CN1213752C - 变应性和炎性疾病的治疗 - Google Patents

变应性和炎性疾病的治疗 Download PDF

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CN1213752C
CN1213752C CNB018043593A CN01804359A CN1213752C CN 1213752 C CN1213752 C CN 1213752C CN B018043593 A CNB018043593 A CN B018043593A CN 01804359 A CN01804359 A CN 01804359A CN 1213752 C CN1213752 C CN 1213752C
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L·M·萨尔蒙
R·R·罗尔伯
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

本文公开了利用地洛拉他定来制备用于治疗和/或预防与人上和下气道变应性和炎性疾病有关的充血的药物，该药物包含治疗和/或预防有效量的地洛拉他定。

Description

变应性和炎性疾病的治疗
                      本发明背景
本发明涉及利用地洛拉他定(desloratadine)来制备用于治疗和/或预防与变应性和炎性疾病如变应性鼻炎有关的充血的药物。
美国专利4,659,716中公开的地洛拉他定是用于治疗动物包括人变应性反应的非镇静性抗组胺药。美国专利5,695,997中公开了包含地洛拉他定的药物组合物及其利用地洛拉他定来治疗和预防疾病如变应性鼻炎的方法。
鼻充血/不通气是患有变应性疾病如变应性鼻炎病人的长期症状。然而，现有抗组胺药对与变应性疾病有关的鼻充血/不通气的治疗尚无效。与变应性鼻炎有关的充血现已通过给予包含抗组胺药物和减充血剂伪麻黄碱的组合产品治疗。例如，Claritin D12和D24的商品是氯雷他定和伪麻黄碱的组合物并且“Allegra-D”的商品为fexofenadine和伪麻黄碱的组合物。见Physicians Desk Reference2000。
然而，给予伪麻黄碱可引起不需要的副作用。与伪麻黄碱有关的副作用包括失眠、头晕、虚弱、震颤或心律失常。这些和其他不需要的副作用可导致患有与变应性疾病有关的充血的病人逃避或中断用含有伪麻黄碱的药物治疗。
需要临床有效的含有非镇静性抗组胺药物的治疗剂，它能够治疗或预防与人气道变应性和炎性疾病有关的充血而不产生含伪麻黄碱药物可能产生的不良副作用。也就是说，需要一种可提供减充血剂作用的非镇静性抗组胺来减少其他减充血剂如伪麻黄碱的量，或消除其他减充血剂如伪麻黄碱的需要。
                      本发明概要
本发明提供治疗和/或预防与人气道变应性和炎性疾病有关的充血的方法，它包括给予所述治疗和/或预防有效量的地洛拉他定。本发明也提供一种治疗和/或预防人与季节性或长期的变应性鼻炎有关的充血的方法，它包括用所述治疗和/或预防有效量的地洛拉他定给药。本发明进一步提供一种治疗和/或预防与变应性和炎性疾病有关的充血的方法，它包括将地洛拉他定与减小量的一种或多种补充用减充血剂如伪麻黄碱一起联合给药。
                      本发明详述
短语“气道变应性和炎性疾病”是指那些在鼻至肺的上和下气道中发现的变应性和炎性疾病和症状。典型的上和下气道变应性和炎性疾病包括季节性和长期的变应性鼻炎、非变应性鼻炎、哮喘包括变应性和非变应性哮喘、窦炎和感冒。
术语“充血”是指鼻至肺的上和/或下气道梗阻、不通或阻塞，包括鼻充血。
在有效地治疗或预防与气道变应性和炎性疾病有关的充血中，地洛拉他定的量将随着病人的年龄、性别、体重和变应性和炎性疾病的严重性而不同。典型地，有效地治疗或预防所述变应性和炎性疾病的地洛拉他定量为大约2.5mg/天-大约45mg/天，优选地为大约2.5mg/天-大约20mg/天或者为大约5.0mg/天-大约15mg/天，或者大约为5.0mg/天-大约10mg/天，更优选地为大约5.0mg/天-大约7.5mg/天，并且最优选地为大约5.0mg/天，单剂量或分次剂量服用，或者5.0mg/天，单剂量服用。
美国专利4,659,716中公开了制备地洛拉他定、含它的药物组合物及其利用地洛拉他定和含它的药物组合物来治疗哺乳动物变应性反应的方法。美国专利5,595,997中公开了含地洛拉他定的药物组合物及其利用地洛拉他定来治疗和预防各种疾病，例如变应性鼻炎的方法。地洛拉他定购于Schering Corporation，kenilworth，N.J.
地洛拉他定的药物组合物可采用任何方式给药，例如口服给药，非胃肠道，例如皮下(“SC”)、肌肉内(“IM”)、静脉内(“IV”)和腹膜内(“IP”)给药，局部或阴道内给药或通过吸入(通过口腔或鼻内)给药。优选地，地洛拉他定通过口服给药。
所述药物组合物可通过将地洛拉他定或其相当量的可药用盐与适宜的惰性固体或液体可药用载体或稀释剂组合来配制。地洛拉他定可通过与相当量的可药用酸混合转化为可药用酸加成盐。典型地，适宜的可药用酸包括无机酸，例如HNO3、H2SO4、H3PO4、HCl、HBr，有机酸包括但不限制于乙酸、三氟乙酸、丙酸、乳酸、马来酸、琥珀酸、酒石酸、葡萄糖醛酸和枸橼酸以及烷基和芳基磺酸，如对甲苯磺酸、2-萘磺酸或甲磺酸。优选的可药用盐为三氟乙酸盐、甲苯磺酸盐、甲磺酸盐和氯化物。地洛拉他定游离碱比其酸加成盐更稳定并且在本发明药物组合物中使用地洛拉他定游离碱是更优选的。
固体形式的制剂包括粉剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。粉剂和片剂可以包含大约5-大约95％的活性组分。适宜的固体载体是本领域已知的，例如碳酸镁、硬脂酸镁、滑石粉、糖或乳糖。片剂、粉剂、扁囊剂和胶囊剂可以以适用于口服给药的固体剂型使用。可药用载体及其各种组合物制备方法的实例可见于A.Gennaro(ed.)，Remington’s Pharmaceutical Sciences，第18版，(1990)，Mack Publishing Co.，Easton，Pennsylvania。
液体形式的制剂包括溶液剂、悬浮液和乳剂。可提到的实例为非肠道注射用的水或水-丙二醇溶液。固体形式的制剂可以在使用前转化为口服给药的液体制剂。通过静脉内、肌肉内或皮下注射的非肠道用形式通常为无菌溶液剂形式并且可以包含滋补剂(tonicity agent)(盐或葡萄糖)和缓冲剂。不透明剂可包含在口服溶液剂、悬浮液和乳剂中。液体形式的制剂也可以包括鼻内给药的溶液剂。
适用于吸入给药的气雾剂可包括溶液剂和可以与可药用载体如惰性压缩气体，例如氮气共用的粉末形式的固体。
也包括在使用前不久转化为口服或非肠道给药用液体形式制剂的固体形式制剂。所述液体形式包括溶液、悬浮液和乳液。
本发明化合物也可以是透皮释放的。透皮组合物可采用霜剂、洗剂、气雾剂和/或乳剂形式并且可包含在基质的透皮贴中或包含在本领域常规的储器型制剂中。
另外，本发明包括地洛拉他定和其他减充血剂的组合物。由于地洛拉他定具有减充血剂作用，与其他抗组胺和减充血剂的组合物相比，所述其他减充血剂的量可减少。可与地洛拉他定组合使用的其他减充血剂包括伪麻黄碱、苯福林和苯丙醇胺。
优选地，药物组合物以单位剂量形式存在。在所述形式中，所述制剂可再分成适宜大小的、包含适宜量(例如获得所需要目的有效量)活性组分的单位剂量。
地洛拉他定特别适用于治疗和预防需要所述治疗和/或预防的病人季节性变应性鼻炎的鼻症状(不通气/充血、鼻溢、鼻痒、喷嚏)和非鼻症状(眼痒/眼灼烧、流泪/泪溢、红眼、耳痒/腭痒)，其中包括鼻充血。
已在四项双盲、随机临床试验中，通过3200例季节性变应性鼻炎患者证明了地洛拉他定的临床功效和安全性。这些临床研究的结果证明了地洛拉他定在患有季节性鼻炎的成人和青少年患者的治疗中的功效。
所有研究的功效终点为总症状得分、总鼻症状得分、总非鼻症状得分和在功效试验中的健康生活质量分析。地洛拉他定(每天一次5mg)明显降低总症状得分(关于鼻溢、喷嚏、充血/不通气、鼻痒、眼痒/眼灼烧、流泪、红眼和耳痒/腭痒的各得分总和)。在减轻鼻症状方面，地洛拉他定(5mg)明显比空白(无效对照剂)更有效(p＜O.01)。在地洛拉他定研究中所分析的一个重要功效终点是AM NOW总症状得分。该参数测定24小时后至服用第二天剂量前病人总症状的减轻。在5mg-20mg的剂量范围内，在全部24小时的给药间隔内保持统计学显著性(p＜0.05)减少。
                      实施例
通过地洛拉他定在SAR患者中进行随机、平行组、双盲、空白控制研究所收集的数据来描述地洛拉他定对鼻充血/不通气的作用。具有≥2年季节性变应性鼻炎病史的患者(12-75岁；所收集的n＝659-662/组)在登记时间每天一次接受地洛拉他定(5mg或7.5mg)或空白PO共14天。评价研究期间病人鼻充血/不通气的严重性(0＝无，1＝轻度，2＝中度，3＝严重的)。评价与基线值相比，症状严重性得分在14天内的平均改变情况。各治疗组在基线关于鼻充血/不通气的平均症状严重性得分为2.4，表示病人在接受治疗前患有中度-严重的鼻充血。地洛拉他定显著性减轻鼻充血/不通气(5mg和7.5mg下地洛拉他定分别相对空白，为P＝0.02和0.01)以及总症状严重性。
这些数据表明，与抗组胺不同，地洛拉他定具有附加效用，它显著性减轻SAR患者持久的变应性症状，如鼻充血/不通气。

Claims (4)

1.地洛拉他定在制备用于治疗和/或预防与需要治疗和/或预防人气道变应性和炎性疾病有关的充血的药物中的应用，该药物包含治疗和/或预防有效量的地洛拉他定。
2.地洛拉他定在制备用于治疗和/或预防与需要治疗和/或预防人季节性或长期变应性鼻炎有关的充血的药物中的应用，该药物包含治疗和/或预防有效量的地洛拉他定。
3.地洛拉他定在制备用于治疗和/或预防与需要治疗和/或预防人变应性和炎性疾病有关的充血的药物中的应用，该药物包含治疗和/或预防有效量的地洛拉他定和一种或多种其他减充血剂的组合。
4.权利要求3的应用，其中所述减充血剂为伪麻黄碱。
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WO2001056571A1 (en) 2001-08-09
HK1046367A1 (zh) 2003-01-10
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HUP0204048A2 (hu) 2003-03-28
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US6432972B2 (en) 2002-08-13
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