인체혈장 중 에탐부톨의 HPLC 분석법의 검증 및 단일용량 투여에 의한 약물동태 연구

곽혜선,박경호,최준식,송진아,성민경,장정옥,이화정 한국약제학회 2005 Journal of Pharmaceutical Investigation Vol.35 No.2

An HPLC method was employed for the determination of ethambutol in human plasma. After addition of internal standard (IS, octylamine, 2 μg/mL) and alkalinization of the plasma with 5 M sodium hydroxide, the drug and IS were extracted into the mixture of chloroform and diethyl ether (40:60, v/v). Following a 15-min vortex-mixing and a 10-min centrifugation, the organic phase was spiked with 100 pL of phenylethylisocyanate (2000 μg/mL) for chemical derivatization, mixed for 5 min and evaporated to dryness under a stream of nitrogen. The residue was reconstituted with 100 μL of mobile phase and 20 pL was injected into Cl8 column with a mobile phase consisting of methanol:water (70:30, v/v). The samples were detected utilizing an ultraviolet detector at 200 nm. The method was specific and validated with a limit of 0.15 μg/mL. Infra- and inter-day precision and accuracy were acceptable for all quality control samples including the lower limit of quantification. The applicability of this method was demonstrated by analysis of human plasma after oral administration of a single 1200-mg dose to 20 healthy subjects. From the plasma ethambutol concentration vs. time curves, the mean AUC was 9.61 ± 1.64 μg hr/mL. and Cmax of 2.68 μg/mL reached 2.73 hr after administration. The mean biological half-life of ethambutol was 3.46 ± 1.21 hr. Based on the results, this simple and validated assay could readily be used in any pharmacokinetic studies using humans.

국내 희귀의약품의 현황 및 과제 : 희귀질환에 대한 의약품 공급을 중심으로

김희은,곽혜선 이화여자대학교 약학연구소 2008 藥學硏究論文集 Vol.- No.17

This study was aimed to investigate the curretit status and expectations of orphan drugs in Korea. The Korea Orphan Drug Center was established to supply many medicines for the patients with rare diseases. Among the medicines supplied by the Center, the number designated as the orphan drugs by the K-FDA is quite few. However, a few of medicines are not under circulation even if the items are designated as the orphan drugs. Neoplasm-related medicines, infectious and parasitic disease-related medicines, endocrine, nutritional and metabolic disease-related medicines are the ones circulated most. There are several unapproved drugs among the medicines supplied by the Center. It's because the director of the Center can import the goods without a process to getting an approval from the KFDA. The Korea Orphan Drug Center has contributed to the selection of the medicines for treating the rare disease. On the contrary, some problems remain in the supply process. The safety and effectiveness of the medicines supplied by the Center are not guaranteed. So far, rare diseases have no apecific legal definition, and therefore are only referred to in terms of the population of patients, which prevent from establishing the lange of medicines. The introduction of Special Access Program ot Access to Unapproved Therapeutic Goods will be the solution ot these problems, In addition, it is, another solution to keep intimate relations with the Rare and Intractable Disease Center and the Medicine Safety Infonnation Center which will be open soon.

사람 혈장 중 부메타니드의 HPLC 분석법 검증 및 단일 용량 투여에 의한 약물동태 연구

박혜영,곽혜선,전인구 한국약제학회 2005 Journal of Pharmaceutical Investigation Vol.35 No.1

A high-performance liquid chromatographic method was employed for the determination of bumetanide in human plasma. After addition of internal standard (IS, naproxen) and acidification of the plasma with 1 M hydrochloric acid, the drug and IS were extracted into dichloromethane. The organic phase was back-extracted into 1 M sodium bicarbonate solution and 50 μl of the aqueous phase was injected onto a reversed-phase C18 column with a mobile phase consisting of methanol : water : glacial acetic acid = 65 : 35 : 1. The samples were detected utilizing a fluorescence detector (excitation wavelength 235 nm, emission wavelength 405 nm). The method was specific and validated with a lower limit of 5 ng/mL. Intra- and inter-day precision and accuracy were acceptable for all quality control samples including the lower limit of quantification. The applicability of the method was demonstrated by analysis of plasma after oral administration of a single 2 mg dose to 24 healthy subjects. From the plasma bumetanide concentration vs. time curves, the mean AUC was 246.5 ± 73.8 ng hr/mL and C_(max) of 132.1 ± 40.9 ng/mL reached 1.2 hr after administration. The mean biological half-life of bumetanide was 1.1 ± 0.2 hr. Based on the results, this simple and validated assay method could readily be used in any pharmacokinetic or bioequivalence studies using humans.

국내 독감백신 투여현황과 투여 결정에 영향을 주는 요인에 관한 연구

정주연,정선영,곽혜선 이화여자대학교 약학연구소 2005 藥學硏究論文集 Vol.- No.15

This study was aimed to determine influenza vaccination coverage in 2004 in Korean and investigate the factors associated with vaccination. Documentation of vaccination status and baseline data was conducted by a survey using questionnaire sheets. Baseline data and vaccination status were documented on 1465 people out of whom 60.1% received the influenza vaccine. Forth-seven percent of the responders were male; 4% were aged 1-12, 32% were aged 13-39, 32% were aged 40-64 and 32% were aged 65 or older. Twenty-three percent reported a chronic illness, increasing their risk for complications from influenza. Predictors of influenza vaccination were: older age (OR=11.7, 95% CI 5.1-26.8), the presence of chronic illness (OR=2.3, 95% CI 1.1-4.7), previous vaccination(OR=1.8, 95% CI 1.1-2.8), belief that influenza vaccine is effective in preventing influenza (OR=2.5, 95% CI 1.1-5.7) and education level (OR=1.7, 95% CI 1.0-2.7). Immunization rates were much higher in those who will take immunization again (OR=10.4 95% CI 5.5-19.6). Factors affecting the decision on immunization were self-determination (43.6%), public relations (24.1%), recommendation from family members or friends (22.4%) and consulting with health professionals (5.8%). The main reason not to take influenza vaccine was the thought that they are healthy (50.1%). Overall, influenza vaccine coverage was high in those aged 65 or older. Immunization against influenza was influenced more by existing medical problem and belief about th vaccine's effectiveness, rather than sex or residence.

Enhanced bioavailability of piroxical via salt formation with ethanolamines

Gwak, Hye-Sun,Choi, Jun-Shik,Choi, Hoo-Kyun 이화여자대학교 약학연구소 2005 藥學硏究論文集 Vol.- No.16

Piroxicam can be ionized as a zwitterion that has two pKa values (pKa_(1) = 1.86 and pKa_(1) = 5.46). Consequently, piroxicam has a low solubility in both polar and nonpolar media, and a low lipophilicity, which results in a low permeability. Three piroxicam-ethanolamine salts were prepared, which had a higher area under the curve (AUC) than piroxicam. There were minimal differences in the AUC among the salt forms. It was reported that the piroxicam triethanolamine salt had a lower permeability across the::kin than piroxicam but it had a higher oral bioavaitability. Piroxicam monoethanolamine showed the highest C_(max) followed by piroxicam diethanolamine and piroxicam Iriethanolarnine. The dissolution rates of piroxicam and its salts were similar at pH 1.2. Piroxicam monoethanolamine showed the highest dissolution rate at pH 6.8, which was followed by the piroxicam diethanolamine and piroxicam triethanolarnine salts. The order of dissolution rate at pH 6.8 matched the order of C_(max) or the AUC after oral administration.

In Vitro Percutaneous Absorption of Tenoxicam from Pressure-sensitive Adhesive Matrices across the Hairless Mouse Skin

Gwak, Hye-Sun,Chun, In-Koo The Pharmaceutical Society of Korea 2001 Archives of Pharmacal Research Vol.24 No.6

To investigate the feasibility of developing a new tenoxicam plaster, the effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from a pressure-sensititre adhesive (PSA) matrices across the dorsal hairless mouse skin were studied. Vehicles employed in this study were propylene glycol (PC)-oleyl alcohol (OAI), PG-oleic acid (OA), and diethylene glycol monoethyl ether (DCMI)-propylene glycol monolaurate (PCML) cosolvents with/without fatty acids. In this studys amines such as triethanolamine (TEA) and tromethamine (TM) were additionally used as a solubilized. Among PSAs used, $Duro-Tak^{\circledR}$87-2510 showed much higher release rate than either $Duro-Tak^{\circledR}$ 87-2100 or $Duro-Tak^{\circledR}$87-2196. The relatively high flux rate was obtained with the formulation of DCMI-PCML (40:60, v/v) with 3% OA and 5% TM, and the flux increased as a function of the dose;the initial flux up to 12 h was $4.98{\pm}1.38{\;}{\mu\textrm{g}}/{\textrm{cm}^2}/h$ at the tenoxicam dose of $50{\;} mg/70{\;}{\textrm{cm}^2}$. This flux was much higher than that of a commercial piroxicam patch ($Trast^{\circledR}$) ($1.24{\pm}0.73{\;}{\mu\textrm{g}}/$\textrm{cm}^2/hr$) with almost only one-third that of the commercial patch. Therefore, these observations indicated that these composition of tenoxicam plaster may be practically applicable.

Effect of Vehicles and Enhancers on the in vitro Skin Penetration of Aspalatone and Its Enzymatic Degradation Across Rat Skins

Gwak, Hye-Sun,Chun, In-Koo The Pharmaceutical Society of Korea 2001 Archives of Pharmacal Research Vol.24 No.6

The feasibility of skin penetration was studied for aspalatone (AM, acetylsalicylic acid maltol ester), a novel antithrombotic agent. In this studys hairless mouse dorsal skins were used as a model to select composition of vehicle and AM. Based on measurements of solubility and partition coefficient, the concentration of PC that showed the highest flux for AM across the hairless mouse skin was found to be 40%. The cumulative amount permeated at 48 h, however, appear inadequate, even when the PC concentration was employed. To identify a suitable absorption enhancer and its optimal concentration for AM, a number of absorption enhancers and a variety of concentration were screened for the increase in transdermal flux of AM. Amongst these, linoleic acid (LOA) at the concentration of 5% was found to have the largest enhancement factor (i.e., 132). However, a further increase in AM flux was not found in the fatty acid concentration greater than 5%, indicating the enhancement effect is in a bell-shaped currie. In a study of the effect of AM concentration on the permeation, there was no difference in the permeation rate between 0.5 and 1% for AM, below its saturated concentration. At the donor concentration of 2%, over the saturated condition, the flux of AM was markedly increased. A considerable degradation of AM was found during permeation studies, and the extent was correlated with protein concentrations in the epidermal and serosal extracts, and skin homogenates. In rat dorsal skins, the protein concentration decreased in the rank order of skin homogenate > serosal extract > epidermal extract. Estimated first order degradation rate constants were $6.15{\pm}0.14,{\;}0.57{\pm}0.02{\;}and{\;}0.011{\pm}{\;}0.004{\;}h^{-1}$ for skin homogenate, serosal extract and epidermal extract, respectively. Therefore, it appeared that AM was hydrolyzed to some extent into salicylmaltol by esterases in the dermal and subcutaneous tissues of skin. taken together, our data indicated that transdermal delivery of AM is feasible when the combination of PC and LOA is used as a vehicle. However, since AM is not metabolically stable, acceptable degradation inhibitors may be nervessary to fully realize the transdermal delivery of the drug.

Effect of Vehicles and Enhancers on the In Vitro Permeation of Melatonin through Hairless Mouse Skin

Gwak, Hye-Sun,Kim, Seung-Ung,Chun, In-Koo The Pharmaceutical Society of Korea 2002 Archives of Pharmacal Research Vol.25 No.3

The effects of vehicles and penetration enhancers on the in vitro permeation of melatonin through dorsal hairless mouse skin were investigated. Propylene glycol laurate (PGL), isopropyl myristate (IPM), propylene glycol monolaurate (PGML) and propylene glycol monocaprylate (PGMC) showed high permeation fluxes and PGL, PGML and PGMC decreased lag time significantly. In both of the binary co-solvents of diethylene glycol monoethyl ether (DGME)-PGL and DGME-IPM, the highest fluxes were achieved at 20% of DGME, which were $10.5{\pm}1.5$ and $9.1{\pm}2.4{\;}{\mu\textrm{g}}/cm^2/h$, respectively. Among fatty acids used as a permeation enhancer, capric acid and oleic acid in DGME-PGL (80:20 v/v) showed relatively high enhancing effects. Capric acid also shortened the lag time of melatonin from $2.4{\pm}0.7{\;}to{\;}1.3{\pm}0.2{\;}h$. Oleic acid, however, failed to shorten the lag time. Therefore, for effective solution formulations in terms of permeation flux and lag time, capric acid-containing DGME-PGL (80 : 20 v/v) could be used to enhance the skin permeation of melatonin.

Bioequivalence Evaluation of Two Atenolol Tablet Preparations in Korean Healthy Male Volunteers

Gwak, Hye-Sun,Chun, In-Koo The Korean Society of Applied Pharmacology 2007 Biomolecules & Therapeutics(구 응용약물학회지) Vol. No.

This study was conducted to compare the bioavailability of two brands of atenolol (50 mg) tablets, which are a generic product of $Ditent^{\circledR}$ (Daewon Pharmaceutical Co., Ltd., Korea) and an innovator product $Tenormin^{\circledR}$ (Hyundai Pharm. Ind. Co., Ltd., Korea), in 20 healthy Korean male volunteers. The volunteers received a single 50 mg dose of each atenolol formulation according to a randomized, two-way cross-over design. The washout period between treatments was 1 week. Plasma samples were obtained over a 24-hour interval, and atenolol concentrations were determined by HPLC with a fluorescence detector. From the plasma atenolol concentration vs. time curves, the following parameters were compared: area under the plasma concentration-time curve ($AUC_{0-24}$), peak plasma concentration ($C_{max}$), time to reach peak plasma concentration ($T_{max}$), and terminal first order elimination half-life ($t_{1/2}$). No statistically significant difference was obtained between the $T_{max}$ values, and the logarithmic transformed $AUC_{0-24}$ and $C_{max}$ values of the two products. The 90% confidence interval for the ratio of the logarithmically transformed AUC and $C_{max}$ values of $Ditent^{\circledR}$ over those of $Tenormin^{\circledR}$ were calculated to be between 0.85 and 1.04, and 0.89 and 1.07, respectively; both were within the bioequivalence limit of 0.80-1.25. The mean of $T_{max}$ in $Tenormin^{\circledR}$ group was 3.1 hour, and that in Ditent$^{\circledR}$ group was 3.2 hour. The values of $t_{1/2}$ between the two products were found comparable, and the mean values were 5.2 hour in the both products. Based on these results, it was concluded that $Ditent^{\circledR}$ was comparable to $Tenormin^{\circledR}$ in both the rate and extent of absorption, indicating that $Ditent^{\circledR}$ was bioequivalent to the reference product, $Tenormin^{\circledR}$.

Pharmacogenomic Study for Individualized Warfarin Therapy

GWAK Hye-Sun,KIM Han-Oll,LEE Na-Ra,CHOI Yun-Jeong,CHANG Byung-Chul 大韓藥學會 2010 大韓藥學會 總會 및 學術大會 Vol.2010 No.2