CN117100992A - 一种水溶性米诺地尔微针及其制备方法和应用 - Google Patents
一种水溶性米诺地尔微针及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种水溶性米诺地尔微针，所述微针包括底座和针尖，所述微针由微针基质液制备而得，所述微针基质液包括成针材料和米诺地尔。本发明中成针材料为水溶性高分子聚合物。本发明通过超声使米诺地尔均匀分散在成针材料中，再将其制备成水溶性米诺地尔微针。本发明所制备的水溶性米诺地尔微针具有足够的穿刺皮肤的能力，可负载更多的米诺地尔。与现有技术相比，本发明所制备的米诺地尔微针能够提高米诺地尔透皮吸收效率，降低米诺地尔的用量及其所带来的副作用，增发效果明显，使用方便快捷，患者依从性更好，具有广阔的临床应用前景。
Description
技术领域
本发明涉及药物制剂技术领域，具体涉及一种水溶性米诺地尔微针及其制备方法和应用。
背景技术
脱发是最普遍，同时也是最痛苦的皮肤疾病之一，严重影响着患者的自尊、心理健康和社会地位。脱发可分为不可逆的瘢痕性脱发和可逆的非瘢痕性脱发，非瘢痕性脱发最为常见，包括雄激素脱发、斑秃、静止期脱发。生活环境、遗传和激素水平等均可能导致脱发。近年来随着生活节奏的加快和生活压力的增加，脱发的发病率也逐渐增加，且有年轻化的趋势。
米诺地尔是临床上最常用的生发药物，其主要临床剂型是酊剂，使用时将其喷在脱发区域然后用手按摩促进药物的吸收。但米诺地尔需长期使用才能见效，而且由于皮肤角质层屏障的存在，米诺地尔的吸收率仅为1.6％导致其疗效受限。米诺地尔在水中溶解性差，故在溶解时需在处方中加入大量的乙醇和丙二醇，长期使用则存在头皮瘙痒、红肿和过敏性接触性皮炎等不良反应，长期使用出现的油腻感也是降低患者依从性的原因之一。
微针，其设计概念是通过微细加工方式将能成针材料制成微米级别的针。目前微针包括固体微针、中空微针、涂层微针和可溶性微针。固体微针和中空微针一般由金属或硅制成，针尖存在断裂风险，涂层微针则载药量较低。可溶性微针一般由可溶的生物相容性材料制备。可溶性微针在应用于皮肤时，能够在角质层上无痛地形成对应形状和大小的微孔，而不会触及真皮层以及神经组织，针尖溶解后药物释放到皮肤中，增加了药物的透皮吸收效率，同时可以避免了固体微针针尖断裂在皮肤中的风险，并且微针使用时对头皮的机械刺激也有利于头发的再生。
目前临床上使用的米诺地尔外用剂型存在透皮吸收差、患者依从性差以及手臂、脸毛发异常增生等问题，亟需开发新的米诺地尔剂型，提高米诺地尔透皮吸收效率，增加患者依从性，避免毛发的异常增生，最终改善米诺地尔的生发效果。
本发明提供了一种水溶性米诺地尔微针，该微针由微针基质液制备。本发明首次通过超声制备得到含米诺地尔的微针基质液，超声使米诺地尔成为大小均一的微粒并均匀分散在基质液中，无需添加助溶剂，成分简单、安全。使用较高分子量聚合物可保证制备的微针在具有较高载药量的同时保证针尖形态完整。最终制备得到的水溶性米诺地尔微针与现有技术相比，米诺地尔透皮吸收效率更高，使用更加方便，治疗脱发效果更好。
发明内容
本发明提供一种水溶性米诺地尔微针，所述微针负载高剂量的米诺地尔，可解决现有外用制剂透皮吸收效率低、使用不便及患者依从性低等问题。
本发明所述的米诺地尔微针包括底座和针尖，所述微针由微针基质液制备而得，所述微针基质液包括成针材料和米诺地尔。本发明中成针材料为水溶性高分子聚合物。
本发明所述的微针具有良好的生物相容性。
本发明所述微针其针尖为圆锥体或多棱锥体，针体高度为50-1500μm，优选为100-1000μm，更优选为600-800μm；针尖的宽度或直径为1-35μm，优选为2-20μm，更优选为2-10μm；针体末端的宽度或直径为50-500μm，优选为100-400μm，更优选为200-350μm。
本发明所述水溶性高分子聚合物选自透明质酸、聚乙烯吡咯烷酮、共聚维酮、丝素蛋白、聚乙烯醇、壳聚糖、胶原蛋白、明胶、羟丙基甲基纤维素、硫酸软骨素、糊精、羧甲基纤维素、羧甲基壳聚糖、硫酸葡聚糖、糖原、直链淀粉、羟丙基纤维素、糖苷及上述材料的改性衍生物中的至少一种；优选为透明质酸、聚乙烯吡咯烷酮、共聚维酮、丝素蛋白、聚乙烯醇、壳聚糖及上述材料的改性衍生物中的至少一种。
本发明所述水溶性高分子聚合物分子量为10-1000KDa，优选为200-800KDa，更优选为200-500KDa。
本发明所述水溶性高分子聚合物与米诺地尔的质量比为50～0.1:1，优选为20～1:1。
本发明提供一种适用于水溶性米诺地尔微针的制备方法，制备方法简单、通用性好，可用于多种高分子材料制备米诺地尔微针。
本发明进一步提供一种米诺地尔微针的制备方法，所述制备方法为，将成针材料溶解为溶液，再将米诺地尔均匀分散在溶液中得到微针基质液，最后将微针基质液填充进模具中，干燥后，得到水溶性米诺地尔微针。
本发明进一步提供一种米诺地尔微针的制备方法，所述制备方法是取适量成针基质液涂敷于微针模具上，通过加压、减压、离心中的一种或多种方法，使成针基质液填充进微针模具空腔中，干燥，剥离，得到米诺地尔微针。
微针基质液采用超声法制备，通过超声使米诺地尔粉末均匀分散在高分子溶液中，超声功率为1-300W，优选为150-250W，超声时间为0.1-30min，优选为5-15min。
在其中一些实施例中，采用加压方式制备微针，具体方法为，将成针基质液铺于微针模具上后，再将微针模具置于加压密封容器中加压即可，加压压力为0.001-0.9MPa，优选为0.2-0.5MPa，加压时间为1-60min，优选为3-20min。
在其中一些实施例中，采用减压方式制备微针，具体方法为，将成针基质液涂敷于微针模具上后，再将微针模具置于减压密封容器中减压即可，真空压力为-0.01–-0.1MPa，优选为-0.07–-0.095MPa，减压时间为1-100min，优选为5-30min。
本发明的有益效果是：
与普通水溶性微针相比，本发明的水溶性米诺地尔微针具有更高的载药量，无需使用助溶剂便可制备水溶性米诺地尔微针，避免了助溶剂造成的副作用。
与现有临床剂型相比，本发明的水溶性米诺地尔微针的透皮吸收率高，可减少米诺地尔的用量。本发明的水溶性米诺地尔微针的使用方便快捷，仅需按压给药2min，无需专业医务人员参与，患者可自主给药依从性高。
同时，本发明的水溶性米诺地尔微针给药时微针对头皮的机械刺激可与药物发挥协同作用促进生发。
本发明的水溶性米诺地尔微针可促进毛囊附近血管新生，改善毛囊供血，激活WNT/β-catenin信号通路；促进静止期毛囊进入生长期，促进毛囊新生，从而起到预防和/或治疗脱发的作用。
附图说明
图1为实施例1制备的水溶性米诺地尔微针图。
图2为实施例1制备的水溶性米诺地尔微针皮肤穿刺表征图。
图3为实施例1水溶性米诺地尔微针促进睾酮诱导雄激素脱发小鼠毛发再生。
具体实施方法
以下实施例是对本发明进一步说明，但并非是对本发明范围的限制。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
实施例1
一微针制备
将透明质酸钠(300kDa)溶解在超纯水中，再加入米诺地尔粉末，使米诺地尔与透明质酸钠比例为5：1，200W超声10min，再补加透明质酸钠使米诺地尔与透明质酸钠比例为1：1，继续200W超声5min，得到成针基质液。取60μL成针基质液铺到微针模具上，将微针模具针体放入加压舱中，压力调整为0.3MPa，加压时间3min。将加压后的微针模具整体放入干燥器中，室温下干燥5h，剥离后得到水溶性米诺地尔微针。
二穿刺效果
取小鼠皮肤，将微针按压在皮肤上3min，取下底座，用0.4％的台盼蓝溶液染色1min，然后将皮肤表面多余的台盼蓝溶液冲洗掉，可观察到明显的穿刺效果，如图二所示，表明本发明所制备水溶性米诺地尔微针机械性能满足要求，可有效穿刺皮肤。
三针尖载药量测定
刮取微针针尖，将微针针尖溶于70％甲醇水溶液中，使用HPLC测定米诺地尔含量。测得微针针尖米诺地尔含量为390.5μg。
四米诺地尔微针治疗雄激素脱发效果
实验动物：7周龄龄C57BL/6小鼠
分组：
1空白对照组
2模型组
3空白微针组
4米诺地尔微针组
5 2％米诺地尔外用组
处理方法：所有小鼠于第0天背部脱毛。1组脱毛后不做处理，2、3、4、5组小鼠脱毛部位从第1天起每天涂抹0.5％睾酮乙醇溶液(50％乙醇)至第21天；3、4组小鼠于第1、3、5、7、9、11、13、15天使用对用微针按压3min，5组小鼠于第1、3、5、7、9、11、13、15天每天脱毛部位涂抹2％米诺地尔。
实验结果：空白对照组小鼠第21天时脱毛部位毛发已完全恢复，模型组小鼠毛发生长受到抑制，空白微针组和2％米诺地尔外用组仅部分小鼠出现毛发再生现象，而米诺地尔微针组所有小鼠均出现大面积的毛发再生。说明本发明的水溶性米诺地尔微针现对于常规的米诺地尔外用制剂具有更好的诱导毛发再生效果。
实施例2-5不同成针材料制备的水溶性米诺地尔微针
参照实施例1的制备方法，通过调整水溶性高分子聚合物的种类以及水溶性聚高分子合物和米诺地尔浓度，得到了如表1所示的具有不同载药量的微针。
表1实施例1-8中不同水溶性高分子聚合物的水溶性米诺地尔微针的载药量
本发明的水溶性米诺地尔微针具有较高的载药量，使用方便快捷，能有效穿刺皮肤将米诺地尔直接递送到皮肤内，提高了米诺地尔的透皮吸收效。与临床常用的米诺地尔酊剂相比，本发明的水溶性米诺地尔微针治疗雄激素脱发的效果更好，可有效促进雄激素脱发模型小鼠的毛发再生。
以上所述仅是本发明的优选实施例而已，并非对本发明做任何形式上的限制，虽然本发明已以优选实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案的范围内，当可利用上述揭示的技术内容做出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。
Claims (9)
1.一种水溶性米诺地尔微针，其特征在于所述微针包括底座和针尖，所述微针由微针基质液制备而得，所述微针基质液包括成针材料和米诺地尔。
2.根据权利要求1所述的水溶性米诺地尔微针，其中所述成针材料包括水溶性高分子聚合物，所述水溶性高分子聚合物的分子量为10-1000KDa，所述水溶性高分子聚合物为透明质酸、聚乙烯吡咯烷酮、共聚维酮、丝素蛋白、聚乙烯醇、壳聚糖、胶原蛋白、明胶、羟丙基甲基纤维素、硫酸软骨素、糊精、羧甲基纤维素、羧甲基壳聚糖、硫酸葡聚糖、糖原、直链淀粉、羟丙基纤维素、糖苷中的至少一种。
3.根据权利要求1所述的水溶性米诺地尔微针，其中所述针尖为圆锥体或多棱锥体，所述针体高度为50-1500μm，针尖的宽度或直径为1-35μm，所述针体末端的宽度或直径为50-500μm。
4.根据权利要求1所述的水溶性米诺地尔微针，所述水溶性高分子材料与米诺地尔的质量比为50-0.1：1。
5.一种如权利要求1-4任一所述的水溶性米诺地尔微针的制备方法，所述制备方法为，将成针材料溶解为溶液，再将米诺地尔均匀分散在溶液中得到微针基质液，最后将微针基质液填充进模具中，干燥后，得到水溶性米诺地尔微针。
6.根据权利要求5所述的水溶性米诺地尔微针的制备方法，所述微针基质液的制备方法为超声法，超声功率为20–300W，超声时间为1–30min。
7.根据权利要求5所述的水溶性米诺地尔微针的制备方法，所述微针的制备方法为加压法或减压法中的至少一种方法。
8.根据权利要求7所述的适用于水溶性米诺地尔微针的制备方法，所述加压法的加压压力为0.1-0.9MPa，加压时间为1-20min；所述减压法的减压压力为-0.01–-0.1MPa，减压时间为1-40min。
9.根据权利要求1-4任一所述的水溶性米诺地尔微针或根据权利要求5-7所述的制备方法制备的水溶性米诺地尔微针在制备预防和/或治疗脱发药物中的应用。
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