CN107115302A - 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 - Google Patents
包含cox‑2抑制剂的可稀释配制的胃肠外组合物 Download PDFInfo
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- CN107115302A CN107115302A CN201710474394.8A CN201710474394A CN107115302A CN 107115302 A CN107115302 A CN 107115302A CN 201710474394 A CN201710474394 A CN 201710474394A CN 107115302 A CN107115302 A CN 107115302A
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Abstract
本发明提供一种粉剂形式的药用组合物,其包含:(a)治疗有效量的至少一种水溶性治疗药物,所述治疗药物选自选择性COX‑2抑制药物及其前体药物和盐,例如帕瑞考昔钠,所述水溶性治疗药物的总量占所述组合物的约30%至约90%(重量),(b)一种胃肠外可接受的缓冲剂,所述缓冲剂量为所述组合物的约5%至约60%(重量),以及任选(c)其它胃肠外可接受的赋形剂成分,所述赋形剂成分的总量不超过所述组合物的约10%(重量)。所述组合物可以用胃肠外可接受的溶剂液体稀释配制成注射溶液。提供一种用于制备所述组合物的冷冻干燥方法。
Description
本申请是以下申请的分案申请:申请日:2002年4月2日;申请号:02810765.9(PCT/US02/10252);发明名称:同上。
发明领域
本发明涉及水溶性选择性环加氧酶-2(COX-2)抑制药物及其盐和前体药物,尤其是帕瑞考昔,例如其钠盐(帕瑞考昔钠)形式。帕瑞考昔是选择性COX-2抑制药物伐地考昔的水溶性前体药物。更具体地说,本发明涉及水溶性选择性COX-2抑制药物及其盐和前体药物的胃肠外给药制剂,例如注射制剂。甚至更具体地说,本发明涉及制备成为粉剂、胃肠外给药前在水性载体中稀释配制的所述制剂。本发明还涉及制备所述可稀释配制制剂的方法、应用所述制剂的治疗方法以及所述制剂在生产药物中的应用。
发明背景
环加氧酶(COX)的抑制作用据信至少是非甾体抗炎药(NSAID)通过抑制前列腺素合成而发挥其特征性抗炎、退热和镇痛效应的主要机制。治疗药物量的常规NSAID例如酮咯酸、双氯芬酸、萘普生及其盐既抑制组成型表达的COX-1,又抑制环加氧酶的炎症相关或诱导型COX-2同种型。COX-1产生正常细胞功能所需的前列腺素,抑制COX-1看起来引起与应用常规NSAID有关的某些毒副作用。与此不同,选择性抑制COX-2而基本上不抑制COX-1获得抗炎、退热、镇痛和其它有用的治疗效果,同时最小化或消除所述毒副作用。因此,在1999年首次进入市场的选择性COX-2抑制药物如塞来考昔和罗非考昔代表本领域内一大进步。这些药物配制成为多种口服给药剂型。
对于多种药物来说,胃肠外给药途径在具体情况下比口服给药提供许多好处,胃肠外给药途径包括皮下注射、肌内注射和静脉内注射。例如,胃肠外给药通常比口服给药在更短时间内获得治疗有效的药物血清浓度。静脉注射尤其如此,药物通过静脉注射直接进入血流。胃肠外给药因为消除了由于代谢、结合食物和其它原因引起的胃肠道损失,所以还导致预测性更好的药物血清浓度。出于相似原因,胃肠外给药常常允许减少剂量。胃肠外给药一般是紧急情况下的优选给药方法,并且也用于治疗不配合、昏迷或在其它情况下不能或不愿接受口服药物的患者。
市场上注射形式的NSAID相对较少。胃肠外应用的非选择性NSAID如酮咯酸氨丁三醇盐是有效的镇痛药,但与所述非选择性NSAID的典型副作用有关。这些副作用包括上胃肠道溃疡和出血,在老年患者中尤其如此;肾功能减退,这可能导致液体潴留和高血压加重;以及抑制血小板功能,这可能使患者倾向于出血增多,例如在手术期间。所述副作用已经严重限制非选择性NASID胃肠外制剂的应用。
因此,假如能够提供选择性COX-2抑制药物的胃肠外给药制剂,这将是本领域内的另一个显著进步。
已知通过真空冷冻干燥(冻干)治疗药物的水溶液的方法制备胃肠外制剂。参见例如Remington:The Science and Practice of Pharmacy,第19版(1995),MackPublishing,第1544-1546页,根据Remington,当治疗药物的量非常少时,通常向治疗药物中加入赋形剂以增加固体量,以便使获得的粉剂更容易看到。“一些人认为理想情况是干燥产品填料占据与原始溶液基本相同的体积。为达到此目的,原始产品的固体含量必须在约5%到25%之间。为此,最有用的物质是磷酸钠或磷酸钾、柠檬酸、酒石酸、明胶和糖类如葡萄糖、甘露醇和葡聚糖,这些物质通常组合应用。”Remington,在上述引文中。
在Talley等的美国专利第5,932,598号中公开的帕瑞考昔是选择性COX-2抑制药物的水溶性前体药物类中的一种。给予患者帕瑞考昔后,帕瑞考昔快速转化成为实质上水不溶性的选择性COX-2抑制药物伐地考昔。帕瑞考昔暴露于水时,例如溶解于水时,也转化为伐地考昔。帕瑞考昔尤其是帕瑞考昔的盐如钠盐的水溶解度比大多数选择性COX-2抑制药物如塞来考昔和伐地考昔要高,这引起人们开发帕瑞考昔用于胃肠外应用的兴趣。具有下面结构式(I)的帕瑞考昔,其本身显示对COX-1和COX-2的弱体外抑制活性,而伐地考昔(II)对COX-2有强抑制活性,但却是COX-1的弱抑制剂。
已知其它水溶性选择性COX-2抑制药物和前体药物。例如,Carter等的美国专利第6,034,256号公开了一系列据说可用作选择性COX-2抑制药物的水溶性苯并吡喃,包括化合物(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-羧酸(III)及其盐。
虽然已经概括地提议使用这些和其它选择性COX-2抑制药物和前体药物用于胃肠外给药,但至今还没有描述所述药物或前体药物的药学上可接受的注射制剂。如下面的公开内容以帕瑞考昔为例所清楚陈述的,许多问题困扰试图制备所述制剂的配方设计师。本发明提供这些问题的解决方案。
发明简述
在一个实施方案中,现在提供粉剂形式的药用组合物,所述药用组合物包含(a)治疗有效量的至少一种选自选择性COX-2抑制药物及它们的前体药物和盐的水溶性治疗药物,所述治疗药物的总量占所述组合物的约30%至约90%(重量),(b)胃肠外可接受的缓冲剂,所述缓冲剂量为所述组合物的约5%至约60%(重量),以及任选(c)其它胃肠外可接受的赋形剂成分,所述赋形剂成分的总量不超过所述组合物的约10%(重量)。所述组合物可以在胃肠外可接受的溶剂液体(优选水性液体)中稀释配制,形成注射溶液。
可以通过下述方法制备上述组合物,所述方法包括下述步骤:冻干包含所述治疗药物、所述缓冲剂以及任选的其它赋形剂成分的水溶液,形成可以容易地稀释配制的粉剂;所述方法代表本发明的另一个实施方案。
本发明的再一个实施方案是通过稀释配制所述组合物而制备的注射溶液。
本发明的又一个实施方案是一种制成品,该制成品包括在无菌条件下装入单位剂量的所述组合物的密封小瓶。
本发明的另一个实施方案是一种治疗或预防患者的COX-2介导的疾病或紊乱的方法,所述方法包括(a)在生理可接受体积的胃肠外可接受溶剂液体中稀释配制单位剂量所述组合物,形成注射溶液,和(b)将所述溶液通过胃肠外途径注射到患者体内。
在所有上面的实施方案中,尤其优选的治疗药物是帕瑞考昔的水溶性盐。惊人的是,发现帕瑞考昔在胃肠外给药时通过转化为伐地考昔而表现实质上与等剂量伐地考昔本身相等的抗炎和镇痛效果。因此,根据本发明的又一实施方案,提供一种治疗或预防患者的COX-2介导性疾病或紊乱的方法,所述方法包括胃肠外给予所述患者帕瑞考昔或其盐,所给予的帕瑞考昔剂量在摩尔量上等于伐地考昔的治疗有效剂量。
本发明的又一实施方案是制成品,所述制成品包括其中装有无菌、可胃肠外给药的组合物的密封小瓶,所述组合物包含帕瑞考昔或其盐,帕瑞考昔剂量等于伐地考昔的治疗有效剂量。
附图简述
图1陈述从实施例3的人体药物动力学研究获得的数据,数据显示在(a)静脉内(IV)注射1ml药团(bolus)内的20mg帕瑞考昔;以及(b)口服给予配制成为速释片剂的20mg伐地考昔后,从0小时到72小时的平均伐地考昔血浆浓度。
发明详述
本发明的药用组合物包含作为治疗药物的以下组分:
(a)水溶性选择性COX-2抑制药物;
(b)选择性COX-2抑制药物的水溶性盐,而不论所述药物本身
是否是水溶性的;
(c)选择性COX-2抑制药物的水溶性前体药物,而不论所述药
物本身是否是水溶性的;
(d)选择性COX-2抑制药物的前体药物的水溶性盐,而不论所
述前体药物本身是否是水溶性的。
在所述组合物中可以存在一种以上所述治疗药物,但一般优选仅包括一种所述选择性COX-2抑制药物或其前体药物或盐。包含选择性COX-2抑制药物的前体药物或所述药物或前体药物的盐的组合物可以包含少量所述药物本身,例如在假如所述前体药物或盐在生产、贮存、处理或使用时容易地转化为所述药物的情况下。
术语“水溶性”当在本文中应用于治疗药物时,指在患者体内治疗有效量的所述试剂在20-25℃和胃肠外可接受的pH下可溶于水,所述水的体积少于胃肠外给予患者单一剂量可接受的最大体积。优选治疗药物的溶解度在20℃和pH7.4的水中溶解度大于约0.1mg/ml。更优选的治疗药物在20℃和pH7.4的水中溶解度大于约0.5mg/ml。
本文应用的选择性COX-2抑制药物或者本文应用的前体药物或盐在体内所转化成为的选择性COX-2抑制药物表现相对于COX-1对COX-2的选择性抑制,选择性系数至少50,优选至少100。所述药物包括但不限于下面所列专利和出版物中公开的化合物,下面所列的每项专利和出版物都单独通过引用结合到本文中。
Reitz和Li的美国专利第5,344,991号。
Norman等的美国专利第5,380,738号。
Reitz等的美国专利第5,393,790号。
Lee的美国专利第5,401,765号。
Huang和Reitz的美国专利第5,418,254号。
Koszyk和Weier的美国专利第5,420,343号。
Talley和Rogier的美国专利第5,434,178号。
Black等的美国专利第5,436,265号。
Talley等的美国专利第5,466,823号。
Ducharme等的美国专利第5,474,995号。
Lee和Bertenshaw的美国专利第5,475,018号。
Lee等的美国专利第5,486,534号。
Lau等的美国专利第5,510,368号。
Prasit等的美国专利第5,521,213号。
Ducharme等的美国专利第5,536,752号。
Cromlish等的美国专利第5,543,297号。
Talley等的美国专利第5,547,975号。
Ducharme等的美国专利第5,550,142号。
Gauthier等的美国专利第5,552,422号。
Desmond等的美国专利第5,585,504号。
Adams等的美国专利第5,593,992号。
Lee的美国专利第5,596,008号。
Lau等的美国专利第5,604,253号。
Guay和Li的美国专利第5,604,260号。
Lipsky等的美国专利第5,616,458号。
Khanna等的美国专利第5,616,601号。
Weier等的美国专利第5,620,999号。
Talley等的美国专利第5,633,272号。
Lau等的美国专利第5,639,780号。
Talley等的美国专利第5,643,933号。
Adams等的美国专利第5,658,903号。
Talley等的美国专利第5,668,161号。
Huang和Reitz的美国专利第5,670,510号。
Lau的美国专利第5,677,318号。
Dellaria和Gane的美国专利第5,681,842号。
Nicolai等的美国专利第5,686,460号。
Weier等的美国专利第5,686,470号。
Talley等的美国专利第5,696,143号。
Ducharme等的美国专利第5,710,140号。
Adams等的美国专利第5,716,955号。
和Teulon的美国专利第5,723,485号。
Reitz等的美国专利第5,739,166号。
Lazer等的美国专利第5,741,798号。
Adams等的美国专利第5,756,499号。
Isakson和Talley的美国专利第5,756,529号。
Kreft等的美国专利第5,776,967号。
Beers和Wachter的美国专利第5,783,597号。
Black等的美国专利第5,789,413号。
Nicolai和Teulon的美国专利第5,807,873号。
Dube等的美国专利第5,817,700号。
Failli等的美国专利第5,830,911号。
Atkinson和Wang的美国专利第5,849,943号。
Sartori等的美国专利第5,859,036号。
Dube等的美国专利第5,861,419号。
Sartori和Teulon的美国专利第5,866,596号。
Failli的美国专利第5,869,524号。
Adams等的美国专利第5,869,660号。
Rossen等的美国专利第5,883,267号。
Zhi等的美国专利第5,892,053号。
Black等的美国专利第5,922,742号。
Adams和Garigipati的美国专利第5,929,076号。
上面引用的美国专利第5,932,598号
Khanna等的美国专利第5,935,990号。
Haruta等的美国专利第5,945,539号。
Yamazaki等的美国专利第5,958,978号。
Guay等的美国专利第5,968,958号。
Nicolai和Teulon的美国专利第5,972,950号。
Marnett和Kalgutkar的美国专利第5,973,191号。
Belley等的美国专利第5,981,576号。
Haruta等的美国专利第5,994,381号。
Haruta等的美国专利第6,002,014号。
Li等的美国专利第6,004,960号。
Hopper等的美国专利第6,005,000号。
Belley等的美国专利第6,020,343号。
DeLaszlo和Hagmann的美国专利第6,020,347号。
上面引用的美国专利第6,034,256。
Corley等的美国专利第6,040,319号。
Davies等的美国专利第6,040,450号。
Adams等的美国专利第6,046,208号。
Friesen等的美国专利第6,046,217号。
Black等的美国专利第6,057,319号。
DeNanteuil等的美国专利第6,063,804号。
ChabrierdeLassauniere和Broquet的美国专利第6,063,807号。
LeBlanc等的美国专利第6,071,954号。
Cook等的美国专利第6,077,868号。
Sui和Wachter的美国专利第6,077,869号。
Ferro等的美国专利第6,083,969号。
Spohr等的美国专利第6,096,753号。
Wang等的美国专利第6,133,292号。
国际专利公布号WO 94/15932。
国际专利公布号WO 96/19469。
国际专利公布号WO 96/26921。
国际专利公布号WO 96/31509。
国际专利公布号WO 96/36623。
国际专利公布号WO 96/38418。
国际专利公布号WO 97/03953。
国际专利公布号WO 97/10840。
国际专利公布号WO 97/13755。
国际专利公布号WO 97/13767。
国际专利公布号WO 97/25048。
国际专利公布号WO 97/30030。
国际专利公布号WO 97/34882。
国际专利公布号WO 97/46524。
国际专利公布号WO 98/04527。
国际专利公布号WO 98/06708。
国际专利公布号WO 98/07425。
国际专利公布号WO 98/17292。
国际专利公布号WO 98/21195。
国际专利公布号WO 98/22457。
国际专利公布号WO 98/32732。
国际专利公布号WO 98/41516。
国际专利公布号WO 98/43966。
国际专利公布号WO 98/45294。
国际专利公布号WO 98/47871。
国际专利公布号WO 99/01130。
国际专利公布号WO 99/01131。
国际专利公布号WO 99/01452。
国际专利公布号WO 99/01455。
国际专利公布号WO 99/10331。
国际专利公布号WO 99/10332。
国际专利公布号WO 99/11605。
国际专利公布号WO 99/12930。
国际专利公布号WO 99/14195。
国际专利公布号WO 99/14205。
国际专利公布号WO 99/15505。
国际专利公布号WO 99/23087。
国际专利公布号WO 99/24404。
国际专利公布号WO 99/25695。
国际专利公布号WO 99/35130。
国际专利公布号WO 99/61016。
国际专利公布号WO 99/61436。
国际专利公布号WO 99/62884。
国际专利公布号WO 99/64415。
国际专利公布号WO 00/01380。
国际专利公布号WO 00/08024。
国际专利公布号WO 00/10993。
国际专利公布号WO 00/13684。
国际专利公布号WO 00/18741。
国际专利公布号WO 00/18753。
国际专利公布号WO 00/23426。
国际专利公布号WO 00/24719。
国际专利公布号WO 00/26216。
国际专利公布号WO 00/31072。
国际专利公布号WO 00/40087。
国际专利公布号WO 00/56348。
欧洲专利申请号0 799 823。
欧洲专利申请号0 846 689。
欧洲专利申请号0 863 134。
欧洲专利申请号0 985 666。
本文使用的优选选择性COX-2抑制药物、或本文使用的前体药物或盐在体内被转化成为的选择性COX-2抑制药物是式(IV)的化合物:
其中:
A是取代基,选自部分不饱和或不饱和的杂环基以及部分不饱和或不饱和的碳环,优选杂环基选自吡唑基、呋喃酮基、异唑基、吡啶基、环戊烯酮基和哒嗪酮基;
X是O、S或CH2;
n是0或1;
R1是至少一个取代基,选自杂环基、环烷基、环烯基和芳基,并任选在可取代位置上被一个或多个基团取代,所述基团选自烷基、卤烷基、氰基、羧基、烷氧羰基、羟基、羟烷基、卤烷氧基、氨基、烷基氨基、芳基氨基、硝基、烷氧基烷基、烷基亚硫酰基、卤、烷氧基和烷硫基;
R2是甲基、氨基或氨羰基烷基;
R3是一个或多个选自以下的基团:氢基(hydrido)、卤、烷基、链烯基、链炔基、氧代基、氰基、羧基、氰烷基、杂环氧基、烷氧基、烷硫基、烷羰基、环烷基、芳基、卤烷基、杂环基、环烯基、芳烷基、杂环基烷基、酰基、烷硫基烷基、羟烷基、烷氧羰基、芳羰基、芳烷羰基、芳链烯基(aralkenyl)、烷氧基烷基、芳基硫代烷基、芳氧基烷基、芳烷基硫代烷基、芳烷氧基烷基、烷氧基芳烷氧基烷基、烷氧羰基烷基、氨羰基、氨基羰基烷基、烷基氨基羰基、N-芳基氨基羰基、N-烷基-N-芳基氨基羰基、烷基氨基羰基烷基、羧基烷基、烷基氨基、N-芳基氨基、N-芳烷基氨基、N-烷基-N-芳烷基氨基、N-烷基-N-芳基氨基、氨基烷基、烷基氨基烷基、N-芳基氨基烷基、N-芳烷基氨基烷基、N-烷基-N-芳烷基氨基烷基、N-烷基-N-芳基氨基烷基、芳氧基、芳烷氧基、芳基硫代、芳烷基硫代、烷基亚硫酰基、烷基磺酰基、氨基磺酰基、烷基氨基磺酰基、N-芳基氨基磺酰基、芳基磺酰基和N-烷基-N-芳基氨基磺酰基,R3任选地在可取代位置上被一个或多个选自以下的基团取代:烷基、卤烷基、氰基、羧基、烷氧基羰基、羟基、羟烷基、卤烷氧基、氨基、烷基氨基、芳基氨基、硝基、烷氧基烷基、烷基亚硫酰基、卤、烷氧基和烷硫基;和
R4选自氢基和卤。
本发明的组合物尤其用于具有式(V)的选择性COX-2抑制药物的水溶性盐、前体药物和前体药物的盐、或其同分异构体或互变异构体:
其中R5是甲基或氨基,R6是氢或C1-4烷基或烷氧基,X′是N或CR7,其中R7是氢或卤素,而Y和Z独立地是碳原子或氮原子,它们限定五元环或六元环的相邻原子,所述五元环或六元环任选地在一个或多个位置上被氧代基、卤、甲基或卤甲基取代。优选的所述五元环或六元环是仅在一个位置上取代的环戊烯酮、呋喃酮、甲基吡唑、异唑和吡啶环。
例如,本发明的组合物适于塞来考昔、地拉考昔、伐地考昔、罗非考昔、艾托考昔、2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-1-酮和2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮,最优选伐地考昔。可用于本发明组合物的尤其有用的伐地考昔的前体药物是帕瑞考昔,更优选其水溶性盐,例如帕瑞考昔钠。
在本发明的组合物和方法中使用的帕瑞考昔可以用例如上面引用的美国专利第5,932,598中陈述的方法制备。
本发明的组合物也可用于具有式(VI)的化合物及其药学上可接受的盐:
其中X″是O、S或N-低级烷基;R8是低级卤烷基;R9是氢或卤素;R10是氢、卤素、低级烷基、低级烷氧基或卤烷氧基、低级芳烷基羰基、低级二烷基氨基磺酰基、低级烷基氨基磺酰基、低级芳烷基氨基磺酰基、低级杂芳烷基氨基磺酰基或5元或6元含氮杂环磺酰基;R11和R12独立地是氢、卤素、低级烷基、低级烷氧基或芳基。
尤其有用的式(VI)的化合物是(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-羧酸,尤其是其水溶性盐形式,例如钠盐。该化合物可以用例如上面引用的美国专利第6,034,256中陈述的方法制备。
在本发明可稀释配制粉剂组合物中存在一种或多种选自以上的治疗药物,其总量以重量计占所述组合物的约30%至约90%,优选约40%至约85%,更优选约50%至约80%。
所述缓冲剂一般是主要的赋形剂成分,其量以重量计占所述组合物的约5%至约60%,优选约10%至约60%,更优选约20%至约50%。在本发明的一个实施方案中,所述可稀释配制粉剂组合物基本上由所述治疗药物和所述缓冲剂组成。
选择所述缓冲剂使得在用生理可接受体积的胃肠外可接受溶剂液体稀释配制时提供所述组合物的pH,所述缓冲剂(a)胃肠外可接受,(b)与完全在所述溶剂液体的溶液内的所述治疗药物一致,以及(c)提供介质,所述治疗药物在稀释配制后表现出可接受的化学稳定性至少约1小时。合适的缓冲剂例如可以选自磷酸钠和磷酸钾、柠檬酸钠和柠檬酸钾、乙醇胺、二乙醇胺和三乙醇胺、2-氨基-2-(羟甲基)-1,3-丙二醇(氨丁三醇)等以及它们的混合物。优选的缓冲剂是磷酸氢二钠和磷酸氢二钾以及氨丁三醇。特别优选的缓冲剂是磷酸氢二钠,例如无水磷酸氢二钠、七水合磷酸氢二钠、十二水合磷酸氢二钠等。
在一个实施方案中,所述组合物稀释配制后pH约7至约9,优选约7.5至约8.5,例如约8。如果需要,在所述组合物中除包括所述缓冲剂外,还可以包括少量酸(如磷酸)和/或碱(如氢氧化钠),以调节pH。
除所述缓冲剂(如果存在的话)外的赋形剂在稀释配制前占所述组合物的不超过约10%(重量),优选不超过约5%(重量)。本文的术语“赋形剂”包括除水外所述组合物的所有非治疗活性成分。在本发明的一个实施方案中,基本不存在除所述缓冲剂以外的赋形剂。
惊人的是,已经发现重要的是在所述组合物中包括不超过约10%(重量)、优选不超过约5%(重量)、最优选基本不包括除缓冲剂外通常在可稀释配制胃肠外制剂中用作膨胀剂的成分。尤其是优选所述组合物不包含广泛使用的膨胀剂甘露醇,或者如果包括甘露醇,其存在的量占所述组合物的不超过约10%(重量),优选不超过5%(重量)。根据本发明,相信通过最小化作为所述组合物成分的所述膨胀剂尤其是甘露醇的量,或者完全排除所述膨胀剂尤其是甘露醇用作所述组合物的成分,能够保证所述治疗药物可接受的化学稳定性。
任选地可以在所述组合物中包括至多约0.5%(重量)的一种或多种防腐剂。合适的防腐剂的例子包括羟苯甲酯、羟苯丙酯、苯酚和苯甲醇。
本发明的可稀释配制粉剂组合物优选包含少于约5%、更优选少于约2%、最优选少于约1%(重量)的水。通常水分含量约0.5%至约1%(重量)。在所述治疗药物有在水的存在下降解或转化为较不可溶形式的趋势的情况下,保持水分含量在该低水平特别重要。本发明的粉剂组合物在封口小瓶内贮存于室温(约20-25℃)时所述治疗药物可接受的化学稳定性至少约30天,优选至少约6个月,最优选至少约2年。
本文中“可接受的化学稳定性”指所述组合物在确定时间长度(如约30天、约6个月或约2年)后,通过所述治疗药物化学纯度的标准试验,例如管理当局批准所需的测试。所述测试的一个例子是“总共5%,单一杂质1%的规则”,即候选药物的制备物必须不含有超过总共5%的杂质,并且任一单一杂质不超过1%。
在所述治疗药物是帕瑞考昔的情况下,例如采取帕瑞考昔钠的形式,过一段时间后组合物内可能出现部分转化为伐地考昔。因为伐地考昔本身在治疗上是有活性的选择性COX-2抑制药物(事实上帕瑞考昔的治疗功效依赖于在体内转化为伐地考昔),所以所述转化并不导致治疗效果的损失。然而,因为伐地考昔在水中溶解度非常低,所以需要在稀释配制前最小化所述转化,以便能够保证所述治疗药物的完全溶解。在计划用于胃肠外给药的溶液中,通常不希望存在颗粒,例如由于存在相当大数量的伐地考昔而产生的颗粒。
惊人的是,发现通过从所述组合物中减少或优选排除膨胀剂如甘露醇,可以极大减少可稀释配制粉剂组合物内帕瑞考昔到伐地考昔的转化。这在下面的实施例1和2中举例说明。如实施例1所述,除缓冲剂外具有不超过10%(重量)赋形剂的本发明的组合物表现出非常高水平的帕瑞考昔化学稳定性,而如实施例2所述,除缓冲剂外含有较高水平赋形剂的组合物表现出更大程度的帕瑞考昔到伐地考昔的转化。
本发明的另一实施方案是注射溶液组合物,通过用胃肠外可接受的溶剂稀释配制如本文提供的粉剂组合物而制备所述注射溶液组合物,所述溶剂优选水性溶剂。在所述溶液组合物中,所述治疗药物的化学稳定性有限,在这种情况下优选给药前在短时间内稀释配制所述组合物,例如给药前约1小时内。在其它情况下所述治疗药物可能在溶液中表现出相对高水平的化学稳定性,在这样的情况下,稀释配制后在短时间内给药不是关键的。
在所述治疗药物是帕瑞考昔的情况下,例如采取帕瑞考昔钠的形式,在水溶液内一段时间后可能出现部分转化为高度不溶性的伐地考昔,导致形成固体颗粒。如上文指出的,在注射制剂中一般不希望存在固体颗粒;因此,在本发明帕瑞考昔组合物的具体情况下,优选稀释配制后在短时间内给予注射溶液,例如在稀释配制后约1小时内。
通过维持水性介质处于约7或更高的pH,可以极大降低所述介质中帕瑞考昔到伐地考昔的转化率。此外,帕瑞考昔钠本身在水中的溶解度受到pH的强烈影响。例如,20℃下平衡溶解度从pH7.3的1.0mg/ml升到pH7.8的18mg/ml,然后升到pH8.2的220mg/ml。在更高浓度下也可以制备帕瑞考昔钠的过饱和溶液。提供生理可接受性、良好的短期化学稳定性以及良好的帕瑞考昔钠溶解度的优选pH范围是约7.5至约8.5,更优选约7.8至约8.2,例如约8.0。
可以使用任何已知的胃肠外可接受的溶剂液体稀释配制本发明的粉剂组合物。注射用水适用,但通常提供低渗溶液。因此,通常优选法使用包含如葡萄糖或氯化钠等溶质的水性液体。举例来说,适用的有0.9%注射用氯化钠USP、制菌性0.9%注射用氯化钠USP、5%注射用葡萄糖USP以及注射用5%葡萄糖和0.45%氯化钠USP。乳酸化林格氏注射液USP较不合适,至少在所述治疗药物是帕瑞考昔钠的情况下如此,因为有形成晶体的趋势。
用于稀释配制的所述溶剂液体的合适体积取决于患者的年龄和体重、所述治疗药物的溶解度和给药量以及其它因素,但合适的体积一般从约0.25ml至约5ml,优选约0.5ml至约2ml。例如,在帕瑞考昔钠的情况下,20mg剂量一般能够在约1ml任何上述溶剂液体中方便地稀释配制,而40mg剂量通常适用2ml所述溶剂液体体积。
本发明的粉剂组合物最好具有足够的空隙度,以允许所述治疗药物在所述溶剂液体中稀释配制时能够快速溶解。使用如下文所述制备所述粉剂的方法,能够获得高度空隙度。所述方法是本发明的另一实施方案,在本文中专门就帕瑞考昔钠和七水合磷酸氢二钠进行描述;然而,技术人员知道可以按照本发明容易地将所述方法应用于其它治疗药物和/或其它缓冲剂。
在该方法中,将帕瑞考昔钠和作为缓冲剂的七水合磷酸氢二钠溶于水中,形成水溶液。最好使用注射用水作为溶剂。帕瑞考昔钠和所述缓冲剂在所述溶液中相互之间的相对浓度与这些成分在最终组合物中的所需相对浓度一致。这些成分的绝对浓度并不是关键的;然而,考虑到工艺效率,通常优选帕瑞考昔钠的浓度尽量高到可以方便制备并且没有超过溶解度限制的风险。如果需要,可以在该步骤中加入其它制剂成分。加入顺序不是关键的,但强烈优选最后加入帕瑞考昔钠以保证快速而完全的溶解。
任选但优选将所述溶液除菌,例如通过一个或多个除菌滤器,然后定量分装进一个或多个小瓶。每个小瓶容纳定量容积的溶液,所述溶液包含所需单位剂量帕瑞考昔钠。在小瓶上放置冷冻干燥塞子,所述冷冻干燥塞子上有允许升华的开口。最好所述小瓶和塞子是无菌的,并且在无菌操作条件下进行灌注。
然后将所述塞上塞子的小瓶置于冷冻干燥室内,并冷冻干燥所述小瓶的内容物,最好以三个阶段循环进行冷冻干燥。
在所述冷冻干燥循环的第一阶段,冷冻每个小瓶内的溶液到低于所述溶液玻璃态化温度以下的温度。对于包含帕瑞考昔钠和磷酸氢二钠的本发明组合物,玻璃态化温度是约-20℃。可以通过本领域已知的任何技术测量玻璃态化温度,例如通过应用冻干显微镜或通过测量电阻。该冷冻阶段的合适温度一般是约-30℃至约-60℃,例如约-40℃至约-50℃。从室温逐渐降低温度到所需冷冻温度,一般在约1小时至约5小时的时间内,更一般约2小时至约4小时。然后保持温度在所述冷冻温度,一般保持约0.5小时至约24小时的时间,更一般约0.75小时至约3小时。
在优选冷冻干燥过程的冷冻阶段中,温度首先从室温相当快速地降至约-20℃,例如在约0.25小时至约1小时、更优选约0.5小时至约0.75小时的时间内完成降温。然后更进一步将温度逐渐从约-20℃降至约-30℃,例如在约1小时至约4小时、更优选约1.5小时至约3小时的时间内完成降温。虽然不希望受理论的束缚,但是相信这种逐渐降温保证溶液完全冷冻。然后相当快速地将温度从约-30℃降到最终的冷冻温度,所述最终冷冻温度最好是约-40℃,例如在约0.1小时至约1小时、更优选约0.25小时至约0.5小时的时间内完成降温。已经发现如上所述的分步冷冻阶段往往提供看起来没有裂缝的固体的冻干终产品。
在所述冷冻干燥循环的第二阶段中,在所述冷冻干燥室内抽真空,实现冻干。该阶段在本文中被描述为“第一个干燥”阶段。一般合适的真空是约25至约500μmHg(约25至约500毫托),优选约50至约300μmHg。在该第一个干燥阶段期间,逐渐升高温度,任选在温度保持恒定的各个时间段之间升高温度。优选用氮气吹扫维持真空。在该阶段期间冰从冷冻溶液中升华,形成部分干燥的饼状物。
在优选冷冻干燥过程的第一个干燥阶段内,首先在约1小时至约5小时、优选约2小时至约4小时的时间内将温度从冷冻温度(如约-40℃)升至约0℃,然后在约0℃保持相当长的一段时间,例如约6小时至约12小时,优选约8小时至约10小时。最好在所述第一个干燥阶段期间使用约150至约300μmHg的真空。
在所述冷冻干燥循环的第三阶段,在真空下完成干燥。该阶段在本文中被描述为“第二个干燥阶段”。同样通常适用约25至约500μmHg、优选约50至约300μmHg的真空,最好在氮气吹扫下维持真空。在该第二个干燥阶段期间升高温度,最好升高到室温以上水平,例如约40℃,去除剩余的水分,提供水分含量低于约5%、优选低于约2%、更优选低于约1%(重量)的粉剂。
在优选冷冻干燥过程的第二干燥阶段中,在约1小时至约4小时、优选约1.5小时至约3小时的时间内将温度从约0℃升高至约40℃,然后在约40℃保持约3小时至约12小时,优选约4小时至约8小时。在所述第二干燥阶段期间最好使用约150至约300μmHg的真空。任选在所述第二干燥阶段的最后阶段,当温度维持在约40℃时,将真空降低至约25至约75μmHg。
全部冷冻干燥循环时间一般是约18小时至约36小时。延长循环时间通常不损害对终产品的质量,但增加工艺成本。根据本文提供的信息,通过常规测试能够发现产品质量和工艺经济学的最佳组合,所述最佳组合根据几个因素而有所不同,这些因素包括使用的具体冷冻干燥设备、冻干溶液内成分的准确组成和浓度、选定的治疗药物和缓冲剂等等。然而,一般而言,发现适用约18小时至约24小时的循环时间。在使用磷酸氢二钠作为缓冲剂的帕瑞考昔钠组合物的情况下,已经发现缩短循环时间到实质上少于约18小时(例如到16.5小时)导致终产品收缩的发生率增加,而这不利于稀释配制时所需的快速溶解。
完成所述冷冻干燥循环后,释放真空,并使温度回到室温。随后为所述小瓶加盖、封口,防止从空气中再吸收水分并且维持无菌。
本发明的再一实施方案是一种制成品,所述制成品包括密封小瓶,最好是玻璃小瓶,所述小瓶在无菌条件下装入单位剂量的本文所述粉剂组合物。在一个具体实施方案中,提供用上文所述方法制备的所述制成品。所述小瓶最好具有足以允许原位稀释配制所述组合物的容积。一般而言,方便使用约1ml至约10ml、优选约2ml至约5ml的容积。
本文术语“小瓶”用来指任何小容器,所述小容器有盖,适于包装单位剂量的可稀释配制的粉剂,最好是在无菌条件下包装。技术人员知道本发明的该实施方案包括包装的等同形式,例如安瓿、一次性注射器和注射器药筒。
任选地所述小瓶包括两个区室,一个区室容纳所述可稀释配制粉剂,一个区室容纳足以溶解所述粉剂的溶剂液体。在所述小瓶中,通过一个孔相互连接所述两个区室,在所述孔上可以使用一个塞子,防止所述粉剂与所述溶剂液体的接触直到准备使用所述小瓶。当使用时,通过任何合适的工具分开或刺穿所述塞子,使所述液体接触所述粉剂。所述合适的工具例如一种装置,例如施加压力或驱动针头穿过所述塞子的柱塞。所述多区室小瓶的例子包括用于注射器的双室药筒或例如使用Pharmacia Corporation的以商标Act-O-销售的双室小瓶。
适于制备和或置于小瓶内、形成本发明制成品的本发明粉剂组合物的单位剂量是这样的量:当胃肠外给予患有COX-2介导的病症或疾病的患者所述量治疗药物时,足以提供治疗益处。例如,在本发明帕瑞考昔钠组合物的情况下,合适的单位剂量一般包含约1mg至约200mg、优选约5mg至约120mg、更优选约10mg至约100mg、例如约20mg、约40mg或约80mg帕瑞考昔。当所述治疗药物不是帕瑞考昔时,合适单位剂量是在治疗上等同于上面指示剂量范围内的帕瑞考昔的量。
本发明的组合物用于治疗和预防各种各样的由COX-2介导性疾病,包括但不限于特征为炎症、疼痛和/或发热的疾病。所述组合物尤其可用作抗炎药,例如用于治疗关节炎,其额外的好处是有害副作用明显少于缺乏对COX-2的选择性优于对COX-1的选择性的常规NSAID组合物。具体地说,本发明组合物与常规NSAID组合物相比,胃肠毒性和胃肠刺激的潜力降低,所述胃肠毒性和胃肠刺激包括胃肠上部溃疡和出血。因此,在禁忌常规NSAID的情况下,本发明组合物尤其可用作所述NSAID的替代物,所述禁忌常规NSAID的情况例如患有消化性溃疡、胃炎、局限性肠炎、溃疡性结肠炎、憩室炎或有胃肠损害复发史的患者;患有胃肠出血、凝结疾病的患者,所述胃肠出血、凝结疾病包括贫血,例如血凝血酶原过少、血友病或其它出血问题;肾病患者;或手术前患者或摄入抗凝药的患者。
设想的组合物用于治疗多种关节炎疾病,包括但不限于类风湿性关节炎、脊椎关节病、痛风性关节炎、骨关节炎、系统性红斑狼疮以及青少年关节炎。
所述组合物用于治疗哮喘、支气管炎、月经性痉挛、早产、腱炎、粘液囊炎、变应性神经炎、巨细胞病毒感染、细胞凋亡(包括HIV诱导的细胞凋亡)、腰痛、肝病(包括肝炎)、皮肤相关疾病(例如银屑病、湿疹、痤疮、烧伤、皮炎和紫外辐射损伤(包括晒斑))以及术后炎症(包括眼科手术后的炎症,所述眼科手术例如白内障手术或屈光手术)。
所述组合物用于治疗胃肠病症,例如炎性肠病、局限性回肠炎、胃炎、过敏性肠综合征和溃疡性结肠炎。
所述组合物用于治疗下面疾病中的炎症:偏头痛、动脉外膜炎结节、甲状腺炎、再生障碍性贫血、霍奇金病、硬皮病(sclerodoma)、风湿性发热、I型糖尿病、神经肌肉接头病(包括重症肌无力)、白质病(包括多发性硬化)、结节病、肾病综合征、贝赫切特综合征、多肌炎、龈炎、肾炎、过敏反应、损伤后出现的肿胀包括脑浮肿、心肌缺血等等。
所述组合物用于治疗眼病,包括但不限于下面炎症疾病:眼内炎、巩膜外层炎、视网膜炎、虹膜炎、睫状体炎、脉络膜炎、角膜炎、结膜炎和睑炎,眼睛一个部分以上的炎症疾病,如视网膜脉络膜炎、虹膜睫状体炎、虹膜睫状体脉络膜炎(也称为眼色素层炎)、角结膜炎、睑结膜炎等;其它COX-2介导的视网膜病,包括糖尿病性视网膜病;眼畏光;眼睛任何组织的急性损伤,包括术后损伤,如白内障手术或角膜移植手术后的急性损伤;术后眼部炎症;手术中的瞳孔缩小;角膜移植物排斥;眼的新血管形成,例如视网膜新血管形成,包括在损伤或感染后出现的新血管形成;黄斑变性;囊状黄斑水肿;晶状体后纤维组织形成;新血管形成性青光眼(neovascular glaucoma);以及眼痛。
所述组合物用于治疗肺部炎症,例如与病毒感染和囊性纤维变性有关的肺部炎症,以及用于骨吸收,例如与骨质疏松有关的骨吸收。
所述组合物用于治疗某些中枢神经系统疾病,例如皮质痴呆包括阿尔茨海默病、神经变性以及由于中风、局部缺血和创伤导致的中枢神经系统损害。术语“治疗”在本文中包括对痴呆的部分或完全抑制,所述痴呆包括阿尔茨海默病、血管性痴呆、多梗死性痴呆、早老性痴呆、酒精性痴呆和老年性痴呆。
所述组合物用于治疗过敏性鼻炎、呼吸窘迫综合征、内毒素休克综合征和肝病。
所述组合物用于治疗疼痛,包括但不限于术后疼痛、牙痛、肌肉痛和癌症引起的疼痛。例如,所述组合物用于缓解多种病症中的疼痛、发热和炎症,所述病症包括风湿性发热、流感和其它病毒感染包括普通感冒、腰背痛和颈痛(low back and neck pain)、痛经、头痛、牙痛、扭伤和劳损、肌炎、神经痛、滑膜炎、关节炎包括类风湿性关节炎、退化性关节病(骨关节炎)、痛风和强直性脊椎炎、粘液囊炎、烧伤以及外科和牙科手术后的损伤。
所述组合物用于治疗和预防炎症相关心血管病,包括血管病、冠状动脉病、动脉瘤、血管排斥、动脉硬化、动脉粥样硬化包括心脏移植物动脉粥样硬化、心肌梗塞、栓塞、中风、血栓形成包括静脉血栓形成、心绞痛包括不稳定心绞痛、冠状动脉斑炎症、细菌引起的炎症包括衣原体引起的炎症、病毒引起的炎症以及与外科手术有关的炎症,所述外科手术例如血管移植包括冠状动脉旁路手术、换血管术手术包括血管成形术、放置斯滕特印模(stent placement)、动脉内膜切除术或其它涉及动脉、静脉和毛细管的侵袭性手术。
所述组合物用于治疗患者的血管生成相关性疾病,例如用于抑制肿瘤血管生成。所述组合物用于治疗瘤形成,包括转移癌;眼科病症例如角膜移植排斥、眼新血管形成、视网膜新血管形成包括损伤或感染后的新血管形成、糖尿病性视网膜病、黄斑变性、晶状体后纤维组织形成和新血管性青光眼;溃疡性疾病如胃溃疡;病理性但非恶性的病症,例如血管瘤,包括幼稚型血管瘤、鼻咽的血管纤维瘤以及骨的无血管性坏死;以及雌性生殖系统的疾病如子宫内膜异位。
所述组合物用于预防和治疗良性和恶性肿瘤以及瘤形成,包括癌症,例如结肠直肠癌、脑癌、骨癌、上皮细胞衍生的瘤形成(上皮细胞癌)如基底细胞癌、腺癌、胃肠癌如唇癌、口腔癌、食管癌、小肠癌、胃癌、结肠癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌如鳞状细胞癌和基底细胞癌、前列腺癌、肾细胞癌以及其它已知的影响全身上皮细胞的癌症。设想本发明组合物特别有用的瘤形成是胃肠癌、巴特雷食管、肝癌、膀胱癌、胰癌、卵巢癌、前列腺癌、宫颈癌、肺癌、乳腺癌和皮肤癌。所述组合物也可用于治疗放射疗法引起的纤维变性。所述组合物也可用于治疗患有腺瘤性息肉的患者,包括患有家族性腺瘤性息肉病(FAP)的患者。此外,所述组合物可用于预防有FAP风险的患者体内形成息肉。
所述组合物通过抑制收缩性前列腺素类合成而抑制前列腺素类引起的平滑肌收缩,并因此可用于治疗痛经、早产、哮喘和嗜酸粒细胞相关性疾病。它们也可用于减少骨丢失,尤其是经绝后妇女的骨丢失(即治疗骨质疏松),以及用于治疗青光眼。
本发明组合物的优选应用是用于治疗类风湿性关节炎和骨关节炎,用于一般性地控制疼痛(特别是口腔手术后疼痛、全身性手术后疼痛、矫形外科手术后疼痛以及骨关节炎的急性突发),用于治疗阿尔茨海默病以及用于化学预防结肠癌。
本发明组合物除可以用于人类治疗外,还可用于兽医治疗宠物(companionanimal)、不同寻常的动物、家畜等等,尤其是哺乳动物。更具体地说,本发明组合物可用于治疗马、狗和猫的COX-2介导性疾病。
本发明还涉及治疗其中需要使用COX-2抑制药物进行治疗的病症或疾病的方法,所述方法包括胃肠外给予本发明的稀释配制组合物到需要所述组合物的患者。用于预防、减轻或缓解病症或疾病的给药方案最好对应于一日一次或一日两次的治疗,但可以根据多种因素改变。这些因素包括患者的类型、年龄、体重、性别、饮食状况和医学病症以及疾病的性质和严重性。因此,实际使用的给药方案可以变化很大,并因此可以偏离上面所述的优选给药方案。
可以用上面指示的给药方案开始初始治疗。治疗一般根据需要持续几周到几个月或几年的时间,直到已经控制或消除所述病症或疾病。可以通过本领域熟知的任何方法常规监测接受本发明稀释配制组合物治疗的患者,以确定治疗的有效性。从所述监测获得的连续数据分析允许在治疗期间修改治疗方案,以便在任何时间点给予最佳有效剂量,并且以便可以确定治疗时间。这样,可以在疗程内合理地改变治疗方案和给药计划,以便给予表现出满意有效性的最少量所述组合物,并且使得给药仅持续成功治疗所述病症或疾病的时间。
本文术语“胃肠外给药”包括注射和/或输注组合物进入或穿透患者的皮肤,并且包括真皮内给药、皮下给药、肌内给药、静脉内给药、髓内给药、关节内给药、滑膜内给药、脊柱内给药、鞘内给药和心内给药。可以使用任何已知用于胃肠外注射或输注药物的装置实现所述给药。
已经发现:当胃肠外给予人类患者帕瑞考昔时,帕瑞考昔快速完全地转化为伐地考昔。因此,惊人的是,甚至在需要快速开始治疗效果的情况下,帕瑞考昔(采取帕瑞考昔钠的形式)的治疗有效剂量等于口服给予的伐地考昔治疗有效剂量。本文中术语“等于”指在摩尔量或绝对量(即重量)上相等。根据分子量,1mg帕瑞考昔的完全转化产生约0.85mg伐地考昔。为实用目的,在考虑1mg帕瑞考昔等同于1mg伐地考昔时不产生大的误差。
因此,根据本发明的实施方案,提供治疗人类患者的COX-2介导性疾病的方法,所述方法包括胃肠外给予所述患者帕瑞考昔或其盐,给予的帕瑞考昔剂量等同于伐地考昔的治疗有效剂量。最好按约1mg至约200mg的日剂量给予帕瑞考昔或其盐例如钠盐。更优选的日剂量是约5mg至约120mg,更优选约10mg至约100mg,例如约20mg、约40mg或约80mg帕瑞考昔。
在图1举例说明的一个特别惊人的发现中,帕瑞考昔到伐地考昔的转化如此迅速和完全,以致胃肠外给予(例如静脉内给予)人类患者帕瑞考昔与口服给予速释形式相等剂量的伐地考昔本身相比,提供显著更早的伐地考昔血浆浓度峰值。
在本发明的另一实施方案中,提供包含封口小瓶、最好是玻璃小瓶的制成品,所述封口小瓶容纳有无菌的可胃肠外给药的组合物,所述组合物包含等于治疗有效剂量伐地考昔的帕瑞考昔剂量的帕瑞考昔或其盐。帕瑞考昔的剂量最好是约1mg至约200mg,更优选约5mg至约120mg,最优选约10mg至约100mg,例如约20mg、约40mg或约80mg。所述帕瑞考昔最好作为帕瑞考昔钠存在。任选所述小瓶是如上文所述的多区室小瓶。
本发明的治疗方法还包括帕瑞考昔或本发明组合物与选自阿片类物质和其它镇痛药的一种或多种药物的联合治疗,所述其它镇痛药其中包括麻醉性镇痛药、μ受体拮抗剂、κ受体拮抗剂、非麻醉性(即非成瘾性)镇痛剂、单胺摄取抑制剂、腺苷调节剂、大麻素衍生物、P物质拮抗剂、神经激肽-1受体拮抗剂和钠通道阻滞剂。优选的联合治疗包括应用本发明组合物以及一种或多种选自以下的化合物:醋氯芬酸、阿西美辛、e-乙酰氨基己酸、对乙酰氨基苯酚、醋氨沙洛、乙酰苯胺、乙酰水杨酸(阿司匹林)、S-腺苷甲硫氨酸、阿氯芬酸、阿芬太尼、烯丙罗定、阿明洛芬、阿洛普令、阿法罗定、二乙酰水杨酸铝、氨芬酸、氨氯苯嗪、3-氨基-4-羟丁酸、2-氨基-4-甲吡啶、氨丙吡酮、氨基比林、阿米西群、水杨酸铵、安吡昔康、呱氨托美丁、阿尼利定、安替比林、水杨酸安替比林、安曲非宁、阿扎丙宗、苄达酸、贝诺酯、苯洛芬、苄哌立隆、苄达明、苄吗啡、柏莫洛芬、贝齐米特、α-没药醇、溴芬酸、p-溴乙酰苯胺、5-溴水杨酸乙酸酯、溴水杨醇、布西丁、布氯酸、布可隆、丁苯羟酸、布马地宗、丁丙诺啡、布他西丁、丁布芬、布托啡诺(butophanol)、乙酰水杨酸钙、卡马西平、卡比芬、卡洛芬、卡沙兰、三氯叔丁醇、氯西诺嗪、水杨酸胆碱、辛可芬、桂美辛、西拉马多、环氯茚酸、氯美辛、氯尼他秦、氯尼辛、氯吡酸、丁香(clove)、可待因、溴甲可待因、磷酸可待因、硫酸可待因、克罗丙胺、克罗乙胺、地索吗啡、右奥沙屈、右吗拉胺、地佐辛、地恩丙胺、双氯芬酸钠、二苯米唑、联苯吡胺、二氯尼柳、双氢可待因、盐酸二氢可待因酮烯醇、双氢吗啡、乙酰水杨酸二羟铝、地沙美多、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、diprocetyl、安乃近、地他唑、屈昔康、依莫法宗、恩芬那酸、依匹唑、依他佐辛、依特柳酯、乙水杨胺、依索庚嗪、依托沙秦、乙甲噻丁、乙基吗啡、依托度酸、依托芬那酯、依托尼秦、丁香酚、联苯乙酸、芬布芬、芬克洛酸、芬度柳、非诺洛芬、芬太尼、芬替酸、非普地醇、非普拉宗、夫洛非宁、氟芬那酸、氟诺洛芬、氟苯乙砜、氟吡汀、氟丙喹宗、氟比洛芬、磷柳酸、龙胆酸、格拉非宁、葡美辛、水杨酸乙二醇酯、愈创蓝油烃、氢可酮、氢吗啡酮、羟哌替啶、异丁芬酸、布洛芬、异丁普生、水杨酸咪唑、吲哚美辛、吲哚洛芬、三苯唑酸、isoladol、异美沙酮、异尼辛、伊索克酸、伊索昔康、凯托米酮、酮洛芬、酮咯酸、p-乳酰N-酰乙氧基苯胺、来苯胺、左啡诺、洛芬太尼、氯那唑酸、氯诺昔康、洛索洛芬、赖氨酸乙酰水杨酸、乙酰水杨酸镁、甲氧芬那酸、甲芬那酸、哌替啶、美普他酚、5-氨基水杨酸、美他佐辛、盐酸美沙酮、左美丙嗪、甲嗪酸、甲氧夫啉、美托酮、莫非布宗、莫苯唑酸、吗拉宗、吗啡、盐酸吗啡、硫酸吗啡、水杨吗啉、麦罗啡、萘丁美酮、纳布啡、水杨酸1-萘酯、萘普生、那碎因、奈福泮、尼可吗啡、尼芬那宗、尼氟酸、尼美舒利、5′-硝基-2′-丙氧基乙酰苯胺、去甲左啡诺、去甲美沙酮、去甲吗啡、诺匹哌酮、奥沙拉秦、阿片、奥沙西罗、奥沙美辛、丙嗪、羟考酮、羟吗啡酮、羟布宗、阿片全碱、瑞尼托林、帕沙米特、喷他佐辛、哌立索唑、非那西丁、苯吗庚酮、非那佐辛、盐酸非那吡啶、非诺可、苯哌利定、非诺吡酮、乙酰水杨酸苯酯、保泰松、水杨酸苯酯、非尼拉朵、吡酮洛芬、匹米诺定、哌布宗、哌立酮、piprofen、吡拉唑酸、哌腈米特、吡罗昔康、普拉洛芬、丙谷美辛、普罗庚嗪、γ-二甲哌替啶、丙帕他莫、丙吡兰、右丙氧芬、异丙安替比林、普罗喹宗、丙替嗪酸、雷米那酮、瑞芬太尼、甲硫利马唑、醋水杨胺、水杨苷、水杨酰胺、水杨酰胺o-醋酸、水杨基硫酸、双水杨酯、沙维林、西美曲特、水杨酸钠、舒芬太尼、柳氮磺吡啶、舒林酸、过氧化物歧化酶、舒洛芬、琥布宗、他尼氟酯、替尼达普、替诺昔康、特罗芬那酯、粉防已碱、噻唑丁炎酮、噻洛芬酸、噻拉米特、替利定、替诺立定、托芬那酸、托美丁、曲马多、tropesin、维米醇、联苯丁酸、希莫洛芬、扎托洛芬和佐美酸(参见The Merck Index,第12版,Therapeutic Category and Biological ActivityIndex,S.Budavari编辑(1996),页码:Ther-2到Ther-3和Ther-12(镇痛药(牙科)、镇痛药(麻醉性)、镇痛药(非麻醉性)、消炎药(非甾类))。
尤其优选的联合治疗包括应用帕瑞考昔或本发明组合物以及阿片样物质,更具体地说其中所述阿片样物质是可待因、哌替啶、吗啡或它们的衍生物。
可以通过任何途径给予在与帕瑞考昔或本发明组合物的联合疗法中使用的药物,所述途径例如胃肠外途径、口服途径、局部途径等。
实施例
下面实施例举例说明本发明的各个方面,但不应当认为下面的实施例是限制本发明。
实施例1
如下所述制备可稀释配制粉剂组合物,所述粉剂组合物本文命名为制剂A-D,分别包含5、10、20和40mg剂量帕瑞考昔钠形式的帕瑞考昔。
首先,制备具有表1所示组合物的用于冷冻干燥的溶液。用于冷冻干燥的溶液A-D分别对应于制剂A-D。
表1.用于冷冻干燥的溶液A-D的组成
在制备上述每种用于冻干的溶液时,将七水合磷酸氢二钠溶于合适体积的注射用水中,用1M磷酸将所得溶液的pH调到8.1。将帕瑞考昔钠溶于该溶液中。检查pH,如果需要,就用1M磷酸或1N氢氧化钠再次调整pH,加入水,将体积调整到目标体积,形成用于冻干的溶液。每种制备溶液的体积都足以制备几个单位剂量的组合物(如表1所指出的每单位剂量1ml或2ml溶液)。
所述用于冻干的溶液通过两个0.2μm除菌滤器,将1ml或2ml所述溶液在无菌条件下分别灌入2ml或5mlI型未处理的无热原透明玻璃小瓶中。按重量计量所述灌注。每种溶液几批的平均密度是1.005g/ml。在一个独立的测试中,发现帕瑞考昔钠不结合除菌滤器。
用无菌冷冻干燥塞子(有一个开口允许升华)部分塞住所述小瓶,将所述小瓶置于预先除菌的冷冻干燥室内,进行冷冻干燥循环。使用的典型循环如表2所述。使用无菌氮气充满所述小瓶的顶部空间,并在循环完成时打破真空。当所述小瓶还在所述室内时,用塞子完全塞住所述小瓶。当从所述室取出所述小瓶时,立即用咬边的(crimp into place)揭开式(flip-off)铝封盖封住所述小瓶,室温贮存,避光。
表2.典型冷冻干燥循环
得到的制剂A-D在所述小瓶内形成外观良好的饼状物,即所述饼状物没有裂缝或收缩。粉剂X射线衍射(PXRD)分析指出:所述饼状物是无定形的。甚至在70℃贮存12周后,PXRD分析显示所述饼状物的物理性状没有改变,并且没有观察到收缩的迹象。
分析制剂A、B和C(5、10和20mg帕瑞考昔)内的残余水分含量,并分析伐地考昔,作为化学稳定性的指标。对新鲜制备的样品和在70℃贮存12周的样品通过HPLC进行伐地考昔分析。如表3所示的,数据显示极好的化学稳定性,甚至在高温下贮存12周后仅有少于0.5%的伐地考昔。
表3.制剂A-C的稳定性
参数 | A | B | C |
水(%),新鲜样品 | 1.6 | 1.4 | 0.8 |
伐地考昔(%),新鲜样品 | 0.06 | 0.07 | 0.03 |
伐地考昔(%),在70℃贮存12周 | 0.45 | 0.37 | 0.36 |
测试制剂D(40mg帕瑞考昔)的pH和残余水分含量,并在新鲜制备以及在不同温度下贮存4、8和12周后通过HPLC分析帕瑞考昔和伐地考昔。如表4所示的数据,显示极好的化学稳定性,甚至在高温下贮存12周后仅有少于0.5%的伐地考昔。帕瑞考昔和伐地考昔百分率以不含赋形剂为准表示。
表4.制剂D的稳定性
在1ml注射用0.9%氯化钠USP内稀释配制制剂A-C,在2ml注射用0.9%氯化钠USP内稀释配制制剂D。所述饼状物立即溶解。
实施例2
如下所述制备本文称为制剂E-J的可稀释配制粉剂组合物,制剂E-J每种都包含帕瑞考昔钠形式的20mg帕瑞考昔。首先制备具有如表5所示组成的冷冻干燥用溶液。用于冷冻干燥的溶液E-J分别对应于制剂E-J。制备所述溶液和所述冻干粉剂组合物采用类似于制备实施例1制剂A-D所采用的程序。
可以注意到制剂E-J分别包含超过约10%除缓冲剂(磷酸氢二钠或氨丁三醇)以外的赋形剂成分。为比较目的在本文中陈述这些制剂。
表5.用于冷冻干燥的溶液E-J的组成
分析新鲜制备以及在不同温度下贮存4周后的制剂E-J内的帕瑞考昔和伐地考昔。帕瑞考昔和伐地考昔百分率以不含赋形剂为准表示,示于表6。
表6.制剂E-J的稳定性
可以注意到,制剂E-J的化学稳定性比本发明的制剂A-D要差。制剂F和I除磷酸氢二钠外各包含30mg甘露醇,它们在该实施例测试的制剂中显示最高的稳定性,但在55℃或70℃贮存4周后仍然比制剂A-D显示更高水平的帕瑞考昔到伐地考昔的转化。制剂E、G、H和J的化学稳定性差得难以接受。
此外,制剂E-J没有一种在稀释配制时立即溶解。制剂I除甘露醇和磷酸氢二钠外含200mg聚乙二醇4000,在试图稀释配制制剂时溶解尤其缓慢和困难。
实施例3
在药代动力学研究中确定人类受试者体内的伐地考昔血浆浓度。在11名健康成人受试者中,一次静脉内(IV)给予1ml药团内的20mg剂量采用帕瑞考昔钠形式的帕瑞考昔,或者用240ml水口服给予速释片剂形式的一次20mg剂量伐地考昔。受试者在服药后1小时、2小时和3小时饮用180ml水。
使用经过验证的高效液相色谱(HPLC)程序测定伐地考昔血浆浓度。图1显示服药后0到24小时的平均伐地考昔血浆浓度。
静脉内给予帕瑞考昔钠比口服给予伐地考昔更早达到最大伐地考昔血浆浓度。
实施例4
在一个单一中心、单一剂量、随机化、双盲、使用安慰剂作对照的平行组24小时研究中,一组224名患者(每个治疗组54名患者),该组患者需要拔除两颗同侧嵌塞性第三磨牙并进行骨切除,患者包括18到45岁的男性和女性,将该组患者随机化,接受4ml体积0.9%氯化钠内的单一优先静脉内剂量20mg、40mg或80mg帕瑞考昔或安慰剂。
手术结束30分钟后开始,每两小时评价疼痛水平直到24小时,除非作疼痛评价的患者没有苏醒。患者按照0-3等级并在有从“无疼痛”到“极度疼痛”的连续区的表上评价疼痛。患者一经要求即给予药物止痛。在最后一次安排好的评价或在给予抢救药物之前,要求患者评价所述研究药物延缓疼痛的有效性。
使用存活率分析技术分析抢救药物时间(TRM)。使用如Miller(1981)在Survival Analysis,第74-75页.NewYork:John Wiley&Sons中所述调整过的Kaplan-Meier产物限度估计量,计算每个治疗组该事件的中值时间。使用Simon和Lee(1982),Cancer Treat.Rep.66,37-42的方法,计算该事件中值时间的百分之九十五(95%)置信区间。对于TRM,直到24小时评价都不需要抢救药物的患者被认为在24小时经过审查。因为除给予抢救药物而放弃研究的患者在他们放弃研究的时候接受审查。
在中值TRM(表7)的基础上,单一剂量帕瑞考昔20mg、40mg和80mg导致比安慰剂显著更长的TRM。帕瑞考昔40mg和80mg的中值TRM值相互之间没有显著性差异,但它们比帕瑞考昔20mg的TRM都显著更长。
帕瑞考昔治疗组内接受抢救药物的患者比例(也示于表7)比安慰剂治疗组显著更低;在该参数上,帕瑞考昔40mg和80mg治疗组之间没有显著性差异。
表7.抢救药物的时间(TRM)
关于患者对于所述研究药物有效性的评价,每个帕瑞考昔治疗组内患者的分数都显著高于安慰剂治疗组内的患者分数;在帕瑞考昔40mg和80mg治疗组之间没有显著性差异。在帕瑞考昔40mg治疗组的患者中,92%评价研究药物为“好”或“极好”。
Claims (34)
1.一种粉剂形式的药用组合物,其包含:
(a)治疗有效性总量的帕瑞考昔或其盐,所述治疗有效性总量为所述组合物的30%至90%重量;
(b)胃肠外可接受的缓冲剂,其含量为所述组合物的5%至60%重量;
(c)所述帕瑞考昔和缓冲剂的量以所述组合物的90%至100%重量存在;
所述组合物可用胃肠外可接受的溶剂液体稀释配制成注射溶液。
2.权利要求1的组合物,其中所述帕瑞考昔或其盐为帕瑞考昔钠。
3.权利要求1的组合物,其中所述帕瑞考昔或其盐的量以所述组合物的40%至85%重量存在。
4.权利要求1的组合物,其中所述帕瑞考昔或其盐的量以所述组合物的50%至80%重量存在。
5.权利要求1的组合物,其中所述缓冲剂的量以所述组合物的20%至50%重量存在。
6.权利要求1的组合物,其由所述帕瑞考昔或其盐和所述缓冲剂组成。
7.权利要求1的组合物,其中所述缓冲剂选自磷酸钠和磷酸钾、柠檬酸钠和柠檬酸钾、单乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇和它们的混合物。
8.权利要求1的组合物,其中所述缓冲剂选自磷酸氢二钠和磷酸氢二钾、二碱式磷酸盐和它们的混合物。
9.权利要求1的组合物,其中所述缓冲剂是磷酸氢二钠。
10.权利要求1的组合物,其重配后的pH值为7至9。
11.权利要求1的组合物,所述组合物具有足够空隙度以在稀释配制时快速溶解所述帕瑞考昔或其盐。
12.用胃肠外可接受的溶剂重配粉剂制备的可注射溶液,所述粉剂包含:
(a)治疗有效性总量的帕瑞考昔或其盐,所述治疗有效性总量为所述粉剂的30%至90%重量;
(b)胃肠外可接受的缓冲剂,其量为所述粉剂的5%至60%重量;
(c)其中所述帕瑞考昔和缓冲剂的量以所述粉剂的90%至100%重量存在。
13.权利要求12的溶液,其中所述溶剂是水性溶剂。
14.权利要求12的溶液,所述溶液的pH为7.5至8.5。
15.权利要求13的溶液,其中所述水性溶剂包括葡萄糖或氯化钠或这二者。
16.用胃肠外可接受的溶剂重配粉剂制备的可注射溶液,所述粉剂包含:
(a)治疗有效性总量的帕瑞考昔钠,所述治疗有效性总量为所述粉剂的30%至90%重量;
(b)胃肠外可接受的缓冲剂,其量为所述粉剂的5%至60%重量;
(c)其中所述帕瑞考昔和缓冲剂的量以所述粉剂的90%至100%重量存在。
17.权利要求16的溶液,其中所述溶剂是水性溶剂。
18.权利要求17的溶液,所述溶液的pH为7.5至8.5。
19.权利要求17的溶液,其中所述水性溶剂包括葡萄糖或氯化钠或这二者。
20.一种制成品,所述制成品包括密封小瓶,所述小瓶中装有无菌的单位剂量的权利要求1-11中任一项的组合物。
21.权利要求20的制成品,其中所述小瓶是多区室小瓶。
22.一种制成品,所述制成品包括密封小瓶,所述小瓶中装有无菌的单位剂量的权利要求2的组合物。
23.权利要求22的制成品,其中所述帕瑞考昔钠以1mg至200mg帕瑞考昔剂量存在。
24.权利要求22的制成品,其中所述帕瑞考昔钠以5mg至120mg帕瑞考昔剂量存在。
25.权利要求22的制成品,其中所述帕瑞考昔钠以10mg至100mg帕瑞考昔剂量存在。
26.权利要求22的制成品,其中所述小瓶是多区室小瓶。
27.一种制备可重配的选择性COX-2抑制组合物的方法,所述方法包括冷冻干燥一种水性溶液的步骤,所述水性溶液除水以外,还包含:
(a)治疗有效性总量的帕瑞考昔或其盐,所述治疗有效性总量为所述组合物的30%至90%重量,
(b)胃肠外可接受的缓冲剂,其量为所述组合物的5%至60%重量,
(c)其中所述帕瑞考昔和所述缓冲剂的量以90%至100%重量存在,
所述冷冻干燥步骤产生可快速重配的粉剂形式;所述组合物用胃肠外可接受的溶剂液体重配制成注射溶液。
28.权利要求27的方法,其中所述帕瑞考昔或其盐是帕瑞考昔钠。
29.权利要求28的方法,其中所述缓冲剂是磷酸氢二钠。
30.权利要求29的方法,其中在所述冷冻干燥步骤前,所述溶液是通过用注射用水溶解帕瑞考昔钠和磷酸氢二钠制得,所述溶液除菌后定量分装到小瓶中,每支小瓶装有一定体积的单位剂量帕瑞考昔钠溶液,然后将所述小瓶放入冷冻干燥室内。
31.权利要求30的方法,其中在制备所述溶液的步骤中,最后加入帕瑞考昔钠。
32.权利要求29的方法,其中所述冷冻干燥步骤包括一个冷冻阶段、一个第一干燥阶段和一个第二干燥阶段。
33.权利要求32的方法,其中:
(a)在所述冷冻阶段中,温度在1小时至5小时的时间内降低至-30℃至-60℃的冷冻温度,然后在所述冷冻温度下保持0.5小时至24小时;
(b)在所述第一干燥阶段中,抽真空25至500μm Hg,并在1小时至5小时的时间内将温度从冷冻温度升高至0℃;和
(c)在所述第二干燥阶段中,在25至500μm Hg的真空下,在1小时至4小时的时间内将温度从0℃升高到室温以上的水平,并在该升高的温度下保持3小时至12小时;结果获得水分含量低于2%重量的粉剂。
34.权利要求32的方法,其中总冷冻干燥循环时间为18小时至24小时。
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