盐酸西那卡塞片的体内外相关性研究
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摘要
目的:考察盐酸西那卡塞片的体外溶出行为和体内药动学过程,并进行体内外相关性(IVIVC)评价。方法:采用高效液相色谱法(HPLC),测定盐酸西那卡塞片在8种溶出介质[p H 1.2盐酸溶液、p H 2.0盐酸溶液、p H 4.5醋酸盐缓冲液、p H 6.8磷酸盐缓冲液、水、人工胃液(SGF)、饱腹人工肠液(Fe SSIF)、空腹人工肠液(Fa SSIF)]中的累积溶出度(Q),并绘制溶出曲线。采用HPLC-质谱联用法测定盐酸西那卡塞片的血药浓度;选择12名健康男性受试者,在空腹或饱腹(高脂食物)状态下单剂量口服盐酸西那卡塞片75 mg,测定给药前(0 h)与给药后0.5、1、2、3、4、6、8、12、24 h时的血药浓度,并绘制平均血药浓度-时间曲线。采用DAS3.0软件计算饱腹组受试者体内累积吸收百分数(F),并与该制剂相应时间点的体外Q值作线性回归,进行IVIVC评价。结果:盐酸西那卡塞片在8种溶出介质中的溶出曲线存在较大差异;空腹组和饱腹组受试者的AUC_(0→t)、AUC_(0→∞)和c_(max)组间比较,差异均有统计学意义(P<0.05),表明高脂食物对该制剂的体内药动学过程有明显影响;该制剂在饱腹组受试者体内的F值与其体外在Fe SSIF中的Q值的相关系数最高(0.977 9),表明存在良好的IVIVC(A级)。结论:盐酸西那卡塞片在Fe SSIF中(桨法,50 r/min)的体外溶出行为与其体内药动学过程存在良好的相关性,可用于预测该制剂在体内的释放和吸收情况。
OBJECTIVE: To investigate the in vitro dissolution behavior and in vivo pharmacokinetics of Cinacalcet hydrochloride tablets, and to evaluate its in vivo-in vitro correlation(IVIVC). METHODS: HPLC method was adopted to determine the accumulative dissolution(Q) of Cinacalcet hydrochloride tablets in 8 kinds of medium [p H 1.2 hydrochloric acid solution,p H 2.0 hydrochloric acid solution,p H 4.5 acetate buffer solution,p H 6.8 phosphate buffer solution,water,artificial gastric fluid(SGF),full belly artificial intestinal fluid(Fe SSIF),fasting artificial intestinal fluid(Fa SSIF)],and the dissolution curves were drawn. HPLC-MS method was used to determine the blood concentrations of Cinacalcet hydrochloride tablets. A total of 12 healthy male volunteers were selected and given single oral dose of Cinacalcet hydrochloride tablets 75 mg under the state of fasting or satiety(high-fat food). The blood concentration of cinacalcet hydrochlorid was determined before medication(0 h)and0.5,1,2,3,4,6,8,12,24 h after medication. Average blood concentration-time curves were drawn. The in vivo accumulative absorption percentage(F)of satiety group was calculated by using DAS 3.0 software. Linear regression of F with in vitro Q was carried out to analyze its IVIVC. RESULTS:There was great difference among dissolution curves of Cinacalcet hydrochloride tablets in 8 kinds of dissolution mediums. There were differences of AUC0→t,AUC0→∞and cmaxbetween fasting group and satiety group,with statistical significance(P<0.05),showing high-fat food had significant effect on in vivo pharmacokinetics. Correlation coefficient of in vivo F in satiety group with in vitro Q of the tablets in Fe SSIF was highest(0.977 9),manifesting good IVIVC(class A).CONCLUSIONS:The in vitro dissolution behavior of Cinacalcet hydrochloride tablets in Fe SSIF(paddle method,50 r/min)is well associated with its in vivo pharmacokinetics,which can be used for predicting in vivo dissolution and absorption of the tablets.
OBJECTIVE: To investigate the in vitro dissolution behavior and in vivo pharmacokinetics of Cinacalcet hydrochloride tablets, and to evaluate its in vivo-in vitro correlation(IVIVC). METHODS: HPLC method was adopted to determine the accumulative dissolution(Q) of Cinacalcet hydrochloride tablets in 8 kinds of medium [p H 1.2 hydrochloric acid solution,p H 2.0 hydrochloric acid solution,p H 4.5 acetate buffer solution,p H 6.8 phosphate buffer solution,water,artificial gastric fluid(SGF),full belly artificial intestinal fluid(Fe SSIF),fasting artificial intestinal fluid(Fa SSIF)],and the dissolution curves were drawn. HPLC-MS method was used to determine the blood concentrations of Cinacalcet hydrochloride tablets. A total of 12 healthy male volunteers were selected and given single oral dose of Cinacalcet hydrochloride tablets 75 mg under the state of fasting or satiety(high-fat food). The blood concentration of cinacalcet hydrochlorid was determined before medication(0 h)and0.5,1,2,3,4,6,8,12,24 h after medication. Average blood concentration-time curves were drawn. The in vivo accumulative absorption percentage(F)of satiety group was calculated by using DAS 3.0 software. Linear regression of F with in vitro Q was carried out to analyze its IVIVC. RESULTS:There was great difference among dissolution curves of Cinacalcet hydrochloride tablets in 8 kinds of dissolution mediums. There were differences of AUC0→t,AUC0→∞and cmaxbetween fasting group and satiety group,with statistical significance(P<0.05),showing high-fat food had significant effect on in vivo pharmacokinetics. Correlation coefficient of in vivo F in satiety group with in vitro Q of the tablets in Fe SSIF was highest(0.977 9),manifesting good IVIVC(class A).CONCLUSIONS:The in vitro dissolution behavior of Cinacalcet hydrochloride tablets in Fe SSIF(paddle method,50 r/min)is well associated with its in vivo pharmacokinetics,which can be used for predicting in vivo dissolution and absorption of the tablets.
引文
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[10]WANI TA,KHALIL YN,DARWISH I,et al.Highly sensitive and simple validated ultra-performance liquid chromatography/tandem mass spectrometry method for the determination of cinacalcet in human plasma[J].Curr Pharm Anal,2014,10(1):51-57.
[11]ROTHE H,LIANGOS O,PETERMANN A,et al.Calcimimetic drugs and biomarkers[J].Recent Pat Biomarkers,2014,4(1):53-59.
[2]刁宗礼,郭维康,刘莎,等.继发性甲状旁腺功能亢进的药物治疗进展[J].中国全科医学,2015,18(26):3245-3247.
[3]NEVILLE D,JENKINS S,MANSER D.Nanoparticulate cinacalcet compositions:US 9012511[P].2015-04-21.
[4]胡钟芳,宋敏,杭太俊.色谱-质谱联用技术研究盐酸西那卡塞的有关物质[J].中国药科大学学报,2016,47(6):719-726.
[5]王闪闪,樊伟明,陈娟,等.制备方法对无定形盐酸西那卡塞的影响[J].中国药科大学学报,2016,47(3):317-323.
[6]李林羚,胡雪峰,杨玉雷,等.盐酸西那卡塞的工艺研究[J].中国新药杂志,2013,22(7):834-836.
[7]SILVERBERG SJ,CLARKE BL,PEACOCK M,et al.Current issues in the presentation of asymptomatic primary hyperparathyroidism:proceedings of the fourth international workshop[J].J Clin Endocrinol Metab,2014,99(10):3580-3594.
[8]杨文涛,杨磊,姜伟化,等.盐酸西那卡塞固体分散体片的制备及溶出度评价[J].中国药剂学杂志:网络版,2014(2):53-61.
[9]刘为中,李乐乐,李志云.盐酸西那卡塞片的体外溶出一致性[J].中国医药工业杂志,2016,47(8):1047-1051.
[10]WANI TA,KHALIL YN,DARWISH I,et al.Highly sensitive and simple validated ultra-performance liquid chromatography/tandem mass spectrometry method for the determination of cinacalcet in human plasma[J].Curr Pharm Anal,2014,10(1):51-57.
[11]ROTHE H,LIANGOS O,PETERMANN A,et al.Calcimimetic drugs and biomarkers[J].Recent Pat Biomarkers,2014,4(1):53-59.