CN113425694A - 一种石斛生物碱口腔崩解片剂及其制备方法 - Google Patents
一种石斛生物碱口腔崩解片剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及用酶解法获取石斛生物碱并制备得到的一种石斛生物碱口腔崩解片剂及其制备方法。本发明一种石斛生物碱口腔崩解片剂,包括石斛生物碱和可药用辅料,可药用辅料包括崩解剂、稳定剂、稀释剂和粘合剂,所述的崩解剂是交联羧甲基纤维素钠、胶态二氧化硅及柠檬酸的混合物。本发明一种石斛生物碱口腔崩解片剂,崩解剂采用交联羧甲基纤维素钠、胶态二氧化硅及柠檬酸按特定比例混合,在保证在口腔中快速崩解,口感好,无沙砾感,稳定性好且具备较好的生物利用度。
Description
技术领域
本发明涉及一种石斛生物碱,尤其涉及用酶解法获取石斛生物碱并制备得到的一种石斛生物碱口腔崩解片剂及其制备方法。
背景技术
石斛作为药用最早载于2000年以前的《神农本草经》和东汉的《名医别录》,许多古今名师和经典的良方多有石斛。我国常见的有金钗石斛、铁皮石斛、樱石斛、棒节石斛、大苞鞘石斛、细茎石斛、春石斛等。铁皮石斛(Dendrobium officinale Kimura et Migo)为兰科(Orchidaceae)石斛属(Dendrobium)多年生草本植物,始载于《神农本草经》,为我国传统的名贵中药材,被誉为“中华九大仙草之首”。《中国药典》记载,铁皮石斛具有益胃生津、滋阴清热等功效。现代药理研究表明,铁皮石斛具有增强免疫力、降血压、降血糖、抗肿瘤、抗氧化等作用。
传统医学认为铁皮石斛具有益胃生津,滋阴清热之功效。现代药理研究证明,石斛属植物具有抗肿瘤、增强机体免疫力、抗血小板聚集、治疗白内障等作用;其有效成分主要为石斛多糖、石斛碱、毛兰素等。其中石斛生物碱可用于预防和治疗关节炎,保护消化道粘膜急性或慢性损伤,特别用于防治急性的慢性消化道溃疡,此外还有报道石斛生物碱具有调节雌性激素分泌和促进卵泡发育、降低心率、抑菌、镇痛、改善记忆力减退等作用。
生物碱是铁皮石斛中重要的活性成分之一,具有降血糖、抗白内障、减轻肝脏脂肪变性、改善胃肠道运动、抗炎、抗肿瘤等药理作用。铁皮石斛中生物碱的含量较低、约为0.02%。虽然铁皮石斛中生物碱含量较低,但就其中所含的特有生物碱成分而言,铁皮石斛的质量要好于其他石斛。目前铁皮石斛生物碱提取方法在提取率、纯度和溶剂等方面存在的问题。
口腔崩解片无需冲服,也无需咀嚼即可在口腔中迅速崩解,随后随自然吞咽进入肠胃,相对其他剂型,其能为吞咽功能不佳的患者或缺水环境下服用提供了很大的方便,对其他患者也提供了最大程度的使用便利。石斛生物碱的水溶性较差,普通片剂的生物利用度不高,因此如何提高其生物利用度是其主要的改进方向。
发明内容
本发明的目的在于解决石斛生物碱水溶性差导致的生物利用度较低的问题及制剂稳定性不好的问题,提供一种崩解速度快、无沙砾感、稳定性好的石斛生物碱口腔崩解片剂。
本发明的另一目的在于提供一种石斛生物碱口腔崩解片剂的制备方法。
为了实现上述发明目的,本发明采用如下技术方案:
一种石斛生物碱口腔崩解片剂,包括石斛生物碱和可药用辅料。
进一步的,所述的可药用辅料包括崩解剂、稳定剂、稀释剂和粘合剂。
进一步的,所述的崩解剂是交联羧甲基纤维素钠、胶态二氧化硅及柠檬酸的混合物。
进一步的,所述的交联羧甲基纤维素钠、胶态二氧化硅及柠檬酸的重量百分比是2:1:1。
进一步的,所述的稳定剂是聚乙二醇和甘油。
进一步的,所述的稀释剂是甘露醇、蔗糖、乳糖、山梨醇、木糖醇中的一种或多种混合。
一种石斛生物碱口腔崩解片剂的制备方法,包括如下步骤:
(1)取石斛生物碱,与稀释剂、部分崩解剂混合均匀;
(2)将粘合剂配制成一定浓度的溶液,并将稳定剂溶于其中后,加入上述混合粉中,湿法制软材;
(3)将软材过筛,筛网目数可在14目~40目之间,得到湿颗粒;
(4)将湿颗粒置40℃~70℃烘箱或流化床干燥,整粒;
(5)取干颗粒,加入润滑剂、香精、甜味剂、剩余崩解剂,混合均匀;
(6)压片即得。
所述的石斛生物碱是通过酶解法获得。
本发明一种石斛生物碱口腔崩解片剂,崩解剂采用交联羧甲基纤维素钠、胶态二氧化硅及柠檬酸按特定比例混合,在保证在口腔中快速崩解,口感好,无沙砾感,稳定性好且具备较好的生物利用度。并且,发明口腔崩解片剂的石斛生物碱是通过酶解法获得,铁皮石斛生物碱提取率和纯度高。
附图说明
图1:中各配方的崩解时限图;
图2:铁皮石斛生物碱标准曲线。
具体实施方式
主要试剂来源:
石斛生物碱:申请人从铁皮石斛中提取获得;
交联羧甲基纤维素钠、胶态二氧化硅、柠檬酸购自安徽山河药用辅料股份有限公司;
聚乙二醇、甘油、甘露醇购自上海阿拉丁生化科技股份有限公司。
实施例1:石斛生物碱口腔崩解片制备。
配方1:石斛生物碱10%、甘露醇62%、聚乙二醇3%、甘油1%、交联聚维酮4%、蔗糖10%、硬脂酸镁2%、交联羧甲基纤维素钠4%、胶态二氧化硅2%、柠檬酸2%;
配方2:石斛生物碱10%、甘露醇62%、聚乙二醇3%、甘油1%、交联聚维酮4%、蔗糖10%、硬脂酸镁2%、交联羧甲基纤维素钠2%、胶态二氧化硅3%、柠檬酸3%
配方3:石斛生物碱10%、甘露醇62%、聚乙二醇5%、甘油1%、交联聚维酮4%、蔗糖10%、硬脂酸镁2%、交联羧甲基纤维素钠8%;
配方4:石斛生物碱10%、甘露醇62%、聚乙二醇5%、甘油1%、交联聚维酮4%、蔗糖13%、硬脂酸镁2%、交联羧甲基纤维素钠4%、胶态二氧化硅4%;
配方5:石斛生物碱10%、甘露醇62%、聚乙二醇5%、甘油1%、交联聚维酮4%、蔗糖10%、硬脂酸镁2%、交联羧甲基纤维素钠4%、柠檬酸4%。
制备过程:
1、将石斛生物碱、甘露醇、蔗糖、交联羧甲基纤维素钠、胶态二氧化硅和柠檬酸混合均匀;
2、将聚乙二醇和甘油溶于水,并加入上述混合粉和交联聚维酮,湿法制软材;
3、将软材过30目筛,得到湿颗粒;
4、将湿颗粒置50℃烘箱干燥,干燥后过30目筛整粒;
5、取干颗粒,加入硬脂酸镁,混合均匀;
6、压片即得。
实施例2:石斛生物碱口腔崩解片的崩解时限
采用静态液滴法测定崩解时限:各去5片片剂置于10目筛网上,取滴定管置片剂正上方,管尖下沿距片剂表面垂直距离为2cm。滴定管内装满37℃水,使水以2ml/min匀速滴落至片剂,记录片剂溶解并从筛网中全部漏下的时间即为崩解时限。结果见下表及图1。
表:实施例1中各配方石斛生物碱口腔崩解片剂的崩解时限测定结果
从上表及图1可知,配方1~配方4制备得到的石斛生物碱口腔崩解片剂的崩解时限均在30s内,符合口腔崩解片的要求;其中,配方1和配方2的崩解时限最快。
实施例3:石斛生物碱口腔崩解片剂的稳定性。
高温试验:样品置于密封洁净的干燥器中,60℃恒温条件下放置10天.分别于第0,5,10天取样,依各项试验方法检测,分别比较,试验结果见表2。
高湿试验:样品置于恒湿密闭洁净容器中,于25℃、相对湿度92%条件下放置10天。分别于第0,5,10天取样,依各项试验方法检测,分别比较,试验结果见表2。
强光照射试验:样品置于照度4500Lx光照度下放置10天。分别于第0,5,10天取样,依各项试验方法检测,分别比较,试验结果见表2。
崩解时间测定:采用静态液滴法测定崩解时限;
口感评价:健康志愿者清洁口腔后,取药片置于舌面,不饮水不咀嚼,崩解完全后记录是否有砂砾感;
含量测定:HPLC法测定含量。
表2:
由上表的稳定性数据显示,配方3和配方5的外观在稳定性第10天时出现微黄;配方1~配方5在高温高湿强光条件下10日后含量仍能维持在药典规定的范围内,崩解时间也变化不大,符合药典的要求,但是配方1和配方2的含量几乎没大的变化,尤其是配方1稳定性更好,崩解时限也无变化。
实施例4:石斛生物碱的提取
主要试剂和仪器
铁皮石斛:铁皮石斛野生植株采自云南绿春;
铁皮石斛生物碱标准品:成都格普特生物科技有限公司;
球磨机:湖南弗卡斯实验仪器有限公司,型号F-P400;
纤维素酶、半纤维素酶:北京鸿润宝顺科技有限公司,3000U/g;
胰酶、氨肽酶:夏胜(北京)生物科技开发有限公司;
紫外可见分光光度计756PC:上海仪天科学仪器有限公司;
氢氧化钠、碳酸钙:西安天正药用辅料有限公司;
乙醇、乙酸乙酯、氯仿:上海安谱实验科技股份有限公司;
其他试剂和仪器均为常规国产种类和型号。
实例1:
将新鲜的原料铁皮石斛茎条100g,清洗干净、干燥,置于90℃中干燥2h,干燥后切成2cm的短条。将切好的铁皮石斛短条与氢氧化钠质量比1:0.5混合,在球磨机中球磨至均匀,球磨后的粉末中加入水搅拌溶解,溶液中加入重量比1:0.3的纤维素酶和半纤维素酶,添加量为铁皮石斛质量的3%,在pH=5、30℃下反应为2h。然后调节pH=8,添加重量比1:2的氨肽酶和胰酶,添加量为铁皮石斛质量的1%,在30℃下反应1h。酶解结束后,灭酶、冷却、过滤。所得的滤渣用90%乙醇和10%乙酸乙酯的混合液,重复浸提、过滤三次,合并滤液、蒸干,获得生物碱,称重。
实例2:
将新鲜的原料铁皮石斛茎条100g,清洗干净、干燥,置于85℃中干燥2h,干燥后切成2cm的短条。将切好的铁皮石斛短条与碳酸钙质量比1:1混合,在球磨机中球磨至均匀,球磨后的粉末中加入水搅拌溶解,溶液中加入重量比1:0.6的纤维素酶和半纤维素酶,添加量为铁皮石斛质量的5%,在pH=5、35℃下反应为1.5h。然后调节pH=9,添加重量比1:5的氨肽酶和胰酶,添加量为铁皮石斛质量的1.5%,在35℃下反应1.5h。酶解结束后,灭酶、冷却、过滤。所得的滤渣用80%乙醇和20%乙酸乙酯的混合液,重复浸提、过滤三次,合并滤液、蒸干,获得生物碱,称重。
对比1:
取方法参照实例1,浸提溶剂为90%的乙醇水溶液,重复浸提、过滤三次,合并滤液、蒸干,获得生物碱,称重。
对比2:
参照专利CN108164541A的方法,取铁皮石斛100g,粉碎,按料液比为1:12向铁皮石斛中加入水,用饱和石灰水调节pH=9,在功率为310W下微波提取3次,每次提取18min,提取液合并、过滤,滤液分两次进行浓缩,加入3倍量乙醇,在1-4℃下放置11h,过滤,沉淀用乙醇洗涤3-4次,干燥至恒重,即得生物碱,称重。
对比3
参照张利等人(铁皮石斛中石斛多糖与石斛碱的纤维素酶法提取研究)的方法,干燥的铁皮石斛100g,经粉碎后过80目筛,用石油醚脱脂。脱脂后的铁皮石斛加入温水,加入0.5%的纤维素酶液,在pH=5.0、50℃下酶解1.5h后立即升温至90℃灭酶,迅速冷却过滤。滤渣加入90%乙醇浸提0.5h,过滤,滤渣再加入90%乙醇浸提0.5h,过滤。合并二次过滤滤液,回收乙醇,剩余液中加入氯仿,萃取石斛碱,回收氯仿得生物碱,称重。
表 不同方法制备的生物碱质量及提取率
组别 | 生物碱(mg) | 提取率(mg/g,%) |
实施例1 | 18.3 | 18.3 |
实施例2 | 17.7 | 17.7 |
对比例1 | 14.2 | 14.2 |
对比例2 | 10.6 | 10.6 |
对比例3 | 12.3 | 12.3 |
从上表中可以看出,采用本发明的提取方法,提取生物碱的总量明显高于对比例2-3,并且采用乙醇和乙酸乙酯的混合液浸提生物碱也优于仅采用乙醇浸提。
对比试验:
采用酸性染料比色法测定生物碱的纯度。称取生物碱标准品1mg,用氯仿溶解后,用容量瓶定容至100mL,配制成10μg/mL的生物碱标准品溶液。分别取标准品溶液1、2、4、6、8mL,用氯仿稀释至10mL。依次加入pH=4.5的邻苯二甲酸氢钾缓冲液5mL及0.04%溴甲酚绿溶液1mL,漩涡震荡3min,室温静置30min。将氯仿层用氯仿浸泡过的脱脂棉过滤,取滤液5mL,加入1mL的0.01mol/L氢氧化钠无水乙醇溶液,混合摇匀。用分光光度计在650nm下测定其吸光度,生物碱浓度X,吸光度值Y,根据测定数据绘制铁皮石斛生物碱标准曲线(图2),获得标准曲线方程Y=0.1028X-0.009,R2=0.995。
表2 标准品生物碱浓度与吸光度值关系
分别取上述方法制备的生物碱1mg,氯仿溶解、定容至100mL,取5mL、用氯仿稀释至10mL,如上方法依次加入邻苯二甲酸氢钾缓冲液和溴甲酚绿溶液,漩涡震荡、室温静置。氯仿层用氯仿浸泡过的脱脂棉过滤,滤液加氢氧化钠无水乙醇溶液混合摇匀。在650nm下用分光光度计测定吸光度,计算生物碱的浓度和纯度。
表 不同方法制备的生物碱的纯度
组别 | 吸光度值 | 生物碱浓度(μg/mL) | 生物碱纯度(%) |
实例1 | 0.487 | 4.8249 | 96.50 |
实例2 | 0.482 | 4.7763 | 95.53 |
对比1 | 0.464 | 4.6012 | 92.02 |
对比2 | 0.455 | 4.5136 | 90.27 |
对比3 | 0.446 | 4.4261 | 88.52 |
从上表中可以看出,采用实例1的提取方法,提取生物碱的纯度明显高于对比2-3,同样采用乙醇和乙酸乙酯的混合液浸提生物碱的纯度也优于仅采用乙醇浸提。
综上所述,本专利的铁皮石斛的提取方法解决了铁皮石斛生物碱提取率和纯度低的问题。
Claims (8)
1.一种石斛生物碱口腔崩解片剂,包括石斛生物碱和可药用辅料。
2.根据权利要求1所述的石斛生物碱口腔崩解片剂,其特征在于所述的可药用辅料包括崩解剂、稳定剂、稀释剂和粘合剂。
3.根据权利要求2所述的石斛生物碱口腔崩解片剂,其特征在于所述的崩解剂是交联羧甲基纤维素钠、胶态二氧化硅及柠檬酸的混合物。
4.根据权利要求3所述的石斛生物碱口腔崩解片剂,其特征在于所述的交联羧甲基纤维素钠、胶态二氧化硅及柠檬酸的重量百分比是2:1:1。
5.根据权利要求2所述的石斛生物碱口腔崩解片剂,其特征在于所述的稳定剂是聚乙二醇和甘油。
6.根据权利要求2所述的石斛生物碱口腔崩解片剂,其特征在于所述的稀释剂是甘露醇、蔗糖、乳糖、山梨醇、木糖醇中的一种或多种混合。
7.根据权利要求1~6任何一项所述的石斛生物碱口腔崩解片剂的制备方法,其特征在于包括如下步骤:
(1)取石斛生物碱,与稀释剂、部分崩解剂混合均匀;
(2)将粘合剂配制成一定浓度的溶液,并将稳定剂溶于其中后,加入上述混合粉中,湿法制软材;
(3)将软材过筛,筛网目数可在14目~40目之间,得到湿颗粒;
(4)将湿颗粒置40℃~70℃烘箱或流化床干燥,整粒;
(5)取干颗粒,加入润滑剂、香精、甜味剂、剩余崩解剂,混合均匀;
(6)压片即得。
8.根据权利要求1~6所述的石斛生物碱口腔崩解片剂,其特征在于所述的石斛生物碱是通过酶解法获得。
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