201039876 六"、發明說明： 【發明所屬之技術領域】 本發明敘述用於將一或多種物質，像是藥物，酉己進 淚管塞貯器之方法及設備’更特定言之，在一些實施例 中’為關於將包括賦形劑的藥物成分配進淚管塞腔穴之 方法及裝置。201039876 Six "Invention Description: [Technical Field of the Invention] The present invention describes a method and apparatus for one or more substances, such as drugs, into a lacrimal plug receptacle, more specifically, in some In the examples 'is a method and apparatus for dispensing a drug comprising an excipient into a lacrimal plug cavity.
【先前技術】 樂物通常施用於眼部以用於治療 ::用以輸送藥物到眼部的習知方法 睛 局部施用的藥物能夠穿透角膜並且組 農度水平。用於眼部疾 々内達到治 或是注射施用，但這樣〕、樂物可經由口服 望的藥理作用，且其使：二：*低，而無法擁有期 變得複雜，㈣射H為=的全身_作用而 現今，大部份的目Γγ的風險。 :送，雖然在某些施用二物為採取以眼滴劑進行局部 :。當-滴液體落到目心下:能產生效果，但效能不 眼驗之間的囊袋，滿/時’會使結獏囊，位於眼睛與 =邊緣的外溢到而=該_體的大部份因為由 ^分該滴液體，^失。此外1在眼部表面的 釋。 會因流入淚點而便藥物濃度被祷 3 201039876 因此，有用於配藥至眼部區域的替代方法及裝置是 有益的。 【發明内容】 本發明係關於經由淚管塞給藥之裝置，並包括在淚 管塞腔穴中貯放藥物之方法及設備，其中將淚管塞插入 淚點後，可將該藥物輸送給病人。 【實施方式】 本發明包括用於形成淚管塞之設備及方法，該淚管 塞可用來輸送活性劑至單一或兩鼻淚管與至眼部的淚 液。在一些實施例中，散佈活性劑的定位係於能夠將活 性劑釋放進淚液的位置，且較佳為附隨釋放進鼻淚管情 形為最少。一些實施例包括用於形成淚管塞之設備及方 法，該淚管塞包含主要由以下組成與由以下組成：一淚 管塞主體，具有一第一端以及一第二端；一表面，延伸 於該二端之間；一貯器，包含在該淚管塞主體内，其中 該貯器包含主要由以下所組成與由以下組成：一含活性 劑之材料以及一活性劑，其中該活性劑在含活性劑之材 料中，係具有連續性或不連續性濃度梯度。該淚管塞可 額外包含一定義區域，像是淚管塞中的開口，其更有利 於洗滌或是使活性劑從淚管塞腔穴到淚管塞鄰近區域 的其他散布。一些較佳的實施例包括一有助於散佈活性 劑的區域，包含一直徑小於含有活性成分之腔穴直徑的 開口。 4 201039876 本發明額外提供可用一經控制方式將活性劑輸送 進淚管塞内腔穴的裝置及其使用與製造方法。 已知可經由插入一桿狀或其他剛性或半剛性物品 以充填淚管塞中的腔穴。該桿狀物可包括一藥品或其他 藥物。然而，淚點的實體狀況包括實體操作以及水分的 存否。將桿狀藥物插入淚管塞中可能是困難的。 定義： 0 本文中所使用的術語「活性劑」指能夠治療、抑制 或預防一失調症狀或疾病的藥劑。活性劑的實例包括， 但不限於，藥物以及營養食品。較佳的活性劑能夠治 療、抑制或預防眼、鼻及喉部當中一或多者的失調症狀 或疾病。 本文中所使用的術語「淚管塞」指一種大小與形狀 適於分別經由上、下之淚點而插入眼部的上、下之淚小 管的裝置。 〇 本文中所使用的術語「開口」指一種本發明之裝置 中位於淚管塞主體上的一開口，其大小與形狀能使活性 劑通過。較佳為，僅有活性劑能夠通過開口。開口可以 膜、篩、格桃覆蓋，或是無覆蓋。該膜、篩或格拇可以 是具多孔、具半多孔、具滲透性、具半滲透性以及生物 可分解當中之一或多者。 現在參考圖1，圖1A中繪示有一淚管塞裝置101， 其具有一開口 102可與淚管塞主體中形成的一腔穴105 形成液體連通。在圖1B中，一分注器尖頭103放置於 201039876 開口 102的鄰近，用以配送一材料1〇4通過開口 ι〇2進 入腔穴105。在圖1C中，顯示腔穴1〇5已被分注器尖 頭103填滿含活性劑之材料1〇4。活性劑的實例包括以 下的一或多者.比馬前列素（bimatoprost);具有含量 多於0%且少於25%之乙烯乙酸乙烯酯 (ethyleneoxynalacetate，EVA)膜的比馬前列素。 在本發明的各種實施例中，將含有一或多種活性劑 的材料104以及其中的一種活性劑以高黏度小劑量方 式貯放於淚管塞裝置的腔穴1〇5内。例如’在一些實施 例中’材料104的黏度在1厘泊到超過looooooQ百 萬）厘泊之間。此外’一些實施例包括存放小劑量的材 料104，像是在10皮升到1〇,〇〇〇(一萬）皮升之間。材料 104也可包括一或多種賦形劑。該賦形劑可能係材料 104中提供高黏度特性的成份。 該腔穴可以是淚管塞設計可支援的任何大小及/或 形狀。在一些實施例中，腔穴105的容量約在1〇到1〇〇 奈升之間。一些特定的實施例包括一容量約在4〇奈升 到50奈升之間的腔穴。例如，可插入分注器尖頭的一 腔穴開口 102直徑可能約〇 1 mm到0.4 mm，且腔穴105 深度約0.5 mm到約2.0 mm。在一些較佳實施例中，開 口 102的直徑約0.2 mm且該腔穴的深度約15 mm。實 施例的另一較佳面向可包括一直徑為〇 385 mm且長度 為1.5 mm，且腔穴容量為175 nL之設計。 可使該活性劑以散布方式，遍佈於含活性劑之材料 104，或將其溶解於材料1〇4中。或者，該活性劑可能 201039876 包3在材料1〇4内的爽雜物、 於材料ΠΜ内。另一選擇為，^^液滴内，或微包覆 , 至材料104 B - ‘ 舌性劑可以共價鍵鍵結 4，且猎由水解、酵素 還有另擇是，該活性方式釋放。 中。 J在材枓104内的貯器 根據本發明的一些實施例 式從淚管塞裝置⑻㈣Λ f生劑可以—經控制方 含守iJ 控制方式意指藉由使用- 才料1〇4，其中該活性劑係在材料1〇4各處 一;Γ濃度梯度’或使用不連續性的濃度梯度，[Prior Art] Music is usually applied to the eye for treatment :: a conventional method for delivering a drug to the eye. The locally administered drug is capable of penetrating the cornea and the degree of composting. It is used for treatment or injection in eye diseases, but it can be treated by oral administration, and it makes: 2: * low, but the possession period becomes complicated. (4) Shoot H is = The whole body _ role and nowadays, most of the risks of gamma. : Sent, although in some applications two substances are taken locally with eye drops: When the drip liquid falls to the eye: it can produce an effect, but the effect is not between the capsules, the full/time 'will make the sac, the overflow of the eye and the edge = and the _ body is large Partly because of the drop of the liquid, ^ lost. In addition, 1 is released on the surface of the eye. The concentration of the drug will be prayed for the inflow of the punctum. 3 201039876 Therefore, it is beneficial to have alternative methods and devices for dispensing to the eye area. SUMMARY OF THE INVENTION The present invention relates to a device for administration via a punctal plug, and includes a method and apparatus for storing a drug in a lacrimal plug cavity, wherein the drug can be delivered to the punctal plug after insertion into the punctum patient. [Embodiment] The present invention includes an apparatus and method for forming a punctal plug that can be used to deliver an active agent to a single or two nasolacrimal duct and tears to the eye. In some embodiments, the dispersing of the active agent is positioned at a location capable of releasing the active agent into the tear fluid, and preferably with minimal release into the nasolacrimal duct. Some embodiments include an apparatus and method for forming a punctal plug comprising a composition consisting essentially of: a punctal plug body having a first end and a second end; a surface extending Between the two ends; a reservoir contained in the body of the punctal plug, wherein the reservoir comprises a composition consisting essentially of: an active agent-containing material and an active agent, wherein the active agent In the active agent-containing material, there is a continuous or discontinuous concentration gradient. The punctal plug may additionally include a defined area, such as an opening in the punctal plug, which is more conducive to washing or otherwise spreading the active agent from the lacrimal plug cavity to the vicinity of the punctal plug. Some preferred embodiments include a region that facilitates the dispersion of the active agent, including an opening having a diameter smaller than the diameter of the cavity containing the active ingredient. 4 201039876 The present invention additionally provides a means for delivering the active agent into the lumen of the lacrimal plug in a controlled manner and methods of use and manufacture thereof. It is known to fill a cavity in a punctal plug by inserting a rod or other rigid or semi-rigid article. The shaft can include a drug or other drug. However, the physical condition of the punctum includes physical manipulation and the presence of moisture. Inserting a rod-shaped drug into a punctal plug can be difficult. Definitions: 0 The term "active agent" as used herein refers to an agent that is capable of treating, inhibiting or preventing a disorder or disease. Examples of active agents include, but are not limited to, pharmaceuticals as well as nutraceuticals. Preferred active agents are capable of treating, inhibiting or preventing dysregulation or disease in one or more of the eyes, nose and throat. The term "tears plug" as used herein refers to a device that is sized and shaped to be inserted into the upper and lower lacrimal canal of the eye via the upper and lower punctum, respectively. The term "opening" as used herein refers to an opening in the device of the present invention located on the body of the punctal plug that is sized and shaped to allow passage of the active agent. Preferably, only the active agent is able to pass through the opening. The opening can be covered by a membrane, a sieve, a peach or no cover. The membrane, sieve or lattice may be one or more of porous, semi-porous, permeable, semi-permeable, and biodegradable. Referring now to Figure 1, a tearpipe plug device 101 is illustrated in Figure 1A having an opening 102 for fluid communication with a cavity 105 formed in the body of the punctal plug. In Fig. 1B, a dispenser tip 103 is placed adjacent the opening 102 of 201039876 for dispensing a material 1 through 4 into the cavity 105 through the opening ι. In Fig. 1C, it is shown that the cavity 1〇5 has been filled with the active agent-containing material 1〇4 by the dispenser tip 103. Examples of the active agent include one or more of the following: bimatoprost; bimatoprost having an ethyleneoxynalacetate (EVA) film in an amount of more than 0% and less than 25%. In various embodiments of the invention, the material 104 containing one or more active agents and one of the active agents are stored in the cavity 1〇5 of the punctal plug device in a high viscosity, low dose manner. For example, 'in some embodiments, the material 104 has a viscosity of between 1 centipoise and more than looooooQ million centipoise. Further, some embodiments include storing a small dose of material 104, such as between 10 picoliters to 1 inch, 〇〇〇 (10,000) picolitres. Material 104 can also include one or more excipients. The excipient may be a component of material 104 that provides high viscosity characteristics. The cavity can be any size and/or shape that the punctal plug design can support. In some embodiments, the volume of the cavity 105 is between about 1 Torr and 1 Torr. Some specific embodiments include a cavity having a capacity of between about 4 nanoliters and 50 nanoliters. For example, a cavity opening 102 into which the dispenser tip can be inserted may have a diameter of about mm 1 mm to 0.4 mm, and the cavity 105 has a depth of about 0.5 mm to about 2.0 mm. In some preferred embodiments, the opening 102 has a diameter of about 0.2 mm and the cavity has a depth of about 15 mm. Another preferred aspect of the embodiment may include a design having a diameter of 385 mm and a length of 1.5 mm and a cavity capacity of 175 nL. The active agent may be dispersed throughout the active material-containing material 104 or dissolved in the material 1〇4. Alternatively, the active agent may be 201039876 package 3 in the material 1 〇 4 of the inclusions in the material ΠΜ. Alternatively, the ^^ droplets, or micro-coated, to the material 104 B - ‘ the lingual agent can be covalently bonded 4 and the hunt is hydrolyzed, the enzyme and, alternatively, the active mode is released. in. The reservoir in J is in accordance with some embodiments of the present invention from the punctal plug device (8) (4) 生 sheng agent can be controlled by the control party iJ control means by using - only 1 〇 4, where The active agent is in the material 1〇4; the Γ concentration gradient' or the concentration gradient using discontinuity,
It:釋放。還有的實施例包括-裝置，其在加 (burst)」或立即釋放。 恭^ 括一2參考圖2 ’其為本發明'些實施例的實例，包 Ϊ 200，料將*有活性成分的材料 子放進淚管塞裝置1G1的腔穴1G5中（繪示 〇 —)。一般來說’泉200包括一貯器，像是n 2(M，安梦 泵體207内並連接，以與分注器尖頭203構成液體^ 通。例如，_可包括-可移式注射器。成夜發連 匣201可由聚碳酸酯、不銹鋼或其他剛性或半 材料製成。在-些較佳的實施例中，該E係由可消毒並 f存放過程中能禁得住加熱的材料製成。此外，在一些 實施例中’ 201有鄰近分注器尖頭203的-端及遠^ 邊分注器尖頭的一端，其中鄰近分注器尖頭的一端可包 ，一用於將S 201緊固至分注器主體2〇2的螺紋旋轉鎖 疋(lure lock)機構。也可用其他的鎖定或固定機構將匣 7 201039876 201緊固至鄰近分注器尖頭203並可與其有液體連通的 位置。因此，一些實施例可包括聚碳酸酯或不銹鋼注射 器的設計。 一些實施例可包括一「智慧泵（smartpump)」，像 是具電腦控制針閥，用以控制啟動和停止以及材料流的 黏度範圍，的正壓泵。一電腦控制針閥具有主動式閥調 節以控制流動特性，例如像是：與泵送含活性劑之材料 104相關的打開、關閉和吸回動作。在一些實施例中， 泵内部的無效體積(dead volume)範圍從約0.025 ec到 0.3 cc之間。該程度的控制使本發明能配送非常小量的 含活性劑之材料104。一些實施例可包括配送5〇皮升 或更少的量，且在一些較佳的實施例中，配送的量在 20皮升到60皮升之間。於另一個層面，含活性劑之材 料104的黏度範圍從丨厘泊到超過_〇，_厘泊。其 他實:_括在500，_厘泊到3,5〇〇，_厘泊之間的 黏度範圍。-泵機構實例可包括—高壓正排量泵，像是 那些由nScript，lnc所提供作為商業使用的高壓正排量 泵。 一些較佳的實施例將包括-或多加熱源204-206， 當具有活性成分之材料置於以下之-或多者中：a) ϋ 201 ’ b) 〃左器主體2〇2及c)分注器尖頭如3，時 :於^熱該材料。例如，該加熱源可包括以下的-或多 •电=兀件’熱電裝置及加熱的流體路徑。如繪示， f ΓνΓ*例中’—加熱源、2G5可沿著匣2Q1的邊緣放 <、雜成分之材料刚在E 201中時能保持在 201039876 2:显的二f I:例也包括在果體2〇7中或鄰近於泵體 求，心據要=2〇4。一些實施例也包括溫度需 其叮根據要貝丁放賦形劑的材料性質而作調整。 在另-個面向中，本發 探測器206。該溫度探測 用度 ::!=Γ表示 刀的值度。貝施例可包括一 ο :::==，量:在-二其 度。典型來說，施加較高熱量將降成低 =刚的黏 Γ的黏度，而使得可施加較小的壓力便可 分之材料m移動通過淚管塞活打讓3活性成 說，可在贼及8(rt的溫度 ^⑽。舉例來 〇 配送-含活性成分之材料1〇4迅刀注盗尖頭203 中，溫度係在啊及听之間。在—2佳的實施例 :’將配送含有活性材料之材料HM的 =到在贼及阶的溫度之間。在—此二〇二也， 的=放ί::腔，管塞101加熱可讓i子具備額外 基於Λ不同的實施例中，〜較佳的溫度可 材料1〇4中包“賦二用tr生成令’含活性成分之 9 201039876 現在參考圖3，其為一透視圖，繪示一具有一分注 器尖頭301及一快速替換式尖頭底座3〇2的泵2〇〇。該 快速替換式尖頭底座使操作員容易移除/更換尖頭。如 圖3中所繚示，在一些實施例中，泵體可安置於— 軌道304上，或安置於其他可在一維、二維或三維方向 運動的機械或自動機設備上。在一些實施例中可控制該 運動，透過自動化控制運動並使分注器尖頭3〇1能對^ 淚管塞（圖3中未繪示）。而在另一個面向中，一些實 知例可包括一自動視覺系統，以幫助自動對準塞子並對 之進行充填。 雖未與任何特疋的理論相關，但普遍相信含活性劑 的材料104在釋放活性劑的期間内不會進行顯著的化 學降解者，會藉纟擴散作用’㈣基質釋放活性劑到襄 置的釋放表面，這是指與個人的體液接觸之含活性劑材 料104的表面。根據菲克定律（Fiek，s Uw )，局部濃度 梯度、具有材料D之活性劑的擴散度、以及裝置截面形 狀的空間變化會在各時地影響活性劑經由含活性劑之 材料104的擴散輸量或擴散通量。 一些作為不例的實施例可包括賦形劑與活性劑的 混合材料。預混合的設備和製料包括雙螺桿混煉、混 屯混合、溶劑混合或噴霧乾燥或其他的混合機制。一化 合物實例可包括.作為—活性劑的25%比馬前列素；作 為第-賦形劑含量37.5%的乙稀_乙稀醇（咖⑽以邮 acetate’EVA)以及作為第二職形劑含量π。的聚己 内酯（polycaprolactone，PCL )。 10It: Released. Still other embodiments include - a device that is "burst" or immediate release. [2] Referring to Figure 2, which is an example of some embodiments of the present invention, a package 200 is used to place a material having an active ingredient into the cavity 1G5 of the punctal plug device 1G1 (showing 〇- ). Generally, the 'spring 200 includes a reservoir, such as n 2 (M, Anman pump body 207 and connected to form a liquid communication with the dispenser tip 203. For example, _ may include - a movable syringe The night hair canopy 201 can be made of polycarbonate, stainless steel or other rigid or semi-material. In some preferred embodiments, the E is made of a material that can be sterilized and can withstand heating during storage. In addition, in some embodiments '201 has an end adjacent to the tip of the dispenser tip 203 and one end of the distal dispenser tip, wherein one end adjacent the dispenser tip can be wrapped, one for the S 201 is a threaded rotary lure lock mechanism that is fastened to the dispenser body 2〇 2. Other locking or securing mechanisms can be used to secure the 匣7 201039876 201 to the adjacent dispenser tip 203 and can be liquid therewith. The location of the communication. Accordingly, some embodiments may include the design of a polycarbonate or stainless steel syringe. Some embodiments may include a "smartpump" such as a computer controlled needle valve to control start and stop and materials. Flow viscosity range, positive pressure pump. A computer control The valve has active valve adjustment to control flow characteristics, such as, for example, opening, closing, and retracting actions associated with pumping the active agent-containing material 104. In some embodiments, the internal dead volume range of the pump From about 0.025 ec to about 0.3 cc. This degree of control allows the present invention to dispense a very small amount of active agent-containing material 104. Some embodiments may include dispensing 5 ounces of skin or less, and in some cases In a preferred embodiment, the amount dispensed is between 20 picoliters and 60 picolitres. On another level, the viscosity of the active agent-containing material 104 ranges from 丨 centipoise to more than 〇, _ centipoise. _ enclosed in the viscosity range between 500, _ centipoise to 3, 5 〇〇, _ centipoise. - Pump mechanism examples can include - high pressure positive displacement pumps, such as those provided by nScript, lnc for commercial use High Pressure Positive Displacement Pumps. Some preferred embodiments will include - or multiple heating sources 204-206, when the material with the active ingredient is placed in one or more of the following: a) ϋ 201 ' b) 〃 left body 2 〇 2 and c) The tip of the dispenser is 3, when: heat the material. For example, the heating source can include the following - or more - electrical = component 'thermoelectric devices and heated fluid paths. As shown, f ΓνΓ* in the case of '-heat source, 2G5 can be placed along the edge of 匣2Q1<, the material of the impurity component can be maintained at 201039876 when it is just in E 201 2: obvious two f I: Included in or near the body 2〇7, the heart is = 2〇4. Some embodiments also include the temperature required to be adjusted depending on the nature of the material of the bedding excipient. In another aspect, the present detector 206. The temperature detection cost ::!=Γ indicates the value of the knife. The shell example can include a ο :::==, quantity: in - two degrees. Typically, the application of higher heat will reduce the viscosity of the low = just adhesive, so that a small pressure can be applied to divide the material m through the tear duct plug to let the 3 activity become said, in the thief And 8 (rt temperature ^ (10). For example, the distribution - the material containing the active ingredient 1 〇 4 fast knife tip 203, the temperature is between ah and listen. In the best example: 'will The distribution of the material HM containing the active material is between the temperature of the thief and the step. In the case of the second 也, also, the 放:: cavity, the heating of the plug 101 allows the i to have an additional implementation based on Λ In the example, the preferred temperature is 1 〇 4, and the package contains the active ingredient 9 201039876. Referring now to Figure 3, it is a perspective view showing a dispenser tip. 301 and a quick-replaceable tip base 3〇2 pump 2. The quick-change tip base allows the operator to easily remove/replace the tip. As illustrated in Figure 3, in some embodiments, The pump body can be placed on the track 304 or placed on other mechanical or robotic equipment that can move in one, two or three dimensions. In some embodiments, the motion can be controlled by automatically controlling the motion and enabling the dispenser tip 3〇1 to be able to align the tear duct plug (not shown in Figure 3). In the other aspect, some know An example may include an automated vision system to assist in automatically aligning and filling the plug. Although not related to any particular theory, it is generally believed that the active agent-containing material 104 will not be significantly present during the release of the active agent. The chemical degradation agent will rely on the diffusion effect of the (4) matrix to release the active agent to the release surface of the device, which refers to the surface of the active agent-containing material 104 that is in contact with the body fluid of the individual. According to Fick's law (Fiek, s Uw) The local concentration gradient, the diffusivity of the active agent with material D, and the spatial variation of the cross-sectional shape of the device can affect the diffusion flux or diffusion flux of the active agent through the active agent-containing material 104 at each time. Embodiments may include a mixture of excipients and active agents. The premixed equipment and materials include twin screw mixing, mixing, solvent mixing or spray drying or other mixing mechanisms. Examples of the compound may include, as an active agent, 25% bimatoprost; as a first-excipient content of 37.5%, ethylene-ethyl alcohol (coffee (10) with acetate 'EVA) and as a second-form agent π. Polycaprolactone (PCL). 10
201039876 可將該預混合材料以丸粒方式裝載進經加熱或未 經加熱的注射器200。丸粒並非必要條件；該材料1〇4 的形式可以為以下-或多者：粉劑、疏鬆材質及其他介 質。此外，在一些實施例令，像是那些希望能避免將活 性劑暴露於多重熱循環及/或盡量減少氣泡的實施例， 該經加熱的注射器可直接連接到微混煉機，以使該預混 合材料直接供給壯上所料—奈料量配送系統，而 不需要將其冷卻至室溫或更低。同樣地 ’在^ "~些實施(例 卜含活性狀㈣可以―融化形式供給至絲米配送 系統。 ，本發明的另—個面向’活性劑濃度的局部梯度可 =由在含活性劑㈣1〇4中的一位置，相對於另一位 置’放置較多量的活性劑加以控制。或者 :^弟度’這代表材料m的—區域具有一 2 = 在基質相祕域處，濃度會突财變成不同的 亦可藉由改變含活性劑材料刚之化學虹 活性劑擴散度。 〜者喊财同位置的 此外’賴之剖面雜的㈣變 度。例如，若材料104是筆直韓 用术控職政 的活性劑濃度，當材料1()4於端^接其具有均勻 歸體的平均時，擴散度會：^遠小於材料 開放端的材請面積係不大於材二截=置 半，逆代表所決定截面積，係垂 如 的 主要維度。 31於活性劑運輸使用的 201039876 為習該領域之技藝人士應瞭解’根據要如何改變— 或更多局部濃度梯度、來自於材料D的活性劑擴散度及 裴置之剖面形狀的空間變化，可有許多種釋放方弋又1 包括但不限於’第一級、第二級、二相式、脈“ 例如，活性劑濃度與擴散度+之任一或兩者 、冬 =材料的表面往中央增加’俾以能有更多初/釋放。 Ϊί:者或兩者會增加或減少，且接著在材料内再 度、t二釋放變化。藉由改變局部濃度梯 ::多釋放變化的能力，可消除對於裝二:速= 貯器或腔 内。在-些實施射，淚管塞主狀=的材料貯藏在 遷性，這代傭右θ 體為對活性劑具不 、代表僅有h的活性劑能夠通過， ::有至少-供活性劑能夠經此釋放 淚吕基主 j盘有-臈或具$參透性之材 亥開口可 需量通過。 」使活性劑以治療所 可用於本發明裝置之含 納活性劑的材料，且不會改㈣^材抖係任何能夠容 與眼液接觸時，不會產著/劑的化學特性’且當 ，，含活性劑之材物理溶解。 田其接觸通常存在於哺乳 β刀解性，這代表 ，顯著分解。此外，含活性劑㈣ϋ活性物質時不會 解或水解其中之—或其 料能夠藉由擴散、分 谡數方式，釋放活性劑。較 201039876 佳為，含活性劑之材料係聚合物 或多種的聚合物所製成的材料。 <表“係由- 當=性劑的材料與活性劑組合時，該材料亦可含 ^或夕，不、錢水且不具生物可分解性，但可使活性 Μ自其擴散出來的材料。例如，若含 為 聚合物材料’則該材料可由一 ：為： 中之聚合物為不溶於水且不具生物可二性。、、且、、 Ο &適用於含活性劑之材料的聚合物材料包括，但不限 ^疏水性及親水性的可吸收以及不可吸收聚合物。適 ，的疏水性不可吸收聚合物包括，但不限於，乙烯-乙 、醇（EVA」）、氟化聚合物，包括但不限於，聚四氣 埽（「PTFE」）以及聚二氟亞乙烯（「ρ·」）、聚丙稀、 乙稀、聚異丁烯、尼龍、聚胺甲酸酯、聚丙烯酸醋以 ^基丙烯酸S旨、聚乙烯棕櫚酸醋、聚硬脂酸乙稀醋、 :十四酸乙烯酯、氰基丙烯酸酯、環氧樹脂、矽樹脂、 〇 ^疏水性或親水性單_叙絲物，以及其與親水 唑或疏水性聚合物及賦形劑形成的摻合物。 可用於本發明的親水性不可吸收之聚合物包括（但 =限於）交聯的聚乙二醇、聚(環氧乙烷）、聚（丙二醇）、 =(乙烯醇）、聚（丙烯酸羥乙酯）或聚（曱基丙烯酸羥乙 軋）、聚（乙烯础咯烧酮）、聚丙烯酸、聚（乙基噁唑林）， =及聚(二曱基丙烯醯胺），其與疏水性或親水性單體的 共聚物，以及其與親水性或疏水性聚合物及賦形劑的摻 合物。 13 201039876 可採用的疏水性可吸收聚合物，包括但不限於，脂 肪族聚酯、脂肪酸衍生聚酯、聚（胺基酸）、聚（醚酯）、 聚（酯醯胺）、聚烯烴草酸酯、聚醯胺、聚（亞胺碳酸酯）、 聚石反知^日、聚原酸醋、聚氧雜酯（polyoxaesters)、聚酸 胺酯、含胺基之聚氧雜酯、磷脂類、聚（酐卜聚丙烯反 丁烯一S日、聚磷氮烯（p〇iyphOSphazenes)，以及以上之 摻合物。可用的親水性可吸收聚合物之實例包括（但不 限於）多醣以及碳水化合物，其包括但不限於，交聯的 澡酸鹽、玻尿酸、聚葡萄醣、果膠、羥乙基纖維素、羥 丙基纖維素、結冷膠、瓜爾膠、曱殼素（keratin sulfate )、 軟骨素、硫酸皮膚素）、蛋白質，其包括但不限於，膠 原蛋白、明膠、纖維蛋白、白蛋白以及卵白蛋白），以 及磷脂，其包括但不限於，磷酸膽鹼衍生物以及聚硫代 甜菜驗（polysulfobetains))。 更佳地’含活性劑的材料係聚己内酯多元醇 (polycaprolactone)的聚合物材料。仍屬更佳為，該材 料係分子量為介於約10,000與800,000之間的聚(ε-己内 酯 Xpoly(epsilon-caprolactone))與乙烯乙酸乙烯酯 (ethylene vinyl acetate)。以聚合物材料的整體重量為 準，使用重量百分比約0°/〇至約100%的聚己内酯與重量 百分比約100%至約0%的乙烯乙酸乙烯酯，且較佳為， 會使用各約50%的聚己内酯與乙烯乙酸乙烯酯。 所使用的聚合物材料的純度較佳應大於約99%，且 活性劑的純度較佳應大於約97%。熟習該領域之技藝人 士應瞭解，在進行化合作用時，化合作用進行時的條件 14 201039876201039876 The premixed material can be pelletized into a heated or unheated syringe 200. Pellets are not a requirement; the material 1〇4 may be in the form of one or more of the following: powder, loose material and other media. Moreover, in some embodiments, such as those embodiments where it is desirable to avoid exposing the active agent to multiple thermal cycles and/or to minimize air bubbles, the heated syringe can be directly coupled to the micro-kneader to The mixed material is directly supplied to the desired material distribution system without cooling it to room temperature or lower. Similarly, in the implementation of "^", the activity (4) can be supplied to the silk rice distribution system in the form of melting. Another partial gradient of the present invention for the concentration of the active agent can be determined by the active agent. (4) A position in 1〇4, which is controlled by placing a larger amount of active agent relative to the other position. Or: ^^ degree 'this means that the area of the material m has a 2 = at the secret phase of the matrix phase, the concentration will It is also possible to change the diffusion degree of the chemical-active agent of the chemical-containing material by changing the chemical agent material. The singularity of the singularity of the singularity of the singularity of the singularity of the singularity of the singularity of the singularity of the singularity. The concentration of active agent in the occupational administration, when the material 1 () 4 is connected to the end with its average of the average, the degree of diffusion will be: ^ far less than the open end of the material, the area is not greater than the material two = half, The inverse represents the determined cross-sectional area and is the main dimension of the vertical. 31 201039876 used in the transport of active agents. Those skilled in the art should understand 'depending on how to change - or more local concentration gradients, activity from material D Agent diffusion and The spatial variation of the cross-sectional shape of the device may have a variety of release modes including, but not limited to, 'first stage, second stage, two phase, pulse', for example, either active agent concentration or diffusivity + or Both, winter = the surface of the material increases toward the center to 'have more initial/release. Ϊί: either or both will increase or decrease, and then release again within the material, t two. By changing the local concentration Ladder:: The ability to release more changes can be eliminated for the second: speed = reservoir or cavity. In some implementations, the material of the lacrimal plug is stored in the migration, this generation of the right θ body is the right The active agent has no, representative of only h-active agent can pass, :: at least - for the active agent to be able to pass through the tear-based base plate with - 臈 or with a permeability of the material can be passed. The active agent is used to treat the active agent-containing material that can be used in the device of the present invention, and does not change the chemical properties of the agent when it can be contacted with the eye liquid. , the material containing the active agent is physically dissolved. The contact of the field is usually present in the mammalian β knife solution, which Table, significant decomposition. In addition, the active agent (iv) active substance does not dissolve or hydrolyze therein - or its material can release the active agent by means of diffusion and fractionation. It is better than 201039876, the material containing active agent A material made of a polymer or a plurality of polymers. <Table "From - when the material of the agent is combined with the active agent, the material may also contain or not, money, water and biodegradable a material that allows the active enthalpy to diffuse out of it. For example, if it is a polymeric material, the material may be one: the polymer in the middle is insoluble in water and non-biologically identifiable. , Ο & Polymeric materials suitable for materials containing active agents include, but are not limited to, hydrophobic and hydrophilic, absorbable and non-absorbable polymers. Suitable hydrophobic non-absorbable polymers include, but are not limited to, ethylene-ethyl, alcohol (EVA), fluorinated polymers including, but not limited to, polytetrafluoroethylene ("PTFE") and polydifluoroethylene ("ρ·"), polypropylene, ethylene, polyisobutylene, nylon, polyurethane, polyacrylic acid vinegar, acrylic acid S, polyethylene palmitate, polyethylene stearate, s A tetravinyl acrylate, a cyanoacrylate, an epoxy resin, an anthraquinone resin, a hydrophobic or hydrophilic monospin, and a blend thereof with a hydrophilic azole or a hydrophobic polymer and an excipient. Hydrophilic non-absorbable polymers useful in the present invention include, but are limited to, crosslinked polyethylene glycol, poly(ethylene oxide), poly(propylene glycol), =(vinyl alcohol), poly(hydroxy acrylate) Ester) or poly(hydroxyethyl methacrylate), poly(vinyl ketone), polyacrylic acid, poly(ethyl oxazole), = and poly(dimercaptopropene amide), which are hydrophobic Or a copolymer of a hydrophilic monomer, and a blend thereof with a hydrophilic or hydrophobic polymer and an excipient. 13 201039876 Hydrophobic absorbable polymers that may be used, including but not limited to, aliphatic polyesters, fatty acid derived polyesters, poly(amino acids), poly(ether esters), poly(esteramines), polyolefin grasses Acid esters, polyamines, poly(imine carbonates), polysulfide antibiotics, polyortanoic acid vinegars, polyoxaesters, polyamine esters, amine-containing polyoxaesters, phospholipids Classes, poly(anhydrides, polybutylene-S-days, polyphosphazenes (p〇iyphOSphazenes), and blends of the above. Examples of useful hydrophilic absorbable polymers include, but are not limited to, polysaccharides and Carbohydrates, including but not limited to, cross-linked bath salts, hyaluronic acid, polydextrose, pectin, hydroxyethyl cellulose, hydroxypropyl cellulose, gellan gum, guar gum, keratin sulfate ), chondroitin, dermatan sulfate), proteins including, but not limited to, collagen, gelatin, fibrin, albumin, and ovalbumin), and phospholipids including, but not limited to, phosphorylcholine derivatives and polysulfide Beet test (polysulfobetains)More preferably, the active agent-containing material is a polymeric material of polycaprolactone. Still more preferably, the material has a molecular weight of between about 10,000 and 800,000 poly(epsilon-caprolactone) and ethylene vinyl acetate. Using from about 0°/〇 to about 100% by weight of polycaprolactone and from about 100% to about 0% by weight of ethylene vinyl acetate, based on the total weight of the polymeric material, and preferably, will be used About 50% of each of polycaprolactone and ethylene vinyl acetate. The purity of the polymeric material used should preferably be greater than about 99%, and the purity of the active agent should preferably be greater than about 97%. Skilled people familiar with the field should be aware of the conditions under which the cooperation will take place during the process of chemical cooperation 14 201039876
的含活性劑之材料，來降低該含活性劑之材 cP和4,000,000 cp之間的黏度。 可藉由加熱包含在配送泵中或正 如上所述且如下面申請專利範圍所進一步定義， 發明提供處理淚管塞之方法及實施該方法之設備，以及 由此形成的淚管塞。 【圖式簡單說明】 圖1為根據本發明的一些實施例，所繪示之一淚管 塞以及貯放於淚管塞的方法。 圖2圖2A為根據本發明的一些實施例，繪示用於 在淚管塞貯放的設備。 ' 圖3根據本發明的一些實施例，繪示用於在淚管塞 貯放設備的另一面向。 15 201039876 【主要元件符號說明】 101.. .淚管塞裝置 102.. .開口 103.. .分注器尖頭 104.. .材料 105.. .腔穴 200.. .泵 201·..匣 202.. .分注器主體 203.. .分注器尖頭 204.. .加熱源 205.. .加熱源 206.. .加熱源（溫度探測器） 207.. .泵體 301.. .分注器尖頭 302.. .快速替換式尖頭底座 303.. .泵體 304.. .軌道An active agent-containing material to reduce the viscosity between the active agent-containing material cP and 4,000,000 cp. The invention can be provided by a method of treating a punctal plug and a device for performing the method, and a tear duct plug formed thereby, by heating contained in a dispensing pump or as further described above and as further defined in the following patent claims. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram showing a tear duct plug and a method of storing it in a punctal plug, in accordance with some embodiments of the present invention. 2 and 2A illustrate an apparatus for storage in a punctal plug, in accordance with some embodiments of the present invention. Figure 3 illustrates another orientation for use in a punctal plug storage device, in accordance with some embodiments of the present invention. 15 201039876 [Description of main component symbols] 101.. . Tears plug device 102.. Opening 103.. Dispenser tip 104.. .Materials 105.. Cavity 200.. .Pump 201·..匣 202.. . Dispenser body 203.. . Dispenser tip 204.. Heating source 205.. Heating source 206.. Heating source (temperature detector) 207.. Pump body 301.. . Dispenser tip 302.. Quick replacement tip base 303.. Pump body 304.. . Track
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