丄 坎、發明說明 【發明所屬之技術領域】 本發明係關於一種局部傳送藥物的裝置及方法；詳言 疋’係關於一種植入式系統，該系統一旦被密封至一組織 或器官中後，即可使欲傳送至—標的組織之藥物不致被暴 露到該標的組織周園的其他組織及流體中，同時還可維持 —定程度的藥量於該哺乳動物局部組織或系統内。同時揭 露的還包括治療疾病的裝置與方法。 【先前技術】 已有許多研究專注於可植入至哺乳動物體内一預先選 定位置的藥物傳送裝置上。迄今，也研發出許多不同類型 的手術植入式藥物傳送裝置，該等裝置並已取得專利，將 詳細介绍如下。 授與Ashton等人之美國專利第6,2 17,895號、第6,001，386 號、第5,902,598號、及第5,836,935號揭示一種可局部傳送 —低溶解度藥劑至身體内部的手術植入式藥物傳送裝置。 該裝置包括一含有藥劑的内核，經由一可控制該藥物釋放 速率的通透性聚合物鍍膜而與周圍組織隔絕。哚 邊衮置係自 植入位置處多方向傳送藥物，使該位置所有择接 、’°稱均暴露在 藥物下。此外，該藥物的釋出係透過一裊法 、曷生物所分解 但可使藥物穿過其中的聚合物鍍膜這類複齄μ 难的技術來控 制。 3 1323667 美國專利第4,3 78,01 6號揭示了一種用來傳送一種活性 因子到一哺乳動物體内特定位置的手術植入式藥物傳送裝 置。該裝置包含一可植入到哺乳動物體内之减體可通透的 膜袋（membranous sack) ’及一流體不可通透的由、_ J甲2管’該 中空管的一端係連接到袋内，另一端則留至於喃 、用乳動物體 外。該管可作為通至該膜袋的通道’待該膜 久谈植入至哺 乳動物體内.後，一含有細胞的小包（envel〇Pe)可藉由該管被 引入至膜袋中。在將該含有細胞的小包植入至膜袋後，該 細胞即可產生一活性因子’並於梢後穿過膜袋擴散至被植 入者的周圍组織或器官内° 美國專利第5，182，111號揭示了一種用來傳送一種活性 因子到一預選定位置（例如，一哺乳動物體内的組織或器官） 的手術植入式藥物傳送裝置。該裝置包含一由半通透式膜 所形成的空間’其内包含至少一種可產生專一性活性因子 的第一型細胞及可產生一放大因子的第二型細胞。由該第 二型細胞所製造的放大因子之後可誘導第一型細胞產生該 活性因子。 美國專利第4,479,796號揭示了 —種手術植入式的分散 器，其係可將一預選定藥物直接擴散傳送至血液中。簡言 之，該分散器係手術植入至與一血管對齊處。該分散器内 包納_可置換的細胞小管’微組織’其係可製造並分泌藥 物至通過該小管的血液中。 美國專利第4,3 09,776號揭示了一種血管内藥物傳送裝 1323667 簟，其具有一室，該室内具有可供手術植入至血管壁的植 入細胞。該裝置包含一可容許由該植入細胞所製造之荷爾 蒙通過並由該室擴散至血液中的孔狀壁。授與Avery等人之 美國專利第6,251，090號、第5,830，173號、第5,725,493號揭 帝一種藥物傳送裝置，其包含一經由管線連接到玻璃體腔 之可充填的儲存槽。此傳送裝置涉及眼框内侵入，因此限 制了其之應用，特別是針對那些需要保持標的組織完整的 應用而言。 美國專利第6,416,777號、第6,413,540號專利揭示了一 種裝置’該裝置一旦被安裝至Tenon氏囊（Tenon，s capsule) 之下，並與鞏膜接觸，即可開始傳送藥物至眼睛中。這類 系統係由一層無法為意欲傳送藥物所通透的外層所組成， 藉以降低藥物被眼睛周圍流體沖掉的機率。該裝置的外型 係有助於其被植入鞏膜以下的空間，同時還可參照其所揭 不將裝置植入並保持於下斜肌的方法，避免裝置自植入位 置處滑移至靠近視網膜黃斑區（macula area)。但該等專利中 並未揭示如何將該裝置密封植入至鞏膜或標地組織内的方 *4* 此外’這些裝置的設計並非如雙-室儲存槽所示適於用 來傳送一種以上的藥劑，此外，該等專利中未揭示如何填 充儲存槽埠，以便重新定位對液態藥物的位置。 需使用皮下密封式裝置的需求係來自對藥劑及組織的 特徵公 ^衍。在諸多藥物相關的因素中，包括有效毒理濃度 些微差異、在抵達標地組織前其易於失活的特性或高度 5 1323667 不安定性、長期且穩定的釋出曲線（特別式針對慢性病而 言）、及其在液態或凝膠狀態下的可利用度。組織因素主要 係與該藥物所需之表型專一性相關，同樣重要的是與周圍 组織不易受該藥物毒性傷害相關。 由於藥物可能自裝置-组織介面附近滲出之故，使某些 非常重要的藥物（包括毒性藥物及其他專一性更高的藥物）無 法被應用在藥物傳送裝置内•除了應被暴露的位置外生 成血管型胜肽絕對不可以被暴露到其他組織位置。如果目 標係要增加血流並刺激微血管生長，則如果該等生成血管 型胜肽在穿過輩膜之前即暴露於眼睛周圍的血管組織的 話，除了將使生成血管的效果消散外，還會提高植入處的 血流及血漿，並加逮該等活性劑的分解及中和。此外在 該位置處所發生的生物程序將會隨著任一來自傳送裝置之 藥物的釋出模式而改變’無論該藥劑係處於活性狀態與否。 發炎反應係哺乳動物自我痊癒過程中的一種基本反 應，其中涉及多種化學、生物及細胞因子的參與，最後並 導致组織*.组4痕的生成及身料外來物的反應為一受 傷有機體及手術傷害後常見的反冑，特別是對暴露至惰性 或免疫性物質的情況而t。這些反應的產生係為了透過一 連串反應來使受傷的組键+ ^ ^ 、个队又埼叼殂蜾重组，通常結果係該受傷組織將 被強化或外來物會被隔絕。 過去十年對眼睛周固植入物的經驗多半應歸功於用來 治療虹膜脫落的圓形元件及青光眼手術用的過濾裝置。因 6 為上述目的之故，測試過許多聚合物，且多年累積的經驗 顯布在眼晴周圍植入物被植入後，會發生程度不一的植入 物包被現象（encapsulation)。即使對已廣泛使用的醫學產品 (如發膠）而言，在植入的第3天，即可觀察到包被現象。但 是，& ’身體對義肢或結構性植入物的纖維化反應並不會造成 太大的傷害。相反的，其甚至可對植入物提供欲求的機性 安定性，以提高其結構性功能。欠缺一種將藥物傳送裝置 达、封至皮下組織的方法’不僅影響所攜藥物如何作用及其 與周圍組織作用的方式，也會影響周圍組織對該藥物及該 傳送系統的反應。這類系統的包被現象及在藥物儲存槽與 器官表面生成的疤痕組織’將明顯改變藥物釋出的模式， 並改變其擴散出表面的主要決定因子（該表面主要係由特徵 已知的膜所構成），及某些因子的擴散係數。 在眼科學上，已有許多專門研究鞏膜（眼球最外層的膜 層）特徵的研究在進行。許多研究均採用眼睛周圍（periocuUr；) 注射的方式來傳送藥物。Edelhauser等人對鞏膜作為通透性 膜的功能進行了許多研究。其體外試驗的結果已由體内試 驗進一步獲得證實，顯示眼睛周圍（periocular)注射方式可 將藥物傳送至眼睛内部组織。其結果顯示高達7〇 Kda的分子 可擴散通過鞏膜並到達眼内空間，即使其中存在著一壓力 梯度亦然。雖然這類特性的真正機制尚未十分清楚（特別是 這些大分子可越過諸如血液-視網膜阻障這類具高度選擇性 的組障結構而到達玻璃體内空間的機制尚未十分清楚），但 7 丄 β 性可由鞏膜膠原蛋白的多孔性特徵來解釋。確實， 尺保護、可穿越鞏膜的途徑已經被使用多年，且被 證明*^^ 有玫地來施用某些藥物。抗發炎固醇藥物係被注射 穿過結膜到達輩膜以下的空間並與鞏膜直接接觸，其容許 藥物朝向眼内空間擴散，而達到提供治療性藥劑至眼睛各 層組織的目的。已提供具欲求安全性及等效性或超級有效 疋可到達系統的途徑且不具其副作用的寄存固醇配方。但 是’由於這些注射並無法使眼晴周圍组織免於暴露於注射 藥劑之下，因此大部分的注射藥物係被系統性地吸收到周 圍組織而被帶離注射位置。因此，此種注射藥劑為短效藥 劑。 莱些其他藥物因為所需通過眼晴膜層的濃度過高，會 導致嚴重的過敏或對周圍组織造成毒性，因此無法以此種 眼晴周圍注射途徑來施用。由於在這種眼睛周圍注射途徑， 藥劑消散得相當快（此主要係由眼睛周園軟組織的清洗機制 所致，或因發炎細胞、免疫球蛋白及血漿組成使該等藥劑 在到達其標地組織前即已失活所致），因此需使用高濃度 藥劑6 在某些狀況下，例如眼内炎（endophthamitis)，所使用 的眼内濃度係可於短時間内提供高量抗生素予眼晴内。但 是，對慢性病患者而言，一而再，再而三的眼睛内注射卻 容易造成併發症（可能來自注射操作程序或直接注射所提供 的即時高濃度藥劑所致）。此外，並非永遠都可使用眼內注 工323667 射法，諸如葡萄膜炎之類的發炎狀況，特別是諸如Behcet氏 症候群之類的嚴重異常’即使侵入程度最低的眼内注射都 可能導致嚴重且長期性的低張（即，低滲透壓）情況。由於癌 細胞可能脫離原位而分散至整個眼球’因此眼.癌也需要非 侵入式的治療。 兒童身上最常見的眼内腫瘤-視網膜母細胞瘤是一種適 合進行局部化療藥劑傳送的眼睛疾病。其臨床特徵為癌細 胞係種植在玻璃體膠狀物質上，目前該疾病係以系统性化 療進行治療。而系統性治療往往因為無法在欲治療位置處 達到具療效的藥劑濃度而導致治療失敗，最後並因而必須 摘除眼球。將藥劑直接施用在玻璃體上幾乎是不可能，因 為此舉極可能導致癌細胞脫離原位而擴散開來，直接導致 患者死亡》 局部治療為另一種選擇，目前也正在臨床試驗階段。 目前已有一些令人欣喜的結果，但同時也有某些毒性副作 用被報導。在特定狀況中，眼球内高濃度細胞毒性藥劑， 例如硬化麵，可能會在患者有限的生命中造成預期外的副 ’特別是視網膜母細胞瘤係更易因基因突變而受到二 胞增生的影響。如果將眼睛周圍注射之藥劑與眼睛外 &綠组織隔離，也可獲得類似的藥劑治療效果，因其可 提供 4S 1 釋出且對眼球组織及光學神經造成更低的副作 此外’由於與藥劑接觸的介面區域（其係決定藥劑穿過 膜的擴散速率的主要因素）係清楚定義，因此也可達成該 1323667 等藥劑的控制釋出。藥物與鞏膜上特定區域接觸的位置也 可避免更敏感组織（例如，光學神經）暴露於該等高濃度的毒 性藥劑之下。 .區域治療已被詳細研究且在許多狀況下被證明十分有 效。雖然基於聚合物技術的藥物傳送系統已改善了治療藥 劑在標地組織中的生物可利用性及藥動學特性但欠缺局 部專一性仍是該技術在臨床應用上的—大限制。 新類型的治療藥劑提供了些微希望，但無法迅速有效 且專一性地傳送這類藥劑至標地组織也限制了其在體外試 驗上的成就。許多這類藥劑在進行雔内試驗時，並無法產 生與體外試驗相同的實驗結果。 此外，一旦器官這類天然組障為手術所打破時，癌症 細胞及感染性藥劑可分散至其他器官或甚至整個系統。上 述系統在不直接傳送藥劑至標的組織間質的情況下，仍可 透過釋放藥劑至腔室或周圍组織空間及流體的方式來提供 治療效果。此最終可導致器官自任一周圍結構中吸收藥劑。 但這類系統缺乏專一性且當藥劑_周圍組織具有毒性的情 況下，並不適於臨床使用。而當藥劑可能啟動病理反應時， 這個問題就變得更嚴重。對使用病毒基因載體、生物活性 因子抑制劑及非專一性敏感劑的情况來說，這種問題就更 常見了。 貼布傳送系統係研發來經皮膚或黏膜傳送或釋放藥 劑《這類系統的設計有一與皮膚或黏膜表皮層接觸的介面， 10 0/ 藥劑即是經由此介面而 散釋出。另一介面通常是標的身 體組織的外面，亦即，徘 子！皮傳送系統而言，係指外在 境；對經黏膜傳送•手餘尤丄 ' w，則疋腸腔或口腔。在設計遠 類裝置時的主要考量A过故讲 為保護釋出藥劑不會被腸胃、口腔及 鼻通道之分泌液所破墙， m 並说在之後容許更多藥劑到達循 環系統’而非直接作用在標的组織或器官上。 對經黏膜傳送裝置 置而S ，任何來自外表面的釋出 腔道酵素、菌叢或物理 失活機制所中和掉’或是經遠端 吸收後而抵達循環$社 *、-无’此也是大部分藥劑傳送系統的最 終目的。這類經皮膚哎… 虱黏膜傳达的貼布系統從未朝向手術 植入系統方向研發，；Α 也從未針對其暴露於體内流體下（即， 血液、結缔组織考/-£_ JL—- 風任何細胞反應）後之生物可相容性進行任 何研究。其可能的 應用係被暴露於身體體液下，因此不 受到嚴重的發炎J5 u 欠反應攻擊且並不需要非常高的生物可相 性。 諸如供釋出藥劑的聚合物阻障及供眼用的聚合物系 統，與經皮膚或黏膜傳送的貼布系統擁有某些相同的特徵。 其目的並非直接傳送藥劑到角膜或結膜或任—特定的眼晴 結構上，ifij疋以多方向釋放藥劑至身體分泌液中例如眼 淚層。藥劑自撕裂層開始擴散穿過眼睛表面，之後到達眼 淚排出系統及鼻咽黏膜，再次使其他组織暴露於可能的毒 性副作用下。這類系統可提供長效釋出，但為非專一性的 長效釋出’其影響會朝向所有周圍组織（亦即，結膜、LID皮 1323667 膚、角膜、淚腺系統）消散。 系統一樣，這類系統係設計 非用來手術植入的產品，而 已。 一如經皮膚或黏膜傳送的貼布 來提供非侵入式長效釋放，並 只是附在身趙或黏膜表面上而 實驗及臨床證據鞍 嗎不田器g表面暴露於高量藥劑下 時，也可能導致其内部鏟吾成如& 藥量到達&療劑量，甚至高過系統 性施用所能達到的治癢麻 ® « .劑量。器&及组織的潛在擴散性將 在以下討論，以及以发决、Α , 其作為治療路徑的優點等，也一併討 論如下。 具生物活性的胜肤乃是天然存在於生物程序中的必須 物質’但在疾病狀態下(例如，癌症、脈絡層新血管膜），則 可能存在或不存在（例如，缺血性心肌部位）》將這類因予往 上或往T調降將可改善疾病狀態’且將其作為有效治療藥 劑時，將需要能將其以夠量長期且持續的送到標的组織 内。相同保護調控傳送也見於基因載體、反義藥劑、抗生 素、細胞毒性劑、帛素，某些荷爾蒙等之傳送上。其他已 知的敏感劑也需要特定作用，此外，為標的组織再吸收的 藥劑之後將用來定義特定治療(亦即化療、雷射、輻射或熱 治療）的效用，如限制或提高其效果以及對治療位置的副作 用等。 局部藥物傳送用來治療顱内癌的效果，目前正在臨床 試驗階段。某些源自神經的腫瘤，例如膠原母細胞瘤目前 受到相當高的關注。這些腫瘤係以標準手術切除加上外部 12 1323667 輻射治療方式進行治療。由於椬公 田於這類腫瘤會入侵周園腦部组 織，因此經常會在切除部位邊绫 ^ ^ _ γ 復發。基於這些特性及腫 瘤對系統性化療沒有反應的愔沉下，s此開始考量局部傳 送藥劑、it感劑及胜肽載趙，並以其在患者生命品質上的 影響研究其作為一種治療選擇的可能性。BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a device and method for locally delivering a drug; in particular, it relates to an implantable system which, once sealed into a tissue or organ, The drug to be delivered to the target tissue is not exposed to other tissues and fluids in the target tissue, while maintaining a certain amount of drug in the mammalian local tissue or system. Also disclosed are devices and methods for treating diseases. [Prior Art] A number of studies have focused on drug delivery devices that can be implanted into a preselected location in a mammal. To date, many different types of surgically implantable drug delivery devices have been developed, which have been patented and will be described in detail below. A surgically implantable drug delivery device that delivers a low solubility agent to the interior of the body is disclosed in U.S. Patent Nos. The device includes a core containing a drug that is isolated from surrounding tissue via a permeable polymer coating that controls the drug release rate.衮 The edge placement system delivers the drug in multiple directions from the implantation site, so that all the selected locations and the '° are exposed to the drug. In addition, the release of the drug is controlled by a technique that is decomposed by a sputum, a sputum, or a polymer coating that allows the drug to pass through. A surgical implantable drug delivery device for delivering an activity factor to a specific location in a mammal is disclosed in U.S. Patent No. 4,3,78,01, the disclosure of which is incorporated herein by reference. The device comprises a permeable permeable membrane sac that can be implanted into a mammalian body and a fluid impermeable permeable tube, one end of which is connected to one end of the hollow tube Inside the bag, the other end is left to the outside of the animal. The tube can be used as a passage to the membrane bag. After the membrane is implanted into the mammal for a long time, a cell-containing packet (envel〇Pe) can be introduced into the membrane pouch by the tube. After the cell-containing pouch is implanted into the membrane pouch, the cell can produce an active factor' and diffuse through the membrane pocket after the tip to the surrounding tissue or organ of the implanted object. U.S. Patent No. 5, No. 182,111 discloses a surgically implantable drug delivery device for delivering an active agent to a preselected location (e.g., a tissue or organ in a mammal). The device comprises a space formed by a semi-permeable membrane comprising at least one type 1 cell capable of producing a specific activity factor and a second type of cell capable of producing a magnification factor. The amplification factor produced by the type 2 cell can then induce the first type of cell to produce the active factor. U.S. Patent No. 4,479,796 discloses a surgically implantable disperser for delivering a preselected drug directly into the blood. Briefly, the disperser is surgically implanted into alignment with a blood vessel. The disperser contains a replaceable cell tubule 'micro-tissue' which is capable of producing and secreting a drug into the blood that passes through the tubule. U.S. Patent No. 4,309,776 discloses an intravascular drug delivery device 1323667, which has a chamber with implanted cells for surgical implantation into the vessel wall. The device comprises a perforated wall that allows passage of hormones made by the implanted cells and diffuses from the chamber into the blood. A drug delivery device comprising a fillable storage tank connected to a vitreous chamber via a line is disclosed in U.S. Patent Nos. 6,251,090, 5,830,173, 5,725,493 issued to A. This delivery device involves intrusion into the eye frame, thus limiting its application, especially for applications that need to maintain the integrity of the target tissue. U.S. Patent Nos. 6,416,777 and 6,413,540 disclose a device which, once installed under the Tenon's capsule and in contact with the sclera, begins to deliver the drug into the eye. This type of system consists of an outer layer that is not transparent to the intended delivery of the drug, thereby reducing the chance of the drug being washed away by fluid around the eye. The appearance of the device facilitates its implantation into the space below the sclera, while also avoiding the method of implanting and retaining the device in the inferior oblique muscle, preventing the device from slipping to the vicinity from the implantation site. The macula area of the retina. However, these patents do not disclose how to seal the device into the sclera or the ground tissue*4*. Moreover, the design of these devices is not suitable for transmitting more than one type as shown in the dual-chamber storage tank. Medicaments, in addition, do not disclose how to fill the storage tank in order to reposition the position of the liquid medication. The need for a subcutaneous sealed device is derived from the characterization of the agent and tissue. Among the many drug-related factors, including slight differences in effective toxicological concentrations, their inability to deactivate before reaching the target tissue, or a high degree of long-term and stable release curve (in particular for chronic diseases) 5 1323667 And its availability in liquid or gel state. The tissue factor is primarily related to the phenotypic specificity required for the drug, and it is equally important that it is not susceptible to the toxicity of the surrounding tissue. Because the drug may ooze near the device-tissue interface, certain very important drugs (including toxic drugs and other more specific drugs) cannot be used in the drug delivery device • except where it should be exposed The angiogenic peptide must not be exposed to other tissue locations. If the target is to increase blood flow and stimulate microvascular growth, if the angiogenic peptides are exposed to the vascular tissue around the eyes before passing through the adult membrane, in addition to dissipating the effect of generating blood vessels, it will increase. The blood flow and plasma at the implant, and the decomposition and neutralization of the active agents are added. In addition, the biological procedure occurring at that location will change with any release mode of the drug from the delivery device' whether the pharmaceutical system is active or not. The inflammatory response is a basic reaction in the self-healing process of mammals, involving the involvement of a variety of chemical, biological and cytokines, and finally leads to the formation of tissue 4 and the appearance of foreign bodies as an injured organism and Common ruminants after surgical injury, especially when exposed to inert or immunological substances. These reactions are generated by recombining the injured group key + ^ ^ and the team through a series of reactions. Usually, the injured tissue will be strengthened or the foreign object will be isolated. Much of the experience of periocular implants over the past decade has been attributed to circular elements used to treat iris shedding and filtration devices for glaucoma surgery. Because of the above-mentioned objectives, many polymers have been tested, and years of accumulated experience have revealed that implant implants of varying degrees can occur after implantation of the implant around the eye. Even for medical products that have been widely used (such as hair spray), the coating phenomenon can be observed on the third day of implantation. However, the &' body does not cause much damage to the fibrotic response of prosthetic or structural implants. Conversely, it can even provide the desired mechanical stability of the implant to enhance its structural function. The lack of a means of reaching and sealing the drug delivery device to the subcutaneous tissue not only affects how the drug is carried and its interaction with the surrounding tissue, but also affects the surrounding tissue's response to the drug and the delivery system. The coating phenomenon of such systems and the scar tissue formed on the drug storage tank and organ surface will significantly change the mode of drug release and change the main determinant of its diffusion surface (the surface is mainly composed of membranes with known characteristics). The composition, and the diffusion coefficient of certain factors. In ophthalmology, many studies have been conducted to study the characteristics of the sclera (the outermost layer of the eyeball). Many studies have used the method of injection around the eyes (periocuUr;) to deliver drugs. Edelhauser et al. have conducted many studies on the function of the sclera as a permeable membrane. The results of its in vitro tests have been further confirmed by in vivo tests, showing that periocular injections deliver the drug to the internal tissues of the eye. The results show that molecules up to 7 〇 Kda can diffuse through the sclera and reach the intraocular space, even if there is a pressure gradient. Although the true mechanism of such properties is not well understood (especially the mechanism by which these macromolecules can reach the intravitreal space with highly selective barrier structures such as blood-retinal barriers), 7 丄β Sex can be explained by the porous nature of scleral collagen. Indeed, the rule of the ruler, the path that can pass through the sclera has been used for many years, and it has been proven that *^^ has some medicine to administer certain drugs. Anti-inflammatory steroid drugs are injected through the conjunctiva to the space below the orbital membrane and in direct contact with the sclera, which allows the drug to diffuse into the intraocular space for the purpose of providing therapeutic agents to various layers of the eye. A sterol formulation with a safety and equivalence or super effective achievable system that does not have side effects has been provided. However, because these injections do not protect the tissues surrounding the eye from exposure to the injectables, most of the injected drugs are systematically absorbed into the surrounding tissue and taken away from the injection site. Therefore, such an injection is a short-acting drug. Some other drugs that are used because of the high concentration of the eye layer that is required to pass through the eye may cause severe allergies or toxicity to surrounding tissues, and therefore cannot be administered by such a peripheral injection route. Due to the injection route around this eye, the agent dissipates quite quickly (this is mainly caused by the cleaning mechanism of the soft tissue of the eye, or by the composition of the inflammatory cells, immunoglobulins and plasma to allow the agents to reach their target tissues. It has been inactivated before, so it is necessary to use a high concentration of the drug 6 In some cases, such as endophitis, the intraocular concentration used can provide a high amount of antibiotics to the eye in a short period of time. . However, for patients with chronic conditions, repeated intraocular injections are likely to cause complications (possibly due to injection procedures or immediate high-concentration agents provided by direct injection). In addition, intraocular injection 323667 can not always be used, such as inflammatory conditions such as uveitis, especially serious abnormalities such as Behcet's syndrome', even the least invasive intraocular injection can cause serious and Long-term low-tension (ie, low osmotic pressure) conditions. Since cancer cells may detach from the original position and disperse throughout the eyeball, the cancer is also required for non-invasive treatment. The most common intraocular tumor in children, retinoblastoma, is an eye disease that is suitable for the delivery of local chemotherapeutic agents. Its clinical feature is that the cancer cell line is planted on the vitreous gelatinous substance, which is currently treated with systemic chemotherapy. Systemic treatment often results in failure of treatment due to the inability to achieve a therapeutic concentration at the site of treatment, and ultimately the eyeball must be removed. It is almost impossible to apply the agent directly to the vitreous, because it is very likely to cause the cancer cells to disengage from the original and spread, which directly leads to the death of the patient. Local treatment is another option and is currently in clinical trials. There have been some encouraging results, but some toxic side effects have also been reported. In certain situations, high concentrations of cytotoxic agents in the eye, such as the hardened surface, may cause an unexpected episode in the patient's limited life. In particular, retinoblastoma is more susceptible to cytogenesis due to genetic mutations. A similar agent treatment effect can also be obtained if the agent injected around the eye is isolated from the extraocular & green tissue, as it provides 4S 1 release and causes lower side effects on the eye tissue and optical nerves. Since the interface area in contact with the agent, which is the primary factor determining the rate of diffusion of the agent through the film, is clearly defined, controlled release of the agent such as 1323667 can also be achieved. The location of the drug in contact with a particular area of the sclera also prevents exposure of more sensitive tissue (e.g., optical nerves) to such high concentrations of toxic agents. Regional treatment has been studied in detail and has proven to be very effective in many situations. Although drug delivery systems based on polymer technology have improved the bioavailability and pharmacokinetic properties of therapeutic agents in the tissue, the lack of local specificity is still a major limitation of the technology in clinical applications. New types of therapeutic agents offer little hope, but the inability to deliver such agents to the tissue in a rapid, efficient and specific manner also limits their success in in vitro testing. Many of these agents do not produce the same experimental results as in vitro tests when tested in the sputum. In addition, once a natural component such as an organ is broken by surgery, the cancer cells and infectious agents can be dispersed to other organs or even the entire system. The above system can provide therapeutic effects by releasing the agent to the chamber or surrounding tissue space and fluid without directly delivering the agent to the target interstitial tissue. This ultimately can result in the organ absorbing the agent from any surrounding structure. However, such systems lack specificity and are not suitable for clinical use when the surrounding tissue is toxic. This problem becomes more serious when the agent may initiate a pathological response. This problem is more common in the case of viral gene vectors, bioactive factor inhibitors, and non-specific sensitizers. The patch delivery system is developed to deliver or release the drug through the skin or mucous membrane. "These systems are designed to have an interface with the skin or mucosal epidermis, and the 10/agent is released through this interface. The other interface is usually the outside of the target body tissue, that is, the scorpion! In the case of the skin delivery system, it refers to the external environment; for the transmucosal transmission, the hand is especially 丄 ' w, then the intestine cavity or the mouth. The main consideration when designing a far-end device is that the release of the drug is not broken by the secretions of the gastrointestinal, oral and nasal passages, and m is said to allow more agents to reach the circulatory system afterwards instead of directly Act on the target tissue or organ. For the transmucosal delivery device, any neutralizing enzymes, flora or physical inactivation mechanisms from the outer surface are neutralized or transferred to the circulation after being absorbed by the distal end. It is also the ultimate goal of most drug delivery systems. This type of transdermal 哎... 贴 mucous membrane delivery system has never been developed in the direction of surgical implant systems; Α has never been exposed to fluids in the body (ie, blood, connective tissue test /-£ _ JL - the wind biocompatibility after any cell reaction) was studied. Its possible applications are exposed to body fluids and are therefore not subject to severe inflammatory J5 u underreaction and do not require very high biocompatibility. Polymer barriers such as polymer barriers for release of medicaments and ophthalmic polymer systems have some of the same characteristics as transdermal or mucosal delivery systems. The purpose is not to deliver the agent directly to the cornea or conjunctiva or to any specific eye structure, and ifij疋 releases the agent in multiple directions into the body's secretions, such as the tear layer. The agent begins to diffuse through the surface of the eye from the tear layer and then reaches the tear discharge system and the nasopharyngeal mucosa, again exposing other tissues to possible toxic side effects. Such systems provide long-acting release, but are non-specific long-acting release' effects that dissipate toward all surrounding tissues (ie, conjunctiva, LID skin 1323667 skin, cornea, lacrimal gland system). Like systems, such systems are designed for products that are not surgically implanted. As a patch delivered through the skin or mucous membrane to provide non-invasive long-acting release, and is only attached to the body or mucosal surface and experimental and clinical evidence that the surface of the saddle is not exposed to high doses, It may cause the internal shovel to reach the dose of & dose, even higher than the systemic application can achieve the itch? The potential spread of the && organization and organization will be discussed below, as well as the advantages of the decision, Α, as a treatment path, etc., as discussed below. Bioactive skin is the essential substance naturally present in biological procedures' but in the state of disease (eg, cancer, choroidal neovascular membrane), there may or may not be present (eg, ischemic myocardial site) "Reducing this type of disease to or from T will improve the disease state' and when it is used as an effective therapeutic agent, it will need to be able to deliver it to the target tissue in a long-term and continuous manner. The same protective regulatory delivery is also found in the delivery of gene vectors, antisense agents, antibiotics, cytotoxic agents, alizarin, certain hormones, and the like. Other known sensitizers also require a specific effect. In addition, the agent that is resorbed for the target tissue will then be used to define the utility of a particular treatment (ie, chemotherapy, laser, radiation, or heat treatment), such as limiting or enhancing its effectiveness. And side effects on the treatment location. The effect of topical drug delivery for the treatment of intracranial cancer is currently in clinical trials. Certain nerve-derived tumors, such as collagenblastoma, are currently receiving considerable attention. These tumors were treated with standard surgical resection plus external 12 1323667 radiation therapy. Since this type of tumor invades Zhouyuan brain tissue, it often recurs at the edge of the resection site ^ ^ _ γ. Based on these characteristics and the tumors that have not responded to systemic chemotherapy, it began to consider local delivery of agents, sensitizers and peptides, and studied their effects on the quality of life of patients as a treatment option. possibility.
Brem等人報導控制釋放内含3(：\1；的聚合物可延長復發 性膠原母細胞瘤患者的生命期。這類聚合物係以在最初24 小時内可釋放50%藥物，及到丨2〇小時可釋放95%藥物的方 式製備而成Q 另一報導則指出出現手術周圍併發症的機率相當高， 例如傷口感染及中風，同時也不比傳統療法更有效。讓組 織暴露於高濃度的治療藥劑下會提高療效卻不會出現系統 性副作用，但同時也會増加局部副作用的風險，通常係指 和劑量相關的副作用。 前技並未發現一選擇性及保護性的局部傳送系統可實 質地改善治療效果，以及讓從前絕不可接受使用的該等對 周圍组織具潛在毒性的藥劑成為可加以利用的藥劑，且前 技系統係設計來傳送藥劑至植入位置，但卻未對其附近正 常组織提供任何保護作用。 舉例來說，有許多研究致力於開發將生物活性藥劑傳 送到心肌或心肌表面空間的局部療法。目前心包滲漏症候 群（pericardial effusion syndrom)及轉移性腫瘤對局部傳送 化療藥劑（經導管傳送5 -氟尿嘧啶及順鉑至心肌周固内部）的 13 1323667 反應最好。此技術可有效提供心肌表面空間高量藥物，但 如果慢性長期使用，則可能出現二次感染風險》Brem et al. reported that controlled release of a polymer containing 3 (:\1; prolongs the lifespan of patients with recurrent collagen blastoma. This type of polymer releases 50% of the drug in the first 24 hours, and to 丨2 hours of release of 95% of the drug is prepared. Another report indicates that there is a high probability of complications surrounding the surgery, such as wound infections and strokes, and is no more effective than traditional therapies. Exposure of tissues to high concentrations Therapeutic agents will improve the efficacy without systemic side effects, but at the same time increase the risk of local side effects, usually referring to dose-related side effects. The prior art did not find a selective and protective local delivery system can be substantial To improve the therapeutic effect, as well as to make the potentially toxic agents of the surrounding tissue that have never been acceptable for use become available agents, and the pro-system is designed to deliver the agent to the implantation site without The nearby normal tissue provides any protection. For example, there are many studies dedicated to the development of delivery of bioactive agents to the myocardium or myocardial surface. Inter-local therapy. Currently, pericardial effusion syndrom and metastatic tumors respond best to 13 1323667, which delivers local chemotherapeutic agents (transporting 5-fluorouracil and cisplatin to the inner periphery of the myocardium). Effectively provide high dose of drugs on the surface of the myocardium, but if chronic chronic use, there may be a risk of secondary infection.
Darsino等人所進行的一項精緻實驗蘋示洋地黃毒贰 (digoxin)和利多卡因在各種心臟組織中（包括瓣膜）的藥動學 研究》其結果顯示在心臟周圍注射這些化合物後，其於心 臟組織中呈不規則分布模式。對諸如心率不整及心臟功能 失調的患者而言，最好是一藥劑係能對同一器官一預定位 置具專一性。相較於其他心臟組織，在20至60分鐘内，心 房吸收洋地黃毒贰以及心蹲週圍内主動脈吸收洋地黃毒貳 及利多卡因兩種藥物的量最高。在30至60分鐘内，利多卡 因係均勻分布在LV壁上，至於50微克的洋地黃毒贰則主要 集中在心臟表層下。此分布模式限制了以心臟表面内途經 方式來施用這些藥劑，因為在這些區域將會需要較高量的 藥劑。同一作者在另一實驗中又指出相較於左心房深層而 言，注射到心臟周圓的乙胺碘呋酮（AMI0DAR0NE)濃度在 心臟表面下的量是較高的，至於血液中，則測不到該等藥 物。這些藥劑的較佳分布最好是某些區域對藥劑具有較高 的吸收。注射將使整個心肌表面暴露在藥劑下，而不同區 威的再吸收速率並不相同’因此產生了一非控制式的表面 傳送模式。 生物活性藥劑作為治療藥劑的效用視其傳送途徑而 定。對某些生物活性剤而言’其天然形式使其較易失活或 在到達標的组織前即已為許多天然存在的因子所飽和β某 14 1323667 些生長因子及其他化合物會增加心肌梗塞區域血管的新 生。Uchida等人在一種狗的心肌梗塞模型試驗中顯示透過導 管在心贜周園内注射基礎纖維母細胞生長因子（bFGF)及肝 素硫酸鹽可有效促進血管增生且相較於心肌表面下梗塞區 域’可搶救較多的心肌表面梗塞區域。在豬的慢性心臟梗 塞模型系統上所做的進一步實驗再次證實在心臟周圍内注 射基礎纖維母细胞生長因子（bFGF)及肝素硫酸鹽可有效促 進血管增生。雖然動物試驗的結果令人欣喜，但是否能以 前述設備（包括心導管手術）在人類患者身上施用藥劑仍是一 大疑問。 °使用此種施用 病惡化及眼睛血 或被抑制，因此 ’如果血管生長 將不一。為使其 響的區域作用， 病理區域在經藥 種局部、持續、 達到上述目的， ’可潛在的使更 注射的優點，且 也有人考慮過血管内施用途徑，同時 驗。但相較於安慰劑組，其結果並未更佳 途控的一大隱憂是其潛在使視網膜血管疾 管增生的風險。 血管生長因子傾向於與其受器相結合 其在到達組織深層前即已被飽和β結果是 因子在組織層中的分布不均勻，其效果也 flb到達心肌深層’必須使其不會和不欲影 並使其作用侷限於特定病理區域，使特定 物長時間作用後能使藥物抵達组織深層。_ 保護且具選擇性傳送藥物的方法，將較能 且副作用較低；藉由最小侵入式植入過程 多患者受益。此種策略提供了心臟周固内 15 1323667 其效果相當於心臟内注射的效果β 已有許多研究致力於生物活性劑的局部使用。血管增 生抑制劑係潛在可治療眼血管增生疾病（例如，早老型視網 膜病變及年齡相關的退化性黃斑，&兩種疾病都是導致早 產新生兒眼盲或老人眼盲的主要原因）的工具。 【内容】 依據本發明一實施例，提供一種植入式、密封的藥物 傳送系統’其可提供局部持績釋出治療藥劑，直接且選擇 性的釋出至哺乳動物内部器官、組織或系統中。一較佳實 施例包括一隔絕的藥物儲存槽，其係用來經由介面傳送藥 劑使其選擇性的暴露在標的组織結構中。該裝置對介面的 控制係透過由此所描述之密封方法所提供的密封機制來達 成。 所揭示者為一種簡單、新穎之可提供局部或系統性治 療藥劑的方法，其係可直接、單向及保護傳送藥劑至一哺 乳動物的器官、组織或系統。本發明裝置可以一較佳方式 傳送治療藥劑到一為體内液體所圍繞的特定组織上，且只 讓標的组織暴露於高劑量的治療藥劑下一段長時間，並避 免周園組織結構產生任何不欲求的副作用》 在一實施例中，該藥物儲存槽係藉由一層無法為所攜 治療藥劑通透的聚合物層而與周圍結構和液體相隔絕。在 裝置的座上提供了一傳送埠或介面窗，以提供内含藥劑可 16 ^23667 釋出至標的組 關的環繞的密 有可控制介面 送埠或介面窗 以一生物可分 劑係包含在— 覆蓋的緩慢釋 的組織接觸。 連接該裝置至 一系列結構組 密封的狀態。 本發明可 资ij裘哺乳動物 績量的治療藥 平台及移植器 植入一可摺疊 擇性的傳送一 織或系統中’ 保藥劑單向擴 構中。本發明 過敏劑、磁性 或诊斷。可參 織的通道。該介面窗係藉由一與設計結構相 封方式而與组織表面形成密封，以確保其具 擴教機制所需之充分的皮下密封程度。該傳 可以一治療藥劑無法通透的結構層覆蓋，或 解的結構層覆蓋。在某痤情况下，該治療藥 植入時該傳送埠或介面窗不需為任何物質所 出配方中’使得儲存槽内的藥丸可直接與標 在—實施例中，該裝置座包含一連接機制以 標的組織》此係藉由一系列結構來提供，該 合後係可使系統與標的組織間能達到一皮下 提供一治療性或預防性的治療藥劑或生理藥 的器& 、組織或系統中。本發明可提供—持 劑或生理藥劍至人工器官、細胞結構或組織 官或組織中。本發明可藉由最小侵入程序移 、彈性或可伸展開來的藥物傳送裝置，以選 冶療性或生理性劑至一哺乳動物的器官、組 藉由一長效、保護性釋出藥劑的方式，可確 散通過標的介面’並避免藥劑消散至周圍結 也提供哺乳動物器官或组織一種選擇性傳送 或輻射性藥劑，其係可提供這些結構的治療 照下附圖示及詳細說明進一步了解本發明。 17 1323667 【實施方式】 本發明領域係關於一種局部藥物傳送裝置《本發明所 述系統係可用於疾病的治療或是可用於需要局部傳送治療 藥劑至一哺乳動物器官之疾病狀況的治療。本發明系统係 設計來應用在一组織或器e表面，並於該組織或器官表面 上執行釋放篥劑的功能。本發明包括一可提供控制釋放治 療性藥劑使穿過並分布於一器官或组織層的裝置。達到本 發明目的的方法包含設計出可容許—藥物儲存槽皮下密封 至一標的組織表面的結構，並保持其與皮膚密封的特性使 擴散藥物模式能維持一段長時間。本發明實施例也包括可 容許回填藥劑至儲存槽或或回充入一種以上治療藥劑之有 效使用期限長的結構。 本發明系統也設計成可應用在任何一種器官或組織的 表面。附圖示出其於眼睛上的應用，然同樣方法亦可應用 於其他器官及组織上。 第1圖為人類眼睛的橫切面示意圖；欲了解本發明系 統，必須先了解所示各種結構彼此間的關係。 眼睛的線性結構包括前面的角膜（9)及後面的鞏膜（1)。 角膜（9)上覆蓋了一層可曝露於環境中的眼淚層，至於鞏膜（1) 則是由眼周圍組織（6)所園繞，這些组織包括Ten〇n氏囊及眼 外肌肉。鞏膜與眼晴後段結構相關，角膜則與眼睛前段結 構相關’由晶狀趙將其彼此隔開，主要係形_空腔（Gavity)。 該空腔前端係填滿體液溶液（8)，後端則填滿玻璃體狀凝膠 18 1323667 (4)»在某些情沉下，該玻璃體狀凝膠係可被體液溶液或合 成物質所取代，例如矽嗣油或氣禮。該體液溶液係由睫狀 體（7)所製造’當過量時會導致眼壓升高最後造成音光眼。 降低IOP的方法之一就是干擾想液溶液的製造過程。至於玻 璃體狀凝膠則是某些殘留的胚胎結構，佔據了大部分的眼 晴後段結構體積，其係由水及一種膠原蛋白-蛋白多醣網路 所組成，且终身不會被置換。鞏膜係與内部脈絡膜（2)相關， 該脈絡膜（2)係由源自視網膜的血管網路Bruch氏膜、視網膜 色素表皮（RPE)底膜、及RPE所組成。這些結構在由視網膜（3) 最内層上光受體所主導的視覺過程中扮演非常重要的角 色。脈絡膜往前延伸在視網膜鋸齒緣變成平坦部（10)。脈絡 膜、平坦部、旁壁及虹膜均由葡萄膜組織構成，也是眼晴 中會受到發炎、感染的位置。鞏膜係位於角膜神經節細胞 後方一稱為淚篩處的多孔性結構。角膜軸突延伸形成光學 神經’其係負責傳遞視覺訊號至腦視覺皮質處。 第2圖為眼睛的組織橫切面示意圖，所示為鞏膜（15)、 脈絡膜（14)、RPE複合體（13)、視網膜（12)及玻璃體狀凝膠（u) 間的關係。 第3圖為本發明裝置的上視圖。本發明系統包含一由聚 合物結構所建置而成的儲存槽式的主體，較佳是（但不限於） 射出成型、壓缩成型、轉移並擠出模製成型，視所用的聚 合物、共聚物 '或基質而定。聚合物的選擇端視所欲植入 的组織或器官種類而定。較佳（但不限於）聚乙埽、矽酮、水 19 1323667 合膠、聚-鄰酯類、聚乙二酸、聚乳酸、聚己内酯、聚乙缔 醇或其之任一衍生物。結構16係設計來穩定皺摺縫線。密 封座18將使氣閉密封與標的组織表面間的密封效果達到最 大。 第4圖為實施例的橫切面示意圖’其包含一内含藥劑的 儲存槽20。外表面I9係與密封座2丨一樣繼續延續，可藉由 使用一黏著層22來提供與標的組織表面24間的氣閉密封。 第5圖為具有兩.個生物可相容儲存槽的本發明裝置的产 斷面概圖》儲存槽係由内壁28所分隔，其延伸超過標的組 織表面曲線，如弧線29所示，以提供與組織間的氣閉密封 效果’並避免藥劑在到達表面30前與組織發生作用。同時 也揭示缝線安定器26。 第6囷示出具有兩個生物可相容儲存槽32、分隔内壁 31、具有黏性層33於其上之密封底座34的底侧圖。 第7囷為單一儲存槽實施例35的底側圖及其與密封底 座36'黏著層37、外表面39及縫線安定器間的關係。較 佳是，密封底座36的外部曲線係與標的组織曲線相符。 第8囷為將本發明裝置ο應用於眼睛上的實施例。在此 實施例中，該眼睛内係具有一稱為「視網膜母細胞瘤」的 眼内腫瘤’其係主要發生在兒童期的一種眼内腫瘤。以周 圍切開術（peritomy)切開鞏膜相鄰組織，使鞏膜表面41暴露 出來。以一般標準技術將眼外肌肉4〇分離開來以便能更 全面地控制所|露出㈣鞏膜區$。一旦將該鞏膜區域表 20 1323667 面的眼周圍組織清除乾淨後，以施用器或手將植入物42(在 此例中係攜帶了具細胞毒性的藥劑）放置到定點。缝線4 5則 從植入物的一面穿過到另一面，使其穿越並固定安定器44 以容許密封底座42產生適度的緊閉效果並使密封效果達到 最大。缝線需穿過整個鞏膜厚度。在植入後，肌肉得到釋 放且結膜也可回到原來覆蓋眼睛表面的位置並縫在靠近角 膜處。 第9圖為植入物49被縫在組織46時的上視圖。縫線安定 器47讓缝線可將植入物固定在定點，但主要是在植入裝置 與標的表面間產生氣閉效果。 第10圖為將與鞏膜表面接觸之本發明裝置内表面的底 視圖。介面窗55係被密封底座54所圍繞。密封底座54最外 部邊緣係被塗覆上一黏劑層53。 第11圖為本發明裝置被應用到組織表面時的橫斷面 圖’所示出者為儲存槽與组織間的介面6〇。此外還揭示了 密封底座5 8與標的組織間關係。在此例中，氣閉效果係藉 由使用一黏劑層59覆蓋底座58的方式來達到。 第12圓為本發明裝置與標的组織65間的橫斷面示意 圖’所示出者為密封底座63與鞏膜65間的介面，及由一黏 劑層64所提供的皮下密封效果。 第13圖為靠近鞏膜71之一單腔67裝置的橫斷面示意 圏°同時還揭示充填該儲存槽的方法。裝置外表面66包含 一充填埠68，最好係由可自我密封的橡膠製成。藥物、容 21 1323667 易或懸浮液係經由一插套管或針頭裝置69而被注入.也可 使用一沖洗_抽吸裝置來抽取任何殘留的溶液並以新溶液或 藥劑回填入該儲存槽。充填埠68係被建置成具有一角度， 該較度係適合其所在位置以插入針頭69。 第〗4囷為裝置内表面的底視圊，示出密封底座75、黏 劑層76、外表面73、縫線安定器72及一可聯絡外部環境與 内部儲存槽77之充填埠74之間的關係。該充填埠較佳係於 模製該外表面72之模製過程中一併製作，且後來再經併入 具自我密封效果之橡膠於埠之空腔或洞内的第二製程製作 完成，該等具自我密封效果之橡膠最好（但不限於）是碎酮。 埠74的位置及其存取儲存槽的角度最好是使其能插入充填 針頭裝置或插套管。 第15圖為裝置的上視圖，顯示出充填埠78與外表面79 間的關係。為改善自我密封的效果，視外表面79的厚度而 定，可將其建置成可增加隧道長度並使埠78的氣閉密封效 果達到最大。 第16囷示出本發明裝置84與一组織表面82間的關係。 需知密封底座85係被多個洞83變成具多孔性，以容許一具 有密封效果的縫線被用在該底座85上。另一種變化是沿著 密封底座表面建造一圍繞著該表面的較窄的通道，以適合 植入手術期間以手動或自動方式將縫線連續缝在該底座 上。 第17囷為裝置87應用於一人類眼晴鞏膜表面上的例 22 予，其係以縫線88來達到使底座密封於標的組織β 第18圖揭示一建置在裝置外表面95之通道94的實例， 通道穿過該裝置以提供底座與標的組織間的密封效果》該 通道94係為了能符合一環狀元件而設置的，該環狀元件較 佳係由（但不限於）矽酮製成。 第19圖為本發明裝置應用於眼晴並位於與鞏膜89接觸 且在環狀元件93之下的位置。該環狀元件93係藉由與視網 膜分離處理相關但非視網膜分離程序之建置技術進行置 放。一旦該環狀元件被固定後，底座即可發揮其氣閉密封 的功能。 第20圖顯示裝置98之應用，在此例中，其係為一環狀 元件97之下的雙腔裝置。藉由此方法，靠在鞏膜上的裝置 可藉一氣閉密封位置99達到皮下密封效果。此外，其他裝 置可置放在環狀元件9 7下的任一位置，視必須傳送的治療 藥劑的劑量及數目而定。 第21囷揭示一内表面的另一種變化，其中一生物可分 解聚合物100被塗覆在内含藥劑的儲存槽内面。此鍍層較佳 係施加在庇座與黏劑層1 〇 1之間。其係藉由沿著該生物可分 解聚合物100最外為設置一系列窗型小口的方式來完成。此 實施例也可有許多變化，該等變化係習知技藝人士可輕易 思及的，將於下文討論》 第22圖為本發明裝置底視圖，顯示主體丨〇3、缝線安定 器102、密封底座105'内生物可分解層ι〇6及黏劑層ι〇4間 23 1323667 的關係。 第23圖為本發明裝置與眼睛間關係的橫斷面圏。 該裝置包含-單腔108’其内具有藥物溶液並為一生物 解鍵層111所固持以防止該兮祕：堯笼： **々工琢，谷液滲漏或在皮下氣閉密封 前即被暴露至组織。該鍍層lu具有—結構性功能一 溶解後，藥劑或藥物即會暴露至鞏膜並穿透眼晴各層β 發明詳細說明 在一實施例中，本發明涉及一種選擇性傳送治療 至一哺乳動物器官、組織或系統的新方法，其係藉由 植入一可與皮膚形成密封的裝置系統，該裝置系統係 供一治療藥劑之長效、保護性釋出，確保該治療藥劑 向擴散穿過標的组織介面，並避免藥劑消散至相鄰結構 本發明係基於一些預期外的發現所發展出來的， 預期外的發現包括藥劑係可安全、可預期的以治療性 防性藥量被傳送至特定組織，即使是局部組織，其係 透過對器官表面所暴露的藥劑量的控制，及透·過對藥 露至身體内部組織及流體的控制來達成。此可藉由渗 劑、物理、學或生物性處理來維持器官表面可讓藥劑通 在透過一密封機制將交換介面隔離或侷限於一特定區 達成。 可透過使用藥物相關的聚合物、滲透壓劑來達到 露於器官表面之藥物的控制，最好是以一種藥物無法 此處 可分 完成 旦其 藥劑 手術 可提 係單 中。 該等 或預 藉由 劑暴 透壓 過， 域來 對暴 通透 24 1323667 的聚合物來覆鍍藥物儲存槽，其中無法通過該聚合物的藥 物為活性劑，並避免藥劑消散至相鄰結構或流體成產生毒 性或使其利用性較標的組織為高等。此可藉由一系列設# 來維持裝置與標的組織間之皮下密封關係的結構來達成β 本發明人發現相較於習知傳送藥物至组織或器官的方 式而言，本發明系統可提供更多優點，並容許從前認為因 專一性不夠而無法用於臨床治療的藥劑，可再次被使用於 疾病治療中，因此本發明此種新穎的藥物傳送方式有助於 發展新藥或找出習知藥物的替代藥，並用於治療疾病。 本發明也容許開發新的治療方式，例如開發器官移植、 組織再生技術、人工器官或组織移植。此將可提供任一需 依賴在生物體内併入或維持一植入物的新技術所需的治療 性或生理性支持。 儲存槽中的藥物可與其他藥劑、聚合物或滲透壓劑相 關或混合。可提供多層藥劑，在傳送了第一層藥劑後可 接著傳送第二層藥劑。也可使用一種多室儲存槽，其同樣 具有-内壁可將空腔加以隔$。主趙ΒΙ包括可區分空腔的 壁。較佳是該區分壁可稍微延伸超過其相對高度至鞏膜之 弧線或表面，以在介面處分隔％ 〜 ▲ 阳召寺室結構。此可使不同藥 劑在到達其標的表面前彼此湛人* & m & a * 从％成合或作用的機率被降至最 低。An exquisite experiment by Darsino et al. showed that the pharmacokinetic study of digoxin and lidocaine in various heart tissues (including valves) showed that after injection of these compounds around the heart, Irregular distribution pattern in cardiac tissue. For patients with arrhythmia and dysfunction of the heart, it is preferable that a system can be specific to a predetermined position of the same organ. Compared with other heart tissues, the absorption of digoxigenin and the absorption of digoxigenin and lidocaine in the aorta around the heart is the highest in 20 to 60 minutes. Lidocaine is evenly distributed on the LV wall within 30 to 60 minutes, and 50 micrograms of digitalis are mainly concentrated under the surface of the heart. This pattern of distribution limits the administration of these agents in a manner that is within the surface of the heart, as higher amounts of the agent will be required in these areas. In the other experiment, the same author also pointed out that the concentration of amiodarone (AMI0DAR0NE) injected into the heart circumference is higher under the surface of the heart than in the deep left atrium. As for the blood, it is measured. Less than these drugs. Preferably, the preferred distribution of these agents is such that certain areas have a higher absorption of the agent. The injection will expose the entire surface of the myocardium to the agent, while the rate of resorption of the different regions will be different. This results in an uncontrolled surface transport pattern. The utility of a bioactive agent as a therapeutic agent depends on its delivery route. For some biologically active purines, 'the natural form makes it more susceptible to inactivation or is saturated with many naturally occurring factors before reaching the target tissue. β 14 1423667 Some growth factors and other compounds increase myocardial infarction areas. Newborn blood vessels. Uchida et al. showed in a model of myocardial infarction in dogs that the injection of basal fibroblast growth factor (bFGF) and heparin sulfate in the pericardium can effectively promote vascular proliferation and can be rescued compared to the infarcted area of the myocardium. More areas of myocardial surface infarction. Further experiments on the pig's chronic heart infarction model system have again confirmed that injection of basic fibroblast growth factor (bFGF) and heparin sulfate around the heart is effective in promoting vascular proliferation. Although the results of animal testing are encouraging, the ability to administer medications to human patients with the aforementioned devices, including cardiac catheterization, remains a major concern. ° Use of this type of application is worsened and the blood of the eyes is suppressed, so 'if the blood vessels grow will be different. In order to make the area of the sound, the pathological area is locally, continuously, and achieves the above purpose, which may potentially make the injection more advantageous, and some people have considered the intravascular route of administration, and the comparison. However, the results are not better than the placebo group. A major concern is the potential risk of retinal vascular disease. Angiogenic factors tend to bind to their receptors. They are saturated before reaching the deep tissue. The result is that the distribution of factors in the tissue layer is not uniform, and the effect of flb reaching the deep layer of the myocardium must be such that it does not and does not affect And its effect is limited to a specific pathological area, so that the specific object can make the drug reach the deep tissue after prolonged action. _ Protected and selectively delivered drugs will be more effective and have fewer side effects; more patients benefit from minimally invasive implantation procedures. This strategy provides the effect of intracardiac injection on the effect of intracardiac injection. 15 1323667 There have been many studies dedicated to the topical use of bioactive agents. Angiogenesis inhibitors are potentially useful tools for the treatment of ocular vascular proliferative disorders (eg, premature retinopathy and age-related degenerative macula, & both diseases are the leading causes of blindness in premature newborns or blindness in the elderly) . [Contents] According to an embodiment of the present invention, there is provided an implantable, sealed drug delivery system that provides a local performance release therapeutic agent for direct and selective release into a mammalian internal organ, tissue or system . A preferred embodiment includes an isolated drug storage reservoir for selectively exposing the drug to the target tissue structure via the interface. The interface control of the device is achieved by the sealing mechanism provided by the sealing method described herein. Disclosed is a simple, novel method of providing a topical or systemic therapeutic agent that delivers the agent, tissue or system directly, unidirectionally, and in a protective manner to a mammal. The device of the present invention can deliver the therapeutic agent to a specific tissue surrounded by the body fluid in a preferred manner, and expose only the target tissue to a high dose of the therapeutic agent for a long period of time, and avoid the formation of the surrounding tissue structure. Any undesired side effects. In one embodiment, the drug reservoir is isolated from surrounding structures and liquids by a layer of polymer that is not permeable to the therapeutic agent being carried. A transfer port or interface window is provided on the seat of the device to provide a surrounding controllable interface or interface window for the release of the contained agent 16^23667 to the target group. In contact with the slow release of the tissue. Connect the unit to a series of structural group seals. The present invention is capable of implanting a therapeutic drug platform and a transplanter for mammalian performance in a collapsible transport or weaving system. The present invention is an allergic agent, magnetic or diagnostic. A channel that can be woven. The interface window is sealed to the tissue surface by a sealing structure to ensure a sufficient degree of subcutaneous sealing for the expansion mechanism. The transmission can be covered by a structural layer that is not transparent to the therapeutic agent, or covered by a structural layer. In some cases, when the therapeutic agent is implanted, the transfer port or interface window does not need to be formulated for any substance, so that the pill in the storage tank can be directly labeled with the embodiment, and the device holder includes a connection. The mechanism is provided by the subject organization. This is provided by a series of structures that enable the system and the target tissue to provide a therapeutic or prophylactic therapeutic or physiological agent between the system and the target tissue. In the system. The present invention can provide a carrier or a physiological sword to an artificial organ, cell structure or tissue or tissue. The present invention can be used to selectively or protectively release a medicament by a minimally invasive procedure, a flexible or extensible drug delivery device for selecting a therapeutic or physiological agent to a mammalian organ or group. In a manner that scatters through the target interface 'and avoids dissipating the agent to the surrounding node and also provides a selective delivery or radiation agent to the mammalian organ or tissue, which provides a treatment for these structures. Know the invention. 17 1323667 The present invention relates to a topical drug delivery device. The system of the present invention is useful in the treatment of diseases or in the treatment of conditions requiring local delivery of a therapeutic agent to a mammalian organ. The system of the present invention is designed to be applied to a tissue or device e surface and to perform the function of releasing the tincture on the surface of the tissue or organ. The present invention includes a device that provides controlled release of a therapeutic agent for passage through and distribution to an organ or tissue layer. A method of achieving the objects of the present invention involves designing a structure that allows the drug reservoir to be subcutaneously sealed to a target tissue surface and maintains its seal with the skin to maintain the diffusion drug pattern for a prolonged period of time. Embodiments of the invention also include structures that allow for backfilling of the medicament to the reservoir or for refilling more than one therapeutic agent for a useful period of time. The system of the invention is also designed to be applied to the surface of any organ or tissue. The figures show their application to the eye, but the same method can be applied to other organs and tissues. Figure 1 is a schematic cross-sectional view of a human eye; to understand the system of the present invention, it is necessary to first understand the relationship of the various structures shown. The linear structure of the eye includes the anterior cornea (9) and the posterior sclera (1). The cornea (9) is covered with a layer of tears that can be exposed to the environment. The sclera (1) is surrounded by tissue around the eye (6). These tissues include the Ten〇n's capsule and the extraocular muscles. The sclera is related to the structure of the posterior segment of the eye, and the cornea is related to the structure of the anterior segment of the eye. The crystal is separated from each other by the lens, mainly the gavity. The front end of the cavity is filled with the body fluid solution (8), and the rear end is filled with the vitreous gel 18 1323667 (4)»In some cases, the vitreous gel system can be replaced by a body fluid solution or a synthetic substance. For example, oyster sauce or gas ceremony. The body fluid solution is made of the ciliary body (7). When excessive, it causes an increase in intraocular pressure and finally causes an eye of the sound. One of the ways to reduce IOP is to interfere with the manufacturing process of the solution. As for the glassy gel, it is a residual embryonic structure that occupies most of the post-clear structure volume, which is composed of water and a collagen-proteoglycan network and will not be replaced for life. The sclera is associated with the internal choroid (2), which consists of the retinal vascular network Bruch's membrane, the retinal pigment epidermal (RPE) basement, and RPE. These structures play a very important role in the visual process dominated by photoreceptors on the innermost layer of the retina (3). The choroid extends forward in the retina serrated edge to become a flat portion (10). The choroid, flat, side wall, and iris are all composed of uveal tissue, which is also the site of inflammation and infection in the eye. The sclera is located behind a corneal ganglion cell and is called a porous structure called a tear screen. The corneal axons extend to form an optical nerve, which is responsible for transmitting visual signals to the visual cortex of the brain. Figure 2 is a schematic cross-sectional view of the tissue of the eye showing the relationship between the sclera (15), the choroid (14), the RPE complex (13), the retina (12), and the vitreous gel (u). Figure 3 is a top view of the apparatus of the present invention. The system of the present invention comprises a storage tank type body constructed of a polymer structure, preferably (but not limited to) injection molding, compression molding, transfer and extrusion molding, depending on the polymer used, Copolymer 'or matrix'. The choice of polymer depends on the type of tissue or organ to be implanted. Preferably, but not limited to, polyacetamidine, anthrone, water 19 1323667 gelatin, poly-o-esters, polyoxalic acid, polylactic acid, polycaprolactone, polyethylhydrin or any derivative thereof . The structure 16 is designed to stabilize the crease lines. The seal 18 will maximize the sealing effect between the gas-tight seal and the target tissue surface. Fig. 4 is a schematic cross-sectional view of the embodiment, which comprises a reservoir 20 containing a medicament. The outer surface I9 continues as the sealing seat 2, and a gas-tight seal with the target tissue surface 24 can be provided by the use of an adhesive layer 22. Figure 5 is a cross-sectional view of the apparatus of the present invention having two biocompatible storage tanks. The storage tank is separated by an inner wall 28 that extends beyond the surface of the target tissue as shown by arc 29 to provide The hermetic sealing effect with the tissue 'and avoids the action of the agent on the tissue before reaching the surface 30. The suture ballast 26 is also disclosed. The sixth side shows a bottom side view of the two biocompatible storage tanks 32, the partitioned inner wall 31, and the sealing base 34 having the adhesive layer 33 thereon. Section 7 is a bottom side view of Example 35 of a single storage tank and its relationship to the sealing base 36' adhesive layer 37, outer surface 39 and suture ballast. Preferably, the outer curve of the sealing base 36 conforms to the target tissue curve. Section 8 is an embodiment in which the device of the present invention is applied to the eye. In this embodiment, the intraocular system has an intraocular tumor called "retinoblastoma", which is an intraocular tumor mainly occurring in childhood. The sclera adjacent tissue is incised by a peritomy to expose the scleral surface 41. The extraocular muscles are separated by a standard technique to provide a more comprehensive control of the exposed (four) scleral area. Once the tissue around the eye on the surface of the scleral region 20 1323667 is removed, the implant 42 (in this case, the cytotoxic agent is carried) is placed at a fixed point with an applicator or hand. The suture 4 5 passes from one side of the implant to the other, passing it through and securing the ballast 44 to allow the sealing base 42 to produce a moderate tighting effect and maximize sealing. The suture needs to pass through the entire scleral thickness. After implantation, the muscles are released and the conjunctiva can return to its original position covering the surface of the eye and sewed close to the cornea. Figure 9 is a top view of the implant 49 when it is sewn to the tissue 46. The suture stabilizer 47 allows the suture to secure the implant at a fixed point, but primarily creates a gas-tight effect between the implant device and the target surface. Figure 10 is a bottom plan view of the inner surface of the device of the present invention in contact with the surface of the sclera. The interface window 55 is surrounded by a sealed base 54. The outermost edge of the sealing base 54 is coated with an adhesive layer 53. Figure 11 is a cross-sectional view of the device of the present invention applied to the surface of the tissue. The device shown is the interface between the reservoir and the tissue. It also reveals the relationship between the sealing base 58 and the target tissue. In this case, the air-closing effect is achieved by covering the base 58 with an adhesive layer 59. The 12th circle is a cross-sectional view between the device of the present invention and the target tissue 65. The illustration shows the interface between the sealing base 63 and the sclera 65, and the subcutaneous sealing effect provided by an adhesive layer 64. Figure 13 is a cross-sectional illustration of a single lumen 67 device adjacent to the sclera 71. Also disclosed is a method of filling the reservoir. The outer surface 66 of the device includes a filling bowl 68, preferably made of self-sealing rubber. The drug, volume 21 1323667 is easy or suspension is injected through a cannula or needle device 69. A flushing device can also be used to extract any residual solution and backfill the reservoir with a new solution or agent. . The filling cassette 68 is constructed to have an angle that is suitable for its position to be inserted into the needle 69. The fourth view is the bottom view of the inner surface of the device, showing the seal base 75, the adhesive layer 76, the outer surface 73, the suture ballast 72, and a filling port 74 that can contact the external environment and the internal storage tank 77. Relationship. Preferably, the filling crucible is produced in a molding process for molding the outer surface 72, and is later completed by a second process in which a rubber having a self-sealing effect is incorporated into the cavity or cavity of the crucible. The rubber with a self-sealing effect is preferably, but not limited to, a ketone. Preferably, the position of the iliac 74 and its access to the reservoir are such that it can be inserted into a filling needle device or cannula. Figure 15 is a top view of the device showing the relationship between the filling dam 78 and the outer surface 79. To improve the self-sealing effect, depending on the thickness of the outer surface 79, it can be constructed to increase the length of the tunnel and maximize the gas-tight sealing effect of the crucible 78. Figure 16 shows the relationship between the device 84 of the present invention and a tissue surface 82. It is to be understood that the sealing base 85 is made porous by the plurality of holes 83 to allow a suture having a sealing effect to be applied to the base 85. Another variation is to create a narrower channel around the surface of the sealing base to accommodate continuous or continuous stitching of the suture to the base during the implantation procedure. The seventh step is the application of the device 87 to the surface of a human eye sclera, which is achieved by suture 88 to seal the base to the target tissue. Figure 18 shows a passage 94 built into the outer surface 95 of the device. An example of a passage through the device to provide a sealing effect between the base and the target tissue. The passage 94 is provided for conforming to a ring member, preferably by, but not limited to, anthrone. to make. Figure 19 is a view of the device of the present invention applied to the eye and located in contact with the sclera 89 and below the annular member 93. The annular element 93 is placed by a technique associated with the retinal membrane separation process but not the retinal separation procedure. Once the ring member is secured, the base functions as a hermetic seal. Figure 20 shows the application of device 98, which in this example is a dual chamber device under a ring member 97. By this method, the device resting on the sclera can achieve a subcutaneous sealing effect by a gas-tight sealing position 99. In addition, other devices can be placed anywhere under the ring member 97, depending on the dosage and number of therapeutic agents that must be delivered. Another 21st aspect of the invention discloses another variation of the inner surface in which a biodegradable polymer 100 is coated on the inner surface of a reservoir containing the medicament. This plating is preferably applied between the pedestal and the adhesive layer 1 〇 1 . This is accomplished by providing a series of window-shaped apertures along the outermost portion of the biodegradable polymer 100. There are many variations to this embodiment, which are readily apparent to those skilled in the art and will be discussed below. Figure 22 is a bottom view of the device of the present invention showing the main body 丨〇3, the suture ballast 102, The relationship between the biodegradable layer ι〇6 and the adhesive layer ι〇4 in the sealed base 105' is 23 1323667. Figure 23 is a cross-sectional view of the relationship between the device and the eye of the present invention. The device comprises a single chamber 108' having a drug solution therein and held by a biodegradable layer 111 to prevent the secret: 尧 cage: ** 々 琢, valley liquid leakage or before subcutaneous gas sealing Being exposed to the tissue. The coating layer lu has a structural function, and after dissolution, the agent or drug is exposed to the sclera and penetrates the layers of the eye. The invention is described in detail. In one embodiment, the invention relates to a selective delivery treatment to a mammalian organ, A new method of tissue or system by implanting a device system that forms a seal with the skin, the device system providing a long-lasting, protective release of a therapeutic agent to ensure diffusion of the therapeutic agent through the target group Weaving the interface and avoiding the dissipating of the agent to adjacent structures. The present invention has been developed based on some unexpected findings, including the discovery that the drug system can be safely and predictably delivered to a particular tissue with a therapeutic anti-therapeutic amount. Even if it is a local tissue, it is achieved by controlling the amount of the drug exposed on the surface of the organ, and by controlling the drug to the internal tissues and fluids of the body. This maintenance of the organ surface by osmotic, physical, scientific or biological treatment allows the agent to be isolated or confined to a particular zone by a sealing mechanism. The drug-related polymer and osmotic agent can be used to control the drug exposed on the surface of the organ. It is best to use a drug that cannot be separated here. These or pre-extrusion agents are used to coat the drug storage tank against the polymer of 24 1323667, wherein the drug that cannot pass the polymer is the active agent, and the agent is prevented from dissipating to the adjacent structure. Or the fluid is toxic or makes the utilization of the tissue higher than the standard. This can be achieved by a series of structures that maintain the subcutaneous sealing relationship between the device and the target tissue. The inventors have discovered that the system of the present invention provides a means of delivering drugs to tissues or organs. More advantages, and allowing agents that were previously considered to be ineffective for clinical treatment due to insufficient specificity, can be used again in the treatment of diseases, so the novel drug delivery method of the present invention can help develop new drugs or find out conventional knowledge. An alternative to drugs and used to treat diseases. The invention also allows for the development of new treatment modalities such as the development of organ transplants, tissue regeneration techniques, artificial organs or tissue transplants. This will provide any therapeutic or physiological support required to rely on new techniques for incorporating or maintaining an implant in vivo. The drug in the reservoir can be associated with or mixed with other agents, polymers or osmotic agents. A multi-layered medicament can be provided which can then deliver a second layer of medicament after delivery of the first layer of medicament. It is also possible to use a multi-chamber storage tank which also has an inner wall which separates the cavity by $. The main Zhao Wei includes walls that can distinguish the cavity. Preferably, the dividing wall may extend slightly beyond its relative height to the arc or surface of the sclera to separate the %~ ▲ Yang Zhao Temple structure at the interface. This allows the different agents to be minimized in their ability to merge or act from % before reaching their target surface.
介面窗可覆鍍上和或包含—A 含種可幫助藥物擴散至組織 的促進劑，例如酵素。膠原酶、& 4呢、則列腺素類似物、基質金 25 1323667 屬蛋白酶、水合酶均為可改善鞏膜或組織表面擴散性質的 酵素。復鍍程序較佳是在壓製固體藥物時完成或是在製備 藥物期間完成並與其聚合物或載劑混合。如果所需為一穩 定、長效釋出，可使覆鍍層均勻分散整個儲存槽’或偈限 該覆鍍層於將與鞏膜接觸之内部表面。視促進劑與活性治 療藥劑間的反應及安定度，可在儲存槽内部表面併入一層 促進劑層。較佳是使用一諸如膠原、明膠、乙二酸、纖維 素及乳酸等生物可分解物質製備。或者，可以任何一種不 會直接干擾藥劑自儲存槽釋出且不會干擾藥劑暴露於標的 組織過程的物質來製造。換言之，並不預期可攜帶促進劑 的物質會在藥物釋出速率上扮演任何重要的角色，而是促 進劑本身在標的組織表面上的作用。吾人稱此層為含有藥 劑或促進劑之功能層，其將會影響擴散速率及以後該給定 藥劑的藥動學特性。 一種由可快速生物分解聚合物所構成的内層，較往是 由明膠、水合酸、甲基纖維素、聚乙二酸、聚乳酸所建構 而成以容許液體、粉末及黏性物質被保持在儲存槽内，其 在组織表面上亦可保持安定。此過程較佳是藉由將該層置 放於密封底座及黏合層間來完成，同時還容許該黏合廣與 密封底座間能保持強的黏合性。環繞介面窗的一個随道也 讓該層能被珍萌或任何類似密封座或裝置的物質，建構出 一圈可符合並容納於隧道内的物而使該層藉由機械性置放 或黏性結合方式而陷於隧道内》 26 1323667 介面窗，亦即儲存槽被暴露至標的组織之處，被一外 壁由聚合物延伸所形成的密封底座所圍繞，或是該底座可 由多種不同聚合物經過黏合機制或以黏劑將其膠黏在一起 後所形成。密封底座的外表面可由不同的组件组成，該密 封組件，過去係透過機械性方式併入在主體組件中，該核 裝置，圩包限一層可用來固持一液體或黏液於儲存槽中的 聚合物，避免藥劑過早被暴露在外或避免滲漏，或使前述 促進劑載劑層安定。此方法很像一種處理三明治的方法， 且後來介面窗區域將成為決定 在的干擾的主要因子。之後， 件將會具有前述特徵，以容許 形成皮下密封狀態。 藥物儲存槽和標的表面間存 用來當作密封底座的密封組 裝置與暴露的標的組織間可 可用來建構本發明襞置的材料包括，但不限於，聚乙 烯、矽酮、水合膠、聚-鄰薛、聚乙二酸、聚乳酸、聚聚己 内醋、聚乙烯醇、聚乙#咯酮、及其之任何衍生物；和諸 如糖越酸、纖維蛋白、甲基纖維素、膠原蛋白明膠之類 的生物相容聚合物及其之任何衍生物，均可用來建構本發 明裝置的其他部分。 較好是利用經過設計的 的表面，以容許並保護治療 藉由使用一藥物無法通透的 向流動的目的。至於該外表 視藥劑及載體聚合物的性質 結構’使裝置能皮下密封於標 性藥劑能流過標的介面表面。 外表面’可達成讓藥劑只能單 面是否能讓外部體液通過，則 而定’以及是否需要使用一溶 27 1323667 解劑來調控藥劑自性由址丄^ _ 馈存槽中的釋出〃這類藥劑釋放機制可 能是簡單的利用進A故 艰入藥物儲存槽的流體將藥物/聚合物溶 解，或是使用渗透厭^ %盤劑來調控流入的水量及藥劑通過標的 表面前的溶解速率β 如引此所述實施例係藉由併入一系列結構來達成 使裝置得以皮下雄、封於標的表面。第一個結構即是密封底 座其主要係由可達成密封的方式組成’其延伸超過介面 窗的表面係為了増加達成密封所需的接觸面積，無論該接 觸面是否已覆鍍了一層黏性物與否。同時，該密封底座較 佳是能符合標的表面本身的曲線，雖然通常設計上會採用 更大的孤度來達成較佳的密封狀態，特別是所用材料為彈 性材料的情況下。合併使用一或多種或多種其他特性來達 到最大密封效果’這些輔助性結構也有助於達到藥物之控 制釋出的目的。 第一種辅助性結構為一 buckle缝線安定器或縫線安定 器。此係為沿著外表面所設置並建構的突起物、通道或随 道，用以防止當以缝線將装置固定於組織上時，縫線不致 滑出植入物外。視裝置體積大小及所欲植入標的組織的位 置而定，可設置一或多個這類缝線安定器結構。較佳是， 這類缝線安定器係由用來製造外表面的相同材料模製而 成。或者’其也可採用不同材料製作並於稍後的模製過程 中被併入裝置中。 第二種輔助性裝置為一種buckling隨道帶或屋如 %思部，其係 28 1323667 由一可穿越整個外表面直徑而壓緊於外表面上 成’以容許一環繞元件被置放並提供裝置與標 需的密封狀態。較佳是’其係於模製過程中被 外表面上。 第三種輔助性裝置為沿著底座設置的多個 過以固定裝置底座的孔洞。該等孔洞最好是在 座的過程中一並被設置在底座周邊❶或者，以 作密封底座，同時使用一襯墊環繞其較薄的邊 來可使用一自動裝置來施加縫線。 上述用來使藥劑傳送裝置得以皮下密封於 主要係要降低在藥物-組織介面間的擴散機制中 周園液體的干擾。此外，其對於避免組織被暴 的藥劑毒性上也扮演了相當重要的角色。 藥劑溶解前的流體傳輸主要是透過兩種不 生。第一種為由橫越器官表面的滲透屋或壓力 的擴散作用。第二種是橫越聚合物外壁主要由 與外部組織間的滲透壓梯度及聚合物特性所驅 用。 在與藥劑通過生物膜相關的因子中’表面 藥劑提供者側的藥劑濃度、及藥劑的分子量係 以提供組織特定位置處欲求的藥量。其他需考 括膜的特性及藥物在组織内的藥動學特性。雖 係屬於生物性因子，但可在其暴露於裝置及藥 的機制所組 的表面間所 建構在裝置 可讓缝線穿 模製密封底 彈性材料製 緣，以便將 標的的方法 來自組織與 露在不必要 同的機制產 梯度所驅動 介於儲存槽 動的擴散作 接觸面積、 彼此平衡， 量的因予包 然這些因子 劑之前，藉 29 1323667 由物理、化學或生物方法加以改變。換言之，該可通透的 藥劑之生物可利用性及藥動學特性將隨著其可能穿越的路 徑的不同而有所變化，因此將有助於了解哪些化合物的组 合使用才是恰當的。 本發明系統也可以有許多種不同的變化及呈現方式。 舉例來說，本發明裝置可攜帶一促進劑，較佳是（但不限於） 酵素及蛋白質，例如白蛋白。其外表面可由載劑無法通透 的聚合物组成，較佳（但不限於）係由矽酮、聚乙二酸、聚乳 酸、衍生物、聚乙浠醇、丙烯酸酯、甲丙浠酸酯、纖維素、 膠原蛋白、金屬、任一上述聚合物之衍生物或相關物質， 或任何其他具有無法讓載劑通過之特性的材料所製成。 裝置外表面可包括一充填埠，較佳（但不限於）係由可自 我密封的材料所製成，例如矽酮橡膠。目前的設計採用多 至裝置’同時在裝置中也建製了多個充填埠。這些結構係 建置在外表面，以聯絡外面環境與儲存槽内部。為使該埠 在植入手術後仍可被輕易認出，以一種生物相容、輻射敏 感的標記物或染科來標記該埠。或者，設計該埠使其延伸 超過裝置外表面並設置其位置於裝置主體上較易接近的地 方》 本發明裝置係可摺疊或具有彈性，以便於能由小手術 切口中植入身體内部，並能緊密的貼近不規則器官表面。 本發明包括藉由控制藥物通過一標的裝置介面來選擇 性的施用一欲求藥劑量至哺乳動物器官、组織或系統的方 30 法。巧·以错存槽中的藥剁與組織介面 牧钱觸或透過生物 可分解聚合物接觸，該等聚合物較佳（但 限於）是由明膠、 己内齒、糖❹、纖維素、聚乙二酸、聚乳酸、及其〇 生物》這些化合物和或组合物可以是壓敏、 ' . 、熱敏、光敏、 或化學敏感式化合物和或组合物。 活性劑可以用諸如脂肪微粒或微球體之類的膠囊形式 來提供。 包含在 手術植入本發明裝置至哺乳動 因此，本發明亦 物身體後，以局步'保護性且持久方式單向直接傳送藥物 穿過標的組織介面，並避免藥劑消散至周圍組織、流體内 的方法。本發明方法涉及將裝載了藥劑的裝置介面窗與標 的組織接觸的步驟。本發明方法還包括以黏劑、固定或缝 線或其之組合方式將裝置皮下密封至標的組織的步驟。為 了建構一黏性層，較佳（但不限於）是使用水合膠、糖醛酸、 及纖維蛋白黏劑。其係以兩面都含黏劑的薄膜或薄層被併 入於密封底座中’或是以預先在密封底座内側施加黏劑的 方式將其併入。為將黏劑固定，較佳係沿著密封底座内表 面設置多個腔室、一個單獨的腔室或一通道系統。較佳是 在裝置模製過程中同時製作這些密封結構。在黏劑與底座 接觸後，可在黏劑層上設置另一薄層。該薄層較佳是不會 和黏劑產生反應並可於植入手術前被撕下來。在上述結構 中使用該暴露出來的密封底座可使黏劑固持於該處，同時 還可容許植入手術前使用該等黏劑，特別是當所欲使用的 31 1323667 黏劑係為諸如纖維蛋白之類的生物性黏劑時β 裝置可和-人工器官、一可供細胞或生物性藥劑使用 的合成或生物性平台、一可供組織或細胞再生的平台和/或 移植組織或器目間形成介面。 一 本發明方法可藉由手術植入一 了通過介面窗單向傳送 藥劑益使其他表面無法為載劑通過之裝置至標的组織或器 官’而在哺乳動物器官中❹】局部或系祕，生理性或藥 理性效果。 一 該等藥劑可以是預防性治療藥劑。 帶一渗透壓劑。 …或裝置可攜 可透過在手術植入後使用—第二種藥劑（無論其係為化 學性質、物理性質或生物性質）來啟動 气增加藥劑的效果或 擴散作用° 可以本發明進行治療的疾病例子包 括（仁不限於）心肌缺 氧性疾病、肝癌、直腸癌所致之瀰漫性 肝炎、膀胱癌、腎 上腺癌、神經母細胞癌、腎臟癌及胰魅 π呢癌。本發明裝置可 被載入欲求的活性藥劑（即，藥物和/吱 或前驅椠）且可被植入 及連接在一原予或組織表面上。舉例决4 ^ 平』果說’該裝置可被黏 在心包表面來傳送藥劑至心包空間，謅 承儲存槽中的藥物擴 散至整個心臟肌肉中。該裝置也可穿過 牙過心包上的小孔被直 接黏在心肌上（需知心包是一種囊袋，容 夕平並非細胞，而係 源自其他組織表面；但心肌則大半是如& w J入干之細胞，源自最终成為 肌肉細胞且具有一明顯可區分表面的心 3^包表面）。本發明裝 32 1323667 置較佳是不被植入在心肌内來傳送藥物至深層肌肉或特定 細胞群，最好是盡量不採用這類侵入式技術。因此，當必 須植入時，本發明裝置最好是不會破壞所欲治療组織的結 構β 在—實施例中，本發明揭示許多在眼睛上的應用，因 眼睛提供了許多可安裝本發明裝置的位置。在眼科學上， 該裝置較佳是位於可與鞏膜互相接觸的位置◊或者，位在 俗稱鞏膜之眼晴最外層與玻璃體間的一膠體空間（可藉由鞏 膜切開術到達該位置），或甚至在視網膜下的空間。對視網 膜下的空間而言，可使用鞏膜切開術或視網切開術來插入 該植入物。可以本發明裝置治療的眼疾及本發明裝置的其 他應用包括（但不限於）眼内癌，即視網膜神經母細胞癌黑 色素瘤、斑劣變，傳送生長因子、抗血管生成因子、光敏 劑（可被雷射光激發者）、基因載體等至眼球後極（即，膠體 及 層）本發明可應用在青光眼的治療上，即藉由本發 明裝置傳送柷音光眼藥物直接穿過鞏膜至睫狀體。本發明 裝置也可應用在色素層视網膜炎的治療上，在不須危及移 植物之眼内手術的情況下’傳送生長因子或免疫抑制性藥 物來保護移植的視網膜或RPE層。 本發明係專為植入而非體表面之應用所做的設計。藉 由本發月可標定身體或眼晴内部一特定組織•·同時也考 慮到許多藥物事實上只對特定組織或細胞(而非其他组織或 胞）具備專性。當處於周固组織可能會被一傳送藥物傷 33 丄：)U00/ 害的情況下，本發明藉由將藥物傳送矣特定组織的方式提 供了-較前技更為優異的系統。 除了治療局部性疾病外’本發明也真有系統性優點。 使用本發明裝置系統來傳送生長因子直糖尿病患者胰臟可 改變該系统性疾病的狀況。使用本發明系統施用適當藥劑 至一因直腸癌所致瀰慢性肝炎這類無法運作的肝臟上，可 降低腫瘤的體積且可使病症回到回缩狀態。除了治療外， 本發明裝置也可用於目標在改善患者生活品質的治療上， 以避免使用諸如手術切除這類更具侵犯性的介入方式。因 此’即使姑息式療法也可藉助本發明來完成。本發明裝置 對於具有一可將本發明裝置介面窗加以密封以利藥物傳送 又獨特表面的腫瘤或欲治療器官而言，特別有用。 傳送本發明裝置所負載藥物的方法可能涉及多種手動 或經過注射器之植入技術。本發明裝置可於可直接目視或 典法直接目視的方式下被植入，例如超音波、MRI、CT掃 瞄、腹視鏡等。 雖然本發明技術内容已藉由實施例加以闡述，然在此 所揭π之先驅性發明，仍有許多本發明說明書所未記載的 變化或改良，此等變化或改良應視為仍屬本發明發明範脅。The interface window can be plated and or contain -A promoters that help the drug spread to the tissue, such as enzymes. Collagenase, & 4, adenine analogues, matrix gold 25 1323667 Protease, hydratase are enzymes that improve the diffusion properties of the sclera or tissue surface. The replating procedure is preferably accomplished when the solid drug is compressed or during the preparation of the drug and mixed with its polymer or carrier. If a stable, long-lasting release is desired, the coating can be evenly dispersed throughout the reservoir' or the coating can be applied to the interior surface that will contact the sclera. Depending on the reaction and stability between the accelerator and the active therapeutic agent, a layer of accelerator may be incorporated into the interior surface of the reservoir. It is preferably prepared using a biodegradable material such as collagen, gelatin, oxalic acid, cellulose, and lactic acid. Alternatively, any material that does not directly interfere with the release of the agent from the reservoir and that does not interfere with exposure of the agent to the target tissue process can be made. In other words, it is not expected that the substance carrying the promoter will play any important role in the rate of drug release, but rather the role of the promoter itself on the surface of the target tissue. This layer is referred to as a functional layer containing a drug or accelerator which will affect the rate of diffusion and the pharmacokinetic properties of the given agent in the future. An inner layer composed of a rapidly biodegradable polymer, which is constructed of gelatin, hydrated acid, methyl cellulose, polyoxalic acid, or polylactic acid to allow liquid, powder, and viscous substances to be retained. In the storage tank, it can also remain stable on the surface of the tissue. This process is preferably accomplished by placing the layer between the sealing base and the bonding layer, while also allowing for a strong bond between the bonding and the sealing base. An accompanying channel around the interface window also allows the layer to be embossed or any material like a seal seat or device that constructs a circle of material that conforms to and fits within the tunnel so that the layer is mechanically placed or adhered The interface is trapped in the tunnel. 26 1323667 Interface window, that is, where the storage tank is exposed to the target tissue, surrounded by a sealed base formed by the extension of the polymer wall, or the base can be composed of a variety of different polymers. It is formed by a bonding mechanism or by sticking it together with an adhesive. The outer surface of the sealing base may be composed of different components that have been mechanically incorporated into the body assembly. The core device is limited to a layer of polymer that can hold a liquid or mucus in the storage tank. To avoid premature exposure of the agent or to avoid leakage, or to stabilize the aforementioned accelerator carrier layer. This method is much like a method of handling sandwiches, and later the interface window area will be the main factor in determining the interference. Thereafter, the piece will have the aforementioned features to allow for a subcutaneous seal state. The materials used to construct the device of the present invention between the drug storage tank and the target surface as a sealed base and the exposed target tissue include, but are not limited to, polyethylene, fluorenone, hydration glue, poly - adjacent Xue, polyoxalic acid, polylactic acid, poly-caprolactone, polyvinyl alcohol, polyethyl ketone, and any derivatives thereof; and such as sugar acid, fibrin, methyl cellulose, collagen Biocompatible polymers such as protein gelatin and any derivatives thereof can be used to construct other parts of the device of the present invention. It is preferred to utilize a designed surface to permit and protect the treatment by using a drug that is impervious to flow. As for the nature of the exogenous agent and the carrier polymer, the structure allows the device to be subcutaneously sealed to the surface of the target interface. The outer surface 'can be achieved whether the agent can only pass the external body fluid on one side, then 'and whether it needs to use a solution of 27 1323 667 to regulate the release of the drug from the site 丄 ^ _ feeding tank 〃 The release mechanism of this type of agent may be simply to dissolve the drug/polymer by the fluid entering the drug storage tank, or to use an osmotic agent to regulate the amount of water flowing in and the dissolution rate of the agent before passing through the surface of the target. The embodiment as described herein is achieved by incorporating a series of structures to achieve a subcutaneous, sealed surface of the device. The first structure is the sealing base which is mainly composed of a sealable way. The surface extending beyond the interface window is required to achieve the sealing contact area, whether or not the contact surface has been coated with a layer of adhesive. Whether or not. At the same time, the sealing base preferably conforms to the curve of the target surface itself, although it is generally designed to achieve greater sealing by achieving greater sealing, especially if the material used is an elastomer. Combine the use of one or more or more of the other features to achieve maximum sealing. These auxiliary structures also help to achieve the controlled release of the drug. The first auxiliary structure is a buckle stitch stabilizer or a stitch stabilizer. This is a projection, channel or channel disposed and constructed along the outer surface to prevent the suture from slipping out of the implant when the device is secured to the tissue with the suture. One or more such suture ballast structures may be provided depending on the size of the device and the location of the tissue to be implanted. Preferably, such suture ballasts are molded from the same material used to make the outer surface. Alternatively, it can also be made of different materials and incorporated into the device during a later molding process. The second auxiliary device is a buckling belt or a house such as a part of the department, the system 28 1323667 is pressed into the outer surface by a diameter that can pass through the entire outer surface to allow a surrounding component to be placed and provided The sealed state of the device and the standard. Preferably, it is attached to the outer surface during the molding process. A third type of auxiliary device is a plurality of holes disposed along the base that pass through the base of the fixture. Preferably, the holes are provided in the periphery of the base or in the periphery of the base to serve as a sealed base, while a liner is used to surround the thinner edges to apply the suture using an automated device. The above-described use of the drug delivery device to be subcutaneously sealed is primarily intended to reduce the interference of the peripheral liquid in the diffusion mechanism between the drug-tissue interface. In addition, it plays a very important role in avoiding the toxicity of the drug in which the tissue is violent. The fluid transport before the dissolution of the agent is mainly through two kinds of non-production. The first is the diffusion of the permeate or pressure across the surface of the organ. The second is that the outer wall of the polymer is driven primarily by the osmotic pressure gradient and polymer properties with the external tissue. The concentration of the agent on the surface of the drug provider side and the molecular weight of the drug in the factors related to the passage of the drug through the biofilm provide the desired amount at the specific site of the tissue. Others need to consider the properties of the membrane and the pharmacokinetic properties of the drug in the tissue. Although it is a biological factor, it can be constructed between the surfaces of the mechanism exposed to the device and the drug. The device allows the suture to be molded into the sealing bottom elastic material to make the target method from the tissue and the dew. In the unnecessarily the same mechanism, the production gradient is driven by the diffusion of the storage tank as the contact area, balanced with each other, and the amount of the factor is preliminarily covered by these factors, by 29 1323667 by physical, chemical or biological methods. In other words, the bioavailability and pharmacokinetic properties of the permeable drug will vary with the path it may traverse, and will therefore help to understand which combination of compounds is appropriate. The system of the present invention can also have many different variations and presentations. For example, the device of the present invention can carry an enhancer, preferably, but not limited to, an enzyme and a protein such as albumin. The outer surface may be composed of a polymer which is impermeable to the carrier, preferably, but not limited to, anthrone, polyoxalate, polylactic acid, derivatives, polyethylenol, acrylate, and propionate. , cellulose, collagen, metal, derivatives of any of the above polymers or related substances, or any other material having properties that do not allow the passage of the carrier. The outer surface of the device may comprise a filling crucible, preferably, but not limited to, made of a self-sealing material, such as an anthrone rubber. The current design uses as many as the device' while also creating multiple filling ports in the device. These structures are built on the outer surface to contact the outside environment and the interior of the storage tank. In order for the tendon to be readily recognized after implantation, the fistula is labeled with a biocompatible, radiosensitive marker or dye. Alternatively, the crucible is designed to extend beyond the outer surface of the device and position it on a relatively accessible portion of the device body. The device of the present invention is foldable or resilient so as to be implantable into the body from a small surgical incision, and Can be close to the surface of irregular organs. The invention includes a method of selectively administering a desired dose to a mammalian organ, tissue or system by controlling the passage of the drug through a standard device interface. It is better, but not limited to, by gelatin, internal tooth, glycocalyx, cellulose, poly. The compounds and or compositions of oxalic acid, polylactic acid, and the like may be pressure sensitive, ', heat sensitive, photosensitive, or chemically sensitive compounds and or compositions. The active agent can be provided in the form of a capsule such as a fat microparticle or a microsphere. Included in the surgical implantation of the device of the present invention to the mammal. Therefore, after the invention is also in the body, the drug is directly transmitted through the target tissue interface in a one-step 'protective and durable manner', and the agent is prevented from dissipating into the surrounding tissue and fluid. Methods. The method of the present invention involves the step of contacting the device interface window loaded with the agent with the target tissue. The method of the present invention also includes the step of subcutaneously sealing the device to the target tissue in the form of an adhesive, a fixation or a suture or a combination thereof. In order to construct a viscous layer, it is preferred, but not limited to, to use hydrated gum, uronic acid, and fibrin glue. It is incorporated in a sealed base with a film or a thin layer containing adhesive on both sides or incorporated in advance by applying an adhesive on the inside of the sealed base. In order to secure the adhesive, it is preferred to provide a plurality of chambers, a separate chamber or a channel system along the inner surface of the sealing base. Preferably, these sealing structures are fabricated simultaneously during the molding of the device. After the adhesive is in contact with the base, another thin layer can be placed on the adhesive layer. Preferably, the layer does not react with the adhesive and can be torn off prior to implantation. The exposed sealing base is used in the above structure to hold the adhesive there, and also allows the adhesive to be used before the implantation, especially when the desired 31 1323667 adhesive is such as fibrin. A biological adhesive such as a beta device and an artificial organ, a synthetic or biological platform for use in a cell or biological agent, a platform for tissue or cell regeneration, and/or a transplanted tissue or device Form an interface. A method of the present invention can be performed by surgically implanting a unidirectional delivery of a drug through an interface window to make the other surface unable to pass the device through the device to the target tissue or organ 'in the mammalian organ 局部 local or secret, Physiological or pharmacological effects. One such agent may be a prophylactic therapeutic agent. With an osmotic pressure agent. ... or the device can be used after the surgical implantation - the second agent (whether it is chemical, physical or biological) to initiate the effect or spread of the gas-enhancing agent. The disease which can be treated by the present invention Examples include (not limited to) myocardial hypoxic diseases, liver cancer, diffuse hepatitis caused by rectal cancer, bladder cancer, adrenal cancer, neuroblastic cancer, kidney cancer, and pancreatic cancer. The device of the present invention can be loaded with the desired active agent (i.e., drug and/or precursor or precursor) and can be implanted and attached to the surface of the original or tissue. For example, the device can be adhered to the surface of the pericardium to deliver the medicament to the pericardial space, and the drug in the reservoir is diffused throughout the heart muscle. The device can also be directly adhered to the myocardium through a small hole in the pericardium (required that the pericardium is a capsular bag, and Rong Xiping is not a cell, but is derived from the surface of other tissues; but the myocardium is mostly like & w J into the stem cells, derived from the heart that eventually becomes muscle cells and has a clearly distinguishable surface. Preferably, the present invention is not implanted in the myocardium to deliver the drug to deep muscles or specific cell populations, preferably such invasive techniques are employed as much as possible. Thus, when it is necessary to implant, the device of the present invention preferably does not destroy the structure of the tissue to be treated. In the embodiment, the present invention discloses many applications on the eye, since the eye provides a number of mountable inventions. The location of the device. In ophthalmology, the device is preferably located in a position in contact with the sclera or in a colloidal space between the outermost layer of the eye and the vitreous (which can be reached by sclerectomy), or Even in the space under the retina. For the space under the opticureum, a sclerectomy or retina can be used to insert the implant. Eye diseases that can be treated by the device of the invention and other uses of the device of the invention include, but are not limited to, intraocular cancer, ie, retinal neuroblastoma melanoma, plaque deterioration, transmission growth factor, anti-angiogenic factor, photosensitizer ( The invention is applicable to the treatment of glaucoma by using the device of the present invention, that is, the transilluminating agent directly passes through the sclera to the ciliary body by the device of the present invention, that is, the posterior pole of the eyeball (ie, the colloid and the layer) . The device of the present invention can also be applied to the treatment of retinitis of the pigmentation to deliver a growth factor or immunosuppressive drug to protect the transplanted retina or RPE layer without jeopardizing the intraocular surgery of the transplanted plant. The present invention is designed for applications that are implanted rather than body surfaces. A specific organization within the body or eye can be calibrated by this month. • It is also considered that many drugs are in fact only specific to a particular tissue or cell (rather than other tissues or cells). In the case where the peripheral solid tissue may be injured by a drug delivery, the present invention provides a system superior to the prior art by delivering the drug to a specific tissue. In addition to treating localized diseases, the present invention also has systemic advantages. The use of the device system of the present invention to deliver growth factors to the pancreas of a diabetic patient can alter the condition of the systemic disease. The use of the system of the present invention to administer an appropriate agent to an inoperable liver such as chronic hepatitis caused by rectal cancer reduces the volume of the tumor and allows the condition to return to a retracted state. In addition to treatment, the device of the present invention can also be used to treat a patient's quality of life in order to avoid the use of more aggressive interventions such as surgical resection. Therefore, even palliative care can be accomplished by means of the present invention. The device of the present invention is particularly useful for having a tumor or a subject to be treated which can seal the interface window of the device of the present invention to facilitate drug delivery and a unique surface. The method of delivering the drug loaded by the device of the present invention may involve a variety of manual or syringe implant techniques. The device of the present invention can be implanted in a manner that can be directly visualized or directly visualized, such as ultrasound, MRI, CT scan, laparoscopic, and the like. Although the technical content of the present invention has been described by way of example, there are many variations or modifications not described in the description of the present invention, and such changes or improvements are considered to remain the present invention. Invention threats.
【圖式簡單說明J 第1圓為眼睛的橫切面示意圖； 第2圓為眼睛的组織橫切面示意囷； 34 1323667 第3囷為本發明裝置的上視圖； 第4囷為本發明裝置密封至眼睛後的橫切面示意囷； 第5囷為具有兩個生物可相容儲存槽的本發明裝置概 rffl _ 圃， 第6囷為具有兩個生物可相容儲存槽之本發明裝置的前 視囷，其密封底座及内部具生物黏性層的鍍層； 第7圖為本發明裝置的前視圖，所示者係其與缝線安定 器、儲存槽、密封座及黏性鍍層間的關係； 第8圏為眼睛的平視囷及本發明系統與使用方法的示意 圖； 第9圖為本發明裝置與器官或組織表面間關係的上視 ret · 圓， 第10圖為本發明一單腔室裝置與密封座及黏性鍍層間 關係的前視圖； 第11圖為本發明装置與器官表面間關係及達到與標的 组織皮下密封方法的示意圖； 第12圖為本發明裝置應用於眼睛上的橫斷面示意圖； 第13囷為本發明裝置應用於眼睛及充填其儲存槽之方 法的橫斷面示意圖； 第14圖為本發明系統與其儲存槽、充填埠、缝線安定 器及密封座間關係的前視圖； 第15圖為本發明系統與其充填埠（可自外表面區分）、儲 存槽及密封座間關係的上視圖； 35 1323667 第16圖為本發明裝置應用於一器官表面及以周圍缝線 穿過底座孔將裝置密封於皮下之方法的上視圖； 第17囷為本發明裝置應用於一眼睛鞏膜表面及將其底 座密封於標的組織皮下之方法的平視圓： 第18圖為設計用來固定一桶或使装置底座密封至組織 表面的環狀帶安定器； 第19圖為本發明裝置應用於眼睛及藉由使用環狀元件 將其密封至鞏膜表面之方法的平視圖； 第20圖為藉由使用環狀元件將本發明裝置應用且密封 至一人類眼睛鞏膜上的後視圖及橫斷面示意圖： 第21圖為具有一生物可分解聚合物鍍層以提供内含之 儲存槽安定性之本發明裝置的前視圖； 第22圖為本發明裝置與其内生物可分解層及諸如缝線 安定器及周圍黏性鍍層之類的密封裝置間關係的前面上視[The diagram simply illustrates J. The first circle is a schematic view of the cross section of the eye; the second circle is the cross section of the tissue of the eye; 34 1323667 is the top view of the device of the present invention; the fourth is the device seal of the present invention. The cross-section to the back of the eye is indicative of 囷; the fifth is a device of the invention having two biocompatible storage tanks, the sixth device being the front of the device of the invention having two biocompatible storage tanks Depending on the 囷, its sealed base and the inner layer of the bio-adhesive layer; Figure 7 is a front view of the device of the present invention, shown in its relationship with the suture ballast, the storage tank, the sealing seat and the viscous coating Figure 8 is a schematic view of the eye and the system and method of use of the present invention; Figure 9 is a top view ret · circle of the relationship between the device and the organ or tissue surface of the present invention, and Figure 10 is a single cavity of the present invention Front view of the relationship between the chamber device and the sealing seat and the viscous plating; Figure 11 is a schematic view showing the relationship between the device and the surface of the device and the method of subcutaneous sealing to the target tissue; Figure 12 is a view of the device of the present invention applied to the eye Cross section Figure 13 is a cross-sectional view showing the method of applying the device to the eye and filling the storage tank thereof; Figure 14 is a front view showing the relationship between the system of the present invention and its storage tank, filling bowl, suture ballast and sealing seat; Figure 15 is a top view of the relationship between the system of the present invention and its filling cartridge (which can be distinguished from the outer surface), the storage tank and the sealing seat; 35 1323667 Figure 16 is a view of the device of the present invention applied to the surface of an organ and through the base with surrounding sutures A top view of a method of sealing a device to the skin under a skin; a 17th view is a plan view circle of the method of the present invention applied to the surface of an eye sclera and sealing the base thereof under the skin of the target tissue: Figure 18 is a design for fixing a a barrel or an annular band ballast that seals the base of the device to the surface of the tissue; Figure 19 is a plan view of the method of applying the device to the eye and sealing it to the surface of the sclera by using a ring member; Rear view and cross-sectional view of a device of the invention applied and sealed to a human eye sclera using a ring member: Figure 21 is a biodegradable polymer plated A front view of the apparatus of the present invention providing stability of the contained storage tank; Figure 22 is a front view showing the relationship between the apparatus of the present invention and the biodegradable layer therein and a sealing device such as a suture ballast and a surrounding adhesive coating Top view
El · 園， 第23圖為本發明裝置的橫斷面圖，該裝置包含一生物 可分解内層、一密封底座及一生物黏性鍍層，及其與鞏膜 間的關係。 【元件代表符號簡單說明】 1 鞏膜 2 脈絡膜 3 視網膜 4 玻璃體狀凝膠 6 眼周圍组織 36 睫狀體 角膜 玻璃體狀凝膠 8 體液溶液 10 平坦部 12 視網膜 RPE複合體 14 脈絡膜 鞏膜 16 結構 18 密封座 外表面 20 藥劑儲存槽 密封座 22 黏著層 24 組織表面 縫線安定器 27 内壁 29 弧線 表面 31 内壁 儲存槽 33 黏性層 密封底座 35 密封底座 37 黏著層37 縫線安定器 39 外表面 眼外肌肉 41 鞏膜表面 密封底座 43 安定器 45 缝線 组織 47 缝線安定器 缝線 49 植入物 密封底座 53 黏劑層 密封底座 55 介面窗 密封底座 59 黏劑層El Garden, Figure 23 is a cross-sectional view of the device of the present invention comprising a biodegradable inner layer, a sealed base, and a bioadhesive coating, and its relationship to the sclera. [Simplified description of the symbol of the component] 1 Sclera 2 Choroidal 3 Retina 4 Vitreous gel 6 Peripheral tissue 36 Ciliary body Corneal vitreous gel 8 Body fluid solution 10 Flat section 12 Retinal RPE complex 14 Choroidal sclera 16 Structure 18 Seal Seat outer surface 20 drug storage tank sealing seat 22 adhesive layer 24 tissue surface stitching ballast 27 inner wall 29 arc surface 31 inner wall storage tank 33 adhesive layer sealing base 35 sealing base 37 adhesive layer 37 stitching stabilizer 39 outer surface Muscle 41 Scleral surface seal base 43 Ballast 45 Suture tissue 47 Stitch ballast suture 49 Implant seal base 53 Adhesive layer seal base 55 Interface window seal base 59 Adhesive layer
37 错存槽與组織間的介面63 密封底座 黏劑層 裝置外表面 充填埠 縫線安定器 充填埠 黏劑層 充填埠 組織表面 本發明裝置 密封底座 縫線 本發明裝置 通道 密封底座 裝置 生物可分解聚 縫線安定器 黏劑層 生物可分解層 生物可分解鍍 65 67 71 73 75 77 79 83 85 87 89 93 95 97 99 合物 101 103 105 108 鞏膜 單腔 鞏膜 外表面 密封底座 儲存槽 外表面 多個洞 密封底座 本發明裝 鞏膜 環狀元件 裝置外表面 環狀元件 氣閉密封位置 黏劑層 主體 密封底座 單腔37 interface between the storage tank and the tissue 63 sealing base adhesive layer device outer surface filling quilting line ballast filling 埠 adhesive layer filling 埠 tissue surface device sealing base stitching device of the invention device channel sealing base device biological Decomposed poly stitch line stabilizer layer biodegradable layer biodegradable plating 65 67 71 73 75 77 79 83 85 87 89 93 95 97 99 Compound 101 103 105 108 Scleral single cavity scleral outer surface sealing base storage groove outer surface Multiple hole sealing base, the invention has a scleral ring element device, an outer surface, a ring element, a gas sealing position, an adhesive layer, a main body sealing base, a single cavity
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