소염진통제의 경피투여 제제의 개발과 평가

이계주(Gye Ju Lee),홍석천(Seok Cheon Hong),우종수(Jong Su Woo),이덕근(Duck Kun Lee),김은희(Eun Hee Kim),남진경(Jin Kyung Nam),박종범(Jong Bum Park),황성주(Sung Joo Hwang) 한국약제학회 1998 한국약제학회 총회 및 학술대회 요지집 Vol.- No.28

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이온교환수지를 이용한 새로운 오메프라졸 복합체 개발

이계주(Gye Ju Rhee),이기명(Ki Myung Lee),김은영(Eun Young Kim),이창현(Chang Hyun Lee),황성주(Sung Ju Hwang) 대한약학회 1994 약학회지 Vol.38 No.3

Omeprazole(OMZ)-cholestyramine(CHL) and various OMZ-Dowex resin complexes were prepared by reaction between OMZ and activated resins in O.lN NaOH solution. And their physical properties were tested by means of infrared(IR), differential scaning caloimeter(DSC), X-ray diffraction. Chemical stability of OMZ-CHL was increased markedly compared with OMZ and the decomposition of OMZ-CHL followed the pseudo first-order kinetics and the rate constants were 2.743 X 10-4/day at 20oC, 7.83 X 10-3/day under 80% RH and 1.68 X 10-2/day 1 under UV radiation, respectively. On the other hand, the rate constants of OMZ were 2.996 X 10-4/day at 20oC, 1.17 X 10-2/day under 85% RH, and 4.07 X 10-2/day under UV radiation, respectively. The rates of dissolution of OMZ-CHL bulk and OMZ-CHL tablet were 100% and more than 85% in 15 minutes, respectively, which ere increased than OMZ base and OMZ-tablet. In the acute toxicological test, the value of oral LD50(mouse) was 4.608g/kg. OMZ-CHL was pelletized using lactose, polyethyleneglycol(PEG), D-sorbitol, Avicel PH 101, sodium laurylsulfate and polyvinylpyrrolidone(PVP) K-30, and enteric coated with HPMCP, Myvacet, acetone, ethanol and cetanol, of which dissolution rate was found to be more than 85% in 10 minutes. From the above results, it was found that OMZ-CHL is a useful means for development of new oral dosage forms of OMZ.

오메프라졸과 Hydroxypropyl-beta-cyclodextrin의 포접화합물 형성과 특성

이계주(Gye Ju Rhee),황성주(Sung Joo Hwang),이기명(Ki Myung Lee) 대한약학회 1993 약학회지 Vol.37 No.4

Inclusion complex of omeprazole(OMZ) with hydroxypropyl-beta-cyclodextrin(HP-beta-CD) was prepared by freeze-drying method. The complexation was confirmed by means of UV, CD, IR, DSC, XRD and 1H-NMR spectra. The benzimidazole moiety of OMZ might be found to be included into the cavity of HP-beta-CD and the inclusion complex appeared to be AL type. The stoichiometric ratio of OMZ : HP-beta-CD was found to be 1 : 1, and the stability constants of the inclusion complex by solubility and UV method were about 34 and 45 M-1, respectively. The dissolution of OMZ was significantly enhanced from powder and. yablet of OMZ-HP-beta-CD complex when compared to those of OMZ alone, and oil-to-water partition coefficient of OMZ-HP-beta-CD complex was significantly higher than that of OMZ alone. Therefore, it was expected that the bioavailability of OMZ could be improved markedly by inclusion complexation of OMZ with HP-beta-CD.

제산제 알루미나수화물의 콜로이드성과 제산능

이계주(Gye Ju Rhee),이기명(Ki Myung Lee) 대한약학회 1991 약학회지 Vol.35 No.4

Rheological, colloidal and micromeritical properties were followed to investigate aging mechanisms of hydrous aluminum oxide suspension using Zeta-meter systems, BET adsorption apparatus, Master sizer and electronmicroscope. The results indicate that hydrous aluminum oxide suspension revealed plastic flow with thixotropy. The viscosity, thixotropy and yield value were increased with increasing concentration. During aging process, the viscosity and thixotropic index were increased by an addition of glycerin, however, sorbitol stabilized aging process of the suspension being accompanied with growth of particle size and reduction in specific surface area, pore area and pore volume, and consistency. Diminution of adsorptive power of the particles was also protected by addition of sorbitol to hydrous aluminum oxide suspension. From these results, one of aging mechanism of hydrous aluminum oxide suspension assumed growth and/or crystallization of colloidal particles in aqueous suspension.

국소치료용 구강점막패취의 제제설계 및 약제학적 특성

이계주(Gye Ju Rhee),서현주(Hyun Joo Suh),이덕금(Duck Geun Lee),박종범(Jong Bum Park),신광현(Kwang Hyun Shin),황성주(Sung Joo Hwang) 대한약학회 1998 약학회지 Vol.42 No.2

In order to ameliorate disadvantages of buccal ointments and mucoadhesive tablets used for the treatment of aphthosis, a thin mucoadhesive patch containing triamcinolone acetonide was designed and evaluated for the pharmaceutical properties. The adhesive gel layer consisting of Noveon AA-1, hydroxypropylcellulose-M and ethylcellulose N 100, and the protective gel layer of ethylcellulose N 100, Eudragit RSPO and castor oil have been formulated and various properties such as viscosity of drug gel layer, thickness, in vitro adhesion time, adhesive strength, surface pH, content uniformity and drug release are tested. The mean viscosity of drug-containing gel layer was found to increase with increasing amount of Noveon OAA-1 or hydroxypropylcellulose-M. The optimum formulation showed the thickness of 171 mcm, surface pH of 4.6, in vitro adhesion time of 8 hours and adhesive strength of 272.7g/sheet. The drug content of each patch was relatively homogeneous with the value of 273+/-6.77g. Drug release study showed that compared to mucoadhesive tablet, the patch showed a faster drug release. Drug release was delayed by hydroxypropylcellulose-M, but not by ethylcellulose N 100. The patches prepared were nonirritant and the muco adhesion was better than the commercial product (AftachR) on the market. Based on these results, this mucoadhesive patch is expected to be an effective dosage form for the treatment of aphthosis.

HPLC법에 의한 종합감기약중 구성성분의 동시 정량

이창현,이계주,Lee, Chang-Hyun,Rhee, Gye-Ju 대한약학회 1988 약학회지 Vol.32 No.4

A simple and sensitive HPLC method was developed for the simultaneous determination of ten kinds of active ingredients formulated in commercial cough-cold mixtures. A group of Pseudoephedrine HCl, dl-Methylephedrine HCl, Noscapine, Chlorophenylamine maleate, Dextromethorphan HBr and Phenylpropanolamine HCl were determined at 254nm using a Novapak $C_{18}$ column with mobile phase consisting of a mixture of methanol-acetonitrile-1, 4dioxane-tetrahydrofuran-water(12 : 20 : 20 : 5 : 43, pH4.7) containing 0.013M-dioctyl sodium sulfosuccinate. The another group of Acetoaminophen, Caffeine, Guaifenesin and Ethenzamide were also determined at 254nm using a Novapak $C_{18}$ column as the stationary phase, and a mixture of methanol-1% aqueous acetic acid (3 : 7). The results indicate that these methods are accurate and precise with relative standard deviation of not more than 1% (n=5) for the above active ingredients.

오메프라졸 함유 직장좌제의 약물속도론적 연구

이창현(Chang Hyun Lee),황성주(Sung Joo Hwang),권광일(Kwang Il Kwon),이계주(Gye Ju Rhee) 대한약학회 1993 약학회지 Vol.37 No.5

The pharmacokinetics and relationship between in vitro dissolution and in vivo fraction absorbed were investigated after intravenous(iv) injection of omeprazole(OMZ), oral administration of OMZ capsules and rectal administration of 8 types of suppositories. The plasma concentration of OMZ (Cp)-time (t) curve after iv. administration fitted a two-compartment open model and the equation which best fitted the p kinetics of OMZ was Cp = 13.936 e-8.78t + 2.973 e-0.716t. The bioavailabilities of OMZ in Witepsol H15 base (Supp-2) and PEG 4000 base (Supp-6) suppositories were 40.7% and 33.4%, respectively, which are higher(p<0.001) than 13% of oral administration of capsule. The avoidance fractions of the first-pass metabolism for Supp-2 and Supp-6 suppositiories were 31.8% and 23.4%, respectively, suggesting that the rectal application of OMZ may be a more adequate route of administration than oral one.

오메프라졸의 안정화를 위한 에칠렌디아민 복합체 개발

오세종,김은영,김길수,김윤정,이계주,Oh, Sea-Jong,Kim, Eun-Young,Kim, Kil-Soo,Kim, Yuon-Jeung,Lee, Gye-Ju 한국약제학회 1995 Journal of Pharmaceutical Investigation Vol.25 No.1

To stabilize omeprazole(OMP), ethylenediamine(ED) complex of omeprazole(OMPED) was prepared by reaction between OMP and ED in methanol, and the complex formation was confirmed by the instrumental analysis, i.e., IR, DSC, EA, NMR, MS and XRD. The rates of decomposition of OMP and OMPED in aqueous solution and the shelf lives at standard temperature were measured by accelerated stability analysis. The results are summarized as follows; The mole ratio of OMP and ED in OMPED complex is 1:1, the energy of formation within OMPED might be combined between polar imidazole group of OMP with induced a dipole amine group in the readily polarizable ED molecule. At standard temperature the degradation rate constant of OMP in aqueous solution is $2.540{\times}10^{-2}\;hr^{-1}$ and the shelf life is 4.15 hrs, and in the case of OMPED the degradation rate constant is $7.986{\times}10^{-4}\;hr^{-1}$ and the shelf life is 131.96 hrs. So, the OMPED has about 31 times longer shelf life than OMP. The activation energy of OMP and OMPED are 5.23 and 18.55 kcal $mole^{-1}$ respectively. The stability of OMP is dependent chiefly on pH in the solutions and it decomposes readily in acidic medium by hydrogen ion catalized reaction but becomes stable beyond pH 9.0. In case of the ED-complex, OMPED is stable in neutral as well as in dilute acidic solutions even in pH 6, OMPED is very stable to light(UV), that is, the rate constant and shelf life of OMP are $k=1.0188{\times}10^{-2}\;day^{-1}$, $T_{90%}=4.5 \;days$, on the other hand, the those of OMPED are $k=7.138{\times}10^{-4}\;day^{-1}$, $T_{90%}=64.1\;days$, respectively. From the above results, it is thought that new dosage forms could be developed by using the OMPED as a potential OMP complex.

오메푸라졸 함유 직장좌제의 제제설계

이창현(Chang Hyun Lee),황성주(Sung Joo Hwang),오세종(Sea Jong Oh),이계주(Gye Ju Rhee) 대한약학회 1993 약학회지 Vol.37 No.4

In order for formulation of rectal containing OMZ, the OMZ suppositories were prepared using water-soluble base, PEG 4000 base and oil-soluble base, Witepsol H 15. Chemical stability of OMZ in suppositories was increased when Witepsol H 15 was used as a suppository base and arginine was added as a stabilizer. The decomposition of OMZ in suppository bases followed the first-order kinetics and their rate constants were 0.11 day-1(t1/2 = /6.25 days) for Witepsol H 15 suppository and 0.48 day-1 (t1/2 = /1.43 days) for PEG 4000 suppository, respectively. On the other hand, the decomposition rate constants of Witepsol suppository and PEG suppository stabilized with arginine were 3.89 X 10-1(t1/2 = 171.1 days) and 8.76 X 10-3 day (t1/2 = 79.9 days), respectively. Shelf-lives of the Witepsol and PEG suppositories stabilized with arginine were t90% = 291.8 days and t90%=282.1 days at 35oC and 75% RH, respectively. The dissolution test of OMZ suppositories was performed by rotating dialysis cell(RDC) method and the release rate constant was calculated by the simplified Higuchi''s equation, Q''=K'' t1/2. Dissolution of OMZ from suppositories was augmented as arginine was added, particle size of OMZ was reduced and a suitable surfactant such as SLS was added. RDC method was more appropriate and available than Paddle method to evaluate the dissolution rate of lipophilic-base suppositoies. Arginine was found to be a very useful exipient for the enhancement of stability and dissolution of OMZ in suppositories.

오메프라졸과 베타-시클로덱스트린과의 포접화합물 형성에 따른 특성

소재일(Jae Il So),이창현(Chang Hyun Lee),이계주(Gye Ju Rhee) 대한약학회 1991 약학회지 Vol.35 No.5

To increase the stability and bioavailability of Omeprazole(OMP), which is used newly as a proton-pump inhibitor, inclusion complex of OMP with beta-cyclodextrin(beta-CD) was prepared by coprecipitation method and its characteristics were ascertained by means of solubility test, DSC, IR, and the accelerated stability analysis. The type of OMP inclusion complex is classified as Bs-type on phase solubility diagram, and the stoichiometric ratio of OMP: P-CD complex is 1 : 2 and formation constant is 80.82/mole. The solubility of the complex could be increased remarkably by complexation compare with OMP. Degradation process of both OMP and OMP complex followed apparent first-order kinetics, of which degradation rate constants and activation energies are k25 = 8.1 X 10-4/day, Ea = 22 Kcal/mole (OMP), and k25 = 4.65 X 10-6/day, Ea = 35 Kcal/mole (complex), respectively. These results show the increase of the stability and solubility of OMP markedly, therefore it is believed that the improvement of stabilization for OMP by inclusion complexation might be practically available.