cm2 sample. 3. Test the adhesion of this layer as follows. Method Description Equipment Analysis Libra (Measurement Accuracy ± 0.5 mg) ; Wilburks mixer with fixed device; ruler with millimeter scale; chronograph, scalpel, tube with plug of 2 cm inside diameter. Procedure Use a scalpel to cut the coated carrier 4x1 square The coated area of the centimeters. The sample was placed in a stoppered measuring tube. Then, it was shaken for 2 minutes at a Wilburks mixer (frequency about 1000 rpm). Remove the sheet and reweigh the remaining Amount of coated material (exfoliation: mg/cm 2 ) Calculation: Peeling (mg/cm 2 ) Remaining weight (mg) - container weight (mg) 4 cm ^ 2 Result carrier material peeling (mg / cm ^ 2 ) Oprah Gold® Lyoph. Collagen 2.1 Willispan® Specialty (3mm) Lyoph. Collagen 1.2 Willispan @Spezi and (丨mm) Gel 2.1 Ace® Patch (ZVP609) Poly Gledin / Gathering Sultanone 14.3 Teptan® NU nitrite oxidized cellulose 9.2 Collagen sponge Nikonme collagen, foamed type 0.15 34 (Please read the back note first and then fill out this page) This paper scale applies to Chinese national standards (CNS) A4 size (210X297 mm) V. INSTRUCTIONS (31) Comment All the carriers except the Nicomame collagen sponge are not elastic after coating. The S-hai sample must be cut very carefully. If scissors are used, most of the coated material will peel off because the layer itself is hard. Ais suction (§) stickers show almost no connection with the coated material. When shaking for a short time, 'all the covers It will peel off (like "carpet,"). There is a noticeable difference between Nikonme's collagen sponge and other carrier materials. The elastic procedure for wet coating of the carrier 1 The coating of different carriers will be A 2X4.5 cm2 carrier was coated with a Taike Compaq 8 coating suspension. The amount of the coating suspension was in accordance with the Taikecomb specification (5 5 mg fibrinogen/cm 2 ). Dry the sample. 2. Prepare each coated carrier as a sample of approximately 5-7 cm2. Measure the exact starting area of the dried sample 3. Wet the sample and place it on an elastic latex sheet that has been attached to a special device A detailed description of the private order. Then the pressure is applied to the latex sheet j to expand it. After 2 times of swelling and loosening, the sheet is re-expanded for the third time. The carrier measured at the highest expansion point Method Description Equipment / Chemicals · Peristaltic pump (IKA PA-SF); 1324524 V. Description of invention (32) Pressure buffer bottle (3 discharge ports); \^0 pressure gauge (〇-250 mbar); glass Funnel (0 opening 1 ··30 亳m, opening 2: 15 mm); ketone tube and clamp, latex gloves (Semper med), scalpel meter scale ruler, scissors; physiological saline solution. Procedure The following equipment was tightly connected to the outlet pressure buffer via air via an anthrone tube: a) Peristaltic pump b) Pressure gauge c) Glass funnel/opening 2 Cut out from latex gloves - double sheets of approximately 8x8 cm2. The sheet is airtightly secured to the glass funnel/opening 1. The coating cutter was cut into a coating carrier having a coating area of about 5-7 square centimeters. The sample area (starting area) was measured. The sample was covered with a saline solution and placed on a latex sheet. The latex was then manually pressurized for about 1 minute. The latex sheet was relaxed using a peristaltic pump applying a pressure of about 70 mbar. The latex sheet was relaxed and repeated twice. At the third expansion, the area (length and degree) of the coated vehicle was measured at the highest point of the expanded latex sheet. Calculation: With a number of rows, see the paper size standard (QJS) A4 specification (21 () χ 297 gong)

•…Ί' ; · (請先閲讀背面之注意事項再填寫本頁) 訂— -36 1324524 A7 B7 五、發明説明（33 ) ’彈性"因子 在第三次膨脹時的載劑面積 樣品的起始面積 結果 載劑 物質 彈性因子 歐普拉斯金® Lyoph.膠原質 1.78 威羅斯潘®專長(3毫米） Lyoph.膠原質 1.53 威羅斯潘@斯佩滋而（1毫米） 凝膠 1.79 愛斯吸®貼片（ZVP609) 聚葛萊克丁/聚戴可珊酮 1.0 泰普坦柏®NU尼特 氧化的纖維素 1.15 膠原質海綿尼康梅得 膠原質，發泡型 1.55 (請先閲讀背面之注意事項再填寫本頁) 評論 弄溼的膠原質海綿尼康梅得（泰可康柏S)之彈性為產 品的重要特徵之一。彈性在胸及腹部外科上為不可缺的。 在膠合後該載劑應該能夠遵循例如肺或腸的膨脹及鬆弛移 動。特別地，愛斯吸@顯示出一點彈性都沒有，其會立即地 從被覆上分離。已塗敷的威羅斯潘@斯佩滋而及歐普拉斯金 ®在測試期間顯示出結構上的缺陷。 將已塗敷的載劑使用在内視鏡外科中 程序： 1. 不同的載劑之被覆 將每個面積2x4平方公分的載劑以泰可康柏S被覆懸浮 液塗敷。被覆懸浮液的量符合泰可康柏規格（5.5毫克纖 維蛋白原/平方公分）。乾燥該樣品。 2. 經塗敷的載劑樣品使用於内視鏡外科的處理及因此處理 37 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1324524 A7B7 五、發明説明（34 ) 的被覆損失利用數位照相設備文件化。 方法說明 設備 安德達克：内視鏡工具，其設計成可在内視鏡外科中使用 泰可康柏®!：參見第7圖）。 數位照相設備。 研究的載劑之表列 載劑 載劑材料 歐普拉斯金® Lyoph.膠原質 威羅斯潘®專長(3mM) Lyoph.膠原質 威羅斯潘®斯佩滋而（1 mM) 凝膠 愛斯吸®貼片（ZVP609) 聚葛萊克丁 /戴可珊酮 泰普坦柏®NU尼特 氧化的纖維素 膠原質海綿尼康梅得 膠原質，發泡型 程序 每個載劑所採取的照片順序： 1. 照片：無塗敷及已塗敷的載劑樣品之文獻。 2. 照片：將塗敷的樣品塞入内視鏡設備（安德達克）。該樣 品必需手動平坦化以使其能夠繞著引導的“栓”捲 繞。然後將樣品小心地塞入直徑10毫米的鋼管。 部分塞入安德達克管之樣品文獻。 3. 照片：小心地將樣品推出。之後該樣品必需為無摺疊狀。 由於此處理而從載劑分裂出來之被覆收集在載劑 旁邊。在塞入内視鏡設備後的無摺疊樣品及由於 38 (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準（CNS) A4規格（210X297公釐） 1324524 A7 B7 五、發明説明（35 ) 此處理之被覆損失的文獻。 評論 .在内視鏡外科中的泰可康柏S(已塗敷之馬膠原質海綿 /尼康梅得）為該產品最需要的應用。泰可康柏S可塞入内視 鏡設備。此設備之管通常直徑為10-13毫米。為了塞入管 子，需先平坦化泰可康柏S然後繞著引導的“栓’’捲繞，然後 小心地塞入管子。因此，被覆與載劑的連接及在其自身中 必需夠強，而且該產品在乾燥狀態必需具有足夠的彈性而 可彎曲及捲繞。當帶至外科場所時，泰可康柏S可小心地 從管子拉出。然後其必需展開且放至創傷表面。此經常需 要一些調整。因此，該層對載劑的附著力應該足夠地強以 便抵擋此處理。 結果 結果可從附件的第1 -6圖看見。如下估計固定用敷料之 被覆材料· 歐普拉斯金® 30-40% 威羅斯潘®專長 60-70% 威羅斯潘@斯佩滋而 50% 泰克坦柏(Tacotamp)®NU 尼特 60-70% 愛斯吸®貼片（ZVP609) 95% 膠原質海錦尼康梅得 <5% 因為愛斯吸@為一種非常堅硬的載劑，對被覆的附著力 非常差。因此已塗敷的愛斯吸®在此研究中幾乎遺失全部的 39 (請先閲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準（CNS) A4規格（210X297公釐） 1324524 A7 _______B7 fi '發明説明（36 ) '~ —~ «。比較至已塗敷的尼康梅得之勝原質海綿且它研究 ㈣劑全部具有—平坦的塗敷表面。因此，該被覆鋪在載 劑上像-“平坦的地毯”。此會導致乾燥的塗敷載劑具有相 t無彈性的結構。彎曲或捲繞經常會使被覆其自身斷裂。 在將塗敷的載劑塞人内視鏡設備之管子且無摺疊樣 A之後，除了尼康梅得的膠原質海料，全部的載劑皆會 遺失相當多之被覆，所以會遺留大面積無被覆的材料。 《康梅得膠原質海锦的結構及紋理為泰可康柏S可在 具高彈性的基礎。尼康梅得膠原質海綿為 #泡型且具有多㈣的内腔。這些腔室在表面上切割成腔 洞。這些腔洞可增大被覆物的表面。在被覆期間該被覆 S浮液會均勻地分佈到結構化的表面上4乾燥期間包 含纖維蛋白原及凝血酶二者之溶液以固態固定至腔洞。因 此泰可康柏S可切割成想要的尺寸，且可在僅有小量損失 或絲毫無損失下將被覆材料塞入内視鏡設備。 比較至全部其它研究的塗敷載劑，乾泰可康柏s的高 | 彈性為一大優點。 實例3 活性組分之劑量研究測試 活性組分的劑量可利用二種不同測量附著力強度的 實驗模型來測量：在老鼠肝上的抗張強度、在老鼠腎中抗 提昇的組織壓力之附著強度。 A_在老鼠肝土的抗張強度 在經麻醉的老鼠之左肝葉上製造一個1 X丨公分且深約 本紙張尺度適财關家標準（CNS) A4規格⑵QX297公爱) 「〇•...Ί' ; · (Please read the notes on the back and fill out this page) Order — -36 1324524 A7 B7 V. INSTRUCTIONS (33) 'Flexibility' factor for the carrier area sample at the third expansion Starting area results Carrier material Elasticity factor Oprahkin® Lyoph. Collagen 1.78 Welospan® Specialty (3 mm) Lyoph. Collagen 1.53 Willispan @Spezi (1 mm) Gel 1.79 Ace Suction® Patch (ZVP609) PolyGradin/Polycoxanone 1.0 Teptan® NU Nitin Oxidized Cellulose 1.15 Collagen Sponge Nikonme Collagen, Foaming Type 1.55 (Please read the back Precautions and then fill in this page) Comment on the elasticity of the wet collagen sponge Nikonme (Tecco Compaq S) is one of the important features of the product. Elasticity is indispensable in thoracic and abdominal surgery. The carrier should be capable of following, for example, swelling and relaxation of the lungs or intestines after gluing. In particular, Ace Suck @ shows no elasticity at all, it will immediately separate from the cover. The coated Willispan @Spezi and Oprahkin ® showed structural defects during the test. Application of the coated vehicle to endoscopic surgery Procedure: 1. Different carrier coatings Each of the 2 x 4 cm 2 carriers was coated with a Tekcombe S coating suspension. The amount of the coated suspension is in accordance with the Taike Compaq specification (5.5 mg of fibrinogen/cm 2 ). The sample was dried. 2. The coated carrier sample is used in endoscopic surgery and therefore processed. 37 The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1324524 A7B7 V. Coverage loss of invention description (34) Documented using digital camera equipment. Method Description Equipment Anderdak: Endoscopic tool designed to be used in endoscopic surgery Tektronix®!: see Figure 7). Digital camera equipment. The carrier of the study is listed as the carrier carrier material. Oprahkin® Lyoph. Collagen Velospan® Specialty (3mM) Lyoph. Collagen Velospan® Spezia (1 mM) Gel Ace ® Patch (ZVP609) Poly Glycidine / Decoxanone Tep Tambo® NU Nit Oxidized Cellulose Collagen Sponge Nikonme Collagen, Foaming Procedure The sequence of photos taken for each carrier: 1. Photo: Literature of uncoated and coated carrier samples. 2. Photo: Insert the coated sample into the endoscope device (Anderck). The sample must be manually flattened to enable it to be wound around the leading "plug". The sample was then carefully inserted into a 10 mm diameter steel tube. Partially inserted into the sample documentation of the Anddak tube. 3. Photo: Carefully push the sample out. The sample must then be unfolded. The coating split from the carrier due to this treatment is collected next to the carrier. Unfolded sample after insertion into the endoscope device and due to 38 (please read this on the back of the page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1324524 A7 B7 V. Invention Explanation (35) The literature on the loss of this treatment. Comment. Tekcombe S (coated horse collagen sponge / Nicomame) in endoscopic surgery is the most needed application for this product. The Tyco Compaq S can be inserted into an endoscope device. The tube of this device is usually 10-13 mm in diameter. In order to insert the tube, it is necessary to flatten the Tektronix S and then wind around the guided "plug" and then carefully insert the tube. Therefore, the connection between the coating and the carrier must be strong enough in itself. Moreover, the product must be sufficiently flexible to be bent and wound in a dry state. When brought to a surgical site, the Tecco Compo S can be carefully pulled out of the tube. It must then be deployed and placed on the wound surface. Some adjustment is required. Therefore, the adhesion of this layer to the carrier should be strong enough to withstand this treatment. The results can be seen in Figures 1 - 6 of the annex. The coating material for the fixed dressing is estimated as follows. · Oprahkin® 30-40% Willispan® Specialty 60-70% Willispan @斯佩滋50% Tektronix® NU nit 60-70% Ace® Patch (ZVP609) 95% Collagen海锦尼康梅得<5% Because Aiskin@ is a very hard carrier, the adhesion to the coating is very poor. Therefore, the coated Acekin® almost lost all 39 in this study (please Read the notes on the back and fill out this page. Applicable to China National Standard (CNS) A4 Specification (210X297 mm) 1324524 A7 _______B7 fi 'Invention Description (36) '~ —~ «Compared to the coated Nikonmeide Shengyuan Sponge and its research (4) agents all have a flat coated surface. Therefore, the coating is spread on the carrier like a "flat carpet". This results in a dry coating carrier having a phase t inelastic structure. Bending or winding often causes it to be coated. Self-breaking. After the coated carrier is plugged into the tube of the endoscopic device without the folding sample A, except for the collagen seaweed of Nikonme, all the carriers will lose a considerable amount of coating, so it will be left behind. A large area of uncoated material. The structure and texture of the concanic collagen jelly is based on the high elasticity of the Tektronix S. The Nikonmey collagen sponge is a #bubble type with multiple (four) lumens. These chambers are cut into cavities on the surface. These cavities increase the surface of the coating. During the coating, the coated S floats are evenly distributed onto the structured surface. 4 During the drying period, it contains fibrinogen and coagulation. a solution of the two enzymes The state is fixed to the cavity. Therefore, the Tektronix S can be cut to the desired size, and the coated material can be inserted into the endoscope device with only a small loss or no loss of silk. Compare to all other studies The carrier, the high value of the dry Taike Kangbo s | elasticity is a big advantage. Example 3 Dose study of the active component The dose of the active component can be measured using two different experimental models for measuring the strength of adhesion: in the mouse liver Tensile strength, adhesion strength against tissue stress in rat kidneys. A_ Tensile strength in rat liver soil. A 1 X cm and deep paper on the left hepatic lobe of anesthetized mice. Standard Scale for Financial Control (CNS) A4 Specification (2) QX297 Public) "〇

、一*m (請先閲讀背面之注意事項再填寫本頁) 1324524 A7B7 五、發明説明（37 ) 1毫米的創傷以產生滲出性出血。該創傷以一片1X1公分泰 可康柏S封口且與彈簧秤連接。測量撕下泰可康柏S時的張 力。 B.在老鼠腎中抗提昇的組織壓力之附著強度„ 在經麻醉的老鼠之左腎上藉由切除約四分之一的主 體而產生一平滑而強烈出血的創傷。該創傷以泰可康柏S 測試薄片封口。藉由封閉靜脈引流及泵入等滲壓的檸檬酸 鹽溶液（pH7.2)至腎臟而提昇組織壓力。測量泰可康柏S開 始分離時的壓力。 表1 包含不同量的纖維蛋白原之泰可康柏S的附著強度 組成物層 附著強度（平均± SD) 纖維蛋白原， 毫克/平方公分 凝血酶， IU/平方公分 在老鼠肝上的抗張強 度，牛頓/平方公分 n=5 在老鼠腎中抗提昇的 組織壓力之附著強 度，毫巴 n=5 0 0 0.20±0.02 47±9 0 2.40 0.20±0.03 63±16 1.3 1.73 0.30+0.06 81 土 12 2.92 1.85 0.39±0.05 101±13 5.10 1.87 0.39 土 0.03 110±13 7.22 1.82 0.38±0.02 97+13 10.02 1.75 0.40±0.07 87±10 41 (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準（CNS) A4規格（210X297公釐） 1324524 A7B7 五、發明説明（38 ) 表2 包含不同量的凝血酶之泰可康柏S的附著強度 組成物層 附著強度(平均土 SD) 纖維蛋白原， 毫克/平方公分 凝血酶， IU/平方公分 在老鼠肝上的抗張強 度，牛頓/平方公分 n=5 在老鼠腎中抗提昇的 組織壓力之附著強 度，毫巴 n=5 0 0 0.20±0.02 47±9 6.15 0 0.27±0.01 57±10 4.72 0.92 0.39 土 0.02 84±9 5.10 1.87 0.39 土 0.03 110±13 4.78 4.95 0.35 土 0.02 97 土 9 4.70 9.63 0.30±0.02 109±13 4.75 19.83 0.27+0.03 91±20 (請先閲讀背面之注意事項再填寫本頁) 所獲得的結果顯露出在數種變化間有相當大的差 異。在人類纖維蛋白原的含量固定為約5毫克/平方公分 時，人類凝血酶的最理想範圍為0.9至10 I.U./平方公分。 在人類凝血酶的含量固定為約2 I.U./平方公分時，人類纖 維蛋白原的最理想範圍為2.9至7.2毫克/平方公分。 這些活體内測試確定纖維蛋白原（4_3-6.7毫克/平方公 分）及凝血酶（1.5-2.5 IU/平方公分）二者之濃度，其可使用 在其它泰可康柏配方中（泰可康柏®及泰可康柏H)，對泰可 康柏S來說亦可產生最大的黏合強度。 實例4 泰可康柏S在狗的脾臟及肝臟病灶封口上之功效 此研究的目標為在狗的脾臟及肝臟病灶模型中比較 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1324524 A7 I____________ 五、發明説明（39 ) 泰可康柏Η(含抗蛋白酶肽）與泰可康柏s(不含抗蛋白酶肽） 的止血功效。選擇對脾臟切口及刺穿（0_5公分深）以模仿滲 出性出血。進行顱侧肝葉尖端的切除以模仿一強烈出血的 表面創傷（2至3平方公分）。敷貼泰可康柏η或泰可康柏s貼 片可做為釗傷止血的唯一方法（將相同的貼片使用在相同 的狗之脾臟及肝臟病灶中）。在外科手術48小時後進行驗 屍’因為此週期為臨床進行時再出血_的最高風險期。 一產品皆可達成完全止血。在48小時驗屍時並無觀察 到二級出血的情況’粗略的觀察沒有或組織地檢驗也沒有。 同樣地’當評估覆蓋著各別的貼片以止血及治療創傷 之脾臟及肝臟病灶時，在敷貼泰可康柏Η或泰可康柏s的多 條狗之間並無組織學上的差異。在外科手術後並無觀察到 二級出血_的病例。 血球計算貢料顯示出二處理群組具有類似的結果，其 在外科手術48小時後白血球計算有溫和地提高。在群組之 間或在與任何其它關心評估的參數時間之間並無差異。同 樣地，凝結測試顯示出相關的抗蛋白酶肽之存在或缺乏少 並無差異。在外科手術48小時後在二處理群組中血液纖 «白原的含量皆明顯地提#。白血球計算及金液纖維蛋 自原含量之提昇可歸因於射卜科損傷的炎症反應而不視為 泰可康柏Η或S的中毒副作用。 可推斷的是在處理狗的滲Α性及帛烈出血的實質創 傷時，泰可康柏S(無抗蛋白酶肽）與泰可康柏η(含抗蛋白酶 肽）可發揮相同的功效。在選擇的條件下凝塊之穩定性不受 本紙張尺度適用中國國家標準（CNS) Α4規格（21〇χ297公楚）, a * m (please read the note on the back and then fill out this page) 1324524 A7B7 V. Description of the invention (37) 1 mm of trauma to produce exudative bleeding. The wound was sealed with a piece of 1X1 cm Tektronix S and attached to a spring balance. The tension when tearing down the Tecco Compaq S was measured. B. Adhesion strength of tissue pressure against elevated tissue in mouse kidneys „ A smooth and intense bleeding wound is produced on the left kidney of an anesthetized mouse by cutting about a quarter of the subject. The wound is Tektronix. Cypress S test sheet seal. Increase tissue pressure by closing the venous drainage and pumping an isotonic citrate solution (pH 7.2) to the kidney. Measure the pressure at which Teccomba S begins to separate. Table 1 contains different Adhesion strength of the amount of fibrinogen of Tecco Compaq S layer adhesion strength (mean ± SD) fibrinogen, mg / cm ^ 2 thrombin, tensile strength of IU / cm ^ 2 on rat liver, Newton / Square centimeters n=5 Adhesion strength of tissue pressure against elevated tissue in rat kidney, mbar n=5 0 0 0.20±0.02 47±9 0 2.40 0.20±0.03 63±16 1.3 1.73 0.30+0.06 81 Tu 12 2.92 1.85 0.39 ±0.05 101±13 5.10 1.87 0.39 Soil 0.03 110±13 7.22 1.82 0.38±0.02 97+13 10.02 1.75 0.40±0.07 87±10 41 (Please read the note on the back and fill out this page) This paper scale applies to Chinese national standards. (CNS) A4 specification (210X 297 mm) 1324524 A7B7 V. INSTRUCTIONS (38) Table 2 Adhesion strength of Tikcombo S containing different amounts of thrombin Composition layer adhesion strength (average soil SD) fibrinogen, mg/cm 2 thrombin , IU/cm ^ 2 tensile strength in rat liver, Newton / square centimeter n = 5 adhesion strength of anti-promoting tissue pressure in rat kidney, mbar n = 5 0 0 0.20 ± 0.02 47 ± 9 6.15 0 0.27 ±0.01 57±10 4.72 0.92 0.39 Soil 0.02 84±9 5.10 1.87 0.39 Soil 0.03 110±13 4.78 4.95 0.35 Soil 0.02 97 Soil 9 4.70 9.63 0.30±0.02 109±13 4.75 19.83 0.27+0.03 91±20 (Please read the back first The results obtained are based on the following.) The results obtained are quite different among several changes. When the human fibrinogen content is fixed at about 5 mg/cm 2 , the optimal range of human thrombin is 0.9 to 10 IU/cm 2 . The optimal range of human fibrinogen is 2.9 to 7.2 mg/cm 2 when the human thrombin content is fixed at about 2 IU/cm 2 . These in vivo tests determine fibrinogen. 4_3-6.7 mg/cm 2 ) and thrombin (1.5-2.5 IU/cm 2 ), which can be used in other Teccompal formulations (Tecco Compaq® and Tecco Compaq H). It also produces maximum bond strength for Tecco Comp. Example 4 Efficacy of Tecco Compaq S on Dog Spleen and Liver Lesion Seals The objective of this study was to compare Chinese paper standards (CNS) A4 specifications (210 x 297 mm) in dog spleen and liver lesion models. 1324524 A7 I____________ V. INSTRUCTIONS (39) The hemostatic effect of Tecco cypress (containing anti-protease peptide) and Teccomber s (without anti-protease peptide). Spleen incision and puncture (0-5 cm deep) were chosen to mimic exudative bleeding. A resection of the cranial hepatic tip was performed to mimic a severely bleeding surface lesion (2 to 3 cm2). Apply Tektronix η or Tecco Compaq s patch as the only way to stop bleeding (use the same patch in the same dog's spleen and liver lesions). The autopsy was performed 48 hours after the surgery because this cycle is the highest risk period for re-bleeding during clinical practice. A product can achieve complete hemostasis. No secondary bleeding was observed during the 48-hour autopsy. 'There was no rough observation or no tissue test. Similarly, when assessing the coverage of individual patches to stop bleeding and treat traumatic spleen and liver lesions, there is no histological relationship between multiple dogs applied to Tecco cypress or Teccomber s. difference. No cases of secondary bleeding were observed after surgery. The blood cell calculation tribute showed similar results for the two treatment groups, which had a mild increase in white blood cell calculations 48 hours after surgery. There is no difference between the groups or between the time of the parameters with any other concerns. Similarly, the coagulation test showed little or no difference in the presence or absence of the relevant anti-protease peptide. After 48 hours of surgery, the blood fiber «whites content was clearly raised in the second treatment group. The calculation of white blood cells and the increase in the content of gold fiber fiber from the original content can be attributed to the inflammatory reaction of the cytoplasmic injury and is not considered as a toxic side effect of taikekang cypress or S. It can be inferred that Tektronix S (no anti-protease peptide) and Tekcomb η (containing anti-protease peptide) can exert the same effect when dealing with the dog's osmotic and brutal bleeding. The stability of the clot under the selected conditions is not subject to the Chinese National Standard (CNS) Α4 specification (21〇χ297 public)

-、1Τ_ (請先閱讀背面之注意事項再填寫本頁) 43 五、發明説明（40) 抗蛋白酶肽的存在與否影響。 實例5 泰可康柏S及泰可康柏η在止血、創傷封口效應及抗吸附上 的比較··在豬上的實驗研究 研究目的 本測试没计來評估在豬中誘發的脾臟病灶上止血纖 維網的直接功效及短期阻抗。 材料及方法 在研究中使用24頭雌豬。隨機地測試2組止血纖維 網：含抗蛋白酶肽的泰可康柏Η及不含抗蛋白酶肽的泰可 康柏S。 在外科手術當日，該動物接受一直接地填塞在標準的 2x3公分病灶上之纖維網，該病灶在脾臟的腹面部分上利 用外科手術造成。 評估纖維網的直接及止血效應，藉由計算水泡（bHster) 的數目及測量停止出血所需的時間。亦注意泰可康柏9及§ 的黏附性。 在72小時後，藉由增加脾内的壓力（鉗住靜脈血管）來 調查二材料的短期表現及阻抗。 當壓力到達幾乎穩定的狀態時，大量給藥腎上腺素 IV(0.02毫克或〇.〇4毫克）以增加動脈的壓力，可與多巴酚丁 胺鹽酸化物輸液相關或無關。 藉由這些藥理學物質，引用在每個動物上經泰可康柏 Η及S修復的病灶之破裂出血壓力。 1324524 五、發明説明（41 ) 結果 在脾臟病灶外科手術時，在處理之止血效應間並無偵 測到差異。 在72小時後做第二次觀察時，二纖維網的巨觀外觀仍 然相同。 在二實驗群組間實際的壓力測量及破裂阻抗並無明 顯地不同。 該材料並無發生破裂。在使用泰可康柏§的4個動物中 及在使用泰可康才白Η的2個動物中觀察到㊆火土出血（在群組 4中有一個具額外的水泡）。 組織檢驗建議抗蛋白酶肽可在纖維網結構上發揮一 保護效應，抗蛋白酶肽似乎可藉由減輕纖維網的降解而修 飾細微的樣式（pattern)。並無觀察到有特定的細胞樣式。 結論 已在24隻豬的標準脾臟病灶模型上研究2種泰可康柏 配方（S及H)的直接止血活性。 二材料在功效、對病灶的黏附性及對實質的容量彈性 之表現上類似。其功效則令人印象深刻。 在外科手術後第72小時藉由增加脾内壓力（藉由機械 及藥理學方法）研究其對生物降解及蛋白質水解的阻抗，且 記錄泰可康柏Η及S纖維網的局部抵抗。可証明2種材料的 阻抗並無明顯的差異。 但是，組織病理學的研究結果指出泰可康柏s的蛋白 質分解之降解務微地比泰可康柏Η更明顯。 1324524 A7 _______Β7_ 五、發明説明（42 ) 使用泰可康柏S或泰可康柏Η做為唯一的止血方法以 封住豬中強烈出血的脾臟病灶（病灶表面2公分Χ3公分、深 度3-5毫米；每群組η=12)。在72小時後藉由綁紮脾臟靜脈 而增加脾内壓力。其後，藉由注入腎上腺素額外地增加脾 内壓力。觀察該些豬在貼片下之再出血跡象或血泡的發 生。在驗屍後進行樣品組織病理（在以泰可康柏Η及S封口 的病灶處）。 泰可康柏S及泰可康柏η可發揮類似的功效、對病灶的 黏附性及對實質的容量彈性。 實例6 可吸收的泰可康柏S及泰可康柏Η在創傷封口的止血 效應及阻抗上之比較：在豬的急性胰臟炎模型上之實驗性 研究 研究目的 該測試設計來評估在豬中誘發之急性胰臟炎模型中 止血纖維網在脾臟病灶上的直接功效及短期阻抗。 材料及方法 使用20隻雌豬來研究。隨機地測試2組止血纖維網： 含抗蛋白酶肽的泰可康柏Η及不含抗蛋白酶肽的泰可康柏 S ° 在外科手術當日，該些動物接受一纖維網直接地填塞 在脾臟的腹面部分以外科手術造成之標準2x3公分病灶 上。 藉由計數水泡數目及測量停止出血所需的時間來評 本紙張尺度適用中國國家標準（CNS) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)-, 1Τ_ (Please read the notes on the back and fill out this page) 43 V. INSTRUCTIONS (40) The presence or absence of anti-protease peptides. Example 5 Comparison of Tecco Compaq S and Tecco Compaq η in hemostasis, wound sealing effect and anti-adsorption. · Experimental study on pigs. Objectives This test did not count to evaluate spleen lesions induced in pigs. The direct efficacy and short-term impedance of the hemostatic fiber web. Materials and Methods 24 female pigs were used in the study. Two groups of hemostatic fibers were randomly tested: Tecco cypress containing anti-protease peptide and Tecco Compaq S without anti-protease peptide. On the day of surgery, the animal received a web that was grounded to a standard 2x3 cm lesion that was surgically created on the ventral portion of the spleen. Evaluate the direct and hemostatic effects of the fiber web by calculating the number of blisters (bHster) and measuring the time required to stop bleeding. Also note the adhesion of Tecco Compaq 9 and §. After 72 hours, the short-term performance and impedance of the two materials were investigated by increasing the pressure in the spleen (clamping the venous blood vessels). When the pressure reaches an almost stable state, a large amount of adrenaline IV (0.02 mg or 〇.〇4 mg) is administered to increase the arterial pressure, which may or may not be related to the dobutamine hydrochloride hydrochloride infusion. With these pharmacological substances, the rupture bleeding pressure of the lesions repaired by Tekcombe and S in each animal was cited. 1324524 V. INSTRUCTIONS (41) Results During surgery for spleen lesions, no differences were detected between the hemostatic effects of the treatment. When the second observation was made after 72 hours, the giant appearance of the two fiber webs remained the same. The actual pressure measurements and fracture impedances between the two experimental groups were not significantly different. The material did not break. Seven fires were observed in four animals using Tecco Compaq and in two animals using Tektronix to be white (one in group 4 with additional blisters). Tissue testing suggests that anti-protease peptides may exert a protective effect on the structure of the web, and the anti-protease peptide appears to modify the subtle pattern by reducing the degradation of the web. No specific cell patterns were observed. Conclusion The direct hemostatic activity of two tycocomb formulas (S and H) has been studied on a standard spleen lesion model of 24 pigs. The two materials are similar in efficacy, adhesion to the lesion, and performance of the volumetric elasticity of the substance. Its efficacy is impressive. The impedance to biodegradation and proteolysis was investigated by increasing intrasplenic pressure (by mechanical and pharmacological methods) at 72 hours after surgery, and the local resistance of the Tecco cypress and S fiber web was recorded. It can be shown that there is no significant difference in the impedance of the two materials. However, the results of histopathological studies indicate that the degradation of the protein degradation of the Tecco Compaq is more pronounced than that of the Tektronix. 1324524 A7 _______Β7_ V. Description of invention (42) Use Tecco Compaq S or Tecco cypress as the only hemostasis method to seal spleen lesions with strong bleeding in pigs (2 cm in lesion surface, 3 cm in depth, depth 3-5 Mm; η=12) per group. The intrasplenic pressure was increased after 72 hours by ligating the spleen vein. Thereafter, the intrasplenic pressure is additionally increased by injecting adrenaline. Observe the signs of rebleeding or the occurrence of blood bubbles in the pigs under the patch. Sample histopathology was performed after autopsy (at the lesions sealed with Tecco cypress and S). Tecco Compaq S and Tecco Compaq η can exert similar effects, adhesion to lesions and volumetric elasticity to the substance. Example 6 Comparison of the hemostatic effect and impedance of the absorbable Tecco Compaq S and Tecco Kangbo in wound closure: an experimental study on the acute pancreatitis model of pigs. The purpose of this test was to evaluate the design in pigs. The direct efficacy and short-term impedance of the hemostatic network on the spleen lesions in the induced acute pancreatitis model. Materials and Methods 20 female pigs were used for the study. Randomly tested two groups of hemostatic fibrils: Tekcombs with anti-protease peptide and Teccomber S. without anti-protease peptides On the day of surgery, the animals received a web directly packed in the spleen. The ventral portion is on a standard 2x3 cm lesion caused by surgery. By counting the number of blisters and measuring the time required to stop bleeding, the paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm) (please read the notes on the back and fill out this page)

46 1324524 A7 _________B7 五、發明説明（43 ) 估纖維網的直接止血效應。亦注意泰可康柏H&s的黏附 性。 然後，使用一無菌注射器刺穿膽囊，收集膽汁且將1〇 毫升的膽汁透過威爾松氏（Wirsung，s)導管注入以便引發胰 臟炎。在外科手術之前及之後的每天監視血液的酵素程度 (脂肪分解酵素及澱粉酵素程度）。 將數小片的泰可康柏Η及S放置在騰臟實質與腸連接 的地方。 在72小時後，藉由增加脾内壓力（鉗住靜脈血管及藥理 學方法）研究泰可康柏Η及S的酵素降解之短期表現及阻 抗。 當壓力到達幾乎穩定狀態時，在〇 〇2至〇 〇4毫克/分鐘 的正腎上腺素輸液後給藥大量的IV腎上腺（〇 〇2毫克或〇 〇4 毫克）以增加動脈壓力，可與多巴酚丁胺鹽酸化物灌注 0.3-0.6¾克/分鐘相關或無關。 藉由這些藥理學物質，注意每個動物之經泰可康柏Η 及S修復的病灶之破裂出企壓力。46 1324524 A7 _________B7 V. INSTRUCTIONS (43) Estimate the direct hemostatic effect of the fiber web. Also note the adhesion of Tecco Compaq H&s. Then, the gallbladder was pierced using a sterile syringe, bile was collected and 1 ml of bile was injected through a Wirsung (s) catheter to induce pancreatitis. Monitor the level of blood enzymes (lipase and amylase levels) daily before and after surgery. Place a small piece of Tecco cypress and S in a place where the spleen is connected to the intestine. After 72 hours, the short-term performance and resistance of the enzyme degradation of Tecco cypress and S were studied by increasing intra-spleen pressure (clamping venous vessels and pharmacological methods). When the pressure reaches an almost steady state, a large amount of IV adrenal gland (〇〇2 mg or 〇〇4 mg) is administered after 正2 to 〇〇4 mg/min of norepinephrine infusion to increase arterial pressure. The infusion of bazobutamine hydrochloride is 0.3-0.63⁄4 g/min related or unrelated. With these pharmacological substances, attention is paid to the rupture of the lesions of each animal by the Tecco cypress and S-repaired lesions.

I 、结I 纟脾臟中’二材料在直接止血功效、對病灶的黏附性 纟對實質的容量彈性上之表現類似。其功效非常令人印象 深刻。 在第3曰時巨觀地檢驗二纖維網，雖然酵素狀態為劇 烈的（特別是在第2曰的血液中），其仍未改變，在第4曰時 其仍然在腹膜液争。 本紙張尺度適用中國國家檩準（QfS) Α4規格（2獻297公楚)I, knot I 纟 spleen 'two materials in the direct hemostasis, adhesion to the lesion 纟 on the actual capacity elasticity of the similar. Its efficacy is very impressive. At the third sputum, the two fiber webs were examined giantally. Although the enzyme state was severe (especially in the blood of the second sputum), it remained unchanged, and at the fourth sputum it was still in the peritoneal fluid. This paper scale applies to China National Standard (QfS) Α 4 specifications (2 offers 297 public Chu)

(請先閱讀背面之注意事項再填寫本頁) .訂· -47 - 1324524 A7 B7 五、發明説明（44 ) 在增加脾臟壓力後第72小時，可明瞭二材料的阻抗並 無明顯差異。 在泰可康柏S群組令材料有一個發生破裂。使用泰可 康柏S中有1隻動物及使用泰可康柏^1令有2隻動物觀察到 病灶出企（在泰可康柏Η群組中有一個水泡）。 組織病理學研究結果指出泰可康柏s與泰可康柏11在 降解上並無明顯的差異。在脾臟中並無觀察到有特定的細 胞樣式。甚至在胰臟樣品中，泰可康柏H&s片在與高濃度 的騰臟酵素接近接觸時並無顯示出任何主要的改變。 結論 總而言之，在所關心之於增加的胰臟酵素環境狀態中 的抗破裂上，在泰可康柏S及泰可康柏η間並無顯示出明顯 的差異。 並無偵測到泰可康柏Η及S纖維網二者改質之特定巨 觀或微觀的證據。 在具急性胰臟炎的豬標準脾臟病灶模型（2公分χ3公分 的病灶表面，深約3毫米；η=1〇/組）中研究泰可康柏8及泰 可康柏Η的止jk功效，該胰臟炎藉由在威爾松氏導管中逆 行地;主入膽汁且隨後結紮胰臟導管而誘發。在姨臟導管择 紮處在胰臟上亦敷貼小片的泰可康柏Η及S。在外科手術72 小時後’藉由綁紮脾臟的靜脈及靜脈内的腎上腺素注射增 加脾内壓力。 在脾臟上泰可康柏S及泰可康柏Η於直接止血功效、對 病灶的黏附性及抗增加的脾内壓力上有類似地表現，雖然 本紙張尺度適用中國國家標準（CNS) A4規格（210X 297公釐） (請先閲讀背面之注意事項再填寫本頁) .、fT· 48 叫4524 、發明說明（ 45 姨臟的酵素程度有顯著的增加（如比較至基本程度，在血液 令的澱粉酶及脂肪分解酵素增加20-100倍及在腹膜液中的 胰臟酵素增加10-100倍）。組織病理學研究結果指出泰可康 柏S及泰可康柏H在降解上無明顯的差異。在脾臟上並無觀 察到特定的細胞樣式。甚至在胰臟樣品上在泰可康柏H&s 與高濃度胰臟酵素接近地接觸時，泰可康柏H&s的黏附性 和組織病理學無顯示出任何主要的差異。 因此，在此高度緊張的豬急性胰臟炎模型中在泰可康 柏S及泰可康柏H之間並無顯示出特定的巨觀或微觀上之 差異。 實例7 可吸收的泰可康柏Η及泰可康柏S之腦組織反應及效率的 比較：在兔模型中在正常凝結下及在局部過度纖維素溶解 期間的實驗性研究 此研究的目標為比較桊可康柏S及泰可康柏η在神經 外科敷貼上的功效。在兔中在正常凝結條件下（腦組織反應 ~BTR ’ η=12/兔，合格的η=ι〇)及在過度纖維素溶解條件下 (HF)藉由局部的r_tpA施加（η=1〇兔）誘發腦病灶。在每個半 球製造三個皮質病灶（每隻動物總共有6個病灶；鑽孔的腦 病灶深3毫米及直徑4毫米）。 BTR系列 將母半球三個病灶中的二個取出各別地以泰可康柏Η 或泰可康柏S處理，及每半球一個病灶則留白做為控制 組。在該些病灶以泰可康柏Η或S封口之後，在高倍率具連 本紙張尺度適用中國國家標準（CNS) Α4規格（21〇χ297公楚） (請先閲讀背面之注意事項再填寫本頁) ’、tT— -49 1324524 五、發明説明（46 ) A7 B7 續的低流速鹽液沖洗下測量出血時間。在將全部的病灶完 成止血之後，藉由靜脈内的腎上腺素注射（〇〇1毫克/公斤的 腎上腺素）誘發高動脈壓，因此增加平均動脈壓力（MAp)到 至少120mrnHg。在此程序期間觀察到再繼續出血。在降低 map至正常值之後表皮再次封閉。驗屍時間為第3及第7曰 (n=5每組的兔）。在第3日驗屍之前對三隻動物進行核磁共 振呈像。在驗屍時粗略地觀察病灶處及採取組織病理學樣 品。 HF系列 如BTR系列所描述般設定病灶後，在全部的病灶以泰 可康柏S或泰可康柏H任一種封口之前，將r_tpA滴下到病灶 之上（每個病灶為〇.3毫克的r_tPA(在0.5毫升的鹽液中））。在 高倍率及連續以鹽液低沖洗之下測量出血時間。在第ia (n-7)及第3日（n=3)驗屍時進行粗略地觀察。為了比較的理 由在3日採取組織病理學樣品。 在全部的研究程序期間，在泰可康柏s及泰可康柏11間 並無明顯的差異，不論在封口功效、容許增加的map及出 也時間週期上’或在組織病理學上。在hf系列的全部動物 中明瞭劇烈的出血不僅在病灶處，而是在整個表皮面。雖 然在這些劇烈的狀況下，泰可康柏s再次地發揮了與泰可 康柏Η類似的功效。 實例8 泰可康柏Η及泰可康柏s在神經外科手術上的應用：腦組織 反應及止血效率 本紙張尺歧财關家標準(CNS)aW^X297公釐)_ (請先閱讀背面之注意事項再填寫本頁)(Please read the precautions on the back and fill out this page.) Order -47 - 1324524 A7 B7 V. INSTRUCTIONS (44) At 72 hours after the spleen pressure is increased, it is clear that there is no significant difference in the impedance of the two materials. In the Tecco Compaq S group, there was a crack in the material. One animal in the Tektronix Compaq S was used and two animals were observed to have a lesion (a blister in the Tektronix group). The histopathological study showed that there was no significant difference in the degradation between Tecco Compaq and Tecco Compaq 11 . No specific cell pattern was observed in the spleen. Even in pancreatic samples, Tecco Compaq H&s tablets did not show any major changes when in close contact with high concentrations of sterilized enzymes. Conclusion In summary, there was no significant difference between Tyco Compaq S and Tecco Compaq in the resistance to rupture in the environment of increased pancreatic enzymes. No specific macro or micro evidence of the modification of both the Tektronix and the S fiber network was detected. Study on the efficacy of the cocaine cytoplasmic model of porcine standard spleen with acute pancreatitis (2 cm χ 3 cm lesion surface, depth about 3 mm; η = 1 〇 / group) The pancreatitis is induced by retrograde in a Welson's catheter; primary bile and subsequent ligation of the pancreatic duct. Small pieces of Tecco cypress and S were also applied to the pancreas at the selection of the smear catheter. After 72 hours of surgery, the intrasplenic pressure was increased by injecting spleen veins and intravenous adrenaline injections. In the spleen, Taikekampai S and Tecco Kangbo have similar performances in direct hemostasis, adhesion to lesions, and increased intra-spleen pressure, although this paper scale applies Chinese National Standard (CNS) A4 specifications. (210X 297 mm) (Please read the precautions on the back and fill out this page) ., fT· 48 is called 4524, invention description (45 visceral enzymes have a significant increase in degree (if compared to the basic level, in the blood order) Amylase and lipolytic enzymes increased by 20-100 times and pancreatic enzymes in peritoneal fluid increased 10-100 times. Histopathological study showed that Tecco Compaq S and Teccomba H had no significant degradation. The difference: no specific cell pattern was observed on the spleen. Even in the pancreas sample, the adhesion of Teccomba H&s was observed when Tekcombe H&s was in close contact with high concentrations of pancreatic enzymes. And histopathology did not show any major differences. Therefore, in this highly stressed model of acute pancreatitis in pigs, there was no specific macroscopic or microscopic relationship between Tecco Compaq S and Tecco Compaq H. The difference between the above. Example 7 Absorbable Comparison of Brain Tissue Reactions and Efficiency of Compaq and Tecco Compaq S: Experimental Study in Normal Rabbits Under Normal Condensation and During Local Excess Cellulose Dissolution The goal of this study was to compare 桊可康柏 S And the efficacy of Taike Kangbai η in neurosurgical application. Under normal coagulation conditions in rabbits (brain tissue response ~BTR 'η=12/rabbit, qualified η=ι〇) and conditions in excessive cellulose dissolution Lower (HF) induced brain lesions by local application of r_tpA (η = 1 rabbit). Three cortical lesions were created in each hemisphere (a total of 6 lesions per animal; bored brain lesions 3 mm deep and diameter) 4 mm). The BTR series takes two of the three lesions of the mother hemisphere separately and treats them with Tecco cypress or Tecco Compaq S, and one lesion per hemisphere is left as a control group. After the lesion is sealed with Taikekangbai or S, the Chinese National Standard (CNS) Α4 specification (21〇χ297 public) is applied to the high-magnification paper size (please read the note on the back and fill in the page) , tT— -49 1324524 V. Description of invention (46) A7 B7 continued low flow The bleeding time was measured by rapid saline flushing. After all the lesions were hemostasis, high arterial pressure was induced by intravenous adrenaline injection (〇〇1 mg/kg of adrenaline), thus increasing mean arterial pressure (MAp). To at least 120mrnHg. Continued bleeding was observed during this procedure. The epidermis was closed again after reducing the map to normal. The post-mortem time was 3rd and 7th (n=5 rabbits per group). Before the third day of autopsy Three magnetic resonance imaging images were performed on the animals. The lesions were roughly observed at the time of autopsy and histopathological samples were taken. The HF series was set as described in the BTR series, and all lesions were treated with Tecco Compaq S or Tektronix. Before any closure of Compaq H, r_tpA was dropped onto the lesion (each lesion was 毫克.3 mg of r_tPA (in 0.5 ml of saline)). The bleeding time was measured at high magnification and continuously with low saline wash. A rough observation was made during the ia (n-7) and the third day (n=3) autopsy. For the reason of comparison, a histopathological sample was taken on the 3rd. There were no significant differences between Tyco Compaq s and Tecco Compaq 11 during all study procedures, regardless of sealing efficacy, allowable increase in map and time period, or histopathology. In all animals of the hf series, severe bleeding was seen not only at the lesion but throughout the epidermis. Although in these severe conditions, Tecco Compaq once again played a similar role to Tektronix. Example 8 Application of Taikekangbai and Taike Kangbais in neurosurgery: brain tissue reaction and hemostasis efficiency (CNS) aW^X297 mm)_ (Please read the back first) Note on this page)

-50 1324524-50 1324524

在神，.二外科手術時使用流體纖維蛋白密封膠來大規 杈地止血。在廣泛的公告資料中並無腦組織對泰可康柏@ (請先閲讀背面之注意事項再填寫本頁) 的反應，且抗纖維素溶解的藥劑（即抗蛋白酶肽）使用仍然 有爭議。 ^咖州_蝴_估在皮質病 灶上敷貼泰可康_(咖）及泰可康柏S(TCS)後之短期局 部的腦組織反應（如肖空白的控制病灶（CL)比較），使用組 織學的方法及現代的呈像技術。 •訂—丨. 第二目的為研究泰可康柏Η及S產品在正常凝結下 (BTR群、.且）及在局部誘發劇烈地過度纖維素溶解後（hf群 組）的止血功效’及評估抗蛋白酶肽在止血品質及黏附力量 之製備上是否有任何影響。 材料及方法 在22隻幼兔系列中，在每個半球上製得三個皮質病 灶。十二隻動物分配在腦組織反應（BTR)組及1〇隻在過度 纖維素溶解（HF)組。 在BTR中，將動物的二個病灶各別地填上泰可康柏η 及泰可康柏S，同時第三個留空做為控制組。測量出血時 間，且監視由於誘發的高動脈壓而發生的再出血。在進行 外科及組織學檢驗後在第3及第7日殺死動物。在三個btr 動物上’在第3日時僅在安樂死前針對腦水腫進行核磁共振 呈像的評估。 在HF動物中，預先地以重組的組織纖維蛋白溶酶原活 本紙張尺度ϋ關家標準_) A4規格（21GX297公釐)~~ -~- 51 1324524 A7 I----B7 _ ___ 五、發明説明（48 ) 化劑（rt-PA)誘發劇烈的局部過度纖維素溶解之狀況，—個 半球的三個病灶全部以泰可康柏Η處理及其它半球以泰可 康柏S處理。測量出血時間且在第3曰時在三隻動物中進行 組織學的檢驗。 結果 在毛常凝結（BTR動物）下’以TCH及TCS止血比無止血 劑明顯地較快（ρ<〇·〇〇1)。此說明二產品在出血時間之間無 差異（p=〇.294) ’但是這些時間一致地比空白病灶的那些 較短（p<0.001)。 在誘發的高動脈壓期間在24個TCH病灶中有1個、24 個TCS中有3個及24個控制組病灶中有19個發生再出血。止 血劑的存在一致地防止在劇烈地增加動脈壓力期間再出血 (Chi平方= 16.3 ; ρ>〇_〇〇1)。依次地，在動脈壓力增加期間 缺乏TCH或TCS則顯示出有80%的風險發生再出血。 支過度纖維素溶解群A(HF動物）中出血睹肋的吒計學 分析說明二產品在出血時間之間並無差異（有正負號排列 的檢驗：p=0.927及T測試：p=〇.4l〇2)。 最後地，在99.73%的安全區間中（D<3sd D=ns)，排除 相同產品在一者减結狀況下在止血功效間之明顯差異。 結論 泰可康柏Η及泰可康柏S在腦組織中不會引起任何特 定的組織學改變。二產品具有好的腦實質生物共存性如 匕們不會比單獨的病灶誘發更多組織反應。形態學地註明 並無關於組合產品的副作用。組織學檢驗顯露出在二產品 本紙張尺度適用中關家鮮（CNS) Α4規格（2歡297公釐) '~~ -In the case of God, the second surgery, fluid fibrin sealant is used to stop bleeding in large scale. There is no brain tissue response to Tektronix @ (please read the note on the back and fill out this page) in a wide range of announcements, and the use of anti-cellulose-dissolving agents (ie, anti-protease peptides) remains controversial. ^Caizhou_Butterfly_Evaluate the short-term local brain tissue response (such as Xiao blank control lesion (CL) comparison) after applying Tektronix _ (caffe) and Tecco Compaq S (TCS) on cortical lesions. Histological methods and modern imaging techniques. • Book-丨. The second objective is to study the hemostatic effect of the Tekcombe and S products under normal coagulation (BTR group, and) and after locally induced severe hypercellulose dissolution (hf group) and Evaluate whether anti-protease peptides have any effect on the quality of hemostasis and the preparation of adhesion strength. Materials and Methods Three cortical lesions were produced on each hemisphere in a series of 22 young rabbits. Twelve animals were assigned to the brain tissue response (BTR) group and 1 〇 only in the excessive cellulose dissolution (HF) group. In the BTR, the two lesions of the animal were individually filled with Tekcombe η and Tecco Compaq S, while the third was left as a control group. The bleeding time was measured and the rebleeding due to the induced high arterial pressure was monitored. Animals were sacrificed on days 3 and 7 after surgical and histological examinations. On three btr animals, on the third day, only the cerebral edema was evaluated for NMR imaging before euthanasia. In HF animals, the recombinant tissue plasminogen is used in advance to measure the paper size. _) A4 size (21GX297 mm)~~ -~- 51 1324524 A7 I----B7 _ ___ Inventive Note (48) The agent (rt-PA) induces a severe local excessive cellulose dissolution condition. All three lesions in one hemisphere are treated with Tecco cypress and the other hemispheres are treated with Tecco Comp. The bleeding time was measured and histological examination was performed in three animals at the third sputum. Results In the hair coagulation (BTR animals), hemostasis with TCH and TCS was significantly faster than that of no hemostatic agents (ρ<〇·〇〇1). This indicates that the two products did not differ between bleeding times (p = 294.294)' but these times were consistently shorter than those of the blank lesions (p < 0.001). During the induced high arterial pressure, recurrence occurred in 1 of 24 TCH lesions, 3 of 24 TCS, and 19 of 24 control group lesions. The presence of a hemostatic agent consistently prevents re-bleeding during violent increases in arterial pressure (Chi square = 16.3; ρ > 〇_〇〇1). In turn, the lack of TCH or TCS during an increase in arterial pressure showed an 80% risk of rebleeding. The sputum analysis of the hemorrhagic ribs in the excessive cellulose-dissolved group A (HF animals) showed that there was no difference between the two products in the bleeding time (test with positive sign arrangement: p=0.927 and T test: p=〇. 4l〇2). Finally, in the 99.73% safety interval (D<3sd D=ns), the significant difference in hemostatic efficacy of the same product in one of the reduced conditions was excluded. Conclusion Tekcombe and Tektronix S do not cause any specific histological changes in brain tissue. The two products have good coexistence of brain parenchymal organisms such as we do not induce more tissue reactions than lesions alone. Morphologically stated there is no side effect on the combined product. Histological examination revealed in the two products This paper scale applies to Zhongguanjia Xian (CNS) Α 4 specifications (2 Huan 297 mm) '~~ -

、一11— (請先閲讀背面之注意事項再填寫本頁), 11 - (Please read the notes on the back and fill out this page)

Claims (1)

Translated fromChinese

1324524 Al 六、申請專利範圍 第091101273號專利再審查案申請專利範圍修正本 修正日期：98年11月 1_ 一種固態組成物，其基本上由下列所組成： a)—種具有至少二種下列物理性質的膠原蛋白載劑： 彈性模數範圍為5-100 N/cm2， 在、度為 1-10 mg/cm3，1324524 Al VI. Patent Application No. 091101273 Patent Reexamination Application Patent Scope Amendment Revision Date: November, 1998 1_ A solid composition consisting essentially of the following: a) - The species has at least two of the following physics Nature of collagen carrier: The elastic modulus range is 5-100 N/cm2, and the degree is 1-10 mg/cm3.腔至直fe大於0.75 mm且小於4 mm，和/或平均腔室 直禋小於3 mm ;以及 其中該膠原蛋白載劑具有一個或多個活性邊，且在該 等邊上有以一為2-10 mg/cm2的數量存在之固態纖維 蛋白原混合物，以及 固態凝血酶係以為1.5-5.5 IU/cm2的數量存在且係均 勻地被分佈並被固定。 2. 如申請專利範圍第1項所述之固態組成物，其中該膠原 蛋白載劑係為一種膠原蛋白海綿，該海綿包含來自於哺The cavity to straight fe is greater than 0.75 mm and less than 4 mm, and/or the average chamber diameter is less than 3 mm; and wherein the collagen carrier has one or more active edges and there is one on the sides The solid fibrinogen mixture present in an amount of -10 mg/cm2, and the solid thrombin system are present in an amount of 1.5-5.5 IU/cm2 and are uniformly distributed and fixed. 2. The solid composition according to claim 1, wherein the collagen carrier is a collagen sponge, the sponge comprising乳動物來源、轉殖基因來源或重組來源的膠原蛋白型式 I物質。 3. 如申請專利範圍第1項中所述之固態組成物，其中該膠 原蛋白載劑具有一個或多個活性邊，其中纖維蛋白原係 以一為5.5 mg/cm2的數量存在，以及該凝血酶係以一為 15-5.5 IU/cm2的數量存在。 4. 如申請專利範圍第3項中所述之固態組成物，其中該膠 原蛋白載劑具有一個或多個活性邊，其中纖維蛋白原係 以一為5_5 mg/cm2的數量存在，以及該凝血酶係以一為A source of milk animal, a source of transgenic genes, or a collagen-type substance of recombinant origin. 3. The solid composition of claim 1, wherein the collagen carrier has one or more active edges, wherein the fibrinogen is present in an amount of 5.5 mg/cm2, and the coagulation The enzyme is present in an amount of from 15 to 5.5 IU/cm2. 4. The solid composition of claim 3, wherein the collagen carrier has one or more active edges, wherein the fibrinogen is present in an amount of 5-5 mg/cm2, and the coagulation Enzyme system-54- '申請專利範圍 2·0 IU/cm2的數量存在。 5. 如申請專利範圍第1項所述之固態組成物，其中該纖維 蛋白原係純化自一天然來源。 6. 如申清專利範圍第1項所述之固態組成物，其中該纖維 蛋白原為人類的。 7·如申请專利範圍第1項所述之固態組成物，其中該纖維 蛋白原為轉殖基因的或重組的。 8·如申請專利範圍第1項所述之固態組成物，其中該凝血 酶係純化自一天然來源。 9. 如申請專利範圍第1項所述之固態組成物，其中該凝血 梅為人類的。 10. 如申請專利範圍第1項所述之固態組成物，其中該凝血 酶為轉殖基因的或重組的。 11. 一種用於止血、組織封口及組織膠合之材料，其包含一 具有至少二種下列物理性質的彈性載劑： 彈性模數範圍為5-100 N/cm2， 密度為 1-10 mg/cm3， 腔至直徑大於0.75 mm且小於4 mm ,和/或平均腔 室直徑小於3 mm ; 以及其進一步包含一由固態纖維蛋白原與固態凝 血酶所構成之混合物，並且不包含任何抗纖维素溶解的 藥劑，諸如抗蛋白酶肽、ε-胺基己酸或α2抗纖維 溶酶， 。 該固態纖維蛋白原及該固態凝血酶 岬以—種方式被 六、申請專利範圍 固疋至该載劑，而使得當一經塗敷的材料樣品在一威伯 菲克斯授拌器（Vibrofix shaker)上以-為大約1〇〇〇 rpm 的頻率被搖晃2分鐘時，其剝落少於丨Gmg/em2以及， 若°亥°’里塗敷的載劑材料被塞入至一内視鏡設備之 後再予以移開’該材料實質上無改變並且具有一低於 20%之經塗敷材料的固定用敷料（咖），以做為該載劑 之彈性以及該固態纖維蛋白原與該固態凝血酶的固態 附著力的一種指標； 该材料實質上為空氣緊密的及液體緊密的且具有 至少1.25的彈性因子，其係藉由—包含下狀測試而被 測定:將經塗敷的載劑固定至一乳膠薄片，藉由施加壓 力三次來膨脹乳膠且在第三次時測量位於乳膠薄片膨 脹的最高點的該經塗敷的載劑面積，以及比較該經塗敷 的載劑的膨脹面積與該經塗敷區域的該起始面積。 以一種用於組織封口的產品，其包含： a) —種具有至少二種下列物理性質的载劑： 彈性模數範圍為5-100 N/cm2， 密度為 1 -1 〇 mg/cm3， 腔至直徑大於0.7且小於4mm，和/或具有—平约 腔室直徑小於3mm ;以及 b) 其中該載劑具有一個或多個活性邊，其中纖維蛋白原 係以一為2-10 mg/cm2的數量存在，以及該凝血酶係 以一為1.5-2.5 IU/cm2的數量存在。 13.—種用於止血的產品，其包含： 申請專利範圍 a) 一種具有至少二種下列物理性質的載劑： 彈性模數範圍為5-100 N/cm2， 在、度為 1 -10 mg/cm3， 腔至直彳望大於〇.75mm且小於4mm，和/或具有一平均 腔室直徑小於3mm ;以及 )其中该载劑具有一個或多個活性邊，其中纖維蛋白 原係以一為2-10 mg/cm2的數量存在，以及該凝血誨 係以一為1.5-2.5 IU/cm2的數量存在。 4 — .—種用於組織膠合的產品，其包含： a) 一種具有至少二種下列物理性質的載劑·· 彈性模數範圍為5-100 N/cm2， 雄'度為 1 -1 〇 mg/cm3， 腔至直徑大於〇.75mm且小於4mm ,和/或具有一平均 腔至直控小於3mm ;以及 b) 其中該載劑具有一個或多個活性邊，其中纖維蛋白 原係以-為2-10 mg/cm2的數量存在，以及該凝血酶 係以一為1.5-2.5 Ιϋ/cm2的數量存在。 •如申請專利範圍第12-14項中任何一項所述的產品，其 係用於胃腸系統的外科干預，諸如食道、胃小腸大 腸直腸’於實質的器官，諸如肝臟、脾臟、胰臟、腎 臟、肺臟、腎上腺、甲狀腺及淋巴結；心血管外科胸 外科’包含在氣管、支氣管以及肺臟外科；在耳、鼻及 喉⑽T)領域料科干預，包含牙科外科；婦科、泌尿 科、灰管、骨頭(例如骨鬆質切除)及急救外科； 六、申請專利範圍 :間I:漏膽及—管及在胸及肺外科手術 16·如申請專利範圍第12·14項中任何—項所述的產品其 為-種生物可降解的聚合物，諸如聚琉璃祕 I，多皂基酸’例如乳酸、葡萄糖酸、羥基丁酸；纖維 素；凝膠或膠原蛋白，諸如_膠原蛋自料例如一 參 土本上由#原蛋白型式！纖維所組成的膠原蛋白海綿。 17.如申請專利範圍第12·14項所述的產品，其中該載劑具 個或夕個/舌性邊’其中纖維蛋白原係以—為4 ㈣咖2的數量存在，以及該凝金酶係以一為HU IU/cm2的數量存在。 申"3專利範圍第17項所述的產品，其中該載劑具有一 個或多個活性邊，苴由 '、中纖維蛋白原係以一為5.5 mg/cm2 的數里存在’以及該凝血酶係以m似啦2的數量 存在。 19·如申請專利範圍第12_14項中任何_項所述的產品，其 中錢維蛋白原為人類的、純化自一天然來源，或是為 轉殖基因的或重組的人類纖維蛋白原。 申-月專利範圍第12_14項中任何—項所述的產品，其 中該纖維蛋白原係純化自一天然來源。 申。月專利範圍第1()·12項中任何—項所述的產品其 中該纖維蛋白原為轉殖基因的或重組的。 申。月專利範圍第1G_ 12項中任何—項所述的產品，其 中該凝血_為人類的、純化自—天•然來源，或是為轉殖 -58- 六、申請專利範圍 基因的或重組的人類凝血酶。 23,如申請專利範圍第10-12項中任何-中該凝血酶係純化自一天然來源。 24·如申請專利範圍第UM2項中任何一 中該凝血酶為轉殖基因的或重組的 項所述的產品，其 項所述的產品，其-54- 'The patent application range exists in the range of 2·0 IU/cm2. 5. The solid composition of claim 1, wherein the fibrinogen is purified from a natural source. 6. The solid composition of claim 1, wherein the fibrinogen is human. 7. The solid composition of claim 1, wherein the fibrinogen is transgenic or recombinant. 8. The solid composition of claim 1, wherein the thrombin is purified from a natural source. 9. The solid composition of claim 1, wherein the blood coagulation is human. 10. The solid composition of claim 1, wherein the thrombin is a transgenic or recombinant. 11. A material for hemostasis, tissue sealing and tissue gluing comprising an elastic carrier having at least two of the following physical properties: an elastic modulus in the range of 5-100 N/cm2 and a density of 1-10 mg/cm3 a cavity to a diameter greater than 0.75 mm and less than 4 mm, and/or an average chamber diameter of less than 3 mm; and further comprising a mixture of solid fibrinogen and solid thrombin, and not comprising any anti-cellulosic A dissolved agent such as an anti-protease peptide, ε-aminocaproic acid or α2 anti-plasmin. The solid fibrinogen and the solid thrombin are fixed in the manner of the patent application to the carrier in such a manner that when the coated material sample is in a Wibofix shaker (Vibrofix shaker) When the upper side is shaken for 2 minutes at a frequency of about 1 rpm, the peeling amount is less than 丨Gmg/em2 and, if the carrier material coated in °°°' is inserted into an endoscope device Thereafter, the material is substantially unchanged and has a coating dressing of less than 20% of the coating material as the elasticity of the carrier and the solid fibrinogen and the solid coagulation. An indicator of the solid state adhesion of an enzyme; the material is substantially air tight and liquid tight and has an elastic factor of at least 1.25, which is determined by including an underlying test: fixing the coated carrier To a latex sheet, the latex is expanded by applying pressure three times and the coated carrier area at the highest point of expansion of the latex sheet is measured at the third time, and the expanded area of the coated carrier is compared with The coated The starting area of the area. A product for tissue sealing comprising: a) a carrier having at least two of the following physical properties: an elastic modulus in the range of 5 to 100 N/cm 2 and a density of 1 -1 〇 mg/cm 3 , cavity Up to a diameter greater than 0.7 and less than 4 mm, and/or having a flat cavity diameter of less than 3 mm; and b) wherein the carrier has one or more active edges, wherein the fibrinogen is 2-10 mg/cm2 The amount is present, and the thrombin is present in an amount of 1.5-2.5 IU/cm2. 13. A product for hemostasis comprising: Patent Application a) A carrier having at least two of the following physical properties: an elastic modulus in the range of 5-100 N/cm2, a degree in the range of 1 -10 mg /cm3, the cavity to the right is greater than 〇.75mm and less than 4mm, and/or having an average chamber diameter of less than 3mm; and) wherein the carrier has one or more active edges, wherein the fibrinogen is The amount of 2-10 mg/cm2 is present, and the coagulation system is present in an amount of 1.5-2.5 IU/cm2. 4 — A product for tissue gluing comprising: a) a carrier having at least two of the following physical properties: • an elastic modulus in the range of 5-100 N/cm 2 and a male 'degree 1 -1 〇 Mg/cm3, cavity to diameter greater than 75.75 mm and less than 4 mm, and/or having an average lumen to direct control less than 3 mm; and b) wherein the carrier has one or more active edges, wherein the fibrinogen is - It is present in an amount of 2-10 mg/cm2, and the thrombin is present in an amount of 1.5-2.5 Ιϋ/cm2. The product according to any one of claims 12-14, which is for use in a surgical intervention of the gastrointestinal system, such as the esophagus, the small intestine of the small intestine, in the parenchymal organs, such as the liver, the spleen, the pancreas, Kidney, lung, adrenal gland, thyroid and lymph nodes; Cardiovascular Surgery Thoracic Surgery' is included in the trachea, bronchi, and lung surgery; in the ear, nose, and throat (10)T), including dental surgery; gynecology, urology, gray tube, Bone (such as bone cancellous resection) and emergency surgery; Sixth, the scope of application for patents: between I: leaking gallbladder and tube and in thoracic and pulmonary surgery 16 as described in any of the patent application scope 12-14 The product is a biodegradable polymer, such as poly silicate I, poly soap acid 'such as lactic acid, gluconic acid, hydroxybutyric acid; cellulose; gel or collagen, such as _ collagen egg self-feeding, for example A ginseng on the #原蛋白型! A collagen sponge composed of fibers. 17. The product of claim 12, wherein the carrier has an eve or a lingual edge, wherein the fibrinogen is present in an amount of 4 (four) coffee 2, and the condensate The enzyme system is present in an amount of one HU IU/cm2. The product of claim 17, wherein the carrier has one or more active sides, and the sputum is present by ', medium fibrinogen in a number of 5.5 mg/cm2' and the coagulation The enzyme is present in an amount of m like 2 . 19. The product of any of clauses 12 to 14, wherein the provitamin is human, purified from a natural source, or is a transgenic or recombinant human fibrinogen. The product of any one of clauses 12 to 14, wherein the fibrinogen is purified from a natural source. Shen. The product of any one of clauses 1 to 12 of which the fibrinogen is transgenic or recombinant. Shen. The product of any of the items of the first aspect of the invention, wherein the blood coagulation is human, purified from the source of the natural source, or is transgenic -58-six, patented or recombinant Human thrombin. 23. The thrombin is purified from a natural source as in any of claims 10-12. 24. The product according to any one of the claims UM2, wherein the thrombin is a transgenic gene or a recombinant product, the product thereof,