CN114886915B - 用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液 - Google Patents
用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液 Download PDFInfo
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- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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Abstract
本发明提供一种用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液及其制备方法,涉及医药技术领域。本发明的注射液其由二十碳五烯酸纳米乳液和玻璃酸钠溶液混合而成。本发明的复合二十碳五烯酸的玻璃酸钠注射液,不仅可以通过玻璃酸钠恢复关节液的正常粘弹性起到润滑和渗透压缓冲的作用,同时还可将二十碳五烯酸带入关节软骨微环境,通过调节炎症反应减缓骨关节进程,发挥治疗骨关节炎的作用。
Description
技术领域
本发明涉及医药技术领域,特别是涉及一种用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液。
背景技术
骨关节炎(Osteoarthritis,OA)是一种由多因素引起的软骨变性、纤维化、磨损剥脱,软骨下骨硬化、囊性变,关节边缘骨赘形成,滑膜炎症增生,进而导致关节功能障碍的慢性退行性疾病。随着人口老龄化的加剧,满足日益增长的骨关节炎治疗需求具有重要意义。
目前,骨关节炎的治疗方式是药物与非药物治疗相结合,必要时进行手术治疗。以最常见的膝骨关节炎为例,早期保守治疗主要包括两类治疗方式:第一类为口服药物,包括氨基葡萄糖、非甾体类抗炎药、曲马多及阿片类镇痛剂等;第二类为膝关节腔注射制剂,包括玻璃酸钠(Hyaluronic acid,HA)、糖皮质激素和富血小板血浆等。其中,曲马多及阿片类镇痛剂是单纯的中枢类镇痛药物,氨基葡萄糖、非甾体类抗炎药、糖皮质激素、富血小板血浆通过抑制炎症反应减缓骨关节炎症状,玻璃酸钠注射液通过补充膝关节腔粘弹性减缓骨关节炎症状。
内源性玻璃酸钠是一种由浅层软骨细胞合成的大分子量蛋白多糖,广泛存在于关节滑液、滑膜和软骨细胞外基质(Extracellularmatrix,ECM)中。玻璃酸钠不仅可以为关节腔提供粘弹性、润滑和保持组织水分,还可以通过发挥渗透压缓冲液的作用来维持软骨微环境稳定。在人体内,每天约有1/3的玻璃酸钠会被降解及再合成,并通过关节腔的淋巴循环清除,最后在肝窦内皮细胞降解。随着年龄的增长,内源性玻璃酸钠的分子量会不断下降;随着骨关节炎的进展,内源性玻璃酸钠的合成总量也在不断减少。因此,通过关节腔注射(Intra-articular injection)补充外源性玻璃酸钠来弥补关节炎进展中由于内源性玻璃酸钠分子量及合成总量下降造成的软骨组织功能丢失,是目前常用的骨关节炎治疗手段之一。大量研究显示,现有的玻璃酸钠注射液主要包括两个作用阶段:初始的生物力学作用阶段和紧随其后的生理学作用阶段。在进行关节腔玻璃酸钠注射治疗后,骨关节炎关节腔的滑液被正常的外源性高分子量玻璃酸钠替代,这不仅帮助关节液恢复正常的粘弹性,还起到了润滑和渗透压缓冲的作用,从而在注射早期有效缓解骨关节炎患者的疼痛。
作为目前临床广泛使用的关节腔粘弹性补剂,玻璃酸钠注射液具有较高的安全性,一定程度减少了非甾体类抗炎药的使用剂量和副作用。研究表明,随着外源性玻璃酸钠的逐渐降解(数小时至数天),其作用也快速消退,这种暂时性的粘弹性补剂替代治疗仅仅可以起到短期(数天至数周)缓解患者疼痛的作用。目前临床广泛使用过的玻璃酸钠注射液的主要功能依赖于粘弹性的短时间补充和覆盖软骨后对炎症因子的暂时隔绝,不具备真正的抗炎作用,功能较为单一。
发明内容
基于此,有必要针对现有的玻璃酸钠注射液功能单一的问题,提供一种用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,将二十碳五烯酸和玻璃酸钠制备成乳化效果好、稳定性好的注射液,注射至体内后玻璃酸钠和二十碳五烯酸同时发挥作用,不仅可以通过玻璃酸钠恢复关节液的正常粘弹性起到润滑和渗透压缓冲的作用,同时还可将二十碳五烯酸带入关节软骨微环境,通过调节炎症反应减缓骨关节进程,发挥治疗骨关节炎的作用。
本发明提供的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其由二十碳五烯酸纳米乳液和玻璃酸钠溶液混合而成。
研究表明二十碳五烯酸(Eicosapentaenoic acid,EPA)可以通过其显著的生物学抗炎作用阻止、延缓骨关节炎的进程,但是现有技术中还未有将二十碳五烯酸与玻璃酸钠复合得到多功能注射液的报道。发明人发现纳米乳化的二十碳五烯酸可以稳定分散于玻璃酸钠溶液中,得到的注射液注射到关节腔内,可以降低炎症反应水平,还能够补充关节液粘弹性。
在其中一个实施例中,所述二十碳五烯酸纳米乳液和玻璃酸钠溶液的混合重量比为1:(10~50)。如高于此比例,则会显著改变玻璃酸钠溶液的粘弹性和流变学性质;低于此比例,则会降低药效。
在其中一个实施例中,所述二十碳五烯酸纳米乳液为采用磷脂聚乙二醇进行界面稳定的二十碳五烯酸水相纳米乳液。
采用磷脂聚乙二醇(DSPE-PEG)将二十碳五烯酸制备成纳米乳化液,与玻璃酸钠有较好的相容性,纳米乳化液与玻璃酸钠混合后可以得到稳定性好的注射液,射液被注射至体内后玻璃酸钠和二十碳五烯酸同时发挥作用,不仅可以通过玻璃酸钠恢复关节液的正常粘弹性起到润滑和渗透压缓冲的作用,同时还可将二十碳五烯酸带入关节软骨微环境,通过调节炎症反应减缓骨关节进程,发挥治疗作用,对现有玻璃酸钠注射液进行了功能补充。
在其中一个实施例中,所述二十碳五烯酸纳米乳液的水合粒径尺寸为100~220nm。
在其中一个实施例中,所述二十碳五烯酸纳米乳液中二十碳五烯酸的浓度为45~55mg/mL。
在其中一个实施例中,所述玻璃酸钠溶液中玻璃酸钠的质量浓度为90%~98%。该玻璃酸钠溶液的动态粘弹性较稳定,在不同频率范围的粘度为初始动态粘度的90%~110%。如玻璃酸钠的浓度低于此浓度,则会显著影响粘度和粘弹性,改变流变学性质。
在其中一个实施例中,所述玻璃酸钠溶液采用临床级玻璃酸钠注射液,如日本生化学工业株式会社生产的商品名为阿尔治的玻璃酸钠注射液。
在其中一个实施例中,所述复合二十碳五烯酸的玻璃酸钠注射液通过以下方法制备得到:
S1、将二十碳五烯酸和磷脂聚乙二醇共同溶解到有机溶剂并分散于水中,超声或剪切乳化,去除有机溶剂,得到二十碳五烯酸纳米乳液;
S2、将二十碳五烯酸纳米乳液和玻璃酸钠溶液混合,即得。
采用经过FDA认证的可用于临床的磷脂聚乙二醇作为媒介,有助于将脂溶性的二十碳五烯酸稳定地分散于玻璃酸钠注射液中,成功构建出复合纳米乳化二十碳五烯酸的玻璃酸钠注射剂,同时保证药物的安全性。
在其中一个实施例中,所述磷脂聚乙二醇中聚乙二醇嵌段的分子量为1800~2200Da。
在其中一个实施例中,所述磷脂聚乙二醇中聚乙二醇嵌段末端基为:羟基、甲氧基、氨基、羧基、叠氮基、炔基、马来酰亚胺基、琥珀酰亚胺基、二苯并环辛烯基、环氧基、丙烯酸酯基、甲基丙烯酸酯基、甲基丙烯酸酰胺基、乙烯基、乙烯基砜、巯基、醛基、苯甲醛基、生物素、卤素、酰肼、4-硝基苯酯、降冰片烯基或巯基吡啶。
在其中一个实施例中,所述磷脂聚乙二醇中聚乙二醇嵌段末端基上还修饰有蛋白、多肽、抗体或荧光素。
在其中一个实施例中,所述有机溶剂为二氯甲烷。
在其中一个实施例中,S1中二十碳五烯酸和磷脂聚乙二醇的质量比为(70~80):(10~20)。在此质量比例下,制备得到的二十碳五烯酸纳米乳的尺寸合适,并且稳定性高。
与现有技术相比,本发明具有以下有益效果:
本发明的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,在关节腔注射后,不仅可以通过外源性玻璃酸钠恢复关节液的正常粘弹性,起到润滑和渗透压缓冲的作用,同时还可将二十碳五烯酸带入关节软骨微环境,通过调节炎症反应减缓骨关节炎进程,发挥一定的治疗作用。该注射液具备良好的抗炎功能,可以有效减少非甾体类抗炎药的使用剂量和副作用。本发明的注射剂在不显著改变原玻璃酸钠注射液的粘度和粘弹性等性质的基础上,额外增加了抗炎作用,对现有玻璃酸钠注射液进行了功能补充。本发明是在对本领域的深度了解的基础上提出的,不是简单的将具有抗炎作用的二十碳五烯酸纳米乳液和临床用玻璃酸钠关节注射液混合,而是在具备了解了两种组份如何互相影响的情况下设计产生的。在本发明中,引入二十碳五烯酸纳米乳液,在一定组份比例下不改变关节注射液的的粘弹性、润滑和缓冲作用,又能保持二十碳五烯酸良好的纳米分散性、可注射行和稳定性,提高抗炎药物有效作用时间和生物利用度,两种组份在本发明特定的纳米剂型改进和组份优化条件下具有协同增效作用。
附图说明
图1为EPA的化学结构式。
图2为EPA纳米乳结构示意图。
图3为EPA纳米乳液稳定性测试结果。
图4为DLS及透射电镜测试结果。
图5为粘度和粘弹性测试结果。
图6为复合二十碳五烯酸的玻璃酸钠注射液用于骨关节炎治疗示意图。
图7为复合二十碳五烯酸的玻璃酸钠注射液用于小鼠骨关节炎治疗的结果。
具体实施方式
为了便于理解本发明,以下将给出较佳实施例对本发明进行更全面的描述。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
以下实施例中的原料,除非特殊说明,均为市售购得。
实施例1
一种复合二十碳五烯酸的玻璃酸钠注射液,通过以下方法制备得到:
(1)取75mg二十碳五烯酸(EPA,结构式如图1所示)和15mg磷脂聚乙二醇(DSPE-PEG2k)于圆底EP管内,加入300μL二氯甲烷溶解,得到二十碳五烯酸有机溶液。
(2)在4mL西林瓶内加入1.5mL纯水,再加入上述二十碳五烯酸有机溶液,将西林瓶置入超声震荡仪中,置于冰浴中充分震荡,再放入超声细胞破碎仪中,在冰浴中进行乳化至乳化物粒径为200nm左右,加入至干净的旋蒸瓶,使用旋蒸仪蒸去二氯甲烷,得到二十碳五烯酸纳米乳液(即EPA纳米乳液)。乳化过程中,可以通过以下方法测试乳化物粒径:在四通比色皿中加入少量纯水,加入少量纳米乳液,混匀后放入激光粒度仪中测量粒径。纳米乳化液中二十碳五烯酸纳米乳结构如图2所示。
(3)将EPA纳米乳化液用0.22μm滤膜过滤除菌,与临床使用的玻璃酸钠注射液(日本生化学工业株式会社,阿尔治)混合,EPA纳米乳液与玻璃酸钠注射液的混合重量比为1:10,即得复合二十碳五烯酸的玻璃酸钠注射液。
实验例1
稳定性实验。
取0.05mL EPA(EPA常温下为无色至淡黄色透明液体),加入1mL水中,震荡超声混合均匀后放置5分钟,结果如图3左图所示,体系发生分层,结果表明EPA在水中不稳定。
取实施例1制备过程中的EPA纳米乳液,用纯水或PBS稀释成不同浓度,在25℃下放置14天,结果如图3右图所示,从左到右浓度依次为10,5,2,1,0.5,0.2,0.1,0.01mg/mL,从图中可以看出,实施例1中制备的EPA纳米乳液具有极好的稳定性。
实验例2
动态光散射(Malvern Nanosizer)测试纳米乳液的粒径和粒径分布。
将实施例1中制备的EPA纳米乳液(50mg/mL)稀释合适的倍数,使原始散射光强在300kHz counter rate左右,使用488nm入射光,入射角度90°,于25℃下测试。通过分析散射光强度随时间的随机涨落关系,得到相关性系数随时间的衰减关系,使用累差法拟合出相关性系数,反演后可以计算出纳米粒子的平移扩散系数(Df),从而可以根据StokesEinstein方程计算出纳米粒子的流体力学水合半径(Dh)粒径分布和粒径的统计平均值。使用透射电子显微镜(Hitachi,Japan)观察纳米乳液形貌,将稀释后的EPA纳米乳液(0.2mg/mL)取7μL滴到400目铜网上,自然干燥后使用重金属试剂进行染色,完全干燥后通过在80kV加速电压下观察纳米粒子形貌。动态光散射显示EPA纳米乳液的平均直径为158.7±77.9nm,透射电镜可以清楚显示EPA纳米乳液的纳米形貌(如图4)。
实验例3
粘度和粘弹性测试。
取实施例1中制备得到的复合二十碳五烯酸的玻璃酸钠注射液,以及实施例1中使用的现有的玻璃酸钠注射液(日本生化学工业株式会社,阿尔治),使用哈克旋转流变仪测试粘度和粘弹性。将样品加入到20mm直径平椎板(1°锥角)间,测试不同剪切速率下的粘度值。固定剪切应变1%,测试不同剪切频率下样品的储存模量(G')和损耗模量(G”)值。
结果如图5所示,实验结果显示实施例1的注射液的粘度与剪切模量与现有的玻璃酸钠注射液相比没有显著差异。
实验例4
动物实验
1.实验方法:选取出生8周的C57BL/6J小鼠进行造模。使用1%戊巴比妥钠腹腔麻醉,剂量为40mg/kg。在无菌环境下准备小鼠膝关节皮肤,2%碘伏消毒,沿髌韧带内侧缘切开约0.5cm大小的切口,逐层切开后暴露膝关节,显微镜下离断前交叉韧带,消毒,缝合关节囊及皮肤。假手术对照(sham surgery)组仅暴露膝关节后缝合。
本实验使用48只小鼠,造模后随机分为4组,每组12只小鼠,分别为:假手术对照组,前交叉韧带离断(anterior cruciate ligament transection,ACLT)组、HA组和复合二十碳五烯酸的玻璃酸钠(EPA-HA)组。
术后1周开始膝关节注射(假手术对照组和前交叉韧带离断组注射生理盐水),每次10μL,连续注射4周后,于第5周收取膝关节样本。将取出标本进行多聚甲醛固定,脱钙后进行石蜡包埋,6μm切片后分别进行苏木精-伊红(hematoxylin-eosin,HE)染色和番红O(safraninO,SO)染色。
2.实验结果和分析
实验结果如图7所示。根据HE染色结果(图7A)分析不同条件下小鼠膝关节软骨厚度(cartilage thickness)、透明软骨与钙化软骨厚度的比值(hyaline cartilage/calcified cartilage,HC/CC)。如图7C所示,sham组的软骨厚度为51.8±8.85μm,ACLT组和HA组的软骨厚度(25.9±4.44μm,22.67±3.53μm)较sham组明显降低,但是,EPA-HA组的软骨厚度(38.8±5.64μm)较ACLT组和HA组明显提高。如图7D所示,sham组的HC/CC为0.75±0.22,ACLT组和HA组的HC/CC(0.44±0.1,0.35±0.1)较sham组明显降低,但是,EPA-HA组(0.50±0.1)较ACLT组和HA组明显提高。根据SO染色结果(图7B)分析不同条件下小鼠骨关节炎OARSI评分。如图7E所示,Sham组的OARSI评分为0.58±0.19,ACLT组和HA组的评分(5.33±0.47,2.5±0.5)较sham组升高明显,但是,EPA-HA组的评分(1.25±0.56)较ACLT组和HA组明显降低。
由上述结果可知,1)前交叉韧带离断造模可以导致小鼠膝关节软骨厚度明显降低、钙化软骨明显增多、OARSI评分明显升高,表现出典型的骨关节炎症状;2)单纯的玻璃酸钠注射无法阻止骨关节炎的病理进程;3)与玻璃酸钠注射组相比,实施例1中制备得到的复合二十碳五烯酸的玻璃酸钠注射液可以明显增加小鼠膝关节软骨厚度、减少钙化软骨比例、降低OARSI评分,具备治疗骨关节炎的作用。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (8)
1.一种用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,其由二十碳五烯酸纳米乳液和玻璃酸钠溶液混合而成,所述二十碳五烯酸纳米乳液和玻璃酸钠溶液的混合重量比为1:10;
所述二十碳五烯酸纳米乳液为采用磷脂聚乙二醇进行界面稳定的二十碳五烯酸水相纳米乳液;
所述二十碳五烯酸纳米乳液中二十碳五烯酸的浓度为45~55mg/mL。
2.根据权利要求1所述的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,所述二十碳五烯酸纳米乳液的水合粒径尺寸为100~220nm。
3.根据权利要求1所述的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,所述玻璃酸钠溶液中玻璃酸钠的质量浓度为90%~98%。
4.根据权利要求1所述的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,所述复合二十碳五烯酸的玻璃酸钠注射液通过以下方法制备得到:
S1、将二十碳五烯酸和磷脂聚乙二醇共同溶解到有机溶剂并分散于水中,超声或剪切乳化,去除有机溶剂,得到二十碳五烯酸纳米乳液;
S2、将二十碳五烯酸纳米乳液和玻璃酸钠溶液混合,即得。
5.根据权利要求4所述的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,所述磷脂聚乙二醇中聚乙二醇嵌段的分子量为1800~2200Da。
6.根据权利要求4所述的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,所述磷脂聚乙二醇中聚乙二醇嵌段末端基为:羟基、甲氧基、氨基、羧基、叠氮基、炔基、马来酰亚胺基、琥珀酰亚胺基、二苯并环辛烯基、环氧基、丙烯酸酯基、甲基丙烯酸酯基、甲基丙烯酸酰胺基、乙烯基、乙烯基砜、巯基、醛基、苯甲醛基、生物素、卤素、酰肼、4-硝基苯酯、降冰片烯基或巯基吡啶。
7.根据权利要求6所述的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,所述磷脂聚乙二醇中聚乙二醇嵌段末端基上还修饰有蛋白、多肽、抗体或荧光素。
8.根据权利要求4所述的用于治疗骨关节炎的复合二十碳五烯酸的玻璃酸钠注射液,其特征在于,S1中二十碳五烯酸和磷脂聚乙二醇的质量比为(70~80):(10~20)。
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