Yun Ji Hye
(NRL of Pharmaceutical Technology, College of Pharmacy, Chungnam National University)
,
Myung Ja Hye
(NRL of Pharmaceutical Technology, College of Pharmacy, Chungnam National University)
,
Kim Hye Jin
(NRL of Pharmaceutical Technology, College of Pharmacy, Chungnam National University)
,
Lee Sibeum
(NRL of Pharmaceutical Technology, College of Pharmacy, Chungnam National University)
,
Park Jong-Sei
(Lab Frontier, Co., Ltd.)
,
Kim Won
(Lab Frontier, Co., Ltd.)
,
Lee Eun-Hee
(Green Cross Reference Laboratory)
,
Moon Cheol Jin
(Green Cross Reference Laboratory)
,
Hwang Sung-Joo
(NRL of Pharmaceutical Technology, College of Pharmacy, Chungnam National University)
The purpose of the present study was to develop a standard protocol for imidapril hydrochloride bioequivalence testing. For this reason, a specific LC-MS method was developed and validated for the determination of imidapril in human plasma. A solid-phase extraction cartridge, $Sep-pak^{R}$
The purpose of the present study was to develop a standard protocol for imidapril hydrochloride bioequivalence testing. For this reason, a specific LC-MS method was developed and validated for the determination of imidapril in human plasma. A solid-phase extraction cartridge, $Sep-pak^{R}$ C18, was used to extract imidapril and ramipril (an internal standard) from deproteinized plasma. The compounds were separated using a XTerra $MS^{R}$?C18 column ($3.5 {\mu}m, 2.1\times150 mm$) and $acetonitrile-0.1\%$ formic acid (67:33, v/v) adjusted to pH 2.4 by 2 mmol/L ammonium formic acid, as mobile phase at 0.3 mL/min. Imidapril was detected as m/z 406 at a retention time of ca. 2.3 min, and ramipril as m/z 417 at ca. 3.6 min. The described method showed acceptable specificity, linearity from 0.5 to 100 ng/mL, precision (expressed as a relative standard deviation of less than $15\%$), accuracy, and stability. The plasma concentration-versus-time curves of eight healthy male volunteers administered a single dose of imidapril (10 mg), gave an $AUC_{12hr}$ of imidapril of $121.48\pm35.81 ng mL^{-1} h$, and $C_{max} and T_{max}$ values of $32.59\pm9.76 ng/mL and 1.75\pm0.27 h$. The developed method should be useful for the determination of imidapril in plasma with sufficient sensitivity and specificity in bioequivalence study.
The purpose of the present study was to develop a standard protocol for imidapril hydrochloride bioequivalence testing. For this reason, a specific LC-MS method was developed and validated for the determination of imidapril in human plasma. A solid-phase extraction cartridge, $Sep-pak^{R}$ C18, was used to extract imidapril and ramipril (an internal standard) from deproteinized plasma. The compounds were separated using a XTerra $MS^{R}$?C18 column ($3.5 {\mu}m, 2.1\times150 mm$) and $acetonitrile-0.1\%$ formic acid (67:33, v/v) adjusted to pH 2.4 by 2 mmol/L ammonium formic acid, as mobile phase at 0.3 mL/min. Imidapril was detected as m/z 406 at a retention time of ca. 2.3 min, and ramipril as m/z 417 at ca. 3.6 min. The described method showed acceptable specificity, linearity from 0.5 to 100 ng/mL, precision (expressed as a relative standard deviation of less than $15\%$), accuracy, and stability. The plasma concentration-versus-time curves of eight healthy male volunteers administered a single dose of imidapril (10 mg), gave an $AUC_{12hr}$ of imidapril of $121.48\pm35.81 ng mL^{-1} h$, and $C_{max} and T_{max}$ values of $32.59\pm9.76 ng/mL and 1.75\pm0.27 h$. The developed method should be useful for the determination of imidapril in plasma with sufficient sensitivity and specificity in bioequivalence study.
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문제 정의
The purpose of the present study was to develop a standard protocol for imidapril hydrochloride bioequivalence testing. For this purpose, a LC/MS method involving the detection of the m/z of imidapril at 406 and that of ramipril at 417 (used as an internal standard) was developed and validated for the determination of imidapril in human plasma.
제안 방법
For this purpose, a LC/MS method involving the detection of the m/z of imidapril at 406 and that of ramipril at 417 (used as an internal standard) was developed and validated for the determination of imidapril in human plasma. After the validation stage, a bioavailability study was performed by administering a Tanatril® tablet (10 mg as imidapril hydrochloride, Dong-A Pharm. Co.) orally once to 8 healthy male volunteers and then determining the pharmacokinetic parameters. Based on the pharmacokinetic data, bio으quivalence test conditions for imidapril hydrochloride, i.
) orally once to 8 healthy male volunteers and then determining the pharmacokinetic parameters. Based on the pharmacokinetic data, bio으quivalence test conditions for imidapril hydrochloride, i.e., sampling time, washout period, and the detected analytical method, were determined and the final bioeq니ivalence test guideline for imidapril hydrochloride was prepared.
Blood samples were taken at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 h after imidapril administration from eight healthy male volunteers. The samples were immediately centrifuged at 4000 rpm for 10 min, and the separated plasma samples were stored under -20℃.
5, 2, 5, 10, 20, 50, and 100 ng/mL) of imidapril in h니man plasma, inter-day and intra-day precisions were investigated. Intra-day precision and accuracy were determined by repeating six times during one day, and inter-day precision was determined by repeating this testing once a day for six consecutive days. Samples were prepared at each concentration and assayed to determine intra-/ inter- day accuracies, which were expressed precision as relative standard deviation (RSD).
Processed sample stability test was performed by analyzing first intra-day calibration curve samples after intra-day analysis.
Processes sample stability testing was performed by analyzing first intra-day calibration curve samples after intra-day analysis. The error (%) of imidapril ranged from 0.
The developed method was used determine imidapril in plasma samples. One Tanatril® tablet (imidapril hydrochloride, 10 mg) was administered enterally to eight healthy male volunteers.
To determine the precision of the method at these eight concentrations (0, 0.5, 2, 5, 10, 20, 50, and 100 ng/mL) of imidapril in h니man plasma, inter-day and intra-day precisions were investigated. Intra-day precision and accuracy were determined by repeating six times during one day, and inter-day precision was determined by repeating this testing once a day for six consecutive days.
To examine the linearity of imidapril, calibration standards at eight concentrations (0, 0.5, 2, 5, 10, 20, 50 and 100 ng/mL in plasma) were prepared and assayed. A linear model was fitted to the concentration-versus-peak area ratio data by least-squares regression.
대상 데이터
1. Chemical structures of (1) imidapril (R=C2H5i C2oH27N306HCI =441.9, monoisotopic exact mass=405) and imidaprilat (active metabolite, R=H, C18H23N3O6), (2) ramipril 5=41&5, mnoisotopic exact mass=416).
All other reagents were of analytical grade. H이ium (99.9999%) as a collision gas and nitrogen (그99%) as a sheath and auxiliary gas were purchased from the J니ng-ang Industrial Company (Daejeon, Korea).
The nitrogen generator (System Instruments, Daejeon, Korea) and the Agilent Chemstation and Broker data analysis were used for all LC-MS analyses. The c이umn was an XTerra® MS C18 (3.5 pm, 2.1x150 mm) from Waters (USA). A Sep-pak® 6 cc (500 mg) C18 cartridge was purchased from Waters (Milford, MA, USA) for solid phase extraction of imidapril hydrochloride and ramipril.
이론/모형
5, 2, 5, 10, 20, 50 and 100 ng/mL in plasma) were prepared and assayed. A linear model was fitted to the concentration-versus-peak area ratio data by least-squares regression.
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