CN106880659A - 一种兽用苦参种子黄酮缓释微丸及其制备 - Google Patents
一种兽用苦参种子黄酮缓释微丸及其制备 Download PDFInfo
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Abstract
本发明属于兽药制剂技术领域,具体涉及一种可替代抗生素起预防杀菌作用的中药缓释药物制剂,具体地说,涉及一种主要针对反刍动物具有过瘤胃保护的兽用苦参种子黄酮缓释微丸及其制备工艺。本发明所述微丸由40%~45%的主药、15%~30%的蜡质材料、15%~20%的卡波姆、10%~20%的乙基纤维素和1%~5%的抗黏剂及矫味剂组成。利用卡波姆pH敏感的特点,通过瘤胃与皱胃pH环境的变化控制卡波姆的溶胀,以达到药物缓释及定位释放的目的,省去了包衣过程,制备工艺简单快速,重复性好。本发明还提供了一种熔融高速搅拌技术制备缓释微丸的方法,具有生产效率高、微丸稳定性好、省时省力的优点。
Description
技术领域
本发明属于兽药制剂技术领域,具体涉及一种可替代抗生素起预防杀菌作用的中药缓释药物制剂,具体地说,涉及一种主要针对反刍动物具有过瘤胃保护的兽用苦参种子黄酮缓释微丸及其制备工艺。
背景技术
市场上的抗菌药大部分是以抗生素为代表的西药抗菌药,抗生素因其抑菌杀菌效果显著,通常作为首选抗菌药使用,但是抗生素有其不可忽视的缺陷:副作用大、易产生耐药性。目前抗生素滥用情况严重,特别是在兽药领域,经常在动物饲料中大量添加抗生素,以预防动物发生感染性疾病。这不仅导致了药源性疾病的增加以及细菌耐药性的增强,还使许多动物产品中抗生素含量超标,直接危害人类健康。
中药抗菌较西药有明显的优势:中药活性成分不仅对细菌有直接杀灭作用,它还能逆转细菌耐药性,尤其是,还能够通过调节机体的免疫状态,提高动物自身的抗病能力,因此抗菌中药可作为预防用药供动物长期使用。研究兽用抗菌中药及其制剂对于畜牧业感染性疾病的防治具有重要意义。
苦参是传统的抗菌中药,其中含有的生物碱和黄酮是公认的抗菌成分。目前上市的苦参制剂主要是以苦参生物碱为主要成分的注射液、栓剂、片剂、胶囊剂和洗液等,并且以上制剂的有效成分均来自于苦参根,但野生苦参数量稀少,再者根的利用不具有可持续性,影响了苦参及其制剂的广泛应用。而苦参种子每年都可以进行采摘且不会损坏植株,可长期利用。发明人经过前期提取、分离纯化、体外抑菌、HPLC分析及核磁共振扫描研究发现,苦参种子中发挥抗菌作用的有效成分主要为黄酮类成分。因而苦参种子中的黄酮成分就具有了一定的研究价值
目前并无苦参种子黄酮类成分用于制剂的研究报道,在已上市的苦参制剂中也没有缓释微丸剂型。缓释微丸除了具有微丸自身制剂方面的优势外,在兽用药领域还有特殊的功用。普通兽用固体制剂通常采用饲料拌服的给药方式,由于动物天生的味觉和嗅觉的敏感性导致了其对药物摄入的选择性,通常会影响口服药物的疗效,而微丸可以起到掩味的作用,不影响动物的摄食,具有饲喂方便、节约养殖成本的优点。
反刍动物如牛、羊等的胃由瘤胃、网胃、辫胃、皱胃组成。瘤胃是反刍动物的第一胃,pH约为6.0-7.0,内有大量瘤胃微生物,可帮助反刍动物消化纤维素和合成大量菌体蛋白。皱胃是反刍动物胃的第4部分,功能类似单胃动物的胃,该胃附有消化腺体,可分泌消化酶,pH约在1.05-1.32之间。当动物出现细菌感染时,可采用的治疗措施主要为口服及注射抗菌药。但由于反刍动物特殊的消化生理结构,如果口服,抗菌药会被瘤胃中的微生物分解,降低药效,同时抗菌成分也会杀死瘤胃中的微生物,致使动物出现消化障碍。注射给药需要考虑操作难度和危险性的问题,因而有一定的局限性。
在现有专利中,申请号为201610585227.6和申请号为201510606163.9的专利分别公开了一种过瘤胃金霉素微丸及其制备方法和一种过瘤胃包被恩诺沙星微丸及其制备方法,但这两种微丸主药均为抗生素,仍然无法避免抗生素长期使用带来的弊端,而且需要先制备丸芯,再包衣,工艺复杂,成本较高。在本发明中,发明人创新性地将pH敏感型亲水凝胶卡波姆用于微丸的制备中,通过瘤胃与皱胃pH环境的变化控制卡波姆的溶胀,以达到药物缓释及定位释放的目的,省去了包衣过程,制备工艺简单,大大降低了生产成本。另外,选择水不溶性的乙基纤维素作为填充剂,以避免微丸在进入皱胃之前,吸收胃液中的水分崩解。发明人对苦参种子提取液进行初步纯化,将得到的黄酮类成分采用熔融高速搅拌法做成骨架型缓释微丸,微丸不仅能通过瘤胃,在皱胃中定位消化,而且还具有制备方便、缓释效果好、能有效避免包衣制剂包衣层老化的弊端。
发明内容
本发明所要解决的技术问题是提供一种反刍动物过瘤胃保护的兽用苦参种子黄酮缓释微丸及其制备工艺。本发明既可以弥补市场上苦参种子黄酮制剂的空白,又可以在兽用抗菌药市场上一定程度地取代抗生素类药物,减少耐药菌的产生,同时还可以提供一种可供反刍动物服用的、给药方便且不影响反刍动物正常的消化生理过程的缓释微丸制剂。本发明还提供了一种熔融高速搅拌技术制备缓释微丸的方法,具有生产效率高、微丸稳定性好、省时省力的优点。
本发明的实施方案如下:
本发明提供一种可替代抗生素起预防杀菌作用的兽用苦参种子黄酮缓释微丸,按重量计,所述微丸是由40%~45%的主药、15%~30%的蜡质材料、15%~20%的卡波姆、10%~20%的乙基纤维素和1%~5%的抗黏剂及矫味剂组成。
进一步地,所述主药为苦参种子黄酮醇提物的稠膏、干膏或干粉,其主要活性药物成分为含有苦参酮、降苦参酮、苦参醇、槐属二氢黄酮及其它带有异戊烯基侧链的总黄酮。提取方法为超声提取法。
更进一步地,其中所述的蜡质材料可以为单硬脂酸甘油酯、氢化蓖麻油、固体石蜡、硬脂酸、十六醇、十八醇中的单一组分或它们的混合物,优选氢化蓖麻油与十六醇组成的混合物。
其中所述的抗黏剂可以为氯化钙、硫酸钾、滑石粉、高岭土的单一组分或它们的混合物,优选滑石粉。
其中所述的矫味剂可以为甘草甜素、甜菊苷、阿司帕坦的单一组分或它们的混合物,优选甜菊苷。
本发明所述的苦参种子黄酮缓释微丸,其中微丸粒径优选为0.5mm~1.5mm。
本发明所述的上述方法,其中缓释微丸采用熔融高速搅拌技术制备。
本发明制备的苦参种子黄酮缓释微丸,步骤如下:
(1)将主药、蜡质材料、卡波姆、乙基纤维素和抗黏剂及矫味剂共同过100目筛混合均匀。
(2)采用高速熔融搅拌法,将上述混合物倒入熔融锅内,边搅拌边升温,直到形成符合粒径要求的微丸为止,将微丸趁热过14~18目筛。
发明人采用熔融高速搅拌技术,通过大量的试验探索,发现了本发明苦参种子黄酮缓释微丸的处方和制备工艺,通过此法制得的缓释微丸圆整度高、粉体学性质良好、稳定性高、掩味效果好,且具有很好的体外释放性能。本发明所制微丸可通过便于操作的饲料拌服的方式供动物服用,不影响反刍动物正常的消化过程,同时有效避免了抗菌药对瘤胃微生物的破坏以及微生物对药物的分解,缓释效果良好,能充分达到预防动物被感染以及抗菌的目的。
附图说明
图1为实施例1~3的苦参种子黄酮缓释微丸的体外释放曲线;
具体实施方式
通过下面具体的实施方式对本发明进行进一步的阐述,但并不意味本发明的实施局限于此。
实施例1:
以生产本发明苦参种子黄酮缓释微丸100g为例,所用到的主药及辅料质量配比如下:
制备方法:将主药与辅料分别过100目筛,按处方量分别称取并过筛混匀,倒入熔融锅中,启动仪器,设定初始温度为50℃,初始转速为250rpm,随后以1℃/4min的速度升温,以50r/5min的速度提高转速,直至75℃,2min后停止加热及搅拌,趁热过14~18目筛。
实施例2:
以生产本发明苦参种子黄酮缓释微丸100g为例,所用到的主药及辅料质量配比如下:
制备方法同实施例1
实施例3:
以生产本发明苦参种子黄酮缓释微丸100g为例,所用到的主药及辅料质量配比如下:
制备方法同实施例1
实施例4:
以生产本发明苦参种子黄酮缓释微丸100g为例,所用到的主药及辅料质量配比如下:
制备方法:将主药与辅料分别过100目筛,按处方量分别称取并过筛混匀,倒入熔融锅中,启动仪器,设定初始温度为55℃,初始转速为250rpm,随后以1℃/4min的速度升温,以50r/5min的速度提高转速,直至80℃,2min后停止加热及搅拌,趁热过14~18目筛。
实施例5:
以生产本发明苦参种子黄酮缓释微丸100g为例,所用到的主药及辅料质量配比如下:
制备方法同实施例4
实验:体外释放度测定
样品:三批苦参种子黄酮缓释微丸样品(规格分别为含主药40%、45%,分别按照实例1、实施例2、实例3所述方法制得)
测定方法,按照2015版兽药典一部附录释放度的测定方法进行,称取适量苦参种子黄酮缓释微丸(相当于苦参种子黄酮0.30g)置于溶出杯中,释放介质为0.1mol/L的盐酸,设定转速为100r/min,设定温度为37℃,分别于1、2、4、6、9、12、15、18、21、25h时取样,采用紫外分光光度法测定苦参种子黄酮的含量,计算累积释放度。释放曲线如图1所示,可以看出本发明的微丸在2h时主药的释放度在10%以内,15h时累积释放度约为70%,比普通颗粒剂释放时间延长了将近20倍,可以表明本发明能达到缓释的效果,延长用药间隔。
Claims (6)
1.一种可替代抗生素起预防杀菌作用的兽用苦参种子黄酮缓释微丸,由40%~45%的主药、15%~30%的蜡质材料、15%~20%的卡波姆、10%~20%的乙基纤维素和1%~5%的抗黏剂及矫味剂组成。
2.如权利要求1所述的兽用苦参种子黄酮缓释微丸,其特征在于,主药为苦参种子黄酮醇提物的稠膏、干膏或干粉,其主要活性药物成分为含有苦参酮、降苦参酮、苦参醇、槐属二氢黄酮及其它带有异戊烯基侧链的总黄酮。提取方法为超声提取法。
3.如权利要求1所述的兽用苦参种子黄酮缓释微丸,其特征在于,其中所述的蜡质材料可以为单硬脂酸甘油酯、氢化蓖麻油、固体石蜡、硬脂酸、十六醇、十八醇中的一种或多种组成的混合物,优选氢化蓖麻油与十六醇组成的混合物。
4.如权利要求1所述的兽用苦参种子黄酮缓释微丸,其特征在于,将pH敏感型亲水凝胶卡波姆用于微丸的制备中,通过瘤胃与皱胃pH环境的变化控制卡波姆的溶胀,以达到药物缓释及定位释放的目的。
5.如权利要求1所述的兽用苦参种子黄酮缓释微丸,其特征在于,采用水不溶性辅料乙基纤维素作为填充剂,以避免微丸进入皱胃之前在胃液中崩解。
6.一种制备权利要求1-5所述的兽用苦参种子黄酮缓释微丸的方法,其特征在于采用熔融高速搅拌技术制备,具体包括如下步骤:
(1)将主药、填充剂、蜡质材料、亲水凝胶材料和抗黏剂共同过100目筛混合均匀。
(2)采用高速熔融搅拌法,将上述混合物倒入熔融锅内,边搅拌边升温,直到形成符合粒径要求的微丸为止,将微丸趁热过14~18目筛。
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