CN115737668A - 一种甲钴胺眼用制剂及其应用 - Google Patents
一种甲钴胺眼用制剂及其应用 Download PDFInfo
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- CN115737668A CN115737668A CN202211423845.2A CN202211423845A CN115737668A CN 115737668 A CN115737668 A CN 115737668A CN 202211423845 A CN202211423845 A CN 202211423845A CN 115737668 A CN115737668 A CN 115737668A
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- mecobalamin
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- ophthalmic
- ophthalmic preparation
- eye
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Abstract
本发明提供了一种甲钴胺眼用制剂及其制备方法和应用,属于滴眼剂技术领域。本发明提供的甲钴胺眼用制剂成分包括甲钴胺原药和原花青素,所述甲钴胺原药与原花青素的质量比为0.02~0.1:0~0.5;所述甲钴胺眼用制剂的剂型为滴剂、水凝胶制剂和脂质体制剂中的一种或几种。本发明以甲钴胺作为活性成分,原花青素作为甲钴胺的协同剂,所得甲钴胺眼用制剂能够促进角膜神经再生、促进角膜上皮愈合,能够有效抑制角膜新生血管生成改善角膜知觉。本发明提供的甲钴胺眼用制剂解决了甲钴胺长期全身应用导致的并发症,弥补了角膜神经再生领域低价用药的空白,且增加了无创用药的选择范围,为神经营养性角膜炎的治疗提供了的新的选择。
Description
技术领域
本发明涉及眼用制剂技术领域,特别涉及一种甲钴胺眼用制剂及其应用。
背景技术
神经营养性角膜炎是周围性三叉神经麻痹时角膜上皮愈合障碍的一种变性疾病,属于一种严重的致盲性眼病。三叉神经麻痹可以发生由颅内手术、注射药物、肿瘤、颅骨骨折、感染等因素引起,也可以发生在中枢,并伴有面神经麻痹的相关症状神经营养性角膜炎。临床上按照严重程度分为泪膜异常及上皮改变期(Ⅰ期),持续性上皮缺损期(Ⅱ期)和角膜溃疡期(Ⅲ期)3个阶段。治疗原则是阻断角膜损伤进展。针对Ⅰ期轻度,临床给予眼部润滑剂(如不含防腐剂的人工泪液),停用有毒性眼用制剂;Ⅱ期中度,采用角膜绷带镜和单层羊膜移植或者自体血清滴眼;Ⅲ期重度,采用睑裂缝合、结膜瓣遮盖、多层羊膜移植等外科方式恢复眼表完整性。目前传统的治疗手段未能很好地解决角膜神经损伤的根本问题,均为对症治疗。在所有传统治疗无效后,角膜移植是最后的抢救选择,但是由于神经营养问题没有根本解决,角膜移植术后植片很难存活。
甲钴胺是维生素B12的衍生物,与非活性的维生素B12相比,甲钴胺更容易进入神经细胞器中。甲钴胺可参与物质的甲基转化反应及核酸、蛋白质和脂类代谢,促进神经细胞内核酸和蛋白质以及神经髓鞘的合成,从而修复受损伤的周围神经。鉴于甲钴胺具有良好的神经保护作用,目前临床已应用于青光眼、糖尿性视网膜病变、中心性浆液性脉络膜视网膜病变、视神经损伤、眼外肌麻痹等眼科疾病的治疗。
目前,使用甲钴胺治疗眼科疾病时,其剂型多为口服剂或注射剂。然而,甲钴胺的长期全身应用容易导致并发症,例如,长期口服甲钴胺会导致神经敏感性增加,患者会出现频繁性头痛,也会引起局部感觉异常,出现频繁性发热,甚至会导致出汗的症状。如果肌肉注射甲钴胺注射液会引起注射部位出现剧烈疼痛,而长期注射会导致局部发生血栓的可能性增大,从而可能会影响到正常的血液循环,最终会导致局部皮肤表面出现粗糙、干结,甚至皮肤发硬。
发明内容
有鉴于此,本发明目的在于提供一种甲钴胺眼用制剂,本发明提供的甲钴胺眼用制剂对于神经营养性角膜炎具有良好的疗效,且能够避免长期全身应用导致的并发症。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种甲钴胺眼用制剂,成分包括甲钴胺原药和原花青素,所述甲钴胺原药与原花青素的质量比为0.02~0.1:0~0.5;所述甲钴胺眼用制剂的剂型为滴剂、水凝胶制剂和脂质体制剂中的一种或几种。
优选的,当所述甲钴胺眼用制剂的剂型为滴剂时,包括以下百分含量的组分:
优选的,所述缓冲剂为透明质酸钠、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾和枸橼酸钠中的一种或几种。
优选的,所述渗透压调节剂为丙二醇、甘油和聚乙二醇中的一种或几种。
优选的,所述pH调节剂为枸橡酸、枸椽酸钠、硼酸、磷酸氢二钠、磷酸二氢钠、醋酸、醋酸钠、氢氧化钠和盐酸中的一种或几种。
优选的,当所述甲钴胺眼用制剂的剂型为水凝胶制剂时,包括以下百分含量的组分:
优选的,当所述甲钴胺眼用制剂的剂型为脂质体制剂时,包括以下百分含量的组分:
优选的,所述甲钴胺眼用制剂的pH值为6~8。
优选的,当所述甲钴胺眼用制剂的剂型为滴剂时,所述甲钴胺眼用制剂的渗透压摩尔浓度为260~320mOsm/kg。
本发明提供了上述甲钴胺眼用制剂在制备治疗神经营养性角膜炎药物中的应用。
本发明提供了一种甲钴胺眼用制剂,成分包括甲钴胺原药和原花青素,所述甲钴胺原药与原花青素的质量比为0.02~0.1:0~0.5;所述甲钴胺眼用制剂的剂型为滴剂、水凝胶制剂和脂质体制剂中的一种或几种。本发明以甲钴胺作为活性成分,甲钴胺是维生素B12的两种活化辅酶形式之一,甲钴胺可以增强神经元甲基化,加速神经细胞生长和降低同型半胱氨酸水平,具有良好的神经保护作用。本发明使用原花青素作为甲钴胺的协同剂,原花青素含有多种多酚类化合物,广泛存在于多种植物的花、树皮、果皮及种子中。目前原花青素已经被证实具有多种有益活性,其自身特异性的化学结构使其具有很强的抗氧化、抗菌、抗炎症及抗糖尿病等多种促健康活性。原花青素可以保护受损的视网膜神经节细胞、抑制视网膜新生血管。原花青素与甲钴胺协同作用,不仅可以加强对角膜神经的修复,而且可以进一步抑制角膜新生血管。本发明提供的甲钴胺眼用制剂能够促进角膜神经再生、促进角膜上皮愈合,能够有效抑制角膜新生血管生成改善角膜知觉。本发明提供的甲钴胺眼用制剂解决了甲钴胺长期全身应用导致的并发症,为神经营养性角膜炎的治疗提供了的新的选择,且成本低廉。
附图说明
图1为甲钴胺脂质体电镜照片;
图2为实验小鼠眼部大体照;
图3为角膜共聚焦激光显微镜成像结果。
具体实施方式
本发明提供了一种甲钴胺眼用制剂,成分包括甲钴胺原药和原花青素,所述甲钴胺原药与原花青素的质量比为0.02~0.1:0~0.5,优选为0.02~0.1:0.1~0.5,更优选为0.05~0.08:0.2~0.4;所述甲钴胺眼用制剂的剂型为滴剂、水凝胶制剂和脂质体制剂中的一种或几种。
在本发明中,所述甲钴胺眼用制剂的pH值优选为6~8,更优选为6.5~7.5。
在本发明中,当所述甲钴胺眼用制剂的剂型为滴剂时,包括以下百分含量的组分:
在本发明中,当所述甲钴胺眼用制剂的剂型为滴剂时,所述甲钴胺眼用制剂称为甲钴胺眼用滴剂。
以质量百分含量计,本发明提供的甲钴胺眼用滴剂包括0.02~0.1%的甲钴胺原药,优选为0.05~0.08%。在本发明中,所述甲钴胺原药的纯度优选为0.05%。本发明以甲钴胺作为活性成分,甲钴胺是维生素B12的两种活化辅酶形式之一,甲钴胺可以增强神经元甲基化,加速神经细胞生长和降低同型半胱氨酸水平,具有良好的神经保护作用。
以质量百分含量计,本发明提供的甲钴胺眼用滴剂包括0.1~0.5%的原花青素,优选为0.3~0.4%。在本发明中,原花青素是一种常见的植物提取物,含有多种多酚类化合物,广泛存在于多种植物的花、树皮、果皮及种子中。目前原花青素已经被证实具有多种有益活性,其自身特异性的化学结构使其具有很强的抗氧化、抗菌、抗炎症及抗糖尿病等多种促健康活性。原花青素可以保护受损的视网膜神经节细胞、抑制视网膜新生血管。
以质量百分含量计,本发明提供的甲钴胺眼用滴剂包括缓冲剂0.1~1.0%,优选为0.4~0.6%。在本发明中,所述缓冲剂优选为透明质酸钠、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾和枸橼酸钠中的一种或几种。在本发明中,所述缓冲剂起到的作用是减少刺激性、提高稳定性和增强疗效。
以质量百分含量计,本发明提供的甲钴胺眼用滴剂包括渗透压调节剂0.1~5.0%,优选为1.0~3.0%。在本发明中,所述渗透压调节剂优选为乙醇、丙二醇、甘油和聚乙二醇中的一种或几种。在本发明中,所述聚乙二醇的分子量优选为200~400。在本发明中,所述甲钴胺眼用滴剂的渗透压摩尔浓度优选为260~320mOsm/kg,更优选为280~300mOsm/kg。
以质量百分含量计,本发明提供的甲钴胺眼用滴剂包括pH值调节剂0.001~0.004%。在本发明中,所述pH调节剂优选为枸橡酸、枸椽酸钠、硼酸、磷酸氢二钠、磷酸二氢钠、醋酸、醋酸钠、氢氧化钠和盐酸中的一种或几种。
以质量百分含量计,本发明提供的甲钴胺眼用滴剂包括余量的注射用水。
在本发明中,所述甲钴胺眼用滴剂的制备方法,优选包括以下步骤:
将原花青素、缓冲剂、渗透压调节剂溶于部分注射用水中,再加入甲钴胺、pH调节剂和剩余注射用水,得到甲钴胺眼用滴剂。
在本发明中,所述部分注射用水与剩余注射用水的体积比优选为3~7:7:3,更优选为1:1。
在本发明中,当所述甲钴胺眼用制剂的剂型为水凝胶制剂时,包括以下百分含量的组分:
在本发明中,当所述甲钴胺眼用制剂的剂型为水凝胶制剂时,所述甲钴胺眼用制剂称为甲钴胺眼用水凝胶剂。
以质量百分含量计,本发明提供的甲钴胺眼用水凝胶剂包括0.02~0.1%的甲钴胺原药,优选为0.05~0.08%。在本发明中,所述甲钴胺原药的纯度优选为0.05%。
以质量百分含量计,本发明提供的甲钴胺眼用水凝胶剂包括0.1~0.5%的原花青素,优选为0.3~0.4%。
以质量百分含量计,本发明提供的甲钴胺眼用水凝胶剂包括4.5~5.5%的明胶,优选为5%。
以质量百分含量计,本发明提供的甲钴胺眼用水凝胶剂包括0.45~0.55%的羧甲基纤维素,优选为0.5%。
以质量百分含量计,本发明提供的甲钴胺眼用水凝胶剂包括0.17~0.18%的N-羟基磺基琥珀酰亚胺钠盐,优选为0.175%。
以质量百分含量计,本发明提供的甲钴胺眼用水凝胶剂包括余量的注射用水。
在本发明中,所述甲钴胺眼用水凝胶剂的制备方法,优选包括以下步骤:
将甲钴胺原药、原花青素、明胶与水超声混合,得到混合液;
将所述混合液与羧甲基纤维素、N-羟基磺基琥珀酰亚胺钠盐混合,进行交联反应,得到甲钴胺眼用水凝胶剂。
在本发明中,所述超声混合的功率优选为200~400W,更优选为300W;时间优选为20~30min,更优选为25min。
在本发明中,所述超声混合的温度优选为30~50℃,更优选为40℃。
在本发明中,所述交联反应的温度优选为室温,时间优选为1~2h,更优选为1.5h。
在本发明中,当所述甲钴胺眼用制剂的剂型为脂质体制剂时,包括以下百分含量的组分:
在本发明中,当所述甲钴胺眼用制剂的剂型为脂质体制剂时,所述甲钴胺眼用制剂称为甲钴胺眼用脂质体剂。
以质量百分含量计,本发明提供的甲钴胺眼用脂质体剂包括0.02~0.1%的甲钴胺原药,优选为0.05~0.08%。在本发明中,所述甲钴胺原药的纯度优选为0.05%。
以质量百分含量计,本发明提供的甲钴胺眼用脂质体剂包括0.1~0.5%的原花青素,优选为0.3~0.4%。
以质量百分含量计,本发明提供的甲钴胺眼用脂质体剂包括0.08~0.15%的卵磷脂,优选为0.1~0.12%。
以质量百分含量计,本发明提供的甲钴胺眼用脂质体剂包括0.02~0.05%的胆固醇,优选为0.03~0.04%。
以质量百分含量计,本发明提供的甲钴胺眼用脂质体剂包括余量的水。在本发明中,所述水优选为纯水。
在本发明中,所述甲钴胺眼用脂质体剂的制备方法,优选包括以下步骤:
将甲钴胺原药、原花青素、卵磷脂、胆固醇、有机溶剂超声混合,去除有机溶剂,得到脂质体薄膜;
将所述脂质体薄膜与缓冲溶液超声混合,进行固液分离,所得固体与水混合,微滤后得到甲钴胺眼用制剂。
在本发明中,所述有机溶剂优选为醇溶剂与氯仿的混合液,所述醇溶剂优选为甲醇和/或乙醇;在本发明中,所述醇溶剂和氯仿的体积比优选为1:3。
在本发明中,所述超声混合的功率优选为200W,时间优选为10min。
在本发明中,所述去除有机溶剂的方式优选为减压蒸馏。在本发明中,所述减压蒸馏优选在搅拌的条件下进行,所述搅拌的速率优选为100rpm。在本发明中,所述去除有机溶剂的温度优选为30℃。
在本发明中,所述缓冲溶液优选为PBS缓冲溶液。在本发明中,所述超声的优选为200W,时间优选为15~20min。
在本发明中,所述固液分离的方式优选为离心。
在本发明中,所述微滤使用的微滤膜的孔径优选为0.22μm。
本发明提供了上述甲钴胺眼用制剂在制备治疗神经营养性角膜炎药物中的应用。
下面结合实施例对本发明提供的甲钴胺眼用制剂及其应用进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
甲钴胺眼用滴剂的配方如下:
所述甲钴胺眼用制剂的pH值为6.5。
所述甲钴胺眼用滴剂的制备方法,包括以下步骤:
(1)将甲钴胺原药、原花青素、透明质酸钠、聚乙二醇400溶于0.5ml注射用水中;
(2)加入醋酸和0.5ml注射用水,搅拌均匀,调节pH值为6.0~8.0;过滤,灭菌后的药液检验合格后,在百级环境下,灌装0.3~0.5mL此药液至1mL单剂量避光包装塑料容器中,封口,即得成品甲钴胺眼用制剂。
实施例2
甲钴胺眼用水凝胶剂的配方如下:
所述甲钴胺眼用水凝胶剂的制备方法,包括以下步骤:
(1)向离心管中加入50mg明胶、0.5mg甲钴胺原药和5mg原花青素;
(2)向步骤(1)的离心管中加入1mL注射用水;
(3)将上述混合体系在30℃~50℃水浴下超声20min使其完全溶解,形成均匀溶液;
(4)向步骤(3)的离心管中加入4.5mg的羧甲基纤维素和1.8mg N-羟基磺基琥珀酰亚胺钠盐的催化剂;
(5)将步骤(4)中所得到的盛有混合溶液的离心管室温放置1h,得到甲钴胺眼用水凝胶剂。
实施例3
甲钴胺脂质体制剂的配方如下:
所述甲钴胺脂质体制剂的制备方法,包括以下步骤:
(1)向离心管中加入15mg卵磷脂、5mg胆固醇、7.5mg甲钴胺原药、1mg原花青素;
(2)向步骤(1)的离心管中加入10mL甲醇与氯仿的混合液(甲醇:氯仿=1:3);
(3)将上述混合体系在室温下超声10min使其完全溶解,形成均匀溶液,置于10mL圆底烧瓶中。在30℃恒温水浴锅内以100rpm转速进行减压蒸馏,除去油剂溶剂形成薄膜;
(4)将(3)圆底烧瓶置于真空干燥机中过夜,第二天加入10mL PBS缓冲液(pH=7.4)于37℃水浴锅旋转水合2小时,使脂质体脱膜;
(5)冰浴下探头超声2秒,间歇3秒,重复操作15-20min,功率200w;
(6)16000rpm离心40分钟,弃上清液后取沉淀物,加纯水15ml后超声30min,过孔径为0.22μm微孔滤膜,得到甲钴胺脂质体制剂。
所得甲钴胺脂质体制剂的电镜照片如图1所示。
对比例1
对照甲钴胺眼用滴剂的配方如下:
所述甲钴胺眼用制剂的pH值为6.0~8.0。
对照甲钴胺眼用滴剂的制备方法与实施例1相同。
性能测试
甲钴胺眼用制剂的动物实验如下:
(1)6~8周C57BL/6小鼠,雄性,体重20~25g,购自北京维通利华实验动物技术有限公司。在山东第一医科大学附属眼科研究所动物实验室进行动物饲养。温度控制在22±2℃,湿度控制在60±10%,12h明暗循环,给予自由饮食。
(2)实验分组:30只6~8周C57BL/6雄性小鼠(体重20~25g)随机分为5组,每组6只,分别为:
1.对照组
2.对照甲钴胺眼用滴剂点眼组(对比例1)
3.重组人神经营养因子滴眼剂点眼组
4.甲钴胺联合原花青素点眼组(实施例1)
5.甲钴胺水凝胶结膜下植入组(实施例2)
(3)小鼠神经营养不良性角膜炎模型
用6%戊巴比妥钠溶液(1ml/100g)对小鼠进行腹腔麻醉,侧卧位固定于手术台上,用Vannas剪刀沿颞侧角巩膜缘将球结膜周向切开90度,注意不要损伤眶后静脉丛。用无齿显微镊仔细分离筋膜、外直肌和结缔组织后,用无齿颞轻轻推动鼻结膜穹窿,将眼睛向鼻侧旋转约120度,注意不要损伤角膜,暴露视神经。三叉神经睫状神经分支位于靠近视神经处。旋转眼球后,在直接观察下,用锋利的镊子在靠近视神经的后巩膜处损伤睫状神经,整个过程中,不能伤到其他组织,复位球结膜。术毕涂氧氟沙星眼膏。
(4)模型处理
对照组每日PBS液点眼,每日4次;对照甲钴胺眼用滴剂点眼组每日甲钴胺滴眼液点眼,每日4次;重组人神经营养因子滴眼剂点眼组每日重组人神经营养因子滴眼液点眼,每日4次;甲钴胺联合原花青素点眼组每日点眼4次;甲钴胺水凝胶结膜下植入组,将约0.02mg的负载甲钴胺的水凝胶缓释材料植入结膜下。
(5)裂隙灯拍照
使用眼科检查用裂隙灯,在第7天拍摄具有代表性的眼部大体照。图2为实验小鼠眼部大体照。结果显示,对照组角膜基质混浊,部分角膜上皮缺损,新生血管比较明显,对照甲钴胺眼用滴剂点眼组、重组人神经生长因子点眼组、甲钴胺联合原花青素点眼组、甲钴胺水凝胶结膜下植入组小鼠的角膜新生血管不明显,证实该甲钴胺眼用制剂,促进了角膜上皮愈合,抑制了角膜新生血管的生成。表现为甲钴胺联合协同剂原花青素点眼组小鼠角膜新生血管面积降低、角膜上皮愈合,角膜透明度优于对照甲钴胺眼用滴剂的效果,并且治疗效果不弱于重组人神经生长因子滴眼液。在治疗过程中未发现明显副作用。
(6)取材
术后14天取材。断头法处死小鼠,迅速完整取出小鼠眼球,放入含4%甲醛的PBS中4℃固定15min。在解剖镜下修剪并去除多余的组织获得具有完整角巩缘结构的角膜组织,并放射状剪成4瓣或6瓣以便于角膜组织的平铺,放入含4%甲醛的PBS中4℃固定45min。将角膜在PBS中洗涤5次,10min/每次,在室温下用含20%山羊血清的封闭缓冲液(含0.3%Triton-X-100的PBS)透化封闭1小时。然后将角膜在β-tubulin III的封闭缓冲液中在室温下孵育2小时。再用PBS洗涤6次,10min/次,将角膜上皮朝上铺片,用含DAPI抗荧光淬灭缓冲甘油封片,避光保存,然后进行共聚焦激光显微镜成像。所得结果如图3所示。结果显示,对照组角膜神经末梢没有再生,对照甲钴胺滴眼剂点眼组、重组人神经生长因子点眼组、甲钴胺联合原花青素点眼组小鼠的角膜神经末梢均有再生,证实该甲钴胺眼用制剂促进了角膜神经末梢再生,并且甲钴胺联合协同剂原花青素点眼组再生神经的密度优于对照甲钴胺滴眼剂点眼组,再生神经形态优于重组人神经生长因子滴眼液点眼组。
以上所述仅是本发明的优选实施方式,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的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种甲钴胺眼用制剂,成分包括甲钴胺原药和原花青素,所述甲钴胺原药与原花青素的质量比为0.02~0.1:0~0.5;所述甲钴胺眼用制剂的剂型为滴剂、水凝胶制剂和脂质体制剂中的一种或几种。
3.根据权利要求2所述的甲钴胺眼用制剂,其特征在于,所述缓冲剂为透明质酸钠、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾和枸橼酸钠中的一种或几种。
4.根据权利要求2所述的甲钴胺眼用制剂,其特征在于,所述渗透压调节剂为丙二醇、甘油和聚乙二醇中的一种或几种。
5.根据权利要求2所述的甲钴胺眼用制剂,其特征在于,所述pH调节剂为枸橡酸、枸椽酸钠、硼酸、磷酸氢二钠、磷酸二氢钠、醋酸、醋酸钠、氢氧化钠和盐酸中的一种或几种。
8.根据权利要求1所述的甲钴胺眼用制剂,其特征在于,所述甲钴胺眼用制剂的pH值为6~8。
9.根据权利要求1所述的甲钴胺眼用制剂,其特征在于,当所述甲钴胺眼用制剂的剂型为滴剂时,所述甲钴胺眼用制剂的渗透压摩尔浓度为260~320mOsm/kg。
10.权利要求1~9任意一项所述甲钴胺眼用制剂在制备治疗神经营养性角膜炎药物中的应用。
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