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Capsule Formulations (capsule + formulations)
Selected AbstractsDetermination of glycyrrhetic acid in human plasma by HPLC-MS method and investigation of its pharmacokineticsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2008W.-J. Zhao PhD Summary Objective:, To develop a high performance liquid chromatography mass spectrometry (HPLC-MS) method for the determination of the glycyrrhetic acid (GA) in human plasma and for the investigation of its pharmacokinetics after the oral administration of 150 mg diammonium glycyrrhizinate test and reference capsule formulations. Methods:, The GA in plasma was extracted with ethyl acetate, separated on a C18 column with a mobile phase of methanol (5 mmol/L ammonium acetate),water (85 : 15, V/V) and analysed using a MS detector. Ursolic acid (UA) was used as internal standard. The target ions were m/z 469·5 for GA and m/z 455·6 for UA, the fragment voltages were 200 V and 100 V for GA and UA respectively. Results:, The calibration curve was linear over the range of 0·5,200 ng/mL (r = 0·9974). The limit of quantification for GA in plasma was 0·5 ng/mL, the recovery was 76·0,80·0%, and the inter- and intra-day relative standard deviations (RSD) were <12%. The pharmacokinetic parameters of GA after a single dose of 150 mg diammonium glycyrrhizinate test and reference were as follows: the half life (t1/2) 9·65 ± 3·54 h and 9·46 ± 2·85 h, the time to peak concentration (Tmax) 10·95 ± 1·32 h and 11·00 ± 1·30 h, the peak concentration (Cmax) 95·57 ± 43·06 ng/mL and 103·89 ± 49·24 ng/mL; the area under time-concentration curve (AUC0,48 and AUC0,,) 1281·84 ± 527·11 ng·h/mL and 1367·74 ± 563·27 ng·h/mL, 1314·32 ± 566·40 ng·h/mL and 1396·97 ± 630·06 ng·h/mL. The relative bioavailability of diammonium glycyrrhizinate capsule was 98·88 ± 12·98%. Conclusion:, The assay was sensitive, accurate and convenient, and can be used for the determination of GA in human plasma. Comparison of the bioavailability and pharmacokinetic profile of GA indicated that the test and reference capsules were bioequivalent. [source] Automated determination of venlafaxine in human plasma by on-line SPE-LC-MS/MS.JOURNAL OF SEPARATION SCIENCE, JSS, Issue 4 2009Application to a bioequivalence study Abstract A new automated SPE-LC-ESI-MS/MS method was developed and validated to quantify venlafaxine in human plasma using fluoxetine as an internal standard. The analytes were automatically extracted from plasma by C18 SPE cartridges, separated on a C8 RP column and analyzed by MS in the multiple reaction-monitoring (MRM) mode. The method has a chromatographic run time of 4.0 min and a linear calibration curve over the range of 0.25,200 ng/mL (r >0.997). The between-run precisions, based on the percent RSD for replicate quality controls (0.75; 80, and 200 ng/mL), were < 8.5% for all concentrations. The between-run accuracies, based on the percent relative error, were < 4.0%. This method was successfully employed in a bioequivalence study of two venlafaxine capsule formulations (test formulation from Eurofarma (Brazil) and Efexor XR, reference formulation, from Wyeth-Whitehall, Brazil) in 48 healthy volunteers of both sexes who received a single 150 mg dose of each formulation. More than 3000 samples were analyzed eliminating the analyst's exposure to hazardous organic solvents normally employed in off-line liquid,liquid extractions. The 90% confidence interval (CI) of the individual ratio geometric mean for Test/Reference was 91.6,103.4% for AUC0,48 h and 102.2,112.6% for Cmax. Since both 90% CI for AUC0,48 h and Cmax were included in the 80,125% interval proposed by the US Food and Drug Administration (FDA) and the Brazilian National Health Surveillance Agency (ANVISA), the test formulation was considered bioequivalent to Efexor XR according to both the rate and extent of absorption. [source] Liquid chromatography/electrospray ionization tandem mass spectrometry validated method for the simultaneous quantification of sibutramine and its primary and secondary amine metabolites in human plasma and its application to a bioequivalence studyRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 23 2006Deepak S. Jain A high-throughput and sensitive bioanalytical method using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) has been developed for the estimation of sibutramine and its two metabolites (M1 and M2). The extraction of sibutramine, its metabolites and imipramine (internal standard (IS)) from the plasma involved treatment with phosphoric acid followed by solid-phase extraction (SPE) using a hydrophilic-lipophilic balanced HLB cartridge. The SPE eluate without drying and reconstitution was analyzed by LC/MS/MS, equipped with a with turbo ion spray (TIS) source, operating in the positive and multiple reaction monitoring (MRM) acquisition mode. Sample preparation by this method yielded extremely clean extracts with quantitative and consistent mean recoveries; 95.12% for sibutramine, 92.74% for M1, 95.97% for M2 and 96.60% for the IS. The total chromatographic run time was 3.0,min with retention times of 2.51, 2.13, 2.09,min for sibutramine, M1, M2 and imipramine, respectively. The developed method was validated in human plasma matrix, with a sensitivity of 0.1,ng/mL (coefficient of variance (CV), 2.07%) for sibutramine, 0.1,ng/mL (CV, 3.59%) for M1 and 0.2,ng/mL (CV, 4.93%) for M2. Validation of the method for its accuracy, precision, recovery, matrix effect and stability was carried out especially with regard to real subject sample analysis. The response was linear over the dynamic range 0.1 to 8.0,ng/mL for sibutramine and M1, and 0.2 to 16.0,ng/mL for M2 with correlation coefficients of r,,,0.9959 (sibutramine), 0.9935 (M1) and 0.9943 (M2). The method was successfully applied for bioequivalence studies in 40 human subjects with 15,mg capsule formulations. Copyright © 2006 John Wiley & Sons, Ltd. [source] Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2001Michael G. Hall Aims NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. Methods A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Results Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg kg,1 body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (± s.d.) AUC(0,,) (capsule 602 ± 154 vs solution 602 ± 146 µg ml,1 h) or t½ (capsule 55 ± 13 vs solution 54 ± 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,,) and Cmax increased linearly with dose. Following administration of 1 mg NTBC kg,1 in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol ml,1. Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol ml,1 following a dose of 4 mg kg,1 body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione kg,1, but returned to background levels during the following 24 h period. Conclusions NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use. [source] | |||||||||||||