CN115400101A - 一种达格列净复合口腔膜剂及其制备方法 - Google Patents
一种达格列净复合口腔膜剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及药物制剂技术领域,具体公开一种达格列净复合口腔膜剂及其制备方法。所述达格列净复合口腔膜剂,包括如下质量百分比的各组分:主药:40%~45%,纳米纤维素:35%~40%,增塑剂:5%~10%,填充剂:5%~8%,矫味剂:3%~5%,着色剂:2%~3%和脱模剂:1%~2%,所述主药为质量比为0.8~1.2:0.8~1.2的达格列净和平卧菊三七提取物。本申请以纳米纤维为成膜材料,能够交织成比表面积大、表面富含功能基团的网状结构,与其它组分互相配合,形成外观良好、崩解迅速、韧性较好且高温较稳定、生物降解性好的膜剂。
Description
技术领域
本发明涉及药物制剂技术领域,尤其涉及一种达格列净复合口腔膜剂及其制备方法。
背景技术
糖尿病是一种发病率极高的慢性疾病,主要病理分型为Ⅰ型(胰岛素依赖型)和Ⅱ型(非胰岛素依赖型)糖尿病。目前,由于各种环境因素和长期不良的生活习惯而引起的代谢综合征进展成为Ⅱ型糖尿病约占全部糖尿病患者的90%以上。
达格列净,中文化学名为:(2S,3R,4R,5S,6R)-2-[3-(4-乙氧基苯甲基)-4-氯苯基]-6-羟甲基四氢-2H-吡喃-3,4,5-三醇,是一种口服活性SGLT2抑制剂,已经在美国获批上市的用来治疗II型糖尿病药物。达格列净通过使肾小管中的葡萄糖不能顺利重吸收进入血液而随尿液排出,从而降低血糖浓度,但是这也使得尿液中血糖含量升高,患者可能会出现严重的尿糖,造成尿道或者生殖系统的感染,同时服用此药物也会对肾功能造成一定的损伤。
口溶膜剂是一种在口腔内快速溶解的口服药物薄膜制剂。与其他种类的口服固体制剂相比,口溶膜制剂具有诸多优势,例如剂量准确、服用方便、口腔内快速溶解、起效快、吞咽方便、不会引起窒息等等,提高了患者的顺应性。研究过程中发现,成膜材料是口溶膜剂中最关键的组分,也决定着口溶膜制剂在口腔内的溶解速度、溶解时间以及口感。目前常用的成膜材料在最终口溶膜制剂中的重量百分含量都大于40%,容易导致膜剂相互粘连或者膜剂崩解速度慢等诸多问题,如果这些成膜材料的含量降低至40%以下,则制备的口溶膜制剂在韧性、强度等方面会非常差从而导致产品难以生产、保存、运输或临床取用。
发明内容
针对现有达格列净单独使用易造成生殖系统感染、肾功能损伤、口溶膜剂含量高等问题,本发明提供一种达格列净复合口腔膜剂。
以及,本发明还提供达一种格列净复合口腔膜剂的制备方法。
为达到上述发明目的,本发明实施例采用了如下的技术方案:
一种达格列净复合口腔膜剂,包括如下质量百分比的各组分:主药:40%~45%,纳米纤维素:35%~40%,增塑剂:5%~10%,填充剂:5%~8%,矫味剂:3%~5%,着色剂:2%~3%和脱模剂:1%~2%,所述主药为质量比为0.8~1.2:0.8~1.2的达格列净和平卧菊三七提取物。
相对于现有技术,本申请提供的达格列净复合口腔膜剂具有以下优势:
本申请通过添加的平卧菊三七提取物能通过增加机体清除自由基能力,抑制其对胰岛细胞的损伤,使细胞的分泌功能恢复正常水平,同时氧化自由基水平的降低增加了细胞的抗氧化能力,改善细胞肥大,缓解肾小球硬化症状;采用平卧菊三七提取物与达格列净复配使用,不仅可以有效的降低血糖,还可以降低尿液中的糖含量,避免造成一些不必要的感染,此外平卧菊三七还可以降低机体血清尿酸,尿素氮浓度,进而保护二型糖尿病者的肾脏功能。
本申请以纳米纤维为成膜材料,能够交织成比表面积大、表面富含功能基团的网状结构,与其它组分互相配合,形成外观良好、崩解迅速、韧性较好且高温较稳定、生物降解性好的膜剂。
可选的,所述纳米纤维素包括质量比为3.8~4.2:2.8~3.2:2.8~3.2的第一纤维素、第二纤维素和第三纤维素,且所述第一纤维素的粘度为150~250mPa·s,所述第二纤维素的粘度为750~850mPa·s,所述第三纤维素的粘度为48000~52000mPa·s。
本申请通过优选的不同粘度的纤维素进行复配,形成韧性优异、透明性好、崩解时间短的膜剂。
可选的,所述主药为质量比为1:1的达格列净和平卧菊三七提取物。
本申请通过优选的两组分的配比,不仅显著降低血糖,还能保护肾脏,减小尿道生殖道感染的几率。
可选的,所述增塑剂为质量比为2~3:1~2的纳米木质素和聚多巴胺。
本申请优选的增塑剂组分具有载药能力和粘合功能,通过优选的纳米木质素和聚多巴胺的比例,显著提高主药的释放速度,得到药物快速释放的速溶膜剂。
可选的,所述填充剂为淀粉。
可选的,所述矫味剂为木糖醇。
本申请优选的矫味剂能明显改善口腔膜剂的口感,在口中溶解时具有清凉的感觉,明显提高患者顺应性和体验感。
可选的,所述着色剂为食用色素。
可选的,所述脱模剂为甘油。
进一步地,本发明还提供一种达格列净复合口腔膜剂的制备方法,至少包括以下步骤:
步骤一、按照上述的原料配比称取各组分
步骤二、将各组分加入到蒸馏水中,混合均匀,真空脱气5h~6h,得膜液;
步骤三、将所述膜液均匀涂布于玻璃板上,于30℃~35℃条件下真空干燥2h~3h成膜,冷却、切割,得到达格列净复合口腔膜剂。
相对于现有技术,本申请提供的达格列净复合口腔膜剂的制备方法,具有以下优势:
本申请提供的制备方法简单,制备的膜剂外观均匀完整,厚薄一致,色泽均匀,无明显气泡,化学和物理性质稳定、起效迅速,有利于进行工业化批量生产。
本申请制备的口腔膜剂体积小、量轻而薄,应用、携带及运输方便,使用安全环保,可以满足快节奏、高压力都市人群的需求。
本申请制备的口腔膜剂服用时无需用水,无需咀嚼,该膜剂在口腔中接触唾液时可迅速崩解,且具有口感清凉舒适,吸收快,生物利用度高,稳定性好,毒副作用低且具有保护肾脏的功能,还提高患者用药的安全性和顺应性。
可选的,步骤三中,所述涂布的厚度为0.2mm~0.3mm。
本申请通过优选的涂布厚度能够得到膜厚适中、崩解时间短的膜剂。
可选的,步骤三中,所述切割的规格为0.8cm2~1.5cm2。
可选的,步骤一中,所述主药与所述蒸馏水的质量比为:2.2~2.5:100~150。
可选的,所述冷却具体为:10℃~30℃条件下冷却30min~60min。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1
本发明实施例提供一种达格列净复合口腔膜剂,包括如下质量百分比的各组分:主药:45%,纳米纤维素:35%,增塑剂:8%,淀粉:5%,木糖醇:3%,食用色素:2%和甘油:2%,所述主药为质量比为1:1的达格列净和平卧菊三七提取物。
上述纳米纤维素为质量比为4:3:3的第一纤维素、第二纤维素和第三纤维素,所述第一纤维素的粘度为200mPa·s,所述第二纤维素的粘度为800mPa·s,所述第三纤维素的粘度为50000mPa·s。
上述增塑剂为质量比为2:1的纳米木质素和聚多巴胺。
上述达格列净复合口腔膜剂的制备方法,包括以下步骤:
步骤一、按照上述的原料配比称取各组分
步骤二、按照主药与蒸馏水2.2:100的质量比,将主药加到蒸馏水中,再加入剩余的组分,搅拌混合均匀,真空脱气5h,得膜液;
步骤三、将所述膜液均匀涂布于玻璃板上,涂布厚度为0.2mm,再于30℃条件下真空干燥3h成膜,15℃条件下冷却40min,切割至规格为1cm2,得到达格列净复合口腔膜剂。
实施例2
本发明实施例提供一种达格列净复合口腔膜剂,包括如下质量百分比的各组分:主药:40%,纳米纤维素:32%,增塑剂:10%,淀粉:8%,木糖醇:5%,食用色素:3%和甘油:2%,所述主药为质量比为0.8:1.2的达格列净和平卧菊三七提取物。
上述纳米纤维素为质量比为3.8:3.2:3.2的第一纤维素、第二纤维素和第三纤维素,且所述第一纤维素的粘度为150mPa·s,所述第二纤维素的粘度为850mPa·s,所述第三纤维素的粘度为52000mPa·s。
上述增塑剂为质量比为3:2的纳米木质素和聚多巴胺。
上述达格列净复合口腔膜剂的制备方法,包括以下步骤:
步骤一、按照上述的原料配比称取各组分
步骤二、按照主药与蒸馏水2.5:150的质量比,将主药加到蒸馏水中,再加入剩余的组分,搅拌混合均匀,真空脱气5.5h,得膜液;
步骤三、将所述膜液均匀涂布于玻璃板上,涂布厚度为0.25mm,再于32℃条件下真空干燥2.5h成膜,20℃条件下冷却50min,切割至规格为0.8cm2,得到达格列净复合口腔膜剂。
实施例3
本发明实施例提供一种达格列净复合口腔膜剂,包括如下质量百分比的各组分:主药:43%,纳米纤维素:40%,增塑剂:5%,淀粉:5%,木糖醇:4%,食用色素:2%和甘油:1%,所述主药为质量比为1.2:0.8的达格列净和平卧菊三七提取物。
上述纳米纤维素为质量比为4.2:2.8:2.8的第一纤维素、第二纤维素和第三纤维素,所述第一纤维素的粘度为250mPa·s,所述第二纤维素的粘度为750mPa·s,所述第三纤维素的粘度为48000mPa·s。
上述增塑剂为质量比为2.5:1.5的纳米木质素和聚多巴胺。
上述达格列净复合口腔膜剂的制备方法,包括以下步骤:
步骤一、按照上述的原料配比称取各组分
步骤二、按照主药与蒸馏水2.3:130的质量比,将主药加到蒸馏水中,再加入剩余的组分,搅拌混合均匀,真空脱气6h,得膜液;
步骤三、将所述膜液均匀涂布于玻璃板上,涂布厚度为0.3mm,再于35℃条件下真空干燥2h成膜,30℃条件下冷却30min,切割至规格为0.12cm2,得到达格列净复合口腔膜剂。
为了更好的说明本发明实施例提供的达格列净复合口腔膜剂的特性,下面将实施例1制备的达格列净复合口腔膜剂进行性能检测。
试验例
动物抗糖药效试验
1材料与方法
1.1实验动物
选用健康雄性Wistar大鼠30只,体重200克~220克。
1.2建立Ⅱ型糖尿病大鼠模型
适应性喂养大鼠一周后,分成对照组和造模组。对照组随机选取10只大鼠,予普通饲料喂养,不做任何处理。造模组选取剩余的20只大鼠,喂养高糖高脂饲料(基础饲料64.5%、猪油10%、蛋黄粉5%、胆固醇2%、胆酸钠0.5%、蔗糖18%)。将上述对照组和造模组分别饲养6周,对其血糖进行监测,其血糖平均值如下表1所示。
表1造模前大鼠血糖监测表(x±s,mmol/L)
造模:上述造模组饲养6周后,禁食12h,按35mg/kg单次腹腔注射2%链脲佐菌素STZ溶液(pH值4.4)进行造膜。对照组饲养6周,禁食12h,注射同等剂量生理盐水。三天后测定大鼠尾静脉血糖含量,若血糖含量≥16.7mmol/L可参与后续实验,血糖低于16.7mmol/L的大鼠不参与实验。
1.3动物实验分组
造模后将可参与试验的大鼠继续适应性喂养1周后,分别检测其血糖浓度,各组的平均血糖如下表2所示。
表2成模后各组大鼠血糖监测表(x±s,mmol/L)
组别 | 数量/n | 成模1周 |
对照组 | 10 | 5.80±0.64 |
造模组 | 20 | 29.57±2.34 |
试验:将造模组的20只糖尿病大鼠随机均分为A组和B组。A组:每日给予实施例1制备的达格列净复合口腔速溶膜剂10mg/kg(1mL/100g)灌胃;B组和对照组分别采用等量蒸馏水(1mL/100g)灌胃。灌胃共16周,灌胃期间各组动物自由进食和进水。
灌胃期间,分别于第1周、第4周、第8周以及第16周监测大鼠的血糖,结果如下表3所示;分别于第16周分别检测大鼠的肾脏醛糖还原酶(AR)活性以及大鼠血清尿素氮含量,结果分别如下表4和表5所示。
表3试验过程中各组大鼠的血糖检测表(x±s,mmol/L)
组别 | n | 第1周 | 第4周 | 第8周 | 第16周 |
空白组 | 10 | 5.70±0.60 | 5.78±0.69 | 5.79±0.72 | 6.32±5.64 |
A组 | 10 | 27.74±2.00 | 23.83±4.03 | 16.82±4.64 | 9.46±3.57 |
B组 | 10 | 28.07±3.93 | 26.01±3.55 | 23.90±4.09 | 18.67±5.36 |
表4各组大鼠肾脏醛糖还原酶(AR)活性结果(x±s)
表5各组大鼠血清尿素氮含量(x±s,mmol/L)
组别 | 例数 | 尿素氮 |
空白组 | 10 | 6.27±0.65 |
A组 | 10 | 6.36±0.38 |
B组 | 10 | 12.18±0.77 |
从表3-表5中数据可以看出,采用本申请实施例1制备的达格列净复合口腔膜剂,不仅可有效抑制AR活性,对链脲佐菌素(STZ)模型大鼠有显著降糖作用,同时也可氧化自由基水平的降低增加了细胞的抗氧化能力,对大鼠的肾脏功能也得到良好的保护。
本次肾脏检测指标主要为血清尿素氮,其中尿素氮是体内蛋白质代谢的最终产物。当肾小球发生病变时,血清尿素氮水平余氧化自由基的能力下降,导致过氧化脂(LPO)水平升高,糖尿病大鼠肾脏过氧化脂水平与血清尿素氮(BUN)水平正相关,随肾脏损伤程度变化。由表5数据,在使用本申请制备的达格列净复合口腔膜剂后尿素氮含量明显降低,小鼠肾脏功能明显改善。
实施例2~3制备的达格列净复合口腔膜剂均达到与实施例1基本相同的治疗效果。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换或改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种达格列净复合口腔膜剂,其特征在于:包括如下质量百分比的各组分:主药:40%~45%,纳米纤维素:35%~40%,增塑剂:5%~10%,填充剂:5%~8%,矫味剂:3%~5%,着色剂:2%~3%和脱模剂:1%~2%,所述主药为质量比为0.8~1.2:0.8~1.2的达格列净和平卧菊三七提取物。
2.如权利要求1所述的达格列净复合口腔膜剂,其特征在于:所述纳米纤维素包括质量比为3.8~4.2:2.8~3.2:2.8~3.2的第一纤维素、第二纤维素和第三纤维素,且所述第一纤维素的粘度为150~250mPa·s,所述第二纤维素的粘度为750~850mPa·s,所述第三纤维素的粘度为48000~52000mPa·s。
3.如权利要求1所述的达格列净复合口腔膜剂,其特征在于:所述主药为质量比为1:1的达格列净和平卧菊三七提取物。
4.如权利要求1所述的达格列净复合口腔膜剂,其特征在于:所述增塑剂为质量比为2~3:1~2的纳米木质素和聚多巴胺。
5.如权利要求1所述的达格列净复合口腔膜剂,其特征在于:所述填充剂为淀粉;和/或
所述矫味剂为木糖醇;和/或
所述着色剂为食用色素;和/或
所述脱模剂为甘油。
6.一种达格列净复合口腔膜剂的制备方法,其特征在于:至少包括以下步骤:
步骤一、按照如权利要求1~5任一项所述的原料配比称取各组分
步骤二、将各组分加入到蒸馏水中,混合均匀,真空脱气5h~6h,得膜液;
步骤三、将所述膜液均匀涂布于玻璃板上,于30℃~35℃条件下真空干燥2h~3h成膜,冷却、切割,得到达格列净复合口腔膜剂。
7.如权利要求6所述的达格列净复合口腔膜剂的制备方法,其特征在于:步骤三中,所述涂布的厚度为0.2mm~0.3mm。
8.如权利要求6所述的达格列净复合口腔膜剂的制备方法,其特征在于:步骤三中,所述切割的规格为0.8cm2~1.5cm2。
9.如权利要求6所述的达格列净复合口腔膜剂的制备方法,其特征在于:步骤一中,所述主药与所述蒸馏水的质量比为:2.2~2.5:100~150。
10.如权利要求6所述的达格列净复合口腔膜剂的制备方法,其特征在于:所述冷却具体为:10℃~30℃条件下冷却30min~60min。
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CN105193772A (zh) * | 2015-10-28 | 2015-12-30 | 陈跃坚 | 一种沙格列汀口腔膜剂及其制备方法 |
CN106727445A (zh) * | 2016-12-21 | 2017-05-31 | 河北科技大学 | 一种达格列净口腔膜剂及其制备方法 |
CN106924317A (zh) * | 2015-12-30 | 2017-07-07 | 北京万源普达医疗科技有限公司 | 一种平卧菊三七提取物的制备方法及降血糖的中药制剂 |
CN113456615A (zh) * | 2021-07-06 | 2021-10-01 | 青岛科技大学 | 一种含有纳米木质素的矫味口腔膜剂及其制备方法 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105193772A (zh) * | 2015-10-28 | 2015-12-30 | 陈跃坚 | 一种沙格列汀口腔膜剂及其制备方法 |
CN106924317A (zh) * | 2015-12-30 | 2017-07-07 | 北京万源普达医疗科技有限公司 | 一种平卧菊三七提取物的制备方法及降血糖的中药制剂 |
CN106727445A (zh) * | 2016-12-21 | 2017-05-31 | 河北科技大学 | 一种达格列净口腔膜剂及其制备方法 |
CN113456615A (zh) * | 2021-07-06 | 2021-10-01 | 青岛科技大学 | 一种含有纳米木质素的矫味口腔膜剂及其制备方法 |
Non-Patent Citations (1)
Title |
---|
吴磊等: "平卧菊三七的化学成分及生物活性研究进展", 《现代食品科技》, vol. 38, no. 8, pages 334 - 351 * |
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