CN116585265A - 一种用于防治老年痴呆的组合物及其制备方法 - Google Patents
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Abstract
本发明公开了一种用于防治老年痴呆的组合物及其制备方法,涉及老年痴呆症治疗药物技术领域;其原料由肠溶药物4‑8份、玛咖提取物4‑8份、水溶性的海藻酸/海藻酸盐1‑3份、聚丙酰胺0.1‑0.5份、泊洛沙姆0.5‑2份、甘油3‑8份、聚卡波非0.1‑0.5份和去离子水80‑90份组成;所述肠溶药物是表面包覆有肠溶层的另一份玛咖提取物微粉,所述肠溶层由丙烯酸树脂和肠溶材料组成;所述玛咖提取物为平均粒径不超过300μm微粉。本发明提供的组合物不仅能促进肠道快速吸收玛咖提取物,还能延长组合物在肠道中停留的时间,促进药物的充分吸收;对老年痴呆的防治效果也较好。
Description
技术领域
本发明涉及老年痴呆症治疗药物技术领域,特别涉及用于防治老年痴呆的组合物。
背景技术
老年痴呆是老年期和老年前期常见的一组慢性进行性神经退行性疾病,是老年人群中的常见病和多发病。在我国,65岁以上人群的痴呆症发生率约为7.5%,85岁以上群体的发生率更是超过了40%,已成为老年人中仅次于心脑血管疾病和恶性肿瘤的重要致死疾病。老年痴呆患者的认知功能、社交能力和生活自理能力均不同程度受损,给患者家庭和社会都带来了很大负担。临床上以记忆障碍、失语、失用、失认、视空间技能损害,执行功能障碍以及人格和行为改变等全面性痴呆表现为特征,病因迄今未明。根据认知能力和身体机能的恶化程度可将老年痴呆症分成三个时期,即轻度、中度和重度痴呆三个阶段。β位淀粉样蛋白前体蛋白切割酶1(BACE1,又称β-分泌酶)是淀粉样蛋白生成途径中的限速步骤。与认知正常的人相比,老年痴呆症、阿尔茨海默病(AD)的大脑中的BACE1蛋白浓度和活性显著升高。因此,BACE1被认为是AD早期有希望的治疗靶点,因此不同的BACE1抑制剂已经被研究出来。
玛咖提取物是一种从玛咖中提取出来的含有玛咖酰胺、玛咖烯、玛咖多糖等功能成分的混合物。玛咖提取物能溶于水和乙醇,如果直接服用,随着肠道蠕动速度较快,真正能被有效吸收的量较少,因此需要通过制成能够在肠道中更长时间停留,或者能控制和促进肠道吸收的剂型。因此,如果将玛咖提取物作为原料,制备治疗老年痴呆的药物,就需要解决上述玛咖提取物在肠道吸收时存在的问题。
发明内容
针对以上现有技术的不足,本发明提供了一种用于防治老年痴呆的组合物及其制备方法,具体通过以下技术实现。
一种用于防治老年痴呆的组合物,其原料由肠溶药物4-8份、玛咖提取物4-8份、水溶性的海藻酸/海藻酸盐1-3份、聚丙酰胺0.1-0.5份、泊洛沙姆0.5-2份、甘油3-8份、聚卡波非0.1-0.5份和去离子水80-90份组成;所述肠溶药物是表面包覆有肠溶层的另一份玛咖提取物微粉,所述肠溶层由丙烯酸树脂和肠溶材料组成;所述玛咖提取物为平均粒径不超过300μm微粉。
玛咖(玛卡):味辛、性温,归肺、肾经;具有补肺生津、益肾壮阳的功效,可用于肺痿不张、腰膝酸软、阳痿、早泄、精少、月经不调等症。玛咖中的功效成分(例如玛咖烯、玛咖酰胺等)能够通过抑制BACE1蛋白的产生,有效降低老年痴呆症、阿兹海默症等病症的发病概率,对老年痴呆症、阿兹海默症也具有一定治疗效果。
优选地,上述组合物中,所述肠溶药物的制备方法是:
P1、将玛咖提取物微粉和肠溶材料加在丙酮-水溶液中混合均匀,制成第一混合液;另将丙烯酸树脂溶解于无水乙醇中制成第二混合液,分别超声震荡;
P2、再将第一混合液和第二混合液混合均匀,超声震荡,真空干燥后制成成品;
所述玛咖提取物微粉、肠溶材料和丙烯酸树脂的质量比为1:(1.2-1.5):(0.3-0.5)。
优选地,所述肠溶药物的制备方法中,所述丙酮-水溶液的丙酮的质量分数为30-50%。
优选地,所述肠溶材料为邻苯二甲酸醋酸纤维素酯。
优选地,其原料由肠溶药物7份、玛咖提取物7份、水溶性的海藻酸/海藻酸盐2份、聚丙酰胺0.4份、泊洛沙姆1份、甘油5份、聚卡波非0.4份和去离子水85份组成。
本发明还提供了一种上述组合物的制备方法,包括以下步骤:
S1、将水溶性的海藻酸/海藻酸盐、聚丙酰胺、玛咖提取物溶解在质量分数为30-50%的乙醇水溶液中,冷冻干燥,获得表面包覆有水溶性的海藻酸/海藻酸盐的微粉;
将聚卡波非和占总量40-50%的去离子水混合均匀,制成第一溶液备用;将微粉、泊洛沙姆、甘油加至剩余的去离子水中混合均匀制成第二溶液;
S2、将第一溶液和第二溶液混合均匀,最后加入肠溶药物混匀得到液态的组合物成品。
与现有技术相比,本发明的有益之处在于:本发明制备的组合物,是一种液态成品;其功效成分为玛咖提取物,并且成品中的玛咖提取物存在两种形式,一种分散游离在液态成品中,另一种被肠溶药物和丙烯酸树脂包覆后分散在液体中;采用这种特殊形式的组合物,不仅能促进肠道快速吸收玛咖提取物,还能延长组合物在肠道中停留的时间,促进药物的充分吸收。
具体实施方式
下面将对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动条件下所获得的所有其它实施例,都属于本发明保护的范围。
以下实施例和对比例所使用的玛咖提取物为市场采购所得,平均粒径100-150μm。玛咖提取物还可以根据实际条件自行制备获得。例如,具体制备方法可以是:用水将块状干燥的玛咖原料粉碎,加水煮沸,然后浸提浓缩制成浸提膏;最后真空干燥、粉碎后获得微粉。
以下实施例和对比例所制备的防治老年痴呆的组合物的制备方法为:
S1、将水溶性的海藻酸/海藻酸盐、聚丙酰胺、玛咖提取物溶解在质量分数为50%的乙醇水溶液中,冷冻干燥,获得表面包覆有水溶性的海藻酸/海藻酸盐的微粉;
将聚卡波非和占总量50%的去离子水混合均匀,制成第一溶液备用;将微粉、泊洛沙姆、甘油加至剩余50%的去离子水中混合均匀制成第二溶液;
S2、将第一溶液和第二溶液混合均匀,最后加入肠溶药物混匀得到液态的组合物成品。
以下实施例和对比例中,所使用的肠溶药物的制备方法是:
P1、按照质量比1:1.5:0.5取咖提取物微粉、肠溶材料和丙烯酸树脂,将玛咖提取物微粉和肠溶材料加在丙酮-水溶液(质量比1:1)中混合均匀,制成第一混合液;另将丙烯酸树脂溶解于无水乙醇中制成第二混合液,分别超声震荡;
P2、再将第一混合液和第二混合液混合均匀,超声震荡,真空干燥后制成成品。
试验例
以下组合物共分为六组,原料配方分别如下:
第一组:肠溶药物7g、玛咖提取物7g、海藻酸钠3g、聚丙酰胺0.4g、泊洛沙姆1g、甘油5g、聚卡波非0.4g和去离子水85g组成。
第二组:肠溶药物4g、玛咖提取物8g、海藻酸钠3g、聚丙酰胺0.1g、泊洛沙姆0.5g、甘油8g、聚卡波非0.1g和去离子水80g组成。
第三组:肠溶药物8g、玛咖提取物4g、海藻酸钠1g、聚丙酰胺0.5g、泊洛沙姆2g、甘油3g、聚卡波非0.5g和去离子水90g组成。
第四组:肠溶药物2g、玛咖提取物2g、海藻酸钠1g、聚丙酰胺0.1g、泊洛沙姆1g、甘油2g、聚卡波非0.6g和去离子水88g组成。
第五组:肠溶药物14g、泊洛沙姆1g、甘油5g、聚卡波非0.4g和去离子水85g组成;即不含有玛咖提取物、海藻酸钠和聚丙酰胺,肠溶药物的用量增加至14g。
第六组:玛咖提取物14g、海藻酸钠2g、聚丙酰胺0.4g、泊洛沙姆1g、甘油5g、聚卡波非0.4g和去离子水85g组成;即不含有肠溶药物。
3、玛咖提取物的肠道吸收效果试验:
(1)对SD大鼠随机分为40组,每组5只;
(2)空白对照组:生理盐水每天一次,每次2ml,同时饲料喂养;实验组:给予上述六组的组合物灌胃,每天一次,每次2ml,同时采用不含玛咖相关成分的饲料喂养。
阳性对照:取玛咖提取物微粉用去离子水溶解至浓度为15%;每天一次,每次2ml,同时采用不含玛咖相关成分的饲料喂养;
试验组:给予上述六组的组合物灌胃,每天一次,每次2ml,同时采用不含玛咖相关成分的饲料喂养。
(3)采用HPLC法测定小鼠血液中的玛咖提取物(玛咖酰胺)的含量。
在每次灌胃后0.5h、1.5h,分别在大鼠尾部静脉采取大鼠血清,10μL;
色谱条件和相关操作:用十八烷基硅烷键合硅胶为填充剂,检测波长为203nm,流速为1.0mL/min,柱温为25℃。
0-10min,A相(5%磷酸溶液)70%,B相乙腈30%;10-32min,A相(5%磷酸溶液)20%,B相乙腈80%;32-37min,A相(5%磷酸溶液)5%,B相乙腈95%;B相乙腈80%;37-40min,A相(5%磷酸溶液)70%,B相乙腈30%;
按干燥品计算,总玛咖酰胺含量=N-苄基亚麻酰胺含量+N-苄基亚油酰胺含量+N-苄基十六碳酰胺含量。
每天小鼠血液中的总玛咖酰胺含量如下表所示,单位mg/mL。
注:与模型组比较,**P<0.01,***P<0.001
从上述检测结果通过对比各组和阳性对照的比较,可以看到采用本发明的原料和制备方法制备的组合物(第一、二、三组),在第0.5h时大鼠血清中就已经存在较高含量的玛咖酰胺,说明在第0.5h时小鼠的肠道就已经快速有效吸收了相当含量的玛咖有效成分,能够有效促进玛咖提取物的吸收。
当改变各原料的用量时(第四组)时,由于肠溶药物和玛咖提取物都明显减少,导致0.5h和1.5h时大鼠血液中的总玛咖酰胺含量都明显减少。
当不含有玛咖提取物、海藻酸钠和聚丙酰胺,将肠溶药物用量增加至14g时(第五组),第0.5h和1.5h的大鼠血液中总玛咖酰胺含量提升也很慢,这可能是由于缺少海藻酸钠和聚丙酰胺,虽然肠溶药物含量增加,但在肠道停留时间过短;并且因为缺少玛咖提取物,导致第0.5h的总玛咖酰胺含量较低。
当不含有肠溶药物,将玛咖提取物含量提升至14g时(第六组),可以看到第0.5h的总玛咖酰胺含量非常显著地上升,说明玛咖提取物被快速吸收,第1.5h后的含量也非常显著地上升;但第2天和第3天的0.5h的总玛咖酰胺含量则相比前一天出现明显下降,这可能是由于缺少肠溶药物的使用,部分玛咖提取物被快速吸收,但也有相当一部分在肠道停留时间较短而被排出体外,吸收的玛咖提取物在随后时间里也会随着尿液等途径排出。
阳性对照中,每天的第0.5h时总玛咖酰胺含量与当天第1.5h相比提升明显,但是与前一天的第0.5h相比提升不大,说明阳性对照的吸收药物较快,但由于在肠道停留时间较短,药物浓度波动较大,并不稳定。
4、组合物对BACE1蛋白的抑制作用评价。
参考文献《BACE1-siRNA纳米复合物对阿尔茨海默病模型小鼠学习记忆和相关蛋白表达的影响》(张璇等,中国新药杂志,2015年第24卷第22期)公开的检测方法。
(1)6月龄的APP/PS1双转基因模型小鼠40只,雌雄各半;6月龄同窝阴性对照C57BL/6小鼠2只,雌雄各半。
(2)空白对照一:C57BL/6小鼠,不作任何处理,正常饲料喂养;
空白对照二:使用生理盐水对APP/PS1双转基因模型小鼠每天灌胃一次,每次2ml,同时饲料喂养;
阳性对照:取玛咖提取物颗粒用去离子水溶解至浓度为5%;对APP/PS1双转基因模型小鼠每天灌胃一次,每次2ml,同时采用不含玛咖相关成分的饲料喂养;
试验组:对APP/PS1双转基因模型小鼠给予上述六组的组合物灌胃,每天一次,每次2ml,同时采用不含玛咖相关成分的饲料喂养。
(3)试验方法
采用Western blotting法分别检测小鼠脑组织中BACE1及下游产物Aβ的蛋白表达量的变化。与空白对照一和空白对照二相比,发现试验组和阳性对照组的BACE1及Aβ灰度值降低有显著性差异(P<0.05),进一步分析发现,试验组的BACE1及Aβ灰度值降低更为明显,结果有显著性差异(P<0.01)。正常小鼠脑内BACE1及Aβ的蛋白表达量低于其他各组。该结果表明,本发明提供的组合物,能一定程度抑制BACE1基因以及其下游产物Aβ蛋白的表达。
以上具体实施方式详细描述了本发明的实施,但是,本发明并不限于上述实施方式中的具体细节。在本发明的权利要求书和技术构思范围内,可以对本发明的技术方案进行多种简单改型和改变,这些简单变型均属于本发明的保护范围。
Claims (6)
1.一种用于防治老年痴呆的组合物,其特征在于,其原料由肠溶药物4-8份、玛咖提取物4-8份、水溶性的海藻酸/海藻酸盐1-3份、聚丙酰胺0.1-0.5份、泊洛沙姆0.5-2份、甘油3-8份、聚卡波非0.1-0.5份和去离子水80-90份组成;所述肠溶药物是表面包覆有肠溶层的另一份玛咖提取物微粉,所述肠溶层由丙烯酸树脂和肠溶材料组成;所述玛咖提取物为平均粒径不超过300μm微粉。
2.根据权利要求1所述的用于防治老年痴呆的组合物,其特征在于,所述肠溶药物的制备方法是:
P1、将玛咖提取物微粉和肠溶材料加在丙酮-水溶液中混合均匀,制成第一混合液;另将丙烯酸树脂溶解于无水乙醇中制成第二混合液,分别超声震荡;
P2、再将第一混合液和第二混合液混合均匀,超声震荡,真空干燥后制成成品;
所述玛咖提取物微粉、肠溶材料和丙烯酸树脂的质量比为1:(1.2-1.5):(0.3-0.5)。
3.根据权利要求1所述的用于防治老年痴呆的组合物,其特征在于,所述肠溶药物的制备方法中,所述丙酮-水溶液的丙酮的质量分数为30-50%。
4.根据权利要求1所述的用于防治老年痴呆的组合物,其特征在于,所述肠溶材料为邻苯二甲酸醋酸纤维素酯。
5.根据权利要求1所述的用于防治老年痴呆的组合物,其特征在于,其原料由肠溶药物7份、玛咖提取物7份、水溶性的海藻酸/海藻酸盐2份、聚丙酰胺0.4份、泊洛沙姆1份、甘油5份、聚卡波非0.4份和去离子水85份组成。
6.权利要求1-5任一项所述的用于防治老年痴呆的组合物的制备方法,其特征在于,包括以下步骤:
S1、将水溶性的海藻酸/海藻酸盐、聚丙酰胺、玛咖提取物溶解在质量分数为30-50%的乙醇水溶液中,冷冻干燥,获得表面包覆有水溶性的海藻酸/海藻酸盐的微粉;
将聚卡波非和占总量40-50%的去离子水混合均匀,制成第一溶液备用;将微粉、泊洛沙姆、甘油加至剩余的去离子水中混合均匀制成第二溶液;
S2、将第一溶液和第二溶液混合均匀,最后加入肠溶药物混匀得到液态的组合物成品。
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