CN117045613A - 一种治疗糖尿病周围神经病变的药物组合物及其制备方法 - Google Patents
一种治疗糖尿病周围神经病变的药物组合物及其制备方法 Download PDFInfo
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Abstract
一种治疗糖尿病周围神经病变的药物组合物的制备方法,具体是将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉;将甲钴胺、粘合剂、填充剂、崩解剂、润滑剂混合,得甲钴胺混粉;将胞磷胆碱钠混粉与甲钴胺混粉在双层压片机上压制,得到双层双释素片;将双层双释素片用遮光包衣剂来包衣。本发明制备的治疗糖尿病周围神经病变的药物组合物,通过将胞磷胆碱钠和甲钴胺制备成双层片,有效保障了药效成分的含量均匀性、在片剂中的分布均匀性和药效稳定性,减少患者服药次数和辅料摄入量,提高患者使用依从性。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种治疗糖尿病周围神经病变的药物组合物及其制备方法。
背景技术
周围神经病(DPN)变属于糖尿病神经病变中最常见的一类,是糖尿病最常见的慢性并发症之一,糖尿病患者出现与周围神经功能障碍相关的症状,临床表现为对称性疼痛和感觉异常,下肢症状较上肢多见。发病率高,是引起糖尿病足溃疡及下肢截肢的高危因素,现已成为糖尿病患者致残、致死的主要原因。
普遍使用甲钴胺进行糖尿病周围病变的治疗,甲钴胺通过促进核酸和蛋白质合成及脑磷脂合成卵磷脂,促进髓鞘形成和轴突再生而修复受损的神经组织。而胞磷胆碱钠片通过合成磷脂酰胆碱,能修复神经细胞膜,增加供应神经的血管的血流灌注,改善周围神经病理损伤,主要用于急性颅脑外伤及脑手术后的意识障碍。上述两种药物目前仍在不同疾病领域应用,但已有研究证明胞磷胆碱钠及甲钴胺两者合用对糖尿病周围神经病变的改善起协同作用,较单独使用甲钴胺进行糖尿病周围神经病变治疗效果更优。为此,将两者制成复方制剂可以减少服药次数,增加患者使用依从性。
发明内容
本发明目的在于提供一种治疗糖尿病周围神经病变的药物组合物,本发明的胞磷胆碱钠与甲钴胺制成双层片药物组合物,解决了复合制剂中药物含量不均匀、分布不均匀的问题,保障了药效稳定性。
本发明另一目的在于提供上述药物组合物的制备方法。
本发明目的通过如下技术方案实现:
一种治疗糖尿病周围神经病变的药物组合物,其特征在于:所述药物组合物为双层片结构,具体为胞磷胆碱钠层和甲钴胺层,其中胞磷胆碱钠层包括胞磷胆碱钠、粘合剂、填充剂、崩解剂和润滑剂;甲钴胺层包括甲钴胺、粘合剂、填充剂、崩解剂和润滑剂。
进一步,所述胞磷胆碱钠层中,粘合剂为羧甲基纤维素钠、羟丙纤维素、乙基纤维素和羟乙纤维素中的至少一种,所述填充剂为微晶纤维素、甘露醇、山梨醇、乳糖和玉米淀粉中至少一种,所述崩解剂为交联聚维酮,所述润滑剂为硬脂酸镁、硬脂酸钙和硬脂富马酸钠中任意一种。
进一步,按照重量份计,所述胞磷胆碱钠层中,胞磷胆碱钠为50~200份,粘合剂为10~100份,填充剂为50~200份,崩解剂为20~50份,润滑剂为1~10份。
进一步,所述甲钴胺层中,粘合剂为聚氧乙烯、聚乙二醇、聚乙烯醇和聚维酮中的至少一种,所述填充剂为微晶纤维素、甘露醇、山梨醇、乳糖和玉米淀粉中至少一种,所述崩解剂为羧甲淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠或交联聚维酮,所述润滑剂为硬脂酸镁、硬脂酸钙和硬脂富马酸钠中任意一种。
进一步优选地,所述填充剂为甘露醇和乳糖质量比为2:1组成。
进一步优选地,所述粘合剂为聚乙二醇4000。
进一步,按照重量份计,所述甲钴胺层中,甲钴胺为0.5~1份,粘合剂为5~10份,所述填充剂为20~60份,崩解剂为5~30份,润滑剂为0.1~0.3份。
进一步,所述药物组合物是将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉,将甲钴胺、粘合剂、填充剂、崩解剂、润滑剂混合,得甲钴胺混粉;然后将胞磷胆碱钠混粉与甲钴胺混粉在双层压片机上压制,得到双层双释素片,最后采用遮光包衣剂来包衣制得。
进一步,当填充剂为甘露醇和乳糖质量比为2:1组成时,先将甲钴胺与乳糖及崩解剂的30%进行搅拌混合后,然后再加入甘露醇与崩解剂的30%进行混合,最后再加入其余组分混合。
一种治疗糖尿病周围神经病变的药物组合物及其制备方法,其特征在于:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉;
S2)制备甲钴胺混粉:将甲钴胺、粘合剂、填充剂、崩解剂、润滑剂混合,得甲钴胺混粉;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来包衣。
进一步,所述制备甲钴胺混粉是将甲钴胺与30%的崩解剂和30%的填充剂混合均匀后,再加入剩余崩解剂、剩余填充剂、粘合剂、崩解剂和润滑剂进行混合。
进一步,所述胞磷胆碱钠层中,粘合剂为羧甲基纤维素钠、羟丙纤维素、乙基纤维素和羟乙纤维素中的至少一种,所述填充剂为微晶纤维素、甘露醇、山梨醇、乳糖和玉米淀粉中至少一种,所述崩解剂为交联聚维酮,所述润滑剂为硬脂酸镁、硬脂酸钙和硬脂富马酸钠中任意一种。
进一步,按照重量份计,所述胞磷胆碱钠层中,胞磷胆碱钠为50~200份,粘合剂为10~100份,填充剂为50~200份,崩解剂为20~50份,润滑剂为1~10份。
进一步,所述甲钴胺层中,粘合剂为聚氧乙烯、聚乙二醇、聚乙烯醇和聚维酮中的至少一种,所述填充剂为微晶纤维素、甘露醇、山梨醇、乳糖和玉米淀粉中至少一种,所述崩解剂为羧甲淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠或交联聚维酮,所述润滑剂为硬脂酸镁、硬脂酸钙和硬脂富马酸钠中任意一种。
进一步优选地,所述填充剂为甘露醇和乳糖质量比为2:1组成。
进一步优选地,所述粘合剂为聚乙二醇4000。
进一步,按照重量份计,所述甲钴胺层中,甲钴胺为0.5~1份,粘合剂为5~10份,所述填充剂为20~60份,崩解剂为5~30份,润滑剂为0.1~0.3份。
进一步,所述包衣剂为含深色氧化铁的包衣剂。
最具体的,一种治疗糖尿病周围神经病变的药物组合物的制备方法,其特征在于,按如下步骤进行:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉,按照重量份计,胞磷胆碱钠为50~200份,粘合剂为10~100份,填充剂为50~200份,崩解剂为20~50份,润滑剂为1~10份;
S2)制备甲钴胺混粉:将甲钴胺与30%的崩解剂混合均匀后,再与剩余崩解剂粘合剂、填充剂、和润滑剂混合,得甲钴胺混粉,按照重量份计,甲钴胺为0.5~1份,粘合剂为5~10份,所述填充剂为20~60份,崩解剂为5~30份,润滑剂为0.1~0.3份;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来包衣。
进一步优选地,当填充剂为甘露醇和乳糖质量比为2:1组成时,先将甲钴胺与乳糖及崩解剂的30%进行搅拌混合后,然后再加入甘露醇与崩解剂的30%进行混合,最后再加入其余组分混合。
本发明中通过将胞磷胆碱钠和甲钴胺制备成片,减少药物对人体的副作用,具体将两种药物成分制成双层片,从而解决两者之间的释放干扰。但是制备的双层片中在制备组合物过程中发现,由于两种药物中甲钴胺用量极少,与胞磷胆碱钠及辅料的含量差异较大,导致制备的片剂中有效组分的含量分布均匀性较差,使得制备的片剂组合物之间存在药物组分成分含量的差异,药效稳定性差,以及片剂内部有效成分的分布均匀性差,双层片药物释放不一致,使得片剂药效难以保证。
本发明中通过调节胞磷胆碱钠层和甲钴胺层中的辅料种类及配比,使得甲钴胺在层中具有优异的分布均匀性,且与胞磷胆碱钠混合后能够实现两中药效成分的崩解、释放溶出等达到一致性,从而保证药效稳定性。尤其在制备甲钴胺层时,选择以甘露醇和乳糖质量比为2:1组成填充剂,并与崩解剂按照分步混合的制备混粉,有效提高了甲钴胺在片中的分布均匀性,再与胞磷胆碱钠层中的崩解剂的选择配合,实现了双层片中有效成分的释放一致性的提高。
本发明具有如下技术效果:
本发明制备的治疗糖尿病周围神经病变的药物组合物,,减少患者服药次数和辅料摄入量,提高患者使用依从性。通过将胞磷胆碱钠和甲钴胺制备成双层片,有效提高了药效成分的含量均匀性、在片剂中的分布均匀性,从而有效提高了双层片的药效稳定性。
具体实施方式
下面通过实施例对本发明进行具体的描述,有必要在此指出的是,以下实施例只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制,该领域的技术人员可以根据上述本发明内容对本发明作出一些非本质的改进和调整。
实施例1
一种治疗糖尿病周围神经病变的药物组合物的制备方法,药物组合物中各组成成分如表1所示:
按如下步骤制备:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉;
S2)制备甲钴胺混粉:将甲钴胺与30%的崩解剂和30%填充剂混合均匀后、再加入剩余崩解剂、粘合剂、剩余填充剂、和润滑剂进行混合,得甲钴胺混粉;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来进行包衣,制得双层片组合物。
实施例2
一种治疗糖尿病周围神经病变的药物组合物的制备方法,药物组合物中各组成成分如表2所示:
表2
按如下步骤制备:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉;
S2)制备甲钴胺混粉:先将甲钴胺与乳糖、30%崩解剂进行搅拌混合后,然后再加入甘露醇和30%崩解剂进行混合,最后再加入剩余的崩解剂、粘合剂、崩解剂和润滑剂混合,得甲钴胺混粉;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来包衣,制得双层片组合物。
性能测试:
(1)通过将各方案中制备的胞磷胆碱钠与甲钴胺双层片组合物,样本数量为10,测定其内部药物成分的含量,以每1片双层片中胞磷胆碱钠和甲钴胺的计算含量均值为100%。
(2)按照《中国药典》2015年版释放测试方法第一法进行测定,以0.01mol/L盐酸溶液作为溶出介质,溶出介质体积为900mL,转速为100r/min,每隔10min取样检测胞磷胆碱钠和甲钴胺的溶出度,检测结果如表1所示。随机抽取8个样本,检测结果如表3所。
表3:
实施例1制备的双层片组合物中胞磷胆碱钠的含量分布均匀,分布范围在98~102%之间,甲钴胺的分布范围稍大一些,在90~106%之间,依然呈现出较好的分布均匀性,实施例2中胞磷胆碱钠和甲钴胺的含量分布分别为98~101%和98~102%之间,甲钴胺的分布均匀性较实施例1有进一步提高。
对比例1:
一种治疗糖尿病周围神经病变的药物组合物的制备方法,药物组合物中各组成成分如表4所示,制备方法与实施例2一致。
表4:
对比例2
一种治疗糖尿病周围神经病变的药物组合物的制备方法,药物组合物中各组成成分如表5所示,制备方法与实施例2一致。
表5:
对比例1和对比例2制备的双层片组合物的含量均匀性、崩解时间如表6所示。
表6:
对比例1与实施例1相比,将胞磷胆碱钠层中的崩解剂交联聚维酮更换成了低取代羟丙基纤维素,对比例2与实施例2相比,是胞磷胆碱钠层中粘合剂更换成了聚乙烯醇。从最终检测结果可知,当胞磷胆碱钠层中的崩解剂和粘合剂更换成与甲钴胺层中相同的低取代羟丙基纤维素和聚乙烯醇,双层片组合物的崩解速率出现了不同程度的下降。
对比例3
所有组分比例与实施例2一致,制备步骤如下:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉;
S2)制备甲钴胺混粉:先将甲钴胺与30%崩解剂、30%甘露醇和乳糖按照2:1组成的填充剂混合,然后再加入剩余的崩解剂、剩余填充剂、粘合剂和润滑剂混合,得甲钴胺混粉;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来包衣,制得双层片组合物。
对比例4
所有组分比例与实施例2一致,制备步骤如下:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉;
S2)制备甲钴胺混粉:先将甲钴胺与30%崩解剂混合,然后加入剩余崩解剂、填充剂、粘合剂、崩解剂和润滑剂混合,得甲钴胺混粉;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来包衣,制得双层片组合物。
对比例3和对比例4制备的双层片组合物的含量均匀性、崩解时间等性能检测结果如表7所示。
表7:
与实施例2相比,对比例3中崩解剂和填充剂的添加方式不同,与实施例1的添加方式一致,胞磷胆碱钠的含量范围在98~102%之间,与实施例1持平,而甲钴胺含量在89~106%之间,较实施例1含量均匀性下降。与实施例2相比,对比例4中的崩解剂添加方式不同,制备的双层片组合物中胞磷胆碱钠和甲钴胺的含量范围分别为98~103%之间和70~113%之间,含量均匀性极差,且崩解时间较实施例2出现了明显的延长。
实施例3
一种治疗糖尿病周围神经病变的药物组合物的制备方法,药物组合物中各组成成分如表8所示。
表8:
本实施例制备的双层片组合物的平均崩解时间为11s,胞磷胆碱钠的含量在99.1~101.8%,甲钴胺的含量在97.9~102.7%之间。
实施例4
一种治疗糖尿病周围神经病变的药物组合物的制备方法,药物组合物中各组成成分如表9所示。
表9:
本实施例制备的双层片组合物的平均崩解时间为11s,胞磷胆碱钠的含量在98.4~101.5%,甲钴胺的含量在98.2~102.8%之间。
在检测溶出一致性的过程中,选择各方案制备的双层片中胞磷胆碱钠和甲钴胺含量均在99~101%之间片剂进行释放测定。测定结果如表10所示。
表10:
从上表可以看出,对比例1-4中胞磷胆碱钠和甲钴胺在整个释放过程的释放速率均出现不同程度差异,正是由于在双层片中药效成分的分布均匀性差,导致在相同时间下,药效释放一致性出现明显的偏差。
Claims (6)
1.一种治疗糖尿病周围神经病变的药物组合物及其制备方法,其特征在于:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉;
S2)制备甲钴胺混粉:将甲钴胺、粘合剂、填充剂、崩解剂、润滑剂混合,得甲钴胺混粉;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来包衣。
2.如权利要求1所述的一种治疗糖尿病周围神经病变的药物组合物及其制备方法,其特征在于:所述的所述胞磷胆碱钠层中,粘合剂为羧甲基纤维素钠、羟丙纤维素、乙基纤维素和羟乙纤维素中的至少一种,所述填充剂为微晶纤维素、甘露醇、山梨醇、乳糖和玉米淀粉中至少一种,所述崩解剂为交联聚维酮,所述润滑剂为硬脂酸镁、硬脂酸钙和硬脂富马酸钠中任意一种。
3.如权利要求1或2所述的一种治疗糖尿病周围神经病变的药物组合物及其制备方法,其特征在于:按照重量份计,所述胞磷胆碱钠层中,胞磷胆碱钠为50~200份,粘合剂为10~100份,填充剂为50~200份,崩解剂为20~50份,润滑剂为1~10份。
4.如权利要求1-3任一项所述的一种治疗糖尿病周围神经病变的药物组合物及其制备方法,其特征在于:所述甲钴胺层中,粘合剂为聚氧乙烯、聚乙二醇、聚乙烯醇和聚维酮中的至少一种,所述填充剂为微晶纤维素、甘露醇、山梨醇、乳糖和玉米淀粉中至少一种,所述崩解剂为羧甲淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠或交联聚维酮,所述润滑剂为硬脂酸镁、硬脂酸钙和硬脂富马酸钠中任意一种。
5.如权利要求1-4任一项中所述的一种治疗糖尿病周围神经病变的药物组合物及其制备方法,其特征在于:按照重量份计,所述甲钴胺层中,甲钴胺为0.5~1份,粘合剂为5~10份,所述填充剂为20~60份,崩解剂为5~30份,润滑剂为0.1~0.3份。
6.一种治疗糖尿病周围神经病变的药物组合物的制备方法,其特征在于,按如下步骤进行:
S1)制备胞磷胆碱钠混粉:将胞磷胆碱钠、粘合剂、填充剂、崩解剂、润滑剂混合,得胞磷胆碱钠混粉,按照重量份计,胞磷胆碱钠为50~200份,粘合剂为10~100份,填充剂为50~200份,崩解剂为20~50份,润滑剂为1~10份;
S2)制备甲钴胺混粉:将甲钴胺与30%的崩解剂和30%填充剂混合均匀后,再与剩余崩解剂粘合剂、剩余填充剂、和润滑剂混合,得甲钴胺混粉,按照重量份计,甲钴胺为0.5~1份,粘合剂为5~10份,所述填充剂为20~60份,崩解剂为5~30份,润滑剂为0.1~0.3份;
S3)将步骤S1的胞磷胆碱钠混粉与步骤S2的甲钴胺混粉在双层压片机上压制,得到双层双释素片;
S4)将步骤S3中的双层双释素片用遮光包衣剂来包衣。
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