CN113599538B - 一种特立帕肽超分子缓释纳米粒及其制备方法 - Google Patents
一种特立帕肽超分子缓释纳米粒及其制备方法 Download PDFInfo
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- CN113599538B CN113599538B CN202110954081.9A CN202110954081A CN113599538B CN 113599538 B CN113599538 B CN 113599538B CN 202110954081 A CN202110954081 A CN 202110954081A CN 113599538 B CN113599538 B CN 113599538B
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Abstract
本发明属于药物制剂领域。本发明涉及特立帕肽超分子缓释纳米粒及其制备方法。本发明制备得到特立帕肽超分子缓释纳米粒可以延缓特立帕肽的释放,延长特立帕肽在血液循环中的滞留时间,提高其生物利用度,且具有靶向性和光热效应。
Description
技术领域
本发明属于医药制剂领域,涉及一种特立帕肽超分子缓释纳米粒及其制备方法。
背景技术
骨质疏松症是全身性的慢性疾病。目前,全世界已有超过2亿人患有骨质疏松症,骨质疏松症的严重后果是发生骨质疏松性骨折(脆性骨折),从而导致患者较高的致残率和死亡率。目前临床上批准或研究中用于治疗骨质疏松症的药物主要是骨吸收抑制剂,抑制破骨细胞的作用,但是大部分的骨吸收抑制剂会出现严重不良反应(如残余骨折风险高达60%,心血管疾病患病风险增加等)。而特立帕肽是第一个上市的骨合成促进剂,可以增强成骨细胞的活性,对骨的生成有促进作用,其独特的治疗机制使其具有广阔的应用前景。但特立帕肽属于蛋白类药物,不稳定性,在体内吸收消除迅速,无靶向性,生物利用度低等缺点阻碍了其临床应用。环糊精具有略呈锥形的中空圆筒立体环状结构,外缘亲水而内腔疏水,它的疏水性内腔可包络适当的客体,并改变客体的化学性质,增强药物的稳定性,延长其作用时间。碳纳米管具有管状空腔结构,表面疏水性强,比表面积大,载药量高,跨膜能力强,无免疫原性,具备良好的光热转换能力,可以用于治疗骨缺损,促进成骨细胞作用,刺激骨重建和新骨的形成,具有协同特立帕肽治疗骨质疏松症的潜力,也可用作载体材料,直接递送药物。聚乳酸-羟基乙酸共聚物纳米粒,能改善药物释放行为的能力,延长药物作用时间,减少给药频率优点。植酸是天然存在的多磷酸化碳水化合物,能特异性结合骨组织的主要成分羟基磷灰石(Ca10(PO4)6(OH)2),而经植酸修饰后的聚乳酸-羟基乙酸共聚物纳米粒,除具有缓释特性外,兼具良好的骨组织靶向作用。
经查询专利及文献,目前尚无碳纳米管环糊精超分子纳米体系载带多肽类药物的任何研究报道,目前尚无特立帕肽碳纳米管环糊精超分子缓释纳米粒的任何研究报道。本发明制备得到的特立帕肽超分子缓释纳米粒可以延缓特立帕肽的释放,延长特立帕肽在血液循环中的滞留时间,提高其生物利用度,且具有靶向性和光热效应,有助于骨缺损创面生长,可用于治疗骨质疏松症。
发明内容
本发明所要解决的技术问题是提供特立帕肽超分子缓释纳米粒及其制备方法。特立帕肽超分子缓释纳米粒克服了其稳定性差,消除速度快,生物利用度低等缺点,可保持较长时间的血药浓度,具有缓释作用,能减少给药次数,提高患者的顺应性,降低毒副作用。本发明提供的特立帕肽超分子缓释纳米粒制备工艺简单,成本较低,易于控制,易于工业化生产。本研究为特立帕肽提供了可供选择的新型载体,具有明显的实用意义,社会和经济价值。
本发明提供的特立帕肽超分子缓释纳米粒,其特征在于:制剂中各组分重量比为:特立帕肽0.5-1.5份,环糊精20-60份,碳纳米管5-15份,聚乳酸-羟基乙酸共聚物100-300份,蒸馏水1(水相1)200-800份,聚乙烯醇0.1-0.5份,植酸33-99份,蒸馏水2(水相2)3800-5200份。所述环糊精为羟丙基-β-环糊精、磺丁基-β-环糊、α-环糊精、γ-环糊精、δ-环糊精中的一种或多种;所述碳纳米管为单壁碳纳米管、多壁碳纳米管中的一种或多种;所述聚乳酸-羟基乙酸共聚物为乳酸和羟基乙酸聚合而成,两种单体摩尔比为25:75、50:50、75:25中的一种或两种混合物。本发明提供的特立帕肽超分子缓释纳米粒,制备步骤如下:(1)碳纳米管环糊精复合物的制备方法:称取处方量的碳纳米管和环糊精,边研磨边滴加0.5-3mL乙醇,研磨10-30分钟,然后加入10-25mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理1-4小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干12-36小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷、三氯甲烷、丙酮、乙酸乙酯、无水乙醇中的一种或几种有机溶剂中混合形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,加入到有机相A中,在冰浴下超声3-5分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌5-10分钟后,再次超声处理3-5分钟得到乳状物E,搅拌4-5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
本发明提供的特立帕肽超分子缓释纳米粒平均粒径约为100nm(图1)。本发明提供的特立帕肽超分子缓释纳米粒对骨组织具备一定的靶向性。将植酸作为靶向基团加入到制剂中,制备成特立帕肽超分子缓释纳米粒,然后对其与羟基磷灰石的结合进行考察。特立帕肽超分子缓释纳米粒与羟基磷灰石的结合率为(82.13±2.41)%,而不含植酸的特立帕肽超分子缓释纳米粒与羟基磷灰石结合率为(13.70±2.41)%(图2)。特立帕肽超分子缓释纳米粒对骨组织具备一定靶向性的原因分析如下:羟基磷灰石作为人体骨骼最主要成分,其中的Ca2+可与植酸中的磷酸基团主动发生强烈螯合作用,使其具有一定的骨组织靶向性。本发明提供的特立帕肽超分子缓释纳米粒能减缓特立帕肽的释放,达到缓释作用。有文献报道,骨质疏松症局部微环境为酸性(pH~4.0),而特立帕肽在pH 4.0的乙酸盐缓冲液中,前4小时快速释放,10小时累积释放至(90.26±0.43)%,168小时累积释放到(99.98±0.64)%,而特立帕肽超分子缓释纳米粒在10小时累积释放至(58.46±2.36)%,之后一直持续缓慢释放至168小时,累积释放(85.73±2.15)%(图3)。特立帕肽在pH 7.4的磷酸盐缓冲液中前4小时快速释放,12小时累积释放至(89.53±1.68)%,168小时累积释放到(99.89±0.89)%,而特立帕肽超分子缓释纳米粒在12小时累积释放(51.99±0.93)%,之后一直缓慢持续释放至168小时,累积释放到(82.63±2.22)%(图4)。特立帕肽超分子缓释纳米粒具有缓释作用的原因分析如下:特立帕肽在两种释放介质中均符合一级释放模型,其释药过程可能主要以膜控为主的扩散作用导致的,而特立帕肽超分子缓释纳米粒在pH 4.0的乙酸盐缓冲液介质中符合Weibull模型,其释药过机制可能为Fickian扩散和溶胀相结合;在pH 7.4的磷酸盐缓冲液中符合Ritger-peppas模型,其释药过机制可能为扩散和骨架溶蚀/溶胀相结合。由于释药机制从扩散转变为扩散和溶蚀/溶胀相结合,使特立帕肽超分子缓释纳米粒达到缓释作用。本发明提供的特立帕肽超分子缓释纳米粒经近红外激光照射后,小鼠胚胎成骨细胞(MC3T3-E1)活性较未经照射细胞活性显著增强(图5)。相同浓度的特立帕肽超分子缓释纳米经红外激光照射,细胞培养24小时后,成骨细胞活性比未经过红外光照射的细胞活性明显提高,分别为(104.60±14.62)%和(88.09±11.07)%。经红外光照射,细胞培养48小时后,成骨细胞活性较未经照射的细胞活性更高,分别为(98.42±22.58)%和(87.46±16.57)%。本发明的特立帕肽超分子缓释纳米粒经过照射后细胞活性增强的原因可能是:碳纳米管能够有效地将近红外光转换成热,增加了细胞成骨因子的表达,增强细胞活性,从而促进骨再生。本发明提供的特立帕肽超分子缓释纳米粒体内给药后,血药浓度-时间曲线下面积相对于游离药物显著提高(图6),为游离药的12.37倍,体内的平均滞留时间是游离药的67.28倍。且特立帕肽超分子缓释纳米粒消除速度明显比游离药更慢,清除率减慢至游离药的7.59%。由图5可知,游离药约1小时血药浓度趋近于0,而特立帕肽超分子缓释纳米粒在72小时浓度趋近于0,并在各个时间点的血浆浓度均高于游离药。以上结果表明,将特立帕肽制备成特立帕肽超分子缓释纳米粒后,能显著提高特立帕肽的生物利用度,延缓药物体内消除速度,延长药物在血液循环保留时间。本发明的制剂生物利用度明显提高的原因可能有:(1)聚乳酸-羟基乙酸共聚物大分子构建成纳米粒壳结构,包封特立帕肽,可控制封装蛋白质缓慢释放并保护其免于降解;(2)环糊精包封药物,可以延长药物生物半衰期,延长作用时间;(3)制剂由植酸修饰,具有一定的骨组织靶向性。
本发明不同于通常研究报道的特立帕肽的递送载体和制备工艺。特立帕肽的递送载体研究报道的有:壳聚糖包衣的聚乳酸羟基乙酸共聚物注射用微囊、鼻腔给药脂质体制剂、壳聚糖纳米粒及硫醇化壳聚糖纳米粒等。目前尚未见碳纳米管环糊精超分子系统载带多肽药物的研究,尚未见多肽超分子缓释纳米粒的研究,尚未见特立帕肽纳米粒超分子缓释纳米粒的研究,尚未见植酸修饰的特立帕肽超分子缓释纳米粒的研究。本发明首次将特立帕肽与碳纳米管环糊精复合物形成超分子核心,以聚乳酸-羟基乙酸共聚物作为缓释骨架材料,外层修饰骨靶向基因植酸。该纳米粒能延缓特立帕肽的释放,延长特立帕肽在血液循环中的滞留时间,提高其生物利用度,兼具靶向性和光热效应。
附图说明
图1为本发明制得的特立帕肽超分子缓释纳米粒的粒径。
试验条件:采用马尔文激光粒度仪测定特立帕肽超分子缓释纳米粒的粒径。
结果显示:特立帕肽超分子缓释纳米粒平均粒径为(114.03±2.38)nm,PDI为0.148±0.012。
图2为本发明制得的特立帕肽超分子缓释纳米粒和不含植酸特立帕肽超分子缓释纳米粒与羟基磷灰石的结合率。
试验条件:制备特立帕肽超分子缓释纳米粒2份,第1份不加羟基磷灰石,第2份加入羟基磷灰石,两份均孵育12小时后离心,取上清液稀释后进行测定游离植酸含量,将第1份不加羟基磷灰石中上清液中植酸含量记为PA1,第2份加羟基磷灰石处理后上清液中的植酸含量记为PA2,按公式(PA1-PA2)/PA1×100%计算结合率,平行操作3组。制备不含植酸的特立帕肽超分子缓释纳米粒2份,其他操作同上,计算结合率。
结果显示:特立帕肽超分子缓释纳米粒与羟基磷灰石的结合率为(82.13±2.41)%,而不含植酸的特立帕肽超分子缓释纳米粒与羟基磷灰石结合率为(13.70±2.41)%,研究结果说明特立帕肽超分子缓释纳米粒具有一定的骨组织靶向性。
图3为本发明制得的特立帕肽超分子缓释纳米粒和特立帕肽在pH 4.0的乙酸盐缓冲液体外释放曲线。
试验条件:采用动态膜透析法考察特立帕肽和特立帕肽超分子缓释纳米粒的体外释药行为。分别取游离药和特立帕肽缓释纳米粒(特立帕肽的含量相同)置预先处理过的透析袋,扎紧袋的两端,平行操作3份,放入pH 4.0的乙酸盐缓冲液释放介质中。置于37℃恒温水浴摇床,分别于固定时间点取出等量释放介质,同时立即补充等温等体积的同种释放介质,后测定不同时间点所取释放介质中的特立帕肽浓度,计算累计释放率,绘制曲线。
结果显示:特立帕肽溶液在0-4小时快速释放,10小时累积释放至(90.26±0.43)%,168小时累积释放到(99.98±0.64)%;特立帕肽超分子缓释纳米粒在10小时累积释放至(58.46±2.36)%,之后一直持续缓慢释放至168小时,累积释放(85.73±2.15)%,与游离药相比,具有一定缓释作用。
图4为本发明制得的特立帕肽超分子缓释纳米粒和特立帕肽在pH 7.4的磷酸盐缓冲液体外释放曲线。
试验条件:采用动态膜透析法考察特立帕肽和特立帕肽超分子缓释纳米粒的体外释药行为。分别取游离药和特立帕肽缓释纳米粒(主药含量相同)置预先处理过的透析袋,扎紧袋的两端,平行操作3份,放入pH 7.4的磷酸盐缓冲液释放介质中。置于于37℃恒温水浴摇床,分别于固定时间点取出等量释放介质,同时立即补充等温等体积的同种释放介质,后测定不同时间点所取释放介质中的特立帕肽浓度,计算累计释放率,绘制曲线。
结果显示:特立帕肽溶液在0-4小时快速释放,12小时累积释放至(89.53±1.68)%,168小时累积释放到(99.89±0.89)%;特立帕肽超分子缓释纳米粒在12小时累积释放(51.99±0.93)%,之后一直缓慢持续释放至168小时,累积释放到(82.63±2.22)%,与游离药相比,具有一定缓释作用。
图5为本发明制得特立帕肽超分子缓释纳米粒的光热效应。
试验条件:将小鼠胚胎成骨细胞(MC3T3-E1)接种于96孔板内,在37℃、5% CO2的环境下培养24小时至细胞贴壁,向细胞中分别加入特立帕肽超分子缓释纳米粒。在808nm波长下,用近红外光以4W·cm-2,42.5℃照射细胞10分钟,1天1次。在37℃、5% CO2的环境下继续培养24小时、48小时。随后,加入20μL噻唑蓝试剂,孵育4小时。小心去除含噻唑蓝的培养基,将150μL二甲基亚枫加入每个孔中。震荡15分钟后,用酶标仪测定样品在490nm处的吸光值。以上试验均重复3次。以没有经过任何处理的细胞作为对照组,以未加入任何细胞或者试剂孔的紫外-可见吸收值为空白组,按照公式细胞存活率(%)=(试验组吸光度值-空白组吸光度值)/(对照组吸光度值-空白组吸光度值)×100%,计算细胞存活率。
结果显示:经红外激光照射,细胞培养24小时后,成骨细胞活性比未经过红外光照射的细胞活性高,分别为(104.60±14.62)%和(88.09±11.07)%。而经红外照射,细胞培养48小时后,照射后成骨细胞活性为(98.42±22.58)%,活性高于未经照射的活性。
图6为本发明制得特立帕肽超分子缓释纳米粒血药浓度时间曲线图。
试验条件:12只雄性SD大鼠(在给药前禁食12小时,但不禁水),随机分为2组,每组6只,分别尾静脉注射特立帕肽、本发明提供的特立帕肽超分子缓释纳米粒,给药剂量为每只大鼠100μg·kg-1(以特立帕肽计)。给药后定时采血,进行药代动力学研究。
结果显示:游离药在大鼠体内快速消除,在约1小时浓度趋近于0,特立帕肽超分子缓释纳米粒消除速度明显比游离药更慢,在72小时浓度趋近于0,表明将特立帕肽制备成特立帕肽超分子缓释纳米粒后可延长其在血液循环时间,具有缓释作用。特立帕肽超分子缓释纳米粒在各个时间点的血浆药物浓度始终高于游离药。
具体实施方式
为了进一步说明本发明及其优点,给出了下列特定的实施例,应理解这些实施例仅有于具体说明而不是作为本发明范围的限制。
实施例1:
配方中含有的各组分的重量组成比为:特立帕肽0.5份,羟丙基-β-环糊精20份,单壁碳纳米管5份,聚乳酸-羟基乙酸共聚物(乳酸与羟基乙酸的单体比为50:50,以下简称为:L:G为50:50)100份,蒸馏水1(水相1)200份,聚乙烯醇0.1份,植酸33份,蒸馏水2(水相2)3800份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加0.5mL乙醇,研磨10分钟,然后加入10mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理1小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干12小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声3分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌5分钟后,再次超声处理3分钟得到乳状物E,搅拌4小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例2:
配方中含有的各组分的重量组成比为:特立帕肽0.6份,磺丁基-β-环糊精21.3份,α-环糊精14.2份,单壁碳纳米管2份,多壁碳纳米管4.8份,聚乳酸-羟基乙酸共聚物(L:G为25:75)227.3份,蒸馏水1(水相1)691份,聚乙烯醇0.46份,植酸75份,蒸馏水2(水相2)4564份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加0.5mL乙醇,研磨15分钟,然后加入12mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理1小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干24小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于丙酮形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声4分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌5分钟后,再次超声处理4分钟得到乳状物E,搅拌5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例3:
配方中含有的各组分的重量组成比为:特立帕肽0.7份,α-环糊精41.8份,多壁碳纳米管7.7份,聚乳酸-羟基乙酸共聚物(L:G为25:75)82份,聚乳酸-羟基乙酸共聚物(L:G为75:25)164份,蒸馏水1(水相1)746份,聚乙烯醇0.32份,植酸81份,蒸馏水2(水相2)4191份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加1.5mL乙醇,研磨15分钟,然后加入20mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理2小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干12小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于丙酮、乙酸乙酯中形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声3分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌8分钟后,再次超声处理3分钟得到乳状物E,搅拌4.5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例4:
配方中含有的各组分的重量组成比为:特立帕肽0.8份,羟丙基-β-环糊精15份,γ-环糊精30份,单壁碳纳米管8.6份,聚乳酸-羟基乙酸共聚物(L:G为50:50)175.7份,聚乳酸-羟基乙酸共聚物(L:G为75:25)87.9份,蒸馏水1(水相1)527份,聚乙烯醇0.35份,植酸87份,蒸馏水2(水相2)4818份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加2mL乙醇,研磨20分钟,然后加入15mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理3小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干36小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于三氯甲烷形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声4分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌10分钟后,再次超声处理4分钟得到乳状物E,搅拌4.5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例5:
配方中含有的各组分的重量组成比为:特立帕肽0.9份,δ-环糊精36.8份,磺丁基-β-环糊精12.3份,多壁碳纳米管3.2份,单壁碳纳米管7.3份,聚乳酸-羟基乙酸共聚物(L:G为75:25)281.8份,蒸馏水1(水相1)636份,聚乙烯醇0.4份,植酸93份,蒸馏水2(水相2)4946份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加3mL乙醇,研磨15分钟,然后加入10mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理2小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干18小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于无水乙醇形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声3分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌10分钟后,再次超声处理3分钟得到乳状物E,搅拌5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例6:
配方中含有的各组分的重量组成比为:特立帕肽1份,磺丁基-β-环糊精40份,多壁碳纳米管10份,聚乳酸-羟基乙酸共聚物(L:G为50:50)200份,蒸馏水1(水相1)500份,聚乙烯醇0.3份,植酸66份,蒸馏水2(水相2)4500份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加1mL乙醇,研磨10分钟,然后加入15mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理3小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干12小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声3分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌3分钟后,再次超声处理3分钟得到乳状物E,搅拌4小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例7:
配方中含有的各组分的重量组成比为:特立帕肽1.1份,羟丙基-β-环糊精39.6份,γ-环糊精13.1份,单壁碳纳米管11.4份,聚乳酸-羟基乙酸共聚物(L:G为75:25)32.3份,聚乳酸-羟基乙酸共聚物(L:G为25:75)150.4份,蒸馏水1(水相1)255份,聚乙烯醇0.13份,植酸57份,蒸馏水2(水相2)4055份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加1.2mL乙醇,研磨12分钟,然后加入12mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理2小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干12小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷、乙酸乙酯形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声3分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌4分钟后,再次超声处理3分钟得到乳状物E,搅拌5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例8:
配方中含有的各组分的重量组成比为:特立帕肽1.1份,羟丙基-β-环糊精56.4份,单壁碳纳米管12.3份,聚乳酸-羟基乙酸共聚物(L:G为75:25)154.5份,蒸馏水1(水相1)418份,聚乙烯醇0.17份,植酸51份,蒸馏水2(水相2)3927份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加2mL乙醇,研磨25分钟,然后加入20mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理3小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干24小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷、乙酸乙酯形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声4分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌4分钟后,再次超声处理3分钟得到乳状物E,搅拌4.5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例9:
配方中含有的各组分的重量组成比为:特立帕肽1.2份,磺丁基-β-环糊精30.9份,多壁碳纳米管13.2份,聚乳酸-羟基乙酸共聚物(L:G为50:50)102.3份,聚乳酸-羟基乙酸共聚物(L:G为25:75)34.1份,蒸馏水1(水相1)364份,聚乙烯醇0.25份,植酸45份,蒸馏水1(水相1)527份,蒸馏水2(水相2)4309份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加2mL乙醇,研磨10分钟,然后加入15mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理3小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干24小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于乙酸乙酯、无水乙醇形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声4分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌6分钟后,再次超声处理4分钟得到乳状物E,搅拌5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例10:
配方中含有的各组分的重量组成比为:特立帕肽1.3份,磺丁基-β-环糊精27.3份,单壁碳纳米管14.1份,聚乳酸-羟基乙酸共聚物(L:G为75:25)118.2份,蒸馏水1(水相1)309份,聚乙烯醇0.21份,植酸39份,蒸馏水2(水相2)4182份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加3mL乙醇,研磨25分钟,然后加入25mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理4小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干24小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷、乙酸乙酯形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声4分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌5分钟后,再次超声处理3分钟得到乳状物E,搅拌4.5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例11:
配方中含有的各组分的重量组成比为:特立帕肽1.4份,γ-环糊精7.9份,羟丙基-β-环糊精15.7份,单壁碳纳米管5.9份,聚乳酸-羟基乙酸共聚物(L:G为25:75)156.8份,聚乳酸-羟基乙酸共聚物(L:G为50:50)52.3份,蒸馏水1(水相1)582份,聚乙烯醇0.43份,植酸69份,蒸馏水2(水相2)5073份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加2mL乙醇,研磨15分钟,然后加入10mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理3.5小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干36小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于三氯甲烷、无水乙醇形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声5分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌5分钟后,再次超声处理5分钟得到乳状物E,搅拌4小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
实施例12:
配方中含有的各组分的重量组成比为:特立帕肽1.5份,磺丁基-β-环糊精20份,羟丙基-β-环糊精40份,多壁碳纳米管3份,单壁碳纳米管12份,聚乳酸-羟基乙酸共聚物(L:G为25:75)75份,聚乳酸-羟基乙酸共聚物(L:G为75:25)225份,蒸馏水1(水相1)800份,聚乙烯醇0.5份,植酸99份,蒸馏水2(水相2)5200份。
制备方法:(1)碳纳米管环糊精复合物的制备方法:称取处方量的碳纳米管和环糊精于研钵中,边研磨边滴加2mL乙醇,研磨25分钟,然后加入20mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理3.5小时,结束后蒸发除去乙醇,在75℃真空干燥箱中烘干24小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷、乙酸乙酯形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声5分钟得到乳状液C。另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌8分钟后,再次超声处理4分钟得到乳状物E,搅拌5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
Claims (1)
1.一种特立帕肽超分子缓释纳米粒,其特征在于,制剂中各组分重量比为:
所述环糊精为羟丙基-β-环糊精、磺丁基-β-环糊精、α-环糊精、γ-环糊精、δ-环糊精中的一种或多种;所述碳纳米管为单壁碳纳米管、多壁碳纳米管中的一种或多种;所述聚乳酸-羟基乙酸共聚物为乳酸和羟基乙酸单体摩尔比为25:75、50:50、75:25中的一种或多种混合物;所述蒸馏水1为水相1,所述蒸馏水2为水相2;
所述的一种特立帕肽超分子缓释纳米粒的制备方法包括下列步骤:(1)碳纳米管环糊精复合物的制备方法:将处方量的碳纳米管和环糊精边研磨边滴加0.5-3mL乙醇,研磨10-30分钟,然后加入10-25mL乙醇溶液,溶解研钵中的糊状物后移至烧瓶,超声处理1-4小时,再蒸发除去乙醇,在75℃真空干燥箱中烘干12-36小时,将得到的产物研磨即得碳纳米管环糊精复合物;(2)将处方量的聚乳酸-羟基乙酸共聚物溶解于二氯甲烷、三氯甲烷、丙酮、乙酸乙酯、无水乙醇中的一种或几种有机溶剂中形成有机相A,将处方量的特立帕肽和碳纳米管环糊精复合物溶解于水相1形成混合溶液B,并加入到有机相A中,在冰浴下超声3-5分钟得到乳状液C;另称取聚乙烯醇和植酸溶解于水相2配制成外水相溶液D,将乳状液C在搅拌条件下加到外水相溶液D中,搅拌5-10分钟后,再次超声处理3-5分钟得到乳状物E,搅拌4-5小时,使有机相完全挥发即得特立帕肽超分子缓释纳米粒。
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