清肺消炎颗粒的制备工艺及药物动力学研究
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摘要
本文主要对清肺消炎颗粒的提取工艺、挥发油的包合工艺、成型工艺及其体内药物动力学进行研究,为清肺消炎颗粒的进一步开发和研究提供科学的实验依据,也为清肺消炎颗粒的质控研究提供方法学参考。
目的：清肺消炎方为我院呼吸科的经验处方,全方由葛根、石膏、荆芥等7味中药组成,具有清肺宣肺、止咳平喘的功效,临床常用于治疗由热毒袭肺引起的上呼吸道感染、肺炎等症。此方制剂原为汤剂,临床应用多年,疗效显著。为使该方剂应用过程中更好地服务于患者,质量有效可控,提高患者的用药依从性,本课题将其研发为颗粒剂。从制备工艺、挥发油包合工艺、成型工艺及其体内药物动力学等方面进行系统研究。
方法：①葛根素的提取工艺研究。根据单因素试验并参考相关文献资料认为溶媒倍数、提取温度、提取时间为影响葛根素提取率的主要因素,进一步以葛根素含量和浸膏得率为考察指标,进行正交试验,对葛根素的提取工艺研究进行优选,并对试验结果进行验证。②荆芥挥发油的包合工艺研究。以包合率和包合物中的实际含油量为评价指标,分别采用超声法,搅拌法和研磨法,对荆芥挥发油包合工艺进行优选,确定最佳包合工艺方法,并对试验结果进行验证。③除杂工艺研究。采用乙醇醇沉法、壳聚糖沉淀法和离心法,以葛根素含量、澄清度和浸膏得率为考察指标,确定最佳澄清工艺条件。④成型工艺研究。将水提醇沉所得浸膏和荆芥挥发油以及辅料混匀,以溶化性、休止角和吸湿百分率为考察因素,采用综合评分法,优选辅料种类和用量。⑤制剂质量检查。参照《中国药典》2010年版一部附录IC颗粒剂项下规定对清肺消炎颗粒进行常规检查。⑤药物动力学研究。采用HPLC法,测定给药后小鼠血浆及各脏器组织中葛根素的含量,进行血药浓度分析,并计算其药动学参数。
结果：①制剂最佳提取工艺为A3B1C3,即加药材30倍量的水,80℃煎煮3h,共1次。结果表明该工艺稳定可行。②采用三种方法制备了荆芥包合物,实验结果表明以超声法所得到的包合物包合率最大,次之为搅拌法,研磨法所得的包含物包合率最小。③综合改善药粉吸湿性、颗粒成型性和经济成本等指标,最终确定可溶性淀粉：糊精(2：1)作为本品辅料。④清肺消炎颗粒符合《中国药典》2010年版一部附录IC颗粒剂项下规定。⑤药物动力学研究结果表明,葛根素在小鼠体内的药动学过程符合一室开放模型,主要药动学参数Cmax为1.575μg·L-1, tmax为1.000 h,t1/2a为0.3281 h,AUC为6.039μg·L-1·h-1。
结论：清肺消炎颗粒的提取及成型工艺简便,稳定可行；荆芥挥发油的包合工艺包合率高,适合工业化大生产；清肺消炎颗粒的体内药物动力学测定方法准确可靠,从而为更好地评价清肺消炎颗粒的药效作用,为制剂的进一步开发和临床应用打下了良好的基础。
This study aimed to investigate optimum condition for preparation of Qingfeixiaoyan granules, including preparation of essential oils from Herba Schizonepetae, preparation process and pharmacokinetics.
Objective:Qingfeixiaoyan recipe, composed of Radix Puerariae, Herba Schizonepetae, Gypsum Fibrosuum, etc, is an empirical prescription in our hospital. With the effects of anti-inflammatory and relieving cough and asthma, the recipe was widely applied in the treatment of respiratory disease such as cough, colds, fever and chronic bronchitis. The original prescription was decoction. It had been applied clinically for many years and got significant effects. In order to serve the patients better during applieation, to get a well-controlled quality and to promote the paitients' compliance, we changed the recipe into granule and did a systematic research on aspects of extraction process, preparation process, quality standard and preparation preliminary stability.
Methods:①Hot water extraction. Orthogonal array design was employed to optimize the ratio of water to raw material (X1:10-30 mL/g), extraction time (X2:1-3 h) and extraction temperature(X3:80-100℃) to obtain a high puerarin yield from recipe.②Including preparation of essential oils from Herba Schizonepetae. Clathrate compounds were prepared for inclusion complex yield and experimental oil contents in inclusion complex by ultrasonic-assisted technique, electric blender technique and incorporation technique, respectively.③The extract which comes from the preparing procedures of water extraction and alcohol precipitation was mixed with accessories (soluble starch and dextrin).④According to the Chinese pharmacopoeia 2010 version of I appendix C, Qingfeixiaoyan granules were carried through a routine inspection under the provisions of the granules.⑤Pharmacokinetics of orally administered at a dose of 61.6g/kg granules were investigated in mice. The effective puerarin concentrations in serum and organs were measured using HPLC and concentration-time data analyzed with Pharmacokinetical Kinetics Software.
Results:①The optimum condition was A3B1C3, i.e., a ratio of water to raw material of 30 mL/g and extraction time of 3 h at 80℃.②Evaluated by inclusion complex yield and experimental oil contents in inclusion complex, ultrasonic was the best technique.③Analyzed by improve powder hygroscopicity, particle formability and economic cost, soluble starch and dextrin at the ratio of 2:1 as this auxiliary material was considered in this experiment.④The Qingfeixiaoyan granules were correspond with China pharmacopoeia 2010 version of I appendix C granules under rules.⑤The pharmacokinetic parameters were determined after ig of granules to mice. The main pharmacokinetic parameters of puerarin in mice were Cmax=1.575μg·L-1, tmax=1.000 h, t1/2α=0.3281 h, and AUC=6.039μg·L-1·h-1.
Conclusion:The method to extract puerarin from recipe is simple and feasible. It can provide the scientific basis for further development of preparation of Qingfeixiaoyan granules. The preparation process and including preparation were reasonable and feasible. The HPLC method is steady and accurate with a good repeatability which can be used for pharmacokinetic analysis of puerarin. This study established a solid pharmaceutical basis for future research.
目的：清肺消炎方为我院呼吸科的经验处方,全方由葛根、石膏、荆芥等7味中药组成,具有清肺宣肺、止咳平喘的功效,临床常用于治疗由热毒袭肺引起的上呼吸道感染、肺炎等症。此方制剂原为汤剂,临床应用多年,疗效显著。为使该方剂应用过程中更好地服务于患者,质量有效可控,提高患者的用药依从性,本课题将其研发为颗粒剂。从制备工艺、挥发油包合工艺、成型工艺及其体内药物动力学等方面进行系统研究。
方法：①葛根素的提取工艺研究。根据单因素试验并参考相关文献资料认为溶媒倍数、提取温度、提取时间为影响葛根素提取率的主要因素,进一步以葛根素含量和浸膏得率为考察指标,进行正交试验,对葛根素的提取工艺研究进行优选,并对试验结果进行验证。②荆芥挥发油的包合工艺研究。以包合率和包合物中的实际含油量为评价指标,分别采用超声法,搅拌法和研磨法,对荆芥挥发油包合工艺进行优选,确定最佳包合工艺方法,并对试验结果进行验证。③除杂工艺研究。采用乙醇醇沉法、壳聚糖沉淀法和离心法,以葛根素含量、澄清度和浸膏得率为考察指标,确定最佳澄清工艺条件。④成型工艺研究。将水提醇沉所得浸膏和荆芥挥发油以及辅料混匀,以溶化性、休止角和吸湿百分率为考察因素,采用综合评分法,优选辅料种类和用量。⑤制剂质量检查。参照《中国药典》2010年版一部附录IC颗粒剂项下规定对清肺消炎颗粒进行常规检查。⑤药物动力学研究。采用HPLC法,测定给药后小鼠血浆及各脏器组织中葛根素的含量,进行血药浓度分析,并计算其药动学参数。
结果：①制剂最佳提取工艺为A3B1C3,即加药材30倍量的水,80℃煎煮3h,共1次。结果表明该工艺稳定可行。②采用三种方法制备了荆芥包合物,实验结果表明以超声法所得到的包合物包合率最大,次之为搅拌法,研磨法所得的包含物包合率最小。③综合改善药粉吸湿性、颗粒成型性和经济成本等指标,最终确定可溶性淀粉：糊精(2：1)作为本品辅料。④清肺消炎颗粒符合《中国药典》2010年版一部附录IC颗粒剂项下规定。⑤药物动力学研究结果表明,葛根素在小鼠体内的药动学过程符合一室开放模型,主要药动学参数Cmax为1.575μg·L-1, tmax为1.000 h,t1/2a为0.3281 h,AUC为6.039μg·L-1·h-1。
结论：清肺消炎颗粒的提取及成型工艺简便,稳定可行；荆芥挥发油的包合工艺包合率高,适合工业化大生产；清肺消炎颗粒的体内药物动力学测定方法准确可靠,从而为更好地评价清肺消炎颗粒的药效作用,为制剂的进一步开发和临床应用打下了良好的基础。
This study aimed to investigate optimum condition for preparation of Qingfeixiaoyan granules, including preparation of essential oils from Herba Schizonepetae, preparation process and pharmacokinetics.
Objective:Qingfeixiaoyan recipe, composed of Radix Puerariae, Herba Schizonepetae, Gypsum Fibrosuum, etc, is an empirical prescription in our hospital. With the effects of anti-inflammatory and relieving cough and asthma, the recipe was widely applied in the treatment of respiratory disease such as cough, colds, fever and chronic bronchitis. The original prescription was decoction. It had been applied clinically for many years and got significant effects. In order to serve the patients better during applieation, to get a well-controlled quality and to promote the paitients' compliance, we changed the recipe into granule and did a systematic research on aspects of extraction process, preparation process, quality standard and preparation preliminary stability.
Methods:①Hot water extraction. Orthogonal array design was employed to optimize the ratio of water to raw material (X1:10-30 mL/g), extraction time (X2:1-3 h) and extraction temperature(X3:80-100℃) to obtain a high puerarin yield from recipe.②Including preparation of essential oils from Herba Schizonepetae. Clathrate compounds were prepared for inclusion complex yield and experimental oil contents in inclusion complex by ultrasonic-assisted technique, electric blender technique and incorporation technique, respectively.③The extract which comes from the preparing procedures of water extraction and alcohol precipitation was mixed with accessories (soluble starch and dextrin).④According to the Chinese pharmacopoeia 2010 version of I appendix C, Qingfeixiaoyan granules were carried through a routine inspection under the provisions of the granules.⑤Pharmacokinetics of orally administered at a dose of 61.6g/kg granules were investigated in mice. The effective puerarin concentrations in serum and organs were measured using HPLC and concentration-time data analyzed with Pharmacokinetical Kinetics Software.
Results:①The optimum condition was A3B1C3, i.e., a ratio of water to raw material of 30 mL/g and extraction time of 3 h at 80℃.②Evaluated by inclusion complex yield and experimental oil contents in inclusion complex, ultrasonic was the best technique.③Analyzed by improve powder hygroscopicity, particle formability and economic cost, soluble starch and dextrin at the ratio of 2:1 as this auxiliary material was considered in this experiment.④The Qingfeixiaoyan granules were correspond with China pharmacopoeia 2010 version of I appendix C granules under rules.⑤The pharmacokinetic parameters were determined after ig of granules to mice. The main pharmacokinetic parameters of puerarin in mice were Cmax=1.575μg·L-1, tmax=1.000 h, t1/2α=0.3281 h, and AUC=6.039μg·L-1·h-1.
Conclusion:The method to extract puerarin from recipe is simple and feasible. It can provide the scientific basis for further development of preparation of Qingfeixiaoyan granules. The preparation process and including preparation were reasonable and feasible. The HPLC method is steady and accurate with a good repeatability which can be used for pharmacokinetic analysis of puerarin. This study established a solid pharmaceutical basis for future research.
引文
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