• Journal of Pharmaceutical Investigation
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• v.32 no.3
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• pp.215-221
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• 2002

Cephradine is a first generation cephalosporin and has broad spectrum antibacterial activity against gram-positive and gram-negative microorganisms, through inhibition of bacterial cell wall synthesis. Cephradine is useful for treatment of infections of the urinary and respiratory tract, skin and soft tissues. The purpose of the present study was to evaluate the bioequivalence of two cephradine capsules, Cefradine Yuhan (YuHan Corporation) and Broadcef (Ilsung Pharmaceuticals Co. Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The cephradine release from the two cephradine capsules in vitro was tested using KP VII Apparatus II method with various different kinds of dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty normal male volunteers, $23.10{\pm}2.90$ years in age and $67.69{\pm}8.04\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one capsule containing 500 mg as cephradine was orally administered, blood was taken at predetermined time intervals and the concentrations of cephradine in serum were determined using HPLC method with UV detector. The dissolution profiles of two cephradine capsules were very similar at all dissolution media. Besides, the pharmacokinetic parameters such as $AVC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters using logarithmically transformed $AVC_t\;and\;C_{max}$ and untransformed $T_{max}$. The results showed that the differences in $AVC_t,\;C_{max}\;and\;T_{max}$ between two capsules based on the Cefradine Yuhan were -2.87%, -0.96% and -4.85%, respectively. There were no sequence effects between two capsules in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of 1og(0.8) to log(1.25) $(e.g.,\;log(0.93){\sim}log(1.02)\;and\;log(0.88){\sim}log(1.13)\;for \;AVC_t\;and\;C_{max},\;respectively)$. The 90% confidence interval using untransformed data was within ${\pm}20%$ $(e.g., \;-17.54{\sim}7.78\;for\;T_{max})$. All parameters met the criteria of KFDA guideline for bioequivalence, indicating that Broadcef capsule is bioequivalent to Cefradine Yuhan capsule.

• Journal of Pharmaceutical Investigation
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• v.32 no.2
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• pp.135-140
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• 2002

Cefadroxil is a semi-synthetic cephalosporin active against many Gram-positive and Gram-negative bacteria. The drug has been used for the treatment of the urinary and respiratory tract infections when caused by susceptible strains of the designated microorganism. The purpose of the present study was to evaluate the bioequivalence of two cefadroxil capsules, Duricef (Bo Ryung Pharmaceutical Co. Ltd.) and Hanacef (Korean Pharmaceutical Co. Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The cefadroxil release from the two cefadroxil capsules in vitro was tested using KP VII Apparatus II method with various different kinds of dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty four normal male volunteers, $21.58{\pm}2.43$ years in age and $70.74{\pm}10.29$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one capsule containing 500 mg as cefadroxil was orally administered, blood was taken at predetermined time intervals and the concentrations of cefadroxil in serum were determined using HPLC with UV detector. The dissolution profiles of two cefadroxil capsules were very similar at all dissolution media. The pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t\;and\;C_{max}$ and untransformed $T_{max}$. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two capsules based on the Duricef were 0.05%, -5.29% and 4.53%. There were no sequence effects between two capsules in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log(1.25) $(e.g.,\;log(0.95){\sim}log(1.05)\;and\;log(0.87){\sim}log(1.02)$ for $AUC_t\;and\;C_{max}$, respectively). The 90% confidence interval using untransformed data was within ${pm}20%$ $(e.g.,\;-6.75{\sim}15.74\;for\;T_{max})$. All parameters met the criteria of KFDA guideline for bioequivalence, indicating that Hanacef capsule is bioequivalent to Duricef capsule.

• Journal of Pharmaceutical Investigation
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• v.29 no.2
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• pp.145-149
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• 1999

Bioequivalence of two cefixime capsules, test drug ($Cepirin^R$ capsule: Cheiljedang Corp.) and reference drug ($Suprax^R$ capsule: Dong A Pharm. Com.), was evaluated according to the guidelines of Korea Food and Drug Administration (KFDA). Sixteen healthy volunteers were divided randomly into two groups and administered the drug orally at the dose of 400 mg as cefixime in a $2{\times}2$ crossover study. There was a 1-week washout period between the administrations. Blood samples were taken at predetermined time intervals for 12 hour and the plasma concentration of cefixime was determined with a HPLC method. $AUC_{0-12hr}$ (area under the plasma concentration-time curve form time zero to 12 hour), $C_{max}$ (maximum plasma drug concentration) and $T_{max}$ (time to reach $C_{max}$) were estimated from the plasma drug concentrationtime data. Analysis of variance (ANOVA) revealed no difference in $AUC_{0-12hr}$, $C_{max}$ and $T_{max}$ between the formulations. The apparent differences of these parameters between the formulations were less than 20% (i.e., 8.62, 11.10 and 0.00% for $AUC_{0-12hr}$, $C_{max}$ and $T_{max}$,respectively). The powers $(1-{\beta})$ for $AUC_{0-12hr}$ $C_{max}$ and $T_{max}$ were over 0.9. Minimal detectable difference $({\Delta})$ at ${\alpha}=0.05$, $1-{\beta}=0.8$ were less than 20% (i.e., 12.84, 11.05 and 17.99% for $AUC_{0-12hr}$, $C_{max}$ and $T_{max}$, respectively). The 90% confidence intervals $({\delta})$ for these parameters were also within ${\pm}20%$ (i.e., $-0.53{\le}{\delta}{\le}17.76$, $3.23{\le}{\delta}{\le}18.97$ and $-12.81{\le}{\delta}{\le}12.81$ for $AUC_{0-12hr}$, $C_{max}$ and $T_{max}$, respectively). These results satisfied the criteria of KFDA guideline for bioequivalence, indicating the two formulations of cefixime were bioequivlent.

• Journal of Pharmaceutical Investigation
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• v.31 no.1
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• pp.57-62
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• 2001

Azelastine, a phthalazinone derivative, is an antiallergic agent which demonstrates histamine $H_1-receptor$ antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Thus, azelastine may be useful in the management of both asthma and allergic disorders. The purpose of the present study was to evaluate the bioequivalence of two azelastine hydrochloride tablets, $Azeptin^{TM}$ (Bu Kwang Pharmaceutical Co., Ltd.) and $Azela^{TM}$ (Kyung Dong Pharmaceutical Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Eighteen normal male volunteers, $22.44{\pm}2.01$ years in age and $61.99{\pm}6.18\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After two tablets containing 1 mg of azelastine hydrochloride per tablet were orally administered, blood was taken at predetermined time intervals and the concentrations of azelastine in serum were determined using HPLC with fluorescence detector. Pharmacokinetic parameters such as $AUC_t$, $C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters. The results showed that the differences in $AUC_t$, $C_{max}\;and\;T_{max}$ between two tablets were -6.45%, -2.60% and -7.14%, respectively, when calculated against the $Azeptin^{TM}$ tablet. The powers $(1-{\beta})$ for $AUC_t\;and\;C_{max}$ were 96.65% and 88.47%, respectively. Minimum detectable differences $({\Delta})$ at ${\alpha}=0.05$ and $1-{\beta}=0.8$ were less than 20% (e.g., 14.40% and 17.65% for $AUC_t\;and\;C_{max}$, respectively). The 90% confidence intervals were within ${\pm}20%$ (e.g., $-14.87{\sim}1.97$ and $-12.92{\sim}7.72$ for $AUC_t\;and\;C_{max}$, respectively). Two parameters met the criteria of KFDA for bioequivalence, indicating that $Azela^{TM]$ tablet is bioequivalent to $Azeptin^{TM}$ tablet.

• Journal of Pharmaceutical Investigation
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• v.31 no.4
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• pp.281-287
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• 2001

Rebamipide is a novel anti-gastric ulcer agent that has been reported to increase the synthesis of mucus, to increase the mucosal concentration of prostaglandin, and to promote rapid ulcer healing. The purpose of the present study was to evaluate the bioequivalence of two rebamipide tablets, $Mucosta^{TM}$ (Otsuka Korea Pharmaceutical Co., Ltd.) and $Rebamide^{TM}$ (Kyung Dong Pharmaceutical Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The rebamipide release from the two rebamipide tablets in vitro was tested using KP VII Apparatus II method at pH 6.8 dissolution media. Twenty normal male volunteers, $24.20{\pm}2.26$ years in age and $66.19{\pm}9.41\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 100 mg of rebamipide was orally administered, blood was taken at predetermined time intervals and the concentrations of rebamipide in serum were determined using HPLC method with fluorescence detector. The dissolution profiles of two rebamipide tablets were very similar at pH 6.8 dissolution media. Besides, the pharmacokinetic parameters such as $AUC_t$, $C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters. The results showed that the differences in $AUC_t$, $C_{max}\;and\;T_{max}$ between two tablets based on the $Mucosta^{TM}$ were -2.57%, 5.77% and -1.47%, respectively. Minimum detectable differences $({\Delta})$ at ${\alpha}=0.05$ and $1-{\beta}=0.8$ were less than 20% (e.g., 12.62% and 17.63% for $AUC_t,\;and\;C_{max}$, respectively). The powers $(1-{\beta})$ at ${\alpha}=0.05$, ${\Delta}=0.2$ for $AUC_t\;and\;C_{max}$ were above 99.00% and 88.56%, respectively. The 90% confidence intervals were within ${\pm}20%$ (e.g., $-9.96{\sim}4.82$ and $-4.54{\sim}16.09$ for $AUC_t\;and\;C_{max}$, respectively). Two parameters met the criteria of KFDA for bioequivalence, indicating that $Rebamide^{TM}$ tablet is bioequivalent to $Mucosta^{TM}$ tablet.

• Journal of Pharmaceutical Investigation
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• v.30 no.1
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• pp.55-59
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• 2000

Bioequivalence of two cisapride tablets, test drug ($Cisple^{\circledR}$ tablet: Hanmi Pharm Co., Ltd.) and reference drug ($Prepulsid^{\circledR}$ tablet: Janssen Pharm. Co., Ltd.), was evaluated according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty two healthy male volunteers were divided randomly into two groups and administered the drug orally at the dose of 10 mg as cisapride in a $2{\times}2$ crossover study. There was a week washout period between administrations. Blood samples were taken at predetermined time intervals for 36 hr and the plasma concentration of cisapride was determined by a HPLC method. $AUC_{0-36hr}$ (area under the plasma concentration-time curve from time zero to 36 hr), $C_{max}$ (maximum plasma drug concentration) and $T_{max}$ (time to reach $C_{max}$) were estimated from the plasma drug concentration-time data. Analysis of variance (ANOVA) revealed no difference in $AUC_{0-36hr},\;C_{max}\;and\;T_{max}$ between two products. The apparent differences of these parameters between two products were less than 20% (i.e., 5.38, 6.17 and 0.00% for $AUC_{0-36hr},\;C_{max}\;and\;T_{max},$ respectively). The powers $(1-\beta)$ for $AUC_{0-36hr},\;C_{max}\;and\;T_{max}$ were over 0.9. Minimal detectable differences $(\Delta)$ at ${\alpha}=0.05,\;1-{\beta}=0.8$ were less than 20% (i.e. 17.67, 14.84 and 19.72% for $AUC_{0-36hr},\;C_{max}\;and\;T_{max},$ respectively). The 90% confidence intervals $(\delta)$ for these parameters were also within ${\pm}20%$ $(i.e.\;-4.97\;{\le}{\delta}{\le}\;15.73,\;-2.53{\le}{\delta}{\le}\;14.86\;and\;-11.55{\le}{\delta}{\le}\;11.55$ for $AUC_{0-36hr},\;C_{max}\;and\;T_{max},$ respectively). These results satisfied the criteria of KFDA guidelines for bioequivalence, indicating the two tablets of cisapride were bioequivalent.

• Journal of Pharmaceutical Investigation
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• v.30 no.1
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• pp.61-65
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• 2000

Doxazosin, a postsynaptic selective ${\alpha}1-adrenoceptor$ antagonist, is a potent antihypertensive agent which reduces peripheral resistance and blood pressure by vasodilatation of peripheral vessels. It is also used in the treatment of urinary obstruction by benign prostatic hypertrophy. The purpose of the present study was to evaluate the bioequivalence of two doxazosin tablets, $Cardura^{TM}$ (Pfizer Korea Ltd.) and $Cardil^{TM};$ (Kyungdong Pharmaceutical Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Sixteen normal male volunteers, $24.19{\pm}2.48$ years in age and $62.41{\pm}6.66$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 2 mg of doxazosin was orally administered, blood was taken at predetermined time intervals and the concentrations of doxazosin in serum were determined with an HPLC method using spectrofluorometric detector. Pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two tablets were -1.54%, -1.51 % and 3.42%, respectively, when calculated against the $Cardura^{TM}$ tablet. The powers $(1-{\beta})$ for $AUC_t,\;C_{max}\;and\;T_{max}$ were all more than 99.00%. Minimum detectable differences $(\Delta)$ at ${\alpha}=0.05\;and\;1-{\beta}=0.8$ were all less than 20% (e.g., 12.73%, 12.84% and 13.01% for $AUC_t,\;C_{max}\;and\;T_{max}$, respectively). The 90% confidence intervals were all within :${\pm}20%$ (e.g., $-8.97{\sim}5.90,\;-9.01{\sim}6.00\;and\;-4.16{\sim}11.05\;for\;AUC_t,\;C_{max}\;and\;T_{max},\;respectively)$. All of the above para- meters met the criteria of KFDA for bioequivalence, indicating that $Cardil^{TM}$ tablet is bioequivalent to $Cardura^{TM}$ tablet.

• Journal of Pharmaceutical Investigation
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• v.36 no.5
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• pp.343-348
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• 2006

The purpose of the present study was to evaluate the bioequivalence of two zolpidem tartrate tablets, Stilnox tablet(Sanofi-aventis Korea, reference product) and Zanilo tablet(ChoDang Pharm Co., Ltd., Korea, test product), according to the guidelines of Korea Food and Drug Administration(KFDA). After adding an internal standard(cimetropium), 250 ${\mu}L$ plasma samples were extracted using 1.3 mL of ethyl acetate. Extracted compounds were analyzed by HPLC with triple-quadrupole mass spectrometry. This method for determination of zolpidem is proved accurate and reproducible with the limit of quantitation of 1 ng/mL in human plasma. Twenty-four healthy male Korean volunteers received each medicine at the zolpidem tartrate dose of 10 mg in a $2{\times}2$ crossover study. There was one-week washout period between the doses. Plasma concentrations of zolpidem were monitored for over a period of 8 hr after the administration. $AUC_{0-t}$(the area under the plasma concentration-time curve) was calculated by the linear trapezoidal rule. $C_{max}$(maximum plasma drug concentration) and $T_{max}$(time to reach $C_{max}$) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed $AUC_{0-t}$ and $C_{max}$. No significant sequence effect was found for all of the bio-availability parameters indicating that the crossover design was properly performed. The 90% confidence intervals for the log transformed data were acceptable range of log 0.8 to log 1.25(e.g., log 0.92-log 1.06 for $AUC_{0-t}$, log 0.96-log 1.13 for $C_{max}$). The major parameters, $AUC_{0-t}$ and $C_{max}$ met the criteria of KFDA for bioequivalence indicating that Zanilo tablet is bioequivalent to Stilnox tablet.

• Journal of Pharmaceutical Investigation
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• v.29 no.4
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• pp.355-360
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• 1999

Triflusal is a new antithrombotic agent which inhibits both platelet cyclooxygenase and c-AMP phosphodiesterase activity. The purpose of the present study was to evaluate the bioequivalence of two triflusal capsules, $Disgren^{TM}$ (Myung-In Pharmaceutical Co., Ltd.) and $Tigriri^{TM}$ (Hana Pharmaceutical Co., Ltd.) according to the guidelines of Korea Food and Drug Administration (KFDA). Eighteen normal male volunteers, $22.94{\pm}1.83$ in age and $63.7l{\pm}10.43$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one capsule containing 300 mg of triflusal was orally administered, blood was taken at predetermined time intervals and the concentrations of triflusal in serum were determined using HPLC method with UV detector. Pharmacokinetic parameters such as $AUC_t$ $C_{max}$ and $T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters. The results showed that the differences in $AUC_t$ $C_{max}$ and $T_{max}$ between two capsules were -0.30%, 0.81 % and -3.03%, respectively when calculated against the $Disgren_{TM}$ capsule. The powers $(1-{\beta})$ for $AUC_t$ $C_{max}$ and $T_{max}$ were 98.29%,84.73% and 81.02%, respectively. Minimum detectable differences $({\Delta})$ at ${\alpha}=0.1$ and $1-{\beta}=0.8$ were all less than 20% (e.g., 12.91%, 18.46% and 19.65% for $AUC_t$ $C_{max}$ and $T_{max}$ respectively). The 90% confid,ence intervals were all within ${\pm}20%$(e.g., $-8.97{\sim}8.37$, $-11.58{\sim}13.22$ and $-16.23{\sim}10.17$ for $AUC_t$ $C_{max}$ and $T_{max}$, respectively). All of the above parameters ($1-{\beta}, {\Delta}$ and 90% confidence intervals) met the criteria of KFDA for bioequivalence, indicating that $Tigriri^{TM}$ capsule is bioequivalent to $Disgren^{TM}$ capsule.

• Journal of Pharmaceutical Investigation
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• v.30 no.3
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• pp.213-218
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• 2000

Ondansetron is a potent, highly selective 5-hydroxytryptamine3(5-HT3) receptor- antagonist, for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiography, and the treatment of post-operative nausea and vomiting. The purpose of the present study was to evaluate the bioequivalence of two ondansetron tablets, $Zofran^{TM}$, (Glaxo Wellcome Korea Ltd.) and Hana ondansetron (Hana Pharmaceutical Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Eighteen normal male volunteers, $23.56{\pm}1.79$ year in age and $67.35{\pm}8.35\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 8 mg of ondansetron was orally administered, blood was taken at predetermined time intervals and the concentrations of ondansetron in serum were determined using HPLC with UV detector. Pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two tablets were 7.53%, -0.23% and -3.92%, respectively when calculated against the $Zofran^{TM}$, tablet. The powers $(1-{\beta})$ for $AUC_t,\;C_{max}\;and\;T_{max}$ were above 99.00%, above 99.00% and 84.99%, respectively. Minimum detectable differences $(\Delta)\;at\;{\alpha}=0.1\;and\;1-{\beta}=0.8$ were all less than 20% (e.g., 12.25%, 10.88% and 18.37% for $AUC_t,\;C_{max}\;and\;T_{max}$, respectively). The 90% confidence intervals were all within ${\pm}20%$ (e.g., $-0.70{\sim}15.76,\;-7.53{\sim}7.08\;and\;-16.27{\sim}8.42\;for\;AUC_t,\;C_{max}\;and\;T_{max}$, respectively). All of the above parameters met the criteria of KFDA for bioequivalence, indicating that Hana ondansetron tablet is bioequivalent to $Zofran^{TM}$, tablet.