TWI314867B - Reconstitutable parenteral composition - Google Patents
Reconstitutable parenteral composition Download PDFInfo
- Publication number
- TWI314867B TWI314867B TW091106757A TW91106757A TWI314867B TW I314867 B TWI314867 B TW I314867B TW 091106757 A TW091106757 A TW 091106757A TW 91106757 A TW91106757 A TW 91106757A TW I314867 B TWI314867 B TW I314867B
- Authority
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- Taiwan
- Prior art keywords
- composition
- therapeutic agent
- pelican
- sodium
- weight
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 182
- 239000003814 drug Substances 0.000 claims description 76
- 241000272194 Ciconiiformes Species 0.000 claims description 55
- 229940124597 therapeutic agent Drugs 0.000 claims description 46
- 238000011282 treatment Methods 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 32
- 238000009472 formulation Methods 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000000872 buffer Substances 0.000 claims description 23
- 239000000843 powder Substances 0.000 claims description 22
- 159000000000 sodium salts Chemical class 0.000 claims description 22
- 229940002612 prodrug Drugs 0.000 claims description 21
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- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 19
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 9
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 9
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- 239000011734 sodium Substances 0.000 claims description 9
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
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- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 4
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- IBOFVQJTBBUKMU-UHFFFAOYSA-N 4,4'-methylene-bis-(2-chloroaniline) Chemical compound C1=C(Cl)C(N)=CC=C1CC1=CC=C(N)C(Cl)=C1 IBOFVQJTBBUKMU-UHFFFAOYSA-N 0.000 claims 1
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- WAZQAZKAZLXFMK-UHFFFAOYSA-N deracoxib Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 WAZQAZKAZLXFMK-UHFFFAOYSA-N 0.000 claims 1
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Description
1314867 A7 B7 五、發明説明(1 ) 發明範圍 本發明係有關於水溶性選擇性環加氧酶-2(COX-2)抑制 劑及其鹽類與前藥,且特定言之為沛力可喜,如其鈉鹽型 式(沛力可喜鈉鹽)。沛力可喜係選擇性C0X-2抑制劑華帝可 喜(valdecoxib)之水溶性前藥。更特定言之,本發明有關於 非經腸遞送(如注射)水溶性選擇性C0X-2抑制劑及其鹽類 與前藥之調配物。又更特定言之,本發明係有關於製備為 粉末狀之該調配物,其可於非經腸投藥前於液體載劑中再 組成。本發明亦有關於製備該可再組成調配物之方法、使 用該調配物之治療方法、及以該調配物製造藥劑之用法。 發明背景 環加氧酶(COX)酵素之抑制咸信至少為非類固醇消炎藥 (NASIDs)經抑制前列腺素合成發揮其特獨特的消炎、退熱 及止痛作用之首要機制。傳統NASIDs(如凱特羅拉克 (ketorolac)、戴可婁分那克(diclofenac)、納普羅仙(naproxen) 及其鹽類)於治療劑量時可同時抑制原構性表現COX-1及炎 症相關性或可誘導性C0X-2異構型之環加氧酶。對 C0X-1(其可產生正常細胞功能所需之前列腺素)之抑制會 導致某些與使用傳統NASID有關之不良副作用。相對地, 選擇性抑制C0X-2而實質上未抑制C0X-1則可於減少或移 除該不良副作用時同時保有消炎、退熱及止痛及其它有用 的治療作用。選擇性C0X-2抑制劑(如協勒可喜(celecoxib) 及羅非可喜(rofecoxib))最初於1999年上市,其可代表該技 藝之重大發展。這些藥物經調配成為各種口服投藥的劑型》 -4 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1314867 A7 B7 五、發明説明(2 ) 非經腸投藥途徑包含皮下、肌肉注射及靜脈注射;對多 種藥物而言,其於特定狀況下可提供許多優於口服遞送之 好處。如非經腸投藥比口服投藥典型上可於較短時間内達 到藥物之治療有效血清濃度。尤其是將藥物直接注入血流 中的靜脈注射。由於排除了在胃腸道代謝、與食物結合及 其它原因下的損失,非經腸投藥亦較能預測藥物血清濃 度。由於相同的原因,非經腸投藥通常所需劑量較低。於 緊急情況下非經腸投藥通常係藥物輸送之較佳方法,且亦 可適用於治療不願合作、不省人事、或其它無法或不願接 受口服投藥之病患。 市售NSAID產品極少有可注射型式。現成可供非經腸用 途之非選擇性NSAID(如飢特羅拉克唆美沙胺(tromethamine) 鹽類)為有效的止痛劑,但仍附帶有典型的該類非選擇性 NSAID之副作用》這些副作用包含上胃腸道潰瘍及出血(特 別在年長病患);腎功能降低,其可能導致體液滯留並加劇 高血塵;及抑制血小板功能,其可能使病患容易出血,如 在手術時。該類副作用嚴重的限制了非選擇性NSAID之非 經腸調配物的用途。 因此如有一種可供非經腸遞送之選擇性C0X-2抑制藥物 之調配物,則將為本技藝中重大之進步》 已知可將該治療劑之水性溶液經由凍乾(冷凍-乾燥)法 製備成非經腸調配物。見於如雷明頓(Remington)所著:The Science and Prarti〇e of Pharmacy,第 19 版(1995),Mack Publishing ’第Ι544·ΐ546頁。據雷明頓所載,當治療劑份量 -5 - 本纸張尺度逋用中國國家標準(CNS) Α4規格(210 X 297公釐) 1314867 A7 B7 五、發明説明(3 ) 非常少時,通常可添加賦形劑至治療劑中來增加固體份 量,以便使所產生粉末較易辨識。“有人認為最好將乾燥產 物製成與原溶液相近的體積。為達此目的,原產品之固體 含量須介於約5至25%間。在已知適用於此目的之各種物質 中,最適合者(通常為混合物)為磷酸鈉或鱗酸钟、棒檬酸、 酒石酸、明膠及碳水化合物(如葡萄糖、甘露糖醇及糊精)。,’ 雷明頓引述。 沛力可喜(揭露於美國專利號5,932,598,塔雷(Talley)等人) 係種選擇性C0X-2抑制劑水溶性前藥。沛力可喜於對病 患投藥後可迅速地轉化為實質上非水溶性之選擇性C0X-2 抑制劑華帝可喜。沛力可喜在接觸水後亦可轉化為華帝可 喜,如溶於水中時。與多數選擇性C0X-2抑制劑(如協勒可 喜及華帝可喜)相較之下,沛力可喜(特別係沛力可喜鹽類 (如鈉鹽))較高的水溶性已引起研發適合非經腸用途沛力可 喜之興趣。沛力可喜之結構如下式(I),其本身顯示微弱的 活體外COX-1及C0X-2之抑制活性,而華帝可喜(Π)對C0X-2 具有強抑制活性但對C0X-1的抑制活性差。
(Π) 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1314867 A7 B7 五、發明説明(4 ) 尚有其它已知水溶性之選擇性C0X-2抑制劑及前藥。如 卡爾特(Carter)等人之美國專利號6,034,256中揭露了 一系列 的水溶性苯并吡喃,其據稱可用作為選擇性COX-2抑制 劑,其中包含(S)-6,8-二氯-2-(三氟甲基)-2Η-1-苯并吡喃-3-羧酸(III)化合物及其鹽類。 〇
裝 訂
雖然此類選擇性COX-2抑制劑及前藥已經一般性建議可 用於非經腸投藥,但到目前為止並無任何描述該藥物或前 藥之藥學上可接受的可注射調配物。由以下揭露的内容中 可清楚發現調劑者在嘗試製配該類調配物(以沛力可喜而 言)時所遭遇到.的眾多問題。本發明可提供這些問題之解決 方法。 發明概要 於一具體實施例中,本發明現今提供一種粉末型式之醫 藥組合物,其中包括,(a)至少一種選自選擇性COX-2抑制 劑及其鹽類與前藥之水溶性治療劑,其治療有效劑量組成 約30%至約90%组合物重量,(b) —種劑量約5%至60%組合 物重量之非經腸可接受緩衝劑;及視需要之(c)其它非經腸 可接受賦形劑成分,其總量不大於約10%組合物重量。該 組合物可於非經腸可接受溶劑液體(較佳為水性液體)中再 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1314867 A7 B7 五、發明説明(5 ) 組成以形成可注射溶液。 上述組合物的製備方法可包㈣乾水性溶液等步驟,其 :水性溶液包含治療劑、緩衝劑及視需要含其它賦形劑 成分以形成可隨時再组成之粉末,該方法代表本發明更進 一步之具體實施例❶ 本發明更進-步之具體實施例係一種藉由再組成组合 物而製備之可注射溶液。 本發明更進-步之具體實施例係一種製造商品,其中包 括内含單位劑量的無菌本發明組合物之密封小藥瓶。 本發明更it 具體實施例係一種治療或預防由 C0X-2媒介性疾病或失調之病患的方法,該方法包括⑷將 單位劑量之組合物於生理上可接受量之非經腸可接受溶劑 液體中再組成以形成可注射溶液,及(b)藉非經腸途徑對 病患注射該溶液》 於上述所有具體實施例中,特佳之治療劑係沛力可喜之 水;谷性鹽類。令人驚訝地是發現沛力可喜於非經腸投藥後 可轉化成為華帝可喜,且其消炎及止痛作用實質上相當於 同劑量之華帝可喜。因此,如本發明更進一步之具體實施 例中,其係提供病患一種治療或預防c〇x_2媒介性疾病或 失調之方法,該方法包括非經腸投予病患沛力可喜或其鹽 類,其中沛力可喜劑量相當於華帝可喜“之莫耳治療有效 量。' 本發明更進一步之具體實施例係一種製造商品,其包括 一密封小藥瓶’内含有包括沛力可喜或其鹽類之無菌可非 * 8 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1314867 A7
經腸遞送组合物 療有效量。 ,其中沛力可喜劑量相當於華帝可喜之治 圖1呈現得自實例3之人類藥物動力學研究之數據顯 不(a)靜脈注射(IV)含20毫克沛办可喜之丨毫升巨量藥;及 口服20毫克調配為立即釋放片劑之華帝可4。至”“後 (平均華帝可喜血漿濃度》 發明詳述 (a) 本發明之醫藥組合物包括以下治療劑: 一水溶性選擇性COX-2抑制藥物;
(b) —選擇性COX-2抑制藥物之水溶性鹽類,無論其原 物為水溶性與否;或 《 ' 、 (c)—選擇性COX-2抑制藥物之水溶性前藥,無論其原 藥物為水溶性與否》 ' 組合物中可同時使用多種該類治療劑,但通常較佳為僅 包含一種該選擇性C0X_2抑制藥物或其鹽類或前藥。包括 選擇性COX-2抑制藥物鹽類或前藥之組合物可含少量原藥 物,如在製造、儲存、處理或使用過程中由其鹽類或前藥 所轉化的原藥物。 在此用於描述治療劑之“水溶性” 一詞係指對病患治療 有效量之藥劑可於20-25。(:溶於水中,且其pH值可為非經腸 途徑所接受’水的總量須低於病患由非經腸單次劑量投藥 可接受之上限。治療劑於2〇。(:及pH 7.4之水溶性較佳為大 於約0.1毫克/毫升。更佳之治療劑於2〇〇c&pH7 4之水溶性 9 - 適用中S國家標準(CNS) A4規格(210 X 297公釐) 1314867 A7 B7 五、發明説明(7 ) 大於約0.5毫克/毫升。 在此所實用之選擇性COX-2抑制藥物,或在生體中可轉 化的鹽類或前藥,其所顯示相對於COX-1之選擇性抑制 COX-2的選擇係數應至少為50,較佳為至少100 »該類藥物 包含(不限於)本專利及下列文獻所揭露之化合物,其中各 文獻以引用的方式併入本文中。 U.S. Patent No. 5,344,991 to Reitz & Li. U.S. Patent No. 5,380,738 to Norman et al. U.S. Patent No. 5,393,790 to Reitz et al. U.S. Patent No. 5,401,765 to Lee. U.S. Patent No. 5,418,254 to Huang & Reitz. U.S. Patent No. 5,420,343 to Koszyk & Weier. U.S. Patent No. 5,434,178 to Talley & Rogier. U.S. Patent No. 5,436,265 to Black et al. U.S. Patent No. 5,466,823 to Talley et al. U.S. Patent No. 5,474,995 to Ducharme et al. U.S. Patent No. 5,475,018 to Lee & Bertenshaw. U.S. Patent No. 5,486,534 to Lee et al. U.S. Patent No. 5,510,368 to Lau et al. U.S. Patent No. 5,521,213 to Prasit et al. U.S. Patent No. 5,536,752 to Ducharme et al. U.S. Patent No. 5,543,297 to Cromlish et al. U.S. Patent No. 5,547,975 to Talley et al. U.S. Patent No, 5,550,142 to Ducharme et al. -10 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)
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線 1314867 A7 B7 五、發明説明(8 ) U.S. Patent No. 5,552,422 to Gauthier et al. U.S. Patent No. 5,585,504 to Desmond et al. U.S. Patent No. 5,593,992 to Adams et al. U.S. Patent No. 5,596,008 to Lee. U.S. Patent No. 5,604,253 to Lau et al. U.S. Patent No. 5,604,260 to Guay & Li. U.S. Patent No. 5,616,458 to Lipsky et al. U.S. Patent No. 5,616,601 to Khanna et al. U.S. Patent No. 5,620,999 to Weier et al. U.S. Patent No. 5,633,272 to Talley et al. U.S. Patent No. 5,639,780 to Lau et al. U.S. Patent No. 5,643,933 to Talley et al. U.S. Patent No. 5,658,903 to Adams et al. U.S. Patent No. 5,668,161 to Talley et al. U.S. PatentNo. 5,670,510 to Huang & Reitz. U.S. Patent No. 5,677,318 to Lau. U.S. Patent No. 5,681,842 to Dellaria & Gane. U.S. Patent No. 5,686,460 to Nicolai et al. U.S. Patent No. 5,686,470 to Weier et al. U.S. Patent No. 5,696,143 to Talley et al. U.S. Patent No. 5,710,140 to Ducharme et al. U.S. Patent No. 5,716,955 to Adams et al. U.S. Patent No. 5,723,485 to Giingor & Teulon. U.S. Patent No. 5,739,166 to Reitz et al. -11 - 本纸張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1314867 A7 B7 五、發明説明(9 ) U.S. Patent No. 5,741,798 to Lazer et al. U.S. Patent No. 5,756,499 to Adams et al. U.S. Patent No. 5,756,529 to Isakson & Talley. U.S. Patent No. 5,776,967 to Kreft et al. U.S. Patent No. 5,783,597 to Beers & Wachter. U.S. Patent No. 5,789,413 to Black et al. U.S. Patent No. 5,807,873 to Nicolai" & Teulon. U.S. Patent No. 5,817,700 to Dube et al. U.S. Patent No. 5,830,911 to Failli et al. U.S. Patent No. 5,849,943 to Atkinson & Wang. U.S. Patent No. 5,859,036 to Sartori et al. U.S. Patent No. 5,861,419 to Dube et al. U.S. Patent No. 5,866,596 to Sartori & Teulon. U.S. Patent No. 5,869,524 to Failli. U.S. Patent No. 5,869,660 to Adams et al. U.S. Patent No. 5,883,267 to Rossen et al. U.S. Patent No. 5,892,053 to Zhi et al. U.S. Patent No. 5,922,742 to Black et al. U.S. Patent No. 5,929,076 to Adams & Garigipati. Above-cited U.S. Patent No. 5,932,598. U.S. Patent No. 5,935,990 to Khanna et al. U.S. Patent No. 5,945,539 to Haruta et al. U.S. Patent No. 5,958,978 to Yamazaki et al. U.S. Patent No. 5,968,958 to Guay et al. -12 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐) A7 B7 1314867 五、發明説明(10 ) U.S. Patent No. 5,972,950 to Nicolai' & Teulon. U.S. Patent No. 5,973,191 to Marnett & Kalguthar. U.S. Patent No. 5,981,576 to Belley et al. U.S. Patent No. 5,994,381 to Haruta et al. U.S. Patent No. 6,002,014 to Haruta et al. U.S. Patent No. 6,004,960 to Li et al. U.S, Patent No. 6,005,000 to Hopper et al. U.S. Patent No. 6,020,343 to Belley et al. U.S. Patent No. 6,020,347 to DeLaszlo & Hagmann. Above-cited U.S. Patent No. 6,034,256. U.S. Patent No. 6,040,319 to Corley et al. U.S. Patent No. 6,040,450 to Davies et al. U.S. Patent No. 6,046,208 to Adams et al. U.S. Patent No. 6,046,217 to Friesen et al. U.S. Patent No. 6,057,319 to Black et al. U.S. Patent No. 6,063,804 to De Nanteuil et al. U.S. Patent No. 6,063,807 to Chabrier de Lassauniere & Broquet. U.S. Patent No. 6,071,954 to LeBlanc et al. U.S. Patent No. 6,077,868 to Cook et al. U.S. Patent No. 6,077,869 to Sui & Wachter. U.S. Patent No. 6,083,969 to Ferro et al. U.S. Patent No. 6,096,753 to Spohr et al. U.S. Patent No. 6,133,292 to Wang et al. -13 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) A7 B7 1314867 五、發明説明(11 )
International Patent Publication No. WO 94/15932. International Patent Publication No. WO 96/19469. International Patent Publication No. WO 96/26921. International Patent Publication No. WO 96/31509. International Patent Publication No. WO 96/36623. International Patent Publication No. WO 96/38418. International Patent Publication No. WO 97/03953. International Patent Publication No. WO 97/10840. International Patent Publication No. WO 97/13755. International Patent Publication No. WO 97/13767. International Patent Publication No. WO 97/25048. International Patent Publication No. WO 97/30030. International Patent Publication No. WO 97/34882. International Patent Publication No. WO 97/46524. International Patent Publication No. WO 98/04527. International Patent Publication No. WO 98/06708. International Patent Publication No. WO 98/07425. International Patent Publication No. WO 98/17292. International Patent Publication No. WO 98/21195. International Patent Publication No. WO 98/22457. International Patent Publication No. WO 98/32732. International Patent Publication No. WO 98/41516. International Patent Publication No. WO 98/43966. International Patent Publication No. WO 98/45294. -14 - 本紙張尺度逋用中圉B家標準(CNS> A4规格(210 x 297公釐) A7 B7 1314867 五、發明説明(12 )
International Patent Publication No. WO 98/47871. International Patent Publication No. WO 99/01130. International Patent Publication No. WO 99/01131. International Patent Publication No. WO 99/01452. Intemationai Patent Publication No. WO 99/01455. International Patent Publication No. WO 99/10331. International Patent Publication No. WO 99/10332. International Patent Publication No. WO 99/11605. International Patent Publication No. WO 99/12930. International Patent Publication No. WO 99/14195. International Patent Publication No. WO 99/14205. International Patent Publication No. WO 99/15505. International Patent Publication No. WO 99/23087. International Patent Publication No. WO 99/24404. International Patent Publication No. WO 99/25695. International Patent Publication No. WO 99/35130. International Patent Publication No. WO 99/61016. International Patent Publication No. WO 99/61436. International Patent Publication No. WO 99/62884. International Patent Publication No. WO 99/64415. International Patent Publication No. WO 00/01380. International Patent Publication No. WO 00/08024. International Patent Publication No. WO 00/10993. International Patent Publication No. WO 00/13684. -15 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) A7 B7 1314867 五、發明説明(13 )
International Patent Publication No. WO 00/18741. International Patent Publication No. WO 00/18753. International Patent Publication No. WO 00/23426. International Patent Publication No. WO 00/24719. International Patent Publication No. WO 00/26216. International Patent Publication No. WO 00/31072. International Patent Publication No. WO 00/40087. International Patent Publication No. WO 00/56348.
European Patent Application No. 0 799 823.
European Patent Application No. 0 846 689.
European Patent Application No. 0 863 134.
European Patent Application No. 0 985 666. 在此所用之較佳選擇性COX-2抑制藥物,或於身體中可 轉化的鹽類或前藥,為式(IV)化合物 (X)"
其中: A係一種取代基,其係選自部分不飽和或不飽和雜環基 及部分不飽和或不飽和碳環,較佳為選自下列之 -16 - 本紙張尺度適用中國國家揉準(CNS) A4规格(210X297公釐) A7 B7 1314867 五、發明説明(14 ) 雜環基團:吡唑基、呋喃基、異噁唑基、吡啶基、 環戊缔嗣基與峨嗪嗣基(pyridazinonyl), X 係 0、S 或 CH2 ; ϋ係0或1 ί R1至少為一取代基,其係選自雜環基、環烷基、環烯基 及芳基,且其可取代位置可視需要以選自如下之一 或多個殘基所取代:烷基、南烷基、氰基、羧基、 燒氧羰基、經基、經烷基、齒烷氧基、胺基、烷胺 基、芳胺基、硝基、燒氧燒基、燒亞橫酿基、齒素、 烷氧基及烷硫基; R2係甲基、胺基或胺基羰基烷基; R3係一或多個選自下列之殘基:選自氫基、鹵素'烷基、 烯基、炔基、氧代、氰基、羧基、氰烷基、雜環氧 基、烷氧基、烷硫基、烷羰基、環烷基、芳基、 鹵烷基、雜環基、環烯基、芳烷基、雜環烷基、醯 基、烷硫烷基、羥烷基、烷氧羰基、芳羰基、芳烷 羰基、芳烯基、烷氧烷基、芳硫烷基、芳氧烷基、 芳烷硫基烷基、芳烷氧烷基、烷氧芳烷氧烷基、烷 氧羰烷基、胺羰基、胺羰烷基、烷胺羰基、Ν-芳胺 羰基、Ν-烷基-Ν-芳胺羰基、烷胺羰烷基、羧烷基、 烷胺基、Ν-芳胺基、Ν-芳烷胺基、Ν-烷基-Ν-芳烷胺 基、Ν-烷基-Ν_芳胺基、胺烷基、烷胺烷基、Ν-芳胺 烷基、Ν-芳烷胺烷基、Ν-烷基-Ν-芳烷胺烷基、Ν-烷基-Ν芳胺烷基、芳氧基、芳烷氧基、芳硫基、芳 -17 - 本纸張尺度適用中國國家標準(CNS) Α4规格(210X297公釐) 1314867 A7 B7 五、發明説明( 燒硫基、烷亞磺醯基、烷磺醯基、胺磺醯基、烷胺 績酿基、N-芳胺磺醯基、芳磺醯基與Ν·烷基_N-芳 胺續酿基,R3可取代位置可視需要以選自如下之一 或多個殘基所取代:烷基、齒烷基、氰基、羰基、 燒氧幾基、羥基、羥烷基、齒烷氧基、胺基、烷胺 基、芳胺基 '硝基 '烷氧烷基、烷亞磺醯基、齒素、 烷氧基與烷硫基;且 R4係選自氫化基與鹵素。 特別適合本發明組合物者為如式選擇性c〇X 2抑制 劑之水溶性鹽類與前藥: 0. R5〆
其中R5係甲基或胺基困’ r6係氫或Cm燒基或垸氧基團, 係賤CR,其中r7係氣或齒素,且Y與Z各為竣或氮原子 其疋義鄭接五到U環中的原子,該環可視需要將— 多個位置以氧、㈣、甲基或由化甲基基團取代;或其 構物互又異構物、醫藥上可接受鹽類或前藥。該五到 原子環較佳為取代位不超過__處之環戍稀嗣、吱喃銅、 基吡唑、異噁唑與吡啶環。 以說明的立場而士 m ° ’適用於本發明組合物者為下列各
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1314867 A7 B7 Γ前藥:協勒可喜、德拉可喜(―)、 , #^(r〇feC〇X^ ^ ΓΛ // )_3_卜(甲心基)苯基]·2_環戊缔-1·嗣與 基)苯基1 3 i2m) 4_(3_減·3_Ψ4 ΐ·Τ氧基)·5 _ [4.(甲項殖 !太:酮;最特定言之為華帝可喜。特別適 】本t明組合物之華帝可喜前藥為沛力可喜,更特定言之 為帀力可喜納鹽。 運用於本發明组合物與方法之沛力可喜可以前述us
Patent No. 5,932,598中所示方法製備。 本發明組合物亦可採用結構式如式㈤之化合物:
其中X"係0、S或N-低級烷基;R8係低級南烷基;r9係氫或 鹵素,R10係氫、鹵素、低級烷基、低級烷氧基或鹵烷氧基、 低級芳烷羰基、低級二烷胺磺醯基 '低級烷胺磺醯基、低 級芳烷胺磺醯基、低級雜芳烷胺磺醯基、或5_或6_原子數 含氮雜環磺醯基;而R11與R12分別為氫、鹵素、低級烷基、 低級炫氧基、或芳基;以及其藥學上可接受之鹽類。 特別適用之式(VI)化合物為(s)_6,8_二氯·2(三氟甲 基)-2Η-1-苯并吡喃-3-羧酸,特定言之為其水溶性鹽類型 式,如鈉鹽。該化合物可以前述美國專利第6,〇34,256號中 -19 - 本紙張尺度適用中g國家揉準(CNS) Α4規格(210 X 297公釐)
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線 1314867 A7 B7 五、發明説明(17 ) 所示方法製備。 將一或多種選自前所揭露之治療劑運用於本發明可再 組成粉末组合物中,其使用量佔組合物重量約30%至约 90%,較佳為約40%至約85%,且更佳為約50%至約80%。 緩衝劑含量佔組合物重量約5%至約60%,較佳為約10% 至約60%,且更佳為約20%至約50%,其通常為主要的賦形 劑成分。於本發明之一具體實施例中,該再組成粉末組合 物實質上包含治療劑及緩衝劑。 選擇適當緩衝劑,使組合物在生理上可接受量之非經腸 可接受溶劑液體中再組成時,其pH值可(a)為非經腸途徑所 接受,(b)符合完全存於溶劑液體之溶液中的治療劑,且(c) 可提供適當的媒介物使再組成後其中之治療劑表現出可接 受之化學穩定性達約1小時以上。適當緩衝劑實例可選自磷 酸鈉及磷酸鉀、檸檬酸鈉及檸檬酸鉀、單-、雙-及三乙醇 胺、2-胺基-2-(羥甲基)-1,3-丙二醇(啜美沙胺)等、及其混合 物。較佳之缓衝劑為二鹼基鈉與磷酸鉀與啜美沙胺。特佳 之緩衝劑為二鹼基磷酸鈉,如二鹼基磷酸鈉之無水合物、 七水合物、十二水合物等。 於一具體實施例中,當再組成時,該組合物之pH為約7 至約9 ’較佳為約7.5至約8.5,如約為8。若有需要,除緩衝 劑以外,組合物中尚可加入少量酸(如磷酸)、及/或鹼(如氫 氧化鈉)來調整pH值。 若有除緩衝劑外之賦形劑存在,其於再組成前之含量應 低於約10%,較佳為低於約5%組合物總重量。"賦形劑”一 -20 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 裝 訂
1314867 A7 B7___ 五、發明説明(18 ) 詞在此包含該組合物中除了水份以外之所有非治療活性成 分。於本發明之一具體實施例中’除緩衝劑外實質上並無 賦形劑存在。 令人驚訝地,吾人發現相當重要的是在本組合物中所包 含之緩衝劑以外的常用再組成非經腸調配物填充劑應低於 總重樣之約10%,較佳為低於約5%,且最佳為實質上不包 含。特定言之,组合物中較佳排除廣泛使用的填充劑-甘露 糖醇,若或含有甘露糖醇,其含量應低於组合物重量之約 10°/〇,較佳為低於約5%。根據本發明,咸信藉由將组合物 中之填充劑(特定言之為甘露糖醇)成分減量(或完全排 除)’則可確保治療劑擁有可接受之化學穩定性。 本發明组合物可視需要包含一或多種防腐劑,其重量最 多可達約0.5%。適當之防腐劑實例包含羥苯甲酸甲酯、對 羥苯甲酸丙酯、酚與苯甲醇。 ~T再組成之本發明組合物粉末所含水分的重量比例較 佳低於約5%,更佳為低於約2% ,且最佳為低於約1%。典 型之水含量係約0.5%至約1%重量。當治療劑遇水容易降解 或轉化成不易溶型態時,控制水含量就十分重要。當貯存 於室溫(約20-25。〇之密封瓶切,本發明㈣組合:所顯 不之治療劑可接受化學穩定性至少可維持約3〇天,較佳為 至少約6個月’最佳為至少約2年。 “可接受化學穩定性”在此係指該組合物在指定的時間 :匕如約30天、約6個月或約2年),其中的治療劑仍可通過 千純度標準試驗,如由管制當局所要求認定者。該試驗 -21 -
1314867 A7 ___- _ B7 _. ._ 五、發明説明(19 ) 之實例為“整體5%、單劑1。/。不純度法則,,,即受試藥物製備 物整體不純度須低於5%,且任何單一不純物之不純度須低 於 10/〇。 當治療劑係沛力可喜時(如沛力可喜鈉鹽型式),其於一 段時間後在組合物中可能部分轉化為華帝可喜。由於華帝 可喜本身即具有選擇性COX-2抑制藥物之治療活性(實際上 沛力可喜之治療活性即仰賴於其在體内轉化為華帝可 喜),這種轉化不會造成治療作用的損失。然而,因華帝可 喜極度難溶於水,故於再組成前須儘量減少此種轉化,以 確保治療劑可完全溶解。供非經腸投藥之溶液中通常不應 含有微粒,如多量之華帝可喜所導致產生者。 令人驚訝地發現將再組成粉末狀組合物中的填充劑(如 甘露糖醇)減量或較佳為去除後可大符降低組合物中的沛 力可喜轉化為華帝可喜的情況。其說明請見以下實例1及 2本發明組合物中除緩衝劑外若含有低於1 重量之賦形 劑,可顯示相當高程度之沛力可喜化學穩定性(如實例1所 顯示)’但本發明組合物中除緩衝劑外若含更高濃度之賦形 劑,則會顯示更多的沛力可喜轉化成華帝可喜(如實例2所 顯示)。 本發明進一步之具體實施例係—種藉再組成粉末組合 物製備而成之可注射溶液组合物,在此其係溶於一非經腸 可接受溶劑,較佳為水性溶劑^於該類溶液組合物中,若 治療劑之化學穩定性有限,則其較佳為於投藥前短時間内 再組成絃组合物,如於約投藥前!小時内。若治療劑於溶液 -22 - 本紙張尺度速用中圉闺家揉準(CNS) A4规格(210X297公羞)
1314867 A7 ___ B7五、發明説明(20 ) 中可顯示相當高度之化學穩定性,則在此情況下不須限定 其於再組成後須儘速投藥。 當治療劑為沛力可喜時(如為沛力可喜鈉鹽鹽型式),經 過一段時間後其於水溶液中會部分轉化為難溶之華帝可 喜,並因而導致固體顆粒的形成。如上所述,固體顆粒的 出現通常不利於可注射調配物;因此以本發明之沛力可喜 組合物的特定實例而言,可注射溶液於再組成後較佳為短 期内投藥,如於再組成後約1小時之内。 將介質pH值維持於約7或更高值,則沛力可喜於水性介 質中轉化為華帝可喜之比率會大符降低。此外,沛力可喜 麵鹽本身之水溶性受pH值影響甚巨《如,其2〇。<:時之平衡 溶解度自pH 7.3之1_〇毫克/毫升上升至pH 7.8之18毫克/毫升 以及pH 8.2之220毫克/毫升。亦可製備更高濃度之沛力可喜 納鹽過飽和溶液。可提供生理學上可接受性、良好短期化 學穩定性與良好沛力可喜鈉鹽溶解度之較佳pH範圍為約 7.5至約8.5 ’更佳為約7.8至約8.2,如約8.0。 任何已知非經腸可接受溶劑液體皆可用於再組成本發 明组合物粉末。注射用水亦適用,但其一般會造成低張溶 液。因此’其通常較佳為使用含有溶質(如葡萄糖或氣化鈉) 之水性液體。如,0.9%氣化鈉注射液USP、抑菌〇 9%氣化 麵注射液USP、5 %葡萄糖注射液USP、及5%葡萄糖與 〇·45 %氣化鈉注射液USP皆適用《含乳糖之林格式(Ringer,s) 注射液USP較不適合,尤其當治療劑係沛力可喜鈉鹽時, 因其易於形成結晶。
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用於再组成之溶劑液體的適當份量取決於病患之年齡 與體重、治療劑溶解度與劑量及其它因子’但通常為约〇.25 毫升至約5毫升,較佳為約0.5毫升至约2毫升。如,在使用 沛力可喜鈉鹽時,20毫克之劑量通常可便利地於約}毫升任 何上述溶劑液體中再組成,而40毫克劑量則通常適合溶於2 毫升之溶劑液體中。 、
本發明粉末組合物較佳具有充分的多孔性以便於再組 成時使治療劑快速溶於溶劑液體中β利用如下所述之方法 來製備粉末可獲得高度多孔性。該法係本發明進—步之且 體實施例,且以下描述係特以沛力可喜㈣及二驗基鱗酸 裝 鈉七水口物為參考,然而,應瞭解此法亦可應用於其它如 本發明之治療劑及/或其它緩衝劑。 訂
於此方法巾’沛力可喜Μ與作為缓_之:龄基鱗酸 納七水合物可溶於水中以形成水性溶液。較佳為使用注射 用水作為溶劑。溶液中所含沛力可喜鋼鹽與緩衝劑之各成 分間相對濃度等同於其於最終組合物中各成分間的相對濃 度。這些成分之絕對濃度並無嚴格要求;然而,以製法效 率之觀點而言,製備時在不超過溶解度的限度下,較佳通 常=量提高沛力可喜納鹽之濃度。若需要可㈣步驟添 :後二Γ配成分。添加之順序並無嚴格要求,但強烈推薦 取後添加4力可喜Μ以確保快速與完全溶解。 視需要(但較佳為)無菌處理,如通過一或多個 …遽器,並隨即計量分裝入_或多個小藥瓶中。每一 小藥舐裝入含有所需沛力可喜鈉鹽單位劑量之定量溶液。
1314867
=有可供昇華發生之開口的;東乾瓶塞安置 小=瓶塞較佳為無菌,且填裝係於無菌狀態下二 物:=小藥瓶置於康乾室内並;東乾小藥瓶之内容 物凍乾法較佳為三相循環。 ^乾循環第m將各小藥瓶巾之溶液料至溶液 《玻璃化轉變溫度以下。對包括沛力可喜μ與二龄基鱗 酸鈉(本發明組合物而言,其玻璃化溫度係約-抓。玻璃 化概度可藉此項技藝中任何已知方法來測量,如藉由使用 冷來-乾燥顯微鏡或藉電阻測量法。冷;東間期之適當溫度典 ,為約-30°C至約-60°C,如約·4〇β(:至約_5(rc。溫度逐步由 至風降低至所需之冷凍溫度’典型上需約丨至約5小時,較 典型為約2至約4小時。隨後維持該冷凍溫度,典型期間為 約0.5至約24小時,較典型為約〇 75至约3小時。 於較佳凍乾方法之冷凍間期,溫度首先相當迅速地由室 溫降至約-2(TC,如於約0.25至約1小時,更佳為約0.5至約 0.75小時内。溫度再逐漸由約_2〇〇c降至約·3(Γ(:,如於約1 至約4小時’更佳為約1 5至約3小時内。在不受限於理論之 前題下,咸信該種逐步降溫法可確保該溶液完全冷凍。溫 度接著相當迅速地由約_3(TC降至最終冷凍溫度(較佳為約 -40°C ),如於約〇,1至約1小時,更佳為約0.25至約0.5小時 内β已發現如上所述階梯式冷凍間期易使最终冷乾產物呈 現完整固體而無破裂。 於凍乾循環之第二間期,將凍乾室抽取成真空以進行冷 來乾燥。該間期在此稱為“初級乾燥”期。一般適合的真空 -25 -本紙張尺度逋用中國囷家標準(CNS) Α4规格(210 X 297公釐) A7 B7
1314867 程度為約25至約500微米汞柱(約25至約500毫托(torr)),較佳 為約50至約300微米汞柱。在初級乾燥期,溫度逐步升高, 其可視需要分段上升,而各階段之間溫度保持不變。真空 狀態較佳以氮氣流維持。在此間期,冰晶自冷凍溶液中昇 華,形成一部分乾燥餅塊。 於較佳凍乾方法之初級乾燥期,首先於約1至約5小時, 較佳為約2至約4小時内,將溫度由冷凍溫度(如約_4〇t至約 〇 C )升高’接著保持於約〇°c —長段時間,如約6至約小 時,較佳為約8至約10小時。在初級乾燥間期,較佳採用之 真空狀態為約150至約300微米汞柱。 於;東乾循環第三間期中,乾燥係於真空下完成。該間期 在此稱為為^一次乾燥期。同樣地,一般適合之真空狀態 為約25至約500微米汞柱,較佳為約50至約3〇〇微米汞柱, 其真空較佳以氮氣流維持。於二次乾燥期時將溫度升高, 較佳升到室溫之上(如約40°C ),以便驅離剩餘水分而製備 溼度低於約5%,較佳為低於約2%,更佳為低於約1 %重量 之粉末。 於較佳凍乾方法之二次乾燥期間,首先將溫度自約〇°C 升高至約40 °C,時間為約1至約4小時,較佳為約1.5至約3 小時,隨後維持約40°C共約3至約12小時,較佳為約4至約8 小時。二次乾燥期之真空狀態較佳採用約150至約300微米 汞柱。在二次乾燥期的最後階段,當溫度保持在約4(TC時, 可視需要將真空降至約25至約75微米汞柱。 整體凍乾循環時間典型為約18至約36小時。延長循環時 -26 -
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本纸張尺度適用中國困家樣準(CNS) A4規格(210 X 297公爱) 1314867 A7 B7 五、發明説明(24 ) - 間通常無害於最終產物之品質但會增加製作成本。利用以 在此所提供的資訊為基礎之例行試驗可發現產品品質與製 作經濟性义最佳組合,且其組合可因多種因素而改變包 含所使用(特疋;東乾設備、欲;東乾溶液中之特定組合物及 成分;農度所選擇义治療劑及緩衝劑等。然而通常約Μ 至約24小時之循環時間都很合適。在以二龄基構酸納做為 緩衝劑之沛力可喜納里鹽組合物之情$兄下,已發現當將循 環時間實質縮短至約18小時(如16.5小時)以下時,易導致最 終產物崩塌的發生率增加,這點有礙往後再組成時所需的 快速溶解。 於凍乾循環結束時,解除真空並讓溫度回復至室溫。再 將小藥瓶加蓋並密封以預防其由空氣中再吸收水分並維持 無菌狀態。 本發明進一步具體實施例為一種製造物品,其包括一密 封小藥瓶(較佳為玻璃小藥瓶),其中裝有如本發明之粉末 組合物並以單位劑量及無菌狀態提供。於一特定之具體實 施例中,此種製造商品係藉如上述方法來製備提供。小藥 瓶容量較佳為足供組合物於原地進行再組成。一般較便利 之谷量為約1毫升至約10毫升,較佳為約2毫升至約5毫升。 在此“小藥瓶’’ 一詞係用以代表任何適用於包裝單位劑 量再組成粉末之在、閉小型容器’其較佳為無菌狀態。應瞭 解功能相同之包裝型式,如安報(ampou丨.e)、拋棄式注射器 與注射器藥筒(syringe cartridge)皆包含於本發明具體實施 例中。 -27 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐)
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1314867 A7 B7 小藥瓶可視需要包括二個隔間,-隔間含再組成粉末且 另-隔間含足以溶解該粉末之溶劑液想。在該種小藥瓶 中’兩隔間可經由小孔互通,在小藥藏使用之前始終以瓶 塞堵住小孔以防止粉末與溶劑液體接觸β使用時,藉由任 何適當工具分離或刺穿瓶塞使液體與粉末接觸如二種可 施加壓力或驅使注射針穿過瓶塞之活塞裝置。_多隔間 小藥瓶之實例包含供注射器使用之雙·室藥筒與雙室小藥 瓶,如法瑪西亞(Pharmacia)公司所提供者,其商標名為 Act-0-Vial® 〇 以本發明組合物粉末的單位劑量而言,適用於製備及/ 或置於小藥瓶内以構成本發明製造商品之份量包括了足量 之治療劑,以便在非經腸投藥後對(:〇又_2媒介性疾病或失 調病患提供療效。如在使用本發明沛力可喜鈉鹽組合物之 情況下,適當的單位劑量通常含約1毫克至約200毫克,較 佳為約5毫克至約120毫克,且更佳為約10毫克至約1〇〇毫克 (如約20毫克、約40毫克或約80毫克)之沛力可喜。當治療劑 並非沛力可喜時,適當的單位劑量係可產生等同於上述劑 量範圍沛力可喜之療效者。 本發明組合物可用於治療及預防許多由COX-2所媒介的 失調,包含(但不限於)特徵為發炎、疼痛及/或發熱等之失 調。該組合物特別適合作為消炎劑,如治療關節炎,其額 外優點為副作用明顯低於傳統的NSAID組合物,因後者缺 乏對可區分COX-1之COX-2選擇性。特定言之,本發明组合 物之胃腸毒性及胃腸刺激性(包含上胃腸道潰瘍及出血)低 -28 - 本纸張尺度適用中國國家標準(CNS> A4规格(210X 297公爱)
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線 A7 B7 1314867 五、發明説明(26 ) 於傳統NS AID組合物。因此,本發明組合物特定言之可作 為傳統NSAID的另一選擇,即當NSAID成為禁忌用藥之情 況’如消化性溃瘍、胃炎、局部腸炎、溃瘍性結腸炎、憩 至炎或有復發病史之胃腸病灶;胃腸出血、凝血失調(包含 貧血,如低凝血酶原、血友病或其它出血性問題);腎病、 或手術前之病患或服用抗凝血劑之病患。 經過考量的組合物可用於治療各種關節炎失調,其包含 (但不限於)風溼性關節炎、脊椎關節病、痛風性關節炎、 骨關節炎、全身性紅斑性狼瘡與幼年性關節炎。 該組合物可用於治療氣喘、支氣管炎、經痛、早產(preterm labor)、腱炎、黏液囊炎、過敏性神經炎、巨細胞毒感染、 細胞凋亡(包含HI V-引發性細胞自溶)、腰痛、肝病(包含肝 炎)、皮膚相關疾病’如乾癖、濕疹、粉刺、燒傷、皮膚炎 與紫外線輕射傷害(包含暖傷)、與手術後炎症(包含眼科手 術,如白内障手術或屈光手術)。 該組合物可用於治療胃腸疾病,如炎症性腸病、克隆氏 (Crohn s)病、胃炎、過敏性腸症候群(irritabie bowel syndrome) 與潰瘍性結腸炎β 該組合物可用於治療下列疾病之炎症,如偏頭痛、結節 性動脈周圍炎、甲狀腺炎、再生不能性貧血、霍奇金氏症 (Hodgkin、)、硬皮病、風濕熱、第!型糖尿病、神經肌接合 病(包含重症肌無力)、白質病(包含多發性硬化症)、肉狀瘤 病、腎病症候群、畢協氏(Behcet's)症候群、多肌炎、齒銀 炎、腎炎、過敏症、創傷後腫脹(包含腦水腫、心肌局部缺 -29 - 本纸張尺度逋用中國國家標準(CNS) A4规格(210X297公釐) 1314867 A7 B7 五、發明説明(27 ) 血及類似疾病)。 該組合物可用於治療眼睛失調,包含(不限於)炎症性失 調,如眼内炎、上鞏膜炎、視網膜炎、虹膜炎、曉狀禮炎.、 脈絡膜炎、角膜炎、結膜炎及瞼炎、眼晴多部分炎症性失 調,如視網膜脈絡膜炎、虹膜睫狀體炎、虹膜睫狀禮脈絡 膜炎(亦稱為葡萄膜炎)' 角膜結膜炎、瞼結合膜炎等;其 它C0X-2媒介性視網膜病變’包含糖尿病視網膜病變;眼 睛畏光;任何眼睛组織之急性創傷,包含術後傷口(如白内 障或角膜移植手術);手術後眼晴發炎;手術期内曈孔縮 小;角膜移植排斥;眼睛(如視網膜)血管新生,包含創傷 或感染後血管新生;黃斑部退化;囊狀黃斑部水腫;晶狀 體後纖維組織增生;新生血管性音光眼;與眼睛痛。 該組合物可用於治療肺炎,如與病毒感染及囊性纖維瘤 相關者’亦可用於骨質再吸收,如與骨質疏鬆相關者。 該组合物可用於治療某些中樞神經系!统失調,如皮質性 療呆’其包含阿茲海默氏(Alzheimer’s)病、神經變性、及因 中風、局部缺血及外傷所產生之中樞神經系統損害。於本 文中“治療”一詞包含部分或完全抑制癡呆症,包含阿茲海 默氏病、血管性癡呆、多發梗塞性癡呆、早老性②代巧如以) 癡呆、酒毒性癡呆及老年癡呆症。 該組合物可用於治療過敏性鼻炎、呼吸痛苦症候群 (respiratory distress syndrome)、内毒素休克症候群及肝病。 該組合物可用於治療疼痛,包含(但不限於)術後疼痛、 牙痛、肌肉痛、及癌症引起之疼痛β如該.組合物可用於解 -30 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 裝 訂
線 28 1314867 A7 B7 五除爹懇誤現4疼痛)、發熱及發炎,如包含風濕熱、流行性 感冒及其它病毒感染,其包含感冒 '下背痛及頸痛、經痛、 頭痛、牙痛、扭傷及拉傷、肌炎、神經痛、滑膜炎、關節 炎(包含類風濕性關節炎、退化性關節疾病(骨關節炎)、痛 風及僵直性脊椎炎)、黏液囊炎、燒傷、及手術與牙科術後 之傷口。 該組合物可用於治療及預防炎症-相關性心血管失調,包 含血管疾病、冠狀動脈疾病、動脈瘤、血管排斥、動脈硬 化、動脈粥樣硬化(包含心臟移植動脈粥樣硬化)、心肌梗 塞、栓塞 '中風、血栓形成(包含靜脈血栓形成)、心绞痛(包 含不規則心绞痛)、冠狀斑發炎(coronary plaqUe inflammation)、細菌引發性炎症(包含衣原體引發性炎症)、 病毒引發性炎症、與手術步驟相關之炎症,如血管移植(包 含冠狀動脈繞道手術)、血管修復術(包含放置血管支架、 動脈内膜切除術)、或其它涉及動脈、靜脈及微血管之侵入 性手術。 該組合物可用於治療病患之血管生成-相關失調,如抑制 腫瘤血管生成。該組合物可用於治療贅瘤形成(包含轉 移),眼科疾病,如角膜移植排斥、眼睛血管新生、視網膜 血管新生(包含創傷或感染後之血管新生)、糖尿病視網膜 病變、黃斑部退化、晶體後纖維素增生與血管新生性青光 眼;潰瘍性疾病,如胃潰瘍;病理性(但為非惡性)疾病, 如血管瘤(包含嬰兒血管瘤)、鼻咽部血管纖維瘤及骨血管 壞死;與女性生殖系統失調(如子宮内膜異位)。 -31 - 本紙張尺度適用中國國家揉準(CNS) A4規格(210X297公釐) 1314867 A7 _____ B7 _ 五、發明説明(29 ) 該組合物可用於預防及治療良性與惡性腫瘤及贅瘤形 成’其包含癌症,如結腸直腸癌、腦癌、骨癌、上皮細胞-衍生之贅瘤形成(上皮細胞癌),如基底細胞癌、腺癌、胃 腸癌,如唇癌、口腔癌、食道癌、小腸癌、胃癌、結腸癌、 肝癌、膀胱癌、胰臟癌、卵巢癌、子宮頭癌、肺癌、乳癌、 皮膚癌(如鱗狀細胞癌及基底細胞癌)、前列腺癌、腎細胞 癌、及其它全身上下已知的上皮細胞癌症。本發明組合物 預期特別適用之贅瘤形成為胃腸道癌症、巴瑞特氏食道症 (Barrett’s esophagus)、肝癌、膀胱癌、胰臟癌、卵巢癌、前 列腺癌、子宮頸癌、肺癌、乳癌及皮膚癌。該組合物亦可 用於治療因放射療法所產生之纖維變性。該組合物亦可用 於治療罹患腺瘤息肉(包含患有遺傳性腺瘤息肉病(FAP))之 病患。此外,該組合物可用於易罹患FAP之病患以預防息 肉形成。 該組合物可藉由抑制收縮性前列腺素合成而抑制由前列 腺素所引起之平滑肌收縮,並因此可用於治療經痛、早產、 氣喘與嗜伊紅球相關失調。其亦可用於減少骨質喪失,特 別係對停經後的女性(即骨質疏鬆症之治療)、及治療音光 眼。 本發明组合物較佳係適用於治療風溼性關節炎及骨關 節炎、一般性疼痛管理(特定言之為口腔手術後疼痛、一般 手術後疼痛、整形手術後疼痛、及骨關節炎之急性爆發)、 阿茲海默氏症(Alzheimer’s)症之治療、與結腸癌之化學預防 (chemoprevention) 〇 -32 - 本纸張尺歧財g g家料(CNS) A4规格(21()X297公幻 - ' 1314867 A7 B7 除了用於治療人類外,本發明组合物可用於獸醫學治療 寵物、野生動物、畜牧動物及類似者,特定言之為哺乳動 物。更特定言之,本發明組合物可用於治療馬、狗及貓之 C0X-2媒介性失調。 本發明進一步係關於一種治療需要以c〇x_2抑制藥物處 理的疾病或失調之醫療方法,該方法包括對需此治療之病 患非經腸投予再组成之本發明組合物。可預防、緩和或改 善疾病或失調之劑量攝生法較佳為相當於每日一次或每曰 二次的治療,但可依多種因素而加以修改。這些因素包含 病患類型、年齡、體重、性別、飲食、及醫療狀況與失調 之性質及嚴重性。因此,實際應用之劑量攝生法變化甚大, 並因此可能超出上述之較佳劑量攝生法。 起始治療可依上述劑量攝生法開始進行。治療通常可依 需要持續數週至數月或數年,直到病況或失調獲得控制或 消除。以再组成之本發明组合物進行治療的病患可藉任何 此項技藝中已知之方法例行監測以便測定療效。持續分析 監測的資料可供治療期間修改治療攝生法以便於各時間點 皆能投予最理想之有效劑量,並可決定治療期長短。依此, 於治療期間可理性地修改治療攝生法與給劑計劃,如此可 投予最少的組合物用量而獲得滿意的效果,並可控制投藥 期不超過成功治療疾病或失調的實際所需。 “非經腸投藥”在此包括將組合物注射及/或灌注進入或 通過病患之皮膚’並包含皮内、皮下、肌肉、靜脈、髓内、 -33 - 本紙張尺度適用中國國家樣準(CNS) A4規格(210X297公爱)
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1314867 A7 -----— B7 五、發明説明(31 ) 動脈、滑膜内、椎管内、鞘内及心臟途徑。任何已知可 用於非經知注射或灌注藥物之裝置皆可用利用。 已發現當對人類病患非經腸投予沛力可喜時,其可快速 並完全轉化為華帝可喜。因此令人驚訝地,即使在需要快 速療效時,沛力可喜(如沛力可喜鈉鹽鹽型式)之治療有效 量即相當於口服投予華帝可喜之治療有效量。本文中“相务 於”一詞意指莫耳數量或絕對量(即重量)相當。以分子量而 言,完全轉化1毫克沛力可喜可產生約〇85毫克之華帝可 喜。實際上,將1毫克沛力可喜視為相當於i毫克之華帝可 喜亦不致產生巨大誤差。 因此根據本發明具體實施例,其可提供治療人類病患 C0X-2媒介性失調之-種方法,其包括對病患非經腸投予 沛力可喜或其鹽類,且沛力可喜之劑量相當於華帝可喜之 治療有效量。較佳地,沛力可喜或其鹽類(如鈉鹽)係以每 日劑量約1毫克至約200毫克進行投藥。更佳之每^劑量約5 毫克至約120毫克之沛力可喜,更佳為約1〇毫克至約ι〇〇毫 克,如約20毫克、約40毫克或約80毫克之沛力可喜。 圖1所顯示者為特別令人訝異的發現,即對人類病患非 經腸(如靜脈注射)投予沛力可喜後其轉化為華帝可喜^速 度如此的快速且完全,故其所提供的華帝可喜血漿濃度峰 值之出現速度遠快於直接口服投予同劑量、即時釋出型之 華帝可喜<» 於本發明進一步之具體實施例中提供―種製造商品,其 包括一密封小藥瓶(較佳為玻璃小藥瓶),其中所含之無菌 -34 - 本纸張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1314867 A7 B7 五、發明説明(32 ) 可非經腸遞送組合物包括沛力可喜或其鹽類,且沛力可喜 劑量相當於治療有效量之華帝可喜。沛力可喜劑量較隹為 約1毫克至約200毫克,更佳為約5毫克至約120毫克,且最 佳為約10毫克至約100毫克,如約20毫克、約40毫克或约80 毫克。沛力可喜較佳為沛力可喜鈉鹽鹽。小藥瓶可視需要 為上述之多隔間小藥瓶。 本發明之治療方法進一步包含沛力可喜或本發明組合 物與一或多種選自類鴉片與其它止痛劑類藥物之混合治療 法,後者藥物特定言之包含麻醉性止痛劑、Mu接受器拮抗 劑、Λ:接受器拮抗劑、非麻醉性(即非-成瘾性)止痛劑、單 胺攝取抑制劑、腺甘酸調節劑、類大麻衍生物、物質P拮 抗劑、神經激肽-1接受器拮抗劑與鈉通路阻斷劑。較佳混 合治療法包括使用本發明組合物與一或多種選自以下各物 所組成之群的化合物:阿協可婁分那克(aceclofenac)、阿協 梅塔信(acemetacin)、e-乙酿胺基己酸(e-acetamidocaproic acid)、乙酿胺基分(acetaminophen)、乙酿胺基沙婁 (acetaminosalol·)、乙酿苯胺、乙睹水楊酸(阿斯匹靈 (aspirin))、S-腺苷甲硫胺酸、阿爾可婁分那克(alclofenac)、 阿爾分塔尼爾(alfentanil)、晞丙基普羅定(allylprodine)、阿 爾密諾_普羅分(alminoprofen)、阿婁信普林(aloxiprin)、阿爾 發普羅定(alphaprodine)、銘武(乙酿水楊酸鹽)、阿姆分那克 (amfenac)、胺基可婁仙諾撒仁(aminochlorthenoxazin)、3-胺 基-4-羥丁酸、2-胺基-4-曱基吡啶、胺基普羅皮隆 (aminopropylon)、胺基皮林(aminopyrine)、安米西區印 -35 - 本纸張尺度適用中圉國家標準(CNS) A4規格(210X297公釐) 1314867 A7 B7 五、發明説明(33 ) (amixetrine)、水楊酸按、阿姆皮羅西坎(ampiroxicam)、阿姆 透梅汀 瓜西爾(amtolmetin guacil)、阿尼離力定 (anileridine)、安替比林(antipyrine)、水楊酸安替_比林、安 塔非寧(antrafenine)、 阿帕榮(apazone)、本大傑克 (bendazac)、本諾力里(benorylate)、本諾歐撒普羅分 (benoxaprofen)、本茲派皮力龍(benzpiperylon)、本茲胺 (benzydamine)、千基嗎啡(benzylmorphine)、伯摩普羅分 (bermoprofen)、貝齊超麥德(bezitramide)、α-甜沒藥醇 (α-bisabolol)、布羅姆分那克(bromfenac) '對·乙酿溪苯胺、 5-溴水楊酸乙酯、溴撒力金寧(bromosaligenin)、布西汀 (bucetin)、布可婁西酸(bucloxic acid)、布可婁姆(bucolome)、 布非克撒梅克(bufexamac)、布梅戴表(bumadizon)、布普力 語啡(buprenorphine)、布塔西 ί丁(butacetin)、布提布分 (butibufen)、布透分諾(butophanol)、乙酿水楊酸_、氧,甲酸 氮呼(carbamazepine)、卡爾必分(carbiphene)、.卡爾普羅分 (carprofen)、卡爾撒蘭(carsalam)、氯代丁醇、可婁仙諾克撒 仁(chlorthenoxazin)、膽磁水楊酸鹽' 辛可芳(cinchophen)、 辛梅塔信(cinmetacin)、西拉馬竇(ciramadol)、可力達那克 (clidanac)、可婁梅塔信(clometacin)、可婁耐塔仁 (clonitazene)、可婁尼信(clonixin)、可婁皮拉克(clopirac)、 丁香、可待因(codeine)、可待因甲基溴化物、磷酸可待因、 硫酸可待因、可羅普羅酿胺(cropropamide)、可羅提酿胺 (crotethamide)、迪越嗎钟(desomorphine)、迭克趙撒朵 (dexoxadrol)、迭克措摩疏胺(dextromoramid.e)、迪柔信 -36 - 本纸張尺度適用中8國家棣準(CNS) A4規格(210X297公釐) A7 B7 1314867 五、發明説明(34 ) (dezocine)、二安普羅麥德(diampromide)、二可婁分那克鈉 (diclofenac sodium)、二分那密柔(difenamizole)、二分皮拉麥 德(difenpiramide)、二福祿尼梭(diflunisal)、二氫可待因·、 二氫可待因酮晞醇乙酸酯、二氫嗎啡、二羥基鋁乙酿水楊 酸鹽、二門諾撒多(dimenoxadol)、二美分普天諾 (dimepheptanol)、二甲基赛安丁烯(dimethylthiambutene)、二 氧雜非太丁酸酯(dioxaphetyl butyrate)、二皮潘酮 (dipipanone)、二普羅協提(diprocetyl)、二吡喃酮(dipyrone)、 二塔柔(ditazol)、卓西亢(droxicam)、依摩爾發榮 (emorfazone)、英分那米克酸(enfenamic acid)、依匹力柔 (epirizole)、依迫塔柔心(eptazocine)、依特爾撒雷特 (etersalate)、依仙查麥德(ethenzamide)、依媳黑普塔仁 (ethoheptazine)、依避克撒仁(ethoxazene)、乙基甲基赛安丁 烯(ethylmethylthiambutene)、乙燁嗎啡、依透多拉克 (etodolac)、依透分那梅特(etofenamate)、依透耐塔仁 (etonitazene)、丁子香.盼、非爾比那克(felbinac)、分布芬 (fenbufen).、分可婁齊克酸(fenclozic acid)、.分多跑 (fendosal) ' 分語普羅分(fenoprofen)、分塔耐(fentanyl)、分 提阿查克(fentiazac)、非普拉定語(fepradinol)、非普拉柔 (feprazone)、福拉克塔分林(floctafenine)、福氣分那米克酸 (flufenamic acid)、福氣諾克撒普羅分(flunoxaprofen)、福氯 歐瑞松(fluoresone)、福氯迫汀(flupirtine)、福氯普羅夸榮 (fluproquazone)、福樂二普羅分(flurbiprofen)、佛司佛赠 (fosfosal)、二羧基苯甲酸、葛拉分寧(glafenine)、葛路卡美 -37 - 本紙俵尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1314867 A7 B7 五、發明説明(35 ) 塔信(glucametacin)、乙二醇水楊酸酯、瓜阿茹連 (guaiazulene)、亥卓寇康(hydrocodone)、亥卓摩風 (hydromorphone)、禮基佩西定(hydroxypethidine)、依布分那 克(ibufenac)、依布普羅分(ibuprofen)、依布普羅撒姆 (ibuproxam)、異 ρ比嗅水楊酸酿(imidazole salicylate)、引朵美 撒信(indomethacin)、引朵普羅分(indoprofen)、異非柔拉克 (isofezolac)、異拉多(isoladol)·、異美撒;東(isomethadone)、異 尼克心(isonixin)、異克協佩克(isoxepac)、異克西卡姆 (isoxicam)、銅貝米;東(ketobemidone)、嗣普羅分.(ketoprofen)、 III特羅拉克、p-乳分尼太德(p-lactophenetide)、雷夫塔胺 (lefetamine)、雷佛分諾(levorphanol)、婁分塔尼爾 (lofentanil)、婁那柔拉克(lonazolac)、婁爾語克新卡姆 (lornoxicam)、婁克颼普羅分(loxoprofen)、離胺酸乙醯水楊 酸、乙酿水楊酸鎂、梅可婁分那米克酸(meclofenamic acid)、 梅分那米克酸(mefenamic acid)、梅普力定(meperidine) '梅 普塔齊諾(meptazinol)、梅题胺(mesalamine)、梅塔柔心 (metazocine)、氫氣酸梅撒束(methadone hydrochloride)、梅趟 三美普拉仁(methotrimeprazine)、梅提亞齊尼克酸(metiazinic acid)、梅透佛林(metofoline)、梅透碰(metopon)、摩非丁氮 酮(mofebutazone)、摩非柔拉克(mofezolac)、摩拉榮 (morazone)、嗎啡、氫氯酸嗎啡、硫酸嗎啡、水楊酸嗎林、 米洛啡(myrophine)、—那布梅同(nabumetone)、那爾布啡 (nalbuphine)、水楊酸-1-茶g旨、那普羅仙(naproxen)、那爾先 (narceine) ' 尼佛潘姆(nefopam)、尼 口嗎啡(nicomorphine)、 -38 - 本纸張尺度適用中國國家標準(CNS) A4規格(21〇X297公釐)
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1314867 A7 B7 五、發明説明(36 ) 尼分那榮(nifenazone)、尼福氯米克酸(niflumic acid)、尼美 蘇來德(nimesulide)、5'-确基·2'-丙氧基乙醯苯胺 (5’-nitro-2’-propoxyacetanilide) 、 正雷.佛分語 (norlevorphanol)、正梅.撒;東(normethadone)、正嗎啡 (normorphine)、正皮潘朗(norpipanone)、歐爾撒拉仁 (olsalazine)、鴻片、歐克撒協普羅(oxaceprol)、歐克撒梅塔 信(oxametacine)、歐克撒普羅仁(oxaprozin)、歐克西口凉_ (oxycodone)、歐克西嗎風(oxymorphone)、歐克西分丁氮嗣 (oxyphenbutazone)、器粟力頓(papaveretum)、帕拉耐林 (paranyline)、柏爾撒麥德(parsalmide)、五柔新(pentazocine)、 佩力聰克撒(perisoxal)、分那協汀(phenacetin)、分那多克 _ (phenadoxone)、分那柔新(phenazocine)、氫氣酸分那柔p比 症(phenazopyridine hydrochloride)、分錯寇(phenocoll)、分诺 佩力定(phenoperidine)、分諾 p比咬嗣(phenopyrazone)、苯基 乙酿水楊酸鹽、苯基丁氮銅(phenylbutazone)、苯基水楊酸 鹽、分耐拉密多(phenyramidol)、皮克透普羅分 (piketoprofen)、皮米諾定(piminodine)、派普布榮 (pipebuzone)、胡椒酿酮(piperylone)、派普羅分(piprofen)、 皮拉柔拉克(pirazolac)、皮力岔麥德(piritramide)、皮羅西卡 姆(piroxicam)、普蘭諾普羅分(pranoprofen)、普羅葛盧梅塔 信(proglumetacin)、普羅黑普塔仁(proheptazine)、普羅梅多 (promedol)、普羅帕協塔摩(propacetamol)、普羅皮蘭姆 (propiram)、普羅普歐克西分(propoxyphene)、普羅皮分那榮 (propyphenazone)、普羅夸榮(proquazone)、普羅提齊尼克酸 -39 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐) 1314867 A7 B7 五、發明説明(37 ) (protizinic acid)、雷米分那榮(ramifenazone)、雷米分塔尼爾 (remifentanil)、靈馬柔林姆.梅提爾硫酸里(rimazolium metilsulfate)、水楊酸乙殖胺、水楊酸答、水楊酿胺、水楊 醯胺〇-乙酸、水揚基硫酸、撒爾撒爾特(salsalte)、撒爾佛林 (salverine)、西密柴德(simetride)、水楊酸納、蘇分塔尼爾 (sufentanil)、撒爾發撒拉仁(sulfasalazine)、撒林戴克 (sulindac)、超氧物歧化酶、蘇普羅分(suprofen)、蘇克西布 榮(suxibuzone)、塔爾尼福祿梅特(talniflumate)、天尼碟迫 (tenidap)、天諾克西卡姆(tenoxicam)、帖羅分那梅特 (terofenamate)、帖創準(tetrandrine)、<»塞嗤琳 丁氮嗣 (thiazolinobutazone)、提亞普羅分尼克酸(tiaprofenic acid)、 提亞酿胺(tiaramide)、提離定(tilidine)、提諾力定 (tinoridine)、托爾分那米克酸(tolfenamic acid) '托爾梅汀 (tolmetin)、創梅多(tramadol)、措佩新(tropesin)、維敏諾 (viminol)、仙布新(xenbucin)、新摩普羅分(ximoprofen)、查 爾透普羅分(zaltoprofen)與柔梅皮拉克(zomepirac)(請見The Merck Index,第 12版,Therapeutic Category and Biological Activity Index, ed. S. Budavari (1996), pp. Ther-2 to Ther-3 and Ther-12 (Analgesic (Dental), Analgesic (Narcotic), Analgesic (Nonnarcotic),Anti-inflammatory (Nonsteroidal))。 特佳的混合療法包括使用沛力可喜或本發明组合物與類 鴉片化合物,更特定言之,其中類鴉片化合物係可待因、 梅普力定、嗎》#或其衍生物》 -40 - 本纸張尺度適用中困國家標準(CNS) A4规格(210X297公釐) 1314867 A7
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訂
1314867 A7 __B7 五、發明説明(39 ) 調整至預定容量而形成凍乾用溶液◊製備成之各溶液份量 應足供製備數單位劑量之組合物(如表1所示每單位劑量為 1毫升或2毫升溶液p 將凍乾溶液通過二组0.2微米之杜拉魄爾(Durap〇re@)滅 菌濾器並將1毫升或2毫升之溶液分別無菌裝填至2毫升或5 笔升、第I型、未處理、去致熱原、透明玻璃小藥瓶中。測 量填裝物重量。各溶液多組之平均密度為丨〇〇5克/毫升。於 另一試驗中發現沛力可喜鈉鹽並不會與滅菌濾器結合。 室溫中,避免光照。 _表2.典型凍乾循捃 間期 描述 冷凍 1·75小時内由室溫降至-50。C 維持-50°C共7.0小時 初級乾燥 1.5小時内由-50°C升至15 維持15°C共2.25小時 1.0小時内由15°C升至45〇C 維持45°C共16·5小時 真空300微米汞柱 以拱菌凍乾瓶塞(具有一開口以容許昇華)局部堵塞小藥 瓶後,將其置於事先準備之無菌凍乾室並進行凍乾循環。 所採用尤典型循環描述於表2中。無菌氮氣可用以填充小藥 瓶之内容物上空間並於循環結束時用於解放真空。將小藥 瓶於凍乾室中完全封塞。自凍乾室移出後,立即以可撬開 式(flip-off)銘封卷繞固定瓶塞而將小藥瓶密封,再貯存於 -42 - A7 B7 1314867 五、發明説明(4〇 ) 二次乾燥 5.0小時内由45°C降至室溫 真空300微米汞柱 全部循環時間 36小時 產生之調配物A-D在小藥瓶中所形成之餅塊外表良好, 即餅塊無破裂或崩塌。粉末X-射線衍射(PXRD)分析顯示餅 塊為非結晶型。甚至貯藏於70°C中12週後,PXRD分析顯示 該餅塊之物理特性並無變化,且未見到崩塌的證據。 分析調配物A、B及C(5、10及20毫克沛力可喜)之殘餘水 含量,並作為華帝可喜之化學穩定性的指標》以HPLC對新 製備樣本及貯存於70t中12週之樣本進行華帝可喜分析》 表3所列之數據顯示極佳之化學穩定性,甚至在經過12週的 高溫貯藏之後,華帝可喜之濃度仍低於0.5%。 表3.調配物A-C之穩定性 變數 A B C 新鮮樣本之水分(%) 1.6 1.4 0.8 新鮮樣本之華帝可喜(%) 0.06 0.07 0.03 於70°C中貯存12週後之華帝可 0.45 0.37 0.36 喜(%) 測試調配物D(40毫克沛力可喜)之pH值及殘餘水分並以 HPLC分析新製備以及於各種溫度貯存4、8及12週後之沛力 可喜與華帝可喜。表4所列之數據顯示出色的化學穩定性, 甚至在經過12週的高溫貯藏之後,華帝可喜之濃度仍低於 0.5%。沛力可喜及華帝可喜之百分比係以不含賦形劑之基 -43 - 本纸張尺度適用中國固家標準(CNS) A4規格(210 X 297公釐) 1314867 五、發明説明(41 A7 B7
_96.9 0.04 96.8 96.8 95.4 97.3 96.6 無數據 40°c, 12 週 550C,4 週 550C, 8 週 55°C, 12 週 70oC,4 週 70oC,8 週 70oC, 12 週 0.05 0.07 0.09 0.14 0.20 0.36 1.29 1‘03 0.84 0.87 0.90 0.77 無數據 7.8 8.0 7.8 7.9 8.0 7.8 無數據 將調配物A-C再組成為1毫升、調配物d再組成為2毫 升之0,9%氣化鈉注射液USP »餅塊可立即溶解。 實例2 如下所述製備在此稱作調配物E-J之再组成粉末狀組合 物,其分別含20毫克劑量之沛力可喜,其型式為沛力可喜 鈉鹽。首先製備含表5所列组合物之供凍乾溶液β凍乾之溶 液E-J分別相當於調配物E-J。溶液與凍乾粉末組合物之製 備可藉由類似實例1之調配物A-D的方法。 應注意的是除緩衝劑(二鹼基磷酸鈉或啜美沙胺)外,調 配物E-J各含高於約10%之賦形劑成分。在此添加這些調配 物係供比較之用。 -44 - 本紙張尺度適用中圏國家標竿(CNS) Α4規格(21〇x 297公釐) 1314867 五、發明説明(42 A7 B7 液 物 成分 Ε
F 沛力可喜鈉鹽 (毫克) 二驗基鱗酸納 七水合物(毫 克) 啜美沙胺(毫 克) 甘露糖醇(毫 克) 甘胺酸(毫克) 聚乙二醇 4000 (毫克)
G Η 21.18 21.18 2.68 21.18 21.18 21.18 21.18 2.68 2.68 2.68 1.2 1.2 30 30 30 30 13.5 13.: 200 磺丁基-β-環 糊精(毫克) 15
分析新製備與於各種溫度貯存4週後的調配物Ε_;中乏沛 力可喜與華帝可喜。表6中沛力可喜及華帝可喜之百分比係 以不含賦形劑之基準來顯示e -45 - 本纸乐尺度逋用中困®家棣準(CNS) A4规格(210X297公爱) 1314867
五、發明説明( A7 B7
急>!·調配物E-J之穩定性
沛力可喜 99.00 99.40 104.3 102.2 90.46 99.86 沛力可喜 4週 沛力可喜 i^jj0C,4 週 沛力可喜 i^U〇°C,4ia 華帝可喜 製備 華帝可喜 (%),50c, 4调 華帝可喜 (%),55°C,4週 華帝可喜 (%), 70°C, 4 週 95.71 95.76 100.0 98.04 90.17 98.76 98.79 87.60 0.19 0.20 1.43 9.03 99.00 98.00 0.17 0.12 0.26 0.89 98.37 82.77 0.25 0.19 1.72 15.08 98.03 87.57 97.41 92.81 85.58 90.00 0.26 0.16 0.20 0.19 1.38 5.26 0.13 0.43 0.95 0.14 1.04 8.81 應注意調配物E-J顯丨出比本發明調配物ad較差之化學 穩定性❶調配物中除二鹼基磷酸鈉外,各含3〇毫克甘 露糖醇,此二者顯示出本實例所測試調配物中最佳的穩定 性,但於55。(:或70。(:貯存4週後,其沛力可喜轉化為華帝可 喜的幅度仍遠大於調配物A_D。調配物E、G、11與1之化學 -46 - A7 B7 1314867 五、發明説明(44 ) 穩定性更差到無法接受的地步。 此外’當再組成時,調配物E-J無一可立即溶解。調配物 I中含有200毫克聚乙二醇4000以及甘露糖醇與二鹼基磷鹼 鈉’其於再組成時溶解特別缓慢且難溶乂 實例3 以藥物動力學試驗檢查人類病患之華帝可喜血漿濃 度。對11名健康成年人’給予單劑1毫升巨量靜脈注射(IV)20 毫克沛力可喜(採用沛力可喜鈉鹽),或口服给予單劑即時 釋出錠型的20毫克華帝可喜以及240毫升的水。病患於投藥 1、2與3小時後飲用180毫升的水。 使用有效性高效性能液相層析法(HPLC)測定華帝可喜 血漿濃度。投藥後0至24小時之華帝可喜平均血漿濃度顯示 於圖1。 靜脈注射投予沛力可喜鈉鹽可較口服投予華帝可喜更 早達到華帝可喜最大血漿濃度。 實例4 在一項單一中心、單劑、隨機、雙盲、有安慰劑-控制組、 平行分組之24-小時研究中’有一組224名病患(每治療組有 56名)必須拔除兩側已填補之第三臼齒(包含骨質切除),其 中包含年齡18-45歲之男性與女性,術前隨機接受單劑靜脈 注射’劑量為置於4毫升0.9%氣化鈉中之20毫克、4〇毫克或 80毫克之沛力可喜、或安慰劑. 於手術終止後30分鐘開始,除未能清醒接受疼痛評估之 病患以外,每隔2小時評估疼痛程度直至第24小時。由病患 -47 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公⑴
装
1314867 A7 B7 五、發明説明(始) 在一張列有由“不痛’’到“最痛”之0-3級連續程度來評估疼 痛程度。病患可要求投予救據藥物治療β在最後一次例行 評估或投予救援藥物治療之前,病患須評估受試藥物延緩 疼痛的效果。 使用殘存分析技術(survival analysis techniqpes)分析給予 救援藥物治療的時間(TRM)。使用卡普蘭-麥爾產品限制估 算器(Kaplan-Meier product limit estimator)計算各治療组至 事件發生之中間時間值,並包含米勒所描述的調整(Miller (1981) in Survival Analysis, pp. 74-75. New York : John Wiley & Sons)。採用赛門與李的方法(Simon & Lee (1982),Cancer Treat. Rep. 66,37-42)計算事件發生中間時間值之95%信心 區間。對TRM而言,到24小時評估結束仍不需救援藥物治 療之病患於第24小時進行詳細審查。對非因採用救援藥物 治療而退出之病患亦於其退出研究時進行審查。 基於TRM中間值(表7),單一劑量之沛力可喜20毫克、 毫克與80毫克比安慰劑可導致明顯較久的TRM。沛力可喜 40毫克與80毫克之TRM中間值並無明顯差異,但雨者皆明 顯比沛力可喜20毫克之TRM來得長久。 沛力可喜治療組接受救援藥物治療(亦見於表7)之病患 比例遠低於安慰劑治療組;40毫克與80毫克沛力可喜治療 组間在這項變數並無顯著差異。 -48 - 本紙張尺度逋用中國®家棣準(CNS) A4規格(21〇x297公釐)
m % A7 B7 1314867 五、發明説明(46 ) 表7.給予救援藥物治療前時間(TRM) 治療組 TRM中間值 95%信心區間 服用救援藥物 治療之病患 安慰劑 2小時51分 2小時16分至3小 時16分 93% 沛力可喜20 毫克 6小時17分 4小時04分至11 小時17分 78% 沛力可喜40 毫克 >24小時 11小時04分至>24 小時 48% 沛力可喜80 毫克 12小時00分 6小時24分至16 小時37分 59% 關於病患對於此試驗藥物治療之效果評估,各沛力可喜 治療組之病患評分遠高於安慰劑治療組;40毫克與80毫克 沛力可喜治療組間並無顯著差異。在40毫克沛力可喜治療 組之病患中,有92%將此試驗藥物治療評為“良好“或“絕 佳”。 -49 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)
Claims (1)
- Α8 /偷 ^Θβ D8 充 1. 13 M863?757號專利申請案 中文申έ青專利範圍替換本(93年7另 申請專利範圍 種粉末型式、用以治療或預防c〇x_2媒介性疾病或失 調之醫藥組合物,其包括 (a) —種選自選擇性c〇x_2抑制劑及其鹽類與前 藥之水浴性治療劑,其治療有效量佔組合物3〇%至卯%之 重量; (b) —種佔組合物重量5%至6〇%之非經腸可接受缓衝 劑;及 (c) 其它非經腸可接受賦形劑成分,其總量為〇至1〇〇/。 之組合物重量; 其中Μ組合物可於一種非經腸可接受溶劑液體中再組 成而形成可注射溶液。 2 ·如申請專利範圍第1項之組合物’其中之治療劑包括一種 選自下列之選擇性C0X-2抑制劑之水溶性鹽類或前藥: 千妨勒可喜(celecoxib)、德拉可喜(deracoxib)、華帝可喜 (valdecoxib)、羅非可喜(rofec〇xib)、依透力可喜 (etoricoxib)、2-(3,5-二氟苯基)_3-[4_(甲磺醯基)苯基]_2_環 戊烯-卜酮與2-(3,4-二氟苯基)-4-(3-羥基-3-甲基-1-丁氧 基)-5-[4-(甲確酿基)苯基]_3-(2Η)-ι»比嗪酮。 3 ·如申請專利範圍第1項之組合物,其中之治療劑包括華帝 可喜之水溶性鹽類或前藥。 4 ·如申請專利範圍第1項之組合物,其中之治療劑包括沛力 可喜(parecoxib)或其鹽類。 5 ·如申請專利範圍第1項之組合物,其中之治療劑包括沛力 可喜納鹽。 本纸張尺度適用中國圉家標準(CNS) A4規格(210X 297公釐) 裝 訂 本、葉嘧五後是否變更原實質内容 1314867 &'申請專利範圍 A BCD ’如申靖·專利範圍第1項之組合物,其中之治療劑包括 (S)-6,8-二氣-2-(三氟甲基)-2Η-1-笨并吡喃_3_羧酸或其水 溶性鹽類。 7-如申請專利範圍第1項之組合物,其中之治療劑份量佔該 組合物重量40至85百分比》 8.如申請專利範圍第丨項之組合物,其中之治療劑份量佔該 組合物重量50至80百分比。 9 ·如申請專利範圍第1項之組合物,其中之緩衝劑份量佔該 组合物重量10至60百分比。 10 ·如申請專利範圍第1項之組合物,其中之緩衝劑份量佔該 组合物重量20至50百分比。 11 ·如申請專利範圍第1項之組合物,其基本上係由治療劑及 緩衝劑所組成。 12 ·如申請專利範圍第1項之組合物,其中之緩衝劑係選自磷 酸鈉及磷酸钟、檸檬酸鈉與檸檬酸神、單_、雙_及三乙 醇胺、噪美沙胺(tromethamine)及其丨昆合物。 13 ·如申請專利範圍第1項之組合物’其中之緩衝劑係選自二 驗基鱗酸鈉與钾與嗓美沙胺。 14.如申請專利範圍第1項之組合物,其中之緩衝劑為二鹼基 $粦酸納。 15 ·如申請專利範圍第1項之組合物,當再組成時其pH值為7 至9 〇 16_如申請專利範圍第1項之組合物,其擁有充足的多孔性以 供治療劑再組成(reconstitution)時快速溶解。 -2 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐) AS B8 C8 D8 1314867 六、申請 17.一種用以治療或預防COX-2媒介性疾病或失調之可注射 落液,其係經由將如申請專利範圍第丨项之組合物再組成 於非經腸可接受溶劑中而製備成的。 18 ·如申請專利範圍第i 7項之溶液,其中之溶劑係水性溶劑。 19·如申請專利範圍第18項之溶液’其中之治療劑係沛力可 喜鈉鹽。 2〇.如申請專利範圍第19項之溶液,其pH值為7.5至8 5。 21_如申請專利範圍第18項之溶液,其中之水性溶劑包含葡 萄糖及/或氯化納。 22. 如申請專利範圍第1項之組合物’其係於密封小藥瓶中之 單位劑量形式。 23. 如申請專利範圍第22項之組合物’其中該組合物包括作 為治療劑之沛力可喜鈉鹽,劑量為I毫克至200毫克之沛 力可喜。 24. 如申凊專利範圍第22項之組合物,其中該組合物包括作 為治療劑之沛力可喜鈉鹽’劑量為5毫克至120毫克之沛 力可喜。 25. 如申請專利範圍第22項之組合物,其中該組合物包括作 為治療劑之沛力可喜鈉鹽’劑量為1 〇毫克至i 〇〇毫克之沛 力可喜。 26·如申請專利範圍第22項之組合物,其中該小藥瓶為多隔 間小藥瓶。 27.—種製備可再組成(reconstitutable)選擇性COX-2抑制组 合物之方法,其包括冷凍乾燥一水性溶液之步驟,且謗 本紙張尺度適用中國國家揉準(CNS) A4規格(210X 297公釐) 1314867 六、申請專利範圍 水性溶液組合物中除水以外包括: (a) 至少一種選自選擇性c〇x_2抑制劑及其鹽類與前 藥之治療劑,其治療有效量佔組合物3〇%至9〇%之重量 (b) —種佔組合物重量5%至6〇%之非經腸可接受緩衝 劑;及 (c) 其它非經腸可接受賦形劑成分,其總重量為〇 10% ; 且該凍乾步驟產生可快速再組成之粉末調配物。 28. 如申請專利範圍第27項之方法’其中之治療劑係沛力 喜鈉鹽。 其中之緩衝劑係二鹼暴 29. 如申請專利範圍第28項之方法 磷酸鈉。 其中於凍乾步驟之前 製 30. 如申請專利範圍第29項之方法 先將沛力可喜鈉鹽與二鹼基磷酸鈉溶於注射用水中以 備溶液,滅菌後計量裝入小藥瓶中,每瓶各裝填本有 單位劑量之沛力可喜鈉鹽的份量,並將小藥瓶置於凍乾 31. 如申請專利範圍第30項之方法’其中在製備溶液的 中,該沛力可喜係最後加入。 ‘鸯 冷 32. 如申請專利範圍第29項之方法,其中之;東乾步帮勺 凍期、初_級乾燥期與二次乾燥期。 33. 如申請專利範圍第32項之方法,其中: (a)在冷凍期,其溫度係以丨至5小時的時間降到 。 至-60°C之冷凍溫度並維持該冷凍溫度〇 = _3〇 0 0至24小 -4 - 本紙張尺度適用中圃國家揉準(CNS) A4规格(210X 297公复) 8 8 8 8 A BCD 1314867 六、申請專利範圍 時; (b) 在初級乾燥期,抽取真空至25至500微米汞柱,且 以1至5小時的時間將溫度自冷凍溫度升高至0°C ; 且 (c) 在二次乾燥期中,於25至500微米汞柱之真空中, 以1至4小時的時間將溫度係自0°C升至高於室溫並 維持此溫度3至12小時; 所產生粉末之水含量低於2%(以重量而言)。 34.如申請專利範圍第33項之方法,其中之整體凍乾循環時 間為約18至約24小時。 -5 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
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Country Status (46)
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6929954B2 (en) | 2000-11-02 | 2005-08-16 | Chromaceutical Advanced Technologies, Inc. | Method for producing purified hematinic iron-saccharidic complex and product produced |
EP2275075A3 (en) * | 2000-11-02 | 2011-08-10 | Chromaceutical Advanced Technologies, Inc. | Method of measuring an iron-saccharidic complex |
WO2003041705A1 (en) * | 2001-11-13 | 2003-05-22 | Pharmacia Corporation | Oral dosage form of a sulfonamide prodrug such as parecoxib |
EP1485362A1 (en) * | 2002-03-15 | 2004-12-15 | Pharmacia Corporation | Crystalline parecoxib sodium |
US7964568B2 (en) * | 2003-05-30 | 2011-06-21 | Chromaceutical Advanced Technologies, Inc. | Synthesis of high molecular weight iron-saccharidic complexes |
DE10327674A1 (de) * | 2003-06-20 | 2005-01-05 | Awd.Pharma Gmbh & Co. Kg | Injizierbare Darreichungsform von Flupirtin |
EP1895983A2 (en) * | 2005-05-27 | 2008-03-12 | Panacea Biotec Ltd. | Injectable compositions and process for preparation of such compositions |
WO2007129961A1 (en) * | 2006-05-09 | 2007-11-15 | Astrazeneca Ab | Parenteral formulation comprising proton pump inhibitor sterilized in its final container by ionizing radiation |
JP5466006B2 (ja) * | 2006-09-03 | 2014-04-09 | テックフィールズ バイオケム カンパニー リミテッド | 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ |
US20080279930A1 (en) * | 2007-05-07 | 2008-11-13 | Bernd Terhaag | Controlled-Release Flupirtine Compositions, Compacts, Kits and Methods of Making and Use Thereof |
MX2010005932A (es) * | 2007-11-29 | 2010-06-15 | Alltranz Inc | Metodos y composiciones para mejorar la viabilidad de poros de microaguja. |
KR100967490B1 (ko) * | 2009-11-21 | 2010-07-07 | 곽철호 | 하수구의 배출 처리 구조 |
JP2014532713A (ja) | 2011-11-02 | 2014-12-08 | ハルシオン,インコーポレイテッド | 創傷処置の方法及び組成物 |
WO2013096650A2 (en) | 2011-12-23 | 2013-06-27 | Pioneer Surgical Technology | Continuous matrix with osteoconductive particles dispersed therein, method of forming thereof, and method of regenerating bone therewith |
CN102512383A (zh) * | 2011-12-25 | 2012-06-27 | 天津市嵩锐医药科技有限公司 | 供注射用的帕瑞昔布钠药物组合物 |
CN104771370B (zh) * | 2014-01-14 | 2020-07-24 | 南京圣和药业股份有限公司 | 帕瑞昔布钠冻干粉针剂及其制备方法 |
RU2016136430A (ru) | 2014-02-11 | 2018-03-15 | Др. Редди'С Лабораторис Лтд. | Парентеральные композиции целекоксиба |
CN105726496B (zh) * | 2014-12-12 | 2019-05-28 | 湖南科伦药物研究有限公司 | 一种帕瑞昔布钠冻干粉剂、其制备方法及其粉剂产品 |
CN105125506A (zh) * | 2015-08-18 | 2015-12-09 | 上海秀新臣邦医药科技有限公司 | 一种注射用帕瑞昔布钠及其制备方法 |
CN105168152B (zh) * | 2015-08-27 | 2018-06-01 | 上海华源药业(宁夏)沙赛制药有限公司 | 一种帕瑞昔布钠冻干粉及其制备方法 |
US11243028B2 (en) * | 2018-12-14 | 2022-02-08 | Fortunata, LLC | Systems and methods of cryo-curing |
EP3932397A4 (en) | 2019-03-01 | 2022-12-07 | Eurofarma Laboratórios S.A. | FREEZE-DRIED PHARMACEUTICAL COMPOSITION OF NON-STEROIDAL ANTI-INFLAMMATORY |
CN110960493B (zh) * | 2019-12-30 | 2022-03-11 | 山东罗欣药业集团股份有限公司 | 一种帕瑞昔布钠冻干制剂及其制备方法 |
CN113456597B (zh) * | 2020-03-30 | 2023-02-14 | 石药集团欧意药业有限公司 | 一种注射用帕瑞昔布钠及其制备方法 |
CN116421569B (zh) * | 2023-06-15 | 2023-09-05 | 四川尚锐生物医药有限公司 | 一种注射用帕瑞昔布钠药物组合物及其制备方法 |
Family Cites Families (105)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4434163A (en) * | 1981-06-01 | 1984-02-28 | Pfizer Inc. | Water-soluble benzothiazine dioxide salts |
US4797388A (en) * | 1984-05-21 | 1989-01-10 | Cetus Corporation | Pharmaceutical compositions with galactitol as carrier |
US4677195A (en) * | 1985-01-11 | 1987-06-30 | Genetics Institute, Inc. | Method for the purification of erythropoietin and erythropoietin compositions |
US5036060A (en) * | 1988-07-25 | 1991-07-30 | Fujisawa Usa, Inc. | Cyclophosphamide |
US5616458A (en) | 1990-03-14 | 1997-04-01 | Board Of Regents, University Of Tx System | Tripterygium wilfordii hook F extracts and components, and uses thereof |
US5604260A (en) | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
US5543297A (en) | 1992-12-22 | 1996-08-06 | Merck Frosst Canada, Inc. | Human cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2 activity |
EP0764644A1 (en) | 1993-01-15 | 1997-03-26 | G.D. Searle & Co. | Use of medicaments containing 3,4-diaryl furans and analogs thereof for treating a gastrointestinal condition |
US5380738A (en) | 1993-05-21 | 1995-01-10 | Monsanto Company | 2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents |
US5436265A (en) | 1993-11-12 | 1995-07-25 | Merck Frosst Canada, Inc. | 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents |
US5474995A (en) | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
US5593992A (en) | 1993-07-16 | 1997-01-14 | Smithkline Beecham Corporation | Compounds |
US5344991A (en) | 1993-10-29 | 1994-09-06 | G.D. Searle & Co. | 1,2 diarylcyclopentenyl compounds for the treatment of inflammation |
US5401765A (en) | 1993-11-30 | 1995-03-28 | G. D. Searle | 1,4,5-triphenyl pyrazolyl compounds for the treatment of inflammation and inflammation-related disorders |
US5434178A (en) | 1993-11-30 | 1995-07-18 | G.D. Searle & Co. | 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation |
US5466823A (en) | 1993-11-30 | 1995-11-14 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides |
US5475018A (en) | 1993-11-30 | 1995-12-12 | G. D. Searle & Co. | 1,5-diphenyl pyrazole compounds for treatment of inflammation |
US5393790A (en) | 1994-02-10 | 1995-02-28 | G.D. Searle & Co. | Substituted spiro compounds for the treatment of inflammation |
US5418254A (en) | 1994-05-04 | 1995-05-23 | G. D. Searle & Co. | Substituted cyclopentadienyl compounds for the treatment of inflammation |
AU2424895A (en) | 1994-05-04 | 1995-11-29 | G.D. Searle & Co. | Substituted spirodienes for the treatment of inflammation |
BE1008307A3 (fr) | 1994-06-16 | 1996-04-02 | Europharmaceuticals Sa | Sel de nimesulide hydrosoluble, solution aqueuse le contenant, sa preparation et son utilisation. |
US5486534A (en) | 1994-07-21 | 1996-01-23 | G. D. Searle & Co. | 3,4-substituted pyrazoles for the treatment of inflammation |
JPH10504542A (ja) | 1994-07-27 | 1998-05-06 | ジー.ディー.サール アンド カンパニー | 炎症処置用の置換チアゾール化合物 |
US5616601A (en) | 1994-07-28 | 1997-04-01 | Gd Searle & Co | 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation |
US5620999A (en) | 1994-07-28 | 1997-04-15 | Weier; Richard M. | Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation |
US5521213A (en) | 1994-08-29 | 1996-05-28 | Merck Frosst Canada, Inc. | Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 |
US5420343A (en) | 1994-08-31 | 1995-05-30 | G. D. Searle & Co. | Derivatives of aromatic cyclic alkylethers |
US5585504A (en) | 1994-09-16 | 1996-12-17 | Merck & Co., Inc. | Process of making cox-2 inhibitors having a lactone bridge |
US5696143A (en) | 1994-09-20 | 1997-12-09 | Talley; John J. | Benz G! indazolyl derivatives for the treatment of inflammation |
US5547975A (en) | 1994-09-20 | 1996-08-20 | Talley; John J. | Benzopyranopyrazolyl derivatives for the treatment of inflammation |
ATE185797T1 (de) | 1994-10-27 | 1999-11-15 | Merck Frosst Canada Inc | Stilben-derivate verwendbar als cyclooxygenase-2 hemmer |
US5739166A (en) | 1994-11-29 | 1998-04-14 | G.D. Searle & Co. | Substituted terphenyl compounds for the treatment of inflammation |
JP2636819B2 (ja) | 1994-12-20 | 1997-07-30 | 日本たばこ産業株式会社 | オキサゾール系複素環式芳香族化合物 |
JP3181190B2 (ja) | 1994-12-20 | 2001-07-03 | 日本たばこ産業株式会社 | オキサゾール誘導体 |
CA2206978A1 (en) | 1994-12-21 | 1996-06-27 | Merck Frosst Canada Inc. | Diaryl-2-(5h)-furanones as cox-2 inhibitors |
US5552422A (en) | 1995-01-11 | 1996-09-03 | Merck Frosst Canada, Inc. | Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents |
CA2211320C (en) | 1995-01-31 | 2007-03-20 | Merck Frosst Canada Inc. | 5-methanesulfonamido-3h-isobenzofuran-1-ones as inhibitors of cyclooxygenase-2 |
US5596008A (en) | 1995-02-10 | 1997-01-21 | G. D. Searle & Co. | 3,4-Diaryl substituted pyridines for the treatment of inflammation |
US5686470A (en) | 1995-02-10 | 1997-11-11 | Weier; Richard M. | 2, 3-substituted pyridines for the treatment of inflammation |
US5633272A (en) | 1995-02-13 | 1997-05-27 | Talley; John J. | Substituted isoxazoles for the treatment of inflammation |
JP3802581B2 (ja) | 1995-03-01 | 2006-07-26 | 富山化学工業株式会社 | 新規なビフェニル誘導体またはその塩およびそれらを含有する抗炎症剤 |
NZ304886A (en) | 1995-04-04 | 1998-11-25 | Glaxo Group Ltd | Imidazo [1,2a] pyridine derivatives, preparation and pharmaceutical compositions thereof |
US5691374A (en) | 1995-05-18 | 1997-11-25 | Merck Frosst Canada Inc. | Diaryl-5-oxygenated-2-(5H) -furanones as COX-2 inhibitors |
US5510368A (en) | 1995-05-22 | 1996-04-23 | Merck Frosst Canada, Inc. | N-benzyl-3-indoleacetic acids as antiinflammatory drugs |
US5639780A (en) | 1995-05-22 | 1997-06-17 | Merck Frosst Canada, Inc. | N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors |
US5604253A (en) | 1995-05-22 | 1997-02-18 | Merck Frosst Canada, Inc. | N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors |
AU708964B2 (en) | 1995-05-25 | 1999-08-19 | G.D. Searle & Co. | Method of preparing 3-haloalkyl-1h-pyrazoles |
US5643933A (en) | 1995-06-02 | 1997-07-01 | G. D. Searle & Co. | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US5658903A (en) | 1995-06-07 | 1997-08-19 | Smithkline Beecham Corporation | Imidazole compounds, compositions and use |
US5739143A (en) | 1995-06-07 | 1998-04-14 | Smithkline Beecham Corporation | Imidazole compounds and compositions |
GB9514518D0 (en) | 1995-07-15 | 1995-09-13 | Sod Conseils Rech Applic | Guanidine salt inhibitors of NO synthase and cyclooxygenase |
JPH0977664A (ja) | 1995-09-13 | 1997-03-25 | Yakult Honsha Co Ltd | シクロオキシゲナーゼ−2特異的阻害剤及び抗炎症剤 |
US5756529A (en) | 1995-09-29 | 1998-05-26 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides for use in veterinary therapies |
US5981576A (en) | 1995-10-13 | 1999-11-09 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
US6020343A (en) | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
US6057319A (en) | 1995-10-30 | 2000-05-02 | Merck Frosst Canada & Co. | 3,4-Diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to cox-2 inhibitors |
US6046208A (en) | 1996-01-11 | 2000-04-04 | Smithkline Beecham Corporation | Substituted imidazole compounds |
ZA97175B (en) | 1996-01-11 | 1997-11-04 | Smithkline Beecham Corp | Novel substituted imidazole compounds. |
KR19990077164A (ko) | 1996-01-11 | 1999-10-25 | 스티븐 베네티아너 | 신규 치환된 이미다졸 화합물 |
US5746546A (en) * | 1996-01-24 | 1998-05-05 | Stabilizer, Inc. | Soil stabilization composition and method |
US5789413A (en) | 1996-02-01 | 1998-08-04 | Merck Frosst Canada, Inc. | Alkylated styrenes as prodrugs to COX-2 inhibitors |
GB9607503D0 (en) | 1996-04-11 | 1996-06-12 | Merck Frosst Canada Inc | Bisaryl cyclobutenes derivatives as cyclooxygenase inhibitors |
US5807873A (en) | 1996-04-04 | 1998-09-15 | Laboratories Upsa | Diarylmethylidenefuran derivatives and their uses in therapeutics |
US5908858A (en) | 1996-04-05 | 1999-06-01 | Sankyo Company, Limited | 1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses |
PL195955B1 (pl) * | 1996-04-12 | 2007-11-30 | Searle & Co | Związek, pochodna benzenosulfonamidu, sposób jegowytwarzania, kompozycja farmaceutyczna zawierająca go oraz jego zastosowanie |
US5922742A (en) | 1996-04-23 | 1999-07-13 | Merck Frosst Canada | Pyridinyl-2-cyclopenten-1-ones as selective cyclooxygenase-2 inhibitors |
US5883267A (en) | 1996-05-31 | 1999-03-16 | Merck & Co., Inc. | Process for making phenyl heterocycles useful as cox-2 inhibitors |
US5741798A (en) | 1996-06-03 | 1998-04-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | 2-benzyl-4-sulfonyl-4H-isoquinolin-1,3-diones and their use as antiinflammatory agents |
US5677318A (en) | 1996-07-11 | 1997-10-14 | Merck Frosst Canada, Inc. | Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents |
US5861419A (en) | 1996-07-18 | 1999-01-19 | Merck Frosst Canad, Inc. | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
US5776967A (en) | 1996-07-26 | 1998-07-07 | American Home Products Corporation | Pyranoindole inhibitors of COX--2 |
FR2751966B1 (fr) | 1996-08-01 | 1998-10-30 | Union Pharma Scient Appl | Nouveaux derives 1,2-diarylindoles, leurs procedes de preparation, et leurs utilisations en therapeutique |
FR2751964B1 (fr) | 1996-08-01 | 1998-10-30 | Union Pharma Scient Appl | Nouveaux derives diarylmethylene carbocycliques, leurs procedes de preparation, et leurs utilisations en therapeutique |
US5830911A (en) | 1996-08-14 | 1998-11-03 | American Home Products Corporation | Pyranoindole and tetrahydrocarbazole inhibitors of COX-2 |
US6005000A (en) | 1996-08-22 | 1999-12-21 | Oxis International, Inc. | 5,5-Disubstituted-3, 4-dihydroxy-2(5H)-furanones and methods of use therefor |
FR2753449B1 (fr) | 1996-09-13 | 1998-12-04 | Union Pharma Scient Appl | Nouveaux derives 3,4-diaryloxazolone, leurs procedes de preparation, et leurs utilisations en therapeutique |
US5972950A (en) | 1996-10-08 | 1999-10-26 | Laboratories Upsa | 1,2-diarylmethylene derivatives, their methods of preparation and their uses in therapeutics |
US5681842A (en) | 1996-11-08 | 1997-10-28 | Abbott Laboratories | Prostaglandin synthase-2 inhibitors |
US5869524A (en) | 1996-11-12 | 1999-02-09 | American Home Products Corporation | Indene inhibitors of COX-2 |
US6096753A (en) | 1996-12-05 | 2000-08-01 | Amgen Inc. | Substituted pyrimidinone and pyridone compounds and methods of use |
DE69727199T2 (de) | 1996-12-09 | 2004-11-18 | Pfizer Inc. | Benzimidazol-Verbindungen |
DK0946507T3 (da) | 1996-12-10 | 2004-01-26 | Searle & Co | Substituerede pyrrolylforbindelser til behandling af inflammation |
US5973191A (en) | 1996-12-30 | 1999-10-26 | Vanderbilt University | Selective inhibitors of prostaglandin endoperoxide synthase-2 |
US5929076A (en) | 1997-01-10 | 1999-07-27 | Smithkline Beecham Corporation | Cycloalkyl substituted imidazoles |
US5783597A (en) | 1997-03-04 | 1998-07-21 | Ortho Pharmaceutical Corporation | 2,5-disubstituted thiophenes: inhibitors of 5-lipoxygenase and inducible cyclooxygenase (COX-2) enzymes, composition and use |
EP0863134A1 (en) | 1997-03-07 | 1998-09-09 | Merck Frosst Canada Inc. | 2-(3,5-difluorophenyl)-3-(4-(methyl-sulfonyl)phenyl)-2-cyclopenten-1-one useful as an inhibitor of cyclooxygenase-2 |
US6071954A (en) | 1997-03-14 | 2000-06-06 | Merk Frosst Canada, Inc. | (methylsulfonyl)phenyl-2-(5H)-furanones with oxygen link as COX-2 inhibitors |
US6004960A (en) | 1997-03-14 | 1999-12-21 | Merck Frosst Canada, Inc. | Pyridazinones as inhibitors of cyclooxygenase-2 |
US6034256A (en) | 1997-04-21 | 2000-03-07 | G.D. Searle & Co. | Substituted benzopyran derivatives for the treatment of inflammation |
US6046217A (en) | 1997-09-12 | 2000-04-04 | Merck Frosst Canada & Co. | 2,3,5-trisubstituted pyridines as inhibitors of cyclooxygenase-2 |
RS49982B (sr) * | 1997-09-17 | 2008-09-29 | Euro-Celtique S.A., | Sinergistička analgetička kombinacija analgetičkog opijata i inhibitora ciklooksigenaze-2 |
US6040450A (en) | 1997-09-25 | 2000-03-21 | Merck & Co., Inc. | Process for making diaryl pyridines useful as cox-2-inhibitors |
FR2769311B1 (fr) | 1997-10-07 | 1999-12-24 | Union Pharma Scient Appl | Nouveaux derives 3,4-diarylthiazolin-2-one ou -2-thione, leurs procedes de preparation et leurs utilisations en therapeutique |
US6133292A (en) | 1997-10-30 | 2000-10-17 | Merck Frosst Canada & Co. | Diaryl-5-alkyl-5-methyl-2-(5H)-furanones as selective cyclooxygenase-2-inhibitors |
US6020347A (en) | 1997-11-18 | 2000-02-01 | Merck & Co., Inc. | 4-substituted-4-piperidine carboxamide derivatives |
FR2771412B1 (fr) | 1997-11-26 | 2000-04-28 | Adir | Nouveaux derives de pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
KR100414998B1 (ko) | 1998-04-24 | 2004-01-13 | 머크 앤드 캄파니 인코포레이티드 | Cox-2 억제제의 합성방법 |
WO1999059583A1 (en) * | 1998-05-18 | 1999-11-25 | Merck & Co., Inc. | Method for treating or preventing chronic nonbacterial prostatitis and prostatodynia |
KR100295206B1 (ko) | 1998-08-22 | 2001-07-12 | 서경배 | 디아릴벤조피란유도체및이를함유하는시클로옥시게네이즈-2저해제조성물 |
US6277878B1 (en) | 1998-09-07 | 2001-08-21 | Pfizer Inc | Substituted indole compounds as anti-inflammatory and analgesic agents |
US6077869A (en) | 1998-10-29 | 2000-06-20 | Ortho-Mcneil Pharmaceutical, Inc. | Aryl phenylhydrazides as selective COX-2 inhibitors for treatment of inflammation |
US6077868A (en) | 1999-07-20 | 2000-06-20 | Wisconsin Alumni Research Foundation | Selective inhibition of cyclooxygenase-2 |
US6083969A (en) | 1999-10-20 | 2000-07-04 | Ortho-Mcneil Pharaceutical, Inc. | 1,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles as selective inhibitors of cyclooxygenase-2 and antiinflammatory agents |
NZ542734A (en) * | 2000-03-24 | 2007-06-29 | Pharmacia Corp | Use of amidino compounds as nitric oxide synthase inhibitors for treating arthritis |
AR031135A1 (es) * | 2000-10-10 | 2003-09-10 | Upjohn Co | Composiciones de antibiotico topico para el tratamiento de infecciones oculares |
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