CN1522697A - 预防偏头痛复发的药物组合物 - Google Patents
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Abstract
本发明涉及依利曲坦或其可药用盐或其组合物在制备用于预防偏头痛复发的药物中的应用,和5HT1B/1D受体激动剂或其可药用盐或其组合物在制备用于预防偏头痛复发的双重释放、缓释、延迟释放、控释、或脉冲释放药物组合物中的应用。
Description
本发明是申请号为99808737.8、发明名称为“预防偏头痛复发”的中国专利申请的分案申请。
技术领域
本发明涉及依利曲坦(eletriptan)在制备用于预防偏头痛复发的药物中的应用。
背景技术
据表明,5HT1B/1D受体激动剂,例如称为“曲坦类(triptans)”的化合物能高度有效地治疗偏头痛。这种曲坦衍生物的实例包括依利曲坦、舒马曲坦、那拉曲坦、里扎曲坦(rizatriptan)、唑密曲坦(zolmitriptan)、奥莫曲坦(almotriptan)、和福罗瓦曲坦(frovatriptan)。
WO-A-92/06973中公开了Eletriptan,即3-([1-甲基吡咯烷-2(R)-基]甲基)-5-(2-苯基磺酰基乙基)-1H-吲哚。WO-A-96/06842中公开了优选的依利曲坦氢溴酸盐。WO-A-99/01135中公开了包含依利曲坦半硫酸盐和咖啡因的药物制剂。
偏头痛通常分成两种类型,“有先兆偏头痛”和“无先兆偏头痛”。该先兆是开始引起或伴随发作的病灶性神经病症状。
有先兆偏头痛通常定义为这样的自发性、复发性病症,其自身表现为神经病症状发作,发作明确集中在大脑皮层或脑干,通常逐渐发展5-20分钟,并持续不到60分钟。神经病先兆症状之后,通常马上或者在不到1小时的症状消除间歇之后发生头痛、恶心和/或畏光。这种偏头痛通常持续4-72小时,但是可能完全消除。
无先兆偏头痛通常定义为自身表现是发作持续4-72小时的自发性、复发性病症。这种偏头痛的典型特征是疼痛位于单侧、搏动性性质、中等或严重强度、通过常规身体活动而加重、并伴有恶心、畏光或畏声。
大多数患者仅遭受无先兆偏头痛发作的折磨。而且频繁遭受有先兆偏头痛发作的患者似乎也遭受无先兆偏头痛发作的折磨。在偏头痛发作(有先兆或无先兆)前数小时或一天或两天可能会出现“先兆症状”。这些症状通常由全身性特征组成,例如机能亢进、活动减退、抑郁、渴望特殊食物、反复打哈欠、以及类似非典型症状。
偏头痛复发被归类为和偏头痛本身区分开的病症,并且可定义为,在首次治疗后24小时内、从首次治疗后2小时内没有任何或有轻度偏头痛的状态复发到中等或严重偏头痛。
有证据表明,虽然曲坦类衍生物可有效地缓解偏头痛,但是这类衍生物实际上会导致偏头痛复发病症以一定比率发生,该比率是所用特定曲坦类衍生物的特征。实际上当使用曲坦类衍生物时,对于每次偏头痛发作,典型偏头痛复发的发生率大约是30%。
必须将治疗偏头痛、即治疗已发生的偏头痛,或者治疗偏头痛复发、即治疗已发生的偏头痛复发,与预防偏头痛复发、即治疗预期会发生偏头痛复发的患者以防止偏头痛复发明确区别开来。应当注意,并非所有患者都会发生上述偏头痛复发。
迄今为止,没有任何5HT1B/1D受体激动剂被表明能预防偏头痛复发,并且对于任何特定化合物,不能简单地预测它们能预防偏头痛复发,即使现有技术中指出这些化合物能够治疗偏头痛时也是如此。实际上,目前没有任何“曲坦类化合物”被指出能预防偏头痛复发。不能预测预防偏头痛复发的原因在于,偏头痛复发的病因学是未知的。此外,对于有发生偏头痛复发倾向的患者的特征,或者对于有可能复发的偏头痛的特征,人们了解的很少。
《头痛》(Cephalalgia),14,330-338(1994)公开,口服100mg剂量的舒马曲坦能在2小时内消除60%的偏头痛发作,但是头痛可能在24小时内复发。如果2小时后再服用一片舒马曲坦片剂,这并不能提高初始效力,并且既不能预防也不能延迟偏头痛复发。然而,再服用一片舒马曲坦片剂能高度有效地治疗已发生的偏头痛复发。另外,《神经病学》(Neurology),45,1505-1509(1995)公开,对于通过皮下给药6mg舒马曲坦而获得成功治疗的偏头痛发作,有大约40%可能在24小时内发生偏头痛复发。然而,先皮下给药6mg舒马曲坦之后,再口服100mg舒马曲坦不能预防偏头痛复发,但是能显著延迟偏头痛复发的时间。
发明内容
现在已经惊奇地发现,依利曲坦可用于预防偏头痛复发。
因此,本发明涉及依利曲坦、或其可药用盐或其组合物在制备用于预防偏头痛复发的药物中的应用。
此外,本发明还涉及预防偏头痛复发的方法,包括给患者施用有效量的依利曲坦、或其可药用盐或其组合物。
依利曲坦的可药用盐包括其酸加成盐和碱盐。
合适的酸加成盐是与能形成无毒盐的酸形成的,这种盐的实例有盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、磷酸氢盐、乙酸盐、马来酸盐、富马酸盐、乳酸盐、酒石酸盐、柠檬酸盐、葡萄糖酸盐、琥珀酸盐、糖二酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、和扑酸盐。
合适的碱盐是与能形成无毒盐的碱形成的,这种盐的实例有钠盐、钾盐、钙盐、镁盐和锌盐。
有关合适盐的综述,见Berge等人的《药物科学杂志》(J.Pharm.Sci.),1977,66,1-19。
用于本发明的优选的依利曲坦盐是氢溴酸盐和硫酸盐、包括半硫酸盐。
依利曲坦的多晶型物、溶剂化物和放射标记衍生物或它们的可药用盐也包括在本发明范围内。
依利曲坦的可药用溶剂化物及其可药用盐包括其水合物。
依利曲坦的可药用盐可通过将依利曲坦的溶液与所需的酸或碱(视情况而定)混合而轻易地制得。盐可从溶液中沉淀出来,并且可通过过滤来收集,或者可通过将溶剂蒸发来回收。
依利曲坦或其盐可独自给药,但是通常是与根据给药途径和标准药物实践选择的适当药物赋形剂、稀释剂或载体混合在一起给药。
例如,依利曲坦或其盐可以以可含有矫味剂或着色剂的片剂、胶囊剂、卵状制剂、酏剂、溶液剂或悬浮剂的剂型口服或舌下给药,以立即或者缓释施用。
这种片剂可含有赋形剂例如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸二钙、和甘氨酸,崩解剂例如淀粉、交联羧甲基纤维素钠和一些复合硅酸盐,以及制粒粘合剂例如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶。此外,这种片剂还可包含润滑剂例如硬脂酸镁、甘油二十二烷酸酯和滑石。
还可采用相似类型的固体组合物,例如填充在明胶胶囊中的填充物。对于这种胶囊剂,优选的赋形剂包括乳糖或奶糖以及高分子量聚乙二醇。对于水悬浮剂和/或酏剂,可将依利曲坦或其盐与多种甜味剂或矫味剂,着色剂或染料,乳化剂和/或悬浮剂,稀释剂例如水、乙醇、丙二醇和甘油,以及它们的组合物混合在一起。
依利曲坦或其盐还可通过非胃肠道注射,例如静脉内、腹膜内、鞘内、心室内、胸骨内、颅内、肌内或皮下注射来给药,或者其可通过输注技术来给药。依利曲坦最好以无菌水溶液的剂型给药,该无菌水溶液可含有其它物质例如足以使该溶液与血液等渗的盐或葡萄糖。如果需要的话,应当将该水溶液适当缓冲(优选缓冲至pH为3-9)。通过本领域技术人员众所周知的标准制药技术,可在无菌条件下轻易地制备合适的非胃肠道给药制剂。
为了对人类患者口服和非胃肠道给药,依利曲坦或其盐的日剂量水平通常为0.1-4mg/kg(以单剂量或均分剂量给药)。
因此,依利曲坦或其盐的片剂或胶囊剂可含有5-240mg、优选5-100mg活性化合物,并且根据具体情况每次施用一个或两个或更多个。不论怎样,都将由医师决定对具体患者最适合的实际剂量,该实际剂量将取决于特定患者的年龄、体重和反应。上述剂量是示范性的平均剂量。当然,在个别情况下,可能需要更高或更低的剂量范围,并且这种剂量范围也在本发明范围内。
依利曲坦或其盐还可以鼻内给药,或者通过吸入给药,并且可方便地以干粉吸入剂或气雾剂的形式从使用合适推进剂的加压容器或喷雾器中施用,所述推进剂有例如二氯二氟甲烷,三氯氟甲烷,二氯四氟乙烷,氢氟烷烃例如1,1,1,2-四氟乙烷(HFA 134A[商标])或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA[商标]),二氧化碳或其它适当气体。对于加压气雾剂,可通过提供阀门来决定剂量单位以递送计量剂量。加压容器或喷雾器可包含该活性化合物的溶液或悬浮液,例如使用乙醇和推进剂作为溶剂的混合物,还可包含润滑剂例如脱水山梨醇三油酸酯。可配制在吸入器或吹入器中使用的、包含依利曲坦或其盐与合适粉末基质例如乳糖或淀粉的粉状混合物的胶囊或药筒。或者,可通过从未加压单位或多剂量泵型装置中递送来鼻内施用依利曲坦或其盐。优选的鼻内施用制剂包括含有依利曲坦或其盐和咖啡因或环糊精的制剂。
或者,依利曲坦或其盐可以以栓剂或阴道托剂的形式施用,或者可以以洗剂、溶液剂、霜剂、软膏剂或扑粉剂的形式局部施用。还可以通过使用皮肤贴剂来透皮施用依利曲坦或其盐。
为了局部施用到皮肤上,可将依利曲坦或其盐配制成含有悬浮在或溶解在例如下述一种或多种物质的混合物内的活性化合物的适当软膏剂:矿物油、液状凡士林、白凡士林、丙二醇、聚氧乙烯聚氧丙烯复合物、乳化蜡和水。或者,可将依利曲坦或其盐配制成悬浮在或溶解在例如下述一种或多种物质的混合物内的合适洗剂或霜剂:矿物油、脱水山梨醇一硬脂酸酯、聚乙二醇、液状石蜡、多乙氧基醚60、鲸蜡基酯蜡、鲸蜡醇、2-辛基十二烷醇、苯甲醇和水。
WO-A-92/06973、WO-A-96/06842和WO-A-99/01135中公开了依利曲坦或其盐的优选制剂。用于预防偏头痛复发的依利曲坦或其盐的特别优选的制剂包括双重释放、缓释、控释、延迟释放、或脉冲释放制剂。
设计缓释剂型以在将该剂型施用给患者后的持久时间内将依利曲坦释放到患者胃肠道内。合适的剂型包括:
(a)其中依利曲坦或其可药用盐包埋在基质内、并且依利曲坦或其盐是通过扩散或侵蚀而从该基质内释放出来的剂型,
(b)其中依利曲坦或其可药用盐位于包衣有速率控制膜的多颗粒核内部或其上面的剂型,
(c)其中依利曲坦或其可药用盐位于包含药物可渗透包衣的剂型中、并且药物是通过钻孔从中释放的剂型,
(d)其中依利曲坦或其可药用盐是经由半透膜释放、并且该半透膜使得药物能穿过该膜或者通过该膜内的液体填充孔来扩散的剂型,和
(e)其中依利曲坦以离子交换复合物的形式存在、并且该离子交换复合物能有效地控制释放“盐”形式的该活性化合物(例如通过使用合适的阴离子交换树脂例如聚苯乙烯磺酸钠)的剂型。
本领域技术人员应当理解,获得缓释效果的某些上述手段可结合使用,例如可在多颗粒内形成包含该活性化合物的基质和/或将所述基质包衣上有具有孔的可渗透包衣。
设计脉冲释放制剂以在将该剂型施用给患者后的持久时间内以脉冲方式释放该活性化合物。这种释放可以以立即释放或缓释的形式进行。通过在胃肠道特定位点释放药物或者通过在预定时间后释放药物可实现延迟释放。脉冲释放制剂可以呈片剂或多颗粒或二者的结合体。合适的剂型包括:
(a)渗透势引发释放的剂型(参见例如US 3952741),
(b)压缩包衣双层片剂(参见例如US 5464633),
(c)含有可侵蚀塞的胶囊(参见例如US 5474784),
(d)S状释放的小丸剂(参见例如US 5112621),和
(e)包衣有或含有依赖于pH的聚合物的制剂,所述聚合物包括虫胶、邻苯二甲酸酯衍生物、聚丙烯酸衍生物、和巴豆酸共聚物。
双重释放制剂可将即释形式的活性化合物与缓释形式的活性化合物结合起来。例如,可形成双层片剂,其中一层包含即释形式的依利曲坦,另一层包含包埋在基质内并且可从该基质中通过扩散或侵蚀释放出来的依利曲坦。双重释放制剂还可以将即释形式的活性化合物与脉冲释放形式的活性化合物结合起来。例如,含有可侵蚀塞的胶囊可首先释放活性化合物,经过预定时间后,其它活性化合物以即释或缓释形式释放出来。
优选的药物双重释放形式包括
(a)立即释放,然后是控制释放;
(b)立即释放,然后是零级释放;
(c)立即释放,然后是S型释放;和
(d)双重脉冲释放。
设计延迟释放制剂以在给药后预定时间释放活性化合物。从延迟释放制剂中的释放可以是立即释放或缓释。
控制释放制剂使得能够控制活性化合物的释放速率或释放时间或者二者都能被控制,并包括缓释、脉冲释放、双重释放和延迟释放制剂。
现在已经惊奇地发现,以双重释放、缓释、延迟释放、控释、或脉冲释放制剂施用5HT1B/1D受体激动剂或其可药用盐能预防偏头痛复发。
可使用的5HT1B/1D受体激动剂的其它实例包括舒马曲坦、那拉曲坦、里扎曲坦、唑密曲坦、奥莫曲坦、和福罗瓦曲坦。
可使用的双重释放、缓释、延迟释放、控释、和脉冲释放制剂是上述用于依利曲坦的这类制剂。
因此,本发明还提供了:
a)用于预防偏头痛复发的双重释放、缓释、延迟释放、控释、或脉冲释放药物组合物,其中包含5HT1B/1D受体激动剂或其可药用盐和可药用赋形剂、稀释剂或载体;
b)5HT1B/1D受体激动剂或其可药用盐或其组合物在制备用于预防偏头痛复发的双重释放、缓释、延迟释放、控释、或脉冲释放药物组合物中的应用;和
c)预防偏头痛复发的方法,包括给患者施用有效量的包含5HT1B/1D受体激动剂或其可药用盐的双重释放、缓释、延迟释放、控释、或脉冲释放药物组合物。
具体实施方式
药理数据
给正遭受急性偏头痛发作的患者口服片剂形式的40或80mg依利曲坦(以氢溴酸盐形式)。首次给药后,如果在首次给药后8小时内发生偏头痛复发,或者如果首次给药后在尽可能接近8小时的时刻没有发生任何偏头痛复发,给在2小时内表现出偏头痛缓解的所有患者再施用一定剂量(与首次给药的剂量强度相同)的依利曲坦(以氢溴酸盐形式),或者施用安慰剂。
如果在第一次偏头痛发作后至少48小时患者遭受了第二次急性偏头痛发作,重复上述方案。
所获得的关于第一次和第二次偏头痛发作后的偏头痛复发比率(RR)的结果列于下表中。
给药程序 | 40mg-安慰剂 | 40mg-40mg | 80mg-安慰剂 | 80mg-80mg |
第一次发作RR% | 16.6 | 7.0 | 12.5 | 6.2 |
第二次发作RR% | 10.2 | 3.3 | 11.2 | 6.1 |
上表中的这些数据表明,依利曲坦预防了偏头痛复发,这是因为,成功地治疗了首次偏头痛之后,当再次施用依利曲坦时,发生偏头痛复发的患者数目与施用安慰剂相比至少减半了。
Claims (28)
1.用于预防偏头痛复发的双重释放、缓释、控释、延迟释放、或脉冲释放药物组合物,其中包含依利曲坦或其可药用盐。
2.权利要求1的药物组合物,其为双重释放药物组合物。
3.权利要求1的药物组合物,其为缓释药物组合物。
4.权利要求1的药物组合物,其为控释释放药物组合物。
5.权利要求1的药物组合物,其为延迟释放药物组合物。
6.权利要求1的药物组合物,其为脉冲释放药物组合物。
7.权利要求2的药物组合物,其中含有依利曲坦或其可药用盐,其释放方式为先立即释放,然后是S型释放。
8.权利要求2的药物组合物,其中含有依利曲坦或其可药用盐,其释放方式为先立即释放,然后是控制释放。
9.权利要求2的药物组合物,其中含有立即释放形式的依利曲坦或其可药用盐,还含有缓释形式的另外的依利曲坦或其可药用盐。
10.权利要求2的药物组合物,其中含有立即释放形式的依利曲坦或其可药用盐,还含有脉冲释放形式的另外的依利曲坦或其可药用盐。
11.权利要求6的组合物,其中的释放是以缓释形式进行的。
12.权利要求6的组合物,其为S型释放颗粒。
13.权利要求3的组合物,其中依利曲坦或其可药用盐存在于多颗粒核心之中或之上,所述核心涂覆有速率控制膜。
14.权利要求5的组合物,其中的释放为缓释形式。
15.权利要求1-14任一项的组合物,其为口服给药形式。
16.用于预防偏头痛复发的药物组合物,其中包含依利曲坦或其可药用盐、和可药用赋形剂、稀释剂或载体。
17.用于预防偏头痛复发的双重释放、缓释、控释、延迟释放、或脉冲释放药物组合物,其中包含依利曲坦或其可药用盐、和可药用赋形剂、稀释剂或载体。
18.权利要求17的组合物,其中所述组合物是双重释放组合物。
19.权利要求16、17或18的组合物,其中所述组合物还包含咖啡因或环糊精。
20.用于预防偏头痛复发的双重释放、缓释、延迟释放、控释、或脉冲释放药物组合物,其中包含5HT1B/1D受体激动剂或其可药用盐、和可药用赋形剂、稀释剂或载体。
21.权利要求20的药物组合物,其为双重释放药物组合物。
22.权利要求20的药物组合物,其为缓释药物组合物。
23.权利要求20的药物组合物,其为延迟释放药物组合物。
24.权利要求20的药物组合物,其为控释药物组合物。
25.权利要求20的药物组合物,其为脉冲释放药物组合物。
26.权利要求20-25任一项的药物组合物,其中所述5HT1B/1D受体激动剂选自舒马曲坦、那拉曲坦、里扎曲坦、唑密曲坦、奥莫曲坦、和福罗瓦曲坦。
27.5HT1B/1D受体激动剂或其可药用盐或其组合物在制备用于预防偏头痛复发的双重释放、缓释、延迟释放、控释、或脉冲释放药物组合物中的应用。
28.权利要求27的应用,其中所述5HT1B/1D受体激动剂选自舒马曲坦、那拉曲坦、里扎曲坦、唑密曲坦、奥莫曲坦、和福罗瓦曲坦。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103385876A (zh) * | 2012-05-08 | 2013-11-13 | 四川滇虹医药开发有限公司 | 一种夫罗曲坦的药物组合物及其制备方法 |
CN103385876B (zh) * | 2012-05-08 | 2016-01-13 | 四川滇虹医药开发有限公司 | 一种夫罗曲坦的药物组合物及其制备方法 |
CN104523709A (zh) * | 2014-12-22 | 2015-04-22 | 青岛正大海尔制药有限公司 | 一种含有琥珀酸夫罗曲坦的复方缓释制剂 |
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