CN115337285A - 一种盐酸阿呋唑嗪缓释微丸胶囊及其制备方法 - Google Patents
一种盐酸阿呋唑嗪缓释微丸胶囊及其制备方法 Download PDFInfo
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Abstract
本发明属于缓释制剂领域,具体涉及一种盐酸阿呋唑嗪缓释微丸胶囊及其制备方法。本发明提供的盐酸阿呋唑嗪缓释微丸胶囊包括载药微丸、缓释包衣层、胶囊壳,所述载药微丸包含盐酸阿呋唑嗪、填充剂、增塑剂、缓释骨架材料、润滑剂、稳定剂;缓释包衣层包括成膜材料、增塑剂、润滑剂。本发明通过骨架型和膜控型协同控制,优化制备工艺,解决了释放效果差、稳定性差等问题,适合工业大生产。
Description
技术领域
本发明属于缓释制剂领域,具体涉及一种盐酸阿呋唑嗪缓释微丸胶囊及其制备方法。
背景技术
前列腺增生(BPH)是中老年男性常见疾病之一,随全球人口老年化发病日渐增多。前列腺增生的发病率随年龄递增,但有增生病变时不一定有临床症状。城镇发病率高于乡村,而且种族差异也影响增生程度。前列腺增生的早期由于代偿,症状不典型,随着下尿路梗阻加重,症状逐渐明显,临床症状包括储尿期症状,排尿期症状以及排尿后症状。由于病程进展缓慢,难以确定起病时间。
阿呋唑嗪盐酸盐(Alfuzosine HCl)是阿尔法肾上腺素受体的强有力阻滞剂,是广泛用于治疗良性前列腺增大的制剂。但是阿呋唑嗪盐酸盐体内半衰期较为短暂,且在十二指肠和空肠阶段具有极强的吸收率。因此,初期开发出的制剂需要每天投药2-3次,非常不方便。盐酸阿呋唑嗪口服缓释制剂给药后以预定的速度恒定缓慢释放,而不像传统制剂会快速释放药物。与相应的普通制剂,如速释片,胶囊,口服液相比,可以提高患者的顺应性并增加药物疗效。缓释制剂的主要优点是可以减少服药频率以及避免服用普通制剂出现的血药浓度峰谷现象。缓释制剂可以在相对较长的时间内保持血药浓度稳定在有效血药浓度范围内,从而提高药物的安全性。对此为临床提供一种安全有效、质量可靠、制备生产效率高,辅料用量适中,药物释放稳定的盐酸阿呋唑嗪缓释制剂很有必要,鉴于此,提出本发明。
发明内容
为克服现有技术的不足,本发明的第一个目的在于提供一种稳定性高、释放效果优、含量均匀度高的盐酸阿呋唑嗪缓释胶囊,采用骨架型和膜控型协同控制,有利于药物的释放,避免了血药浓度的峰谷现象,使盐酸阿呋唑嗪达到持续释放的效果,解决了释放效果差、稳定性以及含量均匀性低的问题,提高药物的安全性和有效性,释放曲线重现性好,适合工业大生产。
具体而言,本发明的技术方案如下:
本发明提供了一种盐酸阿呋唑嗪缓释微丸胶囊,包括载药微丸、缓释包衣层、胶囊壳,所述载药微丸包含盐酸阿呋唑嗪、填充剂、增塑剂、缓释骨架材料、润滑剂、稳定剂;缓释包衣层包括成膜材料、增塑剂、润滑剂。
进一步的,所述的增塑剂为邻苯二甲酸二乙酯、氯化石蜡、三醋酸甘油酯、柠檬酸甘油酯、二乙酰单甘油酯中的一种或多种;所述的填充剂为糊精、乳糖、淀粉、微晶纤维素、蔗糖中的一种或多种;所述的润滑剂为硬脂酸镁和/或滑石粉。
进一步的,所述的增塑剂为三醋酸甘油酯、柠檬酸甘油酯、二乙酰单甘油酯中的一种或多种。
进一步的,所述的缓释骨架材料选自巴西棕榈蜡、蜂蜡、硬脂醇、羟丙甲纤维素、乙基纤维素中的一种,所述的成膜材料均为甲基丙烯酸-丙烯酸乙酯共聚物,优选为EudragitL30D-55。
进一步的,所述的稳定剂为海藻糖、甘氨酸、二丁基羟基甲苯、葡甲胺、黄原胶中的一种或多种。
具体的,所述的稳定剂为甘氨酸和/或葡甲胺,优选为,甘氨酸和葡甲胺的重量组分比为1:1。
具体的,所述的载药微丸按百分比计包含:盐酸阿呋唑嗪2%-10%,填充剂80%-92%,增塑剂0.1%-2%,缓释骨架材料2%-5%,润滑剂2%-4%,稳定剂1%-3%;所述的缓释包衣层按百分比计包含:成膜材料40%-60%,增塑剂1%-5%,润滑剂1%-6%,纯净水30%-55%。
优选的,载药微丸按百分比计包括盐酸阿呋唑嗪7%,填充剂83%,增塑剂1%,缓释骨架材料4%,润滑剂3%,稳定剂2%;缓释包衣层按百分比计优选为,成膜材料50%,增塑剂3%,润滑剂4%,纯净水43%。
本发明的第二个目的在于提供一种制备盐酸阿呋唑嗪缓释微丸胶囊的方法,所制备的载药微丸采用挤出滚圆工艺进行制备,采用流化床对载药微丸进行包衣,具体包括如下步骤:
(1)载药丸制备:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒,挤出,滚圆,干燥;
(2)缓释包衣层制备;
(3)胶囊充填。
具体的,所述步骤(1)中滚圆过程分三阶段,第一阶段:转盘转速40-80rmp、1-5min;第二阶段:转盘转速100-190rmp、1-5min;第三阶段:30-90rmp、3-20min,微丸粒度范围0.4-0.8mm;所述步骤(2)中缓释包衣层制备为:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为3.0%~5.0%;步骤(3)中采用4#明胶胶囊对微丸进行胶囊充填。
与现有技术相比,本发明的有益效果在于:
(1)优选缓释骨架材料和成膜材料,骨架型和膜控型协同控制有利于药物的释放,使得缓释效果更优,有效达到持续释放的效果,药效平稳持久;
(2)优选增塑剂的种类和配比,增强药品柔韧性,不易脆碎,提高药品质量;
(3)优选稳定剂种类和比例,使得药物稳定性提高,含量均匀性高,释放曲线重现性好;
(4)采用挤出滚圆制备载药微丸,流化床包衣,优化滚圆工艺和包衣增重范围,提高药品含量均匀性高。
附图说明
图1实施例1-5体外累积释放度图
图2对比实施例1-7体外累积释放度图
具体实施方式
为了使本发明的目的、技术方案更加清楚明白,以下结合实施例,对本发明做进一步的说明,但是本发明的保护范围并不限于这些实施例,实施例仅用于解释本发明。本领域技术人员应该理解的是,凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1:20000粒
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,滚圆过程分三阶段,第一阶段:转盘转速60rmp、2min;第二阶段:转盘转速150rmp、3min;第三阶段:60rmp、10min,得到微丸粒度0.6mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸;
(5)包衣:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为4%;
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
实施例2:20000粒
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,滚圆过程分三阶段,第一阶段:转盘转速60rmp、2min;第二阶段:转盘转速150rmp、3min;第三阶段:60rmp、10min,得到微丸粒度0.6mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸;
(5)包衣:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为5%
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
实施例3:20000份
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,滚圆过程分三阶段,第一阶段:转盘转速60rmp、2min;第二阶段:转盘转速150rmp、3min;第三阶段:60rmp、10min,得到微丸粒度0.6mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸;
(5)包衣:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为3%;
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
实施例4:20000粒
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,滚圆过程分三阶段,第一阶段:转盘转速40rmp、5min;第二阶段:转盘转速100rmp、5min;第三阶段:30rmp、3min,微丸粒度范围0.4mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸;
(5)包衣:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为4%;
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
实施例5:20000粒
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,滚圆过程分三阶段,第一阶段:转盘转速80rmp、1min;第二阶段:转盘转速190rmp、1min;第三阶段:90rmp、20min,微丸粒度范围0.8mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸;
(5)包衣:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为4%;
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
对比实施例1:20000粒
制备方法:
同实施例1的制备方法。
对比实施例2:20000粒
制备方法:
同实施例1的制备方法。
对比实施例3:20000粒
制备方法:
同实施例1的制备方法。
对比实施例4:20000粒
制备方法:
同实施例1的制备方法。
对比实施例5:20000粒
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,滚圆过程分三阶段,第一阶段:转盘转速60rmp、2min;第二阶段:转盘转速150rmp、3min;第三阶段:60rmp、10min;得到微丸粒度0.6mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸;
(5)包衣:将润滑剂、增塑剂、成膜材料加入到纯化水中,匀化搅拌,得到包衣液,包衣增重为8%;
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
对比实施例6:20000粒
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,转盘转速120rmp、15min;得到微丸粒度0.6mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸;
(5)包衣:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为4%;
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
对比实施例7:20000粒
制备方法:
(1)制软材:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒得到软材;
(2)挤出:将步骤(1)中得到的软材倒入挤出机中进行挤出,得到碎颗粒;
(3)滚圆:将步骤(2)中得到颗粒倒入滚圆机中滚圆,滚圆过程分三阶段,第一阶段:转盘转速60rmp、2min;第二阶段:转盘转速150rmp、3min;第三阶段:60rmp、10min;得到微丸粒度0.6mm;
(4)干燥:将步骤(3)中得到的湿微丸倒入流化床中进行干燥得到干燥微丸:
(5)包衣:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为4%;
(6)胶囊充填:步骤(5)中的微丸采用4#明胶胶囊进行胶囊充填。
验证实施例
释放试验
释放度照溶出度与释放度测定法(中国药典2020年版四部通则0931第二法)测定。采用第二法装置,以0.1mol/L的盐酸溶液900mL为溶出介质,转速每分钟50转,依法操作,经1小时、2小时、4小时、6小时、8小时、10小时、12小时、14小时分别取样10mL。滤过,并及时在操作容器中补充相同温度的溶出介质10mL,精密量取续滤液5mL,置100mL量瓶中,用0.1mol/L的盐酸溶液稀释至刻度,作为供试品溶液;取利鲁唑对照品适量,精密称定,加0.1mol/L盐酸溶液溶解并定量稀释制成每1mL中约含10μg的溶液,作为对照品溶液。分别取供试品溶液和对照品溶液,照紫外-可见分光光度法(中国药典2015年版四部通则0401),在254nm的波长处分别测定吸收度,计算每片在不同时间的释放量。
表1体外累积释放度(%)
含量均匀度
含量及含量均匀度测定照紫外-可见分光光度法(中国药典2015年版四部通则0401)测定。供试品溶液:取本品20片,精密称定,研细,精密称取细粉适量,置250mL量瓶中,加0.1mol/L盐酸溶液使其溶解(必要时超声)并稀释至刻度,摇匀,滤过,精密量取续滤液5mL,置100mL量瓶中,用0.1mol/L盐酸溶液稀释至刻度,摇匀。对照品溶液:取照品适量,精密称定,加0.1mol/L盐酸溶液溶解并定量稀释制成每1mL中约含10μg的溶液。测定法:取供试品溶液与对照品溶液,在244nm的波长处分别测定吸光度,计算。
表2含量均匀度表
脆碎度试验
取10粒载药微丸和25粒直径为7mm的玻璃珠一起放在脆碎仪中旋转10min,然后将物料置孔径为26目筛中,置于振荡器中振揺5min,收集并称定通过筛网的细粉,计算细粉占微丸重的质量百分数。
表3细粉占微丸重的质量百分数
由表1-3可以看出,按本发明处方组成及制备工艺所得的药品与对比实施例产品相比,缓释效果更优,有效达到持续释放的效果,释放曲线重现性好,药效平稳持久,柔韧性好,不易脆碎,稳定性高,含量均匀性高,药物的安全性和有效性更优。
Claims (10)
1.一种盐酸阿呋唑嗪缓释微丸胶囊,包括载药微丸、缓释包衣层、胶囊壳,其特征在于,所述载药微丸包含盐酸阿呋唑嗪、填充剂、增塑剂、缓释骨架材料、润滑剂、稳定剂;缓释包衣层包括成膜材料、增塑剂、润滑剂;所述的增塑剂为邻苯二甲酸二乙酯、氯化石蜡、三醋酸甘油酯、柠檬酸甘油酯、二乙酰单甘油酯中的一种或多种。
2.根据权利要求1所述的盐酸阿呋唑嗪缓释微丸胶囊,其特征在于,所述的填充剂为糊精、乳糖、淀粉、微晶纤维素、蔗糖中的一种或多种;所述的润滑剂为硬脂酸镁和/或滑石粉。
3.根据权利要求1所述的盐酸阿呋唑嗪缓释微丸胶囊,其特征在于,所述的增塑剂为三醋酸甘油酯、柠檬酸甘油酯、二乙酰单甘油酯中的一种或多种。
4.根据权利要求1所述的盐酸阿呋唑嗪缓释微丸胶囊,其特征在于,所述的缓释骨架材料选自巴西棕榈蜡、蜂蜡、硬脂醇、羟丙甲纤维素、乙基纤维素中的一种;所述的成膜材料为甲基丙烯酸-丙烯酸乙酯共聚物,优选为EudragitL30D-55。
5.根据权利要求1所述的盐酸阿呋唑嗪缓释微丸胶囊,其特征在于,所述的稳定剂为海藻糖、甘氨酸、二丁基羟基甲苯、葡甲胺、黄原胶中的一种或多种。
6.根据权利要求1所述的盐酸阿呋唑嗪缓释微丸胶囊,其特征在于,所述的稳定剂为甘氨酸和/或葡甲胺,优选为,甘氨酸和葡甲胺的重量组分比为1:1。
7.根据权利要求1所述的盐酸阿呋唑嗪缓释微丸胶囊,其特征在于,所述的载药微丸按百分比计包含:盐酸阿呋唑嗪2%-10%,填充剂80%-92%,增塑剂0.1%-2%,缓释骨架材料2%-5%,润滑剂2%-4%,稳定剂1%-3%;所述的缓释包衣层按百分比计包含:成膜材料40%-60%,增塑剂1%-5%,润滑剂1%-6%,纯净水30%-55%。
8.根据权利要求7所述的盐酸阿呋唑嗪缓释微丸胶囊,其特征在于,所述的载药微丸按百分比计优选为盐酸阿呋唑嗪7%,填充剂83%,增塑剂1%,缓释骨架材料4%,润滑剂3%,稳定剂2%;所述的缓释包衣层按百分比计优选为,成膜材料50%,增塑剂3%,润滑剂4%,纯净水43%。
9.一种制备权利要求1所述盐酸阿呋唑嗪缓释微丸胶囊的制备方法,其特征在于,包括如下步骤:
(1)载药丸制备:将盐酸阿呋唑嗪预溶解于纯化水中,与填充剂、润滑剂、稳定剂倒入制粒机中,混合,加入缓释骨架材料、增塑剂、适量的纯化水,制粒,挤出,滚圆,干燥;
(2)缓释包衣层制备;
(3)胶囊充填。
10.根据权利要求9所述的方法,其特征在于,所述步骤(1)中滚圆过程分三阶段,第一阶段:转盘转速40-80rmp、1-5min;第二阶段:转盘转速100-190rmp、1-5min;第三阶段:30-90rmp、3-20min,微丸粒度范围0.4-0.8mm;所述步骤(2)中缓释包衣层制备为:将润滑剂、增塑剂加入到纯化水中,匀化搅拌,将成膜材料倒入,搅拌,得到包衣液,包衣增重为3.0%-5.0%。
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