CN111671911B - 一种治疗盆底失驰缓型便秘的药物组合物及其制备方法 - Google Patents
一种治疗盆底失驰缓型便秘的药物组合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种治疗盆底失驰缓型便秘的药物组合物及其制备方法,该药物组合物主要以药学上可接受的渗透性泻药与抗焦虑药物,其中渗透性性泻药与抗焦虑药物的重量比是2~8:1,该药物组合物的药物联合具有显著的协同作用,通过特定的药物配比,显著减轻了两种药物对人体的毒副作用,著降低肛门肌肉尤其是括约肌的压力,降低肛直肠最大自主收缩压和肛直肠静息压,提高药物组合物的疗效,具有广阔的的医疗应用前景。
Description
技术领域
本发明属于医药技术领域,具体涉及一种治疗盆底失驰缓型便秘的药物组合物及其制备方法。
背景技术
便秘是临床上最常见的胃肠道症状之一,常表现为排便费力、排便次数减少、排便硬结或干球便、排便不尽感、肛门直肠堵塞感,甚至用手法辅助排便。慢性便秘在过去相当长的时期内被人们所轻视,近年来,便秘的患病率逐渐升高,且有研究显示其与急性心脑血管疾病、痴呆、结直肠癌发病有着密切关系,已引起越来越多的关注。
2000年推出了罗马II标准,国际上对便秘的概念以罗马II标准为通用标准。即便秘是指粪便干结、排便困难或排便不尽感和排便次数减少。从病因学上慢性便秘可以分为器质性便秘和功能性便秘。器质性便秘主要是由于器质性病因引起的便秘,慢性便秘的器质性病因主要有胃肠道疾病(肠道肿瘤、先天性巨结肠等)、肛周疾病(直肠脱垂、直肠前突)、神经系统疾病(多发性硬化、帕金森病、脑卒中、脊髓损伤及周围神经病变)、内分泌或代谢性疾病(糖尿病肠病、甲状腺功能低下、甲状旁腺疾病)和精神病,同时还应排除药物性因素(阿片类药物、抗胆碱药、抗抑郁药、钙通道拮抗剂、抗酸剂、铁剂、抗腹泻药、利尿剂、抗组胺药等)引起的便秘。
盆底失驰缓型便秘在中医学中属“便秘”范畴,盆底失弛缓综合征是盆底肌反射性或随意性异常而引起的一组症候群,其临床特征为排便时盆底肌群不能协调松弛或异常收缩,盆底出口阻力增高,引起排便困难等症状。其病名的演变来源于对病因不断的研究。目前认为,该疾病为一组综合症候群,除了便秘症状外,还可能合并肠易激综合征、排尿困难、肛门直肠痛、帕金森氏病等多种疾病,其可能的病因涉及盆底整体肌群(横纹肌和平滑肌)、周围神经调节(骶副交感神经、阴部神经)、中枢神经调节(中枢、脊髓及多发性神经元损伤及外伤)、发育异常、心理及行为异常、脑-肠轴调节异常等多因素有关。
目前针对盆底失驰缓型便秘的治疗方法多样,其中主要以中医治疗为主,中医治疗历史悠久,主要依托于临床经验辩证治疗,治疗方法因人而异,其中一部分医生主张以“益气养阴调气”法为主,通过改善直肠感觉功能,提高括约肌反应性来进行治疗。另一部分医生认为盆底失驰性便秘为阳气不足,肠道失温煦而导致的阴寒凝结,糟粕不下,治疗上主要以补通塞温阳益气为主。目前中医治疗盆底失驰缓型便秘临床疗效判定标准不一,治疗缺乏远期评估性,同时起效较慢,尚不能从根本上解决问题。
针灸针刺治疗是近年来新兴起的治疗盆底失驰缓型便秘的方式,通过针灸刺激穴位以及脉冲电刺激改善血液供应,进一步修复受损失的神经,纠正肛门直肠以及盆底肌肉的不协调运动,降低排便时的肛管直肠压力。经过论证该方法对盆底失驰缓型便秘治疗有效,但是效果不持久,常会出现病情的反复,治疗不彻底。
西医治疗通常需要进行饮食干预,必要的时候要结合Kegel法等盆底治疗疗法锻炼盆底肌肉的协调性,目前治疗中通常药用到缓泻剂进行治疗,虽然能起到一定的效果,但是疗效不彻底,不能从根本上解决问题。
生物反馈疗法是建立在行为干预疗法中成长起来的一种全新的治疗方法,该方法一方面能够改善盆底失驰缓患者的病症,另一方面可以改善患者的心理状况,提高生活质量。但是生物反馈疗法的疗程较长,并且整个过程中需要患者的不断训练,一方面增加了患者治疗的负担,另一方面该方法最终成功率较低。
严重的情况下需要手术进行干预,研究表明多数手术治疗早期都能收到较好的效果,但是虽着时间的推移,该病症容易复发,另外术后瘢痕的再次形成会造成患者术后排便问题的重现,手术治疗的远期治疗效果欠佳。
根据分析,目前治疗盆底失驰缓型便秘的方法中缺乏一种治疗效果好,显效快并且作用持久的药物,亟需研究人员针对以上问题进行解决。
发明内容
针对现有盆底失驰缓型便秘临床治疗中缺乏有效治疗药物的现状,本发明提供一种可以显著改善盆底失驰缓型便秘症状并可该症状标本兼治的药物组合物,该药物组合物治疗作用全面、毒副作用低和价格低廉,医药应用前景十分广阔,具体采用如下技术方案。
一种治疗盆底失驰缓型便秘的药物组合物,其特征在于,所述药物组合物含有药学上可接受的渗透性性泻药与抗焦虑药物,其中渗透性性泻药与抗焦虑药物的重量比是2~8:1。
本发明的药物组合物含有渗透性性泻药和抗焦虑药物物活性成分,由于两种药物活性成分的作用机制不同,组成组合物后对盆底失驰缓型便秘治疗效果将更加全面,并且两药合用有协同作用,其在增加患者日均排便量、增强患者肠道推进力方面以及降低肛门括约肌的反应灵敏度均明显优于相同剂量的单方;此外,该药物组合物中两种活性成分在有效降低肛门括约肌的压力,改善肛门括约肌的电位振幅及平均时限方面也存在明显的协同作用,经过试验论证提示该药物组合物对盆底失驰缓型便秘有着明显的治疗优势。发明人通过合理选择组合物中渗透性性泻药和抗焦虑药物的用量配比,选择合适的药物剂型,使药物组合物在有效治疗便秘的同时又可最大程度地降低各自的毒副作用。动物实验研究发现将本发明所提供的组合物制备成外用制剂具有疗效确切和使用方便的优势。渗透性性泻药和抗焦虑药物联合应用组成复方后,药物成分明确、性质稳定、相互影响较小,便产品疗效确切,有利于生产制备时质量的控制,非常适合工业化大生产。
所述渗透性性泻药与抗焦虑药物的重量份比例为1:1-5:1,优选为3:1-5:1,更优选为4:1,
优选的,所述的渗透性性泻药为聚乙二醇或低聚糖中的一种,所述的抗焦虑药物为丁螺环酮、帕罗西汀、西酞普兰中的一种。
优选的,所述的聚乙二醇的聚合度为50-10000的整数,优先为500-5000,更优选为4000,其中聚乙二醇的聚合度对治疗效果影响显著,聚合度在一定范围内的的聚乙二醇在配合导泻药时效果发挥更佳。
所述低聚糖为乳果糖、果糖、半乳糖、乳糖中的一种或多种。
优选的,所述药物组合物为口服制剂或外用制剂。
优选的,所述口服制剂为片剂、胶囊剂。滴丸剂、散剂或分散片。
优选的,所述外用制剂为栓剂、乳膏剂或凝胶剂。
本发明另一目的是提供一种治疗盆底失驰缓型便秘的药物组合物包括如下步骤:
(1)活性成分的制备:取重量份比例的渗透性性泻药与抗焦虑药物,将其干燥、粉碎、混合;
(2)向混合物中加入药学可接受的辅料赋形剂或者辅助成分,即得。
其中上述药物组合物的辅料赋形剂经大量实验筛选,栓剂适用的赋形剂包括但不限于半合成椰油脂、可可脂、明胶。
凝胶剂适用赋形剂包括但不限于卡波姆、纤维素类衍生物。
软膏剂适用赋形剂包括但不限于单硬脂酸甘油酯、石蜡、白凡士林、液状石蜡、丙二醇、对羟基苯甲酸乙酯、司盘80。
片剂适用赋形剂包括但不限于微晶纤维、羧甲基淀粉钠、硬脂酸盐、淀粉。
胶囊剂适用赋形剂包括但不限于微粉硅胶、甘露醇、糖粉、羧甲基淀粉钠。
本发明的另一目的是提供上述药物组合物在制备治疗慢性便秘药物中的用途,优选的所述药物组合物在制备治疗盆底失驰缓型便秘药物中的用途。本发明所述的药物组合物用于治疗盆底失驰缓型便秘特别是治疗盆底失驰缓型便秘便秘时,取得了预料不到的治疗效果,两种特定配比的药物在盆底失驰缓型便秘的治疗中体现出了显著的协同作用。
本发明药物组合物用于慢性便秘特别是盆底失驰缓型便秘的预防或治疗时,可以选用合适的活性组分配比的药物组合物给药,优选为口服给药或外用给药,给药时可选用本发明公开的药物剂型及其他合适剂型,如本发明上文所公开的片剂、胶囊剂、颗粒剂、栓剂、乳膏剂等药物制剂。
本发明所提供的组合物用于治疗慢性便秘特别是功盆底失驰缓型便秘时,取得了如下突出的预料不到的技术效果:
1)两种药物活性成分的作用机制不同,组成组合物后对便秘治疗效果更加全面,本发明保护的药物组合物通过特定的药物配比,减轻了两种药物对人体的毒副作用,同时两种作用机制完全不同的药物在特定的药物配比下起到协同作用,提高药物组合物的疗效,尤其对盆底失驰缓型便秘的疗效显著。
2)药物组合物中的两种活性成分特定比例下在改善盆底失驰缓型便秘的多种指标存在协同作用。并且经过实验证明活性组分的单一用药效果并没有组合用药的效果好,本发明通过合理配置组合物中两种组分的配比有效解决了盆底失驰缓型便秘的困扰。
3)经过实验证明,对盆底失驰缓型便秘具有重要作用的肛直肠压力在使用本发明保护的组合物后肛肠压力显著降低,证明本药物组合物在底失驰缓型便秘的治疗方面效果显著。
具体实施方式
为了更好的理解本发明,下面通过对本发明较佳具体实施例的描述,详细解释说明本发明,但不以任何形式限制本发明。
一、制剂的制备
实施例1复方片剂的制备
制备工艺:将丁螺环酮和聚乙二醇4000与微晶纤维素混合,向混合物中加入6%PVP乙醇溶液,然后过20目筛制粒。湿颗粒在50℃干燥,干燥后颗粒过20目筛整粒,筛出干粒中的细粉,与硬脂酸镁混匀,然后再与干颗粒混匀,压片,即得。
实施例2复方栓剂的制备
制备工艺:取吐温置于器皿中与甘油混合,搅拌均匀,加入处方量的帕罗西汀和乳果糖,继续搅拌均匀后注入涂有润滑剂的栓模至稍溢出模口为度,冷却,凝固后削去溢出部分,脱模,质检,包装。
实施例3分散片的制备
制备工艺:按处方量称取西酞普兰、聚乙二醇5000混合均匀,以微晶纤维素为填充剂,聚乙烯吡咯烷酮为崩解剂,60%乙醇溶液为黏合剂,微粉硅胶为助流,用流化床一步制粒,然后压片,即得。
实施例4乳胶剂的制备
制备工艺:将卡波姆缓慢加入到处方量40%的水中,边加边搅拌直至形成透明的凝胶基质,将丁螺环酮和聚乙二醇4000加入适量水中,再加入基质中,搅拌均匀,加入甘油、纯化水至全量,三乙醇胺调节PH值至中性,即得。
实施例5:乳膏剂的制备
制备工艺:按处方量取硬脂酸、白凡士林、水浴加热至熔化,混匀,作为油相。另外取适量的纯化水,将帕罗西汀和半乳糖溶解到水中。
取十二烷基硫酸钠、纯化水、尼泊金乙脂混合加热至72℃左右,作为水相。待油相温度为76℃左右时,搅拌下将帕罗西汀和半乳糖溶液加入其中,并使温度保持在76℃左右。将搅拌均匀后的油相,在慢速搅拌下,缓缓加入水相中,后加速搅拌25min,停止搅拌,即得乳膏。
对比实施例复方片剂的制备
制备工艺同实施例1
二:药效学实施例
药物组合物对盆底失驰缓型便秘小鼠模型的影响
试验目的
实验组小鼠采用皮下注射吗啡方式诱导建立盆底失驰缓型便秘小鼠模型,记录小鼠粪便重量,利用活性炭灌胃法试验比较实验组与对照组小鼠结肠传输功能;利用免疫组化技术比较两组小鼠结肠组织中CAJAL细胞数量。
材料
无特殊病原体SPF级ICR鼠90只(),雌雄各半,体重20~25克;小鼠代谢笼;注射用盐酸吗啡(药品批号H21022436,规格10mg/支);生理盐水;一抗(sc-168,200mg/L);二抗(羊抗兔抗体),组合物为实施例1所得片剂,对比例所用组合物为对比实施例1所得片剂。
试验方法和步骤
慢传输型便秘小鼠模型的建立
ICR鼠90只,随机分为1个模型对照组、1个正常对照组、1个阳性药对照组以及6个实验组,每组10只。对以上小组进行如下处理:实验组、模型对照组以及阳性药组小鼠皮下注射盐酸吗啡2.0mg/(kg·d),正常对照组注射等量生理盐水。其中,6个实验组分别为:丁螺环酮组;聚乙二醇4000组;对比实施例组;实施例组合物高组;实施例组合物中组;实施例组合物低剂组。阳性药组使用普芦卡必利处理。所有小鼠置入小鼠代谢笼中,SPF级环境饲养。适应性喂养3天后,每3天记录一次小鼠大便粒数、大便干重及小鼠体重,计算小鼠日均排便重量(g)。以小鼠日均排便量减少,且日均排便量与正常对照组相比具有显著性差异作为慢传输型便秘小鼠模型的建立成功的标志,造模成功后停止注射给药。
小鼠日均排便重量的测定,给与造模成功后的小鼠按照如下给药方案给药:
丁螺环酮组小鼠灌胃给药丁螺环酮,给药剂量按照丁螺环酮计1.8mg/(kg·d);聚乙二醇4
000组给药剂量均为1.8mg/(kg·d),灌胃给药;
对比实施例组为灌胃给药2mg/(kg·d)对比实施例1的药物组合物;
阳性药组为给药2mg/(kg·d)的普芦卡必利制剂
高剂量组灌胃给药4mg/(kg·d)实施例1的片剂;
中剂量组灌胃给药2mg/(kg·d)实施例1的片剂;
低剂量组为灌胃给药1mg/(kg·d)实施例1的片剂;
正常对照组和模型对照组给与蒸馏水,每隔1天记录一次小鼠大便粒数、大便干重及小鼠体重,计算小鼠日均排便重量(g)。
肠道传输功能测定
用活性炭灌胃法测定首粒黑便排出时间。停药1周的所有小鼠禁食24小时,经口灌入100mg/ml活性炭悬液2ml。从活性炭灌胃完毕开始时计时,记录从灌胃到首粒黑便排出的时间。首粒黑便排出时间越长表明慢传输型便秘程度越大。
免疫组化标记小鼠结肠组织ICC及小鼠结肠组织ICC数量的比较
实验结束后颈椎脱臼法处死,剖腹取出幽门到直肠末端全部肠道,分别取每只小鼠远端结肠组织2~3处,6%甲醛溶液固定,石蜡包埋连续切片(厚度:4~5μm);脱蜡和水化后,切片放入pH8.0的EDTA缓冲液,煮沸15min,保温10min,室温冷却;PBS液(pH7.6)冲洗3次,每次5min;每张切片滴加50μl3%双氧水以阻断内源性过氧化物酶的活性,室温下孵育10min;PBS液(pH7.6)冲洗3次,每次5min;去除血清,分别加入一抗(1∶500)50μl,37℃孵育60min,PBS液冲洗3次,每次5min;去除PBS液,分别加入生物素标记的二抗(1∶50)50μl,室温孵育10min;PBS液冲洗3次,每次3min;去除PBS液,加50μl链霉菌抗生物素—过氧化物酶溶液,室温孵育10min;PBS液冲洗3次,每次3min;去除PBS液,加2滴新鲜配制的DAB,显微镜下观察3~10min;自来水冲洗;苏木精复染,0.1%HCl乙醇分化,流水冲洗返蓝;梯度乙醇脱水干燥(二甲苯透明),中性树胶封固,细胞质呈棕色为阳性反应。每张切片选择五个高倍镜视野(×200),应用Lecia RX250型图像分析系统及Qwin软件标记并计算c-kit阳性细胞面积。c-kit阳性细胞面积与正常组小鼠相比越小,表明慢传输型便秘程度越大。
试验数据的统计学处理
实验数据录入SPSS22.0统计软件包,统计方法选用t检验,p<0.05为差异有显著性意义。
表1组合物对盆底失驰缓型便秘小鼠的影响
&&与正常对照组比较,p<0.01;
*与模型对照组相比,p<0.05;**与模型对照组相比,p<0.01;
※与丁螺环酮组相比,p<0.05;※※与丁螺环酮组组相比,p<0.01;
§与聚乙二醇4000组相比,p<0.05;§§与聚乙二醇4000组相比,p<0.01;
#与阳性药组(普芦卡必利)相比,p<0.05;§§与阳性药组(普芦卡必利)相比,p<0.01;
★与对比实施例组相比,p<0.05;★★与对比实施例组相比,p<0.01。
实验结果:
(1)与正常组相比较,模型组小鼠的排便量、首粒黑便排除时间以及c-kit阳性的细胞面积均具有显著性差异(p<0.01),表明小鼠建模成功。
(2)与模型组相比,采用服用实施例1所得组合物高中低剂量的小鼠的排便量、首粒黑便排出时间以及c-kit阳性细胞面积均具有显著性差异(p<0.05),而采用组合物中的任何一种单一成分,小鼠的排便量、首粒黑便排出时间以及c-kit阳性细胞面积均未呈现出显著性差异(p>0.05)。这表明两种活性成分仅在组合使用时对盆底失驰性便秘的治疗效果显著,仅仅采用单一成分达不到预期的治疗效果。
(3)与阳性药组对比,采用高剂量与中剂量的实施例1的药物组合物在测试的三项指标中均具有显著性差异,并且根据测试的结果采用高剂量与中剂量的实施例1的药物组合物的治疗效果更好,试验证明实施例1的药物组合物治疗效果更好。
(4)与对比实施例相比,采用实施例1所得药物组合物的三个测量指标结果具有显著性差异,而模型组与对比实施例之间没有统计学意义,说明药物组合物中两种活性成分的组成配比对治疗效果十分重要。
采用实施例2、实施例3、实施例4、实施例5进行上述实验与采用实施例1的药物组合物取得同样的效果。
实验例二:肛直肠测压情况
盆底失驰性便秘是盆底肌反射性或随意性异常而引起的一组症候群,其临床特征为排便时盆底肌群不能协调松弛或异常收缩,盆底出口阻力增高,引起排便困难,因此要解决此病症必须能够显著降低肛门肌肉尤其是括约肌的压力,降低肛直肠最大自主收缩压和肛直肠静息压,因此需要探究药物对肛门直肠压力的影响。
采用上述同样的造模方法和实验例进行实验,得到如下表2结果
表2各组药物对肛直肠压力的影响
&&与正常对照组比较,p<0.01;
*与模型对照组相比,p<0.05;**与模型对照组相比,p<0.01;
※与丁螺环酮组相比,p<0.05;※※与丁螺环酮组相比,p<0.01;
§与聚乙二醇4000组相比,p<0.05;§§与聚乙二醇4000组相比,p<0.01;
#与阳性药组(普芦卡必利)相比,p<0.05;##与阳性药组(普芦卡必利)相比,p<0.01;
★与对比实施例组相比,p<0.05;★★与对比实施例组相比,p<0.01。
结果分析
根据实验结果可以得出,模型组的静息压、最大自主收缩压以及抑制反射值均高于正常对照组,两组具有显著性差异(p<0.01),表明小鼠建模成功。
实验证明除模型组以外其他各组对小鼠的在施药后均对静息压、最大自主收缩压以及抑制反射值具有影响,但是实施例1组合物中剂量用药后的效果更好。
利用相同的条件采用实施例2、3、4、5的组合物进行如上实验,所得结果与上述利用实施例1的结果一致。
以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (2)
1.一种药物组合物在制备治疗盆底失驰缓型便秘药物的用途,其特征在于,所述药物组合物由药学上可接受的丁螺环酮、聚乙二醇4000、微晶纤维素、6%PVP乙醇溶液以及微粉硅胶组成,其中丁螺环酮、聚乙二醇4000、微晶纤维素、6%PVP乙醇溶液以及微粉硅胶的重量比为4:1:2:5:0.5,所述药物组合物为口服制剂。
2.如权利要求1所述的药物组合物在制备治疗盆底失驰缓型便秘药物的用途,其特征在于,所述口服制剂为片剂、胶囊剂、滴丸剂、散剂或分散片。
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