• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1993년도 제2회 신약개발 연구발표회 초록집
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• pp.178-178
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• 1993

생리활성 펩타이드류의 경점막 수송을 검토하기 위하여 토끼의 비강, 직장, 질 또는 눈 점막 구출액에서의 메치오닌엔케팔린 (Met-Enk) 및 그 합성 유사체인 [D-알라$^2$]-메치오닌엔케팔린아미드 (YAGFM)의 효소적 분해를 억제하고자 수종 효소억제제를 검토하였다. 방법: 토끼의 질, 직장 및 비강 점막을 차례로 적출하여 신속히 Valia-Chien투과셀에 마운팅하고, 눈의 각막은 절취하여 따로 각막 투과셀에 마운팅한 다음 등장 인산염 완충액 3.5ml씩으로 8시간씩 3회 추출하여 점막측 및 장막측 추출액을 제조하였다. 추출 완료 직후 이들 추출액에 Met-Enk 또는 YAGFM 50$\mu\textrm{g}$/ml의 농도로 첨가하고 여러 효소억제제를 단독 또는 혼합하여 첨가한 조건에서 37$^{\circ}C$에서 60 rpm으로 24시간 동안 흔들면서 경시적으로 시료를 취하여 잔존 펩타이드의 양을 HPLC법으로 정량하여 속도론적으로 비교 검토하였다. 이 연구에 사용한 효소억제제로는 아미노펩티다제의 억제제인 amastatin (AM), bestatin (BS). 엔케팔리나제 A의 억제제로 알려진 thiophan (TP), 엔케팔리나제 B의 억제작용이 있는 것으로 밝혀진 thimerosal (TM), metalloenzyme의 억제제인 에데트산나트륨 (EDTA) 등을 검토하였고 또 $\beta$-시클로덱스트린 유도체인 디메칠-$\beta$-시클로덱스트린과 2-히드록시프로필-$\beta$-시클로덱스트린이 펩타이드의 분해억제효과도 함께 검토하였다.

• Journal of Pharmaceutical Investigation
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• 제27권3호
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• pp.165-171
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• 1997

Ibuprofen, a nonsteroidal antiinflammatory, analgesic and antipyretic drug, has several limitations in clinical application because of low solubility in water and gastrointestinal irritation. Effect of ibuprofen/$2-Hydroxypropyl-{\beta}-cyclodextrin\;(HP{\beta}CD)$ inclusion compound on release of suppository was investigated. Complex formation was confirmed by $^{1}H-\;and\;^{13}C-NMR$ spectroscopy. The release of ibuprofen from suppository base in vitro was significantly increased by the complexation with $HP{\beta}CD$. The release of ibuprofen from hydrophilic base was faster than that from hydrophobic base. In vivo studies, the release rate of ibuprofen from suppository was accelerated after rectal administration in complex form. This results suggested that ibuprofen/$HP{\beta}CD$ complex can be practically used for suppository to have faster effect of ibuprofen with reduced side effect.

• Journal of Pharmaceutical Investigation
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• 제23권1호
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• pp.11-18
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• 1993

Inclusion complex of ibuprofen with $2-Hydroxypropyl-{\beta}-cyclodextrin\;(HP-{\beta}-CD)$ in aqueous solution and in the solid state was evaluated by the solubility method and the instrumental analysis such as infrared spectroscopy, thermal analysis and x-ray diffractometry. The aqueous solubility of ibuprofen was increased linearly with the increase in the concentration of $HP-{\beta}-CD$, showing an $A_L$ type phase solubility diagram. The results showed that the dissolution rate of ibuprofen was significantly increased by complexation with $HP-{\beta}-CD$. $Ibuprofen-HP-{\beta}-CD$ complex enhanced the mean plasma concentration levels and the area under plasma concentration-time curve after oral administration compared to those of the drug alone. It is concluded that the complex of ibuprofen with $HP-{\beta}-CD$ increases the dissolution rate and improves the bioavailability of the ibuprofen by the formation of a water-soluble complex.

• Journal of Pharmaceutical Investigation
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• 제27권4호
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• pp.295-301
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• 1997

Nitrendipine, a slightly soluble calcium channel blocking agent forms a solid dispersion system with $hydroxypropyl-{\beta}-cyclodextrin$, which exhibits better dissolution characteristics than the uncomplexed drug. The dissolution rate of nitrendipine was markedly increased in solid dispersion system in pharmacopeial disintegration media at pH 1.2 and pH 6.8. Four different dosage forms of nitrendipine were administered to rats: (a) nitrendipine in the solution of PEG 400; (b) nitrendipine solid dispersion system with $hydroxypropyl-{\beta}-cyclodextrin$ in a molar ratio of 1:2 by solvent evaporation method and administered in capsule form; (c) physical mixture of nitrendipine with $hydroxypropyl-{\beta}-cyclodextrin$ in a molar ratio of 1:2 and administered in capsule form; (d) nitrendipine alone administered in capsule form. Relative bioavailability after the oral administration of various dosage forms to rats with a dose of 10 mg/kg equivalent to nitrendipine was compared with that of nitrendipine in the solution of PEG 400. The AUC of solid dispersion was significantly bigger than that of nitrendipine powder. $T_{max}$ of solid dispersion was significantly shorter and $C_{max}$ was higher than that of nitrendipine powder. These results indicate that the bioavailability of nitrendipine could be improved markedly by inclusion complexation. An interesting correlation also appears to exist between the in vitro dissolution data and the area under the plasma concentration-time curves.

• 대한화학회지
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• 제36권5호
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• pp.770-779
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• 1992

$Fe(CO)_5와 알킨일리튬의 반응에서 생성된 아실 음이온 착물을 CH_3CH_2OSO_2F로 처리하는 방법으로 5종의 철 알킨일카르벤 착물 유도체(1)들을 합성하였다. [R-C≡C-C(OCH_2CH_3)]Fe(CO)_4(R = n-프로필, 시클로헥실, t-부틸, 트리메틸실릴, 페닐). 트리메틸시릴기가 치환된 유도체(1d)와 8종의 열린 고리 1,3-디엔과의 반응에서 {\eta}^3-비닐카르벤 착물 유도체(2)를 주생성물로 얻었다.$

• Journal of Pharmaceutical Investigation
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• 제30권1호
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• pp.33-37
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• 2000

One of the methods to increase the solubility of a drug is to use complexation with a cyclodextrin. Due to the hydrophobic nature of the interior cavity of the cyclodextrin, it has been known that undissociated lipophilic drugs can be included within the cyclodextrin by hydrophobic interaction. Recently, inclusion of hydrophilic or dissociated form of a drug has been investigated. In this study, the synergism of pH and complexation with $hydroxypropy-{\beta}-cyclodextrin\;(HP\;{\beta}\;CD)$ to increase the solubility of two oxicam derivatives was investigated. In addition, the effect of partition coefficient of dissociated and undissociated form of the drug on the extent of complexation with HP ${\beta}$ CD was studied. The solubility was measured by equilibrium solubility method. The solubility of tenoxicam and piroxicam increased exponentially with an increase in solution pH above the pKa of the drug in the presence and absence of HP ${\beta}$ CD. The solubility of the drugs increased linearly as a function of HP ${\beta}CD$ concentration at fixed pH. Although the stability constant of ionized species is less than that of the unionized species, the concentration of the ionized drug complex is greater than that of the unionized drug complex due to higher concentration of ionized species at pH 7.3.

• 대한화학회지
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• 제50권4호
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• pp.291-297
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• 2006

Cyclopropyl 링과 할로겐 원소가 결합된 붕소원자 사이의 hyperconjugation 효과를 알아보기 위하여 CPDFB와 CPCFB 분자의 여러 conformation과 transition state 구조들에 대해 DFT와 ab initio 방법을 사용하여 다양한 레벨에서 구조최적화 및 NBO 분석을 수행하였다. 그 결과 주요 상호작용 형태는 화합물에 따라 단일결합 오비탈 (C1-C3, C2-C3) n* (B9) 또는 *(B9-Cl11) 오비탈로 전자를 제공하는 것이었고 이때 안정화 에너지는 CPDFB 분자의 경우 6.63 kcal/mol, CPCFB 분자의 경우는 conformation에 따라 6.97(E-form)/6.79(Z-form) kcal/mol 이었다. 또한, BF2와 BFCl 기의 내부회전에 의한 회전장벽의 크기는 각각 5.3~6.7 kcal/mol과 5.7~6.5 kcal/mol로 기존에 보고된 실험값과 잘 일치함을 보였다. 마지막으로 CPCFB 분자의 conformers 중에서 Z-form이 global minimum으로 확인되었고 E-form 보다 0.2 kcal/mol 정도 안정하였다.

• 대한화학회지
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• 제42권6호
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• pp.646-651
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• 1998

기체크로마토그래피에서 황화합물의 분자구조와 용리시간과의 관계를 연구하였다. 분석대상인 황화합물은 황화수소, 이산화항, 이황화탄소, 에틸메르캅탄, 황화이메틸, 이소프로필메르캅탄, 노말프로필메르캅탄, 황화에틸메틸, 황화이에틸, t-부틸메르캅탄, 테트라히이드로티오핀, 티오핀, 2-클로르티오핀이었다. 다중선형회귀분석방법으로 용리시간과 분자의 설명인자 사이의 상관관계를 설명할 수 있었다. 기체크로마토그래피에서 오븐 온도 프로그램을 30$^{\circ}C$에서 10.5분간 유지 후 15$^{\circ}C$/min 비율로 150$^{\circ}C$까지 증가하는 것으로 설정하였다. SAS를 사용하여 사대적 용리시간에 대한 예측식을 다음과 같이 얻을 수 있었다. $RRT=0.121bp+14.39dp-8.94dp^2+0.0741sqmw-35.78\;(N=8,\;R^2=0.989, \;Variance=0.175,\;F=66.21)$. 상대적 용리시간은 끓는점, 분자량의 제곱근 및 분자쌍극자모멘트의 함수이며 끓는점에 의한 영향이 가장 컸다. 무극성 컬럼 사용시 분자쌍극자모멘트가 0.805D에서 용리시간이 가장 길었다. 분자구조가 평면성을 띠면서 대칭성이 높은 물질은 용리속도가 작았다. 훈련세트(training set)에서 SAS 프로그램을 통해 얻은 예측식의 상관계수의 제곱$(R^2)$은 0.989이며 분산은 0.175이다. 시험세트(testing set)에서 3개의 황화합물에 대하여 예측식을 통해 얻은 상대적 용리시간과 관측된 값 사이의 분산은 0.432 이었다.

• 약학회지
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• 제56권3호
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• pp.164-172
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• 2012

This study was aimed to increase the solubility, dissolution and permeation rates of atorvastatin calcium (ATC) using bile salt and/or 2-hydroxypropyl-${\beta}$-cyclodextrin ($HP{\beta}CD$). From solubility studies, sodium deoxycholate (SDC) among bile salts studied was found to have the highest solubilizing effect on ATC ($4.4{\pm}0.4$ mg/ml), and the order of increasing solubility was SDC>sod. cholate>sod. glycocholate>sod. taurodeoxycholate>sod. taurocholate>conjugated bile acid. ATC solid dispersions were prepared at various ratios of drug to SDC and/or $HP{\beta}CD$, and evaluated by differential scanning calorimetry (DSC), dissolution studies and dissolution-permeation studies. DSC curves showed amorphous state of ATC in the physical mixture and solid dispersion. Dissolution rates of ATC-SDC solid dispersions and physical mixture were markedly increased at pH 6.8, but decreased at pH 1.2 with greater proportions of SDC due to the precipitation of SDC, compared with that of drug alone. On the other hand, dissolution rates of ATC-$HP{\beta}CD$ solid dispersion and physical mixture at pH 1.2 were varied with the ratio of drug to carriers. From duodenal permeation studies, it was found that fluxes of ATC (donor dose: 0.5 mg/3.5 ml) in the presence of 25 mM sodium glycocholate, SDC, sod. cholate and sod. taurocholate $(5.7{\pm}0.9$, $5.6{\pm}0.9$, $4.8{\pm}0.7$ and $4.6{\pm}0.9\;{\mu}g/cm^2/hr$, respectively) were enhanced, compared with drug alone ($3.4{\pm}0.9\;{\mu}g/cm^2/hr$). In the dissolution-permeation studies, 1 : 9 : 10 (w/w) ATC-SDC-$HP{\beta}CD$ solid dispersion increased the flux 2.2 times, compared with 1 : 5 : 4 (w/w) ATC-lactose-corn starch mixture as control. In conclusion, solid dispersions with bile salt and $HP{\beta}CD$ were found to be an effective means for increasing the dissolution and permeation rates of ATC.