CN102778762B - 载药型隐形眼镜及其制备方法 - Google Patents
载药型隐形眼镜及其制备方法 Download PDFInfo
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- CN102778762B CN102778762B CN201210235641.6A CN201210235641A CN102778762B CN 102778762 B CN102778762 B CN 102778762B CN 201210235641 A CN201210235641 A CN 201210235641A CN 102778762 B CN102778762 B CN 102778762B
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Abstract
本发明关于一种载药型隐形眼镜及其制备方法,此载药型隐形眼镜具有一隐形眼镜本体,隐形眼镜本体至少包含有一双性混成纳米载体,其上载有药物分子。本发明更借助药物分子的光或热敏感性差异,以分别制作出两种不同类型的包覆型及浸药型的载药型隐形眼镜。本发明利用具有良好药物包覆能力和生物兼容性极高的双性混成纳米载体包覆药物分子,达到药物分子长期缓慢释放至眼睛组织里,使药物的损失、对人体产生副作用机率降至最低,以达到医疗、保健的目的。
Description
技术领域
本发明涉及一种隐形眼镜相关技术,尤其涉及一种可局部药物释放以长期释放药物分子的载药型隐形眼镜及其制备方法。
背景技术
长久以来,眼睛视力的受损和退化困扰着人们,对于眼睛视力的受损,以近视者为例,人们通常会借助配戴有度数的框架眼镜或隐形眼镜,以使眼睛能够看得清楚;尤其是对视力不佳的人来说,隐形眼镜是一种非常方便的选择。
目前隐形眼镜大致可分为硬式镜片与软式镜片,其中软式镜片之材质通常为硅水凝胶(silicone hydrogels)、聚丙烯酰胺(polyacrylamide,PAA)或聚甲基丙烯酸羟乙酯(PHEMA)…等,对配戴者于使用过程中有较佳的舒适感,且因其售价较为便宜,因此为现今市场之主流。然而,制作隐形眼镜的材质虽然已经经过极大的改良,但因配戴隐形眼镜所致的过敏问题迄今仍然存在,隐形眼镜配戴者常会因隐形眼镜本身水分减少而感到眼睛干涩刺痛;而为了能继续佩戴隐形眼镜,佩戴者必须经常以湿润溶液润湿隐形眼镜。再者,若眼睛本身因故发生发炎或是干涩刺痛时,有时需要点些药水或是一些保养药水等,但大部分的药水都不能于佩戴隐形眼镜时点用,制造成佩戴者的不便。
另一方面,不管有无佩戴隐形眼镜,一般使用者于使用眼药水时,在眼睛滴入眼药水之后,眼药水会因眨眼、泪液稀释、排出等反射性动作而有所损失,以至于约低于5%的剂量被眼睛所吸收;此外,药物停留至眼睛时间并不长,一旦药物分子进入血液循环之中,可能会引发一些副作用。
有鉴于此,本发明遂提出一种载药型隐形眼镜及其制备方法,以应用于眼睛疾病的预防及治疗,并改善上述缺失。
发明内容
本发明之主要目的在提供一种载药型隐形眼镜及其制备方法,其利用具有良好药物包覆能力和生物兼容性极高的纳米载体包覆药物或药物分子溶液浸泡,并使其均匀分散于隐形眼镜之中,使佩戴者得以利用其所配戴的载药型隐形眼镜进行局部药物释放,达到医疗、保健之目的。
本发明之另一目的在提供一种载药型隐形眼镜及其制备方法,其使获得的载药型隐形眼镜于佩戴时,药物分子可透过镜片缓慢释放,达到药物分子长期释放(>24h)至眼睛组织里,使药物的损失、对人体产生副作用机率降至最低。
本发明之再一目的在提供一种利用简易制程制作载药型隐形眼镜的方法。
为达到上述目的,本发明提出的载药型隐形眼镜主要包括有一隐形眼镜本体,其至少包含有一双性混成纳米载体,此双性混成纳米载体上载有药物分子,使药物分子分布于隐形眼镜本体内或是形成于隐形眼镜本体表面。
其中,此双性混成纳米载体为有机无机的双性几丁聚醣及二氧化硅混成的纳米载体。
另外,本发明提出的载药型隐形眼镜的制备方法的第一个实施态样,其方法包括:于一药物分子溶液中加入双性混成纳米载体,并均匀搅拌成一混合溶液;再将此混合溶液与一隐形眼镜原料充分混合后,注入至少一模具中;经过进行照光固化成型,于脱模后,即取得第一种包覆型的载药型隐形眼镜。
本发明所提出的载药型隐形眼镜的制备方法的第二个实施态样,其方法包括:将一药物分子溶液、双性混成纳米载体及隐形眼镜原料均匀搅拌成一混合溶液;再将此混合溶液喷涂至一隐形眼镜本体表面,使隐形眼镜本体上形成一薄膜;最后即可取得第二种包覆型的载药型隐形眼镜。
最后,本发明所提出的药型隐形眼镜的制备方法的第三个实施态样,其方法包括:将一双性混成纳米载体溶液及一隐形眼镜原料均匀搅拌成一混合溶液;再将此混合溶液注入至少一模具中,并进行照光固化成型,于脱模后先取得载体式隐形眼镜;然后将此载体式隐形眼镜浸泡于一药物分子溶液中,直至浓度达到动态平衡为止,以得到浸药型的载药型隐形眼镜。
本发明采用上述技术方案,具有以下优点:
本发明利用具有良好药物包覆能力和生物兼容性极高的纳米载体包覆药物或药物分子溶液浸泡,并使其均匀分散于隐形眼镜之中,使佩戴者得以利用其所配戴的载药型隐形眼镜进行局部药物释放,使药物分子可透过镜片缓慢释放,达到药物分子长期释放(>24h)至眼睛组织里,使药物的损失、对人体产生副作用机率降至最低,有助于减少漏药情形发生,确实可达到医疗、保健的目的。再者,本发明所使用的制程简单,使其应用更为广泛。
附图说明
图1为本发明使用的有机无机的双性几丁聚醣及二氧化硅混成的纳米载体(silica-CHC)的化学结构式及其自组装的示意图。
图2为本发明于制备第一种包覆型的载药型隐形眼镜的流程图。
图3为本发明于制备第二种包覆型的载药型隐形眼镜的流程图。
图4为本发明于制备浸药型的载药型隐形眼镜的流程图。
图5为本发明的载药型隐形眼镜中纳米载体的添加量相对于含水量的结果示意图。
图6为本发明使用阿奇霉素(Azithromycin)的包覆型隐形眼镜于不同温度下的释放情形示意图。
图7(a)为具有本发明的药物载体以及不具有药物载体的载药型隐形眼镜的维他命B12释放情形示意图。
图7(b)为本发明的在不同维他命B12药物浓度下的载药型隐形眼镜的释放情形示意图。
图8(a)为本发明使用的有机无机的双性几丁聚醣及二氧化硅混成的纳米载体的扫描式电子显微镜影像。
图8(b)为本发明的载药型隐形眼镜的扫描式电子显微镜影像。
附图标记说明:I-碳主链;Ⅱ-羧基改质的亲水端;Ⅲ-长碳链改质的疏水端。
具体实施方式
本发明有关一种局部药物释放技术(local drug delivery system),以配戴的隐形眼镜进行局部药物释放,达到医疗、保健目的。亦即本发明利用具有良好药物包覆能力和生物兼容性极高的纳米载体包覆药物分子,并使其均匀分散于隐形眼镜中而制成;当隐形眼镜配戴于眼睛上时,药物分子可透过镜片缓慢释放,达到药物分子长期释放(>24小时)至眼睛组织里,不但可长时间缓慢释放,更使药物的损失、对人体产生副作用机率降至最低。
本发明之载药型隐形眼镜主要包含有一隐形眼镜本体,其至少包含有一双性混成纳米载体,此双性混成纳米载体上载有亲水性或疏水性的药物分子,此双性混成纳米载体及其所载的药物分子分布于隐形眼镜本体内,或是形成于隐形眼镜本体表面;且双性混成纳米载体的大小在20~300纳米的透明纳米球体,其含量介于0.01~5重量百分比(wt%)之间。双性混成纳米载体赏所载的药物分子可为维他命A、维他命B12、维他命C、维他命E、阿奇霉素(azithromycin)、氟米龙醋酸酯(fluorometholone facetate)、枯草杆菌(bacitracin)、新霉素(neomycin)、硫酸多粘菌素B(polymyxin B sulfate)、盐酸羟四环素(Oxytetracycline HCl)、红霉素(erythromycin)、地塞米松(dexamethasone)、乙酸培尼皮质醇(prednisolone acetate)、缩苹酸梯莫洛(timolol maleate)或皮质醇(hydrocortisone)等。
其中,此双性混成纳米载体在本实施例中使用有机无机的双性几丁聚醣及二氧化硅混成的纳米载体。再者,就本发明所使用的几丁聚醣(chitosan)为一具生物兼容性材料,已被广泛用于生物技术上。本发明使用由几丁聚醣改质修饰而成之双性有机无机的几丁聚醣纳米载体(silica-CHC),其系具高生物兼容性,于水中具有自组装(self-assembly)之情形,其核壳(core-shell)结构扮演着物理屏障的角色-调节药物释放,可以减少包覆的内容物随着高分子在水溶液中膨润现象的产生而扩散溢出。
本发明提出的载药型隐形眼镜可依据药物分子对光或热的敏感性的不同可分为包覆型的载药型隐形眼镜以及浸药型的载药型隐形眼镜,对光或热稳定的药物分子可以选择包覆型的载药型隐形眼镜,对光或热敏感的药物分子则选择浸药型的载药型隐形眼镜;其中包覆型的载药型隐形眼镜又可分为药物分子直接与隐形眼镜原料混合制作成隐形眼镜,以及利用喷涂于隐形眼镜本体上形成含药物分子的薄膜,不管是何种型式,本发明的载药型隐形眼镜皆可有效达到局部缓慢药物释放的功效。
接续,针对各种型式的载药型眼镜的制备方法详述如后,然在说明各制备方法之前,先简单说明本发明使用的有机无机的双性几丁聚醣及二氧化硅混成的纳米载体。
如图1及附件1所示,此即为于本发明中,双性混成纳米载体所使用的有机无机的双性几丁聚醣及二氧化硅混成的纳米载体的化学结构式及其自组装的示意图,如图所示,几丁聚醣在碳主链I上具有羧基改质的亲水端Ⅱ和长碳链改质的疏水端Ⅲ,使其在水溶液中具有自组装形成之混成壳层(core-shell)纳米微粒的功能。此纳米载体的制备方法为:将0.25克具有羧基改质亲水端(carboxylgroup)和长碳链改质疏水端(hexanoyl group)之有机双性几丁聚醣溶于50毫升的去离子水中,室温下搅拌24小时,使其完全溶解形成一有机双性几丁聚醣溶液(0.5wt%)。将160微升的3-氨基丙基三甲基硅氧烷(3-aminopropyltrimthoxysilane,以下简称APTMS)或胺丙烷基三甲氧基硅烷(APTES),此为无机硅烷基偶联剂;和0.012g之1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,以下简称EDC),此为催化剂;缓慢加入于上述的有机双性几丁聚醣溶液中,并于室温下搅拌24小时,以形成一有机无机混合溶液。将上述的有机无机混合溶液利用一透析膜以75v%(体积百分比)的乙醇进行透析24小时,再以无水酒精进行透析24小时,以产生一透析产物。将上述之透析产物以烘箱烘干,以取得如图所示之有机无机的双性几丁聚醣及二氧化硅混成的纳米载体粉末(以下简称为silica-CHC)。
另外,于本发明实施例中所使用的隐形眼镜原料的组成及制备方法为:利用甲基丙烯酸-2-羟乙酯(2-hydroxyethyl methacrylate,HEMA)及0.5~5v%(体积百分比)的甲基丙烯酸(methacrylate acid,MAA)混合单体作为本体材料,使其均匀混合之;再以二甲基丙烯酸乙二醇酯(ethylene glycol dimethylacrylate,GDMA)做为交联剂、偶氮二异丁腈(2,2’-Azobisisobutyronitrile,AIBN)做为光起始剂,与上述的HEMA-MAA混合单体均匀混合之,此即作为本发明的各实施例之隐形眼镜原料,用以制作载药型隐形眼镜。然而,此原料为本发明使用的一具体范例而已,当不限定于此,举凡市面上各种隐形眼镜原料,皆可用来制作本发明的载药型隐形眼镜。
首先请参阅图2,此为第一种包覆型的载药型隐形眼镜的制造方法,如图所示,如步骤S10,将药物分子先溶解于极性有机溶剂,例如乙醇(ethanol)、聚乙二醇(PEG)、聚丙二醇(PPG)、二甲基亚砜(DMSO)或四氢呋喃(THF)至少其中之一或其任意组合,之后使用去离子水稀释至预定药物分子浓度,使其完全溶解,以得到一药物分子溶液。接续如步骤S12所示,将双性混成纳米载体(silica-CHC)粉末添加至药物分子溶液中,于室温下搅拌24小时,以得到一混合溶液。如步骤S14所示,再以转速8000rpm离心20分钟,取上层液可计算得知包覆率,下层液取出与上述之隐形眼镜原料均匀混合之,并注入模具中;最后如步骤S16所示,以紫外光进行照光固化,于脱模后,再以缓冲溶剂多次冲洗表面未反应完全的单体,进而藉此得到此载药型隐形眼镜。
第二种包覆型的载药型隐形眼镜的制造方法请参阅图3所示,如步骤S20,将前述的药物分子溶液(其制作方法如前面所述,于此不再赘述)、双性混成纳米载体与作为隐形眼镜原料的高分子聚合物均匀搅拌成一混合溶液,此高分子聚合物的主要化学成份为聚甲基丙烯酸-2-羟乙酯(poly(2-hydroxyethylmethacrylate),PHEMA)及聚甲基丙烯酸(poly methacrylate acid,PMAA)以100:0.5至100:5的固定比例混合的聚合物,如前所述的隐形眼镜原料即为其中一具体范例;接续如步骤S22所示,将此混合溶液喷涂至一现有的隐形眼镜本体表面,使该隐形眼镜本体上形成一薄膜,其厚度为0.5~10微米(micrometers),此即含有载有药物分子的双性混成纳米载体的薄膜以藉此得到如步骤S24所示的此载药型隐形眼镜。
本发明的浸药型的载药型隐形眼镜的制备方法如图4所示,首先如步骤S30所示,先制备双性混成纳米载体溶液,其将silica-CHC纳米载体粉末添加至去离子水中所形成,并于室温下搅拌24小时,以转速8000rpm离心20分钟。接续如步骤S32所示,将下层液之双性混成纳米载体溶液取出与上述之隐形眼镜原料均匀混合之,以得到一混合溶液。如步骤S34所示,将此混合溶液注入模具中,再以紫外光进行照光固化,脱模后,以缓冲溶剂多次冲洗表面未反应完全的单体,据此得到载体式隐形眼镜。最后,如步骤S36,将药物分子先溶解于极性有机溶剂或去离子水中,以得到药物分子溶液,并将上述制得之载体式隐形眼镜浸泡于此药物分子溶液中,经24小时后,待其浓度达到动态平衡,再取出以缓冲溶剂冲洗表面,即可获得此种载药型隐形眼镜。
含水量测试:
本发明将利用前述制备方法所制得之载体式隐形眼镜依不同的纳米载体添加量进行含水量试验,以了解使用本发明之载药型隐形眼镜中纳米载体的添加量相对于含水量的差异。将上述的具有载体式隐形眼镜于烘箱中烘干,秤重(Wd),之后浸泡于生理食盐水中,于室温下放置三天,待其饱和状态,将表面水分擦干,秤重(Ww);之后将此镜片置于一密闭容器内,每隔一段时间,秤重(Wt)。
经由计算:含水量(Water Retention)(%)=100%×(Wt-Wd)/(Ww-Wd),以此即可得知其含水量。实验结果如图5所示,在此含水量测试当中,为了提高含水量,除了一般隐形眼镜会添加之单体MAA外,本发明所使用之药物载体在此尚扮演着如上述单体同样的角色。由图5可知,添加silica-CHC纳米载体所测得之含水量,相较于单纯只加入单体MAA可再提高10%~25%(24~72h),添加silica-CHC纳米载体的含水量更高,此原因在于,silica-CHC纳米载体的化学结构上具有多量的Si-OH官能基,故可增加其亲水性。
药物释放:
本发明分别将第一种包覆型的载药型隐形眼镜与浸药型的载药型隐形眼镜分别进行药物分子的释放试验,以了解使用本发明之载药型隐形眼镜的药物释放效果。
就包覆型的载药型隐形眼镜而言,在此所采用的药物分子为抗生素-阿奇霉素(Azithromycin),此为一种疏水性药物分子,其化学结构设计上属于azalides类的抗生素(属于macrolides类药物的亚群)中第一个可供口服使用的抗生素。此为广效型抗生素对革兰氏阳性菌、革兰氏阴性菌、厌氧菌、衣原体、螺旋体等均较敏感。此种药物分子的释放情形如图6所示,由图可知,释放出的Azithromycin药物量可随温度改变;推测原因是温度愈高,药物分子振荡频率愈高,因而扩散出较多的量。在计量上,可随周围环境做调整,具发展成客制化之功能性隐形眼镜的潜力。
就浸药型的载药型隐形眼镜而言,在此所采用的药物分子为维生素-维他命B12(VitaminB12),此为一种亲水性药物,此药物分子为一抗恶性贫血因子,是一高度吸湿性的红色结晶粉末,易溶于水及酒精中,在遇光、强酸或碱中,略不稳定。试验结果如图7(a)及图7(b)所示,由图7(a)可证实,本发明所采用之具药物载体(CA)的载药型隐形眼镜释放亲水性药物(VitaminB12)速度缓慢于不具载体(free CA)的载药型隐形眼镜;此原因在于,本发明所采用的药物载体(CA),其混成壳层(core-shell)及多孔(大小约2-10nm,BET分析结果)结构扮演着调节药物释放的角色,可以减少包覆之药物分子随着高分子在水溶液中膨润现象的产生而扩散溢出。而随着药物分子浓度愈趋增加,其释放药物速度亦愈趋增快,如图7(b)所示,此原因在于,浓度愈高之药物分子于水中释放时,由于欲达到内外浓度差平衡,因此倾向释放更多药物分子。
影像分析:
由扫描式电子显微镜(scanning electron microscopy,SEM)可知:本发明所采用的有机无机的双性几丁聚醣及二氧化硅混成的纳米载体,其在水中进行自组装之后,所形成之粒子大小约为100nm,图8(a)所示。而图8(b)图所示则为CHC-silica纳米载体分散于本发明的载药型隐形眼镜的情形。
因此,本发明利用具有良好药物包覆能力和生物兼容性极高的纳米载体包覆药物或药物分子溶液浸泡,并使其均匀分散于隐形眼镜之中,使佩戴者得以利用其所配戴的载药型隐形眼镜进行局部药物释放,使药物分子可透过镜片缓慢释放,达到药物分子长期释放(>24h)至眼睛组织里,使药物的损失、对人体产生副作用机率降至最低,有助于减少漏药情形发生,确实可达到医疗、保健的目的。再者,本发明所使用的制程简单,使其应用更为广泛。
以上这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
Claims (13)
1.一种载药型隐形眼镜的制备方法,包括下列步骤:
将一药物分子溶液、双性混成纳米载体及隐形眼镜原料均匀搅拌成一混合溶液;
将该混合溶液喷涂至一隐形眼镜本体,使该隐形眼镜本体上形成一薄膜;以及
取得至少一载药型隐形眼镜。
2.如权利要求1所述的载药型隐形眼镜的制备方法,其特征在于,该药物分子溶液的制备方法更包括:
将药物分子与极性有机溶剂充分混合;以及
利用去离子水稀释至一预定药物分子浓度,以取得该药物分子溶液。
3.如权利要求2所述的载药型隐形眼镜的制备方法,其特征在于,该有机溶剂为乙醇(ethanol)、聚乙二醇(PEG)、聚丙二醇(PPG)、二甲基亚砜(DMSO)或四氢呋喃(THF)至少其中之一或其任意组合。
4.如权利要求2所述的载药型隐形眼镜的制备方法,其特征在于,该药物分子为维他命A、维他命B12、维他命C、维他命E、阿奇霉素(azithromycin)、氟米龙醋酸酯(fluorometholone facetate)、枯草杆菌(bacitracin)、新霉素(neomycin)、硫酸多粘菌素B(polymyxin B sulfate)、盐酸羟四环素(Oxytetracycline HCl)、红霉素(erythromycin)、地塞米松(dexamethasone)、乙酸培尼皮质醇(prednisolone acetate)、缩苹酸梯莫洛(timolol maleate)或皮质醇(hydrocortisone)。
5.如权利要求1所述的载药型隐形眼镜的制备方法,更包括:以一缓冲溶剂冲洗该载药型隐形眼镜。
6.如权利要求1所述的载药型隐形眼镜的制备方法,其特征在于,该双性混成纳米载体为有机无机的双性几丁聚醣及二氧化硅混成的纳米载体。
7.一种载药型隐形眼镜的制备方法,包括下列步骤:
将一双性混成纳米载体溶液及一隐形眼镜原料均匀搅拌成一混合溶液;
将该混合溶液注入至少一模具中,并进行照光固化成型,于脱模后即取得至少一载体式隐形眼镜;以及
将该载体式隐形眼镜浸泡于一药物分子溶液中,直至浓度达到动态平衡为止,以得到至少一载药型隐形眼镜。
8.如权利要求7所述的载药型隐形眼镜的制备方法,其特征在于,该药物分子溶液的制备方法更包括:
将药物分子溶解于极性有机溶剂或去离子水中。
9.如权利要求8所述的载药型隐形眼镜的制备方法,其特征在于,该有机溶剂为乙醇(ethanol)、聚乙二醇(PEG)、聚丙二醇(PPG)、二甲基亚砜(DMSO)或四氢呋喃(THF)至少其中之一或其任意组合。
10.如权利要求8所述的载药型隐形眼镜的制备方法,其特征在于,该药物分子为维他命A、维他命B12、维他命C、维他命E、阿奇霉素(azithromycin)、氟米龙醋酸酯(fluorometholone facetate)、枯草杆菌(bacitracin)、新霉素(neomycin)、硫酸多粘菌素B(polymyxin Bsulfate)、盐酸羟四环素(Oxytetracycline HCl)、红霉素(erythromycin)、地塞米松(dexamethasone)、乙酸培尼皮质醇(prednisolone acetate)、缩苹酸梯莫洛(timolol maleate)或皮质醇(hydrocortisone)。
11.如权利要求7所述的载药型隐形眼镜的制备方法,更包括:以一缓冲溶剂冲洗该载体式隐形眼镜。
12.如权利要求7所述的载药型隐形眼镜的制备方法,其特征在于,该双性混成纳米载体为有机无机的双性几丁聚醣及二氧化硅混成的纳米载体。
13.如权利要求7所述的载药型隐形眼镜的制备方法,其特征在于,该照光固化为紫外线照光固化。
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Patent Citations (2)
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CN1674841A (zh) * | 2002-06-05 | 2005-09-28 | 佛罗里达大学研究基金会有限公司 | 眼科给药体系 |
CN100369593C (zh) * | 2002-06-05 | 2008-02-20 | 佛罗里达大学研究基金会有限公司 | 眼科给药体系 |
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EP2805710A1 (en) | 2014-11-26 |
EP2543358A1 (en) | 2013-01-09 |
CN102778762A (zh) | 2012-11-14 |
TW201302244A (zh) | 2013-01-16 |
US8623400B2 (en) | 2014-01-07 |
US20130011460A1 (en) | 2013-01-10 |
EP2543358B1 (en) | 2015-04-29 |
EP2805710B1 (en) | 2018-04-18 |
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