CN109238995B - 一种测定交联透明质酸凝胶体外酶解性能的方法 - Google Patents
一种测定交联透明质酸凝胶体外酶解性能的方法 Download PDFInfo
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- CN109238995B CN109238995B CN201810999774.8A CN201810999774A CN109238995B CN 109238995 B CN109238995 B CN 109238995B CN 201810999774 A CN201810999774 A CN 201810999774A CN 109238995 B CN109238995 B CN 109238995B
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- enzymolysis
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- hyaluronic acid
- hyaluronidase
- absorbance
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 124
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Abstract
本发明公开了一种测定交联透明质酸凝胶体外酶解性能的方法，该方法以细菌透明质酸酶酶解交联透明质酸凝胶，然后采用紫外‑可见分光光度法测定酶解过程中产生的酶解液，通过吸光度测定交联透明质酸凝胶的体外酶解性能及酶解率。本方法根据不同透明质酸酶对透明质酸降解产物的不同，选择降解产物能够被紫外检测到的细菌透明质酸酶为降解酶，酶解后无须过滤除去未降解的交联透明质酸凝胶颗粒，也无须加热灭活透明质酸酶，直接通过紫外‑可见分光光度法即可实现降解率的快速检测。本发明方法简便、快速、耗时短、花费低、可重复性高，既可以通过计算酶解率来进行单一交联HA产品的质量控制，也可以通过酶解时间来进行不同交联HA产品之间的性能比较。
Description
技术领域
本发明涉及一种测定交联透明质酸凝胶体外酶解性能的方法，属于交联透明质酸检测技术领域。
背景技术
透明质酸(HA)是由(1→3)-2-乙酰氨基-2-脱氧-β-D-葡萄糖-(1→4)-O-β-D-葡糖醛酸双糖重复单位所组成的直链多聚糖，广泛存在于人体组织中。HA在体内容易受到透明质酸酶的作用而迅速降解，体内存留时间短。为了延长其体内持续时间，常将透明质酸进行交联，常用的交联剂有1,4-丁二醇二缩水甘油醚(BDDE)、二乙烯基砜(DVS)等。目前国内外市场上已有多种交联HA产品上市，产品涉及美容整形、隔离防护、眼科手术、关节腔注射、手术防护等领域。
交联HA在体内最终都会被机体降解吸收，但是其降解速度远远慢于非交联HA。交联HA在体内降解主要是受体内透明质酸酶的影响。一般的，HA交联程度越高，抗酶解能力越强，降解越慢。因此交联HA的降解性质是反映HA交联程度、体内维持时间以及安全性的一个关键参数。由于在体内研究交联HA降解性质费时费力，不利于作为交联HA的质控指标，因此迫切需要一种简便快速，能侧面反映交联HA体内降解性质的测定交联HA体外酶解性能的方法。
专利CN105572062A描述了一种交联透明质酸钠凝胶体外酶解率的检测方法，该方法是将交联透明质酸钠凝胶通过体外透明质酸酶酶解，酶解后滤去剩余的凝胶颗粒，对滤液进行糖醛酸含量检测来计算酶解率。该方法酶解时间长，酶解50％需要10h以上，过滤过程容易产生误差，糖醛酸含量检测也较繁琐。
专利CN102495154B描述了一种水相凝胶渗透色谱法检测交联透明质酸体外酶解的方法，该方法将微小颗粒状的交联透明质酸用透明质酸酶进行酶解，通过检测透明质酸酶解后的分子量变化来确定交联透明质酸是否酶解完全。该方法操作过程中需要使用水相凝胶渗透色谱(GPC)检测分子量变化，操作繁琐、成本高，且该方法仅适合于交联剂为1，2,7,8-二环氧辛烷的交联透明质酸，对于其他交联剂没有涉及。
专利CN102323344B提供了一种对高分子透明质酸钠降解产生的透明质酸片段发生的结构变化进行定量检测的方法，该方法分别采用高效液相色谱法和咔唑法同时测定透明质酸片段的含量，并利用其差值对不同方法制备的透明质酸片段的结构变化进行定量。该方法采用高效液相色谱法，成本较高。
从上述现有技术可以看出，目前测定交联HA体外酶解性能的方法大多还是存在操作繁琐、耗时长、成本高等缺陷。目前尚没有一种简便、快捷、成本低的方法来检测交联透明质酸凝胶体外降解情况。
发明内容
为了解决现有技术中存在的不足，本发明提供了一种测定交联透明质酸凝胶体外酶解性能的方法，该方法使用细菌透明质酸酶为降解酶，通过紫外-可见分光光度法测定交联透明质酸凝胶的体外酶解情况，简便、快速、可重复性高、成本低，适用于交联透明质酸凝胶的质量控制和不同交联透明质酸产品之间的性能比较。
1971年，Meyer根据透明质酸酶作用机制的不同，将透明质酸酶分为三类：第一类为内切β-N-乙酰氨基葡萄糖苷酶，主要来源于动物睾丸、溶酶体、下颌腺等，其作用于β-1,4糖苷键，HA为底物时降解终产物为四糖；第二类为细菌透明质酸酶，也称为HA裂解酶，该酶作用于β-1,4糖苷键，通过β消除反应断裂β-1,4糖苷键得到4,5-不饱和双糖结构；第三类为内β-葡萄糖醛酸苷酶，可以从水蛭唾液腺和十二指肠虫体内获得，该酶作用于β-1,3糖苷键，降解HA的终产物为四糖和六糖。经过研究发现，当采用细菌透明质酸酶对交联HA进行酶解时，酶解产物中的不饱和双糖单位能够在波长232nm处有吸收，通过紫外法检测降解产物的吸光度可以反映不同时间段的交联透明质酸凝胶降解情况，也可以对比不同交联透明质酸产品之间的降解情况差异，简便易行。当降解完全后，降解产物的吸光度趋于稳定。
根据上述机理，本发明提供了一种测定交联透明质酸凝胶体外酶解性能的方法，该方法包括以细菌透明质酸酶酶解交联透明质酸凝胶，然后采用紫外-可见分光光度法测定酶解过程中产生的酶解液的步骤。
进一步的，所述细菌透明质酸酶是一种透明质酸裂解酶，是能够将透明质酸降解产生4,5-不饱和双键结构的透明质酸酶。优选的，所述细菌透明质酸酶为申请人自行研发的细菌透明质酸酶，该细菌透明质酸酶可以由保藏号为CGMCC No.5744的芽孢杆菌发酵制得，即保藏号为CGMCC No.5744的芽孢杆菌的发酵产物，也可以根据专利CN201210499375.8中提到的氨基酸序列通过人工合成得到，其氨基酸序列如SEQ ID NO:1所示。
进一步的，上述方法中，采用紫外-可见分光光度法测定酶解过程中产生的酶解液，通过吸光度测定交联透明质酸凝胶的体外酶解性能及酶解率。所述的紫外-可见分光光度法，是指采用紫外分光光度计测定酶解过程中产生的酶解液的吸光度。测定吸光度时，选择波长在232nm处的吸光度。
进一步的，所述酶解过程中产生的酶解液指的是从透明质酸酶加入开始到最终酶解结束的时间段中任意时间点产生的酶解液，例如透明质酸酶加入的时间为t0，酶解结束的时间为tm，酶解液指的即为在t0～tm时间范围内任意时间点酶解产生的酶解液。通过检测不同时间点的酶解液的吸光度，可以反映出交联透明质酸凝胶产品在体外的酶解情况，既可以用于单一交联透明质酸凝胶产品的质量控制，又可以用于不同交联透明质酸凝胶产品之间的性能比较。
进一步的，本发明方法通过吸光度计算酶解率，酶解率＝At/Ae，其中At为各时间点的吸光度值，Ae为酶解终点的吸光度值。当检测得到的吸光度稳定时，将出现吸光度稳定值的第一个时间点视为酶解终点。
进一步的，本发明方法可以适合于多种交联剂制得的交联透明质酸凝胶，所述交联剂可以为1,4-丁二醇二缩水甘油醚(BDDE)、二乙烯基砜(DVS)、碳二亚胺、聚乙二醇类或氨基酸类。所述聚乙二醇类交联剂包括聚乙二醇二缩水甘油醚、四臂星形聚乙二醇环氧化物等，所述氨基酸类交联剂包括L-赖氨酸、L-精氨酸等。
进一步的，用细菌透明质酸酶酶解交联透明质酸凝胶时，所用的酶解介质为磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、生理盐水、磷酸二氢钾-氢氧化钠-氯化钠缓冲液、磷酸二氢钾-磷酸氢二钾-氯化钠缓冲液、添加0.01％氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01％氯化钙的生理盐水中的一种，其中优选为磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、生理盐水、添加0.01％氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01％氯化钙的生理盐水，最优选为添加0.01％的氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01％的氯化钙的生理盐水。该酶解介质的pH为6.0-7.5，优选pH为6.5。当酶解介质选择以上介质时，因为溶液体系中含有氯离子、钠离子、磷酸盐离子、钙离子，这些离子对本酶解反应均有促进作用，特别是钙离子的加入，能大幅提高酶解速率；同时该体系渗透压与人体和交联HA凝胶都等渗，能更好的反应交联HA凝胶的体内酶解性能。
进一步的，酶解温度为37-45℃，优选为37-42℃，最优选为42℃。
进一步的，本发明测定交联透明质酸凝胶体外酶解性能的方法包括以下具体步骤：
(1)取细菌透明质酸酶，用酶解介质配制成酶液。
(2)将交联透明质酸凝胶与酶解介质混合均匀，然后加入步骤(1)的酶液，混合均匀；
(3)将步骤(2)的混合液在酶解温度下进行酶解，设定取样时间点，每个时间点得到的酶解液用紫外分光光度计测定232nm处吸光度。
进一步的，每个时间点的间隔可以根据需求进行调整和选择，优选每个取样时间点的各间隔时间相同。当检测得到的吸光度稳定时，将出现吸光度稳定值的第一个时间点视为酶解终点。各时间点的吸光度(At)/酶解终点的吸光度(Ae)即为各时间点的酶解率。
进一步的，步骤(1)中，所述酶解介质如上所述，优选为磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、生理盐水、添加0.01％氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01％氯化钙的生理盐水，最优选为添加0.01％的氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01％的氯化钙的生理盐水。酶解pH为5.0-8.0，优选为6.0-7.5，最优选pH为6.5。所述酶液中细菌透明质酸酶的浓度为300IU/mL～1500IU/mL。
进一步的，步骤(2)中，交联透明质酸和细菌透明质酸酶的用量关系为1mg透明质酸对应细菌透明质酸酶75IU–375IU。
进一步的，步骤(3)中，酶解温度为37-45℃，优选为37-42℃，最优选为42℃。
进一步的，控制酶液的浓度、酶与交联透明质酸的用量关系、酶解温度等参数，控制达到酶解终点的时间为1-3h，以便于各交联透明质酸凝胶产品之间的比较。
本发明具有以下优点：
本方法根据不同透明质酸酶对透明质酸降解产物的不同，选择降解产物能够被紫外检测到的细菌透明质酸酶为降解酶，酶解后无须过滤除去未降解的交联透明质酸凝胶颗粒，也无须加热灭活透明质酸酶，直接通过紫外-可见分光光度法即可实现降解率的快速检测。本发明方法简便、快速、耗时短、花费低、可重复性高，既可以通过计算酶解率来进行单一交联HA产品的质量控制，也可以通过酶解时间来进行不同交联HA产品之间的性能比较。
附图说明
图1为不同交联透明质酸凝胶的体外酶解情况图。
具体实施方式
下面结合实施例和附图对本发明做进一步说明，但本发明不受下述实施例的限制。
实施例1酶的种类筛选
分别将①HA动物酶(源于牛睾丸，H3506，Sigma Aldrich)、②市售细菌HA酶(56177-10MG，SigmaAldrich)和③自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)用磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 7.0)配制成1200IU/mL的酶液，称取交联HA凝胶(交联剂BDDE，HA含量20mg/mL)0.4g(称量量相当于HA含量8mg)，每种酶平行两份，加入磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 7.0)2mL，涡旋混匀，再加入配制好的酶液2mL，涡旋10s。混合液置于42℃水浴。自置于水浴之后开始计时，每隔10min取样50μL供试液，供试液加入3mL磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 7.0)稀释，立即使用紫外分光光度计测定232nm处吸光度，以磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 7.0)作空白对照，记录交联HA凝胶在不同酶中的每个时间点的吸光度，结果见下表1。
表1
| HA酶 | 10min | 20min | 30min | 40min | 50min | 60min | 70min | 80min | 90min |
| ① | 0.007 | 0.006 | 0.008 | - | - | - | - | - | - |
| ② | 0.018 | 0.035 | 0.033 | 0.039 | 0.047 | 0.050 | 0.062 | 0.064 | 0.071 |
| ③ | 0.118 | 0.188 | 0.248 | 0.281 | 0.297 | 0.311 | 0.323 | 0.350 | 0.351 |
续表1
| HA酶 | 100min | 110min | 120min | 130min | 140min | 150min | 180min | 210min | 240min |
| ① | - | - | - | - | - | - | - | - | - |
| ② | 0.081 | 0.093 | 0.082 | 0.090 | 0.091 | 0.096 | 0.104 | 0.111 | 0.120 |
| ③ | 0.351 | - | - | - | - | - | - | - | - |
由表1可见，HA动物酶的酶解产物在232nm处没有吸收；市售细菌HA酶的酶解产物虽然在232nm处有吸收，但是吸光度较低，误差大，且相同酶活情况下4h时仍然没有酶解完全，耗时较长；而自制细菌HA酶的酶解产物在232nm处有吸收，且吸光度较高，在相同酶活条件下，酶解时间适宜，数据稳定，酶解条件易控。因此，细菌HA酶的酶解产物可以采用紫外-可见吸光光度法来测定降解率，优选使用自制细菌HA酶时效果最佳。
实施例2酶解介质和pH的筛选
配制不同pH值的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(PBS)，pH分别为5.0、5.5、6.0、6.5、7.0、7.5、8.0，将自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)用上述酶解介质分别配制成1200IU/mL的酶液，称取交联HA凝胶(交联剂BDDE，HA含量20mg/mL)0.4g(称量量相当于HA含量8mg)，每种酶解介质平行两份，加入酶解介质2mL，涡旋混匀，再加入配制好的酶液2mL，涡旋10s。混合液置于42℃水浴。自置于水浴之后开始计时，每隔10min取样50μL供试液，供试液加入3mL酶解介质稀释，立即使用紫外分光光度计测定232nm处吸光度，以对应的酶解介质作空白对照，记录交联HA凝胶在不同pH的酶解介质中酶解完全所用时间，结果见下表2。
表2
由表2可见，自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)适宜的pH范围较宽，酶解介质在pH 5.0-8.0范围内均可，当pH在6.0-7.5之间时能在1-3h内酶解完全，其中pH 6.5时酶解最快。酶解时间过长，浪费时间，酶解时间过短，不利于各产品之间酶解性能的比较，因此优选酶解时间为1-3h，优选pH为6.0-7.5。
取pH均为7.0的①磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、②生理盐水、③磷酸氢二钠-磷酸二氢钠缓冲液、④添加0.01％氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、⑤添加0.01％氯化钙的生理盐水、⑥磷酸二氢钾-氢氧化钠-氯化钠缓冲液、⑦磷酸二氢钾-磷酸氢二钾-氯化钠缓冲液、⑧磷酸氢二钠-柠檬酸-氯化钠缓冲液、⑨巴比妥钠-盐酸-氯化钠缓冲液、⑩纯化水，将自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)用上述酶解介质分别配制成1200IU/mL的酶液，称取交联HA凝胶(交联剂BDDE，HA含量20mg/mL)0.4g(称量量相当于HA含量8mg)，每种酶解介质平行两份，加入酶解介质2mL，涡旋混匀，再加入配制好的酶液2mL，涡旋10s。混合液置于42℃水浴。自置于水浴之后开始计时，每隔10min取样50μL供试液，供试液加入3mL酶解介质稀释，立即使用紫外分光光度计测定232nm处吸光度，以对应的酶解介质作空白对照，记录交联HA凝胶在不同酶解介质中酶解完全所用时间和每个时间点的吸光度，结果见下表3和4。
表3
表4
续表4
由表3和表4可见，因为加入⑩纯化水后交联HA凝胶立即吸水膨胀，膨胀后的凝胶不能很好的反应和预测交联HA在体内的酶解性能指标，因此不选择纯化水作为酶解介质；③磷酸氢二钠-磷酸二氢钠缓冲液也因为渗透压太低，交联HA凝胶也一定程度的吸水膨胀，导致紫外吸光度不稳定，也不适合作为酶解介质。⑧磷酸氢二钠-柠檬酸-氯化钠缓冲液酶解完全时间超过4h，时间过长，这可能是柠檬酸对酶解有抑制作用。⑨巴比妥钠-盐酸-氯化钠缓冲液数据反常，可能是巴比妥在232nm处也有吸光度造成干扰。①磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、②生理盐水、④添加0.01％氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、⑤添加0.01％氯化钙的生理盐水、⑥磷酸二氢钾-氢氧化钠-氯化钠缓冲液、⑦磷酸二氢钾-磷酸氢二钾-氯化钠缓冲液做酶解介质时，酶解时间均在1-3h内，这是因为氯离子、钠离子、磷酸盐离子、钙离子这些离子对本酶解反应均有促进作用，而当选择④和⑤作为介质时，酶解时间最短，这是因为钙离子的促进作用更强。
①磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、②生理盐水、④添加0.01％氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、⑤添加0.01％氯化钙的生理盐水做介质时，数据稳定，酶解时间更适宜，因此优选这四个介质做酶解介质，其中最优选④和⑤。
实施例3酶解温度筛选
将自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)用生理盐水配制成1200IU/mL的酶液。称取交联HA凝胶(交联剂BDDE，HA含量20mg/mL)0.4g(称量量相当于HA含量8mg)，每个温度平行两份，加入生理盐水2mL，涡旋混匀，再加入配制好的酶液2mL，涡旋10s。混合液分别置于37℃、42℃、45℃水浴。自置于水浴之后开始计时，每隔10min取样50μL供试液，供试液加入3mL生理盐水稀释，立即使用紫外分光光度计测定232nm处吸光度，以生理盐水作空白对照。记录不同温度下每个时间点的吸光度，结果见下表5。
表5
续表5
由表5可见，相同条件下，在37℃、42℃和45℃下均能在2h以内将产品降解完全，但是42℃时自制细菌HA酶的酶解速度最快，因此选择42℃为最优酶解温度。
实施例4酶的浓度及酶的用量筛选
将自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)，用生理盐水配制成不同浓度的酶液，酶的浓度分别为100IU/mL、200IU/mL、300IU/mL、500IU/mL、700IU/mL、900IU/mL、1100IU/mL、1300IU/mL、1500IU/mL、1700IU/mL。称取交联HA凝胶(交联剂BDDE，HA含量20mg/mL)0.4g(称量量相当于HA含量8mg)，每个浓度平行两份，加入生理盐水2mL，涡旋混匀，再加入配制好的酶液2mL，涡旋10s。混合液置于42℃水浴。自置于水浴之后开始计时，每隔10min取样50μL供试液，供试液加入3mL生理盐水稀释，立即使用紫外分光光度计测定232nm处吸光度，以生理盐水作空白对照。记录酶解完全所用时间，结果见下表6。
表6
由表6可见，酶浓度为100IU/mL时，完全酶解需要4小时，时间过长，不利于紫外可见分光光度计的读数稳定；酶浓度为1700IU/mL时，酶解时间过短，造成产品之间酶解时间差异太小，不利于比较。综合考虑，选择酶浓度在300～1500IU/mL之间，酶与底物HA量的关系为75-375IU/mg之间，这样酶解时间适中(1～3h之内)。
实施例5单一产品的体外酶解率测定
将自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)用磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 6.5)配制成500IU/mL的酶液。称取交联HA凝胶(交联剂BDDE，HA含量20mg/mL)0.4g(称量量相当于HA含量8mg)，平行三份，加入磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 6.5)2mL，涡旋混匀，再加入配制好的酶液2mL，涡旋10s。混合液置于42℃水浴。自置于水浴之后开始计时，每隔30min取样50μL供试液，供试液加入4mL磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 6.5)稀释，立即使用紫外分光光度计测定232nm处吸光度，以磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液(pH 6.5)作空白对照。
按照下式计算酶解率：
酶解率(％)＝At/Ae×100％，
其中At为各时间点的吸光度值，Ae为酶解终点的吸光度值。
最终酶解率取三份的平均值。
酶解率结果见下表7。
表7
| 时间(min) | 30 | 60 | 90 | 120 | 150 |
| 酶解率(％) | 25.5 | 43.7 | 76.3 | 92.7 | 100 |
实施例6不同交联透明质酸凝胶产品的体外酶解性能比较
将自制细菌HA酶(源自芽孢杆菌CGMCC No.5744，华熙福瑞达生物医药)用生理盐水配制成1000IU/mL的酶液。称取5种不同的交联HA凝胶样品各适量，将各交联HA凝胶样品分别加入生理盐水2mL，涡旋混匀，再分别加入配制好的酶液2mL，涡旋10s。混合液置于42℃水浴。自置于水浴之后开始计时，每隔10min取样50μL供试液，供试液加入5mL生理盐水稀释，立即使用紫外分光光度计测定232nm处吸光度，以生理盐水作空白对照，直至吸光度稳定视为酶解终点，将出现吸光度稳定值的第一个时间点定为产品体外完全酶解的时间。记录每一时间点的吸光度，以吸光度对时间作图，比较五种产品的体外酶解性能。五种交联透明质酸凝胶信息见下表8，五种交联透明质酸凝胶体外酶解情况见图1。
从图1可以看出，HA-5降解最快，60min、70min和80min时的吸光度相近，即吸光度趋于稳定，所以HA-5的体外完全酶解时间为60min；HA-2和HA-3降解速率相当，体外完全酶解时间为80min；HA-1约90min后吸光度稳定；HA-4降解最慢，体外完全酶解时间为110min。通过降解曲线上升阶段的斜率可以比较每种产品的降解速率，斜率越大，降解速率越快。通过比较可以看出，采用聚乙二醇类交联剂所得的交联透明质酸凝胶的抗酶解能力最强。
表8
序列表
<110> 华熙福瑞达生物医药有限公司、山东华熙海御生物医药有限公司
<120> 一种测定交联透明质酸凝胶体外酶解性能的方法
<160> 1
<170> SIPOSequenceListing 1.0
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<212> PRT
<213> Artificial Sequence
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Val Lys Thr Pro Ala Asn Ala Asp Ser Ile Arg Val Gln Leu Phe Phe
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Ala Ser Ser Lys Val Ser Trp Val Ser Ala Asp Pro Ser Ile Ala Thr
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Val Asp Asn Gly Lys Val Thr Gly Val Asn Pro Gly Gly Thr Thr Ile
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Met Ala Phe Thr Asp Asn Gly Leu Ala Ala Thr Ser Thr Val Lys Val
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Ile Lys Asn Asp Gly Ile Glu Arg Pro Glu Val Thr Gln Leu Asp Leu
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Gln Pro Lys Glu Leu Glu Leu Gly Ser Gly Gln Val Arg Leu Leu Gln
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Ala Ile Ile Ala Pro Ala Thr Ala Asp Ala Glu Lys Leu Val Trp Ser
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Ser Ser Asn Glu Ala Val Ala Ser Ile Gln Lys Gly Leu Ile Glu Ala
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Lys Ala Ser Gly Thr Ala Val Ile Thr Val Glu Thr Glu Asp Gly Ser
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Leu Lys Ser Glu Ser Gln Ile Thr Val Thr Asp Ala Val Val Asp Glu
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Tyr Asp Gln Leu Arg Lys Lys Trp Lys Ser Leu Met Thr Gly Leu Asp
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Ser Tyr Asp Pro Thr Asn Val Arg Met Asn Glu Met Ile Gln Asn Gln
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Arg Ser Phe Leu Trp Ile Asn Phe Ala Ser Thr Asp Asn Ser Ala Asp
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Ile Arg Asp Ser Tyr Arg Asn Leu Thr Thr Met Ala Lys Ala Phe Ala
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Asn Glu His Ser Ser Leu Tyr Arg Asn Pro Gln Leu Leu Lys Asp Ile
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Val Gln His Glu Asn Ile Ala Tyr Asn Gly Ser Tyr Gly Ile Val Leu
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Ile Glu Gly Leu Thr Asp Met Leu Glu Leu Leu Ser Asn Ser Thr Trp
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Gln Val Thr Asp Pro Lys Val Thr Asn Val Tyr Asp Trp Ile Glu Thr
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Thr Ile Ile Lys Ser Val Ile Arg Met Ala Gln Phe Ala Pro Glu Pro
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Thr Tyr Leu Asp Tyr Phe Lys Asn Ala Gly Asn Phe Arg Asp Ile Thr
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Leu Ala Lys Gln Leu Leu Glu Lys Gln Glu Val Thr Pro Arg Gly Asp
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Leu Asp Phe His Lys Thr Phe Ala Ser Met Asp Arg Val Val His Arg
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Lys Ser Gly Tyr Ala Phe Gly Ile Ser Met Tyr Ser Asn Arg Ile Gln
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Asn Tyr Glu Asp Met Asn Asp Glu Asn Arg Lys Gly Trp Tyr Thr Gly
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Glu Gly Met Thr Tyr Leu Tyr Asn Gly Asp Leu Ala Gln Tyr Ser Asp
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Ser Tyr Asp Ala Trp Asn Ser Ser Leu Ile Ala Lys Lys Ser Trp Phe
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Met Phe Asp Asn Glu Ile Val Ala Leu Gly Ala Gly Ile Thr Ser Ser
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Glu Asp Arg Asn Val Glu Ser Ile Val Glu Asn Arg Lys Ile Arg Asn
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Asp Gly Ser Asn Gln Leu Val Ile Asn Gly Glu Thr Leu Asn Leu Ser
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Asn Gly Gly Gln Asn Gln Thr Met Ala Ala Lys Trp Ala Phe Leu Glu
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Gly Asn Val Pro Gly Ala Asp Ile Gly Tyr Tyr Phe Pro Glu Gly Lys
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Met Leu Thr Ile Lys Lys Glu Glu Arg Thr Gly Ala Trp Lys Asp Ile
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Asn Tyr Gly Gly Pro Ala Glu Ala Ile Lys Arg Ser Tyr Thr Thr Met
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Trp Phe Asp His Gly Val Arg Pro Glu Gln Asp Thr Tyr Ser Tyr Val
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Pro Asp Ile Thr Ile Leu Arg Asn Asp Ser Ala Val Gln Ala Val Gln
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Asp Val Lys Glu Asn Ile Ile Gly Ala Asn Phe Trp Lys Asp Glu Lys
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Gln Ser Ala Gly Pro Leu Thr Val Tyr Gln Lys Ala Ser Val Thr Met
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Gln Glu Lys Asp Gly Val Leu Glu Ile Ala Val Cys Asp Pro Thr Met
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Ala Lys Leu Lys Met Ile Pro Ser Gln Lys Gly Asn Ser Pro Asn Ser
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Ile Arg
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Claims (16)
1.一种测定交联透明质酸凝胶体外酶解性能的方法，其特征是：包括以细菌透明质酸酶酶解交联透明质酸凝胶，然后采用紫外-可见分光光度法测定酶解过程中产生的酶解液的步骤；通过吸光度计算交联透明质酸凝胶的体外酶解率，所述酶解率=各时间点的吸光度值/酶解终点的吸光度值，当检测得到的吸光度稳定时，将出现吸光度稳定值的第一个时间点视为酶解终点；酶解介质为磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、生理盐水、磷酸二氢钾-氢氧化钠-氯化钠缓冲液、磷酸二氢钾-磷酸氢二钾-氯化钠缓冲液、添加0.01%氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01%氯化钙的生理盐水中的一种。
2.根据权利要求1所述的方法，其特征是：所述细菌透明质酸酶是一种透明质酸裂解酶，特点是能够将透明质酸降解产生4,5-不饱和双键结构的透明质酸酶。
3.根据权利要求1或2所述的方法，其特征是：所述细菌透明质酸酶的氨基酸序列如SEQID NO:1所示，来源于保藏号为CGMCC No.5744的芽孢杆菌。
4.根据权利要求1或2所述的方法，其特征是：所述酶解过程中产生的酶解液指的是从透明质酸酶加入开始到最终酶解结束的时间段中任意时间点产生的酶解液。
5.根据权利要求1或2所述的方法，其特征是：测定波长232 nm处的吸光度。
6.根据权利要求1或2所述的方法，其特征是：酶解温度为37-45℃。
7.根据权利要求6所述的方法，其特征是：酶解温度为37-42℃。
8.根据权利要求6所述的方法，其特征是：酶解温度为42℃。
9.根据权利要求1或2所述的方法，其特征是：从酶解开始到酶解终点的时间为1-3h。
10.根据权利要求1或2所述的方法，其特征是：酶解介质为磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液、生理盐水、添加0.01%氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01%氯化钙的生理盐水；酶解时的pH为6.0-7.5。
11.根据权利要求10所述的方法，其特征是：酶解介质为添加0.01%的氯化钙的磷酸氢二钠-磷酸二氢钠-氯化钠缓冲液或添加0.01%的氯化钙的生理盐水。
12.根据权利要求10所述的方法，其特征是：酶解时的pH为6.5。
13.根据权利要求1所述的方法，其特征是：制备交联透明质酸凝胶所用的交联剂为1,4-丁二醇二缩水甘油醚、二乙烯基砜、碳二亚胺、聚乙二醇类或氨基酸类；所述聚乙二醇类交联剂包括聚乙二醇二缩水甘油醚、四臂星形聚乙二醇环氧化物，所述氨基酸类交联剂包括L-赖氨酸、L-精氨酸。
14.根据权利要求1或2所述的方法，其特征是：包括以下具体步骤：
（1）取细菌透明质酸酶，用酶解介质配制成酶液；
（2）将交联透明质酸凝胶与酶解介质混合均匀，然后加入步骤（1）的酶液，混合均匀；
（3）将步骤（2）的混合液在酶解温度下进行酶解，设定取样时间点，每个时间点得到的酶解液用紫外分光光度计测定232 nm处吸光度。
15.根据权利要求14所述的方法，其特征是：步骤（1）中，所述酶液中细菌透明质酸酶的浓度为300IU/mL~1500IU/mL。
16.根据权利要求14所述的方法，其特征是：步骤（2）中，交联透明质酸和细菌透明质酸酶的用量关系为1 mg透明质酸对应细菌透明质酸酶75–375 IU。
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