CN114504547A - 一种改性玻璃酸钠水凝胶复合注射液及其制备方法 - Google Patents
一种改性玻璃酸钠水凝胶复合注射液及其制备方法 Download PDFInfo
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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Abstract
本申请提供一种包含轻度改性玻璃酸钠的水凝胶复合注射液的制备方法，将该改性玻璃酸钠与多巯基聚乙二醇交联剂反应形成的水凝胶颗粒，以及将其与玻璃酸钠溶液混合得到的水凝胶复合注射液。该注射液用于缓解关节疼痛，治疗退行性关节炎，生物相容性较好，可实现一次给药，长期起效，增加患者顺应性，并且几乎没有交联剂残留，使得该注射剂的应用非常安全。
Description
技术领域
本发明涉及化学、医药领域，具体地说，将玻璃酸钠通过加成反应进行轻度官能团改性，并将该改性玻璃酸钠与特定的聚乙二醇衍生物交联形成聚合物水凝胶，以及该水凝胶与玻璃酸钠溶液形成的混合注射液。该注射液可用于治疗退行性关节炎，缓解关节疼痛。
背景技术
透明质酸又称玻璃糖醛酸(hyaluronic acid，简称HA)，是由N-乙酰葡萄糖胺与β-D-葡萄糖醛酸二糖单位为基本结构单元的生物活性大分子，玻璃酸钠是透明质酸的钠盐形式，两者的物理化学性质几乎相同。
透明质酸及其盐是生物体内普遍存在的酸性黏多糖，人的皮肤、软骨、眼玻璃体和关节滑液中均含有较高浓度的HA。当发生骨关节炎和类风湿性关节炎等关节疾病时，关节滑液中透明质酸的浓度和分子量明显降低。补充外源性透明质酸可显著提高滑液的黏稠性和润滑功能，起到保护软骨、减少组织间的磨擦，促进关节愈合和再生、缓解疼痛、增加关节活动度的作用。骨关节腔内注射HA凝胶治疗骨关节病，克服了激素治疗的副作用，由于HA具有良好的生物相容性、高黏弹性和无毒副作用等优点，HA的润滑与缓冲作用使其成为治疗骨关节病的首选材料。已有的动物试验与临床试验均表明，HA水凝胶以及普通玻璃酸钠对于治疗踝关节炎、膝关节炎等骨关节疾病时，均具有良好的治疗与修复作用。玻璃酸钠作为关节滑液粘滞度补偿剂，常用于治疗退行性关节炎，缓解关节疼痛。
然而，由于透明质酸机械强度低，易扩散，并且容易被人体内透明质酸酶所分解，存在时间短，作用效果极易降低。如将其结构进行化学修饰或交联成更大的网状结构，则不仅能避免上述缺点，而且能在给药体系上获得长足发展。天然HA为线性多糖，分子中羟基的存在使HA改构和交联成为可能。二乙烯基砜(divinyl sulfone，简称DVS)是一种较常用的交联剂，通过透明质酸的羟基，可使HA在室温下快速交联，经DVS交联的HA水凝胶具有微孔结构，在水溶液中平衡吸附量明显高于普通HA，可用于预防术后粘连。同时，透明质酸与玻璃酸钠交联后相对分子量和分子体积明显增大，形成连续的大分子网状结构，使其在水中可溶胀但不溶解，流变性能得到改善，在人体内的存留时间延长，机械强度和稳定性显著提高，且生物相容性仍然良好。
近40年来关于HA衍生物的制备及应用有着数量可观的研究进展，集中在HA分子中羧基、羟基、乙酰氨基和还原末端的衍生和交联，生成长效、生物相容性好的HA衍生物：用于软组织填充，修复塌陷的疤痕和皱纹，如Hylan B凝胶(商品名：Hylaform，Biomatrix公司研制)；用于关节腔内注射治疗骨关节炎，如Hylan G-F20(商品名：Synvise)等；通过多种方式与药物结合，达到缓释、控释、靶向等作用，制成微球、脂质体等。
而普通未交联的透明质酸与玻璃酸钠存在代谢过快、注射次数过多、感染风险增大的问题。交联玻璃酸钠凝胶中交联剂残留大大降低了该产品在医疗美容领域的生物相容性，并造成人体对交联剂的诸多过敏反应，过多的交联剂甚至给人体带来致癌的风险，因此需尽可能减少凝胶中交联剂的存在。
专利CN103834053A公开了一种可注射交联透明质酸凝胶的制备方法，该产品具有交联剂残留少、体内降解时间长的优势，但仅用于美容填充修复，不用于关节炎治疗。
专利CN110016152A公开了一种交联填充用玻璃酸钠凝胶的制备方法，该产品具有一定生物相容性，但使用丙酮、甲苯等毒性有机溶剂对凝胶进行脱水处理，残留溶剂对人体具有安全隐患。
发明内容
本发明提供了一种改性玻璃酸钠聚合物及其水凝胶复合注射液的制备方法，该注射液具有质量稳定、起效时间长、患者顺应性好的优势。
为实现上述目的，本发明提供如下技术方案：
第一方面，本发明提供了一种改性玻璃酸钠水凝胶，由玻璃酸钠与交联剂在碱性条件下发生加成反应而衍生化形成的改性玻璃酸钠与合适的二官能团或多官能团交联剂发生控制反应，形成相应的水凝胶。
更具体地，该水凝胶由调节了酸碱度的HA-VS水溶液(体积比为0.5％-2.0％)与溶解0.5-20份交联剂所得水溶液发生控制反应形成。
具体地说，该改性玻璃酸钠由溶解玻璃酸钠所得水溶液与DVS所得水溶液发生加成反应而形成。
优选地，该反应的交联剂为二乙烯基砜(DVS)，体积比为1％～50％。
优选地，该反应使用的多巯基聚乙二醇是二巯基聚乙二醇。
第二方面，本发明提供了一种玻璃酸钠水凝胶复合注射液，可实现一次给药，长期起效，增加患者顺应性。具体地说，该复合制剂由改性玻璃酸钠水凝胶与玻璃酸钠水溶液以合适的比例混合制成。加入磷酸盐缓冲液配制成玻璃酸钠溶液，加入水凝胶颗粒，混合均匀后即可得到改性玻璃酸钠聚合物水凝胶复合注射液。优选地，玻璃酸钠水凝胶颗粒加入质量比为1％-20％。
本发明还涉及将该复合注射液用于治疗骨关节炎、退行性关节炎等关节炎疾病，缓解关节疼痛的应用。
本发明的有益效果：
本发明提供了一种改性玻璃酸钠水凝胶复合注射液，该制剂可实现一次给药，并且长期起效，增加患者顺应性。动物试验已证实，本发明对兔膝骨关节炎的软骨退变具有明显的修复作用。
另外，本发明在制备工艺上，将玻璃酸钠改性时使用的DVS浓度较低，使用量少，反应时间适中，在本发明工艺条件下得到的改性玻璃酸钠产品质量稳定，改性结果较好，适合工业化生产；而且，在制备水凝胶工艺上，本发明使用交联剂的比例更加合理，能够使交联反应趋于完全，交联剂几乎无残留，使最终所得产品非常安全。
具体实施方式：
通过以下给出的本发明的具体实施例可以进一步清楚地了解本发明，但它们不是对本发明的限定。
改性玻璃酸钠的制备
实施例1
取玻璃酸钠原料药，使用注射用水配制3％玻璃酸钠溶液4L；称取84.3g氢氧化钠，溶解于2668ml注射用水，将该氢氧化钠溶液溶解于前述玻璃酸钠溶液，混合均匀，再加入15％DVS溶液90ml，反应16分钟；之后再加入适量HCl溶液，调节反应液的酸碱度，直至pH介于4.5-5之间，终止反应；将反应溶液超滤洗涤，超滤后进行冻干，得到改性玻璃酸钠产品(HA-VS1)。
取所得HA-VS产品，加入缓冲液，加水搅拌溶解，使HA-VS浓度为1.0％。取10g该溶液，再加入改性玻璃酸钠约四分之一物质的量的交联剂水溶液，搅拌混合均匀后，于30-40℃静置反应24h。使用不锈钢筛网，将水凝胶挤压过筛，得到改性玻璃酸钠水凝胶颗粒。结果：在该配方下，水凝胶颗粒成品中未检出聚乙二醇交联剂，且成品的溶胀度较好，质量尚可。
实施例2
取玻璃酸钠原料药，使用注射用水配制3％玻璃酸钠溶液4L；称取84.3g氢氧化钠，溶解于2668ml注射用水，将该氢氧化钠溶液溶解于前述玻璃酸钠溶液，混合均匀，再加入15％DVS溶液90ml，反应16分钟；之后再加入适量HCl溶液，调节反应液的酸碱度，直至pH介于4.5-5之间，终止反应；将反应溶液超滤洗涤，超滤后进行冻干，得到改性玻璃酸钠产品(HA-VS)。
取所得HA-VS产品，加入缓冲液，加水搅拌溶解，使HA-VS浓度为25.0％。取10g该溶液，再加入改性玻璃酸钠约四分之一物质的量的交联剂水溶液，搅拌混合均匀后，于30-40℃静置反应24h。使用不锈钢筛网，将水凝胶挤压过筛，得到改性玻璃酸钠水凝胶颗粒。结果：在该配方下，水凝胶颗粒成品中未检出聚乙二醇交联剂，且成品的溶胀度良好，质量较优。
实施例3
取玻璃酸钠原料药，使用注射用水，配制3％玻璃酸钠溶液4L；称取84.3g氢氧化钠，溶解于2668ml注射用水，将该氢氧化钠溶液溶解于前述玻璃酸钠溶液，混合均匀，再加入15％DVS溶液90ml，反应16分钟；之后再加入适量HCl溶液，调节反应液的酸碱度，直至pH介于4.5-5之间，终止反应；将反应溶液超滤洗涤，超滤后进行冻干，得到改性玻璃酸钠产品(HA-VS)。
取所得HA-VS产品，加入缓冲液，加水搅拌溶解，使HA-VS浓度为50％。取10g该溶液，再加入改性玻璃酸钠约四分之一物质的量的交联剂水溶液，搅拌混合均匀后，于30-40℃静置反应24h。使用不锈钢筛网，将水凝胶挤压过筛，得到改性玻璃酸钠水凝胶颗粒。结果：在该配方下，水凝胶颗粒成品中未检出聚乙二醇交联剂，且成品的溶胀度较好，质量较好。
改性玻璃酸钠水凝胶复合注射液的制备
实施例4
量取200ml注射用水，加入磷酸氢二钠56.6mg，一水磷酸二氢钠18.9mg，氯化钠1.806g，配制磷酸盐缓冲溶液并将其无菌过滤；加入折干的1.75g玻璃酸钠，搅拌至溶解；取实施例1所得改性玻璃酸钠水凝胶颗粒15g，过两次24目筛网后，取10g过筛后的样品按照1％的比例倒入玻璃酸钠溶液中混合溶胀30min，将其灌装，于121℃灭菌，得到复合注射液成品(HA-VS-HA-1)。
实施例5
量取200ml注射用水，加入磷酸氢二钠56.6mg，一水磷酸二氢钠18.9mg，氯化钠1.806g，配制磷酸盐缓冲溶液并将其无菌过滤；加入折干的1.75g玻璃酸钠，搅拌至溶解；取实施例1所得改性玻璃酸钠水凝胶颗粒15g，过两次24目筛网后，取10g过筛后的样品按照10％的比例倒入玻璃酸钠溶液中混合溶胀30min，将其灌装，于121℃灭菌，得到复合注射液成品(HA-VS-HA-2)。
实施例6
量取200ml注射用水，加入磷酸氢二钠56.6mg，一水磷酸二氢钠18.9mg，氯化钠1.806g，配制磷酸盐缓冲溶液并将其无菌过滤；加入折干的1.75g玻璃酸钠，搅拌至溶解；取实施例1所得改性玻璃酸钠水凝胶颗粒15g，过两次24目筛网后，取10g过筛后的样品按照20％的比例倒入玻璃酸钠溶液中混合溶胀30min，将其灌装，于121℃灭菌，得到复合注射液成品(HA-VS-HA-3)。
为验证本发明所提供的玻璃酸钠水凝胶复合注射液在兔骨关节炎的治疗作用，发明人开展了相关实验。
实验动物：
新西兰兔，普通级，雌雄各半，18周龄(2.0-2.5kg)，购自上海甲干生物科技有限公司(许可证号：SCXK(沪)2010-0028)。饲养于安徽省医学科学研究院动物室(许可证号：SYXK(皖)2014-006)，自由饮食，动物合格证号：2010002802146。
实验药物：
注射液供试品：实施例5所得制品(HA-VS-HA-2)。对照品为玻璃酸钠(HA，商品名：Hylaform)。炎症模型造模方法：兔进行全身麻醉，无菌条件下行膝内侧髌骨旁切口，仔细解剖内侧副韧带，切断并切除内侧副韧带长约0.5cm；打开关节腔，切除内侧半月板。行抽屉试验确认前交叉韧带已完全断裂，生理盐水冲洗后复位髌骨，丝线缝合关节囊和皮肤。造模4周后X线检查见关节腔变窄、骨质硬化甚至可见骨赘形成，即认为兔膝骨关节炎模型造模成功。
分组及给药方法：
将模型动物随机分为模型组、HA-VS-HA-2组和对照HA组，另设假手术组，每组动物6-8只。造模4周后开始给药(膝关节腔注射)，HA组每天给药1次，每次0.4ml；HA-VS-HA-2组每天给药1次，每次0.4ml；模型组与假手术组每天给予生理盐水1次，每次0.8ml。自第一次给药5周后处死动物，收集动物膝关节等标本。
评分检查：
1.X线放射检查
在造模4周后以戊巴比妥钠(30mg/kg)随机麻醉6只模型动物和2只假手术组动物，进行手术侧膝关节X线检查，观察动物关节腔大小、骨赘形成、骨质硬化等变化，以判定模型成型情况；给药结束前同法处理动物，行手术侧膝关节X线检查。并以凯尔格伦-劳伦斯(Kellgren-Lawrence)分级标准进行评分。
Kellgren-Lawrence分级标准共分5级：
0级：完全正常，无X线片改变；
1级：可疑的关节腔狭窄(joint space narrowing，JSN)和可能的唇样性增生；
2级：明确的骨赘(osteophyte，OP)形成及可能的JSN；
3级：中等OP及明确的JSN，骨质硬化及可能的骨形态改变；
4级：较大的OP，明确的JSN，严重骨质硬化，骨畸形。
表1展示了玻璃酸钠制剂对OA兔膝关节X线评分的影响。如表1所示，普通玻璃酸钠(HA组)给药后可减少重度OA兔(4级)的数量；同时HA-VS-HA-2组较模型组显著改善膝关节X线评分。
2.兔膝关节Pelletier评分
给药结束处死动物后取膝关节标本，包括股骨髁和胫骨平台。肉眼观察有无关节积液和滑膜增生。在手术显微镜下观察大体标本股骨内、外髁及胫骨内、外侧平台软骨表面退变情况，按Pelletier大体评分标准进行评分：0分，关节面完整，色泽如常；1分，关节面粗糙，有小的裂隙且色泽灰暗；2分，关节面糜烂，软骨缺损深达软骨表层或中层；3分，关节面溃疡形成，缺损深达软骨深层；4分，软骨剥脱，软骨下骨质暴露。
表2为各种玻璃酸钠制剂对OA兔膝关节的Pelletier评分表。观察OA模型兔发现，模型组动物关节面糜烂，软骨颜色灰暗，部分软骨缺损深达软骨深层，未见软骨剥脱；而HA-VS-HA-2、HA给药可改善关节软骨面损伤，软骨光泽明亮。与模型组比较，HA-VS-HA-2、HA给药后均可显著降低膝关节Pelletier评分(P<0.05)，改善软骨损伤。可见，相比起普通玻璃酸钠，本发明玻璃酸钠水凝胶复合注射液对兔膝骨关节炎的软骨退变的修复作用更为明显。
Claims (7)
1.一种改性玻璃酸钠水凝胶的制备方法，其特征在于，包括以下步骤：
(1)取玻璃酸钠原料药制成玻璃酸钠溶液，调节pH至碱性后加入一定浓度交联剂，然后加入一定浓度盐酸溶液猝灭反应，超滤，冻干处理得到改性玻璃酸钠；
(2)取改性玻璃酸钠，加入一定量的多巯基聚乙二醇进行交联反应制备成水凝胶，整粒，得到水凝胶颗粒。
2.如权利要求1所述的改性玻璃酸钠聚合物的制备方法，其特征在于，步骤(1)中，加入的交联剂为二乙烯基砜，体积比为1％～50％。
3.如权利要求1所述的改性玻璃酸钠聚合物的制备方法，其特征在于，步骤(2)中，使用的多巯基聚乙二醇是二巯基聚乙二醇。
4.一种改性玻璃酸钠水凝胶复合注射液的制备方法，其特征在于，包括以下步骤：取玻璃酸钠原料药，加入磷酸盐缓冲液配制成玻璃酸钠溶液，加入权利要求1所制的水凝胶颗粒，混合均匀后得到改性玻璃酸钠聚合物水凝胶复合注射液。
5.如权利要求4所述的改性玻璃酸钠水凝胶复合注射液的制备方法，其特征在于，复合注射液中玻璃酸钠水凝胶颗粒加入质量比为1％～20％。
6.一种改性玻璃酸钠水凝胶复合注射液，其特征在于，由权利要求4所述的方法制备得到。
7.如权利要求6所述的改性玻璃酸钠水凝胶复合注射液用于治疗骨关节炎、退行性关节炎等关节炎疾病、缓解关节疼痛的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023084110A1 (de) * | 2021-11-15 | 2023-05-19 | Bauerfeind Ag | Entzündungshemmendes viskosupplementierendes mittel enthaltend hyaluronsäure |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023084110A1 (de) * | 2021-11-15 | 2023-05-19 | Bauerfeind Ag | Entzündungshemmendes viskosupplementierendes mittel enthaltend hyaluronsäure |
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Application publication date: 20220517 |