CN102670607A - 复方盐酸氨溴索组合物及其制备方法 - Google Patents

复方盐酸氨溴索组合物及其制备方法 Download PDF

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CN102670607A
CN102670607A CN2012101692797A CN201210169279A CN102670607A CN 102670607 A CN102670607 A CN 102670607A CN 2012101692797 A CN2012101692797 A CN 2012101692797A CN 201210169279 A CN201210169279 A CN 201210169279A CN 102670607 A CN102670607 A CN 102670607A
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汪六一
汪金灿
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Hainan Weikang Pharmaceutical Qianshan Co Ltd
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Abstract

一种复方盐酸氨溴索组合物及其制备方法,涉及医药领域,以质量百分比为0.1%~99.9%的盐酸氨溴索和99.9%~0.1%的东莨菪碱为主药,和甘露醇加到注射用水中;搅拌溶解后加入NaOH溶液调节pH值到5.0;加入0.1%的活性炭搅拌30分钟;滤除活性炭,药液再经0.45μm和0.22μm微孔滤膜过滤;过滤后的药液罐装至大盘或西林瓶中;送入冷冻干燥机中,降温至-40℃,保温2小时;缓慢升温至-5℃~0℃升华干燥,再升温至35℃后,保温3小时;冷冻干燥结束后出箱,得到注射用盐酸氨溴索和东莨菪碱的冻干粉针;在无菌条件下粉碎冻干粉针,过180目筛,得到盐酸氨溴索和东莨菪碱的无菌冻干粉;以冻干粉为原料制备各种剂型。本发明提供的制备方法科学合理,方便制成各种剂型。

Description

复方盐酸氨溴索组合物及其制备方法
技术领域:
本发明涉及医药领域,尤其涉及一种复方盐酸氨溴索组合物及其制备方法。
背景技术:
慢性阻塞性肺病(chronic obstructive pulmonary diseases,COPD)是一种具有气流受限特征的可以预防和治疗的疾病,气流受限不完全可逆、呈进行性发展。COPD主要累及肺脏,但也可引起全身(或称肺外)的不良效应。COPD是呼吸道常见病,随着年龄增加,老年人的气道纤毛清除功能减退,肺抗氧化作用减退,老年人容易患COPD。
烟草烟雾等慢性刺激物作用于肺部,使肺部出现异常炎症反应。COPD可累及气道、肺实质和肺血管,表现为出现以中性粒细胞、巨噬细胞、淋巴细胞浸润为主的慢性炎症反应。这些细胞释放炎症介质与气道和肺实质的结构细胞相互作用,进而促使T淋巴细胞(尤其是CD+8)和中性粒细胞及嗜酸性粒细胞在肺组织聚集,释放白三烯B4(LTB4)、白介素8(IL-8)、肿瘤坏死因子α(TNF-α)等多种介质,引起肺结构的破坏。氧化、抗氧化失衡和蛋白酶、抗蛋白酶失衡以及自主神经系统功能紊乱,胆碱能神经张力增高等进一步加重COPD肺部炎症和气流受限。遗传易患性在发病中起一定作用。
COPD累及中央气道、外周气道、肺实质和肺血管。中央气道(气管、支气管以及内径大于2-4mm的细支气管)表层上皮炎症细胞浸润,粘液分泌腺增大和杯状细胞增多使粘液分泌增加。在外周气道(内径小于2mm的小支气管和细支气管)内,慢性炎症导致气道壁损伤和修复过程反复发生。修复过程中发生气道壁结构重构,胶原含量增加及瘢痕组织形成,这些改变造成气道狭窄,引起固定性气道阻塞。
COPD肺实质受累表现为小叶中央型肺气肿,累及呼吸性细支气管,出现管腔扩张和破坏。病情较轻时病变部位常发生于肺的上部区域,当病情进展后,可累及全肺,伴有肺毛细血管床的破坏。
COPD肺血管的改变以血管壁的增厚为特征,早期即可出现。表现为内膜增厚,平滑肌增生和血管壁炎症细胞浸润。晚期继发肺心病时,可出现多发性肺细小动脉原位血栓形成。COPD急性加重期易合并深静脉血栓形成及肺血栓栓塞症。
发明内容:
本发明的目的在于提供一种复方盐酸氨溴索组合物及其制备方法,该复方制剂用于治疗慢性阻塞性肺病,有很强的协同作用,疗效迅速。
本发明的具体技术方案为:
一种复方盐酸氨溴索组合物,其特征在于,该组合物主药为:质量百分比为0.1%~99.9%的盐酸氨溴索和99.9%~0.1%的东莨菪碱。
一种用复方盐酸氨溴索组合物制备复方制剂的方法,其特征在于,具体操作步骤为:
a.将0.1%~99.9%的盐酸氨溴索、99.9%~0.1%的东莨菪碱和主药5~10倍的甘露醇加到注射用水中;
b.搅拌溶解后加入NaOH溶液调节pH值到5.0;
c.加入0.1%的活性炭搅拌30分钟;
d.滤除活性炭,药液再经0.45μm和0.22μm微孔滤膜过滤;
e.过滤后的药液罐装至大盘或西林瓶中;
f.送入冷冻干燥机中,降温至-40℃,保温2小时;
g.缓慢升温至-5℃~0℃升华干燥,再升温至35℃后,保温3小时;
h.冷冻干燥结束后出箱,得到注射用盐酸氨溴索和东莨菪碱的冻干粉针;
i.在无菌条件下粉碎冻干粉针,过180目筛,得到盐酸氨溴索和东莨菪碱的无菌冻干粉;
j.以冻干粉为原料制备各种剂型。
所述剂型有片剂、酊剂、栓剂、胶囊剂、软膏剂、乳膏剂、糊剂、眼用制剂、丸剂、植人剂、糖浆剂、气雾剂、粉雾剂、喷雾剂、膜剂、颗粒剂、口服溶液剂、口服混悬剂、口服乳剂、散剂、鼻用制剂。
盐酸氨溴索主要作用于呼吸道分泌细胞,调节粘液性及浆液性物质的分泌,使浆液分泌增加,还能够裂解痰液中的酸性糖蛋白的多糖纤维,抑制粘液腺和杯状细胞中酸性蛋白合成,降低痰液的粘稠度,使痰液变得稀薄,易于排出;同时该药也可增加呼吸道纤毛的运动频率和强度,促进痰液排出,增加呼吸道自净作用。而且盐酸氨溴索具有明显的抗氧化作用,在反应性的自由氧基团的肺部疾病发病中都起到重要的作用。它可以清除氧化物H-,Hocl减弱支气管粘膜损害的高反应性,刺激细胞PS的分泌。此外,氨溴索还能激活细胞内的谷胱甘肽系统,促进细胞内的谷胱甘肽(GSH)的合成,从而对抗氧自由基的破坏作用。
东莨菪碱可对抗受损细胞产生的氧自由基,具有抗氧化和清除过氧化物的作用。在长时间接触邻苯三酚的成年大鼠心肌的研究中发现,东莨菪碱能有效抑制超氧化物的生成和邻苯三酚所引起的大鼠心肌功能损伤,对氧自由基引起的心脏功能失调有一定效果。东莨菪碱可显著降低缺血再灌注的兔肾经脉血中LPO含量,减少自由基引发的脂质过氧化反应,对兔肾缺血再灌注损伤具有保护作用;可防止外源性H2O2损伤大鼠红细胞膜蛋白疏基;对次黄嘌呤-黄嘌呤氧化酶体系中产生的超氧阴离子自由基有显著的剂量依赖性清除作用,清除效果略低于超氧化物歧化酶(SOD)。
东莨菪碱不仅抑制内毒素脂多糖(LPS)诱导的内皮细胞表达纤溶酶原激活物抑制剂1(Pal-1)蛋白和mRNA表达,而且抑制其基础水平的Pal-1表达,从而发挥抗血栓形成作用。东莨菪碱可能通过NF-κB途径抑制LPS所致的内皮细胞Pal-1表达增强。东莨菪碱能抑制血栓素B2的合成,防止血小板聚集和释放,防止微血栓形成,抑制抗原抗体复合物沉积。
东莨菪碱具有平滑肌松弛、解除血管痉挛、改善微循环的作用,可抑制腺体分泌。东莨菪碱可作用于气道黏膜及平滑肌上的胆碱能受体,有效地抑制气道的胆碱能神经功能,降低迷走神经张力,促使支气管、毛细支气管扩张和气道分泌物减少,从而使喘息减轻,哮鸣音减少,临床症状好转,促进疾病的恢复。此外,东莨菪碱还有镇静大脑皮层的作用,更有降低机体耗氧量,解除小动脉痉挛,改善脑组织缺氧状态,阻断多器官功能损伤等良效。
本发明提供的制备方法科学合理,方便制成各种剂型,制备的复方制剂可:1)降低痰液的粘稠度,使痰液变得稀薄,促进痰液排出,增加呼吸道自净作用;2)增加人体抗氧化作用,有利于COPD患者增强自身免疫力;3)可兴奋呼吸中枢,解除支气管与血管平滑肌痉挛,降低心脏前后负荷,有利于心功能的恢复,同时也能解除心、脑、肺、肾等组织微小动脉痉挛,改善微循环和组织细胞的缺氧状态,改善气道上皮表面清除功能,从而预防和治疗COPD。
具体实施方式:
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施例,进一步阐述本发明。
实施例一、一种注射用盐酸氨溴索东莨菪碱冻干粉针的制备,以1000支计
1.处方
Figure BDA0000169194521
2.制备工艺
将处方量的盐酸氨溴索、东莨菪碱和甘露醇加到注射用水中,搅拌溶解后加入NaOH溶液调节pH值5.0,加入0.1%的活性炭搅拌30分钟,滤除活性炭,药液再经0.45μm和0.22μm微孔滤膜过滤,罐装,送入冷冻干燥机中,降温至-40℃,保温2小时后,缓慢升温至-5℃~0℃升华干燥,再升温至35℃后,保温3小时,冷冻干燥结束,出箱。
实施例二、一种盐酸氨溴索东莨菪碱片的制备,以1000粒计
1.处方
2.制备工艺
将处方量的盐酸氨溴索、东莨菪碱和甘露醇加到注射用水中,搅拌溶解后加入NaOH溶液调节pH值5.0,加入0.1%的活性炭搅拌30分钟,滤除活性炭,药液再经0.45μm和0.22μm微孔滤膜过滤,罐装至大盘中,送入冷冻干燥机中,降温至-40℃,保温2小时后,缓慢升温至-5℃~0℃升华干燥,再升温至35℃后,保温3小时,冷冻干燥结束,出箱。在无菌条件下粉碎大盘冻干的冻干品,过180目筛,得到盐酸氨溴索和东莨菪碱的无菌冻干粉。
将处方量的三氯蔗糖、薄荷脑混合,加入盐酸氨溴索东莨菪碱冻干粉混合均匀,再加入微晶纤维素、乳糖交联聚维酮、羟丙基纤维素混合均匀,最后加入硬脂酸镁、二氧化硅混合均匀,用直接压片法制片,制片时控制湿度在50%以下。
实施例三、一种盐酸氨溴索东莨菪碱注射液的制备,以1000支计
1.处方
Figure BDA0000169194524
2.制备工艺
将处方量的盐酸氨溴索、东莨菪碱和甘露醇加到注射用水中,搅拌溶解后加入NaOH溶液调节pH值5.0,加入0.1%的活性炭搅拌30分钟,滤除活性炭,药液再经0.45μm和0.22μm微孔滤膜过滤,罐装至大盘中,送入冷冻干燥机中,降温至-40℃,保温2小时后,缓慢升温至-5℃~0℃升华干燥,再升温至35℃后,保温3小时,冷冻干燥结束,出箱。在无菌条件下粉碎大盘冻干的冻干品,过180目筛,得到盐酸氨溴索和东莨菪碱的无菌冻干粉。
将冻干粉和氯化钠加注射用水80%,搅拌溶解后,加0.05%活性炭搅拌吸附15分钟,粗滤脱碳,用枸橼酸-磷酸氢二钠缓冲液(pH4.0)调节PH至4.5~5.5,加注射用水至全量,再用0.22μm滤膜精滤,测定pH、渗透压和含量合格后,用安瓿瓶罐装2ml封口,于121℃灭菌15分钟。
以上显示和描述了本发明的基本原理、主要特征以及本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (3)

1.一种复方盐酸氨溴索组合物,其特征在于,该组合物主药为:质量百分比为0.1%~99.9%的盐酸氨溴索和99.9%~0.1%的东莨菪碱。
2.一种用权利要求1所述组合物制备复方制剂的方法,其特征在于,具体操作步骤为:
a.将0.1%~99.9%的盐酸氨溴索、99.9%~0.1%的东莨菪碱和主药5~10倍的甘露醇加到注射用水中;
b.搅拌溶解后加入NaOH溶液调节pH值到5.0;
c.加入0.1%的活性炭搅拌30分钟;
d.滤除活性炭,药液再经0.45μm和0.22μm微孔滤膜过滤;
e.过滤后的药液罐装至大盘或西林瓶中;
f.送入冷冻干燥机中,降温至-40℃,保温2小时;
g.缓慢升温至-5℃~0℃升华干燥,再升温至35℃后,保温3小时;
h.冷冻干燥结束后出箱,得到注射用盐酸氨溴索和东莨菪碱的冻干粉针;
i.在无菌条件下粉碎冻干粉针,过180目筛,得到盐酸氨溴索和东莨菪碱的无菌冻干粉;
j.以冻干粉为原料制备各种剂型。
3.根据权利要求2所述的制备复方制剂的方法,其特征在于:所述剂型有片剂、酊剂、栓剂、胶囊剂、软膏剂、乳膏剂、糊剂、眼用制剂、丸剂、植人剂、糖浆剂、气雾剂、粉雾剂、喷雾剂、膜剂、颗粒剂、口服溶液剂、口服混悬剂、口服乳剂、散剂、鼻用制剂。
CN2012101692797A 2012-05-28 2012-05-28 复方盐酸氨溴索组合物及其制备方法 Pending CN102670607A (zh)

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