CN108310195B - 一种治疗特发性肺纤维化的中药组合物及其制备方法和应用 - Google Patents
一种治疗特发性肺纤维化的中药组合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种治疗特发性肺纤维化的中药组合物及其制备方法和应用。其原料组成为:红参7~10份,生黄芪18~21份,熟地黄22~25份,五味子8~10份,炒苦杏仁7~10份,桔梗10~14份,黄芩10~14份,金银花28~32份,川贝母10~15份,炙枇杷叶16~20份,丹参16~20份,当归10~14份,地龙10~14份,生甘草5~8份。本发明中药组合物所选药材配伍相宜,组方精炼,各中药按照“君臣佐使”的配伍关系相互配合、共同使用,从而作用于病灶,在功能上相辅相成,在药性上相制相佐,使用方便,安全,舒适,无毒副作用,临床收效甚佳,具有广泛的应用价值。
Description
技术领域
本发明属于中药技术领域,具体涉及一种治疗特发性肺纤维化的中药组合物及其制备方法和应用。
背景技术
特发性肺纤维(Idiopathic pulmonary fibrosis,特发性肺纤维化)是指原因不明,出现在成人,局限于肺,进行性致纤维化的间质性肺炎,其组织病理学和放射学表现为普通型间质性肺炎。特发性肺纤维化预后较差,死亡率远远高于许多癌症。其临床主要表现为渐进性劳力性气促,限制性通气功能障碍伴弥散功能(DLCO)降低,低氧血症,影像学上的双肺弥漫性病变,最终发展为弥漫性肺纤维化和蜂窝肺,导致呼吸功能衰竭而死亡。
目前,治疗特发性肺纤维化尚无特效药。纵观2011年至今的国际指南,制定特发性肺纤维化的临床诊断标准具有革命性意义,但针对治疗却甚是尴尬。基于2014年美国胸科协会(ATS)最新公布的治疗特发性肺纤维化药物的试验结果,吡非尼酮和尼达尼布治疗特发性肺纤维化得到国际专家的一致认可。但诊治指南中治疗强推荐仅为长期氧疗,药物治疗信心明显不足,针对治疗意愿强烈的患者,仅给予弱推荐应用吡非尼酮、尼达尼布、糖皮质激素治疗。近两年吡非尼酮进入中国医疗市场,治疗效果反馈意见有待商榷,但其副作用是显而易见的,光过敏、肝功及胃肠道损害尤为突出。因此,发挥传统中医优势,研发一种无毒副作用、治疗效果好的治疗特发性肺纤维化的中药药物是亟待解决的问题。
发明内容
针对上述特发性肺纤维化的危害及治疗困境,本发明的目的在于发挥中医特色,提供一种疗效显著、成本低廉、毒副作用小的治疗特发性肺纤维化的中药组合物。特发性肺纤维化归属于中医的“肺痿”、“肺痹”、“喘证”等范畴。中医理论认为本病的发生基于先天禀赋不足,责之于肺肾。肺主气,气虚则寒,气不化津,津聚为痰;气虚则血瘀,痰瘀痹阻肺络。另气虚及阴,阴虚则内热,肺燥阴竭,肺失濡养。痰瘀痹阻,阴津亏耗,致隐匿性起病。如若外邪引触,同气相求,风热袭肺首当其冲,进一步消灼肺津,变为涎沫,导致疾病急性发作或加重。故其基本病机为肺燥津伤,肺气上逆;肾失摄纳,气无所主。
病位在肺,与肾、脾密切相关,久则累及于心。肺为娇脏,喜润恶燥,赖胃(脾)输津以濡润,且为水之上源,主持全身水津的输布。若津气亏耗,肺失濡养,则肺虚致痿;肾为气之根,肾主纳气,助肺司气之摄纳,维持呼吸之深度。肾元亏虚,摄纳失常,致气不归元,气逆于肺,则入少出多,临床可见静息状态喘息,动则加剧。脾主运化,“脾为生痰之源,肺为贮痰之器”,“脾胃为后天之本,气血生化之源”。子病及母,日久肺脾两虚,脾虚湿胜,聚湿成痰,上干于肺,肺失宣降。脾虚生化乏源,四肢百骸无以所养,加重气虚。肺肾俱虚,日久心气心阳衰竭,不能鼓动血脉运行,导致血行淤滞,临床可见面色、指甲、唇甲青紫,甚则喘汗致脱,而至阴阳离决,危及生命。本病总属本虚标实,本虚责之于气阴两虚,标实责之于痰瘀热。
根据“虚则补之,实则泻之”的中医治疗方案,申请人根据传统中医理论和长期实践积累,认为特发性肺纤维化的治法治则为“培补摄纳、祛邪调气”;其中,培补摄纳重在补肺益肾,祛邪重在化痰通络、活血化瘀、清热解毒。肺主宣降,条畅气机亦须兼顾。
为实现上述技术目的,本发明采用如下技术方案:
本发明的第一个方面,提供一种治疗特发性肺纤维化的中药组合物,其原料组成为:
红参7~10份,生黄芪18~21份,熟地黄22~25份,五味子8~10份,炒苦杏仁7~10份,桔梗10~14份,黄芩10~14份,金银花28~32份,川贝母10~15份,炙枇杷叶16~20份,丹参16~20份,当归10~14份,地龙10~14份,生甘草5~8份。
进一步的,本发明治疗治疗特发性肺纤维化的中药组合物,其原料组成为:
红参9份,生黄芪20份,熟地黄24份,五味子9份,炒苦杏仁9份,桔梗12份,黄芩12份,金银花30份,川贝母12份,炙枇杷叶18份,丹参18份,当归12份,地龙12份,生甘草6份;
方药中原材料的药性及功效如下:
红参:甘,微苦,温。归心、肺、脾经。大补元气,补脾益肺,生津,安神。《用药法象》:“人参甘温,能补肺中元气;肺气旺则四脏之气皆旺,精自生而形自盛,肺主诸气故也。”
生黄芪:甘,微温。归脾、肺经。补气升阳,益卫固表,利水消肿,托疮生肌。
熟地黄:甘,微温。归肝、肾经。补血滋阴,益精填髓。
五味子:酸,甘,温。归肺、心、肾经。敛肺滋肾,生津敛汗,涩精止泻、宁心安神。
炒苦杏仁:苦,微温,有小毒。归肺、大肠经。止咳平喘,润肠通便。
桔梗:苦,辛,平。归肺经。宣肺祛痰,利咽,排脓。
黄芩:苦,寒。归肺、胃、胆、大肠经。清热燥湿,泻火解毒,凉血止血,除热安胎。
金银花:甘,寒。归肺、心、胃经。清热解毒,疏散风热。
川贝母:苦,甘,微寒。归肺、心经。清热化痰,润肺止咳,散结消肿。
炙枇杷叶:苦,微寒。归肺、胃经。清肺化痰止咳,降逆止呕。
丹参:苦,微寒。归心、肝经。活血调经,凉血消痈,安神。
当归:甘,辛,温。归肝、心、脾经。补血,活血,调经,止痛,润肠。
地龙:咸,寒。归肝、脾、膀胱经。清热息风,通络,平喘,利尿。
生甘草:甘,平。归心、肺、脾、胃经。益气补中,清热解毒,祛痰止咳,缓急止痛,调和药性。
本发明的治疗特发性肺纤维化的中药组合物中,各原料组分是一个有机的整体,缺一不可。发明人在研发过程中发现,减少上述组合物中的任何一种原料组分,或以具有相似药性的原料药对本发明中药组合物的原料组分进行替换,则中药组合物整体的作用效果显著降低;在本发明的中药组合物的基础上再增加其他的原料组分,中药组合物的整体效果并未有明显的改善,甚至有中药组合物的整体效果降低的情况出现。
上述治疗特发性肺纤维化的中中药组合物可直接将各原料粉碎,混合均匀后使用;或加水煎煮;也可以按照其他方法制备。在本发明的一个具体实施方式中,上述治疗特发性肺纤维化的中药组合物的制备方法为:
S1.取红参入水单独浸泡0.5~1.5h,另十三味原料药共同入水浸泡,其中川贝母先捣碎再入药共同浸泡0.5~1.5h;
S2.煎红参,武火烧至水沸,调整为文火煎煮0.3~0.6h,取药汁;然后进行第二遍熬制,加适量开水,文火再煎煮0.2~0.5h,两次取汁合并,备用;
S3.除红参外其余十三味药武火烧至水沸,调整为文火煎煮0.3~0.6h,取汁;然后进行第二遍熬制,加适量开水,文火再煎煮0.2~0.5h,再取汁;两次取汁合并,备用;
S4.取步骤S2.和S3.药汁合并烧沸即得。
其中,所述步骤S2.和S3.顺序可进行调换。
进一步的,所述步骤S1.中,
红参与水的质量体积比为3g:100ml,浸泡时间为1h;
剩余十三味原料药与水的质量体积比为194g:2000ml,浸泡时间为1h;
进一步的,所述步骤S2.中,第一次文火煎煮时间为30min;第二次文火煎煮时间为20min;
进一步的,所述步骤S3.中,第一次文火煎煮时间为30min;第二次文火煎煮时间为20min;
经试验验证,采用上述制备方法,可以最大限度的提取出中药组合物中的有效成分并保证有效成分的活性,从而保证产品的临床效果。
上述中药组合物在制备治疗特发性肺纤维化的药物制剂中的应用也是本发明保护的范围。
本发明的第二个方面,提供一种治疗特发性肺纤维化的药物制剂,由上述中药组合物和药学上可接受的辅料制备而成。
上述药物制剂可以制成各种药物剂型,如汤剂、丸剂、胶囊剂、片剂、散剂、颗粒剂或口服液等。
本发明中的上述药物制剂中药学上可接受的辅料包括但不限于:稀释剂包括但不限于,山梨醇、甘露醇、淀粉、乳糖、粉状或微晶状纤维素、二钙磷酸盐,三钙磷酸盐、糖和相似物;填充剂:羧甲基纤维素钠、PVP-K30、羟丙基纤维素、淀粉浆、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、胶化淀粉等;崩解剂:干淀粉、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素等;润滑剂:硬脂酸镁、滑石粉、十二烷基硫酸钠或微粉硅胶;其它辅料包括结合剂、流动剂、复合形成剂、释放控制剂、膜衣剂、塑化剂、着色剂、调味剂、甜味剂、黏度增强剂、保存剂或抗氧化剂中的一种或多种。
本发明的中药制剂,共计14味中药。特发性肺纤维化可谓疑难病症,世界性难题,现代医学上尚无特效药。而本发明依据“整体观念、辨证论治”治疗理念,发挥中医药“简便验廉”特色,用药精简,立意明确,治以培补摄纳、祛邪调气。红参大补元气,“肺气旺则四脏之气皆旺,精自生而形自盛,肺主诸气故也”,故为君药。黄芪、五味子、熟地黄与红参相合,助红参益气,同时滋补肺肾;炒苦杏仁、桔梗、川贝母、炙枇杷叶、地龙止咳化痰;丹参、当归活血化瘀、养血和营,共为臣药,旨在辅助君药益气补虚的同时,兼顾痰瘀痹阻肺络的主要病机。黄芩、金银花清热解毒,不仅可以清肺热,还可佐治益气类用药后助阳化热,金银花芳香透达,使药性灵活,共为佐药。生甘草不仅清热解毒、止咳化痰,同时可以调和药性,用为使药。
本发明有益技术效果:本发明中药组合物着眼于补益肺肾、化痰祛瘀,用药精简严谨,体现原则如下:一、肺肾同补。特发性肺纤维化临床主要表现为低氧血症所致的呼吸困难,中医责之于肺失于主气,肾失纳气,故肺肾同补。二、补敛宣降。红参、黄芪主补气,五味子主敛气,补敛共用则相得益彰;桔梗主升,炒苦杏仁、炙枇杷叶主降,宣降有序则有利于气机恢复。三、气血同调。一味丹参功同四物,当归甘、辛、温。甘则补益,辛则能行能散,芳香理气,两者合用补血、活血、行气,气血同调。四、虫类药的应用。强调虫类药在治疗特发性肺纤维化中的重要地位,特发性肺纤维化影像为肺间质纤维化样改变,责之于痰瘀阻络,而虫类药善行剔络,地龙尤其善于平喘、通络。
本发明中药组合物所选药材配伍相宜,组方精炼,各中药按照“君臣佐使”的配伍关系相互配合、共同使用,从而作用于病灶,在功能上相辅相成,在药性上相制相佐,使用方便,安全,舒适,无毒副作用,临床收效甚佳,具有广泛的应用价值。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本申请提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本申请的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
结合具体实例对本发明作进一步的说明,以下实例仅是为了解释本发明,并不对其内容进行限定。如果实施例中未注明的实验具体条件,通常按照常规条件,或按照销售公司所推荐的条件;在本发明没有特别限定,均可通过商业途径购买得到。
实施例1
红参9份,生黄芪20份,熟地黄24份,五味子9份,炒苦杏仁9份,桔梗12份,黄芩12份,金银花30份,川贝母12份,炙枇杷叶18份,丹参18份,当归12份,地龙12份,生甘草6份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药2000体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实施例2
红参10份,生黄芪18份,熟地黄23份,五味子8份,炒苦杏仁10份,桔梗11份,黄芩10份,金银花28份,川贝母10份,炙枇杷叶16份,丹参20份,当归10份,地龙14份,生甘草5份;
制备方法:取红参入305体积份水中单独浸泡60分钟,另13味药在2020体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实施例3
红参9份,生黄芪19份,熟地黄22份,五味子10份,炒苦杏仁9份,桔梗12份,黄芩12份,金银花30份,川贝母12份,炙枇杷叶20份,丹参18份,当归13份,地龙10份,生甘草8份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药在2050体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实施例4
红参8份,生黄芪20份,熟地黄25份,五味子8份,炒苦杏仁10份,桔梗14份,黄芩14份,金银花32份,川贝母14份,炙枇杷叶20份,丹参16份,当归12份,地龙10份,生甘草7份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药2010体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实施例5
红参8份,生黄芪21份,熟地黄22份,五味子10份,炒苦杏仁9份,桔梗12份,黄芩12份,金银花30份,川贝母10份,炙枇杷叶18份,丹参18份,当归10份,地龙13份,生甘草8份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药2005体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实验例1
红参9份,熟地黄24份,炒苦杏仁9份,桔梗12份,黄芩12份,金银花30份,川贝母12份,炙枇杷叶18份,丹参18份,当归12份,地龙12份,生甘草6份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药2000体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实验例2
红参9份,生黄芪20份,熟地黄24份,五味子9份,炒苦杏仁9份,黄芩12份,金银花30份,炙枇杷叶18份,丹参18份,当归12份,地龙12份,生甘草6份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药2000体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实验例3
红参9份,生黄芪20份,熟地黄24份,五味子9份,炒苦杏仁9份,桔梗12份,黄芩12份,金银花30份,川贝母12份,炙枇杷叶18份,地龙12份,生甘草6份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药2000体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
实验例4
红参9份,生黄芪20份,熟地黄24份,五味子9份,炒苦杏仁9份,桔梗12份,黄芩12份,连翘30份,川贝母12份,炙枇杷叶18份,丹参18份,川芎12份,地龙12份,生甘草6份;
制备方法:取红参入300体积份水中单独浸泡60分钟,另13味药2000体积份水中浸泡60分钟,其中川贝母先捣碎再入药共同浸泡。其后先煎红参,武火烧至水沸,调整为文火煎煮30分钟,取得药汁,之后进行第二遍熬制,加适量开水,文火再煎煮20分,两次取汁合并。其余13味药浸泡后武火烧至水沸,调整为文火煎煮30分钟,取汁;之后进行第二遍熬制,加适量开水,文火再煎煮20分钟后,再取汁;两次取汁合并;其后将红参药汁倒入其中,共同烧沸即可。
验证实验
本申请动物验证实验均在山东中医药大学实验动物中心完成,使用动物为成年SD大鼠,SPF级,雌雄各半,体重180~220g,由山东大学实验动物中心提供(生产许可证号:SYXK(鲁)20130009)并于山东中医药大学实验动物中心SPF级实验室饲养,使用许可证号:SYXK(鲁)20110019,给予常规动物饲料。动物适应性饲养3天后进行试验。
1.中药组合物安全性试验
取禁食20小时以上的SD大鼠27只,以生药量3g生药/mL按40mL/(kg·d)的剂量灌胃给药实施例1-5及实验例1-4汤剂(每组随机分配3只SD大鼠),给药后观察两周,结果显示无试验大鼠死亡,因此无法按常规测定LD50,故继而进行最大给药量测定试验。
选取SD大鼠60只,随机分配为给药组和对照组,每组6只,雌雄各半,给药组用含生药3g生药/mL的药液按80mL/(kg·d)的剂量灌胃给药,每天2次。对照组给予同等体积生理盐水。给药后小鼠正常饲养,试验期间观察动物在一般行为、皮毛、饮食、体重变化、粪便有无异常改变,并观察有无中毒症状及死亡(如有死亡,则进行解剖及病理学检验),连续观察两周。两周后复称体重,处死动物进行解剖,解剖观察心、肺、肝、肾、脾、胃、肠、膀胱、肾上腺、胸腺、胰腺、甲状腺、***、子宫、卵巢、睾丸、***、脑等做组织学观察,结果均未发现异常病理性改变,提示本发明的中药组合物临床应用剂量安全。
2.动物模型构建及给药效果试验
2.1试验方法
将SD大鼠随机分为11组,每组8只,其中包括1个正常对照组:不造模不给药;5个实验组:造模后分别灌胃给予实施例1-5组方1-5所得液体制剂(分别依次命名为实验组1-5);4个阳性对照组:造模后分别灌胃给予实验例1-4所得液体制剂(分别依次命名为实验组6-9);1个病理对照组:造模并灌胃给予生理盐水。实验药物及对照药物均于造模成功后第2日给药,每日给药1次,以生药量3g生药/mL按10mL/(kg·d)的剂量灌胃3周。
实验造模:大鼠腹腔注射10%水合氯醛0.35ml/100g体重麻醉后仰面固定于35度倾斜鼠板上,将光源直接照射于大鼠咽喉部皮肤表面,左手垫纱布向外向上提起舌头,可见咽喉部有一明显亮点,从大鼠口腔,右手水平***18号套管针到达咽喉部时,压低针尾,使针头抬高15-30度角,轻轻***气管,长度约为3/4个针的长度,拔出枕芯。将棉球薄片置于套管针外口,若棉球薄片随呼吸前后摆动,则说明套管针已经***气管,若棉球薄片不随呼吸前后摆动,可能套管针误入食道,应立即拔出重新***。向气管插管内快速注射0.2%博来霉素溶液,用量为5mg/kg体重,即0.25ml/100g,假手术组注射等体积的生理盐水,并继续向气管内快速推注0.3ml空气,之后立即将大鼠直立旋转,以使药液在双肺内分均匀。动物清醒后随意进食。造模后第7天时肺泡炎明显,第14天肺泡炎减轻,肺间质纤维化开始形成,第28天时肺间质纤维化已成为主要病变,造模成功。
2.2试验检测指标
对试验结束后的SD大鼠按常规病理学方法进行固定、包埋、切片,将病理切片作HE和Masson染色,观察肺泡炎和肺纤维化程度。目前以Szapiel等(Szapiel S V,Elson N A,Fulmer J D,et al.Bleomycin-induced interstitial pulmonary disease in thenude,athymic mouse[J].American Review of Respiratory Disease,1979,120(4):893)的半定量法运用较为广泛。本发明亦采用此法。
肺泡炎分级:
0级:无肺泡炎;
I级:轻度肺泡炎,肺泡间隔因细胞浸润增宽,病变范围占全肺的20%以下;
II级:中度肺泡炎,病变范围超过全肺的20%~50%;
III级:弥漫性肺泡炎,病变范围超过全肺50%。
肺间质纤维化分级:
0级:无肺间质纤维化;
I级:轻度肺间质纤维化,受累范围少于全肺的20%;
II级:中度肺间质纤维化,受累范围占全肺的20%~50%,肺泡结构紊乱;
III级:重度肺间质纤维化,受累范围超过全肺的50%,肺泡融合,肺实质结构紊乱。
HYP含量测定:采用碱分解法对各组试验大鼠肺组织中HYP含量(mg/g)进行测定。
2.3统计分析
试验数据用平均值±标准差表示,计量资料以T检验分析比较各组间的差异。P<0.05视为有显著差异。评价时考虑统计学差异和生物学意义。
2.4试验结果
各组大鼠肺泡炎程度分级比较见下表1:
表1
各组大鼠肺纤维化程度分级比较见下表2:
表2
各组大鼠肺组织中HYP含量见表3:
表3
由上表1、表2可知,本发明的中药组合物对于特发性肺纤维化模型的大鼠肺泡炎和肺纤维化程度均具有显著的减轻作用(与病理对照组相比P<0.05),其中,实验组1即采用实施例1的中药组合物疗效最为显著,同时,减少或替换本申请中药组合物中的某一味或某几味药物(实验组6-9)后,虽然同样对大鼠肺纤维化起到一定的抑制作用,但是作用效果明显减弱,这表明本发明中药组合物作为一个统一整体,各药物之间相互配合、共同作用。
同时,各组大鼠肺组织中HYP含量见表3,27d肺纤维化已经非常明显,其HYP含量:正常对照组为(624.3±70.8)mg/g,病理对照组高达(1304.1±224.6)mg/g,实施例1-5即实验组1-5中HYP含量则显著低于病理对照组(P<0.05),说明本发明中药组合物使得肺组织中的HYP含量降低,而从实验组6-9同样可以看出,减少或替换本申请中药组合物中的某一味或某几味药物,其对HYP含量升高的抑制作用明显减弱,特别是实验组9(实验例4)与病理对照组相比,未见明显改善作用(P>0.05)。
上述实验结果表明,本发明中药组合物能够明显改善特发性肺炎纤维化模型的肺泡炎、巨噬细胞泡沫样改变、纤维细胞活化和胶原纤维增生等症状,降低肺组织中HYP含量,对特发性肺纤维化具有明显的改善作用。
3.临床试验
3.1临床资料
为验证本发明中药组合物对特发性肺纤维化的治疗效果,选取在山东中医药大学附属医院肺病科中符合2011年美国胸科学会(ATS)/欧洲呼吸学会(ERS)/日本呼吸学会(JRS)/拉丁美洲胸科学会(ALAT)指定的IPF非创伤性诊断标准的特发性肺纤维化患者180例进行临床观察试验,将该180例患者随机分为治疗1-5组和对照组1组各30例,各组患者之间的病情、症状轻重程度基本一致,无显著差异,具有可比性。
3.2治疗方法
治疗1-5组:分别服用实施例1-5制备的中药组合物汤剂,用量为每天服用2次,每次服用250ml,连用10周;
3.3疗效判定标准
临床疗效判定:(1)改善:肺总量(TLC)或肺活量(VC)较治疗前增加10%,一氧化碳弥散量(DLCO)较治疗前增加至少15%,动脉血氧饱和度(SaO2)较治疗前增加至少4%,动脉氧分压(PaO2)较治疗前增加至少4mmHg;(2)恶化:肺总量(TLC)或肺活量(VC)较治疗前下降至少10%,一氧化碳弥散量(DLCO)较治疗前下降至少15%,动脉血氧饱和度(SaO2)较治疗前下降至少4%,动脉氧分压(PaO2)较治疗前下降至少4mmHg;(3)稳定:介于改善和恶化之间。
3.4统计分析
试验数据用平均值±标准差表示,计量资料以T检验分析比较各组间的差异。P<0.05视为差异有统计学意义。
3.5试验结果
各治疗组与对照组的疗效比较见下表4:
表4
由表4可知,治疗组1-5的治疗效果均略优于采用吡非尼酮的对照组,其中,治疗组1的治疗效果最优,同时,需要说明的是,在治疗过程中发现,服用对照组吡非尼酮患者中出现光过敏、呕吐、皮疹、嗜睡等副作用人数较多(有8人),而服用本申请中药组合物的各治疗组中仅治疗组4报道2例出现轻微呕吐症状。进一步的,治疗组1与对照组1特发性肺纤维化患者治疗前后肺功能检测结果分别见表5和表6。由表5和表6可知,本申请中药组合物对肺功能改善效果亦优于对照组1。
表5治疗组1特发性肺纤维化患者治疗前后肺功能检测结果
表6对照组1特发性肺纤维化患者治疗前后肺功能检测结果
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,对于本领域的技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (10)
1.一种治疗特发性肺纤维化的中药组合物,其特征在于,其原料组成为:
红参7~10份,生黄芪18~21份,熟地黄22~25份,五味子8~10份,炒苦杏仁7~10份,桔梗10~14份,黄芩10~14份,金银花28~32份,川贝母10~15份,炙枇杷叶16~20份,丹参16~20份,当归10~14份,地龙10~14份,生甘草5~8份。
2.根据权利要求1所述的一种中药组合物,其特征在于,其原料组成为:
红参9份,生黄芪20份,熟地黄24份,五味子9份,炒苦杏仁9份,桔梗12份,黄芩12份,金银花30份,川贝母12份,炙枇杷叶18份,丹参18份,当归12份,地龙12份,生甘草6份。
3.权利要求1或2所述的中药组合物的制备方法,其特征在于,所述方法包括为:
S1.取红参入水单独浸泡0.5~1.5h,另十三味原料药共同入水浸泡,其中川贝母先捣碎再入药共同浸泡0.5~1.5h;
S2.煎红参,武火烧至水沸,调整为文火煎煮0.3~0.6h,取药汁;然后进行第二遍熬制,加适量开水,文火再煎煮0.2~0.5h,两次取汁合并,备用;
S3.除红参外其余十三味药武火烧至水沸,调整为文火煎煮0.3~0.6h,取汁;然后进行第二遍熬制,加适量开水,文火再煎煮0.2~0.5h,再取汁;两次取汁合并,备用;
S4.取步骤S2.和S3.药汁合并烧沸即得。
4.根据权利要求3所述的中药组合物的制备方法,其特征在于,
所述步骤S1.中,
红参与水的质量体积比为3g:100ml,浸泡时间为1h;
剩余十三味原料药与水的质量体积比为194g:2000ml,浸泡时间为1h。
5.根据权利要求3所述的中药组合物的制备方法,其特征在于,
所述步骤S2.中,
第一次文火煎煮时间为30min;第二次文火煎煮时间为20min。
6.根据权利要求3所述的中药组合物的制备方法,其特征在于,
所述步骤S3.中,
第一次文火煎煮时间为30min;第二次文火煎煮时间为20min。
7.权利要求1或2所述中药组合物在制备治疗特发性肺纤维化的药物制剂中的应用。
8.一种治疗特发性肺纤维化的药物制剂,其特征在于,由权利要求1或2所述中药组合物和药学上可接受的辅料制备而成。
9.根据权利要求8所述药物制剂,其特征在于,所述药物制剂剂型包括汤剂、丸剂、胶囊剂、片剂、散剂、颗粒剂或口服液。
10.根据权利要求8所述药物制剂,其特征在于,所述药学上可接受的辅料包括稀释剂、填充剂、崩解剂、润滑剂、结合剂、流动剂、复合形成剂、释放控制剂、膜衣剂、塑化剂、着色剂、调味剂、甜味剂、黏度增强剂、保存剂、抗氧化剂中的一种或多种。
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