CN105434365B - 一种口服胶束微球的制备方法及其应用 - Google Patents
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Abstract
本发明涉及口服胶束微球的制备方法及其应用,可有效解决现有药物口服生物利用度低,吸收差,毒副作用较大,药物突释造成胃内不适的问题,方法是,将PEG5000‑PLGA5000、大豆磷脂溶解作为水相,将2‑ME超声溶解在甲醇中,逐滴加入到水相中,得胶束混悬液;用超纯水将羧甲基壳聚糖制成羧甲基壳聚糖溶液,用磷酸缓冲液将聚丙烯酸树脂制成聚丙烯酸树脂溶液,将羧甲基壳聚糖溶液和聚丙烯酸树脂溶液混合,得微球材料混合溶液;取胶束混悬液与微球材料混合溶液磁力搅拌,用超纯水稀释1‑3倍,经喷雾干燥得胶束微球。本发明可以实现载药胶束的肠靶向缓释,延长胶束的肠吸收时间,提高小肠对载药胶束的吸收率,明显提高药物的口服生物利用度,提高药效。
Description
技术领域
本发明涉及医药领域,特别是一种口服胶束微球的制备方法及其应用。
背景技术
临床上有些水中难溶性药物如大多数抗癌药因为口服生物利用度低而只能采用静脉注射给药方式进行疾病的治疗。静脉给药需要频繁的注射,患者的依从性较差,血药浓度波动较大导致明显的毒副作用。口服给药患者可自行用药,患者依从性高。这些药物口服后生物利用度低主要是因为可能存在明显的肝首过效应、胃肠不稳定或代谢、肠吸收外排或吸收饱和等障碍。目前这些药物的普通制剂(药物以分子状态进行胃肠吸收),口服后难以克服这些障碍导致生物利用度很低。随着社会的发展和生活水平的提高,口服药物的开发必然成发展趋势。
2-甲氧基***(2-ME)是一种水难溶性抗癌药,主要通过抗血管生成效应和抗瘤生成效应用于治疗乳腺癌,***癌等病症。口服给药存在明显的肝首过效应和肠吸收饱和机制。目前其口服制剂给药无效。因此,如何解决2-甲氧基***水难溶性,提高2-甲氧基***的口服疗效是需要认真解决的技术问题。
发明内容
针对上述情况,为克服现有技术之缺陷,本发明之目的就是提供一种口服胶束微球的制备方法及其应用,可有效解决现有药物口服生物利用度低,吸收差,毒副作用较大,药物突释造成胃内不适的问题。
本发明方法解决的技术方案是,由以下步骤实现:
(1)、制备胶束混悬液:
35-50℃水浴下,将80-100mg PEG5000-PLGA5000、5-10mg大豆磷脂(PC-80,磷脂酰胆碱含量>80%,注射级)溶解在2-4ml水中,作为水相,将2-5mg 2-ME超声溶解在400-600μL甲醇中,然后逐滴加入到水相中,700-1000rpm搅拌9-12h,过0.45μm滤膜,得胶束混悬液,4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖(黏均分子量为2.5×100000)制成质量浓度1-2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂(Eudragit L100)制成质量浓度1-2%聚丙烯酸树脂溶液,用1mol/L的NaOH调节溶液的pH至5-7,将羧甲基壳聚糖溶液和聚丙烯酸树脂溶液按照体积比1︰1-3混合,搅拌均匀,得微球材料混合溶液;取步骤(1)制得的胶束混悬液与微球材料混合溶液按照体积比1︰1-2在磁力搅拌下混合均匀,用超纯水稀释1-3倍,经喷雾干燥得胶束微球。
所述方法制备的胶束微球在制备抗癌药物中的应用。
本发明可以实现载药胶束的肠靶向缓释,延长胶束的肠吸收时间,相应的延长载药胶束在血液中滞留时间,而且一定程度上克服肝首过效应、肠吸收饱和和吸收外排等障碍,提高小肠对载药胶束的吸收率,一定程度上克服水难溶性药物的口服吸收的障碍,可以明显提高这些药物的口服生物利用度,从而发挥应有的药理作用,提高药效,有显著的经济和社会效益。
具体实施方式
以下结合实施例对本发明的具体实施方式做详细说明。
实施例1
一种胶束微球的制备方法,由以下方法实现:
(1)、制备胶束混悬液:
35℃水浴下,将80mg PEG5000-PLGA5000、10mg大豆磷脂(PC-80,磷脂酰胆碱含量>80%,注射级)溶解在4ml水中,作为水相,将5mg 2-ME超声溶解在500μL甲醇中,然后逐滴添加到水相当中,900r/min搅拌9h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖(黏均分子量为2.5×100000)制成质量浓度1%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂(Eudragit L100)制成质量浓度2%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至6,将羧甲基壳聚糖溶液和聚丙烯酸树脂(Eudragit L100)溶液按照体积比1︰3混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰2在磁力搅拌下混合均匀,用超纯水稀释2倍,经喷雾干燥得胶束微球。
实施例2
一种胶束微球的制备方法,由以下方法实现:
(1)、制备胶束混悬液:
45℃水浴下,将80mg PEG5000-PLGA5000、10mg大豆磷脂(PC-80,磷脂酰胆碱含量>80%,注射级)溶解在2ml水中,作为水相,将2mg 2-ME超声溶解在400μL甲醇中,然后逐滴添加到水相当中,1000r/min搅拌10h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖(黏均分子量为2.5×100000)制成质量浓度2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂(Eudragit L100)制成质量浓度2%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至6.5,将羧甲基壳聚糖溶液和聚丙烯酸树脂(Eudragit L100)溶液按照体积比1︰1混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰1在磁力搅拌下混合均匀,用超纯水稀释1.5倍,经喷雾干燥得胶束微球。
实施例3
一种胶束微球的制备方法,由以下方法实现:
(1)、制备胶束混悬液:
40℃水浴下,将100mg PEG5000-PLGA5000、10mg大豆磷脂(PC-80,磷脂酰胆碱含量>80%,注射级)溶解在3ml水中,作为水相,将4mg 2-ME超声溶解在500μL甲醇中,然后逐滴添加到水相当中,1000r/min搅拌12h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖(黏均分子量为2.5×100000)制成质量浓度2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂(Eudragit L100)制成质量浓度1%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至5,将羧甲基壳聚糖溶液和聚丙烯酸树脂(Eudragit L100)溶液按照体积比1︰1混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰1在磁力搅拌下混合均匀,用超纯水稀释1倍,经喷雾干燥得胶束微球。
实施例4
一种胶束微球的制备方法,由以下方法实现:
(1)、制备胶束混悬液:
50℃水浴下,将90mg PEG5000-PLGA5000、8mg大豆磷脂(PC-80,磷脂酰胆碱含量>80%,注射级)溶解在3ml水中,作为水相,将3mg 2-ME超声溶解在400μL甲醇中,然后逐滴添加到水相当中,1000r/min搅拌10h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖(黏均分子量为2.5×100000)制成质量浓度2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂(Eudragit L100)制成质量浓度1%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至7,将羧甲基壳聚糖溶液和聚丙烯酸树脂(Eudragit L100)溶液按照体积比1︰2混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰1在磁力搅拌下混合均匀,用超纯水稀释3倍,经喷雾干燥得胶束微球。
本发明方法制备的胶束微球可有效用于制备抗癌药物,实现胶束微球在制备抗癌药物中的应用。
本发明所述方法经过反复多次试验,均得出相同或相近的结果,相关实验资料如下:
本发明的胶束微球制剂抗皮下肿瘤活性的试验数据具体如下:
1.动物:SPF级Balb/c小鼠,雌性,42士2日龄,体重19±2g,由湖南斯莱克景达实验动物有限公司提供。合格证编号:SCXK(湘)2011-0003。每组动物数:阴性对照组10只,给药组每组10只。
2.移植瘤:小鼠乳腺癌细胞(4T1)
3.体内抗瘤活性:取冻存的4T1细胞株,快速复苏后于37℃、5%C02及饱和湿度条件下,培养24h后换液,继续培养,待细胞长满培养瓶底部70~80%时,传代1次,以后每2~3d传代1次,传至4~5代以后,开始大量培养。
将生长状态良好的对数生长期4T1细胞,胰酶消化,离心收集细胞,用生理盐水将细胞浓度调节成5×106个·ml-1的细胞悬液,在无菌超净工作台中,按每只0.2ml细胞悬液量接种于Balb/C小鼠右侧腹部皮下***周围,共30只。接种10d后随机分组,按照分组不同给药。阴性对照组即每天口服1次生理盐水,连续给药21天;阳性对照组2-甲氧基***(2-ME)每天口服给药(po)一次,共21次。第21天处死动物,称体重、瘤重,计算各组平均瘤重,求出肿瘤抑制率并进行t检验,优选出最佳治疗组,结果见表1。
表1 2-甲氧基***胶束微球口服抗肿瘤效应
通过皮下种植4T1载瘤小鼠药效学研究,以口服生理盐水为阴性对照组,由表1可知,2-ME胶束微球口服制剂在两个剂量下的试验组均具有显著的抗肿瘤效果,肿瘤生长抑制率均高于80%,高剂量组的疗效明显高于低剂量组的疗效。而其他的2-ME制剂包括静注胶束组和口服胶束组,口服原料药微球组肿瘤生长抑制率均低于50%,抗肿瘤效果不理想。可见,单独口服胶束或单独口服微球组抗肿瘤效果均较差,而2-ME胶束微球口服制剂具有显著的理想的抗肿瘤效果,说明胶束和微球的联合制备的两相转运体系胶束微球对2-ME而言是一个抗肿瘤有效的口服制剂。
本发明将水难溶性药物包封在胶束中,再将载药胶束和pH敏感性高分子材料混合喷雾干燥制备成pH敏感性胶束微球,口服给药,一定程度上克服这些药口服吸收的障碍,明显提高其这些药的口服生物利用度。本发明采用聚乙二醇-聚乳酸乙醇酸共聚物材料(其中聚乳酸乙醇酸共聚物材料的乳酸/乙醇酸的摩尔比是1/1-3/1)制备载药胶束,再将其与高分子材料水溶液混合喷雾干燥成微球。高分子材料为羧甲基壳聚糖和丙烯酸树脂的混合物,其中羧甲基壳聚糖的质量百分比为10-40%。
本发明口服胶束微球用于一些水难溶性药物如抗癌药的口服给药,载药胶束可明显提高难溶性药物的溶解度,胶束的纳米尺寸和亲水性外壳可防止胶束进入血液后被人体内网状内皮组织***识别吸收,延长药物在血液循环***中的滞留时间,同时,由于肿瘤组织血管具有高渗透性和高滞留性,聚合物胶束的小粒径有利于药物在肿瘤组织的滞留和堆积,赋予对肿瘤组织的被动靶向作用。pH敏感性的胶束微球,可以减少胃液对胶束稳定性的影响,减少载药胶束在胃液的损失,可以实现载药胶束的肠靶向缓释,延长胶束的肠吸收时间,相应的延长载药胶束在血液中滞留时间,而且一定程度上克服肝首过效应、肠吸收饱和和吸收外排等障碍,提高小肠对载药胶束的吸收率,可以明显提高这些药物的口服生物利用度,改变原来用原料药制备的普通制剂口服无效的现状,使其口服有效,并经临床试验,取得了非常满意的疗效,有关资料如下:
临床对108例肿瘤患者试用,其中乳腺癌58人、***癌50人,按原有同类抗肿瘤药物治疗方案进行,温开水冲服,服用6个月后统计疗效,采用SPSS 11.5统计软件单因素方差比较分析,P<0.01,比同类药物提高疗效40%以上,有极显著性差异,具体结果如下:
症状明显改善者58人,其中乳腺癌32人、***癌26人,占53.7%;
症状改善者40人,其中乳腺癌22人、***癌18人,占37%;
无效10人,其中乳腺癌4人、***癌6人,占9.3%,连续用药5年以上,平均生命存活5年以上者70人,2-4年者21人,1年左右者17人,可见本发明纳米粒微球有效改变了原同类难溶性口服药物生物利用度低、疗效低的问题,开拓了***药物的新途径,具有很强的实用性,有显著的经济和社会效益。
Claims (6)
1.一种口服胶束微球的制备方法,其特征在于,由以下步骤实现:
(1)、制备胶束混悬液:
35-50℃水浴下,将80-100mg PEG5000-PLGA5000、5-10mg大豆磷脂溶解在2-4ml水中,作为水相,将2-5mg 2-甲氧基***超声溶解在400-600μL甲醇中,然后逐滴加入到水相中,700-1000rpm搅拌9-12h,过0.45μm滤膜,得胶束混悬液,4℃保存;所述的大豆磷脂为PC-80,磷脂酰胆碱含量>80%,注射级;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖制成质量浓度1-2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂(Eudragit L100)制成质量浓度1-2%聚丙烯酸树脂溶液,用1mol/L的NaOH调节溶液的pH至5-7,将羧甲基壳聚糖溶液和聚丙烯酸树脂溶液按照体积比1︰1-3混合,搅拌均匀,得微球材料混合溶液;取步骤(1)制得的胶束混悬液与微球材料混合溶液按照体积比1︰1-2在磁力搅拌下混合均匀,用超纯水稀释1-3倍,经喷雾干燥得胶束微球;所述的羧甲基壳聚糖黏均分子量为2.5×100000。
2.根据权利要求1所述的口服胶束微球的制备方法,其特征在于,由以下步骤实现:
(1)、制备胶束混悬液:
35℃水浴下,将80mg PEG5000-PLGA5000、10mg大豆磷脂溶解在4ml水中,作为水相,将5mg 2-甲氧基***超声溶解在500μL甲醇中,然后逐滴添加到水相当中,900r/min搅拌9h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖制成质量浓度1%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂制成质量浓度2%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至6,将羧甲基壳聚糖溶液和聚丙烯酸树脂溶液按照体积比1︰3混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰2在磁力搅拌下混合均匀,用超纯水稀释2倍,经喷雾干燥得胶束微球。
3.根据权利要求1所述的口服胶束微球的制备方法,其特征在于,由以下步骤实现:
(1)、制备胶束混悬液:
45℃水浴下,将80mg PEG5000-PLGA5000、10mg大豆磷脂溶解在2ml水中,作为水相,将2mg 2-甲氧基***超声溶解在400μL甲醇中,然后逐滴添加到水相当中,1000r/min搅拌10h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖制成质量浓度2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂制成质量浓度2%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至6.5,将羧甲基壳聚糖溶液和聚丙烯酸树脂溶液按照体积比1︰1混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰1在磁力搅拌下混合均匀,用超纯水稀释1.5倍,经喷雾干燥得胶束微球。
4.根据权利要求1所述的口服胶束微球的制备方法,其特征在于,由以下步骤实现:
(1)、制备胶束混悬液:
40℃水浴下,将100mg PEG5000-PLGA5000、10mg大豆磷脂溶解在3ml水中,作为水相,将4mg 2-甲氧基***超声溶解在500μL甲醇中,然后逐滴添加到水相当中,1000r/min搅拌12h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖制成质量浓度2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂制成质量浓度1%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至5,将羧甲基壳聚糖溶液和聚丙烯酸树脂溶液按照体积比1︰1混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰1在磁力搅拌下混合均匀,用超纯水稀释1倍,经喷雾干燥得胶束微球。
5.根据权利要求1所述的口服胶束微球的制备方法,其特征在于,由以下步骤实现:
(1)、制备胶束混悬液:
50℃水浴下,将90mg PEG5000-PLGA5000、8mg大豆磷脂溶解在3ml水中,作为水相,将3mg 2-甲氧基***超声溶解在400μL甲醇中,然后逐滴添加到水相当中,1000r/min搅拌10h,过0.45μm滤膜,得胶束混悬液,冰箱4℃保存;
(2)、制备胶束微球:
用超纯水将羧甲基壳聚糖制成质量浓度2%的羧甲基壳聚糖溶液,用pH7.4的磷酸缓冲液将聚丙烯酸树脂制成质量浓度1%聚丙烯酸树脂溶液,并且用1mol/L的NaOH调节溶液的pH至7,将羧甲基壳聚糖溶液和聚丙烯酸树脂溶液按照体积比1︰2混合并且搅拌均匀,得微球材料混合溶液,取步骤(1)所得胶束混悬液与微球材料混合溶液按照体积比1︰1在磁力搅拌下混合均匀,用超纯水稀释3倍,经喷雾干燥得胶束微球。
6.权利要求1或2-5任一项所述方法制备的口服胶束微球在制备抗癌药物中的应用。
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