• 한국임상약학회지
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• 제19권1호
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• pp.50-60
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• 2009

Highly variable drugs (within-subject variability greater than 30%) have been difficult to meet current regulatory acceptance criteria using a reasonable number of study subjects. In this study, we reviewed previous studies presenting alternative approaches for bioequivalence evaluation of highly variable drugs, and focused on an approach for widening the bioequivalence acceptance limits using within-subject variability. We discussed the suggested five solutions for highly variable drug including the deletion of $C_{max}$ of the bioequivalence criteria, direct expansion of bioequivalence limit, multiple dose studies in steady state, bioequivalence assessment on the metabolite, add-on study, and widening the bioequivalence acceptance limits based on reference variability. The methods for widening of bioequivalence limits based on reference variability are scaled average bioequivalence containing within-subject variability on reference drug (${\sigma}_{WR}$), population bioequivalence derived from total variability on reference drug (${\sigma}_{TR}$) and test drug (${\sigma}_{TT}$), and individual bioequivalence derived from subject by formulation interaction variability (${\sigma}_D$) and within subject variability on reference drug (${\sigma}_{WR}$) and test drug (${\sigma}_{TR}$). To apply these methods, the switching variability (${\sigma}_0$) will have to be set by the regulatory authorities. The proposals of bioequivalence evaluation approach for the highly variable in Korea are presented for both of new drug and reevaluation drug.

• 한국임상약학회지
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• 제23권3호
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• pp.206-212
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• 2013

Purpose: The aim of this study was to investigate the effect of nimodipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Methods: Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of nimodipine (0.5 or 2 mg/kg) in rats. The effect of nimodipine on the P-glycoprotein as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Results: Nimodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $10.2{\mu}M$. Compared to those animals in the oral control group (warfarin without nimodipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (0.5 mg/kg, P<0.05; 2 mg/kg, P<0.01) by 31.3-57.6%, and the peak plasma concentration ($C_{max}$) was significantly higher (2 mg/kg, P<0.05) by 29.4% after oral administration of warfarin with nimodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.31- to 1.58-fold and the absolute bioavailability of warfarin with nimodipine was significantly greater by 64.1-76.9% compared to that in the control group (48.7%). In contrast, nimodipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Conclusion: Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism rather than P-glycoprotein-mediated efflux by nimodipine.

• Preventive Nutrition and Food Science
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• 제19권4호
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• pp.321-326
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• 2014

In this study, we developed a method to quantify esculetin (6,7-dihydroxycoumarin) in plasma and tissues using HPLC coupled with ultraviolet detection and measured the level of esculetin in rat plasma after oral administration. The calibration curve for esculetin was linear in the range of 4.8 ng/mL to 476.2 ng/mL, with a correlation coefficient ($r^2$) of 0.996, a limit of detection value of 33.2 ng/mL, and a limit of quantification value of 100.6 ng/mL. Recovery rates for the 95.2 ng/mL and 190.5 ng/mL samples were 95.2% and 100.3%, within-runs and 104.8% and 101.0% between-runs, respectively. The relative standard deviation was less than 7% for both runs. In the pharmacokinetic analysis, the peak plasma esculetin level was reached 5 min after administration ($C_{max}=173.3ng/mL$; $T_{1/2}=45min$; $AUC_{0{\sim}180min}=5,167.5ng{\cdot}min/mL$). At 180 min post-administration (i.e., after euthanasia), esculetin was only detectable in the liver ($30.87{\pm}11.33ng/g$) and the kidney ($20.29{\pm}7.02ng/g$).

• 한국전기전자재료학회논문지
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• 제16권7호
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• pp.573-578
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• 2003

Low temperature selective epitaxial growth of Si and SiGe has been obtained using an industrial single wafer chemical vapor deposition module operating at reduced pressure. Epitaxial Si and heteroepitaxial SiGe deposition with Ge content about 20 % has been studied as extrinsic base for self-aligned heterojunction bipolar transistors(HBTs), which helps to reduce the parasitic resistance to obtain higher maximum oscillation frequencies(f$\_$max/). The dependence of Si and SiGe deposition rates on exposed windows and their evolution with the addition of HCl to the gas mixture are investigated. SiH$_2$Cl$_2$ was used as the source of Si SEG(Selective Epitaxial Growth) and GeH$_4$ was added to grow SiGe SEG. The addition of HCl into the gas mixture allows increasing an incubation time even low growth temperature of 675∼725$^{\circ}C$. In addition, the selectivity is enhanced for the SiGe alloy and it was proposed that the incubation time for the polycrystalline deposit on the oxide is increased probably due to GeO formation. On the other hand, when only SiGe SEG(Selective Epitaxial Growth) layer is used for extrinsic base, it shows a higher sheet resistance with Ti-silicide because of Ge segregation to the interface, but in case of Si or Si/SiGe SEG layer, the sheet resistance is decreased up to 70 %.

• Journal of Pharmaceutical Investigation
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• 제32권1호
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• pp.27-33
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• 2002

A self-microemulsifying drug delivery system(SMEDDS) composed of Cremophor $EL^{\circledR},\;Labrasol^{circledR}$, and Lauroglycol $FCC^{circledR}$ was prepared for the enhancement of solubility, dissolution rate and bioavailability of ibuprofen(IBP), which is water-insoluble but soluble in oils and surfactants. Phase diagram with various regions including microemulsion area was depicted. The SMEDDS was encapsulated in soft gelatin capsules and their dissolution characteristics in various media were observed in comparison to the generic products commercially available in the market. Soft capsules of SMEDDS formulation showed better dissolution profiles, especially in acidic condition, than the others. For the period of 1 hr dissolution in pH 1.2 medium, it reached over 70% dissolution from soft capsules, compared to less than 40% dissolution from commercial reference tablets. On the other hand, in vivo pharmacokinetic parameters were obtained after oral administrations of different IBP preparations to Sprague Dawley rats. SMEDDS formulation showed higher $C_{max}$ and greater $AUC_{0-5hr}$ than the suspension of reference tablet or IBP powder. Therefore, it is possible to conclude that a newly developed soft capsules employing SMEDDS provides an alternative preparation to improve oral bioavailability of IBP.

• Journal of Pharmaceutical Investigation
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• 제30권4호
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• pp.235-239
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• 2000

Ipriflavone (3-phenyl-7-isopropoxy-4H-1-benzopyran-4-one, IP) is a well-known antiosteoporotic drug with poor bioavailability. In the previous study, we reported that the IP formulation prepared by spray-drying method with polyvinylpyrrolidone (PVP) (SIP) was very effective in improving the bioavailability of IP. In this study, we examined the effects of molecular weight and mixture ratios of PVP to IP on the systemic absorption of IP following oral administration of SIP at a dose of 50 mg/kg to rats. In the effect of molecular weight, the Cmax of spray-dried IP with PVP K30 (SIP-K30) was significantly higher than those of spray-dried IP with PVP 360 (SIP-360), spray-dried IP with PVP K90 (SIP-K90), and spray-dried IP with PVP K17 (SIP-K17) (p<0.05). The AUC of SIP-K30 was about 2, 3, and 5.5 times higher than those of SIP-360, SIP-K90, and SIP-K17, respectively. The AUC value of SIP-K30 was significantly greater than those of SIP-K17 and SIP-K90 (p<0.05) except for SIP-360. In the ratio of PVP K30 to drug, the $C_{max}$ and the AUC value of 3 : 7 IP-PVP solid dispersion were similar to those of 5 : 5 IP-PVP and significantly higher than those of the other solid dispersions (p<0.05). It was concluded that the spray-dried IP with PVP K30 at the ratio of 3:7 (w/w) was the best formulation for improving the bioavailability of IP.

• 한국의류학회지
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• 제32권2호
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• pp.340-347
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• 2008

A prototype of 3D clothing design system with a direct pattern development function was suggested, reflecting intuitive design functions and design modifications while considering the fit of clothing patterns with the 3D human body in the virtual 3D space. The research method was as follows. Clothing models were created using a 3D design tool, 3ds max on the surface of 3D human body model made by scanning an actual human body. 3D illustrations were completed by revising the fit and sizing of the human body and clothing models. 2D T-shirt pattern was produced 3D illustrations using from a 3D scanning data modeling solution RapidForm 2004, a 2D conversion program for 3D data called 2C-AN, and Yuka CAD. As a result, the following conclusions were made. The fit of the clothing and human body can be adjusted by reflecting individual body figure characteristics and 3D illustrations over the actual 3D body model. Furthermore, intuitive design support functions were intensified overcoming the weak point of existing 3D clothing design system by developing the direct clothing design in the virtual 3D space. 3D illustration design modifications can be directly reflected on clothing patterns from 3D illustrations by 3D clothing design system developed in this study.

• Journal of Microbiology and Biotechnology
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• 제22권12호
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• pp.1705-1713
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• 2012

A gene encoding ${\beta}$-glucosidase was cloned from Weissella cibaria 37, an isolate from human feces. Sequence analysis showed that the gene could encode a protein of 415 amino acids in length, and the translated amino acid sequence showed homology (34-31%) with glycosyl hydrolase family 1 ${\beta}$-glucosidases. The gene was overexpressed in E. coli BL21(DE3) using pET26b(+) and a 50 kDa protein was overproduced, which matched well with the calculated size of the enzyme, 49,950.87 Da. Recombinant ${\beta}$-glucosidase was purified by using a his-tag affinity column. The purified ${\beta}$-glucosidase had an optimum pH and a temperature of 5.5 and $45^{\circ}C$, respectively. Among the metal ions (5mM concentration), $Ca^{2+}$ slightly increased the activity (108.2%) whereas $Cu^{2+}$ (46.1%) and $Zn^{2+}$ (56.7%) reduced the activity. Among the enzyme inhibitors (1 mM concentration), SDS was the strongest inhibitor (16.9%), followed by pepstatin A (45.2%). The $K_m$ and $V_{max}$ values of purified enzyme were 4.04 mM and 0.92 ${\mu}mol/min$, respectively, when assayed using pNPG (p-nitrophenyl-${\beta}$-D-glucopyranoside) as the substrate. The enzyme liberated reducing sugars from carboxymethyl cellulose (CMC).

• Journal of Microbiology and Biotechnology
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• 제18권5호
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• pp.852-858
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• 2008

An extracellular protease (Mc1) was isolated from the nematode-trapping fungus Monacrosporium cystosporium by gel filtration, anion-exchange, and hydrophobic interaction chromatographies. This protease had a molecular mass of approximately 38 kDa and displayed an optimal activity at pH 7-9 and $56^{\circ}C$ (over 30 min). Its proteolytic activity was highly sensitive to the serine protease inhibitor PMSF (phenylmethylsulfonylfluoride, 0.1 mM), indicating that it belonged to the serine-type peptidase group. The Michaelis constant ($K_m$) and $V_max$ for substrate N-Suc-Ala-Ala-Pro-Phe-pNA were $1.67{\times}10^{-4}\;M$ and 0.6071 $OD_{410}$ per 30 s, respectively. This protease could degrade a broad range of substrates including casein, gelatin, BSA (bovine serum albumin), and nematode cuticle. Moreover, the enzyme could immobilize the free-living nematode Panagrellus redivivus and the pine wood nematode Bursaphelenchus xylophilus, suggesting that it might playa role in infection against nematodes. The encoding gene of Mc1 was composed of one intron and two exons, coding for a polypeptide of 405 amino acid residues. The deduced amino acid sequence of Mcl showed 61.4-91.9% identity to serine proteases from other nematode-trapping fungi. Our results identified that Mcl possessed biochemical properties including optimal reaction condition and substrate preference that are different from previously identified serine proteases.

• Journal of Microbiology and Biotechnology
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• 제18권7호
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• pp.1221-1226
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• 2008

The soft rot bacterium Pectobacterium wasabiae is an economically important pathogen of many crops. A new phytase gene, appA, was cloned from P. wasabiae by degenerate PCR and TAIL-PCR. The open reading frame of appA consisted of 1,302 bp encoding 433 amino acid residues, including 27 residues of a putative signal peptide. The mature protein had a molecular mass of 45 kDa and a theoretical pI of 5.5. The amino acid sequence contained the conserved active site residues RHGXRXP and HDTN of typical histidine acid phosphatases, and showed the highest identity of 48.5% to PhyM from Pseudomonas syringae. The gene fragment encoding the mature phytase was expressed in Escherichia coli BL21 (DE3), and the purified recombinant phytase had a specific activity of 1,072$\pm$47 U/mg for phytate substrate. The optimum pH and temperature for the purified phytase were pH 5.0 and 50$^{\circ}C$, respectively. The $K_m$ value was 0.17 mM, with a $V_{max}$ of 1,714 $\mu$mol/min/mg. This is the first report of the identification and isolation of phytase from Pectobacterium.