CN117045582A - 一种可传递药物的水凝胶角膜接触镜微针及其制备方法 - Google Patents
一种可传递药物的水凝胶角膜接触镜微针及其制备方法 Download PDFInfo
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Abstract
本发明提供一种可传递药物的水凝胶角膜接触镜微针,制备方法为:将壳聚糖粉末溶于乙酸溶液中配置成壳聚糖溶液,过滤、透析后,加入药物并搅拌溶解,随后依次添加多巴胺盐酸盐和高碘酸钠溶液并混合均匀,室温下放置一段时间,导入微针模具中,制备形成含药物微针针尖;将甲基丙烯酸羟乙酯和N‑乙烯基吡咯烷酮混合摇匀,加入引发剂,搅拌均匀;将混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入恒温干燥箱中反应一段时间,经过剥离后得到水凝胶角膜接触镜微针。本发明水凝胶角膜接触镜微针中,药物包埋在微针内部,可减少药物对正常组织的接触与刺激,且水凝胶角膜接触镜微针具有良好的缓释作用,可实现药物的有效传递。
Description
技术领域:
本发明属于新材料技术领域,具体涉及一种可传递药物的水凝胶角膜接触镜微针及其制备方法。
背景技术:
现阶段眼科疾病对于眼科疾病的治疗,重要的难点是局部给药,传统的给药方式主要为眼部直接给药或者眼内注射,其中眼部直接给药主要采用液体或半固体型制剂,如滴眼液或眼膏,但因结膜囊体积有限、泪液分泌和角膜屏障作用等因素,直接给药的生物利用度低(<5%),需要进行多次给药才能达到目标药物浓度。此外,要通过组织屏障到达目标部分,所需的药物浓度也比较高,而过高的药物浓度也会引起对正常组织的损害,引发一定的副作用。为了实现药物的直接传递,腔内或玻璃体注射也是目前常用一种给药方式。这种方式虽然能够穿透角膜屏障,但存在感染、出血等并发症风险,且此种方法有一定疼痛性,给患者带来不便。因此需一种高安全性和高效角膜渗透性的眼用药物剂型。
随着药物载体的发展,很多措施被用来增加药物的透过性以及实现药物的可控释放。而角膜接触镜由于直接和角膜接触,可以延长药物停留时间、控制药物的持续释放,且不影响日常的视觉功能,被广泛的用于眼药载体。且在药物传递领域引起了广泛的关注。然而对于分子量比较大的药物,药物要通过角膜屏障依然具有一定的难度。
微针(Microneedles,MN)是一种新型的物理促透技术,微针由基座和针尖阵列组成,针体一般高10-2000微米、宽10-50微米。微针的长度、大小和形状可根据治疗的需求进行个体化设计。微针可以对针型的设计实现穿过表皮层到达真皮层,产生微米级尺寸的细微通道,将药物置于表皮或上部真皮层,无需通过角质层即可参与循环,发挥药理反应。微针有足够的长度可以刺穿皮肤的角质层但不与组织深处的毛细血管、神经接触,因此其使用具有微创、近乎无痛性等特点。基于此,本发明提供一种可传递药物的水凝胶角膜接触镜微针及其制备方法,可在不损伤组织的前提下,提高分子量较大的药物的给药效果。
发明内容:
本发明的目的是针对现有技术的不足,提供一种可传递药物的水凝胶角膜接触镜微针及其制备方法,在水凝胶角膜接触镜药物载体的基础上设计了水凝胶角膜接触镜微针,所得水凝胶微针具有可以实现药物的有效传递,同时减少药物对正常组织的接触与刺激。
本发明采用以下技术方案:
(一)本发明提供一种可传递药物的水凝胶角膜接触镜微针的制备方法,包括以下步骤:
S1、含药物微针针尖的制备:将壳聚糖粉末溶于乙酸溶液中配置成壳聚糖溶液,将壳聚糖溶液进行过滤、透析后,加入药物并搅拌溶解,随后依次添加多巴胺盐酸盐和高碘酸钠溶液并混合均匀,室温下放置一段时间,导入微针模具中,制备形成含药物微针针尖;
S2、水凝胶角膜接触镜微针的制备:将甲基丙烯酸羟乙酯和N-乙烯基吡咯烷酮混合摇匀,然后加入引发剂,搅拌均匀;将上述混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入恒温干燥箱中反应一段时间,经过小心剥离后得到水凝胶角膜接触镜微针。
进一步的,所述S1中,乙酸溶液浓度为0.2M;所述壳聚糖溶液中,壳聚糖的浓度为0.5-5wt%,进一步的为1-3wt%,最优为2wt%。
进一步的,所述S1中,药物为N,N,N',N'-四(2-吡啶基甲基)乙二胺(TPEN)、1-(2,4,6-三甲基苯基)-3-(环十二烷基)咪唑鎓氯化物(ZX1)、乙二胺四乙酸钙(Ca-EDTA)以及葛根素中的一种或一种以上,进一步的为N,N,N',N'-四(2-吡啶基甲基)乙二胺(TPEN)、1-(2,4,6-三甲基苯基)-3-(环十二烷基)咪唑鎓氯化物(ZX1)、乙二胺四乙酸钙(Ca-EDTA),最优为N,N,N',N'-四(2-吡啶基甲基)乙二胺(TPEN)、1-(2,4,6-三甲基苯基)-3-(环十二烷基)咪唑鎓氯化物(ZX1)。
进一步的,所述S1中,药物的浓度为0.1-5mg/mL,进一步的为0.2-3mg/mL,最优为1-2mg/mL。
进一步的,所述S1中,多巴胺盐酸盐的浓度为2-20mg/mL,进一步的为5-10mg/mL,最优为5-7mg/mL;所述高碘酸钠溶液中高碘酸钠的浓度为80mg/mL,壳聚糖溶液与所添加的高碘酸钠溶液的体积比为1000:1-20:1,进一步的为200:1-40:1,最优为100:1。
进一步的,所述S1中,溶液配好后于室温下放置时间为10min-2h,进一步的为30min-1h,最优为30min;导入微针模具的方式为离心导入或真空导入,优选采用离心导入;采用离心导入时,离心转速为500-5000rpm,进一步的为1000-4000rpm,最优为2000-3000rpm,离心时间为2-20min,进一步的为5-10min,最优为5min;导入微针模具后,用刮刀去除微针模具中针尖上层多余的凝胶待用。
进一步的,所述S2中,甲基丙烯酸羟乙酯(HEMA)和N-乙烯基吡咯烷酮(NVP)的混合摩尔比为7.4:2;
进一步的,所述S2中,引发剂为等摩尔比的过硫酸铵和N,N,N',N'-四甲基乙二胺,引发剂的浓度为2mM-10mM,进一步的为3mM-7mM,最优为5mM。
进一步的,所述S1中,透析过程为:将过滤后的壳聚糖溶液放入去离子水(pH为6-6.5)进行透析,透析时间为20min,截留分子量1万;所述S2中,恒温干燥箱温度为60℃,反应时间不少于1h。
进一步的,所述微针模具与角膜形状适配,微针模具的材料为聚二甲基硅氧烷;所述微针模具包括基座,基座上设置有用于水凝胶角膜接触镜成形的圆形凹槽,圆形凹槽下表面设置有若干个用于微针成形的针形槽;所述基座的高度为8mm,直径为35mm;所述圆形凹槽直径为25mm,圆形凹槽的高度为2mm;所述针形槽的高度为0.5mm,针形槽的最大直径为0.26mm,针形槽间距为0.65mm。
(二)本发明还提供一种可传递药物的水凝胶角膜接触镜微针,由以上所述的制备方法制备得到,所述水凝胶角膜接触镜微针包括水凝胶角膜接触镜和微针;所述水凝胶角膜接触镜厚度为2mm;所述微针底座直径为0.26mm,微针高度为0.5mm,微针间距为0.65mm。
本发明的有益效果:
(1)本发明提供了一种可传递药物的水凝胶角膜接触镜微针及其制备方法,在水凝胶角膜接触镜药物载体的基础上设计了水凝胶角膜接触镜微针,药物包埋在微针内部,可减少药物对正常组织的接触与刺激,且水凝胶角膜接触镜微针具有良好的缓释作用,可实现药物的有效传递;
(2)本发明提供了一种用于微针制备的水凝胶新材料,所述水凝胶新材料对角膜无刺激作用,安全性强;
(3)本发明所制备的水凝胶角膜接触镜微针具有良好的透光性,平衡含水量高,佩戴舒适型强。
附图说明:
图1为本发明微针模具俯视图;
图2为本发明微针模具侧剖图;
图3为实施例与对比例所制备的水凝胶微针在37℃下PBS中累积释放曲线图。
具体实施方式:
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
本实施例提供一种可传递药物的水凝胶角膜接触镜微针的制备方法,包括:
步骤一、含药物微针针尖的制备:
将壳聚糖粉末溶于0.2M的乙酸溶液中配置成浓度为2wt%的壳聚糖溶液;将壳聚糖溶液进行过滤除去微量未分散的不溶物质,随后放入去离子水中透析(截留分子量1万)20min;加入N,N,N',N'-四(2-吡啶基甲基)乙二胺(TPEN),得到2.5mg/mL的TPEN壳聚糖溶液,搅拌使其完全溶解;随后在上述溶液中加入多巴胺盐酸盐,使溶液中多巴胺盐酸盐的浓度为5mg/mL,然后在上述溶液中加入体积分数为0.1%的80mg/mL的高碘酸钠溶液,放置30min;将配置好的液体加入微针模具中以3000rpm离心5min,用刮刀去除微针模具中针尖上层多余的凝胶待用。
步骤二、水凝胶角膜接触镜微针的制备:
将2mL甲基丙烯酸羟乙酯(HEMA)和465μL N-乙烯基吡咯烷酮(NVP)加入到10mL离心管中进行混合摇匀,然后加入14mg过硫酸铵和等摩尔比的N,N,N',N'-四甲基乙二胺,搅拌均匀;将上述混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入60℃的恒温干燥箱中反应1小时后,小心将水凝胶角膜接触镜微针剥离。
实施例2
本实施例提供一种可传递药物的水凝胶角膜接触镜微针的制备方法,包括:
步骤一、含药物微针针尖的制备:
将壳聚糖粉末溶于0.2M的乙酸溶液中配置成浓度为1wt%的壳聚糖溶液;将壳聚糖溶液进行过滤除去微量未分散的不溶物质,随后放入去离子水中透析(截留分子量1万)20min;加入1-(2,4,6-三甲基苯基)-3-(环十二烷基)咪唑鎓氯化物(ZX1),得到1mg/mL的ZX1壳聚糖溶液,搅拌使其完全溶解;随后在上述溶液中加入多巴胺盐酸盐,使溶液中多巴胺盐酸盐的浓度为10mg/mL,然后在上述溶液中加入体积分数为1%的80mg/mL的高碘酸钠溶液,放置60min;将配置好的液体加入微针模具中以2000rpm离心10min,用刮刀去除微针模具中针尖上层多余的凝胶待用。
步骤二、水凝胶角膜接触镜微针的制备:
将2mL甲基丙烯酸羟乙酯(HEMA)和465μL N-乙烯基吡咯烷酮(NVP)加入到10mL离心管中进行混合摇匀,然后加入14mg过硫酸铵和等摩尔比的N,N,N',N'-四甲基乙二胺,搅拌均匀;将上述混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入60℃的恒温干燥箱中反应1小时后,小心将水凝胶角膜接触镜微针剥离。
实施例3
本实施例提供一种可传递药物的水凝胶角膜接触镜微针的制备方法,包括:
步骤一、含药物微针针尖的制备:
将壳聚糖粉末溶于0.2M的乙酸溶液中配置成浓度为3wt%的壳聚糖溶液;将壳聚糖溶液进行过滤除去微量未分散的不溶物质,随后放入去离子水中透析(截留分子量1万)20min;加入N,N,N',N'-四(2-吡啶基甲基)乙二胺(TPEN),得到2mg/mL的TPEN壳聚糖溶液,搅拌使其完全溶解;随后在上述溶液中加入多巴胺盐酸盐,使溶液中多巴胺盐酸盐的浓度为10mg/mL,然后在上述溶液中加入体积分数为0.5%的80mg/mL的高碘酸钠溶液,放置45min;将配置好的液体加入微针模具中以5000rpm离心2min,用刮刀去除微针模具中针尖上层多余的凝胶待用。
步骤二、水凝胶角膜接触镜微针的制备:
将2mL甲基丙烯酸羟乙酯(HEMA)和465μL N-乙烯基吡咯烷酮(NVP)加入到10mL离心管中进行混合摇匀,然后加入14mg过硫酸铵和等摩尔比的N,N,N',N'-四甲基乙二胺,搅拌均匀;将上述混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入60℃的恒温干燥箱中反应1小时后,小心将水凝胶角膜接触镜微针剥离。
实施例4
本实施例提供一种可传递药物的水凝胶角膜接触镜微针的制备方法,包括:
步骤一、含药物微针针尖的制备:
将壳聚糖粉末溶于0.2M的乙酸溶液中配置成浓度为2wt%的壳聚糖溶液;将壳聚糖溶液进行过滤除去微量未分散的不溶物质,随后放入去离子水中透析(截留分子量1万)20min;加入N,N,N',N'-四(2-吡啶基甲基)乙二胺(TPEN),得到3mg/mL的TPEN壳聚糖溶液,搅拌使其完全溶解;随后在上述溶液中加入多巴胺盐酸盐,使溶液中多巴胺盐酸盐的浓度为7mg/mL,然后在上述溶液中加入体积分数为1%的80mg/mL的高碘酸钠溶液,放置90min;将配置好的液体加入微针模具中以5000rpm离心3min,用刮刀去除微针模具中针尖上层多余的凝胶待用。
步骤二、水凝胶角膜接触镜微针的制备:
将2mL甲基丙烯酸羟乙酯(HEMA)和465μL N-乙烯基吡咯烷酮(NVP)加入到10mL离心管中进行混合摇匀,然后加入14mg过硫酸铵和等摩尔比的N,N,N',N'-四甲基乙二胺,搅拌均匀;将上述混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入60℃的恒温干燥箱中反应1小时后,小心将水凝胶角膜接触镜微针剥离。
实施例5
本实施例提供一种可传递药物的水凝胶角膜接触镜微针的制备方法,包括:
步骤一、含药物微针针尖的制备:
将壳聚糖粉末溶于0.2M的乙酸溶液中配置成浓度为1.5wt%的壳聚糖溶液;将壳聚糖溶液进行过滤除去微量未分散的不溶物质,随后放入去离子水中透析(截留分子量1万)20min;加入Ca-EDTA,得到3mg/mL的Ca-EDTA壳聚糖溶液,搅拌使其完全溶解;随后在上述溶液中加入多巴胺盐酸盐,使溶液中多巴胺盐酸盐的浓度为10mg/mL,然后在上述溶液中加入体积分数为2%的80mg/mL的高碘酸钠溶液,放置30min;将配置好的液体加入微针模具中以4000rpm离心5min,用刮刀去除微针模具中针尖上层多余的凝胶待用。
步骤二、水凝胶角膜接触镜微针的制备:
将2mL甲基丙烯酸羟乙酯(HEMA)和465μL N-乙烯基吡咯烷酮(NVP)加入到10mL离心管中进行混合摇匀,然后加入14mg过硫酸铵和等摩尔比的N,N,N',N'-四甲基乙二胺,搅拌均匀;将上述混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入60℃的恒温干燥箱中反应1小时后,小心将水凝胶角膜接触镜微针剥离。
对比例1
将2mL甲基丙烯酸羟乙酯和465μL N-乙烯基吡咯烷酮加入到10mL离心管中进行混合摇匀,然后加入TPEN,得到2.5mg/mL的TPEN单体溶液,加入14mg过硫酸铵和等摩尔比的N,N,N',N'-四甲基乙二胺,将上述混合物注入空白的微针模具中,加上盖玻片密封模具,然后放入60℃的恒温干燥箱中反应1小时后,小心将水凝胶角膜接触镜微针剥离。
试验例1
将本发明实施例所制备的水凝胶角膜接触镜微针进行透光性、平衡含水量、针尖的临界压强以及药物释放量的测定。
(1)透光性测试:
通过观察法表征水凝胶角膜接触镜微针的透明性。结果表明,实施例1~5所制备的水凝胶角膜接触镜微针均具有良好的透光性。
(2)平衡含水量测试:
将实施例1~5所制备的水凝胶样品置于足量的蒸馏水中,溶胀至质量恒定后取出,用滤纸小心吸干表面的水分,在室温下称量其质量M1(g),然后将水凝胶在60℃干燥箱中干燥至恒定重量,称量其质量M2(g)。平衡含水量EWC(%)=(M1-M2)/M1×100%。
结果表明,实施例1~5所制备的水凝胶角膜接触镜微针平衡含水量在45-55%之间,对折后无明显裂纹,具有一定的韧性,表明实施例1~5所制备的双层水凝胶微针具备角膜接触镜的通常特性。
(3)针尖的临界压强:
将实施例1~4与对比例1所制备的水凝胶角膜接触镜微针针尖朝上固定在力学测试机传感器上。当针尖接触到上方平台时,开始测量微针针尖阵列的受力情况,同时通过光学显微镜观察针尖的状态,当针尖发生破坏的时候,记录受力情况,根据针尖的面积计算出临界压强。
结果表明,水凝胶微针针尖处的临界压强分别为115MPa(对比例1)、443MPa(实施例1)、650MPa(实施例2)、405MPa(实施例3)、716MPa(实施例4)。从理论上说,当针尖的压强超过400MPa时,针尖就有刺破表皮的可能。因此实施例2-4中的微针理论上可刺破表皮。
(4)药物释放量的测定:
将在恒温干燥箱中反应后的水凝胶角膜接触镜微针置于PBS中,并置于37℃恒温水浴中,通过紫外分光光度计检测不同释放时间段的药物浓度在特定波长的吸光度,通过标准曲线计算药物的溶度,从而得到药物的累积释放量。
图3为对比例1和实施例1、3、4的体外药物释放曲线。由图3可知,相较于对比例,本发明实施例1、3、4中药物缓慢从微针中释放出来,特别实施例4中的水凝胶微针对药物控释性能明显。因此,本发明所制备的水凝胶角膜接触镜微针具有良好的缓释性能。
以上仅是本发明的优选实施方式,本发明的保护范围并不仅局限于上述实施例,凡属于本发明思路下的技术方案均属于本发明的保护范围,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前提下的若干改进和润饰,应视为本发明的保护范围。
Claims (10)
1.一种可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,包括以下步骤:
S1、含药物微针针尖的制备:将壳聚糖粉末溶于乙酸溶液中配置成壳聚糖溶液,将壳聚糖溶液进行过滤、透析后,加入药物并搅拌溶解,随后依次添加多巴胺盐酸盐和高碘酸钠溶液并混合均匀,室温下放置一段时间,导入微针模具中,制备形成含药物微针针尖;
S2、水凝胶角膜接触镜微针的制备:将甲基丙烯酸羟乙酯和N-乙烯基吡咯烷酮混合摇匀,然后加入引发剂,搅拌均匀;将上述混合物滴加到已包括含药物微针针尖的微针模具中,加上盖玻片密封模具,放入恒温干燥箱中反应一段时间,经过剥离后得到水凝胶角膜接触镜微针。
2.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述S1中,乙酸溶液浓度为0.2M;
所述壳聚糖溶液中,壳聚糖的浓度为0.5-5wt%。
3.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述S1中,药物为N,N,N',N'-四(2-吡啶基甲基)乙二胺、1-(2,4,6-三甲基苯基)-3-(环十二烷基)咪唑鎓氯化物、乙二胺四乙酸钙以及葛根素中的一种或一种以上;
所述药物的浓度为0.1-5mg/mL。
4.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述S1中,多巴胺盐酸盐的浓度为2-20mg/mL;
所述高碘酸钠溶液中高碘酸钠的浓度为80mg/mL,壳聚糖溶液与所添加的高碘酸钠溶液的体积比为1000:1-20:1。
5.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述S1中,溶液配好后于室温下放置时间为10min-2h;导入微针模具的方式为离心导入或真空导入,采用离心导入时,离心转速为500-5000rpm,离心时间为2-20min;导入微针模具后,用刮刀去除微针模具中针尖上层多余的凝胶待用。
6.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述S2中,甲基丙烯酸羟乙酯和N-乙烯基吡咯烷酮的混合摩尔比为7.4:2。
7.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述S2中,引发剂为等摩尔比的过硫酸铵和N,N,N',N'-四甲基乙二胺,引发剂的浓度为2mM-10mM。
8.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述S1中,透析过程为:将过滤后的壳聚糖溶液放入去离子水进行透析,透析时间为20min,截留分子量1万;
所述S2中,恒温干燥箱温度为60℃,反应时间不少于1h。
9.根据权利要求1所述的可传递药物的水凝胶角膜接触镜微针的制备方法,其特征在于,
所述微针模具与角膜形状适配,微针模具的材料为聚二甲基硅氧烷;
所述微针模具包括基座,基座上设置有用于水凝胶角膜接触镜成形的圆形凹槽,圆形凹槽下表面设置有若干个用于微针成形的针形槽;
所述基座的高度为8mm,直径为35mm;所述圆形凹槽直径为25mm,圆形凹槽的高度为2mm;所述针形槽的高度为0.5mm,针形槽的最大直径为0.26mm,针形槽间距为0.65mm。
10.权利要求1~9任意一项所述的制备方法制备的可传递药物的水凝胶角膜接触镜微针,其特征在于,
所述水凝胶角膜接触镜微针包括水凝胶角膜接触镜和微针;
所述水凝胶角膜接触镜厚度为2mm;
所述微针底座直径为0.26mm,微针高度为0.5mm,微针间距为0.65mm。
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