纳米碳酸钙肠溶生物黏附片的制备及其驱铅效果研究
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摘要
一、目的
基于阻断铅肠肝循环的原理研制新型驱铅药物,选择纳米碳酸钙为驱铅模型药物,将其制备成肠溶生物黏附片(NCaEBT),使其兼具小肠上端定位和生物黏附双重特点,建立NCaEBT的新型质量评价方法,通过在普通家犬体内的驱铅效果实验,评价其是否具有较好的驱铅效果。并通过NCaEBT、普通碳酸钙片(CCaDT)与醋酸钙肠溶生物黏附片(CaAEBT)三者之间的驱铅效果比较,初步探讨NCaEBT及CCaDT的驱铅作用机制,为临床铅中毒预防和治疗药物的开发与研究提供理论基础。
二、方法
1 NCaEBT的制备工艺研究
NCaEBT的制备分为片芯处方筛选和肠溶包衣工艺两个部分。片芯处方筛选采用生物黏附型和崩解型两种处方颗粒混合压片的方法,其中选择羟丙基甲基纤维素(HPMC)和卡波姆(CP)为生物黏附型辅料,微晶纤维素(MCC)和羧甲基淀粉钠(CMS-Na)为崩解型辅料制备NCaEBT片芯,在单因素实验考察的基础上,选择对片芯释放度影响较大的因素作为自变量,采用星点设计-效益面优化法,优化NCaEBT片芯的处方及制备工艺。肠溶包衣工艺研究中分别考察三种pH5.5肠溶敏感材料：Eudragit L100-55、Eudragit L 30D-55和羟丙基甲基纤维素邻苯二甲酸酯(HPMCP 5.5)对包衣效果的影响,确定肠溶衣材料；在此基础上,分别考察肠溶衣不同增重对NCaEBT在人工胃液和pH6.0醋酸缓冲液中状态和释放度的影响,确定包衣增重大小。
2 NCaEBT的质量评价研究
对优化工艺条件下制得的NCaEBT分别进行鉴别、检查、片重差异、含量测定、释放度和黏附力评价,其中采用紫外分光光度法来评价NCaEBT的释放度,采用酸碱滴定法来测定NCaEBT中纳米碳酸钙的含量,以黏附力测定装置测定NCaEBT的黏附力。
3 NCaEBT在普通家犬内的驱铅效果研究
选取普通家犬25条,随机分成5组,分别为：空白对照组,染铅对照组,CCaDT组,CaAEBT组和NCaEBT组,4个染铅组持续隔天染铅7次,造模成功后,分别给予各组药物,持续驱铅治疗30天,分别收集家犬给药前1天及给药第7,15,22,30天24h内的尿液和粪便及2mL静脉血样,比较各实验组在血铅、尿铅和粪铅水平的变化程度,初步阐述NCaEBT和CCaDT的驱铅作用机理。
三、结果
1 NCaEBT的制备工艺研究
NCaEBT的制备分为片芯处方筛选和肠溶包衣工艺两个部分。片芯处方筛选在单因素实验的基础上,选择HPMC和CP作为自变量,以星点设计-效益面优化法优化片芯处方,片芯处方优化采用多元线性方程拟合的相关系数优于多项式方程,优化处方中各辅料用量分别为：HPMC 20mg、CP25mg、MCC 25mg和2.5%的CMS-Na;肠溶包衣工艺研究时发现以Eudragit L100-55作为肠溶衣材料时制备的NCaEBT的效果优于Eudragit L30D-55和HPMCP 5.5的效果,故选择Eudragit L100-55作为肠溶衣材料,肠溶包衣增重大小对NCaEBT在人工胃液和醋酸缓冲液中的状态和释放度有影响,当包衣增重为10%时制备的NCaEBT的效果理想、符合要求,最终确定包衣增重为10%。
2 NCaEBT的质量评价研究
NCaEBT的质量评价结果发现：片剂色泽均匀、光洁、无杂斑；鉴别反应结果理想：片重差异符合中国药典规定；以酸碱滴定法测定NCaEBT中纳米碳酸钙含量的方法重现性好、精密度高,三批样品含量测定均符合要求；紫外分光光度法间接评价NCaEBT释放度的方法稳定、可控,三批样品的释放度均较为理想；黏附力测定装置测得的NCaEBT黏附力准确,黏附力测定结果均大于20g·cm-2。
3 NCaEBT在普通家犬内的驱铅效果研究
4个染铅组在各时间点的血铅水平比较发现：除NCaEBT稍有优势外,4个染铅组之间并无太大的差异；4个染铅组在各时间点的尿铅水平比较发现：CaAEBT组具有相对较强的优势,CCaDT组次之,NCaEBT组也具有一定的尿铅排泄能力；4个染铅组在各时间点的粪铅水平比较发现：NCaEBT组具有明显的优势,CCaDT组和CaAEBT组未具有显著的粪铅排泄能力。
四、结论
1本实验制备的NCaEBT通过体外质量评价初步证实其具有小肠上端定位和生物黏附双重性能。
2动物实验初步证实NCaEBT可以通过阻断铅的肠肝循环,增加铅从粪便的排泄量实现驱铅效果,而普通碳酸钙剂主要通过钙离子与铅在体内的竞争性拮抗,促进铅从尿液的排泄量而达到驱铅作用。
OBJECTIVE
We chose nanometer calcium carbonate as model drug used in treatment of lead intoxication, and developed it to a new dosage form: nanometer calcium carbonate enteric-coated bioadhesive tablets (NCaEBT), making sure that the new dosage form had the characteristic of both upper small intestine targeting and bioadhesion. At the same time, we established the new quality assessment, evaluated the removing lead effect of NCaEBT through the removing lead experiment in Dogs(Canis familiaris), moreover, through the comparison of removing lead effect among NCaEBT, CCaDT and CaAEBT, initially investigate the removing lead mechanisms of NCaEBT and CCaDT, which may provide the foundation for developing new drugs in treatment of lead intoxication.
METHODS
1 Preparation Technology of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
Preparation technology of NCaEBT included two parts:screening formulation of pellet and investigating the coating technology. The pellet of NCaEBT was prepared with two different granules, selecting HPMC and CP as bioadhesive material and selecting MCC and CMS-Na as disintegrating agent. Basing on the results from the single factor experiment, we chose the more influential factors as independent variable, to optimize the formulation of pellet of NCaEBT preparation by central composite design/response surface methodology. In the enteric coating technology, through the effect of three pH5.5 enteric coating materials: Eudragit L100-55, Eudragit L 30D-55 and HPMCP 5.5 on the technology of NCaEBT to determine the best enteric coating materials, and through the effect of coating level on the NCaEBT in simulated gastrointestinal tract environment to determine the best amount of coating materials.
2 Study on quality assessment of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
Assessing the quality of NCaEBT included sample identification, tablet weight variation, assaying, release property and bioadhesive force. The release property of NCaEBT was evaluated by ultraviolet spectrophotometry. The content of NCaEBT was determined by acid-base titration. The bioadhesive force of NCaEBT was evaluated by the bioadhesive equipment.
3 Study on the effect of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets on the removing lead in Dogs(Canis familiaris)
Twenty five dogs(Canis familiaris) were randomLy divided into five groups:blank control group, dying lead control group, CCaDT group, CaAEBT group and NCaEBT group. Dogs in four lead exposed groups were intraperitoneally injected the Pb2+ on alternate days of total 7 times. After cessation of lead exposure, the dogs were administrated the drugs for 30 days of treatment therapy. At 7st,15st,22st,30st day of the experiment during 24h total urine and feces of each 25 dogs were collected, at the same time,2mL of blood of each 25 dogs were obtained through femoral vein bleeding. Through comparing the blood lead, urinary lead and fecal lead levels of all groups to elucidate the removing lead mechanisms of NCaEBT and ordinary calcium tablets.
RESULTS
1 Preparation Technology of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
Preparation technology of NCaEBT included two parts:screening formulation of pellet and investigating the coating technology. Basing on the results from the single factor experiment, we chose HPMC and CP as independent variable. The results of central composite design/response surface methodology showed that regression coefficients of first order model was higher than second order and third order quadratic models, Optimized formulation of pellet of NCaEBT consisted of HPMC20mg,CP 25mg, MCC 25mg and 2.5% CMS-Na. In enteric coating technology, we found NCaEBT coated with the Eudragit L100-55 were better than Eudragit L 30D-55 and HPMCP 5.5, so we determined the Eudragit L100-55 as enteric coating materials, the coating level of Eudragit L100-55 was about 10%.
2 Study on quality assessment of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
The results of quality assessment were found that appearance of NCaEBT was uniformity and smooth, the identification reaction was reliable, and tablet weight variation met the Chinese pharmacopeia regulation. The determination method of nanometer calcium carbonate in NCaEBT by acid-base titration was reliable and precise. And the determination of sample contents in three batches met the standardization. The determination method of NCaEBT release property by ultraviolet spectrophotometry was stabile and accurate, the determination of sample release property in three batches was ideal. At the same time, the determination method of bioadhesive property of NCaEBT was also accurate, the results of the adhesive forces of NCaEBT was 24.9g·cm-2.
3 Study on the effect of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets on the removing lead in Dogs(Canis familiaris)
Blood lead levels in four groups after administrating showed that besides the NCaEBT group had the slight effect, there were no significant differences between four groups. Urinary lead levels in four groups after administrating showed that the CaAEBT group had great effect, CCaDT group was second, and the NCaEBT group also had slight effect compared to the control group. Fecal lead levels in four groups after administrating showed that besides the NCaEBT group had the notable and great effect on fecal lead excretion, CCaDT group and CaAEBT group had no significant effect compared to the control group.
CONCLUSION
1 NCaEBT prepared in our experiment was testified that it had the characteristic of both upper small intestine targeting and bioadhesion in vitro assessment.
2 NCaEBT had the removing lead effect through increasing the fecal lead excretive levels by interference with the enterohepatic circulation of praecipitatum displacement reaction, and ordinary calcium carbonate tablets had the removing lead effect mostly by increasing the urinary lead excretive levels.
基于阻断铅肠肝循环的原理研制新型驱铅药物,选择纳米碳酸钙为驱铅模型药物,将其制备成肠溶生物黏附片(NCaEBT),使其兼具小肠上端定位和生物黏附双重特点,建立NCaEBT的新型质量评价方法,通过在普通家犬体内的驱铅效果实验,评价其是否具有较好的驱铅效果。并通过NCaEBT、普通碳酸钙片(CCaDT)与醋酸钙肠溶生物黏附片(CaAEBT)三者之间的驱铅效果比较,初步探讨NCaEBT及CCaDT的驱铅作用机制,为临床铅中毒预防和治疗药物的开发与研究提供理论基础。
二、方法
1 NCaEBT的制备工艺研究
NCaEBT的制备分为片芯处方筛选和肠溶包衣工艺两个部分。片芯处方筛选采用生物黏附型和崩解型两种处方颗粒混合压片的方法,其中选择羟丙基甲基纤维素(HPMC)和卡波姆(CP)为生物黏附型辅料,微晶纤维素(MCC)和羧甲基淀粉钠(CMS-Na)为崩解型辅料制备NCaEBT片芯,在单因素实验考察的基础上,选择对片芯释放度影响较大的因素作为自变量,采用星点设计-效益面优化法,优化NCaEBT片芯的处方及制备工艺。肠溶包衣工艺研究中分别考察三种pH5.5肠溶敏感材料：Eudragit L100-55、Eudragit L 30D-55和羟丙基甲基纤维素邻苯二甲酸酯(HPMCP 5.5)对包衣效果的影响,确定肠溶衣材料；在此基础上,分别考察肠溶衣不同增重对NCaEBT在人工胃液和pH6.0醋酸缓冲液中状态和释放度的影响,确定包衣增重大小。
2 NCaEBT的质量评价研究
对优化工艺条件下制得的NCaEBT分别进行鉴别、检查、片重差异、含量测定、释放度和黏附力评价,其中采用紫外分光光度法来评价NCaEBT的释放度,采用酸碱滴定法来测定NCaEBT中纳米碳酸钙的含量,以黏附力测定装置测定NCaEBT的黏附力。
3 NCaEBT在普通家犬内的驱铅效果研究
选取普通家犬25条,随机分成5组,分别为：空白对照组,染铅对照组,CCaDT组,CaAEBT组和NCaEBT组,4个染铅组持续隔天染铅7次,造模成功后,分别给予各组药物,持续驱铅治疗30天,分别收集家犬给药前1天及给药第7,15,22,30天24h内的尿液和粪便及2mL静脉血样,比较各实验组在血铅、尿铅和粪铅水平的变化程度,初步阐述NCaEBT和CCaDT的驱铅作用机理。
三、结果
1 NCaEBT的制备工艺研究
NCaEBT的制备分为片芯处方筛选和肠溶包衣工艺两个部分。片芯处方筛选在单因素实验的基础上,选择HPMC和CP作为自变量,以星点设计-效益面优化法优化片芯处方,片芯处方优化采用多元线性方程拟合的相关系数优于多项式方程,优化处方中各辅料用量分别为：HPMC 20mg、CP25mg、MCC 25mg和2.5%的CMS-Na;肠溶包衣工艺研究时发现以Eudragit L100-55作为肠溶衣材料时制备的NCaEBT的效果优于Eudragit L30D-55和HPMCP 5.5的效果,故选择Eudragit L100-55作为肠溶衣材料,肠溶包衣增重大小对NCaEBT在人工胃液和醋酸缓冲液中的状态和释放度有影响,当包衣增重为10%时制备的NCaEBT的效果理想、符合要求,最终确定包衣增重为10%。
2 NCaEBT的质量评价研究
NCaEBT的质量评价结果发现：片剂色泽均匀、光洁、无杂斑；鉴别反应结果理想：片重差异符合中国药典规定；以酸碱滴定法测定NCaEBT中纳米碳酸钙含量的方法重现性好、精密度高,三批样品含量测定均符合要求；紫外分光光度法间接评价NCaEBT释放度的方法稳定、可控,三批样品的释放度均较为理想；黏附力测定装置测得的NCaEBT黏附力准确,黏附力测定结果均大于20g·cm-2。
3 NCaEBT在普通家犬内的驱铅效果研究
4个染铅组在各时间点的血铅水平比较发现：除NCaEBT稍有优势外,4个染铅组之间并无太大的差异；4个染铅组在各时间点的尿铅水平比较发现：CaAEBT组具有相对较强的优势,CCaDT组次之,NCaEBT组也具有一定的尿铅排泄能力；4个染铅组在各时间点的粪铅水平比较发现：NCaEBT组具有明显的优势,CCaDT组和CaAEBT组未具有显著的粪铅排泄能力。
四、结论
1本实验制备的NCaEBT通过体外质量评价初步证实其具有小肠上端定位和生物黏附双重性能。
2动物实验初步证实NCaEBT可以通过阻断铅的肠肝循环,增加铅从粪便的排泄量实现驱铅效果,而普通碳酸钙剂主要通过钙离子与铅在体内的竞争性拮抗,促进铅从尿液的排泄量而达到驱铅作用。
OBJECTIVE
We chose nanometer calcium carbonate as model drug used in treatment of lead intoxication, and developed it to a new dosage form: nanometer calcium carbonate enteric-coated bioadhesive tablets (NCaEBT), making sure that the new dosage form had the characteristic of both upper small intestine targeting and bioadhesion. At the same time, we established the new quality assessment, evaluated the removing lead effect of NCaEBT through the removing lead experiment in Dogs(Canis familiaris), moreover, through the comparison of removing lead effect among NCaEBT, CCaDT and CaAEBT, initially investigate the removing lead mechanisms of NCaEBT and CCaDT, which may provide the foundation for developing new drugs in treatment of lead intoxication.
METHODS
1 Preparation Technology of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
Preparation technology of NCaEBT included two parts:screening formulation of pellet and investigating the coating technology. The pellet of NCaEBT was prepared with two different granules, selecting HPMC and CP as bioadhesive material and selecting MCC and CMS-Na as disintegrating agent. Basing on the results from the single factor experiment, we chose the more influential factors as independent variable, to optimize the formulation of pellet of NCaEBT preparation by central composite design/response surface methodology. In the enteric coating technology, through the effect of three pH5.5 enteric coating materials: Eudragit L100-55, Eudragit L 30D-55 and HPMCP 5.5 on the technology of NCaEBT to determine the best enteric coating materials, and through the effect of coating level on the NCaEBT in simulated gastrointestinal tract environment to determine the best amount of coating materials.
2 Study on quality assessment of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
Assessing the quality of NCaEBT included sample identification, tablet weight variation, assaying, release property and bioadhesive force. The release property of NCaEBT was evaluated by ultraviolet spectrophotometry. The content of NCaEBT was determined by acid-base titration. The bioadhesive force of NCaEBT was evaluated by the bioadhesive equipment.
3 Study on the effect of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets on the removing lead in Dogs(Canis familiaris)
Twenty five dogs(Canis familiaris) were randomLy divided into five groups:blank control group, dying lead control group, CCaDT group, CaAEBT group and NCaEBT group. Dogs in four lead exposed groups were intraperitoneally injected the Pb2+ on alternate days of total 7 times. After cessation of lead exposure, the dogs were administrated the drugs for 30 days of treatment therapy. At 7st,15st,22st,30st day of the experiment during 24h total urine and feces of each 25 dogs were collected, at the same time,2mL of blood of each 25 dogs were obtained through femoral vein bleeding. Through comparing the blood lead, urinary lead and fecal lead levels of all groups to elucidate the removing lead mechanisms of NCaEBT and ordinary calcium tablets.
RESULTS
1 Preparation Technology of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
Preparation technology of NCaEBT included two parts:screening formulation of pellet and investigating the coating technology. Basing on the results from the single factor experiment, we chose HPMC and CP as independent variable. The results of central composite design/response surface methodology showed that regression coefficients of first order model was higher than second order and third order quadratic models, Optimized formulation of pellet of NCaEBT consisted of HPMC20mg,CP 25mg, MCC 25mg and 2.5% CMS-Na. In enteric coating technology, we found NCaEBT coated with the Eudragit L100-55 were better than Eudragit L 30D-55 and HPMCP 5.5, so we determined the Eudragit L100-55 as enteric coating materials, the coating level of Eudragit L100-55 was about 10%.
2 Study on quality assessment of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets
The results of quality assessment were found that appearance of NCaEBT was uniformity and smooth, the identification reaction was reliable, and tablet weight variation met the Chinese pharmacopeia regulation. The determination method of nanometer calcium carbonate in NCaEBT by acid-base titration was reliable and precise. And the determination of sample contents in three batches met the standardization. The determination method of NCaEBT release property by ultraviolet spectrophotometry was stabile and accurate, the determination of sample release property in three batches was ideal. At the same time, the determination method of bioadhesive property of NCaEBT was also accurate, the results of the adhesive forces of NCaEBT was 24.9g·cm-2.
3 Study on the effect of Nanometer Calcium Carbonate Enteric-coated Bioadhesive Tablets on the removing lead in Dogs(Canis familiaris)
Blood lead levels in four groups after administrating showed that besides the NCaEBT group had the slight effect, there were no significant differences between four groups. Urinary lead levels in four groups after administrating showed that the CaAEBT group had great effect, CCaDT group was second, and the NCaEBT group also had slight effect compared to the control group. Fecal lead levels in four groups after administrating showed that besides the NCaEBT group had the notable and great effect on fecal lead excretion, CCaDT group and CaAEBT group had no significant effect compared to the control group.
CONCLUSION
1 NCaEBT prepared in our experiment was testified that it had the characteristic of both upper small intestine targeting and bioadhesion in vitro assessment.
2 NCaEBT had the removing lead effect through increasing the fecal lead excretive levels by interference with the enterohepatic circulation of praecipitatum displacement reaction, and ordinary calcium carbonate tablets had the removing lead effect mostly by increasing the urinary lead excretive levels.
引文
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