CN101128196A - 用于治疗呼吸系统疾病的抗胆碱能药和白三烯受体拮抗剂的组合 - Google Patents
用于治疗呼吸系统疾病的抗胆碱能药和白三烯受体拮抗剂的组合 Download PDFInfo
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- CN101128196A CN101128196A CNA2006800061530A CN200680006153A CN101128196A CN 101128196 A CN101128196 A CN 101128196A CN A2006800061530 A CNA2006800061530 A CN A2006800061530A CN 200680006153 A CN200680006153 A CN 200680006153A CN 101128196 A CN101128196 A CN 101128196A
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明涉及包含局部用(吸入)抗胆碱能药和吸入或口服白三烯(LT)受体拮抗剂(BLT-和CysLT-受体拮抗剂)的用于治疗呼吸系统疾病包括过敏性鼻炎、支气管哮喘和慢性阻塞性肺病(COPD)的组合。本发明进一步包含该组合以局部应用(吸入)制剂的呈现和在例如Novolizer的吸入装置中的应用。
Description
本发明涉及包含局部用(吸入)抗胆碱能药和吸入或口服白三烯(LT)受体拮抗剂(BLT-和CysLT-受体拮抗剂)的用于治疗呼吸系统疾病包括过敏性鼻炎、支气管哮喘和慢性阻塞性肺病(COPD)的组合。本发明进一步包含该组合以局部应用(吸入)制剂的呈现和在例如Novolizer的吸入装置中的应用。
过敏性鼻炎影响20%的成年人群和多达40%的儿童。尽管鼻炎自身不不会威胁生命(除非伴随严重的哮喘或过敏反应),但是因该病导致的发病率仍然显著。过敏性鼻炎常与其它病症共存,诸如哮喘、鼻窦炎、鼻息肉、过敏性结膜炎和特应性皮炎。鼻炎还可明显地降低生活质量,生产力,学习能力等。此外,对鼻炎的治疗不充分可导致其它病症,包括窦、耳和下呼吸道的感染。针对过敏性鼻炎的有效疗法需要理解该病的病理生理学和各种炎症机理的作用。照此,多种种类的药物可供临床医师用于治疗过敏性鼻炎患者。这些药物中有第2代抗组胺类药和抗胆碱能药、鼻内用皮质类固醇和肥大细胞稳定剂。近来已经将白三烯(LT)受体拮抗剂加入到治疗模式中。
过敏性鼻炎的机理为典型的过敏性疾病。有关其病理生理学,在鼻炎与哮喘之间存在若干相似性。将鼻炎定义为鼻膜的炎症且其特征在于由下列症状的任意组合组成的综合症状:喷嚏、鼻充血、鼻瘙痒和鼻漏。迄今为止,组胺H1受体拮抗剂、减充血药、色甘酸钠、皮质类固醇、cysLT-受体拮抗剂和抗胆碱能药为最常用于治疗鼻炎的药理学活性剂。
影响工业化国家中多达10%个体的支气管哮喘的特征在于支气管收缩、慢性气道炎症、气道高反应性和粘膜水肿。气道重塑和改变的非胆碱能非肾上腺素能神经传递可促成不可逆的气道阻塞和肺功能降低。支气管哮喘在过去20年来已经显现为全世界范围内重要的公共健康问题。尽管数据表明目前的哮喘疗法使得死亡率有限地下降,但是它仍然是显著的保健问题。它在世界范围内仍然是可防止的住院治疗的主要原因之一并且导致损失几百万个工作日。随着哮喘患病率的增加,与该病相关的花费也显著上升。
哮喘的病理生理学涉及分子和细胞相互作用的错综复杂的网络,不过,每个个别因素的贡献在患者与患者之间可能不同,这取决于环境和刺激物。哮喘表型出现中的主要参与者包括触发刺激物,诸如变应原自身;产生多种细胞因子包括IL-5、GM-CSF、IL-3、IL-4和IL-13和趋化因子诸如嗜酸细胞活化趋化因子、黏着分子等的细胞,诸如T细胞、上皮细胞和肥大细胞。近来在理解哮喘的炎症和免疫机理方面的进展已经表明了可预防或逆转哮喘潜在的异常的许多潜在可能的治疗途径。
目前,药物疗法为治疗哮喘的主要途径。可得到短效和长效吸入β2-肾上腺素受体激动剂。短效β2-肾上腺素受体激动剂目前基于需要用于快速缓解症状。近年来,长效吸入β2-肾上腺素受体激动剂在控制哮喘特别是在患有中度到重度哮喘的患者中具有日益增加的作用。抗毒蕈碱药在缓解哮喘发作方面的功效低于β2肾上腺素受体激动剂(Rodrigo和Rodrigo,Chest 2002;121:1977-87)。然而,随着引入新的抗胆碱能药tiotropium,抗胆碱能药在呼吸系统疾病中的应用将大大增加。吸入的皮质类固醇已经成为了慢性哮喘的主要疗法。它们是可利用的在临床上最有效的治疗,但可能产生严重的继发效应,并且对皮质类固醇耐药的哮喘患者无效。
慢性阻塞性肺病(COPD)也极为常见。该病的特征在于伴随炎症反应的进行性气流受限。回顾来自全世界的数据可以清楚地看出,烟草并非COPD的唯一原因。全世界老龄化的增加也是一定的风险因素。COPD的患病率在3%-10%之间,并且有稳定增加的趋势。虽然COPD是疾病和死亡的主要原因,但是很慢才将其视为公共健康问题,尽管COPD的死亡率上升,而大部分心血管疾病的死亡率下降(Hurd Chest2000;117(2Suppl):1S-4S)。另外,COPD给个体和社会均施加了显著的经济负担。
总体而言,对有关COPD的发病机理的了解远低于哮喘。近期研究大大扩展了对COPD潜在的发病机理的理解。因此,公认COPD也是一种炎性疾病。从目前的发病机理观点来看,嗜中性粒细胞、CD8+淋巴细胞和巨噬细胞与其介质可能在COPD的发病机理中起关键作用。
目前的处置集中在改善患有COPD的患者的肺功能。在该方法中的第一步为戒烟。有证据表明减少吸烟或戒烟可以使得某些呼吸参数改善。支气管扩张药(β2-肾上腺素受体激动剂和抗胆碱能药)为目前主要的症状疗法。短效和长效吸入β2-肾上腺素受体激动剂,诸如沙丁胺醇、非诺特罗、沙美特罗、福莫特罗为针对症状的COPD治疗中的确立的治疗剂。在短效抗毒蕈碱药中,广泛使用异丙托铵。近来,在世界范围内现已引入了对M3-毒蕈碱受体具有一定偏好的长效抗胆碱能药(Hansel和Barnes,Drugs Today(Barc)2002;38:585-600)。抗胆碱能药也可以有效地用于治疗马的COPD。2,400ug/马剂量的异丙托铵为对患有COPD的马的有效支气管扩张药(Duvivier等Equine Vet J1999;31:20-4,Bayly等Equine Vet J.2002Jan;34(1):36-43)。目前,尚未解决对COPD的抗炎疗法。全身和吸入糖皮质激素在COPD中的应用在过去的20年内显著增加。已经基于以下依据测试了它们,即干扰COPD中的炎症应改变该病的病程。尽管吸入的皮质类固醇具有经证实的在控制哮喘中的裨益,但是直到最近才有证据支持其在非哮喘性的与吸烟相关的COPD中的功效(Bonay等Drug Saf 2002;25:57-71)。吸入的皮质类固醇对表征COPD的炎症过程的影响相对较小(Adcock和Chung,Curr Opin Investig Drugs 2002;3:58-60)。
气流阻塞和气道炎症为过敏性鼻炎/哮喘和COPD的特征。存在有力的证据,即气道炎症为患有鼻炎、哮喘和COPD的患者的主要潜在问题。尽管鼻炎/哮喘和COPD各自中的气道炎症涉及不同的细胞类型,但是两种疾病均具有与细胞浸润和活化相关的慢性炎症性质。过敏性鼻炎和支气管哮喘的主要特征在于嗜酸性粒细胞和CD4淋巴细胞,而嗜中性粒细胞、CD8淋巴细胞和巨噬细胞表现出在COPD的发病机理中起主要作用。
哮喘-和COPD-样的疾病还可发生在动物例如马中。有证据表明LTB4和LTD4可以促成马COPD的发病机理(Marr等Res Vet Sci 1998;64:219-24)。在马中,显然在LT产生与胆碱能系统之间存在关联。通过毒蕈碱受体介导的气道中的嗜中性粒细胞炎症和支气管痉挛为马的COPD的特征。据报导LT参与COPD的加剧。实际上,诸如LT这类介质加强了马气道中的胆碱能反应(Olszewski等Am J Physiol 1999;276:L522-9)。还有证据表明胆碱能活化(乙酰胆碱)刺激肺泡巨噬细胞释放脂氧合酶-衍生的产物(LTB4和CysLT)(Sato等Am J Physiol1998;274:L970-9)。
鼻病毒是50%以上的呼吸道感染的原因。鼻病毒感染(例如普通感冒)的并发症,包括例如哮喘的表现或加剧,在某些群体中可能显著。因此,通过使用适当的疗法将可能的不良结果减少到最低限度具有巨大的优势。近来已经证实鼻病毒感冒诱发支气管炎症,5-LO途径蛋白表达显著增强(Seymour等J Infect Dis 2002;185:540-4),表明LT在这些气道中的产生增加。因此,LT拮抗剂表现出能够减轻病毒感染后的肺部症状(Bisgaard等Am J Respir Crit Care Med 2003;167:379-83)。此外,众所周知抗胆碱能药如异丙托铵提供了对伴随普通感冒的鼻漏和喷嚏的特效缓解(Hayden等Ann Intern Med 1996;125:89-97)。
白三烯类(LT)为过敏性气道疾病诸如哮喘和鼻炎的病理生理学的重要介质,并且它们还参与COPD。通过LT介导的主要效应为支气管收缩、气道炎症、水肿和粘液分泌过多。
通过5-脂氧合酶的花生四烯酸代谢产生一组生物活性脂质,称作白三烯类(LT)。LTB4为白细胞趋化的有效激活物。半胱氨酰LT(LTC4、LTD4、LTE4)造成致痉活性,先前描述为过敏的慢反应物质(SRS-A)。这些炎症介质由多种细胞类型产生,包括肥大细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和单核细胞。它们通过结合和活化特异性受体(LTB4在BLT受体,半胱氨酰LT在cysLT1-受体)发挥其生物学作用。这以一系列事件发生,导致人气道平滑肌收缩、趋化作用和增加的血管通透性、粘液分泌过多、纤毛运动减少。这些作用使得它们在哮喘、过敏性鼻炎和COPD疾病中起重要作用。
CysLT-受体拮抗剂(例如扎鲁司特、孟鲁司特、普仑司特),其它LT-受体拮抗剂的衍生物,诸如L-648,051、MK-571、维鲁司特(MK-0679)、泊比司特(SK&F 104353)、AS-35、ICI 204、219等)代表了对成年人和儿童哮喘和过敏性鼻炎特别是运动和阿司匹林诱发的哮喘的有效和良好耐受的治疗。它们还可以具有在COPD中的临床应用。近来提示一种cysLT-受体拮抗剂扎鲁司特可以增加患有COPD的患者的潮气量和肺泡通气量(Bu等Chin Med J 2003;116(3):459-461)。
即使没有对于LTB4在人哮喘和特征在于显著的嗜中性粒细胞浸润的其它呼吸系统疾病诸如COPD中的另外贡献的令人注目的临床数据,但是可能LTB4的趋化特性更为重要(Daniel和O′Byrne,Am Rev RespirDis 1991;143:S3-5)。在患有COPD的患者中,与增强的氧化应激并行发生的是嗜中性粒细胞合成趋化因子LTB4的能力增加,并可最终促使嗜中性粒细胞向COPD患者气道中浸润/活化(Santus等Am J RespirCrit Care Med 2004;[Epub在印刷前])。另外,在患有COPD的患者中存在呼出的LTB4的选择性增加(Montuschi等Thorax 2003;58:585-8)。
已经将抗胆碱能药接受为上和下气道疾病、鼻炎、哮喘和COPD的重要治疗方式。用于本发明的毒蕈碱受体拮抗剂为长效化合物。这一类型的任何化合物都可以用于本联合疗法手段中。
另一种季铵抗胆碱能化合物格隆溴铵由四种立体异构体组成。格隆溴铵属于所谓的抗胆碱能药并且在乙酰胆碱受体位点拮抗神经递质乙酰胆碱。该作用导致显著的支气管扩张和粘液分泌减少。它从粘膜中吸收差,因此减少了抗胆碱能副作用(Ali-Melkkila等ActaAnaesthesiol Scand 1993;37:633-42)。格隆溴铵结合M1-M3受体不具有选择性。然而,动力学研究显示格隆溴铵从M3毒蕈碱受体缓慢解离(Haddad等Br J Pharmacol 1999;127:413-20)。与tiotropium类似,这一行为解释了格隆溴铵的相对受体选择性及其长作用持续时间。实际上,有证据表明外消旋格隆溴铵在哮喘和COPD患者中产生显著的和持久的支气管扩张作用(Walker等Chest 1987;91:49-51,Schroeckenstein等J Allergy Clin Immunol 1988I;82:115-9,Gilman等Chest 1990;98:1095-8,Cydulka和Emerman,Ann EmergMed 1995;25:470-3)。另外,局部用抗胆碱能药(例如异丙托铵或格隆溴铵)在过敏性鼻炎中的应用在减轻症状方面既安全又有效(Milford等J Laryngol Otol 1990;104:123-5,Meltzer J AllergyClin Immunol 1992;90:1055-64)。由于鼻炎、哮喘和COPD的特征在于粘液分泌增加,诸如格隆溴铵这类抗胆碱能药的抑制分泌作用是它们在对这些疾病的治疗中的额外的优势。
目前用于哮喘和COPD的疗法并不令人满意。对鼻炎情况相同,其中尽管存在表面上令人满意的疗法,但是相对简单的鼻部疾病可以进一步发展成支气管哮喘。鉴于这些疾病的高发病率,所以本发明要解决的问题在于提供改善的,更为有效和更为便利的治疗干预。
可以按照本发明,通过局部用抗胆碱能药与至少一种白三烯受体-拮抗剂的组合解决这一问题。
BLT-和CysLT-受体的拮抗剂减轻了上和下气道中的炎症过程(例如鼻炎、哮喘和COPD)。因此,LT-受体-拮抗剂的这些作用导致患有气道疾病包括过敏性鼻炎、支气管哮喘或COPD的患者的粘膜和支气管功能改善。这两类药物即抗胆碱能药(尤其是R,R-格隆溴铵)和LT-受体-拮抗剂的药效学特性彼此补充并且产生了对所述疾病更为有效的治疗,从而导致全身的接触减少至最低限度。本发明LT-受体拮抗剂和抗胆碱能药的组合在疗效、安全性、起效和作用持续时间或副作用方面优于单一化合物,即惊人地以超加方式起作用。另外,还增加了患者的依从性。
实验部分
不仅TNFα,IL-2也在炎性气道疾病中起重要作用。已知在某些形式的哮喘(例如内源性哮喘和职业性哮喘)中,特定T细胞亚群特别产生IL-2(Ricci等;J Investig Allergol Clin Immunol 1994;4:214-20)。此外,过敏性患者具有可以受诱导分泌IL-2的特殊T细胞群(McHugh等;Clin Exp Allergy 1993;23:137-44)。还证实一种cys LT-受体拮抗剂扎鲁司特能够特别减少卵清蛋白致敏的BrownNorway大鼠的IL-2表达(Lin等;Clin Exp Allergy 2002;32:960-6)。因此,通过使用人外周血单核细胞(PBMC)研究了R,R-格隆溴铵与cysLT-受体拮抗剂联用对TNFα和白细胞介素(IL)-2释放的影响。根据赫尔辛基和东京国际宣言,这些研究得到了大学伦理委员会的批准。
通过密度梯度离心从健康供体的肝素化血样中分离PBMC。将等体积的Hanks缓冲液(Life Technologies,Heidelberg,Germany)加入到肝素化全血样品中。将用最多40ml血/Hanks混合物覆盖的15mlHistopaque-1077(Sigma,Deisenhofen,Germany)在室温下离心30分钟(2000rpm)。将包含PBMC的可见条带转入新试管并且用Hanks-缓冲液洗涤两次。最终将细胞接种在含有Glutamax I(Gibco BRL,Eggenstein)和10%FCS(Boehringer Mannheim,Penzberg,Germany)的RPMI 1640培养基(Life Technologies,Heidelberg,Germany)中。在分离后,在37℃和5%CO2中,在补充了10%胎牛血清(FCS)的RPMI1640培养基中将PBMC培养过夜。通过贴壁方法将单核细胞与其它细胞分离,通过更换培养基除去未贴壁的细胞。
在37℃和5%CO2中,以106个细胞/ml重新悬浮细胞并且在24-孔组织培养平板(Falcon Becton Dickinson Labware)中以500ul体积温育。在与测试物质(0.5ul/500ul培养基)一起预温育30分钟后,用脂多糖(LPS)(100ng/ml)刺激细胞。代替LPS,用TPA(佛波醇-12-肉豆蔻酸酯-13-乙酸酯)(25nM)和伊屋诺霉素(1ug/ml)刺激IL-2释放。在所示的时间,通过离心使细胞沉淀。收集上清液并且保持冷冻在-80℃下,直到进行蛋白质测定;用RLT裂解缓冲液(Qiagen,Hilden,Germany)裂解细胞并且冷冻在-80℃下至分析时为止。
通过夹心式ELISA,使用匹配的抗体对(Pharmingen,Heidelberg,Germany)进行培养物上清液中的细胞因子测定。用在pH 9.5的0.1M碳酸盐缓冲液中的抗-细胞因子单克隆抗体(mAb)将ELISA平板(Maxisorb,Nunc)包被过夜。洗涤后,用测定稀释剂(Pharmingen,Heidelberg,Germany)将平板封闭1小时并且再次洗涤。将适当稀释的上清液样品和标准品按一式两份分配并且在室温下将平板温育2小时。洗涤平板,与操作检测剂(生物素化的抗-细胞因子抗体和抗生物素蛋白-辣根过氧化物酶缀合物)一起温育1小时。洗涤后,加入底物(TMB和过氧化氢)。通过添加1M H3PO4终止反应。在微量平板读出器(Dynatech)中在450nm(参比570nm)读取平板。将结果表示为无化合物存在下刺激的细胞产生细胞因子的对照水平的百分比。
在LPS-刺激时,单核细胞的基础TNFα释放从150pg/ml增加至3,208pg/ml。单独的R,R-格隆溴铵直至10umol/l也不影响LPS-诱导的TNFα释放。TPA/伊屋诺霉素显著刺激了从PBMC释放IL-2(从0pg/ml[在检测限下]至5,300pg/ml)。与TNFα类似,直至10umol/l单独的R,R-格隆溴铵对刺激的IL-2释放没有影响。
cysLT-受体拮抗剂孟鲁司特以浓度依赖性方式抑制TNFα释放。孟鲁司特的IC50值等于2.45±0.85nmol/l。同时添加10umol/l的R,R-格隆溴铵不影响孟鲁司特的IC50(2.58nmol/l)。
孟鲁司特显著抑制了IL-2释放,IC50值为0.88±0.14nmol/l。同时添加10umol/l的R,R-格隆溴铵令人意外和非常显著地以超加的方式将IC50降至0.26±0.07nmol/l(p=0.0023)。
概括地说,基于本实验研究,我们的结论是R,R-格隆溴铵可以显著增强cysLT-受体拮抗剂的抗炎活性。
实施例
本发明关注的联合疗法包含给予至少一种cysLT-或BLT-受体拮抗剂与长效抗胆碱能化合物,以便预防上或下气道疾病情况的发作或治疗存在的疾病和减轻气道炎症。可将所述的化合物共同在单一剂型中给予或可将它们在不同的剂型中给予。可以同时给予它们或可将它们在时间上接近地或远隔地给药,诸如在早晨给予一种药物,而在晚上给予第二种药物。可以预防性地使用这种组合,或在症状已经发生后给予。在某些情况中,该组合可以用于防止气道疾病进展或阻止诸如肺功能这类功能下降。
这些药物,即抗胆碱能药和LT-受体拮抗剂,通常作为气雾剂或作为吸入粉末给药。本发明关注在一种药物给药后给予另一种药物或在一种递药形式诸如吸入器中共同给予两种药物,后一种情况是将两种药物置于同一吸入器中的一个或甚至多个容器中。制剂配制在本领域技术人员技能范围内。迄今为止,所有已知的LT-受体拮抗剂均为口服可生物利用的并且作为片剂给药。然而,有证据表明LT-受体拮抗剂在局部给予时也有效。LT-受体拮抗剂L-648,051用于哮喘局部气雾剂疗法的潜在作用是有希望的(Young Agents Actions 1988;23(Suppl):113-9)。LT-受体拮抗剂MK-571完全抑制了豚鼠结膜中的体内趋化反应,表明不仅在过敏性结膜炎而且在过敏性鼻炎和哮喘中的有用性(Chan Eur J Pharmacol 1990;191:273-80)。吸入的LT-受体拮抗剂ICI 204,219显著保护哮喘受试者对抗运动诱发的支气管收缩(Makker Am Rev Respir Dis 1993;147:1413-8)。吸入的LT-受体拮抗剂维鲁司特(MK-0679)导致哮喘受试者的平均FEV1显著改善(Lammers,Pulm Pharmacol 1992;5:121-5)。吸入的LT-受体拮抗剂AS-35以剂量依赖性方式在通气豚鼠中抑制了抗原诱发的支气管收缩(Bando,Arzneimittelforschung 1994;44:754-7)。吸入的LT-受体拮抗剂泊比司特(SK&F 104353)显著抑制了哮喘受试者中LT诱发的支气管收缩(Christie,J Allergy Clin Immunol 1991;88:193-8)。因此,吸入的LT-受体拮抗剂如L-648,051适合于吸入疗法(Evans,BrJ.Clin Pharmacol 1989;28:125-35)。
将扎鲁司特局部给药入眼有效抑制了大鼠过敏性结膜炎实验模型中的症状发生和介质释放(Papathanassiou等Inflamm Res 2004;53:373-6)。
可以将活性组分每天给予1-8次,这足以表现出所需的活性。优选将活性成分每天给予约1次或4次,更优选每天1次或2次。长作用持续时间使得每日给药两次是可能的。如果活性成分以固定组合的形式存在,那么对患者给药更为简便,因为两种活性组分包含在一个装置中。
可以对成年人口服给予1-100mg/天的LT-受体拮抗剂,例如孟鲁司特,其中优选5-20mg/天,这取决于气道炎症的强度。在鼻用喷雾剂或滴剂中,LT受体拮抗剂例如孟鲁司特在组合中的浓度可以在0.01-5%。LT受体拮抗剂优选的浓度为0.1%-2%。在压力定量气雾剂或用于吸入的干粉中,LT受体拮抗剂例如孟鲁司特在组合中的剂量可以在每剂0.05-10mg,优选每剂0.2-5mg的范围内。
可以从压力定量气雾剂或用于吸入的干粉中给予吸入的抗胆碱能药,例如外消旋格隆溴铵,其对映体之一尤其是R,R-格隆溴铵或其混合物及其盐、溶剂化物和水合物,其量对成年人而言为1-500ug/天,优选5-100ug/天。在鼻用喷雾剂或滴剂中,本发明抗胆碱能药成分例如格隆溴铵的浓度可以在0.0001%-0.5%的范围内。R,R-格隆溴铵优选的浓度为0.001-0.1%。
关注的是同时或在极为接近的时间给予两种活性剂。或者,可以在早晨服一种药物,而在当天稍后服另一种药,或在另一种方案中,可以一种药物每天给予两次并且另一种药物每天给予一次,与每天两次给药中的一次同时或分开。优选同时一起给予两种药物。
就兽医应用而言,可以单独或与吸入或口服LT-受体拮抗剂联合对马给予抗胆碱能药,例如格隆溴铵,用量为1-32ug/kg/天,优选4-16ug/kg/天。可以以10-1,000mg/天的量对马给予cysLT-受体拮抗剂,例如孟鲁司特,优选50-200mg/天,这取决于气道炎症的强度。BLT-受体拮抗剂的所需剂量取决于其受体亲和力和在受体位点的利用度。
制剂和生产方法
本发明描述了一种组合,其中单独或联合给予的抗胆碱能药诸如R,R-格隆溴铵与LT-受体拮抗剂例如孟鲁司特、扎鲁司特和/或普仑司特同时给予,作为单独物质依次给予或以所述方式作为固定组合给予。
按照本发明,可以同时、依次或彼此独立地,局部(通过鼻内或通过吸入)作为固定的组合或单独的物质或口服与局部联用而给予所述的活性物质。如果存在单独的制剂,那么将它们适应彼此而配制并且在剂量单位中包含可存在于组合中的相同量和相应重量比的相应活性化合物。
可以将口服或局部给药的组合物配制成不同的药学上可接受的给药剂型,例如鼻用喷雾剂或滴鼻剂、片剂、薄膜包衣片、胶囊或颗粒。局部用剂型还可以包括乳剂、糊剂、霜剂和/或凝胶。
除活性化合物外,本发明的药物制剂还可以包含另外的成分,诸如防腐剂、稳定剂、等渗剂、增稠剂、混悬液稳定剂、用于pH调节的赋形剂、缓冲系统、湿润剂和其它例如着色剂。
抗微生物的防腐物质包括例如:苯扎氯铵、三氯叔丁醇、硫柳汞、对羟基苯甲酸甲酯、对羟苯甲酸丙酯、山梨酸及其盐、乙二胺四乙酸钠、苯乙醇、盐酸氯己定和溴化氯己定、醋酸氯己定、二葡糖酸氯己定、氯甲酚、苯汞盐、苯氧基乙醇、氯化和溴化十六烷基吡啶鎓。
乙二胺四乙酸钠和苯扎氯铵的组合适合于用作防腐剂。乙二胺四乙酸钠的使用浓度为0.05-0.1%且苯扎氯铵的使用浓度为0.005-0.05%wt,均以组合物为基准。
用于调节制剂等渗性或同渗浓度的合适的赋形剂例如为:氯化钠、氯化钾、甘露糖醇、葡萄糖、山梨醇、甘油、丙二醇。一般而言,这些赋形剂的使用浓度为0.1-10%。
本发明的制剂还可以包括合适的缓冲系统或其它用于pH调节的赋形剂,以便建立和维持数量级为4-8,优选5-7.5的pH。合适的缓冲系统例如为柠檬酸盐、磷酸盐、氨基丁三醇、甘氨酸、硼酸盐、乙酸盐。这些缓冲系统可以由诸如柠檬酸、磷酸一钠、磷酸二钠、甘氨酸、硼酸、四硼酸钠、乙酸、乙酸钠这类物质制备。另外的赋形剂也可以用于pH调节,诸如盐酸或氢氧化钠。
为了制备包含水不溶性活性化合物的稳定的含水混悬液,合适的混悬液稳定剂和合适的湿润剂对以适当方式分散和稳定悬浮的药物物质而言也是必要的。
合适的混悬液稳定剂为水溶性或部分水溶性聚合物:它们包括:例如甲基纤维素(MC)、羧甲基纤维素钠(Na-CMC)、羟丙基甲基纤维素(HPMC)、聚乙烯醇(PVAL)、聚乙烯吡咯烷酮(PVP)、聚丙烯酸、聚丙烯酰胺、胞外多糖胶(Gelrite)、水合氧化铝(Unemul)、糊精、环糊精、乙酸邻苯二甲酸纤维素和微晶纤维素(不同类型的Avicel)与羧甲基纤维素钠的混合物。可以将这些物质同时用作增稠剂以便增加粘度且由此延长药物物质与应用部位组织的接触。
合适的湿润剂例如为苯扎氯铵、氯化十六烷基吡啶鎓、泰洛沙泊、各种聚山梨醇酯类(Tween)且还有聚乙氧基化物质和泊洛沙姆。
为了鼻部给予本发明的溶液或混悬液,本领域中有多种装置可用来产生液滴、小滴和喷雾。例如,可以通过包括玻璃、塑料或金属配药管的滴器(或吸移管)将制剂给予到鼻道中。可以通过本领域众所周知的鼻内泵配药器或挤压瓶产生细液滴和细雾。
本发明还包括包含一个或多个单位脱水剂量的一种或多种药物物质与任何所需的制剂赋形剂的试剂盒,以备通过添加适量的无菌或非无菌水制备溶液或混悬液。
按照本发明,可以通过同时、依次或彼此独立的方式,经吸入作为固定的组合或单独的物质或口服合并吸入的方式给予活性物质。
作为可吸入组合物,可以考虑加压压力定量气雾剂、干粉或不含抛射剂的吸入溶液。在后者中甚至有无菌的、备用的或恰在使用前制备的作为在含水和/或有机介质中的可喷雾组合物的吸入溶液、混悬液或浓缩物。这些剂型属于本发明的组成部分。
含有抛射剂的加压压力定量气雾剂可以包含在抛射剂中的溶液或分散体形式的活性R,R-格隆溴铵和至少一种LT-受体拮抗剂。可以用于本发明吸入气雾剂的抛射剂为众所周知的:主要应用卤代烃衍生物TG134a和TG227或其混合物。此外,通常加入去污剂(例如油酸)、稳定剂(例如乙二胺四乙酸钠)、共溶剂(例如丙二醇、聚乙二醇、甘油)、抗氧化剂(例如抗坏血酸)、润滑剂(例如聚氧乙烯-甘油基-三油酸酯)或缓冲系统或其它用于pH调节的赋形剂(例如盐酸)。活性组分可以具有至多5um的平均颗粒直径。
乙醇与聚氧乙烯-25-甘油基-三油酸酯(商品名:Tagat TO)的组合可以适当地以0.5-1.5%浓度用作去污剂/稳定剂/共溶剂/润滑剂复合物。
通过现有技术的吸入器,即所谓的加压计量吸入器(=pMDI)给予本发明上述包含抛射剂的气雾剂、溶液或混悬液。可以给它们安装负责计量和释放活性成分的不同大小的金属或塑料杆。
干粉包含单独或与药学上合适的生理学上无害的载体混合的活性抗胆碱能药和/或至少一种LT-受体拮抗剂。所述的载体可选自已知为干粉吸入组合物中的载体的物质,例如单糖类(例如葡萄糖、阿拉伯糖)、二糖类(例如乳糖、蔗糖、麦芽糖)、寡糖和多糖类(例如葡聚糖)和糖醇类(例如山梨醇、甘露糖醇)。
最佳可利用技术在于主要以乳糖一水合物使用乳糖。所用赋形剂产生颗粒大小分布至多约500um,优选的平均颗粒直径约为110-290um。活性组分可以具有至多4um的平均颗粒直径。
可以借助于现有技术的干粉吸入装置例如Novolizer给予本发明的吸入粉末。可以将吸入粉末预计量入胶囊(例如明胶)或泡罩(铝袋)或恰在使用前从整体贮器中计量。抗胆碱能药和至少一种LT-受体拮抗剂可以以固定组合存在于其中或两种活性成分可以在单独的包装单元中,可以将它们彼此独立地从一个装置或来自两个或多个不同装置的药包中给药或同时给药。
下列实施例将解释例示本发明,但不限定它。
实施例1
包含格隆溴铵的喷鼻剂或滴鼻剂
R,R-格隆溴铵 | 0.0070g |
羟丙基甲基纤维素 | 0.1000g |
乙二胺四乙酸钠 | 0.0500g |
苯扎氯铵 | 0.0125g |
山梨醇溶液70% | 6.6000g |
纯水 | 至100ml |
溶液的制备
将80%的纯水导入合适的安装搅拌器的容器中。向其中依次加入格隆溴铵、羟丙基甲基纤维素、苯扎氯铵、乙二胺四乙酸钠和山梨醇溶液并且通过搅拌溶解。使用纯水补足至终体积并且搅拌。通过具有0.2um孔径的滤膜过滤溶液并且将其分配入瓶中。
实施例2
包含孟鲁司特(1%)的喷鼻剂或滴鼻剂混悬液
孟鲁司特 | 1.0000g |
Avicel RC 591 | 1.1000g |
聚山梨醇酯80 | 0.1000g |
乙二胺四乙酸钠 | 0.0500g |
苯扎氯铵 | 0.0200g |
山梨醇溶液70% | 6.0000g |
纯水 | 至100ml |
混悬液的制备
将80%的纯水导入合适的安装搅拌器的具有匀化装置的容器中并且以高速匀化其中的Avicel RC 591。然后通过搅拌溶解聚山梨醇酯80、山梨醇溶液、乙二胺四乙酸钠和苯扎氯铵这些物质。随后以高速匀化其中的活性化合物孟鲁司特,直到获得均匀混悬液为止。然后用纯水补足至终体积并且进一步匀化。然后对混悬液排气以便除去产生的气泡。然后将所得混悬液分配入瓶。
实施例3
包含R,R-格隆溴铵和孟鲁司特的喷鼻剂或滴鼻剂
R,R-格隆溴铵 | 0.0070g |
孟鲁司特 | 1.0000g |
Avicel RC 591 | 1.1000g |
聚山梨醇酯80 | 0.1000g |
乙二胺四乙酸钠 | 0.0500g |
苯扎氯铵 | 0.0200g |
山梨醇溶液70% | 6.0000g |
纯水 | 至100ml |
制备
将80%的纯水导入合适的安装搅拌器的具有匀化装置的容器中并且以高速匀化其中的Avicel RC 591。然后通过搅拌溶解R,R-格隆溴铵和赋形剂聚山梨醇酯80、山梨醇溶液、乙二胺四乙酸钠和苯扎氯铵。随后以高速匀化其中的活性化合物孟鲁司特,直到获得均匀混悬液为止。然后用纯水补足至终体积并且进一步匀化。然后对混悬液排气以便除去产生的气泡。然后将所得混悬液分配入瓶。
实施例4
每单剂量含有20ug格隆溴铵和2.5mg孟鲁司特的吸入用干粉
R,R-格隆溴铵 | 20.000g |
孟鲁司特 | 2500.000g |
乳糖 | 9480.000g |
吸入用干粉的制备:
将20g用量的微粉化格隆溴铵与180gα乳糖一水合物混合,使该混合物过0.5mm筛目的筛并且最终再次混合。将得到的混合物与1800gα乳糖一水合物混合(=混合物2)。将该混合物分成两部分。掺合第一部分格隆溴铵/乳糖混合物2和2,500g微粉化孟鲁司特,使该混合物过0.8mm筛目的筛并且最终再次混合(=混合物3)。首先掺合混合物3和7,500g乳糖;最后掺合该混合物与第二部分格隆溴铵/乳糖混合物2(=混合物4)。使该混合物过0.8mm筛目的筛。随后再次混合并且将得到的粉末混合物填充入每单剂量释放12mg粉末的干粉吸入器。
从粉末吸入器中释放每单剂量20ug格隆溴铵和2.5mg孟鲁司特并且施用于患者气道。
实施例5:
每单剂量含有50ug格隆溴铵和2.5mg孟鲁司特的加压压力定量气雾剂
R,R-格隆溴铵 | 0.840g |
孟鲁司特 | 42.000g |
糖精钠 | 1.800g |
Tagat TO | 23.400g |
无水乙醇 | 23.400g |
HFA 227 | 加至2340.000g |
加压压力定量气雾剂的制备:
将用量为2000g的1,1,1,2,3,3,3,七氟丙烷(=HFA 227)在-55℃的温度下冷却并且在搅拌的同时与23.4g聚氧乙烯-25-甘油基-三油酸酯(商品名:Tagat TO)在23.4g无水乙醇中的溶液混合。
随后加入0.840g微粉化格隆溴铵和42.000g微粉化孟鲁司特以及1.800g微粉化糖精钠并且将产生的混悬液充分匀化。在进一步冷却和搅拌的同时,给该混悬液填充冷却的抛射剂227至2340g并且在再次混合后填充入金属罐,用每次启动释放100ul混悬液的计量阀封闭。
每次启动释放50ug格隆溴铵和2.5mg孟鲁司特。
Claims (22)
1.用于治疗呼吸系统疾病包括过敏性鼻炎、支气管哮喘、COPD或普通感冒的抗胆碱能药和至少一种白三烯抑制剂的组合。
2.权利要求1的组合,其中抗胆碱能药为外消旋格隆溴铵,其对映体之一尤其是R,R-格隆溴铵,或其非对映异构体之一,或它们的生理学可接受的盐或其混合物。
3.权利要求2的组合,其中抗胆碱能药为R,R-格隆溴铵或其生理学可接受的盐。
4.权利要求1的组合,其中白三烯抑制剂选自孟鲁司特、扎鲁司特、普仑司特、L-648,051、MK-571、维鲁司特(MK-0679)、泊比司特(SK&F 104353-Z2)、AS-35、ICI 204,219、托鲁司特(LY 171,883)或其生理学可接受的盐。
5.权利要求4的组合,其中白三烯抑制剂的每日剂量为1-100mg,优选5-20mg。
6.权利要求1-5中任意一项的组合,其中R,R-格隆溴铵的每日剂量为1-500ug。
7.权利要求1-6中任意一项的组合,其中R,R-格隆溴铵的每日剂量为5-100ug。
8.用于治疗呼吸系统疾病包括过敏性鼻炎、支气管哮喘、COPD或普通感冒的药物,包含抗胆碱能药和至少一种白三烯抑制剂。
9.权利要求8的药物,其特征在于抗胆碱能药为外消旋格隆溴铵,或其对映体之一尤其是R,R-格隆溴铵,或其非对映异构体之一,或它们的生理学可接受的盐或其混合物。
10.权利要求9的药物,其特征在于它包含R,R格隆溴铵或其生理学可接受的盐。
11.权利要求8的药物,其中活性物质以固定组合混合而易于利用,如果合适与常用赋形剂、辅剂和添加剂一起制成适合于吸入应用的药物形式。
12.权利要求8的药物,其中活性物质以单独的包装单元的形式利用,可以以这样的方式从单独的包装单元中取这两种物质,使得它们可以同时吸入应用。
13.权利要求12的药物,其中可以彼此独立地应用活性物质。
14.权利要求11-13之一的药物,其特征在于它为含有或不含抛射剂的可吸入气雾剂。
15.权利要求11-13之一的药物,其特征在于它为可吸入干粉。
16.权利要求11-13之一的药物,其特征在于它为可吸入混悬液或溶液。
17.权利要求11-16之一的药物,在吸入器中呈现。
18.局部用抗胆碱能药和至少一种白三烯抑制剂或它们的生理学可接受的盐在生产用于治疗哺乳动物呼吸系统疾病包括过敏性鼻炎、支气管哮喘、COPD或普通感冒的药物中的应用。
19.权利要求18的应用,其特征在于抗胆碱能药为外消旋格隆溴铵,其对映体或非对映异构体之一,或它们的生理学可接受的盐或其混合物。
20.权利要求19的应用,其特征在于抗胆碱能药为R,R-格隆溴铵或其生理学可接受的盐。
21.权利要求18的应用,其特征在于哺乳动物为猫、狗或马。
22.权利要求18的应用,其中所述疾病的特征在于阻塞性成分或潜在炎症,如哮喘和慢性阻塞性肺病(COPD)。
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CN115792229A (zh) * | 2022-01-28 | 2023-03-14 | 华中科技大学同济医学院附属同济医院 | 鼻分泌物中tPA在制备鼻息肉及其预后检测剂中的应用 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113613657A (zh) * | 2019-01-10 | 2021-11-05 | 江阴优培尔康药业有限公司 | 含有白三烯受体拮抗剂的新型配制品 |
CN115792229A (zh) * | 2022-01-28 | 2023-03-14 | 华中科技大学同济医学院附属同济医院 | 鼻分泌物中tPA在制备鼻息肉及其预后检测剂中的应用 |
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EP1863476A1 (en) | 2007-12-12 |
RU2420285C2 (ru) | 2011-06-10 |
DK1863476T3 (en) | 2016-05-17 |
CA2595791C (en) | 2013-10-08 |
JP4991693B2 (ja) | 2012-08-01 |
EP1863476B1 (en) | 2016-02-03 |
RU2007138270A (ru) | 2009-04-27 |
WO2006097250A1 (en) | 2006-09-21 |
HRP20160373T1 (hr) | 2016-05-06 |
MX2007011273A (es) | 2007-11-08 |
NO340405B1 (no) | 2017-04-18 |
JP2008533072A (ja) | 2008-08-21 |
HK1114013A1 (en) | 2008-10-24 |
NO20075287L (no) | 2007-12-05 |
US20060211729A1 (en) | 2006-09-21 |
PL1863476T3 (pl) | 2016-07-29 |
HUE027076T2 (en) | 2016-08-29 |
NZ560206A (en) | 2009-09-25 |
CA2595791A1 (en) | 2006-09-21 |
ES2570332T3 (es) | 2016-05-17 |
CY1117571T1 (el) | 2017-04-26 |
SI1863476T1 (sl) | 2016-05-31 |
US8268864B2 (en) | 2012-09-18 |
AU2006224842B2 (en) | 2011-09-29 |
AU2006224842A1 (en) | 2006-09-21 |
CN101128196B (zh) | 2013-01-02 |
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