TWI290835B - Fine particle subconjunctival administration drug delivery system - Google Patents
Fine particle subconjunctival administration drug delivery system Download PDFInfo
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- TWI290835B TWI290835B TW092103600A TW92103600A TWI290835B TW I290835 B TWI290835 B TW I290835B TW 092103600 A TW092103600 A TW 092103600A TW 92103600 A TW92103600 A TW 92103600A TW I290835 B TWI290835 B TW I290835B
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- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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Description
1290835 玫、發明說明 .....J - ; ..Ϊ- . Λ·..·.:....· I :: . : (發明說明應敘明:發明所屬之技術銪Μ · 5又力Γ川蜀(议術请域、先則技術、內容、實施方式及圖式簡單說明) (一)發明所屬之技術領 本發明係關於網膜、脈絡膜、視神經等後眼部之藥物輸 送系統。 (二)先前技術
網月旲、脈絡Μ及視神經等之後眼部疾病多爲難治性疾病 ’因此寄望具功效治療法之開發。對於眼疾病,點眼藥投 與樂物之治療是最普遍的,但網膜、脈絡膜及視神經等之 後眼部藥物幾乎不移行。再者,即使移行也極難持續組織 中的藥物濃度。 因此,對後眼部疾病之藥物投與方法,已嘗試靜脈注射 、經口投與、玻璃狀體注射。靜脈注射或經口投與,目標 部位後眼部之藥物移行量極微量,且不欲之藥物全身作用( 副作用)也強烈顯現。
由於玻璃狀體注射是直接注射藥物於眼內,後眼部之藥 物移行量比靜脈注射或經口投與多。有關玻璃狀體注射之 後眼部藥物輸送系統,總論整理於j 0 u r n a 1 0 f 0 c u 1 a r pharmacology and therapeutics , ( 200 1 ) 17/4,393-401 。然而,玻璃狀體注射爲需要高度技術之投與法,由於伴 隨相當的痛苦,病人的負擔也很大,因此多次投與極爲困 難。 對於這些投與法,結膜下注射的技術比較簡便,因此比 _ 6 - 1290835 玻璃狀體注射的眼組織障害少,且對病人的負擔也少。結 膜下注射後的藥物移行性亦已被發表(Inves t . Ophthalmol . Visual Sci. 18(3)250-255,1979),由於半衰期非常短, 長時間持續藥物的後眼部組織中濃度是困難的。因此,爲 持續藥物的組織中濃度而必須多次投與,多次投與使病人 的負擔變大。 爲避免多次投與’已知之持續眼內藥物濃度之方法爲靜 脈內投與藥物-高分子結合體之方法(Inves t . Ophthalmol . Visual Sci. 40 ( 1 ) 2690 - 2696,1 99 9 ),或注入含有藥物之 微小球於玻璃狀體之方法(特開2 0 0 0 - 2 4 7 8 7 1 )。 如上所述,習知技術中,結膜下注射後持續藥物的組織 中濃度是困難的’因此希望硏發由結膜下注射之後眼部之 持續的藥物輸送系統。 (三)發明內容 發明之掲示 由本發明者們努力硏究的結果發現:若結膜下投與含有 藥物之徐放性微粒子,非常有用於作爲後眼部之持續的藥 物輸送系統。 本發明係關於結膜下投與含有藥物之微粒子而用於後眼 部之藥物輸送系統。又本發明係關於具有含藥物之微粒子 之注射劑,可使藥物移行於後眼部之結膜下注射劑。由結 膜下投與含有藥物之微粒子,比靜脈注射或經口投與之後 眼部的移行性更佳’全身作用的副作用也較少。且相較於 玻璃狀體注射,因手技簡便病人的負擔也較少。再者,藉 一 7- 1290835 由含有樂物於微粒子’可長時間維持目標組織中的藥物濃 度。 本發明中組成微粒子之材料以生物體分解性或生物體溶 解性高分子爲佳,具體例如聚乳酸、乳酸-乙醇共聚物、乳 酸-己內酯共聚物、聚硬石膏、聚原酸酯、聚胺己內酯、聚 丙烯基氰基丙烯酸酯、聚羥烷醇酸、聚磷酸酯、聚胺基酸 、聚α -羥基酸等之生物體分解性高分子;動物膠(ge丨a t丨n ) 、膠原(c ο 1 1 a g e η )、透明質酸、葡聚糖、澱粉、藻酸鈉、 洋菜膠、支鏈源粉(pullulan)、白蛋白、角叉萊膠 (carrageenin)、果膠、黃原膠、葛倫膠(gelan gum)、酪 蛋白、殼聚糖、血纖維蛋白質等之天然高分子;間丙烯酸 共聚物、聚乙烯醇、羥丙基甲基纖維素、羥丙基甲基纖維 素乙酸酯、羥乙基纖維素、羧甲基纖維素、甲基纖維素、 聚乙烯吡咯酮、聚乙二醇、聚烷基丙烯醯酸等之合成高 分子。 這些高分子物質的分子量無特別限制可依據微粒子所含 之藥物種類、藥物的有效治療濃度、藥物的放出期間等適 宜選擇。 本發明中微粒子的粒子徑較佳爲 50nm〜150 //m。粒子徑 5 Onm以下之微粒子製造困難,粒子徑150// m以上因粒子太 大不宜作爲注射劑。更佳之粒子徑爲2 0 0 n m〜7 5 // m。 本發明之藥物輸送系統可用於網膜、脈絡膜及視神經之 疾病的治療或預防。具體的疾病例如種種原因引起之炎症 ,病毒或細菌的感染症,網膜脈絡膜血管新生引起之炎症 一 8 - 1290835 ,網膜缺血引起之疾病,青光眼引起之視神經障害。更具 體說明如葡萄膜炎,細胞巨大病毒網膜炎,老化性黃斑變 性症,糖尿病性網膜症,增殖性玻璃狀體網膜症,網膜剝 離,網膜色素變性症,網膜中心靜脈閉塞症,網膜中心動 脈閉塞症等。
微粒子所含之藥物無特別限制,可依據所針對的疾病適 宜選擇藥物。具體例如β -美沙松(b e t a m e t h a s ο n e ),德沙美 沙松(dexamethasone),氟經脫皮留醇(triamcinolone), 脫氫皮留醇(prednisolone),氟***(fluoromethalone) ,經可體松(hydrocortisone),黃體酮(progesterone)等 之類固醇劑或其衍生物;溴芬艾克(b r 〇 m 〇 f e n a c ),代可羅 芬艾克(diclofenac)等之抗炎症劑;TNF - α抑制劑、PDE-IV 抑制劑、ICE抑制劑等之細胞激素抑制劑,環孢子素 (c y c 1 〇 s ρ 〇 r i η )、太可利馬斯(t a c r ο 1 i m u s )等之免疫抑制劑 :甘環微爾(gancyclovir)、阿環微爾(acyclovir)、干擾 素冷等之抗病毒劑;歐福羅生素(ofloxacin)、克拉力黴素 (clarithromycin)、紅黴素(erythromycin)等之抗菌劑; 氟尿嚼Π定、胺甲碟D令(m e t h 〇 t r e X a t e )、MMP抑制劑等之抗 癌劑;內司達丁( endos t at in)、VEGF抑制劑、反意義寡核 苷酸、PKC抑制劑、附著因子抑制劑、血管靜止性類固醇 等之血管新生抑制劑;MK-801、塞摩羅(thymolol )、肌酸 (c r e a t i n e )、牛磺酸(t a u r i n e )、BDNF等神經保護劑,神 經營養因子、乙醯羅拉醯胺(acetazolamide)等之碳酸酐酶 抑制劑;尿激酶等之血栓溶解劑等等。藥物含於微粒子中 一 9- 1290835 ,可爲平均分散於微粒子內之基質型或以藥物作爲核心將 微粒子膠囊化之膠囊型爲佳。 微粒子含有之藥物量可依據對應之藥物種類、有效治療 濃度、藥物的放出期間、症狀等適宜增減。藥物的含有量 爲微粒子重量的0.01〜95%,較佳爲重量的0.1〜20%。 本發明之微粒子可使用習知製粉所用之粉碎法,相分離 法(凝聚法),噴霧乾燥法,超臨界流體法,界面沉著法, 界面反應法製造。更具體例如界面沉著法之液中乾燥法(J . Control. Release, 2, 3 43 - 3 52,( 1 9 85 )),界面反應法之 界面聚合法(Int· J. Pharm·, 28, 125-132 (1986)),自 動乳化溶劑擴散法(J. Control. Release,25,89-98 ( 1 993 ))等等。從這些製造法,考慮微粒子的粒子徑或所含 之藥物種類、性質或含量等等,可適宜選擇適當的製造法 〇 微粒子的具體製造例如含有抗炎症劑β -美沙松之藥物, 使用之微粒子材料聚乳酸,於下述實施例顯示含有藥物之 微粒子製造例。 本發明之效果以下述之網脈絡膜藥物濃度測定試驗項詳 細說明,使用β -美沙松爲藥物例,結膜下投與含有β -美沙 松之微粒子,測定網脈絡膜中之藥物濃度,發現可持續網 脈絡膜中之藥物濃度。 本發明之藥物輸送系統,微粒子係被投與於結膜下。結 膜下之投與方法可使用常用的結膜下注射。如先前技術項 所述,結膜下注射手技比較簡便,而且病人的負擔也較少 -1 0 - 1290835 再者,使用本發明之系統後,可十分有效率送達藥物至 目標部位之網膜、脈絡膜或視神經等後眼部,故可減低藥 物的投與量,亦可期待副作用的減輕效果。 用於本發明藥物輸送系統之微粒子,爲可投與於結膜下 ,投與劑型以注射劑爲佳。注射劑可使用廣泛使用之注射 劑製劑化技術製備。舉例而言,可將氯化鈉等滲透壓調整 劑,磷酸鈉等緩衝劑,聚山梨酸酯80等界面活性劑,甲基 纖維素等增黏劑之常用添加劑及微粒子,添加至注射用蒸 餾水以製備製劑。再者,可使用不用針之高壓式注射器, 不做成注射劑而能原封不動投與微粒子。 以下顯示微粒子之製造例,製劑之製備例,藥物濃度測 定試驗及脈絡膜血管新生抑制試驗之結果。 (四)實施方式 1施本發明之最佳熊樣 1.含有藥物之微粒子之製造方法 可用於本發明藥物輸送系統之微粒子之製造例如下所示 〇 β-美沙松(0.025g)及重量平均分子量20000之聚乳酸 (〇.25g)溶解於苯甲醇(1.5mL),所得溶液爲藥物/聚合物溶 液。於均質器中均質化(5000rpm)2 · 0%( w/v )聚乙烯醇水溶 液(3 OinL ),滴下藥物/聚合物溶液於其中。滴下終了後,開 始均質化此混合物5分鐘製備0/W乳液。使用攪拌機攪梓 (3 00。111)超純水,滴下製備之0/%乳液於其中,滴下終了 1290835 後,開始攪拌1小時。攪拌終了後,離心分離所得懸浮液 ,去除上淸液。爲洗淨沉澱物’添加超純水(3 OmL )以分散 沉澱,再次離心分離去除上淸液。此項操作再進行一次。 經由篩子篩選洗淨之沉澱物得到粒子徑50ηπι〜75//m之粒子 。經由冷凍乾燥所得粒子得到含有β -美沙松之微小球。 2. 製劑之製備方法 含有β-美沙松之微小球粉末( 442mg)分散於4mL溶劑中 (0.4%(〜^)聚山梨酸酯80/2.6%(〜^)甘油水溶液),所得 分散液爲含有β -美沙松之微小球注射劑。 3. 網脈絡內藥物濃度測定試驗 使用含有β -美沙松之微小球注射劑,依照下述方法測定β -美沙松之網脈絡膜內濃度。使用下述之β -美沙松懸浮劑作 爲對照組進行濃度測定。比較β -美沙松之微小球投與組與 懸浮劑投與組之β -美沙松的網脈絡膜內濃度。爲構成 1 % ( w / ν )濃度β -美沙松之β -美沙松懸浮劑,將β -美沙松懸浮 於溶劑中(0 · 4 % ( w / ν )聚山梨酸酯8 0 / 2 · 6 % ( w / ν )甘油水溶液) 〇 1) 將鹽酸氧伯普甘(HC1 oxybuprocaine)(0.5%(w/v)) 眼藥水點藥於日本白兔的兩眼以麻醉眼表面。 2) 使用27G針之注射器,每一眼投與100 // L含β-美沙 松之微小球注射劑於上部結膜下。由於微小球中之β -美沙 松含有率爲約4 · 6 % ( w / ν ),因此β -美沙松含的投與量爲約 5〇〇 Μ g。對照組是使用27G針之注射器,每一眼投與50 # l 之1%(W/V)P_美沙松懸浮劑於上部結膜下。 -12- 1290835 3)投與後第2、7、14、21、28日屠宰兔子,摘出各眼 球後回收網脈絡膜,以高速液相色層分析測定網脈絡膜內 之β -美沙松濃度。 藥物經時的濃度推移結果示於表1。從表1明確得知β _ 美沙松懸浮劑於網脈絡膜內之β -美沙松濃度,在7日後爲 約0 · 9 6 // g / g組織,1 4日後則在偵測界限以下。相較於此 ’含有β -美沙松之微小球於網脈絡膜內之β -美沙松濃度, 即使在2 8日後爲約0 · 0 9 // g / g組織,可維持網脈絡膜中藥 物濃度。 表1網脈絡膜中之β-美沙松濃度(//g/g組織) 對照組(懸浮劑) 微小球注射劑 投與2曰後 0.54± 0.35 0.70± 0.26 7日後 0.96± 0.54 0.18 14日後 偵測界限以下 0·17± 0.06 21日後 偵測界限以下 0.10± 0.02 28日後 偵測界限以下 0.09± 0.02 (表中所示網脈絡膜中之β -美沙松濃度爲3或4眼的平均 値土標準誤差。微小球注射劑之7曰値,因4眼中有2眼 在偵測界限以下,故以2眼的平均値表示。) 4.脈絡膜血管新生抑制試驗 含有β -美沙松之微小球注射劑的脈絡膜血管新生抑制效 果,使用雷射誘發大鼠脈絡膜血管新生模式,以下述方法 進行檢討。使用僅含有溶劑(0 · 4 % ( w / ν )聚山梨酸酯 80/2 .6%(w/v)甘油水溶液)之微小球注射劑作爲對照,進行 1290835 如下述之操作。 1 )於大鼠經由肌肉內投與 5%(w/v)鹽酸***(HC1 ketamine)注射液及2%(w/v)鹽酸艾克司拉寧(HC1 xylazine) 注射液之混合物(7 : 1 ) lnil/kg將大鼠全身麻醉,對兩眼點 藥 0.5%(w/v)卓皮卡麥(tropicamide)/0.5%(w/v)鹽酸脫氫 腎上腺素(HC1 phenylephrine)眼藥水使之散瞳後,以氪雷 射光凝固裝置進行光凝固。光凝固係將焦點對準於網脈深 層並避開粗的網膜血管,每1眼於8處散布狀地實施(凝固 條件:點大小100 μ m,出力1 OOmW,凝固時間0 · 1秒)。光 凝固後,進行眼底攝影,確認雷射照射部位。 2) 光凝固後緊接著使用裝有30G針之微針筒,於大鼠 上部結膜下每一眼投與5 0 // 1含有β -美沙松之微小球注射 劑。對照組是於上部結膜下每一眼投與50 // 1僅含有溶劑 (0.4%(w/v)聚山梨酸酯 80/2.6%(w/v)甘油水溶液)之微小 球注射劑。 3) 光凝固14日及28日後,從尾靜脈注入10%(w/v)螢 光素水溶液0 . 1 m 1,然後進行螢光眼底攝影。以螢光眼底 攝影不能看到螢光漏出點者判定爲陰性,可看到螢光漏出 點者爲陽性。依照下述計算式,從相較於雷射照射8處的 點爲陽性點之比例,算出血管新生表現率(% )。再者,顯示 太過輕度螢光者以發現2點爲陽性1計數。 新生血管表現率(%) = (螢光漏出點數/雷射照射點數U100 所得結果以平均値±標準誤差表示。統計分析是使用 Student’s t檢定。具統計意義爲兩側5%。 - 14- 1290835 含有β -美沙松之微小球的脈絡膜血管新生抑制效果示於 表2。光凝固I4日後之對照組的血管新生表現率爲60. 9土 4.4%,含有美沙松之微小球的血管新生表現率爲12. 5 土 2 . 4%,顯示具統計意義之脈絡膜血管新生抑制作用。再者 ,光凝固28日後之對照組的血管新生表現率爲73 · 4± 6 · 0% ,含有β _美沙松之微小球的血管新生表現率爲1 2 · 5 ± 2 · 4% ,顯示具統計意義之脈絡膜血管新生抑制作用。根據以上 結果淸楚明白,經由結膜下投與含有β -美沙松之微小球, 即使在1 4日及28日後仍顯示脈絡膜血管新生抑制作用。 表2含有β-美沙松之微小球之血管新生表現率(%) 對照組 微小球組 14曰後 60.9± 4.4 12.5± 2.4 28日後 73.4± 6.0 12.5± 2.4 (表中各組之血管新生表現率以8眼的平均値±標準誤差 表示) 產業上之可利用件 藉由本發明可提供結膜下投與之後眼部之優良藥物輸送 系統。 )圖式之簡蜇説明:無 - 15 -
Claims (1)
- 年月日修(更)正本 96· 8. - t]_ 第9210365ΤΪ「微粒結膜下投與藥物輸送系統」專利申請案 (2007年δ月1曰修正) 拾、.申請專利範圍. 1 · 一種藥物輸送系統’其係於結膜下投與含有藥物之微粒 子之後眼部之藥物輸送系統,該微粒子的粒子徑爲 200nm〜1 5 0 μηι 〇 2 · —種結膜下注射劑,其係具有含藥物之微粒子之結膜下 注射劑,該微粒子的粒子徑爲2 0 0 n m〜1 5 0 μ m,且可使藥 物移行於後眼部。 3 ·如申請專利範圍第1項之藥物輸送系統,其中微粒子的 粒子徑爲200nm〜75μπι。 4 ·如申請專利範圍第1項之藥物輸送系統,其中該微粒子 係由生物體分解性或生物體溶解性高分子所組成。 5 ·如申請專利範圍第1項之藥物輸送系統,其中後眼部爲 網膜、脈絡膜、視神經、玻璃狀體、或水晶體。 6 ·如申請專利範圍第1項之藥物輸送系統,其中藥物係爲 網I吴、脈絡膜、視神經、玻璃狀體、或水晶體疾病之治 療或預防用藥物。 7 ·如申請專利範圍第1項之藥物輸送系統,宜φ藥物爲抗 炎症劑’免疫抑制劑’抗病毒劑’抗癌劑,血管新生抑 制劑’抗血检劑’視神經保護劑’抗菌劑或抗真菌劑。 8·如申請專利範圍第1項之藥物輸送系統,其中微粒子是以聚 乳酸形成之微小球。 9 ·如申請專利範圍第1項之藥物輸送系統,其中藥彳勿爲β _ II、沙 1290835 松(betamethasone) 〇 1 〇.如申請專利範圍第2項之結膜下注射劑,其中微粒子的粒 子徑爲200nm〜75//m。 1 1.如申請專利範圍第2項之結膜下注射劑,其中該微粒子係 由生物體分解性或生物體溶解性高分子所組成。 1 2.如申請專利範圍第2項之結膜下注射劑,其中後眼部爲網 膜、脈絡膜、視神經、玻璃狀體、或水晶體。 1 3.如申請專利範圍第2項之結膜下注射劑,其中藥物係爲網 膜、脈絡膜、視神經、玻璃狀體、或水晶體疾病之治療或 預防用藥物。 14. 如申請專利範圍第2項之結膜下注射劑,其中藥物爲抗炎 症劑,免疫抑制劑,抗病毒劑,抗癌劑,血管新生抑制劑 ,抗血栓劑,視神經保護劑,抗菌劑或抗真菌劑。 15. 如申請專利範圍第2項之結膜下注射劑,其中微粒子是以 聚乳酸形成之微小球。 16·如申請專利範圍第2項之結膜下注射劑,其中藥物爲β-美 沙松(b e t a m e t h as ο n e) 〇
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2003
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- 2003-02-21 CN CNA038044064A patent/CN1638734A/zh active Pending
- 2003-02-21 PT PT03705377T patent/PT1484054E/pt unknown
- 2003-02-21 SI SI200332201T patent/SI1484054T1/sl unknown
- 2003-02-21 DK DK03705377.4T patent/DK1484054T3/da active
- 2003-02-21 US US10/505,393 patent/US20050089545A1/en not_active Abandoned
- 2003-02-21 KR KR1020107019620A patent/KR20100102749A/ko not_active Application Discontinuation
- 2003-02-21 AU AU2003211238A patent/AU2003211238A1/en not_active Abandoned
- 2003-02-21 EP EP03705377A patent/EP1484054B1/en not_active Expired - Lifetime
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- 2003-02-21 CA CA2476935A patent/CA2476935C/en not_active Expired - Fee Related
- 2003-02-21 ES ES03705377T patent/ES2393086T3/es not_active Expired - Lifetime
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EP1484054A1 (en) | 2004-12-08 |
CA2476935C (en) | 2013-05-28 |
CY1113423T1 (el) | 2016-06-22 |
DK1484054T3 (da) | 2012-11-26 |
KR20100102749A (ko) | 2010-09-24 |
KR20040084931A (ko) | 2004-10-06 |
CA2476935A1 (en) | 2003-08-28 |
EP1484054B1 (en) | 2012-08-29 |
PT1484054E (pt) | 2012-11-28 |
US20050089545A1 (en) | 2005-04-28 |
EP1484054A4 (en) | 2007-12-12 |
ES2393086T3 (es) | 2012-12-18 |
SI1484054T1 (sl) | 2012-12-31 |
WO2003070219A1 (fr) | 2003-08-28 |
CN1638734A (zh) | 2005-07-13 |
TW200303218A (en) | 2003-09-01 |
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