16(2)-3(p ).fm

Size: px

Start display at page:

Download "16(2)-3(p ).fm"

대로 오
5 years ago
Views:

1 w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No k v p w w sƒ B Á z C Á½ k B Á B Á B Á x B Á x D Á x C Á ³ C Á E B w w w C w w D ƒm w w w E œw Bioequivalence Study on Two Talniflumate Preparations Commercially Available in Korean Uy Dong Sohn a, Ji Hoon Jeong b, Kyung Tae Kim a, Young Rae Cho a, Young Sil Min a, Hyun Ju Song a, Hyun Dong Je c, Sung Hyuk Yim b, Yong Kyoo Shin b, Seong Wan Cho d a College of Pharmacy and b College of Medicine, Chung Ang University, Seoul, , Republic of Korea c College of Pharmacy, Catholic University of Daegu, Gyeongbuk, , Korea d Department of Pharmaceutical Engineering, Konyang University, Nonsan-city, Chungnam, , Republic of Korea The aim of the present study was to evaluate the bioequivalence of two talniflumate preparations. We used Somalgen tablet (Kun Wha Pharmaceutical Co., Korea.) as a reference drug for bioequivalence of Crimain tablet (Samjini Pharmaceutical Ind. Co., Korea), and performed this whole study according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty four healthy male volunteers, 22.8±2.2 years in age and 64.6±5.3 kg in body weight, were divided into two groups and a randomized 2 2 cross-over study was employed. After one tablet containing 370 mg of talniflumate was orally administered, blood was taken at predetermined time intervals and the concentrations of talniflumate in plasma were determined using HPLC method with UV-detector. The analysis system was validated in specificity, accuracy, precision and linearity. These items of the analysis condition in this study conform to the guideline of KFDA. The pharmacokinetic parameters such as AUC t and C max were calculated using the analysis condition we established and ANOVA test was utilized for the statistical analysis of the parameters using logarithmically transformed AUCt and Cmax. Mean±SD of reference drug and test drug in AUC t and C max were 1.27±0.58 (µg/ml hr) and 0.27±0.13 (µg/ml) and 1.14±0.46 (µg/ml hr) and 0.26±0.10 (µg/ml) respectively. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to logg (1.25) for AUC t and C max, respectively. These results indicate that Samjin talniflumate tablet is bioequivalent to reference drug, Somalgen tablet. G Keywords Talniflumate, Bioequivalence, HPLC k v p l x ü p, (, m),, r, š ü v y (prodrug) xk 1-3).» v w» w š v w k v p š z w sƒ š 4). k v p Correspondence to : w w w Tel: , Fax: udsohn@cau.ac.kr w p n z šx (T max ) 154 šx (C max ) 423 ng/ml» 121 š š 5). w sƒ w k v p wš j x w w sƒ w w sƒ wš w. w sƒw» w w q k C max x š w (AUC) sƒ w x t t z e z w x z w ü ³ w w. 101

2 102 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 vx vx œš mw z w, vx, n, x, e wš, w xz» š l w. x w w,,, x x yw mw,» ƒ vx w, w x» ( t t š y, 2001, 9, 5) e» w wš» w vx w. <vx» w > Á 19 ~55 Á y š ü (v w q,, { ü ) Á ƒ t p Á w x, x yw, vx ww š q Á vx y < w > ƒ x p w ( sw) w. Áx : Lymphocytes, Monocytes, Eosinophils, Hemoglobin, Hematocrit,WBC, RBC, Platelet, Neutrophil, Basophils Áx yw : Fasting glucose, BUN, Creatinine, Total Protein, Albumin, sgot, sgpt, Alkaline Phosphatase, Total Bilirubin, Total Cholesterol Á : Specific Gravity, Color, ph, Glucose, Albumin, Bilirubin, WBC, blood Á : ü (,, er,,», ), y z(x, ). vx, ü wš vx z w w. z x z w xƒ z w. vx n x x 6 x ƒ vx» k z wš 7 ¾ x w. vx heparin-locked catheter ewš blank x ƒƒ 10 ml xw. w x w» w x x vx» w. x x 1, x 2, 3, x 1 ƒ g. vx w n 8 l x ƒ ƒ 1 (k v p 370 mg) 240 ml wì n w. vx x š w 2 w. x x»ƒ k v p n š m 3 15 w 6). vx w, w { x š w 1 {» w š, x z n n z 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, w. x i.v. catheter û xq w» w 2ml x ü š vx y x» x» 10 ml x w. x z i.v. catheter w x š w» w xq w. x x 3000 rpm 10 w x w. x v p p»š p w 70 w deep freezer ¾ w.»» x y w š x z w x w k v p w. ü t œw v w k (Fisher Scientific., Fair Lawn, NJ, U.S.A), xq (, Korea) qt, Milli Q(Millipore Co., Milford, MA, U.S.A) 18 MΩ-cm m k w.»k p 1 w. w j m v(hplc/uv) x»». - HPLC: Younglin SP930D HPLC Pump Midas type 830 Autosampler Younglin UV730 Detector Autochro Data Module (Younglin autochro win - Chromatography Data System) - Balance: Sartorius analytic balance -»: Union 5KR, Hanil

3 k v p w Voltex mixer : CM-1000 Eyela x k v p v t t d wš ƒ 1000 µg/mlƒ 100% MeOH ƒw w k z w 0.1, 0.5, 1, 1.5, 3, 5 µg/ml t. 100 µl w» w k k.» œx 500 µl ƒwš 1 w 0.02, 0.1, 0.2, 0.3, 0.6, 1 µg/ml spiked blood sample w. spiked blood sample ü t k (Diluted 0.5 µg/ml with 100% MeOH) 1000 µl y ƒw z 1 vortexingw z 3,100 rpm 20 w 100 µl w HPLC w w j m v j w w. x w» w, w x 5 ww ü x wš w 5 x ww. x y w z w. vx l ƒ w -70 C w o x ew, w w z 100 µl HPLC w. w HPLC/UV (mobile phase) acetonitrile : 0.1M sodium acetate (adjusted ph6.4 with acetic acid) 37 : 63 yww w Column Luna C 18, mm (Phenomenox, USA) w š Column 25 C o w. 1.2 ml/min w š» UV» q 288 nm w. x j m l ü t v j w k v p v j w w l x k v p w. 24, vx, ƒƒ 22.8±2.2, 174.2±4.1 cm, 64.6±5.3 kg x w vx» m w. p x w HPLC w j m Fig. 1, 2, 3, v v j 6.9, ü t v j 6.0 š, v ü t (I.S.)»k x (Fig. 1). v 0.02 ( w ), 0.1, 0.2, 0.3, 0.6, 1 µg/ml t ƒw x 14. 5w w HPLC w, x l w v ü y = x (R 2 = , y = x (R 2 = yw ùkü š w w (Fig. 2). w sƒ w x» sƒw 4). x w sƒ w w e x - š l w x - š w (AUCt), š x (Cmax) w š x (Tmax) š w. Tmax w x s ƒw ye w x m v (K-BE Test 2002, ver ) w α( )= 0.05 w. š vx x vx w Fig. 1. Chromatograms of (A) blank human plasma, (B) blank human plasma spiked with taniflumate and internal standard. (C) human plasma taniflumate peak.

4 104 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 š. Fig. 2. Mean (ÛS.D, n=24) plasma concentration-time curves of talniflumatel following oral administration of referrence (ù) and test drug (ø)., y ( w ), y, š w w» w inter-day, intra-day validation w. v 0.02, 0.1, 0.2, 0.3, 0.6, 1 µg/ml w validation Table 1, 2 ùkü. Inter-day validation C.V.(coefficient of variation) 2.14% 12.46%, accuracy 97.44% %. Intra-day validation C.V.(coefficient of variation) 4.27% 10.10% š, accuracy w 97.60% %. j m y (S/N ratio) 5 w x w 0.02 µg/ml w. x talniflumate w HPLC 0.02 µg/ml 1 µg/ml w x w, p,, y q l ƒ vx AUC n z 15 ¾ ƒ vx x - š l Õ œ w w. Cmax ƒ vx x - š l ƒ x w, Tmax ƒ vx x - š l š x w w. ƒ vx q k w Table 3 vx -x š Fig. 2 ùkü. x m w x» sƒw 7). x w sƒ w w e x - š l w x - š w (AUCt), š x (Cmax) w š x (Tmax) š w. Tmax w x s ƒw ye w x m v (K-BE Test 2002, ver ) w α( )= 0.05 w. m yw AUC s³e 90% log <δ<log log 0.8 log 1.25 ü w q» g (Table 4). sƒw AUC w w. m yw Cmax s³e 90% log <δ<log log 0.8 Table 1. Intra-day Accuracy of the HPLC analysis for talniflumate in Human plasma IntradayG(µg/ml) AG(Ratio) BG(Ratio) CG(Ratio) DG(Ratio) EG(Ratio) Mean SD C.V.G(%) AccuracyG(%) 0.02 ( w ) Table 2. Inter-day Accuracy of the HPLC analysis for talniflumate in Human plasma InterdayG(µg/ml) 1G(Ratio) 2G(Ratio) 3G(Ratio) 4G(Ratio) IntradayGRatio Mean Mean SD C.V.G(%) AccuracyG(%) 0.02G( w )

5 k v p w 105 Table 3. Bioavailability parameters s in normal and logarithmic scales for each volunteer obtained after oral administration of test and reference of talniflumate tablet AUC Cmax Tmax Reference drug test drug Reference drug test drug Reference drug test drug No. A A A A A A A A A A A A B B B B B B B B B B B B Average S.D Table 4. Statistical results of bioequivalence evaluation in AUCt between two talniflumate tablets Anova F F table Group or Sequence Subjects / Group Period Drug least significant difference (%) % confidence interval lower limit upper limit Table 5. Statistical results of bioequivalence evaluation in Cmax between two talniflumate tablets Anova F F table Group or Sequence Subjects / Group Period Drug least significant difference (%) % confidence interval lower limit upper limit log1.25 ü w q» g. sƒw Cmax w w (Table 5). ww x j (k v p 370 mg) y q y (k v p 370 mg) w w x w ùkù w w š. w.

6 106 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 š x 1. Criddle, D.N., Meireles, A., Macedo, L.B., Leal-Cardoso, J.H., Scarparo, H.C. and Jaffar, M. : Comparative inhibitory effects of niflumic acid and novel synthetic derivatives on the rat isolated stomach fundus. J. Pharm. Pharmacol. 54(2), 283 (2002). 2. Dreiser, R.L., Ditisheim, A., Charlot, J. and Lopez, A. : A double blind, placebo controlled study of niflumic acid gel in the treatment of acute tendinitis. Eur J. Rheumatol. Inflamm. 11(2), 38 (1991). 3. Sauvage, J.P., Ditisheim, A., Bessede, J.P. and David, N. : Double-blind, placebo-controlled, multi-centre trial of the efficacy and tolerance of niflumic acid ('Nifluril') capsules in the treatment of tonsillitis in adults. Curr. Med. Res. Opin. 11(10), 631 (1990). 4. Jang, D.J., Park, J.S., Ko, H.R., Jee, J.P., Kim, J.K., Kim, S.T. and Kim, C.K. : Simultaneous determination of niflumic acid and its prodrug, talniflumate in human plasma by high performance liquid chromatography. Biomed Chromatogr. 19(1), 32 (2005). 5. Knight, D. : Talniflumate (Genaera). Curr. Opin. Investig. Drugs 5(5), 557 (2004). 6. Lee, H.W., Won, K.J., Cho, S.H., Ha, Y.H., Park, WS., Yim, H.T., Baek, M., Rew, J.H., Yoon, S.H., Yim, S.V., Chung, J.H. and Lee, K.T. : Quantitation of niflumic acid in human plasma by high-performance liquid chromatography with ultraviolet absorbance detection and its application to a bioequivalence study of talniflumate tablets. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 821(2): 215 (2005). 7. t t š y, w x» ( ).

14.531~539(08-037).fm

14.531~539(08-037).fm G Journal of the Korea Concrete Institute Vol. 20, No. 4, pp. 531~539, August, 2008 š x y w m š gj p { sƒ z 1) * 1) w w Evaluation of Flexural Strength for Normal and High Strength Concrete with Hooked