CN1222852A - 含鼻内类固醇和抗组胺剂的鼻喷雾剂 - Google Patents
含鼻内类固醇和抗组胺剂的鼻喷雾剂 Download PDFInfo
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- CN1222852A CN1222852A CN 97195225 CN97195225A CN1222852A CN 1222852 A CN1222852 A CN 1222852A CN 97195225 CN97195225 CN 97195225 CN 97195225 A CN97195225 A CN 97195225A CN 1222852 A CN1222852 A CN 1222852A
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Abstract
本发明涉及鼻子给药的药物组合物,包括a)安全有效量的糖皮质类固醇,它选自倍氯米松、氟尼缩松、氟替卡松、莫米松、布地奈德,其药学上可接受的盐和它们的混合物;b)安全有效量的速效抗组胺,它选自阿伐斯汀、卡比沙明、苯海拉明、氯苯那敏、溴苯那敏、右氯苯那敏、多西拉敏、氯马斯汀、异丙嗪、阿利马嗪、甲地嗪、羟嗪、美吡拉敏、rocastine、曲吡拉敏、美克洛嗪、曲普利啶、阿扎他定、赛庚啶、苯茚胺,它们的药学上可接受的盐和它们的混合物;和c)水性的鼻内载体,其中组合物不含辣椒素,优选的是没有粉末或颗粒。本发明也涉及治疗与季节有关或四季不断的过敏性鼻炎的方法,包括给予安全有效量的本发明鼻内药物组合物。
Description
技术领域
本发明涉及包括安全有效量的糖皮质类固醇和抗组胺的新颖的鼻喷雾剂组合物。
发明背景
过敏性疾病是全世界急性和慢性疾病的主要病因。这些疾病通常以急性或慢性鼻炎形式存在。过敏性鼻炎的症状是鼻、眼和腭部刺激，打喷嚏和过度分泌。这些症状在暴露于过敏源后发作。主要的过敏源通常是草和/或树木花粉，因此，过敏性鼻炎在春季和夏季很为常见。
据信，过敏性鼻炎的症状是这样产生的：组胺对H-1受体的刺激，然后激活副交感神经，导致鼻分泌物和鼻塞的增加。组胺最初从致敏的肥大细胞组织中释放。当空中传播的过敏源与和肥大细胞膜相连的特异性的IgE抗体组合时就导致了过敏。
抗组胺和/或减充血剂是治疗过敏性鼻炎传统的药物。其它的治疗方法包括使用色甘酸钠(cromolyn sodium)、高渗盐溶液或免疫疗法。
Hagen等在美国专利4,767,612揭示了将鼻内皮质类固醇的疗法作为治疗过敏性鼻炎的有效手段；在此并入供参考。但是，由于鼻内皮质类固醇的作用很缓慢(通常在1-3天产生活性)，且偶有“突破性”的症状，故这些化合物的效果是有限的。由于相似的理由，这类产品也会使使用者难以顺从。
虽然过敏性鼻炎领域有许多阐述揭示，但人们仍需要另外一些没有刺激性的粉末或颗粒以及诸如辣椒素刺激性的药物的制剂，所述的制剂能迅速地改善、减轻症状，同时也让使用者易于接受。
本发明者业已发现，通过使鼻皮质类固醇与速效抗组胺组合不仅能延迟作用明显降低的时间，而且所得的本发明组合物也能促进与季节有关或四季不断的过敏性鼻炎的症状的缓解。另外，将抗组胺与鼻类固醇组合使症状缓解更为改善(如促进鼻和眼睛症状减轻)。此外，鼻内给予抗组胺需要的剂量低于口服给药需要的剂量，从而减少了潜在的令人讨厌的副作用(如瞌睡)。通过解决这类问题，本发明的组合物也有助于改善全体病人的接受性。
因此，本发明的一个目的是提供在治疗与季节有关或四季不断的过敏性鼻炎的症状中有效的药物组合物。
本发明的另一个目的是提供用来治疗与季节有关或四季不断的过敏性鼻炎的没有刺激剂的药物组合物。
本发明的再一个目的是提供治疗季节性或四季不断的过敏性鼻炎的安全有效方法。
这些目的和其它目的将从下列阐述中得以显然。
发明综述
本发明涉及鼻子给药的药物组合物，包括：
a)安全有效量的糖皮质类固醇，它选自倍氯米松、氟尼缩松、氟替卡松、莫米松、布地奈德，其药学上可接受的盐和它们的混合物；
b)安全有效量的速效抗组胺，它选自阿伐斯汀、卡比沙明、苯海拉明、氯苯那敏、溴苯那敏、右氯苯那敏、多西拉敏、氯马斯汀、异丙嗪、阿利马嗪、甲地嗪、羟嗪、美吡拉敏、rocastine、曲吡拉敏、美克洛嗪、曲普利啶、阿扎他定、赛庚啶、苯茚胺，它们的药学上可接受的盐和它们的混合物；和
c)水性的鼻内载体，
其中组合物不含辣椒素，优选的是没有粉末或颗粒。
本发明也涉及治疗与季节有关或四季不断的过敏性鼻炎症状的方法，包括给予安全有效量的本发明鼻内药物组合物。
“与季节有关或四季不断的过敏性鼻炎的症状”表示眼和腭部刺激、打喷嚏、粘膜分泌过度、鼻子充血和发痒。
本文的“安全有效量”表示有效地减轻和/或治疗症状的量，其中的活性组分对人体没有副作用，相应地具有合理的危险/得益比。
本文使用的“速效”指给药后15-30分钟即发生作用。
组合物的pH优选的是约5-9，最佳为约5.5-7。
除非特别指出，本文的所有百分数和比率是以重量为基。另外，除非特别指出，所有的测量都在25℃下作出。
发明详述
本发明的组合物含有如下所述的必不可少的组分及其各种任选的组分。
更具体的是，本发明组合物供鼻内给药，含治疗安全有效量的本文所述药物。它们优选地是等渗水溶液、悬浮液或粘稠的组合物，它们都可被缓冲成选定的pH。必不可少的组分
糖皮质激素药
该类试剂具有有效的糖皮质激素活性和弱的盐皮质激素活性。最常用于本发明的糖皮质激素包括选自倍氯米松、氟尼缩松、氟替卡松、莫米松、布地奈德，其药学上可接受的盐和它们的混合物的物质。
当糖皮质激素用于本发明组合物时，其存在浓度宜为约0.001-0.1％，最佳为约0.01-0.1％。
抗组胺药
最常用于本发明的抗组胺是速效组胺H-1受体拮抗剂。这类H-1受体抗组胺选自下组抗组胺药：烷基胺、乙醇胺、亚乙二胺、哌嗪、吩塞秦、哌啶。
速效抗组胺的例子包括阿伐斯汀、卡比沙明、苯海拉明、氯苯那敏、溴苯那敏、右氯苯那敏、多西拉敏、氯马斯汀、异丙嗪、阿利马嗪、甲地嗪、羟嗪、美吡拉敏、rocastine、曲吡拉敏、美克洛嗪、曲普利啶、阿扎他定、赛庚啶、苯茚胺，它们的药学上可接受的盐和它们的混合物。没有理论的限制，据信抗组胺另外改善了糖皮质激素的释放，促进了糖皮质激素的作用。当用于本发明组合物时，抗组胺组分优选的存在浓度为约0.01-3.0％，最好是约0.01-1％。
药物上可接受的水性鼻内载体
本发明的一个其它必不可少组分是药学上可接受的鼻内载体。优选的是，鼻内组合物是等渗的，即，其渗透压与血液和泪液的相同。本发明组合物所需的等渗性可用，如已经存在的氯化钠，或诸如右旋糖、硼酸、柠檬酸、酒石酸钠、磷酸钠、磷酸钾、丙二醇或其它无机或有机溶质待的药学上可接受的试剂。氯化钠对于含钠离子的缓冲液特别优选，进一步的氯化钠等价物的例子在Remington’sPharmaceutical Sciences 1491-1497页(alfonso Gennaro第18版，1990)得以揭示，在此并入供参考。
最适用的是水性、等渗盐水溶液载体。这些溶液通常含氯化钠作为盐，在Remington’s Pharmaceutical Sciences,第17版(1985)835页中完全揭示，在此并入供参考。溶液中的盐存在水平为约0.01-2％，优选的是约0.5-1.0％，最好是约0.5-0.75％。
任何上述抗组胺和糖皮质激素组合通过与无毒性的药学上可接受的鼻内载体配制成制剂，它可常规地鼻内给予温血动物，以得到所需的治疗反应。合适的无毒性药学上可接受的鼻内载体是本技术领域公知的，在Remington’sPharmaceutical Sciences，第17版，1985中充分揭示。很明显，对合适的载体形式的选择将根据所需的特定的鼻剂型的真正性质而定，如药物是否被配制成鼻溶液(用作滴剂或喷雾剂)、鼻悬浮剂、鼻油膏剂、鼻凝胶剂或其它鼻制剂。优选的鼻剂型是溶液、悬浮剂和凝胶剂，除了抗组胺和糖皮质激素外，它通常在大量水(优选的是纯水)中还含氯化钠。也可存在少量其它组分，如pH调节剂(如，诸如NaOH的碱)、乳化剂或分散剂、缓冲剂、防腐剂、湿润剂和成胶剂(如甲基纤维素)。
较好的是，组合物通过对鼻粘膜局部给予安全有效量组合物来治疗鼻症状。施加于鼻粘膜的抗组胺和糖皮质激素组合量和给药频率根据个体需要而改变，但是，推荐的是局部给药范围是每天给予一次到三次，优选的是每天给予两次，最好的是每天给予一次。实践上，选定的治疗组合物通常被制备成单位剂型或使特定治疗有效量的选定的抗组胺药和糖皮质激素的组合发挥作用。在特定的场合下，使用这些剂型或多剂型单位的部分。典型的剂型单位是每剂(如50-150毫克喷雾组合物)可释放约0.5-50mcg糖皮质激素药和约5-75毫克抗组胺药。典型的剂量是含有每个鼻孔1-3次喷雾。
任选的组分
另外的抗组胺可被任选地掺入本发明组合物。这类抗组胺药优选地包括持效大于6小时的药物。这类抗组胺药的例子包括特非那定、氮斯汀、西替利嗪、阿司咪唑、依巴斯汀、酮替芬、洛度沙胺、氯雷他定、左卡巴斯汀、美喹他嗪、奥沙米特、司他斯汀、他齐茶碱、替美斯汀或其药学上可接受的盐和它们的混合物。也可使用上述抗组胺的活性代谢物。美国专利3,878,217和4,254,129(分别于1975,4,15和1981,3,3颁布，授予Carr等)，美国专利5,375,693(1994,12,27授予Woosley等)和欧洲专利648759揭示了这类代谢物的例子。
用于本发明的任选组分包括减充血剂。用于本发明的减充血剂可选自拟交感剂；其例子包括伪麻黄碱、去氧麻黄碱(desoxyephedrine)、丙己君、苯丙醇胺、赛洛唑啉、苯福林、四氢唑林、萘甲唑林、羟甲唑啉、曲马唑啉和它们的药学上可接受的盐。5-(2-咪唑啉基氨基)苯并咪唑化合物也可用作减充血剂。也可使用这些减充血剂的混合物。
当拟交感剂用于本发明组合物时，它可以较好约0.01-0.5％，最好的是约0.05-0.1％的浓度掺入。
本发明组合物也可含黄嘌呤衍生物，如咖啡因和甲基黄嘌呤之类。黄嘌呤可以约0.01-1％，最好是约0.1-0.5％的浓度掺入组合物。也可混入黄嘌呤衍生物的混合物。
本发明组合物也可含有抗过敏药。合适的抗过敏剂包括，但不限于，色甘酸钠、酮替芬、N-烯丙基-(二氯-3,4-苄基)-2-甲基氨基-2-丙醇-1、AP-582(药物设计号3055,Ariad Pharmaceuticals研究)、安多司特、奥沙米特和它们的药学上可接受的盐。也可使用这些抗赤敏剂的混合物。
同样，诸如乙酰基半胱氨酸的化痰剂和诸如异丙托溴铵的抗胆碱药也可用于本发明的组合物。
非鸦片类止痛剂，如噁丙嗪也可任选地用于本发明组合物。噁丙嗪的鼻内使用由Namiki等在Studies on improvement of pharmaceutical preparations prescribedin hospitals.VI.oxaprozin nasal spray，药物设计和释放(Drug Design and Delivery)1982:311-321页阐述，在此并入供参考。优选的非鸦片类止痛剂的例子还包括，但不限于，扑热息痛、乙酰水杨酸、布洛芬、依托立林、芬布芬、非诺洛芬、酮咯酸、氟比洛芬、吲哚美辛、酮洛芬、萘普生，它们药学上可接受的盐、光学活性消旋体和混合物。本文优选使用的是非鸦片类止痛剂的S(+)异构体。美国专利4,522,828(1985,6,11 Sunshine等)揭示了这类药物的其它例子；该专利并入本文供参考。
合成的鸦片止痛剂，如布托菲诺也可掺入本发明的组合物中。Baumel在Migraine:A pharmacologic review with newer options and delivery modalities，神经学1994；44(增补本)：s13-s17页中揭示了布托菲诺的鼻内用途，在此并入供参考。合成的鸦片止痛剂的优选例子包括阿芬他尼、丁丙诺啡、芬它尼、度冷丁、美沙酮、纳布啡、natrexone、右丙氧芬、喷它佐辛、舒芬太尼，它们的药学上可接受的盐及其混合物。
白三烯受体拮抗剂也可掺入本发明的组合物。合适的例子包括，但不限于，诸如Zafirlukast(Zccolate,Zeneca)、MK-571(Merck,Sharp和Dohme)、LY171883、Wy-45,911、LY163443、ONO-RS-411和ONO-RS-347和ICI198.615的实验试剂。欧洲专利318093和Fleisch,J.H.在Development of CysteinylLeukotriene Receptor Antagonists，炎症研究发展(Advances in InflammationResearch)12卷173-189(A.Lewis等编辑1988)一文中详细地讨论了白三烯受体拮抗剂，两篇文献都并入本文供参考。
脂肪氧合酶抑制化合物也可掺入本发明的组合物。合适的例子如美国专利4,873,259(授予Summers等,1989,10,10颁布)和美国专利5,037,853(授予Brooks等，1991,8,6颁布)，在此并入两篇专利全文供参考。
也可使用各种芳香剂组分(如醛和酯)。这些芳香剂类包括，如，薄荷醇、樟脑、桉叶油素、苯甲醛(樱桃、杏仁)；柠檬素(柠檬、酸橙)；橙花醛；癸醛(桔子、柠檬)；C-8醛、C-9醛和C-12醛(柑橘类水果)；甲苯醛(樱桃、杏仁)；2,6-二甲基-辛醛(绿色水果)；和2-十二醛(柑橘、中国柑桔)。适用于本发明另外的芳香剂组分包括美国专利4,136,163(授予Watson等)美国专利4,459,425(授予Amano等)和美国专利4,230,688(授予Rowsell等)中揭示的芳香剂；在此并入供参考。也可使用这些芳香剂的混合物。
组合物的粘度可用药学上可接受的增稠剂维持在选定的水平。甲基纤维素是优选的，因为它经济易得且易于加工。其它合适的增稠剂包括，如黄原胶、微晶纤维素、羧甲基纤维素、脱乙酰壳多糖、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、羟乙基纤维素、羧基乙烯基聚合物、卡波末等，或它们的药用盐。也可使用这类增稠剂的混合物。增稠剂的优选浓度根据选定的试剂而定。重要处在于使用达到选定粘度的用量。粘稠组合物通常从溶液中通过加入这类增稠剂来制备。
本发明优选的组合物含有约0.01-5％湿润剂以抑制粘膜干燥并防止刺激。可使用各种药学上可接受的湿润剂，包括，如山梨醇、丙二醇、聚乙二醇、甘油或其混合物。对于增稠剂，其浓度随选定的试剂而改变，但这些试剂的存在与否或它们的浓度不是本发明的必要特征。
可用治疗上可接受的表面活性剂增加穿过鼻粘膜的吸附。典型用于这些治疗组合物的表面活性剂包括山梨醇的脂肪酸部分酯的聚氧乙烯衍生物，如聚山梨醇酯80、聚氧基40硬脂酸酯、聚氧乙烯50硬脂酸酯和辛氧基醇及其环氧乙基化的叔辛基苯酚甲醛聚合物(Sterling Organics出售，商品名为tyloxapol)或它们的混合物。一般浓度占总重量的0.5-10％。
药学上可接受的防腐剂通常用来增加本发明组合物的货架寿命。苄基醇是合适的，但也可使用各种防腐剂，包括，如对羟苯甲酸酯类，苯乙基醇、乙基汞硫代水杨酸钠、氯代丁醇、醋酸苯汞或苯扎氯铵。本文使用的最佳防腐剂系统包括苯扎氯铵、氯己型葡糖酸酯和EDTA二钠。防腐剂合适的浓度范围占总重量的0.001-2％，根据选定的防腐剂可有合适的改变。这些防腐剂的混合物也可使用。
也可掺入上述任选组分的任何组合。
其它任选组分：本发明乳剂组合中可加入各种另外的组分。这些另外的组分包括能帮助形成成膜性质和制剂实质的各种聚合物，保持组合物抗微生物完整性的防腐剂，抗氧剂和适合美观用的试剂，如芳香剂、色素和着色剂。
组合物也可含少量不溶组分，供肉眼观看用，如热致变色液晶材料，诸如微胶囊化的胆甾烯基酯和化学品为基的手性向列型液晶(nonsterol)，如4-烷基(氧基)苯甲酸(2-甲基丁基)苯基酯，从Hallcrest Glenview，(美国伊利诺斯60025)购得，也可使用这些和上述组分的组合。
实施例
下列实施例进一步揭示和显示了本发明范围里的技术方案。给出的实施例仅供阐述，并非用来限制本发明，因为能作出许多改变但不背离本发明的精神和范围。
实施例1
用类似于下述的常规的混合技术使下列组分结合来制备本发明的鼻内给药药物组合物。
组分 重量％
倍氯米松二丙酸盐，单水合物 0.042
氯苯那敏 0.500
avicel RC-5911 1.200
右旋糖 5.100
聚山梨醇酯80 0.050
苯扎氯铵 0.020
苯乙基醇 0.025
蒸馏水 加到100毫升
1微晶纤维素和羧甲基纤维素钠，FMC公司提供。
在适当大小的容器里将上列组分一个一个地加入水中混合，加入下一个前应先溶解。加完所用组分后，将纯水加到合适的重量。
给药时将约0.5克组合物局部用于鼻子以减轻过敏或过敏样症状。
实施例2
用类似于实施例1所述的常规混合技术混合下列组分来制备本发明的鼻内给药药物组合物。
组分 重量％
氟尼缩松 0.025
氯苯那敏 0.350
左卡巴斯汀 0.0125
丙二醇 2.000
聚乙二醇 1.000
乙二胺四乙酸 0.050
苯扎氯铵 0.010
蒸馏水 加到100毫升
混合上述组分。
将约0.5克组合物局部给药予鼻子，以减轻过敏或过敏样症状。
实施例3
用类似于实施例1所述的常规混合技术混合下列组分来制备本发明的鼻内给药药物组合物。
组分 重量％
曲安奈德 0.050
盐酸阿伐斯汀 0.100
聚山梨醇酯80 0.050
甘油 2.000
羟丙基甲基纤维素 1.000
乙二胺四乙酸 0.050
苯扎氯铵 0.020
蒸馏水 加到100毫升
将约0.5克组合物局部给药予鼻子，以减轻过敏或过敏样症状。
实施例4
用类似于实施例1所述的常规混和技术混合下列组分来制备本发明的鼻内给药药物组合物。
组分 重量％
倍氯米松二丙酸酯，单水合物 0.042
氯苯那敏 0.500
羟甲唑啉 0.050
avicel RC-5911 1.200
右旋糖 5.100
聚山梨醇酯80 0.050
苯扎氯铵 0.020
苯乙基醇 0.025
蒸馏水 加到100毫升
1微晶纤维素和羧甲基纤维素钠，FMC公司提供。
混合上述组分。
将约0.5克组合物局部给药予鼻子，以减轻过敏或过敏样症状。另外，用全部或部分等当量的其它糖皮质激素，如氟替卡松、莫米松、布地奈德，其药学上可接受的盐和它们的混合物，或使用全部或部分的等当量的其它速效抗组胺药，如卡比沙明、苯海拉明、溴苯那敏、右氯苯那敏、多西拉敏、氯马斯汀、异丙嗪、rocastine、阿利马嗪、甲地嗪、羟嗪、美吡拉敏、曲吡拉敏、美克洛嗪、曲普利啶、阿扎他定、赛庚啶、苯茚胺，它们的药学上可接受的盐和它们的混合物，可得到基本相似的结果。此外，上述组合物也可含有拟交感胺类，如伪麻黄碱、苯丙醇胺、苯福林、四氢唑林、萘甲唑林、羟甲唑啉、曲马唑啉、5-(2-咪唑啉基氨基)苯并咪唑化合物，它们的药学上可接受的盐和它们的混合物。本技术领域人员可以很快地了解到其它合适的组分、稀释剂和剂型(或用常规实验途径很容易确定)，它们可进一步掺入上述组合物而不背离本发明的范围和精神。
Claims (10)
1. 一种药物组合物，包括：
a)安全有效量的糖皮质类固醇，它选自倍氯米松、氟尼缩松、氟替卡松、莫米松、布地奈德，其药学上可接受的盐和它们的混合物；
b)安全有效量的速效抗组胺，它选自阿伐斯汀、卡比沙明、苯海拉明、氯苯那敏、溴苯那敏、右氯苯那敏、多西拉敏、氯马斯汀、异丙嗪、阿利马嗪、甲地嗪、羟嗪、美吡拉敏、rocastine、曲吡拉敏、美克洛嗪、曲普利啶、阿扎他定、赛庚啶、苯茚胺，它们的药学上可接受的盐和它们的混合物；和
c)水性的鼻内载体，
其中组合物不含辣椒素。
2. 根据权利要求1所述的组合物，它为等渗水溶液形式。
3. 根据权利要求1或2所述的组合物，其中糖皮质激素为倍氯米松。
4. 根据权利要求1-3任一所述组合物，它进一步包括选自伪麻黄碱、苯丙醇胺、苯福林、四氢唑林、萘甲唑林、羟甲唑啉、曲马唑啉，它们的药学上可接受的盐和它们的混合物的拟交感胺。
5. 根据权利要求1-4任一所述的药物组合物，它进一步包括另外的抗组胺药，所述的抗组胺药选自特非那定、氮斯汀、西替利嗪、阿司咪唑、依巴斯汀、酮替芬、洛度沙胺、氯雷他定、左卡巴斯汀、美喹他嗪、奥沙米特、司他斯汀、他齐茶碱、替美斯汀或其药学上可接受的盐和它们的混合物。
6．根据权利要求1-7任一所述的药物组合物，它进一步包括非类固醇抗炎药。
7．根据权利要求1-8任一所述的药物组合物，它进一步包括脂肪氧合酶抑制剂或拮抗剂。
8．根据权利要求1-7任一所述的药物组合物，它进一步包括非鸦片类止痛剂。
9．一种治疗季节性过敏性鼻炎的方法或前述权利要求任一所述的安全有效量组合物的使用方法。
10．一种用安全有效量的前述权利要求任一所述的组合物来治疗四季不断的过敏性鼻炎的方法。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103260623A (zh) * | 2010-10-06 | 2013-08-21 | 伊斯塔制药公司 | 贝托斯汀组合物 |
| CN103269687A (zh) * | 2011-01-04 | 2013-08-28 | 伊斯塔制药公司 | 贝托斯汀组合物 |
| CN117954002A (zh) * | 2024-01-05 | 2024-04-30 | 苏州腾迈医药科技有限公司 | 分子对关系的展示方法及装置、介质 |
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1997
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103260623A (zh) * | 2010-10-06 | 2013-08-21 | 伊斯塔制药公司 | 贝托斯汀组合物 |
| CN103260623B (zh) * | 2010-10-06 | 2016-11-02 | 伊斯塔制药公司 | 贝托斯汀组合物 |
| CN103269687A (zh) * | 2011-01-04 | 2013-08-28 | 伊斯塔制药公司 | 贝托斯汀组合物 |
| CN103269687B (zh) * | 2011-01-04 | 2016-09-14 | 伊斯塔制药公司 | 贝托斯汀组合物 |
| US10736841B2 (en) | 2011-01-04 | 2020-08-11 | Bausch & Lomb Incorporated | Bepotastine compositions |
| CN117954002A (zh) * | 2024-01-05 | 2024-04-30 | 苏州腾迈医药科技有限公司 | 分子对关系的展示方法及装置、介质 |
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