CN113057979A - 一种牛蟾颗粒的生产制备方法、及制备的牛蟾颗粒和应用 - Google Patents
一种牛蟾颗粒的生产制备方法、及制备的牛蟾颗粒和应用 Download PDFInfo
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Abstract
本发明提供了一种牛蟾颗粒的制备方法,该方法通过将人工牛黄、蟾酥包被空白脂质体,制备得到的牛蟾颗粒完全不影响猪的采食量,同时利于动物服用后对药物活性成分的吸收,保证疗效。
Description
技术领域
本发明涉及兽药制剂技术领域,尤其涉及一种牛蟾颗粒的生产制备方法、及制备的牛蟾颗粒和应用。
背景技术
牛蟾颗粒的成分包括人工牛黄、蟾酥、冰片、黄芩和甘草,其功效是清热解毒、抗病毒,止咳平喘,能防治重症呼吸道疾病与病毒性疾病混合感染、支原体病、迁延不愈性呼吸道病等,主要用于畜禽病毒病和呼吸道疾病。其中主要成分蟾酥是蟾蜍耳后腺及表皮腺体的分泌物,具有显著的抗病毒、抗菌消炎、增强机体免疫力等作用,并且具有低毒、高效、无残留等特点;能够解毒,消肿,强心,止痛,其中的主要活性成分是甙元,为甾族化合物;人工牛黄由牛胆粉、胆酸、猪去氧胆酸、牛磺酸、胆红素、胆固醇、微量元素等加工制成,有清热解毒,化痰定惊之功效,因而牛蟾颗粒广泛应用于畜禽生产养殖过程中。目前,为了方便使用,牛蟾颗粒主要制成中药颗粒剂,可饮水、可拌料。近年来“非洲猪瘟”猖狂,在没有疫苗和特效药物的情况下,业内都在尝试用抗病毒类中成药对其进行预防治疗。通过临床试验发现牛蟾颗粒对该病的预防治疗效果显著。但是,其不足之处在于,牛蟾颗粒中主要成分蟾酥有麻舌感,冰片具有一定刺激性,人工牛黄里的胆酸味苦,按照传统工艺生产的牛蟾颗粒通过拌料或饮水给药时,由于具有上述适口性方面的缺陷,牛蟾颗粒对猪这类味觉灵敏,对口味挑剔的的家畜治疗效果受到影响;并且蟾酥以及人工牛黄在水中的溶解性差,因为其中含有的重要药理活性成分不溶于水,因此牛蟾颗粒溶解后溶液浑浊,配制成的高浓度溶液有时会堵塞管道,给禽类饮水使用造成很大不便;并且也不利于动物服用后对药物活性成分的吸收,从而影响产品临床疗效。
发明内容
本发明目的就是为了弥补现有技术的缺陷,提供一种动物适口性好,同时在水中分散效果好,配制成高浓度溶液后使用方便,吸收效果好的牛蟾颗粒的生产制备方法。
为了实现以上目的,本发明所采用的技术方案是提供一种牛蟾颗粒的制备方法,其中,所述制备方法包括以下步骤:步骤(1)称取4~5重量份人工牛黄、2~3重量份蟾酥、2~3重量份冰片、1000~1200重量份黄芩、200~300重量份甘草;步骤(2)配制pH为3.5~6.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸溶液与0.1mol/L柠檬酸钠溶液体积比为15.5:4.5~3.8:16.2;步骤(3)将所述步骤(1)称取的人工牛黄、蟾酥加入100~150重量份鲜奶中研磨均匀,然后过滤,滤液备用;步骤(4)取7重量份的磷脂和3重量份的胆固醇,加入无水乙醇50份,70~75℃水浴搅拌溶解并挥散乙醇,成膜后加入同样温度的所述步骤(2)配制的柠檬酸缓冲液100份,70~75℃水浴搅拌水化10min,随后室温搅拌30min,充分水化后补加蒸馏水至100份,经微孔滤膜过滤两遍进行整粒,得空白脂质体;步骤(5)依次取所述步骤(4)制备的空白脂质体、所述步骤(3)制备的人工牛黄蟾酥液、碳酸氢钠溶液,混合振荡摇匀,70~75℃水浴中保温15min后,立即用冷水降温,得到人工牛黄蟾酥脂质体粗品;步骤(6)将所述步骤(5)所得的人工牛黄蟾酥脂质体粗品进行低温高速离心处理,制得人工牛黄蟾酥脂质体;步骤(7)将所述步骤(1)称取的冰片加入适量乙醇中溶解完全,加入适量吐温-80,摇匀,得到冰片液;以及步骤(8)将所述步骤(1)称取的黄芩、甘草分别加水煎煮3~4次,将煎液合并、浓缩后喷雾干燥成粉末,与所述步骤(6)得到的物料混匀,然后加入适量水和辅料制粒,低温干燥后均匀喷入所述步骤(7)得到的冰片液,在密闭容器中放置24~48h,即得牛蟾颗粒。作为本发明的一种实施方式,本发明的制备方法中,所述步骤(3)中过滤采用的筛网为80~100目。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(4)中微孔滤膜的孔径为0.8μm。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(5)中碳酸氢钠溶液的浓度为60mg/ml。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(5)中空白脂质体、人工牛黄蟾酥液、碳酸氢钠溶液的体积比为2:1:1,所述冷水降温至4℃。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(6)中低温高速离心的温度为4℃,转速为6000rpm,离心时间15min。
作为本发明的一种实施方式,本发明的制备方法中,所述步骤(2)中配制pH为3.5的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为15.5:4.5,混匀;或
所述步骤(2)中配制pH为5.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为8.2:11.8;或
所述步骤(2)中配制pH为6.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为3.8:16.2。
本发明还提供了所述制备方法制备的牛蟾颗粒。
本发明还提供了所述的牛蟾颗粒在制备治疗畜禽支气管病毒性感染的药物中的应用。
本发明制备的牛蟾颗粒能对患有多种病毒性感染疾病治疗,可对气味敏感的或对气味不敏感的不同的动物均能治疗。
作为本发明的一种实施方式,本发明的应用中,所述畜禽支气管病毒性感染包括猪瘟和鸡毒支原体感染。
本发明的优点是:本发明先通过制备柠檬酸缓冲液、人工牛黄蟾酥液和空白脂质体,主动载药,离心精制,得到包封率高、临床效果好的人工牛黄蟾酥脂质体,然后与黄芩、甘草的水提物混合制粒,均匀喷入冰片液,得到牛蟾颗粒。其中,通过将人工牛黄、蟾酥中的活性成分充分包封在能在水中均匀分散的固体脂质纳米粒中,一方面掩盖了药物的不良气味、口味,改善了药物的适口性,便于猪这类口味敏感性动物的给药,以保证治疗效果。另一方面提高活性成分在水中的稳定性,改善药物颗粒在水中的分散效果,在配制成高浓度溶液不会堵塞管道,便于给药。本发明生产的牛蟾颗粒在水中分散效果好,使用方便,吸收效果好,有利于提高药物疗效,同时又不会影响动物的采食量。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述更为清楚。但这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
本发明实施例中所用到的化学试剂均为分析纯,购自国药集团。本发明所述的实验方法,若无特殊说明,均为常规方法;所述的生物材料,若无特殊说明,均可从商业途径获得。
实施例1本发明牛蟾颗粒的制备
(1)称取4g人工牛黄、2g蟾酥、2g冰片、1000g黄芩、200g甘草备用;
(2)配制pH为3.5的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为15.5:4.5,混匀;
(3)将步骤(1)称取的人工牛黄、蟾酥加入100重量份鲜奶中研磨均匀,然后过滤,滤液备用;
(4)取7g的磷脂和3g的胆固醇,加入无水乙醇50ml,70℃水浴搅拌溶解并挥散乙醇,成膜后加入同温的柠檬酸缓冲液100ml,70℃水浴搅拌水化10min,随后室温搅拌30min,充分水化后补加蒸馏水至100ml,经孔径为0.8μm的微孔滤膜过滤两遍进行整粒,得空白脂质体;
(5)按2:1:1的体积比依次取空白脂质体、人工牛黄蟾酥液、浓度为60mg/ml的碳酸氢钠溶液,混合振荡摇匀,70℃水浴中保温15min后立即用冷水降温,得到人工牛黄蟾酥脂质体粗品;
(6)将步骤(5)所得粗品在4℃,6000rpm条件下进行低温高速离心处理15min,制得人工牛黄蟾酥脂质体。
(7)将步骤(1)称取的冰片加入适量乙醇中溶解完全,加入适量的吐温-80,摇匀,得到冰片液;
(8)将步骤(1)称取的黄芩、甘草分别加水煎煮3-4次,将煎液合并、浓缩后喷雾干燥成粉末,与步骤(6)得到的物料混匀,然后加入适量水和辅料制粒,低温干燥后均匀喷入步骤(7)得到的冰片液,在密闭容器中放置24-48h,即得牛蟾颗粒。
实施例2本发明另一牛蟾颗粒的制备
(1)称取4g人工牛黄、2g蟾酥、2g冰片、1000g黄芩、200g甘草备用;
(2)配制pH为5.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为8.2:11.8;
(3)将步骤(1)称取的人工牛黄、蟾酥加入100重量份鲜奶中研磨均匀,然后过滤,滤液备用;
(4)取7g的磷脂和3g的胆固醇,加入无水乙醇50ml,73℃水浴搅拌溶解并挥散乙醇,成膜后加入同温的柠檬酸缓冲液100ml,73℃水浴搅拌水化10min,随后室温搅拌30min,充分水化后补加蒸馏水至100ml,经孔径为0.8μm的微孔滤膜过滤两遍进行整理,得空白脂质体;
(5)按2:1:1的体积比依次取空白脂质体、人工牛黄蟾酥液、浓度为60mg/ml的碳酸氢钠溶液,混合振荡摇匀,73℃水浴中保温15min后立即用冷水降温,得到人工牛黄蟾酥脂质体粗品;
(6)将步骤(5)所得粗品在4℃,6000rpm条件下进行低温高速离心处理15min,制得人工牛黄蟾酥脂质体。
(7)将步骤(1)称取的冰片加入适量乙醇中溶解完全,加入适量的吐温-80,摇匀,得到冰片液;
(8)将步骤(1)称取的黄芩、甘草分别加水煎煮3-4次,将煎液合并、浓缩后喷雾干燥成粉末,与步骤(6)得到的物料混匀,然后加入适量水和辅料制粒,低温干燥后均匀喷入步骤(7)得到的冰片液,在密闭容器中放置24-48h,即得牛蟾颗粒。
实施例3本发明另一牛蟾颗粒的制备
(1)称取4g人工牛黄、2g蟾酥、2g冰片、1000g黄芩、200g甘草备用;
(2)配制pH为6.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为3.8:16.2;
(3)将步骤(1)称取的人工牛黄、蟾酥加入100重量份鲜奶中研磨均匀,然后过滤,滤液备用;
(4)取7g的磷脂和3g的胆固醇,加入无水乙醇50ml,75℃水浴搅拌溶解并挥散乙醇,成膜后加入同温的柠檬酸缓冲液100ml,75℃水浴搅拌水化10min,随后室温搅拌30min,充分水化后补加蒸馏水至100ml,经孔径为0.8μm的微孔滤膜过滤两遍进行整理,得空白脂质体;
(5)按2:1:1的体积比依次取空白脂质体、人工牛黄蟾酥液、浓度为60mg/ml的碳酸氢钠溶液,混合振荡摇匀,75℃水浴中保温15min后立即用冷水降温,得到人工牛黄蟾酥脂质体粗品;
(6)将步骤(5)所得粗品在4℃,6000rpm条件下进行低温高速离心处理15min,制得人工牛黄蟾酥脂质体。
(7)将步骤(1)称取的冰片加入适量无水乙醇中溶解完全,加入适量的吐温-80,摇匀,得到冰片液;
(8)将步骤(1)称取的黄芩、甘草分别加水煎煮3-4次,将煎液合并、浓缩后喷雾干燥成粉末,与步骤(6)得到的物料混匀,然后加入适量水和辅料制粒,低温干燥后均匀喷入步骤(7)得到的冰片液,在密闭容器中放置24-48h,即得牛蟾颗粒。
实施例4传统工艺牛蟾颗粒的制备
称取4g人工牛黄、2g蟾酥、2g冰片、1000g黄芩、200g甘草;人工牛黄研磨,过100目筛;蟾酥加白酒研磨,用100目筛滤过,滤液与蔗糖粉制成颗粒,过80目筛,用等量递增法与人工牛黄混匀,备用;冰片用乙醇溶解,加吐温-80适量,摇匀,备用;黄芩、甘草分别加水煎煮3次,合并煎液、浓缩后喷雾干燥成粉末,加入人工牛黄和蟾酥的混合物,混匀,加适量的蔗糖和糊精,制成颗粒,低温干燥,均匀喷入冰片液,在密闭容器中放置24h,即得牛蟾颗粒。
实施例5牛蟾颗粒溶水性
溶水性检验方法参考《中华人民共和国兽药典》2015年版二部。分别取本发明实施例1、2、3制备的样品及实施例4传统工艺制备的样品各10g,加入200ml热水中,搅拌5分钟,立即观察。结果记录如表1:
表1溶水性情况统计
从表1可见:本发明实施例1、2、3制备的样品能够完全溶解,溶解后溶液澄清,放置4h后,仍然澄清;传统工艺制备的样品能完全溶解,溶解轻微浑浊,放置4h后,底部有少许沉淀。说明本发明制备的样品溶解性较传统工艺更好,禽类饮水使用,高浓度配液时不会堵塞管道,更有利于动物服用后对药物活性成分的吸收,同时对于饮水使用将更方便。
实施例6临床实例适口性试验
浙江省金华某个猪场,经过临床症状诊断、实验室诊断等手段已确诊感染猪瘟的病猪群体,临床症状明显表现为:采食量下降,喜卧舍角、精神不佳,发热(达40~42℃),心跳加快,呼吸困难,部分咳嗽,眼、鼻有浆液性或粘液性脓性分泌物,皮肤发绀,淋巴结、肾、胃肠粘膜明显出血等,实验室诊断为病毒性瘟疫感染,疑似“非洲猪瘟”。从猪群中随机挑选50头,公母兼有,所挑选的猪个体和精神状态相似,均分5组,实施例1、2、3所制备的牛蟾颗粒1~3和实施例4传统工艺制备的牛蟾颗粒4及空白对照组,进行预防治疗,采食量结果记录如表2,临床疗效情况如表3:
表2适口性情况统计
从表2可见:实施例4即传统工艺生产的产品,前4天采食量逐日减少,第5日不采食,对猪适口性差;本发明生产的牛蟾颗粒适口性好,实施例1制备产品投喂后有两天猪的采食量有极轻微影响,这可能与制备人工牛黄蟾酥脂质体粗品时的温度有关,使得对蟾酥及人工牛黄的包封效果较弱;实施例2、3与空白组比较,完全不影响猪的采食量。说明本发明制备的牛蟾颗粒适口性好,对猪的采食量完全不影响或仅有极轻微影响。
表3临床疗效情况统计
从表3可见:实施例4即传统工艺生产的样品,给药5天病猪症状没有改善;实施例1、2、3制备的样品适口性好,药物吸收好,给药第5天,喜卧舍角、精神不佳,呼吸困难,症状减轻;给药第7天发热(达40~42℃),咳嗽,症状减轻;给药第10天,眼、鼻内的浆液性或粘液性脓性分泌物消失,给药第15天,临床症状完全消失。这说明本发明制备的样品有利于动物治疗期内服用,并保证了对药物活性成分的吸收,以确保疗效。
实施例7、治疗效果临床应用实例
为研究本发明制备的牛蟾颗粒对气味不敏感动物的治疗效果,选择了鸡作为临床应用实验动物。
山东某大型鸡场,经过临床症状诊断,确诊为鸡毒支原体感染,临床症状表现为:咳嗽、喷嚏、气管罗音和鼻炎。病鸡精神沉郁,低头缩颈,食欲减退;咳嗽甩鼻鼻涕堵塞鼻孔、打喷嚏、呼吸困难;少数病鸡眼部出现红肿流泪结膜炎,眼上有清性分泌物。从鸡群中随机挑选2000只,所挑选的鸡个体和精神状态相似,均分为4组,取实施例1、2、3所制备的牛蟾颗粒1~3和实施例4传统工艺制备的牛蟾颗粒4各100g与含主药4.95g的替米考星可溶性粉混溶于66kg水中,鸡自由饮用3天,第4天停用替米考星可溶性粉,继续单用牛蟾颗粒2天,结果见表4:
表4临床疗效情况统计
从表4可见:实施例4即传统工艺生产的产品,给药之后的两天没有明显改善;三天以后症状逐渐减轻,给药5天后,78%病鸡症状减轻;实施例1、2、3制备的样品给药第2天,20%~30%病鸡症状减轻,临床疗效逐日改善,给药第5天后,病鸡93%以上症状减轻。这说明本发明制备的样品对于气味不敏感动物(鸡)的治疗效果也优于传统工艺生产的牛蟾颗粒,显示了良好的治疗效果。
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、等同替換、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种牛蟾颗粒的制备方法,其中,所述制备方法包括以下步骤:
步骤(1)称取4~5重量份人工牛黄、2~3重量份蟾酥、2~3重量份冰片、1000~1200重量份黄芩、200~300重量份甘草;
步骤(2)配制pH为3.5~6.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸溶液与0.1mol/L柠檬酸钠溶液体积比为15.5:4.5~3.8:16.2;
步骤(3)将所述步骤(1)称取的人工牛黄、蟾酥加入100~150重量份鲜奶中研磨均匀,然后过滤,滤液备用;
步骤(4)取7重量份的磷脂和3重量份的胆固醇,加入无水乙醇50份,70~75℃水浴搅拌溶解并挥散乙醇,成膜后加入同温的所述步骤(2)配制的柠檬酸缓冲液100份,70~75℃水浴搅拌水化10min,随后室温搅拌30min,充分水化后补加蒸馏水至100份,经微孔滤膜过滤两遍进行整粒,得空白脂质体;
步骤(5)依次取所述步骤(4)制备的空白脂质体、所述步骤(3)制备的人工牛黄蟾酥液、碳酸氢钠溶液,混合振荡摇匀,70~75℃水浴中保温15min后,立即用冷水降温,得到人工牛黄蟾酥脂质体粗品;
步骤(6)将所述步骤(5)所得的人工牛黄蟾酥脂质体粗品进行低温高速离心处理,制得人工牛黄蟾酥脂质体;
步骤(7)将所述步骤(1)称取的冰片加入适量乙醇中溶解完全,加入适量吐温-80,摇匀,得到冰片液;
步骤(8)将所述步骤(1)称取的黄芩、甘草分别加水煎煮3~4次,将煎液合并、浓缩后喷雾干燥成粉末,与所述步骤(6)得到的物料混匀,然后加入适量水和辅料制粒,低温干燥后均匀喷入所述步骤(7)得到的冰片液,在密闭容器中放置24~48h,即得牛蟾颗粒。
2.根据权利要求1所述的制备方法,其中,所述步骤(3)中过滤采用的筛网为80~100目。
3.根据权利要求1所述的制备方法,其中,所述步骤(4)中微孔滤膜的孔径为0.8μm。
4.根据权利要求1所述的制备方法,其中,所述步骤(5)中碳酸氢钠溶液的浓度为60mg/ml。
5.根据权利要求1所述的制备方法,其中,所述步骤(5)中空白脂质体、人工牛黄蟾酥液、碳酸氢钠溶液的体积比为2:1:1,所述冷水降温至4℃。
6.根据权利要求1所述的制备方法,其中,所述步骤(6)中低温高速离心的温度为4℃,转速为6000rpm,离心时间15min。
7.根据权利要求1所述的制备方法,其中,所述步骤(2)中pH为3.5的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为15.5:4.5,混匀;或
所述步骤(2)中配制pH为5.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为8.2:11.8;或
所述步骤(2)中配制pH为6.0的柠檬酸缓冲液:0.1mol/L柠檬酸溶液,取柠檬酸21.01g,加纯化水1000ml,溶解,摇匀,0.1mol/L柠檬酸钠溶液,取柠檬酸钠29.41g,加纯化水1000ml,溶解,摇匀,两者体积比为3.8:16.2。
8.根据权利要求1~7所述制备方法制备的牛蟾颗粒。
9.根据权利要求8所述的牛蟾颗粒在制备治疗畜禽支气管病毒性感染的药物中的应用。
10.根据权利要求9所述的应用,其中,所述畜禽支气管病毒性感染包括猪瘟和鸡毒支原体感染。
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