TWI333857B - Intranasal pharmaceutical composition for treating non-viral induced airway inflammation or allergic diseases and uses thereof - Google Patents
Intranasal pharmaceutical composition for treating non-viral induced airway inflammation or allergic diseases and uses thereof Download PDFInfo
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- TWI333857B TWI333857B TW096105533A TW96105533A TWI333857B TW I333857 B TWI333857 B TW I333857B TW 096105533 A TW096105533 A TW 096105533A TW 96105533 A TW96105533 A TW 96105533A TW I333857 B TWI333857 B TW I333857B
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- Prior art keywords
- allergic
- allergic diseases
- pharmaceutical composition
- ribavirin
- diseases
- Prior art date
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Classifications
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
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Description
1333857 九、發明說明: 【發明所屬之技術領域】 本發明是有關於可治療過敏性疾病的方法及組合物。 更特定的說,係提供一種以抗感染劑來治療過敏性疾病的 方法及組合物》 【先前技術】 過敏性疾病盛行於大部份的已開發及開發中國家内, 其一般係被界定為由第I型過敏症(亦即,由IgE抗體所媒 介的第I型免疫反應)所引起的功能性失衡(functi〇nal disturbances),且病徵包括花粉熱、支氣管型氣喘、過敏性 鼻炎、異位性皮膚炎及過敏性休克。過敏性疾病已成為當 今文明社會中一項相當嚴重的問題,也造成龐大的社會支 出。在各種過敏病徵當中,最常見的就是過敏性鼻炎。在 某些情況下,甚至可因過敏而導致患者死亡。依據國立台 灣大學附設醫院小兒科在民國八十三年所做的一份統計數 據顯示,在台北市的學生當中,過敏性鼻炎的盛行率超過 33%,此數字約為氣喘的3倍(約1〇〜11%),且每年患病的 人數仍在持續攀升,其中,又以幼兒患者的人數增加最快。 因此許夕研究都致力於要找到一種解決方案,以減輕過 敏性疾病患者的經濟及生理負擔。 身體内過敏反應的最初階段是發展出IgE抗體,其可 與肥大細胞(mast cell)或嗜鹼性白細胞表面上的受體結 «。备過敏原被諸如巨噬細胞之類的抗原表現細胞吞入 5 後’由其細胞膜表面上第二類MHC分子所代表的胜肽將可 被T-細胞表面上的受體認得。這些活化的丁_細胞並可製造 出諸如IL-2、IFN-a、TNF-β (腫瘤壞死因子-β,衍生自Th」 細胞)及 IL-4、IL-5、IL-6、IL-9 及 IL-10 (衍生自 Th-2 細胞) 之類的細胞活化物質(細胞素(Cyt〇kines))。所製造出來的細 胞活化物質會作用在T細胞及B細胞上,以參與後續的細 胞增生及分化。藉由T-細胞表面上的CD40配體與B-細胞 表面上的CD40配體兩者的結合,可活化B_細胞》此外, 隨著IL-4 (來自T-細胞)的加入’ B-細胞會繼續分化成可產 生IgE的細胞。在肥大細胞中,兩分子的igjg可和多價抗 原結合而在細胞膜表面的受體上形成一個架橋,並導致一 系列可引起去顆粒化現象(degranulation)的生化反應。諸如 缉織些員的各種生化介質均會因為此種去顆粒化現象而 自肥大細胞中被免楚出來,並因而可提高微血管㈣$ 、使平滑肌收縮及提高黏液分泌,並與細胞膜上因為花 生四烯酸的代謝而新產生的前列腺言及白三烯素等一起促 成以下現象,包括皮膚出現瘙癢、潮紅、蓴蔴疹、及血管 !·生水腫,呼吸道出現咳漱、窒息、胸部緊縮、呼吸困難及 發舟;心血管系統出現臉色蒼白、低血壓及心律不整現象; 在腸胃道出現噁心、嘔吐及下痢;神經系統出現感覺倒錯、 眩暈、頭痛、抽搐及喪失意識。 目前用來緩解各式過敏症狀的藥物本身都有一些問 題,例如只能提供暫時緩解,或是長期使用會出現副^用 等。已知在對幼兒患者而言相當嚴重的病理性慢性黏液滲 出現象中扮演相當重要角声 制, 茺月邑的1L_6,就無法被抗生素所壓 :也有人建議長期合併使用抗生素及類固醇來屢制 但是,長期施用抗生素及類固醇會導致全身免疫功 -叉到抑制,因此並不是一項好的解決方案。 —本案發明人在經過長期臨床研究及試驗後,終於找到 S種可Λ3療過敏性疾病的新穎治療方法,且不會產生任何 丄作用。本案發明人發現一種核苷酸類似物,雷巴威林 /bavinn)’其具有極佳的抗發炎作用,同時不會產生任何 :作用’因而完成本發明。詳言之’本發明的方法及組合 物可提高-宿主本身的免疫力,藉以抑制發炎並控制過敏 的情況。 【發明内容】 本發明目的在於提供一種用來治療一易感染諸如花粉 熱、支氣管型氣喘、過敏性鼻炎、異位性皮膚炎及過敏性 休克之類的過敏性疾病/或易受諸如花粉熱、支氣管型氣 喘、過敏性鼻炎、異位性皮膚炎及過敏性休克之類的過敏 性疾病之苦的個體的方法及組合物。 因此本啦明一態樣在於提供一種治療一個體的方 法,該個體係易感染過敏性疾病/或易受過敏性疾病之苦, 包含對該個體施用一有效量之抗感染劑,及選擇性地,一 抗發炎劑。 在本發明另一態樣中,本發明提供一種用以治療一個 體的藥學組合物,該個體係易感染過敏性疾病/或易受過敏 7 1333857 性疾病之苦’該組合物包含一有效量之·抗感染劑,並選擇 性地包含一抗發炎劑;及一藥學上可接受的載體。 在一較佳實施例中,本發明提供一種治療過敏性疾病 的方法’包含對—個體施用一有效量之抗感染劑。在此方 法中’並選擇性地包含一抗發炎劑。該抗感染劑係經由鼻 腔施用且其用量為5〜20 pg/每公斤個體體重。在另一實施 例十’此方法更包含在對該個體施用一有效量之抗感染劑
之刖、之後或同時’對該個體施用一有效量之抗發炎劑。 該抗發炎劑可選自吸入性類固醇、白三烯受體頡抗劑及β-2 又體激動劑,且該抗發炎劑的用量為5〜1 〇 pg/每公斤個體 體重°較佳是,該抗感染劑及該該抗發炎劑兩者均係從鼻 腔施用。 在本發明另一較佳實施例中,本發明提供一種用來治 療過敏性疾病的藥學組合物,包含一有效量之抗感染劑。 在此組合物中’該抗感染劑係經由鼻腔施用且其用量為
5〜20 pg/每公斤個體體重。在另一實施例中,此組合物更包 含一有效量之抗發炎劑,其係選自吸入性類固醇、白三烯 受體頡抗劑及β-2受體激動劑。該抗發炎劑可在施用該抗感 染劑之前、之後或同時施用,且其用量為5〜10 pg/每公斤 個體體重。較佳是,該抗感染劑及該該抗發炎劑兩者均係 從鼻腔施用。 以下,將藉由詳細實施說明及實施例來闡述本發明之 其他特點' 目的及優點。 8 1333857 【實施方式】 - 所揭示實施例及所使用的技術名詞均係為了闡述本發 明而用,非用以限制本發明之範疇。本發明範疇也涵蓋未 揭示於此,但對參閱過本說明書之後的任一習知技藝人士 來說顯而易見的實施例。
本發明係有關於過敏性疾病治療上之一種新穎的解決 方案,這些過敏性疾病包括花粉熱、支氣管型氣喘、過敏 性鼻炎、異位性皮膚炎及過敏性休克等類的過敏性疾病, 在本發明方案中係使用一種抗感染劑,並選擇性地包含一 抗發炎劑來進行治療。因此,本發明可提供一種治療過敏 性疾病的方法,該個體係易感染過敏性疾病/或易受過敏性 疾病之苦,該方法包含對該個體施用一有效量之抗感染 劑。在一較佳實施例中,該抗感染劑為雷巴威林(Ribavirin)。
該方法更包含一額外的步驟,即在施用該抗感染劑之 前、之後或同時施用一有效量之抗發炎劑。該抗發炎劑包 括,但不限於,吸入性類固醇、白三烯受體頡抗劑及β-2受 體激動劑。該吸入性類固醇的適當實例包括,但不限於, 諸如布地奈德(budesonide)、倍他米松(betamethasone)、地 塞米松(dexamethasone)、曱潑尼龍(methylprednisolone)、強 的松(prednisolone)、潑尼松(prednisone)、氟尼縮鬆 (flunisolide)、去炎松丙酮化物(triamcinolone acetonide)及 氟替卡松丙酸酯(fluticasone propionate)之類的皮質固醇。 目前市面上有關於該吸入性類固醇的適當商業產品包括, 例如,FLIXONASE、FLIXOTIDE、FLUTICASONE、PULMICORT、FLOVENT、 9 1333857
AEROBID、AZNACORT及ADV AIR。該白三烯受體頡抗劑包括, 但不限於,BLT受體的專一性頡抗劑,例如SB209247、 SC53228、CP195543、CGS25019C 及 LY293111 ;及 CysLTl 受體的 專一性頡抗劑,例如 SR2640、SKF104353、ICI204219、MK476 及LY170680。至於β-2受體激動劑的例子包括,但不限 於’丙卡特羅(procaterol) '淨特羅(zinterol)、沙美物 羅(salmeterol) '福莫特羅(forin〇terol)、特布他林 (terbutaline)及酚丙喘寧(fenoter〇i)。 該抗感染劑和/或抗發炎劑可由相同或不同途徑 施用’例如表面局部塗抹、口腔、鼻腔、靜脈或腹膜 内。較佳是’該抗感染劑和/或抗發炎劑係直接施用到 受測個體的呼吸道内,例如以氣霧性顆粒形式施用到 鼻腔内膜。或者,可由鼻腔施用該抗感染劑,同時則 以表面局部塗抹、口腔、鼻腔、靜脈注射或腹膜内注 射等形式來施用抗發炎劑。
該杬感染劑的用量可在iKSO μβ/每公斤個體體重。但 如果係經鼻腔内膜施用,則其較佳用量在5〜2〇 μ§/每公斤 個體體重。#同時合併使用抗感染劑與抗發炎劑且係經由 :與鼻腔内膜不同的路徑施用時,該抗感染劑的用量較佳 是在5〜30 pg/每公斤個體體重。 抗發炎劑的用量可為〇.5〜〗mg/每公斤個體體重,但較 佳是在5〜1〇 μδ/每公斤個體體重。該抗感染劑及該抗發炎 ,兩者的施用劑量可以相同,也可以不同,臨床醫師並可 無需過度實驗的情況下,依據每—個體的性別、年齡、 10 體重和/或病史來調整。 . 該個體可以是一哺乳類動物,較佳是人類。 本發明一較佳實施例提供一種治療一個體的方法,該 個體係易感染氣管發炎/或易受氣管發炎之苦,該方法包含 對該個體施用一有效量之抗感染劑,及選擇性地施用一 抗發炎劑。該抗感染劑為雷巴威林(Ribavirin),且該抗發炎 劑包括,但不限於,吸入性類固醇、白三烯受體頡抗劑及β_2 受體激動劑。該等適當的吸入性類固醇、白三烯受體頡抗 劑及β-2受體激動劑的實例,如前文所述。此外,抗感染劑 及抗發炎劑的施用途徑、劑量也一如前文所述。 在另一實施例中,本發明提供一種包含氣霧式顆粒於 其中的藥物,其包含一抗感染劑,並選擇性地包括一抗發 火d ’及一藥學上可接党的載體。該藥物係可用於治療諸 如花粉熱、支氣管型氣喘、過敏性鼻炎、異位性皮膚炎及 過敏性休克之類的過敏性疾病。 除非另作定義,否則在此所使用的技術性或科學性名 詞,均採用此領域一般技藝人士所習知的定義,雖然也可 =用與所揭㈣容相當的其他方法靖料來實施本發明, 但以下實施例中將會揭示可用以實施本發明的較佳材料及 方法。所有曾述及的文獻,其内容在此均併入作為參考。 除非另作e兒明,否則所採用的技術均為此領域一般技藝人 士所%知的標準技術’至於所用的材料及方法,均為例示 目的,非用以限制本發明範疇。 氺非另作說明’否則單數名詞「一 (a,an,the)」在此均 1333857 涵蓋其複數形式,。除了在 所有在此用來表示一成分數量的數值大 圍。因此’除非代表相反意涵,否則所有的=為:約略範 求的反應效果或性質來加以變彳卜 i均可視欲 實施例 广 以下實施例僅供闌遠本發明性質及幫助此領域中且備 -般通常知識者來實施本發明之用。所揭示的實施㈣非 用以限制本發明之範_。 動物 BALB/c雌鼠係向國立台灣大學醫學院附設動物中心 (口 4,台北)購買並寄養在該處。所用實驗動物的年齡在6 週〜10週間,且每一實驗所使用的小鼠年齡均大致相當。同 時,動物實驗的流程並獲得國立台灣大學醫學院動物委員 會的認可。
誘使老鼠過敏的卵白蛋白(ovalbumin, OVA)流程及施用雷 巴威林來誘發氣管過反應性(Airway hyper-responsiveness, AHR) 將小鼠隨機分成4組並以腹膜内注射OVA (10 pg)的方 式使其過敏,其中所使用的OVA係在實驗開始前的第〇 天’即先與硫酸銘卸(又稱白礬·(alum),2 mg)形成錯化物。 所有的小鼠並分別在實驗開始後的第14天及第28天,分 12 在邊洗後,立即將她k h 2 丨將肺摘出並以1 0%的中性福馬林固 定,按照一般正常鞋庄忐 . %序處理,並包埋在石臘中,接著製備 出約5微米厚的切片祐c益+主 亚乂棘木素及伊紅(hemztoxylin and eosin)加以染色。技益 、, 接者’以光學顯微鏡進行觀察,結果示於 第4圖中。可知,雷 由巴庳林(第4a及4b圖,分別為30及 10 mg/ml #田巴威林)可有效地抑制細胞浸潤現象並降低 在此OVA·職小鼠模型“巾輯的傷害。 雷巴威林對BAL液中化學增活素㈣⑽心叫之量的治療 效果 ,依據上述方法對OVA-敏感小鼠的肺進行灌洗,並依據 製造商的使用說明,以EUSA試劑套組來測試其中的化學 '曰/舌素3里以嗜伊紅性白血球細胞親合素(e〇taxin)為例, 將所收集的BAL液(BALF)添加到已塗覆有抗-嗜伊紅性白 血球細胞親合素抗體的培養孔中’並放4〇c下隔夜。經過2 小時培育後’以緩衝液清洗培養盤並加入有生物素共軛的 抗體。再於室溫下培育2小時後,加入HRP-抗生物素蛋白, 測量所形成複合物在450 nm下的吸光值(OD),並將該吸光 值轉換成BAL液中嗜伊紅性白血球細胞親合素的濃度。其 他化學增活素,包括KC、IL-4、INF-γ等,均可以類似方法 測得。結果示於第5圖。 從結果可知,在OVA-敏感小鼠中,INF-γ (第5a圖) 及IL-4(第5b圖)的含量高低並不受雷巴威林的影響,但 是,嗜伊紅性白血球細胞親合素(第5d圖)及KC (第5c圖) 15 含量多寡則會因為施用雷巴威林而明顯.下降。此結果暗示 雷巴威林確實對氣喘個體的氣管發炎現象具有治療性的效 果。 &業利用性 本發明優點在於可提供一種過敏性疾病的新穎治療方 法,其係利用一種抗感染劑,及選擇性地包含一抗發炎劑 來達到治療的目的/本發明的方法及藥學組合物可提高一 宿主本身的免疫力,藉以抑制發炎並控制過敏的情況,因 而可治療諸如花粉熱、支氣管型氣喘、過敏性鼻炎、異位 性皮膚炎及過敏性休克之類的過敏性疾病。 雖然本發明已以較佳實施例揭露如上,然其並非用以 限定本發明,任何熟習此技藝者,在不脫離本發明之精神 和範圍内’當可作各種之更動與潤飾,因此本發明之保護 fc圍當視後附之申請專利範圍所界定者為準。 【圖式簡單說明】 為讓本發明之上述和其他目的、特徵、優點與實施例 月b更明顯易懂’所附圖式之詳細說明如下: 第1圖繪示出依據本發明一實施例之OVA流程的示意 圖; 第2圖繪示出依照本發明一較佳實施例,在一 〇VA_ 敏感小鼠中’雷巴威林對該些小鼠因乙醯化曱膽鹼(Mch) 所致之氣管反應性的效果,其中在施用〇VA後,再經由鼻 16 腔施用雷巴咸 (0、10、30 mg/ml),結果以平均值+標準偏 至万式表示,I . 每次結果夂;, 中有5隻小鼠,實驗係重複3次,且 句類似,相較於控制組(沒有雷巴威林處理者), *p<〇.05 ; 1 第 3 圖的枉狀圖顯示雷巴威林對小鼠氣管中細胞 現象的影響,复φ > 中(a)為雷巴威林對3毫升BAL液中之細胞 總數的影變,rk、a &
a lb)為雷巴威林對個別細胞類型之數目的影 單核、’、田胞、嗜中性白血球、嗜伊紅性白企球及淋 巴、、田I ’實驗係重複3 :欠,且每次結果均類似,相較於控 制°且('又有雷巴威林處理者),*p<0.05且、<〇.〇1,;
第4圖的照片顯示出有或無雷巴威林處理之〇va_敏感 J既的肺組織开九癌,其中(A)為經過3〇 mg/ml雷巴威林處理 之〇VA_敏感小鼠肺組織的光學相位差照片;(B)為經過10 爪咖1雷巴威林處理之〇VA_㈣小m織的光學相位差 照片;(c)為未經過雷巴威林處理之OVA_敏感小鼠肺組織 的光學相位差照片,該些組織係經過蘇木素及伊紅染色後 再以光學顯微鏡觀察的結果(原始放大倍數=400倍): 第5圖繪示出由ELISA試驗測得之實施例M之小鼠 的BAL液中⑷INF-γ ’(b) IL-4,(c) KC及(d)嗜伊紅性白 血球細胞親合素之含量,實驗係重複2次,且每次結果均 類似,相較於控制組(沒有雷巴威林處理者),*p<〇 〇5。 【主要元件符號說明】 17
Claims (1)
- t;p4; * 十、申請專利範園: L-〜二 病的鼻用=可~療非病毒所引起的氣管發炎或過敏性疾 病的鼻用樂學組合物, m -., ,. x 匕3 一有效量之雷巴威林做為唯一 的活性成分及一藥學上可接受的載體。 、如申明專利範圍第i項所述之藥學組合物,其中雷 威林的用量在5-20 με/每公斤個體體重。 产鸽3如申請專利範圍第1項所述之藥學組合物,其中該 氣管發炎或過敏性疾病係選自花粉熱、支氣管型氣喘、過 敏性鼻炎、異位性皮膚炎及過敏性休克。 4_一種雷巴威林的用途,其係用來製備可治療非病毒 所引起的氣管發炎或過敏性疾病之經鼻施用的藥物。 5·如請求項4所述之用途,其中該氣管發炎或過敏性 疾病係選自花粉熱、支氣管型氣喘、過敏性鼻炎、異位性 皮膚炎及過敏性休克。 18
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