200808372 九、發明說明： 【發明所屬之技術領域】 本發明有關適於輸送物質至眼、鼻及喉部之一或多個 部位之裝置。本發明尤其有關用於輸送至少一種活性劑之 $淚道塞。 相關申請案 本案主張2006年6月21曰申請之臨時申請案美國編 參號60/805,378的優先權。 、 10 15 20 【先前技術】 人類淚液係由淚腺分泌，流經眼睛表面到達一個位在 眼臉内部末端接合之處的淺池，稱為淚湖。淚液自此處經 由上下眼臉中稱為上淚點及下淚點之小開口排出。淚液自 點個別通過進人上及下淚小管，淚小管為通向淚 囊之v管狀通道。淚囊係為鼻淚管上 管將淚液排入鼻系統内。 77兀淚 活性劑因此可經由淚小管，導入鼻 部及喉部。 而輸达至鼻 酱=翁常投予眼部以治療眼部疾病及病症。習用將 厂’劑輸达至眼部之方式包括局部施用於眼目主。主 特別適於局部投藥，因為在適當地設計之下^ =目月 活性劑可穿透眼目_ 局=加之 部疾病及病症使用之活性=水平。供眼 藥路徑較不佳，因氣，一 ― 〆 "又樂，但該等投 口為經口投樂日夺，活性劑到達眼部之濃度 jjv96345.doc 5 200808372 低’無法具有所需之藥效，且其使用伴隨 全身性副作用，而注射則具有感染之風險。 *、 計ί Γ分之眼用活性劑目前皆使用眼滴劑局部輸送’此 種，雖然對某些應用有效，但卻無效率。當液‘加= if出結膜囊(介於眼睛與眼臉之間的袋狀物) 娄。士冰"JU為/皿出眼瞼邊緣流至臉頰而損 中，稀釋了藥物之濃度。之只貝^刀的滴劑排入淚點 10 【發明内容】 本發明提供可用以將活性 液中之一或兩者的淚道A。π a Α π及S及眼睛淚 提供淚if* 具體實施態樣中，本發明 係由以下部分组成：一太2 基本上由以下部分組成且 15 20 末端及延展於該兩末端之間二有艾末端、第二 内之儲存器，其中於該本體 至少-開口且含有一包含至少且係具有 一種活性劑組成及係ώ S ,丨、 / f J、基本上由至少 . 、 ’、由至父一種活性劑組成之材· e甘 中該本體係活性劑不可滲透。 m抖，且其 【實施方式】 參照圖1，淚道塞本體1〇具 器含有至少一間口 w y 、 痏存时15，此儲存 A取人& 1 13 ’且例如當含活性劑之材料1U鈐社 為t合物材料）溶解、降解時 ，川較佳 /古性剤18係經由開口 13 ljv96345.doc 6 200808372 5 10 15 20 釋出，或活性劑18係單純地自材料u擴散或釋出，視該 材=之性貝而定。活性劑通過而自該塞釋出之開口可位於 該塞本體—之第-末端（如例如圖i所示）、第二末端（如例如 圖2)或第-及第二末端兩端（如例如圖3所示）或沿著直側 ^表面。該開口較佳係位於第—及第二末端中之-或兩端 ^本發明特定具體實施祕中，例如圖3所示，該 體3〇之擴大區段32，其具有適於將淚道塞固 疋於淚小管之尺寸及形狀。 u 就活㈣m送至眼睛淚液而言，淚道塞插人淚小管 淚液：：性：,釋入眼睛淚液中。參照圖4，就輸送至 而…亥淚道塞之本體40上提供領部44，且當該 :^入淚小官時，領部44留置於淚點之外側。就將‘ 性劑輸送至鼻淚管中而士 $…/ 就將活 淚小管中且°，次迢基係插入（較佳係深入地） &中且该活性劑係釋入鼻淚管中。 本發明所使用之術語「淚道塞」係 於經由下或上淚點插人眼睛之下或上淚小管的=形狀適 本發明所使用之術語「活性 可 或預防病症或疾痣夕田、y 係表不可治療、抑制 及營養劑。較佳活性劑；1:不：：包括而不限於藥劑 之-或多種的病症或:丨:一制或預防眼、鼻及喉令 示-===:至少!分水溶性之材料」係表 挪之溶解的溶解度水料在暴路於水性環境時產生可偵 本發明所使用之辭句「生物可降解之材料」係表示一 jjv96345.doc 5 10 15 20 200808372 ，料在暴露於-般存在於哺乳财之生物活性物 生可偵測程度之降解。 、守產 本發明所使用之辭句「不溶 料在暴露於水時未達實質程度地溶解。表不一材 一 #、本毛月所使用之辭句「不可生物降解之材料J係表示 斗if;於一般存在於哺乳類中之 未達實質程度之降解。 ^貝卜# 示僅句「活性劑不可滲透之本體」係表 卢貝貝里之活性劑可通過的本體。 本發明所使用之術語「聚合 種類型之聚合物製得的材料，m由-或多 在例如當聚合物溶解或降至一種活性劑且 時，或當使用將活性劑附接^4制自該聚合物擴散 著自該材料裂解而in聚合物上之前藥並隨之藉 啊了叶农解而釋出時，釋出活性劑。 本發明所使用之術語「開口」係表示 該活性劑可通過之尺寸及形狀的開：:較；係^ 该活性劑可通經該開口。該開σ， ^係僅有 柵之孔或其可未經覆蓋為覆有膜、篩、 孔性、可决读主洛未膜師或柵可為多孔性、半多 太^ 物可降解中之—或多種。 本赉明所使用之「可撓性材料」一、 且不官該材料接觸何種物體皆服貼於其：。料非剛性 本發明所使用之辭句「該儲存哭2二士触 表示該儲存器實質上為整個該本體係相接」係 時’領部可附接於該本體，但如；^ ^本體相接 外為磙本體之一部分〇 ijv96345.doc 8 200808372 y本發明所使用之辭句「重新裝填活性劑」係表示將任 何可债測量之活性劑添加於該淚道塞之儲存器。 ，fx明/函蓋多種用以將活性劑輸送至眼睛淚液或鼻 官中之兩者之淚道塞。該淚道塞較佳係插入下淚小 5 &上淚小官或下及上淚小管兩者。若使用該淚道塞將活 ί·生劑輪运至眼睛淚液，則該淚道塞較佳係於本體之一末端 ^有領部。該領部係為該淚道塞之—部分，自本體之一末 籲端=外，向延伸，使得在該淚道塞插入淚小管後，該領部 至1部分延伸超出該淚點，而位於其外側。一般，該領 10部係延伸超出該塞體約0.2至約1毫米。該淚道塞不具有 領：之部分插入下淚點或上淚點中之一。參考目6，擴大 區1又=2及本體6〇插入一淚點，該領部64放置抵住淚點 之外部，保持該淚道塞不會滑下進入淚小管，因而保持該 淚運塞與眼睛淚液之間的接觸。 ^ α若"亥淚道基係用以將活性劑輸送至鼻淚管，則該淚道 ⑩基可不具有領部，使其可在一或兩淚小管内插至足夠深 度’ U使活性劑釋入淚囊内。圖1至3中描述可用以將活 性劑輸达至鼻淚管之淚道塞的實施例。 數$眾多之本發明淚道塞各具有各種特色及優點。例 2〇 ^ ’特定淚道塞具有一本體，此本體具第一末端、第二末 端及延展於該兩末端之間的侧向表面。該側向表面較佳具 f1貝圓形之外徑，因此，本體較佳係為圓柱形。特定淚 ^基之一部分侧向表面具有大於其餘侧向表面之外徑的外 ^。參考圖2 ’該側向表面之擴大部分22將該淚道塞穩定 9 iiv96345.doc 200808372 或固定於淚小管中。擴大部分可 存在於該側向表面之任一部分，：寸或形狀’且可 該淚道塞穩定於淚小管卜較佳了 至少部分將 5 10 基之末&敍部分可簡便地㈣ ^遏 的形狀，如圖1所示，可具有非錐狀、末端為角形 或可具有一末端為圓點之錐形’如圖1〇所：/體’ 可認知許多形狀中之任一者皆可能。所不。-般技術者 本發明淚道塞之本體可採用二何形狀及 較佳係為長圓柱形。該本體為約〇 8至約乎^體 隹約⑽2.5毫米長度。該本體 二長度’較 較佳0.3至約1.5毫米。 〇 J W至約3’ 祕之本體可完全或部分透明或不透明。該本 2包括著色劑或顏料，使得在將該塞置】 易看得出來。 τ了灵谷 15 ㈣這塞之本體可*任何適當之生物相容物製得，句 籲括（不限於）相，石夕酮摻合物，石夕明共聚物，諸如例如聚 羥基乙基甲基丙烯酸酯（，，ρΗΕΜΑ”）之親水性單體，聚乙二 醇，聚乙烯基吼洛咬酮及甘油，及石夕嗣水凝膠聚合物，^ 如例如美國專利編號 5,962,548、6,020,445、6,099,852、 2〇 6:367,929及6,822,016中所述者，該等專利整體以引用方 式併入本文。其他適當之生物相容性材料係包括例如聚胺 基甲酸乙酯、聚曱基丙烯酸甲酯、聚（乙二醇）；聚（氧化乙 缔）’ ♦(丙一醇）’ ♦(乙缔醇），聚（曱基丙婦酸經基乙醋）； 聚（乙烯基吡咯啶酮）(，，PVP");聚丙烯酸；聚（乙基噚唑啡）； ijv96345.doc 10 200808372 ♦(一曱基丙烯醯胺）；磷脂，諸如例如磷醯膽鹼衍生物； ,½基甜菜鹼；丙烯酸酯，多醣及醣類，諸如例如糖醛酸、 葡聚糖、經基乙基纖維素、羥基丙基纖維素、結冷膠、瓜 =膠:硫酸乙醯肝素、硫酸軟骨素、肝素及藻酸鹽；蛋白 5 =，諸如例如明膠、膠原、白蛋白及卵蛋白；聚胺基酸； 氟^ χΚ合物，諸如例如，聚四氟乙烯（“pTFE”）、聚偏二氟 乙烯（PVDF )及鐵弗龍；聚丙婦；聚乙烯；尼龍；及乙婦 _ 乙烯醇（“EVA，，）。 該基主體之表面可完全或部分經塗覆。該塗層可提供 10以下一或多項性質：幫助插入之潤滑性、改善組織相容性 之黏膜-黏^性及幫助該塞於淚點中保持穩定之結構。適當 ，塗層的貫例包括而不限於明膠、膠原、甲基丙烯酸羥乙 ^ pVP、PEG、肝素、硫酸軟骨素、糖醛酸、合成及天然 ，白質及多醣、硫肽體（thiomers)、聚丙烯酸及脫乙醯基殼 15多糖之硫醇化衍生物、聚丙烯酸、羧甲基纖維素及諸如此 馨類者及其組合物。 ^，本發明淚道塞之特定具體實施態樣具有由可撓性材 1製得之本體，該材料服貼成其所接觸之形狀。該塞可視 情況具有由較該本體不可撓之材料或亦服貼成其所^觸之 20 =狀的材料所形成的領部。當兼具有可撓性本體及較低可 撓性領部之淚道塞插入淚小管時，該領部留置於該淚點之 外部且該淚道塞之本體服貼成淚小管之形狀。該淚道塞之 儲存器及本體較佳係相接。即，該淚道塞之儲存器較 構成整體本體，除該領部外。 π ijv96345.doc 200808372 使用可撓性本體及領部中之4兩者的具體實施態 ，中，该可撓性本體及可撓性領部可由以下材料製得：包 括而不限於尼龍、聚對苯二甲酸乙二醋（‘^五丁”卜聚對苯二 5 10 15 20200808372 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a device suitable for transporting a substance to one or more parts of the eyes, nose and throat. The invention is particularly directed to a lacrimal plug for delivering at least one active agent. Related Applications This case claims the priority of US Provision No. 60/805,378 for the provisional application filed on June 21, 2006. 10 15 20 [Prior Art] Human tears are secreted by the lacrimal glands and flow through the surface of the eye to a shallow pool at the end of the inner face of the eye, called the tear lake. From here, the tears are discharged through a small opening called the upper punctum and the lower punctum in the upper and lower eye faces. The tears are individually passed through the upper and lower lacrimal canal, and the lacrimal canal is a v-tubular passage leading to the lacrimal sac. The lacrimal sac is the nasolacrimal duct that drains the tears into the nasal system. 77 tears The active agent can therefore be introduced into the nose and throat via the canaliculus. And the loss to the nasal sauce = Weng often invested in the eye to treat eye diseases and conditions. The manner in which the agent's agent is delivered to the eye includes topical application to the eye. The main application is particularly suitable for topical administration because, under proper design, the active agent can penetrate the eyesight _ bureau = plus the activity of the disease and condition used = level. The path for the eye medicine is poor, because of the gas, one - 〆 " and music, but the mouth is for oral injection, the concentration of the active agent to the eye jjv96345.doc 5 200808372 low 'can not have the required It is effective and its use is accompanied by systemic side effects, while injections are at risk of infection. *, ί 之 之 眼 活性 活性 活性 活性 目前 目前 活性 活性 活性 活性 活性 活性 活性 活性 活性 活性 活性 活性 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部When the liquid ‘add=if the conjunctival sac (a bag between the eye and the face) 娄. Shi Bing"JU is the edge of the eyelid that flows to the cheek and is damaged, diluting the concentration of the drug. The drops of the scallops are discharged into the punctum. 10 SUMMARY OF THE INVENTION The present invention provides a lacrimal passage A which can be used to treat one or both of the active liquids. π a Α π and S and tears of the eyes provide tears if* In a specific embodiment, the present invention consists of the following components: one too 2 consists essentially of the following parts and 15 20 ends and extends between the two ends An end-end, second inner reservoir, wherein the body is at least-opened and contains one comprising at least one having an active agent composition and a system S, 丨, /f J, substantially from at least . A material composed of a parent active agent. The active agent of the system is impermeable. M-shake, and [Embodiment] Referring to Figure 1, the lacrimal plug body 1 device contains at least one port wy, at the time of storage 15, this storage A takes the person & 1 13 ' and for example when the active agent-containing material When the 1U 钤 为 is a t-material, when dissolved or degraded, the 较佳 较佳 古 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 Released, depending on the material = the nature of the shell. The opening through which the active agent passes may be located at the first end of the plug body (as shown, for example, in Figure i), at the second end (as shown, for example, in Figure 2), or at both ends of the first and second ends (e.g. For example, as shown in Figure 3) or along the straight side surface. Preferably, the opening is located in the - or both ends of the first and second ends. In particular embodiments of the invention, such as shown in Figure 3, the enlarged section 32 of the body has a suitable lacrimal passage. The size and shape of the lacrimal canal. u In terms of live (four) m sent to the eye tears, tear duct plug into the tear duct tears:: sex:, released into the tears of the eyes. Referring to Fig. 4, a collar 44 is provided on the body 40 that is delivered to the lacrimal plug, and when the tear is small, the collar 44 is left on the outer side of the punctum. The agent is delivered to the nasolacrimal duct and the gentleman's tube is inserted into the tracheal canal and the sputum is inserted into the sinus tube. in. The term "diaphragmatic sputum" as used in the present invention is used to insert the lower or upper punctum into the lower or upper lacrimal canal. The shape is suitable for use in the present invention. "Active or preventable condition or disease, y, y The table is not treatable, inhibiting and nourishing agent. Preferred active agent; 1: No:: including but not limited to the pharmacy - or a variety of conditions or: 丨: one system or prevention of eye, nose and throat instructions -=== : At least! The water-soluble material" is the solubility of the water dissolved in the water-borne environment. The phrase "biodegradable material" used in the invention is represented by a jjv96345.doc 5 10 15 20 200808372, is expected to be exposed to the degradation of bioactive substances that are present in the breastfeeding industry. The words used in the present invention, "The insoluble material does not dissolve to a substantial extent when exposed to water. The table is not one material, the phrase used in this month," the non-biodegradable material J is a bucket. If; does not reach a substantial degree of degradation in mammals. ^Beb # Show only the phrase "active body impermeable body" is the body through which Lubeberg's active agent can pass. As used herein, the term "polymerized type of polymer made of material, m is - or more, for example, when the polymer is dissolved or reduced to an active agent, or when the active agent is attached to the device. The polymer is diffused from the material and the prodrug is released on the polymer and then released by the leaf agronomic solution, and the active agent is released. The term "opening" as used in the present invention means that the active agent can be used. Through the size and shape of the opening:: comparison; the active agent can pass through the opening. The opening σ, ^ is only a hole in the grid or it can be uncovered to be covered with a film, sieve, pore, can be read as the main film or the grid can be porous, more than half of the material can be degraded - or a variety. The "flexible material" used by this specification is not subject to any object to which the material is in contact with: Material non-rigid The phrase used in the present invention "the storage cry 2 two-speaker indicates that the storage is substantially connected to the entire system" is that the collar can be attached to the body, but such as; ^ ^ ontology The term "refilling the active agent" as used in the present invention means adding any treasable active agent to the reservoir of the lacrimal plug. , fx Ming / letter cover a variety of lacrimal plugs used to deliver the active agent to the tears or nasal organs of the eye. Preferably, the lacrimal duct plug is inserted into the lower tears 5 & the upper tear or the lower and upper tear ducts. If the lacrimal plug is used to transport the live agent to the tears of the eye, the lacrimal plug is preferably attached to one end of the body and has a collar. The collar is a portion of the lacrimal duct plug that extends from one end of the body to the outer end, such that after the lacrimal plug is inserted into the lacrimal canal, the collar to the portion extends beyond the punctum, and Located on the outside. Typically, the collar 10 extends beyond the plug body by from about 0.2 to about 1 mm. The lacrimal plug does not have a collar: one of the inserts is inserted into one of the lower or upper punctum. Referring to Item 6, the enlarged area 1 is again = 2 and the body 6 is inserted into a punctum, and the collar 64 is placed against the outside of the punctum to keep the lacrimal plug from slipping into the punctum, thereby maintaining the tear plug Contact with tears in the eyes. ^ α If the "Hail Channel base is used to deliver the active agent to the nasolacrimal duct, the lacrimal passage 10 may have no collar so that it can be inserted into one or both of the lacrimal canal to a sufficient depth 'U to activate The agent is released into the lacrimal sac. An embodiment of a lacrimal plug that can be used to deliver an active agent to the nasolacrimal duct is depicted in Figures 1-3. The number of thousands of tear duct plugs of the present invention each has various features and advantages. Example 2 〇 ^ ' A particular lacrimal plug has a body having a first end, a second end, and a lateral surface extending between the ends. The lateral surface preferably has an outer diameter of the circular shape of the f1 shell, and therefore, the body is preferably cylindrical. The lateral surface of one of the specific tear bases has an outer diameter greater than the outer diameter of the remaining lateral surfaces. Referring to Figure 2, the enlarged portion 22 of the lateral surface stabilizes the lacrimal plug 9 iiv96345.doc 200808372 or is fixed in the canaliculus. The enlarged portion may be present on any portion of the lateral surface: inch or shape 'and the lacrimal plug may be stabilized in the lacrimal tube. Preferably, at least a portion of the 5 10 base is at the end of the <RTI ID=0.0> The shape, as shown in Fig. 1, may have a non-tapered shape, the end is angular or may have a tapered end with a dot as shown in Fig. 1 : / body 'can recognize that any of a number of shapes may be . No. The general body of the lacrimal plug of the present invention can be formed into a long cylindrical shape. The body has a length of about 至 8 to about 体 (10) 2.5 mm. The body has a length ' preferably from 0.3 to about 1.5 mm. 〇 J W to about 3' The body of the secret can be completely or partially transparent or opaque. The present 2 includes a colorant or pigment so that the plug can be easily seen. τ了灵谷15 (4) The body of the plug can be made of any suitable biocompatible substance, including (not limited to) phase, the mixture of linaloic acid, and the copolymer of Shi Ximing, such as, for example, polyhydroxyethyl Hydrophilic monomers of methacrylate (,, ρΗΕΜΑ)), polyethylene glycol, polyvinyl ketone and glycerin, and agglomerate hydrogel polymers, such as, for example, U.S. Patent Nos. 5,962,548, 6,020,445 , 6,099, 852, 2, 6: 367, 929, and 6, 822, 016, which are incorporated herein by reference in their entirety. Other suitable biocompatible materials include, for example, polyurethane, polymethyl methacrylate , poly(ethylene glycol); poly(oxyethylene)' ♦ (propanol)' ♦ (glycol), poly(mercapto-butanoic acid by ethyl vinegar); poly(vinylpyrrolidone) (,, PVP"); polyacrylic acid; poly(ethyloxazolyl); ijv96345.doc 10 200808372 ♦ (monodecyl acrylamide); phospholipids such as, for example, phosphonyl choline derivatives; Acrylates, polysaccharides and sugars such as, for example, uronic acid, dextran, thiol Ethyl cellulose, hydroxypropyl cellulose, gellan gum, melon = gum: heparin sulfate, chondroitin sulfate, heparin and alginate; protein 5 = such as, for example, gelatin, collagen, albumin and egg protein; a polyamino acid; a fluorine compound such as, for example, polytetrafluoroethylene ("pTFE"), polyvinylidene fluoride (PVDF), and Teflon; polypropylene; polyethylene; nylon; and women's ethylene Alcohol ("EVA,,"). The surface of the base body may be fully or partially coated. The coating provides one or more of the following properties: mucosal-adhesive properties that aid in the lubricity of the insertion, improve tissue compatibility, and structures that help the plug remain stable in the punctum. Suitably, examples of coatings include, without limitation, gelatin, collagen, hydroxyethyl pVP, PEG, heparin, chondroitin sulfate, uronic acid, synthetic and natural, white matter and polysaccharides, thiomers, A thiolated derivative of a polyacrylic acid and a deacetylated ketone 15 polysaccharide, polyacrylic acid, carboxymethylcellulose, and the like, and combinations thereof. ^, a particular embodiment of the punctal plug of the present invention has a body made of a flexible material 1 that conforms to the shape it is in contact with. The plug may optionally have a collar formed of a material that is inflexible to the body or a material that is also conformed to the shape of the contact. When a lacrimal plug having a flexible body and a lower flexible collar is inserted into the lacrimal canal, the collar is left outside the punctum and the body of the lacrimal plug is shaped into a canaliculus. The reservoir of the lacrimal plug is preferably connected to the body. That is, the reservoir of the lacrimal plug is formed as a unitary body except for the collar. π ijv96345.doc 200808372 In a specific embodiment using both of a flexible body and a collar, the flexible body and the flexible collar can be made of materials including, but not limited to, nylon, poly pairs Ethylene phthalate ('^五丁" Bu poly-p-phenylene 5 10 15 20
甲酸丁二酉旨（“PBT，，）、聚乙稀、聚胺基甲酸乙輯、石夕嗣了 P^TFE^VDF及聚烯烴。由尼龍、pET、pBT、聚乙烯pvDF 〆來婦經製仔之淚道塞—般係使用例如而不限於擠塑、注 =塑Λ熱成形^。由膠乳、㈣基甲酸以旨、㈣或 衣侍之淚遏基一般係使用溶液鑄造法製造。 哭人、月淚，基含有位於該本體内之儲存器，且該儲存 以纺-二：11J t材料。該材料可為任何與該活性劑或欲 ί:达之用劑相容且可依所需方式(例如溶解或降解 劑自該材料釋出)釋出該活性劑之材料。許多 Γ活性劑材料，包括(不限於)聚合物材料(天 ，非聚合物材料包括(不限於)玻璃及黏土， 及諸i機材料包括(不限於)多孔性陶瓷、脂質、蠟 者::;，7_該含活性劑之材料係為 敕辦φ十七a /、 夕一種活性劑係配置於其中、分散於 該儲广1 =於其中。該本體較佳係活性劑不可滲透，且 μ: 有至少—開口，該活性劑係經由該開口釋出。 厂如图4 1 /、有> 或夕個開口，與位於該本體之第一末端 者^圖6不）'-第二末端（如圖5所示）、第一及第二末端兩 本發明'牲〜所不）或位於该本體之其他位置的儲存器連通。 於：體太：具體實施態樣中，當該淚道塞插入淚小管使位 '—鳊之開口朝向眼睛時，該活性劑係釋入眼睛淚液 12 jjv96345.doc 200808372 5 10 15 20 中。或右該塞本體末端之開口朝向鼻淚管，則該活性劑係 =入鼻淚管中。其中該塞係使位於本體末端之開口朝向眼 睛且位於本體末端之另一開口朝向鼻淚管的具體實施態樣 中，該活性劑係同時釋入眼睛淚及鼻淚管兩者中。就具有 領部之淚道塞而言’該淚道塞之開口較佳係位於該領部 2，較佳係為領部之中心部分。當該淚道塞插入淚小管中 寸該開口朝向眼睛，且該活性劑係釋入眼睛淚液中。 一該開口之尺寸係約i奈米至約2.5毫米且較佳約〇 15 氅米至約0.8毫米。不使用位於單一位置之大型開口，而 可使用多個小型開口。 用W造可用於本發明之淚道塞的方法係眾所周 ^。:趙-般係藉注射模塑、洗鑄模塑、轉模或諸如此類 者而衣付。該儲存器較佳係於製造該塞之後 活性劑及含活性劑之材料中之—或兩者。此外:—以= 賦形劑可與單獨或組合有聚合物材料之活性劑結合; 視所選擇之含活性劑材料而定，該活性劑可幾手立 出該：Γ出或該活性劑可於所需時間週期内連續地釋 士1，可使用由一或多種至少部分溶於水之聚合物所 組成的聚合物材料。者兮取人私s 〜心來σ物所 之水性環产下斤，^田°;承&物材料暴露於淚小管或淚液 萝俨取二二：’較佳係溶解且在溶解時釋出該活性劑。 解速率成比例料ίI或多種聚合物的水溶性係直接與其溶 :ΐ(乙部分溶於水之適當聚合物包括而不限 聚地化乙婦）；聚（丙二醇）；聚（乙婦醇）； 丙_基乙醋”聚(乙烯基吼嘻㈣)；聚丙稀 ijv96345.doc 13 200808372 酸；聚（乙基噚唑唯）；聚（二甲基丙烯醯胺）；磷脂，諸如例 如磷醯膽鹼衍生物；聚磺基甜菜鹼；多醣及醣類，包括而 不限於玻糖醛酸、葡聚糖、羥基乙基纖維素、羥基丙基纖 維素、結冷膠、瓜爾膠、硫酸乙醢肝素、硫酸軟骨素、肝 5素及澡酸鹽；蛋白質諸如例如明膠、膠原、白蛋白及卵蛋 白；及聚胺基酸。此例示中之聚合物材料一般可與疏水性 聚合物及單體中之一或兩者共聚或摻合。 10 15 20 可使用備擇之非聚合物材料包括而不限於脂質、蠟或 無機材料。適當之非聚合物材料係包括而不限於羊毛脂、 石蠟、山梨酸酯、卵磷脂、維生素A、D及E、甘油、山 梨糖醇、甘露糖醇、硬脂酸酯、脂肪酸、黃體素、玉米普 質、牛磺酸、穀胱甘肽及諸如此類者。 ” 該含活性劑材料可為 、、v %少徑玍物可降解材 料，該材料在暴露於例如一般存在於哺乳類中之生物活性 物質時部分或完全化學降解。該生物可降解材料較佳可於 體内條件下水解。生物降解可發生得較溶解緩慢，因此若 需要較緩慢、較長時間地釋出該活性劑，則該材料可由一 或多種生物可降解聚合物組成。 適當之生物可降解聚合物包括而不限於乙交酯、丙交 酯、=己内酯及其他羥基酸之聚合物及寡聚物，^其他^ 生無毒或在體内為正常代謝物之物質的生物可降解取入 物。較佳聚（α-經基酸）有聚（乙醇酸）、聚（2_ 水二 I)水妷酸酯、聚（酸酐）、聚（原酯）、聚（磷畊）（poly ljv96345.doc 14 10 15 20 .200808372 (咖sPhazines ))及聚（鱗酯）。聚内酿包括而不限於 =内_)、聚（δ-己内酯）、聚（§•戊内酯）及聚(γ_丁内醋）亦可 二=脫乙醯殼多糖、藻酸鹽、膠原及明膠。本發明特 ;性且生物可降解聚合物的混合物。 h種可洛 較佳具體實施態樣中，該含活性劑之材料係 =:活性劑組合形成-或多條纖維或纖：狀 2- 4:;欠：：質上係為該儲存器之維度或小於該維度， 該儲=體中之… U 錄構可具有適於插入該開口 毫米直徑。長度及。·。5至約2 度較佳係使得該纖維:切 使用於配戴者之淚點中時保留於該儲存4因：在;亥f 或::_之形狀儲= 之特徵’包括(不限於二::二::保二於該，存器内部 此類者的表面。 /、 s χ彳、、文、糙度或諸如 該纖^鎿造。°另_備^^用劑之纖維成形且該塞係環繞 式下投加於該塞儲存器:击該纖維及活性劑可於溶體形 可於溶液形式下導入取=之固化。再另—擇備例中， 體、預聚物及適於經由性劑。該溶液可含有單 之-或多種來交聯者：先、乳化還原及熱自由基聚合t 心另一備擇例中，該纖維可在插入該 jjv96345.doc 15 .200808372 塞中之前或之後單純地浸泡於該活性劑中。 該纖維或纖維狀結構較佳係由聚合物材料且成，更佳 為聚合物材料分子量介於約10，_及8〇 〇〇〇〇之間之聚己 内醋（更佳為聚（ε_己内酯）)及乙烯乙酸乙埽酿。以聚合物材 :„用約0至約100重量百分比聚己内醋及約1〇〇 、’、〇重里百刀比乙烯乙酸乙烯酯，較佳係各約%之聚 己内醋及乙晞乙酸乙_。所使用之聚合 10 15 20 ==且該活性劑較佳係高於约 二=者應明瞭在調配中，進行調配之條 定活性劑不會因製程而降解。聚己内醋及 =乙i乙㈣較佳係與所需之活性劑或用劑組合，微量 ==TQmp_deda隨之擠塑成纖維。該纖維隨 成所為長度並經由-或多個該塞開σ插人該儲存器内。 活^丨於本發明塞中之用量係視所選擇之活性劑或 用H經該淚道塞輪送之劑量、期望之釋出 活性劑與含活性劑之材料的 * = 二=量可達到期望之治療、抑 、又了使用、·、勺0.05至約8，_微克之活性劑的量。 ，定應用之特定淚道塞較佳係二二 小”時重新裝填材料，而其他淚道塞-般係=移戾 ijv96345.doc 16 200808372 :力:=料，之後將淚道塞重新插入淚小管中。 或多生，結合^ 之材料。例如可降解，但該活性劑可自彼擴散 一或多種不、、容於^ ί4係為聚合物材料’則該材料可由 此類聚合物材料;，包：f:可降解之聚合物組成。適當之 聚（甲其兩、κ 、,來烯）、聚（丙二醇）、聚（乙烯醇）、 聚(乙i十坐:):::1)、聚(乙烯基°比咯啶酮)、聚丙烯酸、 10 15 20 水性聚合物及i體C烯醯胺)。此等聚合物可與疏 认v μ -中之一或兩種共聚合或摻合。其他不溶 =!生物可降解之聚合物材料係包括而不限於石夕酮; 單=I物；㈣共聚物，包括（不限於）ρηεμα之親水性 :體’ *乙二_ ’聚乙縣財㈣及甘油，及㈣水凝 膠聚合物’諸如例如美國專利編號5,962,548、6 _ 445、 Μ99,852、6,367,929及6,822,_中所述者，該等專利整 體乂引用方式併入本文，破脂，包括（不限於）鱗醯膽驗衍 生物j聚縣甜菜鹼；多醣及醣類，包括（不限於）玻糖搭 酸、葡聚糖、羥基乙基纖維素、羥基丙基纖維素、結冷膠、 瓜爾膠、硫酸乙醯肝素、硫酸軟骨素及肝素；蛋白質，包 括（不限於）白蛋白及卵蛋白；聚胺基酸；氟化聚合物，包 括（不限於）PTFE、PVDF及鐵弗龍；聚丙烯；聚乙烯；尼 龍；及EVA。或不溶於水或非生物可降解或兩者之適當之 聚合物的其他實例係包括而不限於石夕g同、聚胺基甲酸酯、 氰基丙婦酸酯及聚丙烯酸。 jjv96345.doc 17 200808372 本發明所述之淚道塞可用以輸送各種活性劑，以進行 多種疾病及病況之治療、抑制及預防中的一或多種。每個 淚道塞各可用以輸送至少一種活性劑且可用以輸送不同類 型之活性劑。例如該淚道塞可用以輸送氮箪斯汀鹽酸盘 5 (azelastine HC1)、伊馬斯汀二反丁浠二酸鹽（emadastine difumerate)、伊匹斯、;丁 鹽酸鹽（epinastine HC1)、酮替吩反 丁稀二酸鹽（ketotifen fumerate)、左卡巴斯汀鹽酸鹽 馨（levocabastine HC1)、奥洛他定鹽酸鹽（olopatadine HC1)、 非尼拉敏順丁烯二酸鹽（pheniramine maleate)及構酸安他 ίο 哇口林（antazoline phosphate)，以進行過敏症治療、抑制及預 防中之一或多種。該淚道塞可用以輸送肥大細胞安定劑， 諸如例如色甘酸納（cromolyn sodium)、氯丁三醇洛度沙胺 (lodoxamide tromethamine)、納多羅米鈉（nedocromil sodium) 及貝米洛斯特鉀（permirolast potassium)。 15 該塞裝填活性劑之後，該塞係藉任何簡便方法滅菌， φ 包括而不限於氧化乙烯、高壓加熱、照光及諸如此類者及 其組合。較佳係經由7輻射或使用氧化乙稀進行滅菌。 該淚道塞可用以輸送散瞳劑及睫狀肌麻醉劑，包括（不 限於）阿托品琉酸鹽（atropine sulfate)、後馬托品 2〇 (homatropine)、東良菪驗氳溴酸鹽（8(：〇0〇1&11^116 1161〇、環 戊通鹽酸鹽（cyclopentolate HC1)、托 σ比卡胺（tropicamide)及 苯福明鹽酸鹽（phenylephrine HC1)。該淚道塞可用以輸送眼 用染料，包括而不限於玫瑰紅（rose begal)、西沙胺綠 (sissamine green)、散氰綠（indocyanine green)、妈黃綠素 18 jjv96345.doc 200808372 (fluorexon)及螢光素。 該淚道塞可用以輸送皮質類固醇，包括而不限於地塞 米松（dexamethasone)構酸鈉、地塞米松（dexamethasone)、 氟米龍（fluoTomethalone)、氟米龍乙酸鹽、依碳酸氯替潑諾 5 (loteprednol etabonate)、培尼松龍（prednisolone)乙酸鹽、 培尼松龍（prednisolone)填酸鈉、曱經松（medrysone)、瑞美 松龍（rimexolone)及乙酸氟輕鬆（fluocinolone acetonide)。該 φ 淚道塞可用以輸送非類固醇消炎劑，包括而不限於氟比洛 吩納（flurbiprofen sodium)、舒洛吩（suprofen)、雙氣吩酸納 ίο (diclofenac sodium)、酮洛酸氯 丁三醇（ketorolac tromethamine)、環孢菌素（cyclosporine)、曱嗓呤酸雷帕黴 素（rapamycin methotrexate)、石荒唾嗓吟（azathioprine)及溴麥 角隱亭（bromocriptine)。 該淚道塞可用以輸送抗感染劑，諸如例如且不限於妥 15 布黴素（tobramycin)、莫西沙星（moxifloxacin)、氧氟沙星 _ (ofloxacin)、加替沙星（gatifloxacin)、環丙沙星 (ciprofloxacin)、正大黴素（gentamicin)、磺胺異口号唾酮二乙 醇胺鹽（sulfisoxazolone diolamine)、石黃基乙醯胺鈉（sodium sulfacetamide)、萬古黴素（vancomycin)、多黏菌素 B 2〇 (polymyxin B)、阿米康絲菌素（amikacin)、氟旅酸 (norfloxacin)、左旋氧氣沙星（levofloxacin)、石黃胺異4峻二 乙醇胺鹽（sulfisoxazole diolamine)、石黃基乙酸胺鈉四環素、 去氧經四環素（doxycycline)、雙氯西林（dicloxacillin)、頭 孢菌素（cephalexin)、經胺苄青黴素/克拉維酸（clavulante)、 19 jjv96345.doc 200808372 頭孢曲松（ceftriaxone)、頭孢克肟（cefixime)、紅黴素、氧氟 沙星（ofloxacin)、阿奇黴素（azithromycin)、健大黴素 (gentamycin)、磺胺嘧啶（suifadiazine)及乙胺嘧啶 (pyrimethamine) 〇 5 該淚道塞可用以輸送用於青光眼之治療、抑制及預防 中之一或多種的用劑，包括（不限於）腎上腺素，包括例如： 雙特戊醯腎上腺素（dipivefrin) ; α-2腎上腺素受體，包括例 • 如阿樸洛尼啶（aproclonidine)及溴莫尼啶（brimonidine) ; β-阻斷劑’包括例如貝他索洛（betaxolol)、. 4酮心安 ίο (carteolol)、左布諾洛爾（levobunolol)、三甲苯心安 (metipranolol)及噻馬心安（timolol);直接縮瞳劑，包括例如 卡巴膽鹼（carbachol)及毛果芸香鹼；膽鹼酯酶抑制劑，包 括例如毒扁豆驗及有乙氧鱗醯硫膽驗（echothiophate);碳酸 酐酶抑制劑，包括例如乙酸醋胺（acetazolamide)、伯因唾酿 15 胺（brinzolamide)、朵嗤醯胺（dorzolamide)及美他峻醯胺 _ (methazolamide);前列腺素（prostoglandins)及前列醢胺 (prostamides)，包括例如拉坦前列素（latanoprost)、比馬前 列素（bimatoprost)、爾唯前列素（uravoprost)及烏諾前列酮 西多福韋（unoprostone cidofovir)。 20 該淚道塞可用以輸送抗病毒劑，包括（不限於）福米韋 生鈉（fomivirsen sodium)、膦甲酸鈉（foscarnet sodium)、甘 昔韋爾鈉（ganciclovir sodium)、绳更昔洛韋鹽酸鹽 (valganciclovir HC1)、三氟尿普（trifluridine)、無環鳥苦 (acyclovir)及法昔洛韋（famciclovir)。該淚道塞可用以輸送 20 i)v%345.doc 200808372 局部麻醉劑，包括（不限於)丁卡因鹽酸鹽（tetracaine HCl)、 有丙卡因鹽酸鹽（proparacaine HC1)、丙卡因鹽酸鹽 (proparacaine HC1)及螢光素鈉、丁氧普魯卡因（benoxinate) 及螢光素鈉及丁氧普魯卡因（benoxinate) and約黃綠素 5 (fluorexon)二鈉。該淚道塞可用以輸送抗真菌劑，包括例 如氣康嗤（fluconazol)、氟胞嘴咬（flucytosine)、兩性黴素B (amphotericin B)、依曲康唾（itraconazole)及酮康吐 • (ketocaonazole)。 該淚道塞可用以輸送止痛劑，包括而不限於乙醯胺酚 ίο (acetaminophen)及可待因（codeine)、乙醯胺酚 (acetaminophen)及氫可酮（hydrocodone)、乙酸胺盼 (acetaminophen)、酮洛酸（ketorolac)、布洛吩（ibuprofen)及 曲馬多（tramadol)。該淚道塞可用以輸送血管收縮劑 (vasoconstricors)，包括（不限於）麻黃素鹽酸鹽、萘甲唾琳 15 鹽酸鹽、苯福明鹽酸鹽、四氫唑咁鹽酸鹽及羥間唑啉。最 φ 後，該淚道塞可用以輸送維生素、抗氧化劑及營養劑，包 括而不限於維生素A、D及E、黃體素、牛磺酸、榖胱甘肽、 玉米黃質、脂肪酸及諸如此類者。 由該淚道塞所輸送之活性劑可調配成含有賦形劑，包 20 括（不限於）合成及天然聚合物，包括例如聚乙烯醇、聚乙 二醇、聚丙稀酸、經基甲基纖維素、甘油、經丙甲纖維素 (hypromelos)、聚乙烯基吼洛咬酮、聚丙晞酸（〇&11>〇0〇1)、 丙二醇、經基丙基瓜爾膠、丙氧基醯化葡萄糖（glue am-20)、 羥基丙基纖維素、山梨糖醇、葡萄糖、聚山梨醇酯、甘露 21 jjv96345.doc 200808372 糖醇、葡聚糖、經修飾多醣及樹膠、磷脂及續基甜菜驗。 經由考慮以下非限制實施例可進一步明瞭本發明。 實施例 5 實施例1 1·50克之量藉GPC測量時平均Mw約ι4,〇〇〇且平均 Mn約10,000之ε聚己内醋（講自Aldrich)與1 50克EVA 馨（EVATANETM，Arkema)及 1 ·00 克之比馬前列素（bimatoprost) (Cayman Chemicals)組合，每一者之純度各高於約97 %。 ίο 混合物隨之置入購自DACA Industries, Inc·型號20000雙螺 桿微量調配機中，該調配機裝置有0.25毫米塑模，於67 °C在120轉/分鐘下調配15分鐘。調配之後，混合物於75 °C擠塑成纖維。 將纖維裁成約1.5毫米長度短段並插入購自Surgical 15 Specialties 之 Sharpoint ULTRA™塞之開口中。製造各具 φ 〇·6毫米長度之70個裝有藥物之塞及30個裝有安慰劑之 塞，且製造各具0.8毫米長度之70個裝有藥物之塞及50 個裝有安慰劑之塞。插入纖維時，每一塞各放置於實體顯 微鏡下，使用鑷子將纖維插入每一塞之開口内。隨後將每 2〇 —塞放入玻璃管瓶中且包裝於袋中。之後於約0.2 Kgy/min 在總劑量15 Kgy下進行輻射滅菌。 實施例2 22 ijv96345.doc 200808372 根據實施例i方法製得之塞（其係0.6毫米長度且纖維 直徑約0.2毫米且含有25%w/w)置入裝有i毫升pH為 之經磷酸鹽缓衝鹽水的玻璃管瓶。該管瓶置入37ΐ择育哭 中且溫和攪動。於3、8及24小時且之後每週之間^彳^ 5每份1毫升之試樣並經HPLC分析藥物含量。圖u係為^ 示分析結果之圖。 ' ”' & 實施例3 根據實施例1方法製得之塞（其係〇. 9亳米長度且纖維 具有約0.6毫米直徑並含有25%)置入裝有i毫升？11為74 之經磷酸鹽緩衝鹽水的玻璃管瓶中。該管瓶置入3r>c培育 器中且溫和攪動。於實施例2所設定之間隔收集每份 升之試樣並經肌c分析藥物含量。圖12係為顯示分析結 果之圖。 _ 【圖式簡單說明】 •圖1係為淚道塞的剖面圖，其具有包括擴大區段12 之本體10及位於該本體10内之儲存器15，儲存器含有含 活性劑18之聚合物材料11。該儲存器15具有活性劑 20 通過釋出之開口 13。 圖2係為淚道塞的剖面圖，其具有包括擴大區段22 之本體20及位於該本體20内之儲存器25，儲存器含有含 活性劑28之聚合物材料21。該儲存器25具有活性劑28 通過釋出之開口 23。 jjv96345.doc 23 200808372 n係為淚道塞的剖面圖，其具有包括擴大區段32 之本體30及位於該本體3㈣之儲存器35，儲存器含有含 ^生劑38之聚合物材料31。該儲存器3有 通過釋出之兩開口 33及33，。 5 10 15 20 =4係為淚道塞的剖面圖，其具有包括擴大區段42 =體4: ’位於該本體4〇内之儲存器45，其含有含活性 二之♦合物材料4卜及領部44。該儲存器45具有該活 性劑48通過釋出之開口 43。 之太I5/系為淚道塞的剖面圖，其具有包括擴大區段兄 活性心’ 本體5G内之儲存器55，儲存器含有含 兮之心物材料51’及領部54。該儲存器55具有 該活性劑58通過釋出之開口 53。 之」6係為淚道塞的剖面圖，其具有包括擴大區段62 <本體60，位於該本體6〇內夕辟六π ^ 活性劑68之聚合物材料61，及領部子：二存為含有含 ^ ^ 了 汉读4 64。该儲存器65具有 该活性劑68通過釋出之兩開口 63及63,。 圖7係為淚道塞的剖面圖，其具有由可挽性聚 =得之本體70，位於該本體7Q内^與該本體^接之 材料7卜A該儲存器75具有活性齊！78通過釋出之開 圖8係為淚道塞的剖面圖，其具有由可挽性 ，製得之本體8G，位於該本體⑼内而與讀⑽相接之= 子W5’及領部84。該儲存器、δ5含有含活性劑88之聚合 ijv96345.doc 24 200808372 物材料81，且該儲存器 開口 83 及 83’。 85具有該活性劑通過釋出之兩 Μ ϋ料二維描述㈣4之淚道塞的三維視®，立里 有包括擴大區段92夕士麟oA , , '、吳 5Butyl formate ("PBT,,"), polyethylene, polyurethane, stone, P^TFE^VDF, and polyolefin. Nylon, pET, pBT, polyethylene pvDF The lacrimal plug is generally used, for example, and not limited to, extrusion, injection molding, and thermoforming. The latex, (tetra) carboxylic acid, (4) or the clothing of the tears are generally produced by solution casting. , the tears, the base contains a reservoir located in the body, and the storage is a spun-two: 11 J t material. The material can be any compatible with the active agent or the agent and can be used as needed The means for releasing the active agent (for example, the dissolution or degradation agent is released from the material). Many bismuth active agent materials, including (not limited to) polymeric materials (days, non-polymer materials including (not limited to) glass and clay And the materials of the machine include (not limited to) porous ceramics, lipids, and waxes::; 7_ The material containing the active agent is φ17a /, and an active agent is disposed therein, Dispersed in the reservoir 1 = in. The body is preferably impermeable to the active agent, and μ: has at least - an opening, The agent is released through the opening. The factory is as shown in Fig. 4 1 /, has > or an opening, and is located at the first end of the body ^ Figure 6 does not '' the second end (as shown in Figure 5) The first and second ends of the present invention are connected to a reservoir located at other positions of the body. In: Body: In a specific embodiment, when the lacrimal plug is inserted into the lacrimal canal position - When the opening of the sputum is toward the eye, the active agent is released into the tears of the eye 12 jjv96345.doc 200808372 5 10 15 20 or the right end of the body of the plug faces the nasolacrimal duct, then the active agent = enters the nasolacrimal duct Where the plug is such that the opening at the end of the body faces the eye and the other opening at the end of the body faces the nasolacrimal duct, the active agent is simultaneously released into both the tears of the eye and the nasolacrimal duct. In the case of a lacrimal plug having a collar, the opening of the lacrimal plug is preferably located in the collar 2, preferably as the central portion of the collar. When the lacrimal plug is inserted into the canaliculus, the opening is toward the eye. And the active agent is released into the tears of the eye. The size of the opening is about i Nai Up to about 2.5 mm and preferably about 15 mm to about 0.8 mm. A large opening in a single position is not used, and a plurality of small openings can be used. The method for making the lacrimal plug of the present invention is Zhou ^.: Zhao-like is by injection molding, die-casting, transfer molding or the like. The storage is preferably in the active agent and the active agent-containing material after the plug is made - or two In addition: - the excipient can be combined with an active agent alone or in combination with a polymeric material; depending on the active agent-containing material selected, the active agent can be placed in several hands: scavenging or active The agent can be continuously applied over a desired period of time, and a polymeric material consisting of one or more at least partially water soluble polymers can be used. Take the person's private s ~ heart to σ 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物 物The active agent is taken out. The solution rate proportional material ίI or the water solubility of a plurality of polymers directly dissolves with it: ΐ (the appropriate polymer partially soluble in water includes but not limited to polyethylene); poly(propylene glycol); poly (ethyl alcohol) ); propylene-ethyl acetoacetate poly(vinyl fluorene (tetra)); polypropylene ijv96345.doc 13 200808372 acid; poly(ethylcarbazole); poly(dimethyl methacrylate); phospholipids such as, for example, phosphorus Choline derivatives; polysulfobetaine; polysaccharides and sugars, including but not limited to, viluconic acid, dextran, hydroxyethyl cellulose, hydroxypropyl cellulose, gellan gum, guar gum, Heparin sulfate, chondroitin sulfate, hepatic acid and bath salts; proteins such as, for example, gelatin, collagen, albumin and egg protein; and polyamino acids. The polymer materials in this example are generally compatible with hydrophobic polymers. And one or both of the monomers are copolymerized or blended. 10 15 20 Alternative non-polymer materials may be used including, without limitation, lipids, waxes or inorganic materials. Suitable non-polymer materials include, but are not limited to, lanolin. , paraffin, sorbate, lecithin, vitamins A, D and E, glycerin, sorbitol, mannitol, stearate, fatty acid, lutein, corn granules, taurine, glutathione and the like. ” The active agent-containing material can be, v % A low-profile sputum degradable material that is partially or completely chemically degraded upon exposure to, for example, a biologically active substance typically present in mammals. Preferably, the biodegradable material is hydrolyzable under in vivo conditions. Biodegradation can occur more slowly, so if the active agent is released more slowly and for a longer period of time, the material can be composed of one or more biodegradable polymers. Suitable biodegradable polymers include, without limitation, polymers and oligomers of glycolide, lactide, = caprolactone, and other hydroxy acids, and other substances that are non-toxic or normal metabolites in the body. Biodegradable intake. Preferred poly(α-hydroxy acid) is poly(glycolic acid), poly(2_water di I) hydroxamate, poly(anhydride), poly(orthoester), poly(phosphorus) (poly ljv96345.doc 14 10 15 20 .200808372 (coffee sPhazines )) and poly (scale ester). Poly-emulsions include, but are not limited to, = _), poly (δ-caprolactone), poly (§ valerolactone) and poly (γ-butyrolactone) or two = acetaminophen, alginic acid Salt, collagen and gelatin. A mixture of the present invention and a biodegradable polymer. In a preferred embodiment of the compound, the active agent-containing material is: the active agent is combined to form - or a plurality of fibers or fibers: 2 - 4:; owed: the mass is the reservoir The dimension is less than the dimension, and the U-recorder can have a millimeter diameter suitable for insertion into the opening. Length and. ·. Preferably, 5 to about 2 degrees is such that the fiber is retained in the wearer's punctum when it is used in the wearer's punctum. 4: in the shape of; ha f or::_ shape = characteristic 'includes (not limited to two ::二::保二在此, The surface of such a person inside the memory. /, s χ彳,, text, roughness or such as the fiber. ° Another _ preparation ^ ^ agent fiber formation and The plug is placed in the plug storage device: the fiber and the active agent can be introduced into the solution form in the form of a solution, and the curing can be carried out in the form of a solution. Further, in the alternative, the body, the prepolymer and the suitable agent In the case of a via agent, the solution may contain a single- or multiple kinds of cross-linkers: first, emulsification reduction and thermal radical polymerization t-heart. In another alternative, the fiber may be inserted into the jjv96345.doc 15.200808372 plug Before or after the medium is simply immersed in the active agent. The fiber or fibrous structure is preferably made of a polymer material, more preferably the molecular weight of the polymer material is between about 10, _ and 8 〇〇〇〇〇. Between the vinegar (preferably poly(ε_caprolactone)) and ethylene acetate, the polymer material: „about 0 to about 100% by weight Vinegar and about 1 〇〇, ', 〇 里 里 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 乙烯 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Preferably, it is higher than about two = it should be clear that in the preparation, the formulated active agent will not be degraded by the process. Polyhexyl vinegar and = i i (b) preferably with the required active agent or The combination of the agent, the trace == TQmp_deda is then extruded into a fiber. The fiber is inserted into the reservoir according to the length and is inserted into the reservoir via - or a plurality of the plugs. The selected active agent or the dose of H through the lacrimal plug, the desired release of the active agent and the active agent-containing material * = two = amount can achieve the desired treatment, inhibition, use, ·, spoon 0.05 to about 8, _ micrograms of the amount of active agent. The specific application of the specific lacrimal plug is preferably 22 seconds when refilling the material, while other lacrimal ducts are like 戾 戾 ijv96345.doc 16 200808372 : Force: = material, then re-insert the lacrimal plug into the canaliculus. Or more raw, combined with ^ material. For example, degradable, but the active agent It can be diffused from one or more, and can be used as a polymer material. The material can be composed of such a polymer material; package: f: a polymer that can be degraded. κ, ene, poly(propylene glycol), poly(vinyl alcohol), poly (Ethylene:):::1), poly(vinylpyrrolidone), polyacrylic acid, 10 15 20 water Polymer and i-body C-ene amide. These polymers may be copolymerized or blended with one or both of the v μ - groups. Other insoluble =! Biodegradable polymer materials include, but are not limited to, linaloic acid; mono = I; (iv) copolymer, including (not limited to) ρηεμα hydrophilicity: body ' * 乙二 _ '聚乙县财(d) and glycerol, and (d) hydrogel polymers, such as those described, for example, in U.S. Patent Nos. 5,962,548, 6, 445, s, s, s s s s s s s s s s s s s s s s s s s , including (not limited to) scorpion scorpion derivatives j polyxian betaine; polysaccharides and sugars, including (not limited to) fructose, dextran, hydroxyethyl cellulose, hydroxypropyl cellulose, knots Cold glue, guar gum, acesulfate heparin, chondroitin sulfate and heparin; proteins, including (not limited to) albumin and egg protein; polyamino acids; fluorinated polymers, including (not limited to) PTFE, PVDF and Teflon; polypropylene; polyethylene; nylon; and EVA. Other examples of polymers which are insoluble in water or non-biodegradable or suitable for both include, but are not limited to, Shiyi, polyurethane, cyanopropyl acrylate and polyacrylic acid. Jjv96345.doc 17 200808372 The lacrimal plug of the present invention can be used to deliver various active agents for one or more of the treatment, inhibition and prevention of various diseases and conditions. Each lacrimal plug can be used to deliver at least one active agent and can be used to deliver different types of active agents. For example, the lacrimal plug can be used to deliver azelastine HCl 5, emadastine difumerate, iripes, epinastine HCl, Ketotifen fumerate, levocabastine HC1, olopatadine HCl, olipatamine HCl Pheniramine maleate) and antazoline phosphate for one or more of allergy treatment, inhibition and prevention. The lacrimal plug can be used to deliver mast cell stabilizers such as, for example, cromolyn sodium, lodoxamide tromethamine, nedocromil sodium, and bemicarbonate potassium. (permirolast potassium). 15 After the plug is filled with the active agent, the plug is sterilized by any convenient means, φ including, without limitation, ethylene oxide, high pressure heating, illumination, and the like, and combinations thereof. It is preferred to sterilize via 7 radiation or using ethylene oxide. The lacrimal plug can be used to deliver a mydriatic agent and a ciliary muscle anesthetic, including (not limited to) atropine sulfate, homatropine, and Dongliang test bromate (8). (: 〇0〇1&11^116 1161〇, cyclopentolate HC1, tropicamide and phenylephrine HC1. The lacrimal plug can be used Delivery of ophthalmic dyes including, but not limited to, rose begal, sissamine green, indocyanine green, amygdalin 18 jjv96345.doc 200808372 (fluorexon) and luciferin. The plug can be used to deliver corticosteroids, including but not limited to dexamethasone sodium dexamethasone, dexamethasone, fluoTomethalone, fluorometholone acetate, loteprednol 5 (loteprednol) Etabonate), prednisolone acetate, prednisolone sodium acetate, medrysone, rimexolone, and fluocinolone acetonide. Daosai available To deliver non-steroidal anti-inflammatory agents including, but not limited to, flurbiprofen sodium, suprofen, diclofenac sodium, ketorolac tromethamine , cyclosporine, rapamycin methotrexate, azathioprine, and bromocriptine. The lacrimal plug can be used to deliver anti-infective agents. Such as, for example and not limited to, tobramycin, moxifloxacin, ofloxacin, gatifloxacin, ciprofloxacin, orthomycin (gentamicin), sulfisoxazolone diolamine, sodium sulfacetamide, vancomycin, polymyxin B, amiconoid Amikacin, norfloxacin, levofloxacin, sulfisoxazole diolamine, sulphate acetate tetracycline, deoxygenation Doxycycline, dicloxacillin, cephalexin, ampicillin/clavulante, 19 jjv96345.doc 200808372 ceftriaxone, cefixime, Erythromycin, ofloxacin, azithromycin, gentamycin, suifadiazine, and pyrimethamine 〇5 This lacrimal plug can be used to deliver glaucoma One or more agents for treatment, inhibition, and prevention, including (not limited to) adrenaline, including, for example: dipive adrenaline (dipivefrin); alpha-2 adrenergic receptors, including, for example, Apoulo Aproclonidine and brimonidine; β-blockers' include, for example, betaxolol, ketoneolol, levobunolol, trimethylbenzene Methiranolol and timolol; direct miotic agents, including, for example, carbachol and pilocarpine; cholinesterase inhibitors, including, for example, lentils, have B Echothiophate; carbonic anhydrase inhibitors, including, for example, acetazolamide, brinzolamide, dormolamide, and methazolamide Prostoglandins and prostamides, including, for example, latanoprost, bimatoprost, uravoprost, and unoprostone cedovir ( Unoprostone cidofovir). 20 The lacrimal plug can be used to deliver antiviral agents including, but not limited to, fomivirsen sodium, foscarnet sodium, ganciclovir sodium, ganciclovir salt Acid salt (valganciclovir HC1), trifluridine, acyclovir and famciclovir. The lacrimal plug can be used to deliver 20 i) v% 345.doc 200808372 local anesthetic, including (not limited to) tetracaine hydrochloride (procacaine HCl), procacaine hydrochloride (proparacaine HC1), procaine Hydrochloride (proparacaine HC1) and sodium luciferin, benoxinate and luciferin sodium and benoxinate and fluorexon disodium. The lacrimal plug can be used to deliver antifungal agents including, for example, fluconazol, flucytosine, amphotericin B, itraconazole, and ketoconazole. Ketocaonazole). The lacrimal plug can be used to deliver analgesics including, but not limited to, acetaminophen and codeine, acetaminophen and hydrocodone, acetaminophen, ketoproic acid ( Ketorolac), ibuprofen and tramadol. The lacrimal plug can be used to deliver vasoconstricors, including (without limitation) ephedrine hydrochloride, naphthylpyrazine hydrochloride, phenylfoam hydrochloride, tetrahydrozolium hydrochloride, and Hydroxyzoline. After φ, the lacrimal plug can be used to deliver vitamins, antioxidants, and nutrients, including but not limited to vitamins A, D, and E, lutein, taurine, glutathione, zeaxanthin, fatty acids, and the like. . The active agent delivered by the lacrimal plug can be formulated to contain excipients including, but not limited to, synthetic and natural polymers including, for example, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, transmethyl Cellulose, glycerin, hypromelos, polyvinyl sterolone, polyacrylic acid (〇&11>〇0〇1), propylene glycol, propyl guar, propoxy Glucosamine (glue am-20), hydroxypropylcellulose, sorbitol, glucose, polysorbate, mannose 21 jjv96345.doc 200808372 Sugar alcohol, dextran, modified polysaccharides and gums, phospholipids and contigs Beet test. The invention will be further clarified by considering the following non-limiting examples. Example 5 Example 1 An amount of 1·50 g by GPC, an average Mw of about ι 4, and an average Mn of about 10,000 ε polycaprolactone (from Aldrich) and 1 50 g of EVA NET (Arkema) And a combination of 1 00 g of bimatoprost (Cayman Chemicals), each having a purity greater than about 97% each. The ίο mixture was then placed in a model 20000 twin-screw micro-dispenser from the DACA Industries, Inc. unit with a 0.25 mm mold that was conditioned at 65 rpm for 15 minutes at 120 rpm. After the formulation, the mixture was extruded into fibers at 75 °C. The fibers were cut into short lengths of about 1.5 mm and inserted into the opening of a Sharpoint ULTRATM plug purchased from Surgical 15 Specialties. Made 70 drug-filled plugs and 30 placebo-filled plugs of φ 〇·6 mm length, and made 70 drug-filled plugs of 0.8 mm length and 50 placebo-filled Plug. When inserting the fibers, each plug is placed under a solid microscope and the fibers are inserted into the opening of each plug using tweezers. Each 2 inch plug was then placed in a glass vial and packaged in a bag. Radiation sterilization was then carried out at a total dose of 15 Kgy at about 0.2 Kgy/min. Example 2 22 ijv96345.doc 200808372 A plug prepared according to the method of Example i (which is 0.6 mm in length and having a fiber diameter of about 0.2 mm and containing 25% w/w) is placed in a pH of 1 ml of phosphate. Glass tube bottle flushed with salt water. The vial was placed in a 37-inch cries and gently agitated. Each 1 ml sample was taken at 3, 8 and 24 hours and after each week and the drug content was analyzed by HPLC. Figure u is a graph showing the results of the analysis. ' ” ' & Example 3 The plug prepared according to the method of Example 1 (which is 9 亳 in length and the fiber has a diameter of about 0.6 mm and contains 25%) is placed in a volume of i ml ? In a glass vial of phosphate buffered saline, the vial was placed in a 3r>c incubator and gently agitated. Each liter of sample was collected at intervals set forth in Example 2 and analyzed for drug content via muscle c. Figure 12 A diagram showing the results of the analysis. _ [Simple description of the drawings] Fig. 1 is a cross-sectional view of a lacrimal duct plug having a body 10 including an enlarged section 12 and a reservoir 15 located in the body 10, the reservoir Containing a polymeric material 11 containing an active agent 18. The reservoir 15 has an opening 13 through which the active agent 20 passes. Figure 2 is a cross-sectional view of the lacrimal plug having a body 20 including an enlarged section 22 and located there A reservoir 25 in the body 20, the reservoir containing a polymeric material 21 containing an active agent 28. The reservoir 25 has an opening 23 through which the active agent 28 is released. jjv96345.doc 23 200808372 n is a cross-sectional view of the lacrimal plug , having a body 30 including an enlarged section 32 and located in the body 3 (four) a reservoir 35, the reservoir containing a polymer material 31 containing a biocide 38. The reservoir 3 has two openings 33 and 33 through which it is released. 5 10 15 20 = 4 is a cross-sectional view of the lacrimal plug. Having a reservoir 45 comprising an enlarged section 42 = body 4: 'located within the body 4', containing a material 2 containing active 2 and a collar 44. The reservoir 45 has a release of the active agent 48 Opening 43. The I5/ is a cross-sectional view of the lacrimal duct plug having a reservoir 55 including an enlarged section of the active body 'body 5G, the reservoir containing the heart material 51' and the collar 54. The reservoir 55 has an opening 53 through which the active agent 58 passes. The 6 series is a cross-sectional view of the lacrimal duct plug having an enlarged section 62 < a body 60 located within the body 6 Six π ^ active agent 68 of the polymer material 61, and the collar: two deposits containing ^ ^ Han reading 4 64. The reservoir 65 has two openings 63 and 63 through which the active agent 68 is liberated. Figure 7 is a cross-sectional view of a lacrimal plug having a body 70 that is collapsible, located in the body 7Q, and connected to the body. The reservoir 75 is active! Figure 8 is a cross-sectional view of the lacrimal plug, which has a body 8G made of a pullable property, located in the body (9) and connected to the reading (10) = sub-W5' and collar 84 . The reservoir, δ5, contains polymeric ijv96345.doc 24 200808372 material 81 containing active agent 88, and the reservoir openings 83 and 83'. 85 has a two-dimensional description of the active agent through the release of two ϋ ( (4) 4 three-dimensional view of the lacrimal plug, Lili has an enlarged section 92 Xi Shilin oA, , ', Wu 5
10 QS i^ 之本體90,位於本體90内之儲存哭 =’其含有含劑98之聚合物材料91，及領部％ 态95具有該活性劑98通過釋出之開口 ％。 子 圖1〇係為淚道塞的剖面圖，其具有包括擴大區段ι〇 之本體100，位於該本體1⑻内之儲存器105,領部1〇4: 錐狀圓形末端103。該儲存器1〇5含有含活性劑丨⑽之取 合物材料101，且該儲存器1〇5具有該活性劑ι〇 ς 之開口 103。 、釋出 圖11係為描述實施例2淚道塞之活性劑釋出曲線的 圖12係為描述實施例3淚道塞之活性劑釋出曲線的 φ 【主要元件符號說明】 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 -本體 11 -聚合物材料 12, 22, 32, 42, 52, 62, 92, 102 -擴大區段 2〇 13, 23, 33,，43, 53, 63, 73, 83, 93, 103 -開口 44, 54, 64, 74, 84, 94, 104-領部 15, 25, 35, 45, 55, 65, 75, 85, 95, 105 -儲存器 18, 28, 38, 48, 58, 68, 78, 88, 98, 108 -活性劑 iiv96345.doc 25The body 90 of 10 QS i^, stored in the body 90, is crying = 'the polymer material 91 containing the agent 98, and the collar % state 95 has the opening % through which the active agent 98 is released. Figure 1 is a cross-sectional view of a lacrimal plug having a body 100 including an enlarged section ι, a reservoir 105 located within the body 1 (8), and a collar 1 〇 4: a tapered rounded end 103. The reservoir 1〇5 contains a compound material 101 containing the active agent 丨(10), and the reservoir 1〇5 has an opening 103 of the active agent 〇. Figure 11 is a graph showing the release profile of the active agent of the punctal plug of Example 2, which is a φ describing the release profile of the active agent of the punctal plug of Example 3 [Explanation of main component symbols] 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 - body 11 - polymer material 12, 22, 32, 42, 52, 62, 92, 102 - enlarged section 2〇13, 23, 33,, 43, 53, 63, 73, 83, 93, 103 - opening 44, 54, 64, 74, 84, 94, 104 - collar 15, 25, 35, 45, 55, 65, 75, 85, 95, 105 - reservoir 18, 28, 38, 48, 58, 68, 78, 88, 98, 108 - active agent iiv96345.doc 25