CN105816920B - 一种改性海藻酸钠栓塞微球的制备方法 - Google Patents
一种改性海藻酸钠栓塞微球的制备方法 Download PDFInfo
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- CN105816920B CN105816920B CN201610188793.3A CN201610188793A CN105816920B CN 105816920 B CN105816920 B CN 105816920B CN 201610188793 A CN201610188793 A CN 201610188793A CN 105816920 B CN105816920 B CN 105816920B
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- Prior art keywords
- sodium alginate
- embolism microball
- modified sodium
- modified
- preparation
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical class CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 title claims abstract description 96
- 208000005189 Embolism Diseases 0.000 title claims abstract description 74
- 239000011806 microball Substances 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 43
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 35
- 239000000661 sodium alginate Substances 0.000 claims abstract description 33
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 8
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
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- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 5
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 5
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
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- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Landscapes
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公布一种改性海藻酸钠栓塞微球的制备方法，涉及生物医药材料领域。该制备方法包括以下步骤：(1)用牛磺酸对海藻酸钠改性，合成改性海藻酸钠；(2)以高浓度改性海藻酸钠水溶液为水相，矿物油为油相，通过反相乳化方法用多醛基纤维素交联，制备出改性海藻酸钠栓塞微球。通过牛磺酸对海藻酸钠改性。一方面在栓塞微球中引入大量的磺酸基团，提高了药物的负载率，另一方面降低了海藻酸钠溶液粘度，有利于配制高浓度的海藻酸钠溶液，从而获得规整的海藻酸钠栓塞微球。本发明制备的栓塞微球在介入疗法中具有较好的应用前景。
Description
技术领域
本发明涉及一种生物可降解的药物载体的制备方法，涉及生物医药领域，尤其涉及一种改性海藻酸钠栓塞微球的合成方法。
背景技术
肝细胞肿瘤是干细胞中比较常见的恶性肿瘤之一，患该肿瘤的病例约占世界上诊断出癌症病例的6％，常见的治疗肿瘤方案是采用手术切除法，但是对于中晚期的肿瘤患者来说,介入疗法如化学栓塞(ranscatheter arterial chemoembolization,TACE)是比较理想的治疗方案。在该方法中导管注射到肿瘤组织的栓塞栓塞微球不仅阻断对肿瘤组织的营养供给还可以释放抗肿瘤药物。随着肿瘤组织中抗癌药物浓度的升高，对病变部位起到抑制的作用，从而达到治疗肿瘤的效果。
改性海藻酸钠(SA)又名海藻胶、褐藻酸，是从天然褐藻中提取的天然生物大分子钠盐。因其具有无毒性和良好的生物相容性，来源广泛而被广泛应用于食品、医药等行业。特别是在生物医药材料方面，作为药物载体而备受关注。以海藻酸钠作为原料制备非载药栓塞栓塞微球已有一些报道，但是纯海藻酸钠用来制备载药栓塞微球尚有缺陷:一是缺乏合适的载药基团，海藻酸钠中的羧基是弱电离基团，与正电荷药物作用力不强，因此负载率有限，反应速度慢；二是纯海藻酸钠溶液粘度过高，乳化时间过长，栓塞微球制备困难。戊二醛是一种常用的交联剂，用来交联聚乙烯醇、壳聚糖等高聚物，但是由于其毒性，在医用材料应用领域具有一定局限性。
发明内容
针对上述缺陷，本文首先使用牛磺酸(TA)对海藻酸钠改性，得到改性海藻酸钠(SA-TA)，然后再制备改性海藻酸钠栓塞微球。该栓塞微球可以与抗肿瘤药物相互作用而作为药物载体。海藻酸钠栓塞微球具有无毒，生物相容性好，并且原料来源广泛等优点。改性后的改性海藻酸钠分子中含有大量的磺酸基团。牛磺酸分子中的磺酸基是强电离基团，亲水性极强，将该基团引入到海藻酸钠分子中，可以提高改性海藻酸钠栓塞微球对药物阿霉素的载药率。同时由于磺酸基团的存在，在一定程度上降低了改性海藻酸钠在水溶液中的粘度，对实现高浓度条件下制备海藻酸钠栓塞微球提供了可能。在交联反应中，为了避免小分子戊二醛的毒性，通过高聚物氧化得到多醛基纤维素，以此为交联剂加入到改性海藻酸钠溶液中，通过乳化交联工艺形成栓塞微球。
本发明提供制备一种改性海藻酸钠栓塞微球作为药物载体的技术方案，依次包括以下步骤：
1)将牛磺酸和海藻酸钠通过酰胺化反应得到改性海藻酸钠；
2)将改性海藻酸钠经纯化后冷冻干燥，经蒸馏水溶解，得到改性海藻酸钠水溶液；
3)采用反相乳液交联方法，30℃条件下乳化4h，加入多醛基纤维素作为交联剂制备栓塞微球；
具体的，所述步骤1)中，酰胺化反应的反应体系包含磷酸盐缓冲溶液(PBS，pH6.0)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)、N-羟基丁二酰亚胺(NHS)，25℃条件下机械搅拌24h，其中海藻酸钠结构单元与1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺投料摩尔比为1：1：1。
具体的，所述步骤2)中，酰胺化后的改性海藻酸钠产物经异丙醇沉淀、重新溶解3次后，超纯水透析24h。
具体的，所述步骤3)中，将改性海藻酸钠水溶液作为水相，以矿物油(石蜡油)为油相，控制油水比例5:1～10：1；添加体积百分浓度为2％的Span 80做稳定剂，在30℃条件下分散7h后，加入多醛基纤维素做交联剂，反应20h,得到改性海藻酸钠栓塞微球。
改性海藻酸钠在磷酸盐缓冲溶液中(pH 6.0)中存在-COOH基团，牛磺酸分子中含有-NH2基团，氨基和羧基在一定条件下可以发生酰胺化反应，生成酰胺化产物，当参与酰胺化反应的海藻酸钠和牛磺酸的摩尔量不同时，可以得到不同反应程度的酰胺化产物。因此本发明在设计合成配方时，采取海藻酸钠和牛磺酸的不同投料摩尔比，可以有效地得到含有不同磺酸基含量的改性海藻酸钠的酰胺化产物。
本发明还提供一种改性海藻酸钠栓塞微球在化疗药物载体中的应用。改性海藻酸钠栓塞微球导向肿瘤组织周围的血管中，不仅阻断对肿瘤组织的营养供给，还可以释放抗肿瘤药物，随着肿瘤组织中抗癌药物浓度的升高，可杀灭癌细胞。改性海藻酸钠栓塞微球在体内可以完全降解，通过代谢排出体外。
借由上述方案，本发明至少具有以下优点：
1.由于该栓塞微球表面含有羧基和磺酸基团，可以增强与抗肿瘤药物阿霉素相互作用，因而可以提高载体对药物的负载率；
2.由于该栓塞微球表面含有磺酸基团，吸附药物分子，大大消除了栓塞微球表面物理吸附而引起的药物泄露。
3.交联剂多醛基纤维素代替戊二醛，避免了毒性。
4.改性海藻酸钠栓塞微球无毒，细胞相容性较好，符合人体使用的安全性标准；
5.将酰胺化产物用于合成栓塞栓塞微球，方法简单、条件温和，不需要任何催化剂和其他添加剂，无副产物产生，反应完全，产物纯净。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1改性海藻酸钠的合成路线。
图2改性前后海藻酸钠的红外谱图，其中a：海藻酸钠(SA)；b：牛磺酸(TA)；c：海藻酸钠与牛黄酸酰胺化产物ST11。
图3为本发明中改性海藻酸钠栓塞微球的超景深显微镜照片，其中a：载药前；b：载药后10min；c：载药后24h；d：栓塞微球剖面图。
图4为本发明中改性海藻酸钠栓塞微球的载药曲线。
图5为本发明中改性海藻酸钠载药栓塞微球ST11在不同pH的释放介质中的累计释放率曲线。
图6为本发明中牛磺酸与海藻酸钠以不同摩尔比反应产生的载药栓塞微球在体外模拟体液中的药物释放曲线，其中ST10、ST11、ST12、ST21分别表示酰胺化反应中海藻酸钠与牛磺酸的投料重量比为5：0、5：1.49、5：2.98和5：5.96时的酰胺化产物制备的栓塞微球。
图7为本发明中改性海藻酸钠栓塞微球的细胞毒性结果。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1
1)改性海藻酸钠的制备；
将5g海藻酸钠(SA)加入300mL磷酸盐缓冲溶液(PBS，pH 6.0)中，完全溶解后加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)，机械搅拌20min后加入N-羟基丁二酰亚胺(NHS)和牛磺酸(TA)，其中海藻酸钠(SA)与1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)及N-羟基丁二酰亚胺(NHS)的投料摩尔比为1：1：1，在25℃下反应24h。待反应完成后用反应液2～3倍体积的异丙醇沉淀，再用去离子水重新溶解成饱和溶液，循环操作3次，再经过透析48h和冷冻干燥，得到改性海藻酸钠产物。如表1所示，调节牛磺酸的加入量，得到一系列的改性海藻酸钠产物。
表1改性海藻酸钠合成配方及元素分析结果
SA,TA分别代表海藻酸钠和牛磺酸。
2)多醛基纤维素的制备：
称取2.0g的羧甲基纤维素钠粉末加入到250ml烧瓶中，20g/L羧甲基纤维素钠在水中的粘度为300.0-800.0Mpa.s，再加入80mL蒸馏水，在25℃下不断搅拌使其溶解完全；将1.5g高碘酸钠溶解在20ml蒸馏水中，再缓慢加入到烧瓶里.该反应在25℃下持续进行24小时；然后加入20mL乙二醇到烧瓶中停止反应，30分钟后将混合物倒入透析袋(MWCO 3500)，在蒸馏水中彻底透析，最后通过冷冻干燥得到产品，即为多醛基纤维素。
3)改性海藻酸钠栓塞微球的制备:
将上述改性海藻酸钠ST10配成重量浓度为8％的水溶液，取5mL该溶液加入到50mL含2％(v/v)Span 80的液体石蜡中，待分散均匀后加入3mL的聚乙二醇。30℃条件下乳化4h，加入交联剂多醛基纤维素，其用量是改性海藻酸钠重量的6～9％，预先溶解在体积比为1:1的去离子水与乙醇的混合溶剂中，缓慢滴加到反应体系中去，交联反应24h，反应结束后依次用正己烷、异丙醇洗涤3次，过滤后真空干燥。
实施例2
改性海藻酸钠与牛磺酸重量比为5：1.49，其他合成过程和实施例1相同。
实施例3
改性海藻酸钠与牛磺酸重量比为5：2.98，其他合成过程和实施例1相同。
实施例4
改性海藻酸钠与牛磺酸重量比为5：5.96，其他合成过程和实施例1相同。
实施例5
分别称取一定量的改性产物ST10、ST11，配制成质量分数分别为1％、2％、3％、4％、5％、6％、8％的水溶液，使用粘度计分别测量其粘度变化。
表2改性前后海藻酸钠水溶液粘度变化
表2是在25℃条件下改性前后海藻酸钠的水溶液粘度的变化情况，从表中可以观察到改性后的海藻酸钠粘度较之未改性的海藻酸钠的粘度明显降低，这说明改性海藻酸钠由于磺酸基团的存在，粘度降低。在实验过程中，由于改性海藻酸钠的粘度降低，为高浓度改性海藻酸钠水溶液的制备提供了可能。
实施例6
分别将SA、TA、ST11提纯冷冻干燥后，使用全反射傅里叶红外光谱仪在4000～500cm-1的波数范围内进行红外扫描，得到红外谱图。
图2显示，a、b、c三条曲线存在明显差异，c在1685cm-1处出现一较弱强度的酰胺Ⅰ带特征吸收峰，同时酰胺基会在3500～3300cm-1处会出现一特征吸峰，对比a和c可以看出，c在此处的峰得到了明显加强，说明了c中酰胺基的存在。对比b和c，c中氨基在3000cm-1处的双峰消失了，也从侧面证明了酰胺基的生成。由此可知：酰胺基成功引入到SA-TA中。
实施例7
精确称取20mg干燥过筛后的空白栓塞微球加入到10mL浓度为1.5mg/mL的盐酸阿霉素溶液中，室温下避光磁力搅拌，盐酸阿霉素溶液颜色逐渐变浅，栓塞微球呈深红色。通过使用紫外/可见分光光度计，检测波长在483nm处栓塞微球中盐酸阿霉素的含量，并绘制栓塞微球负载药物曲线。
图3中a～c分别表示载药前、载药10min后和载药24h后的栓塞微球形态。从图中可以看出随着载药时间的增加，栓塞微球颜色逐渐加深，这主要是因为阿霉素的颜色为红色，载药过程中随着时间的增加，栓塞微球包载药物增多，栓塞微球的颜色随之加深；d图是栓塞微球的内部剖面图，从图中可以看出栓塞微球内部存在很多微小的空洞结构。
图4是改性海藻酸钠栓塞微球的药物负载情况图，其中ST10载药率最低，ST21载药率最高。在负载过程中开始时载药速度很快，约在10h后开始趋于平缓。这是因为栓塞微球负载药物时采用的是离子交换法，栓塞微球中磺酸基团含量越多，与阿霉素之间离子交换能力越强，载药率越高。
实施例8
分别称取20mg载药栓塞微球ST10、ST21、ST11、ST12于20mL 0.01M PBS(pH 7.4)的溶液中，将其置于恒温水浴振荡器中，温度控制在37±0.5℃，定点量取5mL上清液，通过紫外/可见分光光度计检测缓冲液中药物含量，重复操作3次取平均值，按下式计算累积释放量。每次取样后补加相同体积的新鲜释放液。
该图显示了不同的的改性海藻酸钠栓塞微球在0.01M PBS(pH 7.4)中的药物释放情况，图中ST10栓塞微球在开始的12h内释放达到最大，随后慢慢趋于平缓，而其他比例栓塞微球在约32h时，栓塞微球的药物累计释放量达到最大，表明功能化的改性栓塞微球具有缓释效果。其原因主要是由于磺酸基团通过电荷吸附药物分子，大大消除了栓塞微球表面物理吸附而引起的突释，起到了缓释药物的作用。
实施例9
改性海藻酸钠栓塞微球的细胞毒性：
在温度为37℃的水浴锅中，迅速解冻-80℃冻存的3T3细胞，将其移入到含有7mL的RPMI-1640培养液的离心管中，以800rpm速度离心，用含有10％小牛血清的RPMI-1640培养液吹打细胞制成单细胞悬液，将其移入到50mL的培养瓶中，在37℃，5％CO2孵箱中培养。
以改性海藻酸钠栓塞微球在生理盐水中的浸提液为研究对象，采用MTT法对其形成的浸提液的细胞毒性进行测试，以约1.2×105/mL将小鼠成纤维细胞接种于96孔板，每孔100μL，分别培养24h和48h，吸出每孔中的原培养液，每孔加入100μL的阴性对照液(样品组是含10％小牛血清的RPMI-1640培养液)、阳性对照液(0.64％苯酚培养基)、样品组(样品组分别含t＝24h和t＝48h的10％小牛血清的RPMI-1640培养液)，继续置于37℃、5％CO2培养箱中培养，分别培养24h、48h。每组设4个平行孔。取出培养板后通过倒置显微镜观察、评价细胞生长状况。后加入MTT 20μL，继续培养4h后，将培养板中的小孔内的液体吸尽后，加入二甲基亚砜，用酶标仪于570nm处测其吸光度值(A)，计算细胞存活率。3T3在不同浓度的栓塞微球浸提液中的细胞存活率,在37℃下，24h和48h的栓塞微球浸提液中培养的3T3细胞，孵育24h后，其细胞的相对增值率均达到90％以上，这表明3T3细胞在以浸提液稀释的细胞培养基中生长状态良好，表明该栓塞微球无细胞毒性，细胞相容性良好。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。
Claims (7)
1.一种改性海藻酸钠栓塞微球的制备方法，依次包括以下步骤：
1)将牛磺酸与海藻酸钠通过酰胺化反应得到改性海藻酸钠产物，所用催化剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺，反应在pH 6.0的磷酸盐缓冲溶液中进行；
2)将得到的改性海藻酸钠溶液用异丙醇沉淀、用去离子水重新溶解，经纯化后冷冻干燥，重新溶解得到改性海藻酸钠水溶液；
3)采用反相乳化交联方法，将高浓度的改性海藻酸钠水溶液分散在矿物油中乳化，再加入多醛基纤维素作为交联剂制备改性海藻酸钠栓塞微球。
2.一种权利要求1所述改性海藻酸钠栓塞微球的制备方法，其特征在于：权利要求1所述步骤1)的投料中，海藻酸钠与牛磺酸的重量比为5:1.49至5:5.96；海藻酸钠在磷酸盐缓冲溶液中的重量百分浓度为1.8wt％；海藻酸钠结构单元与1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺的摩尔比为1：1：1；在25℃温度下机械搅拌，反应24h。
3.一种权利要求1所述改性海藻酸钠栓塞微球的制备方法，其特征在于所述步骤2)中，改性海藻酸钠溶液用2～3倍体积的异丙醇沉淀，再用去离子水重新溶解成饱和溶液，循环操作3次，再经过透析48h和冷冻干燥，重新溶解得到改性海藻酸钠水溶液。
4.根据权利要求1所述的改性海藻酸钠栓塞微球的制备方法，其特征在于所述步骤3)中，使用8～10％高浓度的改性海藻酸钠水溶液，分散在矿物油中，控制油水比例为5:1～10：1；添加体积百分浓度为2％的Span 80做稳定剂，在30℃条件下分散7h。
5.根据权利要求1所述改性海藻酸钠栓塞微球的制备方法，其特征在于加入交联剂多醛基纤维素的用量是改性海藻酸钠重量的6～9％，预先溶解在体积比为1:1的去离子水与乙醇的混合溶剂中，缓慢滴加到反应体系中去。
6.根据权利要求1所述改性海藻酸钠栓塞微球的制备方法，其特征在于多醛基纤维素的制备通过下列步骤完成：
1)称取2.0g羧甲基纤维素钠粉末加入到250ml烧瓶中，所用羧甲基纤维素钠20g/L在水中的粘度为300.0-800.0Mpa.s,再加入80mL蒸馏水，在25℃下不断搅拌使其溶解完全；
2)将1.5g高碘酸钠溶解在20ml蒸馏水中，再缓慢加入到烧瓶里，该反应在25℃下持续进行24小时；
3)然后加入20mL乙二醇到烧瓶中停止反应，30分钟后将混合物倒入透析袋,透析袋的规格是MWCO 3500，在蒸馏水中彻底透析，最后通过冷冻干燥得到产品，即为多醛基纤维素。
7.一种改性海藻酸钠栓塞微球对于抗癌药物阿霉素的负载方法，其特征是首先按照权利要求1所述制备方法得到空白栓塞微球，然后精确称取20mg干燥过筛后的空白栓塞微球加入到10mL浓度为1.5mg/mL的盐酸阿霉素溶液中，室温下避光磁力搅拌，盐酸阿霉素溶液颜色逐渐变浅，栓塞微球呈深红色,通过使用紫外/可见分光光度计，检测波长在483nm处栓塞微球中盐酸阿霉素的含量，并绘制栓塞微球负载药物曲线，负载药物的方式为离子交换法，溶液中含正电荷的阿霉素与负电荷基团磺酸基团通过静电吸附载药，载药率高达35％。
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| CN108636374B (zh) * | 2018-06-06 | 2020-02-18 | 四川大学 | 一种多巴胺接枝磺化海藻酸钠双交联微球及其制备方法和用途 |
| CN110106728B (zh) * | 2019-05-08 | 2021-10-26 | 安徽省翰先纺织科技有限公司 | 涂料印花工艺 |
| CN110327284B (zh) * | 2019-07-18 | 2022-11-22 | 石药集团中诺药业（石家庄）有限公司 | 一种注射用头孢地嗪钠及其制备方法 |
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| CN114404366B (zh) * | 2022-02-17 | 2023-12-15 | 深圳玉莱漫生物科技有限公司 | 苦参总碱透皮吸收纳米微乳 |
| CN115282933B (zh) * | 2022-06-28 | 2024-07-19 | 武汉工程大学 | 一种氨基磺酸盐改性海藻酸钠吸附剂及其制备方法和应用 |
| CN115591006A (zh) * | 2022-09-14 | 2023-01-13 | 苏州大学（Cn） | 天然抗菌的茶多酚-丝素/壳聚糖栓塞微球及其制备方法 |
| CN115634314B (zh) * | 2022-10-28 | 2023-08-04 | 广州贝奥吉因生物科技股份有限公司 | 一种非支撑骨修复凝胶微球及其制备方法 |
| CN116617445B (zh) * | 2023-07-26 | 2023-10-17 | 海杰亚（北京）医疗器械有限公司 | 一种可生物降解的栓塞微球及其制备方法和应用 |
| CN117323294B (zh) * | 2023-09-25 | 2024-05-31 | 至微(深圳)医学科技有限公司 | 一种载药栓塞微球及其制备方法和应用 |
| CN117815434B (zh) * | 2024-03-05 | 2024-05-24 | 山东第二医科大学 | 一种氧化再生纤维素栓塞微球及其制备方法 |
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