CN116077669A - 用于治疗关节痛的糖皮质激素纳米脂质载体、制法及应用 - Google Patents
用于治疗关节痛的糖皮质激素纳米脂质载体、制法及应用 Download PDFInfo
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- CN116077669A CN116077669A CN202211617076.XA CN202211617076A CN116077669A CN 116077669 A CN116077669 A CN 116077669A CN 202211617076 A CN202211617076 A CN 202211617076A CN 116077669 A CN116077669 A CN 116077669A
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Abstract
本发明属于药物制剂技术领域,具体涉及一种用于治疗关节痛的糖皮质激素纳米脂质载体、制法及应用。所述的糖皮质激素纳米脂质载体的制备原料包括糖皮质激素、磷脂和15‑羟基硬脂酸聚乙二醇酯,所述的糖皮质激素、磷脂和15‑羟基硬脂酸聚乙二醇酯的质量比为0.5‑20:20‑140:10‑200。本发明的有益效果为:本发明通过采用包括糖皮质激素、磷脂和15‑羟基硬脂酸聚乙二醇酯为原料,可制备得到具有长效镇痛且镇痛效果好的糖皮质激素纳米脂质载体,且工艺简单可行,可控性强,可连续化批量生产。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种用于治疗关节痛的糖皮质激素纳米脂质载体、制法及应用。
背景技术
骨关节炎(OA)是一种多因素引起的以关节疼痛为主要症状的衰老性疾病,致残率高,给国家和社会造成了沉重负担。镇痛是OA患者就诊的最主要诉求。糖皮质激素(glucocorticoid,GC)是一类药理作用多样的甾体类小分子药物,可通过抑制炎症反应而发挥镇痛作用,已被广泛用于OA镇痛;但GC存在镇痛效果维持时间较短、效果不够显著以及存在安全性隐患等亟待解决的重要问题。如临床使用的曲安奈德速释混悬注射剂,在骨关节炎患者的膝关节平均滞留时间为3.8天,关节腔注射频率较高。因此,降低GC给药频率,延长其骨关节炎镇痛效果,具有重要意义。
近年来,随着生物高分子聚合物材料在医药学领域的广泛应用,基于高分子聚合物的缓释微球逐渐成为新药物制剂的研究热点之一。目前,上市的高分子聚合物缓释微球主要是聚乳酸-羟基乙酸(PLGA)缓释微球。将GC(如曲安奈德、地塞米松、地塞米松棕榈酸酯等)包载在PLGA微球,将其进行关节腔注射后,可延长GC对OA的镇痛效果,但药物在关节腔中的滞留时间和镇痛时间与微球的粒径相关,当微球的粒径大于25μm时,有促进关节炎症发展的风险。另外,PLGA缓释微球的制备工艺复杂,末端灭菌困难,且降解过程中产生的乳酸和羟基乙酸可能造成关节腔内pH降低,从而促进炎症反应的发展。
发明内容
本发明的目的在于针对现有技术中存在的上述问题,提供一种具有长效镇痛且镇痛效果好,质量稳定,安全性高的用于治疗关节痛的糖皮质激素纳米脂质载体、制法及应用。
本发明提供一种用于治疗关节痛的糖皮质激素纳米脂质载体,其制备原料包括糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯,所述的糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯的质量比为0.5-20:20-140:10-200。
本发明特别采用了由磷脂和15-羟基硬脂酸聚乙二醇酯组成的脂质体膜材料,磷脂为脂质体膜结构的基础,15-羟基硬脂酸聚乙二醇酯具有聚乙二醇单酯和15-羟基硬脂酸在内的亲油性基团和聚乙二醇亲水性基团,因而具有一定的乳化性。当采用单一磷脂制备时,得到的溶液透光度差,且有明显的药物晶体出现,而当同时添加了磷脂和15-羟基硬脂酸聚乙二醇酯两种组分以后可制备得到具有良好理化稳定性的纳米脂质载体。优选的,所述的糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯的质量比为2-5:20-140:10-200,进一步优选为4:140:70。
本发明中的磷脂可从常规原料中选择,包括但不限于天然磷脂(例如蛋黄卵磷脂、大豆卵磷脂)、氢化卵磷脂、合成磷脂(例如磷脂酰乙醇胺、磷脂酰胆碱等),优选卵磷脂。糖皮质激素可选自丙酸氯倍他索、醋酸双氟拉松、丙酸地塞米松、二氟泼尼酯、糠酸莫米松、戊酸双氟可龙、倍他米松丁酸丙酸酯、醋酸氟轻松、丙酸丁酸氢可的松、丙酸倍氯米松、丙酸地泼罗酮、戊酸倍他米松、戊酸地塞米松、泼尼松龙醋酸戊酸酯、氟轻松、丁酸氢化可的松、丁酸氯倍他松、丙酸阿氯米松、曲安奈德、醋酸曲安奈德、氟米松新戊酸酯、泼尼松龙、氢化可的松、地塞米松、醋酸地塞米松、地塞米松棕榈酸酯、曲安奈德棕榈酸酯中的一种或多种,优选曲安奈德、地塞米松或其药学上可接受的盐或乙酰化物或棕榈酸酯。所述的盐包括但不限于无机酸、有机酸的盐,无机酸包括但不限于盐酸、硫酸、硝酸,有机酸包括但不限于乙酸(即醋酸)、柠檬酸、乳酸、甲酸。
本发明前述的糖皮质激素纳米脂质载体的制备方法,包括如下步骤:(1)将糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯溶于有机溶剂中,然后除去有机溶剂,得混合物;(2)将混合物用水性介质水化,然后进行冰水浴探头超声,即得;步骤(1)中,所述的有机溶剂包括但不限于氯仿、丙酮、二氯甲烷、甲醇,优选氯仿和/或丙酮,采用减压旋蒸除去有机溶剂;步骤(2)中,所述的水性介质为纯水或缓冲溶液,所述的缓冲溶液包括磷酸盐缓冲液、生理盐水,优选生理盐水,所述的冰水浴探头超声优选功率为300W,时间为5min。
本发明前述的糖皮质激素纳米脂质载体的基础上,可进一步通过常规冷冻干燥的方法制备成为冻干粉针剂。
本发明前述的糖皮质激素纳米脂质载体的制备方法,对制备工艺过程及参数均进行了优选,从而形成了最终的制备方法,1)制备的纳米脂质载体平均粒径在100-150nm,相同剂量下,药效更好,所以达到相同治疗效果,药物使用量会更少,安全性更高,且工艺简单可行,可控性强,可连续化批量生产;2)关节腔滞留实验研究发现,不同材料制备的高分子纳米载体,即使粒径差不多,其在OA模型大鼠关节腔内的滞留时间远远短于本发明制备的纳米脂质载体在OA模型大鼠关节腔内的滞留时间;药效学实验研究发现,前述高分子纳米载体第35天机械缩足阈值和第35天双足负重差/造模后肢重量的比值均明显低于本发明纳米脂质载体。以上结果证实了,本发明限定的制备方法利于制备更具长效镇痛且镇痛效果更好的糖皮质激素纳米脂质载体。
本发明前述的糖皮质激素纳米脂质载体,将其制成治疗关节痛的药物,可有效解决现有的糖皮质激素药物镇痛作用持续时间短,或高分子材料缓释制剂制备工艺复杂且材料降解存在安全性隐患问题。
本发明的有益效果为:
本发明通过采用包括糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯为原料,可制备得到具有长效镇痛且镇痛效果好,质量稳定,安全性高的糖皮质激素纳米脂质载体,且工艺简单可行,可控性强,可连续化批量生产。
附图说明
图1A:细胞编码TNF-α基因的mRNA的相对表达量;
图1B:细胞编码IL-1β基因的mRNA的相对表达量;
图1C:细胞编码IL-6基因的mRNA的相对表达量;
图1D:细胞编码IL-4基因的mRNA的相对表达量;
图1E:细胞编码IL-10基因的mRNA的相对表达量;
图1F:细胞编码iNOS基因的mRNA的相对表达量;
图2:各组样品关节内分布实验结果(n=3);
图3A:OA模型大鼠右后肢机械缩足阈值变化图(n=7);
图3B:OA模型大鼠双足负重差/造模后肢重量的比值变化图(n=7);
图4A:OA模型大鼠右后肢机械缩足阈值变化图(n=7);
图4B:OA模型大鼠双足负重差/造模后肢重量的比值变化图(n=7)。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明的技术方案进行详细的描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式,都属于本发明所保护的范围。
实施例1
将4mg曲安奈德、140mg磷脂E80、70mg15-羟基硬脂酸聚乙二醇酯(HS15)溶于100mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得曲安奈德纳米脂质载体,粒径为103nm。
实施例2
将2mg曲安奈德、100mg磷脂E80、10mg HS15溶于50mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得曲安奈德纳米脂质载体,粒径为140nm。
实施例3
将4mg曲安奈德、20mg磷脂E80、200mg HS15溶于50mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得曲安奈德纳米脂质载体,粒径为123nm。
实施例4
将3mg醋酸曲安奈德、140mg磷脂E80、70mg HS15溶于100mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得醋酸曲安奈德纳米脂质载体,粒径为110nm。
实施例5
将0.5mg曲安奈德、140mg磷脂E80、70mg HS15溶于100mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得曲安奈德纳米脂质载体,粒径为93nm。
实施例6
将10mg曲安奈德、140mg磷脂E80、70mg HS15溶于500mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得曲安奈德纳米脂质载体,粒径为123nm。
实施例7
将15mg醋酸曲安奈德、140mg磷脂E80、70mg HS15溶于300mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得醋酸曲安奈德纳米脂质载体,粒径为142nm。
实施例8
将5mg地塞米松、140mg磷脂E80、70mg HS15溶于50mL氯仿-丙酮混合溶液中,40℃减压旋蒸除去有机试剂,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得地塞米松纳米脂质载体,粒径为118nm。
实施例9
将5mg地塞米松棕榈酸酯、140mg磷脂E80、70mg HS15溶于100mL氯仿-丙酮混合溶液中,40℃减压旋蒸除去有机试剂,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得地塞米松棕榈酸酯纳米脂质载体,粒径为121nm。
实施例10
将20mg地塞米松棕榈酸酯、140mg磷脂E80、70mg HS15溶于200mL氯仿-丙酮混合溶液中,40℃减压旋蒸除去有机试剂,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得地塞米松棕榈酸酯纳米脂质载体,粒径为158nm。
实施例11
将5mg醋酸地塞米松、140mg磷脂E80、70mg HS15溶于100mL氯仿-丙酮混合溶液中,40℃减压旋蒸除去有机试剂,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min),即得醋酸地塞米松纳米脂质载体,粒径为128nm。
实施例12~22
本发明冻干粉针剂的制备,取实施例1~11实施例制备的糖皮质激素纳米脂质载体,经冷冻干燥,即得冻干粉针剂。
对比例1
将3mg曲安奈德、210mg磷脂E80溶于100mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min)后,溶液透光度差,且有明显的药物晶体出现。
对比例2
将3mg醋酸曲安奈德、210mg磷脂E80溶于100mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min)后,溶液透光度差,且有明显的药物晶体出现。
对比例3
将5mg曲安奈德、10mg磷脂E80、200mg HS15溶于100mL氯仿中,40℃减压旋蒸除去氯仿,加入4mL生理盐水水化,经冰水浴探头超声(300W,5min)后,溶液透光度较好,但10min内便有药物晶体析出。
对比例4
将2mg曲安奈德、800mg磷脂E80、1mg HS15溶于50mL氯仿中,40℃减压旋蒸除去氯仿,加入16mL生理盐水水化,经高压均质后,即得曲安奈德纳米脂质载体,粒径为145nm。由于HS15占比较低,该纳米脂质载体在关节内的滞留时间显著缩短。
对比例5
将2mg曲安奈德、200mg PLGA50/50(平均分子量4万)溶于二氯甲烷-丙酮混合溶液中,制成有机相;将PVA溶于水中配置成1%质量-体积浓度的PVA水溶液,作为水相;按照有机相/水相体积比1:10将两相混合,冰水浴中探头超声(300W,8min),再通过旋转蒸发仪除掉有机试剂,即得粒径为156nm的曲安奈德高分子纳米载体。该纳米载体可以顺利包载糖皮质激素(如曲安奈德),但其关节内的滞留时间较短,从而其对OA镇痛的效果也较差。
对比例6
将2mg地塞米松、200mg PLGA50/50(平均分子量4万)溶于二氯甲烷-丙酮混合溶液中,制成有机相;将PVA溶于水中配置成1%质量-体积浓度的PVA水溶液,作为水相;按照有机相/水相体积比1:10将两相混合,冰水浴中探头超声(300W,8min),再通过旋转蒸发仪除掉有机试剂,即得粒径为151nm的地塞米松高分子纳米载体。该纳米载体可以顺利包载糖皮质激素(如地塞米松),但其关节内的滞留时间较短,从而其对OA镇痛的效果也较差。
对比例7
将4mg地塞米松、1000mg磷脂E80、1mg HS15溶于50mL氯仿-丙酮混合液中,40℃减压旋蒸除去氯仿,加入20mL生理盐水水化,经高压均质后,即得地塞米松纳米脂质载体,粒径为149nm。由于HS15占比较低,该纳米脂质载体对OA大鼠关节炎症和疼痛的抑制作用显著降低。
实验例1体外生物学活性考察
将小鼠源巨噬细胞RAW264.7接种在12孔细胞培养板中,待其贴壁后,以脂多糖刺激24h,将培养基更换为含药(曲安奈德溶液或实施例1的曲安奈德纳米脂质载体)培养基,分别记为溶液组和纳米脂质载体组(曲安奈德的浓度为4μg/mL,不加药的培养基处理作为对照),孵育24h后,使用实时荧光定量PCR法测定其中IL-1β、TNF-α、IL-6、IL-10、IL-4以及iNOS的浓度。未经脂多糖处理的细胞和经脂多糖处理但未经曲安奈德处理的细胞分别记为“对照组”和“脂多糖组”,结果见图1A-图1F(*P<0.05,**P<0.01,***P<0.001)。
由图1A-图1F可知,相对于其他处理方法,曲安奈德纳米脂质载体处理可以显著降低巨噬细胞炎症因子基因的表达。
实验例2关节腔滞留实验
对SD大鼠膝关节的关节腔注射碘乙酸钠构建OA大鼠模型,待大鼠膝关节出现肿胀,痛阈显著降低,即得OA大鼠模型。将糖皮质激素用荧光标记物DiD代替,按照实施例1、实施例2、实施例3、对比例4和对比例5制备纳米载体。将DiD溶液、对比例4、对比例5、实施例1、实施例2及实施例3制备的纳米载体分别注射至OA大鼠膝关节腔内(每个关节腔内DiD的剂量为3μg),分别记为DiD溶液组、对照纳米脂质载体组、高分子纳米载体组、纳米脂质载体组1、纳米脂质载体组2及纳米脂质载体组3,于第0d、1d、2d、3d、7d、14d、21d及28d通过小动物活体成像仪考察大鼠炎性关节处的荧光强度。结果见图2。
由图2可知,相对于DiD溶液,本发明制备的纳米脂质载体可以在OA模型大鼠关节腔内的滞留至少可达28天。这些结果表明,本发明的纳米脂质载体在炎性关节腔内具有良好的缓释性。
实验例3药效学实验
对SD大鼠膝关节的关节腔注射碘乙酸钠构建OA大鼠模型,待大鼠膝关节出现肿胀,痛阈显著降低,即得OA大鼠模型。通过关节腔注射方式,对OA模型大鼠分别使用生理盐水、曲安奈德注射液(购于昆明积大制药股份有限公司)以及由对比例5和实施例1制得载曲安奈德纳米载体进行治疗,分别记为生理盐水组、曲安奈德注射液组、曲安奈德高分子纳米载体组以及曲安奈德纳米脂质载体组;另外,在正常大鼠膝关节腔内注射等体积的生理盐水作为正常组。曲安奈德的给药剂量为每个膝关节60μg,于造模后第7天给药,共给药1次。从给药第一天起,每周测量一次各组大鼠的机械缩足阈值及双足负重差值。结果见图3A、图3B。
由图3A、图3B可知,相对于其他方式来说,曲安奈德纳米脂质载体治疗可以更有效的缓解OA大鼠的关节炎症和疼痛。可见,本发明制备的纳米脂质载体在制备用于骨关节炎关节镇痛的药物方面具有很好的应用前景。
实验例4药效学实验
对SD大鼠膝关节的关节腔注射碘乙酸钠构建OA大鼠模型,待大鼠膝关节出现肿胀,痛阈显著降低,即得OA大鼠模型。通过关节腔注射方式,对OA模型大鼠分别使用生理盐水以及由对比例6、对比例7、实施例8制得地塞米松纳米载体进行治疗,分别记为生理盐水组、地塞米松高分子纳米载体组、地塞米松对照纳米脂质载体组以及地塞米松纳米脂质载体组;另外,在正常大鼠膝关节腔内注射等体积的生理盐水作为正常组。地塞米松的给药剂量为每个膝关节80μg,于造模后第7天给药,共给药1次。从给药第一天起,每周测量一次各组大鼠的机械缩足阈值及双足负重差值。结果见图4A、图4B。
由图4A、图4B可知,相对于其他方式来说,地塞米松纳米脂质载体治疗可以更有效的缓解OA大鼠的关节炎症和疼痛。该实验再次证实本发明制备的糖皮质激素纳米脂质载体在制备用于骨关节炎关节镇痛的药物方面具有很好的应用前景。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以所述权利要求的保护范围为准。
Claims (10)
1.一种用于治疗关节痛的糖皮质激素纳米脂质载体,其特征在于,其制备原料包括糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯,所述的糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯的质量比为0.5-20:20-140:10-200。
2.根据权利要求1所述的用于治疗关节痛的糖皮质激素纳米脂质载体,其特征在于,所述的糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯的质量比为2-5:20-140:10-200。
3.根据权利要求2所述的用于治疗关节痛的糖皮质激素纳米脂质载体,其特征在于,所述的糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯的质量比为4:140:70。
4.根据权利要求1所述的用于治疗关节痛的糖皮质激素纳米脂质载体,其特征在于,所述糖皮质激素包括丙酸氯倍他索、醋酸双氟拉松、丙酸地塞米松、二氟泼尼酯、糠酸莫米松、戊酸双氟可龙、倍他米松丁酸丙酸酯、醋酸氟轻松、丙酸丁酸氢可的松、丙酸倍氯米松、丙酸地泼罗酮、戊酸倍他米松、戊酸地塞米松、泼尼松龙醋酸戊酸酯、氟轻松、丁酸氢化可的松、丁酸氯倍他松、丙酸阿氯米松、曲安奈德、醋酸曲安奈德、氟米松新戊酸酯、泼尼松龙、氢化可的松、地塞米松、醋酸地塞米松、地塞米松棕榈酸酯、曲安奈德棕榈酸酯中的一种或多种。
5.根据权利要求1所述的用于治疗关节痛的糖皮质激素纳米脂质载体,其特征在于,所述的磷脂为卵磷脂;和/或,所述的糖皮质激素为曲安奈德、地塞米松或其药学上可接受的盐或乙酰化物或棕榈酸酯。
6.权利要求1-5之一所述的用于治疗关节痛的糖皮质激素纳米脂质载体的制备方法,其特征在于,包括如下步骤:
(1)将糖皮质激素、磷脂和15-羟基硬脂酸聚乙二醇酯溶于有机溶剂中,然后除去有机溶剂,得混合物;
(2)向混合物中加入水性介质水化,然后进行冰水浴探头超声,即得。
7.根据权利要求6所述的用于治疗关节痛的糖皮质激素纳米脂质载体的制备方法,其特征在于,步骤(1)中,所述的有机溶剂为氯仿和/或丙酮;和/或,采用减压旋蒸除去有机溶剂。
8.根据权利要求6所述的用于治疗关节痛的糖皮质激素纳米脂质载体的制备方法,其特征在于,步骤(2)中,所述的水性介质为生理盐水;和/或,所述的冰水浴探头超声的功率为300W,时间为5min。
9.一种用于治疗关节痛的糖皮质激素纳米脂质载体冻干粉针剂,其特征在于:它是由权利要求1-5任一项所述的糖皮质激素纳米脂质载体冷冻干燥制备而成。
10.权利要求1-5之一所述的用于治疗关节痛的糖皮质激素纳米脂质载体在制备治疗关节痛的药物中的应用。
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