CN101700248A - 一种阿司卡托肠溶缓释胶囊的制备方法 - Google Patents
一种阿司卡托肠溶缓释胶囊的制备方法 Download PDFInfo
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Abstract
本发明提供一种制备肠溶缓释胶囊的方法:将阿拉伯胶溶解后与阿司匹林及卡托普利原料药混合,倾入到分散相中,加入环糊精和乳化剂等溶液,高压均质,喷雾干燥,通过控制体系酸碱度、进出风温度等,即得到粉末微球,过筛后与粘合剂等混合均匀,制粒,真空干燥,装入空心肠溶胶囊,包装即得本发明产品;本发明的突出特点是:该技术方法具有构思新颖、设计合理、操作方便,工艺规范和制造成本低廉、患者服用后易被肠道吸收,无胃刺激、患者乐于接受,无环境污染,易于形成工业化批量生产等优点;本发明的重要意义还在于制备的缓释胶囊克服了突释现象;本发明采用的材料具有良好的生物相容性、可降解性;本发明有望开发一种防治心血管疾病的理想药物。
Description
技术领域:本发明属于新药研发领域一种阿司卡托肠溶缓释胶囊的制备方法
背景技术:急性心肌梗塞(AMI)与血栓栓塞性疾病的发病率与死亡率均甚高,如何采取有效措施防治,早已成为举世瞩目的问题.60年代发现阿司匹林(Aspirin,Asp)具抗血小板聚集作用,70年代即用于AMI的防治,但效果并不理想,近年又将Asp与抗凝剂合用,疗效也有争议,且因此而引起的出血性反应,常导致治疗终止.此外,国内尚采用″活血化淤药″进行防治,但疗效如何也尚无定论.
回顾以往对AMI的防治,无论是采用Asp还是抗凝剂,其着眼点均在血栓上而忽略了心血管功能的改善,对本病发生、发展和转归的影响,很难设想一个结构功能完整的血管内皮细胞膜上会产生血栓,也很难设想一个结构功能良好的心肌细胞会出现不可逆性心律失常,由此可见改善心功能,对防治AMI和其它血栓栓塞性疾病的重要性.但血栓形成比竟是这类疾病的一个主要继发病因,直接影响病人的健康及生命,采取有效措施防治血栓形成,仍属十分重要,为此,我们将Asp与卡托普利(Cap)配合应用,系统观察了二者单用和合用对血小板聚集功能、血液流变性和体内血栓形成及血液动力学的影响以及对心肌氧自由基损伤的保护作用等,结果表明,Asp和Cap配合应用在抗血小板聚集和抗血栓形成、改善微循环和血液流变性方面均呈明显的协同作用,且Asp不影响Cap对心功能的改善,也不影响Cap抗氧自由基作用,此对于提高Asp防治心梗和血栓栓塞性疾病的疗效,降低其不良反应,十分有利.因此,在以上研究的基础上,我们开发了一种主要活性成分为Asp和Cap的新型复方肠溶缓释制剂-阿司卡托肠溶缓释胶囊,经查新证明国内外无类同报告,该研究对于提高Asp防治心血管疾病效果、降低不良反应并为开发理想的新型Asp替代药物提供了新的制造技术,具有巨大的社会效益及经济效益.
发明内容:该发明的目的是提供一种以阿拉伯胶和环糊精为主要载体辅料制备阿司卡托肠溶缓释微囊的方法,以弥补已有技术的不足.
本发明采用阿拉伯胶、各种环糊精和Asp及Cap为原料,其具体方法是先将阿拉伯胶溶解,在搅拌条件下将阿拉伯胶溶液和Asp及Cap原料药混合后,倾入到分散相溶液中,并向其中加入环糊精和乳化剂等溶液,高压均质充分乳化,真空脱泡,导入喷雾干燥制粒机,通过控制反应温度、体系酸碱度、均质压力和乳化和脱泡时间以及喷雾干燥制粒机进风温度、出风温度、进料流量、进样温度等,即得到阿司卡托缓释粉末微球,过筛之后与具有生物粘附和药物缓释双重作用载体辅料、粘合剂混合均匀,再用75%乙醇作湿润剂制成颗粒,经低温真空干燥,装入1号空心肠溶胶囊,包装即得本发明产品.
本发明具有构思新颖、设计合理、操作方便,工艺规范和制造成本低廉、患者服用后易被肠道吸收,无胃刺激、患者乐于接受,无环境污染,易于形成工业化批量生产等优点.本发明对原材料有广泛的适用性,所有具有疏水内腔和亲水表面的各种环糊精均可以适用.因此,本发明的原料来源十分广泛.本发明的重要意义还在于阿司卡托缓释胶囊制备中采用了具有生物粘附和药物缓释双重作用和易于糖蛋白寡糖联上的糖残基形成氢键、产生较强的粘液凝胶网状结构、与肠粘膜糖蛋白具较强的粘附作用.的载体辅料,结果使制备的肠溶胶囊性能更加稳定,肠粘附性更强,达到肠内Cap定位释放,克服了水溶性药物缓释制剂易出现的突释现象.本发明采用的各种环糊精可与药物生成包接物以及其具有的良好的抗氧化作用使在小肠的偏碱的环境中不稳定的Cap稳定化.本发明采用的材料安全无毒副作用、具有良好的生物相容性、生物可降解性、成膜性能好等特点.本产品属硬胶囊剂型;性状为肠溶胶囊,为白色或类白色颗粒.本发明有望开发一种治疗和预防心血管疾病的理想药物,具有良好的研究和开发应用前景.因此,该发明技术具有很好经济开发潜力.
具体实施方式:本发明采用阿拉伯胶、各种环糊精和Asp及Cap为原料,先溶解得到阿拉伯胶溶液,阿拉伯胶溶液的浓度是4%-50%,可使用分子量为220,000Da-500,000Da的阿拉伯胶,Cap的添加量是阿拉伯胶的0.1-6倍,在搅拌条件下将阿拉伯胶溶液和Asp及Cap原料药混合后,倾入到分散相中,混合液体积可以是分散相的1/6-1/24,并向其中加入环糊精和乳化剂等溶液,高压均质充分乳化,真空脱泡,导入喷雾干燥制粒机,通过控制反应温度、体系酸碱度、搅拌速度和乳化和脱泡时间以及喷雾干燥制粒机进样温度、进样流量、进风温度、出风温度,即得到阿司卡托缓释粉末微球,过筛之后与具有生物粘附和药物缓释双重作用载体辅料、粘合剂混合均匀,再用75%乙醇作湿润剂制成颗粒,经低温真空干燥,装入1号空心肠溶胶囊,包装即得本发明产品.
阿拉伯胶溶液和Asp及Cap混合溶液的酸碱度可以是pH 1-12,均质压力可以是10-50MPa,均质时间可以是30-120s,为了使混合溶液充分乳化,均质压力可以是40-70mPa,均质时间可以是90-180s,反应温度可以是5-60℃,脱泡时间5-10min,为了使溶液充分脱泡,脱泡时间可以延长到8-15min.
考虑到Cap遇热易氧化、水溶性较高,缓释制剂易于出现药物突释现象,采用了具有生物粘附和药物缓释双重作用和易于糖蛋白寡糖联上的糖残基形成氢键、产生较强的粘液凝胶网状结构、与肠粘膜糖蛋白具较强的粘附作用.的载体辅料,使胶囊性能更加稳定,具有生物粘附和药物缓释双重作用载体材料可以是微晶纤维素、羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙基纤维素(EC)、羟乙基纤维素(HEC),添加量可以是1∶3-1∶5;所使用的调节pH的试剂可以是10%碳酸氢铵,也可以是氢氧化钠、氨水、氢氧化钾,盐酸,醋酸;所使用的分散相可以是稀盐酸溶液,也可以是稀醋酸溶液、去离子水;所使用的乳化剂可以是吐温80,也可以是司盘、十二烷基硫酸钠、单/双甘酯.所使用的粘合剂可以是PVPK30也可以是卡波姆、羧甲基纤维素.
喷雾条件:进样温度可以是10-70℃,进样流量可以是50-500ml/min,进风温度可以是100-300℃,出风温度可以是10-100℃.
喷雾干燥方式得到的阿司卡托缓释粉末微球,过筛之后与具有生物粘附和药物缓释双重作用载体辅料、粘合剂混合均匀,再用75%乙醇作湿润剂制成颗粒,经低温真空干燥,装入1号空心肠溶胶囊,包装即得本发明产品.
本发明采用的各种环糊精可以包括α-环糊精、β-环糊精、γ-环糊精、羧甲基β-环糊精、羟丙基β-环糊精等.
具体实施方式举例:
实施例1
将阿拉伯胶溶解,在搅拌条件下将阿拉伯胶溶液和Asp及Cap原料药混合后,倾入到稀醋酸溶液溶液中,并向其中加入一定量的α环糊精和司盘溶液,调节pH,10MPa均质充分乳化,真空脱泡8min,导入喷雾干燥制粒机,调节喷雾干燥参数为:进样温度10℃、进样流量50ml/min、进风温度100℃、出风温度10℃,即得到阿司卡托缓释粉末微球,过筛之后与HPMCP、PVPK30混合均匀,再用75%乙醇作湿润剂制成颗粒,经低温真空干燥,装入1号空心肠溶胶囊,包装即得本发明产品.
实施例2
将阿拉伯胶溶解,在搅拌条件下将阿拉伯胶溶液和Asp及Cap原料药混合后,倾入到稀盐酸溶液中,并向其中加入一定量的β环糊精和十二烷基硫酸钠溶液,调节pH,30MPa均质充分乳化,真空脱泡10min,导入喷雾干燥制粒机,调节喷雾干燥参数为:进样温度50℃、进样流量200ml/min、进风温度200℃、出风温度50℃,即得到阿司卡托缓释粉末微球,过筛之后与HPMC、卡波姆混合均匀,再用75%乙醇作湿润剂制成颗粒,经低温真空干燥,装入1号空心肠溶胶囊,包装即得本发明产品.
实施例3
将阿拉伯胶溶解,在搅拌条件下将阿拉伯胶溶液和Asp及Cap原料药混合后,倾入到去离子水溶液中,并向其中加入一定量的γ-环糊精和单甘酯溶液,调节pH,50MPa均质充分乳化,真空脱泡15min,导入喷雾干燥制粒机,调节喷雾干燥参数为:进样温度70℃、进样流量500ml/min、进风温度300℃、出风温度100℃,即得到阿司卡托缓释粉末微球,过筛之后与HEC、羧甲基纤维素混合均匀,再用75%乙醇作湿润剂制成颗粒,经低温真空干燥,装入1号空心肠溶胶囊,包装即得本发明产品。
Claims (5)
1.一种阿司卡托肠溶缓释胶囊的制备方法。
2.根据权利要求1所述的一种阿司卡托肠溶缓释胶囊的制备方法,其阿司卡托缓释粉末微球制备方法采用的是喷雾干燥法。
3.根据权利要求1所述的一种阿司卡托肠溶缓释胶囊的制备方法,其肠溶缓释胶囊制备中加入了具有生物粘附和药物缓释双重作用载体辅料。
4.根据权利要求1所述的一种阿司卡托肠溶缓释胶囊的制备方法,其所述的采用的各种环糊精可以包括α-环糊精、β-环糊精、γ-环糊精、羧甲基β-环糊精、羟丙基β-环糊精等。
5.根据权利要求3所述的一种阿司卡托肠溶缓释胶囊的制备中加入了具有生物粘附和药物缓释双重作用载体材料包括微晶纤维素、羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙基纤维素(EC)、羟乙基纤维素(HEC)。
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Cited By (4)
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CN103432145A (zh) * | 2013-07-01 | 2013-12-11 | 宁夏医科大学 | 一种治疗瘢痕的外用西药组合物制剂及其应用 |
CN104127466A (zh) * | 2013-08-23 | 2014-11-05 | 江苏省中医药研究院 | 一种淫羊藿总黄酮口服肠溶制剂及其应用 |
CN108743565A (zh) * | 2018-07-04 | 2018-11-06 | 青岛科技大学 | 一种乙酰水杨酸结肠定位生物粘附型缓释胶囊的制备方法 |
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CN103432145A (zh) * | 2013-07-01 | 2013-12-11 | 宁夏医科大学 | 一种治疗瘢痕的外用西药组合物制剂及其应用 |
CN104127466A (zh) * | 2013-08-23 | 2014-11-05 | 江苏省中医药研究院 | 一种淫羊藿总黄酮口服肠溶制剂及其应用 |
CN104127466B (zh) * | 2013-08-23 | 2018-05-22 | 江苏省中医药研究院 | 一种淫羊藿总黄酮口服肠溶制剂及其应用 |
CN109248319A (zh) * | 2017-07-14 | 2019-01-22 | 郜建敏 | 含有司坦类化合物和阿司匹林的药物组合物 |
CN108743565A (zh) * | 2018-07-04 | 2018-11-06 | 青岛科技大学 | 一种乙酰水杨酸结肠定位生物粘附型缓释胶囊的制备方法 |
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