CN101652065A - 感官可接受的吲哚血清素受体激动剂、口腔剂量制剂和使用其的方法 - Google Patents
感官可接受的吲哚血清素受体激动剂、口腔剂量制剂和使用其的方法 Download PDFInfo
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- CN101652065A CN101652065A CN200880010434A CN200880010434A CN101652065A CN 101652065 A CN101652065 A CN 101652065A CN 200880010434 A CN200880010434 A CN 200880010434A CN 200880010434 A CN200880010434 A CN 200880010434A CN 101652065 A CN101652065 A CN 101652065A
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Abstract
提供了吲哚受体血清素激动剂的感官可接受的口服剂量配方,和制造以及使用其的方法。制剂的一方面在于它们包括吲哚受体血清素激动剂和掩蔽组分。在某些实施方案中,掩蔽组分包括氨基酸和有机酸中的一种或多种。本主题发明可用于各种应用中。
Description
相关申请的交叉引用
依据35 U.S.C.§119(e),本申请要求美国临时专利申请60/961,737(2007年7月23日提交)的申请日的优先权,其内容引入本文作为参考。
引言
尽管头痛病症的流行病学仅仅部分地记载在文献中,但是将其联系在一起,头痛病症是非常常见的。据估计世界范围大约24000万人每年经历偏头痛发病。全国头痛基金会指出大于2950万美国人遭受偏头痛,其中女性受到影响的频繁度是男性的3倍。另外,在发达国家中,张力型或“应力”头痛据估计影响2/3的全部成年男性和超过80%的成年女性。较罕为人知的是慢性每日头痛的流行,尽管世界卫生组织(WHO)估计每20个成年人中的一个每天或几乎每天头痛。三叉神经痛不是常见病症,但是与三叉神经痛发病有关的疼痛已经被描述为人类已知的最严重的疼痛。
不仅头痛痛苦,而且头痛病症可能使所折磨的个体丧失能力。全世界范围,根据WHO,当分析全部“失能寿命损失年(years lived withdisability)”的原因时,偏头痛位列第19位。头痛病症可以对受折磨的个体产生大量的困苦和负担,包括个人受苦、受损的生活质量和高财务费用。反复头痛发病,和常常不断担心下一次发病,可能损害个体的家庭生活、社会生活和在其职业位置上的其的劳动能力。例如,据估计在几乎全部偏头痛患者和60%的张力性头痛患者中社会活动和工作能力下降。最后,长期尝试克服慢性头痛病症还可能使个体易感染于其它疾病。例如,与健康个体相比,在具有偏头痛或剧烈头痛的人中,忧郁的常见率为3倍。
Triptan-型药物,其是血清素(5-羟色胺(hydroxy tryptamine);5-HT)的改良型,已经为治疗偏头痛而开发。Triptan-型药物是显示出受体-选择性性能的血清素能性(serotoninergic)药剂。尽管triptan-型药物的主要作用机理仍然在研究,但理解的是通过经由存在于血管/脑和三叉神经中的血清素5-HT1B、5-HT1D、5-HT1F受体抑制三叉神经末端的过度活性;和通过抑制围绕血管的炎症、超射线透射性和血管舒张,它们减轻了偏头痛的各种症状。
各种制剂,如注射制剂,口服制剂(例如片剂)和鼻用制剂(例如滴鼻剂),已经被开发用于triptan-型药物的给药。尽管如此,在开发用于triptan型药物的新输送系统中兴趣不断。
发明内容
提供了吲哚受体血清素(serotonin)激动剂的感官可接受的(organoleptically)口服剂量制剂,和制造以及使用其的方法。制剂的一方面在于它们包括吲哚受体血清素激动剂和掩蔽组分。在某些实施方案中,掩蔽组分包括氨基酸和有机酸中的一种或多种。本主题发明可用于各种应用中。
定义
如本文中使用的,术语“头痛”包括偏头痛、丛集性头痛、反跳性头痛(rebound headache)、和偏头痛状态(status migrainosus)。“偏头痛”是指以异乎寻常严重的、单侧的、跳动性的头痛疼痛为特征的头痛子集,其通常持续4小时至72小时,并且常常包括以下症状中的一种或多种:恶心、呕吐、对光或声音敏感。如本文中使用的,“偏头痛”包括偏头痛头痛、无先兆的偏头痛、有先兆的偏头痛、和有先兆但无头痛的偏头痛。“复发性头痛”不同地和可互换地称为“反弹性”、“复发性”、“复现性”、“继承性”或“二次”头痛,是指在已经经历最初减轻后偏头痛患者所经历的头痛。复发性头痛可能在偏头痛的最初减轻后的1小时至24小时出现。偏头痛状态(status migrainosus)是指这样的情况,其中患者,通常具有偏头痛的在先历史,遭受连续偏头痛。在偏头痛状态(status migrainosus)中,疼痛是典型的、单侧的和跳动的,并且患者常常丧失能力。
如本文中使用的,“疼痛”包括急性疼痛、慢性疼痛和阵发性疼痛。
如本文中使用的,除非另作说明,术语“治疗”或“治疗疼痛”是指对个体给药所考虑的药剂,其中药剂减轻或预防了正被治疗的个体的病状。“治疗头痛疼痛”、“治疗头痛”或“治疗头部疼痛”是指减轻或预防与头痛病症和三叉神经痛有关的疼痛。
如本文中使用的,除非另作说明,术语“预防”、“防范”或“预防疼痛”是指对个体给药所考虑的药剂,其中药剂减轻或预防了正被预防的个体的病状。“预防头痛疼痛”、“预防头痛”或“预防头部疼痛”是指减轻或预防与头痛病症和三叉神经痛有关的疼痛。
如本文中使用的,术语“吲哚血清素受体激动剂”与“triptan-型药物”可互换地使用并且是指对5-HT1B受体、5-HT1D受体和5-HT1F受体中的一种或多种具有亲合性的药剂;并且影响大脑血管的血管收缩和/或抑制促炎(pro-inflammatory)神经肽释放。吲哚血清素受体激动剂包括吲哚-3-烷基胺结构,如以下更详细地描述。
如本文中使用的,术语“药用可接受的盐”用于描述其中阴离子(或阳离子)没有显著地提供盐的毒性或药理学活性的那些盐,并且,因而,它们是其所涉及的化合物的碱(bases)的药理学当量。可用于形成盐的药用可接受的酸的实例包括但不限于盐酸、氢溴酸、氢碘酸、柠檬酸、乙酸、苯甲酸、扁桃酸、富马酸、琥珀酸、磷酸、硝酸、马来酸、粘酸、羟乙基磺酸、棕榈酸、鞣酸等。药理学成分的活性盐组合可以是游离酸、碱、或者是具有阴离子官能团的盐的形式,如酒石酸氢盐、马来酸盐、柠檬酸盐、氯化物、溴化物、乙酸盐和硫酸盐。官能团的来源可以是天然的或合成的。
如本文中使用的,“药用可接受的载体”或“合适的载体”是指这样的载体,其通常用于本领域中以便促进药剂的存储、给药和/或治疗效果。
如本文中使用的,“治疗有效剂量”、“治疗有效量”或“有效量”是指可用于治疗疼痛的止痛药剂的量。
如本文中使用的,“预防有效剂量”、“预防有效量”或“有效量”是指可用于预防疼痛的止痛药剂的量。
具体实施方式
提供了吲哚受体血清素激动剂的感官可接受的口服剂量制剂,和制造以及使用其的方法。制剂的一方面在于它们包括吲哚受体血清素激动剂和掩蔽组分。在某些实施方案中,掩蔽组分包括氨基酸和有机酸中的一种或多种。本主题发明可用于各种应用中。
在更详细地描述本发明之前,应将理解的是本发明不局限于所述的特定的实施方案,因而其当然可以变化。同样应当理解,本文中使用的术语仅仅是为了描述具体实施方案的目的,和不意图用于进行限制,因为本发明的范围将仅仅受所附权利要求的限制。
在提供了值的范围的情况下,要理解的是每个居中值,至下限单位的十分之一,除非上下文清楚地另外指出,在该范围的上下限之间,和在该所指出的范围中的任何其它所指出的或居中的值,被包括在本发明中。这些较小范围的上下限可独立地被包括在较小范围内并且同样包涵在本发明之中,以在所指出的范围内的任何具体排除的限制为条件。在所指出的范围包括一个或两个限制时,排除那些所包括的限制的任一个或两个的范围也被包括在本发明中。
某些范围在本文中以术语″约″置于之前的数值表示。术语“约”在本文中使用以便提供对于其之后的精确数值以及该术语之后的数值的近似或大致的数值的文字支持。在确定某一数值是否近似或大致于所具体列举的数值时,近似或大致未列举的数值可以是这样的数值,其在其所描述的上下文中,提供了基本上等价的具体所列举的数值。
除非另外定义,本文中使用的全部技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。虽然任何近似或等价于本文中所述的那些的方法和材料还可以用于实施或测试本发明,代表性的说明性的方法和材料现在被描述。
在本说明书中引用的全部出版物和专利在本文中结合作为参考,如同每一个单独的出版物或专利具体地和独立地被指出而结合作为参考并且引入本文作为参考从而公开和描述了根据所引用的出版物的方法和/或材料。任何出版物的引用用于其在申请日之前的公开并且不应被认为承认由于在先发明而使得本发明无资格早于这样的出版物。进一步,所提供的公布日可以不同于实际出版日期,后者可能需要独立地被证实。
注意的是,如本文中使用的,和所附权利要求中使用的,单数形式″a″、″an″和″the″包括多个对象,除非上下文内容明确另外指出。进一步注意的是权利要求可以被撰写以便排除任何任选的元素。就这点而论,在列举权利要求元素,或者使用″否定″限制方面,这种陈述意图用作使用这样的排他术语如″仅仅″、″仅″等等居先基础。
当阅读本公开内容时,如对于本领域技术人员显而易见的,本文中所述的和举例说明的每一单独的实施方案具有分立的组分和特征,其可以容易地与其它数个实施方案的任一个的特征相分开或组合,却没有背离本发明的范围或精神。任何所述方法可以按照所述事件的顺序或者逻辑可行的任何其它顺序来进行。
如上所述,本发明提供了感官可接受的吲哚受体血清素激动剂口服剂量制剂,以及用于制造和使用其的方法。在更详细地进一步描述本发明的方面中,感官可接受的制剂的实施方案首先更详细地进行评述,随后评述制造制剂的某些流程和评述其中可使用制剂的应用的实施方案。
感官可接受的吲哚受体血清素激动剂口服剂量制剂
如上所述,本发明的方面包括感官可接受的吲哚受体血清素激动剂口服剂量制剂。因为该制剂是感官可接受的,它们可以接触接受者的嘴的味道感受器并且通常被认为是接受者的感觉(特别地味觉)可接受的。本发明的感官可接受的制剂是口服制剂,其中吲哚受体血清素激动剂的使人不愉快的和苦味味道被充分地掩蔽。当使用以下实验部分中报道的评估流程时,如果组合物得分为1或以下,例如,0或以下,如-1或以下,包括-2,吲哚受体血清素激动剂的使人不愉快的和苦味味道被认为被充分掩蔽。
吲哚血清素受体激动剂
如上所定义的,术语“吲哚血清素受体激动剂”与“triptan-型药物”可互换地使用并且是指对5-HT1B受体、5-HT1D受体和5-HT1F受体中的一种或多种具有亲合性的药剂;并且影响大脑血管的血管收缩和/或抑制促炎(pro-inflammatory)神经肽释放。所考虑的吲哚血清素受体激动剂包括但不局限于为式I的那些化合物:
式I
其中R1是
其中Y是
或5-或6-元环烷基,其中在一些实施方案中,1、2或3个CH2基团被O、S、或NH替代,该环烷基在一些实施方案中将被氧代基团取代;
X是H,C1-3-烷基,C1-3-烷氧基,卤素,CF3,NO2或NH2;
R3是H或C1-3-烷基;
R4是H,C1-6-烷基或C3-6-链烯基;
R5是H,C1-3-烷基,C3-6-链烯基,芳基,芳基(C1-4亚烷基或C5-7-环烷基;
其中R2是
R6是H或(CH2)r;
R7和R8是相同的或不同的,并且各自独立地是H,或者C1-3-烷基;
R9是H,C1-6-烷基,或者C3-6-链烯基;
m,n和r可以是相同的或不同的并且各自独立地是0-3的整数,例如,各自独立地是0,1,2或3;
p是0或1的整数;和
q是0或1的整数;
前提是当R6是(CH2)r)并且r不是零,通过单个键该基团可以键合到基团NR7(R8)q的氮原子,而在这样情况下,q是零。在一些实施方案中,吲哚血清素受体激动剂是式I的化合物的生理学可接受的盐,或者式I的化合物的溶剂化物,或者式I的化合物的潜药。在一些实施方案中,例如,该激动剂是式I的化合物的琥珀酸盐。
在一些实施方案中,吲哚血清素受体激动剂是式I的化合物,其中R1是CH3HNSO2CH2;R2是-CH2CH2N(CH3)2;和R4是H。这种化合物称为舒马普坦(Sumatriptan)。
在一些实施方案中,吲哚血清素受体激动剂是式I的化合物,其中R1是
R2是-CH2CH2N(CH3)2;和R4是H。该化合物称为佐米曲坦(Zolmitriptan)。
在一些实施方案中,吲哚血清素受体激动剂是式I的化合物,其中R1是
R2是-CH2CH2N(CH3)2;和R4是H。该化合物称为利扎曲普坦(Rizatriptan)。
在一些实施方案中,吲哚血清素受体激动剂是式I的化合物,其中R1是CH3HNSO2CH2;R2是
和R4是H。该化合物称为那拉曲坦(Naratriptan)。
在一些实施方案中,吲哚血清素受体激动剂是式I的化合物,其中R1是
R2是-CH2CH2N(CH3)2;和R4是H。该化合物称为阿莫曲坦(Almotriptan)。
在一些实施方案中,吲哚血清素受体激动剂是(R)-3-[(1-甲基-2-吡咯烷基)甲基]-1H-吲哚-5-[2-(苯磺酰)乙基],还称为依来曲普坦(Eletriptan)。
在一些实施方案中,吲哚血清素受体激动剂是R-(+)3-甲基氨基-6-羧酰氨(carboxamido)-1,2,3,4-四氢咔唑,还称为夫罗曲普坦(Frovatriptan)。
激动剂可以是游离碱或其盐。在一些实施方案中,例如,激动剂是该激动剂的琥珀酸盐,例如,舒马普坦琥珀酸盐。
存在于主题制剂中的吲哚血清素受体激动剂的量可以不同,只要其有效地获得制剂的预定目的,例如,向需要其的受体提供疼痛减轻,如以下进一步评论的。
除吲哚血清素受体激动剂活性剂之外,主题制剂还包括掩蔽组分。掩蔽组分是指这样的组分,其由一种或多种药剂构成,其提供了吲哚血清素受体激动剂苦味的足够掩蔽从而使得制剂是感官可接受的。
在某些实施方案中,掩蔽组分包括氨基酸掩蔽剂和/或有机酸掩蔽剂。因而,所存在的掩蔽剂可以是一种或多种氨基酸,一种或多种有机酸,或一种或多种氨基酸和一种或多种有机酸的组合。
所考虑的氨基酸包括但不局限于:甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸,半胱氨酸,胱氨酸,蛋氨酸,天门冬氨酸,天门冬酰胺,谷氨酸、谷氨酰胺,精氨酸,赖氨酸,5-羟基赖氨酸,组氨酸,苯丙氨酸,酪氨酸,色氨酸,3-羟基脯氨酸,4-羟基脯氨酸,脯氨酸、高半胱氨酸,高胱氨酸,高丝氨酸,鸟氨酸,瓜氨酸,肌氨酸,天冬氨酸,3-氨基丙酸,茶氨酸,2-氨基丁酸,4-氨基丁酸,2-氨基-2-甲基丙酸,2-甲基-3-氨基丙酸,2,6-二氨基庚二酸,2-氨基-3-苯基丁酸,苯基甘氨酸,刀豆氨酸(canavanine),副刀豆氨酸(canaline),4-羟精氨酸,4-羟基鸟氨酸,高精氨酸,4-羟基高精氨酸,β-赖氨酸,2,4-二氨基丁酸,2,3-二氨基丙酸,2-甲基丝氨酸,3-苯基丝氨酸甜菜碱,含硫的氨基酸,如牛磺酸,半胱氨酸亚磺酸,蛋氨酸亚砜和蛋氨酸砜。在某些实施方案中,氨基酸掩蔽剂是谷氨酸或甘氨酸。
所考虑的有机酸包括但不局限于:羟基乙酸,乳酸,甲基乳酸,palycarobxlyic酸,例如苹果酸,柠檬酸,羟基丙二酸,酒石酸,琥珀酸,抗坏血酸,等等。在某些实施方案中,有机酸选自柠檬酸,苹果酸和抗坏血酸。
制剂中存在的掩蔽剂的量是足以掩蔽或隐藏吲哚受体血清素激动剂的苦味并且由此使制剂感官可接受的数量(例如,单独地或者与掩蔽组分的其它掩蔽剂组合)。
如上所述,主题制剂是口服可接受的制剂。制剂可以以许多不同形式存在,其中代表性的形式包括但不局限于舌下制剂,如锭剂(lozenges),片剂,半固体制剂如口服薄膜(oral films),凝胶(gels)和胶(gums)。在某些实施方案中,组合物是被配置成被分配到面颊(buccal)或舌下表面的组合物。适用于面颊(buccal)/舌下输送的制剂包括许多不同制剂或剂型,其包括但不限于快速融化片剂,液体-填充的胶囊,液体喷雾剂或锭剂。或者,药物组合物可以通过将组合物直接放置在口中而被输送到口腔的粘膜,例如,使用凝胶,薄膜,软膏,滴剂或者生物粘合条或片。如本文中使用的,术语“锭剂”意图包括全部剂型(包括锭剂(troches)),其中产品通过冷却含活性材料的糖基或糖醇基(例如山梨糖醇)熔融物质而形成。如本文中使用的,术语“片剂”意图包括由挤压的粉末或颗粒或挤压的膏剂制成的单位剂型。
在某些实施方案中,该组合物可以包括矫臭剂。可以用于本发明的矫臭剂包括并不局限于天然香料,天然水果香料,人造香料,人造水果香料,增香剂或其混合物。天然香料,人造香料或其混合物包括并不局限于,薄荷(例如胡椒薄荷或绿薄荷),柠檬,酸橙(lime),桔子,草莓,薄荷脑,肉桂,香子兰,人造香子兰,巧克力,人造巧克力或泡泡糖。天然水果香料,人造水果香料或其混合物包括并不局限于,樱桃,葡萄,桔子,草莓或柠檬。增香剂包括并不局限于柠檬酸。虽然矫臭剂通常以有效地提供适口香味给液体药物组合物的数量以味道掩蔽组合物的微量组分的形式提供,添加至少一种矫臭剂是优选的;并且,更优选地,可以使用至多两种矫臭剂。用于味道掩蔽组合物中的矫臭剂的范围为约0.01-约0.15克/100mL。通常使用调味料,其数量将不同,这取决于单独的香味,并且可以例如为最终组合物的约0.01%-约10%,按重量/体积计。
甜味剂的实例包括甜味料,人造甜味剂和二肽基甜味剂,例如,单糖,二糖和多糖如木糖,核糖,葡萄糖(glucose),甘露糖,半乳糖,果糖,葡萄糖(dextrose),蔗糖,糖,麦芽糖,部分水解淀粉,或者玉米糖浆固体和糖醇如山梨糖醇,木糖醇,甘露醇,糖精盐,即,糖精钠或钙盐,环己氨磺酸盐,阿糖精(acesulfam-K),甘草酸铵,甘草酸二钾(dipotassium glycyrrhizinate)和游离酸形式的糖精L-天冬氨酰苯基丙氨酸甲酯和其混合物。
当存在时,甜味剂可以以相当于约1-60%重量/体积的整个组合物的数量存在,该数量部分地取决于其它甜味剂成分是否存在和所期望的甜味水平。一般地,使用糖,其含量为约10%-约50%w/v的组合物。要理解的是可以使用甜味剂的组合。甜味剂,当使用时,还可单独使用或者彼此结合使用。当使用人造甜味增强剂时,其可以以最终组合物的约0.05%-约15%重量/体积的量存在。
制剂的某些实施方案可以包括着色剂。可用于本发明的着色剂包括颜料如二氧化钛,其可以以最多约10%重量/体积的数量合并。着色剂可以包括其它染料,其适用于食品、药物和化妆品应用,并且被称为F.D.&C.染料等。上述使用范围可接受的材料可以是水溶性的。示意性的例子包括靛属染料,被称为F.D.&C.蓝No.2,其是5,5′-靛蓝二磺酸的二钠盐。同样,被称为F.D.&C.绿No.1的染料包括三苯甲烷染料并且是4-[4-N乙基-p-磺基苄基氨基)二苯甲叉]-[1-(N-乙基-N-p-锍苄基)-2,5-环己二烯亚胺]的单钠盐。
可以使用任何适宜的制造流程来制造主题制剂。固体剂型可以通过在本领域中是众所周知的用于生产锭剂(lozenges)、片剂、锭剂(troches)、胶囊或咀嚼胶的方法制备并且可以包含这样剂型中已知的其它成分,如酸性调节剂、遮光剂,稳定剂,缓冲剂,调味剂,甜味剂,着色剂,缓冲剂,甜味剂和防腐剂。
例如,本发明的固体制剂可以通过在真空下加热锭剂原料(lozenge base)(例如,糖和液体葡萄糖的混合物)而除去过量水分制备成锭剂。剩余组分然后共混到混合物中。所得的混合物然后被引入连续的圆柱形块(cylindrical mass),从其中形成单独的锭剂。锭剂然后被冷却,进行目视检查并且包装到合适的包装中。一个形式的合适的包装是由金属如铝箔封闭的不透水的塑料材料(例如聚氯乙烯)的泡罩包装。通过施加压力给泡罩而强迫锭剂破裂并且通过金属箔密封,患者取出锭剂。在期望的情况下,乙醇可用于溶解制剂的组分。
可咀嚼固体剂量制剂可以通过用于制备可咀嚼糖果产品和咀嚼胶的方法来制备。例如,可咀嚼固体剂型可以由其中已经添加布洛芬的糖浆的挤出混合物(任选地添加泡沫稳定剂(whipping agent)、湿润剂、润滑剂、香料和着色剂)来制备。(参见:Pharmaceutical Dosage Forms:Tablets,第1卷,第二版编辑H A Lieberman,L Lachman和J BSchwartz出版于1989年)。
因而,通过主题发明提供了各种不同的口服剂量制剂。此外,口服剂量制剂不需要用于其制备的特别程序,因为它们可以容易地使用常规程序制备。例如,味道掩蔽剂、稀释剂、粘结剂或其它合适的添加剂可以被添加到吲哚血清素受体激动剂,向其中添加水或有机溶剂,如果必要的话,并且然后混合均匀以便被压实或被粒化,并且然后与润滑剂混合以便被压实。对于稀释剂,主要地使用糖和一种或多种类型的糖如白糖、棉白糖(powder sugar)、乳糖、果糖、淀粉糖浆、还原麦芽糖、D-甘露醇、D-山梨糖醇和蔗糖。对于粘结剂,使用聚乙烯基吡咯烷酮、羟丙基纤维素、羟基丙基甲基纤维素、玉米淀粉、明胶和阿拉伯胶。对于润滑剂,适当选择和使用硬脂酸镁、滑石、蔗糖脂肪酸酯等。
在某些实施方案中,制造方法的特征可在于包括生产中间组合物的第一步骤,该组合物包括活性剂和掩蔽组分,和然后从中间体组合物生产口服剂量制剂的第二步骤。
使用方法
本发明提供了将治疗数量的吲哚血清素受体激动剂输送给需要其的个体的方法。所述方法的各方面包括将口服剂量制剂给予个体。在实施本发明中,可以将剂量放入受体口中,例如由受体本身或者其看护者,于是受体将制剂保持在其口中而获得期望的益处,其中术语保持(holding)广泛使用从而包括吸入、咀嚼、保持(maintaining)等,这取决于特定类型的制剂,以便活性剂全身给药于患者。
在实施主题方法中,在给定的时间周期(例如在正被治疗的疾病状态的过程)内,制剂可以给药一次或多次,其中当在给定的时间周期内给药多种制剂时,剂量方案可以是每小时的,每日的等等。本发明的各方法包括通过面颊(buccal)或舌下途径将组合物输送给个体。
在本发明的一些方面中,所述方法包括向个体给药药物组合物,其中给药至口腔的面颊(buccal)和/或舌下粘膜表面是通过输送装置进行的。输送装置可以包括但不局限于单位剂量容器、泵喷雾器、滴管、压挤瓶、无空气的且无防腐剂的喷雾器、喷洒器(nebulizers)、剂量吸入器和加压剂量吸入器。输送装置可以被计量使用(metered)以便将精确有效剂量数量(如下所述)给药到口腔。在一些方面中,精确有效剂量数量包含在胶囊、片剂、锭剂或生物粘合片(其被直接放置在口腔内)中。
剂量可以按单剂量或多剂量给药,例如,剂量可以每日给药两次、三次、四次、直至十次,这取决于被治疗的头痛疼痛的类型和严重程度以及个体敏感性。剂量可以以持续释放制剂的形式给药,这可以允许缩宫素肽(oxytocin peptide)以较小频率给药,例如每周六次、每周五次、每周四次、每周三次、每周两次、或每周一次。
主题输送方法将,在某些实施方案中,提供治疗水平的吲哚血清素受体激动剂,例如,足够抑制、预防或降低头痛疼痛的吲哚血清素受体激动剂的水平。“治疗水平”是指在血浆或其它内部身体组织或流体(例如颅液、脑脊液)中提供头痛疼痛的降低、抑制或预防的水平。
通常,可以给药主题制剂的受体是“哺乳动物(mammals/mammalian)”,其中这些术语广泛使用以便描述在哺乳动物纲(mammalia)类中的生物,包括各目(orders:食肉动物(例如狗和猫)、啮齿目(例如小鼠、豚鼠和大鼠)和灵长目(例如人、黑猩猩和猴子)。在某些实施方案中,受体将是人。
在一些实施方案中,主题输送方法治疗头疼,例如,该方法适于头痛的顿挫治疗。在其它实施方案中,主题输送方法预防头痛发生。在一些实施方案中,主题输送方法降低或消除偏头痛的一种或多种症状。
适于使用主题输送方法治疗的个体包括遭受偏头痛的个体;和易于遭受偏头痛的个体,例如具有偏头痛历史的个体。适于使用主题输送方法治疗的个体还包括遭受反跳性头痛的个体。适于使用主题输送方法治疗的个体还包括遭受偏头痛状态的个体。个体可以被诊断为需要主题方法(使用任何适当的流程),并且通常称为在实施主题方法前需要主题方法。在某些实施方案中,方法包括诊断存在头痛并随后给药本发明的制剂来治疗头痛的步骤,例如,其中治疗是指至少在某种程度上将头痛疼痛减轻,如果没有消除头痛疼痛的话。
药剂盒(kit)
还提供了药剂盒,其中主题药剂盒至少包括一种或多种,例如多种,如上所述的感官可接受的口服剂量制剂。药剂盒中的主题制剂可以存在于包装中。药剂盒的制剂可存在于单个袋或类似容器中,以便保存制剂的组合物直到使用。
主题药剂盒还可包括关于如何使用制剂的指令,其中指令一般地包括有关如何给药制剂、剂量时间表等的介绍。指令通常记录在合适的记录介质上。例如,指令可以印刷在基材(如纸或塑料等)上。因而,指令可以存在于药剂盒中,在药剂盒或其组件(即与包装或子包装有关)等的容器的标记中作为包装内嵌物。在其它实施方案中,指令以在合适的计算机可读的存储介质例如CD-ROM、磁盘等上存在电子存储数据文件的形式存在。
提供以下实施例和对比例作为举例说明而非限制。
实施例
I.样品和制备方法
量取适当量的佐米曲坦(Zolmitriptan)、舒马普坦琥珀酸盐和苦味-掩蔽化合物以便实现表1中所示的每一种浓度。每一次量取数量被置于50ml容量瓶中并且将10ml KCl添加到该瓶中,实现50mL来制备各个样品溶液。
表1评估样品组合物
No. | 药物名称 | 药物浓度[ppm] | 掩蔽化合物 | 计算浓度[ppm] |
1 | 佐米曲坦 | 100 | - | - |
2 | 佐米曲坦 | 100 | 谷氨酸 | 200 |
3 | 佐米曲坦 | 100 | 苹果酸 | 300 |
4 | 佐米曲坦 | 100 | 柠檬酸 | 300 |
5 | 佐米曲坦 | 100 | 抗坏血酸 | 300 |
6 | 舒马普坦 | 100 | - | - |
7 | 舒马普坦 | 100 | 谷氨酸 | 200 |
制备30mM KCl+0.3mM酒石酸溶液作为参考溶液。
II.通过味觉传感器测量和数据分析
A.味觉传感器的原理
在此测试中,使用味觉传感器,SA402B(Intelligent SensorTechnology Inc.,Japan)(参见例如Myanaga等,Sensors and Materials(2002)8:455-465;and Nakamura et al.,Chem.Pharm.Bull(2002)50:1589-1593)。该设备包括具有脂质膜传感器的电极部件,机械手和计算机。电极部件由脂质膜传感器和参考电极组成。每一个传感器和参考电极之间的电位差变成输出并且该信号通过机械手送到计算机。可以根据所测量的药物选择脂质膜传感器并且在该测试中使用了六个传感器。这种设计模仿了人味觉机理,其中各种类型的感觉可以通过存在于舌的味觉细胞中的各种受体来感觉。通过制备许多类型的具有不同膜组成的脂质膜传感器,有可能获得针对不同类型的苦味(酸性苦味,来自酸性苦味的余味,碱性苦味(1),碱性苦味(2),来自涩味的余味,涩味)的传感器响应图案。当脂质膜传感器部件被浸入苦味药物的样品溶液中时,由于药物分子和脂质膜之间的静电相互机理以及药物物理吸附入脂质膜中,脂质膜电位变化,同时信号作为信息而取回。这是测量原理。
用于该测试中的脂质膜是聚氯乙烯、增塑剂和脂质的组合。每一个传感器中的脂质膜的组分示于表2中。
表2传感器脂质膜组合物和相应味道
传感器# | 脂质膜组合物 | 味道 |
1 | 十六酸,二辛基苯基-膦酸酯 | 碱性苦味1 |
2 | 磷酸二正癸基酯,二辛基苯基-膦酸酯 | 碱性苦味2 |
3 | 四月桂基溴化铵,二辛基苯基-膦酸酯 | 来自涩味的余味 |
4 | 四月桂基溴化铵,二辛基苯基-膦酸酯 | 涩味 |
5 | 四月桂基溴化铵,2-硝基苯基辛基酯 | 酸性苦味 |
6 | 四月桂基溴化铵,2-硝基苯基辛基酯 | 来自酸性苦味的余味 |
为产生特定的输出图案,在第一和第二传感器中的脂质由于磷酸酯基团具有负电荷,而第三至第六传感器中的脂质由于铵基团具有正电荷。
B.测量方法
在以下程序中测量了各个样品溶液的膜电位。
在测量样品溶液前,测量参考溶液的膜电位Vr(mV)。30mM KCl+0.3mM酒石酸溶液,其相当于人唾液,几乎无味,并且使味觉传感器的输出稳定,被用作参考溶液。接下来,测量样品溶液的膜电位Vs(mV)。在测量样品溶液的膜电位并且用参考溶液冲洗传感器后,再次测量参考溶液的膜电位Vr′(mV)。在这次测量后,用30%乙醇溶液彻底清洁传感器而使其为初始条件。
由于参考溶液相当于人唾液,来自苦味药物的样品溶液的电位差(Vs-Vr)是评估味道的值。在测量样品溶液前后的膜电位的变化(Vr′-Vr)看来是由于苦味药物附着到脂质膜所引起的。这种变化是CAP(由吸附引起的膜电位的变化)值,其代表了在口服苦味药物后保持一段时间的苦味和涩味。
C.数据分析
Weber′s原理教导了,当在两种给定的味道样品之间的浓度差是20%时,人类能够辨别味道强度。换言之,我们可以辨识当浓度差是1.2倍时的味道差别。因此,具有10倍浓度的味道差相当于1.212.6倍。
假设每个溶液的膜电位与参考溶液的膜电位相同,测量了膜电位Vs(mV),因为直到目前的经历表明0.01mM盐酸奎宁溶液的碱性苦味(1)和(2),0.001%异α-酸溶液的涩味,和0.0005鞣酸溶液的酸性苦味没有味道。此外,为每一个溶液(0.1mM盐酸奎宁溶液,0.01%异α-酸溶液,0.005%鞣酸溶液),测量了具有10-倍浓度的溶液的膜电位Vs(mV)。获得了参考溶液和具有10-倍浓度的每个溶液之间的电位差并且将其除以12.6,遵循Weber′s原理,从而是味道等级的一个分区(division)。
基于该数值,由苦味药物的样品溶液和参考溶液之间的电位差计算数值味道值。结果示于表3中。
如以上实施例和对比例所示,佐米曲坦(Zolmitriptan)的苦味由酸性苦味、涩味、碱性苦味1和碱性苦味2组成。证实佐米曲坦(Zolmitriptan)的苦味中的每种元素通过添加谷氨酸、苹果酸、柠檬酸和抗坏血酸而降低(如由表3中的下降的数值所证明的)。
同样,舒马普坦的苦味由涩味、碱性苦味1和碱性苦味2组成。证实舒马普坦的苦味中的每种元素通过添加谷氨酸而降低(如由表3中的下降的数值所证明的)。
表3苦味测量数据
酸性苦味 | 涩味 | 碱性苦味1 | 碱性苦味2 | 来自酸性苦味的余味 | 来自涩味的余味 | |
佐米曲坦 | 8.12 | 4.68 | 2.67 | 1.44 | 0.12 | -0.07 |
佐米曲坦+谷氨酸 | -2.61 | 1.86 | 0.39 | -1.36 | -1.36 | -0.03 |
佐米曲坦+苹果酸 | -2.53 | 2.94 | 0.23 | -1.85 | -1.42 | -0.05 |
佐米曲坦+柠檬酸 | -1.49 | 1.45 | 0.23 | -0.37 | 0.38 | 0.14 |
佐米曲坦+抗坏血酸 | -0.82 | 0.57 | -0.13 | -0.46 | 0.32 | 0 |
舒马普坦 | -2.96 | 0.78 | 0.35 | 2.45 | -0.84 | -0.06 |
舒马普坦+谷氨酸 | -4.71 | -0.14 | -0.22 | 0.54 | -0.88 | -0.28 |
尽管为了清楚理解,前述发明已经通过举例说明和实施例进行了详述,根据本发明的教导本领域技术人员容易显而易见的是在不背离所附权利要求的精神或范围的情况下,可以对其进行某些变化和改变。
因此,前述内容仅仅举例说明了本发明的原理。应当理解的是本领域技术人员将能设计各种配置,其虽然未明确地在本文中描述或显示,但体现了本发明的原理并且包括在其精神和范围内。此外,本文中所叙述的全部实例和条件性语言意图帮助读者理解本发明的原理和本发明人对增进技术所贡献的观念,并且被认为不对这样具体叙述的实例和条件加以限制。此外,在本文中叙述本发明的原理、方面和实施方案以及其具体实施例的全部陈述意图包括其结构和功能等价物。另外,意图这样的等价物包括现在已知的等价物和未来被开发出的等价物,即不考虑结构,实现相同功能的被开发的任何元件。本发明的范围,因此,不意图受限于本文中所示和所述的示范性实施方案。相反地,本发明的范围和精神由所附权利要求具体体现。
Claims (20)
1.吲哚血清素受体激动剂的感官可接受的口服剂量制剂,所述制剂包括:
吲哚血清素受体激动剂;和
掩蔽组分,其中所述掩蔽组分是氨基酸或有机酸。
2.根据权利要求1的制剂,其中所述掩蔽组分是氨基酸。
3.根据权利要求2的制剂,其中所述氨基酸是谷氨酸或甘氨酸。
4.根据权利要求1的制剂,其中所述掩蔽组分包括有机酸。
5.根据权利要求4的制剂,其中所述有机酸选自柠檬酸,苹果酸和抗坏血酸。
6.权利要求1的制剂,其中所述吲哚血清素受体激动剂选自舒马普坦,夫罗曲普坦,佐米曲坦,依来曲普坦,利扎曲普坦,那拉曲坦,和阿莫曲坦或其药用可接受的盐。
7.根据权利要求1的制剂,其中所述口服剂量制剂是口服薄膜,锭剂,片剂,凝胶或胶。
8.输送治疗量的吲哚血清素受体激动剂给其需要的个体的方法,该方法包括:
向所述个体给药吲哚血清素受体激动剂的感官可接受的口服剂量制剂,所述制剂包括:
吲哚血清素受体激动剂;和
掩蔽组分,其中所述掩蔽组分是氨基酸或有机酸。
9.根据权利要求8的方法,其中所述给药包括将所述制剂舌下引入到所述个体。
10.根据权利要求8的方法,其中所述掩蔽组分是氨基酸。
11.根据权利要求10的方法,其中所述氨基酸是谷氨酸或甘氨酸。
12.根据权利要求8的方法,其中所述掩蔽组分包括有机酸。
13.根据权利要求12的方法,其中所述有机酸选自柠檬酸,苹果酸和抗坏血酸。
14.权利要求8的方法,其中所述吲哚血清素受体激动剂选自舒马普坦,夫罗曲普坦,佐米曲坦,依来曲普坦,利扎曲普坦,那拉曲坦,和阿莫曲坦或其药用可接受的盐。
15.根据权利要求8的方法,其中所述口服剂量制剂是口服薄膜,锭剂,片剂,凝胶或胶。
16.根据权利要求8的方法,其中所述方法是治疗头痛的方法。
17.根据权利要求8的方法,其中所述方法是预防头痛的方法。
18.权利要求8的方法,其中该方法提供了有效抑制偏头痛疼痛的个体中的吲哚血清素受体激动剂的水平。
19.药剂盒,其包括吲哚血清素受体激动剂的感官可接受的口服剂量制剂。
20.根据权利要求19的药剂盒,其中所述口服剂量制剂是锭剂,片剂,凝胶或胶。
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US96173707P | 2007-07-23 | 2007-07-23 | |
US60/961,737 | 2007-07-23 |
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CN101652065A true CN101652065A (zh) | 2010-02-17 |
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CN200880010434A Pending CN101652065A (zh) | 2007-07-23 | 2008-07-16 | 感官可接受的吲哚血清素受体激动剂、口腔剂量制剂和使用其的方法 |
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US (1) | US20090028802A1 (zh) |
EP (1) | EP2170063A1 (zh) |
JP (1) | JP2010534660A (zh) |
KR (1) | KR20100020449A (zh) |
CN (1) | CN101652065A (zh) |
AR (1) | AR067649A1 (zh) |
AU (1) | AU2008279414A1 (zh) |
BR (1) | BRPI0809430A2 (zh) |
CA (1) | CA2680238A1 (zh) |
EA (1) | EA200901188A1 (zh) |
IL (1) | IL200676A0 (zh) |
MX (1) | MX2009010424A (zh) |
TW (1) | TW200920413A (zh) |
WO (1) | WO2009014960A1 (zh) |
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US9092411B2 (en) | 2009-08-18 | 2015-07-28 | Miosoft Corporation | Understanding data in data sets |
EP2374448A1 (en) | 2010-04-06 | 2011-10-12 | Labtec GmbH | Oral film formulation |
JP2012036167A (ja) * | 2010-07-16 | 2012-02-23 | Taisho Pharmaceutical Co Ltd | 内服液剤 |
JP5887893B2 (ja) * | 2010-12-10 | 2016-03-16 | 大正製薬株式会社 | 内服液剤 |
JP5887894B2 (ja) * | 2010-12-10 | 2016-03-16 | 大正製薬株式会社 | 内服液剤 |
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US5055461A (en) * | 1989-02-15 | 1991-10-08 | Richardson-Vicks Inc. | Anesthetic oral compositions and methods of use |
US5024997A (en) * | 1990-06-22 | 1991-06-18 | American Home Products Corporation | Palatable ibuprofen solutions |
US5807571A (en) * | 1993-05-06 | 1998-09-15 | Lts Lohmann Therapie-Systeme Gmbh | Transdermal therapeutic systems for administering indole serotonin agonists |
TW442287B (en) * | 1995-06-13 | 2001-06-23 | American Home Produits Corp | Organoleptically acceptable oral pharmaceutical composition comprising the S(+)1,8-diethyl-1-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid (Etodolac) |
GB9523833D0 (en) * | 1995-11-22 | 1996-01-24 | Boots Co Plc | Medical treatment |
US6649186B1 (en) * | 1996-09-20 | 2003-11-18 | Ethypharm | Effervescent granules and methods for their preparation |
GB9710521D0 (en) * | 1997-05-22 | 1997-07-16 | Boots Co Plc | Process |
DE19738855C2 (de) * | 1997-09-05 | 2001-01-04 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System mit haftklebender Reservoirschicht und unidirektional elastischer Rückschicht |
ATE269069T1 (de) * | 1998-04-29 | 2004-07-15 | Sumitomo Pharma | Orale zubereitung enthaltend einen biguanid und eine organische säure |
US6955819B2 (en) * | 1998-09-29 | 2005-10-18 | Zars, Inc. | Methods and apparatus for using controlled heat to regulate transdermal and controlled release delivery of fentanyl, other analgesics, and other medical substances |
US20020110581A1 (en) * | 1999-04-06 | 2002-08-15 | Ream Ronald L. | Over-coated product including consumable center and medicament |
US20050042271A1 (en) * | 1999-11-19 | 2005-02-24 | Xel Herbaceuticals, Inc . | Transdermal delivery system for alkaloids of aconitum species |
US6579878B1 (en) * | 2000-07-07 | 2003-06-17 | Targacept, Inc. | Pharmaceutical compositions and methods for use |
IT1319229B1 (it) * | 2000-10-20 | 2003-09-26 | Savio Macchine Tessili Spa | Dispositivo portarocche perfezionato per avvolgimento di filato conpressione regolata, particolarmente per ritorcitoi a doppia torsione. |
KR20040004638A (ko) * | 2001-05-25 | 2004-01-13 | 에스에스 세야쿠 가부시키 가이샤 | 의약 조성물 |
US20030013753A1 (en) * | 2001-06-05 | 2003-01-16 | Ronald Aung-Din | Transdermal migraine therapy |
JP4792193B2 (ja) * | 2002-08-28 | 2011-10-12 | 久光製薬株式会社 | 貼付剤 |
US20040253307A1 (en) * | 2003-02-04 | 2004-12-16 | Brian Hague | Sugar-free oral transmucosal solid dosage forms and uses thereof |
WO2006042249A2 (en) * | 2004-10-08 | 2006-04-20 | Neuromolecular Pharmaceuticals, Inc. | Methods and compositions for treating migraine pain |
US20060093629A1 (en) * | 2004-10-29 | 2006-05-04 | Buehler Gail K | Dye-free pharmaceutical suspensions and related methods |
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2008
- 2008-07-16 US US12/174,467 patent/US20090028802A1/en not_active Abandoned
- 2008-07-16 JP JP2010518294A patent/JP2010534660A/ja active Pending
- 2008-07-16 CA CA002680238A patent/CA2680238A1/en not_active Abandoned
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- 2008-07-16 WO PCT/US2008/070195 patent/WO2009014960A1/en active Application Filing
- 2008-07-16 KR KR1020097019780A patent/KR20100020449A/ko not_active Application Discontinuation
- 2008-07-16 EA EA200901188A patent/EA200901188A1/ru unknown
- 2008-07-16 EP EP08826651A patent/EP2170063A1/en not_active Withdrawn
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- 2008-07-22 AR ARP080103176A patent/AR067649A1/es not_active Application Discontinuation
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EA200901188A1 (ru) | 2010-04-30 |
TW200920413A (en) | 2009-05-16 |
JP2010534660A (ja) | 2010-11-11 |
IL200676A0 (en) | 2010-05-17 |
AR067649A1 (es) | 2009-10-21 |
WO2009014960A1 (en) | 2009-01-29 |
US20090028802A1 (en) | 2009-01-29 |
CA2680238A1 (en) | 2009-01-29 |
MX2009010424A (es) | 2009-10-20 |
AU2008279414A1 (en) | 2009-01-29 |
KR20100020449A (ko) | 2010-02-22 |
BRPI0809430A2 (pt) | 2014-09-09 |
EP2170063A1 (en) | 2010-04-07 |
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