TWI326216B - A delivery system selected from the group consisting of implant, intrauterine system, intracervical system and intravaginal system - Google Patents

A delivery system selected from the group consisting of implant, intrauterine system, intracervical system and intravaginal system Download PDF

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TWI326216B
TWI326216B TW91119649A TW91119649A TWI326216B TW I326216 B TWI326216 B TW I326216B TW 91119649 A TW91119649 A TW 91119649A TW 91119649 A TW91119649 A TW 91119649A TW I326216 B TWI326216 B TW I326216B
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delivery system
core
membrane
poly
composition
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TW91119649A
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Haapakumpu Timo
Ala-Sorvari Juha
Aaltonen Marko
Keinanen Antti
Ahola Manja
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Bayer Schering Pharma Oy
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1326216 五、發明說明(1 ) 發明領域 本發明係關於一種輸送系統,包含一核心及包裝該核心 的膜*其中該核心及膜本質上由相同或不同的彈性物組成 物(e 1 a s t 〇 m e r c 〇 m ρ 〇 s i t i ο η )構成。 發明背景 專利 US 6,056,976 和 US 6,299,027 及 2000 年 11 月 30 日申請受理之申請案序號US 09/701,547 (相同案:W0 00/00550 )併入參考。 聚矽氧烷,例如聚(二甲基矽氧烷)(PDMS)極適合用於作 爲膜或基質於各種活性劑形式中調節活性劑滲透作用,特 別於植入物及子宮內系統(IUS)。聚矽氧烷爲生理惰性的 ,且有廣泛群類的活性劑能穿越聚矽氧烷膜,此膜亦具有 所需之機械特性》 申請人於2000年11月30日申請受理之申請案序號 09/701,547,揭示一種彈性物組成物含有聚(伸烷氧化物) 類,且聚(伸烷氧化物)類存在於彈性物或聚合物中作爲聚 矽氧烷單位之經烷氧基終止之接枝物,或作爲嵌斷物,該 嵌斷物或接枝物經由矽-碳鍵聯結到聚矽氧烷單位,或作 爲這些形式之混合物。此申請案也揭示此等彈性物的製備 方法。 -申請人獲准之專利US 6,056,976揭示一種彈性物:矽氧 烷爲基礎之彈性物,含有3,3,3-三氟丙基附著於矽氧烷單 位的矽原子,且該輸送系統中該治療用活性劑的釋放速 1326216 五、 發明說明 ( 2) 率 可 經 由該 3, 3,3- 三氟丙 基 量調 整 〇 數 篇 公開 案 揭示 輸送系 統 可釋 放 多於 一 種 的治 療 用活性 劑 〇 例 如專 利 US 5,972, 3 72揭 示 —種 陰 道 環, 含有一 主 體(含有第- -種聚合性物質)及一 中 空內 管 道 。此 環 進一 步 包 括含 藥核 心 置於 該內管 道 中且 由 第— -J - 種 聚 合性 物 質組成 〇 該 聚 合性物 質可 例如矽 彈 性物 例如 PDMS 或 其 含有 氣 基 之 衍 生物 〇 但此 文件未 揭 示核 心 •膜結構。 專 利 US 5, 443, 461揭 示 —種 擴 散性 輸 送 系統 其建 構 爲 兩 隔 間, 各含有 一種治 療 用活性 劑。 這 些 活性 劑 係獨 地 各 白 釋放 0 介於 隔間間 之 壁部 分 ,例 如 可 由熱 塑 性彈 性 物 構 成 。活 性 劑經 配方於 組 成物 中 ,組 成 物 包括 稀 釋劑 如 聚 合 物 混合 物 。聚 乙二醇 混 合物 爲 合適 之 混 合物 寶 列。 專 利 US 5, 496 , 5 5 7呈 現 -種 控 制活 性物 質輸 送 之輸 送 系 統 5 其包含 經璧 圍住之 中 空空 間 並塡 入 該 活性物 質。 此 壁 製 造 自生 物 可分 解聚合 物 ,且 只 有一 塡 補物實 例 ,亦 即 活性 物 質分 散 於蓖 麻油中 〇 因此 該 系統 未 揭 示由 彈 性物 製 成 的 核 心。 此 系統 更進一 步 塗覆 以 非滲 透 性 生物 可分解 聚 合 物 ) 活性 物 質之 擴散速 率 係由 未 覆蓋 該 非 滲透 性 聚合 物 之 壁 表 面控制 。若 壁損壞 時 此種 系 統可 能 出 現問 題 ,亦 即 活性物 質以 未 受控 制之方 式 釋放 〇 此等 釋 放 可能 因 活性 物 質 之 副 作用 或活性 物質中 毒 導致 嚴 重問 題 〇 靈 明 之 冃的 及 槪述 本 發 明之 巨的 係提供 -種輸送系統, -4 - 可在同時間以 1326216 五、 發明說明(3) 固 定 之 預定速率釋放至少兩種不同活性劑。 本 發 明進一步之目的係提供一種輸 送 系 統 甚 至 被 毀 壞 也 不 會對受試者造成任何危險。 再 者 ,本發明旨在提供一種輸送系 統 可 簡 易 且 具 成 本效 益 的生產。 發 明 之 詳細說明 本 發 明揭示於添附之申請專利範圍。 根 據 本發明之系統含有一核心及包 裝 該 核 心 的 膜 其 中 該 核 心及膜本質上由相同或不同的 彈 性 物 組 成 物 構 成 > 其 特 徵爲核心含有至少兩種各具釋 放 速 率 之 治 療 用 活 性 劑 〇 於 是 此核心及膜本質上由相同或不 同 之 進 -- 步 揭 示 於 下 的 彈 性物組成物構成。本申請案中, 專門名 詞 * 彈 性物 組 成物 ”可代表單一彈性物,或由兩彈 Μ生物交 錯 於另 — 方 內 部 製 成之彈性物組成物。 用 於 膜之彈性物組成物爲如此,以 致 使 活 性 劑 具 預 定 且 固 定 的釋放速率。經由彈性物組成 物 之 •ί巳Β 擇 於 是 得 到 本 發 明 之第一目的。第二,核心本質 上 由 彈 性 物 組 成 物 構 成 5 亦即核心爲彈性物基質而活性 劑 分 散 其 中 〇 因 此 , 甚 至 當包裝該核心之膜受損時,活 性 劑 不 會 以 完 全 未 受 控 制 之方式釋放而對受試者造成以 上 提 及 之 問 題 〇 如 此 々ee m 擇 之核心彈性物組成物使活性劑 白 核 心 的 釋 放 速 率 商 於 透 過膜之釋放速率,但足夠低至 -5 - 避 免 任何 問 題 〇 於 1326216 五、發明說明(4) 是釋放速率能單獨經由膜或膜與核心一起控制。亦可能 釋放速率主要由核心控制,而膜只表現於釋放速率之最 終控制。 根據本發明之輸送系統可爲植入物,子宮內系統,子 宮頸內系統或陰道內系統。此等系統之製造揭示於下, 雖然其爲熟知技藝。系統的形狀及大小亦可由熟習該技 藝者自由選擇。很明顯地,根據本發明之系統可應用於 人類及動物。例如當輸送系統爲子宮內系統時,可進一 步含有系統之主體形成結構。於此情形,系統之核心-膜 -結構爲中空,以致能放置在系統之主體上。主體具有T ,s或7之形式。 根據本發明之一具體實施例,核心由含有至少兩種治 療用活性劑之一部分構成。根據本發明之另一具體實施 例’核心由至少兩部分構成,每一部分含有該至少兩種 治療用活性劑之至少一種。該部分之彈性物組成物之選 擇係根據所欲之釋放速率,且可爲相同或不同於每一部 分。根據該具體實施例,其中核心由兩部分或兩部分以 上構成,部分可彼此鄰接或核心之一部分至少部分圍繞 核心之另一部分。結構之任何組合當然有可能存在並在 本發明範圍內。使用數個部分的優點爲釋放速率更易於 控制,因爲活性劑間沒有交互作用。 又根據本發明之一具體實施例,膜由至少兩層構成,每 一層具有一定厚度。各層之厚度可相同或不同,且用於每 1326216 五、 發明說明 (5) — 層 之 彈 性 物組成物亦可爲相同或不同。包裝每一上述核 心 部 分 之 膜 ’其彈性物組成物或膜結構(一或數層)亦可相 同 或 不 同 〇 不同層膜在厚度或材料或二者之組合,給予進 — 步 可 能性於活性劑釋放速率之控制。 根 據 一 具 體實施例,根據本發明之系統進一步含有一空 間 分 開 核 心 之該至少兩部分之至少兩部分,及/或至少一. 分 開 膜 分 開 核心之該至少兩部分之至少兩部分,該分開膜 本 質 上 由 彈 性物組成物構成。例如可能根據本發明製造一 系 統 具 有 由 A、B及C三部分構成之核心,A及B部分經空 間 分 開 B 及C部分經膜分開。A及B部分彼此鄰接而無 空 間 或 膜 介於其間且B及C部分經膜分開之系統,或A及 B 部 分 經 第 一種彈性物組成物所構成之膜分開且B及C部 分 經 不 同 於 第一種彈性物組成物之第二種彈性物組成物所 構 成 之 膜 分 開之系統,亦在本發明範圍內,任何其他組合 亦 同 〇 又 根 據 本 發明之一具體實施例,分開膜對至少一種治 療 用 活 性 劑 爲可滲透或不可滲透。當然可能使用之膜對 第 一 種 活性 劑爲可滲透但對第二種活性劑爲不可滲透。 根 據 本 發 明之一較佳具體實施例,以上提及之彈性物組 成 物 亦 即 核心、膜及分開膜之彈性物組成物係爲相同或 不 同 以 及 cee r±j · ;«目· - 含有 聚 (二甲基矽氧烷)之彈性物組成物, 含有 3 ,3 ,3 -三氟丙基附著於矽氧烷單位矽原子之以矽氧 -7 - 1326216 五、發明說明(6) 烷爲基礎之彈性物之彈性物組成物, •含有聚(伸烷氧化物)類之彈性物組成物,該聚(伸烷氧化 物)類以烷氧基終止之接枝物或嵌斷物經由矽-碳鍵聯結 到聚矽氧烷單位,或以這些形式之混合物呈現,以及 -至少兩種之組合物。 根據本發明之一具體實施例,以矽氧烷爲基礎之彈性物 1中,接近50%的取代基附著於矽氧烷單位之矽原子者爲 3,3,3-三氟丙基。 根據本發明之另一具體實施例,以上提及之聚(伸烷氧 化物)類爲聚(環氧乙烷)類。 以上提及之彈性物組成物進一步詳細討論如下。 又根據本發明之一具體實施例,至少兩種治療用活性 劑之釋放速率是相同或不同。根據本發明之一較佳具體 實施例,治療用活性劑爲荷爾蒙,例如黃體脂酮 (progestin),雌激素(estrogen),抗黃體脂酮或雄激素 (androgen)。此系統亦可包括任何其他治療用活性物質 ,可與給予之荷爾蒙或其他活性劑適當地結合。適合的 治療用活性劑舉例如下。 根據本發明之一具體實施例,治療用活性劑於子宮內 、子宮頸內或陰道內系統之釋放速率爲0.1 -300 /zg/天 。根據本發明之另一具體實施例,治療用活性劑於植入 物之釋放速率爲〇.卜300 /zg/天,這些實例是應用於荷 爾蒙。 1326216 五、發明說明(7) 以上提及之具體實施例的任何組合可能在本發明範圍 內,熟習該技藝者將能發現用於特殊使用之最適合組合 〇 根據本發明系統之製備,對於熟習該技藝者是明顯的 。的確,此系統例如可經由擠壓或製模製造。製備進一 步討論如下。 彈性物組成物 適用於根據本發明系統之一彈性物,特別是用於系統之 膜中的彈性物是含有3,3 , 3 -三氟丙基附著於矽氧烷單位矽 原子之以矽氧烷爲基礎之彈性物。 需知專有名詞“以矽氧烷爲基礎之彈性物”包含由聚(經 二取代之矽氧烷類)構成之彈性物,此處取代基主要爲低 級烷基(較佳爲含1至6碳原子之烷基)或苯基,其中該烷 基或苯基可經取代或未取代。廣泛使用且較佳之此類聚合 物爲聚(二甲基矽氧烷)(PDMS)。 根據本發明,彈性物中附著於矽氧烷單位矽原子之一定 量取代基可爲3,3,3 -三氟丙基。此等彈性物能以不同方法 完成。根據一具體實施例,彈性物之基礎可爲一單交叉聯 結之以矽氧烷爲基礎之聚合物,例如聚(二烷基矽氧院), 此處位於矽原子之一定量烷基可置換以3,3,3 -三氟丙基。 此等聚合物之較佳實施例爲聚(3,3,3 -三鐘<丙基甲基砂氧 烷),其結構如下化合物I所示。 1326216 五、發明說明(8)1326216 V. INSTRUCTION DESCRIPTION (1) Field of the Invention The present invention relates to a delivery system comprising a core and a film encapsulating the core* wherein the core and film are essentially composed of the same or different elastomers (e 1 ast 〇merc 〇m ρ 〇siti ο η ). Background of the Invention The patent application number US 6,056,976 and US 6,299,027 and the application number of the application No. US 09/701,547, filed on Nov. 30, 2000, the same is incorporated herein by reference. Polyoxyalkylenes, such as poly(dimethyloxane) (PDMS), are well suited for use as membranes or substrates to modulate active agent penetration in a variety of active agent forms, particularly in implants and intrauterine systems (IUS). . Polyoxane is physiologically inert, and a wide range of active agents can pass through the polysiloxane film, which also has the required mechanical properties. Applicant's application for acceptance on November 30, 2000 09/701,547, discloses that an elastomer composition contains a poly(alkylene oxide) type, and a poly(alkylene oxide) is present in the elastomer or polymer as a polyoxyalkylene unit terminated by an alkoxy group. The graft, or as an insert, is bonded to the polyoxyalkylene unit via a hydrazone-carbon bond, or as a mixture of these forms. This application also discloses the preparation of such elastomers. - Applicant's patent US 6,056,976 discloses an elastomer: a siloxane-based elastomer containing a ruthenium atom attached to a decane unit of 3,3,3-trifluoropropyl, and the treatment in the delivery system Release rate of the active agent 1326216 V. DESCRIPTION OF THE INVENTION (2) The rate can be adjusted via the 3, 3,3-trifluoropropyl amount adjustment. The disclosure discloses that the delivery system can release more than one therapeutic active agent, for example Patent US 5,972, 3 72 discloses a vaginal ring comprising a body (containing a first polymeric substance) and a hollow inner tube. The ring further includes a drug-containing core disposed in the inner conduit and composed of a -J-polymerizable substance, such as a fluorene-based elastomer such as PDMS or a gas-containing derivative thereof, but the document is not Reveal the core • membrane structure. Patent US 5,443,461 discloses a diffuse delivery system constructed as two compartments each containing a therapeutic active agent. These active agents release the white portion of the partition between the compartments, for example, from thermoplastic elastomers. The active agent is formulated into a composition comprising a diluent such as a mixture of polymers. The polyethylene glycol mixture is a suitable mixture. Patent US 5, 496, 5 5 7 presents a delivery system for controlling the transport of active substances 5 which comprises a hollow space enclosed by a crucible and infiltrated into the active material. This wall is made of a biodegradable polymer and has only one auxiliaries, that is, the active substance is dispersed in ricin oil. Therefore, the system does not reveal the core made of elastic material. The system is further coated with a non-permeable biodegradable polymer. The rate of diffusion of the active species is controlled by the surface of the wall that is not covered by the non-permeable polymer. If the wall is damaged, such a system may have problems, that is, the active substance is released in an uncontrolled manner. Such release may result in serious problems due to side effects of the active substance or poisoning of the active substance. The giant system provides a delivery system, and -4 - can release at least two different active agents at a predetermined rate of fixation at the same time as 1326216. A further object of the present invention is to provide a delivery system that is even destroyed and does not pose any risk to the subject. Furthermore, the present invention is directed to providing a delivery system that is simple and cost effective. DETAILED DESCRIPTION OF THE INVENTION The present invention is disclosed in the scope of the appended patent application. The system according to the invention comprises a core and a membrane encasing the core, wherein the core and membrane consist essentially of the same or different elastomeric composition> characterized in that the core contains at least two therapeutic active agents each having a release rate Thus, the core and the membrane are essentially composed of the same or different elastomeric compositions disclosed in the next step. In the present application, the term "elastic composition" may mean a single elastic material, or an elastic composition formed by interlacing two elastic organisms inside another material. The elastic composition for the film is such that In order to achieve a predetermined and fixed release rate of the active agent, the first object of the present invention is obtained via the composition of the elastomer. Second, the core is essentially composed of an elastomer composition. The substrate is dispersed while the active agent is dispersed. Therefore, even when the membrane encapsulating the core is damaged, the active agent is not released in a completely uncontrolled manner, causing the above-mentioned problems to the subject. The core elastomer composition allows the release rate of the active agent white core to be commensurate with the rate of release through the membrane, but sufficiently low to -5 - to avoid any problems. 1326216 V. Inventive Note (4) is that the release rate can be via membrane alone or The membrane is controlled together with the core. It is also possible that the release rate is mainly determined by the nucleus. The heart is controlled while the membrane is only present in the final control of the release rate. The delivery system according to the invention may be an implant, an intrauterine system, an intrauterine system or an intravaginal system. The manufacture of such systems is disclosed below, although The shape and size of the system are also freely selectable by those skilled in the art. Obviously, the system according to the invention can be applied to humans and animals. For example, when the delivery system is an intrauterine system, the body of the system can be further included. Forming the structure. In this case, the core-membrane-structure of the system is hollow so that it can be placed on the body of the system. The body has the form of T, s or 7. According to one embodiment of the invention, the core contains at least two According to another embodiment of the present invention, the core comprises at least two parts, each part containing at least one of the at least two therapeutic active agents. The selection of the elastic composition of the part Depending on the desired release rate, and may be the same or different from each part. According to this particular embodiment, where the core Two or more parts may be formed, the parts may be adjacent to each other or one part of the core at least partially surrounds another part of the core. Any combination of structures may of course be present and within the scope of the invention. The advantage of using several parts is that the release rate is easier Control, because there is no interaction between the active agents. According to another embodiment of the invention, the film is composed of at least two layers, each layer having a certain thickness. The thickness of each layer may be the same or different, and is used for every 1326216. (5) - The elastomer composition of the layer may be the same or different. The film of each of the core portions of the package may have the same or different elastomer composition or film structure (one or several layers). The thickness or material, or a combination of both, gives the possibility of further control over the release rate of the active agent. According to a specific embodiment, the system according to the present invention further comprises at least two portions of the at least two portions of the spatially separated core, and/or at least one. separating the membranes to separate at least two portions of the at least two portions of the core, the split membrane Essentially composed of an elastomer composition. For example, it is possible to fabricate a system having a core consisting of three parts A, B and C according to the present invention, and portions A and B are separated by a space separation B and C portions. A system in which parts A and B are adjacent to each other without space or film interposed therebetween and portions B and C are separated by a membrane, or portions A and B are separated by a membrane composed of the first elastomer composition and portions B and C are different A membrane-separated system of the second elastomer composition of the first elastomer composition is also within the scope of the invention, any other combination, and in accordance with an embodiment of the invention, the membrane pair is separated At least one therapeutically active agent is permeable or impermeable. It is of course possible to use a membrane that is permeable to the first active agent but impermeable to the second active agent. According to a preferred embodiment of the present invention, the elastic composition of the above-mentioned elastomer composition, that is, the core, the membrane and the separation membrane are the same or different and cere r±j ·; An elastomer composition of (dimethyloxane) containing 3,3,3-trifluoropropyl groups attached to a heptane atom of a helium atom to a helium oxygen-7 - 1326216 V. Description of the invention (6) An elastomer composition of a base elastomer, • an elastomer composition containing a poly(alkylene oxide) type, which is an alkoxy terminated graft or insert via a crucible - a carbon bond to the polyoxyalkylene unit, or a mixture of these forms, and - a combination of at least two. According to a specific embodiment of the present invention, in the elastomer 1 based on decane, nearly 50% of the substituents attached to the ruthenium atom of the siloxane unit are 3,3,3-trifluoropropyl. According to another embodiment of the invention, the above-mentioned poly(alkylene oxide) is a poly(ethylene oxide) type. The elastomer compositions mentioned above are discussed in further detail below. According to still another embodiment of the invention, the release rates of the at least two therapeutically active agents are the same or different. According to a preferred embodiment of the invention, the therapeutically active agent is a hormone, such as a progestin, an estrogen, an anti-luteal fat or an androgen. The system may also include any other therapeutically active substance that can be suitably combined with the hormone or other active agent administered. Suitable therapeutic active agents are exemplified below. According to a particular embodiment of the invention, the release rate of the therapeutic active agent in the uterus, intracervical or intravaginal system is from 0.1 to 300 /zg/day. According to another embodiment of the invention, the release rate of the therapeutically active agent to the implant is 〇. 300 / zg / day, and these examples are applied to the hormone. 1326216 V. INSTRUCTIONS (7) Any combination of the specific embodiments mentioned above may be within the scope of the present invention, and those skilled in the art will be able to find the most suitable combination for special use, the preparation of the system according to the present invention, The artist is obvious. Indeed, this system can be manufactured, for example, by extrusion or molding. The preparation is further discussed below. The elastomer composition is suitable for use in an elastomer according to the system of the invention, in particular in the membrane of the system, which comprises a 3,3,3-trifluoropropyl group attached to the helium atom of the helium oxide. Alkane based elastomer. The term "anthracene-based elastomer" as used herein includes an elastomer composed of a poly(disubstituted alkane), wherein the substituent is mainly a lower alkyl group (preferably having 1 to An alkyl group of 6 carbon atoms or a phenyl group wherein the alkyl group or phenyl group may be substituted or unsubstituted. A widely used and preferred such polymer is poly(dimethyloxane) (PDMS). According to the present invention, a certain amount of the substituent attached to the oxime atom of the oxime unit in the elastomer may be a 3,3,3-trifluoropropyl group. These elastomers can be completed in different ways. According to a specific embodiment, the basis of the elastomer may be a single cross-linked, siloxane-based polymer, such as poly(dialkyl oxime), where one of the ruthenium atoms is quantitatively alkyl replaceable. Take 3,3,3-trifluoropropyl. A preferred embodiment of such polymers is poly(3,3,3-three-bell<propylmethyloxa oxane) having the structure shown below for compound I. 1326216 V. Description of invention (8)

ch3Ch3

化合物I 此類聚合物爲可購商品’其中接近50%位於砂原子之甲 基取代基是置換以3 , 3 , 3 -三氟丙基。“接近50%” 一詞意 指3,3, 3-三氟丙基取代的程度,而實際上低於50%,係因 該聚合物必須含有一定量(約〇 .丨5%的取代基)的可交叉聯 結基如乙烯基或乙烯基-終端基。類似具有較低3,3 , 3 -三 氟丙基取代程度之聚合物可被輕易合成。 3 , 3 , 3 -三氟丙基對活性劑滲透穿越彈性物膜之遲緩效果 ’是視這些基之量而定。再者,此效果高度視所使用之活 性劑而定。若彈性物只由單一聚合物製成,則針對不同活 性劑必需製備並使用含有不同量3,3,3 -三氟丙基之聚合物 〇 根據另一具體實施例,特佳爲對於數種不同活性劑若 需要適合之彈性物時,其係交叉聯結一混合物,該混合 物含有a )未經氟取代之以矽氧烷爲基礎之聚合物,以及 b )經氟取代之以矽氧烷爲基礎之聚合物,此處該聚合物 含有3,3,3 -三氟丙基係附著於矽氧烷單位的矽原子。混 -10- 1326216 五、發明說明(9 ) 合物的第一成分爲未經氟取代之聚合物,可爲任何聚(經 二取代之矽氧烷),此處取代基主要爲低級烷基(較佳爲1 至6碳原子之烷基)或苯基,其中該烷基或苯基可經取代 或未取代。取代基最佳爲1至6碳原子之烷基。較佳的 未經氟取代之聚合物爲PDMS。混合物的第二成分爲經氟 取代之聚合物,例如可爲聚(二烷基矽氧烷),此處一定 量位在矽原子之烷基是置換以3,3, 3 -三氟丙基。此等聚 合物之較佳實例如上述之聚(3,3,3 -三氟丙基甲基矽氧烷) 。此類特佳聚合物爲盡可能含有高量3 ,3,3 -三氟丙基取 代基之聚合物,例如可購買之聚合物商品,其中接近50% 位於矽原子之甲基取代基是經3 , 3,3 -三氟丙基置換。利 用全部或大部分前述提及之聚合物,可獲得具有較大滲 透作用遲緩影響之彈性物。利用增加量之未經氟取代之 矽氧烷爲基礎之聚合物的混合物,可獲得對於活性劑滲 透作用具有較少遲緩影響之彈性物。 可用於本發明之彈性物含有聚(伸烷氧化物)類以至於聚 (伸烷氧化物)類以聚矽氧烷單位之烷氧基-終端接枝物或 以嵌段物呈現於該彈性物中,該接枝物或嵌段物經由矽· 碳鍵聯結到聚矽氧烷單位。聚(伸烷氧化物)亦可以所提選 擇之混合呈現》第二個彈性物可爲以矽氧烷爲基礎之彈性 物,適合之以聚(二甲基矽氧烷)爲基礎之彈性物。該第二 個彈性物可能也包含聚(伸烷氧化物)類。這些聚(伸烷氧 化物)類也可以聚(二甲基矽氧烷)單位之烷氧基。終端接枝 -1 1 - 1326216 五、 發明說明(1〇 ) 物 或 以 嵌段物呈現,該接枝物或嵌段物經由矽-碳鍵 聯 結 到聚 (二甲基矽氧烷)單位—。聚(伸烷氧化物類)亦可以 前述 所 提 選 擇之混合呈現於此彈性物中。 根 據 本發明之一具體實施例,彈性物組成物可爲混 合 物 J 其 包含以矽氧烷爲基礎之彈性物,例如由PDMS構 成 以 及 至 少一含有聚(伸烷氧化物)類之直鏈聚矽氧烷共 聚 物 〇 於 此 情形,聚(伸烷氧化物)類以矽氧烷單位之烷氧基- 終 端 接 枝物或以嵌段物呈現於該聚合物中,該接枝物或嵌 段物 經 由矽-碳鍵聯結到聚矽氧烷單位。當然聚(伸烷 氧 化 物 )類亦可以前述形式之混合呈現於聚合物中。於此 具 體 實 施 例 中,以矽氧烷爲基礎之彈性物也可以含有聚( 伸 烷 氧 化 物 )類,於此情形這些聚(伸烷氧化物)類以聚矽 氧 烷 單 位 之 烷氧基-終端接枝物或以嵌段物呈現於此該彈 性 物 中 ) 該 嵌段物或接枝物經由矽-碳鍵聯結到聚矽氧烷 單 位 〇 聚 (伸烷氧化物)類亦可以前述形式之混合呈現。 當 然 ,彈性物組成物之構成亦可如前述由兩彈性物 內 部 交 織 組 合,以及含有聚(伸烷氧化物)類之至少一直鏈 聚 矽 氧 烷共 聚物。 彈 性 物組成物之聚(伸烷氧化物)類適當者例如聚( 伸 烷 氧 化 物 )類(PEO 類)。 彈 性 物組成物之聚矽氧烷單位之較佳群類爲具有式- (S iR ’R ’,0)qSiR’R,,- 其 中 R’及R’’爲 -1 2 - 1326216 五、發明說明(11) -部分自由基,其爲相同或不同之低級烷基或苯基:於此 Is开;^該院基或本基可經取代或未經取代,或具有下式之 院氧基-終端之聚(伸院氧化物) R I-R -〇-(CH-CH2-0)m-alk, 此處a 1 k爲低級烷基,合適的甲基’ R爲氫或低級烷基 ’ m爲1…30,以及R3爲直鏈或支鏈c2-c6院基, -自氫或烯基到彈性物中其他聚合物鏈形成之部分鍵結, 以及 -可能之部分不反應之基’例如氫,乙烯基或乙烯基-終 端之烯基,以及 -q 爲 1 ...3000。 此處及本發明中一般性敘述之“低級烷基”一詞係代表 C i - C 6院基。 以上提及之自由R’及R’’基爲適當之低級烷基,以甲基 爲佳。 “聚(伸烷氧化物)類”意指該類包含至少兩烷基醚連續 連接到另一者。 根據一較佳具體實施例,聚(伸烷氧化物)群類以具有下 式之聚(伸烷氧化物)嵌段物形式呈現於彈性物中 -13- 1326216 五、發明說明(12) RI -(CH2)y0(CHCH20)m(CH2)y-, or Ri R RiII I -CH2CHCOO(CHCH20)mCOCHCH2- 此處R爲氫,低級烷基或苯基, R,爲氫或低級院基,y爲2…6,以及m爲1…30。 彈性物之組合較佳爲具有聚(環氧乙烷)-PDMS之PDMS以 及具有經氟取代之PDMS。 彈性物組成物較佳含有一塡充劑,例如無定形矽,以賦 予足夠強度於製造自該彈性物之膜。亦可能包括其他添加 劑,然考慮他們對受試者需爲生物可相容且無害。 這些彈性物之製備方法已提供於申請人上述提及之專利 及專利申請案中。 合適材料之進一步實例包括聚乙烯,聚丙烯,聚甲基戊 烯’乙烯/丙烯共聚物,乙烯/丙烯酸乙酯共聚物,乙烯/ 乙酸乙烯酯共聚物,聚碳酸鹽,聚四氟乙烯(PTFE),氟乙 烯丙烯(FEP)’聚亞乙烯氟(PVDF),聚乙酸乙烯酯,聚苯 乙烯,聚醯胺類,聚胺基甲酸乙酯,聚丁二烯,聚異戊_ 間-二烯,氯化聚乙烯,聚乙烯氯,具有乙酸乙烯酯之乙 烯氯共聚物,聚(甲基丙烯酸),聚甲基(甲基)丙烯酸,聚 (亞乙烯)氯,聚(亞乙烯)乙烯,聚(亞乙烯)丙烯,聚乙烯 對-酞酸,乙烯乙酸乙烯酯,聚烷氧酸羥酯聚(乳酸),聚( -14- 1326216 五、發明說明(13) 羥基乙酸),聚(2 -氰基丙烯酸烷酯),聚酐類’聚正醋類 ,乙烯/乙烯醇共聚物’乙烯/乙酸乙烯酯/乙烯醇三聚物 ,乙烯/乙烯氧乙醇共聚物,乙烯/乙烯基/乙酸共聚物’ 乙烯乙烯基/醇共聚物,親水性聚合物如丙烯酸及甲基丙 烯酸酯類之親水性水凝膠,經修改原膠’交鏈聚乙烯醇’ 交鏈、部分水解之聚乙酸乙烯酯,矽彈性物’尤其是醫藥 級聚二甲基矽氧烷類,聚乙烯基甲基矽氧烷類,其他有機 聚矽氧烷類,聚矽氧烷,新戊·間·二烯橡膠’丁基橡膠’ 環氧氯丙烷橡膠類,室溫硫化型之羥基終止之有機聚矽氧 烷類(於固化催化劑存在下添加交鏈劑後,在室溫使彈性 物硬化),兩成分二甲基矽氧烷組成分(其在室溫或提高溫 度下經鈾催化,及能添加交鏈及其混合物)。 ;値入物之製浩 根據本發明之植入物可根據標準技術製造。治療用活性 劑與核心基質聚合物混合,經由造型,鑄造,擠壓,或其 他適用方法加工成所要形狀。膜層可根據已知方法例如經 由機械性伸展,膨脹或沾浸塗覆到核心上。參考資料如美 國專利 US 3,832,252,US 3,854,480,以及 US 4 , 957,1 1 9。製備植入物之特別適用方法揭示於芬蘭專利 FI 97947。此專利揭示壓擠技術,其中含活性成分之預製 棒以外膜包覆。舉例而言,每一此等棒子以另一不含活性 成分之棒子接續。形成之長串於不含活性成分之棒子處被 切割。以此方法,則植入物無需特別於棒子封口。 -15- 1326216 五、發明說明(14) 于宮內’陰道內及子宮頸內系統之製浩 子呂內系統可根據已熟知之技術製作。常用主體具有τ ,S或7之形式。的較佳子宮內系統(IUS,子宮內系統), 陰道內系統或子宮頸內系統是以塑膠材料例如聚乙烯製造 的T型主體。主體由延長膜(柄)構成’該膜的—末端有一 含兩翼之橫斷膜。當此系統位於子宮內時,延長膜及橫斷 膜形成實質之T型片。當此系統位於子宮內時,該系統有 一足夠長之繫線可突出到子宮頸通道。系統亦可爲任何其 他形狀,例如7,S,Ω環或c。I US : s釋放活性劑有一活 性劑貯存器(對應於本發明核心或核心-膜)調整圍繞於延 長膜。亦可能調整一貯存器於I US之一部分以及另一貯存 器至IUS另一部分。活性劑貯存器爲根據本發明之輸送系 統’亦即包裝於膜之核心。根據本發明之子宮內,陰道內 系統及子宮頸內系統於是亦可含有主體,其中裝上含有該 核心及膜之系統。 T型子宮內系統係以傳統製造,首先分開形成主體及貯 存器,然後例如經由拉引將貯存器置於主體上,以及最後 形成一膜覆蓋貯存器,如此形成一核心-膜-結構。 治療用活件劑 可適用於本發明之治療用活性劑代表例包括(以治療分 類分組): . 抗高血壓劑:例如海卓拉哄(hydralazine),麥諾西帝 爾(minoxidil) ’卡普托普瑞爾(capt〇pril),安那拉普瑞 -16- 丨216 五 發明說明 15 爾(enalapril),克羅奈啶(clonidine),普瑞柔辛 (Prazosin),帝布利梭喹(deb risoquine),重氮氧化物 (diazoxide),胍噻陡(guanethidine),甲基多巴 (methyldopa),利瑟平(reser pine),三甲分 (trimethaphan),奈非代平(nifedipine)以及艾思拉代平 (isradipine) > 鈣通道阻斷劑:例如代太吖寧(diltiazem),非羅代平 (felodipine),阿羅代平(amlodipine),奈翠代平 (nitrendipine),奈非代平(nifedipine)以及威拉帕蜜爾 (verapamil); 抗調節不整劑:例如阿密歐大酮(amiodarone),弗力卡 奈德(flecainide),代梭壯醯胺(disopyramide),普康醯 胺(procainamide),麥克斯力特(mexiletene),卩奎奈D定 (quinidine),羅卡卩定(lorcainide)以及畢普利迪爾 (b e p r i d i 1 ); 抗心絞痛劑:例如三硝酸甘油酯(g 1 y c e r y 1 t r i n i t r a t e ) ,四硝酸四丁醋(erythrityl tetranitrate),季戊四醇 四硝酸酯(pentaerythritol tetranitrate),甘露醇六硝 酸醋(mannitol hexanit rate) ’ 全賀利烯(perhexilene) ,異山梨醇糖酐二硝酸(isosorbide dinitrate),奈可拉 帝爾(nicorandil),以及奈卡代平(nicardipine); β -腎上腺素阻斷劑:例如阿普諾醇(a 1 p r e η ο 1 ο 1 ),阿天 諾醇(atenolol),布普諾.醇(bupranolol),卡天歐醇 -17- 1326216 五、發明說明(16) (c a r t e ο 1 ο 1 ),雷比它醇(1 a b e t a 1 ο 1 ),曼陀普羅醇 (metoprolol),那多醇(nadolol),那多梭醇(nadoxolol) ,喝普諾醇(oxprenolol),平多醇(pindolol),普羅普諾 醇(propranolol),梭它醇(sotalol),太模醇(timolol) ,太模醇順-丁燒二酸醋(t i m ο 1 ο 1 m a 1 e a t e );二普羅醇 (bisoprolol),西利普羅醇(celiprolol),以及貝他梭羅 醇(betaxolol); 強心糖音類,例如柔毛洋地黃素(d i g o x i η )以及其他心 臓糖昔類及茶鹼衍生物(theophylline derivatives); 腎上腺素刺激劑:例如腎上腺萊(ad r en a 1 i ne ),麻黃素 (ephedrine),分諾特醇(fenoterol),異普那靈 (isoprenaline),歐系普那靈(orciprenaline),立曼特 醇(rimeterol),沙巴泰醇(salbutamol),沙曼特醇 (salmeterol),特巴泰靈(terbutaline),杜巴他胺 (dobutamine),苯麻黃素(phenylephrine),苯丙醇胺 (phenylpropanolamine),僞麻黃素(pseudoephedrine), 以及多巴胺(dopamine); 血管舒張劑:例如環己杏仁酸鹽(cyclandelate),異梭 普靈(isoxsuprine),馨粟鹼(papaverine),二派立馬朵 (dipyrimadole),異山梨醇糖酐二硝酸(isosorbide dinitrate),酸他命(phentolamine),薛驗醇(nicotinyl alcoho),共-德構克靈(co-dergocrine),薛驗酸 (nicotinic acid),.三硝酸甘油酯(glyceryl trinitrate) -18- 1326216 五、發明說明(17) ,季戊四醇四硝酸醋(pentaerythritol tetranitrate), 以及黃嘌呤醇(xanthinol),文卡胺(vincamine)及奈模代 平(nimodipine); 抗偏頭痛製劑:例如麥角胺(e r g 〇 t a m i n e ),二氫麥角胺 (dihydroergotamine),甲塞蓋德(methysergide),派柔 太分(pizotifen)以及薩瑪徹敦(sumatriptan),以及弗曼 卓酮(f 1 umend r oxone ); 抗凝血劑及溶解血栓劑:例如沃發靈(w a r f a r i η ),代枯 麻洛(d i c o u m a ι· ο 1 ),低分子量肝素如安諾沙肝素 (enoxaparin),鏈激酶(streptokinase)及其活性衍生物 » 止血劑:例如阿普太凝(a p r 〇 t 1 n i η ),傳沙密酸 (tranexamic acid)以及普他命(protamine); 止痛劑及解熱藥包括類鴉片止痛劑,例如巴普諾芬 (buprenorphine),右旋糖莫醯胺(dextromoramide),右 旋糖普丙氧芬(dextropropoxyphene),芬他靈(fentanyl) ,阿芬他靈(alfentanil) ’磺芬他靈(sufentanil),氫嗎 酮(hydromorphone),曼他酮(methadone),嗎啡 (morphine),氧可酮(oxycodone),S 粟堂(papave return) ,戊柔辛(pentazocine),百日銳(pethidine),酹普瑞錠 (phenoperidine),可待因(codeine),二氫可待因 (dhydrocodeine),擴芬他靈(sufentanil)及泰靈錠 (t i 1 idi ne),以及非麻醉形止痛劑如氟酚酸(flugenami c -19- 1326216 五、發明說明(18) acid),吲哚曼他辛(indome t ha c in),艾巴普芬 (ibuprofen),酮普芬(ketoprofen),傳密醇(tramadol) ,氟(分那密酸(flufenamic acid),立嗎柔靈(rimazolium) ,乙醯柳酸(阿斯匹靈),派瑞西他模(paracetamol),以 及酣那 Sl(phenazone); 神經毒素例如辣椒素(c a p s a i c i η ); 類神經疾病用藥:例如巴翠酚衍生物(b u t y r o p h e η ο n e d e r i v a t i v e s ),例如鹵派立醇(h a 1 o p e r i d ο 1 ),或細菌抑 制劑及/或真菌抑制劑,例如泥抑制啶(nystatin)或曼卓 奈疊哩(metronidazole): 安眠藥及鎭靜劑:例如巴比特鹽戊巴比妥 (barbiturates amylobai·bitone),畢托巴比妥 (butobarbitone)和片托巴比妥(pentobarbitone),以及 其他安眠藥及鎭靜劑例水化氯醒(c h 1 〇 r a 1 h y d r a t e ),氯 甲噻哩(chlormethiazole),經哄(hydroxyzine)以及曼普 巴麥特(meprobamate); 抗焦慮劑:例如苯并二吖庚因阿普柔藍 (benzodiazepines alprazolam),布羅馬立朋 (bromazepam),氯氧化二 庚因(chlordiazepoxide),克 羅巴札(clobazam),氯 佩特(chlorazepate),二 PY 朋 (diazepam),弗奈催作朋(flunitrazepam),弗瑞 〇Υ 朋 (flurazepam),羅拉 朋(lorazepam),硝 tJY 朋 (nitrazepam),嗶^ 朋(oxazepam),天瑪朋三 〇Υ 藍 -20 - 1326216 五、發明說明(19)(temazepam triazolam),以及巴斯派酮(buspirone); 類神經疾病及抗精神病用藥:例如酚噻畊 (phenothiazines),氯普哄(chlor promazine),氟酣哄 (fluphenazine),派立賽哄(pericyazine),普酣哄 (perphenazine),普哄(promazine),硫普帕立酸鹽 (thiopropazate),硫立大哄(thioridazine),三氟普哄 (trifluoperazine);以及巴翠酉分(butyrophenone),卓派 立醇(droperidol)以及鹵派立醇(haloperidol); 以及其 他抗精神病用藥例如派模萊德(P i πιοζ i de ),硫西辛 (thiothixene): 抗憂鬱劑:包括二環衍生物例如諾密芬杏(η o m i f e n s i n e ) ,絲徹靈(sertraline),及徹諾酮(trazodone);三環抗 憂鬱劑例如艾咪翠特靈(ami t rypt y 1 ine ),克羅密普胺 (clomipramine),帝西普胺(desipramine),多噻平 (dothiepin),多西平(doxepin),艾密普胺(imipramine) ,正翠特靈(nortriptyline),歐皮普模(opipramol),普 翠特靈(protriptyline)及三密普胺(trimipramine);以 及四環抗憂鬱劑例如麥絲靈(m i a n s e r i η )以及單胺氧化酶 抑制劑如異卡巴立德(i s 〇 c a r b ο X a z i d ),芬立哄 (phenelizine),傳西普胺(tranylcypromine),以及 5 -經 色胺選擇性再攝取抑制劑例如氟苯氧丙胺(f 1 u o x e t i n e ), 氟苯派苯醚(paroxetine),西塔羅普倫(citalopram),氟 彿胺(fluyoxamine),以及絲徹靈(sertraline); -21 - 1326216 五、發明說明(2〇) CNS刺激劑:例如咖啡因,甲基芬奈德酸鹽 (methylphenidate),奈柔酌(nizophenone)及 3-(2 -胺丁 基)吲哚; 抗阿兹海默症劑(anti-A 丨zheimer’s disease agents) 例如他克靈(t a c r i n e ),非梭泰格明(p h y s o s t i g ra i n e ),以 及歐藍 try 庚因(olanzapine); 抗帕金森氏症劑(anti-Parkinson's agents):例如阿 曼他旋(amantadine),苯賽拉寧德(benserazide),碳化 多巴(carbidopa),左旋多巴(levodopa),苯托品 (benztropine),百佩瑞登(biperiden),苯荷梭 (benzhexol),普環旋(procyclidine),以及多巴胺-2 激 動劑例如S ( - ) - 2 - ( N -丙基-N - 2 -噻吩基乙基胺基)-5 -羥基 琳; 抗痙攣劑:例如雙苯內醯脲(phenytoin),瓦普酸 (valproic acid),普立密酮(primidone),酣巴比妥 (phenoba r b i tone),甲酌巴比妥(methylphenobarbitone) ,以及卡巴馬立平(carbamazepine),伊梭蘇西麥 (e t h 〇 s u X i m i d e ),甲蘇西麥(m e t h s u X i m i d e ),苯蘇西麥 (phensuximide),硫噻命(sulthiame)以及克羅那立朋 (clonazepam); 抗催吐劑及抗嘔吐劑:例如酣噻哄(p h e η o t h i a z i n e s ), 普氯普哄(prochloperazine),(g乙基普哄 (thiethylperazine),以及5HT-3受器拮抗劑例如歐丹斯 -22 - 1326216 五、發明說明(21) 鐘(ondansetron)及格藍斯鐘(granisetron),以及代蒙海 卓內特(dimenhydrinate) ’ 二苯氫胺(diphenhydramine) ,曼托克羅普醯胺(metoclopramide),多佩立酮 (domperidone) ’東宕鹼(hyoscine),氫溴酸東宕鹼 (hyoscine hydrobromide) ’ 氫氯酸東宕鹼(hyoscine hyd roch 1 or i de ) ’克立玻普萊德(c 1 ebopr i de )及布羅普萊 德(b romp r i de); 抗發炎劑包括其消旋混合物或各別鏡像物,於此應用時 較佳組合與表皮滲透增強劑製成配方,例如艾巴普芬 (ibuprofen),氟畢普芬(flurbiprofen),酮普芬 (ketoprofen),阿克羅芬那克(aclofenac),代克羅芬那 克(diclofenac),阿洛西匹靈(aloxiprin),阿普羅西 (aproxen),阿斯匹靈,代弗奈沙爾(diflunisal),芬諾 普芬(fenoprofen),因多曼他辛(indomethacin) ’曼芬那 密酸(mefenaniic acid),那普羅西(naproxen),苯基丁氮 酮(phenylbutazone),派洛西康(piroxicam),柳醯胺, 柳酸,蘇靈大(sulindac),帝梭克西蘇靈大 (desoxysulindac),天諾西康(tenoxicam),傳密醇 (tramadol),酮瑞拉克(ketoralac),氟芬尼沙爾 (【111£611丨531),薩薩酸鹽(531$3丨3〖6),三乙醇胺柳酸鹽 (triethanolamine salicylate),胺基啦啉(aminopyrine) ,安太吡琳(antipyrine),氧苯丁氮酮(oxyphenbutazone) ,.阿帕氮酮(apazone),辛大氮酮(cintazone),氟芬那密 -23- 1326216 五、發明說明(22) 酸(flufenamic acid),克羅奈西立爾(clonixeril),克 羅奈辛(clonixin),曼克羅芬那密酸(meclofenamic acid) ,氟奈辛(flunixin),克伊七辛(coichicine),帝曼克辛 (demecolcine),異嘌 D令醇(allopurinol),氧嘌哈醇 (oxypurinol),氫氯酸苯甲胺(benzydamine hydrochloride),代曼方丹(dimefadane),Π弓丨 B朵梭 (indoxole),內嗤(inti· azole),氫氯酸密巴院(mimbane hydrochloride),氫氯酸帕瑞尼立(paranylene hydrochloride),泰翠大胺(tetrydamine),氫氯酸聯苯 姐啉(b e n z i n d 〇 p y r i n e h y d r 〇 c h 1 〇 r i d e ),議普芬 (fluprofen),艾比芬那克(ibufenac),那普梭(naproxol) ,芬比芬(fenbufen),辛克芬(cinchophen),二氟密酮鈉 (diflumidone sodium),芬那莫爾(fenamole),弗太靈 (flutiazin),曼他札醯胺(metazamide),氫氯酸立替醯 胺(letimide hydrochloride),氫氯酸內瑟淀 (nexeridine hydrochloride),辛氮醯胺(octazamide), 模林那哩(molinazole),尼歐辛克芬(neocinchophen), 奈馬 π坐(nimazole),普哩檸檬酸鹽(proxazole citrate) ,泰西康(tesicam),泰西醯胺(tesimide),托曼汀 (tolmetin),卡普芬(carprofen),曼沙拉哄(mesalazine) ,以及三氟密酸鹽(triflumidate); 抗類風濕症劑:例如青黴胺(p e n i c i 1 1 a m i n e ),金硫葡 萄糖(aurothioglucose),金硫蘋果酸鈉(sodium -24 - 1326216 五、發明說明(23) auuthiomaute),胺甲碟呤(methotrexate),以及金諾 @ (aura no fin); 肌肉鬆弛劑:例如巴克羅芬(bacl of en),二BY朋 (d i a z e p a m ),氫氯酸苯 Pfch 啉(c y c 1 o b e n z a p r i n e hydrochloride),丹卓林(dantrolene),甲氧卡巴模 (m e t h o c a r b a m ο 1 ) ’ 歐分那卓靈(〇 r p h e n a d r i n e ),以及奎 寧(qu i n i ne); 用於痛風及高尿酸血症劑:例如異嘌呤醇(an〇purin〇l) ’克伊七辛(coichicine) ’普苯甲酸(probenecid),以及 亞硫壯哗(s u 1 p h i n p y r a ζ ο n e ); 荷爾蒙:例如3 -甲氧基-17a-乙炔基-1,3, 5(10) -雌脂 二烯-1 7-醇[曼斯徹醇(mes t r anol ) ],3 -羥基-1,3 , 5( 10)-雌脂二嫌-17-酮[雌脂酮(estrone)],17β-雌脂二醇,雌 脂三醇’乙炔基雌脂二醇’ 4 -孕烯-3 ,20 -二酮[黃體酮 (progesterone)] ’ d-13-乙基-17α-乙炔基- Ι7β -羥基- 4-性腺嫌-3-酮[d -正孕素(d-norgestrel)]及其醋類,17α-乙炔基-19 -正睪酮[正乙炔單_(norethisterone)]及其醋 類’ 6 -氯-17 -羥基-1α,2α -亞甲基孕-4,6 -二烯-3, 20 -二酮 [賽普特酮(cyproterone)]及其酯類,19 -正羥基黃體酮及 其酯類,6 -氯-17 -乙醯氧基·孕-4,6 -二烯-3 ,20 -二酮[氯 孕酮醋酸鹽(£:111〇1-1113(1丨11〇1^&061&{6)],15,16〇6-亞甲基-及15,16β -亞甲基-17β -羥基-18 -甲基-17oc-乙炔基-4-雌 脂烯-3-酮’ 17α -乙醯氧基- 6α·甲基黃體嗣[甲氧黃體酮醋 -25 - J326216 玉、發明說明(24) 酸鹽(medroxy-progesterone acetate)],90,1〇〇1-孕-4,6-二燃-3,20-二酮[代卓黃體酮((17(11'〇265【61_〇116)],雌 脂二醇-3-甲基乙醚二乙烯雌酚,17α-乙炔基-4-雌脂烯-3β,17β-二醇二醋酸鹽,17α-乙炔基- ΐΐβ -甲基-4雌脂烯 3β , 17β-二醇3,17-二醋酸鹽,1 7α-乙醯氧基-1 ΐβ-甲基· 19 -正孕-4-烯-3-酮,睪酮,睪酮丙酸鹽,睪酮苯乙酸鹽 及其相關雄激素,丙烯基雌脂烯醇,萊諾雌脂烯醇 (lynoestrenol),正孕素(norgestrel),異炔諾酮 (norethyndrel),炔諾酮(norethisterone),炔諾酮乙酸 鹽(norethisterone acetate),孕輝(gestodene),乙基 經基二降孕留嫌炔酮(levonorgestrel),甲氧黃體酮 (medroxyprogesterone) ’ 甲正孕素(megestro",睪酮 (testosterone),甲基睪酮(methyltestosterone),克羅 斯帝伯乙酸鹽(clostebol acetate),卓斯丹諾酮 (drostanolone),夫瑞立博(furazabol),那卓酮氧卓酮 (nandrolone oxandrolone),斯丹柔醇(stanozolol),傳 玻酮乙酸鹽(trenbolone acetate),二氫睪酮,17-α -甲 基-19 -正睪酮以及氟氧曼斯徹酮; 腎上腺皮質激素:例如脫氧皮質酮乙酸鹽 (desoxycor t i cos t e rone acetate),脫氫可地松 (prednisolone); 抗雄激素:例如賽普特酮乙酸鹽(cyproterone acetate) ,氟1泰醯胺(flutamide),奈露泰酸胺(nilutamide),以 -26 - 1326216 五、發明說明(25) 及丹那柔(danazol); 抗雌激素:例如他莫西芬(tamoxifen),托立密芬 (toremifene),克羅密芬(clomifene) ’以及伊皮泰斯丹 酉学(epitiostanol); 芳香酶抑制劑:例如立卓唑(1 e t r ο ζ ο 1 e ),依克西曼斯 烷(exemestane),以及4 -經基·雄脂烧二醇及其衍生物; 5-α還原酶抑制劑:例如發那斯特萊德(finasteride), 圖羅斯特萊德(turosteride); 皮質類固醇類:例如β -麥塞松(betamethasone),β -麥 塞松戊酸鹽(betamethasone valerate),可體松 (cortisone),帝薩麥塞松(dexamethasone),帝薩麥塞松 21-碟酸鹽(dexamethasone 21-phosphate),氟氫可體松 (fludrocortisone),氟麥塞松(flumethasone),氟塞諾 奈德(fluocinonide),氟塞諾奈德帝梭奈德 (fluocinonide desonide),氟塞諾酮(fluocinolone), 氟塞諾酮乙酿奈德(fluocinolone acetonide),氟可托_ (fluocortolone),海塞諾奈德(halcinonide),_ 普酮 (halopredone),氫可體松(hydrocortisone),氬可體松 17 -戊酸鹽(hydrocortisone 17-valerate),氫可體松 17-丁酸鹽(hydrocortisone 17-butyrate),氫可體松 21-乙 酸鹽(hydrocortisone 21-acetate),甲基脫氫皮留醇 (m e t h y 1 p r e d n i s ο 1 ο n e ),脫氫皮留醇(p r e d n i s ο 1 ο n e ),脫 氫皮留醇 21-磷酸鹽(prednisolone 21-phosphate) ’ 脫氫 -27- 1326216 五、發明說明(26)可體松(prednisone),氟經脫皮留醇(triamcinolone),氟/經脫皮留醇乙醒奈德(triamcinolone acetonide); 固醇類抗發炎劑:例如可托達克松(cortodoxone),氟 氫乙醯奈德(丨111(31‘0以061;011丨(^),氟氫可體松 (fludrocortisone),二氟松二乙酸鹽(difluorsone diacetate),氟雄嫌酮乙醯奈德(flurandrenolone acetonide),曼卓松(medrysone),阿西那芬(amcinafel) ’阿西那發(amcinafide),β -麥塞松(betamethasone)及 其其他醋類,氯脫氣可體松(chloroprednisone),克羅可 天酮(clorcortelone),帝西諾酮(descinolone),帝梭奈 德(desonide),二氯松(dichlorisone),二氟普內德 (difluprednate),氟克羅奈德(flucloronide),贏麥塞 松(flumethasone),弗奈沙立德(flunisolide),氟可托 酮(flucortolone),氟麥塞龍(fluoromethalone),氟普 洛龍(fluperolone),氟脫氫皮留醇(fluprednisolone), 麥脫氫可體松(meprednisone),甲基麥戴脫氫皮甾醇 (methylmeprednisolone),佩拉麥塞松(paramethasone) ,可體松乙酸鹽(cortisone acetate),氣可體松環戊丙 酸鹽(h y d r 〇 c 〇 r t i s ο n e c y c 1 〇 p e n t y 1 p r 〇 p i ο n a t e ),可托達 克松(cortodoxone),氟西托奈德(flucetonide),氟氫可 體松乙酸鹽(fludrocortisone acetate),氟雄稀酮乙醯 奈德(flurandrenolone acetonide),曼卓松(medrysone) ,安西那芬(aincinafal),阿西那發(amcinafide),β -麥 -28- 1326216 五、發明說明(27) 塞松(betamethasone),β -麥塞松苯甲酸鹽 (betamethasone benzoate),氯脫氫可體松乙酸鹽 (chlor op rednisone acetate),克羅可天酮乙酸鹽 (clocortolone acetate),帝西諾酮乙酸鹽(descinolone acetonide),帝梭西曼他松(desoximetasone),二氯松乙 酸鹽(dichlorisone acetate),二贏普內德 (difluprednate),氟克羅奈德(flucloronide),氟麥塞 松三甲基乙基酸鹽(flumethasone pivalate),弗奈沙立 德乙酸鹽(flunisolide acetate),氟普洛龍乙酸鹽 (fluperolone acetate),氟脫氫皮留醇戊酸鹽 (fluprednisolone valerate),佩拉麥塞松乙酸鹽 (paramethasone acetate),脫氫可體松酸鹽 (prednisolamate),普尼瓦(prednival),氟經脫皮留醇 己乙醯奈德(triamcinolone hexacetonide),可體瓦柔 (cortivazol),福莫可托(formocortal),以及奈瓦柔 (n i v a ζ ο 1 ); 腦下垂體激素及其活性衍生物或類似物:例如促腎上腺 皮質激素(corticotrophin),促甲狀腺激素(thyrotropin) ,濾泡刺激素(follicle stimulating hormone) ’ 促黃體 生成素(luteinising hormone),以及促性腺激素 (gonadotrophin releasing hormone); 降低血糖劑:例如胰島素,氯磺丙脲(chlorpropamide) ,優降糖(glibenclamide),格立克靈(gliclazide),啦 -29 - 1326216 五、發明說明(28) 石貝ϊ哀己脲(glipizide) ’甲擴氮罩脈(tolazamide),甲苯 磺丁脲(tolbutami de),以及麥特風命(met formin); 甲狀腺激素·例如降血i丐素(c a 1 c i t ο n i η ),甲狀腺素 (thyroxine),以及立歐甲狀腺素(ii〇thyr〇nine),以及 抗甲狀腺激素:例如甲亢平(carbimazole)以及丙基硫尿 啼 n定(propylthiouracil); 其他各種激素劑:例如歐翠歐泰德(〇 c t r e 〇 t i d e ); 腦下垂體激素抑制劑:例如溴克立丁( b r omo c r i p t i n e ) , 排卵誘發劑:例如克羅密芬(c lomiphene ); 利尿劑:例如噻唑化物類(t h i a z i d e s ),相關利尿劑及 環利尿劑’苯卓氟唑化物(bendrof 1 uaz i de ),氯噻唑化物 (chlorothiazide),氯薩立酮(chlorthalidone),多巴胺 (dopamine),環戊唾哩化物(cyclopenthiazide),氫氯噻 唑化物(hydrochlorothiazide),印單醯胺(indapamide) ,曼弗塞(mefruside),甲基氛睡哩化物 (m e t h y c h ο 1 t h i a z i d e ),曼托拉柔(m e t ο 1 a ζ ο n e ),奎寧塞 柔(quinethazone),布曼他奈德(bumetanide),伊薩克萊 尼酸(ethacrynic acid),以及福絲麥德(frusemide),以 及鉀貧乏利尿劑,螺諾乳酮(spironolactone),阿密羅萊 德(amilo ride),以及二阿特嫌(triamterene); 抗利尿劑:例如代斯莫降壓素(d e s m 〇 p r e s s i η ),利降壓 素(lypressin),血管降壓素(vasopressin),包括其活性Compound I is a commercially available product wherein nearly 50% of the methyl substituents at the sand atom are replaced with 3,3,3-trifluoropropyl. The term "close to 50%" means the degree of substitution of 3,3,3-trifluoropropyl, but in fact less than 50%, since the polymer must contain a certain amount (about 〇.丨5% of substituents) Crosslinkable groups such as vinyl or vinyl-terminated groups. Polymers similar to those having a lower degree of 3,3,3-trifluoropropyl substitution can be readily synthesized. The retarding effect of 3,3,3-trifluoropropyl on the penetration of the active agent through the elastomeric film is determined by the amount of these groups. Again, this effect is highly dependent on the active agent used. If the elastomer is made of only a single polymer, it is necessary to prepare and use polymers containing different amounts of 3,3,3-trifluoropropyl for different active agents. According to another embodiment, it is particularly preferred for several If different active agents require a suitable elastomer, they are cross-linked to a mixture comprising a) a non-fluorine-substituted azepine-based polymer, and b) a fluorine-substituted azepine. A base polymer, wherein the polymer contains a 3,3,3-trifluoropropyl group attached to a ruthenium atom of a siloxane unit. Mixing -10- 1326216 V. INSTRUCTION DESCRIPTION (9) The first component of the compound is a fluorine-free polymer, which may be any poly(disubstituted alkoxy alkane), where the substituent is mainly a lower alkyl group. (preferably an alkyl group of 1 to 6 carbon atoms) or a phenyl group, wherein the alkyl group or the phenyl group may be substituted or unsubstituted. The substituent is preferably an alkyl group of 1 to 6 carbon atoms. Preferred polymers which are not fluorine substituted are PDMS. The second component of the mixture is a fluorine-substituted polymer, such as poly(dialkyloxane), where the alkyl group at a certain amount in the ruthenium atom is substituted with 3,3,3-trifluoropropyl. . Preferred examples of such polymers are the poly(3,3,3-trifluoropropylmethyloxirane) described above. Such particularly preferred polymers are polymers which contain as much as possible a high amount of a 3,3,3-trifluoropropyl substituent, such as commercially available polymer products, wherein nearly 50% of the methyl substituents in the ruthenium atom are 3, 3,3 -trifluoropropyl substitution. Elastomers having a large osmotic retardation effect can be obtained by using all or most of the aforementioned polymers. Elastomers having less retarding effects on the penetration of the active agent can be obtained by using an increased amount of a mixture of non-fluorine-substituted oxane-based polymers. The elastomers useful in the present invention contain poly(alkylene oxide)s such that the poly(alkylene oxide)s are alkoxy-terminated grafts in polyoxyalkylene units or are present in the elastomer as blocks. The graft or block is linked to the polyoxyalkylene unit via a ruthenium carbon bond. Poly(alkylene oxide) can also be selected as a mixture of choices. The second elastomer can be a siloxane-based elastomer suitable for poly(dimethyl methoxy oxane)-based elastomers. . The second elastomer may also contain poly(alkylene oxide) species. These poly(alkylene oxide)s can also be alkoxy groups of poly(dimethyloxane) units. Terminal grafting-1 1 - 1326216 V. Description of the invention (1〇) or presented as a block, which is linked to a poly(dimethyloxane) unit via a hydrazone-carbon bond. . Poly(alkylene oxides) may also be present in the elastomer in combination with the foregoing selection. According to a particular embodiment of the invention, the elastomer composition may be a mixture J comprising an anthracene-based elastomer, such as PDMS and at least one poly(alkylene oxide)-containing linear polyfluorene. The oxane copolymer is in this case, the poly(alkylene oxide) is alkoxy-terminated graft in units of decane, or is present in the polymer as a block, the graft or block The substance is linked to the polyoxyalkylene unit via a ruthenium-carbon bond. Of course, poly(alkylene oxides) may also be present in the polymer in a mixture of the foregoing forms. In this embodiment, the siloxane-based elastomer may also contain poly(alkylene oxide)s, and in this case, the poly(alkylene oxides) are alkoxy groups of polyoxyalkylene units. a terminal graft or a block present in the elastomer; the block or graft may be bonded via a fluorene-carbon bond to a polyoxyalkylene unit argon (alkylene oxide). A mixture of forms. Of course, the composition of the elastomer composition may also be interwoven by the inner portion of the two elastomers as described above, and at least the per-chain polyoxyalkylene copolymer containing poly(alkylene oxide). Suitable poly(alkylene oxides) of the elastomer composition are, for example, poly(alkylene oxides) (PEOs). A preferred group of polyoxane units of the elastomer composition has the formula -(S iR 'R ',0)qSiR'R,,- wherein R' and R'' are -1 2 - 1326216 Description (11) - a partial radical, which is the same or different lower alkyl or phenyl: this Is opened; ^ the substituent or the base may be substituted or unsubstituted, or have an alkoxy group of the formula - terminal poly(extension oxide) R IR -〇-(CH-CH2-0)m-alk, where a 1 k is lower alkyl, suitable methyl 'R is hydrogen or lower alkyl 'm Is 1...30, and R3 is a linear or branched c2-c6 yard, - a partial bond formed from hydrogen or alkenyl to other polymer chains in the elastomer, and - possibly a partially unreacted base' Hydrogen, vinyl or vinyl-terminated alkenyl, and -q is 1 ... 3000. The term "lower alkyl" as used herein and generally in the context of the invention refers to the C i - C 6 building. The free R' and R'' groups mentioned above are suitable lower alkyl groups, preferably methyl. "Poly(alkylene oxide)" means that the class comprises at least two alkyl ethers continuously attached to the other. According to a preferred embodiment, the poly(alkylene oxide) group is present in the elastomer in the form of a poly(alkylene oxide) block having the formula: 13-1326216. V. INSTRUCTION (12) RI -(CH2)y0(CHCH20)m(CH2)y-, or Ri R RiII I -CH2CHCOO(CHCH20)mCOCHCH2- where R is hydrogen, lower alkyl or phenyl, R, hydrogen or lower-grade, y It is 2...6, and m is 1...30. The combination of elastomers is preferably PDMS with poly(ethylene oxide)-PDMS and PDMS with fluorine substitution. The elastomer composition preferably contains a hydrazine, such as an amorphous hydrazine, to impart sufficient strength to the film from which the elastomer is made. Other additives may also be included, considering that they are biocompatible and harmless to the subject. The preparation of these elastomers has been provided in the applicant's patents and patent applications mentioned above. Further examples of suitable materials include polyethylene, polypropylene, polymethylpentene' ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, polycarbonate, polytetrafluoroethylene (PTFE) ), fluoroethylene propylene (FEP) 'polyvinylidene fluoride (PVDF), polyvinyl acetate, polystyrene, polydecylamine, polyurethane, polybutadiene, polyisoprene - m-di Alkene, chlorinated polyethylene, polyvinyl chloride, ethylene chloride copolymer with vinyl acetate, poly(methacrylic acid), polymethyl (meth)acrylic acid, poly(ethylene vinyl) chloride, poly(vinylidene) ethylene , poly(vinylidene) propylene, polyethylene p-nonanoic acid, ethylene vinyl acetate, polyalcooxylate poly(lactic acid), poly(-14-1326216, invention description (13) glycolic acid), poly( 2-cyanoacrylates, polyanhydrides, polyacetates, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, ethylene/vinyloxyethanol copolymers, ethylene/vinyl/ Acetic acid copolymer 'ethylene vinyl/alcohol copolymer, hydrophilic polymer Hydrophilic hydrogels of acrylic acid and methacrylate, modified original rubber 'cross-linked polyvinyl alcohol' cross-linked, partially hydrolyzed polyvinyl acetate, 矽 elastics' especially pharmaceutical grade polydimethyl oxime Alkanes, polyvinylmethyl oxanes, other organic polyoxanes, polyoxyalkylenes, neopentadiene diene rubber 'butyl rubber' epichlorohydrin rubber, room temperature vulcanization a hydroxyl terminated organic polyoxyalkylene (hardening the elastomer at room temperature after the addition of a crosslinking agent in the presence of a curing catalyst), a two component dimethyloxane component (which is at room temperature or elevated temperature) Catalyzed by uranium, and can add cross-linking and its mixture). The implant according to the invention can be manufactured according to standard techniques. The therapeutic active agent is mixed with the core matrix polymer and processed into the desired shape via molding, casting, extrusion, or other suitable method. The film layer can be applied to the core according to known methods, for example, by mechanical stretching, expansion or dipping. References are disclosed in U.S. Patent Nos. 3,832,252, 3,854,480, and 4,957,119. A particularly suitable method for preparing implants is disclosed in Finnish patent FI 97947. This patent discloses a compression technique in which a pre-formed rod containing an active ingredient is coated with a film. For example, each of these rods is joined by another rod containing no active ingredient. The long string formed is cut at the rod containing no active ingredient. In this way, the implant need not be particularly sealed with a stick. -15- 1326216 V. INSTRUCTIONS INSTRUCTIONS (14) In the intrauterine vaginal and intrauterine system, the system can be made according to well-known techniques. Common subjects have the form τ, S or 7. The preferred intrauterine system (IUS, intrauterine system), intravaginal system or intrauterine system is a T-shaped body made of a plastic material such as polyethylene. The body is composed of an elongated membrane (handle). The end of the membrane has a transverse membrane containing two wings. When the system is located in the uterus, the elongated membrane and the transverse membrane form a substantial T-shaped sheet. When the system is in the uterus, the system has a sufficiently long line to protrude into the cervix. The system can also be any other shape, such as 7, S, Ω ring or c. I US : s release active agent has an active agent reservoir (corresponding to the core or core-membrane of the invention) tuned around the elongated film. It is also possible to adjust one reservoir to one part of I US and another reservoir to another part of IUS. The active agent reservoir is a delivery system according to the invention', i.e., packaged at the core of the membrane. In the uterus according to the invention, the intravaginal system and the endocervical system may then also comprise a body in which the system containing the core and membrane is fitted. The T-type intrauterine system is conventionally manufactured by first forming a body and a reservoir separately, then placing the reservoir on the body, e.g., via a pull, and finally forming a membrane-covered reservoir, thus forming a core-membrane-structure. Representatives of therapeutic active agents that may be suitable for use in the therapeutic active agents of the present invention include (grouped by treatment): Antihypertensive agents: for example, hydralazine, minoxidil 'Kapp Capt〇pril, Anala Puri-16- 丨216 Five Inventions Description enalapril, clonidine, Prazosin, Dibrizol (deb risoquine), diazoxide, guanethidine, methyldopa, reser pine, trimethaphan, nifedipine and Isradipine > Calcium channel blockers: for example, diltiazem, felodipine, amlodipine, nitrendipine, nepdipine ( Nifedipine) and verapamil; anti-regulatory agents: for example, amiodarone, flecainide, disopyramide, and proconeamine Procainamide), mexiletene, 卩quinai D (quinidine), lorcainide and bepridi 1; anti-angina: for example, g 1 ycery 1 trinitrate , erythrityl tetranitrate, pentaerythritol Pentaerythritol tetranitrate, mannitol hexanit rate 'perhexilene', isosorbide dinitrate, nicorandil, and nai Nicadipine; β-adrenergic blocker: for example, aprenol (a 1 pre η ο 1 ο 1 ), atenolol, bupranolol, cardinal Ethanol-17-1326216 V. Description of invention (16) (carte ο 1 ο 1 ), rabbitol (1 abeta 1 ο 1 ), metoprolol, nadolol, that Nadoxolol, drink oxprenolol, pindolol, propranolol, sotalol, timolol, taijiol cis-butane Diacid vinegar (tim ο 1 ο 1 m a 1 eate ); bisoprolol, celiprolol, and betaxolol; heart sugar, such as digoxi η and other heart glycosides Andophylline derivatives; adrenergic stimulants: eg adrenaine (ad r en a 1 i ne ), ephedrine, fenoterol, isoprenaline ), orciprenaline, rimeterol, salbutamol, salmeterol, terbutaline, dobutamine, dobutamine Phenylphetine, phenylpropanolamine, pseudoephedrine, and dopamine; vasodilators: for example, cyclandelate, isoxorprine ), papaverine, dipyrimadole, isosorbide dinitrate, pHentolamine, nicotinyl alcoho, co-deconstruction (co-dergo Crine), nicotinic acid, glyceryl trinitrate -18- 1326216 V. Description of invention (17), pentaerythritol tetranitrate, and xanthinol, Vincamine and nimodipine; anti-migraine preparations: eg erg 〇tamine, dihydroergotamine, methysergide, 派柔太分(pizotifen) and sumatriptan, and f 1 umend r oxone; anticoagulant and thrombolytic agent: for example, warfari η, dicouma ι · ο 1 ), low molecular weight heparin such as enoxaparin, streptokinase and its active derivatives » Hemostatic agents: for example, aputai condensate (apr 〇t 1 ni η ), transaminic acid ( Tranexamic acid) and protamine; analgesics and antipyretics include opioid analgesics such as buprenorphine, dextromoramide, dextrose propoxyphene (d Extropropoxyphene), fentanyl, alfentanil 'sufentanil', hydromorphone, methadone, morphine, oxycodone ), S papave return, pentazocine, pethidine, phenoperidine, codeine, dhydrocodeine, fenfen Sufentanil and ti 1 idi ne, and non-anaesthetic analgesics such as fluorophenolic acid (flugenami c -19- 1326216 V, invention (18) acid), indomecin (indome) t ha c in), ibuprofen, ketoprofen, tramadol, flufenamic acid, rimazolium, acetaminophen Acid (aspirin), paracetamol, and phenazone; neurotoxins such as capsaicin η; neuropathic drugs: for example, baciphenol derivatives (butyrophe η ο Nedrivatives ), such as haloperol (ha 1 oper Id ο 1 ), or a bacterial inhibitor and/or fungal inhibitor, such as nystatin or metronidazole: sleeping pills and sedatives: for example, barbiturates amylobai · bitone), butobarbitone and pentobarbitone, as well as other sleeping pills and sedatives, ch 1 〇ra 1 hydrate, chlormethiazole , hydroxyzine and meprobamate; anti-anxiety agents: for example, benzodiazepines alprazolam, bromazepam, dihydrogen chloride Chlordiazepoxide), clobazam, chlorazepate, di Phaip (diazepam), flunitrazepam, flurazepam, lorazepam, nitrate tJY 朋 (nitrazepam), 哔^ 朋 (oxazepam), 玛马朋三〇Υ Blue-20 - 1326216 V. Invention description (19) (temazepam triazolam), and buspirone; neurological disease and resistance Psychiatric medication : for example, phenothiazines, chlor promazine, fluphenazine, pericyazine, perphenazine, promazine, thiopyranic acid Thiopropazate, thioridazine, trifluoperazine; and butyrophenone, droperidol, and haloperidol; and other antipsychotics Medications such as P i πιοζ i de, thiothixene: antidepressants: including bicyclic derivatives such as η omifensine, sertraline, and Cherno Trazodone; tricyclic antidepressants such as ami t rypt y 1 ine, clomipramine, desipramine, dothiepin, more Doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine; and tetracycline antidepressant Agent such as maisling (mianseri η And monoamine oxidase inhibitors such as iscarb ο X azid, phenelizine, tranylcypromine, and 5-tryptamine selective reuptake inhibitors such as fluorophenoxy F 1 uoxetine, paroxetine, citalopram, floyoxamine, and sertraline; -21 - 1326216 V. Description of invention (2〇 CNS stimulating agents: for example caffeine, methylphenidate, nizophenone and 3-(2-aminobutyl) hydrazine; anti-Alzheimer's agent (anti-A)丨zheimer's disease agents) such as tacrine, physostig ra ine, and olanzapine; anti-Parkinson's agents: such as Oman Amantadine, besenrazide, carbadopa, levodopa, benztropine, biperiden, benzhox, pu Cyclone e), and a dopamine-2 agonist such as S ( - ) - 2 - ( N -propyl-N - 2 -thienylethylamino)-5-hydroxy lin; an anti-caries agent: for example, bis-benzoquinone (phenytoin), valproic acid, primidone, phenoba rbi tone, methylphenobarbitone, and carbamazepine, issosu Eth 〇su X imide, methsu X imide, phensuximide, sulthiame, and clonazepam; antiemetic and anti-vomiting Agents: for example, phe η othiazines, prochloperazine, (gethyl thiethylperazine), and 5HT-3 receptor antagonists such as udadans-22-1326216 (21) clock (ondansetron) and granisetron, and dimenhydrinate 'diphenhydramine, metoclopramide, doperidone ( Domperidone) 'hyoscine, east of hydrobromide Hyoscine hydrobromide 'hyoscine hyd roch 1 or i de ' Klebopold (c 1 ebopr i de ) and Bromp ri de (b romp ri de); anti-inflammatory Agents include racemic mixtures or individual mirror images, and in this application are preferably formulated in combination with a skin penetration enhancer, such as ibuprofen, flurbiprofen, ketoprofen, Aclofenac, diclofenac, aloxiprin, aproxen, aspirin, diflunisal, fen Fenoprofen, indomethacin 'mefenaniic acid, naproxen, phenylbutazone, piroxicam, willow Indoleamine, salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol, ketoralac, flufenisal ([111£611丨531), sassanate (531$3丨3〖6), triethanolamine (triethanolamine salicylate), aminopyrine, antipyrine, oxyphenbutazone, apazone, cintazone, flufenazone密-23-1326216 V. Description of the invention (22) flufenamic acid, clonixeril, clonixin, meclofenamic acid, flubenone Flunixin, coichicine, demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride, generation Dimenfadane, indoxole, inti azole, mimbane hydrochloride, paranylene hydrochloride, Tai Cui Tetrydamine, benzind 〇pyrinehydr 〇ch 1 〇ride, fluprofen, ibufenac, naproxol, fenbufen (fenbufen), cinchophen, diflux Diflumidone sodium, fenamole, flutiazin, metazamide, lactimide hydrochloride, nexeridine Hydrochloride), octazamide, molinazole, neocinchophen, nimazole, proxazole citrate, tesicam, taixi Tesimide, tolmetin, carprofen, mesalazine, and triflumidate; anti-rheumatic agents: for example penicillamine (penici 1 1 Amine, aurothioglucose, sodium sulphate, sodium sulphate (sodium -24 - 1326216, invention (23) auuthiomaute), methotrexate, and aura no fin; muscle Relaxing agents: for example, bacl of en, diazepam, cyc 1 obenzaprine hydrochloride, dantrolene, methoxycarbameth Ocarbam ο 1 ) ' 欧rphenadrine, and qu ini ne; for gout and hyperuricemia agents: eg isodecyl alcohol (an〇purin〇l) 'Kei Qixin (coichicine) 'probenecid, and sulphur sulphate (su 1 phinpyra ζ ο ne ); hormone: for example, 3-methoxy-17a-ethynyl-1,3,5(10)-estre Diene-1 7-alcohol [mes tr anol], 3-hydroxy-1,3,5(10)-female di- 17-keto [estrone], 17β - Estradiol, estroglycerol 'ethynyl estradiol diol 4 'pregnene-3 , 20 -dione [progesterone] ' d-13-ethyl-17α-ethynyl- Ι7β -hydroxy- 4-gonadin-3-one [d-norgestrel] and its vinegar, 17α-ethynyl-19-n-decyl ketone [n-ethene uni-(northisterone)] and its vinegar '6-Chloro-17-hydroxy-1α,2α-methylenepregna-4,6-diene-3,20-diketone [cyproterone] and its esters, 19-n-hydroxy luteal Ketones and their esters, 6-chloro-17-acetoxy-pregnant-4,6-diene-3,20-dione [chloroprogesterone acetate ( £:111〇1-1113(1丨11〇1^&061&{6)], 15,16〇6-methylene- and 15,16β-methylene-17β-hydroxy-18-methyl -17oc-ethynyl-4-esteren-3-one '17α-acetoxy- 6α·methyl luteal 嗣 [methoxy progesterone vinegar-25 - J326216 jade, invention description (24) acid salt (medroxy -progesterone acetate)],90,1〇〇1-pregnancy-4,6-diflamin-3,20-dione [Dazhuo progesterone ((17(11'〇265[61_〇116)], female Lipodiol-3-methylethyl ether diethestrol, 17α-ethynyl-4-esterene-3β, 17β-diol diacetate, 17α-ethynyl-ΐΐβ-methyl-4 estradiol 3β , 17β-diol 3,17-diacetate, 1 7α-acetoxy-1 ΐβ-methyl·19-n-pregn-4-en-3-one, anthrone, anthrone propionate, anthrone phenylacetic acid Salt and its related androgens, propylene-based estroenool, lynoestrenol, norgestrel, norethyndrel, norethisterone, norethisterone acetate Norethisterone acetate, gestodene, levothorgestrel, methoxyprogesterone (medroxypro) Gesterone) 'Megestrol' (megestro", testosterone, methyltestosterone, clostebol acetate, drostanolone, furazabol , nandrolone oxandrolone, stanozolol, trenbolone acetate, indanone, 17-α-methyl-19-n-fluorenone and fluoro-mans Acetone; adrenocortical hormone: for example, deoxycortic acid acetate (desoxycor ti cos te rone acetate), dehydrocortisone (prednisolone); antiandrogen: for example, cyproterone acetate, fluoro 1 tai Flutamide, nilutamide, -26 - 1326216 V, invention instructions (25) and danazol; antiestrogens: eg tamoxifen, Torrimide Toremifene, clomifene', and epitistanol; aromatase inhibitors: for example, lizozole (1 etr ο ζ ο 1 e ), exercins (exemestane), and 4 - by Male glycerol and its derivatives; 5-alpha reductase inhibitors: for example, finasteride, tusteride; corticosteroids: eg beta-meserone ( Betamethasone), betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fluoride Fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, flusenol Fluocinolone acetonide, fluocortolone, hacinonide, halopredone, hydrocortisone, argon coronasol 17-pentanoic acid Hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methyl dehydropicolol (methy 1 prednis) ο 1 ο ne ), dehydropicol (predn Is ο 1 ο ne ), prednisolone 21-phosphate 'dehydrogenated -27- 1326216 V. Description of the invention (26) prednisone, fluoroacetate (triamcinolone) ), fluorine / trans-retained alcohol, triamcinolone acetonide; sterol anti-inflammatory agent: for example, cortodoxone (cortodoxone), fluorohydrogen hydrazine (丨 111 (31'0 to 061; 011丨(^), fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrysone, cixifen (amcinafel) 'amcinafide, beta-methesone (betamethasone) and its other vinegars, chloroprednisone, clorcortelone, dioxin ( Descinolone), desonide, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide ), flucortolone, fluoromethone Alone), fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone ), cortisone acetate, flu 〇c rtis ο necyc 1 〇penty 1 pr 〇pi ο nate , cortodoxone, fluoride Flucetonide, fludrocortisone acetate, flurandrenolone acetonide, medrysone, aincinafal, asina Amcinafide, β-麦-28- 1326216 V. Description of invention (27) betamethasone, betamethasone benzoate, chlorop dehydrocortisone acetate Rednisone acetate), clocortolone acetate, descinolone acetonide, desoximetasone, dichlorisone acetate, Difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, flupronone acetate Fluperolone acetate), fluprednisolone valerate, paramethasone acetate, prednisolamate, prednival, fluorinated Triamcinolone hexacetonide, cortivazol, formocortal, and niva ζ ο 1 ; pituitary hormones and their active derivatives or Analogs: for example, corticotrophin, thyrotropin, follicle stimulating hormone 'luteinising hormone, and gonadotrophin releasing hormone; lowering blood sugar Agents: for example, insulin, chlorpropamide, glibenclamide, gliclazide, -29 - 1326216 V. Description of the invention (28) glipizide 'tolazamide, tolbutami de, and met formin; thyroid hormones such as 1 丐 (ca 1 cit ο ni η ), thyroxine, and ii thyr〇nine, and anti-thyroid hormones such as carbimazole and propyl thiopurine n Propylthiouracil; other various hormonal agents: eg 欧ctre 〇tide; pituitary hormone inhibitors: eg bromo criptine, ovulation inducing agents: eg clomiphene (c lomiphene ); diuretics: such as thiazides, related diuretics and cyclodiuretics 'bendrof 1 uaz i de , chlorothiazide, chlorthalidone ), dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside, methyl slumber Methych ο 1 thiazide , met ο 1 a ζ ο ne , quinethazone, bumetanide, ethacrynic acid, And frothermide, as well as potassium-poor diuretics, spironolactone, amilo ride, and triamterene; antidiuretics: such as daisy Pressure hormone (desm 〇pressi η ), lypressin, vasopressin, including its activity

-30 - 1326216 五、發明說明(29) 衍生物或類似物; 產科用藥:包括作用於子宮之藥劑例如歐葛美春 (erg om etrine) ’催產素(oxytocin),以及吉米普斯特 (gemepros t); 前列腺素類:例如阿爾普斯塔帝爾(alprostadil),前 列環素(prostacyclin) ’帝諾普斯特(dinoprost)(前列腺 素F2-oc) ’以及密縮普斯托(mis〇prost〇i); 抗微生物劑包括頭孢菌素類(cephalosporins ),例如頭 伊辛素(cepha 1 exi η ) ’西發丁素(cefoxy t i n ),以及頭辛 素(cephalothin); 青黴素類:例如阿莫辛西林(amoxyc i 1 1 i η ),含有克雷 瓦藍尼酸(clavulanic acid)之阿莫辛黴素,安比西林 (ampicillin) ’ 巴卡比西林(bacampicillin),苯噻青黴 素(benzathine penicillin),苯甲基青黴素 (benzylpenicillin) ’ 羧苄基青黴素(carbenicillin), 克羅薩西林(cloxacillin),甲西林(methicillin),苯噻 西林(phenethicillin),苯氧甲基青黴素 (p h e η ο X y m e t h y 1 p e n i c i 1 1 i η ),戴克羅薩西林 (flucloxacillin),曼立歐西林(mezi〇cillin),六氫吡 D定西林(piperacillin),太卡西林(ticarcillin),以及 阿羅西林(azlocillin); 四環類:例如麥諾環黴素(minocycline),氯四環黴素 (chlortetracycline),四環黴素(tetracycline),脫氧 -3 1 - 1326216 五、發明說明(3〇) 環黴素(doxycycline),脫甲基環黴素(demeclocycline) ,甲環黴素(methacycline),以及氧四環黴素 (oxytetracycline),以及其他四環型抗生素; 胺基糖音類:例如阿密康黴素(amikacin),正大黴素 (gentamicin),康黴素(kanamycin),新黴素(neomycin) ,內太黴素(netilmicin),以及托巴雷黴素(tobramycin) f 抗真菌劑類:例如阿莫洛芬(amorolfine),異康納哩 (isoconazole),克羅徹嗎哩(clotrimazole),伊康納哩 (econazole),麥康納哩(miconazole),制黴菌素 (n y s t a t i η ),特比納芬(t e r b i n a f i n e ),比風納哩 (bifonazole),兩性黴菌素(amphotericin),灰黃黴菌 (griseofulvin),酮康納哩(ketoconazole),氟康納哩 (fluconazole)以及氟< 胞喃陡(flucytosine),以及柳酸, 菲札太酮(fezatione),太拉酮(ticlatone),透納菲特酸 鹽(tolnaftate),三醋精(triacetin),鋅,壯噻酮 (pyrithione),以及壯噻酮鈉(sodium pyrithione); 喹啉類:例如萘啶酮酸(n a 1 i d i x i c a c i d ),辛諾薩克辛 (cinoxacin),辛普弗羅薩克辛(ciprofloxacin),安諾薩 克辛(enoxacin),以及正弗羅薩克辛(norfloxacin); 磺胺類:例如駄磺胺唾哩(p h t h a 1 y s u 1 p h t h i a ζ ο 1 e ),石黃 胺辛(sulfadoxine),擴胺嚼 π定(sulphadiazine),擴胺甲 噻哩(sulphamethizole),以及擴胺甲氧曙嗤 -32 - 1326216 五、發明說明(31) (sulphamethoxazole); 碾類例如戴普松(d a p s ο n e ); 各種其他抗生素:例如氯黴素(chloramphenicol),克 林達黴素(clindamycin),紅黴素(erythromycin),紅黴 素碳酸乙酯(erythromycin ethyl carbonate),紅黴素內 酸酯(erythromycin estolate),紅黴素葡萄糖酸酯 (erythromycin glucepate),紅黴素琥珀酸乙酯 (erythromycin ethylsuccinate),紅黴素乳糖酸酯 (erythromycin lactobionate),羅辛舒羅黴素 (rox i t h romyc i η ),林可黴素(1 i ncomyc i η ),內他黴素 (natamycin),硝基咲喃同(nitrofurantoin),狀觀黴素 (s pec t i nomyc i η ),萬古黴素(v ancomyc i η ),吖翠歐納 (aztreonain),粒菌素 IV(colistin IV),麥卓奈丹哩 (metronidazole),太奈丹唑(tinidazole),富西迪酸 (fusidic acid) ’ 三甲氧普立(trimethoprim),以及 2 -硫 壯陡N-氧化物(2-thiopyridine N-oxide);齒化合物類, 特別是碘及碘化合物例如碘-PVP複合物及二碘羥基醌 (diiodohydroxyquin),六氯酣(hexachlorophene),氯己 啶(chlorhexidine);氯胺化合物類;以及過氧化二苯甲 醯; 抗結核病藥:例如伊薩畢妥(ethambutol ),異菸肼 (i s ο n i a z i d ),Pit 哄醯胺(p y r a z i n a m i d e ),利福平 (rifampicin),以及克羅發利命(clofazimine); -33 - 1326216 五、發明說明(32) 抗瘧疾劑:例如原奎寧(p r i m a q u i n e ),吡甲胺 (pyrimethamine),氯奎寧(chloroquine),經氯奎寧 (hydroxychloroquine),奎寧(quinine),麥福羅奎寧 (mefloquine),以及鹵芬翠(halofantrine); 抗病毒劑:例如阿環微爾(acyclovir)及阿環微爾前藥 ’發環微爾(famcyclovir),利杜瓦錠(zidovudine),二 丹諾辛(didanosine),斯塔瓦錠(stavudine),拉密瓦錠 (lamivudine),傑西他並(zalcitabine),薩奎微爾 (saquinavir),印第那微爾(indinavir),利托那微爾 (ritonavir) ’ η -二十二醇(n-docosanol),卓曼他錠 (tromantadine),以及艾朵由立旋(idoxuridine); 驅蟲藥:例如麥並大^(mebendazole),噻並大嗤 (thiabendazole),奈克羅斯醯胺(niclosamide),普利括 提爾(praziquantel),吡喃提爾安博酸鹽(pyrantel embonate),以及二乙基卡巴馬哄(diethylcarbamazine) 細胞毒性劑:例如皴摺狀素(p 1 i c a i n y c i η ),環碟醯胺 (cyclophosphamide),大卡巴哄(dacarbazine),氟尿嚼 D定(fluorouracil)及其前藥,胺甲碟呤(methotrexate), 普卡巴哄(procarbazine),6 -氫硫基嘌呤(6-mercaptopurine),以及黏酣酸(mucophenolic acid); 厭食及重量降低劑包括帝克斯芬氟胺(dexfenfluramine) ,芬氟胺(fenfluramine),二乙基丙酸類 -34 - 1326216 五、發明說明(33) (diethylpropion),馬利多醇(mazindol),以及酣特胺 (phentermine); 用於高血鈣之藥劑:例如鈣三醇(c a 1 c i t r i ο 1 ),二氫速 羥醇(d i h y d r o t a c h y s t e r ο 1 )及其衍生物或類似物; 抗咳嗽劑:例如乙基嗎啡(e t h y 1 m 〇 r p h i n e ),右旋糖甲 氧芬(dextromethorphan),以及服克銳(pholcodine); 法痰劑:例如卡博絲胺酸(c a r b ο 1 c y s t e i n e ),溴黑克辛 (bromhexine),伊麥丁(emetine),康尼分辛(quanifesin) ,促吐素(ipecacuanha),以及皂角苷(saponins); 解除充血劑:例如苯基福林(p h e n y 1 e p h r i n e ),苯基丙 醇胺(phenylpropanolamine),以及僞麻黃素 (pseudoephedrine); 支氣管痙攣鬆弛劑:例如麻黃素(ephedrine),分諾特 醇(fenoterol),歐系普那靈(orciprenaline),立曼特醇 (rimiterol),沙巴泰醇(salbutamol),克羅莫葛利酸鈉 (sodium cromoglycate),克羅莫葛利酸(cromoglycic acid)及其前藥,特巴泰靈(terbutaline),溴化艾普翠平 (ipratropium bromide),沙曼特醇(salmeterol)以及茶 鹼(theophylline)茶鹼和衍生物; 抗組織胺類:例如麥克羅畊(m e c 1 〇 z i n e ),環阱 (cyclizine),氯環哄(chlorcyclizine),經哄 (hydroxyzine),溴苯奈胺(brompheniramine),氯苯奈胺 (chlorpheniramine) ’ 克立嗎斯丁(clemastine) ’ 塞普核. -35- 1326216 五、發明說明(34) 他丁(cyproheptadine),帝克斯氯苯奈胺 (dexchlorphenir amine),二苯氫胺(diphenhydramine) ί 二苯胺(diphenylamine),杜克西胺(doxylamine),麥氫 靈(mebhydrolin),苯奈胺(pheniramine),三波靈銳 (tripolidine),重氮他銳(azatadine),二苯派瑞靈 (diphenylpyraline),甲代拉哄(methdilazine),特芬那 錠(terfenadine),阿斯特密唑(astemizole),羅拉太錠 (loratidine),阿克黎瓦斯丁(acrivastine),辛那黎哄 (cinnarizine),以及仙太黎畊(cetirizine); 局部麻醉劑類:例如巴皮瓦柯驗(b u p i v a c a i n e ),阿曼 梭柯鹼(amethocaine),利格諾柯鹼(lignocaine),利多 柯驗(lidocaine),辛可柯驗(cinchocaine),代巴柯驗 (dibucaine) ’麥皮瓦柯鹼(mepivacaine),普利羅柯鹼 (prilocaine),伊太多柯鹼(etidocaine),微瑞翠柯鹼 (v e r a t 1· i d i n e ),以及普柯鹼(p r 〇 c a i n e )(專一性c ·纖維阻 斷劑); 角質層脂質類,用於提高皮膚屏障修復,例如神經醯胺 類(ceramides),膽固醇,以及游離脂肪酸; 神經與肌肉阻斷劑類:例如號拍酿膽驗(s u x a m e t h ο n i u m ) ’阿卡維尼恩(alcuronium) ’潘卡羅尼恩(pancuronium) ’阿翠卡黎恩(atracurium),葛爾胺(gallamine),他玻 卡瑞靈(tubocurarine) ’以及瓦卡羅尼恩(vecuronium); 戒煙劑類:例如菸鹼(n i c 〇 t i n e ),巴普平恩(b u p r 〇 p i. ο η ) -36 - 1326216 五、發明說明(35)’以及乂波甘(ibogaine); 皮一膚病藥劑:例如維生素A,C,Bi,B2,B6,B12a及E ’維生素E乙酸鹽及維生素E山梨酸鹽,維生素κ ; 去敏感化過敏原’例如房子,灰塵或蝨過敏原; 營養劑類:例如維生素,必需胺基酸以及脂肪; 角質溶解劑類:例如α -羥酸類,羥基乙酸以及柳酸; 抗原生動物劑類,硝基咪唑類:例如曼卓奈疊唑 (metronidazole); 鴉片拮抗劑及激動劑:例如那翠斯酮(naltrexone),那 維斯嗣()’環柔辛(cyclazocine),麥他柔辛(metazocine) ’嗎啡’氧嗎嗣(hydromorphone),曼他嗣(methadone), 芬他靈(fentanyl) ’磺芬他靈(sufentann),阿芬他靈 (alfentanil),巴普諾芬(buprenorphine),戊柔辛 (pentazocine) ’ 以及那羅芬(nai〇rphine); 骨活性劑包括貳磷酸鹽類:例如艾倫卓酸鹽 (alendronate),西馬卓酸鹽(cimadronate),克羅卓酸鹽 (c 1 odrona t e ) ’伊太卓酸鹽(e t i drona t e ),艾並卓酸鹽 (ibandronate),內黎卓酸鹽(neridronate),歐帕卓酸鹽 (olpadronate),帕咪卓酸鹽(pamidronate),萊斯卓酸鹽 (risedronate) ’太流卓酸鹽(tiludronate),印卡卓酸鹽 (1 n c a d ι_ ο n a t e ),[ 1 -羥基-3 - ( 1 -吡咯啶基)-亞丙基]貳磷 酸鹽,Π -羥基-2-咪唑- (1,2-a)吡啶-3-基亞乙基]貳磷酸 鹽’以及唑卓酸鹽(zoledronate); -37 - 1326216 五、發明說明(36) 具有抗黃體酮性質之化合物,例如敘述於W0 〇 1 / 4 7 4 9 〇 者; 抗高血脂劑:例如貝札纖維酸鹽(bezaf ibrate),芬諾 纖維酸鹽(fenof ibrate),可利斯特博(coles t ipol ),以 及司達丁類(statins)。 其他可使用之醫藥活性劑包括抗菌劑,抗糖尿病劑,抗 癲癇劑,抗蕈毒素劑,抗瘤劑,勃起障礙改善劑,免疫抑 制劑,抗原生動物劑,β -阻斷劑,抗帕金森氏症劑,胃-腸劑’脂質調節劑,c Q X - 2抑制劑,白三烧素抑制劑,大 環內酯類,蛋白酶抑制劑,抗骨質疏鬆劑,抗肥胖劑,認 知增強劑,抗尿失禁劑,抗良性攝護腺肥大劑,凝血酶抑 制劑,抗血栓形成劑,血栓溶解劑,纖維蛋白分解劑,血 管痙攣抑制劑,鈣通道阻斷劑,表面糖蛋白受器抑制劑, 抗血小板劑,抗有絲分裂劑,微管抑制劑(m i c r 〇 t ubu 1 e i nh i b i t o r s ),抗分泌劑,肌動蛋白抑制劑,重新塑造抑 制劑,反意義核苷酸(antisense nucleotides),抗代謝 產物劑,抗增殖劑,抗癌症之化療劑,生長激素拮抗劑, 生長因子,放射線治療劑,胜肽,蛋白質,酵素,細胞外 基質化合物,自由基淸除劑,螯合劑,抗氧化劑,抗聚合 酶劑,光動力治療劑,基因治療劑,眩暈用藥,中樞神經 系統用藥,自主神經系統用藥,自主神經節阻斷劑,周邊 神經系統用藥,眼藥,感覺器官用藥,心臟藥,利尿劑, 血管強化劑,血管收縮劑,抗粥樣動脈硬化劑.,血液循環 -38 - 1326216 五、發明說明(37) 藥’呼吸刺激劑’呼吸器官用藥,消化性潰瘍藥,健胃消 化藥’制酸劑,瀉藥,利膽藥,消化性藥,尿道消毒劑, 子宮強狀劑’泌尿生殖器用藥,肛門疾病用藥,營養強化 劑’血液及體液用藥,肝病用藥,解毒藥,習慣性中毒用 藥’治痛風藥,酵素製備物,細胞活化藥,抗腫瘤劑,α -腎上腺素阻斷劑,膽素脂酶抑制劑,抗血管生成因子, 抗牛皮癖劑,抗腹瀉劑,抗白血病劑,抗愛滋病藥,癡呆 用藥’血管收縮素抑制劑,α -及β _激動劑,創傷癒合促 進劑’鈣拮抗劑’胰激素,解痙攣劑,心血管劑,收縮力 影響劑’親生殖腺素,擬交感神經劑,抗真菌劑,血管營 養因子’質子幫浦抑制劑’止癢藥,抗癮用藥,組織胺受 器拮抗劑’免疫抑制劑,以及免疫刺激劑。 除非文章之其他要求,於本說明書中“包含(compris〇 ”、“包含(comprises)” 及“包含(comprising)” 等字 分別意指“包括(i n c 1 u d e ) ” 、“包括(i n c 1 u d e s ) ”及 ‘‘包括(i n c 1 ud i ng ) ” 。亦即當本發明敘述或定義爲包含 指定之特性時’相同發明之各種具體實施例亦可包括額外 特性。提及之參考文獻亦不應解釋爲申請專利範圍之限制 〇 本發明以下列非限制之圖式及實施例更詳細說明如下。 [SI忒夕簡單說明 第1 a及1 b圖舉例說明本發明之第1個具體實施例。 第2圖舉例說明本發明之第2個具體實施例。 -39 - 1326216 五、發明說明(38) 第3圖舉例說明本發明之第3個具體實施例。 - 第4圖舉例說明本發明之第4個具體實施例。 第5圖舉例說明本發明之第5個具體實施例。 第6圖舉例說明本發明之第6個具體實施例。 第7圖舉例說明本發明之第7個具體實施例。 第8圖舉例說明本發明之第8個具體實施例。 第9圖舉例說明實施例1之結果。 第1 0圖舉例說明實施例2之結果。 第11圖舉例說明實施例3之結果。 第1 2,1 3及1 4圖舉例說明實施例4之結果。 圖_式之詳細說明 第la及lb圖舉例說明本發明之第1個具體實施例。第 la圖中顯示根據本發明之植入物1。第ib圖進一步詳細 顯示同一植入物。植入物包裝於膜2中,且其核心由各別 含有治療用活性劑之3及4兩部分構成。又一分開膜5分 開3及4兩部分。 第2圖舉例說明本發明之第2個具體實施例。所示系統 可爲植入物’或子宮內、子宮頸內系統或陰道內系統之— 部分。其由含有6及7兩部分之核心構成,6及7兩部分 各含有治療用活性劑。此具體實施例中沒有膜介於兩部分 間(可視爲在8)’但於該兩部分所用之彈性物組成物不同 。核心包裝於由不同彈性物構成之膜9及10中。 第3圖舉例說明本發明之第3個具體.實施例。此系統含 -40 - 1326216 五、發明說明(39) 有1 1、12及1 3三部分,分別以膜14及1 5分開’分開膜 1 4對部分11中所含之活性劑爲可滲透的以及·對部分1 2中 所含之活性劑爲不可滲透的,分開膜15對部分12·及13 中所含之活性劑爲不可滲透的。該部分1 3含有兩種不同 活性劑。此系統進一步包裝於由1 6、1 7及1 8三部分構成 之膜中。 第4圖舉例說明本發明之第4個具體實施例。此系統由 含有三活性劑之核心20構成,包裝於第一膜19以及較第 一膜19厚之第二膜21中。 第5圖舉例說明本發明之第5個具體實施例。此系統之 核心由22,23及24三部分構成。部分23圍繞部分的部 分22,以及部分24圍繞部分22及部分23。部分22及23 經分開膜27分開,部分23及24經分開膜26分開,以及 部分22及24經分開膜25分開。然後核心經第一膜28、 第二膜29及第三膜30包裝,該第三膜比第一及第二膜厚 。膜間距離爲淸楚顯示之由而誇張的擴大。 第6圖舉例說明本發明之第6個具體實施例。此系統爲 含有主體35之T型子宮內系統。核心由31,32,33及34 四部分構成。每一核心包裝於膜中。核心之部分3 1及3 2 與部分33經一空間而彼此分開。部分33及34爲鄰接而 經分開膜36分開。 第7圖舉例說明本發明之第7個具體實施例。此系統爲 陰道內環,由包裝於第二部分核心41之第一部分核心4〇 -41- 1326216 五、發明說明(4〇) 所構成。此二部分經分開膜38分開,且部分40之內表面 及部分41之外表面分別由包裝於膜37及39中。 第8圖舉例說明本發明之第8個具體實施例。此系統之 核心含有部分42及43,經空間44分開。 實驗部分 本發明以下列非限制實施例進一步舉例說明。 實施例1 製備一植入物,含有目標釋放速率爲50 "g/天之乙基羥 基二降孕甾烯炔酮(levonorges t rel )以及目標釋放速率爲 10//g /天之雌脂二醇(estradiol)。 植入物結構揭示於第2圖。核心之第一部分由含有乙基 羥基二降孕甾烯炔酮之PDMS構成,以及長度爲35 mm。核 心之第二部分由含有雌脂二醇之具有50%PEO之PE0-PDMS 構成,以及長度爲8 mm。 核心部分包裝於由PE0-PDMS以10:90比例構成之膜中 。膜厚度爲0 . 2 mm,植入物之外直徑爲2 · 48 mm。 所得釋放速率圖解於第9圖,其中正方形闡明雌脂二醇 之釋放速率,菱形闡明乙基羥基二降孕甾烯炔酮之釋放速 率。從此圖可知雌脂二醇之目標釋放速率已達到’以及乙 基羥基二降孕甾烯炔酮之釋放速率釋爲60至40 #g/天, 取代目標之50/zg /天。 實施例2 根據實施例1製備一植入物’使用目標釋放速率爲 -42 - 1326216 五、發明說明(41) 50 vg/天之 11-(4-乙醯基苯基)-17-羥基-17-(1,1,2,2,2-五氟乙基)雌脂-4,9 -二烯-3-酮(抗黃體脂酮)及目標釋放 速率爲10//g/天之雌脂二醇爲活性劑。 植入物結構揭示於第2圖。核心之第一部分由含有化合 物1之PEO-PDMS以50 : 50比例構成,以及長度爲34 mm。 核心之第二部分由含有雌脂二醇之具有50%PEO之PEO-PDMS構成,以及長度爲6 mm。 核心部分包裝於由PEO-PDMS以20:80比例構成之膜中 。膜厚度爲〇 . 2 mm,植入物之外直徑爲2 . 48 mm。 所得釋放速率圖解於第1 0圖,其中菱形闡明雌脂二醇 之釋放速率,正方形闡明化合物1之釋放速率。從此圖可 知目標釋放速率已達到。 實施例3 根據實施例1製備一植入物,使用孕稀(gestodene)及 雌脂二醇爲活性劑。 植入物結構揭示於第2圖。核心之第一部分由含有孕稀 之PDMS構成,以及長度爲13 mm。核心之第二部分由含有 雌脂二醇之具有50%PEO之PE0-PDMS構成,以及長度爲 3 0 mm ° 核心部分包裝於由PDMS及甲基三氟丙基-甲基乙烯基矽 氧烷以70 : 30比例構成之膜中。膜厚度爲〇 · 23 mm,植入 物之外直徑爲2.48 mm。 所得釋放速率圖解於第1.1圖,其中菱形闡明孕烯之釋 -43- 1326216 五 '發明說明(42) 放速率,正方形闡明雌脂二醇之釋放速率。 實施例4 根據實施例1製備一植入物,使用7 - (X -甲基-1 9 -正睪 酮(MENT )及孕烯爲活性劑。 植入物結構揭示於第2圖。核心之第一部分由含有重量 6 0%1^1^之經?1催化之?01^構成,具有長度44 111111及直 徑3 . 0 mm。核心之第二部分由含有重量50%孕烯之經過氧 化催化之PDMS構成,具有長度1 2 mm及直徑3 . 0 mm。 兩核心部分皆包裝於由PDMS與經三氟丙基改良之PDMS 之混合物構成的膜中。膜內氟含量變化從重量55%至重量 75%。膜厚度爲分別爲0.25或0.35 mm,於是植入物之外 直徑分別爲3.5或3.7 mm。 所得釋放速率圖解於第1 2至1 4圖,其中第1 2圖闡明 MENT及孕烯從植入物之釋放速率,其中膜的氟含量爲重量 5 5 %以及該膜厚度爲0.25 mm。MENT以三角形表示,孕烯 以菱形表示。從此圖可知兩活性劑的釋放速率實質上固定 達一段時間。第1 3及1 4圖闡明分別於膜之氟含量(重量 55-7 5%)以及厚度(0.25或0.35 _)之作用中’ MENT及孕 烯的釋放速率。從此圖可知釋放速率可藉由氟含量與厚度 之適當選擇而相當準確的調整。舉例而言,從第14圖可 知,孕烯從包裝於具有氟含量爲重量60%及0.25 mm厚度( 以三角形表示)膜之植入物的釋放速率,高於從包裝於具 有氟含量爲重量60%及0.35 mm厚度(以球形表示)膜之植 入物的釋放速率。 -44- 1326216 五、發明說明(43) 主要元件對照說明 1 植入物 2 膜 3 部分3 4 部分4 5 分開膜 6 部分6 7 部分7 8 - 9 膜 10 膜 11 部分11 12 部分12 13 部分13 14 分開膜 15 分開膜 16 部分16 17 部分17 18 部分18 19 第一膜 20 核心 21 第二膜 22 部分22 -45 - 1326216 五、發明說明(44) 23 部分23 24 部分24 25 分開膜 26 分開膜 27 分開膜 28 第一膜 29 第二膜 30 第三膜 3 1 部分31 32 部分32 33 部分33 34 部分34 35 主體 36 分開膜 37 膜 38 分開膜 39 膜 40 第一部分核心 41 第二部分核心 42 部分42 43 部分43 44 空間 -46 --30 - 1326216 V. INSTRUCTIONS (29) Derivatives or analogues; Obstetrics: including agents that act on the uterus such as erg om etrine 'oxytocin', and gemepros t Prostaglandins: eg alprostadil, prostacyclin 'dinoprost (prostaglandin F2-oc)' and sputum (mis〇prost) 〇i); Antimicrobial agents include cephalosporins, such as cepha 1 exi η 'cefoxy tin, and cephalothin; penicillins: eg A Amoxyc i 1 1 i η, amomycin, containing clavulanic acid, ampicillin 'bacampicillin, benzathine penicillin , benzylpenicillin 'carbenicillin, cloxacillin, methicillin, phenethicillin, phenoxymethylpenicillin (p He η ο X ymethy 1 penici 1 1 i η ), flucloxacillin, mezi〇cillin, piperacillin, ticarcillin, and Azalocillin; tetracyclines: for example, minocycline, chlortetracycline, tetracycline, deoxy-3 1 - 1326216 V. Description of invention (3) 〇) Doxycycline, demeclocycline, methacycline, and oxytetracycline, and other tetracyclic antibiotics; amino sugars: For example, amikacin, gentamicin, kanamycin, neomycin, netilmicin, and tobramycin f Fungal agents: for example, amorolfine, isoconazole, clottrimazole, econazole, miconazole, nystatin ( Nystati η ), terbinafine (terb Inafine ), bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole, and fluoride & flucytosine , as well as salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione, and strong ketone Sodium pyrithione; such as quinoline: for example, na 1 idixic acid, cinoxacin, ciprofloxacin, enoxacin, And norfloxacin; sulfonamides: for example, phtha 1 ysu 1 phthia ζ ο 1 e , sulfadoxine, sulphadiazine, amine Sulphamethizole, and amiodarone-32-1326216 V. Inventive Note (31) (sulphamethoxazole); Mills such as dapsson (daps ο ne); various other antibiotics: eg chloramphenicol ( Chloramphenicol), Klin Clindamycin, erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, red mold Erythromycin ethylsuccinate, erythromycin lactobionate, rox ith romyc i η, lincomycin (1 i ncomyc i η ), endomycin Natamycin, nitrofurantoin, s pec ti nomyc i η, vancomycin (v ancomyc i η ), aztreonain, granulin IV Colistin IV), metronidazole, tinidazole, fusidic acid trimethoprim, and 2-sulfur steep N-oxide (2 -thiopyridine N-oxide); especially iodine and iodine compounds such as iodine-PVP complex and diiodohydroxyquin, hexachlorophene, chlorhexidine; chloramine compounds And benzoic acid peroxide; Anti-tuberculosis drugs: eg ethambutol, is ο niazid, Pyrazinamide, rifampicin, and clofazimine; -33 - 1326216 V. INSTRUCTIONS (32) Antimalarial agents: for example, primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine, Maifu Mefloquine, and halofantrine; antiviral agents: for example, acyclovir and acyclovir prodrugs, famcyclovir, zidovudine, Didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, Lito That ritonavir 'n-docosanol, tromantadine, and idoxuridine; anthelmintic: for example, mebendazole, Thiabendazole, Nexrose amide Niclosamide), praziquantel, pyrantel embonate, and diethylcarbamazine cytotoxic agent: for example, p 1 icainyci η Cyclopropylamide, dacarbazine, fluorouracil and its prodrugs, methotrexate, procarbazine, 6-hydrogenthiopurine 6-mercaptopurine), and mucophenolic acid; anorexia and weight reducing agents include dexfenfluramine, fenfluramine, diethylpropionic acid-34 - 1326216 V. (33) (diethylpropion), mazindol, and phentermine; agents for hypercalcemia: for example calcitriol (ca 1 citri ο 1 ), dihydrotachyster ο 1) and its derivatives or analogues; anti-coughing agents: such as ethyl morphine (ethy 1 m 〇rphine), dextromethorphan, and pholcodine; Facial agents: for example, carb ο 1 cysteine, bromhexine, emetine, quanifesin, ipecacuanha, and saponin Saponins; decongestants: for example, pheny 1 ephrine, phenylpropanolamine, and pseudoephedrine; bronchospasm relaxants: ephedrine , fenoterol, orciprenaline, rimiterol, salbutamol, sodium cromoglycate, clomogli Acid (cromoglycic acid) and its prodrugs, terbutaline, ipratropium bromide, salmeterol and theophylline theophylline and derivatives; anti-tissue Amines: for example, mec 1 〇zine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine, chlorpheniramine Standing Clemastine 'Sep nucleus. -35- 1326216 V. INSTRUCTIONS (34) cyproheptadine, dexchlorphenir amine, diphenhydramine ί diphenylamine ( Diphenylamine), doxylamine, mebhydrolin, pheniramine, tripolidine, azatadine, diphenylpyraline, A Methilazine, terfenadine, astemizole, loratidine, acrivastine, cinnarizine, and celestial Cetirizine; local anesthetics: for example, bupivacaine, amethocaine, lignocaine, lidocaine, xinkeke Cinchocaine), dibucaine 'mepivacaine, prilocaine, etidocaine, verat 1 idine, and Procarbazine (pr Caine ) (specificity c · fiber blocker); stratum corneum lipids, used to improve skin barrier repair, such as ceramides, cholesterol, and free fatty acids; nerve and muscle blockers: such as Shooting the succulent test (suxameth ο nium ) 'alcuronium 'pancuronium ' 'atracurium, gollamine, his bocarurine 'and vecuronium; smoking cessation agents: such as nicotine (nic 〇tine), Bappingen (bupr 〇p i. ο η ) -36 - 1326216 V. Description of invention (35) And ibogaine; skin and skin diseases agents: such as vitamins A, C, Bi, B2, B6, B12a and E 'vitamin E acetate and vitamin E sorbate, vitamin κ; desensitized allergens' For example, house, dust or cockroach allergens; nutrient classes: for example, vitamins, essential amino acids and fats; keratolytic agents: for example, alpha-hydroxy acids, glycolic acid and salicylic acid; antigenic animal agents, nitroimidazoles : Such as mantronidazole; opioid antagonists and agonists: for example, naltrexone, Navaxine (cyclazocine), metazocine 'morphine' Hydromorphone, methadone, fentanyl 'sufentann', sufentanil, buprenorphine, pentazocine ' and nai〇rphine; bone active agents include bismuth phosphates: for example, alendronate, cimadronate, c 1 odrona te 'eti drona te, ibandronate, neridronate, olpadronate, pamidronate, leszo (risedronate) 'tiludronate, incacate (1 ncad ι_ ο nate ), [ 1 -hydroxy-3 - ( 1 -pyrrolidinyl)-propylene] phosphonium phosphate , Π-hydroxy-2-imidazole-(1,2-a)pyridin-3-ylethylidene]phosphonium phosphate and zoledronate Ronate); -37 - 1326216 V. INSTRUCTIONS (36) Compounds having anti-progesterone properties, such as those described in WO 〇 1 / 4 7 4 9 ;; anti-hyperlipidemic agents: eg bezaf ibrate ), fenof ibrate, coles t ipol, and statins. Other pharmaceutically active agents that can be used include antibacterial agents, antidiabetic agents, antiepileptic agents, antispasmodic agents, antineoplastic agents, erectile dysfunction improving agents, immunosuppressants, antiprotozoal agents, beta-blockers, anti-par Jinsen's disease agent, stomach-intestinal agent' lipid regulator, c QX-2 inhibitor, leukotriene inhibitor, macrolide, protease inhibitor, anti-osteoporosis agent, anti-obesity agent, cognitive enhancer , anti-urinary incontinence, anti-benign prostatic hypertrophy, thrombin inhibitor, antithrombotic, thrombolytic, fibrinolytic, vasospasm inhibitor, calcium channel blocker, surface glycoprotein receptor inhibition Agents, antiplatelet agents, anti-mitotic agents, microtubule inhibitors (micr 〇t ubu 1 ei nh ibitors ), antisecretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, Anti-metabolite, anti-proliferative, anti-cancer chemotherapeutic, growth hormone antagonist, growth factor, radiotherapy, peptide, protein, enzyme, extracellular matrix compound, self Base degreaser, chelating agent, antioxidant, anti-polymerase agent, photodynamic therapy agent, gene therapy agent, vertigo medication, central nervous system medication, autonomic nervous system medication, autonomic ganglion blocker, peripheral nervous system medication, Eye medicine, sensory organ medication, heart medicine, diuretic, vascular strengthening agent, vasoconstrictor, anti-atherosclerosis. Blood circulation -38 - 1326216 V. Invention description (37) Drug 'breathing stimulator' respiratory organ Medication, peptic ulcer medicine, stomach digestive medicine 'acid generator, laxative, choleretic medicine, digestive medicine, urinary tract disinfectant, uterine strong agent 'urinary genital medicine, anal disease medication, nutritional fortifier 'blood and body fluid Medication, liver disease medication, antidote, habitual poisoning medication 'treatment gout medicine, enzyme preparation, cell activation drug, anti-tumor agent, α-adrenergic blocker, bilirubinase inhibitor, anti-angiogenic factor, anti- Psoriasis, anti-diarrhea, anti-leukemia, anti-AIDS drugs, dementia medication 'angiotensin inhibitors, α- and β-agonists, wound healing Adjuvant 'calcium antagonist' pancreatic hormone, antispasmodic, cardiovascular agent, contractile force affecting agent 'pro-gonadin, sympathomimetic agent, antifungal agent, vascular trophic factor 'proton pump inhibitor' antipruritic, Anti-addictive drugs, histamine receptor antagonists, immunosuppressants, and immunostimulants. Unless otherwise required by the article, the words "compris", "comprises" and "comprising" in this specification mean "including (inc 1 ude )" and "including (inc 1 udes), respectively. "and" includes (inc 1 ud i ng )". That is, when the invention is described or defined as including the specified characteristics, the various embodiments of the same invention may also include additional features. The invention is to be construed as limiting the scope of the invention. The invention is described in more detail below with the following non-limiting drawings and examples. [SI 简单 简单 第 第 第 第 第 第 第 第 第 第 举例 举例 举例 举例 举例 举例 举例 第 第 第Figure 2 illustrates a second embodiment of the present invention. -39 - 1326216 V. DESCRIPTION OF THE INVENTION (38) Figure 3 illustrates a third embodiment of the present invention. - Figure 4 illustrates the present invention. Fourth Embodiment. Fig. 5 illustrates a fifth embodiment of the present invention. Fig. 6 illustrates a sixth embodiment of the present invention. Fig. 7 illustrates a seventh specific embodiment of the present invention. Implementation Figure 8 illustrates an eighth embodiment of the present invention. Figure 9 illustrates the results of Example 1. Figure 10 illustrates the results of Example 2. Figure 11 illustrates the results of Example 3. Figures 1 2, 13 and 14 illustrate the results of Example 4. Figure _ for a detailed description of the first and second embodiments of the present invention, the first embodiment of the present invention is shown in Figure la Implant 1. The ib diagram further shows the same implant in more detail. The implant is packaged in membrane 2, and its core is composed of two and four parts each containing a therapeutic active agent. 3 and 4 parts. Figure 2 illustrates a second embodiment of the invention. The system shown may be part of the implant 'or intrauterine, intrauterine system or intravaginal system. And the core composition of the two parts, the two parts of 6 and 7 each contain a therapeutic active agent. In this embodiment, there is no film between the two parts (which can be regarded as 8)' but the elastic composition used in the two parts The core is packaged in films 9 and 10 made of different elastomers. The figure illustrates a third specific embodiment of the present invention. The system comprises -40 - 1326216. 5. The invention (39) has three parts, namely 1, 1 and 12, and is separated by a membrane 14 and 15 respectively. 1 4 is impermeable to the active agent contained in the portion 11 and is impermeable to the active agent contained in the portion 12, and the separation membrane 15 is impermeable to the active agent contained in the portions 12 and 13 The portion 13 contains two different active agents. The system is further packaged in a film consisting of three portions of 16.6, 17 and 18. Figure 4 illustrates a fourth embodiment of the present invention. The system consists of a core 20 containing a third active agent, packaged in a first film 19 and a second film 21 thicker than the first film 19. Figure 5 illustrates a fifth embodiment of the present invention. The core of this system consists of 22, 23 and 24 parts. Portion 23 surrounds portion 22 of portion and portion 24 surrounds portion 22 and portion 23. Portions 22 and 23 are separated by a split film 27, portions 23 and 24 are separated by a split film 26, and portions 22 and 24 are separated by a split film 25. The core is then packaged through a first film 28, a second film 29, and a third film 30, the third film being thicker than the first and second films. The distance between the membranes is exaggerated and expanded. Figure 6 illustrates a sixth embodiment of the present invention. This system is a T-type intrauterine system containing a body 35. The core consists of four parts: 31, 32, 33 and 34. Each core is packaged in a film. The core portions 3 1 and 3 2 and the portion 33 are separated from each other by a space. Portions 33 and 34 are contiguous and separated by a split film 36. Fig. 7 illustrates a seventh embodiment of the present invention. The system is an intravaginal ring consisting of the first part of the core of the second part of the core 41 4 - 41 - 1326216 5, the description of the invention (4 〇). The two portions are separated by a split film 38, and the inner surfaces of the portions 40 and the outer surfaces of the portions 41 are packaged in the films 37 and 39, respectively. Figure 8 illustrates an eighth embodiment of the present invention. The core of this system contains sections 42 and 43, separated by space 44. Experimental Section The invention is further illustrated by the following non-limiting examples. Example 1 An implant was prepared containing a target release rate of 50 "g/day of ethyl hydroxydigestrel levone and a target release rate of 10//g/day of female fat Estradiol. The implant structure is disclosed in Figure 2. The first part of the core consists of PDMS containing ethyl hydroxydiprone and a length of 35 mm. The second part of the core consists of PE0-PDMS with 50% PEO containing estradiol and a length of 8 mm. The core portion was packaged in a film consisting of PE0-PDMS in a 10:90 ratio. The film thickness is 0.2 mm and the outer diameter of the implant is 2 · 48 mm. The resulting release rate is illustrated in Figure 9, where the square illustrates the release rate of the estradiol, and the diamond illustrates the rate of release of the ethyl hydroxydiprone. From this figure, it is known that the target release rate of the female glycol has reached 'and the release rate of the ethyl hydroxydigestrel is 60 to 40 #g/day, replacing the target of 50/zg/day. Example 2 Preparation of an implant according to Example 1 'Use target release rate was -42 - 1326216 V. Description of the invention (41) 50 vg/day of 11-(4-ethylmercaptophenyl)-17-hydroxy- 17-(1,1,2,2,2-pentafluoroethyl)-strasophilic-4,9-dien-3-one (anti-progesterone) and female with a target release rate of 10/g/day Lipodiol is the active agent. The implant structure is disclosed in Figure 2. The first part of the core consists of a 50:50 ratio of PEO-PDMS containing Compound 1 and a length of 34 mm. The second part of the core consists of PEO-PDMS with 50% PEO containing estradiol and a length of 6 mm. The core portion was packaged in a film consisting of PEO-PDMS in a 20:80 ratio. The film thickness is 〇 2 mm and the outer diameter of the implant is 2. 48 mm. The resulting release rate is illustrated in Figure 10, where the diamonds elucidate the release rate of the estradiol and the squares illustrate the release rate of Compound 1. From this figure, the target release rate has been reached. Example 3 An implant was prepared according to Example 1, using gestodene and estradiol as active agents. The implant structure is disclosed in Figure 2. The first part of the core consists of a PDMS containing gestation and a length of 13 mm. The second part of the core consists of PE0-PDMS with 50% PEO containing estradiol and a length of 30 mm. The core is packaged in PDMS and methyltrifluoropropyl-methylvinyloxirane. In a film of 70:30 ratio. The film thickness is 〇 · 23 mm and the outer diameter of the implant is 2.48 mm. The resulting release rate is illustrated in Figure 1.1, in which the rhombus clarifies the release of the pregnane -43-1326216 five 'invention' (42) rate of release, and the square clarifies the release rate of the estradiol. Example 4 An implant was prepared according to Example 1, using 7-(X-methyl-1 9-n-nonanone (MENT) and pregnane as the active agent. The implant structure is disclosed in Figure 2. Part of the core consists of a weight of 60%1^1^, which is catalyzed by ?1, having a length of 44 111111 and a diameter of 3.0 mm. The second part of the core is oxidized and catalyzed by a weight of 50% pregnane. PDMS consisting of a length of 12 mm and a diameter of 3.0 mm. Both core parts are packaged in a membrane consisting of a mixture of PDMS and PDMS modified with PDDM. The fluorine content in the membrane varies from 55% by weight to weight. 75%. The film thickness is 0.25 or 0.35 mm, respectively, and the outer diameter of the implant is 3.5 or 3.7 mm, respectively. The resulting release rate is shown in Figures 12 to 14, wherein Figure 12 illustrates MENT and pregnane. The release rate from the implant, wherein the fluorine content of the membrane is 55% by weight and the thickness of the membrane is 0.25 mm. MENT is represented by a triangle, and the pregnane is represented by a diamond. From this figure, the release rate of the two active agents is substantially fixed. For a period of time, Figures 13 and 14 illustrate the fluorine content of the membrane (weight 55-7 5%). And the thickness of the thickness (0.25 or 0.35 _), the release rate of 'MENT and pregnane. From this figure, the release rate can be adjusted fairly accurately by the appropriate choice of fluorine content and thickness. For example, as shown in Figure 14 , the rate of release of the pregnane from an implant having a film having a fluorine content of 60% by weight and a thickness of 0.25 mm (indicated by a triangle), higher than the thickness of the package having a fluorine content of 60% and a thickness of 0.35 mm (in a spherical shape) Indicates the release rate of the implant of the membrane. -44- 1326216 V. Description of the invention (43) Comparison of main components 1 Implant 2 Membrane 3 Part 3 4 Part 4 5 Separate membrane 6 Part 6 7 Part 7 8 - 9 Membrane 10 Membrane 11 Part 11 12 Part 12 13 Part 13 14 Separate Membrane 15 Separate Membrane 16 Part 16 17 Part 17 18 Part 18 19 First Membrane 20 Core 21 Second Membrane 22 Part 22 - 45 - 1326216 V. Description of Invention (44 23 parts 23 24 parts 24 25 separation film 26 separation film 27 separation film 28 first film 29 second film 30 third film 3 1 portion 31 32 portion 32 33 portion 33 34 portion 34 35 body 36 separation film 37 film 38 40 first portion 41 second portion of the core portion 42 43 Core portion 42 43 44 39 space apart the membrane film -46--

Claims (1)

1326216 六、申請專利範圍 第9 1 1 1 9649號「選自由植入物、子宮內系統、子宮頸內 系統及陰道內系統所組群組之輸送系統」專利案 (2010年1月11日修正) 六、申請專利範圍 1. 一種選自由植入物、子宮內系統、子宮頸內系統及陰道 內系統所組群組之輸送系統,包含一核心及包裝該核心 之膜,其中該核心及膜本質上由相同或不同的彈性物組 成物(elastomer composition)構成,其特徵爲該核心 由至少一個第一及一個第二部分構成,每一部分含有至 少一種具釋放速率之治療用活性劑,且該系統進一步含 有至少一分開膜分開核心之該至少兩部分中至少兩者, 該分開膜本質上由彈性物組成物構成;,其中該彈性物組 成物係選自由下所組群組: -含有聚(二甲基矽氧烷)之彈性物組成物, -含有3, 3,3 -三氟丙基附著於矽氧烷單位矽原子之以 矽氧烷爲基礎之彈性物之彈性物組成物, -含有聚(伸烷氧化物)類之彈性物組成物,該聚(伸烷 氧化物)類以烷氧基終止之接枝物或嵌斷物經由矽· 碳鍵聯結到聚矽氧烷單位,或以這些形式之混合物 呈現,以及 -至少其兩種之組合物。 2·如申請專利範圍第1項之輸送系統,其中該第—及第二 (以及進一步)部分爲彼此鄰接。 工326216 六、申請專利範圍 3. 如申請專利範圍第1項之輸送系統,其中該第二(或進 一步)部分包裝至少部分之該第一(或第二或進一步)部 分。 4. 如申請專利範圍第1項之輸送系統,其中膜由至少兩層 構成。 5. 如申請專利範圍第4項之輸送系統,其中各層之厚度不 同。 6. 如申請專利範圍第1項之輸送系統,其中進一步含有一 空間分開核心之該至少兩部分中至少兩者。 7. 如申請專利範圍第1項之輸送系統,其中該至少一分開 膜對至少一種治療用活性劑爲可滲透。 8. 如申請專利範圍第1項之輸送系統,其中該至少一分開 膜對治療用活性劑爲不可滲透》 9. 如申請專利範圍第1項之輸送系統,其中以矽氧烷爲基 礎之彈性物1中,接近50%的取代基附著於矽氧烷單位 之矽原子者爲3,3,3 -三氟丙基。 10.如申請專利範圍第 1項之輸送系統,其中聚(伸烷氧化 物)類爲聚(環氧乙烷)類。 11 .如申請專利範圍第1項之輸送系統,其中核心之該至少 兩部分的彈性物組成物是相同的》 12. 如申請專利範圍第1項之輸送系統,其中核心之該至少 兩部分的彈性物組成物是不同的。 13. 如申請專利範圍第1項之輸送系統,其中該至少兩部分 Ε 1326216 六、申請專利範圍 之膜的彈性物組成物是相同的° 14. 如申請專利範圍第1項之輸送系統,其中該至少兩部分 之膜的彈性物組成物是不同的。 15. 如申請專利範圍第4項之輸送系統,其中不同層之膜的 彈性物組成物是相同的。 16. 如申請專利範圍第4項之輸送系統,其中不同層之膜的 彈性物組成物是不同的。 17. 如申請專利範圍第1項之輸送系統,其中分開膜之彈性 物組成物是相同的。 18. 如申請專利範圍第1項之輸送系統,其中分開膜之彈性 物組成物是不同的。 19. 如申請專利範圍第1項之輸送系統,其中至少兩種治療 用活性劑之釋放速率是相同的。 20. 如申請專利範圍第1項之輸送系統,其中至少兩種治療 用活性劑之釋放速率是不同的。 21. 如申請專利範圍第1項之輸送系統,其中釋放速率決定 於核心及膜。 22. 如申請專利範圍第1項之輸送系統,其中釋放速率決定 於膜。 23. 如申請專利範圍第1項之輸送系統,其中該治療用活性 劑爲荷爾蒙。1326216 VI. Patent Application No. 9 1 1 1 9649 "Transportation system selected from the group consisting of implants, intrauterine system, endocervical system and intravaginal system" Patent case (Amended on January 11, 2010) 6. Patent Application Range 1. A delivery system selected from the group consisting of an implant, an intrauterine system, an intracervical system, and an intravaginal system, comprising a core and a membrane encapsulating the core, wherein the core and membrane Essentially consisting of the same or different elastomer composition, characterized in that the core consists of at least one first and a second part, each part containing at least one therapeutically active agent having a release rate, and The system further comprises at least one of at least two of the at least two separate membranes separating the core, the separator membrane consisting essentially of an elastomeric composition; wherein the elastomeric composition is selected from the group consisting of: - containing poly An elastomer composition of (dimethyloxane), an anthracene-based elastomer having a 3,3,3-trifluoropropyl group attached to a helium atom of a heptane a composition of a substance, comprising a poly(alkylene oxide)-based elastomer composition, the poly(alkylene oxide)-based graft or intercalation terminated by an alkoxy group bonded via a ruthenium-carbon bond A polyoxyalkylene unit, or a mixture of these forms, and - at least a combination of the two. 2. The delivery system of claim 1, wherein the first and second (and further) portions are adjacent to each other. 326216. Scope of Application Patent 3. The delivery system of claim 1, wherein the second (or further) portion is at least partially wrapped in the first (or second or further) portion. 4. The delivery system of claim 1, wherein the membrane is composed of at least two layers. 5. For the delivery system of patent application No. 4, the thickness of each layer is different. 6. The delivery system of claim 1, further comprising at least two of the at least two portions of the spatially separated core. 7. The delivery system of claim 1, wherein the at least one separate membrane is permeable to at least one therapeutically active agent. 8. The delivery system of claim 1, wherein the at least one separate membrane is impermeable to the therapeutic active agent. 9. The delivery system of claim 1 wherein the elasticity is based on decane. In the material 1, nearly 50% of the substituents attached to the ruthenium atom of the oxime unit are 3,3,3-trifluoropropyl groups. 10. The delivery system of claim 1, wherein the poly(alkylene oxide) is a poly(ethylene oxide). 11. The delivery system of claim 1, wherein the at least two portions of the elastomeric composition of the core are the same. 12. The delivery system of claim 1, wherein the core of the at least two portions The elastomer composition is different. 13. The delivery system of claim 1, wherein the at least two portions Ε 1326216 VIII, the elastic composition of the film of the patent application range is the same. 14. The delivery system of claim 1, wherein The elastomeric composition of the at least two portions of the film is different. 15. The delivery system of claim 4, wherein the elastomeric compositions of the membranes of the different layers are the same. 16. The delivery system of claim 4, wherein the elastomeric composition of the membranes of the different layers is different. 17. The delivery system of claim 1, wherein the elastomeric composition of the split film is the same. 18. The delivery system of claim 1, wherein the elastomeric composition of the separate membranes is different. 19. The delivery system of claim 1, wherein the release rates of the at least two therapeutically active agents are the same. 20. The delivery system of claim 1, wherein the release rates of the at least two therapeutically active agents are different. 21. The delivery system of claim 1, wherein the release rate is determined by the core and the membrane. 22. The delivery system of claim 1, wherein the release rate is determined by the membrane. 23. The delivery system of claim 1, wherein the therapeutic active agent is a hormone.
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