CN113952318B - 一种用于镇痛的多层微针贴片的制备方法 - Google Patents
一种用于镇痛的多层微针贴片的制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于镇痛的多层微针贴片的制备方法，所述的多层微针贴片包括速溶层、缓释层与背衬层；所述的速溶层搭载局部镇痛药物(如利多卡因)；所述的缓释层搭载非甾体药物(如布洛芬、酮洛芬等)；所述的背衬层以交联透明质酸与医用纱布为材料。本发明所述的多层微针贴片联合施用镇痛药物，在速溶层迅速溶解释放局部镇痛药物缓解疼痛，缓释层缓慢释放非甾体药物延长镇痛效果，从而达到比施用单一药物更好的镇痛效果，显著提高了药物疗效，减少了施药次数。
Description
技术领域
本发明涉及给药系统和方法，具体地，涉及用于镇痛的多层微针贴片及其制备方法。
背景技术
微针(Microneedles)是一种具有微米级阵列结构呈针状的医疗设备，它的高度通常在25至1000μm之间。微针能够穿透角质层进入皮肤进行药物释放，且不会碰到皮下的痛觉神经。目前硅、金属以及聚合物材料是制作微针的主要原材料，其中硅、金属等材料制成的微针生物相容性较差，且针体易破损残留于皮肤内，而聚合物可溶性微针可以在人体内进行溶解或降解，具有操作简便、生物相容性好、安全性高等优点，因此聚合物可溶性微针受到了极大关注。
镇痛药物给药方式的不同，对镇痛作用效果以及其维持药效的时长影响很大，因此需要合理地选择镇痛药物给药方式。目前，镇痛药物常见的给药方式有口服给药与皮下注射给药。其中，口服给药常伴有很大的副作用且药物吸收的效率低下；皮下注射给药病人的服从性较差且操作比较复杂。而基于聚合物可溶性微针对镇痛药物进行给药，不仅操作简单安全无感染，而且不会碰到皮下的痛觉神经，显著提高了患者的服从性。
但是目前现有的聚合物可溶性微针的制备方法并不成熟，所制备出的载镇痛药物的微针镇痛效果起效缓慢，且镇痛时间比较短，实用性不高。
发明内容
针对上述问题，本发明提供了一种具有优良镇痛效果的多层微针贴片及其制备方法，本发明所述的多层微针贴片联合施用镇痛药物，在速溶层迅速溶解释放局部镇痛药物缓解疼痛，缓释层缓慢释放非甾体药物延长镇痛效果，从而达到比施用单一药物更好的镇痛效果，显著提高了药物疗效，减少了施药次数。
本发明采取的技术方案为：
一种用于镇痛的多层微针贴片包括速溶层、缓释层与背衬层；速溶层搭载局部镇痛药物(如利多卡因)；缓释层搭载非甾体药物(如布洛芬、酮洛芬等)；背衬层以交联透明质酸与医用纱布为材料，所述方法包括以下步骤：
S1、在PDMS模具的表面铺上一层厚度为0.2～0.5mm的溶液层，然后将模具置于真空烘箱中室温抽真空3～10min，随后取出模具在30～50℃温度下鼓风干燥0.5～1.5h，得到搭载局部镇痛药物的针尖速溶层。
S2、从注射器中将搭载药物的交联透明质酸水凝胶平铺在PDMS模具表面，形成1.5～5mm的溶液层。然后将模具置于真空箱中，室温下-0.1MPa抽真空5～10min。随后取出模具，在干燥箱中进行干燥(50～70℃，4～10h)，得到搭载非甾体药物的缓释层。
S3、在干燥后的微针模具上平铺一层厚度为0.5～2.5mm的空白交联透明质酸，在干燥箱中进行干燥(50～70℃，4～10h)。然后利用微热压印技术在干燥后的微针模具上压印一块大小相仿的医用纱布形成柔韧背衬层。
优选的，所述的针尖速溶层的形状为圆锥或三棱锥或四棱锥，高度为50-500μm。
优选的，步骤S1中所述的溶液层为PVA、HA、利多卡因按照质量分数比为1:(0.5～3):(1～10)混合得到。
优选的，步骤S1中所述的溶液层在真空烘箱中室温抽真空时间为3～10min。
优选的，步骤S1中所述的溶液层在干燥箱中干燥温度为30～50℃,干燥时间为0.5～1.5h。
优选的，步骤S2中所述的搭载药物的交联透明质酸水凝胶制备过程如下：1)将200ul BDDE加入到装有10ml 0.25M NaOH溶液的烧杯中，混合均匀以制备交联剂溶液；2)称取1g HA粉末添加到交联剂溶液中，将其置于20～50℃环境温度下1～5h以充分混合；3)用0.1M HCL将溶液中和至pH约为6.5～7.5，以中止反应；4)将水凝胶在去离子水中过滤洗涤，去除BDDE残留物和未反应的HA，得到空白交联透明质酸；5)取非甾体药物(如右旋布洛芬)溶于乙醇-水溶液(20～80％浓度)中，将空白交联透明质酸凝胶浸于药物溶液中，静置直至溶液被吸收，得到搭载非甾体药物的交联透明质酸水凝胶。
优选的，步骤S2中，将模具室温下-0.1MPa抽真空5～10min。
优选的，步骤S2中模具的干燥温度为50～70℃，干燥时间为4～10h。
优选的，步骤S3中所述的空白透明质酸的干燥温度为50～70℃，干燥时间为4～10h。
优选的，所述的背衬层采用压印技术来实现。在压印过程中，压印机的下板上，垫上高度与其相仿的金属垫圈，并在模具上方铺一层聚四氟乙烯薄膜，防止压印机上板与微针材料粘连。
优选的，所述的微针贴片为分层结构，包括速溶层、缓释层与背衬层。
本发明具有以下有益效果：
(1)本发明制备的多层微针贴片生物相容性好，能够在机体中降解，安全性高，并且针体具有良好的机械性能，可有效刺入皮肤。
(2)本发明相提供的多层微针贴片采用分层结构，在速溶层迅速溶解释放局部镇痛药物缓解疼痛，缓释层缓慢释放非甾体药物延长镇痛效果，从而达到比施用单一药物更好的镇痛效果，显著提高了药物疗效，减少了施药次数。
(3)本发明中基于压印技术制备的背衬层添加了无纺布，具有柔韧的特点，便于施用在关节不平整部位，从而大幅度提高了多层微针贴片的实用性。
附图说明
图1是多层微针贴片的平面示意图；
图2是多层微针贴片的立体示意图；
图3是多层微针贴片背衬层的压印过程。
具体实施方式
以下是结合附图对具体的实施例的描述，是对本发明所述的一种用于镇痛的多层微针贴片的制备方法作的进一步说明，但本发明的保护范围并不限于这几个实施例。
实施例1
本实施例提供了一种搭载利多卡因和对乙酰氨基酚的多层微针贴片的制备方法，该多层微针贴片包括速溶层、缓释层与背衬层，制备方法包括以下步骤：
S1、PVA、HA、利多卡因按照质量分数比为1:(0.5～3):(1～10)混合得到溶液层，在PDMS模具的表面铺上一层厚度为0.2～0.5mm的溶液层，然后将模具置于真空烘箱中室温抽真空3～10min，随后取出模具在30～50℃温度下鼓风干燥0.5～1.5h，得到搭载局部镇痛药物利多卡因的针尖速溶层。
S2、将10～200ul BDDE加入到装有5～20ml 0.25M NaOH溶液的烧杯中，混合均匀以制备交联剂溶液；称取0.1～10g HA粉末添加到交联剂溶液中，将其置于20～50℃环境温度下1～5h以充分混合；用0.1M HCL将溶液中和至pH约为6.5～7.5，以中止反应；将水凝胶在去离子水中过滤洗涤，去除BDDE残留物和未反应的HA，得到空白交联透明质酸；取对乙酰氨基酚溶于乙醇-水溶液(20～80％浓度)中，将空白交联透明质酸凝胶浸于药物溶液中，静置直至溶液被吸收，得到搭载对乙酰氨基酚的交联透明质酸水凝胶。从注射器中将搭载药物的交联透明质酸水凝胶平铺在PDMS模具表面，形成厚度为0.5～1.5mm溶液层。然后将模具置于真空箱中，室温下-0.1MPa抽真空5～10min。随后取出模具，在干燥箱中进行干燥(50～70℃，4～10h)，得到搭载对乙酰氨基酚的缓释层。
S3、在干燥后的微针模具上平铺一层厚度为1.5～5mm的空白交联透明质酸，在干燥箱中进行干燥(50～70℃，4～10h)。然后利用压印技术在干燥后的微针模具上压印一块大小相仿的医用纱布形成柔韧背衬层。对微针进行脱模，得到一种搭载利多卡因和对乙酰氨基酚的多层微针贴片。
将依照上述步骤得到的搭载利多卡因和对对乙酰氨基酚的多层微针贴片用于生物体内,速溶层迅速溶解释放局部镇痛药物利多卡因缓解疼痛，缓释层缓慢释放非甾体药物对乙酰氨基酚延长镇痛效果，从而达到比施用单一药物更好的镇痛效果，显著提高了药物疗效，减少了施药次数。并且基于压印技术制备的背衬层添加了无纺布,具有柔韧的特点，便于施用在关节不平整部位，从而大幅度提高了多层微针贴片的实用性。
实施例2
本实施例提供了一种搭载利多卡因和曲马多的多层微针贴片的制备方法，该多层微针贴片包括速溶层、缓释层与背衬层，制备方法包括以下步骤：
S1、PVA、HA、利多卡因按照质量分数比为1:(0.5～3):(1～10)混合得到溶液层，在PDMS模具的表面铺上一层厚度为0.2～0.5mm的溶液层，然后将模具置于真空烘箱中室温抽真空3～10min，随后取出模具在30～50℃温度下鼓风干燥0.5～1.5h，得到搭载局部镇痛药物利多卡因的针尖速溶层。
S2、将10～200ul BDDE加入到装有5～20ml 0.25M NaOH溶液的烧杯中，混合均匀以制备交联剂溶液；称取0.1～10g HA粉末添加到交联剂溶液中，将其置于20～50℃环境温度下1～5h以充分混合；用0.1M HCL将溶液中和至pH约为6.5～7.5，以中止反应；将水凝胶在去离子水中过滤洗涤，去除BDDE残留物和未反应的HA，得到空白交联透明质酸。取曲马多溶于乙醇-水溶液(20～80％浓度)中，将空白交联透明质酸凝胶浸于药物溶液中，静置直至溶液被吸收，得到搭载曲马多的交联透明质酸水凝胶。从注射器中将搭载药物的交联透明质酸水凝胶平铺在PDMS模具表面，形成厚度为0.5～1.5mm溶液层。然后将模具置于真空箱中，室温下-0.1MPa抽真空5～10min。随后取出模具，在干燥箱中进行干燥(50～70℃，4～10h)，得到搭载曲马多的缓释层。
S3、在干燥后的微针模具上平铺一层厚度为1.5～5mm的空白交联透明质酸，在干燥箱中进行干燥(50～70℃，4～10h)。然后利用压印技术在干燥后的微针模具上压印一块大小相仿的医用纱布形成柔韧背衬层。对微针进行脱模，得到一种搭载利多卡因和曲马多的多层微针贴片。
将依照上述步骤得到的搭载利多卡因和对曲马多的多层微针贴片用于生物体内,速溶层迅速溶解释放局部镇痛药物利多卡因缓解疼痛，缓释层缓慢释放非甾体药物曲马多延长镇痛效果，从而达到比施用单一药物更好的镇痛效果，显著提高了药物疗效，减少了施药次数。并且基于压印技术制备的背衬层添加了无纺布,具有柔韧的特点，便于施用在关节不平整部位，从而大幅度提高了多层微针贴片的实用性。
实施例3
本实施例提供了一种搭载利多卡因和可待因的多层微针贴片的制备方法，该多层微针贴片包括速溶层、缓释层与背衬层，制备方法包括以下步骤：
S1、PVA、HA、利多卡因按照质量分数比为1:(0.5～3):(1～10)混合得到溶液层，在PDMS模具的表面铺上一层厚度为0.2～0.5mm的溶液层，然后将模具置于真空烘箱中室温抽真空3～10min，随后取出模具在30～50℃温度下鼓风干燥0.5～1.5h，得到搭载局部镇痛药物利多卡因的针尖速溶层。
S2、将10～200ul BDDE加入到装有5～20ml 0.25M NaOH溶液的烧杯中，混合均匀以制备交联剂溶液；称取0.1～10g HA粉末添加到交联剂溶液中，将其置于20～50℃环境温度下1～5h以充分混合；用0.1M HCL将溶液中和至pH约为6.5～7.5，以中止反应；将水凝胶在去离子水中过滤洗涤，去除BDDE残留物和未反应的HA，得到空白交联透明质酸。取可待因溶于乙醇-水溶液(20～80％浓度)中，将空白交联透明质酸凝胶浸于药物溶液中，静置直至溶液被吸收，得到搭载可待因的交联透明质酸水凝胶。从注射器中将搭载药物的交联透明质酸水凝胶平铺在PDMS模具表面，形成厚度为0.5～1.5mm溶液层。然后将模具置于真空箱中，室温下-0.1MPa抽真空5～10min。随后取出模具，在干燥箱中进行干燥(50～70℃，4～10h)，得到搭载可待因的缓释层。
S3、在干燥后的微针模具上平铺一层厚度为1.5～5mm的空白交联透明质酸，在干燥箱中进行干燥(50～70℃，4～10h)。然后利用压印技术在干燥后的微针模具上压印一块大小相仿的医用纱布形成柔韧背衬层。对微针进行脱模，得到一种搭载利多卡因和对可待因的多层微针贴片。
将依照上述步骤得到的搭载利多卡因和对可待因的多层微针贴片用于生物体内,速溶层迅速溶解释放局部镇痛药物利多卡因缓解疼痛，缓释层缓慢释放非甾体药物可待因延长镇痛效果，从而达到比施用单一药物更好的镇痛效果，显著提高了药物疗效，减少了施药次数。并且基于压印技术制备的背衬层添加了无纺布,具有柔韧的特点，便于施用在关节不平整部位，从而大幅度提高了多层微针贴片的实用性。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。在上述说明的基础上还可以做出其它不同形式的变化或改动，均处于本发明专利要求的保护范围之内。
Claims (2)
1.一种用于镇痛的多层微针贴片的制备方法，其特征在于，该方法包括以下步骤：
S1、在PDMS模具的表面铺上一层溶液层，然后将模具置于真空烘箱中室温抽真空，随后取出模具在鼓风干燥，得到搭载局部镇痛药物利多卡因的针尖速溶层；
S2、从注射器中将搭载药物的交联透明质酸水凝胶平铺在PDMS模具表面，形成溶液层；然后将模具置于真空箱中抽真空；随后取出模具，在干燥箱中进行干燥，得到搭载非甾体药物的缓释层；所述非甾体药物选自对乙酰氨基酚、曲马多或可待因；
S3、在干燥后的微针模具上平铺一层空白交联透明质酸，在干燥箱中进行干燥；然后利用压印技术在干燥后的微针模具上压印一块医用纱布形成柔韧背衬层；
所述的针尖速溶层的形状为圆锥或三棱锥或四棱锥；
步骤S1中所述的溶液层为PVA、HA、利多卡因按照质量分数比为1:(0.5～3):(1～10)混合得到；
步骤S1中所述的溶液层在真空烘箱中室温抽真空时间为3～10min；
步骤S1中所述的溶液层在干燥箱中干燥温度为30～50℃,干燥时间为0.5～1.5h；
步骤S2中所述的搭载药物的交联透明质酸水凝胶制备过程如下：1)将200ul BDDE加入到装有10ml 0.25M NaOH溶液的烧杯中，混合均匀以制备交联剂溶液；2)称取1g HA粉末添加到交联剂溶液中，将其置于20～50℃环境温度下1～5h以充分混合；3)用0.1M HCL将溶液中和至pH为6.5～7.5，以中止反应；4)将水凝胶在去离子水中过滤洗涤，去除BDDE残留物和未反应的HA，得到空白交联透明质酸；5)取非甾体药物溶于20～80％乙醇-水溶液浓度中，将空白交联透明质酸凝胶浸于药物溶液中，静置直至溶液被吸收，得到搭载非甾体药物的交联透明质酸水凝胶；
步骤S2中，将模具室温下-0.1MPa抽真空5～10min；模具的干燥温度为50～70℃，干燥时间为4～10h；
步骤S3中所述的空白交联透明质酸的干燥温度为50～70℃，干燥时间为4～10h；
所述的背衬层采用压印技术来实现；在压印过程中，压印机的下板上，垫上金属垫圈，并在模具上方铺一层聚四氟乙烯薄膜。
2.根据权利要求1所述的一种用于镇痛的多层微针贴片的制备方法，其特征在于，所述的微针贴片为分层结构，包括速溶层、缓释层与背衬层。
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