• 약학회지
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• 제45권2호
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• pp.220-226
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• 2001

A bioequivalence study of Lovastati $n^{TM}$ tablets (Dong Sung Pharmaceutical Co., Korea) to Mevaco $r^{TM}$ tablets (Choong Wae Pharmaceutical Co., Korea) was conducted according to the guidelines (No. 98-56) of Korea Food and Drug Administration (KFDA). Each tablet contained 20 mg of lovastatin. Eighteen healthy Korean male subjects received each formulation at a lovastatin dose of 80 mg (i.e., four tablets) in a 2 $\times$ 2 crossover study. There was a washout period of a week between the dose of the two formulations. Plasma concentrations of lovastatin acid were monitored by a GC/MS method for over a period of 12hr after each administration. The area under the plasma concentration-time curve from time zero to 12hr (AUC) was calculated by a linear trapezoidal method. The maximum plasma drug concentration ( $C_{max}$) and the time to reach $C_{max}$ ( $T_{max}$) were compiled from the plasma drug concentration-time data. Analysis of variance (ANOVA) of these parameters revealed that there are no differences in AUC and $C_{max}$ between the formulations. The apparent differences between the formulations in these parameters were 4.87 and 8.03% for AUC and $C_{max}$, respectively. Minimum detectable differences (%) at $\alpha$=0.1 and 1-$\beta$=0.8 were 17.84 and 15.36% for AUC and $C_{max}$ respectively. The 90% confidence intervals were -15.30~5.56 and -17.02-0.95% for AUC and $C_{max}$, respective1y. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating Mevaco $r^{TM}$ tablets and Dong Sung Lovastati $n^{TM}$ tablets are bioequivalent.ivalent.ent.alent.ent.

• Journal of Pharmaceutical Investigation
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• 제28권4호
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• pp.283-288
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• 1998

Lovastatin, one of the potent cholesterol-lowering agents, is an inactive lactone prodrug which is metabolized to its active open acid, lovastatin acid (LVA). Bioequivalence study of two lovastatin preparations, the test drug ($Mevacor^{\circledR}$: Chungwae Pharmaceutical Co., Ltd.) and the reference drug ($Lovaload^{\circledR}$: Chong Kun Dang Pharmaceutical Co., Ltd.), was conducted according to the guidelines of Korea Food and Drug Administration (KFDA). Fourteen healthy male volunteers, $23.9{\pm}3.9$ years old and $67.6{\pm}8.0$ kg of body weight in average, were divided randomly into two groups and administered the drug orally at the dose of 160 mg as lovastatin in a $2{\times}2$ crossover study. Plasma concentrations of lovastatin acid were analysed by HPLC method for 12 hr after administration. The extent of bioavailability was obtained from the plasma concentration-time profiles of total lovastatin acid after alkaline hydrolysis of the plasma samples. By alkaline hydrolysis, trace amounts of unmetabolized lovastatin were converted to lovastatin acid. The $AUC_{0-12hr}$ was calculated by the linear trapezoidal rule method. The $C_{max}$ and $T_{max}$ were compiled directly from the plasma drug concentration-time data. Student's t-test indicated no significant differences between the formulations in these parameters. Analysis of variance (ANOVA) revealed that there were no differences in AUC, $C_{max}$, and $T_{max}$ between the formulations. The apparent differences between the formulations were far less than 20% (e.g., 7.07, 5.77 and 1.18% for AUC, $C_{max}$, and $T_{max}$, respectively). Minimum detectable differences(%) between the formulations at ${\alpha}=0.05$ and $1-{\beta}=0.8$ were less than 20% (e.g., 17.2, 15.1, and 15.9% for AUC, Cmax, and Tmax, respectively). The 90% confidence intervals for these parameters were also within ${\pm}20%$ (e.g.. $-5.20{\sim}19.3$, $-5.00{\sim}16.5$, and $-10.2{\sim}12.5%$ for AUC, $C_{max}$, and $T_{max}$, respectively). These results satisfied the bioequivalence criteria of KFDA guidelines, indicating that the two formulations of lovastatin were bioequivalent.

• 한국임상약학회지
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• 제8권2호
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• pp.107-112
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• 1998

Lovastatin is a lipid lowering agent for the treatment of hypercholesterolemia and belongs to a new class of pharmacologic compounds called the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. By competitively inhibiting HMG CoA reductase, lovastatin disrupts the biosynthesis of cholesterol in hepatic and peripheral cells and increases the synthesis of high-density-lipoprotein HDL) receptors. Following oral administration, the lactone ring of lovastatin is hydrolysed to the active inhibitor of HMG CoA reductase, lovastatin acid. Lovastatin is known to have poor oral absorption and wide individual variation. In this study, bioequivalence test of two lovastatin formulations, the test drug ($Lovaload^{TM}$, Chong Kun Dang Pharmaceutical Co.) and the reference drug ($Mevacor^{TM}$, Chung Wae Pharmaceutical Co.) were conducted according to the guidelines of Korea Food and Drug Administration (KFDA). A total of 18 healthy male volunteers, $31.90\pm3.60$ years old and $72.17\;7.88$ kg of body weight in average, were evaluated in a randomized crossover manner with a 2-week washout period. Concentrations of lovastatin acid in plasma were measured upto 12 hours following a single oral administration of eight tablets (20 mg of lovastatin per tablet) by high-performance liquid chromatography with UV detection at 238 nm. The area under the concentration-vs-time curve from 0 to 12 hours $(AUC_{0-12h})$ was calculated by the trapezoidal summation method. The statistical analysis showed that there are no significant differences in $AUC_{0-12h),\;C_{max}\;and\;T_{max}$ between the two formulations ($6.72\%,\;1.52\%,\;and\;0.88\$, respectively). The least significant differences between the formulations at $\alpha$=0.05 were less than $20\%\;(11.65\%,\;19.73\%,\;and\;14.81\%\;for\;AUC_{0-12h},\;C_{max}\;and\;T_{max}$, respectively). The $90\%$ confidence intervals for these parameters were also within $\pm20\%\;(-1.50{\leq}{\delta}{\leq}15.00$, $-12.50{\leq}{\delta}{\leq}15.50,\;and\;-9.64{\leq}{\delta]{\leq}11.40{\leq}\;for\;\;AUC_{0-12h}$ ,$C_{max}\;and\;T_{max}$, respectively). In conclusion, the new generic product $Lovaload^{TM}$ was proven to be bioequivalent with the reference drug.

• Journal of Pharmaceutical Investigation
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• 제32권4호
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• pp.267-275
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• 2002

A self-microemulsifying drug delivery system (SMEDDS) was developed to increase the dissolution rate, solubility, and ultimately bioavailability of a poorly water soluble drug, lovastatin. SMEDDS was thε mixtures of oils, surfactants, and cosurfactants, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal (GI) tract. Various types of self-emulsifying formulations were prepared using four types of oil (Capryol 90, Lauroglycol 90, Labrafil M 1944 CS and Labrafil M 2125), two surfactants (Cremophor EL and Tween 80), and three cosurfactants (Carbitol, PEG 400 and propylene glycol). Thε efficiency of emulsification was studied using a laser diffraction size analyzer to determine particle size distributions of the resultant emulsions. Optimized formulations selected for bioavailability assessment were Carpryol 90 (40%), Cremophor EL (30%) and Carbitol (30%). SMEDDS containing lovastatin (20 mg and 5 mg) were compared to a conventional lovastatin tablet $(Mevacor^{\circledR},\;20\;mg/tab)$ by the oral administration as prefilled hard gelatin capsules to fasted beagle dogs for in vivo study. The arεa under the serum concentration-time curve from time zero to the last measured time in serum, $AUC_{0{\rightarrow}24h}$, was significantly greater in SMEDDS, suggesting that bioavailability increase 130% and 192% by the SMEDDS, respectively. The self-emulsifying formulations of lovastatin afforded the improvement in absolute oral bioavailability relative to previous data of lovastatin tablet formulation. These data indicate the utility of dispersed self-emulsifying formulations for the oral delivery of lovastatin and potentially other poorly absorbed drugs.

• Journal of Pharmaceutical Investigation
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• 제33권1호
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• pp.7-14
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• 2003

The PVP-based solid dispersion systems (SDs) containing lovastatin (LOS) and solubilizers (sodium lauryl sulfate, tween 80 and oleic acid) were prepared to enhance dissolution rate of practically water insoluble LOS using solvent evaporation method. Two different organic cosolvents either acetone/ethanol or acetonitrile/ethanol were used for the preparation of SDs. The LOS contents were highly decreased when acetone/ethanol cosolvents were used. The decrease of LOS contents was not caused by acetonitrile or acetone, based on HPLC data. The surface morphology as investigated by scanning electron microscope (SEM) and angle of repose as an index of flowability of SDs were highly dependent on the type and amount of solubilizers used. Based on differential scanning calorimetry (DSC) and X-ray powder diffraction data, the SDs made crystalline LOS into amorphous structure or partially eutectic mixtures. The simultaneous use of the solubilizers in SDs was also useful to increase dissolution rate of LOS in gastric or intestinal fluid. The SDs containing solubilizers reached 76% and 60% in gastric and intestinal fluid, respectively but the commercial tablet gave only less than 4%. These solubilizers in SDs could be also applicable for enhancing dissolution and bioavailability of poorly water-soluble drugs.