CN113018278A - 一种含有非甾体抗炎药的外用凝胶贴膏剂及其制备方法 - Google Patents
一种含有非甾体抗炎药的外用凝胶贴膏剂及其制备方法 Download PDFInfo
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- CN113018278A CN113018278A CN202011608896.3A CN202011608896A CN113018278A CN 113018278 A CN113018278 A CN 113018278A CN 202011608896 A CN202011608896 A CN 202011608896A CN 113018278 A CN113018278 A CN 113018278A
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- flurbiprofen
- plaster
- styrene
- copolymer
- graft
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Abstract
本发明公开了一种含有非甾体抗炎药的外用凝胶贴膏剂及其制备方法，属于氟比洛芬类外用凝胶贴膏剂领域。本发明要解决以无机类(或矿物类)作为填充剂导致了凝胶贴膏的膏体偏硬、黏性偏低、药物释放偏缓，以及不同产地的物料导致产品的不可重现性等技术问题；其由支持体、含药膏体层和防黏膜组成，其含药膏体层采用有机类保水树脂作为填充剂，其活性成分为氟比洛芬或其药学上接受药的盐。相对于以往采用无机类或矿物类填充剂的同类产品，本发明的产品具有更好的黏附性和透皮效果，从而实现更好的疗效。
Description
技术领域
本发明属于氟比洛芬类外用凝胶贴膏剂领域；涉及一种含有非甾体抗炎药的外用凝胶贴膏剂及其制备方法，尤其涉及一种含有氟比洛芬及其药用盐的外用凝胶贴膏剂，其由支持体、含药膏体层和防黏膜组成。
背景技术
凝胶贴膏剂曾被称作巴布膏剂或凝胶膏剂，系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。其特征在于，水分含有量高于传统中药膏药(橡胶贴膏剂)，膏体具有适宜的厚度，与皮肤的亲和性优异，对皮肤的刺激性小于传统膏药。凝胶贴膏剂于上世纪中后期，由日本制药公司研发成功并上市，近年来部分产品及相关技术引入我国，在临床上已经被广泛用于治疗骨关节炎、肌肉痛等多种急慢性疼痛类疾病。
代表性产品氟比洛芬凝胶贴膏最初由日本三笠制药株式会社、大协药品工业株式会社、科研制药株式会社等公司开发成功并在日本上市。临床试验结果显示，氟比洛芬凝胶贴膏治疗急慢性疼痛如外伤、关节炎及肩周炎、肌肉痛、腰背痛等效率高达80％以上。
在凝胶贴膏剂的发展历程中，长期以来都是以高岭土、硅藻土、膨润土、白陶土、碳酸钙、氧化锌、微粉硅胶、二氧化硅等为主要的填充介质。这些无机类(或矿物类)填充剂使得凝胶贴膏具有一定的成型性，同时也导致了产品的膏体偏硬、黏性偏低、药物释放偏缓，以及不同产地的物料导致产品的不可重现性等。
以矿物类填充剂高岭土为例，如下述文献1及文献2所述，不同国家不同产地的高岭土间存在较大差异，甚至同一国家内部不同产地的高岭土间也存在一定差异。研究人员发现使用了日本广岛产的高岭土会使凝胶贴膏变硬，使用不便，而使用了日本福岛产的高岭土的凝胶贴膏则容易制备成功。因此，研究人员亟需寻找一种避免使用高岭土等无机类(或矿物类)填充剂，进行凝胶贴膏制备的方法。
另一方面，与传统膏药相比，凝胶贴膏剂产品通常含有大量水分，有的含水比例甚至超过50％(以膏体重量计)。而由于传统高岭土等无机物质类填充剂吸水性一般，在制作凝胶贴膏剂产品时，无机填充剂加入量过少则容易导致凝胶贴膏剂产品的膏体偏软，容易溢出防粘膜或支持体，贴付舒适性差；加入量过多则容易产生凝胶贴膏剂膏体变硬，膏体成形性差，透皮吸收率低等问题。与无机填充剂相比，保水树脂如淀粉接枝丙烯酸共聚物、纤维素接枝丙烯酸共聚物、苯乙烯-异戊二烯-苯乙烯等具有强吸水性，如淀粉接枝丙烯酸共聚物的吸水倍率可接近1000，远优于无机填充剂类。且，凝胶贴膏制剂中通常还配伍使用较多比例的甘油。1种或1种以上保水树脂的联合使用可有效减少凝胶贴膏制剂中水及甘油等液体中水分过多导致的问题。因此，研究人员正在寻找一种使用保水树脂为填充剂，进行凝胶贴膏制备的方法。
文献1：カオリンパップの塑性粘度変動について。棚田成紀，榎本三郎。材料，1972年第21巻第225号：598-601。
文献2：成型パップ剤の製剤設計に関する研究。黒田稔。1986年日本岐阜药科大学学位论文。
发明内容
本发明要解决以无机类(或矿物类)作为填充剂导致了凝胶贴膏的膏体偏硬、黏性偏低、药物释放偏缓，以及不同产地的物料导致产品的不可重现性等技术问题；提供一种采用有机类保水树脂作为填充剂的氟比洛芬及其药用盐的凝胶贴膏剂。
为解决上述技术问题，通过下述技术方案实现：
本发明的含有保水树脂的凝胶贴膏剂是由支持体、含药膏体层和防黏膜组成。其中膏体层除了活性成分外，还含有保水树脂填充剂、增黏剂、交联剂及交联调节剂、吸收促进剂、保湿剂、抗氧化剂、pH调节剂等多种成分；含药膏体层的活性成分为非甾体抗炎药，所述非甾体抗炎药为氟比洛芬及其药用盐或酯。
本发明所述的凝胶贴膏剂，以含药膏体层重量％计，含活性成分0.1重量％-10重量％，纯化水25重量％-75重量％，有机类保水树脂填充剂1重量％-40重量％，增黏剂1重量％-40重量％，交联剂及交联调节剂0.1重量％-10重量％，吸收促进剂0.1重量％-10重量％，保湿剂1重量％-40重量％，抗氧化剂0.1重量％-10重量％，pH调节剂0.1重量％-10重量％。
本发明所述的有机类保水树脂填充剂可选自淀粉接枝共聚物、聚丙烯酸类聚合物、聚乙烯醇类聚合物纤维素接枝共聚物以及苯乙烯类共聚物中的一种或其中的几种任意比的组合；
其中，所述淀粉接枝共聚物可选自淀粉接枝丙烯酸酯、淀粉接枝丙烯酰胺、淀粉接枝丙烯酸、淀粉接枝丙烯腈、淀粉黄原酸盐接枝丙烯酸盐等淀粉接枝共聚物中的一种或其中的几种任意比的组合；
所述聚丙烯酸类聚合物为聚丙烯酸盐、聚丙烯酸盐加聚烯烃、丙烯腈纤维与丙烯酸盐复合物、醋酸乙烯丙烯酸酯中的一种或其中的几种任意比的组合；
所述聚乙烯醇类聚合物为醋酸乙烯不饱和酸共聚物、醋酸乙烯丙烯酸酯共聚物、聚乙烯酸丙烯酰胺接枝共聚物、聚乙烯醇醋酐交联共聚物等聚乙烯醇类聚合物；
所述纤维素接枝共聚物为纤维素接枝丙烯酸盐、纤维素接枝丙烯腈、纤维素黄原酸盐接枝丙烯酸盐、纤维素接枝丙烯酰胺中的一种或其中的几种任意比的组合；
所述苯乙烯类共聚物为苯乙烯-异戊二烯-苯乙烯、苯乙烯-丁二烯-苯乙烯、氢化苯乙烯-丁二烯嵌段共聚物、苯乙烯-乙烯-丙烯-苯乙烯嵌段共聚物中的一种或其中的几种任意比的组合；
其中，有机类保水树脂优选为淀粉接枝丙烯酸共聚物、苯乙烯-异戊二烯-苯乙烯和纤维素接枝丙烯酸共聚物中的两种任意比的组合；
以膏体层重量％计，有机类保水树脂用量为1重量％-40重量％，优选为1重量％-20重量％。
本发明所述的增黏剂可选自羟乙纤维素、羟丙甲纤维素、羧甲纤维素钠等纤维素类及其衍生物，聚乙烯醇、聚乙烯吡咯烷酮、部分中和聚丙烯酸盐、聚丙烯酸或其水溶液、聚丁烯、聚异丁烯、聚丁烯酸等高分子合成材料，明胶、阿拉伯胶、黄原胶、瓜尔胶、西黄蓍胶等动植物胶等其中的一种或其中的几种任意比的组合，其中优选为聚乙烯醇、明胶、聚丙烯酸、羧甲纤维素钠。以含药膏体层重量％计，有机类保水树脂用量为1-40重量％，优选1-20重量％。
本发明所述的交联剂及交联调节剂可选自氯化铝、硫酸铝钾、氢氧化铝、甘羟铝、合成硅酸铝、柠檬酸铝、硅铝酸镁、水硅酸镁、依地酸及其盐等其中的一种或其中的几种任意比的组合，其中优选为甘羟铝、氢氧化铝、依地酸钠。以含药膏体层重量％计，交联剂及交联调节剂含量为0.1-10重量％，优选为0.1-5重量％。
本发明所述的吸收促进剂并无特殊限制具体种类，可选自肉豆蔻酸异丙酯、乳酸薄荷酯、月桂氮卓酮、N-甲基吡咯烷酮、己二酸二乙酯、己二酸二异丙酯、油酸山梨醇酯、倍半油酸山梨醇酯、单硬酯酸聚乙二醇酯、聚氧亚烷基山梨糖醇酐脂肪酸酯等脂肪酸酯,薄荷醇、丙二醇、聚乙二醇等多元醇，聚氧乙烯氢化蓖麻油、聚山梨酯等表面活性剂，以及克罗米通等其中的一种或或其中的几种任意比的组合，其中优选薄荷醇、肉豆蔻酸异丙酯、克罗米通。以含药膏体层重量％计，吸收促进剂用量为0.1重量％-10重量％，优选为0.1重量％-5重量％。
本发明所述的凝胶贴膏剂，保湿剂能抑制从膏体层中的水分的蒸发、防止膏体干燥。可选自乙二醇、丙二醇、丁二醇、甘油、聚乙二醇、液体石蜡、山梨醇溶液、尿素、吡咯烷酮羧酸盐等中的一种或或其中的几种任意比的组合，其中优选甘油、尿素、山梨醇溶液。以含药膏体层重量％计，其用量为1-40重量％，优选1-20重量％。
本发明所述的凝胶贴膏剂，抗氧化剂可选自生育酚、抗坏血酸、柠檬酸、羟苯甲酮、二丁羟基甲苯等其中的一种或其中的几种任意比的组合，其中优选抗坏血酸、二丁羟基甲苯。以含药膏体层重量％计，其用量为0.1-10重量％，优选为0.1-5重量％。
本发明所述的pH调节剂可选自酒石酸、柠檬酸、磷酸、苹果酸或其盐等其中的一种或或其中的几种任意比的组合，其中优选酒石酸、酒石酸钠。以含药膏体层重量％计，pH调节剂用量为0.1重量％-10重量％，优选为0.1重量％-5重量％。
以含药膏体层重量％计，本发明所述的凝胶贴膏剂含水为25重量％-75重量％，优选为35-65重量％。当含水量超过75重量％时，膏体层黏性降低，不利于贴敷，且容易如泥状残留于皮肤上；当含水量不足25重量％时，膏体容易变硬导致无法均一涂布，且容易对皮肤形成刺激。
本发明活性成分为氟比洛芬及其药用盐或药用酯，包括但不限于氟比洛芬、氟比洛芬二乙胺、氟比洛芬三乙胺、氟比洛芬乙醇胺、氟比洛芬二乙醇胺、氟比洛芬三乙醇胺、氟比洛芬-(N-羟乙基哌啶)、氟比洛芬钠、氟比洛芬精氨酸盐、氟比洛芬赖氨酸盐、氟比洛芬酯等其中的一种。
本发明中一种含有非甾体抗炎药的外用凝胶贴膏剂的制备方法是按下述步骤进行的将处方量的非甾体抗炎药及处方量的表面活性剂、抗氧化剂、增黏剂、吸收促进剂混合均匀，得到A溶液；将处方量的有机类保水树脂填充剂粉碎过筛后用纯化水分散均匀，得到B溶液；将处方量的交联剂及交联调节剂、依地酸二钠、pH调节剂在保湿剂中分散均匀，得到C溶液；将A溶液、B溶液和C溶液在搅拌釜内反复搅拌，直至膏体物成均一白色，测定pH值后，移入事先准备好支持体及防黏膜的涂布机内进行涂布、裁切，得到凝胶贴膏产品。
本发明所述的含药膏体层厚度范围可在100-2000μm之间，优选为500-1000μm之间；其支持体宜选用能支撑起胶体层的材料，可选自织布、无纺布、塑料膜、纸、人造丝等其中的一种或多种。
本发明所述的防黏膜可选由聚酯、聚氨酯、聚乙烯、聚丙烯等材料制成。
相对于以往采用无机类或矿物类填充剂的同类产品，本发明的产品具有更好的黏附性和透皮效果，透皮释放度更大，从而实现更好的疗效。
附图说明
图1表示实施例及比较例的凝胶贴膏剂的透皮释放度。
具体实施方式
以下示出具体实施例，对本发明进行具体说明，但本发明不受这些具体实施例的限定。
实施例1-3
将处方量的主药成分氟比洛芬及处方量的薄荷醇、抗坏血酸、聚乙烯醇、聚丙烯酸、肉豆蔻酸异丙酯混合均匀，记为A溶液；将处方量的保水树脂类填充剂(粉碎过筛后)用纯化水分散均匀，记为B溶液；将处方量的甘羟铝、依地酸二钠、酒石酸、水硅酸镁在甘油中分散均匀，记为C溶液；将A、B、C溶液在搅拌釜内反复搅拌，直至膏体物成均一白色。测定pH值后，移入事先准备好无纺布及防黏膜的涂布机内进行涂布、裁切，得到凝胶贴膏产品。
实施例的处方及用量(含药膏体层重量％)如表1所示：
表1
比较例1-3
将处方量的主药成分氟比洛芬及处方量的薄荷醇、抗坏血酸、聚乙烯醇、聚丙烯酸、肉豆蔻酸异丙酯混合均匀，记为A溶液；将处方量的无机类填充剂(粉碎过筛后)用纯化水分散均匀，记为B溶液；将处方量的甘羟铝、依地酸二钠、酒石酸、水硅酸镁在甘油中分散均匀，记为C溶液；将A、B、C溶液在搅拌釜内反复搅拌，直至膏体物成均一白色。测定pH值后，移入事先准备好无纺布及防黏膜的涂布机内进行涂布、裁切，得到凝胶贴膏产品。
比较例的处方及用量(膏体层重量％)如表2所示：
表2
试验方法1
将上述实施例及比较例分别剥去防黏膜，置于倾斜板上，按贴膏剂黏附力测定法第一法(《中国药典2020年版》第四部通则0952)测定各实施例及比较例的黏附力。
试验结果示于表3所示，由该结果(重复测定3次的平均值)可知，实施例1-3的黏附力优良，均能黏住25至26号小球。而比较例1-3能黏住的小球号明显较低。(注：黏住的球号越大表示黏附力越强。)
表3
试验方法2
健康成年猪耳皮，按照标准热分离方法取得角质层，按体外透皮试验测定实施例1-3及比较例1-3的透皮释放度。将切割成合适大小的猪耳皮装载于Franz垂直扩散池内，取各样品切成直径20mm的圆形贴片，将该贴片贴附于猪皮角质层面。以pH为7.4的PBS缓冲溶液作为透皮介质，接收池体积为8ml，设定温度32℃，搅拌速度为100转每分钟。每次取样3ml，然后补加等温的空白接收液。每组样品平行6份，同时平行一份空白作为对照。照高效液相色谱法测定接收液中的氟比洛芬的浓度，最后计算出各试验贴片中氟比洛芬的透皮释放度。
试验结果如下图1所示，由该结果可知，与比较例1-3相比，实施例1-3的透皮释放度更大，具有良好的透皮效果，产品的疗效更好。
Claims (10)
1.一种含有非甾体抗炎药的外用凝胶贴膏剂，由支持体、含药膏体层和防黏膜组成，其特征在于，其采用有机类保水树脂而非无机类或矿物类物质作为填充剂，含药膏体层的活性成分为非甾体抗炎药，所述非甾体抗炎药为氟比洛芬及其药用盐或酯。
2.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述有机类保水树脂为淀粉接枝共聚物、聚丙烯酸类聚合物、聚乙烯醇类聚合物、纤维素接枝共聚物以及苯乙烯类共聚物中的一种或其中的几种。
3.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述淀粉接枝共聚物为淀粉接枝丙烯酸酯、淀粉接枝丙烯酰胺、淀粉接枝丙烯酸、淀粉接枝丙烯腈、淀粉黄原酸盐接枝丙烯酸盐中的一种或其中的几种。
4.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述聚丙烯酸类聚合物为聚丙烯酸盐、聚丙烯酸盐加聚烯烃、丙烯腈纤维与丙烯酸盐复合物、醋酸乙烯丙烯酸酯中的一种或其中的几种。
5.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述聚乙烯醇类聚合物为醋酸乙烯不饱和酸共聚物、醋酸乙烯丙烯酸酯共聚物、聚乙烯酸丙烯酰胺接枝共聚物、聚乙烯醇醋酐交联共聚物中的一种或其中的几种。
6.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述纤维素接枝共聚物为纤维素接枝丙烯酸盐、纤维素接枝丙烯腈、纤维素黄原酸盐接枝丙烯酸盐、纤维素接枝丙烯酰胺中的一种或其中的几种；所述苯乙烯类共聚物为苯乙烯-异戊二烯-苯乙烯、苯乙烯-丁二烯-苯乙烯、氢化苯乙烯-丁二烯嵌段共聚物、苯乙烯-乙烯-丙烯-苯乙烯嵌段共聚物中的一种或其中的几种。
7.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述有机类保水树脂的用量为1重量％-40重量％。
8.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述有机类保水树脂的用量为1重量％-20重量％。
9.根据权利要求1所述的外用凝胶贴膏剂，其特征在于，所述膏体层还包括活性成分0.1重量％-10重量％，增粘剂1重量％-40重量％，交联剂及交联调节剂0.1重量％-10重量％，吸收促进剂0.1重量％-10重量％，保湿剂1重量％-40重量％，抗氧化剂0.1重量％-10重量％，pH调节剂0.1重量％-10重量％，纯化水25重量％-75重量％；所述非甾体抗炎药为氟比洛芬、氟比洛芬二乙胺、氟比洛芬三乙胺、氟比洛芬乙醇胺、氟比洛芬二乙醇胺、氟比洛芬三乙醇胺、氟比洛芬-(N-羟乙基哌啶)、氟比洛芬钠、氟比洛芬精氨酸盐、氟比洛芬赖氨酸盐、氟比洛芬酯中的任意一种。
10.如权利要求1所述的外用凝胶贴膏剂的制备方法，其特征在于，所述制备方法是按下述步骤进行的：
将处方量的非甾体抗炎药及处方量的表面活性剂、抗氧化剂、增黏剂、吸收促进剂混合均匀，得到A溶液；将处方量的有机类保水树脂填充剂粉碎过筛后用纯化水分散均匀，得到B溶液；将处方量的交联剂及交联调节剂、依地酸二钠、pH调节剂在保湿剂中分散均匀，得到C溶液；将A溶液、B溶液和C溶液在搅拌釜内反复搅拌，直至膏体物成均一白色，测定pH值后，移入事先准备好支持体及防黏膜的涂布机内进行涂布、裁切，得到凝胶贴膏产品。
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