CN107929266B - 一种治疗慢性阻塞性肺疾病的贴剂 - Google Patents
一种治疗慢性阻塞性肺疾病的贴剂 Download PDFInfo
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Abstract
本发明提供了一种治疗慢性阻塞性肺疾病的贴剂,由包括背衬层、含药骨架层、粘合剂层和保护层组成,含药骨架层由有效成分丁烯基苯酞、苦参碱、贝母甲素以及药学上可接受的基质构成。本发明还提供了该贴剂的制剂处方及工艺方法。本发明的在一个目的是提供所述贴剂在制备治疗慢性阻塞性肺疾病药物中的应用。本发明贴剂为储库型贴剂,能够直接作用于患处,起效快,疗效好,通过COPD动物模型评价,证实其能呈剂量依赖抑制致敏豚鼠抗原攻击后BALF中嗜酸粒细胞升高,同时高剂量贴剂组嗜酸性粒细胞的比例也有显著下降,提示贴剂有抑制COPD炎症细胞渗出的作用,具有潜在的抗COPD的作用,具有临床应用价值,可用于治疗慢性阻塞性肺疾病。
Description
技术领域
本发明属医药技术领域,具体涉及治疗慢性阻塞性肺疾病的贴剂药物,是一种以丁烯基苯酞、苦参碱、贝母甲素为原料制备的具有治疗COPD药效的贴剂药物。
背景技术
慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease,COPD)是以不完全可逆的气流受限为特征的疾病,是小气道病变(闭塞性细支气管炎)和肺实质破坏(肺气肿)共同作用的结果。COPD是世界范围内严重危害公众健康的主要病种之一,据世卫组织预测,到2030年慢性阻塞性肺病将成为仅次于心脑血管疾病和肿瘤的全世界第三大死因。2007年我国对7个地区20245成年人群进行的调查显示,COPD患病率在40岁以上人群中高达8.2%。COPD不仅仅患病率高,而且病程呈进行性发展,可引起劳动力丧失、生活质量减退,最终导致的致残、致死率也很高。
迄今为止COPD的发病机制尚未完全明了,而普遍认为COPD的发病机制主要包括气道、肺实质和肺血管的慢性炎症、氧化应激、肺部的蛋白酶/抗蛋白酶失衡、慢性黏液高分泌以及自主神经系统功能紊乱(如胆碱能神经受体分布异常)等。根据COPD的主要特征,改善气流受限和控制炎症反应是目前临床上的主要治疗措施。
前期研究中我们以《金匮要略》所载经方“当归贝母苦参丸”复方为基础,通过超临界流体萃取和大孔树脂技术分别精制得到当归挥发油和贝母苦参总生物碱有效部位,从而研发出对COPD具有明确治疗作用的有效组分中药(ZL 200810061131.5)。
我们进一步研究发现,该组方中起主要作用的分别为三种类型的有效成分,通过其有效成分组方,可以发挥更好的药效,通过制剂处方筛选和工艺优化制备贴剂,能够使得药物经皮吸收,发挥良好的药效,同时避免了中药成分复杂带来的临床风险。
发明内容
本发明的目的是提供一种治疗慢性阻塞性肺疾病的贴剂,具有抗慢性阻塞性肺病(COPD)的活性,所述的贴剂由背衬层、含药骨架层、粘合剂层和保护层组成,含药骨架层由有效成分及药学上可接受的基质构成,其中有效成分是由丁烯基苯酞、苦参碱、贝母甲素三种化合物按照质量比丁烯基苯酞10~30%,苦参碱50~70%,贝母甲素10~20%的比例组成。
三种有效成分的结构式如下:
所述含药骨架层中的基质选自乙烯-醋酸乙烯共聚物丙烯酸(EVA)、甲基纤维素(MC-Na)、乙基纤维素(EC)、羧甲基纤维素钠(CMC-Na)、聚乙烯醇(PVA)、聚乙烯吡咯烷酮(PVP)、羟丙基甲基纤维素(HPMC)、聚丙烯(PP)、聚乙烯(PE)、聚对苯二甲酸乙二酯(PET)、聚乙二醇、丙烯酸树脂、西黄蓍胶、明胶中的一种或两种以上的混合物。
所述的粘合剂层选自聚异丁烯类压敏胶、丙烯酸类压敏胶、硅橡胶压敏胶、聚硅氧烷压敏胶、热熔压敏胶、聚丙烯(PP)、聚乙烯(PE)、聚对苯二甲酸乙二酯(PET)中的一种或两种以上混合物,不含药物或含部分药物作为负荷剂量。
所述的粘合剂层中含有天然透皮促进剂,选自薄荷醇、油酸、桉叶油等,用量为0-10%。所述的粘合剂层中含有保湿剂,选自甘油、丙二醇、山梨醇等,用量为0-10%。
所述的含药骨架层中含有天然透皮促进剂、表面活性剂、抑菌剂,天然透皮促进剂选自薄荷醇、油酸、桉叶油等,用量为0-10%。表面活性剂选自硬脂酸,十二烷基苯磺酸钠,季铵化物,卵磷脂,氨基酸型,甜菜碱型,脂肪酸甘油酯,脂肪酸山梨坦(司盘),聚山梨酯(吐温)等,用量为0-10%。抑菌剂选自山梨酸钾、丁香、薰衣草、迷迭香、鼠尾草等,用量为0-10%。
背衬层选自聚四氟乙烯膜、聚酯膜、复合铝箔、聚酯膜等。
本发明的另一个目的是提供所述的贴剂的制备方法,通过以下步骤实现:
(1)先配制空白基质,然后将化合物丁烯基苯酞、苦参碱、贝母甲素加入95%乙醇溶液溶解,加入透皮促进剂、表面活性剂、抑菌剂,搅拌均匀,与空白基质混和均匀得含药骨架层,涂布在背衬层上,烘干;
(2)另取不含药的粘合剂,加入透皮促进剂、保湿剂,混合均匀涂布在保护层上,烘干;
(3)将背衬层上涂有含药骨架层一面与粘合剂层复合;
(4)剪裁成1-100cm2的形状,总厚度≤50mm,得成品。
本发明的再一个目的是提供所述贴剂在制备治疗慢性阻塞性肺疾病药物中的应用。本发明所述的治疗COPD的贴剂的释药面积为1-100cm2,总厚度≤50mm,持续释药时间为1-7天。
本发明贴剂为储库型贴剂,能够直接作用于患处,起效快,疗效好,经Hartley品系豚鼠COPD模型动物实验证明其能呈剂量依赖抑制致敏豚鼠抗原攻击后BALF中嗜酸粒细胞升高,同时高剂量贴剂组嗜酸性粒细胞的比例也有显著下降,提示贴剂有抑制COPD炎症细胞渗出的作用,具有潜在的抗COPD的作用,具有临床应用价值,可用于治疗慢性阻塞性肺疾病。
附图说明
图1是贴剂药物对不同组别豚鼠肺组织炎症的影响(HE染色法×400)。
图2是凝胶贴膏对肺泡灌洗液中白细胞总数及嗜酸性粒细胞比例的影响。
具体实施方式
本发明结合附图和具体实施例作进一步说明。
实施例1
本发明贴剂由背衬层、含药骨架层、粘合剂层和保护层组成,具体各层所用材料如下:
背衬层:聚四氟乙烯膜,
粘合剂层:空白聚异丁烯类压敏胶,
保护层:防粘纸,
含药骨架层有效成分组成如下(100贴):
丁烯基苯酞:苦参碱:贝母甲素按照1:0.5:0.1摩尔比混合,共8g,
明胶 1g
油酸 0.5g
山梨酸钾 0.1g
制备工艺:(1)先将明胶加入水中得空白基质,然后将丁烯基苯酞、苦参碱、贝母甲素加入95%乙醇溶解,加入油酸、山梨酸钾,与空白基质混和均匀得含药骨架层,涂布在聚四氟乙烯膜上,烘干;
(2)取空白聚异丁烯类压敏胶涂布在防粘纸上,烘干;
(3)将步骤(1)涂有有效成分的一面与步骤(2)中涂有聚异丁烯类压敏胶的一面复合;
(4)剪裁成1-100cm2的形状,得成品。
实施例2
本发明贴剂由背衬层、含药骨架层、粘合剂层和保护层组成,具体各层所用材料如下:
背衬层:聚酯膜
粘合剂层:空白丙烯酸类压敏胶
保护层:金属塑料
含药骨架层有效成分组成如下(100贴):
丁烯基苯酞:苦参碱:贝母甲素按照1:0.2:0.5摩尔比混合 共4g
CMC-Na 1.5g
薄荷醇 0.8g
制备工艺:
(1)先将CMC-Na加入水中得空白基质,然后将丁烯基苯酞、苦参碱、贝母甲素加入95%乙醇溶解,,加入0.4g薄荷醇,与空白基质混和均匀得含药骨架层,涂布在聚酯膜上,烘干;
(2)取空白丙烯酸类压敏胶,加入0.4g薄荷醇,搅拌均匀,涂布在金属塑料上,烘干;
(3)将步骤(1)中涂有有效成分的一面与步骤(2)中涂有丙烯酸类压敏胶的一面复合;
(4)剪裁成1-100cm2的形状,得成品。
实施例3.
本发明贴剂由背衬层、含药骨架层、粘合剂层和保护层组成,具体各层所用材料如下:
背衬层:复合铝箔
粘合剂层:空白聚硅氧烷压敏胶
保护层:聚酯膜
含药骨架层有效成分组成如下(100贴):
丁烯基苯酞:苦参碱:贝母甲素按照1:1:0.8摩尔比混合 共10g
聚乙烯醇 1.5g
吐温 0.1g
桉叶油 0.2g
制备工艺:
(1)先将聚乙烯醇加入水中得空白基质,然后将丁烯基苯酞、苦参碱、贝母甲素加入95%乙醇溶解,加入吐温、桉叶油,与空白基质混和均匀得含药骨架层,涂布在复合铝箔上,烘干;
(2)取空白聚硅氧烷压敏胶涂布在聚酯膜上,烘干;
(3)将步骤(1)中涂有有效成分的一面与步骤(2)中涂有聚硅氧烷压敏胶的一面复合;
(4)剪裁成1-100cm2的形状,得成品。
实施例4中试制备
本发明贴剂由背衬层、含药骨架层、粘合剂层和保护层组成,具体各层所用材料如下:
背衬层:聚酯膜
粘合剂层:空白硅橡胶压敏胶
保护层:聚乙烯薄膜
含药骨架层有效成分组成如下(10000贴):
丁烯基苯酞:苦参碱:贝母甲素按照1:1:0.5摩尔比混合 共1000g
羟丙甲基纤维素 160g 甘油 适量
油酸 9g
桉叶油 9g
制备工艺:
(1)先将羟丙甲基纤维素加入水中得空白基质,然后将丁烯基苯酞、苦参碱、贝母甲素加入95%乙醇溶解,加入油酸、桉叶油,与空白基质混和均匀得含药骨架层,涂布在聚酯膜上,烘干;
(2)取空白硅橡胶压敏胶,加适量甘油,混合均匀涂布在聚乙烯薄膜上,烘干;
(3)将步骤(1)中涂有有效成分的一面与步骤(2)中涂有硅橡胶压敏胶的一面复合;
(4)剪裁成1-100cm2的形状,得成品。
实施例5 贴剂药物对COPD模型豚鼠的影响
(1)豚鼠急性吸烟早期COPD模型:依据文献(GUAN Y,LI F F,HONG L.Protectiveeffects of liquiritin apioside on cigarette smoke-induced lung epithelialcell injury[J].Fundam Clin Pharmacol,2012,26(4):473-483.)中的方法为基础,豚鼠在熏烟装置中使用香烟连续吸烟4天,装置内温度维持在25℃左右。第l天,上下午各使用两包万宝路香烟,进行烟雾暴露;第2天,上下午各使用3包香烟进行烟雾暴露;第3天和第4天,上下午各使用5包香烟进行烟雾暴露。每天暴露两次。每包香烟烟雾暴露持续20分钟,在烟雾暴露同时进行通风。最后一次香烟烟雾攻击15h后对实验动物进行处理。空白组使用空气进行暴露。
(2)实验分组:Hartley品系豚鼠,雌雄兼用,体重250-300g,浙江大学实验动物中心提供,合格证号:医动字第20020016号。每一批动物数量和分组情况具体如下:豚鼠分为6组,每组8-12只,雌雄各半:正常对照组,COPD模型组(COPD模型豚鼠),阳性对照组(1mg/kg地塞米松),10mg/kg、20mg/kg、30mg/kg剂量贴剂治疗组(即低、中、高剂量组)。
(3)取气管左主支气管作横切面,肺取左叶,均经4%甲醛固定、漂洗、脱水、透明和石蜡包埋,制备石蜡切片,HE染色观察肺组织炎症细胞浸润及结构变化。
(4)BALF中白细胞计数和分类的测定:
COPD豚鼠末次攻击后股动脉放血处死豚鼠,右肺结扎,用生理盐水1.5ml进行左侧肺支气管肺泡灌洗,分3次,所得灌洗液放置冰上。将肺泡灌洗液振荡摇匀,取50ul,用炎症细胞计数液稀释10倍,用细胞计数板在显微镜下进行计数。余肺泡灌洗液2000rpm离心,取取右肺-80℃保存备用。
以1:3比例加入白细胞计数液,用细胞计数板计数白细胞总数,再以2000rpm离心l0min,取细胞沉淀涂片,凉干后行Wright染色,做细胞分类计数,计算嗜酸性粒细胞绝对数
(5)结果表明与正常豚鼠比较,COPD豚鼠具有非常明显的过敏性炎症反应,白细胞总数、嗜酸粒细胞、中性粒细胞和淋巴细胞明显增多(附图1)。药物贴剂呈剂量依赖抑制COPD豚鼠BALF中嗜酸粒细胞升高,同时高剂量贴剂组嗜酸性粒细胞的比例也有显著下降,提示贴剂具有一定的抑制COPD炎症细胞渗出的作用(附图2)。
Claims (5)
1.一种治疗慢性阻塞性肺疾病的贴剂,所述的贴剂药物由背衬层、含药骨架层、粘合剂层和保护层组成,其特征在于,含药骨架层由有效成分及药学上可接受的基质构成,其中有效成分是由丁烯基苯酞、苦参碱、贝母甲素三种化合物按照质量比丁烯基苯酞10~30%,苦参碱50~70%,贝母甲素10~20%的比例组成,所述的含药骨架层中含有天然透皮促进剂、表面活性剂和抑菌剂,天然透皮促进剂用量选自薄荷醇、油酸、桉叶油,用量为1.5-5.2%,表面活性剂选自硬脂酸,十二烷基苯磺酸钠,季铵化物,卵磷脂,氨基酸型,甜菜碱型,脂肪酸甘油酯,脂肪酸山梨坦,聚山梨酯,用量为0.85%,抑菌剂选自山梨酸钾、丁香、薰衣草、迷迭香、鼠尾草,用量为1.0%。
2.根据权利要求1所述的一种治疗慢性阻塞性肺疾病的贴剂,其特征在于,所述基质选用乙烯-醋酸乙烯共聚物丙烯酸、甲基纤维素、乙基纤维素、羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、羟丙基甲基纤维素、聚丙烯、聚乙烯、聚对苯二甲酸乙二酯、聚乙二醇、丙烯酸树脂、西黄蓍胶、明胶中的一种或两种以上的混合物。
3.根据权利要求1所述的一种治疗慢性阻塞性肺疾病的贴剂,其特征在于,所述粘合剂层选用聚异丁烯类压敏胶、丙烯酸类压敏胶、硅橡胶压敏胶、聚硅氧烷压敏胶、热熔压敏胶、聚丙烯、聚乙烯、聚对苯二甲酸乙二酯中的一种或两种以上混合物,不含药物或含部分药物作为负荷剂量。
4.根据权利要求1所述的一种治疗慢性阻塞性肺疾病的贴剂,其特征在于,背衬层选自聚四氟乙烯膜、聚酯膜、复合铝箔、聚酯膜。
5.根据权利要求1所述的贴剂在制备治疗慢性阻塞性肺疾病药物中的应用。
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