CN105770866A - 一种缓释型降糖药物组合物及其制备方法 - Google Patents
一种缓释型降糖药物组合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种缓释型降糖药物组合物及其制备方法,所述组合物按重量份计,主要是由以下成分组成:可生物降解聚合物80‑200份、温敏性水凝胶30‑70份、D‑苯丙氨酸衍生物3‑10份、葡萄糖激酶2‑10份、褐藻胶5‑12份、桦褐孔菌3‑20份、甲壳素衍生物5‑20份、鞣花酸1‑6份、亚麻油酸1‑5份、大豆低聚糖5‑20份、花生四烯酸乙醇胺2‑8份、果糖酸钙3‑10份、鱼腥草素1‑4份、防腐剂0.2‑1份。本发明的缓释型降糖药物组合物,能够有效改善Ⅱ型糖尿病患者的血糖控制状况,可以达到长期稳定的释放药物,使药物在体内保持适当的浓度和作用时间,减少药物的使用次数和剂量,并且能够降血脂,增强患者的免疫力,预防糖尿病引起的体重过度较轻,对长期控制血糖有一定的益处。
Description
技术领域
本发明涉及糖尿病用药技术领域,具体是涉及一种缓释型降糖药物组合物及其制备方法。
背景技术
糖尿病是以高血糖水平为特征的慢性疾病,可以分成两种类型:I型糖尿病,其导致胰腺停止产生胰岛素,和II型糖尿病,其同时导致胰岛素抵抗增加和胰腺β-细胞功能退化。高血糖则是由于胰岛素分泌缺陷或其生物作用受损,或两者兼有引起。糖尿病时长期存在的高血糖,导致各种组织,特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍。中国有超过9200万成年人患有糖尿病,还有1.5亿人是糖尿病的潜在患者,即大约每10名成年人中就有1名患有糖尿病。格列齐特是第2代磺脲类口服降糖药,该类药物是国际上公认安全有效的口服降血糖药物,为目前成年Ⅱ型糖尿病的常规用药,糖尿病可发生多种并发症,有些还直接威胁到患者的生命。Ⅱ型糖尿病发生心血管疾病和中风的危险性要比普通人群高出2-4倍,患者会因此而减少寿命5-10年。在所有与糖尿病相关的死亡中,有80%左右与心血管疾病(CVD)有关,因此,医学界一直都积极地采取一切措施,尽最大努力来减少Ⅱ型糖尿病心血管危险的因素。
目前,作为治疗型糖尿病药物有很多,普遍存在的缺陷就是药效维持时间短,生物利用度较低,一日内需多次服药。
发明内容
本发明解决的技术问题是提供一种缓释型降糖药物组合物及其制备方法,能够有效改善Ⅱ型糖尿病患者的血糖控制状况,减少药物的使用次数和剂量,对长期控制血糖有一定的益处。
本发明的技术方案是:一种缓释型降糖药物组合物,按重量份计,主要是由以下重量份的成分组成:可生物降解聚合物80-200份、温敏性水凝胶30-70份、D-苯丙氨酸衍生物3-10份、葡萄糖激酶2-10份、褐藻胶5-12份、桦褐孔菌3-20份、甲壳素衍生物5-20份、鞣花酸1-6份、亚麻油酸1-5份、大豆低聚糖5-20份、花生四烯酸乙醇胺2-8份、果糖酸钙3-10份、鱼腥草素1-4份、防腐剂0.2-1份。
进一步地,在上述方案中,所述可生物降解聚合物为甲基化聚乙二醇-乙交酯-丙交酯共聚物。所述甲基化聚乙二醇-乙交酯-丙交酯共聚物的单体摩尔比例的范围为50∶45-20∶60,分子量为10000-50000道尔顿。能够在生理条件下可以自行降解、崩溃或代谢,使药物在体内保持适当的浓度和作用时间。
进一步地,所述温敏性水凝胶选自聚环氧乙烷或聚环氧丙烷,可以达到长期稳定的释放药物,生物相容性好,可自行降解。
进一步地,所述D-苯丙氨酸衍生物选自那格列奈,是一种新型的餐时血糖调节剂,能有效控制餐后血糖水平,不易引起心血管副作用,低血糖的发生率较低。
进一步地,所述甲壳素衍生物为壳寡糖,对人体的免疫调节、抗肿瘤、降血脂、调节血糖、改善肝脏和心肺功能及其他多种生理功能有着重要作用。
进一步地,所述防腐剂为苯甲酸钠,防止药物腐败变质,延长药物有效期,保证药效。
一种缓释型降糖药物组合物,其制备方法为:
(1)按所述配比取可生物降解聚合物80-200份、温敏性水凝胶30-70份、D-苯丙氨酸衍生物3-10份、葡萄糖激酶2-10份、褐藻胶5-12份、桦褐孔菌3-20份、甲壳素衍生物5-20份、鞣花酸1-6份、亚麻油酸1-5份、大豆低聚糖5-20份、花生四烯酸乙醇胺2-8份、果糖酸钙3-10份、鱼腥草素1-4份、防腐剂0.2-1份,备用;
(2)将所述温敏性水凝胶完全溶解于生理盐水中,然后将其加热至50℃保持15-20分钟后再放入0℃冰水中孵化直至形成无色透明的溶液;
(3)将所述可生物降解聚合物分散在去离子水中,滴加入步骤(2)的无色透明溶液,再加入所述D-苯丙氨酸衍生物、葡萄糖激酶、褐藻胶、桦褐孔菌、甲壳素衍生物、鞣花酸、亚麻油酸、大豆低聚糖、花生四烯酸乙醇胺、果糖酸钙、鱼腥草素、防腐剂,搅拌,形成混合溶液,在常压、室温下超声反应10-30min,在常压、5-20℃下静置3-10h,减压浓缩至含水量低于40-45%,即得到所述缓释型降糖药物组合物。
进一步地,所述生理盐水的用量为所述温敏性水凝胶的重量的6-11倍。
进一步地,所述去离子水的用量以所述可生物降解聚合物的浓度之和达到100-450g/L为限。
本发明的有益效果是:本发明的缓释型降糖药物组合物,能够有效改善Ⅱ型糖尿病患者的血糖控制状况,通过可生物降解聚合物与温敏性水凝胶的共同作用,可以达到长期稳定的释放药物,使药物在体内保持适当的浓度和作用时间,而且这两种成分生物相容性好,可以在生理条件下自行降解、崩溃或代谢,减少药物的使用次数和剂量,并且能够降血脂,增强患者的免疫力,预防糖尿病引起的体重过度较轻,对长期控制血糖有一定的益处。
具体实施方式
实施例1:
一种缓释型降糖药物组合物,按重量份计,主要是由以下重量份的成分组成:可生物降解聚合物80份、温敏性水凝胶30份、D-苯丙氨酸衍生物3份、葡萄糖激酶2份、褐藻胶5份、桦褐孔菌3份、甲壳素衍生物5份、鞣花酸1份、亚麻油酸1份、大豆低聚糖5份、花生四烯酸乙醇胺2份、果糖酸钙3份、鱼腥草素1份、防腐剂0.2份。
其中,所述可生物降解聚合物为甲基化聚乙二醇-乙交酯-丙交酯共聚物。所述甲基化聚乙二醇-乙交酯-丙交酯共聚物的单体摩尔比例的范围为50∶45∶60,分子量为10000道尔顿,能够在生理条件下可以自行降解、崩溃或代谢,使药物在体内保持适当的浓度和作用时间。所述温敏性水凝胶为聚环氧乙烷,可以达到长期稳定的释放药物,生物相容性好,可自行降解。所述D-苯丙氨酸衍生物选自那格列奈,是一种新型的餐时血糖调节剂,能有效控制餐后血糖水平,不易引起心血管副作用,低血糖的发生率较低。所述甲壳素衍生物为壳寡糖,对人体的免疫调节、抗肿瘤、降血脂、调节血糖、改善肝脏和心肺功能及其他多种生理功能有着重要作用。所述防腐剂为苯甲酸钠,防止药物腐败变质,延长药物有效期,保证药效。
一种缓释型降糖药物组合物,其制备方法为:
(1)按所述配比取可生物降解聚合物80份、温敏性水凝胶30份、D-苯丙氨酸衍生物3份、葡萄糖激酶2份、褐藻胶5份、桦褐孔菌3份、甲壳素衍生物5份、鞣花酸1份、亚麻油酸1份、大豆低聚糖5份、花生四烯酸乙醇胺2份、果糖酸钙3份、鱼腥草素1份、防腐剂0.2份,备用;
(2)将所述温敏性水凝胶完全溶解于生理盐水中,所述生理盐水的用量为所述温敏性水凝胶的重量的6倍,然后将其加热至50℃保持15分钟后再放入0℃冰水中孵化直至形成无色透明的溶液;
(3)将所述可生物降解聚合物分散在去离子水中,所述去离子水的用量以所述可生物降解聚合物的浓度之和达到100g/L为限,滴加入步骤(2)的无色透明溶液,再加入所述D-苯丙氨酸衍生物、葡萄糖激酶、褐藻胶、桦褐孔菌、甲壳素衍生物、鞣花酸、亚麻油酸、大豆低聚糖、花生四烯酸乙醇胺、果糖酸钙、鱼腥草素、防腐剂,搅拌,形成混合溶液,在常压、室温下超声反应10min,在常压、5℃下静置3h,减压浓缩至含水量低于40%,即得到所述缓释型降糖药物组合物;
(4)将该缓释型降糖药物组合物中按比例加入辅料:15%的预胶化淀粉、2%的羟甲基纤维素、0.02%的氢化植物油等,通过混合、整粒、干燥、制粒、压片等工艺制备成口服片剂。
实施例2:
一种缓释型降糖药物组合物,按重量份计,主要是由以下重量份的成分组成:可生物降解聚合物140份、温敏性水凝胶5份、D-苯丙氨酸衍生物6.5份、葡萄糖激酶6份、褐藻胶8.5份、桦褐孔菌11.5份、甲壳素衍生物12.5份、鞣花酸3.5份、亚麻油酸3份、大豆低聚糖12.5份、花生四烯酸乙醇胺5份、果糖酸钙6.5份、鱼腥草素2.5份、防腐剂0.6份。
其中,所述可生物降解聚合物为甲基化聚乙二醇-乙交酯-丙交酯共聚物。所述甲基化聚乙二醇-乙交酯-丙交酯共聚物的单体摩尔比例的范围为50∶32.5∶60,分子量为30000道尔顿,能够在生理条件下可以自行降解、崩溃或代谢,使药物在体内保持适当的浓度和作用时间。所述温敏性水凝胶为聚环氧丙烷,可以达到长期稳定的释放药物,生物相容性好,可自行降解。所述D-苯丙氨酸衍生物选自那格列奈,是一种新型的餐时血糖调节剂,能有效控制餐后血糖水平,不易引起心血管副作用,低血糖的发生率较低。所述甲壳素衍生物为壳寡糖,对人体的免疫调节、抗肿瘤、降血脂、调节血糖、改善肝脏和心肺功能及其他多种生理功能有着重要作用。所述防腐剂为苯甲酸钠,防止药物腐败变质,延长药物有效期,保证药效。
一种缓释型降糖药物组合物,其制备方法为:
(1)按所述配比取可生物降解聚合物140份、温敏性水凝胶5份、D-苯丙氨酸衍生物6.5份、葡萄糖激酶6份、褐藻胶8.5份、桦褐孔菌11.5份、甲壳素衍生物12.5份、鞣花酸3.5份、亚麻油酸3份、大豆低聚糖12.5份、花生四烯酸乙醇胺5份、果糖酸钙6.5份、鱼腥草素2.5份、防腐剂0.6份,备用;
(2)将所述温敏性水凝胶完全溶解于生理盐水中,所述生理盐水的用量为所述温敏性水凝胶的重量的8.5倍,然后将其加热至50℃保持17.5分钟后再放入0℃冰水中孵化直至形成无色透明的溶液;
(3)将所述可生物降解聚合物分散在去离子水中,所述去离子水的用量以所述可生物降解聚合物的浓度之和达到275g/L为限,滴加入步骤(2)的无色透明溶液,再加入所述D-苯丙氨酸衍生物、葡萄糖激酶、褐藻胶、桦褐孔菌、甲壳素衍生物、鞣花酸、亚麻油酸、大豆低聚糖、花生四烯酸乙醇胺、果糖酸钙、鱼腥草素、防腐剂,搅拌,形成混合溶液,在常压、室温下超声反应20min,在常压、12.5℃下静置6.5h,减压浓缩至含水量低于42.5%,即得到所述缓释型降糖药物组合物;
(4)将该缓释型降糖药物组合物中按比例加入辅料:15%的预胶化淀粉、2%的羟甲基纤维素、0.02%的氢化植物油等,通过混合、整粒、干燥、制粒、压片等工艺制备成口服片剂。
实施例3:
一种缓释型降糖药物组合物,按重量份计,主要是由以下重量份的成分组成:可生物降解聚合物200份、温敏性水凝胶70份、D-苯丙氨酸衍生物10份、葡萄糖激酶10份、褐藻胶12份、桦褐孔菌20份、甲壳素衍生物20份、鞣花酸6份、亚麻油酸5份、大豆低聚糖20份、花生四烯酸乙醇胺8份、果糖酸钙10份、鱼腥草素4份、防腐剂1份。
其中,所述可生物降解聚合物为甲基化聚乙二醇-乙交酯-丙交酯共聚物。所述甲基化聚乙二醇-乙交酯-丙交酯共聚物的单体摩尔比例的范围为50∶20∶60,分子量为50000道尔顿,能够在生理条件下可以自行降解、崩溃或代谢,使药物在体内保持适当的浓度和作用时间。所述温敏性水凝胶为聚环氧乙烷,可以达到长期稳定的释放药物,生物相容性好,可自行降解。所述D-苯丙氨酸衍生物选自那格列奈,是一种新型的餐时血糖调节剂,能有效控制餐后血糖水平,不易引起心血管副作用,低血糖的发生率较低。所述甲壳素衍生物为壳寡糖,对人体的免疫调节、抗肿瘤、降血脂、调节血糖、改善肝脏和心肺功能及其他多种生理功能有着重要作用。所述防腐剂为苯甲酸钠,防止药物腐败变质,延长药物有效期,保证药效。
一种缓释型降糖药物组合物,其制备方法为:
(1)按所述配比取可生物降解聚合物200份、温敏性水凝胶70份、D-苯丙氨酸衍生物10份、葡萄糖激酶10份、褐藻胶12份、桦褐孔菌20份、甲壳素衍生物20份、鞣花酸6份、亚麻油酸5份、大豆低聚糖20份、花生四烯酸乙醇胺8份、果糖酸钙10份、鱼腥草素4份、防腐剂1份,备用;
(2)将所述温敏性水凝胶完全溶解于生理盐水中,所述生理盐水的用量为所述温敏性水凝胶的重量的11倍,然后将其加热至50℃保持20分钟后再放入0℃冰水中孵化直至形成无色透明的溶液;
(3)将所述可生物降解聚合物分散在去离子水中,所述去离子水的用量以所述可生物降解聚合物的浓度之和达到450g/L为限,滴加入步骤(2)的无色透明溶液,再加入所述D-苯丙氨酸衍生物、葡萄糖激酶、褐藻胶、桦褐孔菌、甲壳素衍生物、鞣花酸、亚麻油酸、大豆低聚糖、花生四烯酸乙醇胺、果糖酸钙、鱼腥草素、防腐剂,搅拌,形成混合溶液,在常压、室温下超声反应30min,在常压、20℃下静置10h,减压浓缩至含水量低于45%,即得到所述缓释型降糖药物组合物;
(4)将该缓释型降糖药物组合物中按比例加入辅料:15%的预胶化淀粉、2%的羟甲基纤维素、0.02%的氢化植物油等,通过混合、整粒、干燥、制粒、压片等工艺制备成口服片剂。
药物释放度测量:
将实施例1、实施例2与实施例3制得的该缓释型降糖药物组合物的片剂采用中国药典溶出度检测法测定释放度,条件为桨法,转速为50转/分钟,溶出介质为37℃的900毫升pH值6.8的磷酸盐缓冲液。实施例1、实施例2与实施例3的释放度的对比结果如下,表1为那格列奈释放度,表2为葡萄糖激酶释放度,表3为鱼腥草素释放度。
那格列奈释放度 | 1h | 2h | 4h | 6h | 8h | 10h |
实施例1 | 6% | 21% | 38% | 62% | 81% | 98% |
实施例2 | 10% | 30% | 41% | 66% | 85% | 97% |
实施例3 | 12% | 34% | 45% | 71% | 88% | 99% |
表1
葡萄糖激酶释放度 | 1h | 2h | 4h | 6h | 8h | 10h |
实施例1 | 8% | 14% | 32% | 61% | 87% | 97% |
实施例2 | 12% | 21% | 43% | 65% | 88% | 97% |
实施例3 | 20% | 36% | 64% | 72% | 91% | 98% |
表2
鱼腥草素释放度 | 1h | 2h | 4h | 6h | 8h | 10h |
实施例1 | 3% | 18% | 34% | 57% | 79% | 91% |
实施例2 | 5% | 21% | 37% | 58% | 82% | 93% |
实施例3 | 10% | 27% | 41% | 61% | 86% | 98% |
表3
上述溶出度释放结果表明:本发明利用可生物降解聚合物和温敏性水凝胶与药物共载,达到了减慢药物溶解速度的目的,控制药物释放,使药物在体内保持适当的浓度和作用时间,减少药物的使用次数和剂量,对长期控制血糖有一定的益处。
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。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 (8)
1.一种缓释型降糖药物组合物,其特征在于,按重量份计,主要是由以下重量份的成分组成:可生物降解聚合物80-200份、温敏性水凝胶30-70份、D-苯丙氨酸衍生物3-10份、葡萄糖激酶2-10份、褐藻胶5-12份、桦褐孔菌3-20份、甲壳素衍生物5-20份、鞣花酸1-6份、亚麻油酸1-5份、大豆低聚糖5-20份、花生四烯酸乙醇胺2-8份、果糖酸钙3-10份、鱼腥草素1-4份、防腐剂0.2-1份。
2.如权利要求1所述的一种缓释型降糖药物组合物,其特征在于,所述可生物降解聚合物为甲基化聚乙二醇-乙交酯-丙交酯共聚物。
3.如权利要求1所述的一种缓释型降糖药物组合物,其特征在于,所述温敏性水凝胶选自聚环氧乙烷或聚环氧丙烷。
4.如权利要求1所述的一种缓释型降糖药物组合物,其特征在于,所述D-苯丙氨酸衍生物选自那格列奈。
5.如权利要求1所述的一种缓释型降糖药物组合物,其特征在于,所述防腐剂为苯甲酸钠。
6.如权利要求1-5任意一项所述的一种缓释型降糖药物组合物,其特征在于,其制备方法为:
(1)按所述配比取可生物降解聚合物80-200份、温敏性水凝胶30-70份、D-苯丙氨酸衍生物3-10份、葡萄糖激酶2-10份、褐藻胶5-12份、桦褐孔菌3-20份、甲壳素衍生物5-20份、鞣花酸1-6份、亚麻油酸1-5份、大豆低聚糖5-20份、花生四烯酸乙醇胺2-8份、果糖酸钙3-10份、鱼腥草素1-4份、防腐剂0.2-1份,备用;
(2)将所述温敏性水凝胶完全溶解于生理盐水中,然后将其加热至50℃保持15-20分钟后再放入0℃冰水中孵化直至形成无色透明的溶液;
(3)将所述可生物降解聚合物分散在去离子水中,滴加入步骤(2)的无色透明溶液,再加入所述D-苯丙氨酸衍生物、葡萄糖激酶、褐藻胶、桦褐孔菌、甲壳素衍生物、鞣花酸、亚麻油酸、大豆低聚糖、花生四烯酸乙醇胺、果糖酸 钙、鱼腥草素、防腐剂,搅拌,形成混合溶液,在常压、室温下超声反应10-30min,在常压、5-20℃下静置3-10h,减压浓缩至含水量低于40-45%,即得到所述缓释型降糖药物组合物。
7.如权利要求6所述的一种缓释型降糖药物组合物得制备方法,其特征在于,所述生理盐水的用量为所述温敏性水凝胶的重量的6-11倍。
8.如权利要求6所述的一种缓释型降糖药物组合物得制备方法,其特征在于,所述去离子水的用量以所述可生物降解聚合物的浓度之和达到100-450g/L为限。
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