盐酸小檗碱包被颗粒的制备及药理学研究
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摘要
盐酸小檗碱为传统的抗菌药物,因味苦而限制其在养猪生产中应用。本文以丙烯酸树脂Ⅳ为包衣材料,采用流化床底喷式包衣法制备出盐酸小檗碱包被颗粒,制定了盐酸小檗碱包被颗粒质量标准,并进行了对猪常见致病菌MIC的测定和适口性等研究。
1.研究了不同粘合剂、不同物料配比和不同的包衣增重对颗粒的外观、硬度、粒径和药物溶出情况的影响,确定了盐酸小檗碱包被颗粒的处方。试验结果为,包被最佳处方为:5%聚乙烯吡咯烷酮(PVP)为粘合剂,微晶纤维素(MCC)为赋型剂,淀粉为稀释剂,物料配比黄连素:MCC:淀粉比例为1:0.75:3.25。
2.通过对雾化压力、喷液速度、进风温度、进风量和进风湿度等对包被颗粒质量的影响研究,确定最佳工艺参数。试验结果为,适宜抛丸参数:转速14.5r/min,风量27.5m~3/h;包衣参数:流量10mL/min,引风频率20HZ,旋转频率4HZ,温度55℃,雾化压力0.15Mpa。采用本方法制备盐酸小檗碱包被颗粒,制备工艺简单,粒径均匀,易于工业化生产,具有良好的产业化应用前景。
3.通过对盐酸小檗碱包被颗粒的外观、药物含量、体外药物溶出等的研究,拟定了盐酸小檗碱包被颗粒质量标准。结果表明,颗粒呈黄色,圆整度好、硬度适宜,有较好的流动性。包封率应为90%～95%。包被颗粒在37℃下,pH=2.0溶出介质中1h内溶出度超过80%,但在水中1h内几乎没有药物溶出。包被颗粒的粒径在150～425μm内的不低于80%。
4.参照NCCLS(美国临床实验室标准化委员会)抗生素药敏试验中的微量稀释法测定盐酸小檗碱对几种菌株的最小抑菌浓度(MIC)。试验结果为,盐酸小檗碱对大肠杆菌MIC范围为512～1024μg/mL,对沙门氏菌MIC范围为512～1024μg/mL;对金葡菌MIC为256μg/mL;对巴氏杆菌MIC为256μg/mL;对链球菌MIC为512μg/mL。
5.建立了猪血浆中盐酸小檗碱的高效液相检测方法,并进行了精密度、回收率、最低检出限及定量标准曲线等项研究。结果表明,本方法操作简便,稳定性好、灵敏度高、样品回收率高,样品检测时间短,最低检测浓度为0.5μg/L,可用于盐酸小檗碱的药动学研究。
6.选用健康仔猪3头,分为3组。对照组饲喂基础日粮,处理组Ⅰ盐酸黄连素原料药与饲料混合物,处理组Ⅱ饲喂盐酸小檗碱包被颗粒与饲料混合物。连喂3d,研究包被颗粒的适口性。结果表明,与对照组相比,当盐酸小檗碱添加量为0.5g/kg时,处理组Ⅰ的猪采食量降低了28.74%,而处理组Ⅱ的猪采食量仅降低1.15%;当盐酸小檗碱添加量为1.0g/kg时,处理组Ⅰ的猪采食量降低了42.53%,而处理组Ⅱ的猪采食量降低了12.64%。试验结果表明,包被后有效的掩盖了盐酸小檗碱的苦味,提高了其口服的顺应性。
Berberine hydrochloride is a traditional antibiotics.It is restricted in their application in pig production because of its bitter taste.Objective of this study is to prepare berberine hydrochloride coated particles.The particles was prepared by the Fluidized Bed Spray using polyacrylic resin IV as coating material,and its standard for quality control was establish.Finally,the MIC of Berberine hydrochloride on common pathogens and the palatability of the particles were studied.
1.Study on the effect of different adhesive,different material ratio and different coating gain on the appearance,hardness,particle size and dissolution of particles.The experimental results were that:best prescription was 5% polyvinylpyrrolidone as adhesive,microcrystalline cellulose(MCC) do excipients,starch do diluent,the rate of berberine hydrochloride:MCC:starch was 1:0.75:3.25.
2.Study on the effect of atomization pressure,spouting velocity,inlet air temperature,air output and inlet wind humidity on the quality of coated particles,optimal process parameters.The experimental results were that: operating parameters of Fluidized Bed Spray were that throwing pill speed and air volume were:14.5 r/min and 27.5 m~3/h;coating liquid,cited wind frequency, rotating frequency,temperature and atomization pressure were 10 mL/min,20 HZ,4 HZ,55℃and 0.15 Mpa.The preparation process of the coated particles was simple,even particle size and easy for industrialization.It has a good application prospect.
3.The standard for quality control was established by studying on the appearance,drug content,drug dissolution of the particles.The results showed that:Coated particles were yellow colour,strong hardness,good appearance and fluidity.Encapsulation efficiency was 90%-95%.At 37℃,coated particles were quickly released in pH2.0 solution with a total dissolution more than 80% in one hour,but they were sparely soluble in water.More than 80%particle size was in the range of 150-42 urn.
4.According to the antibiotic susceptibility test in NCCLS,the mimimum inhibitory concentrations(MIC) of berberine hydrochloride on several strains were detected by micro-dilution.The experimental results were that:MIC of berberine hydrochloride on escherichia coli ranged in 512-1024μg/mL,MIC of berberine hydrochloride on salmonella ranged in 512-1024μg/mL; staphylococcus and pasteurellosis bacillus were more sensitive to berberine hydrochloride.MIC of berberine hydrochloride on staphylococcus, pasteurellosis bacillus and streptococcus were 256μg/mL,256μg/mL and 512μgmL respectively.
5.HPLC determination of berberine hydrochloride in swine plasma had been developed.Average recoveries,recovery,detection limit and calibration curve were studied.The results showed that:this method is easy operation,and has well stability,high sensitivity and recovery,short detection time.The minimum detectable concentration of this method was 0.5μg/L.It can be used in pharmacokinetic research of berberine hydrochloride.
6.Three health piglets were used in this test,were divided into 3 groups. The control group fed basic diet,groupⅠfed mixture of diet and berberine hydrochloride raw,groupⅡfed mixture of diet and berberine hydrochloride coated particles respectively,feeding 3 days.The palatability of the particles was investigated by this feeding trial.The results showed that:compared with the control group,when addition of berberine hydrochloride was 0.5 g/kg,intake of groupⅠdecreased 28.74%,while groupⅡdecreased 1.15%;when addition of berberine hydrochloride was 1.0 g/kg,intake of groupⅠdecreased 42.53%,while intake of groupⅡparticles decreased 12.64%.Coating technique cover up the bitterness in berberine hydrochloride efficiently which improved the compliance of oral administration.
1.研究了不同粘合剂、不同物料配比和不同的包衣增重对颗粒的外观、硬度、粒径和药物溶出情况的影响,确定了盐酸小檗碱包被颗粒的处方。试验结果为,包被最佳处方为:5%聚乙烯吡咯烷酮(PVP)为粘合剂,微晶纤维素(MCC)为赋型剂,淀粉为稀释剂,物料配比黄连素:MCC:淀粉比例为1:0.75:3.25。
2.通过对雾化压力、喷液速度、进风温度、进风量和进风湿度等对包被颗粒质量的影响研究,确定最佳工艺参数。试验结果为,适宜抛丸参数:转速14.5r/min,风量27.5m~3/h;包衣参数:流量10mL/min,引风频率20HZ,旋转频率4HZ,温度55℃,雾化压力0.15Mpa。采用本方法制备盐酸小檗碱包被颗粒,制备工艺简单,粒径均匀,易于工业化生产,具有良好的产业化应用前景。
3.通过对盐酸小檗碱包被颗粒的外观、药物含量、体外药物溶出等的研究,拟定了盐酸小檗碱包被颗粒质量标准。结果表明,颗粒呈黄色,圆整度好、硬度适宜,有较好的流动性。包封率应为90%～95%。包被颗粒在37℃下,pH=2.0溶出介质中1h内溶出度超过80%,但在水中1h内几乎没有药物溶出。包被颗粒的粒径在150～425μm内的不低于80%。
4.参照NCCLS(美国临床实验室标准化委员会)抗生素药敏试验中的微量稀释法测定盐酸小檗碱对几种菌株的最小抑菌浓度(MIC)。试验结果为,盐酸小檗碱对大肠杆菌MIC范围为512～1024μg/mL,对沙门氏菌MIC范围为512～1024μg/mL;对金葡菌MIC为256μg/mL;对巴氏杆菌MIC为256μg/mL;对链球菌MIC为512μg/mL。
5.建立了猪血浆中盐酸小檗碱的高效液相检测方法,并进行了精密度、回收率、最低检出限及定量标准曲线等项研究。结果表明,本方法操作简便,稳定性好、灵敏度高、样品回收率高,样品检测时间短,最低检测浓度为0.5μg/L,可用于盐酸小檗碱的药动学研究。
6.选用健康仔猪3头,分为3组。对照组饲喂基础日粮,处理组Ⅰ盐酸黄连素原料药与饲料混合物,处理组Ⅱ饲喂盐酸小檗碱包被颗粒与饲料混合物。连喂3d,研究包被颗粒的适口性。结果表明,与对照组相比,当盐酸小檗碱添加量为0.5g/kg时,处理组Ⅰ的猪采食量降低了28.74%,而处理组Ⅱ的猪采食量仅降低1.15%;当盐酸小檗碱添加量为1.0g/kg时,处理组Ⅰ的猪采食量降低了42.53%,而处理组Ⅱ的猪采食量降低了12.64%。试验结果表明,包被后有效的掩盖了盐酸小檗碱的苦味,提高了其口服的顺应性。
Berberine hydrochloride is a traditional antibiotics.It is restricted in their application in pig production because of its bitter taste.Objective of this study is to prepare berberine hydrochloride coated particles.The particles was prepared by the Fluidized Bed Spray using polyacrylic resin IV as coating material,and its standard for quality control was establish.Finally,the MIC of Berberine hydrochloride on common pathogens and the palatability of the particles were studied.
1.Study on the effect of different adhesive,different material ratio and different coating gain on the appearance,hardness,particle size and dissolution of particles.The experimental results were that:best prescription was 5% polyvinylpyrrolidone as adhesive,microcrystalline cellulose(MCC) do excipients,starch do diluent,the rate of berberine hydrochloride:MCC:starch was 1:0.75:3.25.
2.Study on the effect of atomization pressure,spouting velocity,inlet air temperature,air output and inlet wind humidity on the quality of coated particles,optimal process parameters.The experimental results were that: operating parameters of Fluidized Bed Spray were that throwing pill speed and air volume were:14.5 r/min and 27.5 m~3/h;coating liquid,cited wind frequency, rotating frequency,temperature and atomization pressure were 10 mL/min,20 HZ,4 HZ,55℃and 0.15 Mpa.The preparation process of the coated particles was simple,even particle size and easy for industrialization.It has a good application prospect.
3.The standard for quality control was established by studying on the appearance,drug content,drug dissolution of the particles.The results showed that:Coated particles were yellow colour,strong hardness,good appearance and fluidity.Encapsulation efficiency was 90%-95%.At 37℃,coated particles were quickly released in pH2.0 solution with a total dissolution more than 80% in one hour,but they were sparely soluble in water.More than 80%particle size was in the range of 150-42 urn.
4.According to the antibiotic susceptibility test in NCCLS,the mimimum inhibitory concentrations(MIC) of berberine hydrochloride on several strains were detected by micro-dilution.The experimental results were that:MIC of berberine hydrochloride on escherichia coli ranged in 512-1024μg/mL,MIC of berberine hydrochloride on salmonella ranged in 512-1024μg/mL; staphylococcus and pasteurellosis bacillus were more sensitive to berberine hydrochloride.MIC of berberine hydrochloride on staphylococcus, pasteurellosis bacillus and streptococcus were 256μg/mL,256μg/mL and 512μgmL respectively.
5.HPLC determination of berberine hydrochloride in swine plasma had been developed.Average recoveries,recovery,detection limit and calibration curve were studied.The results showed that:this method is easy operation,and has well stability,high sensitivity and recovery,short detection time.The minimum detectable concentration of this method was 0.5μg/L.It can be used in pharmacokinetic research of berberine hydrochloride.
6.Three health piglets were used in this test,were divided into 3 groups. The control group fed basic diet,groupⅠfed mixture of diet and berberine hydrochloride raw,groupⅡfed mixture of diet and berberine hydrochloride coated particles respectively,feeding 3 days.The palatability of the particles was investigated by this feeding trial.The results showed that:compared with the control group,when addition of berberine hydrochloride was 0.5 g/kg,intake of groupⅠdecreased 28.74%,while groupⅡdecreased 1.15%;when addition of berberine hydrochloride was 1.0 g/kg,intake of groupⅠdecreased 42.53%,while intake of groupⅡparticles decreased 12.64%.Coating technique cover up the bitterness in berberine hydrochloride efficiently which improved the compliance of oral administration.
引文
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