TWI296525B - Novel combination of nonsedating antihistamines with substances which influence leukotriene action, for the treatment of rhinitis/conjunctivitis - Google Patents
Novel combination of nonsedating antihistamines with substances which influence leukotriene action, for the treatment of rhinitis/conjunctivitis Download PDFInfo
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- TWI296525B TWI296525B TW090103054A TW90103054A TWI296525B TW I296525 B TWI296525 B TW I296525B TW 090103054 A TW090103054 A TW 090103054A TW 90103054 A TW90103054 A TW 90103054A TW I296525 B TWI296525 B TW I296525B
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- Prior art keywords
- allergic
- patent application
- rhinitis
- pharmaceutical composition
- nasal
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Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Description
經濟,部智慧財產局員工消費合作社印製 1296525 A7 B7 五、發明説明(1 ) 技術領域 本發明係關於新穎之藥用組成物,它含有不帶有鎭靜 作用之抗組織胺及一種影響白三烯作用之物質,該物質可 爲一種白三烯D 4拮抗劑,一種5 -脂肪氧化酶抑制劑,或 一種5 -脂肪氧化酶一活化蛋白質(F L A P )拮抗劑。 此等組合物適於改進過敏性及/或血管運動性鼻炎或 過敏性結膜炎等之局部治療。 抗組織胺規定安快速移除急性症狀,該急性症狀表現 在變紅,發癢或膨脹,而潛伏在症狀之下的發炎劑成功地 藉由投服包含在組合物內之白三烯拮抗劑而受到控制。 先前技藝 全世界患有過敏性失調症之人口數大幅增加,硏究顯示令 世界所有之孩童及青少年平均有7 . 5 %患上鼻結膜炎( 枯草熱倂合眼症狀學)(氣喘,過敏性鼻結膜炎及異位性 濕疹之患病率的全世界變異:ISAAC,Lancet,351,1 225- 1 332, 1 998 )。在西歐諸國,大約1 4 %之患病率是顯然較高( Annesi-Maesano,I.and Oryszczyn,M.P.:Rhinitis in adolescent s,Results of the ISAAC survey,Revue Francaise d’Allergologie et d’lmmunologie Clinique,38,283-289,1998; Norrman,E.,L.Nystrom,E. Jonsson and N.Stjernberg: Prevalence and incidence of asthma and rhinoconjunctivitis in Swedish teenagers,Europe an Journal of Allergy and Clinical Immunology,53,28-35,1998) 。 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) 7^ I-------ί------IT------^ (請先閲讀背面之注意事項再填寫本頁) 1296525 A7 __ B7 _五、發明説明(2 ) 最近數年來之廣泛硏究活動已導出下列之認知:過敏 性鼻結膜炎在持久性發炎方面來說,係一發炎過程。固然 組織胺仍被認爲是下列症狀之早期的最重要介仲介物以及 被認爲是症狀之最重要觸發物(.該等症狀乃例如變紅,噴 嚏,發癢以及過度分泌(流鼻涕以及流淚),然而進一步 之仲介物被涉及於鼻阻塞,分泌,已涉及於發炎之進展( 例如原發炎細胞之吸引,細胞滲入之增進等)。因此,治 療之標的已由症狀性治療轉移至額外之抗發炎性治療,後 者乃影響潛伏在過敏性失調症下之發炎。組織胺及白三烯 類皆在過敏性早期及晚期中被釋出。 鼻結膜炎之急性症狀(發癢,變紅,膨脹,流鼻涕及 流)可藉助於,除了其他以外,第一代及第二代古典抗組 織胺而輕易加以控制。然而,它們對於潛伏在失調症下之 發炎幾乎沒有治療性中肯的影響力,而且它們之作用永遠 漸進式,通常,過敏性鼻炎(鼻結膜炎)被患者及醫師認 爲是無足輕重之失調症,因此,未受到足夠之治療。因此 ,所謂階段改變乃發生,即,將被認爲非常嚴重之支氣管 性氣喘乃由相對上無害之鼻炎發展而來。基於此理由,不 可能省略的是··甚至過敏性鼻結膜炎都要足夠而強烈地加 以治療。只有如此,病人然後始能於症狀下生活,且然後 ,階段之改變(它在某些狀況下,對生命有危脅)能受到 防止。 .許多動物實驗及臨床硏究指出組織胺及L T S可在鼻 分泌內被偵測出(Yamasaki,U.T.Matsumoto,S. Fuku da,T. 本紙張尺度適用中.國國家標準(CNS ) A4規格(210 X 297公釐) _ (請先閲讀背面之注意事項再填寫本頁) 1296525 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明(3 ) Natayama, H. Nagaya, Y. Ashida. Involvement of thromboxane A2 and histamine in experimental allergic rhinitis of guinea pigs. J. Pharmacol. Exp. Ther.82:1046, 1 997; Pipkorn,U.G Karlsson, L Enerbeck. Cellular response .of the human allergic nasal mucosa to natural allergen exposure. J. Allergy Clin. Immunol. 3 5:234, 1 988; Volovitz, B., S.L. Osur, M. Berstein, P.L. Ogra. Leukotriene C4 release in upper respiratory mucosa during natural exposure to ragweed-sensitive children. J. A .l 1 e r g y C1 i η · I m m u n 01. 8 2:4 1 4,1 9 8 8 )。由於組織胺 H 1 受 體受到阻斷,某些症狀,例如噴嚏,變紅,發癢及鼻內或 眼內過分泌(流鼻涕,流淚)乃重大地減少(Simons, F.E. R.,K.J.Simons. Second generation H1 -receptor antagonists. Ann. Allergy 66··5,1991 )。在過敏性反應之急期中。不論 是否爲局部性,肥大細胞或啫鹼粒細胞之細胞內貯存之去 顆粒作用或空乏化皆顯得突出。此現象乃爲被細胞外或細 胞內鈣所控制之過程。 組織胺,然而,是不僅充作會引發過敏性症狀之一仲 介而已,它亦會藉由影響細胞活性之釋出而作用在過敏性 發炎上。對人類結膜上皮細胞(眼)所作之硏究顯示:組 織胺大幅地增加I 1 — 8及G Μ — C S F (粒細胞巨噬細 胞群體刺激因子)。該釋出可被組織胺H i受體拮抗劑所防 止,即該作用乃經由Η 1受體而被仲介(w.eirner,L.K.,D. A. Gamache, J.Μ. Yanni. Histamine-stimulated cytokine 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ' ' 一只 — (請先閲讀背面之注意事項再填寫本頁) 1296525 A7 B7 經濟,部智慧財產局員工消費合作社印製 五、發明説明(4 ) secretion from human conjunctival epithelial cells: inhibition by histamine Hi-antagonist emedastine. Int.
Arch. Allergy Immunol. 115:288,1998)。此外,吾人知悉 過敏性刺激不僅由肥細胞釋出細胞內貯存之組織胺,亦致 使其他仲介體,例如白三烯重新合成。 白三烯類係屬於花生酸衍生物群之仲介體。它們係發 生酸衍生物,花生酸係一種脂肪酸,爲膜磷脂之一組份。 白三烯類係經由5 —脂肪氧化酶(5 — L 0 X )之催化作 用而由花生酸形成者。目前,只有LTC4,LTD 4及 L T E 4所屬之所謂半胱胺醯基一白三烯類的病原性切題角 色已被證實,白三烯類之作用可由於其受體之受佔領或藉 由其合成之受抑制而發生。除了 5 -脂肪氧化酶受抑制以 外,5 -脂肪氧化酶—活化蛋白質(F L A P )之受抑制 亦能引起白三烯類之合成。 在許多種L T拮抗體中,數個掊抗體,例如zafirlukast, montelukast,pranlukast,等,被用於治療支氣管氣喘。在多種 5 — L〇X抑制劑中,zileuton已上市。所謂F L A P抑制 劑包括,例如Μ K — 5 9 1,Bay X 1005,二者仍在臨床試 驗期中。 多種硏究已證實白三烯類在過敏性失調症中的重要性 。如此,俟過敏原激發後,於早期及晚期內,測定患有過 敏性鼻炎之病人鼻洗出液內之L T濃度明顯著增加( Creticos, P.S., S.P. Peters, N.F. Adkinson. Peptide leukotriene release after antigen challenge in patients 本紙張尺度適用中國國家標準(cns ) a4規格(21 ox297公釐) (請先閱讀背面之注意事項再填寫本頁)
1296525 A7 B7 五、發明説明(5 ) sensitive to ragweed0 (請先閲讀背面之注意事項再填寫本頁) N.Eng. J. Med· 3 10:1 626,1 984)。半胱胺醯基—L T s 可誘起過度分泌(流鼻涕或流淚),但在鼻梗阻上,白三 烯類顯得遠更爲重要。 經濟部智慧財產局員工消費合作社印製 由組織胺所誘發之鼻梗阻係在過敏性反應之早期內存 在,但僅持續數分鐘,然而,由白三烯類所誘起之梗塞則 延至晚期初能觀察到,且於過敏性激發後,持續6 - 8小 時。相對於組織胺而言,於L T激發後,噴嚏及變紅是不 發生(〇kuda,M·,T. Watase,A. Mazewa,C.M. Liu. The role of leukotrine D4 in allergic rhinitis. Ann. Allergy 60: 5 3 7,1 9 8 8 )。然而,俟以L T D 4達到激發作用後,會有嗜 酸性粒細胞之長持久性浸潤作用發生,而該啫酸性粒細胞 最大部份則專司過敏性發炎(Fujika,M.等人,見前)。 這些所謂晚期反應(例如鼻梗塞)可被L T拮抗劑,例如 zafirlukast己夂良(Donnelly, A.L., M. Glass, Μ.C. Minkwitz, T. B. C as ale. The leukotriene D4-receptor antagonist ICI 2042 1 9 relieves symptoms of acute seasonal allergic rhinitis. Am. J. Resp. Crit. Care Med. 151:1734, 1995)( ICI 2042 1 9 = Zafirlukast)。5 — L〇X抑制劑亦可顯著地不 僅在動物實驗內,而且在人體治療內亦可減少過敏性反應 o (Liu,M.C., L.M. Dube, J. Lancaster, and the zileuton study group. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. J. Allergy Clin. Immunol. 98:85 9,1996) 0 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 二只_ 1296525 A7 B7 五、發明説明(6 ) (請先閱讀背面之注意事項再填寫本頁) 在諸抗組織胺藥中,Azelastine爲目前可藉全身性(錠 片)及局部性(鼻內噴灑及眼滴液)利用之唯一活性成份 。因此,即使帶有非強強烈明確之過敏性症狀的病人亦可 成功地受治療。由於多種藥學組成物之原因,病人可視症 狀之性質,嚴重度而個別受azelastine之治療,因此潛伏於 失調症下之發炎可受到抑制。 在諸多最近之抗組織胺藥中,A z e 1 a s t i n e乃爲第一種依 其治療上切題之劑量或濃度,就其抑制在過敏性發炎中扮 演重要角色之白三烯類的合成,被觀察 Tuckermann,U·,Th· Simmet, W. Luck, I. Szelenyi, B.A. Peskar. Inhibition of cysteinyl-leukotriene production by aselastine and its biological significance. Agents and Actions 24:217,1988) 。Azelastine 之該抗白三嫌效果亦 在過敏症內,於受控制之臨床硏究內被偵測。(Shin, Μ.Η. ,F.M. Baroody,D. Proud, A. Kagey-Sobotka, L.M. Lichtenstein, M. Naclerio. The effect of azelastine on the early allergic response. Clin. Exp.Allergy 22:289,1 992 ) ° 經濟部智慧財產局員工消費合作社印製 由於該反應,azelastine之臨床效率(它可與budesonide,一種 糖皮質激素,相匹敵)亦可加以解釋(Wang, D.Y.,Smitz, M. De Waele,P. Clement. Effect of topical applications of budesonide and azelastine on nasal symptoms, eosinophi 1 counts and mediator release in atopic patients after nasal allergen challenge during the pollen season. Int.
Arch. Allergy Immunol. 1 1 4:1 85, 1 997; Gastpar, H., R. 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) 1296525 A7 B7 五、發明説明(7 ) (請先閱讀背面之注意事項再填寫本頁)
Aurich, U. Petzold. Intranasal treatment of perennial rhinitis:Comparison of azelastine nasal spray and budesonide nasal aerosol. Arzn. Forsch. -Drug Res. 43:475, 1993)〇 A zel as tine抑制L T合成以及L T釋出之機制爲獨一性 ,且未被述及在其他抗組織胺之場合中。如所周知,許多 釋出過程係經由細胞內C a 2 +之水平增加而進行,而該細 胞內C a 2 +水平增加係由於作用器細胞之受到過敏性刺激 而發生,蓋因細胞內C a 2 +會啓動白三烯類合成及釋出增 強之決定性步驟。A z e 1 a s t i n e抑制釋出(T a k a n a k a,K.
Effects of azelastine on polymorphonuclear leukocytes: arachidonate cascade inhibition mechanism. Progress Med. 275, 1987; Chand, N., et al. Inhibition of allergic and non-allergic leukotriene formation and histamine secretion by azelastine:Implication for its mechanism of action. Int. 經濟、部智慧財產局員工消費合作社印製
Arch· Allergy Appl. Immunol. 90:67,1989; Senn,N·,et al. Action of azelastine on intracellular Ca2+ in cultured airway smooth muscle. Eur. J. Pharmacol. 205:29, 1991; Chand, N., R.D. Sofia. A. novel in vivo inhibitor of leukotriene biosynthesis:A possible mechanism of action: A mini review. J. Asthm. 3 2:227,1995) o L T受體拮抗劑之作用機轉;^簡單〃。身爲受體拮抗 劑,它們得佔住L T受體。因此,被釋出之白三烯類可接 近其受體,且展示其可被受體仲介之作用。 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X297公釐)_ _ 1〇: ' 一 1296525 A7 B7 五、發明説明(8) 俟鼻內應用之組合物,其含有帶有白三烯一抑制性質 之抗組織胺,以及糖皮質激素,以及若適當的話,減充血 劑,抗過敏劑,溶解黏液劑,非類鴉片型鎭疼劑,脂肪氧 化酶抑制劑以及白三烯類受體拮抗劑者,乃被揭示於E P 0 7 8 0 1 2 7 A 1 ,且被推薦於治療過敏性鼻結膜炎 。抗組織胺與糖皮質激素間之合作必須增加治療之效果。 就鼻炎之局部治療而論,W0 98/48839亦 揭示糖皮質激素型式之抗發炎劑,爲欲增加效率,乃於此 抗發炎劑中加入,例如,至少一種血管收縮劑,一種白三 烯類抑制劑,一種白三烯類抑制劑,一種抗組織胺,一種 抗過敏劑,一種分解黏液劑,一種麻醉劑,一種抗膽素激 性劑或一種種經氨酸酶抑制劑。 如W〇 9 8 / 3 4 6 1 1內所揭示者,用於局部治 療過敏性氣喘之組合物被提議由下列成份所構成:脫乙氧 羰基洛拉他啶(一種不帶有鎭靜作用之抗組織胺藥洛拉他 啶(loratidine)之代謝物)以及一種白三烯類拮抗劑(它 可爲一種白三烯D 4诘抗劑)一種5 -脂肪氧化抑制劑或一 種FLAP拮抗劑。脫乙氧基洛拉他啶必須避免洛拉他啶 與其他不帶有鎭靜作用之抗組織胺劑所帶來之許多不良力 副作用。 A. Roquet等人在”Combined antagonism of leukotrienes and Histamine produces predominant inhibition of allergen -induced early and late phase airway obstruction in asthmatics. Am. J. Respir. Crit. Care Med., 1997,155; 本紙張尺度適用中.國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁) 訂 經廣部智慧財產局員工消費合作社印製 1296525 A7 B7 ---;~—--- 五、發明説明(9 ) (請先閲讀背面之注意事項再填寫本頁) 1 8 5 6 · 1 8 6 3 ” 一文中硏究洛拉他D定(1 o r a t a d i n e ),白三儲類捨 抗劑zafirlukast及上述二種活性成份之組合物於口服上,對 由過敏原所誘發之氣喘性氣道失調症的作用。 由 Merck & Co.,W 〇 9 7 / 2 8 7 9 7 硏究,以經 口或胃腸外投服方式投服洛拉他啶與五種經選擇之白Η燦 掊抗劑,即,monetlukast,zafirlukast,pronlukast, 1 一 ((( R) — 3 — (2 — (6,7 — 一氣基—2 —哇琳基)乙燦 基)苯基)—3— (2 — (. 2-羥基一 2 -丙基)一苯) 硫基)甲基)環丙烷乙酸鈉,1 一((( 1 ( 1 R )〜3 —(2 — ( 2,3 -二氯噻吩基〔3,2 — b〕吡啶—5 一基)一(E) -乙嫌基)苯基)—3 — (2 —(1〜經 基一 1 一甲基乙基)苯基)一丙基)硫基)甲基)環丙烷 乙酸於治療氣喘,過敏及發炎。 就過敏性鼻炎/結膜炎之治療而言,由於被引入之製 劑帶來許多副作用,缺乏治療成功以及在某些場合非專一 性治療等各種原因,具有高度功效及安全性之組合物進一 步爲人們所高度需要。 經濟/部智慧財產局員工消費合作社印製 本發明及於焉依據找出及製出用於治療過敏性鼻炎/ 結膜炎之可利用的新穎組合物。 發明之敘述 本發明乃關於藥學物質之組合物,該組合物不僅可予 口服亦可予局部投服以治療過敏性及/或血管運動性鼻炎 或過敏性結膜炎,此等組合物含有一有效量之①不帶有鎭 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ~ _ 1296525 A7 B7 五、發明説明(1彳) (請先閲讀背面之注意事項再填寫本頁) 別劑量型:①不帶有鎭靜作用的抗組織胺劑(但1〇ratadine 型抗組織胺劑則除外)’宜爲azelastine,但,舉例言之, levocabastme,cetirizine,fexofenadine, mizolastine, astemizole,亦宜,以及②影響白三烯類作用之白三烯類 〇4 捨抗劑’例如,11101^111]^51:,2&^]:111]^51:或pranlukast,或 ③一種5 -脂肪氧化抑制劑,例如z丨1 e u t 〇 n,p i r i p 〇 s t或A W D 23-115或④一種F L A P拮抗劑,例如Μ K — 5 9 1,Μ K 一 8 8 6,B a y x 1 〇 〇 5,該類劑量型適於簡易局部 或經口投服,例如,以噴灑型或滴液型或錠片型等之劑型 存在。 經濟部智慧財產局員工消費合作社印製 依照本發明,由下列成份所構成之新穎組合物可相互同時 ’依序或獨立地,以固定之組合物型式,或於個別物質內 ,予以局部(鼻內或眼內)或經口投服:①一種抗組織胺 劑(唯loratadine型抗組織胺劑則除外),宜爲azelastine,但 ’·舉例 Θ 之’ levocabastine,cetirizine,fexofenadine, mizolastine,astemizole亦宜,以及②影響白三烯類作用之一 種白二嫌D 4括抗劑,例如montelukast,zafirlukast或 p r a η 1 u k a s t或③一種脂肪氧化酶抑制劑,例如z i 1 e u t ο η, pipipost 或 AMD 2 3 — 1 1 5 或④一種 F LA P 拮抗劑 ,例如MK— 591 ,MK— 886 或 Bayxl005 ,它可以其藥學上可接受之鹽類的型式存在。 假若各別之調合物存在時,則這些調合物乃予以相互 修飾,使各別調合物在劑量單位內所含之各別活性成份的 量乃相同於各別活性成份可能存在於組合物內時之量,且 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) 1296525 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明(12) 各別活性成份在個別調合物中之重量比率乃相對於各別成 份可能存在於組合物內時之重量比率。 組合之結果,不僅作用快速發作,而且達到高治療效 率,且伴隨著強大之抗發炎作用.,蓋因前述活性成份間之 作用模式乃爲互補,且亦以類似藥動力學方式運作。作用 之長期間使得病人可以每天投服二次。假若活性成份係以 固定之組合物型式存在時,則病人較易於投服,蓋因二活 性成份包含於單一錠片或單一容器內。 依照本發明,抗組織胺劑成份之濃度可介於由 0 . 0 0 1 %至0 . 5 %組合物內之白三烯類拮抗劑之濃 度可介於由0 · 0 1 %至5 %間。 抗組織胺劑成份之合宜濃度爲0 · 0 5 %至0 · 2 % ,而白三烯類拮抗劑爲0 · 5 %至2 %。 企求之劑量可予每日投服一或二次,抗組織胺劑之個 別劑量爲50 - 500//g,宜爲20 0 — 40 0 //g予 以局部投服,在局部投服上,白三烯D 4拮抗劑之劑量爲 100 — 2000//g 間,宜爲 200 — 1000 //g。 5 — L〇X或F L A P抑制劑係以由5 0 — 2 0 0 0 // g,宜爲2 0 0 — 1 0 0 0 // g範圍之劑量加以投服。 抗組織胺劑(例如azelastine )之劑量介於0.5 — 1 6 m g / 日,宜爲 2 — 8 m g / 曰。 在白三嫌D 4捨抗劑(例如m ο n t e 1 u k a s t)之場合中,個 別劑量自1 一 5〇mg/曰,宜爲5 — 10 mg/曰。 5 — L〇X抑制劑,例如zileuton之口服劑量爲1 — 6 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) _ 15_ (請先閲讀背面之注意事項再填寫本頁) 1296525 Α7 Β7 五、發明説明(14) (請先閲讀背面之注意事項再填寫本頁) 在防腐目的上,乙二胺四乙酸鈉及氯化苯甲烷銨之組 合物宜加以使用。乙二胺四甲酸鈉之使用濃度爲〇 · 0 5 一 0 · 1%,而氯化苯甲烴銨之應用濃度爲〇 · 〇〇 5 -〇· 0 5 % 〇 就適合於調節滲透壓’重量滲透摩爾濃度之適宜的佐 劑而言,氯化鈉,氯化鉀,甘露醇’葡萄糖’山梨糖醇, 甘油或乙二醇等可以大約〇 · 1至1 〇 %之濃度加以使用 〇 組成物屢含有增稠劑,俾增加黏度’進而延長及改進 藥物與人體組織間之接觸,這些增稠劑包括甲基纖維素, 羥甲基·丙基纖維素,羥乙基纖維素,羧甲基纖維素鈉, 聚乙烯醇,聚乙烯基吡咯烷酮,聚丙烯酸酯,聚丙烯醯胺 ,糊精,gellan gum,甲基環氧乙院聚合物(poloxamer) 或纖維素乙酸酯苯二甲酸酯。 經濟部智慧財產局員工消費合作社印製 又,本發明之組成物包含藥學上可接受之緩衝劑,其 係以能夠調節ρ Η以維持於大約4至8間(以5 · 5至 7 · 5爲宜)爲原則,此類型之緩衝液爲檸檬酸鹽,磷酸 鹽,2 -胺基—2 —羥曱基—1,3 —丙二醇( tromethamine ),甘氨酸,硼酸,四硼酸鈉,乙酸及乙酸鈉 。又,進一步之佐劑,例如鹽酸或氫氧化鈉可用於調整 ρ Η ° 本發明將藉助於某些案例而加以說明。 實例1 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) 1296525 A7 B7 五、發明説明(15) 包含azelastine鹽酸鹽鹽酸鹽(〇 · 1 % )之鼻噴灑J 或鼻滴液。 C請先聞讀背面之注意事項存填寫本貢〕
1T
Azelastine鹽酸鹽 O.lOOOOg 羥丙基·甲基纖維素 O.lOOOg 乙二胺四乙酸鈉 0.0500g 氯化苯甲烴銨 0.0125g 一 氫氧化鈉 q.s. ph[sic]6.0 山梨糖醇70% 6.6666g 一 純水 加至10 0 m 1 _ 經濟,部智慧財產局員工消費合作社印製 溶液之調製: 將大約4 5 k g純水引入一帶有攪拌器之容器內° 々一胺四 依序加入活性成份,羥丙基·甲基纖維素’乙一 % 乙酸鈉,氯化苯甲烴銨及山梨糖醇,於攪拌下溶解之° Μ 入純水使生成之溶液總量達4 9 · 5公升,使用1 Ν N a〇Η溶液調整此溶液之ρ Η値至6 · 0。使用純水, 使全量達5 0 · 0公升,攪拌之。使溶液濾經一具有孔口 尺寸0 · 2 // m之膜濾器,將濾液分配於瓶內。 實例2 : . 含有montelukast(l %)之鼻噴灑或鼻滴懸浮液。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1296525 A7 B7 五、發明説明(16)
Montelukast l.OOOOg Avicel RC 591 l.lOOOg Polysorbate 80 O.lOOOg 山梨糖醇溶液70% 6.0000g 乙二胺四乙酸鈉 0.0500g 氯化苯甲烴銨 0.0200g 純水 加至100ml (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 調製: 將4 5 k g水引入一帶有攪拌器及一均化器之容器內 ,基於高速下,於容器內均化Ari cel RC 591。然後,依序 於攪拌下,溶解物質poilysorbate 80,山梨糖醇溶液,乙二 胺四乙酸鈉及氯化苯甲烴銨。 然後以高速均化活性成份m ο n t e 1 u k a s t,直至一均勻之懸 浮液形成爲止。然後,加入純水,使最後容量達5 0公升 ,並進一步予以均化。將懸浮液抽真空,以移除生成之空 氣泡。 然後,將生成之懸浮液分配於瓶中。 實例3 : 包含azelastine鹽酸鹽(0 · 1 %,溶解)及montelukas t(l %,懸浮)之鼻噴灑或鼻滴液。 本紙張尺度適用中.國國家標準(CNS ) A4規格(210 X 297公釐) ~ ' 1296525 A7 B7 五、發明説明(17) Montelukast l.OOOOg Azelastine 鹽酸鹽 O.lOOOg Avicel RC 591 l.lOOOg Polysorbate 80 O.lOOOg 山梨糖醇70% 6.0000g 乙二胺四乙酸鈉 0.0500g 氯化苯甲烴銨 0.0200g 純水. 加至100ml (請先閱讀背面之注意事項再填寫本頁) 經濟,部智慧財產局員工消費合作社印製 調製: 將純水4 5 k g引入一帶有攪拌器及一均化器之適宜 的容器內,於高達下,於容器內均化Avicel RC 591。然後 於攪拌下,依序溶解活性化合物azelastine鹽酸鹽及佐劑 P〇lysorbau8 0,山梨糖醇溶液,乙二胺四乙酸鈉及氯化苯 甲烴銨。 然後,於高速下均化活性成份montelukast,直至形成 一均勻之懸浮液爲止。然後加入純水,使最終容量達5 0 公升,再次予以均化。然後將懸浮液抽真空,以移除生成 之空氣泡。 然後,將生成之懸浮液分配於瓶內。 由某些抗組織胺劑及L T拮抗劑或5 — L Ο X及 F L A P抑制劑之作用光譜,可由導出下列之結論:二物 質之組合物對過敏性鼻結膜炎展示出協乘性作用。 下列藥理硏究乃敘述az e 1 a s ti ne及m ο n te 1 u ka s t以獨自或. 本紙張尺度適用中周國家標準(CNS ) A4規格(210X297公釐) -20- 1296525 A7 B7 五、發明説明(18) (請先閲讀背面之注意事項再填寫本頁) 組合方式,依照鼻炎模式,對褐色那威大鼠所展現之作用 ,取褐色那威大鼠,藉將由卵白蛋白及氫氧化鋁懸浮於生 理食鹽水而成之懸浮液施行雙重腹膜內注射連續二日而予 以自動敏感化。於敏感化後三星期,取一插管,於硫噴妥 鈉麻醉下,以直體步行方式,將插管拎入動物之氣管內, 以維持動物之呼吸,並另取一插管,以逆行方式,將之推 進通過氣管而到達鼻後孔之內部孔口以使灌流鼻腔,並加 以固定。鼻灌流液可滴流出而通過鼻腔,且可被一分級收 集器接收。試驗物質係被懸浮於Tylose內(monteluckast) 或溶解於生理食鹽水內(a z e 1 a s t i n e ),並於過敏原激起作 用前6 0分鐘,被注射腹膜內。爲欲將粘液洗離鼻子,乃 使用輥筒氏泵,使P B S灌流通過鼻腔3 0分鐘(灌流速 率0 . 5 m 1 / m i η )。在局部應用之場合中,將試驗 物質以莫爾濃度之狀況下加至灌流液內,基於過敏原激起 作用前3 0分鐘,將溶液灌流通過鼻子。然後,將血漿指 示劑Evans Blue ( 1 /動物,係溶於P B S內而並1 %強 經濟,部智慧財產局員工消費合作社印製 度之溶液)注入頸靜脈內。有1 5分鐘之中斷時間,於此 期間將灌流液收集。然後,使卵白蛋白之P B S溶液( 1 0 m g /2之卵白蛋白蛋之P B S溶液)灌流鼻腔6 〇 分鐘以達成過敏原之激起作用,於灌流期間,將灌流液收 集在分級收集器內,每1 5分鐘爲一分級收集時間。樣品 之總分級收集數爲5。將樣品離心分離,並置放於微量滴 定枚上,使用Digiscan光度計,於6 2 0 n m之波長下加以 測定。空白値乃自動被扣除,使用A U C程式來計算6 0 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1296525 A 7 _ B7 _ 五、發明説明(19) 分鐘之作用過程。製劑組之物質作用係以%對比賦形劑對 照組之方式加以計算。 於過敏原激起作用後展現之增加的黏膜滲透性將以信 使(例如組織胺及白三烯類)之釋出放式予以評估,俟抗 原接觸後,該現象即使在過敏性人員內亦會發生,且被增 加之流體分泌及鼻梗塞所彰顯。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1296525 A7 ____ B7 _ 五、發明説明(20) 表1 azelastine及montelukast以獨力方式及組合方式(腹膜 ‘ 內投服),在受主動性敏感化及受局部激發之褐色那威大 鼠內,對鼻黏膜滲透性之作用 物質 劑量(mg/kg.,i.p.) 抑制作用以%計 Azelastine 0.01 11 0.1 39 0.3 42 1 47 Montelukast 0.1 7 1 26 3 39 10 44 30 58 Azelastine 0.01 + + 40* montelukast 0.1 * ρ<0.05 ---------衣-- (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 單獨投服0 · 0 1 m g / k g腹膜內注射(i · Ρ . )劑量之a z e 1 a s t i n e,造成血管滲透性1 1 %之小抑制率。 將m ο n t e 1 u k a s t以0 · 1 m g / k g i · p ·之劑量投服時 ,同樣顯現7 %抑制率之稍微活性。而將azelastine以 本紙張尺度適用中.國國家標準(CNS ) A4規格(210X297公釐) h ' 1296525 A7 B7 五、發明説明(21) 0 · 0 lmg/kg i . ρ ·之劑量及 montelukast 以 0 . 1 m g / k g i · p ·之劑量組合投服時,則造成 黏膜血漿外滲作用4 〇 %受抑劑(ρ < 〇 · 〇 5 )。 F L A P 抑制劑 B A Y X 1 0 0 5,以 〇 · 1 m g /
k g 1 · P .之劑量抑制黏膜滲透性3 1 %。A W D 2 3 — 1 1 5 ( 一種5 — L〇X抑制劑),以0 · 0 3至 1 〇 m g / k g之劑量範圍造成血管滲透性之劑量一依賴 性抑制現象(3 7 — 5 4 % )。 (請先閱讀背面之注意事項再填寫本頁) ^^衣.
、1T 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1296525
A B7 五、發明説明(22) 表2 : azel a stine及A WD 23-115以獨力方式及組合方式(局 部應用於灌流液內: 褐色那威大鼠內,雙 1 >,於受自動性敏感化及受局部激發之 f鼻黏膜滲透性之作用 物質 劑量(# mol/1) 抑制作用以%計 A z e 1 a s t i n e 0.003 3 0.01 40 0.03 60 A WD 23-115 0.1 12 0.3 32 1 49 Azelastine + AWD 23-115 0.003 + 0.1 31* *ρ<0·05 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 在局部應用上,組織胺Η 1阻斷劑a z e 1 a st in e,即住在 .0.0 03至0.03#111〇1/1之低濃度下,仍對黏膜血漿外 滲現象展現強大之抑制作用。5 - L〇X抑制劑A W D 2 3 - 1 1 5在0 · 3及1 # m ο 1 / 1之濃度下,以劑 量一依賴性方式分別展示3 2 %及4 9 %血管滲透受抑制 率。假若 azelastine以 0 · 0 03 #mol/l濃度與 AWD 2 3 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X297公釐) 1296525 A7 B7五、發明説明(23)一 1 1 5 ( 0 · 1 // mol/ι )組合投服時,則黏膜外滲之受 抑制率爲3 1 % ( P <〇· 0 5 )。 (請先閲讀背面之注意事項再填寫本頁)
、1T 經濟·部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1296525 η 附件··第90103054號專利申請案中文巧巧書修正頁公告本彳 — 申請曰期 90 年 2 月 12日 案 號 90103054 類 別 (以上各欄由本局填註) 民國96年Μ 23曰呈 年月 g ~ α —_·—.補完 Α4 C4 發明薪型 專利説明書 中 文 :希作 發明 新型 名稱 英 文
Novel combination of nonsedating antihistamines with substii which influence leukotriene action, for the treatment of rhinitis/conjunctivitis_ nee 姓 名 ⑴希爾賈德帕比Poppe, Hildegard C2)朱根恩格爾Engel, Jurgen (2)奋斯特文去瑞勒尼Szelenyi,Istvan ⑴德國 0德國 (3) 德國 國 籍 發明 創作> 住、居所 ⑴德國醉思登凱樂街6號 Kieler Str* 6, D-01109 Dresden, Germany (2)德國亞森諾•恩仁路三號 Erlenveg 3, D-63755 Alzenau, Germany ⑶德國史瓦格D九〇五七一翰得耳街三二號 Handelstrasse 32, D-90571 Schwaig, Germany 裝 訂 姓 名 (名稱)
(1)麥達製藥有限兩合公司 Meda Pharma GmbH & Co* KG 經濟部智慧財產局員工消費合^-社印製 三、申請人 線 國 籍 住、居所 (事務所) 代表人 姓 名 (1)德國 ⑴德國巴德洪堡賓士街一號 Benzstrasse 1, 61352 Bad Homburg, Germany ⑴M斯尤根克洛普Kromp, Hans-Jurgen 吉安德勒Endler, G·
1296525 經濟部智慧財產局員工消費合作社印製 附件2: 第 90103054 號專利! 中文說明書替換頁 民國97年1月|3 BMjL· 五、發明説明(1()) 靜作用的抗組織胺劑(唯loratadine型抗組織胺劑則例外) ,宜爲azelastine,但,舉例言之,levocabastine,cetirizine ,fexofenadine,mizolastine,astemizole,亦宜,以及②會影 響白三烯類作用之白三烯類D 4拮抗劑,例如montelukast, • zafirlukast or pranlukast或③5 -脂肪氧化酶抑制劑,例 如 zileuton,piripost 或 AMD 2 3 — 1 1 5 ( 1 —〔 4 一( D奎啉一 2 —基一甲氧基);基〕一 5 —甲氧基一 1 Η — 口引 唑—3 —醇—二鹽酸鹽或④一種F LAP拮抗劑,例如Μ Κ— 591,ΜΚ— 886,Rayxl〇05,以及,若 適當的話,進一步其藥學上可接受之賦形劑及/或增量劑 或佐劑。 本發明進一步乃關於在哺乳類體內預防及/或治療過 敏性及/或血管運動性鼻炎或過敏性結膜炎的方法,此方 法包含局部或經口投服有效量之一種由下列成份所構成之 組合物:①一種不帶有鎭靜作用之抗組織胺劑(但 loratadine型抗組織胺劑則除外),以azelastne爲宜,但, 舉例而言,levocabastine,cetirizine, fexofenadine, mizolastine,astemizole,亦宜,以及②會影響白三嫌類之作 用的一種白三燏類D 4拮抗劑,例如montelukast,zafirlukas t或p r a η 1 u k a s t或③一種5 —脂肪氧化酶抑制劑,例如z i 1 e u t ο n,pil·ipost或AMD23·115或④一種FLAP拮抗劑,例如M K 一 591,MK - 886,Bayxl〇〇5。投服可以 同時,依序或個別方式進行。 本發明又關於由下列成份所構成之組合物的適宜的個 本纸張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁)
-13- 1296525 附件 2 : 第 90103054 中文說明書替換頁 __民國97年 號專和申請案 : .聲肖 ^ 1為3日修正 y 五、發明説明(13) 克/日間,宜爲0 · 6 — 2克/日間。 (請先閲讀背面之注意事項再填寫本頁〕 在F L A P抑制劑之場合中,劑量爲5 〇 — 2 0 0 0 mg/ 曰,宜爲 1 〇 〇 — 5 0 Omg/ 曰。 前述之抗組織胺劑及白兰烯類拮抗劑化合物,以及彼 等之製法乃爲已知。 依照慣用標準方法,將活性化合物藥學處理成組合物 ,此方法宜將抗組織胺劑以及白三烯類拮抗劑個別或共同 ,假若適宜的話,倂同賦形劑及/或增量劑或佐劑混合, 然後將如此獲得之混合物轉化或適宜之投服劑型。 活性化合物係以混合物之型式予以經口或局部投服, 此混合物含有,視藥學目的,供用之藥學增量劑,佐劑或 賦形劑。 經口投服或局部投服用之組成物可予以調配成不同, 藥學上可接受之投服劑型,例如,鼻噴灑劑,鼻滴液,眼 滴液,錠片,膠囊劑或顆粒劑。 經濟部智慧財產局員工消費合作社印製 除了活性成份以外,本發明之組成物可進一步含有各 種典型之藥用劑型組份,例如抗微生物性防腐劑,滲透劑 ,增稠劑,使p Η調節或緩衝系統用之佐劑。 抗微生物性防腐劑包括,例如,氯化苯甲烴銨,氯化 /溴化十六碳烷基吡啶鑰,氯基丁醇,氯己定乙酸鹽( chlorhexidine acetate),氯己定鹽酸鹽,氯己定二葡萄糖 酸鹽,氯甲酚,對一羥苯甲酸甲酯,對一羥苯甲酸丙酯, 苯氧基乙醇,苯汞鹽,山梨酸,乙汞硫代水楊酸鈉( thiomersal ) 〇 本纸張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -16-
Claims (1)
1296525 A8 B8 C8 D8 六、申請專利範圍 一一、 附*件4A : 第90103054號專利申請案 中文申請專利範圍替換本 (請先閲讀背面之注意事項再填寫本頁) 民國97年1月3日修正 1 · 一種用於治療過敏性鼻炎、血管運動性鼻炎和過 敏性結膜炎之藥學組成物,此藥學組成物包含固定或自由 組成,且適於局部或經口投服,其含有下列之成份: a )佔組成物之0.001重量%至0.5重量%之氮卓斯汀 (azelastine)或其藥學上活性的鹽類, b )佔組成物之〇.〇1重量%至5重量%之一種選自蒙特 魯卡(montelukast)和AWD 23-115之白三烯類拮抗劑或 其藥學上活性的鹽類, c ) 一或多種慣用之藥學載劑、增量劑和佐劑。 2 ·如申請專利範圍第1項之藥學組成物,其係以局 部投服型之劑型存在。 3 ·如申請專利範圍第1項之藥學組成物,其係以經 口投服型之劑型存在。 經濟部智慧財產局員工消費合作社印製 4 ·如申請專利範圍第2項之藥學組成物,其中局部 投服的劑型是噴霧劑。 5 ·如申請專利範圍第2項之藥學組成物,其中局部 投服的劑型是鼻或眼滴液。 本紙張尺度適用中國國家揉率(CNS ) A4規格(210X297公釐)
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PL (1) | PL198357B1 (zh) |
PT (1) | PT1265615E (zh) |
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SK (1) | SK285990B6 (zh) |
TW (1) | TWI296525B (zh) |
UA (1) | UA72587C2 (zh) |
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DK2522365T3 (en) | 2004-11-24 | 2017-02-06 | Meda Pharmaceuticals Inc | Compositions comprising azelastine and methods for its use |
PL1863476T3 (pl) * | 2005-03-16 | 2016-07-29 | Meda Pharma Gmbh & Co Kg | Skojarzenie środków antycholinergicznych i antagonistów receptora leukotrienowego do leczenia chorób układu oddechowego |
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JP2010511632A (ja) | 2006-11-30 | 2010-04-15 | アミラ ファーマシューティカルス,インコーポレーテッド | 5−リポキシゲナーゼ活性化タンパク質インヒビターおよび一酸化窒素モジュレーターを含んでいる組成物および治療法 |
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KR101418404B1 (ko) | 2012-01-06 | 2014-07-10 | 한미약품 주식회사 | 레보세티리진 또는 이의 약학적으로 허용가능한 염 및 몬테루카스트 또는 이의 약학적으로 허용가능한 염을 함유하는 안정한 경구투여용 약학 제제 |
CA2906008C (en) | 2013-03-13 | 2019-07-09 | Flatley Discovery Lab, Llc | Pyridazinone compounds and methods for the treatment of cystic fibrosis |
ES2745041T3 (es) | 2013-03-13 | 2020-02-27 | Inflammatory Response Res Inc | Uso de levocetirizina y montelukast en el tratamiento de trastornos autoinmunitarios |
KR101555908B1 (ko) * | 2013-12-19 | 2015-09-25 | 한미약품 주식회사 | 몬테루카스트 또는 이의 약제학적으로 허용 가능한 염을 포함하는 액상 제제 및 이의 제조방법 |
EP3102209B1 (en) | 2014-02-04 | 2021-04-07 | Bioscience Pharma Partners, LLC | Use of flap inhibitors to reduce neuroinflammation mediated injury in the central nervous system |
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CN110721189A (zh) * | 2019-11-19 | 2020-01-24 | 贵州云峰药业有限公司 | 一种皮肤消毒剂 |
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