CN1237960C - 一种阿斯匹林微球的制备方法 - Google Patents
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Abstract
本发明公开了一种阿斯匹林微球的制备方法。该法采用油包(油包粉末)技术,其内油相为聚己内酯、聚乳酸或聚乳酸共聚物的有机溶液,液体石蜡或植物油为其外油相,乳化剂为司盘。制备时将阿斯匹林的环糊精或环糊精衍生物的包合物用超声波分散在内油相中,再将内油相以中速搅拌乳化于外油相中,然后在20-50℃下挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。本发明可使阿斯匹林的包埋率提高到90-100%,体外药物释放时间延长至7-40天,微球粒径可在30-200μm之间调控以满足不同的使用要求。
Description
技术领域
本发明涉及一种阿斯匹林微球的制备方法。
背景技术
阿斯匹林已经被证明是一种有效的抗血栓剂,除了用于防治心脑血管疾病外还用于妊娠毒血症,偏头痛,痴呆症,突发性耳聋,直肠癌等疾病的防治。但是长期服用引起的胃肠道出血十分普遍,研究表明,在风湿病患者中,服用阿斯匹林引起的胃黏膜红斑达80%,胃腐蚀达40%,胃溃疡达15%。有研究表明,静脉注射制剂和透皮吸收制剂所引起的胃黏膜副作用比口服制剂要小得多,因此,研制能尽量减少或避免其副作用的非肠胃道给药制剂显得十分必要。
药物控释微球在各种药物的控释及多途径给药方面有广泛的应用,如可用作注射、口服、鼻腔吸入、眼部给药、化学栓塞制剂等。目前,关于阿斯匹林微球制备的研究还不多,YANG等人分别用水包油,油包水溶剂挥发法制得阿斯匹林/乙基纤维素微球。水包油溶剂挥发法以二氯甲烷和正庚烷的混合溶剂作为内油相,含重量体积比为2%的吐温60的阿司匹林饱和水溶液为外水相,改变正庚烷和聚合物的浓度所得微球的数均粒径为520-1342μm,包埋率为31.4-98.4%,24小时释放量为45-85%。油包水溶剂挥发法以乙醇和水的混合溶剂为内水相,大豆油为外油相,改变水和聚合物的浓度所得微球的数均粒径为743-1529μm,当外油相未被阿斯匹林饱和前的包埋率最高为17.9%,饱和后的包埋率可达29%,24小时释放量为15.7-46.5%。此外,何文等人以羧甲基淀粉钠为原料,二甲基甲酰氯为交联剂,采用界面缩聚法制备空白微球,用吸附载药法制备了阿斯匹林淀粉微球,粒径在20-100μm,包埋率为79-92.5%,0.5小时累积释放百分率为36.3%,24小时累计释放达93.74%。当采用溶剂挥发法时,因为阿斯匹林既溶于水相又溶于二氯甲烷,大豆油等油相,要想得到较高的包埋率需将外油相或外水相用阿斯匹林饱和,并且由于阿斯匹林在溶剂挥发过程中易结晶,所以只有当聚合物浓度较高,微球粒径较大时才可能得到较高的包埋率。而用吸附载药法,适用的聚合物十分有限。此外上述微球的暴释都较严重,释药时间都不长,故希望得到高包埋率,释药平稳,缓释时间更长的阿司匹林微球制剂。
发明内容
本发明的目的是提供一种阿斯匹林微球的制备方法。
它首先采用饱和水溶液法制得阿斯匹林的环糊精包合物,冷冻干燥后用超声波分散在内油相中,内油相采用乙腈或乙腈和二氯甲烷的混合溶剂,将司盘溶于液体石蜡或植物油中得到外油相,在室温下将内油相以每分钟500-2000转搅拌乳化于外油相中形成油包油乳液,该乳液在20-50℃下挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。
本发明的优点是:
1)将阿斯匹林用环糊精包合后,提高了药物的稳定性和亲水性;
2)与通常的将阿斯匹林直接溶于内油相的油包油乳液-溶剂挥发法相比,将阿斯匹林环糊精包合物粉末直接分散在内油相中,不必饱和外油相,且避免了在溶剂挥发过程中阿斯匹林的结晶析出现象,提高了药物的包埋率(提高到90-100%),减少了释药初期的爆释现象;
3)此法适用范围广,可用于各种能溶于乙腈或乙腈和二氯甲烷的混合溶剂的聚合物的微球制备,且都能得到较高的包埋率。
具体实施方式
本发明首先采用饱和水溶液法制得阿斯匹林的环糊精包合物,具体操作如下:将一定量的环糊精(β-环糊精,2,6-二甲基-β-环糊精,2-羟丙基-β-环糊精和磺烷基-β-环糊精。)溶于水中形成饱和溶液,再将等摩尔的阿司匹林乙醇饱和溶液在恒温下滴加到环糊精饱和溶液中,搅拌1.5小时后,置于冰箱中冷藏过夜,真空抽滤分离得到包合物,冷冻干燥后备用。内油相采用乙腈或乙腈和二氯甲烷的混合溶剂,其中二氯甲烷的体积浓度为0-60%,聚乳酸、聚己内酯、聚(丙交酯-共-乙交酯)或聚(丙交酯-共-己内酯)的浓度为1-200mg/ml,包合物的量为1-200mg/ml。外油相采用液体石蜡或植物油,司盘80或司盘系列的其他型号作为乳化剂,乳化剂和液体石蜡或植物油的重量体积比为0.1-15%。制备时,将阿斯匹林环糊精包合物用超声波分散在内油相中,再将内油相置于搅拌器中,在室温下以每分钟500-2000转搅拌乳化于外油相中形成油包油乳液,该乳液在20-50℃下挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。
本发明先制得阿斯匹林的环糊精包合物,再采用乙腈或乙腈和二氯甲烷的混合溶剂作为内油相,用油包(油包粉)乳液-溶剂挥发技术制备了包有阿斯匹林的聚己内酯,聚乳酸及其共聚物的控释微球,药物体外持续释放时间可在7到40天之间调控。
下面结合实施例作进一步详细说明。
实施例1
内油相采用4ml乙腈溶剂,溶解分子量为25000的聚(丙交酯-共-乙交酯)(摩尔比75∶25)200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为1%。制备时,将100mg的阿斯匹林β-环糊精包合物用超声波分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为90%,微球粒径80-140μm,24小时累积释放20-30%,体外释放时间可达20天左右。
实施例2
内油相采用4ml乙腈溶剂,溶解分子量为25000的聚(丙交酯-共-乙交酯)(摩尔比75∶25)200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为1%。制备时,将50mg的阿斯匹林β-环糊精包合物用超声波分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为100%,微球粒径80-140μm,24小时累积释放15-25%,体外释放时间可达25天左右。
实施例3
内油相采用4ml乙腈溶剂,溶解分子量为30000的聚乳酸200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为1%。制备时,将50mg的阿斯匹林β-环糊精包合物用超声分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为100%,微球粒径80-140μm,24小时累积释放10-15%,体外释放时间可达40天左右。
实施例4
内油相采用4ml乙腈溶剂,溶解分子量为26500的聚(丙交酯-共-己内酯)(摩尔比70∶30)200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为1%。制备时,将50mg的阿斯匹林β-环糊精包合物(粒径<38.5μm)用超声波分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为100%,微球粒径60-120μm,24小时累积释放50%,体外释放时间可达15天左右。
实施例5
内油相采用2ml乙腈和2ml二氯甲烷溶解分子量为23000的聚己内酯200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为5%。制备时,将50mg的阿斯匹林β-环糊精包合物用超声波分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为100%,微球粒径30-80μm,24小时累积释放60%,体外释放时间可达7天左右。
实施例6
内油相采用2ml乙腈溶解分子量为25000的聚(丙交酯-共-乙交酯)(摩尔比75∶25)200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为5%。制备时,将50mg的阿斯匹林β-环糊精包合物用超声波分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为100%,微球粒径40-80μm,24小时累积释放25-35%,体外释放时间可达20天左右。
实施例7
内油相采用4ml乙腈溶解分子量为35000聚(丙交酯-共-乙交酯)(摩尔比75∶25)200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为1%。制备时,将50mg的阿斯匹林2-羟基-β-环糊精包合物用超声波分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为100%,微球粒径80-140μm,24小时累积释放25-35%,体外释放时间可达20天左右。
实施例8
内油相采用4ml乙腈溶解分子量为45000聚(丙交酯-共-乙交酯)(摩尔比75∶25)200mg。外油相为40ml大豆油,司盘80作为乳化剂,其重量体积比为1%。制备时,将50mg的阿斯匹林2,6-二甲基-β-环糊精包合物用超声波分散在内油相中,再将内油相在700rpm搅拌下乳化于外油相中,形成油包油乳液。该乳液在20-30℃挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。所得微球的阿斯匹林包埋率为100%,微球粒径80-140μm,24小时累积释放25-35%,体外释放时间可达25天左右。
Claims (4)
1.一种阿斯匹林微球的制备方法,其特征在于:首先采用饱和水溶液法制得阿斯匹林的环糊精包合物,冷冻干燥后用超声波分散在内油相中,内油相采用乙腈或乙腈和二氯甲烷的混合溶剂,将司盘溶于液体石蜡或植物油中得到外油相,在室温下将内油相以每分钟500-2000转搅拌乳化于外油相中形成油包油乳液,该乳液在20-50℃下挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,室温下自然干燥。
2.根据权利要求1所述的一种阿斯匹林微球的制备方法,其特征在于:所说的环糊精为:β-环糊精,2,6-二甲基-β-环糊精,2-羟丙基-β-环糊精和磺烷基-β-环糊精。
3.根据权利要求1所述的一种阿斯匹林微球的制备方法,其特征在于:所说的内油相采用乙腈或乙腈和二氯甲烷的混合溶剂,其中二氯甲烷的体积浓度为0-60%,聚乳酸、聚己内酯、聚(丙交酯-共-乙交酯)或聚(丙交酯-共-已内酯)的浓度为1-200mg/ml,包合物的量为1-200mg/ml。
4.根据权利要求1所述的一种阿斯匹林微球的制备方法,其特征在于:所说的外油相中司盘和液体石蜡或植物油的重量体积比为0.1-15%。
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CN101007169B (zh) * | 2006-01-23 | 2011-05-25 | 珠海市嘉族生物科技有限公司 | 一种鸡卵黄免疫球蛋白微胶囊及其制备方法和应用 |
CN101444486B (zh) * | 2008-06-20 | 2011-06-08 | 广东药学院 | 一种水溶性药物缓释微球及其制备方法和应用 |
CN101693177B (zh) * | 2009-10-19 | 2012-07-04 | 上海现代药物制剂工程研究中心有限公司 | 基于超声技术的微球制备方法及其装置 |
CN103351483B (zh) * | 2013-07-24 | 2016-05-11 | 济南大学 | 微球型高疏水性淀粉及其制备方法及应用 |
CN103845296B (zh) * | 2014-03-26 | 2016-05-25 | 沈祥春 | 阿司匹林脂微球制剂及其制备方法 |
CN106727362A (zh) * | 2014-12-30 | 2017-05-31 | 北京博恩特药业有限公司 | 一种曲普瑞林微球及其制备方法与应用 |
CN118161464A (zh) * | 2024-05-16 | 2024-06-11 | 文韬创新药物研究(北京)股份有限公司 | 含阿司匹林的药物制剂及其制备方法和应用 |
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