CN116370419A - 一种用于关节腔内注射的药物组合物和应用 - Google Patents
一种用于关节腔内注射的药物组合物和应用 Download PDFInfo
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Abstract
本发明属于药物应用领域，具体涉及了一种用于关节腔内注射的药物组合物和应用。所述药物组合物为以抗炎药物为有效成分，以高分子材料为载体的载药缓释微球，该载药缓释微球粒径为20‑200um之间。其中，所述抗炎药物为皮质类固醇药物或非甾体抗炎药，高分子材料为PLGA。本发明提供的载药缓释微球可用于关节部位注射，有效作用时间延长到21天以上，降低了给药频率。由于药物直接作用在病变部位，达到精准治疗的目的，降低了血液中的药物浓度，减少了全身的副反应。
Description
技术领域
本发明属于药物应用领域，具体涉及一种用于关节腔内注射的药物组合物和应用。
背景技术
骨关节炎为一种退行性病变，系由于增龄、肥胖、劳损、创伤、关节先天性异常、关节畸形等诸多因素引起的关节软骨退化损伤、关节边缘和软骨下骨反应性增生，又称骨关节病、退行性关节炎、老年性关节炎、肥大性关节炎等。临床表现为缓慢发展的关节疼痛、压痛、僵硬、关节肿胀、活动受限和关节畸形等。该病多发生于老龄阶段，青壮年阶段也有发生。随着我国社会步入老龄化阶段，缓解甚至治愈骨关节炎具有极大的社会意义。
用于骨关节炎治疗的药物主要包括甾体类与非甾体类，一般，甾体类的抗炎作用强，但存在水钠潴留，变虚胖，感染危险，骨质疏松等副作用。非甾体类抗炎作用弱，副作用主要是胃肠道反应，还有心血管疾病的风险。
因为口服抗炎药物药效一般且对全身毒性大，所以关节腔内注射抗炎药物成为治疗骨关节炎的最有效疗法之一，该疗法可直接将药物输送到病变关节部位，避免全身毒性，改变药物在体内的分布。注射法虽然高效但仍有局限性，给药后药物有效成分迅速的渗透到体循环中，在关节腔内停留时间短，导致频繁注射，治疗过程痛苦。
于是关节腔内注射的缓释剂型成为了研究热点。而在已知的所有的缓释剂型中，微球是目前技术最成熟应用最广泛的剂型。微球多采用生物相容性好的高分子材料如PCL、PLGA、PLLA等作为骨架，将所载药物均匀分散在微球中。
丙交酯乙交酯共聚物有(poly(lactic-co-glycolic acid)，PLGA)由两种单体—乳酸和羟基乙酸随机聚合而成，是一种可降解的功能高分子有机化合物，具有良好的生物相容性、无毒、良好的成囊和成膜的性能，被广泛应用于制药、医用工程材料和现代化工业领域。在美国PLGA通过FDA认证，被正式作为药用辅料收录进美国药典。
发明内容
基于口服抗炎药的局限性与PLGA的特点，本发明提出一种可用于关节腔内注射，以PLGA作为载体，抗炎药均匀分散在PLGA内的缓释微球，本发明具有传统抗炎药物的治疗作用，而且释放周期长减少治疗痛苦，与此同时因PLGA微球本身特有的延伸性对关节运动具有缓冲减震作用。
所说的微球(microspheres)是指药物溶解和/或分散于高分子材料中形成的微小球状实体，球形或类球形，微球粒径范围一般为20-200μm，一般制备成混悬剂供注射用。
PLGA的特性粘度(intrinsic viscosity)测定方法：将PLGA用氯仿配制成约0.5％(w/v)的溶液，于30℃采用Cannon-Fenske玻璃毛细管粘度计测定其特性粘度。
本发明所述分子量指“重均分子量”，简称为“分子量”
为方便描述，下文对PLGA特性粘度、分子量在其括号中进行表示。如“PLGA(0.5,75000)”表示，特性粘度为0.5dL/g，分子量为75000道尔顿的PLGA。
本发明所述载药量为实际载药量，按照以下方式计算：载药量＝[微球中药物量/(微球中药物量+高分子量)]×100％。
本发明是通过以下技术方案实现的：
本发明提供了一种关节腔内注射的药物组合物，所述药物组合物为以抗炎药物为有效成分，以高分子材料为载体的载药缓释微球，载药缓释微球粒径在20-200um之间。
其中，所述抗炎药物为皮质类固醇药物曲安奈德或非甾体抗炎药中萘普生、塞来昔布、美洛昔康、布洛芬任意一种或不同组合；所述抗炎药物重量含量为10-30％。
本发明所述高分子材料为PLGA，分子量在5000-100000之间，优选地在10000-75000之间，更优选地在15000-40000之间；PLGA重量含量为70-90％。
PLGA的特性粘度在0.10-0.70dL/g之间，优选地在0.15-0.50dL/g之间，更优选地在0.20-0.35dL/g之间。
所述PLGA中单体LA与GA的摩尔比为70-95：5-30。
本发明提供的载药缓释微球由专用溶媒进行混悬后注射至关节腔内使用，给药剂量为32mg/90d(以抗炎药物计)。
本发明还提供了一种用于关节腔内注射的医药组合物在制备治疗骨性关节炎药物中的应用。
本发明的有益效果：
本发明提供的载药缓释微球可用于关节部位注射，将药物有效成分直接作用到病变部位，减少对全身的副作用，药物有效时间可持续21天以上，降低了给药频率，减少治疗痛苦。
具体实施方式
实施例1
称取曲安奈德微球160mg(含曲安奈德32mg)，放置于7ml灭菌后的西林瓶中，量取5ml专用溶媒加入到7ml西林瓶中，进行超声、混悬；混匀后用1ml注射器吸取1ml曲安奈德微球溶液注入经造模后的比格犬左膝关节，并于第3天、第7天，第14天，第21天观察肿胀度、检查支力差。
实施例2
称取布洛芬微球320mg(含布洛芬32mg)，放置于7ml灭菌后的西林瓶中，量取5ml专用溶媒加入到7ml西林瓶中，进行超声、混悬；混匀后用1ml注射器吸取1ml布洛芬微球溶液注入经造模后的比格犬左膝关节，并于第3天、第7天，第14天，第21天观察肿胀度、检查支力差。
实施例3
称取萘普生微球160mg(含萘普生32mg)，放置于7ml灭菌后的西林瓶中，量取5ml专用溶媒加入到7ml西林瓶中，进行超声、混悬；混匀后用1ml注射器吸取1ml萘普生微球溶液注入经造模后的比格犬左膝关节，并于第3天、第7天，第14天，第21天观察肿胀度、检查支力差。
实施例4
称取曲安奈德微球160mg(含曲安奈德32mg)，放置于7ml灭菌后的西林瓶中，量取5ml专用溶媒加入到7ml西林瓶中，进行超声、混悬；称取布洛芬微球320mg(含布洛芬32mg)，放置于7ml灭菌后的西林瓶中，量取5ml专用溶媒加入到7ml西林瓶中，进行超声、混悬；混匀后用1ml注射器分别吸取1ml曲安奈德微球溶液和布洛芬微球溶液注入经造模后的比格犬左膝关节，并于第3天、第7天，第14天，第21天观察肿胀度、检查支力差。
实验结果
本次实施例动物药效学实验以碘乙酸钠致比格犬膝关节炎模型后第4天，一次单侧关节腔分别注射不同实施例供试品1mL/只，分别于给药后3、7、14、21天，检测肿胀度和支力差。在减轻疼痛方面，各实施例均可持续至药后21天。在减轻肿胀度方面，除药后7天时实施例均未见明显减轻比格犬关节肿胀程度外，各实施例均可持续至21天，具有明显的缓释效果。具体数据见表1、表2。
表1肿胀度
表2支力差
Claims (8)
1.一种关节腔内注射的药物组合物，其特征在于，所述药物组合物为以抗炎药物为有效成分，以高分子材料为载体的载药缓释微球；所述载药缓释微球粒径20-200um。
2.根据权利要求1所述的一种关节腔内注射的药物组合物，其特征在于，所述抗炎药物为皮质类固醇药物曲安奈德或非甾体抗炎药中萘普生、塞来昔布、美洛昔康、布洛芬任意一种或不同组合；所述抗炎药物重量含量为10-30％。
3.根据权利要求1所述的一种关节腔内注射的药物组合物，其特征在于，所述高分子材料为PLGA，重量含量为70-90％。
4.根据权利要求3所述的一种关节腔内注射的药物组合物，其特征在于，所述PLGA中单体LA与GA的摩尔比为70-95：5-30。
5.根据权利要求3所述的一种关节腔内注射的药物组合物，其特征在于，所述PLGA的分子量在5000-100000之间。
6.根据权利要求3所述的一种关节腔内注射的药物组合物，其特征在于，所述PLGA的特性粘度在0.10-0.70dL/g之间。
7.一种关节腔内注射的药物组合物制成药物组合物混悬注射的方法，其特征在于，由专用溶媒进行混悬后注射至关节腔内使用。
8.权利要求1-7任一项所述用于关节腔内注射的药用组合物在制备治疗骨性关节炎药物中的应用。
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