CN111443050A - 一种糖胺聚糖制剂中溶出曲线检测的新方法 - Google Patents
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Abstract
本发明的目的在于提供一种检测速度快，灵敏度好，准确度高，重现性好，特别是针对糖胺聚糖制剂溶出曲线的检测方法。可使糖胺聚糖制剂的溶出曲线检测能够简单快速准确的获得结果，从而提高处方优化的效率。开发出如下检测新方法：糖胺聚糖与碱性染料反应，对染料的光吸收有影响，选择648nm作为检测波长，采用对照品外标法计算溶出量。本发明检测速度快，准确度高，重现性好，操作简单。
Description
技术领域
本发明涉及一种糖胺聚糖制剂中溶出曲线检测的方法，属于多组分生化药分析技术领域。
背景技术
糖胺聚糖是一种天然提取的多糖类物质，主要作用是抗血栓，对动脉和静脉均有较强的抗血栓形成作用。适用于治疗有血栓形成危险的血管疾病。其药理作用有：抗凝，Xa因子抑制剂；抗血小板聚集；溶栓，IIa因子抑制剂(通过肝素因子II(HCII)作用于与纤维蛋白结合的凝血酶，降解已形成的血栓)；降血脂，通过降低高血纤维蛋白原和极低密度脂蛋白浓度而改善血液循环，使有血栓形成危险的血管病变病人的血粘度参数恢复正常。临床用于预防动脉粥样硬化(降血脂)；防治心血管疾病；治疗深静脉血栓；治疗下肢静脉溃疡；治疗间歇性跛行；治疗糖尿病肾病；腹膜透析。
以糖胺聚糖为原料制成的口服制剂的溶出曲线检测是重要的质量属性，尤其在处方开发过程中，与对照药品的溶出曲线比对是必须要进行的，但其检测存在难度。原因在于：溶出曲线测定时样品量大，以6粒样品，每粒样品取样时间点为6个来计算，一条曲线的样品量高达36个；测定精度要求高，因低时间点的溶出量低。糖胺聚糖多以效价来定量，但效价测定存在着检测周期长，检测误差大等问题，因而不适合测定口服制剂的溶出曲线的测定。
糖胺聚糖硫酸基和羧基含量高，是已知负电荷密度最高的生物大分子，能与碱性染料反应，对染料的光吸收有影响。能使含氨基的碱性染料如1，9-二甲基亚甲蓝等的光吸收向短波移动，因此产生吸收光谱的变化。有文献报道，采用520nm作为检测波长进行检测，经过光谱扫描和线性实验的筛选，选择648nm做为检测波长，外标法测定溶液中的溶出度。该方法检测速度快，灵敏度好，准确度高，吸光度值符合紫外检测的一般要求。
发明内容
本发明的目的在于提供一种检测速度快，灵敏度好，准确度高，重现性好，特别是针对糖胺聚糖制剂溶出曲线的检测方法。可使糖胺聚糖制剂的溶出曲线检测能够简单快速准确的获得结果，从而提高处方优化的效率。
本发明的测定方法如下步骤所示：
(1)供试品溶液的制备
量取水500ml，置于溶出杯中，设置温度37℃，桨法，转速50转每分钟，分别于5分钟、10分钟、15分钟、30分钟、45分钟、60分钟取样，弃去初滤液，取续滤液，作为供试品溶液。
(2)对照品溶液的制备
取糖胺聚糖对照品约25mg，精密称定，加水溶解并稀释至200ml，作为对照品溶液。
(3)显色剂配制
称取1，9-二甲基亚甲蓝约100mg，加乙醇溶解并稀释至100ml；精密量取10ml，置于1000ml量瓶中，加吐温80 1.0ml，加枸橼酸缓冲液(pH3.5)(取0.1mol/L枸橼酸缓冲液500ml，用0.2mol/L磷酸氢二钠溶液调节pH值至3.5)溶解并稀释至刻度，滤过即得。
备注：该溶液需避光保存。
(4)光谱条件
仪器：UV2550紫外可见分光光度计
检测波长：648nm；
(5)样品检测
分别取水、对照品溶液和供试品溶液各0.3ml，加显色剂5ml，混匀，检测吸光度，空白吸光度减去样品吸光度，外标法计算供试品溶液中糖胺聚糖的浓度。
附图说明
图1为水0.3ml与显色剂5ml反应400～800nm光谱图。
图2为对照品溶液0.3ml与显色剂5ml反应400～800nm光谱图。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述，给出的实施例仅为阐明本发明，而不是限制本发明的范围。
实施例1：检测波长的选择
取糖胺聚糖原料25mg，加水稀释至100ml，作为200％线性储备溶液，分别精密量取200％线性储备溶液各0.25ml、0.5ml、1.0ml、2.0ml、3.0ml、4.0ml、5.0ml、6.0ml、7.0ml置于不同10ml量瓶中，分别加水稀释至刻度，分别得5％、10％、20％、40％、60％、80％、100％、120％、140％的线性对照品溶液。分别精密量取水及线性对照品溶液各0.3ml，加入显色剂5ml，分别进行400～800nm紫外扫描。选择535nm、595nm、648nm三个明显吸收波峰，记录其吸光度，扣除空白后分别对浓度与吸光度进行线性回归计算，具体结果见表1。
表1检测波长选择线性结果
以上数据结果表明：535nm、648nm吸光度与浓度的相关线性系数均大于0.995，线性关系良好，但是535nm初始的吸光度偏低，均在0.1～0.3，648nm供试品的吸光度在0.2～0.6，而紫外检测的吸光度值应在0.2～0.7为宜，因此选择648nm作为最终的检测波长。
实施例2：方法学验证
(1)专属性：取制剂空白辅料，置于溶出杯中，加水500ml，设置温度37℃，桨法，转速50转每分钟，于60分钟取样，过滤，精密量取续滤液0.3ml与显色剂5ml反应，同时取水0.3ml与显色剂5ml反应，二者648nm的吸光度值分别为0.557、0.554，吸光度几乎无差别，说明空白辅料不影响显色反应，专属性良好。
(2)溶液稳定性：取对照品溶液分别于0小时、1小时、4小时、6小时取0.3ml与显色剂5ml反应，吸光度分别为0.226、0.225、0.227、0.228，说明对照品溶液6小时内溶液稳定性良好。
(3)线性：按实施例1中方法，648nm下浓度与吸光度值的相关系数为0.999，线性方程为y＝0.2518x-0.0039，线性关系良好。
(4)准确度：取对照品，加入处方量辅料，加水适量，搅拌，过滤，精密量取续滤液0.3ml与显色剂5ml反应，同法配制6份，同时配制对照品溶液进行准确度计算，准确度分别为98.7％、100.8％、99.2％、102.0％、99.3％、101.0％，说明方法准确度良好。
Claims (3)
1.一种测定糖胺聚糖制剂溶出曲线的检测方法，采用1，9-二甲基亚甲蓝溶液作为显色剂，以糖胺聚糖对照品配制对照品溶液，以制剂样品进行溶出曲线测定，采用紫外可见分光光度法检测，其特征在于：检测波长为600-700nm，溶出曲线样品加入量为0.1ml-0.5ml，显色剂加入量为4-6ml。
2.权利要求1所述检测方法，其特征在于，检测波长为648nm，溶出曲线样品加入量为0.3ml，显色剂加入量为5ml。
3.权利要求1所述检测方法，其特征在于，利用紫外可见分光光度法，按外标法以吸光度计算制剂样品的溶出度，绘制溶出曲线。
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