Evaluation of Anticancer Activity of 4-Vinyl-1-Arylsulfonylimidazolidinones

Kwak, Son-Hyok,Bang, Seong-Cheol,Seo, Hyun-Hee,Shin, Hye-Rim,Lee, Ki-Cheul,Hoang, Le Tuan Anh,Jung, Sang-Hun The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.9

To continue exploration of structure activity relationship of novel 1-(indoline-5-sulfonyl)-4-phenylimidazolidinones (1) reported as anticancer agent with broad spectrum, three 1-(arylsulfonyl)-4-vinylimidazolidinones (2) were synthesized from methyl serinate (3) in 8 steps. Reaction of intermediate 2-phenoxycarbonylaminobut-3-enyl p-toluenesulfonate (10) with arylsulfonamide in the presence of potassium carbonate produced corresponding 2 and N-(4-vinyloxazolidin-2-yl)arylsulfonamide 11 in approximately equal ratio. This reaction is believed to undergo through urea intermediate 16 as shown in scheme 3. 1-Arylsufonyl-4-vinylimidazolidinones 2 show much reduced activity against human colon carcinoma (Colo205), human chronic myelogenous leukemia (K562), and human ovarian adenocarcinoma (SK-OV-3) and compatible activity against human lung carcinoma (A549) compared to 1. Therefore phenyl at 4-position should be the optimum planar motif for the activity of 1.

Evaluation of Anticancer Activity of 4-Vinyl-1-Arylsulfonylimidazolidinones

Son-Hyok Kwak,Seong-Cheol Bang,Hyun-Hee Seo,Hye-Rim Shin,이기철,Le Tuan Anh Hoang,정상헌 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.9

To continue exploration of structure activity relationship of novel 1-(indoline-5-sulfonyl)-4-phenylimidazolidinones (1) reported as anticancer agent with broad spectrum, three 1-(arylsulfonyl)- 4-vinylimidazolidinones (2) were synthesized from methyl serinate (3) in 8 steps. Reaction of intermediate 2-phenoxycarbonylaminobut-3-enyl p-toluenesulfonate (10) with arylsulfonamide in the presence of potassium carbonate produced corresponding 2 and N-(4-vinyloxazolidin- 2-yl)arylsulfonamide 11 in approximately equal ratio. This reaction is believed to undergo through urea intermediate 16 as shown in scheme 3. 1-Arylsufonyl-4-vinylimidazolidinones 2 show much reduced activity against human colon carcinoma (Colo205), human chronic myelogenous leukemia (K562), and human ovarian adenocarcinoma (SK-OV-3) and compatible activity against human lung carcinoma (A549) compared to 1. Therefore phenyl at 4-position should be the optimum planar motif for the activity of 1

케토롤락트로메타민 서방성 펠렛의 약물속도론적 평가

곽손혁(Son Hyok Kwak),황성주(Sung Joo Hwang),장혁,남경완(Kyung Wan Nam),문영걸(Young Girl Moon),이해방(Hai Bang Lee),조선행(Sun Hang Cho),육순홍(Sun Hong Yuk),이한구(Han Koo Lee),정상영(Sang Young Jeong),이영원(Young Won Lee) 한국약제학회 2000 Journal of Pharmaceutical Investigation Vol.30 No.4

To develop a sustained-release preparation containing ketorolac tromethamine, two sustained-release pellet formulations were evaluated with a pharmacokinetic study as compared with a conventional commercial tablets (10 ㎎ Tarasyn^(TM), Roche Korea Ltd.). Two sustained-release formulations were as follows; formulation A was composed of an inner layer containing 75% of drug coated with Eudragit^(TM) RS 100 membrane and an outer layer containing 25% of drug mixed with Eudragit^(TM) NE30D, and formulation B was composed of only an inner layer containing 100% of drug coated with Eudradit^(TM) RS 100 membrane. The dissolution test was performed for two formulations. In case of conventional tablets, 2.5 ㎎ of drug per a dose was administered orally into male Albino rabbit (2.0-2.3 ㎏ of body weight) 3 times at intervals of 4 hours. In case of two sustained formulations, 7.5 ㎎ of drug was administered once orally. Blood samples were withdrawn periodically after the administration, and the blood concentration was determined by HPLC. The conventional tablets showed very high peak-trough fluctuation between administered doses, but two sustained formulations showed less fluctuation. Formulation A with the loading dose showed the time to reach minimum effective concentration (MEC) i.e. the onset time was less than 20 min, while Formulation B had more than 1 hr of the onset time. Formulation A had the more constant plasma level than formulation B. However, formulation B had a time lag, so the plasma level was less than MEC for an initial period of 1 hr. In formulation A, the plasma level was maintained within the therapeutic window (0.3-5 ㎍/㎖) for a long period. Formulation A was thought to be an ideal sustained-release formulation for ketorolac tromethamine oral delivery system.

용매증발법에 의한 부피바카인 microsphere의 제조 및 평가

곽손혁(Son Hyok Kwak),황성주(Sung Joo Hwang),이병철(Byung Chul Lee) 대한약학회 2000 약학회지 Vol.44 No.6

Various bupivacaine-loaded microspheres were prepared from poly (d,l-lactide) (PLA) or poly (d,l-lactic-co-glycolide) (PLGA) by a solvent evaporation method for the sustained release of drug. PLA and PLGA microspheres were prepared by w/o/w and w/o/o multiple emulsion solvent evaporation, respectively. The effects of process conditions such as emulsification speed, emulsifier type, emulsifier concentration and internal/external phase ratio on the characteristics of microspheres were investigated. The prepared microspheres were characterized for their drug loading, size distribution, surface morphology and release kinetics. Drug loading efficiency was higher in the microspheres prepared by w/o/o multiple emulsion than that by w/o/w multiple emulsion mehtod, because the solubility of bupivacaine HCl was decreased in oil phase compared with water phase. The prepared microspheres had an average diameter between 1 and 2mcm in all conditions of two methods. In morphology studies the PLA microspheres showed an irregular shape and smooth surface, but PLGA microspheres had a spherical shape and smooth surface. The release pattern of the drug from microspheres was evaluated on the basis of the burst effect and the extent of the release after 24h. The in vitro release of bupivacaine HCl from microspheres showed a large initial burst release and 60-80% release within one day in all conditions of two methods. The extents of the burst release against PLA and PLGA microspheres were 30-50% and 50-80% within 20min, respectively. This burst release seems to be due to the smaller size of microspheres and the solubility of drug in water.

용매증발법에 의한 부피바카인 마이크로스피어의 제오 및 평가 (II)

곽손현(Son Hyok Kwak),이시범(Sibeum Lee),우종수(Jong Soo Woo),이병철(Byung Chul Lee),황성주(Sung Joo Hwang) 大韓藥學會 2001 약학회지 Vol.45 No.6

Various bupivacaine-loaded microspheres were prepared using poly(d,1-lactide) (PLA) and poly(d ,1-lactic-co-glycolide) (PLGA) by a solvent evaporation method for the sustained release of drug. The effects of process conditions such as drug loading, polymer type and solvent type on the characteristics of microspheres were investigated. The prepared microspheres were characterized for their drug loading, size distribution, surface morphology and release kinetics. Drug loading efficiency and yield of PLGA microspheres were higher than those of PLA microspheres. The prepared microspheres had an average particle size below 5mcm. The particle size range of microspheres was 1.65∼2.24mcm. As a result of SEM, the particle size of PLA microspheres was smaller than that of PLGA microspheres. In morphology studies, micro- spheres showed a spherical shape and smooth surface in all process conditions. In thermal analysis, bupivacaine-loaded microspheres showed no peaks originating from bupivacaine. This suggested that bupivacaine base was molecular-dispersed in the polymer matrix of microspheres. The release pattern of the drug from microspheres was evaluated for 96 hours. The initial burst release of bupivacaine base decreased with increasing the molecular weight of PLGA, and the drug from microspheres released slowly, In conclusion, bupivacaine-loaded microspheres were successfully prepared from poly(d,1-lactide) and poly (d,1-lactic-co-glycolide) polymers with different molecular weights allowing control of the release rate.

경구용 백신수송체용 GFP 함유 마이크로스피어의 제조 및 평가

장혁(Ge Jiang),박종필(Jong Pil Park),곽손혁(Son Hyok Kwak),황성주(Sung Joo Hwang),맹필재(Pil Jae Maeng) 한국약제학회 2000 Journal of Pharmaceutical Investigation Vol.30 No.4

In order to design the oral vaccine delivery system, we prepared the alginate microspheres containing GFP (green fluorescent protein) as a model drug by spray method. To optimize the preparation conditions of microspheres, we investigated the effects of various parameters including nozzle pressure, nozzle opening angle, and concentrations of sodium alginate and calcium chloride. The prepared microspheres were evaluated by measuring their sizes, loading efficiency, and morphology. The particle size of microspheres was affected by the concentration of sodium alginate and calcium chloride, nozzle pressure, and nozzle opening angle. As the concentration of sodium alginate increased, GFP loading efficiency and particles size of microsphere also increased. However, it was observed to be difficult to spray the sodium alginate solution with concentration greater than 1.5% (w/v), due to high viscosity. The pressure over 3 kgf/㎠ didn`t affect the size of particles. As a result, the spraying method enabled us to prepare microspheres for oral vaccine delivery system. In this study, microspheres prepared with 1% (w/v) sodium alginate had greater loading efficiency and better spherical shape.