CN1897929A - 包含5－甲基－2－(2′－氯－6′－氟苯胺基)苯乙酸的药物组合物 - Google Patents

包含5－甲基－2－(2′－氯－6′－氟苯胺基)苯乙酸的药物组合物 Download PDF

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CN1897929A
CN1897929A CNA2004800293098A CN200480029309A CN1897929A CN 1897929 A CN1897929 A CN 1897929A CN A2004800293098 A CNA2004800293098 A CN A2004800293098A CN 200480029309 A CN200480029309 A CN 200480029309A CN 1897929 A CN1897929 A CN 1897929A
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methyl
fluoroanilino
phenylacetic acid
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R－M·丹嫩菲尔塞尔
V·C·格奥尔古西斯
M·Y·哈勒德
T·S·帕特尔
J·西科拉
B·王
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Abstract

本发明涉及适合胃肠外给药的用于治疗环加氧酶－2－介导的疾病或病症的组合物，所述组合物含有5－甲基－2－(2’－氯－6’－氟苯胺基)苯乙酸或其可药用盐，优选为钾盐。本发明还涉及治疗人或哺乳动物环加氧酶－2－介导的疾病或病症的方法，该方法包括胃肠外给予需要此治疗的宿主5－甲基－2－(2’－氯－6’－氟苯胺基)苯乙酸或其可药用盐，优选为钾盐。

Description

包含5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的药物组合物
本发明涉及适宜于胃肠外给药的用于治疗由环加氧酶-2介导的疾病或病症的组合物，该组合物含有5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸或其可药用盐，本发明还涉及通过胃肠外给予5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸或其可药用盐来治疗由环加氧酶-2介导的疾病或病症的方法。
在优选的实施方案中，本发明涉及治疗需要这种治疗的人或动物的由环加氧酶-2介导的疾病或病症的组合物，该组合物包含适宜于5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸或其可药用盐胃肠外给药的液体。
在另一个优选的实施方案中，本发明涉及用于治疗需要这种治疗的人或动物由环加氧酶-2介导的疾病或病症的方法，该方法包括给予治疗有效量的本发明的组合物，即包含适宜于5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸或其可药用盐胃肠外给药的液体的组合物。
在此所提及的所有专利、专利申请和其他的出版物均通过引用并入本文中。但是，如果本说明书与引用的参考文献中的内容相冲突的话，则以本说明书为准。
在美国专利第6,291,523号中，公开了游离形式或其可药用盐形式的5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的用途及其合成方法，根据所述专利文献公开的内容，包括5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸在内的一类化合物尤其可用于与许多疾病或病症有关的疼痛的减轻、发烧和炎症，包括风湿热、与流感或其他病毒感染有关的症状、普通感冒、下背部和颈部的疼痛、痛经、包括偏头痛在内的头痛、牙痛、扭伤和拉伤、肌炎、神经痛、滑膜炎、包括骨关节炎和风湿性关节炎在内的关节炎、退化性关节疾病、痛风和关节强硬性脊椎炎、粘液囊炎、烧伤、以及外科手术和牙科手术后的损伤。当治疗人或动物患上述的任何疾病或病症，如急性疼痛时，需要给予含有5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸或其可药用盐的液体胃肠外给药的制剂。
申请人令人惊奇地发现，可以制备包含5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸或其可药用盐、特别是钾盐的储存稳定的液体胃肠外给药的制剂。5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸，即游离酸相对不溶于水，并在水中可能降解。所以，无法生产储存稳定的胃肠外给药的制剂。而且，5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸，即游离酸，在聚乙二醇(PEG)400中也很不稳定(实验表明，50℃、在100％PEG400的溶液中于暗处放置4周，产生19％的降解，而在相同的条件下，5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的钾盐只产生5％的降解)，并且在丙二醇(PG)中也很不稳定(实验表明，50℃、在100％PG的溶液中暗处放置4周，产生71％的降解，在相同的条件下钾盐只产生7％的降解)。此外，包含5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸和它的可药用盐的溶液对注射或输液部位的刺激性很大，所以，人们通常认为不适宜于制备胃肠外给药的液体制剂。
本发明的液体胃肠外给药制剂，包括5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸可药用盐、特别是钾盐作为药用物质的水混悬剂、优选水溶液。药用物质的浓度可在约10至约80mg游离酸/ml之间，一般在约10至约60mg游离酸/ml之间，优选在约20至约50mg游离酸/ml之间，更优选在约30至约40mg游离酸/ml之间，最优选在约40mg游离酸/ml，在上述各种情况下，5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸钾盐的相当量约为酸的1.13倍。
本发明的制剂通常还包含5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的可药用盐、特别是钾盐的助溶剂，如丙二醇、聚乙二醇400或甘油。一般说来，这样的助溶剂以重量计存在的量约在约5％至约50％之间，优选在约20％至约50％之间，更优选在约25％至约45％之间，特别优选在约30％至约45％之间，更特别优选在约35％至约45％之间，最优选约40％。
本发明的制剂一般也含有表面活性剂，如聚山梨酸酯，例如聚氧乙烯(20)脱水山梨醇单油酸酯(聚山梨酸酯80)、聚氧丙烯-聚氧乙烯嵌段共聚物，如Pluronic F-68(分子量约为7500)，或聚乙氧基化蓖麻油如Cremophor。这样的表面活性剂存在的量以重量计一般在约0.1％至约10％之间，优选在约0.5％至约5％之间，更优选在约1％和约5％之间，特别优选约1％或约2％或3％或4％或5％。
本发明的制剂也包含抗氧剂，如抗坏血酸、维生素E、亚硫酸钠、偏亚硫酸氢钠、谷胱甘肽、硫脲、L-半胱氨酸盐酸盐一水合物、N-乙酰半胱氨酸或单硫代甘油。抗氧剂使用的量取决于抗氧剂的种类，以重量计一般在约0.01％至约4％之间，优选在约0.05％至约3％之间，更优选在约1％至约2％之间，最优选约2％。
药用物质在胃肠外给药制剂的pH值在约8.5至约10.5之间时最稳定，制剂的pH值低于约8.5时含有比较多的环状降解产物，而在pH值高于约10.5时，则氧化降解产物含量增加。所以，本发明的制剂可以包含缓冲剂。例如，适宜的缓冲剂可以是甘氨酸缓冲剂或磷酸盐缓冲剂。
本发明的制剂可以通过将它们的组分与水混合直至得到混悬液或优选澄清溶液而制备。混悬液或优选的澄清溶液中可以通入氮气或其他的惰性气体如氩气，以尽可能地除去溶解氧气，氧气可能增加药用物质的降解。氮气和其他的惰性气体在制剂的容器中的液体上方。优选玻璃容器，如小瓶或安瓿。虽然也可以使用与胃肠外给药相一致的其它适宜容器，但是最优选透明的玻璃容器。由于药用物质对光敏感，因此，可以将在透明玻璃容器内的制剂再用不透光的包装材料，如纸板箱，进行包装。这些制备本发明的制剂的方法是本发明的进一步的实施方案。
在另一个实施方案中，本发明涉及5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的可药用盐、特别是钾盐在制备药物组合物中的用途，该组合物治疗由环加氧酶-2介导的疾病或病症。
下列的实施例意在说明本发明，但对本发明并不构成限制。
实施例：胃肠外给药的溶液
  成分   量
  5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的钾盐   45.2mg
  聚乙二醇400   400mg
  聚山梨酸酯80   20mg
  单硫代甘油   2.0mg
  甘氨酸   7.5mg
  纯水，USP   适量到1ml
  氢氧化钠，USP/NF   适量到pH9.0
将成分混合，向混合物中通入氮气。得到澄清的溶液后，立即将该溶液转移至透明玻璃安瓿中，并在溶液上部充入氮气，然后将安瓿封口。

Claims (21)

1.组合物，该组合物包含5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的可药用盐、助溶剂和表面活性剂。
2.如权利要求1的组合物，该组合物还包含水。
3.如权利要求2的组合物，该组合物以溶液形式存在。
4.如权利要求3的组合物，其中所述助溶剂选自丙二醇、聚乙二醇400和甘油。
5.如权利要求3的组合物，其中所述表面活性剂选自聚山梨酸酯、聚氧丙烯-聚氧乙烯嵌段共聚物和聚乙氧基化蓖麻油。
6.如权利要求3的组合物，该组合物还含有抗氧剂。
7.如权利要求6的组合物，其中所述抗氧剂选自抗坏血酸、维生素E、亚硫酸钠、偏亚硫酸氢钠、谷胱甘肽、硫脲、L-半胱氨酸盐酸盐一水合物、N-乙酰半胱氨酸或单硫代甘油。
8.如权利要求6的组合物，该组合物还包括缓冲剂。
9.如权利要求8的组合物，其中所述缓冲剂选自甘氨酸缓冲剂或磷酸盐缓冲剂。
10.如权利要求8的组合物，其中5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸的可药用盐是钾盐。
11.如权利要求10的组合物，其中的助溶剂是聚乙二醇400。
12.如权利要求11的组合物，其中的表面活性剂是聚山梨酸酯。
13.如权利要求12的组合物，其中的抗氧剂是单硫代甘油。
14.如权利要求13的组合物，其中的缓冲剂是甘氨酸缓冲剂。
15.如权利要求14的组合物，该组合物还包含选自玻璃小瓶和安瓿的玻璃容器。
16.如权利要求15的组合物，其特征在于溶液置于玻璃容器中。
17.使含有5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸钾盐的水溶液中的5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸钾盐化学降解最小化的方法，该方法包括将所述水溶液的pH值调至约8.5-约10.5。
18.增加局部耐受性并同时胃肠外给予含有5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸钾盐的组合物的方法，该方法包括给予水溶液形式的所述盐，其中在水溶液中还含有助溶剂。
19.权利要求18的方法，其特征在于所述助溶剂为聚乙二醇400。
20.治疗环加氧酶-2-介导的疾病或病症的方法，该方法包括胃肠外给予权利要求1的组合物。
21.权利要求20的方法，该方法包括胃肠外给予权利要求14的组合物。
CNA2004800293098A 2003-10-08 2004-10-07 包含5－甲基－2－(2′－氯－6′－氟苯胺基)苯乙酸的药物组合物 Pending CN1897929A (zh)

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