CN111773201A - 一种酚磺乙胺凝胶贴剂及其制备方法 - Google Patents
一种酚磺乙胺凝胶贴剂及其制备方法 Download PDFInfo
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- CN111773201A CN111773201A CN202010835837.3A CN202010835837A CN111773201A CN 111773201 A CN111773201 A CN 111773201A CN 202010835837 A CN202010835837 A CN 202010835837A CN 111773201 A CN111773201 A CN 111773201A
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- etamsylate
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Abstract
本发明涉及医药技术领域，公开了一种酚磺乙胺凝胶贴剂及其制备方法。酚磺乙胺凝胶贴剂是由背衬层、粘贴层、凝胶层和防粘层依次组成；其中，所述的凝胶层包括凝胶基质和药物活性成分酚磺乙胺。本发明经过黏附力测试，并且通过体外溶出试验及体外皮肤渗透试验，证实酚磺乙胺凝胶贴剂具有良好的黏附性能，可反复使用，能透过皮肤有效释放药物，可随时按需要终止给药，减少全身不良反应，安全可靠。
Description
技术领域
本发明涉及制药领域，特别涉及一种酚磺乙胺凝胶贴剂及其制备方法。
背景技术
酚磺乙胺(英文名Etamsylate)，临床用于预防和治疗各种手术前后的出血，也可用于血小板功能不良、血管脆性增加而引起的出血，最早于1962年由Lab.OM在英国申请专利并获批，1981年在我国由武汉武制药有限公司申请并获批上市，目前国内上市销售的有片剂、注射用粉针、注射液、氯化钠注射液和葡萄糖注射液[1]，对于控制手术后的出血，可口服或肌内或静脉内注射250-500mg剂量，必要时每4-6小时重复一次，不良反应有恶心、头痛、皮疹、暂时性低血压等，偶有静脉注射后发生过敏性休克的报道。此外，临床研究发现，滥用止血药或凝血药，有时会在原有疾病的基础上造成血栓形成或加重出血现象，有血栓形成史者应慎用酚磺乙胺[2]。
徐伟[3]，杨涛[4]等先后在临床研究中发现，复发性单纯型过敏性紫癜患儿采用酚磺乙胺治疗可以有效缓解临床症状，提高疗效，具有较高的推广价值，但考虑到酚磺乙胺以注射液或口服的形式给药，药物在全身血液中分散浓度基本一致，在有血栓形成史者中使用可能造成血栓形成或加重出血，并且还可能伴随有恶心、头痛、皮疹、暂时性低血压等的不良反应，酚磺乙胺的现有技术中，除已上市的片剂、注射用粉针、注射液以外，还有一些专利公开了包含酚磺乙胺的外用剂型。中国专利CN 1320931C 公开了一种添加抗菌药、消毒药、消炎药、镇痛药、止血、凝血药、水溶性抗癌药等的医用水凝胶辅料，既可作为轻度皮肤创伤或慢性皮肤疾病的永久性辅料，也可用于严重皮肤组织创伤或烧伤创口的即时关闭，但基于水凝胶敷料的使用方法，若将其用于治疗复发性单纯型过敏性紫癜，在患处涂抹辅料后需再使用纱布或绷带覆盖固定，使用较为繁琐，且不能随时揭贴，便于中止或继续给药。中国专利CN 101700408A公开的一种活性成分包含酚磺乙胺的木葡糖酸醋杆菌纤维素水凝胶敷料同样具有使用繁琐，不能随时揭贴的问题。中国专利CN 107375994A公开了一种医用凝胶创可贴产品，适用于皮肤外伤的止血、灭菌，虽然该发明的活性成分中也包括酚磺乙胺，但没有加入促渗剂，不能保证在皮肤角质层完好的情况下，酚磺乙胺能渗透进入皮下出血处持续发挥药效。中国专利CN 104922740A公开的一种活性成分包含酚磺乙胺的具有止血和防粘连特性的医用高分子复合材料，同样没有促渗剂。中国专利CN 105616478A公开了一种局部麻醉凝胶制剂，其所添加的活性成分较多，包括麻醉药、止血药、消炎药等，配制时需要综合考虑所有成分的溶解性、稳定性，因此包括酚磺乙胺在内的活性成分在加入纯水后，选择调节pH至6-8，而酚磺乙胺本身较为稳定的pH在5.5左右，该发明的凝胶制剂不能优先保证酚磺乙胺的稳定性、又含有麻醉成分，不太适用于酚磺乙胺治疗复发性单纯型过敏性紫癜的日常给药。所以，急需有适应性更广，不良反应更少，顺应性更好的外用局部给药剂型，用于缓解此种病症的临床症状。
发明内容
发明目的：本发明所要解决的技术问题是针对现有技术的不足，提供一种酚磺乙胺凝胶贴剂。
本发明还要解决的技术问题是提供上述酚磺乙胺凝胶贴剂的制备方法。
为了解决上述第一个技术问题，本发明公开了一种酚磺乙胺凝胶贴剂，由背衬层、粘贴层、凝胶层和防粘层依次组成；其中，所述的凝胶层包括凝胶基质和药物活性成分酚磺乙胺。
其中，以酚磺乙胺凝胶贴剂的面积计，所述的酚磺乙胺的含量为0.05-15mg/cm2；优选为0.8-10mg/cm2。
其中，所述的凝胶层中酚磺乙胺与凝胶基质的质量比为1:75-400；优选为1:120-350。
其中，所述的凝胶基质中各组分的质量含量为：10％-25％亲水性聚合物骨架材料， 7％-22％保湿剂，3％-15％促渗剂，0.05％-0.5％交联剂，0.03％-0.3％交联调节剂，0.01％-0.3％抑菌剂和38％-80％去离子水。
优选地，所述的凝胶基质中各组分的质量含量为：15％-21％亲水性聚合物骨架材料， 10％-18％保湿剂，5％-12％促渗剂，0.05％-0.3％交联剂，0.1％-0.3％交联调节剂，0.08％-0.3％抑菌剂和55％-69％去离子水。
其中，所述的亲水性聚合物骨架材料为聚乙烯吡络烷酮、聚乙烯醇、聚丙烯酸钠、卡波姆、羟丙甲纤维素、明胶和羧甲基纤维素钠中的任意一种或几种组合；所述的保湿剂为甘油、聚乙二醇和山梨醇中的任意一种或几种组合；所述的促渗剂为氮酮、丙二醇、薄荷醇、冰片和油酸中的任意一种或几种组合；所述的交联剂为氢氧化铝、甘羟铝、氯化铝和氯化钙中的任意一种或几种组合；所述的交联调节剂为柠檬酸、酒石酸和羟基丁二酸中的任意一种或几种组合；所述的抑菌剂为尼泊金甲酯、尼泊金乙酯和苯扎氯铵中的任意一种或几种组合。
其中，所述的背衬层的材料为聚乙烯、聚丙烯、聚酯和无纺布任意一种。
其中，所述的粘贴层为压敏胶；所述的压敏胶为丙烯酸压敏胶、聚丙烯酸酯压敏胶和硅酮压敏胶中的任意一种。
其中，所述的防粘层为聚乙烯或聚丙烯薄膜。
为解决上述第二个技术问题，本发明公开了上述酚磺乙胺凝胶贴剂的制备方法，其特征在于，包括如下步骤：
(1)制备含药的凝胶基质：根据配方将亲水性聚合物骨架材料、交联剂、促渗剂、抑菌剂与保湿剂混合均匀，得I相；将酚磺乙胺与交联调节剂加入去离子水中溶解，得II相；将I相加入II相，搅拌，得到含药的凝胶基质；
(2)制备粘贴层：将压敏胶均匀涂布在背衬层上，55-85℃烘干，冷却备用；
(3)将步骤(1)制得的含药的凝胶基质加到步骤(2)制得的粘贴层上，盖上防粘层，即得。
步骤(2)中，所述的压敏胶的用量为背衬层质量的3％～20％。
步骤(2)中，所述的压敏胶为市售产品(市售状态为液体状态)经干燥后，所得的压敏胶固体，可粘贴背衬层和凝胶基质。
有益效果：与现有技术相比，本发明具有如下优势：
(1)本发明所公开的酚磺乙胺凝胶贴剂改变了酚磺乙胺的给药途径，加速出血部位的凝血过程，从而减少药物对全身血液的副作用，既能降低传统全身给药方式引起的全身不良反应，及可能形成血栓的风险，又克服传统贴剂释药慢、只能一次性使用的不足，比凝胶敷料使用更方便、不易弄脏衣物；且可多次揭帖，随需要随时终止或继续给药。
(2)本发明经过黏附力测试，并且通过体外溶出试验及体外皮肤渗透试验，证实酚磺乙胺凝胶贴剂具有良好的黏附性能，可反复使用，能透过皮肤有效释放药物，可随时按需要终止给药，减少全身不良反应，安全可靠。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明，本发明的上述和/ 或其他方面的优点将会变得更加清楚。
图1为实施例5中酚磺乙胺凝胶贴剂(含药量为每平方厘米含酚磺乙胺2.5mg) 体外经皮累积渗透曲线。
具体实施方式
下述实施例中所述实验方法，所述的聚乙烯醇均为江西阿尔法高科药业有限公司产品，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
实施例1制备酚磺乙胺凝胶贴剂
含药凝胶基质组分(每100cm2)
制备方法：
(1)含药凝胶基质：将处方量聚乙烯醇、聚乙烯吡络烷酮K30、羧甲基纤维素钠、甘羟铝、氮酮、丙二醇、尼泊金乙酯加入甘油中，搅拌混合均匀，作为I相；将处方量酚磺乙胺、柠檬酸加入去离子水中溶解，作为II相；将I相加入II相，快速搅拌，得到含药凝胶基质；
(2)粘贴层制备：将组成粘贴层的水性丙烯酸胶粘剂829A均匀涂布在背衬层上，涂布重量为背衬层重量的8.5％，55-85℃烘干，冷却备用；
(3)将含药凝胶基质加到粘贴层上，盖上防粘层，剪切包装，即得。
实施例2制备酚磺乙胺凝胶贴剂
含药凝胶基质组分(每100cm2)
制备方法：(1)含药凝胶基质：将处方量聚乙烯醇、聚乙烯吡络烷酮K90、聚乙烯吡络烷酮K30、甘羟铝、氮酮、丙二醇、尼泊金乙酯加入甘油中，搅拌混合均匀，作为I相；将处方量酚磺乙胺、酒石酸加入去离子水中溶解，作为II相；将I相加入II 相，快速搅拌，得到含药凝胶基质；
(2)粘贴层制备：将组成粘贴层的水性丙烯酸胶粘剂829A均匀涂布在背衬层上，涂布重量为背衬层重量的14.5％，55-85℃烘干，冷却备用；
(3)将含药凝胶基质加到粘贴层上，盖上防粘层，剪切包装，即得。
实施例3制备酚磺乙胺凝胶贴剂
含药凝胶基质组分(每100cm2)
制备方法：(1)含药凝胶基质：将处方量聚乙烯醇、明胶、卡波姆、甘羟铝、氮酮、丙二醇、尼泊金乙酯加入甘油中，搅拌混合均匀，作为I相；将处方量酚磺乙胺、酒石酸加入去离子水中溶解，作为II相；将I相加入II相，快速搅拌，得到含药凝胶基质；
(2)粘贴层制备：将组成粘贴层的水性丙烯酸胶粘剂829A均匀涂布在背衬层上，涂布重量为背衬层重量的13.7％，55-85℃烘干，冷却备用；
(3)将含药凝胶基质加到粘贴层上，盖上防粘层，剪切包装，即得。
对比例1制备酚磺乙胺凝胶贴剂
含药凝胶基质组分(每100cm2)
制备方法：(1)含药凝胶基质：将处方量聚丙烯酸钠、聚乙烯吡络烷酮K30、氯化钙、氮酮、丙二醇、尼泊金乙酯加入甘油中，搅拌混合均匀，作为I相；将处方量酚磺乙胺、柠檬酸加入去离子水中溶解，作为II相；将I相加入II相，快速搅拌，得到含药凝胶基质；
(2)粘贴层制备：将组成粘贴层的水性丙烯酸胶粘剂829A均匀涂布在背衬层上，涂布重量为背衬层重量的7.2％，55-85℃烘干，冷却备用；
(3)将含药凝胶基质加到粘贴层上，盖上防粘层，剪切包装，即得。
对比例2制备酚磺乙胺凝胶贴剂
含药凝胶基质组分(每100cm2)
制备方法：
(1)含药凝胶基质：将处方量聚乙烯醇、聚乙烯吡络烷酮K30、羧甲基纤维素钠、甘羟铝、二甲亚砜、尼泊金乙酯加入甘油中，搅拌混合均匀，作为I相；将处方量酚磺乙胺、柠檬酸加入去离子水中溶解，作为II相；将I相加入II相，快速搅拌，得到含药凝胶基质；
(2)粘贴层制备：将组成粘贴层的水性丙烯酸胶粘剂829A均匀涂布在背衬层上，涂布重量为背衬层重量的8.5％，55-85℃烘干，冷却备用；
(3)将含药凝胶基质加到粘贴层上，盖上防粘层，剪切包装，即得。
实施例4酚磺乙胺凝胶贴剂的黏附性能测试
(1)初粘性
初粘性测试方法依据《中国药典》(2015年版四部通则0952)，采用滚球斜坡停止法测定，即将不同大小型号的钢球分别滚过置于倾斜板上的供试品黏性面，根据供试品黏性面能够黏住的最大号钢球，评价其初粘力。
(2)反复粘贴性
在乙醇清洁处理后的钢板上进行连续反复揭贴，直至无法粘住钢板为止，记录揭贴次数。
黏附性能测试结果见表1。
表1为本发明中各实施例黏附性能(初粘性、反复粘贴性)测试结果
测试结果表明，本发明的实施例中所述凝胶贴剂具有良好的黏附性能，达到初粘力 15#钢球以上，反复粘贴性9次以上的技术指标，能够满足一定的黏附性，并且可反复多次使用的要求。
实施例5体外皮肤渗透测试
取实施例1与对比例2各一小块凝胶贴剂去除防粘层，紧密固定在去除皮下脂肪的小鼠腹部皮肤表面上，并在确保没有气泡产生的条件下牢固地固定在改良Franz型扩散池上，扩散面积3.14cm2(d＝2cm)，接收池体积8.5mL。接收池中的介质使用比例为40:60的乙醇/PBS pH＝7.4的磷酸盐缓冲盐溶液。将接收池中的介质保持在37±0.5℃的温度条件下，以300rpm的转速搅拌。在不同时间点(0h、2h、4h、8h、12h、18h、 24h)取样，每次2.0mL，并补充相同体积的新鲜接收介质。每个样品中酚磺乙胺的含量通过0.22μm微孔滤膜过滤后，加入4mL稀硫酸稀释，用0.1M硫酸铈滴定，电位计确定终点，计算酚磺乙胺凝胶贴剂的皮肤渗透量。
实施例5中酚磺乙胺凝胶贴剂的体外皮肤渗透量如图1所示，由图中可以看出，本发明的酚磺乙胺凝胶贴剂经皮渗透效果较好，能有效释放药物。
本发明提供了一种酚磺乙胺凝胶贴剂及其制备方法的思路及方法，具体实现该技术方案的方法和途径很多，以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。
参考文献
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Claims (10)
1.一种酚磺乙胺凝胶贴剂，其特征在于，由背衬层、粘贴层、凝胶层和防粘层依次组成；其中，所述的凝胶层包括凝胶基质和药物活性成分酚磺乙胺。
2.根据权利要求1所述的酚磺乙胺凝胶贴剂，其特征在于，所述的酚磺乙胺的含量为0.05-15mg/cm2。
3.根据权利要求1所述的酚磺乙胺凝胶贴剂，其特征在于，所述的凝胶层中酚磺乙胺与凝胶基质的质量比为1:75-400。
4.根据权利要求1所述的酚磺乙胺凝胶贴剂，其特征在于，所述的凝胶基质中各组分的质量含量为：10％-25％亲水性聚合物骨架材料，7％-22％保湿剂，3％-15％促渗剂，0.05％-0.5％交联剂，0.03％-0.3％交联调节剂，0.01％-0.3％抑菌剂和38％-80％去离子水。
5.根据权利要求4所述的酚磺乙胺凝胶贴剂，其特征在于，所述的亲水性聚合物骨架材料为聚乙烯吡络烷酮、聚乙烯醇、聚丙烯酸钠、卡波姆、羟丙甲纤维素、明胶和羧甲基纤维素钠中的任意一种或几种组合；所述的保湿剂为甘油、聚乙二醇和山梨醇中的任意一种或几种组合；所述的促渗剂为氮酮、丙二醇、薄荷醇、冰片和油酸中的任意一种或几种组合；所述的交联剂为氢氧化铝、甘羟铝、氯化铝和氯化钙中的任意一种或几种组合；所述的交联调节剂为柠檬酸、酒石酸和羟基丁二酸中的任意一种或几种组合；所述的抑菌剂为尼泊金甲酯、尼泊金乙酯和苯扎氯铵中的任意一种或几种组合。
6.根据权利要求1所述的酚磺乙胺凝胶贴剂，其特征在于，所述的背衬层的材料为聚乙烯、聚丙烯、聚酯和无纺布任意一种。
7.根据权利要求1所述的酚磺乙胺凝胶贴剂，其特征在于，所述的粘贴层为压敏胶；所述的压敏胶为丙烯酸压敏胶、聚丙烯酸酯压敏胶和硅酮压敏胶中的任意一种。
8.根据权利要求1所述的酚磺乙胺凝胶贴剂，其特征在于，所述的防粘层为聚乙烯或聚丙烯薄膜。
9.权利要求1～8中任意一项所述的酚磺乙胺凝胶贴剂的制备方法，其特征在于，包括如下步骤：
(1)制备含药的凝胶基质：根据配方将亲水性聚合物骨架材料、交联剂、促渗剂、抑菌剂与保湿剂混合均匀，得I相；将酚磺乙胺与交联调节剂加入去离子水中溶解，得II相；将I相加入II相，搅拌，得到含药的凝胶基质；
(2)制备粘贴层：将压敏胶均匀涂布在背衬层上，55-85℃烘干，冷却备用；
(3)将步骤(1)制得的含药的凝胶基质加到步骤(2)制得的粘贴层上，盖上防粘层，即得。
10.根据权利要求9所述的酚磺乙胺凝胶贴剂的制备方法，其特征在于，步骤(2)中，所述的压敏胶的用量为背衬层质量的3％～20％。
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