CN102048710A - 一种快速溶解的薄膜及其制备方法 - Google Patents
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Abstract
本发明涉及一种快速溶解的薄膜,其特征是该薄膜由0.01-90%活性成分夫罗曲坦,及余量的成膜材料和药用辅料组成。制备方法为将夫罗曲坦、聚合物溶解在水或有机溶剂中或悬浮其他的辅料且涂抹该溶液在硅橡胶纸上或合适的载体物上,在35-65℃,干燥0.5-4小时;将干燥好的半成品,通过剪切割或膜压分离得到所规定大小的膜。
Description
技术领域
本发明涉及药物制剂领域,更具体的说,是一种在口腔中快速溶解的薄膜新剂型及其制备方法。
背景技术
偏头痛,青年女性最常见引起头痛的原因很多,最常见的是偏头痛,其他还有紧张性头痛、面部疾病引起的扩散性头痛、中毒性或代谢性疾病引起的头痛、一些严重器质性疾病引起的头痛。偏头痛是一种周期性发作的神经——血管功能障碍的头痛,为慢性复发性头痛中最常见的一种。它表现为一侧或两侧头部的搏动性或钻痛性疼痛,常伴有恶心、呕吐、厌食、畏光、精神委靡等症状。通常在青春期开始发病,以女性最为多见,常与月经周期有关,而且还常有家族史。偏头痛的致病机理还在研究中,现在认为可能是由于发作性颅内外血管舒缩功能不稳定,以及某些体液物质暂时改变所引起的。研究人员发现头痛急性发作时,患者血中5-羟色胺含量降低,而尿内5-羟吲哚乙酸排泄增加。
偏头痛疼起来头都要炸了偏头痛常发在疲劳、月经期前后、情绪激动、气候变化等时候。头痛最初是开始于一侧额颞部的钝痛,继而扩散至半个头,偶见整个头部疼痛的。疼痛感常比较剧烈,多呈搏动性跳痛或炸裂样疼痛,能持续数小时到1天,进入睡眠后终止,次日可完全恢复。偏头痛会反复发作,可数日或数周1次。偏头痛是一种常见的慢性、反复发作性疾病,在世界范围内广泛流行,严重影响患者的生活质量。夫罗曲坦(Frovatriptan)是新型的选择性5-HT1B/1D受体激动剂,它克服了第一代5-HT1B/1D受体激动剂口服生物利用度低、半衰期短、复发率高的缺点,是成人中、重度偏头痛发作的有效治疗药物。
近来认为偏头痛的发病起源于中枢神经系统,因大脑皮质功能紊乱,同时伴发内分泌及血管舒缩功能障碍而造成头痛发作。现已证实,与偏头痛发病关系密切的是5-HT1受体。夫罗曲坦为选择性5HT1受体激动剂,对神经元5-HT1D及血管选择性5-HT1B受体有高度的亲和性,对5-HT1A,5-HT1F,5-HT7受体有中等的亲和性,主要作用于脑外动脉和颅内动脉,并抑制这些血管的过度扩张。夫罗曲坦对心脏功能和血压无影响,也不影响冠状动脉的血流。
夫罗曲坦口服吸收略差,单次口服本品2.5毫克后,达峰时间约为2~4小时,绝对生物利用度约为20%~30%,食物对其生物利用度无明显影响,但可延迟达峰时间。静脉注射0.8毫克后,平均稳态分布容积约为3.0~4.2升/千克,与血浆蛋白结合率较低,约为15%。它主要通过细胞色素P450代谢,代谢物主要随尿液和粪便排出。静注本品后平均清除率为220~130毫升/分钟,肾清除率占总清除率的40%~45%。与其他曲普坦类抗偏头痛药物相比,夫罗曲坦的消除半衰期最长,约为26小时(约为其他曲普坦类药物的4~8倍),因此,可能对持续时间较长的偏头痛发作有特殊疗效。药物原形及代谢产物通过尿(占32%,其中10%为原形)和粪便(占62%,其中32%为原形)排出体外。
发明内容
本发明的一个的目在于提供一种在口腔中快速溶解的薄膜新剂型。
本发明的第二个的目的在于提供薄膜新剂型的制备方法。
本发明提供的生理可接受薄膜,含有一种或几种活性成分,在口腔中释放药物,迅速被口腔黏膜吸收,对急症病人来说是一种起效快的给药最佳的途经。特别适于粘着并且快速溶解在使用者的口腔中。快速溶解薄膜起效,经口腔或经粘膜释放药学活性物质从而发挥药效。对急症病人来说时间就是生命,所以开发这种快速溶解薄膜剂,是有意义的,也是体现这一剂型的特点。该工艺简单,经济,实用,适合于工业化生产。
本发明还涉及制备特别适合口腔给药的柔软的、非自粘着性薄膜的方法。该方法包括将成膜剂和至少一种稳定剂混合得到成膜混合物;将水溶性组分溶解在水中得到水溶液;将成膜混合物和水溶液混合得到水合聚合物凝胶;混合油类形成油混合物;将油混合物加入水合聚合物凝胶中并且混合,得到均匀乳化凝胶;将该均匀凝胶涂抹在村底上;干燥涂抹好的凝胶得到薄膜。
本发明的具体技术方案如下:
本发明的在口腔中快速溶解的薄膜新剂型,其特征是该薄膜由至少一种或多种活性成分,成膜材料和药用辅料组成。更具体的说薄膜由0.01-90%夫罗曲坦及余量的成膜材料和药用辅料组成。较好的活性成分占总薄膜的0.1-80%。
本发明所述的成膜材料包括多糖类聚合物、纤维素、聚乙烯醇、聚乙烯吡咯烷酮、乙烯吡咯烷酮-醋酸乙烯-共聚物,或支链淀粉、直链淀粉、高级直链淀粉、羟丙基化高级直链淀粉、玉米醇溶蛋白、大豆蛋白分离物。
其中所述的多糖类聚合物为右旋糖苷、糊精、壳多糖、壳聚糖、海藻酸钠、阿拉伯胶、果胶、胶原;纤维素为羧甲基纤维钠、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素。其中所述的成膜材料占薄膜的20-99.7%,
由于中药的复方或单味药各自有效的成分或部位是不同,所以辅料和制备方法是有所选择的:药物达到快速熔解的一个先决条件是在药物以分子形式溶解时需要聚合物具有较好的可溶性、非结晶性,崩解速度是由载体的溶解速度和特殊表面所决定的,快速溶解物质应具有较大的极性,如右旋糖苷、糊精、海藻酸钠、阿拉伯胶,聚乙烯醇、聚乙烯吡咯烷酮和纤维素类,药物和极性基团能够与聚合物产生相互作用,从而具有较好的可溶性。反之,少数极性药物存在高的过饱和浓度,由于温度的原因发生重结晶,使释放速度下降,无定型、溶解性好的载体有利于快速溶解和加快活性物质的释放。
本发明是含有活性物质的聚合物膜,通过涂抹含有活性物质的有机溶剂或水溶液,经干燥,制得。使用的水溶性聚合物为右旋糖苷、糊精、海藻酸钠、阿拉伯胶,聚乙烯醇、聚乙烯吡咯烷酮、乙烯吡咯烷酮-醋酸乙烯-共聚物、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙甲基纤维素、羟丙基纤维素。此外,聚乙烯醇、聚乙烯吡咯烷酮、乙烯吡咯烷酮-醋酸乙烯-共聚物的选择是根据它们在水中或有机溶剂(乙醇)中的溶解性。使用后者在于它的有较高的蒸汽压力和较好的干燥速度。
本发明所述的药用辅料包括增塑剂、表面活性剂、甜味剂、抗粘合剂、矫味剂、稳定剂、增稠剂的一种或几种的混合物。药用辅料一般占薄膜的0-30%,较好为0.01-30%,最佳为0.1-15%。可根据不同药物中的活性成分的理化性质,及生物特性适当的加以调节,例如为了使膜具有较好的可塑性加入:增塑剂(甘油淀粉、丙二醇、聚乙二醇)。抗粘合剂(硬脂酸镁、硬脂酸、乳化剂)。
矫味剂包括天然或人工矫味剂。这些矫味剂可以选自矫味油和矫味芳香剂,或它们的混合物。代表性矫味油包括:留兰香油、肉桂油、薄荷油、丁子香油、月桂油、百里香油适用的还有人工天然或合成水果矫味剂,包括柠檬、葡萄、苹果、香精、柠酸、桉油、薄荷精油等。
矫味剂的用量一般与这样的因素有关,如矫味剂类型、矫味剂本身和预期强度有关。所以,可以为了在最终产物中获得预期的结果可以改变该用量。这种改变是所属领域技术人员无需过多实验就能够作出的。通常,用量为约0至约30重量%,优选约0.1至约15重量%。
甜味剂包括天然和人工甜味剂。例如糖精钠、阿斯巴糖、木糖醇、甘露醇、新橙皮甙、半乳糖、甘草甜素、蔗糖、二氢查斗酮等。一般是该组合物的0%至约10重量%。优选约0.1至约5重量%。为获得预期的甜度,使用的用量根据不同样品而定。
表面活性剂包括脂肪酸的单酸甘油酯和二酸甘油酯类化合物以及聚氧化乙烯山梨糖醇酯,例如Atmos 300、聚山梨酸酯80、司盘65等。表面活性剂的加入量可以是该薄膜的约0.1至约15重量%,优选约0.1至约5重量%。其它适当表面活性剂包括十二烷基硫酸钠等。
稳定剂包括黄原胶、槐树豆胶和角叉菜胶,用量是该薄膜的约0至约10重量%,优选约0.1至约2重量%。其它适用的稳定剂包括瓜子胶等。
乳化剂包括硬脂酸三乙醇胺、季铵化合物;阿拉伯胶、明胶、卵磷脂、胶体镁铝硅酸盐等,用量是该薄膜的约0至约5重量%,优选约0.01至约0.8重量%。
增稠剂包括甲基纤维素、羧甲基纤维素等,用量是约0至约30重量%,优选约0.01至约20重量%。
粘合剂包括淀粉,用量是约0至约30重量%,优选约0.1至约10重量%。
本发明的药膜还可以添加着色剂或色料。着色剂的用量可有效产生预期的色泽。本发明所用的看色剂,包括颜料,例如二氧化钛,其混合量至大约5重量%,并且优选小于约1重量%。色料也可以包括天然食物色素,如红曲、栀子黄、姜黄素,和适用于食品和药物的染料,
本发明的在口腔中快速溶解的薄膜新剂型的制备方法,包括如下步骤:
1)将活性成分、聚合物溶解在水或乙醇、甲醇、正丁醇,丙酮、乙酸乙酯、氯仿中;较好的溶剂为水或乙醇、丙酮、乙酸乙酯等。
2)溶解或悬浮其他的辅料;
3)涂抹该溶液在硅橡胶纸上或合适的载体物上;
4)在35-65℃下干燥0.5-4小时;
5)将干燥好的半成品,通过剪切割或膜压分离得到所规定大小的膜;
6)包装分离得到的膜。
下面通过本发明所采用的活性成分药理实验数据,进一步阐述本发明的积极效果:
近来认为偏头痛的发病起源于中枢神经系统,因大脑皮质功能紊乱,同时伴发内分泌及血管舒缩功能障碍而造成头痛发作。现已证实,与偏头痛发病关系密切的是5-HT1受体。夫罗曲坦为选择性5HT1受体激动剂,对神经元5-HT1D及血管选择性5-HT1B受体有高度的亲和性,对5-HT1A,5-HT1F,5-HT7受体有中等的亲和性,主要作用于脑外动脉和颅内动脉,并抑制这些血管的过度扩张。夫罗曲坦对心脏功能和血压无影响,也不影响冠状动脉的血流夫罗曲坦口服吸收略差,单次口服本品2.5毫克后,达峰时间约为2~4小时,绝对生物利用度约为20%~30%,食物对其生物利用度无明显影响,但可延迟达峰时间。静脉注射0.8毫克后,平均稳态分布容积约为3.0~4.2升/千克,与血浆蛋白结合率较低,约为15%。它主要通过细胞色素P450代谢,代谢物主要随尿液和粪便排出。静注本品后平均清除率为220~130毫升/分钟,肾清除率占总清除率的40%~45%。与其他曲普坦类抗偏头痛药物相比,夫罗曲坦的消除半衰期最长,约为26小时(约为其他曲普坦类药物的4~8倍),因此,可能对持续时间较长的偏头痛发作有特殊疗效。药物原形及代谢产物通过尿(占32%,其中10%为原形)和粪便(占62%,其中32%为原形)排出体外。
药膜的稳定性实验
按照《中药新药研究的技术要求》的有关规定,进行了室温自然留样考察。在室温下于通风干燥处放置十二个月,通过性状、鉴别、溶化性、含量测定、微生物限度等方面对稳定性进行考察。结果表明,夫罗曲坦药膜放置十二个月稳定。
本发明薄膜与已有剂型相比的积极效果在于:
(1)含有活性物质的膜在缺少水的情况下,可服用。聚合物膜在几秒内或1分钟在舌上溶解,含服在口腔或舌下,吞咽服用时会在胃肠中溶解迅速吸收,它们的药物代谢过程是相似的。
(2)与冻干粉相比的优点是制备方法的简单,成本低,此外本品有少量的吸湿性但不必使用昂贵的、不透水蒸汽的包装材料。
(3)此剂型与固体制剂(片剂、胶囊、滴丸等)比较,具有溶解快、起效快,提高生物利用度,特别适用于急症药,如心脑血管、镇痛、安眠等,其优点是药物立即溶解,对吞咽困难的病人也不成问题,同样适合不合作病人的使用(儿童和老人);在旅行或用水不便时,同样可以服用,薄薄一片膜,吞服方便,进入体内后活性治疗成分易于从载体上释放出来,方便患者使用,病人易于接受。
具体实施方式
下面结合实施例对本发明做进一步的说明,实施例仅为解释性的决不意味着它以任何方式限制本发明的范围。
实施例1
夫罗曲坦3.2g,2.5gHPC,6.0g聚乙烯吡咯烷酮,0.02g甜菊糖,0.3g甘油,溶于16ml95%的乙醇中,形成混悬液,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成350微米的膜在35℃干燥30分钟,继续在65℃干燥30分钟,在平面重量为80g/m2下,形成厚度为90微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例2
夫罗曲坦3.2g,甲基纤维素2.0g,乙烯吡咯烷酮-醋酸乙烯-共聚物5.0g,0.02g阿斯巴糖,0.1g黄原胶,0.3g丙二醇,溶于12ml50%的乙醇中,形成混悬液,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成300微米的膜在30℃干燥30分钟,继续在60℃干燥60分钟,在平面重量为100g/m2下,形成厚度为80微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例3
夫罗曲坦3.2g,7.5g乙烯吡咯烷酮-醋酸乙烯-共聚物,0.02g糖精钠,0.3gPEG400,溶于12ml75%的乙醇中,形成混悬液,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形250微米的膜在30℃干燥30分钟,继续在60℃干燥60分钟,在平面重量为80g/m2下,形成厚度为75微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例4
夫罗曲坦0.1g,2.0g甲基纤维素,5.0g乙烯吡咯烷酮-醋酸乙烯-共聚物,0.5g木糖醇,0.05g槐树豆胶,0.3g丙二醇,0.1g薄荷精油,溶于12ml95%的乙醇中,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成300微米的膜在30℃干燥30分钟,继续在65℃干燥30分钟,在平面重量为100g/m2下,形成厚度为80微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例5
夫罗曲坦0.2g,3.5gHPC,3.5g聚乙烯吡咯烷酮,0.02g甜菊糖,0.2g甘油,0.1g聚山梨酸酯80,0.05g的硬脂酸,溶于16ml90%的乙醇中,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成300微米的膜在30℃干燥30分钟,继续在65℃干燥30分钟,在平面重量为100g/m2下,形成厚度为80微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例6
夫罗曲坦0.2g,2.0g黄原胶,3.5g槐树豆胶,1.5g淀粉,0.02g阿斯巴糖,0.2g丙二醇,0.05g的硬脂酸镁,溶于14ml95%的乙醇中,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成350微米的膜在30℃干燥30分钟,继续在60℃干燥60分钟,在平面重量为80g/m2下,形成厚度为50微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例7
夫罗曲坦
3.0g,1.0g黄原胶,2.5g槐树豆胶,1.5g淀粉,0.02g阿斯巴糖,0.2g丙二醇,0.08g的硬脂酸镁,溶于14ml水中,形成凝胶液,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成350微米的膜在30℃干燥30分钟,继续在60℃干燥60分钟,在平面重量为80g/m2下,形成厚度为70微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例8
夫罗曲坦2.5g,1.0gHPC,3.5g聚乙烯吡咯烷酮,0.02g新橙皮甙,0.2g甘油,溶于14ml水中,形成凝胶液,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成300微米的膜在30℃干燥30分钟,继续在60℃干燥60分钟,在平面重量为80g/m2下,形成厚度为80微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例9
夫罗曲坦5.0g,2.0g甲基纤维素,3.0g乙烯吡咯烷酮-醋酸乙烯-共聚物,0.5g木糖醇,0.3g丙二醇,0.1g薄荷精油,溶于12ml50%的乙醇中,形成凝胶液,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成300微米的膜在30℃干燥30分钟,继续在65℃干燥30分钟,在平面重量为90g/m2下,形成厚度为100微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
实施例10
夫罗曲坦0.5g,10g黄原胶,25g角叉菜胶,15g淀粉,0.1g阿斯巴糖,1g聚山梨酸酯80,2g丙二醇,溶于14ml水中,形成凝胶液,此溶液用橡皮刮板涂抹在硅橡胶纸上,所形成250微米的膜在35℃干燥30分钟,继续在65℃干燥30分钟,在平面重量为80g/m2下,形成厚度为60微米的膜,小心从硅橡胶纸上取下,切割成2×3cm的片,即得药膜。
Claims (4)
1.一种快速溶解的薄膜,其特征是该薄膜由0.01-90%活性成分夫罗曲坦,及余量的成膜材料和药用辅料组成。
2.如权利要求1所述的薄膜,其特征是所述的成膜材料包括:右旋糖苷、糊精、壳多糖、壳聚糖、海藻酸钠、阿拉伯胶、果胶、胶原;纤维素为羧甲基纤维钠、甲基纤维素、羟乙基纤维素其成膜材料的重量占薄膜的20-99%。
3.如权利要求1所述的薄膜,其特征是所述的药用辅料为增塑剂、表面活性剂、甜味剂、抗粘合剂、矫味剂、稳定剂、增稠剂其中的一种或几种的混合物;其重量占薄膜总量的0-30%。
4.一种在口腔中快速溶解的薄膜的制备方法,包括如下步骤:
1)将活性成分、聚合物溶解在水或乙醇、甲醇、正丁醇,丙酮、乙酸乙酯、氯仿中;2)溶解或悬浮其他的辅料;3)涂抹该溶液在硅橡胶纸上或合适的载体物上;4)在35-65℃下干燥0.5-4小时;5)将干燥好的半成品,通过剪切割或膜压分离得到所规定大小的膜;6)包装分离得到的膜。
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CN106727446A (zh) * | 2016-12-26 | 2017-05-31 | 广州立白企业集团有限公司 | 成膜组合物、保护膜及应用 |
CN108785289A (zh) * | 2018-09-06 | 2018-11-13 | 北京太阳升高科医药研究股份有限公司 | 盐酸那拉曲坦口溶膜剂及其制备方法 |
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CN106727446A (zh) * | 2016-12-26 | 2017-05-31 | 广州立白企业集团有限公司 | 成膜组合物、保护膜及应用 |
CN106727446B (zh) * | 2016-12-26 | 2019-09-17 | 广州立白企业集团有限公司 | 成膜组合物、保护膜及应用 |
CN108785289A (zh) * | 2018-09-06 | 2018-11-13 | 北京太阳升高科医药研究股份有限公司 | 盐酸那拉曲坦口溶膜剂及其制备方法 |
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