200520761 九、發明說明： 【發明所屬之技術領域】 本發明係關於適合用於治療或預防各種眼睛疾病之眼内 用類固醇懸浮液之方法及組合物。 【先前技術】 臨床眼科學最重要問題之一為眼内和眼表面組織之不良 增生’諸如增生性玻璃體視網膜病變之視網膜色素上皮細 胞之不良增生；缺血性視網膜病（諸如增生性糠尿病視網膜 病或視網膜中央靜脈阻塞後發生之增生性視網膜病）之眼 部血官細胞之不良增生；繼發性白内障眼部之晶狀體上皮 、”也之不良々生’和抗青光眼渡過手術後患者之纖維原細 胞之不良增生。眼内和鞏膜外細胞增生通常伴隨著眼内炎 症’並且炎症又可刺激細胞增生。吾人已熟知皮質類固醇 可減輕眼内炎症，並端視其濃度可以抑制細胞增生。因此， 匕們已經用於許多眼睛疾病，若非局部即是全身給藥。然 而，爲了使藥物在作用部位達到最高濃度，最好直接在所 需作用區域給藥。這樣保證了使可能達到之濃度最高和對 身體其餘部分之副作用較小。舉例而言，該皮質類固醇可 眼内給藥（例如藉由注射）’或以緩釋裝置形式植入體内。 、同特女皮貝醇已經作爲局部眼周注射液用於治療繼發 於葡=膜炎或眼内手術導致之囊樣黃斑水腫。玻璃體内注 十皮貝類固醇也已經試驗性地用於預防或治療增生性玻璃 體視網膜病變、視網膜企管增生、脈絡膜血管增生、靜脈 阻塞、糖尿病視網膜病變、糖尿病黃斑水腫、視網膜色素 94244.doc 200520761 變性、葡萄膜炎和水腫。玻璃體内注射皮質類固醇之安全 性已由先前動物試驗和人體試驗所證實。然而，在一定數 量實例中，對該方法之併發症包括眼内炎。在本文獻中， 推測感染性眼内炎可能為皮質類固醇治療產生之局部免疫 力抑制作用所導致。 【發明内容】 本發明係關於在FDA(美國食品及藥物管理局）對内毒素 雜質限制範圍内，類固醇商品製劑中内毒素含量能夠導致 眼内内毒素含量足以產生眼前房積膿或假性眼内炎等病 情。 本發明之一方面提供了 一種已包裝好之醫藥組合物，其 包括·（1)一種調配用於眼内注射或作爲一緩釋裝置植入眼 内之醫藥組合物，該組合物包括足以用於治療或預防一種 眼部疾病之相當數量的類固醇，且該醫藥組合物之内毒素 /辰度低於0.3 EU/毫升，較佳者低於〇〇3 Eu/毫升，且更佳 者低於0_01 EU/毫升；及（2) —個用於治療或預防該眼部疾 病之該醫藥組合物或裝置之使用標籤和/或説明書。 本發明之另一方面提供了一種低内毒素類固醇組合物在 生産一種用於治療或預防一種眼部疾病之藥物中之應用， 忒類固醇組合物之内毒素濃度低於〇·3 Ευ/毫升，較佳者低 於0.03EU/毫升，且更佳者低於〇·〇1Ευ/毫升；且可調配用 於眼内注射或作爲一緩釋裝置植入眼内。 本發明之另-方面提供了-種治療或預防_種眼部疾病 之方法’其包括藉由眼内注射或作爲一緩釋裝置植入眼内 94244.doc 200520761 來給予患者眼部-種類固醇組合物，該組合物内毒素濃度 低於0·3 EU/毫升，較佳者低於〇〇3 EU/毫升，且更佳者低 於0.01 EU/毫升。 可由本發明治療或預防之眼部疾病包含，但不僅限於： 眼部原發性腫瘤（例如視網膜母細胞瘤）；眼血管增生；眼水 腫，眼睛發炎；慢性眼痛；内源性葡萄膜炎；白塞氏病； 角膜移植；春季角膜結膜炎；木樣角膜結膜炎；乾眼症候 群；前眼葡萄膜色素層炎；蟠尾絲蟲病；視網膜病；視網 膜色素上皮和脈絡膜病變；視網膜退行性病變；糖尿病視 網膜病變；閉角型（急性）青光眼；開角型（慢性）青光眼；先 天性青光眼；繼發性青光眼；視網膜剝離；鐮刀形細胞視 網膜病變；老年性黃斑退化；視網膜血管增生；視網膜下 血官增生；虹膜發紅炎；發炎性病變；慢性後部色素層炎 和全葡萄膜炎；惡性腫瘤；假性神經膠質瘤；新生血管性 青光眼；聯合玻璃體切割術和晶狀體切割術後或其導致之 血官增生；血管病變；視網膜缺血；脈絡膜血管功能不全； 脈絡膜血栓栓塞；視神經血管增生；糖尿病黃斑水腫；囊 樣黃斑水腫；黃斑水腫；視網膜色素變性；視網膜靜脈阻 塞；增生性玻璃體視網膜病變；金管樣條紋症；視網膜動 脈阻塞，及眼睛穿孔或眼外傷導致之血管增生。 在一定具體實施例中，該類固醇為一種皮質類固醇，諸 如地塞米松、潑尼松龍、氟輕鬆或氟輕鬆丙酮化合物、曲 安西龍或丙酮特安皮質醇、氯替泊諾、考地松、或福美咳 4 (flumetholone)、或類似物、衍生物、醫藥可接受性赜、 94244.doc 200520761 1、前藥、或其保護形式。在較佳具體實施例中，該類固 醇為丙’特女皮質醇、氟輕鬆丙酮化合物、或氯替泊諾。 在一較佳具體實施例中，該組合物為—可眼内注射之溶 錢易流動㈣（聚合物或水㈣）。在其它具时施例中， 5物為大小適合植入眼内之可植入緩釋裝置。 在一定具體實施例中，本發明之類固醇組合物可調配成 釋放500从升有效劑量之類固醇，較佳者係⑽微升、5〇微 升或更少。 々Ϊ 一定具體實施例中，本發明之類固醇組合物有内毒素 丁隹貝’、低於ο·1 Eu/愛克類固醇，較佳者低於0 01 Eu/毫 克類固醇’且更佳者低於0.005 EU/毫克類固醇。 在一定具ϋ實施例巾，該組合物或緩釋裝置進―步包括 一種或多種内毒素抑制劑。 在一個具體實施例中，該組合物與—種或多種内毒素抑 制劑共同調配或聯合給藥。 【實施方式】 ⑴概述 近年來曲安西龍和其它類固醇之玻璃體内注射液已經被 廣泛應用。儘管此為_般操作H給與眼部類固醇還是 有危害的。問題之一可能是給藥後不久會出現眼前房積膿 或假性眼内炎。本發明係關於在舰（美國食品及藥物管理 局）對内毒素雜質限制範圍内，類固醇商品製劑中内毒素含 量能夠導致眼内内毒素含量顯著增高或產生此等不良反 94244.doc 200520761 ^•進灯°兄月，給—名72歲慢性囊樣黃斑水腫男性患者 (:力為可以數手指）注射〇1毫升（4毫克）凱洛松（丙綱特安 皮貝醇）°注射後48小時，該患者視力下降至看見手動，並 且發現其有顯著的伴有少量眼前房積膿之前房和玻璃體細 !=:月顯的破璃體薄霧和碎片。因此給該患者玻璃體 牙i射萬古黴素和F_z@e 14天後，該患者玻璃體和前 房之炎症徹底消退1凝膠_凝塊法（該方法可作爲與服 限制所允許之最大量進行對比之限制試驗，其在阿米巴狀 細胞自溶試驗（LAL)驗證指南中提出，可作爲人類和動物非 ”.工腸用藥、生物產品和醫療裝置之終產物檢測方法)分析給 與該患者之飢洛松中内毒素含量。結果顯示凱洛松中内毒 素濃度在1:100稀釋之懸浮液中低於〇.〇3 EU/毫升，相當於 本研究中所用之未稀釋產品中低於3 0 Eu/毫升之含量。 内毒素在用於治療使用之生物源性產品（生物製劑）中之 存在主要的擔心是由於此等分子有不同的、潛在的有害生 物活性。生産生物製劑所用方法保持無菌連同製備裝置之 嚴格方案，有助於確保該產品具有可接受之低内毒素含 量。FDA規定丙酮特安皮質醇化合物中内毒素最高含量為 4.39 EU /毫升。上述研究中所分析之凱洛松明顯低於這一 水平。然而，FDA的規定是基於5 EU作爲70千克個體可接 受内毋素的隶大女全劑量。這提示安全的全身用量約為 0.001 EU/毫升。然而對於眼内注射液，預計該内毒素不會 为佈於全身’ 0 · 1毫升飢洛松（如此處被分析的）將導致玻璃 體内注射之内毒素濃度為約0·1 EU/毫升。此濃度可能導致 94244.doc 200520761 内毒素介導之副反應。上述患者可能已經患有眼内炎，其 可能係由眼内注射訊洛松導致的。當前，沒有涉及fda對 曲安西籠眼内注射劑量之内毒素最大含量之規定。對於一 般使用’ 4’39 EU/笔升可能是適當之最大濃度，但對於眼内 注射液這一含量太高。 玻璃體是細菌生長之良好介f。事實上，過去，動物玻 璃體可用作培養基。細菌作爲外源物質可激發炎症反應。 繼連炎症產物增進了血-眼屏障破壞和炎症細胞補充。眼睛 才貝害之發生是由於炎症細胞裂解釋放的消化酶及細菌產生 的可肖b毋素而‘致。與炎症細胞和毒素接觸之所有組織都 發生損傷。 意識到該問題，本發明提供眼内用類固醇之調配物，其 已絰被純化’當注射入眼睛時，可使玻璃體内毒素濃度低 於〇.〇1⑽毫升，且更佳者低於〇〇〇1 EU/毫升。在一定具 體實施例中，該注射類固醇組合物以溶液或懸浮液形式提 供，其計劃注射體積小於5〇〇微升，且更佳者小於細微升、 微升、或甚.至小於5〇微升。因此，本發明之眼内用類固 醇5周配物包含溶液和懸浮液的内毒素濃度為Μ㈣毫升或 ，低二且更佳者為G ()3EU/毫升或更低。也就是說，對於曲 女西龍製劑，本發明之調配物之内毒素濃度顯著低於舰 所允坪之含量。 :疋具體貧施例中，本發明之類固醇組合物有内毒素 雜，’其低於o·1 Eu/毫克類固醇，較佳者低於0.01 Eu/毫 克類固醇，且更較佳者低於0.005 EU/毫克類固醇。 94244.doc -10- 200520761 本發明同時提供已包裝好之藥物，其包含 含量之適於眼内注射之 _内毋素 ^ 、 頰U醉凋配物，例如體積小於5〇〇 j升或更yH療或預防眼部疾病之使用標鐵和/或 説明書。 本务明之其他方面提供眼内用類固醇之調配物，其已疏 與：重或多種有抑制内毒素作用之製劑 制劑、環孢菌素等）共同調配。 (Π)定義 本説明書所用之”内毒音”一 , ^ Μ β糸私在革蘭氏_陰性細菌 膑外Μ現之糖酉旨類及其代謝物。舉例而言，内毒素可以 用LAL檢測試劑盒（Pyr〇gent pius，㈣摘触. N284)來檢測。 曰綠遽 本説明書所用之，，患者”-詞係指人類或非人類之動物。 ^防詞為技術公認的，當用於與疾病相關情況時， 邊如局部復發（例如疼痛）、高增生性疾病或其他病情時，在 =術中很容易理解’且包含給與患者一種組合 對t接受該組合物之患者，該組合物可降低一種疾病症狀 之毛生革或延遲其發生。因此，舉例而言，視網膜病變之 預防包含_於n賴照人群而言，㈣低了接受 防性治療患者群體之可檢測到之視_病變人數，和/或延 遲了治療組患者可檢測到之視網膜病變的發生，例如 統計和/或臨床顯著量。舉例而言，感染之預防包含，;目對 於未治療對照人群而言，其減少了治療人群中診斷為感毕 的人數’和/或延遲了治療人群感染症狀之發生。舉例而 94244.doc •11- 200520761 曰，疼痛之預防包含，相對於未治療對照人群而言，其降 低了治療人群患者痛感之發生率，或一 %力璉擇為延遲其發 ’’緩釋裝置”意思為一種以控制方式長時間釋放藥物之裝 置。舉例而言，用於本發明之緩釋裝置之實例可在美國專 利號 5,378,475、5,773,019、6,001，386、6,217,8、95、 6,548,〇78、6,375,972、5,902,598、和 6,331，313和美國專利 申請序列號10/714,549之專利中發現，其全文併入本文供參 考。 ” ”治療”一詞意味著逆轉、減輕、改善、降低、抑制、防 止、穩定、預防、緩解、或治療一種疾病、障礙或病情。 典型地’非限制性疾病症狀包含疼痛和炎症。典型地，非 限制性病情包含骨關節炎、類風濕性關節炎、惡性腫瘤、 微生物感染和血管生成。 本説明書所用之π治療有效量”這一短語意思為包括本發 明化合物之化合物、原料、或組合物之量按適於任何醫藥 治療之適當有盈/危險比率可有效產生一些希望得到之治 療效果。 眼睛的玻璃體’忍思為眼睛之玻璃體或玻璃體腔。眼 睛的”水”，意思為眼睛之房水。 (iii)去除内毒素之方法 有許多方法可用於從本發明之醫藥製劑中去除内毒素。 在純化過程中將内毒素雜質減到最少之適宜方法包含⑴使 用無菌溶液和設備將微生物進入減到最少，（ii)在純化過程 94244.doc -12- 200520761 中使用過濾（通常用〇·45微米或〇·22微米濾膜）來去除微生 物’（iii)低溫操作將微生物生長減到最慢，及（iv)向純化物 中加入細菌抑制製劑。顯而易見，此等方法之實踐端視純 化之特性。除了無菌純化技術（亦即，使用所有無菌成分且 在無菌環境中操作之技術）以外，一些微生物經常出現。結 果’内t素出現於終產物中。由於無菌純化之花費通常很 昂貴’因此希望有一種作爲最終步驟可從内毒素中分離出 純化產品之方法。下面討論一部分此等去除内毒素之方法。 從類固醇產品中分離内毒素之容易性部分依賴於該内毒 素與該類固醇之相似性或不同點。舉例而言，各種帶正電 何之渡器已經廣泛用於去除帶負荷電之内毒素，但是此種 刀離不能使用於具有類似於該内毒素特性之帶負電荷之類 固醇。除此之外，内毒素帶有低密度負電荷，其可造成去 除無效。 基於刀子大小的分離技術（如凝膠過濾、層析法、或超渡 法）也可用於分離内毒素和類固醇產品。 也可用親和層析方法，其中内毒素可藉由吸附到肽類抗 生素多黏囷素B而被去除。 專利號為6,365，147之美國專利（全文併入本文供參考）描 述了用固疋金屬親和層析從生物溶液中去除内毒素之方 法。此等方法可用於製備低内毒素類固醇製劑。特異地， d專㈣關於藉由將含有内毒素之溶液暴露於固定金屬親 _層析基貝而從生物溶液中去除内毒素之方法，該層析基 質由金屬離子諸如鋏（m)結合到樹脂上而構成，其中該金屬 94244.doc •13- 200520761 可以選擇性結合溶液中之内毒素。200520761 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to methods and compositions for intraocular steroid suspensions suitable for treating or preventing various eye diseases. [Prior art] One of the most important issues in clinical ophthalmology is the poor proliferation of tissues in the eye and the surface of the eye, such as the poor proliferation of retinal pigment epithelial cells such as proliferative vitreoretinopathy; ischemic retinopathy such as proliferative branuria Retinopathy or proliferative retinopathy that occurs after central retinal vein occlusion) Poor proliferation of blood hemocytes in the eye; Lens epithelium in secondary cataract eyes, "Poor dysplasia" and anti-glaucoma patients after surgery Poor proliferation of fibroblasts. Intraocular and extrascleral cell proliferation is usually accompanied by intraocular inflammation, and inflammation can stimulate cell proliferation. We have been well known that corticosteroids can reduce intraocular inflammation, and depending on its concentration can inhibit cell proliferation. Therefore, daggers have been used in many eye diseases, if not local, it is administered systemically. However, in order to achieve the highest concentration of the drug at the site of action, it is best to administer it directly to the desired area of action. This ensures that the concentration can be achieved. Highest and with less side effects on the rest of the body. For example, the cortex Steroids can be administered intraocularly (e.g. by injection) or implanted in the form of a sustained release device. Tepidol has been used as a local periocular injection for the treatment of secondary meningitis or the eye Cystic macular edema caused by internal surgery. Intravitreal injection of deca shellfish steroids has also been experimentally used to prevent or treat proliferative vitreoretinopathy, retinal enterprise hyperplasia, choroidal vascular hyperplasia, venous obstruction, diabetic retinopathy, diabetic macular edema Retinal pigment 94244.doc 200520761 Degeneration, uveitis, and edema. The safety of intravitreal injection of corticosteroids has been demonstrated in previous animal and human trials. However, in a number of examples, complications of this method include the eye Inflammation. In this document, it is speculated that infective endophthalmitis may be caused by the local immune suppression effect produced by corticosteroid treatment. [Summary of the Invention] The present invention relates to endotoxin in the FDA (United States Food and Drug Administration). Endotoxin content in steroid commercial preparations can cause eye endotoxins within the limits of impurities The content is sufficient to produce conditions such as anterior chamber empyema or pseudoendophthalmitis. One aspect of the present invention provides a packaged pharmaceutical composition comprising: (1) a formulation formulated for intraocular injection or as a sustained release A pharmaceutical composition for implanting a device into an eye, the composition comprising a sufficient amount of a steroid sufficient to treat or prevent an eye disease, and the endotoxin / degree of the pharmaceutical composition is less than 0.3 EU / ml, preferably Less than 0.003 Eu / ml, and more preferably less than 0_01 EU / ml; and (2) a label and / or instructions for use of the pharmaceutical composition or device for treating or preventing the eye disease Another aspect of the present invention provides the use of a low endotoxin steroid composition in the manufacture of a medicament for treating or preventing an eye disease, and the endotoxin concentration of the steroid composition is lower than 0.3 Ev / Milliliter, preferably less than 0.03EU / ml, and more preferably less than 0.001Eυ / ml; and can be formulated for intraocular injection or implanted into the eye as a sustained release device. Another aspect of the present invention provides a method of treating or preventing _ eye diseases, which includes administering eye-type steroids to a patient by intraocular injection or implanted into the eye as a slow-release device 94244.doc 200520761. The composition has an endotoxin concentration of less than 0.3 EU / ml, preferably less than 0.003 EU / ml, and more preferably less than 0.01 EU / ml. Ocular diseases that can be treated or prevented by the present invention include, but are not limited to: primary ocular tumors (such as retinoblastoma); ocular vascular hyperplasia; eye edema, eye inflammation; chronic eye pain; endogenous uveitis Behcet's disease; corneal transplantation; spring keratoconjunctivitis; woody keratoconjunctivitis; dry eye syndrome; anterior uveal uveitis; onchocerciasis; retinopathy; retinal pigment epithelium and choroidal disease; retinal degenerative disease Diabetic retinopathy; closed angle (acute) glaucoma; open angle (chronic) glaucoma; congenital glaucoma; secondary glaucoma; retinal detachment; sickle cell retinopathy; age-related macular degeneration; retinal vascular hyperplasia; subretinal Hematogenous hyperplasia; redness of iris; inflammatory lesions; chronic posterior uveitis and panuveitis; malignant tumors; pseudoglioma; neovascular glaucoma; combined vitrectomy and lensectomy or its causes Hyperplasia of blood vessels; vascular disease; retinal ischemia; choroidal vascular insufficiency Choroidal thromboembolism; Optic neurovascular hyperplasia; Diabetic macular edema; Cystic macular edema; Macular edema; Retinitis pigmentosa; Retinal vein occlusion; Proliferative vitreoretinopathy; Golden tube-like streaks; Retinal artery occlusion, and Eye perforation or eye trauma Vascular hyperplasia. In a specific embodiment, the steroid is a corticosteroid, such as dexamethasone, prednisolone, fluocinolone or fluocinolone acetone compounds, triamcinolone or acetone terancortisol, cloteponol, codysone , Or flumetholone 4, or an analog, derivative, pharmaceutically acceptable tincture, 94244.doc 200520761 1, a prodrug, or a protected form thereof. In a preferred embodiment, the steroid is propionate cortisol, fluocinolone acetone compound, or clotiporol. In a preferred embodiment, the composition is an intraocularly injectable solvent-soluble fluid (polymer or water). In other embodiments, the five objects are implantable sustained-release devices sized to be implanted into the eye. In certain embodiments, the steroid composition of the present invention may be formulated to release an effective dose of 500 liters of steroids, preferably ⑽ microliters, 50 microliters or less. 々Ϊ In a specific embodiment, the steroid composition of the present invention has endotoxin butyrocarbonate ', less than ο · 1 Eu / Ag steroid, preferably less than 0 01 Eu / mg steroid' and more preferably lower At 0.005 EU / mg steroids. In certain embodiments, the composition or extended release device further includes one or more endotoxin inhibitors. In a specific embodiment, the composition is co-formulated or administered in combination with one or more endotoxin inhibitors. [Embodiment] ⑴ Overview In recent years, intravitreal injections of triamcinolone and other steroids have been widely used. Although this is a common practice, H administration of eye steroids can be harmful. One of the problems may be anterior chamber empyema or pseudoendophthalmitis shortly after administration. The present invention relates to the endotoxin content in steroid commercial preparations which can cause the eye endotoxin content to increase significantly or produce such adverse reactions within the limits of the US Food and Drug Administration's limits on endotoxin impurities. 94244.doc 200520761 ^ • Into the light ° Brother, to a 72-year-old male patient with chronic cystic macular edema (: Li Wei can count fingers) injection of 01 ml (4 mg) Carlosone (Protamine pipidol) ° 48 after injection Hours, the patient's vision decreased to see manual, and he was found to be significantly accompanied by a small amount of anterior chamber pus and anterior chamber and vitreous thin! =: Visible broken glass mist and debris. Therefore, the patient's vitreous teeth were injected with vancomycin and F_z @ e 14 days later, the patient's vitreous and anterior chamber inflammation completely subsided. 1 gel_clot method (this method can be performed as the maximum amount allowed by the clothes restriction The comparative limit test, which is proposed in the amoebic cell autolysis test (LAL) verification guide, can be used as a non-human and animal non- "test method for the final product of industrial bowel drugs, biological products and medical devices) analysis and give this The content of endotoxin in hungry pinecone of patients. The results show that the concentration of endotoxin in carlosone is less than 0.03 EU / ml in the 1: 100 dilution suspension, which is equivalent to less than 3 in the undiluted product used in this study. Content of 0 Eu / ml. The main concern of endotoxins in bio-derived products (biological agents) for therapeutic use is due to the different and potentially harmful biological activities of these molecules. The methods used to produce the biological agents remain The sterility together with the rigorous protocol of the preparation device helps to ensure that the product has an acceptable low endotoxin content. The FDA has set a maximum endotoxin content of 4.39 EU / Ml. Carlosone was significantly lower than this level analyzed in the above study. However, the FDA's regulations are based on 5 EU as a full dose of female adult females who are acceptable for 70 kg. This suggests that a safe systemic dose is about It is 0.001 EU / ml. However, for intraocular injections, the endotoxin is not expected to be spread throughout the body. 0 · 1 ml of hunoxazone (as analyzed here) will result in an endotoxin concentration of about 0 for intravitreal injection. · 1 EU / ml. This concentration may cause 9444.doc 200520761 endotoxin-mediated side effects. The above-mentioned patients may already have endophthalmitis, which may be caused by intraocular injection of Xun Luo Song. Currently, no fda is involved. Regulation of the maximum content of endotoxin in the intraocular injection dose of triamcinolone. For general use '4'39 EU / liter may be the appropriate maximum concentration, but this content is too high for intraocular injection. Vitreous body is bacterial growth It is a good medium. In fact, in the past, animal vitreous can be used as a culture medium. Bacteria as exogenous substances can stimulate inflammatory reactions. Subsequent inflammation products promote blood-eye barrier destruction and inflammatory cells. Supplement. Occurrence of eye damage is due to digestive enzymes released by inflammatory cells and the bleaching of bacteria, which is caused by bacteria. All tissues that come into contact with inflammatory cells and toxins are damaged. Aware of this problem, the present invention Provides an intraocular steroid formulation that has been purified. 'When injected into the eye, the concentration of toxins in the vitreous body can be less than 0.01 ml and more preferably less than 0.001 EU / ml. In certain embodiments, the injectable steroid composition is provided in the form of a solution or suspension, and its planned injection volume is less than 500 microliters, and more preferably less than microliters, microliters, or even less than 50 microliters. Therefore, the intraocular steroid 5-week formulation of the present invention contains a solution and a suspension having an endotoxin concentration of Μ㈣mL or lower, and the second lower and better G (3) EU / mL or lower. That is to say, for the formulation of Qu Xixilong, the endotoxin concentration of the formulation of the present invention is significantly lower than that of Yunpingping. : 疋 In a specific lean embodiment, the steroid composition of the present invention has an endotoxin complex, which is lower than o · 1 Eu / mg steroid, preferably lower than 0.01 Eu / mg steroid, and more preferably lower than 0.005. EU / mg steroid. 94244.doc -10- 200520761 The present invention also provides a packaged drug, which contains a content of _endocrine ^ suitable for intraocular injection, a buccal and drunk compound, for example, a volume of less than 500 liters or more yH Use iron and / or instructions for treating or preventing eye diseases. Other aspects of this matter provide formulations for intraocular steroids, which have been formulated with: heavy or multiple endotoxin-inhibiting preparations, cyclosporin, etc.). (Π) Definitions The "endotoxic sound" used in this specification is ^ β β, which is secreted by Gram-negative bacteria, and present glycosides and their metabolites. For example, endotoxins can be detected using a LAL detection kit (Pyrogengent pius, Napkin. N284). As used in this manual, "patient"-word refers to a human or non-human animal. ^ The defense word is technically recognized. When used in a disease-related situation, such as local recurrence (such as pain), high In the case of a proliferative disease or other conditions, it is easy to understand 'intraoperatively' and it includes giving the patient a combination pair of patients who receive the composition, which can reduce or delay the onset of hairskin of a disease symptom. Therefore, for example, In other words, the prevention of retinopathy involves the decrease in the number of detectable visual lesions in the patient group receiving preventive treatment, and / or the delay in the detection of retinopathy in the treatment group. Occur, for example, statistically and / or clinically significant amounts. For example, prevention of infection includes; for untreated control populations, it reduces the number of people diagnosed with a sense of depression in the treated population and / or delays the treatment population The occurrence of symptoms of infection. For example, 94244.doc • 11-200520761, the prevention of pain includes, compared with the untreated control group, it reduces the pain of patients in the treated group. The rate of occurrence, or the one-percent-force option to delay its onset, and the 'slow-release device' means a device that releases the drug for a long time in a controlled manner. For example, examples of sustained release devices for use in the present invention can be found in U.S. Patent Nos. 5,378,475, 5,773,019, 6,001,386, 6,217,8, 95, 6,548, 〇78, 6,375,972, 5,902,598, and 6,331,313 and U.S. patent applications It is found in the serial number 10 / 714,549, which is incorporated herein by reference in its entirety. The term "treatment" means reversing, alleviating, improving, reducing, inhibiting, preventing, stabilizing, preventing, alleviating, or treating a disease, disorder, or condition. Typically, 'non-limiting disease symptoms include pain and inflammation. Typically Non-limiting conditions include osteoarthritis, rheumatoid arthritis, malignancies, microbial infections, and angiogenesis. The phrase "therapeutic effective amount" as used in this specification "means the compounds, materials, Or the amount of the composition at an appropriate profit / risk ratio suitable for any medical treatment can effectively produce some desired therapeutic effect. The vitreous body of the eye is the vitreous body or vitreous cavity of the eye. The "water" in the eyes means the water in the eyes. (iii) Endotoxin removal methods There are many methods for removing endotoxin from the pharmaceutical preparation of the present invention. A suitable method for minimizing endotoxin impurities during purification involves the use of sterile solutions and equipment to minimize microbial entry, and (ii) the use of filtration in the purification process 94244.doc -12- 200520761 (usually 0.45 Micron or 0.22 micron filter) to remove microorganisms' (iii) low temperature operation to minimize microbial growth, and (iv) adding a bacterial inhibitor to the purified product. Obviously, the practice of these methods depends on the nature of purification. In addition to aseptic purification techniques (that is, techniques that use all sterile ingredients and operate in a sterile environment), some microorganisms often occur. As a result, endogenin appears in the final product. Since aseptic purification is usually expensive ', it is desirable to have a method to isolate the purified product from endotoxin as a final step. Some of these endotoxin removal methods are discussed below. The ease with which endotoxins are isolated from steroid products depends in part on the similarities or differences between the endotoxin and the steroid. For example, various positively-charged Hedu devices have been widely used to remove charged endotoxins, but such knife-off cannot be used for negatively charged steroids with characteristics similar to that of endotoxins. In addition, endotoxin has a low density negative charge, which can cause ineffective removal. Knife-size-based separation techniques (such as gel filtration, chromatography, or ultrafiltration) can also be used to separate endotoxin and steroid products. Affinity chromatography can also be used, in which endotoxin can be removed by adsorption to peptide antibiotic polymyxin B. U.S. Patent No. 6,365,147, which is incorporated herein by reference in its entirety, describes a method for removing endotoxin from biological solutions using solid metal affinity chromatography. These methods can be used to make low endotoxin steroid formulations. Specifically, d is dedicated to a method for removing endotoxin from a biological solution by exposing an endotoxin-containing solution to a fixed metal chromatophore, which chromatography matrix is bound to a metal ion such as europium (m). It is made of resin, in which the metal 94244.doc • 13- 200520761 can selectively bind endotoxin in solution.
Wei 等人（Chromatography 23(2):79-84,2002，全文併入本 文供麥考）描述了從大量生物製劑樣品，包括從藥物注射液 (諸如含有類固醇之注射液）中去除内毒素之三種類型親和 薄膜之使用。所使用之該三種薄膜為殼聚糖親和膜 (KFCC517)、疏水和陽離子膜（KFCG316)、和金屬螯合層析 膜（KFCM402)。據報導，在最佳條件下，内毒素從氫化考 地松注射液中去除效率大於94%(從過濾前之1 EU/毫升至 過濾後之0.059 EU/毫升），然而有效成分氫化考地松可 100%回收。預期重複使用相同方法可以進一步降低内毒素 含量，同時沒有大量丟失有效成分，具有高保留率（100%)。 适一點也説明了使用此等膜一般可使從類固醇（其結構中 一般不含有許多陽離子）中分離内毒素變得非常容易。有可 能改變所使用之分離條件（諸如PH、離子強度、和流速）來 實現有效成分回收達到最佳同時保持内毒素去除效率最 高。此等條件由Wei等人討論。 可商業購得之試劑盒（諸如Pierce生物技術之Det〇xi_凝膠 内毒素去除凝膠）也可用於從類固醇溶液中去除内毒素。據 報該凝膠之内毒素去除效率在一次通過中高於。 也可在帶電、疏水或親和介質上進行選擇性結合内毒素 或按分子大小分離内毒素。在PH值高於2之水平上，内毒素 聚合物帶負電荷’且可以結合到正電荷表面（諸如石棉或離 子交換劑）。内毒素也可以結合到脂肪族聚合物上（諸如聚丙 烯、聚乙烯·、聚偏乙烯氟化物、聚四氟乙烯），以及經由疏 94244.doc •14- 200520761 水相互反應九合到疏水層析系統上。也可以藉由使用固定 多黏菌素B之親和層析特異性去除内毒素。除此之外，由於 内毋素主要作爲大分子量複合物存在，因此其通常能夠藉 由超遽或凝膠過;慮方法從所需成分中去除。 用於破壞或去除内毒素之其他方法包括用酸或鹼水解、 氧化、烷基化、和/或加熱處理。 上述方法僅為説明性目的，絕無限制性。許多其它公認 技術方法可用於從生物製劑樣品中（諸如本發明之醫筚^ 類固醇溶液或懸浮液）去除内毒素。也期望用上述方法中之 幾種方法相組合來從生物製劑樣品中（諸如本發明之類固 醇組合物）去除内毒素，且每種方法都可以獨立於其他方法 而重複使用。 (m)與内毒素抑制劑聯合給藥及共同調配 替代或除了眼内用類固醇調配物之純化外，本發明也涵 蓋使用其他能夠抑制内毒素作用之製劑（内毒素抑制劑或 拮抗劑）’例如’可以與本發明之眼内用類固醇組合物共同 調配或聯合給藥之製劑。 在一定具體實施例中，本發明之眼内用類固醇可與環氧 化酶（C〇X)抑制劑，尤其為COX-2抑制劑結合。前列腺素在 内毒素誘導之炎症過程中起重要作用。在炎症情況下， COX-2可由細胞因+、生長因子和細菌内毒素快速誘導。 已經發現非類固醇抗炎藥可以藉由抑制人體花生四烯酸/ 丽列腺素途徑中之酶（包括c〇x)來阻止前列腺素的產生。 在一定較佳具體實施例中，本發明之眼内用類固醇可與 94244.doc -15- 200520761 一種述擇性COX-2抑制劑共同調配或至少聯合給藥。短語，， 環氧化酶_2抑制劑，，或”COX-2抑制劑，，或，’環氧化酶_ Π抑制 劑π包括可特異性抑制cox-2類酶而不顯著抑制cox-丨之製 劑。較佳地，其包括COX—2半數抑制濃度（IC50)少於約0.2 微莫爾/升，、同時對COX-2抑制與對COX- 1抑制之選擇性比 率至少為50 ,更佳者至少1〇〇之化合物。更佳地，該化合物 之COX-1半數抑制濃度大於約1微莫爾/升，更佳者大於1〇 微莫爾/升。 典型C0X-2抑制劑可從由塞萊昔佈（SC-58635)、 DUP-697、氟舒胺（cgp-28238)、美洛西康、6_甲氧基-2萘 乙酸（6_MNA)、偉克適（MK-966)、萘丁美g同（6_mna之前 藥）、尼美舒利、NS-398、SC-5766、SC-58215、T-614、 deracoxib、戊地昔佈、儸菲可西保、依它昔佈、2-(、5_二 氟苯）-3-[4-(甲基磺醯基）苯基]_2-環戊烯_丨酮和2·(3,4•二氟 本Μ-(3_羥基甲基丁氧基）_5-(4_甲基磺醯基）苯 基]-3(2Η)·噠嗪酮；或其組合物組成之群中選出。 在其它具體實施例中，本發明之眼内用類固醇可與環孢 菌素或其一種衍生物聯合給藥。 (ν)典型調配物 可由本發明治療或預防之眼部疾病包括，但不僅限於·· 眼部原發性惡性腫瘤（例如視網膜母細胞瘤）；眼血管增生； 眼水腫；眼睛發炎；慢性眼痛；内源性葡萄膜炎；白塞氏 病’角膜移植；春季角膜結膜炎；木樣角膜結膜炎；乾眼 症候群；前眼葡萄膜炎；靖尾絲蟲病；視網膜病變；視網 94244.doc -16- 200520761 膜色素上皮和脈絡膜病變；視網膜退行性病變；糖尿病視 網膜病變；閉角型（急性）青光眼；開角型（慢性）青光眼；先 天性青光眼；繼發性青光眼；視網膜剝離；鐮刀形細胞視 網膜病變；老年性黃斑退化；視網膜血管增生；視網膜下 血管增生；虹膜發紅炎；發炎性病變；慢性後部色素層炎 和全葡萄膜炎；惡性腫瘤；假性神經膠質瘤；聯合玻璃體 切割術和晶狀體切割術後或其導致之血管增生；血管病 變；視網膜缺血；脈絡膜血管功能不全；脈絡膜血栓拴塞； 視神經血管增生；糖尿病黃斑水腫；囊樣黃斑水腫；黃斑 水腫；視網膜色素變性；視網膜靜脈阻塞；增生性玻璃體 視網膜病Μ ;血管樣條紋症；視網膜動脈阻塞；及眼睛穿 孔或眼外傷導致之血管增生。 在-定具體實施例中，本發明之組合物為去除了内毒素 之皮質類m醇衍生物。此等皮質類固醇化合物包括地塞米 私潑尼松龍、氟輕鬆、氯替泊諾、曲安西龍、考地松、 福美莎龍（fhmethoW)、及類㈣、衍生物、醫藥可接受 性鹽、S|、前藥、共藥物或其㈣形式。在-定較佳具體 實施例中，該類固醇為氣輕鬆丙酮化合物、丙酮特安皮質 醇、或氯替泊諾。 / —定具體實施例中，本發明之組合物包括—種類固醇 (古皮貝頦固醇）’其可調配成緩慢溶於眼睛液體中之懸浮 液，例如經過多於【天之時間，較佳者至少2或4天，甚至至 少1周時間。 在一定具體實施例中 本發明之眼内用類固醇可調配用 94244.doc 17 200520761 於緩慢釋放’例如一有效劑量類固醇在至少3〇天時間内釋 放，甚至更佳者至少為3個月、6個月或甚至12個月。此等 緩釋5周配包括將該類固醇懸浮或放置於一聚合物或水凝膠 中，由此該類固醇可以從該基質和/或該基質之生物降解產 物中擴散而緩慢釋放。在美國專利申請序列號為6〇/482677 和60/501947之專利中描述了特定典型調配物，其全文併入 本説明書供參考。在其它具體實施例中，該類固醇可放於 緩釋裝置中，例如一容器，其大小適於植入眼内。在專利 唬為 5,378,475、5,773,019、6,001,386、6,217,895、 6’548,078、6,375,972、5,902,598、和 6,331，313之美國專利 和美國專利申請序列號為1〇/714,549之專利中描述了此種 適宜裝置，其完整内容併入本文供參考。 在本發明之一個具體實施例中，一種緩釋組合物或裝置 可植入或注射入眼内，因此其可向眼後部釋放類固醇（諸如 皮質類固醇）。在一較佳具體實施例中，該緩釋組合物或裝 置可由玻璃體植入或注射入眼内。然而，該組合物或裝置 可也被植入或注射入脈絡膜區、視網膜下、或鞏膜。此等 給藥方法及製備技術已為所屬技術領域之普通技術人員所 熟知。給樂方法及製備技術在Remington’s Pharmaceutical Scinences 中陳述。 在一定較佳具體實施例中，房水之皮質類固醇濃度保持 低於玻璃體之皮質類固醇濃度，達實質上該緩釋組合物或 裝置壽命。因此，在皮質類固醇釋放期間，房水皮質類固 醇濃度不高於約0.002微克/毫升至約0.01微克/毫升。 94244.doc -18 - 200520761 在一定較佳具體實施例中，可製備該緩釋組合物或裝置 使其按偽零級動力學反應以約i微克/天至约5〇微克/天（諸 如約1微克/天至約10微.克/天）之平均釋放率來釋放該皮質 類固醇。 在本發明之一個具體實施例中，可以製備一種眼科裝 置，其含有氟輕鬆丙酮化合物、丙酮特安皮質醇、或氯替 泊諾作爲有效藥劑以治療有效劑量來減少、治療、或預防 眼睛血管增生（諸如角膜、視網膜或視網膜下之血管增生、 視神經血管增生、由聯合進行玻璃體切割術和晶狀體切割 術導致之血管增生、或由於眼穿孔或眼外傷導致之血管增 生）、視網膜靜脈阻塞、糖尿病視網膜病變、糖尿病黃斑水 腫、視網膜色素變性、慢性後部色素層炎或全葡萄膜炎、 黃斑水腫或囊樣黃斑水腫、閉角型（急性）青光眼、開角型（慢 性）青光眼、先天性青光眼、繼發性青光眼、視網膜剝離、 鐮刀細胞形視網膜病變、老年性黃斑退化、虹膜發紅炎、 發炎性病變、惡性腫瘤、視網膜母細胞瘤、假性神經膠質 瘤、新生血管性青光眼、視網膜缺血、脈絡膜血管功能不 全、脈絡膜血栓栓塞、增生性玻璃體視網膜病變、血管樣 條紋症、或視網膜動脈阻塞。用上述本發明之方法可以選 擇性地去除該製劑中之内毒素，因此該總内毒素含量使得 該製劑適於眼内使用。當手術植入或注射入眼睛坡璃體 時’此等裝置可用於有效競爭或抑制不良的眼睛血管增 生、水腫或炎症。治療完成後，此等裝置可永久放置在玻 ㈤肢内。此等裝置中所用之氟輕鬆丙酮化合物、丙g同特安 94244.doc -19- 200520761 皮質醇、或氯替泊諾之較佳劑量範圍介於約0·01毫克至約 40毫克之間。更佳地，此等裝置含有约〇·ΐ毫克至約6毫克 氟輕鬆丙酮化合物、丙a同特安皮質醇、或氯替泊諾。此等 較佳之有效成分和内毒素變動範圍可以使氟輕鬆丙酮化合 物、丙酮特安皮質醇、或氣替泊諾持續幾小時至5年時間緩 慢釋放，同時將内毒素副反應減至最小。 管本發明就其較佳具體實施例已被詳細描述，然而所 屬技術領域技術人員進行不脫離本發明範圍之各種改變及 等效應用將是顯而易見的。因此，以下申請專利範圍中陳 述之本發明將以法律允許之最廣泛意義解釋。 上述所有專利、申請及參考文獻都全文併入本文供參考。 94244.doc -20-Wei et al. (Chromatography 23 (2): 79-84, 2002, which is incorporated herein in its entirety for McCaw) describes the removal of endotoxin from a large number of biological agent samples, including from pharmaceutical injections, such as steroid-containing injections. Three types of affinity films are used. The three films used are chitosan affinity membrane (KFCC517), hydrophobic and cationic membrane (KFCG316), and metal chelate chromatography membrane (KFCM402). According to reports, under the optimal conditions, the removal efficiency of endotoxin from hydrocortisone injection is greater than 94% (from 1 EU / ml before filtration to 0.059 EU / ml after filtration), but the effective ingredient is hydrocortisone 100% recyclable. It is expected that repeated use of the same method will further reduce endotoxin content without significant loss of active ingredients, with high retention (100%). The appropriate point also shows that the use of these membranes generally makes it very easy to isolate endotoxins from steroids, which generally do not contain many cations in their structure. It is possible to change the separation conditions used (such as pH, ionic strength, and flow rate) to achieve optimal recovery of active ingredients while maintaining the highest efficiency of endotoxin removal. These conditions were discussed by Wei et al. Commercially available kits (such as Pierce Biotech's Detoxix gel endotoxin removal gel) can also be used to remove endotoxin from steroid solutions. The endotoxin removal efficiency of the gel was reported to be higher in one pass. It is also possible to selectively bind endotoxins on charged, hydrophobic or affinity media or to isolate endotoxins by molecular size. At pH levels above 2, endotoxin polymers are negatively charged 'and can bind to positively charged surfaces (such as asbestos or ion exchangers). Endotoxin can also be bound to aliphatic polymers (such as polypropylene, polyethylene ·, polyvinylidene fluoride, polytetrafluoroethylene), and react with each other via hydrophobic 94244.doc • 14- 200520761 to the hydrophobic layer Analysis system. Endotoxin can also be specifically removed by affinity chromatography using polymyxin B immobilized. In addition, because endoprost exists mainly as a large-molecular-weight complex, it can usually be removed from the required ingredients by ultra-plumbing or gelling. Other methods for destroying or removing endotoxin include hydrolysis with acid or base, oxidation, alkylation, and / or heat treatment. The methods described above are for illustrative purposes only and are in no way limiting. Many other recognized technical methods can be used to remove endotoxin from a biological agent sample, such as a medicinal steroid solution or suspension of the present invention. It is also desirable to use a combination of several of the methods described above to remove endotoxin from a biological sample (such as a steroid composition of the invention), and each method can be reused independently of the other methods. (m) In combination with endotoxin inhibitors and co-dispensing alternatives or in addition to the purification of steroid formulations for intraocular use, the present invention also covers the use of other agents (endotoxin inhibitors or antagonists) capable of inhibiting the action of endotoxins' For example, a formulation that can be co-formulated or co-administered with the intraocular steroid composition of the present invention. In certain embodiments, the intraocular steroids of the present invention can be combined with cyclooxygenase (COX) inhibitors, especially COX-2 inhibitors. Prostaglandins play an important role in the process of endotoxin-induced inflammation. In the case of inflammation, COX-2 can be rapidly induced by cytokines +, growth factors, and bacterial endotoxins. Nonsteroidal anti-inflammatory drugs have been found to prevent the production of prostaglandins by inhibiting enzymes (including cox) in the arachidonic acid / lisagretin pathway of the human body. In certain preferred embodiments, the intraocular steroids of the present invention may be co-formulated or at least administered in combination with a selective COX-2 inhibitor of 94244.doc -15-200520761. The phrase, cyclooxygenase_2 inhibitor, or "COX-2 inhibitor," or, "cyclooxygenase_II inhibitor π" includes a specific inhibitor of cox-2 enzymes without significant inhibition of cox- 丨Preferably, it includes a COX-2 half inhibitory concentration (IC50) of less than about 0.2 micromoles / liter, and at the same time a selectivity ratio of COX-2 inhibition to COX-1 inhibition of at least 50, more Preferably, the compound is at least 100. More preferably, the compound has a COX-1 half inhibitory concentration greater than about 1 micromole / liter, and more preferably greater than 10 micromole / liter. Typical COX-2 inhibitors can From celecoxib (SC-58635), DUP-697, flusulosin (cgp-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6_MNA), Wacox (MK-966) , Naftimide g (pre-6-mna drug), Nimesulide, NS-398, SC-5766, SC-58215, T-614, deracoxib, valdecoxib, fencoricoxib, etacoxib , 2- (, 5-difluorobenzene) -3- [4- (methylsulfonyl) phenyl] _2-cyclopentene_one and 2 (3,4 • difluorobenzyl M- (3 _Hydroxymethylbutoxy) _5- (4_methylsulfonyl) phenyl] -3 (2Η) · pyridazinone; or composition thereof Selected from the group. In other specific embodiments, the intraocular steroids of the present invention may be administered in combination with cyclosporin or one of its derivatives. (Ν) Typical formulations include ocular diseases that can be treated or prevented by the present invention , But not limited to ... primary malignant tumors of the eye (such as retinoblastoma); ocular hyperplasia of the eye; eye edema; eye inflammation; chronic eye pain; endogenous uveitis; Behcet's disease 'corneal transplantation; Keratoconjunctivitis in spring; Wood-like keratoconjunctivitis; Dry eye syndrome; Anterior uveitis; Onchocerciasis; Retinopathy; Viewfinder 94244.doc -16- 200520761 Membrane pigment epithelium and choroid disease; Retinal degenerative disease; Diabetes Retinopathy; angle-closure (acute) glaucoma; angle-open (chronic) glaucoma; congenital glaucoma; secondary glaucoma; retinal detachment; sickle cell retinopathy; age-related macular degeneration; retinal vascular hyperplasia; subretinal vascular hyperplasia Redness of iris; Inflammatory lesions; Chronic posterior uveitis and panuveitis; Malignant tumors; Pseudonervation Glioma; Angiogenesis after combined vitrectomy and lensectomy; Angiopathy; Retinal ischemia; Choroidal vascular insufficiency; Choroidal thromboembolism; Optic neurovascular hyperplasia; Diabetic macular edema; Cystic macular edema; Macular Edema; retinal pigment degeneration; retinal vein occlusion; proliferative vitreoretinopathy M; vascular streaks; retinal arterial occlusion; and vascular hyperplasia caused by eye perforation or eye trauma. In specific embodiments, the composition of the present invention It is a cortisol-like alcohol derivative from which endotoxin has been removed. These corticosteroids include dexamethasone, prednisolone, fluocinolone, clotiporon, triamcinolone, codysone, fhmethoW, and hydrazones, derivatives, and pharmaceutically acceptable salts. , S |, prodrug, co-drug, or hydrazone form. In a preferred embodiment of the present invention, the steroid is a gas-releasing acetone compound, acetone cortisol, or clotiporol. /-In a specific embodiment, the composition of the present invention includes-a kind of sterol (gupizide), which can be formulated as a suspension that slowly dissolves in the eye liquid, for example, after more than [time of day, The best is at least 2 or 4 days, or even at least 1 week. In certain embodiments, the intraocular steroids of the present invention may be formulated with 94244.doc 17 200520761 for slow release. For example, an effective dose of steroids is released over a period of at least 30 days, and even better is at least 3 months, 6 Months or even 12 months. These sustained release 5 week formulations include suspending or placing the steroid in a polymer or hydrogel, whereby the steroid can be diffused from the matrix and / or the biodegradable products of the matrix and released slowly. Certain typical formulations are described in U.S. Patent Application Serial Nos. 60/482677 and 60/501947, which are incorporated herein by reference in their entirety. In other embodiments, the steroid can be placed in a sustained release device, such as a container, which is sized to be implanted into the eye. Such suitable devices are described in US Patents 5,378,475, 5,773,019, 6,001,386, 6,217,895, 6'548,078, 6,375,972, 5,902,598, and 6,331,313 and US Patent Application Serial No. 10 / 714,549, which are complete. The contents are incorporated herein by reference. In a specific embodiment of the present invention, a sustained release composition or device is implantable or injectable into the eye so that it releases steroids (such as corticosteroids) to the back of the eye. In a preferred embodiment, the sustained release composition or device can be implanted or injected into the eye from the vitreous. However, the composition or device may also be implanted or injected into the choroid area, subretinal, or sclera. Such administration methods and preparation techniques are well known to those skilled in the art. The dole method and preparation technique are described in Remington's Pharmaceutical Scinences. In certain preferred embodiments, the corticosteroid concentration in the aqueous humor is kept lower than the vitreous corticosteroid concentration for substantially the life of the sustained release composition or device. Therefore, during corticosteroid release, the corticosteroid concentration in the aqueous humor is not higher than about 0.002 µg / ml to about 0.01 µg / ml. 94244.doc -18-200520761 In certain preferred embodiments, the sustained release composition or device can be prepared to react in a pseudo-zero order kinetics from about i μg / day to about 50 μg / day (such as about 1 microgram / day to about 10 micrograms / day) to release the corticosteroid. In a specific embodiment of the present invention, an ophthalmic device may be prepared, which contains fluocinolone acetone compound, acetone cortisol, or clotepono as an effective agent at a therapeutically effective dose to reduce, treat, or prevent eye blood vessels Hyperplasia (such as corneal, retinal or subretinal vascular hyperplasia, optic nerve vascular hyperplasia, vascular proliferation caused by a combination of vitrectomy and lensectomy, or vascular proliferation due to eye perforation or eye trauma), retinal vein occlusion, diabetes Retinopathy, diabetic macular edema, retinal pigment degeneration, chronic posterior uveitis or panuveitis, macular edema or cystoid macular edema, closed angle (acute) glaucoma, open angle (chronic) glaucoma, congenital glaucoma, Secondary glaucoma, retinal detachment, sickle cell retinopathy, age-related macular degeneration, iris redness, inflammatory lesions, malignant tumors, retinoblastoma, pseudoglioma, neovascular glaucoma, retinal ischemia Choroidal vascular function Total, choroidal thromboembolism, proliferative vitreoretinopathy, vascular streaks, or retinal artery occlusion. The method of the present invention described above can selectively remove endotoxin from the preparation, so the total endotoxin content makes the preparation suitable for intraocular use. When surgically implanted or injected into the lenticular body of the eye, these devices can be used to effectively compete or inhibit poor ocular angiogenesis, edema, or inflammation. After treatment, these devices can be permanently placed in the vitreous limb. The preferred dosage range of the fluocinolone acetone compound, propionone tetanone 94244.doc -19-200520761 cortisol, or clotebino used in these devices is between about 0.01 mg to about 40 mg. More preferably, these devices contain from about 0.5 mg to about 6 mg of fluocinolone acetone compound, propazone and terancortisol, or clotebino. These preferred active ingredients and the range of endotoxin fluctuations allow slow release of fluocinolone acetone compound, acetone cortisol, or gastipotonol over a period of several hours to 5 years, while minimizing endotoxin side effects. Although the present invention has been described in detail with respect to its preferred embodiments, it will be apparent to those skilled in the art that various changes and equivalent applications can be made without departing from the scope of the present invention. Therefore, the invention described in the scope of the following patent applications will be interpreted in the broadest sense permitted by law. All of the above patents, applications and references are incorporated herein by reference in their entirety. 94244.doc -20-