CN116270849B - 一种治疗癌痛膏药的制备方法 - Google Patents
一种治疗癌痛膏药的制备方法 Download PDFInfo
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- CN116270849B CN116270849B CN202310501179.8A CN202310501179A CN116270849B CN 116270849 B CN116270849 B CN 116270849B CN 202310501179 A CN202310501179 A CN 202310501179A CN 116270849 B CN116270849 B CN 116270849B
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Abstract
本发明公开了一种治疗癌痛膏药的制备方法,按照质量比准备醋延胡索2份‑9份、燀桃仁2份‑3份、红花2份‑3份、醋乳香2份‑3份、醋没药2份‑3份、制川乌2份‑3份、白芷2份‑6份、花椒2份‑6份、细辛2份‑3份、龙葵2份‑9份、芒硝2份‑6份、白芍2份‑6份、冰片1份‑3份、薄荷脑1份‑3份;芒硝、冰片、薄荷脑取出,其余十一味药味粉碎过筛,加入处方量的1.1‑1.2倍重融化的热熔压敏胶中,冷至80‑90℃,芒硝、冰片、薄荷脑碎成细粉加入,搅匀,摊涂于双向拉伸聚丙烯珠光薄膜上,覆盖医药离型纸,冷却至室温,切卷,贴合于带粘性的卫生用水刺法非织造布上,覆盖医药离型纸,切制成约1000贴,包装,即得。
Description
技术领域
本发明属于中药制剂技术领域,具体涉及一种治疗癌痛膏药的制备方法。
背景技术
癌症已成为严重威胁人类健康的一类疾病,在近50%的癌症患者及超过70%的晚期癌症患者中癌痛从中度到重度普遍存在,严重影响患者的生活质量。目前临床以三阶梯止痛法为标准治疗方案治疗癌痛,而阿片类药物占据重要地位,但其副作用大,易形成依赖性,并且对部分癌痛患者的止痛效果有限。
中药外敷是一种重要的给药方式,通过透皮吸收,中药可直接作用于患处,减少了药物在体内的代谢过程,减轻了药物所致的不良反应,因而具有起效时间短,毒副作用小,且易于接受的优点。
目前已有相关的研究,例如中国专利申请号201110309943.9公开了一种治疗癌痛的膏药及其制备方法,由以下重量份数的原料药制成:斑蝥5-10份、蟾蜍0.3-1份、乳香20-30份、没药20-30份、元胡10-20份、乌药8-15份、樟脑2-5份、月桂氮卓酮2-5份、黄丹3-8份和芝麻油80-100份,该发明的中药原料合理配伍,相辅相成,解毒散结,调气活血,定痛止痛,治疗效果好,能有效缓解癌症病人的疼痛。
又例如中国专利申请号201910277327.6公开了一种缓解癌痛的组合物、膏药贴及其制备方法,包括丁香、全虫、肉桂、半夏、香附、枳壳、薤白和何首乌,该发明还涉及一种缓解癌痛的膏药贴,包括防护层和组合物,所述防护层覆盖在所述组合物的外侧,该发明还涉及一种缓解癌痛的膏药贴的制备方法,其优点在于,与传统的止痛药相比,组合物的止痛效果良好,疼痛缓解率高,不良反应少,改善患者的生活质量;使用方便,价格低廉,便于大规模推广应用。
随着医药工业的不断发展,贴膏剂在我国的医药市场上逐渐得到广泛的应用,以其载药量大、透皮效果好、透气性好、皮肤刺激性小等特点,成为理想的透皮给药载体。
发明内容
本申请人现有的治疗癌痛膏药的制备方法是将药材粉碎后,加凡士林搅拌均匀,摊与纱布上,涂抹于患处,但是在使用过程中,患者反馈凡士林容易通过纱布渗出,污染衣物,同可能引起患处痤疮。针对这些不足,本发明提供了一种治疗癌痛膏药的制备方法,剂型选择贴膏剂,发明人对粉碎工艺、成型工艺等进行研究,最终的结果符合《湖南省医疗机构中药制剂研究基本技术指导原则》相关要求。
为解决上述技术问题,本发明采用以下技术方案:
一种治疗癌痛膏药的制备方法,包括以下步骤:
1)粉碎:按照质量比,准备醋延胡索2份-9份、燀桃仁2份-3份、红花2份-3份、醋乳香2份-3份、醋没药2份-3份、制川乌2份-3份、白芷2份-6份、花椒2份-6份、细辛2份-3份、龙葵2份-9份、芒硝2份-6份、白芍2份-6份、冰片1份-3份、薄荷脑1份-3份;
将以上除芒硝、冰片、薄荷脑以外的醋延胡索、燀桃仁、红花等十一味饮片在60℃-70℃干燥至含水量8%以下,粉碎过80目筛,混匀,得到药粉;
2)融化:将热熔压敏胶加热至135-145℃融化;
3)混合均匀:将步骤2)的热熔压敏胶与步骤1)得到的药粉按照(1.1-1.2):1混合,控制温度在120℃,搅拌1.5-2.0h,关闭加热;
4)加入辅料:待膏体温度降低至80-90℃,将芒硝、冰片、薄荷脑粉加入,搅拌0.5h,搅拌均匀,保温,得到药膏,备用;
5)摊涂:将上步骤得到的药膏摊涂于双向拉伸聚丙烯珠光薄膜上,覆盖医药离型纸,卷成大药卷,并冷却至室温;
6)切卷:将上步骤得到的大药卷切制成大小合适的小药卷;
7)贴合:将切好的小药卷置贴合机上,贴合于带黏性的卫生用水刺法非织造布上,覆盖一层医药离型纸;
8)切片:切制成大小合适的形状;
9)包装。
本发明中:
步骤2)所述的融化,控制热熔压敏胶融化温度为135-145℃,加入药粉后温度可控制在120-130℃,搅拌均匀。
步骤3)所述的将步骤2)的热熔压敏胶与步骤1)得到的药粉按照(1.1-1.2):1混合后,药粉在120℃的热熔压敏胶中搅拌15min,即可到达灭菌作用,按微生物限度要求检测合格,故本步骤中搅拌时间为药粉加入完毕后搅拌1.5-2.0h,加入透皮吸收促进剂后,搅拌时间为0.5h,总体搅拌时间约2.0-2.5h。
步骤4)所述的加入辅料,为保证透皮吸收促进剂(芒硝、冰片、薄荷脑)不受温度影响而流失,故透皮吸收促进剂加入时的温度应控制在80-90℃,混合均匀后立即摊涂,自然冷却至室温,膏体即可定型。
步骤6)所述的切制成大小合适的小药卷,其中小药卷的尺寸是3×4cm。
步骤8)所述的切制成大小合适的形状,是参考现有膏药贴的大小,优选切制约1000贴。
步骤9)所述的包装,是采用双向拉伸聚丙烯、镀铝聚酯或聚乙烯药品包装用复合膜、袋,每袋5贴。
本发明所述的一种治疗癌痛膏药的制备方法,该治疗癌痛膏药,本处方来源于我院长期临床实践中总结的癌痛治疗经验方,具有活血通络,温经止痛,解毒散结的功效。组方原则:其中,川乌、延胡索为辛温之品,叶天士曰:“辛香可入络通血,能开结行瘀”,制川乌去湿寒、逐冷痹,消腿膝肿疼,延胡索散结行血,入肝经而破血,血行痛自除,二者合用可有活血通络、温经止痛、解毒散结之功效,为君药;白芷辛散温通,长于祛风散寒,燥湿理气止痛,乳香、没药活血行气止痛,消肿生肌,龙葵清热解毒,消肿止痛,四药共为臣药;佐以桃仁、红花活血化瘀,消肿止痛,花椒、细辛辛温散寒,通络止痛,白芷养血调经,柔肝止痛,芒硝咸寒,增益延胡索祛瘀止痛之功;冰片、薄荷引经通窍止痛,为使药。全方药物配伍得当,共奏“活血通络,温经止痛,解毒散结”之功效。
与现有技术相比,本发明具有以下优点:
1、本发明所述的一种治疗癌痛膏药的制备方法,本处方来源于我院临床长期临床实践中总结的临床经验方,临床用法为药材粉碎后,加凡士林搅拌均匀,摊与纱布上,涂抹于患处。在使用过程中,患者反馈凡士林容易通过纱布渗出,污染衣物,同可能引起患处痤疮。随着医药工业的不断发展,贴膏剂在我国的医药市场上逐渐得到广泛的应用,以其载药量大、透皮效果好、透气性好、皮肤刺激性小等特点,成为理想的透皮给药载体。因此本品的剂型选择贴膏剂。发明人按现行《湖南省医疗机构中药制剂研究基本技术指导原则》相关要求,对粉碎工艺、成型工艺进行研究,得到了本申请的方法。
2、本发明所述的一种治疗癌痛膏药的制备方法,通过透皮吸收,中药可直接作用于患处,减少了药物在体内的代谢过程,减轻了药物所致的不良反应,因而具有起效时间短,毒副作用小,且易于接受的优点。
3、本发明所述的一种治疗癌痛膏药的制备方法,药物制备成膏药后具有携带方便、易于储存,用药时间不受限制的优点,尤其适合不便服药者或不愿服药者使用,且价格便宜。
附图说明
图1是本发明实施例所述的延胡索TLC的图(列入质量标准);
图2是本发明实施例所述的延胡索TLC的图(不列入质量标准);
图3是本发明实施例所述的延胡索TLC的图(列入质量标准);
图4是本发明实施例所述的红花TLC的图(不列入质量标准);
图5是本发明实施例所述的制川乌TLC的图(列入质量标准);
图6是本发明实施例所述的白芷TLC的图(列入质量标准);
图7是本发明实施例所述的细辛TLC的图(不列入质量标准);
图8是本发明实施例所述的白芍TLC的图(列入质量标准);
图9是本发明实施例所述的重金属检测的图;
图10是本发明实施例所述的砷斑检测的图;
图11是本发明所述的一种治疗癌痛膏药的制备方法的工艺流程图。
具体实施方式
以下通过实施例进一步详细描述本发明,但这些实施例不应认为是对本发明的限制。
实施例1:
一种治疗癌痛膏药的制备方法,包括以下步骤:
1)粉碎:按照质量比,准备醋延胡索2g、燀桃仁3g、红花2g、醋乳香3g、醋没药2g、制川乌3g、白芷2g、花椒6g、细辛2g、龙葵9g、芒硝2g、白芍6g、冰片1g、薄荷脑1g;
将以上除芒硝、冰片、薄荷脑以外的醋延胡索、燀桃仁、红花等十一味饮片在60℃-70℃干燥至含水量8%以下,粉碎过80目筛,混匀,得到药粉;
2)融化:将热熔压敏胶加热至135-145℃融化;
3)混合均匀:将步骤2)的热熔压敏胶与步骤1)得到的药粉按照1.2:1混合,控制温度在120℃,搅拌1.5h,关闭加热;
4)加入辅料:待膏体温度降低至80-90℃,将芒硝、冰片、薄荷脑粉加入,搅拌0.5h,搅拌均匀,保温,得到药膏,备用;
5)摊涂:将上步骤得到的药膏摊涂于双向拉伸聚丙烯珠光薄膜上,覆盖医药离型纸,卷成大药卷,并冷却至室温;
6)切卷:将上步骤得到的大药卷切制成大小合适的小药卷,其中小药卷的尺寸是3×4cm;
7)贴合:将切好的小药卷置贴合机上,贴合于带粘性的卫生用水刺法非织造布上,覆盖一层医药离型纸;
8)切片:切制成大小合适的形状,切制约1000贴;
9)包装:采用双向拉伸聚丙烯、镀铝聚酯或聚乙烯药品包装用复合膜、袋,每袋5贴。
实施例2
一种治疗癌痛膏药的制备方法,包括以下步骤:
1)粉碎:按照质量比,准备醋延胡索9g、燀桃仁2g、红花3g、醋乳香2g、醋没药3g、制川乌2g、白芷6g、花椒2g、细辛3g、龙葵2g、芒硝6g、白芍2g、冰片3g、薄荷脑3g;
将以上除芒硝、冰片、薄荷脑以外的醋延胡索、燀桃仁、红花等十一味饮片在60℃-70℃干燥至含水量8%以下,粉碎过80目筛,混匀,得到药粉;
2)融化:将热熔压敏胶加热至135-145℃融化;
3)混合均匀:将步骤2)的热熔压敏胶与步骤1)得到的药粉按照1.2:1混合,控制温度在120℃,搅拌2.0h,关闭加热;
4)加入辅料:待膏体温度降低至80-90℃,将芒硝、冰片、薄荷脑粉加入,搅拌0.5h,搅拌均匀,保温,得到药膏,备用;
5)摊涂:将上步骤得到的药膏摊涂于双向拉伸聚丙烯珠光薄膜上,覆盖医药离型纸,卷成大药卷,并冷却至室温;
6)切卷:将上步骤得到的大药卷切制成大小合适的小药卷,其中小药卷的尺寸是3×4cm;
7)贴合:将切好的小药卷置贴合机上,贴合于带粘性的卫生用水刺法非织造布上,覆盖一层医药离型纸;
8)切片:切制成大小合适的形状,切制约1000贴;
9)包装:采用双向拉伸聚丙烯、镀铝聚酯或聚乙烯药品包装用复合膜、袋,每袋5贴。
实施例3
一种治疗癌痛膏药的制备方法,包括以下步骤:
1)粉碎:按照质量比,准备醋延胡索5g、燀桃仁2.5g、红花2.5g、醋乳香2.5g、醋没药2.5、制川乌2.5g、白芷4g、花椒4g、细辛2.5g、龙葵5.5g、芒硝4g、白芍4g、冰片2g、薄荷脑2g;
将以上除芒硝、冰片、薄荷脑以外的醋延胡索、燀桃仁、红花等十一味饮片在60℃-70℃干燥至含水量8%以下,粉碎过80目筛,混匀,得到药粉;
2)融化:将热熔压敏胶加热至135-145℃融化;
3)混合均匀:将步骤2)的热熔压敏胶与步骤1)得到的药粉按照1.3:1混合,控制温度在120℃,搅拌1.5h,关闭加热;
4)加入辅料:待膏体温度降低至80-90℃,将芒硝、冰片、薄荷脑粉加入,搅拌0.5h,搅拌均匀,保温,得到药膏,备用;
5)摊涂:将上步骤得到的药膏摊涂于双向拉伸聚丙烯珠光薄膜上,覆盖医药离型纸,卷成大药卷,并冷却至室温;
6)切卷:将上步骤得到的大药卷切制成大小合适的小药卷,其中小药卷的尺寸是3×4cm;
7)贴合:将切好的小药卷置贴合机上,贴合于带粘性的卫生用水刺法非织造布上,覆盖一层医药离型纸;
8)切片:切制成大小合适的形状,切制约1000贴;
9)包装:采用双向拉伸聚丙烯、镀铝聚酯或聚乙烯药品包装用复合膜、袋,每袋5贴。
实验例1:配制工艺路线详细说明
处方:延胡索2份-9份、燀桃仁2份-3份、红花2份-3份、醋乳香2份-3份、醋没药2份-3份、制川乌2份-3份、白芷2份-6份、花椒2份-6份、细辛2份-3份、龙葵2份-9份、芒硝2份-6份、白芍2份-6份、冰片1份-3份、薄荷脑1份-3份;
1.制备工艺研究资料
1.1剂型选择的理由
本处方来源于我院临床长期临床实践中总结的临床经验方,临床用法为药材粉碎后,加凡士林搅拌均匀,摊与纱布上,涂抹于患处。在使用过程中,患者反馈凡士林容易通过纱布渗出,污染衣物,同可能引起患处痤疮。随着医药工业的不断发展,贴膏剂在我国的医药市场上逐渐得到广泛的应用,以其载药量大、透皮效果好、透气性好、皮肤刺激性小等特点,成为理想的透皮给药载体。因此本品的剂型选择贴膏剂。按现行《湖南省医疗机构中药制剂研究基本技术指导原则》相关要求,我们对粉碎工艺、成型工艺进行研究,具体研究内容如下:
1.2粉碎工艺考查
本品以生药粉入药,故需考查粉碎工艺。影响饮片出粉率的主要因素有饮片自身性质和饮片含水量。饮片自身性质可通过改变粉碎方式来优化出粉率,而根据实际生产经验可知,饮片含水量越低越容易粉碎,出粉率也越高。本品药味较多,如采用单独粉碎,则耗时长,不利于生产,也浪费能源。故本品使用混合粉碎的方式以省时节能,提高生产效率。因此本品粉碎工艺只考查含水量对出粉率的影响。
1.2.1饮片含水量对出粉率的影响考查
醋延胡索2份-9份、燀桃仁2份-3份、红花2份-3份、醋乳香2份-3份、醋没药2份-3份、制川乌2份-3份、白芷2份-6份、花椒2份-6份、细辛2份-3份、龙葵2份-9份、白芍2份-6份,粉碎成粗粉,60℃-70℃干燥,称重,粉碎,过80目筛,称重,计算出粉率,并测定水分,结果见表1。
表1出粉率实验结果
编号 | 1 | 2 | 3 |
饮片(g) | 108.03 | 108.08 | 108.12 |
细粉(g) | 96.51 | 99.58 | 101.78 |
出粉率(%) | 89.34 | 92.14 | 94.14 |
水分(%) | 10.24 | 7.24 | 6.14 |
结果表明,饮片60℃-70℃干燥,如需出粉率均在90%以上,则需饮片水分控制在8%以下。
故本品的粉碎工艺为:除樟脑、冰片两味,其余饮片60℃-70℃干燥,控制水分至8%以下,粉碎后过80目筛,混匀。
1.3成型工艺研究
贴膏剂,系指将原料药物与适宜的基质制成膏状物、涂布于背衬材料上供皮肤贴敷、可产生全身性或局部作用的一种薄片状制剂。根据成型工艺与基质的不同,可分为凝胶贴膏和橡胶贴膏。凝胶贴膏指原料药物与适宜的亲水性基质混匀后涂布于背衬材料上制成的贴膏剂。常用基质有聚丙烯酸钠、羧甲纤维素钠、明胶、甘油和微粉硅胶等。实际生产中凝胶贴膏生产工艺复杂,生产周期长,膏体含水量高且黏弹性不足,使用中会因体温升高发生熔化,导致跑膏和脱膏,且容易导致过敏;凝胶贴膏放置时间过长,膏体易失水而硬化,导致无法敷贴。橡胶贴膏生产工艺相对简单,生产周期短,皮肤过敏概率小,使用时不受温度影响,保存时间长,故本品选择橡胶贴膏。
1.3.1基质种类的优选
橡胶贴膏生产中常用溶剂为汽油和正己烷,常用基质有橡胶、热塑橡胶、松香、松香衍生物、凡士林、羊毛脂和氧化锌等,也可用其他适宜溶剂和基质。以橡胶为基质的贴膏生产过程中使用大量汽油等有机溶剂,生产成本高,防爆防火措施要求严格、安全隐患大,在生产过程中药物挥发多,生产厂房和设备投资大,不能生药粉直接入药。热熔压敏胶属于热塑橡胶,使用其作为基质主要有以下优势:
①相对于常规橡胶基质,无需汽油,生产安全、环保,且生产效率高,生产成本低。
②载药量大,药物释放性好,疗效好。
③使用方便,粘附力适中,皮肤过敏概率小,患者依从性更好。
④可生药粉直接入药,工艺简明可控。
综上所述,热熔压敏胶作为基质明显优于橡胶基质,且符合传统制剂备案的基本条件,因此选择其作为本品的基质。
1.3.2基质透皮吸收促进剂的选择
透皮吸收促进剂(Penetration enhancers,PE),是指一种具有能暂时性调节经皮通透性的物质。PE在应用安全无毒的前提下,在临床上能够增强或者提高药物的经皮穿透速率,甚至通过皮肤局部给予就能够有利于治疗病人全身性疾病。贴膏剂常用透皮吸收促进剂有冰片、合成樟脑、薄荷脑、月桂氮酮等。
目前有关单一PE的研究已经较多,李鹏跃等发现薄荷脑在一定浓度范围内能够促进葛根素的渗透,当浓度达到5mg/mL时具有显著促渗作用。周庄等发现3%薄荷脑加3%冰片对青藤碱微乳体外透皮吸收优于单独使用冰片及薄荷脑,王晓颖等研究显示,5%冰片能将钩藤中钩藤碱透皮速率提高2.24倍,5%薄荷脑能将钩藤碱透皮速率提高1.95倍。庞帼敏等报道,冰片和薄荷油对蛇床子素的促渗效果均优于相同用量的氮酮,且以前者较优,盛小茜等研究显示,在乳猪与裸鼠皮肤中,2种制剂中樟脑的渗透系数均大于薄荷脑(P<0.05)。
PE的促渗能力与药物的理化性质有关,单一PE不能同时提高中药复方中多种有效成分的透皮能力,因此联合使用PE是当前中药贴膏剂透皮促渗的研究热点,研究发现部分PE按一定比例组合时能够取得协同作用,比使用单一PE效果更佳,根据王曙东等在不同促渗剂复方红茴香喷雾剂体外透皮吸收的影响研究中指出对槲皮苷的累积渗透及渗透速率影响大小为冰片>薄荷油>氮酮>PEG400,更有文献指出天然透皮促渗其毒性小于合成的促渗透剂,以上研究均说明处方中的冰片可以增加药物透皮吸收效果,但冰片在处方中存在治疗功能,故需要增加其他促渗剂。根据上述研究薄荷脑的促渗透作用仅弱于冰片,故选用薄荷脑作为促渗剂。
综上所述,同时查询相关资料,冰片的熔点在206-209℃、沸点在212℃,薄荷脑的熔点在34-36℃、沸点在215℃,芒硝的熔点32-38℃、沸点330℃。考虑到高温会使芒硝、冰片及薄荷脑受热流失,故加入芒硝、冰片及薄荷脑时应控制在较低温度。
1.3.3成型工艺预实验
本品选择的基质为热熔压敏胶,因此需对生产工艺进行初步考查,为后续工艺研究提供依据。
摸索时,发现热熔压敏胶熔化后,药粉一次性加入,会导致膏体温度快速降低,出现凝固现象,故药粉加入方式应为少量多次加入。
取热熔压敏胶100g,加热,记录热熔压敏胶在以下状态下的温度或者范围:完全融化时温度,药粉从开始加入时温度,全部加入后时温度,加入透皮吸收促进剂后的温度,摊涂时温度,冷却定型时温度,结果见表2。
表2各操作步骤的温度测定结果
项目步骤 | 温度(℃) |
热熔压敏胶融化完全时 | 135-145 |
药粉加入时 | 120-130 |
加入透皮吸收促进剂时 | 80-90 |
摊涂 | 80-85 |
冷却定型 | 室温 |
结果表明,热熔压敏胶融化温度为135-145℃。加入药粉后温度可控制在120-130℃,搅拌均匀后,为保证透皮吸收促进剂不受温度影响而流失,故加入时的温度应控制在80-90℃,混合均匀后立即摊涂,自然冷却至室温,膏体即可定型。
1.3.4基质用量的选择
按处方比例称取饮片适量,将饮片粉碎成细粉后,称取50g,共三份,按药粉重量的1、1.2、1.5倍称取三份热熔压敏胶,如表3所示,加热融化,加入药粉搅拌均匀,加入芒硝、冰片、薄荷脑透皮吸收促进剂,以涂布的难易性、膏体软硬程度、膏体的黏性等作为考查指标,优选基质用量,结果见表4。
表3基质用量的选择
配方号 | 药粉量(g) | 热熔压敏胶(g) |
1 | 50 | 50 |
2 | 50 | 60 |
3 | 50 | 75 |
表4基质用量的选择结果
结果表明,配方2与配方3热熔压敏胶加入量适宜,膏体黏性适中,易于涂布,贴于皮肤上撕落时不会产生不适。而配方1中药粉加入量过大,分散了热熔压敏胶的黏合力,使其贴于皮肤上撕落时有部分残留,无二次敷贴能力。通过实验确定基质用量为药粉重量的1.1-1.2倍。
1.3.5药粉灭菌
本品为全生药粉直接入药,需对灭菌方式进行考查。经查询《中国药典》2020年版第四部通则1421灭菌法中的湿热灭菌,其常用的灭菌温度为116-121℃,灭菌时间根据温度的不同而不同。如本品采用湿热灭菌进行灭菌则会经过两次高温,造成有效成分流失。故本品利用热熔压敏胶与药粉搅拌时的高温进行灭菌。
按处方比例称取饮片适量,将饮片粉碎成细粉后,称取50g,加入到融化热熔压敏胶中,将药粉完全加入后,温度控制在120℃,分别于15分钟、30分钟、45分钟取样,照《中国药典》2020年版四部贴膏剂检查项下微生物限度进行检测,考查到达贴膏剂灭菌标准所用的时间,结果见表5。
表5生药粉灭菌的考查
结果表明,药粉在120℃的热熔压敏胶中搅拌15分钟,即可到达灭菌作用,按微生物限度要求检测合格。
1.3.6搅拌均匀性考查
为保证药物的安全、有效、均一,生药粉与热熔压敏胶须搅拌均匀,故对本品的搅拌均匀性进行考查。
(1)搅拌均匀性预实验
取热熔压敏胶120g,加热融化,称取处方药粉100g,少量多次加入,搅拌桨(转速40-50转/分钟)将药粉与热熔压敏胶进行搅拌,以膏体无肉眼可见颗粒作为搅拌均匀的评价指标,并记录所用时间。加入冰片、芒硝与透皮吸收促进剂后,以膏体颜色是否均匀作为搅拌均匀判断依据。
结果表明,在实验室条件下,药粉与热熔压敏胶搅拌32分钟可混合均匀,加入透皮吸收促进剂后,搅拌5分钟可混匀,但搅拌时间因物料量和设备不同而存在较大差异,故本次实验只具有参考意义。
(2)搅拌均匀性的考查
生产第一批中试样品时,对搅拌均匀性进行了考查。使用设备为YZ-SB75夹层搅拌机,搅拌浆转速为0-50转/分钟。热熔压敏胶加热融化后,少量多次加入药粉,搅拌桨转速控制在30-40转/分钟,将膏体分成上中下三层,从药粉加入完毕开始计时,每隔0.5h进行取样,取样点如图示。将取样的膏体涂布至玻璃板上,透过光照进行观察,以膏体颜色均匀,膏体中无明显团块状为指标,判断搅拌终点,确定本品的搅拌时间,结果见表6。
表6不同搅拌时间取样涂布结果
注:“+”代表膏体颜色均匀,无明显团块状。“-”代表膏体颜色不均匀,有明显团块状。
结果表明,透过光照进行观察,搅拌1.5h和2.0h的涂布样品,其膏体颜色均匀,且无明显团块状,说明药粉与基质已混合均匀。
因透皮吸收促进剂薄荷脑熔点较低,如温度较高会导致薄荷脑挥发而损失,故根据实际生产经验,将冰片、芒硝、薄荷脑加入后,搅拌0.5h后,即可视为搅拌均匀。
故本品搅拌时间为药粉加入完毕后搅拌1.5-2.0h,加入透皮吸收促进剂后,搅拌时间为0.5h,总体搅拌时间约2.0-2.5h。
1.3.7涂布说明
根据预实验结果,膏体温度在80℃时出现部分凝固,故本品涂布时温度不得低于80℃,涂布厚度控制在0.75mm-1.25mm。
1.3.8分切、贴合工艺的说明
成型的膏体切制成大小合适的药卷,放置在药贴合成机上,贴合并裁剪至合适大小,覆盖医药离型纸,包装。
1.3.9成型工艺结论
1.3.10含药量计算
现每1000片贴膏投入生药粉3100g,则本品每贴含药粉3.1g。
2.中试工艺研究
为考查工艺的稳定性,按8倍制剂处方量,参照优选的工艺,制备三批中试样品,对三批中试产品进行检验,有关工艺参数及检测结果见表7,生产设备见表7。
表7三批中试生产技术数据
结论:三批中试结果表明,本工艺参数基本稳定,可适用于批量生产。
表8中试生产设备表
3.工艺小结
3.1将芒硝、冰片称出备用,其余十一味饮片于60℃-70℃干燥,控制水分8%以下,粉碎成细粉,过80目筛,混匀,备用。
3.2将药粉重量1.1-1.2倍的热熔压敏胶,加热融化,加入药粉搅拌均匀,并控制温度在120℃,搅拌1.5-2.0h。关闭加热,待膏体温度降低至80-90℃,将芒硝、冰片、薄荷脑粉加入,搅拌0.5h,搅拌均匀,保温,备用。
3.3将膏体涂布于双向拉伸聚丙烯珠光薄膜,覆盖上医药离型纸,卷成大药卷,冷却至室温定型。将冷却好的大药卷切制成合适大小的药卷,将小药卷置药贴合成机上,剥下医药离型纸,贴合于带黏性的卫生用水刺法非织造布上,覆盖医药离型纸,切制成合适大小,包装,即得。
4.质量研究的试验资料及文献资料
4.1处方中各药味的主要化学成分及理化性质
4.1.1醋延胡索的化学成分
延胡索化学成分主要为两大类,一类为生物碱,二为非生物碱类。生物碱类主要为延胡索甲素、延胡索乙素、延胡索丙素、延胡索丁素、四氢黄连碱、D-海罂粟碱、左旋四氢非洲防己胺、右旋紫堇碱、右旋延胡索甲素、四氢小檗碱、异紫堇球碱、氯仿巴马亭、莎乌拉亭、去氢海罂粟碱等生物碱;非生物碱主要为N5-乙酰基鸟氨酸、腺苷、3β-羟基-齐墩果-11,13(18)-二烯-28-羧酸、大黄素甲醚、大黄素、对羟基苯甲酸、香草酸、β-谷甾醇、胡萝卜苷、山芋酸、2-羟基丙酸、2,3-二羟基丙酸、丁二酸、苹果酸、枸橼酸、软脂酸、硬脂酸等物质。
4.1.2燀桃仁的化学成分
主要含有脂肪油类、苷类、蛋白质和氨基酸、挥发油、甾体及其糖苷等。其中不饱和脂肪酸以9-十六碳烯酸、9-十八碳烯酸。苷类以苦杏仁苷、野樱苷、等氰苷为主要有效成分、此外还分离出扁桃酸-β-龙胆二糖苷、扁桃酸-β-D-吡喃葡萄糖苷、苄基-β-龙胆二糖苷、苄基-β-D-吡喃葡萄糖苷等成分、桃仁总蛋白中可分离出清蛋白、球蛋白、醇溶蛋白、谷蛋白等部分、而必需氨基酸的量占桃仁17种氨基酸。萜类及挥发油主要有苯甲醛、苯甲酸、苯甲醇、α-氧代苯乙腈、罗勒烯、柠檬烯以及樟脑等。
甾体有豆甾醇乙酸酯等。
4.1.3红花的化学成分
主要含有黄酮及黄酮苷类、生物碱类、聚炔类、木脂素类、多糖类等。黄酮及黄酮苷类主要有山柰酚、6-羟基山柰酚、6-hydroxykaempferol-3-O-β-D-glucoside、槲皮素、quercetin-3-O-β-D-glucoside、芦丁、木犀草素、芹菜素、野黄芩素等;生物碱类主要含有N-阿魏酰基-5-羟色胺、N-(p-coumaroyl)serotonin-O-β-D-glucopyranoside、N-阿魏酰基色胺、N-(p-香豆酰基)-5-羟色胺、N-feruloylserotonin-O-β-D-glucopyranoside、N-(p-香豆酰)色胺、4,4″-二(N-p-香豆酰基)5-羟色胺、尿苷、腺苷、腺嘌呤、胸腺嘧啶等;聚炔类主要为(8Z)-decaene-4,6-diyne-1-O-β-D-glucopyranoside、(2E,8Z)-tetradecadiene-4,12,14-triol-1-β-Dglucopyranoside、(2Z)-decaene-4,6-diyne-1-O-β-D-glucopyranoside等;木脂素类主要为二苄基丁内酯、马台树脂醇-4'-O-β-D-呋喃芹糖基-(1→2)-O-β-D-吡喃葡萄糖苷骈双四氢呋喃丁香脂素、鹅掌楸、树脂醇等;红花多糖多以混合物的形式存在,红花经提取、沉淀、干燥、除蛋白与脱色,再经分离纯化得到红花多糖,对其单糖组成及结构进行解析,发现经纯化分离后红花多糖包含2个主要组分。2个组分皆为均一杂多糖,一种由鼠李糖、阿拉伯糖、甘露糖、葡萄糖、半乳糖、木糖6种单糖组成,另一种由鼠李糖、阿拉伯糖、葡萄糖、半乳糖4种单糖组成。
4.1.4醋制乳香的化学成分
乳香含树脂树胶,挥发油。树脂的主要成分为游离α-乳香脂酸、β-乳香脂酸、结合乳香脂酸、乳香树脂烃;树胶为阿糖酸的钙盐和镁盐、西黄芪胶黏素和苦味质;挥发油含蒎稀、茨稀、香桧烯、榄香稀、消旋-柠檬稀、1-壬烯、己醛等。
4.1.5醋制没药的化学成分
没药主要含有树脂、挥发油、树胶,挥发油主要为萜类主要为单萜和倍半萜类,榄香醇、莪术烯、榄香烯、氧化石竹烯、α-檀香烯、荜澄茄烯、石竹烯、古巴烯、茴香脑等成分;树脂类为没药酸、α-白檀酮、没药尼酸、罕没药树脂、罕没药脂酸、没药萜醇、β-谷甾醇、没药甾酮、菜油甾醇、松香酸、香树素α-罕没药酚和β-罕没药酚等;树胶与阿拉伯树胶相似,在水解过程中产生阿拉伯聚糖、半乳聚糖、木聚糖和葡萄糖醛酸等。
4.1.6制川乌的化学成分
制川乌含多种生物碱,主要是乌头碱、异乌头碱、次乌头碱、素馨乌头碱等。
4.1.7白芷化学成分
白芷含脂溶性与水溶性成分主要为香豆素类,含量为0.211%-1.221%,其中主要有氧化前胡0.06%-0.43%,欧前胡素0.1%-0.83%,异欧前胡0.05%-0.15%。
4.1.8花椒的化学成分
主要有挥发油、生物碱、黄酮类、苯丙素类等化合物。挥发油主要含有柠檬烯、桉树脑、水芹烯、β-月桂烯、α-蒎稀、桧萜、松油烯、桧烯、罗勒烯、侧柏烯、丁香烯、4-萜品醇、芳樟醇乙酸酯、芳樟醇、松油醇、沉香醇、胡椒酮和薄荷酮等;生物碱为11-甲氧基白屈菜红碱、去甲基白屈菜红碱、阿尔洛花椒酰胺、茵芋碱、乙酰安诺南碱、青花椒碱、木兰花碱、伪非洲防己碱、德卡林碱、花椒棚碱等;黄酮类主要为芦丁、金丝桃苷、槲皮素、橙皮苷等;苯丙素类主要为绿原酸、芝麻素、赫尼亚林、桉脂素等。
4.1.9细辛的化学成分
细辛主要含马兜铃酸A、α-蒎烯、β-蒎烯、莰烯、月桂烯、香水烯水合物、柠檬烯、1,8-胺树脑、对伞花烃、龙脑、草蒿脑、黄樟醚、甲基丁香油酚、肉豆蔻醚、榄香脂素、α-萜品醇、α-异松油烯、3,5-二甲氧甲苯、α-水芹烯、细辛脑等化学成分。
4.1.10龙葵的化学成分
主要含有生物碱类、皂苷类及其他微量元素。生物碱主要为茄碱、茄解碱、澳洲茄碱、澳洲茄边碱、β-澳洲茄边碱、生物碱苷等;皂苷类主要有uttrosideA(Ⅰ)、uttrosideB(Ⅱ)、提果皂苷元、薯蓣皂苷元;此外还含有6-甲氧基-7羟基香豆素、丁香脂素-4-O-β-D葡萄糖苷、松脂素-4-O-β-D葡萄糖苷、3,4-二羟基苯甲酸、对羟基苯甲酸、3-甲氧基-4-羟基苯甲酸、腺苷、维生素A、叶黄素、β-胡萝卜素。
4.1.11芒硝的化学成分
本品为硫酸盐类矿物芒硝族芒硝,经加工精制而成的结晶体。主含含水硫酸钠(Na2SO4·10H2O)。
4.1.12白芍的化学成分
主要含有单萜及苷类、三萜类及苷类、黄酮类、糅质类组成;单萜及苷类主要为芍药苷、芍药内酯苷、苯甲酰芍药苷、脱苯甲酰芍药苷、氧化芍药苷、氧化芍药苷亚硫酸酯、芍药苷磺酸酯、芍药苷亚硫酸酯、4″-羟基-芍药内酯苷等;三萜类主要为3β-羟基-11-氧代-齐墩果-12-烯-28-酸、11α,12α-环氧-3β,23-二羟基齐墩果-28,13β-交酯、23-羟基白桦酯酸、齐墩果酸、白桦酯酸;黄酮类主要为山奈酚-3-7-di-O-β-D-葡萄糖苷、山奈酚-3-O-β-D-葡萄糖苷、儿茶素、儿茶酸、山奈酚、二氢芹菜素、花青素;糅质主要为没食子酸、没食子酸甲酯、没食子酸乙酯、1,2,3,6-O-四没食子酰基葡萄糖、1,2,3,4,6-O-五没食子酰葡萄糖等。
4.1.13冰片的化学成分
化学成分为2-茨醇,化学式是C10H18O,功能主治开窍醒神,清热止痛。用于热病神昏、惊厥,中风痰厥,气郁暴厥,中恶昏迷,胸痹心痛,目赤,口疮,咽喉肿痛,耳道流脓。
4.2鉴别
乌龙镇痛贴膏由醋延胡索、燀桃仁、红花、醋乳香、醋没药、制川乌、白芷、花椒、细辛、龙葵、芒硝、白芍、冰片其中醋延胡索、制川乌为君药,醋乳香、醋没药、白芷、龙葵为臣药,燀桃仁、红花、花椒、细辛、芒硝、白芍为佐药,冰片为使药。
对醋延胡索、制川乌、醋乳香、醋没药、细辛、白芍、红花、白芷等8个药味进行了薄层色谱研究,其中延胡索、制川乌、白芍、白芷薄层鉴别列入质量标准。
4.2.1薄层鉴别
(1)醋延胡索薄层鉴别
方法一来源:《中国药典》2020年版一部延胡索项下;
取本品4贴,除去盖衬,剪碎,加甲醇50ml,超声处理30分钟,滤过,滤液蒸至近干,除去浮油,残渣加水10ml溶解,用浓氨调Ph值至9-10,用乙醚振摇提取3次,每次10ml,合并乙醚液,挥干,残渣加甲醇1ml使溶解,作为供试品溶液。另取缺延胡索阴性样品4贴,同法制成缺延胡索阴性样品溶液。再取延胡索对照药材0.5g,同法制成对照药材溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取上述三种溶液对照10μl,分别点于同一1%氢氧化钠溶液制备的硅胶G薄层板上,以甲苯-丙酮(9:2)为展开剂,展开,取出,晾干,置碘蒸气中熏3分钟,挥干碘,置紫外光(254nm)下检视。供试品色谱中,在与对照药材色谱相应的位置上,显相同颜色的荧光斑点,且阴性无干扰,见图1,故此鉴别列入质量标准。
图1延胡索TLC(列入质量标准);
方法二来源:《中国药典》2020年版一部延胡索项下;
取本品2贴,除去盖衬,剪碎,加70%乙醇50ml,加热回流1h,过滤,滤液蒸至近干,除去浮油,残渣加水20ml溶解,用浓氨调Ph值至9-10,置D101大孔吸树脂上(柱高10cm,内径1.5cm),先用50ml水进行洗脱,弃取洗脱液,再用20%乙醇50ml进行洗脱,收集洗脱液,蒸干,残渣加甲醇1ml使溶解,作为供试品溶液。另取缺延胡索阴性样品2贴,同法制成缺延胡索阴性样品溶液。再取延胡索对照药材0.5g,同法制成对照药材溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取上述三种溶液对照10μl,分别点于同一硅胶G薄层板上,以甲苯-丙酮(9:2)为展开剂,展开,取出,晾干,置碘蒸气中熏3分钟,挥干碘,置紫外光(365nm)下检视。供试品色谱中,在与对照药材色谱相应的位置上,不显相同颜色的荧光斑点,见图2,故此鉴别不列入质量标准。
图2延胡索TLC(不列入质量标准);
方法三来源:贴膏薄层色谱鉴别研究
取本品2贴,除去盖衬,剪碎,加甲醇50ml,超声处理30分钟,滤过,滤液蒸至近干,除去浮油,残渣加水10ml溶解,用浓氨调Ph值至9-10,用乙醚振摇提取3次,每次10ml,合并乙醚液,挥干,残渣加甲醇1ml使溶解,作为供试品溶液。另取缺延胡索阴性样品2贴,同法制成缺延胡索阴性样品溶液。再取延胡索对照药材0.5g,同法制成对照药材溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取上述三种溶液对照10μl,分别点于同一硅胶G薄层板上,以正己烷-三氯甲烷-甲醇(7.5:4:1)为展开剂,展开,取出,晾干,置碘蒸气中熏3分钟,挥干碘,置紫外光(365nm)下检视。供试品色谱中,在与对照药材色谱相应的位置上,显相同颜色的荧光斑点,且阴性无干扰,见图3,故此鉴别列入质量标准。
图3延胡索TLC(列入质量标准)。
(2)红花薄层鉴别
方法来源:《中国药典》2020年版一部红花项下;
取本品4贴,除去盖衬,剪碎,加80%丙酮溶液50ml,密塞,振摇15分钟,静置,取上清液2ml,作为供试品溶液。另取缺红花阴性样品4贴,同法制成缺红花阴性样品溶液。再取红花对照药材0.5g,加80%丙酮溶液10ml,同法制成对照药材溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取上述三种溶液各5μl,分别点于同一硅胶H薄层板上,以乙酸乙酯-甲酸-水-甲醇(7:2:3:0.4)为展开剂,展开,取出,晾干,置日光下检视。供试品色谱中,在与对照药材色谱相应的位置上,不显相同颜色的斑点,见图4,故此鉴别不列入质量标准。
图4红花TLC(不列入质量标准)。
(3)制川乌薄层鉴别
方法来源:《中国药典》2020年版一部制川乌项下;
取本品5贴,除去盖衬,剪碎,加氨水10ml润湿,乙醚50ml,超声处理30分钟,加入40ml乙醇,取上清液,蒸至近干,除去浮油,残渣加二氯甲烷2ml使溶解,作为供试品溶液。另取缺制川乌阴性样品5贴,同法制成缺制川乌阴性样品溶液。再取双脂型生物碱适量,加三氯甲烷-异丙酮(1:1)制成每ml含1mg的对照品溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取对照品溶液4μl、供试品及阴性10μl,分别点带于同一硅胶G薄层板上,置氨蒸气中饱和20分钟,再以正己烷-乙酸乙酯-甲醇(6.4:3.6:1)为展开剂,展开,取出,晾干,喷以稀碘化铋钾试液,置日光下检视。供试品色谱中,在与对照品色谱相应的位置上,显相同颜色的斑点,且供试品斑点浅于对照品斑点或无相同颜色斑点,此外阴性不存在干扰,见图5,故此鉴别列入质量标准。
图5制川乌TLC(列入质量标准)。
(4)白芷薄层鉴别
方法来源:《中国药典》2020年版第一部白芷项下;
取本品2贴,除去盖衬,剪碎,加乙醇50ml,加超声提取30分钟,加乙醇20ml,取上清液,蒸至近干,除去浮油,残渣加乙酸乙酯2ml使溶解,作为供试品溶液。取缺白芷阴性样品2贴,同法制成缺白芷阴性样品溶液。再取白芷对照药材0.5g,加乙醚30ml,超声提取30分钟,滤过,滤液挥干,残渣加乙酸乙酯2ml溶解,作为对照药材溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取上述溶液各4μl,分别点于同一硅胶G薄层板上,以石油醚-乙醚(3:4)为展开剂,展开,取出,晾干,置紫外灯(254nm)下检视。供试品色谱中,在与对照药材色谱相应的位置上,显相同颜色的荧光斑点,且无阴性干扰,见图6,故此鉴别列入质量标准。
图6白芷TLC(列入质量标准)。
(5)细辛薄层鉴别
方法来源:《中国药典》2020年版第一部细辛项下;
取本品5贴,除去盖衬,剪碎,加甲醇80ml,超声提取45分钟,滤过,滤液蒸至近干,除去浮油,残渣加甲醇2ml使溶解,作为供试品溶液。取缺细辛阴性样品5贴,同法制成缺细辛阴性样品溶液。再取细辛对照药材0.5g,加甲醇30ml,同法制成对照药材溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取上述溶液各10μl,分别点于同一硅胶G薄层板上,以石油醚(60-90℃)-乙酸乙酯(3:1)为展开剂,展开,取出,晾干,喷以1%香草醛硫酸溶液,热风加热至斑点清晰,置日光下检视。供试品色谱中,在与对照药材色谱相应的位置上,显相同颜色的斑点,但阴性存在干扰,见图7,故此鉴别不列入质量标准。
图7细辛TLC(不列入质量标准)。
(6)白芍薄层鉴别
方法来源:《中国药典》2020年版第一部白芍项下;
取本品5贴,除去盖衬,剪碎,加乙醇80ml,加热回流1小时,放冷,取上清液,蒸至近干,除去浮油,残渣加乙醇15ml分次洗涤,滤过,合并滤液,蒸干,残渣加乙醇1ml使溶解,作为供试品溶液。另取缺红花阴性样品5贴,同法制成缺白芍阴性样品溶液。再取红白芍对照药材0.5g,加乙醇50ml,同法制成对照药材溶液。照薄层色谱法(《中国药典》2020年版四部通则0502)试验,吸取上述三种各10μl,分别点于同一硅胶G薄层板上,以二氯甲烷-乙酸乙酯-甲醇-甲酸(40:5:9:0.2)为展开剂,饱和,展开,取出,晾干,喷以5%香草醛硫酸,于105℃加热至斑点清晰。供试品色谱中,在与对照药材色谱相应的位置上,显相同颜色的斑点,且阴性无干扰,见图8,故此鉴别列入质量标准。
图8白芍TLC(列入质量标准)。
4.3重金属与砷盐的检查
对三批中试样品的重金属、砷盐进行了考查,结果见表1。
4.3.1重金属检查
照《中国药典》2020年版四部限量检查法0821第二法。
供试品管制备:取本品2贴,除去盖衬,剪碎,取2g,精密称定,缓缓炽灼至完全炭化,放冷,加硫酸1ml,使湿润,用低温加热至硫酸除尽后,加硝酸0.5ml,蒸干,至氧化氮除尽后,放冷,在500~600℃炽灼至完全灰化,放冷,加盐酸2ml,置水浴上蒸干后,加水15ml,滴加氨试液至酚酞指示液显微粉红色,再加醋酸盐缓冲液(pH 3.5)2ml,微热溶解后,移置纳氏比色管中,加水稀释成25ml,作为供试品管。
标准管制备:取配制供试品溶液的试剂,置瓷皿中,蒸干后,加醋酸盐缓冲液(pH3.5)2ml与水15ml,微热溶解后,移置纳氏比色管中,加标准铅溶液2ml,再加水稀释成25ml,作为标准管。
再在上述两管中加入硫代乙酰胺试液各2ml,摇匀,放置2分钟,同置白纸上,自上向下透视,结果供试品管中的颜色浅于标准管颜色,见图9,结果表明本品重金属的含量低于10ppm,故未列入质量标准正文。
图9重金属检测。
4.3.2砷盐检查
照《中国药典》2020年版四部限量检查法0822第一法。
标准砷斑制备:精密量取标准砷溶液2ml,置A瓶中,加盐酸5ml与水21ml,再加碘化钾试液5ml与酸性氯化亚锡试液5滴,在室温放置10分钟后,加锌粒2g,立即照仪器装置装妥导气管C密塞于A瓶上,并将A瓶置25~40℃水浴中,反应45分钟,取出溴化汞试纸,即得。
供试品砷斑制备:取本品2贴,除去盖衬,剪碎,取2g,精密称定,缓缓炽灼至完全炭化,放冷至室温,加硫酸1ml,使湿润,用低温加热至硫酸蒸气除尽后,放冷,在500~600℃炽灼使完全灰化,放冷,置A瓶中,加盐酸5ml与水21ml,同标准砷斑方法制备,结果三批供试品砷斑的颜色均浅于标准砷斑的颜色,见图10,即本品砷盐的含量均小于1ppm。故未列入质量标准正文。
图10砷斑检测。
表9砷盐、重金属考查结果
4.4检查项目
三批中试样品照《中国药典》2020年版四部制剂通则0122贴膏剂项下进行了含膏量、耐热性、黏附力进行了检查,三批样品耐热性符合规定,并根据三批样品检测结果,制定了本品的含膏量、黏附力的标准。
4.4.1含膏量的检查
本品为橡胶贴膏,照《中国药典》2020年版第四部0122贴膏剂项下【含膏量】第一法检测,用乙酸乙酯做溶剂,结果见表10。
表10含膏量测定结果(n=2)
批号 | 20220916 | 20220919 | 20220921 |
含膏量(g/100cm2) | 11.28 | 11.30 | 11.31 |
经测定三批乌龙镇痛贴膏的含膏量,最高值为11.31g/100cm2,最低值为11.28g/100cm2,三批平均值11.30g/100cm2,综合研判本品的含膏量拟定为在平均值的基础上减少15%,标准为每100cm2含膏量不得少于9.60g。
4.4.2耐热性检查
本品为橡胶贴膏,照《中国药典》2020年版第四部0122贴膏剂项下【耐热性】检测,三批检验结果见表11。
表11耐热性检查结果
结论:本品三批符合《中国药典》2020第四部贴膏剂项下耐热性的有关规定。
4.4.3黏附力检查
本品为橡胶贴膏,照《中国药典》2020版第四部通则0952第二法进行测定,挂载200g砝码,于室温放置1小时,记录试验板移动的距离,结果见表12。
表12黏附力检测结果(n=3)
批号 | 20220916 | 20220919 | 20220921 |
平均距离(mm) | 1 | 2 | 1 |
经测定乌龙镇痛贴膏的黏附力,最高值为3mm,最低值为1mm,考虑到位移单位较小,会应因背衬黏性原因出现较大差距,故综合研判本品的黏附力标准为:取供试品3贴固定于试验板与加载板表面,挂载200g砝码,室温放置1小时后取出,测量试验板与加载板的位移值,试验板与加载板的平均位移距离不得大于5mm。
4.5微生物限度检查方法适用性试验研究
乌龙镇痛贴膏作为非无菌不含药材原粉的皮肤给药制剂,根据药典规定,非无菌不含药材原粉的中药制剂的微生物限度应符合要求,故对乌龙镇痛贴膏进行了微生物限度检查方法适用性实验。
4.6微生物限度检查结果
本品为贴膏剂,按《中国药典》2020年版要求,需做需氧菌、霉菌及控制菌检查,对三批样品进行微生物限度检查,结果均符合规定,结果见表13。
表13三批微生物检测结果
本申请创新点总结:
1.粉碎工艺
本品以生药粉入药,故需考查粉碎工艺。影响饮片出粉率的主要因素有饮片自身性质和饮片含水量。饮片自身性质可通过改变粉碎方式来优化出粉率,而根据实际生产经验可知,饮片含水量越低越容易粉碎,出粉率也越高。本品药味较多,如采用单独粉碎,则耗时长,不利于生产,也浪费能源。故本品使用混合粉碎的方式以省时节能,提高生产效率。因此本品粉碎工艺只考查含水量对出粉率的影响。
醋延胡索2份-9份、燀桃仁2份-3份、红花2份-3份、醋乳香2份-3份、醋没药2份-3份、制川乌2份-3份、白芷2份-6份、花椒2份-6份、细辛2份-3份、龙葵2份-9份、白芍2份-6份,粉碎成粗粉,60℃-70℃干燥,称重,粉碎,过80目筛,称重,计算出粉率,并测定水分,结果见表14。
表14出粉率实验结果
编号 | 1 | 2 | 3 |
饮片(g) | 108.03 | 108.08 | 108.12 |
细粉(g) | 96.51 | 99.58 | 101.78 |
出粉率(%) | 89.34 | 92.14 | 94.14 |
水分(%) | 10.24 | 7.24 | 6.14 |
结果表明,饮片60℃-70℃干燥,如需出粉率均在90%以上,则需饮片水分控制在8%以下。故本品的粉碎工艺为:除樟脑、冰片两味,其余饮片60℃-70℃干燥,控制水分至8%以下,粉碎后过80目筛,混匀。
2.成型工艺
贴膏剂,系指将原料药物与适宜的基质制成膏状物、涂布于背衬材料上供皮肤贴敷、可产生全身性或局部作用的一种薄片状制剂。根据成型工艺与基质的不同,可分为凝胶贴膏和橡胶贴膏。凝胶贴膏指原料药物与适宜的亲水性基质混匀后涂布于背衬材料上制成的贴膏剂。常用基质有聚丙烯酸钠、羧甲纤维素钠、明胶、甘油和微粉硅胶等。实际生产中凝胶贴膏生产工艺复杂,生产周期长,膏体含水量高且黏弹性不足,使用中会因体温升高发生熔化,导致跑膏和脱膏,且容易导致过敏;凝胶贴膏放置时间过长,膏体易失水而硬化,导致无法敷贴。橡胶贴膏生产工艺相对简单,生产周期短,皮肤过敏概率小,使用时不受温度影响,保存时间长,故本品选择橡胶贴膏。
2.1基质种类的优选
橡胶贴膏生产中常用溶剂为汽油和正己烷,常用基质有橡胶、热塑橡胶、松香、松香衍生物、凡士林、羊毛脂和氧化锌等,也可用其他适宜溶剂和基质。以橡胶为基质的贴膏生产过程中使用大量汽油等有机溶剂,生产成本高,防爆防火措施要求严格、安全隐患大,在生产过程中药物挥发多,生产厂房和设备投资大,不能生药粉直接入药。热熔压敏胶属于热塑橡胶,使用其作为基质主要有以下优势:
2.2基质透皮吸收促进剂的选择
透皮吸收促进剂(Penetration enhancers,PE),是指一种具有能暂时性调节经皮通透性的物质。PE在应用安全无毒的前提下,在临床上能够增强或者提高药物的经皮穿透速率,甚至通过皮肤局部给予就能够有利于治疗病人全身性疾病。贴膏剂常用透皮吸收促进剂有冰片、合成樟脑、薄荷脑、月桂氮酮等。/>
目前有关单一PE的研究已经较多,李鹏跃等发现薄荷脑在一定浓度范围内能够促进葛根素的渗透,当浓度达到5mg/mL时具有显著促渗作用。周庄等发现3%薄荷脑加3%冰片对青藤碱微乳体外透皮吸收优于单独使用冰片及薄荷脑,王晓颖等研究显示,5%冰片能将钩藤中钩藤碱透皮速率提高2.24倍,5%薄荷脑能将钩藤碱透皮速率提高1.95倍。庞帼敏等报道,冰片和薄荷油对蛇床子素的促渗效果均优于相同用量的氮酮,且以前者较优,盛小茜等研究显示,在乳猪与裸鼠皮肤中,2种制剂中樟脑的渗透系数均大于薄荷脑(P<0.05)。
PE的促渗能力与药物的理化性质有关,单一PE不能同时提高中药复方中多种有效成分的透皮能力,因此联合使用PE是当前中药贴膏剂透皮促渗的研究热点,研究发现部分PE按一定比例组合时能够取得协同作用,比使用单一PE效果更佳,根据王曙东等在不同促渗剂复方红茴香喷雾剂体外透皮吸收的影响研究中指出对槲皮苷的累积渗透及渗透速率影响大小为冰片>薄荷油>氮酮>PEG400,更有文献指出天然透皮促渗其毒性小于合成的促渗透剂,以上研究均说明处方中的冰片可以增加药物透皮吸收效果,但冰片在处方中存在治疗功能,故需要增加其他促渗剂。根据上述研究薄荷脑的促渗透作用仅弱于冰片,故选用薄荷脑作为促渗剂。
同时查询相关资料,冰片的熔点在206-209℃、沸点在212℃,薄荷脑的熔点在34-36℃、沸点在215℃,芒硝的熔点32-38℃、沸点330℃。考虑到高温会使薄荷脑及芒硝受热流失,故加入芒硝、冰片、薄荷脑时应控制在较低温度。
2.3基质用量的选择
按处方比例称取饮片适量,将饮片粉碎成细粉后,称取50g,共三份,按药粉重量的1、1.2、1.5倍称取三份热熔压敏胶,如表15所示,加热融化,加入药粉搅拌均匀,加入芒硝、冰片、薄荷脑透皮吸收促进剂,以涂布的难易性、膏体软硬程度、膏体的黏性等作为考查指标,优选基质用量,结果见表16。
表15基质用量的选择
配方号 | 药粉量(g) | 热熔压敏胶(g) |
1 | 50 | 50 |
2 | 50 | 60 |
3 | 50 | 75 |
表16基质用量的选择结果
配方号 | 涂布程度 | 膏体黏性 | 肤感 |
1 | 难以涂布,膏体偏硬 | 黏性较差 | 撕落时部分粘附皮肤上 |
2 | 易涂布,软硬适宜 | 黏性适中 | 撕落无痛感 |
3 | 易涂布,软硬适宜 | 黏性适中 | 撕落无痛感 |
结果表明,配方2与配方3热熔压敏胶加入量适宜,膏体黏性适中,易于涂布,贴于皮肤上撕落时不会产生不适。而配方1中药粉加入量过大,分散了热熔压敏胶的黏合力,使其贴于皮肤上撕落时有部分残留,无二次敷贴能力。通过实验确定基质用量为药粉重量的1.1-1.2倍。
工艺小结:
1.将芒硝、冰片称出备用,其余十一味饮片于60℃-70℃干燥,控制水分8%以下,粉碎成细粉,过80目筛,混匀,备用。
2.将药粉重量1.2-1.5倍的热熔压敏胶,加热融化,加入药粉搅拌均匀,并控制温度在120℃,搅拌1.5-2.0h。关闭加热,待膏体温度降低至80-90℃,将芒硝、冰片、薄荷脑粉加入,搅拌0.5h,搅拌均匀,保温,备用。
3.将膏体涂布于双向拉伸聚丙烯珠光薄膜,覆盖上医药离型纸,卷成大药卷,冷却至室温定型。将冷却好的大药卷切制成合适大小的药卷,将小药卷置药贴合成机上,剥下医药离型纸,贴合于带黏性的卫生用水刺法非织造布上,覆盖医药离型纸,切制成合适大小,包装,即得。
实验例2:临床试验
本申请中的膏药组方严谨、配伍科学,对癌痛的治疗效果明确。为观察此膏药对癌痛治疗的临床效果,我们对300例癌痛患者进行了观察,采用随机双盲法分为2组,分别为对照组、治疗组,每组150例。对照组中男性77例,女性73例,其中,肺癌占47例,消化道肿瘤占39例,乳腺癌占35例,其他部位肿瘤占29例。治疗组中男性81例,女性69例,其中,肺癌占43例,消化道肿瘤占41例,乳腺癌占36例,其他部位肿瘤占30例。2组患者均使用盐酸曲马多缓释片进行治疗,100mg,q12h。其中,治疗组患者在口服盐酸曲马多的基础上将本膏药贴于疼痛最明显部位,对照组患者予空白膏药处理,每天敷贴10h,每日更换一次,以10天为一疗程,连续治疗2个疗程后评估治疗效果。观察指标主要包括:疼痛缓解情况(NRS评分),生活质量评估(KPS评分),血清IL-β、IL-6、TNF-α炎症因子水平。
结果发现,治疗组在使用本申请的膏药后NRS评分降低,疼痛缓解率升高,KPS评分升高,生活质量提高,血清中IL-β、IL-6、TNF-α炎症因子水平降低,患者体内炎性反应得到改善。说明本申请膏药可减轻骨转移患者癌痛,其机制可能与抑制炎性因子释放有关。
1.疼痛缓解情况(NRS评分)
通过NRS评分对疼痛缓解情况进行评估,疼痛缓解程度主要分为4个标准:
①完全缓解(CR):无疼痛,NRS评分为0;
②部分缓解(PR):疼痛较前明显减轻,NRS评分减少1/2-3/4;
③轻度缓解(MR):疼痛较前减轻,但仍有明显疼痛,NRS评分减少<1/2;
④无效(NR):疼痛较前无减轻,NRS评分无变化。
疼痛缓解率=(CR+PR)/可评价病例数×100%。
表17 2组患者治疗前后疼痛缓解率比较
组别 | n | CR | PR | MR | NR | 疼痛缓解率% |
对照组 | 150 | 10 | 72 | 68 | 0 | 54.7 |
治疗组 | 150 | 20 | 108 | 22 | 0 | 85.3* |
注:*P<0.05vs对照组。
2.生活质量评估(KPS评分)
通过KPS评分对患者的生活质量进行评估,生活质量主要分为3个标准:
①提高:治疗后-治疗前>10分;
②降低:治疗前-治疗后>10分;
③稳定:治疗后与治疗前无变化。
表18 2组患者治疗前后KPS评分变化比较/>
组别 | n | 治疗前 | 治疗后 |
对照组 | 150 | 59.53±9.06 | 70.24±11.39# |
治疗组 | 150 | 58.07±8.33 | 77.13±12.95#* |
注:#P<0.05vs治疗前,*P<0.05vs对照组。
3.血清IL-β、IL-6、TNF-α炎症因子水平
采集2组患者治疗前24h及治疗结束后空腹静脉血,并用ELISA检测血清中IL-β、IL-6、TNF-α水平。
表19 2组患者治疗前后血清炎性因子水平比较
注:#P<0.05vs治疗前,*P<0.05vs对照组。
实验例3:动物实验
从40只雌性SD大鼠中随机抽取10只作为空白组,其余30只构建骨转移癌痛大鼠模型,并通过行为学检测判断模型是否构建成功。造模成功后将SD大鼠随机分为模型组、膏药组、扶他林组,每组10只。其中,膏药组予本申请膏药外敷于大鼠背部皮肤,去毛,敷贴好后用医用胶带固定,每天8h,1次/日,21天;扶他林组予扶他林外涂于大鼠背部皮肤,去毛,1次/日,21天。给药结束后对大鼠进行行为学检测,观察各组大鼠热痛觉缩足反射潜伏期(PWL)、机械痛觉缩足反射阈值(PWT)变化情况,用ELISA检测SD大鼠血清中PGE 2、TNF-α、IL-6、β-EP水平。
结果发现,本申请膏药组大鼠行为学检测中PWL、PWT较模型组升高,疼痛阈值上升;血清中PGE 2、TNF-α、IL-6含量降低,β-EP含量升高。说明本申请膏药对骨转移癌痛大鼠有镇痛作用,其机制可能与抑制炎性因子、提高内源性阿片肽有关。
表20.各组大鼠PWL水平
组别 | 0d | 7d | 14d | 21d | 28d | 35d |
空白组 | 15.03±1.38 | 15.94±1.61 | 13.98±1.04 | 14.85±1.63 | 13.74±1.06 | 15.24±1.29 |
模型组 | 13.97±1.26 | 8.74±1.65* | 6.75±1.24* | 6.49±1.83* | 5.17±0.97* | 4.09±0.83* |
膏药组 | 14.84±1.52 | 9.02±1.74 | 6.28±1.07 | 9.37±1.54# | 9.84±1.44# | 11.75±1.26## |
扶他林组 | 15.24±1.07 | 9.13±1.52 | 6.71±1.68 | 9.65±1.38# | 9.17±1.33# | 9.13±1.35# |
注:*P<0.05 vs空白组,#P<0.05,##P<0.01 vs模型组。
表21.各组大鼠PWT水平
注:*P<0.05 vs空白组,#P<0.05 vs模型组。
表22.各组大鼠血清PGE 2、TNF-α、IL-6、β-EP水平
注:*P<0.05vs空白组,#P<0.05vs模型组。
以上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制。任何熟悉本领域的技术人员,在不脱离本发明的精神实质和技术方案的情况下,都可利用上述揭示的方法和技术内容对本发明技术方案做出许多可能的变动和修饰,或修改为等同变化的等效实施例。因此,凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所做的任何简单修改、等同替换、等效变化及修饰,均仍属于本发明技术方案保护的范围内。
Claims (5)
1.一种治疗癌痛膏药的制备方法,其特征在于:包括以下步骤:
1)粉碎:按照质量比,准备醋延胡索2份-9份、燀桃仁2份-3份、红花2份-3份、醋乳香2份-3份、醋没药2份-3份、制川乌2份-3份、白芷2份-6份、花椒2份-6份、细辛2份-3份、龙葵2份-9份、芒硝2份-6份、白芍2份-6份、冰片1份-3份、薄荷脑1份-3份;
将以上除芒硝、冰片、薄荷脑以外的醋延胡索、燀桃仁、红花等十一味饮片在60℃-70℃干燥至含水量8%以下,粉碎过80目筛,混匀,得到药粉;
2)融化:将热熔压敏胶加热至135-145℃融化;
3)混合均匀:将步骤2)的热熔压敏胶与步骤1)得到的药粉按照(1.1-1.2):1混合,控制温度在120℃,搅拌1.5-2.0h,关闭加热;
4)加入辅料:待膏体温度降低至80-90℃,将芒硝、冰片、薄荷脑粉加入,搅拌0.5h,搅拌均匀,保温,得到药膏,备用;
5)摊涂:将上步骤得到的药膏摊涂于双向拉伸聚丙烯珠光薄膜上,覆盖医药离型纸,卷成大药卷,并冷却至室温;
6)切卷:将上步骤得到的大药卷切制成大小合适的小药卷;
7)贴合:将切好的小药卷置贴合机上,贴合于带黏性的卫生用水刺法非织造布上,覆盖一层医药离型纸;
8)切片:切制成大小合适的形状;
9)包装。
2.根据权利要求1所述的一种治疗癌痛膏药的制备方法,其特征在于:步骤2)所述的融化,控制热熔压敏胶融化温度为135-145℃,加入药粉后温度控制在120℃,搅拌均匀。
3.根据权利要求1所述的一种治疗癌痛膏药的制备方法,其特征在于:步骤6)所述的切制成大小合适的小药卷,小药卷的尺寸是3×4cm。
4.根据权利要求1所述的一种治疗癌痛膏药的制备方法,其特征在于:步骤8)所述的切制成大小合适的形状,是切制成1000贴。
5.根据权利要求1所述的一种治疗癌痛膏药的制备方法,其特征在于:步骤9)所述的包装,是采用双向拉伸聚丙烯、镀铝聚酯或聚乙烯药品包装用复合膜、袋。
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