盐酸帕罗西汀控释微丸的研究
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摘要
帕罗西汀(paroxetine),是一种高效的选择性5-HT再摄取抑制剂(SSRIs),临床常用的抗抑郁药之一。盐酸帕罗西汀普通片的胃肠道副反应发生率较高(25%),其原因与普通片剂在胃部和小肠上段局部浓度较高有关。为减小胃肠道副反应的发生率,增强用药安全性和患者服药的依从性,本文进行了盐酸帕罗西汀肠溶控释微丸的研究。
根据盐酸帕罗西汀的性质特点,本文首先建立了合理方便的分析方法,并测定其在不同释放介质中溶解度。在盐酸帕罗西汀微丸的初步研究中,本文考察了微丸的包衣工艺和处方因素的作用。采用了底喷流化床包衣法制备载药微丸并对其进行薄膜包衣,考察了投药量、风机风量、物料温度、雾化压力和供液速度等工艺条件,确定了最佳制备工艺。制得微丸载药率均一,粒度均匀、外观光滑圆整,批间重复性好。从Eudragit RS100、RL100和Ethocel(EC)三种渗透型薄膜衣材料中筛选出自身渗透性最低的EC作为控释膜材,进一步考察其浓度、包衣增重、致孔剂种类和用量等处方因素对微丸释放的影响,并对其释药机理进行了初步讨论。单因素考察结果表明,包衣液中聚合物的浓度、包覆量、加入致孔剂的种类和用量均会对影响药物的释放速率。相同的包覆量下,微丸释药速率在一定范围内随EC浓度的增加而减慢。将2%EC确定为包衣液浓度继续试验,随着包衣增重的增大,控释膜的厚度增加,显著减慢微丸的释药速率,随着包衣增重的增加,零级动力学方程的拟合度越高;增重6%及以上的微丸即能按照零级速率释药。致孔剂的溶解性能及用量不同,药物的释放曲线不同,溶解度高的Pore formerⅠ作为致孔剂时比Pore formerⅡ释药快,致孔剂用量的增加则增大控释膜的孔隙率,加快药物释放.微丸释药行为受到致孔剂用量和包衣增重的控制,且合适的致孔剂用量和包衣增重可使药物在预定的时间内均匀恒定地释放,达到理想的释药曲线。
利用人工神经网络预测盐酸帕罗西汀控释微丸的释放,以致孔剂Pore formerⅠ的用量和包衣增重为输入变量,不同时刻微丸的累积释放量为输出,采用线性回归法和相似因子、AIC值比较对神经网络的预测能力进行评价,其拟合精度好,预测准确性高,从而为盐酸帕罗西汀控释微丸的处方优化提供了可行的依据。建立人工神经网络预测并对处方进行优化,以微丸不同时刻的累积释放量为输入变量,致孔剂PoreformerⅡ用量和包衣增重作为输出,训练网络,以达到12h零级释放为目标作处方优化并验证。优化得到的处方释放情况和目标基本一致,所建立的人工神经网络模型能够实现多变量多目标同步优化。
为将控释微丸制成肠溶制剂,本文筛选了Enteric polymerⅠ和Enteric polymerⅡ等肠溶材料,最后确定以Enteric polymerⅡ对优化得到的控释微丸包衣,并填充于明胶胶囊壳内,得到盐酸帕罗西汀肠溶控释胶囊,进行了体外释放和质量标准研究。影响因素试验显示该胶囊对高温、高湿较为敏感,需置阴凉干燥处保存;加速试验2个月,其物理性状、含量、有关物质及释放度均无明显变化,产品质量稳定。
由于以前采用的方法包衣工艺较为繁琐,且包衣过程中影响因素较多,因此本文将Enteric polymerⅡ作为pH敏感的致孔剂加入渗透性膜材EC包衣液中,简化肠溶控释微丸的制备工艺。利用星点设计—效应面法对Enteric polymerⅡ用量、包衣增重和Cremophor EL用量三个因素进行优化,选取三因素五水平安排实验,以0.1M HC1中释放量和缓释的综合评分值作为响应值,并对该设计的模型方程绘制效应面图,利用等高线图的叠加获得优化处方。通过实验的进一步验证,最终确定处方为:EntericpolymerⅡ用量X_1=2.59g,包衣增重X_2=6.40%,Cremophor EL用量X_3=0.18g。经验证该处方的释放能很好符合释放标准,有效地简化了肠溶控释微丸的处方和制备工艺,提高了生产效率。
Paroxetine is an antidepressant agent with a structure totally unrelated to other antidepressant agent such as serotonin reuptake inhibitors or tricyclic or tetracyclic agents. Its action is believed to be linked to the inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamin,5-HT)in the central nervous system(CNS).Commercial tablets of paroxetine has a serious gastroenteric side-effect,which is caused by the locally high concentration in stomach and duodenum.The purpose of the present study was to develop a kind of paroxetine enteric controlled release pellets,which would avoid the gastroenteric side-effect,and which enhance applying safety and the convenience for patients to use.
In the preformulation study,HPLC method and UV method for assay was developed. UV method was utilized to determine the paroxetine content and release of controlled release pellets,HPLC method for enteric capsules.The solubilities of paroxetine in three different kinds of dissolution media were determined.Paroxetine pellets were prepared by a fluid bed spray processor,and the coating process variables were determined and controlled. A suitable pH-independent sustained release pellets system was produced by coating with Ethocel and Pore formerⅠ/Ⅱ.In this research,filtration of a series of EC concentration, Pore formerⅠ/Ⅱand coating level were studied.The diffusion rate of paroxetine during release depends on the permeabilityof the coating and its thickness.The content of pore former had a positive effect on drug release rate,while coating level decreased the released amount.The description of dissolution profiles suggested that the release profiles follow the zero-order equation more fitly as the coating level increased.
This study used an artificial neural network(ANN)to predict drug release from controlled release pellets of paroxetine hydrochloride.The amount of Pore formerⅠand coating level were selected as casual factors,and the accumulative drug release in each sampling time was used as response variables.A set of release parameters and causal factors were used as tutorial data.The predictive ability of the ANN was assessed by comparing the linear regression equations,similarity factors and AIC values of predicted against observed property values.The results showed a fairly good agreement between the observed values of release parameters and the ANN predicted values.Therefore,ANN provides a feasible way of optimizing and estimating drug release from controlled release pellets of paroxetine hydrochloride.The content of Pore formerⅡand coating level were selected as response variable,the accumulative drug release in each sampling time as casual factors,and zero order release for 12 hours as optimized object.The optimal formulation gave satisfactory release profile,since the observed result coincided well with the optimized object.
This study filtrated Enteric polymerⅠandⅡfor enteric coating,and finally selected Enteric polymerⅡto be coated to the pellets optimized by ANN.The enteric controlled release pellets were filled in gelatin hard capsules to carry out in vitro release and quality standard study.Forced degradation studies were performed to provide an indication of the stability-indicating properties and specificity of the procedure.The observed degradations were resolved from the paroxetine peak.The result of stability study showed that the capsules were unstable to hot and moist,stable to light.Pellets should be kept in cool and dry condition.The content and physical character of capsules had no marked change,which placed under 40℃,75%±5%RH for two months.
Since the former preparation method wascomplicated,a new kind of enteric controlled release pellets were developed,in which Enteric polymerⅡwere added to EC coating formulation as a pore former.To optimize the formulation of the EC/ Enteric polymerⅡpellets by a central composite design/response surface methodology. Independent variables were Enteric polymerⅡcontent,coating level and Cremophor EL content,release amount in acid dissolution media and sustained release grade were dependent variables.Response surfaces were delineated according to best-fit mathematic models,and optimum formulation was selected.Optimum formulation was proposed to contain Enteric polymerⅡ2.59g,Cremophor EL 0.18g and 6.40%coating level.The optimum formulation reached the optimized object,accomplished the purpose of simplifying the preparation technics.
根据盐酸帕罗西汀的性质特点,本文首先建立了合理方便的分析方法,并测定其在不同释放介质中溶解度。在盐酸帕罗西汀微丸的初步研究中,本文考察了微丸的包衣工艺和处方因素的作用。采用了底喷流化床包衣法制备载药微丸并对其进行薄膜包衣,考察了投药量、风机风量、物料温度、雾化压力和供液速度等工艺条件,确定了最佳制备工艺。制得微丸载药率均一,粒度均匀、外观光滑圆整,批间重复性好。从Eudragit RS100、RL100和Ethocel(EC)三种渗透型薄膜衣材料中筛选出自身渗透性最低的EC作为控释膜材,进一步考察其浓度、包衣增重、致孔剂种类和用量等处方因素对微丸释放的影响,并对其释药机理进行了初步讨论。单因素考察结果表明,包衣液中聚合物的浓度、包覆量、加入致孔剂的种类和用量均会对影响药物的释放速率。相同的包覆量下,微丸释药速率在一定范围内随EC浓度的增加而减慢。将2%EC确定为包衣液浓度继续试验,随着包衣增重的增大,控释膜的厚度增加,显著减慢微丸的释药速率,随着包衣增重的增加,零级动力学方程的拟合度越高;增重6%及以上的微丸即能按照零级速率释药。致孔剂的溶解性能及用量不同,药物的释放曲线不同,溶解度高的Pore formerⅠ作为致孔剂时比Pore formerⅡ释药快,致孔剂用量的增加则增大控释膜的孔隙率,加快药物释放.微丸释药行为受到致孔剂用量和包衣增重的控制,且合适的致孔剂用量和包衣增重可使药物在预定的时间内均匀恒定地释放,达到理想的释药曲线。
利用人工神经网络预测盐酸帕罗西汀控释微丸的释放,以致孔剂Pore formerⅠ的用量和包衣增重为输入变量,不同时刻微丸的累积释放量为输出,采用线性回归法和相似因子、AIC值比较对神经网络的预测能力进行评价,其拟合精度好,预测准确性高,从而为盐酸帕罗西汀控释微丸的处方优化提供了可行的依据。建立人工神经网络预测并对处方进行优化,以微丸不同时刻的累积释放量为输入变量,致孔剂PoreformerⅡ用量和包衣增重作为输出,训练网络,以达到12h零级释放为目标作处方优化并验证。优化得到的处方释放情况和目标基本一致,所建立的人工神经网络模型能够实现多变量多目标同步优化。
为将控释微丸制成肠溶制剂,本文筛选了Enteric polymerⅠ和Enteric polymerⅡ等肠溶材料,最后确定以Enteric polymerⅡ对优化得到的控释微丸包衣,并填充于明胶胶囊壳内,得到盐酸帕罗西汀肠溶控释胶囊,进行了体外释放和质量标准研究。影响因素试验显示该胶囊对高温、高湿较为敏感,需置阴凉干燥处保存;加速试验2个月,其物理性状、含量、有关物质及释放度均无明显变化,产品质量稳定。
由于以前采用的方法包衣工艺较为繁琐,且包衣过程中影响因素较多,因此本文将Enteric polymerⅡ作为pH敏感的致孔剂加入渗透性膜材EC包衣液中,简化肠溶控释微丸的制备工艺。利用星点设计—效应面法对Enteric polymerⅡ用量、包衣增重和Cremophor EL用量三个因素进行优化,选取三因素五水平安排实验,以0.1M HC1中释放量和缓释的综合评分值作为响应值,并对该设计的模型方程绘制效应面图,利用等高线图的叠加获得优化处方。通过实验的进一步验证,最终确定处方为:EntericpolymerⅡ用量X_1=2.59g,包衣增重X_2=6.40%,Cremophor EL用量X_3=0.18g。经验证该处方的释放能很好符合释放标准,有效地简化了肠溶控释微丸的处方和制备工艺,提高了生产效率。
Paroxetine is an antidepressant agent with a structure totally unrelated to other antidepressant agent such as serotonin reuptake inhibitors or tricyclic or tetracyclic agents. Its action is believed to be linked to the inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamin,5-HT)in the central nervous system(CNS).Commercial tablets of paroxetine has a serious gastroenteric side-effect,which is caused by the locally high concentration in stomach and duodenum.The purpose of the present study was to develop a kind of paroxetine enteric controlled release pellets,which would avoid the gastroenteric side-effect,and which enhance applying safety and the convenience for patients to use.
In the preformulation study,HPLC method and UV method for assay was developed. UV method was utilized to determine the paroxetine content and release of controlled release pellets,HPLC method for enteric capsules.The solubilities of paroxetine in three different kinds of dissolution media were determined.Paroxetine pellets were prepared by a fluid bed spray processor,and the coating process variables were determined and controlled. A suitable pH-independent sustained release pellets system was produced by coating with Ethocel and Pore formerⅠ/Ⅱ.In this research,filtration of a series of EC concentration, Pore formerⅠ/Ⅱand coating level were studied.The diffusion rate of paroxetine during release depends on the permeabilityof the coating and its thickness.The content of pore former had a positive effect on drug release rate,while coating level decreased the released amount.The description of dissolution profiles suggested that the release profiles follow the zero-order equation more fitly as the coating level increased.
This study used an artificial neural network(ANN)to predict drug release from controlled release pellets of paroxetine hydrochloride.The amount of Pore formerⅠand coating level were selected as casual factors,and the accumulative drug release in each sampling time was used as response variables.A set of release parameters and causal factors were used as tutorial data.The predictive ability of the ANN was assessed by comparing the linear regression equations,similarity factors and AIC values of predicted against observed property values.The results showed a fairly good agreement between the observed values of release parameters and the ANN predicted values.Therefore,ANN provides a feasible way of optimizing and estimating drug release from controlled release pellets of paroxetine hydrochloride.The content of Pore formerⅡand coating level were selected as response variable,the accumulative drug release in each sampling time as casual factors,and zero order release for 12 hours as optimized object.The optimal formulation gave satisfactory release profile,since the observed result coincided well with the optimized object.
This study filtrated Enteric polymerⅠandⅡfor enteric coating,and finally selected Enteric polymerⅡto be coated to the pellets optimized by ANN.The enteric controlled release pellets were filled in gelatin hard capsules to carry out in vitro release and quality standard study.Forced degradation studies were performed to provide an indication of the stability-indicating properties and specificity of the procedure.The observed degradations were resolved from the paroxetine peak.The result of stability study showed that the capsules were unstable to hot and moist,stable to light.Pellets should be kept in cool and dry condition.The content and physical character of capsules had no marked change,which placed under 40℃,75%±5%RH for two months.
Since the former preparation method wascomplicated,a new kind of enteric controlled release pellets were developed,in which Enteric polymerⅡwere added to EC coating formulation as a pore former.To optimize the formulation of the EC/ Enteric polymerⅡpellets by a central composite design/response surface methodology. Independent variables were Enteric polymerⅡcontent,coating level and Cremophor EL content,release amount in acid dissolution media and sustained release grade were dependent variables.Response surfaces were delineated according to best-fit mathematic models,and optimum formulation was selected.Optimum formulation was proposed to contain Enteric polymerⅡ2.59g,Cremophor EL 0.18g and 6.40%coating level.The optimum formulation reached the optimized object,accomplished the purpose of simplifying the preparation technics.
引文
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