CN104039314A - 含有左旋西替利或其药用盐和孟鲁司特或其药用盐的用于口服给药的稳定的药物制剂 - Google Patents
含有左旋西替利或其药用盐和孟鲁司特或其药用盐的用于口服给药的稳定的药物制剂 Download PDFInfo
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Abstract
本发明涉及用于预防或治疗过敏性鼻炎或哮喘的用于口服给药的药物制剂,所述制剂包括:(a)包含左旋西替利嗪或其药用盐和有机酸的第一颗粒部分;和(b)包含孟鲁斯特或其药用盐的第二颗粒部分。根据本发明的药物制剂包含有机酸作为稳定剂,其可以有效地抑制左旋西替利嗪和孟鲁司特相关物质的产生,并且因此显示出良好的稳定性。
Description
技术领域
本发明涉及用于预防或治疗过敏性鼻炎或哮喘的用于口服给药的药物制剂(药物剂型),该药物制剂包括:(a)包含左旋西替利嗪或其药用盐和有机酸的第一颗粒部分;和(b)包含孟鲁斯特或其药用盐的第二颗粒部分。
背景技术
“过敏性鼻炎”涉及在鼻粘膜的过敏原暴露后,由IgE-介导的炎症诱发的鼻的症状紊乱。过敏性鼻炎包括这样的症状如鼻漏、鼻塞、鼻痒、喷嚏、眼部瘙痒等。
“哮喘”涉及紊乱,其中呼吸道炎症引起支气管粘膜肿胀并且在支气管中发生肌肉痉挛,这会限制肺中气流的进入和排出。哮喘可以引起这样的症状如呼吸困难、剧烈咳嗽,并且在严重情况下,哮喘持续状态甚至可以导致死亡。
过敏性鼻炎和哮喘可以分别发展,然而,有研究表明接近58%的具有过敏性鼻炎的患者也患有哮喘并且85-95%的具有哮喘的患者也受过敏性鼻炎的困扰,该研究显示出所述两种患者群体间的并发症的高发生率。因此,存在开发联合组合物的需要,该联合组合物具有改善的稳定性和疗效以用于治疗所述两种情况。
同时,西替利嗪是(2-(4-((4-氯苯基)苯基甲基)-1-哌嗪基)乙氧基)乙酸,及其左旋和右旋对映异构体分别公开为“左旋西替利嗪”和“右旋西替利嗪”。
左旋西替利嗪可以通过从西替利嗪的外消旋混合物分离获得,或者通过不对称合成获得,如英国专利号2225321中公开的常规方法或美国专利号4800162和5057427中公开的酶生物催化水解。左旋西替利嗪具有抗组胺剂的特性并且因此可用作抗过敏和抗组胺剂的试剂以及抗惊厥药和支气管扩张药。同样,盐酸左旋西替利嗪已批准用于治疗过敏性鼻炎和并且在Xyzal(Yuhan Corporation)有售。
孟鲁司特是抑制半胱氨酸白三烯类I(CysLT1)受体的拮抗剂,其可用于预防和治疗白三烯介导的疾病。特别地,已经报道孟鲁司特在治疗过敏性鼻炎、特应性皮炎、慢性荨麻疹、窦炎、鼻息肉、慢性阻塞性肺病、结膜炎,包括鼻结膜炎、偏头痛、囊性纤维化、病毒性细支气管炎等中是有效的[参见,例如S.E.Dahlen,Eur.J.Pharmacol.,533(1-3),40-56(2006)]。此外,包含孟鲁司特钠的顺尔宁(MSD)被批准用于治疗成人和儿童患者中的哮喘有两年以上,并且目前在市场上可获得。
存在报道涉及双层片剂形式的药物组合物,包含孟鲁司特钠,其在碱性条件下是稳定的,和盐酸左旋西替利嗪,其在酸性条件下是稳定的。[R.T.Rathod,J.Indian Med.Assoc.,107(8),562-564(2009)]。在制备片剂形式的所述组合物中,难于将孟鲁司特和左旋西替利嗪彼此完全分开。即使在形成双层片剂的情况下,也不能机械地完全分开每种活性成分。而且,需要双层压片机以便制造这样的片剂。
此外,左旋西替利嗪在物化性质方面也是不稳定的,并且难于制备抗老化的稳定产品。存在左旋西替利嗪的3种主要降解产物,该降解产物包括式(I)的相关物质A、式(II)的相关物质B、和式(III)的相关物质F。相关物质A和B通过左旋西替利嗪的水解产生,和相关物质F通过左旋西替利嗪与赋形剂或硬胶囊的释放剂的副反应产生。实际上,左旋西替利嗪显示了在加速度贮存条件下相关物质A、B和F形成的增加的速率,并且因此在胶囊制剂的制造期间,并不易于提供稳定性。
式(I)
式(II)
式(III)
当暴露在光、热、或潮湿下时,已知孟鲁司特是不稳定的,并且产生如式(IV)的孟鲁司特亚砜和式(V)的孟鲁司特顺式异构体的这样的降解产物。根据参考文献[参见M.M.Al Omari等.,J.Pharm.and Biomed.Anal.,45,465-471(2007)],当市售的顺尔宁可嚼片剂暴露在日光下,在3周后,孟鲁司特亚砜的量提高2.4%;并且当0.1M盐酸溶液中的孟鲁司暴露在钠灯下6h时,孟鲁司特顺式异构体的量增加14.6%。如报道所示,并不易于制备抗老化的稳定的孟鲁司特产品。
式(IV)
式(V)
在硬胶囊的制造期间,使用胶囊材料和赋形剂以维持胶囊形状并且使得所述胶囊表面光滑。胶囊材料的实例包括明胶、普鲁兰多糖(支链淀粉,普鲁兰,pullulan)、羟丙基甲基纤维素(羟丙甲基纤维素,羟丙基甲基纤维素)、聚乙烯醇等;并且赋形剂的实例包括二乙酰化单甘油酯、蔗糖脂肪酸酯、月桂基硫酸钠等。同样,诸如矿物油、卵磷脂等的释放剂用于从模具中容易地释放胶囊,所述模具形成胶囊的形状。
本发明的发明人对联合制剂(组合制剂)进行了研究,该联合制剂包含左旋西替利嗪或其药用盐和孟鲁司特或其药用盐作为活性成分。已经发现当左旋西替利嗪和孟鲁司特以分开的片剂制备并且随后填充进硬胶囊中时,由于来自赋形剂和释放剂的材料以及存在于胶囊中的湿润的内含物(水分含量),相比于单独活性成分的片剂形式的组合物,相关物质的量更快速地升高,并且因此活性成分的稳定性劣化。因此,本发明的发明人致力于解决所述问题并且已经发现当在包含左旋西替利嗪的颗粒部分中使用诸如柠檬酸的有机酸时,左旋西替利嗪和孟鲁司特相关物质的生产可以被有效抑制,并且从而具有良好的长时期贮存稳定性,即使在活性成分填充进硬胶囊中后。
发明内容
因此,本发明的目的是提供用于口服给药的药物制剂,该药物制剂包含左旋西替利嗪或其药用盐和孟鲁司特和其药用盐,其中活性成分被装入硬胶囊中以用于良好的长期贮存稳定性,用于预防或治疗过敏性鼻炎或哮喘。
本发明的另一个目的是提供用于制备上述用于口服给药的药物制剂的方法。
根据本发明的目的,提供了用于预防或治疗过敏性鼻炎或哮喘的用于口服给药的药物制剂,该药物制剂包括:
(a)包含左旋西替利嗪或其药用盐和有机酸的第一颗粒部分;和
(b)包含孟鲁司特或其药用盐的第二颗粒部分。
根据本发明的另一个目的,提供了用于制备所述药物制剂的方法,其包括以下步骤:
(i)混合左旋西替利嗪或其药用盐、药用添加剂和有机酸,并将所述混合物制成片剂,其中,基于100份的左旋西替利嗪,所述有机酸的用量为40至1000重量份。
(ii)混合孟鲁司特或其药用盐和药用添加剂并将所述混合物制成片剂;和
(iii)将在步骤(i)中获得的所述左旋西替利嗪片剂和在步骤(ii)中获得的所述孟鲁司特片剂填充进硬胶囊。
根据本发明的又一个目的,提供了通过上述方法制备的胶囊制剂。
附图说明
当结合所述附图时,由本发明的下列说明,本发明的上述和其他的目的以及特征将变得显然。
图1示出了在加速贮存条件(40℃/75%RH)6个月下,用于在实施例1至6和比较例1中获得的胶囊制剂的左旋西替利嗪相关物质的量;
图2示出了在加速的贮存条件(40℃/75%RH)6个月下,用于在实施例1至6和比较例1中获得的胶囊制剂的孟鲁司特相关物质的量;
图3示出了本发明的胶囊制剂的示意图。
具体实施方式
以下,对本发明进行详细说明。
本发明提供了用于预防或治疗过敏性鼻炎或哮喘的药物制剂,其包括(a)包含左旋西替利嗪或其药用盐的第一颗粒部分;和(b)包含孟鲁司特或其药用盐的第二颗粒部分。
本发明的药物制剂使用抗组胺试剂、左旋西替利嗪作为第一活性成分以减少早期过敏性鼻炎和哮喘反应,以及使用抗-白三烯药剂、孟鲁司特作为第二活性成分以治疗和预防晚期鼻炎的主要症状之一,即鼻塞和哮喘。
本发明中包含在所述第一颗粒部分中的左旋西替利嗪或其药用盐例如披露在欧洲专利申请号0058146、0601028和0801064、英国专利号2225320和2225321、美国专利号5478941、和国际专利公开号WO97/37982中。左旋西替利嗪的药用盐可以包括但不限制于药用无毒的有机或无机酸的酸加成盐,如乙酸、柠檬酸、马来酸、琥珀酸、抗坏血酸、盐酸、氢溴酸、硫酸、磷酸等的盐;金属盐(例如,钠盐或钾盐)、铵盐、胺盐、和氨基酸盐,优选左旋西替利二盐酸盐。左旋西替利嗪或其药用盐的每日剂量是0.4至100mg,优选地1至50mg,更优选地2.5至20mg每单位剂量形式。
本发明中包含在第二颗粒部分中的孟鲁司特或其药用盐优选地是孟鲁司特钠。孟鲁司特或其药用盐的每日剂量是0.4至100mg,优选地1至50mg,更优选地2.5至20mg每单位剂量形式。
本发明的药物制剂包含有机酸作为稳定剂,基于100份的左旋西替利嗪,含量为40至1000重量份,优选50至500重量份。
由于胶囊的赋形剂和释放剂,所述有机酸可以减少生产的左旋西替利嗪相关物质和孟鲁司特相关物质的产生。如果所述有机酸的量少于40重量份,则左旋西替利嗪和孟鲁司特稳定性上的作用变得不重要;同时,当给药至身体时,超过1000重量份的有机酸的量可以引起刺激并且不必要的有机酸可以吸入身体系统。
所述有机酸的实例可以选自由以下组成的组:柠檬酸、酒石酸、琥珀酸、谷氨酸、天门冬酸、草酸、苹果酸、乙酸、山梨酸、抗坏血酸、藻酸、富马酸、乳酸和它们的混合物。
本发明的药物制剂可以以选自由粉末、颗粒、小丸、片剂和胶囊,优选以胶囊的形式组成的组的口服固态药物制剂形式制备。
在本发明的一个实施方式中,本发明的药物制剂是胶囊制剂,其包括(a)包含左旋西替利嗪或其药用盐和有机酸的第一颗粒部分;和(b)包含孟鲁司特或其药用盐的第二颗粒部分,其中所述颗粒部分物理上分开填充,并填充进胶囊。
所述第一或第二颗粒部分可以以片剂的形式,优选以微型片剂的形式。
所述第一或第二颗粒部分可以各自进一步包含药用添加剂。所述药用添加剂可以选自由以下构成的组:稀释剂、崩解剂、粘合剂、润滑剂、以及它们的混合物。
所述稀释剂的合适的实例可以包括微晶纤维素、乳糖、ludipress、甘露醇、磷酸二氢钙、淀粉、低取代的羟丙基纤维素、和它们的混合物。基于所述片剂的总重量,所述稀释剂的用量范围可以是从按重量计1至99%,优选按重量计5至95%。
崩解剂的实例可以包括在液体环境中表现出稳定崩解的任何材料,其选自由以下组成的组:交聚维酮、羟基乙酸淀粉钠、交联羧甲基纤维素钠、低取代的羟丙基纤维素、淀粉、藻酸盐或其钠盐和它们的混合物。优选地,所述崩解剂可以是交聚维酮、羟基乙酸淀粉钠、交联羧甲基纤维素钠、低取代的羟丙基纤维素或它们的混合物。基于所述片剂的总重量,所述崩解剂的用量范围可以是从按重量计1至30%,优选地按重量计2至20%。
所述粘合剂的实例可以包括羟丙基纤维素、羟丙基甲基纤维素、聚乙烯基吡咯烷酮、共聚维酮、聚乙二醇、轻质无水硅酸、合成硅酸铝、硅酸盐衍生物如硅酸钙或硅酸铝酸镁、磷酸盐如磷酸氢钙、碳酸盐、如碳酸钙以及它们的混合物。基于所述片剂的总重量,所述粘合剂的用量范围可以是从按重量计1至30%,优选地按重量计2至20%。
润滑剂的实例可以包括硬脂酸、硬脂酸的金属盐、如硬脂酸钙或硬脂酸镁、滑石粉、胶体二氧化硅、蔗糖脂肪酸酯、氢化植物油、高熔点蜡、甘油脂肪酸酯、甘油二十二烷酸酯和它们的混合物。基于所述片剂的总重量,所述润滑剂的用量范围可以从按重量计0.3至5%,优选地按重量计0.5至3%。
此外,包含所述第一或第二颗粒部分的每种片剂可以进一步包含包衣层。所述包衣层可以在选自所述片剂的至少一种表面上形成以完全分开孟鲁司特和左旋西替利嗪。
在本发明中,用于所述包衣层的包衣基质可以是常规的高分子化合物。包衣基质的实例可以包括羟丙基甲基纤维素(羟丙甲纤维素)、羟丙基纤维素、甲基纤维素、乙基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、羟乙基纤维素,但并不限于此。所述包衣基质的量优选地维持在最小以改善生产效率和提供用于给药的最优尺寸的制剂。因此,基于所述片剂的总重量,所述包衣基质的用量范围可以从按重量计0.5至50%,优选地按重量计1至10%。
在本发明的胶囊制剂中,所述胶囊可以是任意的常规硬胶囊,其通常用于药物的制备。用于本发明的所述硬胶囊基质可以选自由以下组成的组:明胶、普鲁兰多糖(NP capsTM等;Capsugel)、羟丙基甲基纤维素和聚乙烯醇。
在本发明中,所述硬胶囊可以具有用于药物制备的任意的常规胶囊尺寸。硬胶囊的内部容积随其尺寸变化:No.00(0.95mL),No.0(0.68mL),No.1(0.47mL),No.2(0.37mL),No.3(0.27mL)和No.4(0.20mL)(Suheung Capsule Co,Korea)。所述胶囊的尺寸可以优选地出于患者的方便是小的;然而,由于填充到所述胶囊中的内含物的质量限制,用于本发明中的所述胶囊的尺寸可以包括No.0,No.1,No.2,No.3,和No.4,优选No.1,No.2,和No.3。
本发明的药物制剂可以用于预防或治疗过敏性鼻炎或哮喘,并且所述过敏性鼻炎可以选自由诸如鼻漏、鼻塞、鼻痒、喷嚏和眼部瘙痒的症状组成的组。
此外,本发明提供了用于制备药物制剂的方法,该方法包括以下步骤:(i)混合左旋西替利嗪或其药用盐、药用添加剂和有机酸,并且将所述混合物制成片剂,其中基于100份的左旋西替利嗪,所述有机酸的用量为40至1000重量份。(ii)混合孟鲁司特或其药用盐和药用添加剂并将所述混合物制成片剂;和(iii)将在步骤(i)中获得的所述左旋西替利嗪片剂和在步骤(ii)中获得的所述孟鲁司特片剂填充进硬胶囊。
所述方法可以进一步包括包被在步骤(i)或(ii)中生产的所述片剂的步骤。本发明中制备的所述胶囊制剂可以通过口服途径等给药。
此外,本发明提供了通过上面的方法制备的胶囊制剂。
本发明的胶囊制剂包括在所述硬胶囊中物理分开的孟鲁司特和左旋西替利嗪,和从而完全分开所述两种总活性成分。因此,在两种活性成分之间的反应性可以最小化并且增强所述制剂的稳定性,从而优化治疗效力。还有利的是,由于用于单一制剂的时间独立的稳定性的评估的预先存在的分析方法也可以用于本发明的制剂,而不是开发新的分析方法。此外,包含在所述第一颗粒部分中的所述有机酸不仅可以增强左旋西替利嗪的稳定性,还稳定孟鲁司特。
下列实施例旨在进一步说明本发明而不限制其范围。
实施例1:联合制剂I的制备
将盐酸左旋西替利嗪、ludipress(BASF)、微晶纤维素、柠檬酸、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000,Colorcon)制备的包衣液涂覆左旋西替利嗪片剂。
同时,将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以得到孟鲁司特片剂。然后,将孟鲁司特片剂用通过在蒸馏水中溶解羟丙基甲基纤维素,羟丙基纤维素,二氧化钛,氧化铁黄,氧化铁红制备的包衣液涂覆。
最终,将由此获得的所述两种片剂填充到主要由明胶组成的No.1硬胶囊中以获得包含10mg孟鲁司特和5mg左旋西利替嗪的胶囊制剂。
实施例2:联合制剂II的制备
除了使用主要由普鲁兰多糖组成的硬胶囊外,重复实施例1的步骤以得到包含10mg孟鲁司特钠和5mg的左旋西替利嗪的胶囊制剂。
实施例3:联合制剂III的制备
除了使用主要由羟丙基甲基纤维素组成的硬胶囊外,重复实施例1的步骤以得到包含10mg孟鲁司特钠和5mg的左旋西替利嗪的胶囊制剂。
实施例4:联合制剂IV的制备
将盐酸左旋西替利嗪、ludipress、微晶纤维素、酒石酸、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000)制备的包衣液涂覆左旋西替利嗪片剂。
同时,将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以得到孟鲁司特片剂。然后,将孟鲁司特片剂用通过在蒸馏水中溶解羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、氧化铁黄、氧化铁红制备的包衣液涂覆。
最终,将由此获得的所述两种片剂填充到主要由明胶组成的No.1硬胶囊中以获得包含10mg孟鲁司特和5mg左旋西利替嗪的胶囊制剂。
实施例5:联合制剂V的制备
将盐酸左旋西替利嗪、ludipress、微晶纤维素、琥珀酸、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000)制备的包衣液涂覆左旋西替利嗪片剂。
同时,将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以得到孟鲁司特片剂。然后,将孟鲁司特片剂用通过在蒸馏水中溶解羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、氧化铁黄、氧化铁红制备的包衣液涂覆。
最终,将由此获得的所述两种片剂填充到主要由明胶组成的No.1硬胶囊中以获得包含10mg孟鲁司特和5mg左旋西利替嗪的胶囊制剂。
实施例6:联合制剂VI的制备
将盐酸左旋西替利嗪、ludipress、微晶纤维素、抗坏血酸、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000)制备的包衣液涂覆左旋西替利嗪片剂。
同时,将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以得到孟鲁司特片剂。然后,将孟鲁司特片剂用通过在蒸馏水中溶解羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、氧化铁黄、氧化铁红制备的包衣液涂覆。
最终,将由此获得的所述两种片剂填充到主要由明胶组成的No.1硬胶囊中以获得包含10mg孟鲁司特和5mg左旋西利替嗪的胶囊制剂。
比较例1:联合制剂VII的制备
将盐酸左旋西替利嗪、ludipress、微晶纤维素、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000)制备的包衣液涂覆左旋西替利嗪片剂。
同时,将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以得到孟鲁司特片剂。然后,将孟鲁司特片剂用通过在蒸馏水中溶解羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、氧化铁黄、氧化铁红制备的包衣液涂覆。
最终,将由此获得的所述两种片剂填充到主要由明胶组成的No.1硬胶囊中以获得包含10mg孟鲁司特和5mg左旋西利替嗪的胶囊制剂。
比较例2:联合制剂VIII的制备
除了使用主要由普鲁兰多糖组成的硬胶囊外,重复比较例1的步骤以获得包含10mg孟鲁司特钠和5mg的左旋西替利嗪的胶囊制剂。
比较例3:联合制剂IX的制备
除了使用主要由羟丙基甲基纤维素组成的硬胶囊外,重复比较例1的步骤以获得包含10mg孟鲁司特钠和5mg的左旋西替利嗪的胶囊制剂。
比较例4:联合制剂X的制备
将盐酸左旋西替利嗪、ludipress、微晶纤维素、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并且加入磷酸,并使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000)制备的包衣液涂覆左旋西替利嗪片剂。
同时,将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以得到孟鲁司特片剂。然后,将孟鲁司特片剂用通过在蒸馏水中溶解羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、氧化铁黄、氧化铁红制备的包衣液涂覆。
最终,将由此获得的所述两种片剂填充到主要由明胶组成的No.1硬胶囊中以获得包含10mg孟鲁司特和5mg左旋西利替嗪的胶囊制剂。
比较例5:联合制剂XI的制备
将盐酸左旋西替利嗪、ludipress、微晶纤维素、氢氧化钠、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并且使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000)制备的包衣液涂覆左旋西替利嗪片剂。
同时,将孟鲁司特钠、D-甘露醇、微晶纤维素、轻质无水硅酸、羟丙基纤维素、羟基乙酸淀粉钠和硬脂酸镁过筛并混合,并使用直径为5.5mm的圆形冲头将混合物压成片剂以得到孟鲁司特片剂。然后,将孟鲁司特片剂用通过在蒸馏水中溶解羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、氧化铁黄、氧化铁红制备的包衣液涂覆。
最终,将由此获得的所述两种片剂填充到主要由明胶组成的No.1硬胶囊中以获得包含10mg孟鲁司特和5mg左旋西利替嗪的胶囊制剂。
比较例6:左旋西替利嗪片剂(单一片剂)的制备
将盐酸左旋西替利嗪、ludipress、微晶纤维素、交联羧甲基纤维素钠、轻质无水硅酸和硬脂酸镁过筛并混合,并且使用直径为5.5mm的圆形冲头将混合物压成片剂以获得左旋西替利嗪片剂。然后,使用通过在蒸馏水中溶解Opadry White(Y-1-7000)制备的包衣液涂覆左旋西替利嗪片剂。
实验实施例1:在加速的条件下的稳定性测试
包含在实施例1至6和比较例1至5中制备的左旋西替利嗪和孟鲁司特和在比较例6中制备的左旋西替利嗪的单一片剂的联合胶囊制剂在以下加速贮存条件下保存。测定所述左旋西替利嗪和孟鲁司特的相关物质(杂质)的量以比较所述制剂的稳定性。在表3和表4以及图1和图2显示了所述结果。
<加速的贮存条件>
贮存条件:包括在40℃,75%RH的HDPE瓶中。
测试持续时间:初始和6个月
分析目标:左旋西替利嗪和左旋西替利嗪相关物质,以及孟鲁司特和孟鲁司特相关物质。
<左旋西替利嗪及其相关物质的分析条件>
柱:使用十八烷基甲硅烷基硅胶(颗粒尺寸:5μm)填充具有不锈管(4.6mm的内径×25cm的长度)的Symmetry Shield RP18柱用于HPLC(Waters)。
洗出液:A-蒸馏水(DW):乙腈:10%三氟醋酸(TFA)=69:30:1(v/v/v)
B–DW:乙腈:10%TFA=29:70:1(v/v/v)
[表1]
洗出条件
时间(min) | A(%) | B(%) |
0 | 100 | 0 |
2 | 100 | 0 |
30 | 25 | 75 |
40 | 100 | 0 |
50 | 100 | 0 |
检测器:UV-吸收检测器(在230nm的吸收)
流速:1.2mL/min
柱温度:30℃
<孟鲁司特及其相关物质的条件分析>
柱:使用二异丙基苯乙基硅胶(颗粒尺寸:5μm)填充具有不锈管(4.6mm的内径×25cm的长度)的Zorbax SB-Phenyl柱(Agilent Zorbax)用于HPLC(Waters)。
洗出液:A–包含0.1%TFA的蒸馏水
B–包含0.1%TFA的乙腈
[表2]
洗出条件
时间(min) | A(%) | B(%) |
0 | 60 | 40 |
20 | 10 | 90 |
30 | 10 | 90 |
31 | 60 | 40 |
35 | 60 | 40 |
检测器:UV-吸收检测器(在230nm的吸收)
流速:1.5mL/min
柱温度:25℃
表3中显示左旋西替利嗪相关物质A、B、F的含量变化,并且在表4中显示了孟鲁司特相关物质,即孟鲁司特亚砜和孟鲁司特顺式异构体的变化。
[表3]
左旋西替利嗪相关物质的变化
[表4]
孟鲁司特相关物质的变化
如表3和表4以及图1和图2所示,根据实施例1至6的使用有机酸作为稳定剂的左旋西替利嗪和孟鲁司特的所述联合胶囊制剂和根据比较例6的所述单一片剂导致在所述加速贮存条件下6个月后不显著的变化,并且因此呈现出特别好的贮存稳定性。
相反,根据比较例1至3的不具有有机酸的左旋西替利嗪和孟鲁司特的所述联合胶囊制剂表明,与实施例1至6的本发明的胶囊制剂在加速的贮存条件下6个月后相比,相关物质增加了将近2至10倍。并且,与包含有机酸的样品相比,包含无机酸,即比较例4,和包含碱化剂即比较例5,的左旋西替利嗪和孟鲁司特的所述联合胶囊制剂呈现出所述相关物质的升高的水平。特别地,明显的是,与其他样品相比,根据实施例1至6的具有有机酸的样品仅允许左旋西替利嗪相关物质F忽略不计的量。因此,已发现作为稳定剂的有机酸可以加入至包含左旋西替利嗪和孟鲁司特的所述胶囊制剂中以用于改善所述制剂的总稳定性。
虽然已经相对于上面所述的具体实施方式描述了本发明,但是应该认识到,可以由本领域的技术人员对发明进行各种修改和变化,它们也落入内由所附权利要求所限定的本发明的范围内。
Claims (15)
1.一种用于预防或治疗过敏性鼻炎或哮喘的用于口服给药的药物制剂,所述药物制剂包括:
(a)包含左旋西替利嗪或其药用盐和有机酸的第一颗粒部分;和
(b)包含孟鲁司特或其药用盐的第二颗粒部分。
2.根据权利要求1所述的用于口服给药的药物制剂,基于100份的左旋西替利嗪或其药用盐,所述药物制剂包含40至1000重量份的量的所述有机酸。
3.根据权利要求2所述的用于口服给药的药物制剂,基于100份的左旋西替利嗪或其药用盐,所述药物制剂包含50至500重量份的量的所述有机酸。
4.根据权利要求1所述的用于口服给药的药物制剂,其中,所述有机酸选自由以下组成的组:柠檬酸、酒石酸、琥珀酸、谷氨酸、天门冬酸、草酸、苹果酸、乙酸、山梨酸、抗坏血酸、藻酸、富马酸、乳酸和它们的混合物。
5.根据权利要求1所述的用于口服给药的药物制剂,其中,所述第一颗粒部分或所述第二颗粒部分为微型片剂的形式。
6.根据权利要求1所述的用于口服给药的药物制剂,所述药物制剂是胶囊制剂。
7.根据权利要求6所述的用于口服给药的药物制剂,其中,所述胶囊是硬胶囊。
8.根据权利要求7所述的用于口服给药的药物制剂,其中,所述胶囊由选自由明胶、普鲁兰多糖、羟丙基甲基纤维素和聚乙烯醇组成的组的材料制成。
9.根据权利要求1所述的用于口服给药的药物制剂,其中,所述第一颗粒部分和所述第二颗粒部分物理上是分开的并且被填充在胶囊中。
10.根据权利要求1所述的用于口服给药的药物制剂,其中,所述第一颗粒部分和所述第二颗粒部分各自独立地进一步包含选自由稀释剂、崩解剂、粘合剂、润滑剂和它们的混合物组成的组中的药用添加剂。
11.根据权利要求5所述的用于口服给药的药物制剂,其中,所述微型片剂还包括包衣层。
12.根据权利要求1所述的用于口服给药的药物制剂,其中,所述过敏性鼻炎选自由鼻漏、鼻塞、鼻痒、喷嚏和眼部瘙痒组成的组。
13.一种用于制备胶囊制剂的方法,所述方法包括以下步骤:
(i)混合左旋西替利嗪或其药用盐、药用添加剂和有机酸,并且将混合物制成片剂,其中,基于100份的左旋西替利嗪或其药用盐,所述有机酸的用量为40至1000重量份;
(ii)混合孟鲁司特或其药用盐和药用添加剂并且将混合物制成片剂;以及
(iii)将在步骤(i)中获得的所述左旋西替利嗪片剂和在步骤(ii)中获得的所述孟鲁司特片剂填充到硬胶囊中。
14.根据权利要求13所述的方法,所述方法进一步包括涂覆在步骤(i)或(ii)中制备的所述片剂。
15.一种通过根据权利要求13所述的方法制备的胶囊制剂。
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ZA201405756B (en) | 2016-08-31 |
US9486528B2 (en) | 2016-11-08 |
RU2614382C2 (ru) | 2017-03-24 |
JO3388B1 (ar) | 2019-03-13 |
BR112014016472A2 (pt) | 2017-06-13 |
AR089666A1 (es) | 2014-09-10 |
ES2671428T3 (es) | 2018-06-06 |
MX2014008059A (es) | 2014-10-06 |
BR112014016472A8 (pt) | 2017-07-04 |
SI2800558T1 (en) | 2018-06-29 |
US20140356422A1 (en) | 2014-12-04 |
HK1200337A1 (zh) | 2015-08-07 |
RU2014132428A (ru) | 2016-02-27 |
TR201807978T4 (tr) | 2018-06-21 |
MX354073B (es) | 2018-02-12 |
SG11201403811VA (en) | 2014-08-28 |
EP2800558A1 (en) | 2014-11-12 |
PL2800558T3 (pl) | 2018-08-31 |
KR101418404B1 (ko) | 2014-07-10 |
EP2800558B1 (en) | 2018-04-11 |
TW201332590A (zh) | 2013-08-16 |
BR112014016472B1 (pt) | 2022-03-15 |
KR20130081013A (ko) | 2013-07-16 |
TWI565482B (zh) | 2017-01-11 |
PT2800558T (pt) | 2018-06-05 |
EP2800558A4 (en) | 2015-08-12 |
JP6163165B2 (ja) | 2017-07-12 |
PH12014501545B1 (en) | 2014-10-08 |
WO2013103262A1 (en) | 2013-07-11 |
CN104039314B (zh) | 2017-07-14 |
PH12014501545A1 (en) | 2014-10-08 |
JP2015503579A (ja) | 2015-02-02 |
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