CN1748685A - 治疗鼻息肉和鼻息肉病的奥苯达唑鼻腔凝胶剂 - Google Patents
治疗鼻息肉和鼻息肉病的奥苯达唑鼻腔凝胶剂 Download PDFInfo
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Abstract
本发明涉及使用奥苯达唑制备鼻腔凝胶剂，并用奥苯达唑的鼻腔凝胶剂治疗鼻息肉和鼻息肉病，还用于在手术治疗、激光治疗等手段治疗鼻息肉后防止鼻息肉复发。
Description
本发明涉及治疗鼻腔息肉的奥苯达唑滴鼻剂、奥苯达唑鼻腔喷雾剂和奥苯达唑鼻腔气雾剂以及它们的应用。
鼻息肉是一种常见病，成年人的发病率在1％-2％左右。根据临床观察，有内源性支气管哮喘的病人鼻息肉的发病率为30％，有阿司匹林不耐受(支气管型)的病人息肉发病率高达50％。鼻息肉的病因迄今不明，计有感染、变态反应、创伤、化学刺激、代谢性疾病、精神因素等学说。
鼻息肉的治疗比较困难，手术治疗易复发，复发率高达15％-20％。其药物治疗通常采用各种类固醇药物，但采用类固醇药物后，会引起对类固醇药物的依赖性。这些原因使得鼻息肉的研究与治疗日益受到重视，发现新的治疗鼻息肉的药物，使之有效，同时不产生依赖性，成为人们关注的焦点。
一、鼻息肉的发病原因：
从组织病理学来说，鼻息肉是鼻腔或鼻窦内灰白色、阻塞性块状组织，含有水肿的液体，起源于鼻腔的完整表层上皮，多为两侧和多发性。组织学分类80％-90％为嗜酸细胞性息肉，是以嗜酸细胞增多为特征的炎性细胞浸润，其它的炎性细胞有肥大细胞、巨嗜细胞、浆细胞和淋巴细胞等。合并支气管哮喘和阿司匹林敏感的鼻息肉属于嗜酸细胞性。在合并纤维囊性变、Kartagener’s综合症(纤毛运动障碍)以及上颌窦后鼻孔息肉是以嗜中性粒细胞增多为特征。
根据临床与病理表现分析，变态反应可能是鼻息肉的病因。鼻息肉的形成是由于多种原因或未知原因的刺激导致鼻粘膜表层损伤、上皮脱落，使成纤维细胞增殖并分泌细胞因子，促进肥大细胞分化和生长，肥大细胞在非特异性因素刺激下发生脱颗粒反映，引起炎性介质的释放和嗜酸细胞浸润，组织胺、LTC4、LTB4等介质增多，造成渗出和水肿；嗜酸细胞释放的MBP、ECP等破坏鼻粘膜血管的神经，使血管通透性增加，进一步加重了炎症反应。由于持续的炎症反应，形成息肉。
另一方面，由于鼻腔粘膜炎性细胞浸润、水肿，压力增加，造成上皮破裂，固有层从缺损处突出，周围的粘膜延续生长，脱出的组织表层上皮细胞化生，形成息肉蒂部，血管长入，并建立血管蒂，腺体被拉长，长入息肉中，形长管状腺体，在炎性反应和重力的作用下，息肉不断增大。
二、鼻息肉的治疗现状：
鼻息肉的现代治疗主张采用糖皮质激素与手术治疗相结合的方法。
(一)手术治疗原则
对于小的单发息肉摘除较为简单，对于多发的和复发的息肉应采用较广泛的手术，目前采用的功能性鼻内窥镜手术(FES)较为测定，可将每个暴露的筛房清除干净。对于多次复发的息肉，主张进行广泛的筛窦和部分蝶窦切除术。也可选择性地采用YAG激光切除鼻息肉，出血少，病人痛苦轻，但不适用与严重的顽固性鼻息肉患者。
对伴有支气管哮喘和阿司匹林敏感的患者也主张行彻底的鼻息肉切除术，手术不仅不会引起和加重哮喘，而且由于手术清除了鼻腔和鼻窦的病灶，恢复了正常的鼻通气功能而使哮喘病情明显好转。但是合并哮喘的病人手术后复发率较高，而且手术不能改变病人对阿司匹林的敏感性和气道的高反应性，因此手术后应进行糖皮质激素治疗。
(二)糖皮质激素治疗
近年来，大量的资料证明糖皮质激素在鼻息肉的治疗中有显著的疗效。因为鼻息肉是鼻腔的持续性炎症性疾病，任何彻底的手术均不能将鼻患肉的病因清除，只有采用糖皮质激素和手术联合治疗，才能延缓和防止息肉的复发。
目前采取的治疗原则是，对于初发的较小的息肉，单纯采用鼻内喷入糖皮质激素治疗，便可使息肉缩小或消失；对于较大的息肉，可加用口服、肌注或下鼻甲粘膜下注射等全身用药，采用鼻内局部喷药作维持治疗，可使部分病人免除手术治疗；对严重的病例，应在接受糖皮质激素治疗后手术，并于手术后坚持一年以上的鼻局部吸入治疗，虽然不能完全阻止复发，但可在较长时间内避免复发。常用的鼻喷剂有丙酸倍氯米松(BDP，beelomethason dipropionate，商品名Beconase)、丁地去炎松(budesonide，商品名Rhinocort)、丙酸氟替卡松(fluticasone propionate，商品名Flonase)、丙炎松(triamcinolone acetonide，商品名Nasacort)、9-去氟肤轻松(flunisolide，商品名Rhinalar)、醋酸曲安缩松等，局部用药不影响鼻腔纤毛系统的功能，但都需要长期用药，虽然有报道即使观察至5年也无副作用发；但也有很多文献报道，持续局部使用糖皮质激素可引起咽部真菌感染。对于有类固醇使用禁忌症者，如骨质疏松、消化性溃疡、严重高血压、糖尿病、精神科疾病、癫痫、青光眼、白内障等，不能使用皮质类固醇治疗鼻息肉。
也有报道采用塞替派(thiotepa)于手术后辅助治疗鼻息肉的报道。塞替派是抗肿瘤药，参与机体的免疫反应，抑制免疫过程的诱导期及增殖期，抑制细胞增殖及变态反应，有减轻充血、阻止再生的作用(新药与临床，1996；15(5)：318)。
三、奥苯达唑简介
奥苯达唑，英文通用名称：Oxibendazole；一般名称：奥苯达唑、丙氧咪唑、Oxibendazole、Equitac、Loditac、Oxibendazolum；化学名：5-丙氧基-苯并咪唑2-氨基甲酸甲酯。为广谱驱虫药。可影响虫体多种生化代谢途径。对蛔虫、钩虫和鞭虫均有明显驱虫作用。与其它驱钩虫药比较，本品不但对十二指肠钩虫疗效好，对美洲钩虫也有较好疗效。2日和3日疗法的虫卵转阴率可达56％-100％。一般驱虫药对鞭虫疗效差，奥克太尔驱鞭虫时虫卵转阴率虽可达70％，但对钩虫和蛔虫无效；而本品不仅对钩虫和蛔虫有效，驱鞭虫的疗效也可达70％左右。
四、迄今，国内外都尚未见任何将奥苯达唑鼻腔凝胶剂用于治疗鼻息肉或防止鼻息肉复发的报道或文献记载。
本发明将奥苯达唑作为单独的有效成分或与其它药物一起配成复方，制成鼻腔给药的剂型，这些剂型包括，但不限于：滴鼻剂、喷雾剂、气雾剂和粉雾剂。
本发明所述的用奥苯达唑或用含奥苯达唑的复方制成的滴鼻剂、喷雾剂、气雾剂和粉雾剂的适应症，包括，但不限于以下病症：鼻息肉和鼻息肉病、慢性鼻窦炎、鼻息肉或鼻息肉病、鼻炎、咽炎、气管炎和支气管炎。
使用本发明所述的用奥苯达唑或用含奥苯达唑的复方制成的滴鼻剂、喷雾剂、气雾剂和粉雾剂，对于鼻息肉或鼻息肉病患者，直接鼻腔给药，可有效地使大的鼻息肉缩小，使小的鼻息肉消失；或于鼻息肉切除术后给药，可阻止鼻息肉的复发；对于鼻炎、咽炎、气管炎和支气管炎，可以缓解炎症症状。
本发明所述的滴鼻剂、喷雾剂和气雾剂，均符合《中华人民共和国药典》(2000年版二部)关于滴鼻剂、喷雾剂和气雾剂的定义。
本发明所述的鼻息肉，是本领域的技术人员所熟知的，现代的医学书籍中有其准确的定义，指鼻腔内的灰白色、荔枝状新生物。其病理学改变如前所述。本发明所述的鼻炎、咽炎、气管炎和支气管炎，也是本领域的技术技术人员所熟知的，现代的医学书籍中有其准确的定义。
通过以下实施例对本发明的奥苯达唑鼻腔凝胶剂的制备、用其治疗鼻息肉或鼻息肉病的应用进行描述。需说明的是，下述实施例只是用来说明而非限制本发明，本领域技术人员所熟知的通过其他给药途径将左旋咪唑用于治疗鼻息肉或鼻息肉病、鼻炎、咽炎、气管炎和支气管炎的技术均在本发明的范围内。
实施例1采用卡泊普制备奥苯达唑鼻腔凝胶剂
称取卡泊普940(Carbopol940)2g；取100ml 80℃左右的无菌蒸馏水；边搅拌边向热水中加入卡泊普，全部加入卡泊普后，持续搅拌12h。待温度降低后，加入100mg奥苯达唑，再加入适量防腐剂，再搅拌30min后，及得奥苯达唑凝胶，分装到鼻腔喷雾剂瓶中或滴鼻剂瓶中，即得奥苯达唑鼻腔凝胶剂。
实施例2采用羟甲基纤维素制备奥苯达唑鼻腔凝胶剂
称取羟甲基纤维素2g；取100ml 80℃左右的无菌蒸馏水；边搅拌边向热水中加入卡泊普，全部加入卡泊普后，持续搅拌12h。待温度降低后，加入100mg奥苯达唑，再加入适量防腐剂，再搅拌30min后，及得奥苯达唑凝胶，分装到鼻腔喷雾剂瓶中或滴鼻剂瓶中，即得奥苯达唑鼻腔凝胶剂。
实施例3采用羟乙基纤维素制备奥苯达唑鼻腔凝胶剂
称取羟乙基纤维素2g；取100ml 80℃左右的无菌蒸馏水；边搅拌边向热水中加入卡泊普，全部加入卡泊普后，持续搅拌12h。待温度降低后，加入100mg奥苯达唑，再加入适量防腐剂，再搅拌30min后，及得奥苯达唑凝胶，分装到鼻腔喷雾剂瓶中或滴鼻剂瓶中，即得奥苯达唑鼻腔凝胶剂。
实施例4采用羟丙甲纤维素制备奥苯达唑鼻腔凝胶剂
称取羟丙甲纤维素2g；取100ml 80℃左右的无菌蒸馏水；边搅拌边向热水中加入卡泊普，全部加入卡泊普后，持续搅拌12h。待温度降低后，加入100mg奥苯达唑，再加入适量防腐剂，再搅拌30min后，及得奥苯达唑凝胶，分装到鼻腔喷雾剂瓶中或滴鼻剂瓶中，即得奥苯达唑鼻腔凝胶剂。
实施例5使用奥苯达唑鼻腔凝胶剂治疗鼻息肉
(1)病例和方法：
鼻息肉大小的判断：参照Johansen等的方法[Johansen LV，et al.Clin Otolaryngol，1993；18：524]，经前鼻镜观察，以鼻甲为参照物记分。鼻息肉未超过中鼻甲缘者记0.5分，超过中鼻甲缘未达下鼻甲上缘者记1分，超过下鼻甲上缘未达下缘者记2分，达到下缘者记3分。减少1.5分为显效，1分为有效。
鼻塞程度按轻、中、重度3分法记录，减少2分为显效，1分为有效。
12例鼻息肉患者中男8例，女4例。平均年龄33岁(25～41岁)。鼻息肉达3分者3例，2分者6例，1分者3例。重度鼻塞4例，中度鼻塞6例，轻度鼻塞2例。
将患者随机分为治疗组(6例)和对照组(6例)，治疗组含鼻息肉3分者2例，2分者3例，1分者1例，重度鼻塞2例，中度鼻塞3例，轻度鼻塞1例；对照组含鼻息肉3分者1例，2分者3例，1分者2例，重度鼻塞2例，中度鼻塞3例，轻度鼻塞1例。对照组采用丙酸倍氯米松喷雾剂治疗，每天鼻腔给药喷三次，持续两周后，第三周改为每天喷二次，第四周改为每天喷一次，疗程为一个月；治疗组采用奥苯达唑鼻腔凝胶剂治疗，每天喷鼻腔给药喷一次，持续用药一个月。
丙酸倍氯米松喷雾剂中，丙酸倍氯米松的剂量为50ug/o.14ml每喷；奥苯达唑鼻腔凝胶剂中，奥苯达唑的剂量为100ug/0.1ml每喷。
于用药两周和用药一个月后复查，观察鼻息肉大小、记分变化、鼻塞减轻程度以及有无副作用发生等。
(2)结果：
鼻息肉大小记分的改变：对照组在治疗一月后，鼻息肉均见明显回缩，其中3分者治疗结束后鼻息肉已越过鼻内孔，1分者有1例鼻患肉消失。治疗组鼻息肉也都明显回缩，3分者2例在治疗结束时均回缩至下鼻甲上缘，2分者有1例、1分者有2例鼻息肉消失。
鼻塞症状的改善：治疗组和对照组中患者的鼻塞症状均有不同程度的改善。治疗组的2例重度塞中，有1例用药1个月后嗅觉有所恢复；对照组的2例重度鼻塞中有1例用药1个月后嗅觉有所恢复。治疗组中度鼻塞改善不明显者1例，对照组中度鼻塞改善不明显者2例。
结论：对于鼻息肉的药物治疗，国外多采用皮质类固醇的鼻腔喷雾或气雾治疗。采用奥苯达唑鼻腔凝胶剂，其疗效与丙酸倍氯米松喷雾剂相似或稍好于丙酸倍氯米松喷雾剂。
实施例6奥苯达唑鼻腔凝胶剂治疗鼻息肉复发
一位55岁女性，确诊多发性鼻息肉，鼻内窥镜手术切除息肉，术后40天，鼻息肉复发，再次摘除复发的息肉。再过40天后复查，鼻息肉又复发。此时改用奥苯达唑鼻腔凝胶剂行鼻局部给药治疗，每天一次，持续一月，复发的鼻息肉变小。继续一月后复查，鼻息肉消失。
Claims (3)
1.将奥苯达唑作为有效成分或有效成分之一制成的鼻腔凝胶剂。
2.奥苯达唑在用于治疗鼻息肉和鼻息肉病的鼻腔凝胶剂的生产中的应用。
3.奥苯达唑在鼻息肉手术治疗、激光治疗等外科治疗后防止鼻息肉复发的鼻腔凝胶剂的生产中的应用。
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