Résumé
Objective:To establish an HPLC method for the content determination of cinacalcet hydrochloride and evaluate the un-certainty in the measurement. Methods:An Inertsil ODS-SP chromatographic column(250 mm×4.6 mm,5 μm) was used,the mo-bile phase was composed of phosphate buffer solution(pH 6.5) and acetonitrile(60: 40),the flow rate was 1.0 ml·min-1,the de-tection wavelength was 272 nm,the column temperature was 30℃ and the injection volume was 20 μl. The content calculation formula-tion was deduced,the influencing factors were determined,and each component was assessed. Results:The resolution between cina-calcet and the impurity was satisfied,the linear relationship within the range of 10-100 μg?ml-1was excellent(r=0.999 9),the av-erage recovery was 101.09% (RSD=0.54%,n=9),and the LOQ was 0.254 μg?ml-1. The expanded uncertainty was 1.22%, and the result of the content determination was(100.74 ± 1.22)% (k=2). Conclusion:The method is simple,fast,selective,ac-curate and reliable,and can provide reference for the development of quality standards for generic drugs. Based on the influencing fac-tors of uncertainty,the main influencing reasons for the determination results can be found out to improve the reliability of determina-tion.
Résumé
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 [pH 1.2 hydrochloric acid solution,pH 2.0 hydrochloric acid solution,pH 4.5 acetate buffer solution,pH 6.8 phosphate buffer solution,water,artificial gastric fluid(SGF),full belly artificial intestinal fluid(FeSSIF),fasting artificial intestinal fluid(FaSSIF)],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)and 0.5,1,2,3,4,6,8,12,24 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 cmax between 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 FeSSIF was highest (0.977 9),manifesting good IVIVC (class A). CONCLUSIONS:The in vitro dissolution behavior of Cinacalcet hydrochloride tablets in FeSSIF(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.
Résumé
@#To develop an LC-MS method for the separation and identification of the related substances in cinacalcet hydrochloride. The separation was carried out on a Thermo BDS Hypersil C18 column(100 mm×4. 6 mm, 2. 4 μm)with mobile phase consisting of 0. 1% ammonium acetate buffer-acetonitrile(93∶7)(A)and acetonitrile(B)by gradient elution. The related substances were identified by electrospray positive ionization high resolution TOF/MS and MS/MS, and verified further through reference substances. Cinacalcet hydrochloride and itsrelated substances were separated under the established LC-MS condition. Ten related substances were detected and identified to be one starting material, one intermediate, four synthetic by-products and five degradation products. It showed that the LC-MS method was useful for separating and identifying the related substances in cinacalcet hydrochloride. And the results obtained are valuable for cinacalcet hydrochloride manufacturing process control and quality assurance.
Résumé
@#In the present study, amorphous cinacalcet hydrochloride was prepared by three different approaches including rotary evaporation, quench-cooling and lyophilization. Physicochemical properties of prepared amorphous cinacalcet hydrochloride such as thermal behavior, dissolution and stability were investigated. Results showed that there was no difference in dissolution and chemical stability for amorphous cinacalcet hydrochloride prepared by these three different methods; however, these amorphous materials exhibited significant difference in thermodynamic behavior and physical stability: (1)They had similar Tg but with significant difference in Tc(135. 2, 129. 6 and 153. 9 °C for the amorphous products prepared by rotary evaporation, lyophilization and quench-cooling, respectively); (2)These amorphous products were easy to recrystallize under an environment with high temperature and humidity, especially that prepared by quench-cooling. This study provides an experimental basis for screening preparation methods of amorphous materials.
Résumé
Secondary hyperparathyroidism is common in patients with chronic kidney disease (CKD). Currently, cinacalcet has evidently improved the management of secondary hyperparathyroidism in patients on hemodialysis. Though, to the best of our knowledge, there are no studies addressing the dose regimen of cinacalcet in CKD stage II to IV. Hence we decided to study and evaluate the efficacy of cinacalcet in the treatment of secondary hyperparathyroidism in two different dose schedules. A total of 174 patients (M: 138, F: 36), ages ranging from 23 to 87 years with CKD stage II –IV not on dialysis and intact PTH (iPTH) >150 pg/dl were enrolled in this study. The study population was divided into two groups. Group I: daily 30 mg cinacalcet hydrochloride and Group II: weekly twice 30 mg cinacalcet hydrochloride. Both groups received cinacalcet hydrochloride 30 mg with the main meal. In group I, 42 patients (48 %) stopped the drug within one month due to various side effects. During the follow up, the levels of iPTH decreased significantly in both the groups within a period of four weeks & persisted till the end of the study. No significant side effects requiring stoppage of the drug were noted in the group II study population. In conclusion, cinacalcet hydrochloride 30 mg twice weekly is a safe regimen in suppressing high PTH levels in CKD patients.