CN1400903A - 用于治疗鼻炎/结膜炎的非镇静抗组胺药物与影响白三烯活性物质的新药物并用 - Google Patents
用于治疗鼻炎/结膜炎的非镇静抗组胺药物与影响白三烯活性物质的新药物并用 Download PDFInfo
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- CN1400903A CN1400903A CN01805047A CN01805047A CN1400903A CN 1400903 A CN1400903 A CN 1400903A CN 01805047 A CN01805047 A CN 01805047A CN 01805047 A CN01805047 A CN 01805047A CN 1400903 A CN1400903 A CN 1400903A
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Abstract
本发明阐述了用于预防和治疗变应性和/或血管舒缩性鼻炎或变应性结膜炎的药学联合配方，此配方由非镇静抗组胺药物与白三烯拮抗剂或5－脂加氧酶抑制剂或FLAP拮抗剂组成，可局部应用或口服。其中非镇静抗组胺药物不包括氯雷他定类药物，白三烯拮抗剂可以是白三烯D4拮抗剂。如果合适，也可进一步加入药用载体和/或增容剂或赋形剂。
Description
本发明所属技术领域
本发明涉及一种由非镇静抗组胺药物和影响白三烯活性物质的全新合成药物，其中影响白三烯活性的物质可以是白三烯D4拮抗剂、5-脂加氧酶抑制剂或5-脂加氧酶-激活蛋白(FLAP)拮抗剂。
此种结合用于改善变应性和/或血管舒缩性鼻炎或者变应性结膜炎的局部治疗效果。
合成药物中的抗组胺药物用于迅速消除急性症状，如红、肿、或骚痒，而病症的基础-炎症可被合成药物中所含的白三烯拮抗剂成功控制。
现今，变应性疾患在世界范围内日益增加。研究表明，世界上平均7.5％的儿童和青少年患有鼻结膜炎(花粉热以及眼症候群)(《哮喘、变应性鼻结膜炎和特应性湿疹症状流行的广泛变异》(worldwide variation in prevalence of symptoms of asthma，allergicrhinoconjunctivitis and atopic eczema)：ISAAC，发表于《手术刀》(Lancet)，351，1225-1332，1998)。在西欧国家，上述疾病的流行尤为显著，大约14％(Annesi-Maesano，I.和Oryszczyn，M.P.：《(青少年鼻炎，ISAAC调查结果》(Rhinitis in adolescents，Results of theISAAC survey)，发表于Revue Francaise d’Allergologie etd’Immunologie Clinique，38，283-289，1998；Norrman，E.，L.Nystrom，E.Jonsson and N.Stjernberg：《瑞典青少年哮喘和鼻结膜炎的流行现状及发病率》(Prevalence and incidence of asthma andrhinoconjunctivitis in Swedish teenagers)，发表于《欧洲变应性疾病和临床免疫学杂志》(European Journal of Allergy and ClinicalImmunology)，53，28-35，1998)。
最近的详细研究表明，变应性鼻结膜炎从其持续的炎症反应方面来看，是一种炎症过程。迄今为止，组胺仍被认为是参与早期炎症的最重要介质、引发症状的最重要触发因子，所述症状包括局部发红、喷嚏、骚痒和高分泌状态(鼻溢，流泪)，此外，包括白三烯在内的介质也参与鼻塞、分泌和炎症进展过程(如，吸引前炎症细胞，促进细胞浸润等)。由此，治疗目的即从单纯对症治疗改为结合抗炎治疗，从而影响变应性疾患的内在炎症。组胺和白三烯(LTs)均在变态反应的早期和晚期阶段释放。
鼻结膜炎的急性症状(骚痒、红、肿、鼻溢和流泪)很容易控制，尤其是在使用常用的第一代和其二代抗组胺药物。但是，这些药物几乎对构成疾患基础、并不断进展的炎症没有疗效。通常，病人及大夫均认为变应性鼻炎(鼻结膜炎)是小病，因此未给予足够的治疗。但导致的结果是引起一种所谓的疾病阶段转换发生，如广为重视的支气管哮喘就是从危害较小的鼻炎发展而来。因此，充分、彻底治疗变应性鼻结膜炎是绝对必须的。只有这样病人才能摆脱病痛，只有这样才能预防某些情况下危害生命的疾病阶段转换。
大量动物实验和临床研究提示，在鼻分泌物中可检测到组胺和白三烯(Yamasaki，U.，T.Matsumoto，S.Fukuda，T.Natayama，H.Nagaya，Y.Ashida：《血栓素A2与组胺参与实验模型豚鼠变应性鼻炎过程》(Involvement of thromboxane A2 and histamine inexperimental allergic rhinitis of guinea pigs)，发表于《药理学与实验治疗学杂志》(J.Pharmacol.Exp.Ther.)，82：1046，1997；Pipkorn，U，G Karlsson，L Enerbeck：《人变应性鼻粘膜自然接触变应原的细胞反应》(Cellular response of the human allergic nasal mucosa tonatural allergen exposure)，发表于《变态反应临床免疫学杂志》(J.Allergy Clin.Immunol.)，35：234，1988；Volovitz，B.，S.L.Osur，M.Berstein，P.L.Ogra：《豚草属敏感儿童自然接触过程中上呼吸道粘膜白三烯C4的释放》(Leukotriene C4 release in upper respiratorymucosa during natural exposure to ragweed-sensitive children)，发表于《变态反应临床免疫学杂志》(J.Allergy Clin.Immunol.)，82：414，1988)。由于组胺H1受体的阻断，明显减轻了一些症状，如喷嚏、局部红肿、骚痒、和鼻粘膜和眼的过度分泌(鼻溢，流泪)(Simons，F.E.R.，K.J.Simons：《二代H1受体拮抗剂》(Second generationH1-receptor antagonists)，发表于《变态反应年评》(Ann.Allergy)，66：5，1991)。在所有变态反应的急性期，明显可见肥大细胞或嗜碱性粒细胞的脱颗粒和胞内储存的耗竭，这种现象并不依赖于反应部位。此过程由胞内或胞外的钙离子调控。
但是组胺并不仅仅作为诱导变应症状的介质起作用，它也可以通过影响细胞因子的释放作用于变应性炎症。一项人结膜上皮细胞(eye)的研究提示组胺明显增加I1-8和GM-CSF(粒细胞巨噬细胞集落刺激因子)的分泌。这种释放可被组胺H1受体拮抗剂所阻断，也就是说，此作用由H1受体介导(Weimer，L.K.，D.A.Gamache，J.M.Yanni：《组胺激发的人结膜上皮细胞细胞因子的分泌：组胺H1受体拮抗剂emedastine的抑制作用》(Histamine-stimulated cytokinesecretion from human conjunctival epithelial cells：inhibition byhistamine Hl-antagonist emedastine)，发表于《国际变态反应免疫学文献》(Int.Arch.Allergy Immunol.)，115：288，1998)。此外，我们知道变应性刺激不仅释放肥大细胞和嗜碱性粒细胞胞内储存的组胺，同时也使其它白三烯等介质重新开始合成。
白三烯(leukotriene)是属于花生酸类的介质，是花生四烯酸衍生物，后者是组成膜磷脂的脂肪酸之一。白三烯在5-脂加氧酶(5-LOX)作用下，由花生四烯酸生成。迄今为止，只有半胱氨酰-白三烯的病理相关作用已被确定，其中包括LT C4、LT D4和LTE4。受体结合或合成抑制均可以激发白三烯活性。除抑制5-脂加氧酶外，抑制5-脂加氧酶-激活蛋白(FLAP)也可以导致白三烯合成的减少。
众多白三烯拮抗剂中，只有少部分已经用于支气管哮喘的治疗中，如Zafirlukast、montelukast和pranlukast等。5-脂加氧酶抑制剂中，zileuton市面上已有售。名为FLAP抑制剂的药物包括如MK-591，BAY×1005，这些药物仍旧处于临床试验阶段。
大量研究已明确了白三烯在变应性疾患中的重要作用。因此，变应原激发后，可在变应性鼻炎患者早期和晚期的鼻灌洗液中检测到白三烯浓度的显著增加(Creticos，P.S.，S.P.Peters，N.F.Adkinson：《变应原刺激后豚草属敏感病人肽类白三烯释放》(Peptide leukotriene release after antigen challenge in patientssensitive to ragweed)，发表于《新英格兰医学杂志》(N.Eng.J.Med.)，310：1626，1984)。半胱氨酰-白三烯可以诱导过度分泌(鼻溢或流泪)，但是白三烯在鼻塞形成过程中的作用看来远远不仅是重要一词所能概括的。
组胺诱发的鼻塞发生于变态反应的早期，并仅持续几分钟，而白三烯引起的鼻塞可持续至变应原激发后6-8小时，在反应晚期也可观察到。与组胺不同，白三烯激发后并无喷嚏和骚痒症状(Okuda，M.，T.Watase，A.Mazewa，C.M.Liu：《白三烯D4在变应性鼻炎中的作用》(The role of leukotriene D4 in allergic rhinitis)，发表于《变态反应年评》(Ann.Allergy)，60：537，1988)。但是采用LT D4激发后，出现长时的嗜碱性粒细胞浸润现象，此细胞主要参与变应性炎症(Fujika.M.等，详见上述)。白三烯拮抗剂，如zafirlukast，可改善这些被称为晚期反应(如鼻塞)的症状(Donnelly，A.L.，M.Glass，M.C.Minkwitz，T.B.Casale：《白三烯D4受体拮抗剂ICI 204219缓解急性季节性变应性鼻炎症状》(The leukotrieneD4-receptor antagonist ICI 204219 relieves symptoms of acute seasonalallergic rhinitis)，发表于《美国呼吸疾病诊断标准与护理医学杂志》(Am.J.Resp.Crit.Care Med.)，151：1734，1995)(ICI 204219＝zafirlukast)。5-脂加氧酶抑制剂在动物实验和人体治疗中也可明显减弱变应性反应(Liu，M.C.，L.M.Dube，J.Lancaster以及zileuton研究组：《5-脂加氧酶抑制剂对哮喘病人的急性和慢性效应：为期6月的随机多中心测试》(Acute and chronic effects of a5-lipoxygenase inhibitor in asthma：a 6-month randomized multicentertrial)，发表于《变态反应临床免疫学杂志》(J.Allergy Clin.Immunol.)，98：859，1996)。
氮卓斯汀(azelastine)是现今抗组胺药物中唯一可以系统(片剂)和局部用药(鼻喷雾和眼药水)的活性物质。因此，就是变应症状非常严重的病人也可得到成功治疗。由于具有不同的制药学配方，病人可依据症状的性质和程度采用氮卓斯汀进行个体化治疗，从而抑制构成疾患基础的炎症。
在现代抗组胺药物中，氮卓斯汀是第一个在疗效剂量或浓度即可观察到对白三烯合成的抑制作用，而白三烯则是参与变应性炎症反应的非常重要的介质(Achterrath-Tuckermann，U.，Th.Simmet，W.Luck，I.Szelenyi，B.A.Peskar：《氮卓斯汀对半胱氨酰-白三烯合成的抑制作用及其生物学重要性》(Inhibition of cysteinyl-leukotrieneproduction by azelastine and its biological significance)，发表于《介质及其作用》(Agents and actions)，24：217，1988)。氮卓斯汀的这种抗白三烯效应也可见于变态反应临床对照研究中(Shin，M.H.，F.M.Baroody，D.Proud，A.Kagey-Sobotka，L.M.Lichtenstein，M.Naclerio：《氮卓斯汀对早期变态反应的作用效应》(The effect ofazelastine on the early allergic response)，发表于《临床实验变态反应学》(Clin.Exp.Allergy)，22：289，1992)。因此，与布地奈德(budesonide)(一种糖皮质激素)相比，氮卓斯汀的临床功效，可以得到解释(Wang，D.Y.，J.Smitz，M.De Waele，P.Clement：《花粉季节遗传特应性病人鼻粘膜经变应原刺激后，局部应用布地奈德和氮卓斯汀对鼻部症状、嗜酸性细胞计数和介质释放的效应》(Effectof topical applications of budesonide and azelastine on nasal symptoms，eosinophil counts and mediator release in atopic patients after nasalallergen challenge during the pollen season)，发表于《国际变态反应免疫学文献》(Int.Arch.Allergy Immunol.)，114：185，1997；Gastpar，H.，R.Aurich，U.Petzold：《常年性鼻炎的鼻内治疗：氮卓斯汀鼻喷雾剂和布地奈德鼻汽雾剂的比较》(Intranasal treatment of perennialrhinitis：Comparison of azelastine nasal spray and budesonide nasalaerosol)，发表于《Arzn.Forsch.-药物研究》(Arzn.Forsch.-DrugRes.)，43：475，1993)。
氮卓斯汀抑制白三烯合成和释放的作用机制很独特，与其它抗组胺药物不同。我们知道，许多释放过程通过细胞内Ca2+水平的升高实现，而胞内Ca2+水平的升高是由于变应性刺激作用于效应细胞所产生，因为胞内Ca2+触发白三烯合成和释放增加的决定性步骤。氮卓斯汀抑制胞内Ca2+释放(Takanaka，K.：《氮卓斯汀对多形核白细胞的效应：花生四烯酸盐级联放大抑制机制》(Effects ofazelastine on polymorphonuclear leukocytes：arachidonate cascadeinhibition mechanism)，发表于《医学进展》(Progress Med.)，275，1987；Chand，N.等：《氮卓斯汀对变应性和非变应性白三烯合成和组胺分泌的抑制作用：作用机制的推理》(Inhibition of allergic andnon-allergic leukotriene formation and histamine secretion byazelastine：Implication for its mechanism of action)，发表于《国际变态反应免疫学文献-增刊》(Int.Arch.Allergy Appl.Immunol.)，90：67，1989；Senn，N.等：《氮卓斯汀对培养呼吸道平滑肌细胞胞内Ca2+的作用》(Action of azelastine on intracellular Ca2+ in culturedairway smooth muscle)，发表于《欧洲药理学杂志》(Eur.J.Pharmacol.)，205：29，1991；Chand，N.，R.D.Sofia：《全新的体内白三烯生物合成抑制剂：作用的可能机制-微型综述》(A novel invivo inhibitor of leukotriene biosynthesis：A possible mechanism ofaction：A mini review)，发表于《哮喘杂志》(J.Asthm.)，32：227，1995)。
白三烯受体拮抗剂的作用机制比较“简单”。作为受体拮抗剂，这些物质与受体结合，因此，释放的白三烯可以到达相应受体部位并发挥作用。此作用由受体介导。
鼻内联合用药已于EP 0 780 127 AL中叙述，并推荐用于变应性鼻结膜炎的治疗，其中联合应用的药物包括一种具有白三烯抑制特性的抗组胺物质和一种糖皮质类固醇，如果需要，也可加入减充血剂、抗变态反应剂、粘液溶解剂(mucolytics)、非阿片类镇痛剂(nonopioid analgesics)、脂加氧酶抑制剂、和白三烯受体拮抗剂。抗组胺药物和糖皮质激素的联合作用可提高疗效。
在鼻炎的局部治疗方面，WO 98/48839也叙述了抗炎物质以皮质类固醇的形式、并与其它物质共同作用以提高疗效的应用，例如，至少一种血管收缩剂、一种白三烯抑制剂、一种抗组胺药物、一种抗变态反应物质、一种粘液溶解剂、一种麻醉剂、一种抗胆碱能药物、或一种神经氨酸苷酶抑制剂。
正如WO 98/3461l中所叙述的，对于变应性哮喘的局部治疗，推荐联合用药，包括descarboethoxyloratidine(非镇静抗组胺药物氯雷他定(loratadine)的代谢产物)和白三烯拮抗剂，其中白三烯拮抗剂可以是白三烯D4拮抗剂、5-脂加氧酶抑制剂、或FLAP拮抗剂。Descarboethoxyloratadine的使用应当避免氯雷他定和其它非镇静抗组胺药物的各种副作用。
A.Roquet等：《哮喘患者白三烯和组胺的联合拮抗产生变应原激发的早期和晚期呼吸道阻塞的明显抑制》(Combinedantagonism of leukotrienes and histamine produces predominantinhibition of allergen-induced early and late phase airway obstruction inasthmatics)，发表于《美国呼吸疾病诊断标准与护理医学杂志》(Am.J.Respir.Crit.Care Med.)，1997，155；1856-1863，研究了变应原激发的哮喘病人口服氯雷他定、白三烯拮抗剂zafirlukast以及二者联合应用的作用机制。
根据Merck & Co.，WO 97/28797的研究，推荐氯雷他定与5种选定的白三烯拮抗剂联合应用，口服或胃肠外应用治疗哮喘、变态反应、和炎症。其中5种白三烯拮抗剂是monetlukast、zafirlukast、pranlukast、1-(((右旋)-3-(2-6，7-双氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)-苯基)硫代)甲基)环丙烷醋酸钠、1-(((1(右旋)-3-(2-(2，3-二氯噻吩并[3，2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)-丙基)硫代)甲基)环丙烷醋酸。
对于变应性鼻炎/结膜炎的治疗而言，由于所介绍药剂的副作用太大，成功治疗病例的缺乏以及一些情况下的非特异性治疗，亟待有效、安全的联合配方的问世。
由此本发明以研究发现为基础，研制了用于治疗变应性鼻炎/结膜炎的全新联合配方。
对本发明的描述
本发明涉及药学物质联合配方局部应用或口服治疗变应性和/或血管舒缩性鼻炎或变应性结模炎的药物方案，其中药学物质包括疗效剂量的非镇静抗组胺药物与影响白三烯活性的白三烯D4拮抗剂、或5-脂加氧酶抑制剂、或者FLAP拮抗剂联合应用，如果合适，也可进一步加入药用载体和/或增容剂或赋形剂。其中非镇静抗组胺药物除氯雷他定类药物外，优选氮卓斯汀、但也可用如左卡巴斯汀(levocabastine)、西替利嗪(cetirizine)、fexofenadine、mizolastine、阿司咪唑(astemizole)等。白三烯D4拮抗剂包括montelukast、zafirlukast、或pranlukast等，5-脂加氧酶包括如zileuton、吡前列素(piripost)、或AWD 23-115(1-[4-(喹啉-2-基-甲氧基)苄基]-5-甲氧基-1H-吲唑-3-酚二氢氯化物)等，FLAP拮抗剂包括如MK-591、MK-886、Bay×1005等。
本发明进一步涉及预防和治疗哺乳动物变应性和/或血管舒缩性鼻炎或变应性结膜炎的一种治疗方案。这种治疗方案是局部或口服应用疗效剂量的非镇静抗组胺药物与影响白三烯活性的白三烯D4拮抗剂、或5-脂加氧酶抑制剂、或者FLAP拮抗剂联合配方。其中非镇静抗组胺药物除氯雷他定类药物外，优选氮卓斯汀、但也可用如左卡巴斯汀、西替利嗪、fexofenadine、mizolastine、阿司咪唑等。白三烯D4拮抗剂包括montelukast、zafirlukast、或pranlukast等，5-脂加氧酶包括如zileuton、吡前列素、或AWD 23-115，FLAP拮抗剂包括如MK-591、MK-886、Bay×1005等。可同时、依次、或独立服用上述药物。
本发明进一步涉及非镇静性抗组胺药物与影响白三烯活性的白三烯D4拮抗剂、或5-脂加氧酶抑制剂、或者FLAP拮抗剂联合配方的适宜个体化剂量剂型方案。其中非镇静抗组胺药物除氯雷他定类药物外，优选氮卓斯汀、但也可用如左卡巴斯汀、西替利嗪、fexofenadine、mizolastine、阿司咪唑等。白三烯D4拮抗剂包括montelukast、zafirlukast、或pranlukast等，5-脂加氧酶包括如zileuton、吡前列素、或AWD 23-115，FLAP拮抗剂包括如MK-591、MK-886、Bay×1005等。这种联合配方可局部应用或口服，如喷雾、药水、或片剂。
抗组胺药物与本发明进一步涉及非镇静性抗组胺药物与影响白三烯活性的白三烯D4拮抗剂、或5-脂加氧酶抑制剂、或者FLAP拮抗剂联合应用的全新配方，也可制成药用盐剂型。根据本发明所述，不同药用盐作为联合配方或单体物质可以同时、依次、或独立应用于局部(鼻内或眼内)或口服。其中非镇静抗组胺药物除氯雷他定类药物外，优选氮卓斯汀、但也可用如左卡巴斯汀、西替利嗪、fexofenadine、mizolastine、阿司咪唑等。白三烯D4拮抗剂包括montelukast、zafirlukast、或pranlukast等，5-脂加氧酶包括如zileuton、吡前列素、或AWD 23-115，FLAP拮抗剂包括如MK-591、MK-886、或Bay×1005等。
如果提供有单独的药物制剂，那么这些药物制剂均经过调整以互相匹配，并包含各自活性成分，其剂量与相应质量比值与联合配方中相同。
由于采用的联合配方，药物不仅会起效快，而且疗效高。此时伴有强大的抗炎效应，其原因在于上述活性成分的作用模式互补，药物动力学行为也相似。长时作用使得一日两次用药成为可能。如果采用固定配方中含有这些活性成分，因为两类活性成分包含于一粒药片或胶囊中，病人服用则更简单一些。
根据本发明，抗组胺成分的浓度可以在0.001％-0.5％范围内。
联合配方中白三烯拮抗剂的浓度可以在0.01％-5％范围内。
抗组胺成分的优选浓度为0.05％-0.2％，白三烯拮抗剂的优选浓度为0.5％-2％。
采用优选剂量，可一日用药一次至两次。抗组胺药物局部应用的个体剂量为50-500μg，优选200-400μg。白三烯D4拮抗剂局部应用的剂量为100-2000μg，优选200-1000μg。
5-脂加氧酶或FLAP抑制剂的剂量为50-2000μg，优选200-1000μg。
抗组胺药物(如氮卓斯汀)的剂量是每日0.5-16mg，优选每日2-8mg。
对于白三烯D4拮抗剂(如montelukast)，个体剂量为每日1-50mg，优选每日5-10mg。
5-脂加氧酶抑制剂(如zileuton)的口服剂量为每日1-6g，优选每日0.6-2g。
FLAP抑制剂的剂量是每日50-2000mg，优选每日100-500mg。
上述抗组胺药物和白三烯拮抗剂化合物和制备程序已经清楚。
化合物的联合配方是根据传统的标准药学方法制备的，优选分别或同时混合抗组胺药物和白三烯拮抗剂，如果合适，也可加入药用载体和/或增容剂或赋形剂，从而将所得的混合物制成适宜服用的剂型。
活性成分以混合物的形式口服或局部应用，其中，为达药用目的，混合物包括传统药学增容剂、赋形剂、或载体。
口服或局部用药的混合物配方的药用剂型可略有不同，如鼻喷雾、鼻药水、眼药水、片剂、胶囊、或颗粒。
根据本发明，除活性成分外，混合物可进一步包括各种典型的药学形式成分，如抗微生物防腐剂、渗透剂、增稠剂、调节pH值的赋形剂、或缓冲体系。
抗微生物防腐剂包括如洁尔灭(benzalkonium)、氯化/溴化十六烷基吡啶、氯代丁醇、醋酸洗必太(chlorhexidine acetate)、盐酸洗必太、二葡糖酸酯(digluconate)洗必太、氯甲酚、羟苯甲酸甲酯、对羟苯甲酸丙酯、苯氧基乙醇、苯基汞盐、山梨酸、硫柳汞。
为防腐起见，优选应用乙二胺四乙酸钠(依地酸钠)和洁尔灭的结合。其中乙二胺四乙酸钠浓度为0.05-0.1％，洁尔灭浓度为0.005-0.05％。
对于调节张力或渗透压的适宜赋形剂，氯化钠、氯化钾、甘露糖醇、葡萄糖、山梨醇、甘油、或丙二醇均可选用，浓度约为0.1-10％。
混合物配方常常包括增稠剂，以提高粘稠度并延长、改善药物和机体的接触作用。这些增稠剂包括甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧基甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、聚丙烯酸酯、聚丙烯酰胺、葡聚糖、胶凝树胶、聚羟亚烃(poloxamer)、或醋酞纤维素(cellulose acetate phthalate)。
此外，根据本发明，混合物还包括药用缓冲体系，从而调节pH值使其处于大约4-8范围内，优选5.5-7.5。缓冲液可以是柠檬酸盐、磷酸盐、氨丁三醇(tromethamine)、甘氨酸、硼酸盐、和醋酸盐。
这些缓冲液也可以从其它物质衍生而来，如柠檬酸、伯磷酸钠或仲磷酸钠(primary or secondary sodium phosphate)、甘氨酸、硼酸、四硼酸钠、醋酸、和醋酸钠。而且，进一步的赋形剂如盐酸或氢氧化钠也可用于调节pH值。
以下将引述一些实施例详细阐述本发明。实施例1
含有盐酸氮卓斯汀(0.1％)的鼻喷雾或鼻药水：
配方制备：
| 盐酸氮卓斯汀 | 0.1000g |
| 羟丙基甲基纤维素 | 0.1000g |
| 乙二胺四乙酸钠 | 0.0500g |
| 洁尔灭 | 0.0125g |
| 氢氧化钠 | q.s.ph 6.0 |
| 山梨醇溶液70％ | 6.6666g |
| 纯水 | 加至100ml |
将约45kg纯水倒入适宜搅拌容器中，依次加入羟丙基甲基纤维素、乙二胺四乙酸钠、洁尔灭、和山梨醇溶液并搅拌，使其溶解。然后用纯水将体积加到49.5升，用1N氢氧化钠溶液调节pH至6.0。再次用纯水将溶液体积加到50升并搅拌混匀。最后采用孔径为0.2μm的膜滤器过滤所得溶液。此时，所得悬浮液就可以分装到小药瓶中。
实施例2：含有montelukast(1％)的鼻喷雾或鼻药水
配方制备：
| Montelukast | 1.0000g |
| 微晶纤维素(Avicel)RC 591 | 1.1000g |
| 多乙氧基醚 | 0.1000g |
| 山梨醇溶液70％ | 6.0000g |
| 乙二胺四乙酸钠 | 0.0500g |
| 洁尔灭 | 0.0200g |
| 纯水 | 加至100ml |
将45kg纯水倒入带有混匀器的适宜搅拌容器中，并以高速旋转混匀微晶纤维素RC 591。然后，依次溶解多乙氧基醚、山梨醇溶液、乙二胺四乙酸钠、和洁尔灭并搅拌。
随后，加入活性成分montelukast，快速搅拌混匀，直至产生均匀的悬浮液。再用纯水将体积加到50升，并进一步混匀。最后抽空悬浮液以除去产生的气泡。
此时，所得悬浮液就可以分装到小药瓶中。
实施例3含有盐酸氮卓斯汀(0.1％，已溶解)和montelukast(1％，悬浮)的鼻喷雾或鼻药水
配方制备：
| Montelukast | 1.0000g |
| 盐酸氮卓斯汀 | 0.1000g |
| 微晶纤维素RC 591 | 1.1000g |
| 多乙氧基醚 | 0.1000g |
| 山梨醇溶液70％ | 6.0000g |
| 乙二胺四乙酸钠 | 0.0500g |
| 洁尔灭 | 0.0200g |
| 纯水 | 加至100ml |
将45kg纯水倒入带有混匀器的适宜搅拌容器中，并以高速旋转混匀微晶纤维素RC 591。然后，依次溶解活性成分盐酸氮卓斯汀、赋形剂多乙氧基醚、山梨醇溶液、乙二胺四乙酸钠、和洁尔灭并搅拌。
随后，加入活性成分montelukast，快速搅拌混匀，直至产生均匀的悬浮液。再用纯水将体积加到50升，并进一步混匀。最后抽空悬浮液以除去产生的气泡。
此时，所得悬浮液就可以分装到小药瓶中。
根据一些抗组胺药物以及白三烯拮抗剂、或5-脂加氧酶和FLAP抑制剂的效应谱，可见两种物质的联合配方对变应性鼻结膜炎症状的治疗具有协同功效。
下述药理学研究阐述了氮卓斯汀和montelukast单独或联合应用，对棕色挪威鼠鼻炎模型的作用。腹腔内注射卵清蛋白和氢氧化铝溶于生理盐水所制成的悬浮液，连续两天共注射2次，以使棕色挪威鼠敏化。敏化后3周，在硫喷妥钠麻醉下将一导管顺行固定于动物气管内以维持呼吸。另取一导管通过气管逆行前进至鼻内孔并固定，用于鼻腔灌洗。这样，鼻腔灌洗液可以由鼻腔一滴一滴地流出，被分段收集器收集。测试物质或悬浮于Tylose(montelukast)，或溶解于生理盐水(氮卓斯汀)，在变应原激发前60分钟腹腔内注射。为了从鼻中除去粘液，选用PBS通过滚子泵鼻腔灌洗30分钟(灌洗率0.5ml/min)。局部应用情况下，将所测试物质以摩尔浓度计算加入灌洗液，在变应原激发之前用此溶液通过鼻腔灌洗30分钟。然后将血浆标记物伊文思蓝(每只动物1ml的1％的PBS溶液)注射入颈静脉，收集灌洗液15分钟。之后给予挪威鼠卵清蛋白PBS溶液(卵白蛋白10mg/ml溶于PBS中)的变应原以激发变态反应，即以此溶液进行鼻腔灌洗60分钟。在此过程中用分段收集器以15分钟为一段收集灌洗液。样本/动物的总量为5。离心样本，经离心后涂于微量滴定板上，采用Digiscan光度计在620nm波长下测定其浓度，之后自动减去空白值。60分钟之后的作用时程采用AUC程序计算。制备组物质的效应由与载体对照的比值来计算。
测定变应原激发后细胞膜通透性的增加作为信使分子释放的指标，其中信使分子包括组胺和白三烯。机体接触变应原后，即使是过敏性人群也会出现此现象，表现为液体分泌增加和鼻腔堵塞。表1：单独或联合应用氮卓斯汀和montelukast对自由活动、敏化以及局部变应原激发的棕色挪威鼠鼻腔粘膜通透性的作用
| 药物 | 剂量(mg/kg，腹腔内注射) | 抑制作用，以％表示 |
| 氮卓斯汀 | 0.01 | 11 |
| 0.1 | 39 | |
| 0.3 | 42 | |
| 1 | 47 | |
| montelukast | 0.1 | 7 |
| 1 | 26 | |
| 3 | 39 | |
| 10 | 44 | |
| 30 | 58 | |
| 氮卓斯汀+montelukast | 0.01+0.1 | 40* |
*p＜0.05
腹腔内单独注射氮卓斯汀0.01mg/kg引起11％的血管通透性的轻微抑制。Montelukast也同样，0.1mg/kg 剂量腹腔注射引起7％的抑制。而腹腔注射0.01mg/kg氮卓斯汀和0.1mg/kg montelukast则产生对粘液浆液溢出物的40％的超加性抑制作用(p＜0.05)。
剂量为0.1mg/kg的FLAP抑制剂BAY×1005(腹腔内注射)可产生31％的鼻粘膜通透性抑制效应。腹腔内注射0.03-10mg/kg剂量范围内的5-脂加氧酶抑制剂AWD 23-115可产生剂量依赖的血管通透性抑制作用(37-54％)。
表2：单独或联合应用氮卓斯汀和AWD 23-115(局部应用灌洗液)对自由活动、敏化以及局部变应原激发的棕色挪威鼠鼻腔粘膜通透性的作用
| 药物 | 剂量(μmol/l) | 抑制作用，以％表示 |
| 氮卓斯汀 | 0.003 | 3 |
| 0.01 | 40 | |
| 0.03 | 60 | |
| AWD 23-115 | 0.1 | 12 |
| 0.3 | 32 | |
| 1 | 49 | |
| 氮卓斯汀+AWD 23-115 | 0.003+0.1 | 31* |
*p＜0.05
局部应用情况下，组胺H1阻断剂氮卓斯汀具有强大的粘液浆液溢出物抑制作用，甚至在0.003-0.03μmol/l的剂量范围内。5-脂加氧酶抑制剂AWD 23-115在0.3和1μmol/l的浓度以剂量依赖的方式产生血管通透性的抑制作用，其抑制程度分别为32％和49％。
如果剂量为0.003μmol/l的氮卓斯汀与AWD 23-115(0.1μmol/l)联合应用，对粘液溢出物的抑制作用可达31％(p＜0.05)。
Claims (20)
1.用于治疗变应性和/或血管舒缩性鼻炎或变应性结膜炎的适于以单个剂量局部用药或口服的药学制剂，包括单独或联合的如下成分：
a)有效剂量的非镇静抗组胺药物或其药用盐，不含氯雷他定类化合物；
b)有效剂量的白三烯拮抗剂或其药用盐，可从下述物质中选择：
b1)白三烯D4拮抗剂，或
b2)5-脂加氧酶抑制剂，或
b3)FLAP拮抗剂，
c)常用的药用载体和/或增容剂或赋形剂。
2.根据权利要求1所述的药学制剂，其中所述非镇静抗组胺药物包括氮卓斯汀，也包括左卡巴斯汀、西替利嗪、fexofenadine、mizolastine、阿司咪唑。
3.根据权利要求1所述的药学制剂，其中所述白三烯D4拮抗剂包括montelukast、zafirlukast、或pranlukast。
4.根据权利要求1所述的药学制剂，其中所述5-脂加氧酶抑制剂包括zileuton、吡前列素、或AWD 23-115。
5.根据权利要求1所述的药学制剂，其中所述FLAP拮抗剂包括MK-591、MK-886、或Bay×1005。
6.根据权利要求1和2所述的药学制剂，其中含有0.001％-0.5％的所述抗组胺成分。
7.根据权利要求1和3所述的药学制剂，其中含有0.01％-5％的所述白三烯D4拮抗剂成分。
8.根据权利要求1和4所述的药学制剂，其中含有0.01％-5％的所述5-脂加氧酶抑制剂成分。
9.根据权利要求1和5所述的药学制剂，其中含有0.01％-5％的所述FLAP拮抗剂成分。
10.根据权利要求1至8所述的药学制剂，其形式为局部用药。
11.根据权利要求1至8所述的药学制剂，其形式为口服。
12.根据权利要求1至8和10所述的药学制剂，其形式为局部用喷雾剂。
13.根据权利要求1至8和10所述的药学制剂，其形式为局部用鼻药水或眼药水。
14.药学联合配方的应用，包括如下成分：
a)有效剂量的非镇静抗组胺药物或其药用盐，不含氯雷他定类化合物；
b)有效剂量的白三烯拮抗剂或其药用盐，可从下述物质中选择：
b1)白三烯D4拮抗剂，或
b2)5-脂加氧酶抑制剂，或
b3)FLAP拮抗剂，以及
c)常用药用载体和/或增容剂或赋形剂，
从而合成同时、依次、或分别应用的，用于预防和治疗变应性和/或血管舒缩性鼻炎或变应性结膜炎的药剂，此药剂可局部用药或口服用药。
15.根据权利要求14所述的药学联合配方的应用，其中所述非镇静抗组胺药物包括氮卓斯汀，也包括左卡巴斯汀、西替利嗪、fexofenadine、mizolastine、阿司咪唑，从而合成局部应用或口服、用于预防和治疗变应性和/或血管舒缩性鼻炎或变应性结膜炎的药剂。
16.根据权利要求14所述的药学物质的联合应用，其中所述
-白三烯D4拮抗剂包括zafirlukast、montelukast、或pranlukast，
-5-脂加氧酶抑制剂包括zileuton、吡前列素、或AWD23-115，
-FLAP拮抗剂包括MK-591、MK-886、或Bay×1005
从而合成局部应用或口服、用于预防和治疗变应性和/或血管舒缩性鼻炎或变应性结膜炎的药剂。
17.局部应用或口服的药剂，具有抗变应性，用于预防和治疗变应性和/或血管舒缩性鼻炎或变应性结膜炎的作用，其成分包括如下物质的固定和自由结合：
a)有效剂量的非镇静抗组胺药物或其药用盐，不含氯雷他定类化合物，
b)有效剂量的白三烯拮抗剂或其药用盐，可从下述物质中选择：
b1)白三烯D4拮抗剂或
b2)5-脂加氧酶抑制剂或
b3)FLAP拮抗剂，以及
c)如果合适，常用的药用载体和/或增容剂或赋形剂。
18.根据权利要求17所述的药剂，其中所述非镇静抗组胺药物包括氮卓斯汀，也包括左卡巴斯汀、西替利嗪、fexofenadine、mizolastine、阿司咪唑。
19.根据权利要求17所述的药剂，其中所述
-白三烯D4拮抗剂包括zafirlukast、montelukast、或pranlukast，
-5-脂加氧酶抑制剂包括zileuton、吡前列素、或AWD23-115，
-FLAP拮抗剂包括MK-591、MK-886、或Bay×1005。
20.根据权利要求1至13和17至19所述的药剂的合成过程，其特征在于所述抗组胺药物和所述白三烯拮抗剂可单独或一起加工，如果合适，还可加入载体和/或增容剂、或赋形剂，这样所得混合物就可转换为适宜的应用剂型。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10007203.8 | 2000-02-17 | ||
| DE10007203A DE10007203A1 (de) | 2000-02-17 | 2000-02-17 | Neue Kombination nichtsedierender Antihistaminika mit Substanzen, die die Leukotrienwirkung beeinflussen, zur Behandlung der Rhinitis/Konjunktivitis |
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| CN1241569C CN1241569C (zh) | 2006-02-15 |
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| US (1) | US6436924B2 (zh) |
| EP (1) | EP1265615B1 (zh) |
| JP (1) | JP5529362B2 (zh) |
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| CN (1) | CN1241569C (zh) |
| AR (1) | AR027528A1 (zh) |
| AT (1) | ATE287266T1 (zh) |
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| BR (1) | BR0108445A (zh) |
| CZ (1) | CZ296395B6 (zh) |
| DE (2) | DE10007203A1 (zh) |
| DK (1) | DK1265615T3 (zh) |
| ES (1) | ES2236189T3 (zh) |
| HK (1) | HK1053792A1 (zh) |
| HU (1) | HU228927B1 (zh) |
| IL (2) | IL151106A0 (zh) |
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| NO (1) | NO328153B1 (zh) |
| NZ (1) | NZ520470A (zh) |
| PL (1) | PL198357B1 (zh) |
| PT (1) | PT1265615E (zh) |
| RU (1) | RU2292208C2 (zh) |
| SK (1) | SK285990B6 (zh) |
| TW (1) | TWI296525B (zh) |
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| CN110721189A (zh) * | 2019-11-19 | 2020-01-24 | 贵州云峰药业有限公司 | 一种皮肤消毒剂 |
| CN116284470A (zh) * | 2023-02-15 | 2023-06-23 | 广西中医药大学 | 一种海蛇尾多糖硫酸酯衍生物的制备方法及应用 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110721189A (zh) * | 2019-11-19 | 2020-01-24 | 贵州云峰药业有限公司 | 一种皮肤消毒剂 |
| CN116284470A (zh) * | 2023-02-15 | 2023-06-23 | 广西中医药大学 | 一种海蛇尾多糖硫酸酯衍生物的制备方法及应用 |
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