CN107281163A - 羧基化合物在促进载药纳米粒微球口服吸收方面的应用 - Google Patents
羧基化合物在促进载药纳米粒微球口服吸收方面的应用 Download PDFInfo
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Abstract
本发明公开了一种羧基化合物在促进载药纳米粒微球口服吸收方面的应用,所述的羧基化合物为羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸。本发明以羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸作为纳米粒口服制剂的吸收促进剂,可显著促进载药纳米粒微球的肠吸收,极大提高其药物的口服生物利用度。本发明采用的吸收促进剂中,枸橼酸、苹果酸、酒石酸都是常用的药用辅料,常常作为口服制剂的矫味剂等,醋酸是食用醋的主要成分,羧甲基壳聚糖是常用的可生物降解的药用载体材料,这些作为纳米粒微球的口服吸收促进剂安全无毒无刺激,具有很好的应用前景。
Description
技术领域
本发明属于医药领域,具体涉及一种羧基化合物在促进载药纳米粒微球口服吸收方面的应用。
背景技术
临床上有些水中难溶性药物如大多数抗癌药,因其口服生物利用度低等原因,只能采用静脉注射的方式给药。但是由于静脉给药存在需要频繁注射,患者依从性较差,血药浓度波动较大导致明显的毒副作用等问题,其应用受到较大的局限性。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。口服给药具有患者可自行用药,患者依从性高等优点。但这些药物口服后生物利用度低的问题亟待解决,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。如多西他赛是一种水难溶性抗癌药,通过加强微管蛋白聚合作用和抑制微管解聚作用破坏肿瘤细胞的有丝分裂而发挥抗肿瘤作用,主要治疗晚期乳腺癌、卵巢癌、非小细胞肺癌等病症。其口服给药存在明显的肝首过效应和肠吸收外排机制,其普通制剂口服给药生物利用度很低,口服抗癌无效。
纳米粒通过将药物包封在其中避免药物与肠道和肝脏的直接接触,改变了药物的口服肠吸收机制和途径,避免了肝脏的首过效应,可有效克服这些药物的口服障碍,一定程度上提高了这些药物的口服生物利用度。但是纳米粒直接口服的肠吸收效率较低,导致纳米粒直接口服仍然存在口服生物利用度较低的问题,难以满足临床应用的要求。因此如何提高纳米粒的口服生物利用度是成功开发其纳米粒口服制剂需要认真解决的技术问题。主要的策略包括对纳米粒进行生物粘附性修饰和应用吸收促进剂等。据目前报道,吸收促进剂主要是可逆地打开细胞间紧密连接而促进纳米粒的肠吸收,是否还有其他的促进吸收机制还在研究中。其应用方法包括两种,第一种是吸收促进剂作为纳米粒的载体材料或化学连接到载体材料上制备载药纳米粒,第二种是吸收促进剂和载药纳米粒混合后应用,从而促进载药纳米粒的肠吸收。目前主要以第一种应用为主。第一种应用常常涉及到化学反应,难度较大,存在有机溶剂残留、增加生物利用度有限等问题,而且合成的材料能否作为药用辅料需要进一步认证。目前已报道的纳米粒口服吸收促进剂仅有去氧胆酸钠、壳聚糖及其衍生物和乙二醇二乙醚二胺四乙酸(EGTA)。其中壳聚糖及其衍生物和乙二醇二乙醚二胺四乙酸(EGTA)都不是药用辅料,只有去氧胆酸钠是药用辅料。由此表明纳米粒的口服吸收促进剂目前研究报道很少,而且品种有限,作为药用辅料的品种更少。因此急需开发新型的纳米粒吸收促进剂以提高其口服生物利用度。
发明内容
为了解决上述问题,本发明的目的是提供一种羧基化合物在促进载药纳米粒微球口服吸收方面的应用,该方法可有效解决现有载药纳米粒口服生物利用度较低的问题。
为了实现上述目的,本发明所采用的技术方案是:
羧基化合物在促进载药纳米粒微球口服吸收方面的应用。
所述的羧基化合物为羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸。
使用时,将载药纳米粒微球与羧基化合物混合均匀,再加水混悬,口服给药。
所述的羧基化合物的用量为载药纳米粒微球质量分数的0.2-2.5%。
所述的载药纳米粒微球的负载药物包括但不局限于多西他赛。
一种羧基化合物在用于制备抗癌药物纳米粒口服制剂中的应用。
本发明的有益效果:
1、本发明以羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸作为纳米粒口服制剂的吸收促进剂,可显著促进载药纳米粒微球的肠吸收,极大提高其药物的口服生物利用度。
2、本发明采用的吸收促进剂中,枸橼酸、苹果酸、酒石酸都是常用的药用辅料,常常作为口服制剂的矫味剂等,醋酸是食用醋的主要成分,羧甲基壳聚糖是常用的可生物降解的药用载体材料,这些作为纳米粒微球的口服吸收促进剂安全无毒无刺激,具有很好的应用前景。
3、本发明的方法避免了对纳米粒载体的化学修饰,简单有效,而且安全无毒无刺激,将极大的推动载药纳米粒口服制剂,尤其是抗癌药物纳米粒口服制剂的开发,具有极大的推广价值和良好的社会经济效益。
具体实施方式
以下结合实施例对本发明的具体实施方式作进一步详细说明。
实施例1
多西他赛纳米粒微球的制备,包括以下步骤:
(1)将多西他赛8mg、PEG5000-PCL10000 150mg、胆固醇32mg、大豆磷脂(PC-80,磷脂酰胆碱含量>80%,注射级)160mg,置于圆底烧瓶中,再加入3mL氯仿和2mL乙醚,在37℃下旋转蒸发。1h后有机溶剂(氯仿和乙醚)蒸发完全,形成一层致密的薄膜,加入4mL PBS,45℃水合30min。冰浴探超2min(工作3s,间歇4s,工作40次),过0.45μm微孔滤膜,得到多西他赛聚合物脂质体混悬液,4℃保存。
(2)用超纯水将羧甲基壳聚糖(粘均分子量为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溶液按照体积比1︰3混合并且搅拌均匀,得到微球材料混合溶液。
(3)取上述制备的多西他赛聚合物脂质体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,制得多西他赛纳米粒微球。
实施例2、不同吸收促进剂对载药纳米粒促进吸收的影响
本发明经过反复多次试验,均得出相同或相近的结果,相关实验资料如下:
1、实验材料及分组
本实验以羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸作为吸收促进剂,来检验羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸对多西他赛纳米粒微球口服生物利用度的影响,具体分组如下:组1:羧甲基壳聚糖;组2:枸橼酸;组3:酒石酸;组4:苹果酸;组5:醋酸。
2、实验动物
SPF级Sprague Dawley大鼠,雌性,体重200±20g,由郑州大学实验动物中心提供。合格证编号:SCXK(豫)2015-0004。
3、实验方法
药动学实验分别将大鼠分成7组,每组动物数为10只。实验前禁食12h,自由饮水。组1-5分别将多西他赛纳米粒微球制剂与吸收促进剂羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸混合均匀,吸收促进剂的用量为载药纳米粒微球质量分数的0.2-2.5%,具体见表1,再加入适量的水混悬后,进行灌胃操作。同时设置仅采用多西他赛纳米粒微球制剂灌胃的空白组和静脉注射多帕菲的对照组。将各组大鼠分别在规定时间点眼眶取血,并置于已经肝素化处理的离心管内,5000rpm离心10min后取血浆。采用高效液相色谱法测定血药浓度,各组对应的药动学参数及吸收促进剂对其的影响见表1。
表1吸收促进剂对多西他赛纳米粒微球制剂口服生物利用度的影响
由表1可知,多西他赛纳米粒微球口服给药时,不同的吸收促进剂可显著提高其口服生物利用度,由此证明本发明提出的吸收促进剂可显著提高载药纳米粒口服生物利用度,可有效提高抗癌药物口服的药效,实现吸收促进剂在制备抗癌药物口服纳米粒制剂中的应用。
以上所述仅为本发明最佳的实施例,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (7)
1.羧基化合物在促进载药纳米粒微球口服吸收方面的应用。
2.根据权利要求1所述的应用,其特征在于,所述的羧基化合物为羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸。
3.根据权利要求1所述的应用,其特征在于,使用时,将载药纳米粒微球与羧基化合物混合均匀,再加水混悬,口服给药。
4.根据权利要求3所述的应用,其特征在于,所述的羧基化合物的用量为载药纳米粒微球质量分数的0.2-2.5%。
5.根据权利要求1-4任一项所述的应用,其特征在于,所述的载药纳米粒微球的负载药物包括但不局限于多西他赛。
6.一种羧基化合物在用于制备抗癌药物纳米粒口服制剂中的应用。
7.根据权利要求6所述的应用,其特征在于,所述的羧基化合物为羧甲基壳聚糖、枸橼酸、酒石酸、苹果酸、醋酸。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108935921A (zh) * | 2018-06-08 | 2018-12-07 | 河南蜀正园食品有限公司 | 营养大豆蛋白粉、制备方法及其在制备营养食品中的应用 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1844202A (zh) * | 2006-03-29 | 2006-10-11 | 武汉大学 | 一种药物载体羧甲基壳聚糖纳米粒子及其制备方法 |
CN1853718A (zh) * | 2005-04-18 | 2006-11-01 | 汕头大学医学院 | 一种新型定位口服药用组合物及其制备方法 |
CN101568330A (zh) * | 2006-06-30 | 2009-10-28 | 伊休蒂卡有限公司 | 用于制备纳米粒形式的生物活性化合物的方法 |
WO2010143942A1 (en) * | 2009-06-12 | 2010-12-16 | Erasmus University Medical Center Rotterdam | Targeted nano-photomedicines for photodynamic therapy of cancer |
CN102210655A (zh) * | 2011-04-11 | 2011-10-12 | 山东大学 | 一种头孢匹胺钠微球及其制备方法 |
CN102961345A (zh) * | 2012-11-20 | 2013-03-13 | 桂林电子科技大学 | 一种雷帕霉素/磁性羧甲基壳聚糖纳米载药微球的制备方法 |
CN103255175A (zh) * | 2013-05-17 | 2013-08-21 | 四川大学 | 一种磁性纳米基因载体系统及其制备和应用 |
WO2015055796A1 (en) * | 2013-10-16 | 2015-04-23 | Université Libre de Bruxelles | Formulations useful in the treatment of proliferative diseases affecting the respiratory tract |
-
2017
- 2017-07-05 CN CN201710540276.2A patent/CN107281163B/zh not_active Expired - Fee Related
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1853718A (zh) * | 2005-04-18 | 2006-11-01 | 汕头大学医学院 | 一种新型定位口服药用组合物及其制备方法 |
CN1844202A (zh) * | 2006-03-29 | 2006-10-11 | 武汉大学 | 一种药物载体羧甲基壳聚糖纳米粒子及其制备方法 |
CN101568330A (zh) * | 2006-06-30 | 2009-10-28 | 伊休蒂卡有限公司 | 用于制备纳米粒形式的生物活性化合物的方法 |
WO2010143942A1 (en) * | 2009-06-12 | 2010-12-16 | Erasmus University Medical Center Rotterdam | Targeted nano-photomedicines for photodynamic therapy of cancer |
CN102210655A (zh) * | 2011-04-11 | 2011-10-12 | 山东大学 | 一种头孢匹胺钠微球及其制备方法 |
CN102961345A (zh) * | 2012-11-20 | 2013-03-13 | 桂林电子科技大学 | 一种雷帕霉素/磁性羧甲基壳聚糖纳米载药微球的制备方法 |
CN103255175A (zh) * | 2013-05-17 | 2013-08-21 | 四川大学 | 一种磁性纳米基因载体系统及其制备和应用 |
WO2015055796A1 (en) * | 2013-10-16 | 2015-04-23 | Université Libre de Bruxelles | Formulations useful in the treatment of proliferative diseases affecting the respiratory tract |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108935921A (zh) * | 2018-06-08 | 2018-12-07 | 河南蜀正园食品有限公司 | 营养大豆蛋白粉、制备方法及其在制备营养食品中的应用 |
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