CN117815113A - 一种可在高温下干燥的可溶性微针及其制备方法和用途 - Google Patents
一种可在高温下干燥的可溶性微针及其制备方法和用途 Download PDFInfo
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- CN117815113A CN117815113A CN202410239468.XA CN202410239468A CN117815113A CN 117815113 A CN117815113 A CN 117815113A CN 202410239468 A CN202410239468 A CN 202410239468A CN 117815113 A CN117815113 A CN 117815113A
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Abstract
本发明属于微针技术领域，具体涉及一种可在高温下干燥的可溶性微针及其制备方法和用途。本发明通过对微针基质材料处方进行筛选使微针干燥的温度可以提高至40℃‑60℃，大大缩短了微针的干燥时间，更加有利于批量化生产。本发明采用的微针制备工艺不需要特殊的设备，只需要普通的真空干燥和高温干燥设备即可。本发明采用两步法，先将针尖基质溶液用真空法快速载入微针模具中，再去除上层含气泡的针尖基质溶液，将处方的背衬层基质溶液加入模具后在40‑60℃干燥脱模后即可得微针。采用上述方法可以很好地解决真空法制备微针过程中气泡难以完全消除的问题。
Description
技术领域
本发明属于微针技术领域，具体涉及一种可在高温下干燥的可溶性微针及其制备方法和用途。
背景技术
微针是一种由金属、硅、聚合物等材料制成，长度为25-2000 μm，针尖呈对称圆锥形或非对称斜面形的微米级的阵列结构。虽然早在二十世纪七十年代人们就提出了微针的概念，但是直到二十世纪九十年代，随着微机电系统（MEMS）技术的发展和成熟，微针产品的加工成型才成为现实。微针递送是一种新型的透皮递送方式，通过微针透过皮肤角质层，可让活性成分渗透进入皮肤而不触及皮下神经，可实现活性成分的无痛施用。目前微针主要分为四类：固体微针：通过对皮肤预处理来增强皮肤渗透性；涂层微针：药物涂敷于微针表面通过插入皮肤溶解于皮下；可溶微针：可溶性的高分子微针针体内溶有药物并最终溶解于皮下；中空微针：药物贮存于中空微针的空腔中从而注入到皮下。
目前，可溶性微针贴片常规的制备方法为将微针的基质材料和活性物质溶于水形成水溶液，通过水溶液浇铸微针阴模，再将溶液常温或低温干燥固化脱模得到可溶性微针。在溶液浇铸过程中需要通过真空、加压、离心、超声等手段辅助填充模具。其中真空法由于操作简便、设备简单因此在生产上较常用。但目前主要存在两方面问题：微针进行常温或低温干燥一般需要12 h以上，时间较长，不利于微针的批量生产。真空法制备过程中微针基质溶液中产生较多的气泡，如不能完全将气泡去除将影响微针的外观，甚至导致微针阵列不完整或微针基质干燥后发生变形。
中国专利CN115400341A提供了一种可以缩短微针干燥时间的方法，先将高分子材料水溶液利用模压成型技术在高温条件下压制成薄片，再将薄片置于微针模具上，利用热压技术将其压入模具中，降低温度干燥后得到可溶性微针。该方法制备微针的时间较短，但压制薄片所需的温度较高（80℃），需要专门的设备和模具，工艺较复杂，且过高的温度不利于活性物质的稳定性。Park等（Efficacy and safety of a new microneedle patch forskin brightening, A Randomized, split-face, single-blind study）报道了另一种可以缩短微针干燥时间的方法。将高浓度的透明质酸钠（HA）溶液直径加入微针模具中，采用5吨的压力加压30s，在50℃条件下干燥1 h可得到微针。此方法与中国专利CN115400341A方法类似，省掉了压制薄片的过程，增加了压制后的高温干燥过程。但是，该方法也是需要专门的加压设备，且文献上没有标明透明质酸钠的具体规格。
发明内容
为解决现有可溶性微针制备方法中存在的技术缺陷，本发明提供了一种新型可在高温下干燥的可溶性微针及其制备方法和用途。
采用本发明所述的可溶性微针制备方法能够很好地解决微针在常温条件下干燥时间较长而在高温条件下易发生变形，难以形成完整的微针阵列，以及真空法制备微针过程中气泡难以完全消除的问题。
本发明的目的可以通过以下技术方案来实现：
在第一个方面中，本发明提供了一种可在高温下干燥的可溶性微针，所述可溶性微针由针尖基质溶液和背衬层基质溶液制成，所述高温是40℃-60℃，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计1-10%水溶性高分子材料和1-10%水溶性小分子材料。
优选地，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计1-5%水溶性高分子材料和1-5%水溶性小分子材料。
所述水溶性高分子材料选自以下一种或多种：透明质酸钠（HA）、羧甲基纤维素钠（CMC）、羟丙基甲基纤维素（HPMC）、硫酸软骨素、葡聚糖、糊精、聚乙烯吡咯烷酮（PVP）、聚乙烯醇（PVA）、蚕丝蛋白、壳聚糖或明胶。
优选地，所述水溶性高分子材料选自以下一种或多种：透明质酸钠、聚乙烯醇或明胶。
优选地，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计2%-3%水溶性小分子材料。
所述水溶性小分子材料选自以下一种或多种：葡萄糖、海藻糖、乳糖、泛醇或维生素C乙基醚。
所述透明质酸钠的分子量范围是50kDa-500kDa。
作为可选的方式，在上述可溶性微针中，所述水溶性高分子材料选自透明质酸钠或者透明质酸钠与另一种水溶性高分子材料的组合，所述透明质酸钠与另一种水溶性高分子材料的重量比范围为1：5-5：1，所述另一种水溶性高分子材料选自：羧甲基纤维素钠、羟丙基甲基纤维素、硫酸软骨素、葡聚糖、糊精、聚乙烯吡咯烷酮、聚乙烯醇、蚕丝蛋白、壳聚糖或明胶。
所述透明质酸钠的分子量范围是200kDa-400kDa。
优选地，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计5%透明质酸钠。
或者，优选地，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计3%透明质酸钠。
或者，优选地，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计3%透明质酸钠和2%聚乙烯醇。
或者，优选地，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计3%透明质酸钠和2%明胶。
作为可选的方式，在上述可溶性微针中，所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计1-10%的多元醇类物质、聚乙二醇类、泊洛沙姆188，聚乙烯醇，羟丙甲基纤维素或聚乙烯吡咯烷酮，所述多元醇类物质选自以下一种或多种：戊二醇、丁二醇或己二醇，所述聚乙二醇类选自以下一种或多种：聚乙二醇400、聚乙二醇6000或聚乙二醇8000。
优选地，所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计1-5%的多元醇类物质。
更优选地，所述多元醇类物质选自丁二醇或己二醇。
作为可选的方式，在上述可溶性微针中，所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计0.1%-2%的亲水性乳化剂，所述亲水性乳化剂选自以下一种或多种：Tween-20、聚乙烯醇、明胶、聚氧乙烯蓖麻油、聚醚硅油或泊洛沙姆188。
优选地，所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计0.5%Tween-20。
优选地，所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计1%聚氧乙烯蓖麻油。
优选地，所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计1%聚醚硅油。
作为可选的方式，在上述可溶性微针中，所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计1-10%的活性成分，所述活性成分选自以下一种或多种：烟酰胺、传明酸、熊果苷、三肽-1铜、肌肽或乙酰基六肽-8。
作为可选的方式，在上述可溶性微针中，所述针尖基质溶液或所述背衬层基质溶液还包含水或者水和其他溶剂组成的混合溶剂，所述其他溶剂选自以下一种或多种：乙醇、丙二醇或甘油。
在第二个方面中，本发明提供了上述第一个方面所述的可溶性微针的制备方法，所述制备方法包括以下步骤：
所述可溶性微针采用两步法制备，先将针尖基质溶液快速载入微针模具的空隙中，去除上层含气泡的针尖基质溶液，再将背衬层基质溶液加入模具后在40-60℃干燥脱模后即得所述可溶性微针。
作为可选的方式，在上述制备方法中，将针尖基质溶液快速载入微针模具的空隙中的方法包括抽真空法、离心法、加压法或水浴超声法，微针模具的材料选自以下一种或多种：聚乙烯、聚丙烯、聚氯乙烯、聚甲醛、尼龙、聚二甲基硅氧烷、聚碳酸酯或聚四氟乙烯。
优选地，将针尖基质溶液快速载入微针模具的空隙中的方法为真空法，具体为置于真空干燥箱中-0.07 MPa抽真空10 min。
优选地，微针模具的材料选自聚二甲基硅氧烷（PDMS）。
作为可选的方式，在上述制备方法中，干燥温度为50℃，干燥时间在2 h以内。
优选地，干燥温度为50℃或60℃，干燥时间为在1 h以内。
在第三个方面中，本发明提供了上述第一个方面所述的可溶性微针或者采用上述第二个方面所述的制备方法制备得到的可溶性微针在制备可溶性微针贴片中的用途。
与现有技术相比，本发明的优势体现在以下方面：
（1）本发明通过对微针基质材料处方进行筛选使微针干燥的温度可以提高至40℃-60℃，大大缩短了微针的干燥时间。可根据微针中活性物质的稳定性选择具体的干燥温度，一般干燥时间为0.5-2h。更加有利于批量化生产。本发明采用的微针制备工艺不需要特殊的设备，只需要普通的真空干燥和高温干燥设备即可。
（2）本发明采用两步法，先将针尖基质溶液用真空法快速载入微针模具中，再去除上层含气泡的针尖基质溶液，将处方的背衬层基质溶液加入模具后在40-60℃干燥脱模后即可得微针。采用上述方法可以很好地解决真空法制备微针过程中气泡难以完全消除的问题。
（3）本发明方法针尖基质可以与背衬层基质相同，也可以不同。例如针尖基质中含活性物质而背衬基质为不含活性物质的空白基质，这种方法可以使活性物质集中于针尖部位，大大减少了活性物质的用量。
附图说明
图1：不同平均分子量HA制备的空白微针照片。
图2：空白微针的显微镜照片。其中，透明质酸钠平均分子量20-40万。
图3：发生变形（左）和未发生变形（右）的54×61阵列微针。
图4：局部析出白色物质（左）和未析出白色物质的25×25阵列微针（右）。
图5：实施例5中5号处方制备的微针照片。照片中显示，剪切后，柔韧性较好。
图6：实施例5中2号处方制备的微针照片。照片中显示，剪切后，柔韧性较差。
图7：针尖含维生素C乙基醚和三肽-1铜的分体式微针的代表性照片。
图8：实施例8中4号处方含维生素C乙基醚和三肽-1铜的一体式微针照片。
图9：10×10阵列微针贴留下的微孔阵列。
图10：乙酰基六肽-8微针组和溶液组的24 h平均累积透皮百分率。
具体实施方式
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
如无特别指出，以下实施例所涉及处方中各种成分的百分比（%）均为质量百分比。
实施例1：采用不同平均分子量的透明质酸钠（HA）制备不含活性物质的空白微针
按表1中处方称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将其注入10×10阵列PDMS微针模具中，将模具置于真空干燥箱中-0.07 MPa抽真空10 min，取出模具，去除模具上方含气泡的微针基质溶液，重新加入新的微针基质溶液，50℃鼓风干燥50 min。取出模具，室温冷却半小时，脱模。结果见图1。
表1：不同空白微针处方
结果发现采用20-40万平均分子量的透明质酸钠HA制备的微针未发生明显变形，显微镜照片见图2，其他透明质酸钠制备的微针均发生不同程度变形。下述各实施例中透明质酸钠分子量均采用20-40万。
实施例2：不同处方对微针基质溶液加入模具后铺展效果的影响
按表1中处方称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将其注入54×61阵列PDMS微针模具中，将基质溶液在模具上铺展均匀，室温放置1h，考察微针基质溶液加入大尺寸模具后的润湿和铺展效果。结果见表2。
表2：不同处方对微针基质溶液加入模具后铺展效果的影响
结果表明Tween-20、PVA、明胶、聚氧乙烯蓖麻油、聚醚硅油等亲水性乳化剂可增加微针基质溶液在PDMS微针模具上的润湿效果，使其在大尺寸模具上铺展均匀。
实施例3：不同处方对微针干燥后形态的影响
按表3中处方称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将其注入54×61阵列PDMS微针模具中，将基质溶液在模具上铺展均匀，置于真空干燥箱中-0.07 MPa抽真空10 min，取出模具，去除模具上方含气泡的微针基质溶液，重新加入新的微针基质溶液，50℃鼓风干燥1h。取出模具，室温冷却半小时，脱模。
表3：不同处方对微针干燥后形态的影响
结果表明小分子糖类（葡萄糖、乳糖、海藻糖）、维生素C乙基醚、泛醇等可防止微针基质干燥后发生变形。见图3。
实施例4：不同处方对含活性物质微针干燥后表面是否有固体析出物的影响
按表4中处方称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将其注入10×10阵列PDMS微针模具中，将模具置于真空干燥箱中-0.07 MPa抽真空10 min，取出模具，去除模具上方含气泡的微针基质溶液，重新加入新的微针基质溶液，60℃鼓风干燥30 min。取出模具，室温冷却半小时，脱模。
表4：不同处方对含活性物质微针干燥后表面是否有固体析出物的影响
结果表明小分子糖类（葡萄糖、乳糖、海藻糖）、维生素C乙基醚、泛醇等可抑制活性物质在微针干燥过程中在其表面析出，见图4。
实施例5：不同处方对微针干燥后柔韧性的影响
按表5中处方称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将其注入10×10阵列PDMS微针模具中，将模具置于水平离心机中，4000 rpm离心5min，取出模具，50℃鼓风干燥50 min。取出模具，室温冷却半小时，脱模。柔韧性评分见表5。
表5：不同处方对微针干燥后柔韧性的影响
结果表明处方中加入聚乙烯醇、己二醇、聚氧乙烯蓖麻油、聚醚硅油等物质可明显地提高微针干燥后的柔韧性。柔韧性较好和较差的微针照片分别见图5和图6。
实施例6：采用不同尺寸模具制备微针时不同温度加热烘干所需的时间
按表5中5号处方称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将其分别注入25×25和54×61阵列PDMS微针模具中，模具参数见表6。将模具置于真空干燥箱中-0.07 MPa抽真空10 min，取出模具，去除模具上方含气泡的微针基质溶液，重新加入新的微针基质溶液。分别采用40℃、50℃、60℃鼓风干燥。考察不同模具不同温度所需的干燥时间，结果见表7。
表6：PDMS微针模具参数表
表7：使用不同模具制备微针在不同温度条件下得干燥时间
结果表明随着鼓风干燥温度的升高，微针所需的干燥时间显著缩短，采用54×61阵列模具制备微针，由于尺寸较大，所需的干燥时间较25×25阵列模具长。干燥温度为40-60℃时，微针的鼓风干燥时间可控制在20-100 min。
实施例7：含美白抗皱活性物质分体式微针的制备
按表8中处方分别称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将针尖基质溶液其注入10×10阵列PDMS微针模具中，将针尖基质溶液在模具上铺展均匀，置于真空干燥箱中-0.07 MPa抽真空10 min，取出模具，去除模具上方含气泡的针尖基质溶液，加入背衬层基质溶液，将背衬层基质溶液在模具上铺展均匀，50℃鼓风干燥1 h。取出模具，室温冷却半小时，脱模，可得到含美白抗皱活性物质的分体式微针。针尖含维生素C乙基醚和三肽-1铜的分体式微针（使用表8中的处方1制备）的代表性照片见图7。
表8：含美白抗皱活性物质分体式微针处方
实施例8：含美白抗皱活性物质一体式微针的制备
按表9中处方称取处方量的原料和去离子水，搅拌混匀至完全溶解，离心或抽真空除气泡，将微针基质溶液分别注入54×61阵列和25×25阵列PDMS微针模具中，将微针基质溶液在模具上铺展均匀,置于真空干燥箱中-0.07 MPa抽真空10 min，取出模具，去除模具上方含气泡的微针基质溶液，重新加入微针基质溶液，将微针基质溶液在模具上铺展均匀，50℃鼓风干燥1 h。取出模具，室温冷却半小时，脱模，可得到含美白抗皱活性物质的一体式微针。微针干燥后的性状见表9，含维生素C乙基醚和三肽-1铜的一体式微针照片见图8。
表9：含美白抗皱活性物质一体式微针处方
实施例9：微针针刺试验
取自制10×10阵列微针（根据表4中的处方2制备）贴在猪皮肤上进行针刺试验，经台盼蓝染色后在显微镜下观察，可看到微针穿刺后留下的微孔阵列。自制10×10阵列微针针刺试验结果显示针刺后可在动物皮肤上留下完整的微孔阵列，刺孔率可达到100%，见图9。
实施例10：微针体外透皮扩散试验
取直径约2.7 cm的圆形巴马香猪皮肤小块共6块，解冻，角质层朝上，3块加乙酰基六肽-8微针（根据表8中的处方3制备），3块加乙酰基六肽-8溶液。皮肤加样后将上述皮肤放入体外透皮扩散池中，用夹子固定，供给池上端用封口膜封闭防止水分挥发。接收池加入8mL生理盐水，200 r/min磁力搅拌，保持温度在37±0.5℃恒温。分别于透皮24 h取样1 mL，样品经0.22 μm的微孔滤膜过滤后用高效液相法进行检测。
微针加样组：将3个10×10阵列微针分别置于皮肤上，轻轻按压1 min，用双面胶将将微针固定在皮肤上。微针中乙酰基六肽-8含量为75 μg。
溶液加样组：将1 mg/mL的乙酰基六肽-8溶液75 μL滴加到皮肤上。
测定了体外透皮试验中样品的含量，结果发现8 h以前的样品含量低于检测限，24h微针组平均体外透皮释放百分比为10.17%，溶液组平均体外透皮释放百分比为4.39%，微针组透皮释放百分比显著高于溶液组，见表10和图10。
表10：乙酰基六肽-8微针和溶液的24h累积透皮百分率（%）
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (10)
1.一种可在高温下干燥的可溶性微针，其特征在于：所述可溶性微针由针尖基质溶液和背衬层基质溶液制成，所述高温是40℃-60℃，所述针尖基质溶液或所述背衬层基质溶液包含以重量百分百计1-10%水溶性高分子材料和1-10%水溶性小分子材料，
所述水溶性高分子材料选自以下一种或多种：透明质酸钠、羧甲基纤维素钠、羟丙基甲基纤维素、硫酸软骨素、葡聚糖、糊精、聚乙烯吡咯烷酮、聚乙烯醇、蚕丝蛋白、壳聚糖或明胶；
所述水溶性小分子材料选自以下一种或多种：葡萄糖、海藻糖、乳糖、泛醇或维生素C乙基醚，
所述透明质酸钠的分子量范围是50kDa-500kDa。
2.根据权利要求1所述的可溶性微针，其特征在于：所述水溶性高分子材料选自透明质酸钠或者透明质酸钠与另一种水溶性高分子材料的组合，所述透明质酸钠与另一种水溶性高分子材料的重量比范围为1：5-5：1，所述另一种水溶性高分子材料选自：羧甲基纤维素钠、羟丙基甲基纤维素、硫酸软骨素、葡聚糖、糊精、聚乙烯吡咯烷酮、聚乙烯醇、蚕丝蛋白、壳聚糖或明胶，
所述透明质酸钠的分子量范围是200kDa-400kDa。
3.根据权利要求1所述的可溶性微针，其特征在于：所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计1-10%的多元醇类物质、聚乙二醇类、泊洛沙姆188，聚乙烯醇，羟丙甲基纤维素或聚乙烯吡咯烷酮，所述多元醇类物质选自以下一种或多种：戊二醇、丁二醇或己二醇，所述聚乙二醇类选自以下一种或多种：聚乙二醇400、聚乙二醇6000或聚乙二醇8000。
4.根据权利要求1所述的可溶性微针，其特征在于：所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计0.1%-2%的亲水性乳化剂，所述亲水性乳化剂选自以下一种或多种：Tween-20、聚乙烯醇、明胶、聚氧乙烯蓖麻油、聚醚硅油或泊洛沙姆188。
5.根据权利要求1所述的可溶性微针，其特征在于：所述针尖基质溶液或所述背衬层基质溶液还包含以重量百分比计1-10%的活性成分，所述活性成分选自以下一种或多种：烟酰胺、传明酸、熊果苷、三肽-1铜、肌肽或乙酰基六肽-8。
6.根据权利要求1所述的可溶性微针，其特征在于：所述针尖基质溶液或所述背衬层基质溶液还包含水或者水和其他溶剂组成的混合溶剂，所述其他溶剂选自以下一种或多种：乙醇、丙二醇或甘油。
7.权利要求1至6中任一项所述的可溶性微针的制备方法，其特征在于：所述制备方法包括以下步骤：
所述可溶性微针采用两步法制备，先将针尖基质溶液快速载入微针模具的空隙中，去除上层含气泡的针尖基质溶液，再将背衬层基质溶液加入模具后在40-60℃干燥脱模后即得所述可溶性微针。
8.根据权利要求7所述的制备方法，其特征在于：在所述制备方法中，将针尖基质溶液快速载入微针模具的空隙中的方法包括抽真空法、离心法、加压法或水浴超声法，微针模具的材料选自以下一种或多种：聚乙烯、聚丙烯、聚氯乙烯、聚甲醛、尼龙、聚二甲基硅氧烷、聚碳酸酯或聚四氟乙烯。
9. 根据权利要求7所述的制备方法，其特征在于：在所述制备方法中，干燥温度为50℃或60℃，干燥时间在2 h以内。
10.权利要求1至6中任一项所述的可溶性微针或者采用权利要求7至9中任一项所述的制备方法制备得到的可溶性微针在制备可溶性微针贴片中的用途。
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| CN115887419A (zh) * | 2022-10-25 | 2023-04-04 | 上海辛禧医药科技事务所 | 一种载药微针贴片及其应用 |
| CN115920222A (zh) * | 2022-11-29 | 2023-04-07 | 成都柔电云科科技有限公司 | 微针及其制备方法、微针贴片及其制备方法 |
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| US20220241570A1 (en) * | 2019-05-16 | 2022-08-04 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Microneedle arrays with undercut features for cutaneous and non-cutaneous drug delivery |
| CN110151736A (zh) * | 2019-07-04 | 2019-08-23 | 蚌埠医学院 | 贴剂及其制备方法 |
| CN112472660A (zh) * | 2019-09-12 | 2021-03-12 | 中科微针（北京）科技有限公司 | 一种含有壬二酸的微针贴片及其制备方法 |
| CN113827544A (zh) * | 2020-06-04 | 2021-12-24 | 中国科学院理化技术研究所 | 一种耐热型可植入式聚合物微针及其制备方法和应用 |
| CN115400341A (zh) * | 2022-08-30 | 2022-11-29 | 华中科技大学 | 一种可溶性聚合物微针及其制备方法 |
| CN115887419A (zh) * | 2022-10-25 | 2023-04-04 | 上海辛禧医药科技事务所 | 一种载药微针贴片及其应用 |
| CN115920222A (zh) * | 2022-11-29 | 2023-04-07 | 成都柔电云科科技有限公司 | 微针及其制备方法、微针贴片及其制备方法 |
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