TW200902025A - Use of an inhibitor of TNF α plus an antihistamine to treat allergic rhinitis and allergic conjunctivitis - Google Patents
Use of an inhibitor of TNF α plus an antihistamine to treat allergic rhinitis and allergic conjunctivitis Download PDFInfo
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- TW200902025A TW200902025A TW097112986A TW97112986A TW200902025A TW 200902025 A TW200902025 A TW 200902025A TW 097112986 A TW097112986 A TW 097112986A TW 97112986 A TW97112986 A TW 97112986A TW 200902025 A TW200902025 A TW 200902025A
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- conjunctivitis
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Description
200902025 九、發明說明： t發明所屬技術領域]1 發明領域 本發明係普遍關於腫瘤壞死因子-a (TNF α )抑制劑、 5 抗組織胺、醫藥物及治療過敏性結膜炎及過敏性鼻炎之領 域。更特定言之，本發明關於於一患者中治療過敏性结膜 炎及過敏性鼻炎之方法，其涉及局部性地投予一包含醫藥 有效量之抗TNFa藥劑及抗組織胺藥劑的組成物。 10 發明背景 在工業國家中，超過10-15%之人口受過敏性鼻炎及/ 或結膜炎所擾。過敏性鼻炎及/或結膜炎係第1型過敏反 應’其係由IgE抗體所媒介。如同部份的對於抗原的過敏 15 反應，產生結合至肥大細胞及嗜鹼細胞表面之IgE，經由對 IgE有專一性之高親合力Fc受體。交聯該IgE分子之抗原 導致涉及釋放預形成中介物質（如：組織胺）、形成及釋放脂 質中介物質及細胞素生成之細胞反應。帶有其中介物質之 肥大細胞可視為過敏性發炎反應起啟及居間作用的中心。 2〇 過敏性鼻炎之臨床症狀包括噴嚏、鼻充血、鼻子癢及 流鼻水。過敏性結膜炎的臨床症狀包括水狀排出物、發紅 及眼驗水腫。這些症狀之強度可能由令人討厭的程度變化 至讓人衰弱的。 200902025 過敏性鼻炎通常和過敏性結膜炎及其它疾病或病症 共存，例如：氣喘、鼻竇炎、過敏性皮膚炎以及出現鼻息 肉。所有這些症狀係常常導致明顯的生活品質損傷。 組織胺係牽連於過敏性鼻炎及過敏性結膜炎。組織胺 5 係由肥大細胞所釋放之一重要的中介物質，組織胺係移居 在鼻黏膜壁上。當被釋放時，已知組織胺會競爭性結合至 局部之組織胺Η,受體且造成喷嚏、鼻子癢及鼻内膜腫 脹。抗組織胺的主要作用係關於其競爭性結合至在標的器 官位置之H,組織胺受體的能力，藉此阻斷組織胺結合至其 10 受體的能力。結合至組織胺受體之抗組織胺化合物已被發 現可用於治療這些病症的徵兆及症狀。大部份此類藥物係 結構上相關於組織胺而結合至其受體的化合物，藉此阻塞 組織胺和其受體的相互反應。 常見的Hi受體拮抗劑（「Hi拮抗劑」）係廣泛地使 15 用為抗組織胺藥劑以治療過敏性結膜炎及過敏性鼻炎。 拮抗劑致標於某些徵兆及症狀，包括：癢覺、打噴嚏以及 和這些病症相關之發炎反應。Η1受體拮抗劑之限制性之一 係其只為抗組織胺而已，主要係提供短期症狀的緩解。 其它供用於過敏性鼻炎之治療包括白三烯素受體拮 20 抗劑、解充血劑、鼻用皮質類固醇、鼻内抗組織胺、鼻内 色苷酸及鼻内反副交感神經生理作用劑。這些治療具有優 點，然而包括類固醇相關副作用（鼻用皮質類固醇）且沒有直 接抗組織胺效果（鼻内色苷酸、白三烯素拮抗劑及鼻内反副 交感神經生理作用劑）。 200902025 腫瘤壞死因子a (TNFa)係一已顯示為在免疫及發炎 反應中扮演重要角色之細胞素，包括過敏性鼻炎及結膜 炎。TNFa係17 kD蛋白質次單元之可溶性同三聚物 (Smith, 1987)。TNFa係衍生自單核細胞及巨嗟細胞，以及 5 其它細胞類型。調節TNFa已被提議為過敏性結膜炎以及 其它和TNFa活化相關之病症的治療方針。 過敏性結膜炎及過敏性鼻炎廣泛的發生率表示對於發 現有效於改善這些病症之徵兆及症狀的治療有一持續性的 需要性。 10 【發明内容】 發明概要 本發明藉由提供新穎之調配物以及用於治療過敏性 結膜炎及過敏性鼻炎之方法克服先前技術的缺點。特別 15 地，本案發明人發現以一 拮抗劑及一抗TNFa化合物之 組合來治療過敏性鼻炎或過敏性結膜炎可提供立即且長效 的緩解。 該過敏性結膜炎可以是季節性過敏性結膜炎、常年性 過敏性結膜炎、春天型結膜炎、巨乳突結膜炎或是特異性 20 角膜結膜炎。 在特定之實施態樣中，擬被治療或預防之疾病係過敏 性結膜炎，且係局部投藥至患者之眼或眼瞼週圍的皮膚的 表面。在其它特定實施態樣中，擬被治療或預防之疾病係 200902025 過敏性鼻炎，且該治療劑係局部投藥至鼻部，例如藉由滴 劑或噴霧劑。 雖然廣泛變化性之過敏性鼻炎及過敏性結膜炎治療 係可利用的，許多者係具有明顯的限制性或是副作用。例 5 如，抗組織胺產品係只有抗組織胺性而已而並不對付過敏 反應的發炎部份，而鼻用皮質類固醇係有和類固醇相關之 副作用。需要有一對於過敏性結膜炎及過敏性鼻炎更有效 的治療方法。 本發明係發現於一患者中治療或預防過敏性結膜炎 10 或過敏性鼻炎的新方法，該方法涉及投予一醫藥有效量之 包括一抗組織胺及一抗TNFa化合物之組成物至一患者。 雖然不希望被限定於任何理論，相信的是，Hl拮抗 劑和抗TNFa化合物的合併因為Η,拮抗劑而提供急性過 敏反應如：噴嚏、鼻充血、鼻子癢及流鼻水之緩解，且因 15為抗TNFa化合物而提供對於過敏的發炎和充血的保護。 本發明之合併產物係沒有類固醇所引發之副作用的風險。 本發明之其它目的、特徵及優點將由以下詳細敘述而變得更 為易於了解的。然而’應被了解的是，該等詳細的欽述及特定的 fe例(同雜指定為本發歡健實絲樣)健提供為說明之目 因為在本發明之概念及範圍内之各種改變及變化係該等技術 項域中具有通常知識者由此詳細敘述可輕易了解的。 【貧施方式】 較佳實施例之詳細說明 200902025 如本說明書中所使用的，「一」或「一者」可表示一或多 個。如申請專利範圍中所使用的，當和「包含」一詞合併使用時’ 該詞「一」或「一者」可表示一或多於一者。如其中所使用的， 「另一」可表示至少一第二者或更多。 5 A.札拮抗劑 當被釋放出來，已知組織胺會競爭性結合至局部組織 胺Hi受體而造成噴嚏、鼻子癢及鼻内膜腫脹。「第一代 抗組織胺」意指一競爭性結合至於標的器官位置之組 織胺受體的藥劑，藉此阻斷組織胺結合至這些受體的能 10 力。這些所謂第一代抗組織胺之範例包括溴苯那敏 (brompheniramine)、二苯胺明（diphenhydramine)、異丙嗓 (promethazine)以及經嗪(hydroxyzine) ° 第一代抗組織胺已被證實有效於預防及緩解噴嚏、鼻 子癢及早期過敏反應的其它症狀，但仍未被發現非常有效 15 於緩解鼻充血，其為過敏性鼻炎之典型的症狀。 抗組織胺之鎮定的副作用已促使所謂第二代抗組織 胺的發展和上市。範例包括：氣雷他定(loratadine)、西替 利嗪（cetirizine)、特非那定（terfenadine)、阿司咪唾 (astemizole)、阿傑拉斯汀（azeiastine)、非索那定 20 (fex〇fenadine)。這些藥劑比第一代抗組織胺為較少親油性 的，導致減少其穿過血液-大腦屏蔽而藉此造成鎮定之能 力。某些此類第二代抗組織胺具有相伴減少反副交感神經 生理作用的效果且因此減少控制流鼻水的效力。 200902025 第三代抗組織胺包括為第二代抗組織胺之代謝物或 異構物的藥劑。範例包括：地氯雷他定(desloratadine)及左 西替利嗪(levocetirizine)。相較於第二代抗組織胺，其優點 看起來為在經改善之安全性及減少之抗蕈毒鹼/反副交感 5 神經生理作用的效果。 局部（鼻内）組織胺Hi-受體拮抗劑、阿傑拉斯汀、左卡 巴斯 >丁（Levocabastine)以及二甲 π定（dimetinden)係一已確 立之抗鼻炎治療法。阿傑拉斯汀係一藥理學獨特的組織胺 H,-受體拮抗劑，其具有廣泛範圍的抗過敏活性。阿傑拉斯 10汀及左卡巴斯汀係全世界可用之鼻噴劑調配物且係經通過 為過敏性鼻炎治療’在美國阿傑拉斯汀也可應用於治療非 過敏性血管舒縮鼻炎。 較佳之受體拮抗劑包括西替利嗪、阿傑拉斯汀、 左卡巴斯'丁、依美斯汀（emedastine)、歐羅帕他定 I5 (olopatadine)、依匹斯汀（epinastine)、苯磺酸貝他斯汀 (bepotastine)、咪唑斯汀(miz〇lastine)、地氯雷他定左西替 利嗓以及二甲咬。更佳地係依美斯;丁、依匹斯、;丁及歐羅帕 他定。 、
B.抗 TNF 2〇 k_TNF化合物」於此係界定為意指-在活體外 (m v叫或活體内（&叫減少、阻斷、抑制、消除或 '、#ί±之藥劑。因此’舉例來說，—抗TNFa係—I：且斷 削減或抑制TNFa作用之藥劑。例如：該抗_τΝρα可以θ、 °成的抑制劑(例如：PDE4抑制劑、JAK3抑制劑或 10 200902025 P38激酶抑制劑）、TNFa拮抗劑（例如：一小分子）、如抑 制TNFct結合至tnf受體的藥劑、一抗體（例如：一抗-TNF 抗體或是一抗_TNF受體之抗體）或是一 TNFa凹坑(例如： 可溶性受體）。一般來說，一抗-TNFcx可以是小分子、胜肽、 5 蛋白質、抗體、DNA、RNA (例如：一 siRNA或是mRNA) 或是一寡核苷酸。此技術領域中具有通常知識者係熟悉於 這些類型之藥齊j。 腫瘤壞死因子（TNF)係一種由經活化之巨噬細胞 (TNF_a)、肥大細胞及某些T細胞(TNF-β)所產生之細胞素， 10其引起大範圍之生物活性，包括：發炎、免疫調節、增殖 性、胞毒性及抗病毒活性。如此處所使用，該「人類TNFa」 一詞係意於指一存在為17kD之分泌型及一 26kD之膜聯合 型的人類細胞素，其具生物活性之形式係由非共價鍵結之 17 kD分子的三聚合體所構成。人類TNFa之結構係進一步 15 於 Pennica 等人（1984)、Davis 等人（1987)及 J〇nes 等人（1989) 之著作中敘述。 舉例來說，「抗-TNFa」包括可以結合TNFa之藥劑， 例如：抗-TNFa抗體。也被包括的抗-TNFa係特定結合至 TNFa之受體分子。抗_TNFa也包括可預防或抑制TNFa合 20 成及/或TNFa釋出的藥劑。 包含在此處所提出之方法中的特定TNFa拮抗劑係 包括益賽普（etanercept)(由 Wyeth-Ayerst Laboratories/Immunex 出售為 ENBREL (可以上市））；因福 利美（infliximab)(由 Centocor 出售為 REMICADE (可以上 11 200902025 市）之一種抗-TNF嵌合體單株抗體）；D2E7人類單株抗體 (劍橋抗體技術）；阿達木單抗(adalimumab)(由亞培(Abbott) 出售為 HUMIRA (可以上市））；CDP-870 、 CDP-571(Humicade，其係於美國第5,994,510號專利中 5 (Celltech)所述之人類化單株抗體）；長效型可溶性TNFa受 體-1 (Amgen); TBP-1(其係一 TNF 結合蛋白（Ares Serono); PASSTNF- a (可以上市）（其係一抗-TNFa多株抗體 (Verigen));英能西普（ienercept)，其係一 TNFR-Ig 融合蛋 白（由Roche出售為TENEFUSE (可以上市））；CytoTAb (可 10 以上市）（PiOtherics) ; TACE，其係一小分子TNFa轉變酵 素抑制劑（Immunex);小分子TNF mRNA合成抑制劑 (Nereus);聚乙二醇化之 p75TNFRFc 突變蛋白（Immunex) 以及TNF ex反義抑制劑。 該技術領域中具有通常知識者係熟悉於這些可被分 15類為抗-TNFa類型之藥劑。有關於抗-TNFa範例之另外的 細節將於以下提出。 l.TNFa合成抑制劑 a· PDE4抑制劑 環形核苷酸特定磷酸二酯酶（PDEs)代表一族群之可 20偟化不同種類之環形核苷單磷酸化物（包括cAMP及cGMP) 水解的酵素。PDE酵素可依據其對於cAMP或cGMP水解 之專一性、其被鈣、新攜鈣蛋白（calm〇dulin)或cgMP調節 之敏感度以及其被不同化合物選擇性抑制而被歸類為丨丨個 族群。PDE 4係cAMP專一性且其抑制作用造成氣管鬆 12 200902025 弛、抗發炎及抗憂鬱的活性。PDE4酵素族群由四種基因 構成，其生成四個指定為PDE4A，PDE4B，PDE4c及pde4d (Wang等人，1997)之PDE4酵素的異構物。磷酸二醋酶 (PDEs)之抑制劑係抑制TNFa合成之一類藥劑。 5 PDE4酵素異構物係位於細胞内之細胞質且係不和任 何已知之膜狀結構相結合。PDE4酵素異構物藉由催化其 自身對於腺苷5’-單磷酸（AMP)之水解而特定地去活化 cAMP。調節CAMP活性在許多生物過程中是重要的，包括 發炎及記憶。 10 PDE4酵素異構物抑制劑，如：洛利普蘭（r〇iipram)、 吡拉米司特(piclamilast)、CDP-840及艾瑞福羅(ariflo)，係 抑制TNFa合成有效的抗發炎劑。除了如咯利普蘭之這些 化合物外，黃°票呤衍生物，如：己酮可可驗(pentoxifylline)、 登布茶驗(denbufylline)以及茶驗，也抑制PDE4。 15 此處所提出之方法意於包含之額外的PDE4抑制劑包 括N-取代di芳基amine化合物之π比咬N-氧化物類似物（如 U.S.專利第7,087,625號所述）’經取代之8-芳基喳琳磷酸 二酯酶-4抑制劑（如U.S·專利第6,740,666號所述）’炔烴-芳基鱗酸二S旨酶-4抑制劑（如U.S.專利第6,743,802號所 20述），1_芳基_ι，8_二氮萘-4-酮鱗酸二醋酶抑制劑（如U.S.專 利第6,677,351及0,541,480號所述），羥基蚓哚（如U.s.專 利第RE38,624, 6,613,794及6,602,89〇號所述呔畊衍生 物(如U.S.專利第6,589,951號所述），三環呔°井衍生物(如 U.S·專利第6,525,055號所述），苯亞甲畊衍生物（如认8.專 13 200902025 利第6,358,973號所述）’具四氫吱喃氧基取代基之苯曱醯 胺（如U.S.專利第6,303,789號所述），二I呼并D弓卜朵_ (diazepinoindolone)(如 U.S.專利第 6,239，130 號）、1_側氧 -1-3-經取代苯基-1,4-二氫-1，8-奈咬-3-叛醯胺鱗酸二酯酶_4 5抑制劑（如U.S.專利第20060058316號公開案），N-經取代 二芳基胺類（如U.S.專利第20050222207號公開案），炔-芳 基磷酸二酯酶-4抑制劑（如u_S.專利第20050070569號公 開案），及奈啶衍生物（如U.S.專利第20040254212號公開 案）。此段所提出之該等專利及專利申請案之各者係於此完 10整地特定併入此案作為參考。 額外的P D E4抑制劑可使用該技術領域中習於此藝者 已知之任何方法鑑定出來。此類方法之範例包括那些在u s. 專利第6,909,002號及u.S.專利公開案第20060019981號 所提出的方法，其各者係於此完整地併入此案作為參考。 15 b· JAK3抑制劑 抑制TNFa生成之另一類藥劑包括傑納斯激酶3(Janus 激酶3 ; JAK3)抑制劑。JAK3使用共通系列（gammac)調節 由細胞素受體而來之訊息傳導。在譯碼出gammaC或JAK3 之基因中的突變導致免疫缺陷。傑納斯激酶3(Jak3)係一 2〇在造血細胞中所表現之酪胺酸激酶，其係和共通系列相 關且係所需於一細胞素族群之訊息傳導，包括介白素-2 (IL-2)，iL_4, IL_7, IL 9 IL15及比_21 ;不論是】认3或是共 通r系列的缺損皆導致嚴重的混合型免疫缺乏（SCIDp 14 200902025 JAK3已被發現為負性調節樹突狀細胞之細胞素生成及存 活（Yamaoka 等人，2005)。 例示性的JAK3抑制劑包括他克莫司（tacrolimus)、 CP-690550, WHI-P131, WHIP-97, WHIP-154, AG490, PS-608504及PNU156804。其它例示性的JAK3抑制劑包括：
/ 2-(111-苯并咪唑-1-基)-9-[1(11)-(3-吡啶）乙基]-8,9-二氫 -7Η-α票吟-8-酮； 10
.f. k 2-(1Η-苯并咪唑-1-基)-9-[4-側氧-l,2,3,4-四氫萘-l(R)-基]-8,9-二氫-7H-嘌呤-8-酮；
15 200902025 l-[9-[6-氟-3,4--8,9-二氫-7H-嘌呤 _2 〜氣-：211-1-笨并11辰喃_4(R)_基]_8-側氧 '基]·1Η-苯并咪唑_6_羰基腈； 5
CU
1-[9-[7-氟 _3,4_ -8,9-二氫-7Η-嘌呤 _2 二氫-2Η-1 -苯并哌喃_4(R)_基]-8-側氧 Ί]-1Η-苯并咪唑_6_幾基腈；以及
2-(1Η-苯并咪0坐 1Λ ^ ^ 基）-9-[5,8-二氟-3,4-二氫-2Η-1-苯 10 并哌喃-4(R)-基]_8 9 _ ^ 』氧_7H_嘌呤冬酮。 c· P38漱酶抑制劑 p38激酶抑制來丨# ^ H係—類已知的化合物。適用之p38激 酶抑制劑包括3(5).雜芳基經取代之吨。坐(旧第5,932,425 波專利）。其它的p38激酶抑制劑包括1·(5·第三丁基-2-/7-15甲苯基_2//_吡唑-3_基)-3_[4-(2-嗎福林基-4-基-乙氧基)萘-1-基]尿素(BIRB 796) ; SB202190 ; SB203580 ; VX-745 以及 VX-702。其它仍有之ρ38激酶抑制劑包括在以下美國專利 案中所述者：美國第 7，189,731; 7，183,287; 7,173,129; 16 200902025 7,135,575; 7,067,540; 6,979,693; 6,696,471; 6,630,485; 6,579,874; 6,479,507; 6,444,696 及 6,316,464 號專利，該等 專利之所有内容係各特定地併入作為參考。 2.TNF拮抗劑 一「TNF拮抗劑」係於此界定為意指一抑制或減少 TNF結合至一 TNF受體的藥劑。該藥劑可以是，舉例來說， 一小分子、一胜肽、—蛋白質、一抗體、一 DNA或是一 RNA。 抗體 10 15 20 在特定之實施態樣中，該TNFa拮抗劑係一抗體。該 「抗體」一詞於此係界定為包括多株抗體、單株抗體 (mAbS)、嵌合體抗體、對抗抗體之抗獨特型（anti.idiotypic ; ami圳抗體，可以溶解贱是經結合型之形式標示之抗獨 特里抗體’以及其片段、區域及衍生物，以任何已知之技 何所提供，舉例，但不限定於，酵素裂解、胜肽合成及重 、’且技術。ITNF抗體包括可結合聊或是辦受體部份 ^藉此:抑制TNF或是伽受體結合之抗體。抗養以 ^係$、財結合TNFa或是了胸受體雜讀此可抑制 或是TNFa受體結合之抗體。 叙M f株抗體」係於此處敎為意指由經—抗原致敏之 =所取㈣種族群抗體分子。一「單株抗體」含 人右眚=上為特疋於—抗原之同種族群抗體分子，該族群 '、相同之抗原決定部位結合位置。單株抗體可由 讀術領域巾具有財一者已知之技術賴得。參考如 17 200902025
Kohler 及 Milstein, 1975; U.S.第 4,376,110 號專利；Ausubel 等人，1992 ; Harlow 及 Lane 1988，Colligan 專人，1993，其 等之内容係於此各特定地併入作為參考。此類抗體可以是 任何免疫球蛋白類型，包括：IgG，IgM，IgE, IgA，GILD以 5 及任何其等之子類型。本發明之一產生單株抗體的融合瘤 可以在活體外、在原位或是活體内培養。在活體内或是在 原位生成高效價之單株抗體是現今較佳之生成方法。 「嵌合體抗體」係一種分子’其不同之部份係取自於 不同之動物種，致此其具有來自於鼠類單株抗體之可變區 10 域及人類免疫球蛋白之固定區域，其係主要用於減少應用 時的致免疫性且增加產率。嵌合體抗體及其製造方法係該 技術領域中已知的。例示性之製造方法係於Cabilly等人， 1984 ; Boulianne 等人，1984 ;及 Neuberger 等人，1985 之文 章所述，其係於此各完整地併入作為參考。 15 一「抗獨特型抗體」（抗_Id)係一辨識獨特決定子之抗 體，該獨特決定因子係一般和抗體之抗原結合位置有關。 可藉由以一擬被製備抗-Id之單株抗體來致敏一相同種及 相同基因型（例如：鼠的品種)之動物作為單株抗體的來源。 該經致敏的動物將辨識且藉由產生針對這些獨特型決定子 20 之抗體（即該抗獨特型抗體）而對該致敏化抗體之獨特型決 定子反應。例示性之製造此類抗體之方法係可見於u. S.第 4,699,880號專利，其係於此完整地併入作為參考。 本發明之抗-TNF抗體可包括至少一重鍵固定區，一 重鏈可變區，一輕鏈可變區及一輕鏈固定區，其中一多株 18 200902025 抗體、一單株抗體、包括至少社 王夕結合TNF之一部份且抑制及 /或中和TNF生物活性之至小 ^ 者的重键可變區或一輕鏈 可變區之片段及/或區域。 抗-TNF抗體包括兩親和力人類-氣類嵌合體抗 抗體以及其具有有效能之針對人類了购之活體内抑制及/ 或中和活性的片段或區域。此類抗體及彼合體抗體可包括 那些藉由使驗純化之重組人類TNFa賴化而產生者或 是其胜肽片段。 有關抗-TNF抗體及製備抗_TNF抗體（包括抗_TNFa抗 10體）之方法的其它資訊可見於us•專利申請案第 20060153846號公開案、U.S·專利申請案第2006〇14〇949 號公開案、u.s.專利申請案第20060121037號公開案、u s 專利申請案第20060024310號公開案、u s專利申請案第
20060024308號公開案、u.S.專利申請案第20060018907 15號公開案、U.S·專利申請案第20050123541號公開案、U.S. 第 7，101，674 號專利、u_S.第 7,060,800 號專利、U_S.第 7,057,022 號專利、U.S.第 6,991,791 號專利、U.S.第 6,835,823 號專利、U.S.第6,790,444號專利、U.S·第6,277,969號專利、 及U.S.第6,270,766號專利，，其等之完整的内容係各特角 20 定地併入作為參考。 較佳之抗體係重組人類抗體。最佳係因福利美 (REMICADE (可以上市）中的活性成份）以及阿達木單抗 (HUMIRA (可以上市）中的活性成份）。 19 200902025 b·其它TNFa拮抗劑 其它的TNFa拮抗劑可藉由干擾TNF成熟而作用。抑 制TNF轉化酵素(TacE)活性之金屬蛋白酶抑制劑已知為 干擾TNF成熟。此類抑制劑之範例如U.S.第5,872,146號 5 專利所提出者，於此併入作為參考。U.S.第5,981,701及 5,695,953號專利敘述可和TNF相互作用而抑制TNF結合 至細胞之非蛋白水解胜肽。 TNFa拮抗劑也包括可溶性tnF受體，其係競爭性抑 制TNF結合至其細胞附著型之受體。舉例來說，益賽普（由 10 Immunex Corporation，西雅圖，華盛頓，出售為ENBREL(可 以上市）)特定地和TNF結合且阻斷其和細胞表面之TNF受 體的相互作用。TNFRl(p55)以及TNFR2 (p75)二者之可溶 性、細胞外部份自然地結合至TNFa且可以是單獨地或是 結合至另一分子而被使用，如同此處所提出之其它ΤΝρα 15拮抗劑。併入這些受體之一或二者之一可溶性片段之TNFa 拮抗劑係於U.S.第5,482,130及5,514,582號專利中提出， 其皆於此併入作為參考。 TNFa拮抗劑也包括抑制TNF訊息傳導之化合物。舉 例來忒，14些化合物可包括抑制結合至TNF受體之細胞内 20結構區且因此抑制或調節由該受體所轉導之訊息的多胜 狀。這些抑制劑係於 U.S.第 5,948,638;5,891,675;5,852 173; 5,849,5〇1; 5,843,675; 5,712,381; 5 563,〇39; 5,789,55〇 及 5,708，142號專利中敘述，該等專利之各者係於此併入作為 參考。 20 200902025 其它適用之TNFcc拮抗劑包括降低組織内τΝρα位準 的藥劑，且包括如 U.S.第 5,994,62〇; 5 981 7〇1; 5 594 1吮 5,336,603及4,565,397號專利中所述之化合物，該等專利 之各者係於此併入作為參考。 5 c·疾病之治療 1·定義 「治療法」及「治療」係意指投以或施用一治療劑至 一患者或是實行一程序或物理療法於一患者用以得到一治 療疾病或健康相關狀況好處之目的。治療包括抑制該狀 10態、疾病或病況，也就是制動或減少該疾病或是至少一該 疾病之臨床或非臨床症狀之發展，或是緩解該疾病，也就 是造成該狀態、疾病或病況或是至少一其臨床或非臨床症 狀的復原。對於-擬被治療之患者的好處係指統計上明顯 地或是至少是該病患或是醫生可察覺的。舉例來說，在本 15發明内文中，過敏性結膜炎可藉由局部性地投予一治療有 效量之抗-組織胺及抗_TNF至眼睛表面以降低結膜的發 癢、發紅及疼痛而被治療。 「如本申請案全文中所使用之該「有療奴好處」或是 「治療上有效地意指促進或増加該患者安康之關 20於該患者狀況之醫療治療的任何事物。這包括，但不限定 於，該等徵兆的頻率或是嚴重程度或是疾病的症狀的減 少。舉例來說，有關過敏性鼻炎的治療，當流鼻水減少則 為得到治療的好處。 21 200902025 一「治療有效量」表示當投予一為了治療狀態、疾病 或病況之哺乳類動物時，一足以產生治療敦果之一化合物 的量。該「治療有效量」將依據該化合物、疾病及其嚴重 程度以及擬被治療的哺乳類動物的年齡、體、生理狀況及 5 反應性而改變。 2.擬被治療之疾病 此處所提出的方法可被應用於治療過敏性結膜炎或 過敏性鼻炎。結膜炎係影響一個體之一眼或兩眼之結膜的 發炎疾病。症狀及徵兆包括眼睛發紅、流淚、分〉'心物多、 10 疼痛及發癢。過敏性結膜炎可以是季節性過敏性結膜炎、 常年性過敏性結膜炎、巨乳突結膜炎、特異性角膜結膜炎 或是春天型結膜炎。鼻炎係鼻内膜之發炎，其可由過敏或 是其它因素而引發，例如：香煙的煙霧、溫度的改變、運 動或壓力。症狀包括喷嚷、鼻充血、鼻子癢及流鼻水。 15 D.醫藥組成物及投藥途徑 本發明之一實施態樣包括藉由投予一藥學有效量之 包括一 Hi拮抗劑及一抗-TNFa化合物之組成物於一患者 而治療過敏性結膜炎或過敏性鼻炎之方法。該投藥係局部 地至眼或鼻子。如此處所使用的，局部性投藥至眼睛包括 20 滴至或放置於眼睛或是置放於眼瞼下方之局部性組成物， 以及施用至眼瞼周圍皮膚及表面之組成物。如此處所使用 的，局部性投藥至鼻子包括藉由將組成物滴入或是喷入鼻 孔及鼻通道而遞送。 22 200902025 被包括在該組成物或是應用於此處所提方法中的藥 物量將會是任何藥學上有效之量且將係依賴多種因素，包 括所選用之藥物的特性及強度。該技術領域中具有通常知 識者將熟知涉及決定一藥物之藥學有效量的因素。 5 在特定實施態樣中，治療劑之總濃度(抗-TNFa及/或抗 組織胺)在該調配物中係約5 % (w/v)或是更少。一般來說， 在本發明之將是由0.0001%至0.5 % (w/v)，較佳係由0.01至 0.2 % (w/v)，且最佳係由0·05至0.2 % (w/v)，然而該抗TNFa 化合物之濃度係由0.0001至5 % (w/v)，較佳係由0.001至1 % 10 (w/v)，且最佳係由 0.01 至0.5 % (w/v)。 1.眼用調配物 在特定實施態樣中，該等組成物係適用於局部施用至 哺乳類動物眼睛。舉例來說，供用於眼用投藥，該調配物 可以是一溶液、一懸浮液、一凝膠或一乳膏。該組成物較 15 佳係經調配為用於以水性溶液之滴劑的形式局部施用於眼 睛。該「水性」一詞典型地表示一水性組成物，其中該載 劑係為>50重量％之含量，較佳係>75重量％且特定為 >90重量％的水。該些滴劑可由一單一劑安瓶而遞送，其中 較佳係無菌的且因此使用該調配物不需抑菌之成份。這些 20 滴劑也可由一多重劑之容器而遞送，特別是當該組成物包 含一防腐之内容物時。可擇地，該滴劑可能由一多重劑之 瓶子而遞送，其較佳係包含一在該調配物被遞送時可將防 腐劑由該調配物中萃出之裝置，該種裝置是該技術領域中 已知的。 23 200902025 在其它方面，本發明之成份可以是以一濃縮凝膠或是 類似的手段可形成置於眼臉下方之不可溶的嵌入物而被遞 送至眼睛。 此外，該等成份可以一皮膚膏、凝膠、乳貧或是乳液 5調配物之方式被置放於外眼瞼及週圍皮膚。 除了活性成份之外，本發明之組成物可包含賦形劑。 例如，該組成物可包括一或多種藥學上可接受之緩衝劑、 防腐劑（包括防腐輔劑）、正常官能調節劑、界面活性劑、溶 解劑、穩定劑、舒適度增加劑、聚合物、軟化劑、pH-調節 10 劑及/或潤滑劑。 適用之緩衝劑包括磷酸鹽、硼酸鹽、檸檬酸鹽、醋酸 鹽及其相似物。防腐劑之範例包括：四元銨化合物，如： 氣化苯二曱烴錢（benzalkonium chloride)、苯度溴銨 (benzododecinium bromide)或是聚 季銨鹽 15 -1 (polyquaternium-1)。其它防腐劑之範例包括高爛酸納、 氣酸鈉、對羥基苯曱酸酯（例如：對羥基苯甲酸曱酯或對 羥基苯甲酸丙酯）、醇類（例如：氯化丁醇、苯曱基醇或是 苯基乙醇）、脈類衍生物（例如：氯己嘴(chlorohexidine)或 疋聚六伸甲基雙脈鹽（polyhexamethylene biguanide ; 2〇 phmb)、高硼酸鈉或是山梨酸。適用之正常官能調節劑包 括甘露醇、氯化鈉、甘油、山梨醇及其相似物。適用之界 面活性劑包括離子性及非離子性界面活性劑，雖然較佳係 非離子性界面活性劑，例如：聚山梨酸酯、聚乙氧基化篦 ^ •油衍生物以及氧代乙基化之三級辛基酚甲醛聚合物 24 200902025 (tyloxapol)。適用之螯合劑包括乙二胺四乙酸鈉及其類似 物。適用之抗氧化劑包括亞硫酸鹽、抗壞血酸鹽、BHA及 BHT。 局部眼用組成物較佳係等滲透的，或是輕微地低滲透 5的以對抗由蒸發及/或疾病所造成淚液之任何高滲透現 象。本發明之組成物一般具有220-320 mOsm/kg範圍的等 參壓’且較佳係具有235-260 mOsm/kg範圍的等滲壓。本 發明之組成物具有5-9範圍的pH，較佳係6.5-7.5範圍的 PH，且更佳係6.8-7.4。 10 在特定實施態樣中，該等治療劑係經調配於一包含有 一或多種淚液取代物的組成物中。多種之淚液取代物係該 技術領域中已知的，包括，但不限定於，單體多元醇，如： 甘油、丙烯乙二醇、及乙烯乙二醇；聚合型多元醇，如： 聚乙烯乙二醇；纖維素酯，如：羥基丙基甲基纖維素；羧 15基甲基纖維素鈉及羥基丙基纖維素；葡聚糖，如：葡聚糖 70，水溶性蛋白質，如：明膠；乙稀聚合物，如：聚乙稀 产t乙烯η比u各酮，以及共聚維_以及卡波姆(carb〇mers)， 卡波姆934P、卡波姆94卜卡波姆及卡波姆974p。 本毛明之調配物可使用於隱形眼鏡或是其它眼用產品。 20 2.鼻用調配物 在特定實施態樣中，本發明之組成物係局部地投予鼻 4局部性鼻用組成物係已知且係包括喷霧及水性喷霧或 =液如*眼用組成物之實例中，鼻用組成物可包含賦形 "丨如，忒組成物可包括一或多種藥學上可接受之緩衝 25 200902025 劑、防腐劑（包括防腐輔劑）、正常官能調節劑、界面活性劑、 溶解劑、穩定劑、舒適度增加劑、聚合物、軟化劑、pH-調節劑及/或潤滑劑。 E.範例 5 以下係包括用以說明本發明之較佳實施態樣的範 例。該等技術領域中具有通常知識者應了解的是，該等範 例中所揭露之技術係遵循由本發明所發現之代表性技術而 良好運作於實施本發明，而因此可被認為是構成本發明實 施之較佳實施態樣。然而，該等技術領域中具有通常知識 10 者依照本揭露應了解的是，可在該所揭露之特定實施態樣 中進行許多改變而仍然得到相似或類似之結果而不偏離本 發明之概念及範圍。 範例1 -局部眼用組成物 成份 數量 （％w/v) 依美斯汀 0.05 益赛普 5.0 二鹽基之磷酸鈉或是丁三醇 鹿(Jromethamine) 0.01-0.5 氯化鈉 0.1-0.8 甘露醇或蔗糖 1-5 聚山梨酸酯80 0.01-0.5 NaOH 及/或 HC1 調整pH 7±2 聚季銨鹽* 0-0.005 純化水 Q. S. 100 15 *如果組成物將被包裝成多劑使用。 範例2 -局部鼻用組成物 26 200902025 成份 數量 （％ w/v) 歐羅帕他定 0.1 阿達木單抗 5.0 二鹽基之填酸鈉 0.01-0.5 氣化納 0.1-0.8 甘露醇或嚴糖 1-5 聚山梨酸酯80 0.01-0.5 NaOH 及/或 HC1 調整 pH 5.5士2 氣化苯二曱烴銨* 0-0.02 純化水 Q. S. 100 *如果組成物將被包裝成多劑使用。 範例3-乳膏組成物 成份 數量 （％ w/v) 歐羅帕他定 0.1 益賽普 5.0 礦物油 0.1-0.5 礦脂 Q.S.100 5 範例4-乳液組成物 成份 數量 （％ w/v) 歐羅帕他定 0.1 益賽普 5.0 棕摘醇(Cetyl Alcohol) 2.6 硬脂醇 0.26 對羥基苯甲酸丙酯 0.05 對羥基苯甲酸甲酯 0.1 丙烯乙二醇 2.0 十二烧基硫酸鈉 0.25 NaOH/HCl Q.S. to pH 5.5 - 7.5 純化水 Q.S. 100 範例5-水性凝膠組成物 成份 數量（％ w/v) 27 200902025 歐羅帕他定 0.1 益賽普 5.0 卡波姆 0.2 - 0.5 氯化苯二甲烴銨 0.01 山梨醇 4.0 NaOH/HCl Q.S. to pH 5.5 - 7.5 純化水 〇.S. 100 此處揭露及請求之所有方法可依據現今之揭露在沒有 過度之實驗下實行。雖然本發明之方法係以較佳之實施態 樣而敘述，該技術領域中具有通常知識者係明顯可了解 5 到，在不偏離本發明之觀念、概念及範圍之情形下係可對 此處所敘述之方法的步驟或步驟的順序進行改變。更特定 而言，將被明白的是，化學上或生理上相關之特定藥劑可 被此處所述之藥劑所取代，然而可達到相同或相似之結 果。該技術領域中具有通常知識者明顯可知的所有此類相 10 似之取代物及修改係視為在所附申請專利範圍所界定之本 發明之概念、範圍及觀念之内。 t圖式簡單說明3 (無） 15 【主要元件符號說明】 (無） 28
Claims (1)
- 200902025 十、申請專利範圍： 1、 一種一醫藥有效量之一Hl拮抗劑以及一醫藥有致量 之一抗TNFa化合物用於製造一用於治療人類患者之 過敏性結膜炎或過敏性鼻炎之藥物的用途，其中該藥 5 物係製造為局部投藥至患者的眼部或鼻子。 2、 如申請專利範圍第1項之用途，其中該過敏性結暝炎 係擇自於以下群組：季節性過敏性結膜炎、常年性過 敏性結膜炎、巨乳突結膜炎、春天型結膜炎及特異性 角膜結膜炎。 10 3 '如申請專利範圍第1項之用途，其中該氏拮抗劑係擇 自於以下群組：西替利唤（cetirizine)、阿傑拉斯汀 (azelastine)、左卡巴斯·汀（ievocabastine)、依美斯 $丁 (emedastine)、歐羅帕他定（〇i〇pata(jine)、依匹斯汀 (epinastine)、苯磺酸貝他斯汀(bep〇tastine)、咪唑斯汀 15 (miz〇lastine)、地氣雷他定（desloratadine)、西替利唤 (levocetirizine)及二曱啶（dimetinden)。 4、如申明專利範圍第1項之用途，其中該η!拮抗劑係擇 自於以下群組.依美斯汀（emedastine) '歐羅帕他定 (olopatadine)及依匹斯汁（epinastine)。 2〇 5、如申清專利範圍第1項之用途，其中該抗-TNFa化合物 係擇自於以下群組：TNFa合成抑制劑及TNF〇^#抗劑。 6、如申凊專利範圍第5項之用途，其中該抗-TNFa化合物 係擇自於TNFa合成抑制劑。 7如申明專利範圍第6項之用途，其中該抗-TNFa化合物 200902025 係擇自於以下群組：PDE4抑制劑、JAK3抑制劑及p38 激酶抑制劑。 8、如申請專利範圍第7項之用途，其中該抗_TNFa化合物 係擇自於PDE4抑制劑。 5 9、如申請專利範圍第7項之用途，其中該抗-TNFct化合物 係擇自於JAK3抑制劑。 10、 如申請專利範圍第9項之用途，其中該抗_TNFa化合物 係擇自於以下群組：他克莫司（tacr〇iimus)、cp_690550, WHI-P131, WHIP-97, WHIP-154, AG490, PS-608504, 0 pNU156804, 2-(lH-苯并《米唑小基比咬） 乙基]-8,9-二氫-7H-嘌呤-8-酮，2-(1Η-苯并咪唑-l-基）-9-[4-側氧-1，2,3,4-四氫萘 _i(r)_ 基]_8,9-二氫-7H-嘌呤-8-酮，1-[9-[6-氟-3,4-二氫-2H-1-苯并哌喃-4(R)-基]-8-側氧-8,9-二氫-7H-嘌呤-2-基]-1H-笨并咪唑-6-5 羰基腈，氟-3,4-二氫-2H-1-苯并哌喃-4(R)- 基]-8-側氧-8,9-二氫-7Η-σ票呤-2-基]-1 Η-苯并p米唾-6-羰基腈以及2-(1Η-苯并咪唑-i_基)_9_[5,8_二氟-3,4-二 氫-2H-1-苯并哌喃-4(R)-基]-8,9-二氫-7H-嘌呤-8-酮。 11、 如申請專利範圍第7項之用途，其中該抗_TNFa化合物 0 係擇自於ρ38激酶抑制劑。 12、 如申請專利範圍第5項之用途，其中該抗_TNFa化合物 係擇自於TNFa拮抗劑。 13、 如申請專利範圍第12項之用途，其中該抗_TNFa化合 物係擇自於抗-TNFa抗體。 30 200902025 14、 如申請專利範圍第13項之用途，其中該抗-TNFa化合 物係擇自於以下群組.：因福利美（infliximab)以及阿達 木單抗(adalimumab)。 15、 如申請專利範圍第1項之用途，其中該抗-TNFa化合物 5 係益賽普（etanercept)。 16、 如申請專利範圍第1項之用途，其中該抗-TNFa化合物 係擇自於以下群組：益賽普、因福利美以及阿達木單 抗。 17、 如申請專利範圍第1項之用途，其中該醫藥有效量之 10 H1 拮抗劑係0.001-1% (w/v)。 18、 如申請專利範圍第17項之用途，其中該醫藥有效量之 H1拮抗劑係0.05-0.2% (w/v)。 19、 如申請專利範圍第1項之用途，其中該醫藥有效量之 抗-TNFa化合物係0.1-8% (w/v)。 15 20、如申請專利範圍第19項之用途，其中該醫藥有效量之 抗-TNFa化合物係1-5% (w/v)。 31 200902025 七、指定代表囷： (一） 本案指定代表圖為：第（）圖。（無) (二) 本代表圖之元件符號簡單說明： (無） 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：
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2008
- 2008-04-10 JP JP2010503203A patent/JP2010523695A/ja active Pending
- 2008-04-10 AR ARP080101489A patent/AR066016A1/es unknown
- 2008-04-10 UY UY31017A patent/UY31017A1/es not_active Application Discontinuation
- 2008-04-10 MX MX2009010946A patent/MX2009010946A/es unknown
- 2008-04-10 AU AU2008240279A patent/AU2008240279A1/en not_active Abandoned
- 2008-04-10 CA CA002682730A patent/CA2682730A1/en not_active Abandoned
- 2008-04-10 US US12/100,715 patent/US20080254029A1/en not_active Abandoned
- 2008-04-10 TW TW097112986A patent/TW200902025A/zh unknown
- 2008-04-10 BR BRPI0810893-5A2A patent/BRPI0810893A2/pt not_active Application Discontinuation
- 2008-04-10 EP EP08745485A patent/EP2131834A2/en not_active Withdrawn
- 2008-04-10 CN CN200880009226A patent/CN101641094A/zh active Pending
- 2008-04-10 WO PCT/US2008/059885 patent/WO2008127975A2/en not_active Ceased
- 2008-04-10 RU RU2009141592/15A patent/RU2009141592A/ru not_active Application Discontinuation
- 2008-04-10 KR KR1020097019961A patent/KR20100014565A/ko not_active Withdrawn
- 2008-04-11 CL CL2008001038A patent/CL2008001038A1/es unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI595090B (zh) * | 2009-09-11 | 2017-08-11 | 美強生營養品美國控股公司 | 益生菌劑 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2008240279A1 (en) | 2008-10-23 |
| KR20100014565A (ko) | 2010-02-10 |
| CN101641094A (zh) | 2010-02-03 |
| CA2682730A1 (en) | 2008-10-23 |
| WO2008127975A2 (en) | 2008-10-23 |
| EP2131834A2 (en) | 2009-12-16 |
| BRPI0810893A2 (pt) | 2014-10-29 |
| CL2008001038A1 (es) | 2009-01-16 |
| AR066016A1 (es) | 2009-07-15 |
| UY31017A1 (es) | 2008-07-03 |
| US20080254029A1 (en) | 2008-10-16 |
| JP2010523695A (ja) | 2010-07-15 |
| MX2009010946A (es) | 2009-10-29 |
| RU2009141592A (ru) | 2011-05-20 |
| WO2008127975A3 (en) | 2009-07-30 |
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