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아지도싸이미딘의 지속성방출형담체로서의 소수성시클로덱스트린유도체
박기배,이광표,서보연 한국약제학회 1996 Journal of Pharmaceutical Investigation Vol.26 No.2
This study has been undertaken to evaluate hydrophobic cyclodextrin(CD) derivatives as a sustained release carrier of azidothymidine(AZT). AZT. which has potent activity against AIDS and AIDS-related complex as thymidine analogue, has been reported that it has significant toxicity and short half life. Therefore, it is necessary to design sustained release oral dosage form to avoid undesirable side effects attributable to an excessive plasma concentration and to reduce the frequency of administration of AZT. Inclusion complexes of AZT with acetyl-β-cyclodextrin (ACβCD) and triacetyl-β-cyclodextrin(TAβCD) were prepared by solvent evaporation methcd. Interactions of AZT with CD were investigated by Differential Scanning Calorimetry(DSC) and Infrared Spectrophotometry(IR). The decreasing order of water solubilities of AZT and AZT-CD inclusion complexes were as follows: AZT (27.873±0.015,㎎/㎖)) AZT-ACβCD (3.377±0.03) > AZT-TAβCD (2.528±0.001). Partition coefficients of AZT-ACβCD and AZT-TAβCD inclusion complexes were increased by 1.27-fold. 1.54-fold in pH 1.2 and 1.32-fold. 1.47-fold in pH 6.8 in comparison with that of AZT. The mean dissolution time (MDT, min) which represents the rapidity of dissolution rate of AZT, AZT-ACβCD. AZT-TAβCD were 5.12. 14.02 and 19.38 min in PH 1.2 and 2.52, 15.19 and 18.19 min in pH 6.8. AZT was very rapidly and completely dissolved in pH 1.2 and pH 6.8 within 5 minutes. But AZT-CD inclusion complexes showed the sustained release pattern in comparison with AZT alone. The simultaneous in situ nasal and jejunal recirculation study to compare the intrinsic absorptivity and the property of absorption sites revealed that the absorption of AZT-TAβCD (N:35.35±1.08% J:27.47±1.18% was more than that of AZT (N: 16.89±2.25%. J:15.86±2.33%. The above results suggest that TAβCD which is a hydrophobic cyclodextrin may serve as sustained release carrier with absorption enhancing effect.
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시클로덱스트린과의 포접에 의한 케토코나졸의 용해성 및 용출 증가
장영수,박기배,이광표,안홍직,서보연 한국약제학회 1994 Journal of Pharmaceutical Investigation Vol.24 No.2
Inclusion complexes of ketoconazole (KT) with α-, β-cyclodextrin (CD) and dimethyl-β-cyclodextrin (DMβCD) in a molar ratio of 1:2 were prepared by freeze-drying and solvent evaporation methods. The interactions of KT with α-CD, β-CD and DMβCD in aqueous solution and in solid state were investigated by solubility study, infrared (IR) spectroscopy and differential scanning calorimetry (DSC). The stability constant of KT-DMβCD inclusion complex (IC) was found to be the largest among three inclusion complexes. Clear differences in IR spectra and DSC curves were observed between inclusion complexes and physical mixtures (PM) of KT-CDs. It was also shown by IR spectra and DSC curves that solvent evaporation method might be superior to the freeze-drying method in preparing the inclusion complexes of KT-CDs. The dissolution rate of KT was markedly increased by inclusion complex formation with CDs in the buffer solution at pH 4.0 and pH 6.8. The mean dissolution time (MDT, min), which represents the rapidity of dissolution, was in the order of KT-DMβCD IC (3.20) < KT-β-CD IC (4.36) < KT-α-CD IC (6.99) < KT-α-CD PM (17.46) < KT-β-CD PM (19.36) < KT-DMβCD PM (28.53). The dissolution rates of KT-CD ICsprepared by solvent evaporation method were faster than those of KT-CD ICs prepared by freeze-drying method.
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시클로덱스트린과의 포접에 의한 케토고나졸의 비점막 흡수증가
박기배,이광표,노현구,안홍직,서보연,온윤성 한국약제학회 1994 Journal of Pharmaceutical Investigation Vol.24 No.2
Inclusion complexes of ketoconazole(KT) with α^-, β^- cyclodextrin(CD) and dimethyl-β-cyclodextrin (CD) and dimethyl-β-cyclodextrin(DMβCD) as nasal absorption enhancer were prepared in 1:2 molar ratios by freeze-drying and solvent evaporation methods. In order to compare with the intrinsic absorptivity of KT in the jejunum(J) and the nasal cavity(N), the in situ simultaneous perfusion method was employed. The in situ recirculation study revealed that KT-CD inclusion complexes with the greater stability constant and the faster dissolution rate proportionally increased the absorption of KT in the J and N of rats. The rank order of apparent KT permeability(P_(app) : ㎝/sec × 10^(-5)±S.E.), corrected by surface area of absorption, was 5.10±0.3(N, KT-DMβCD) >4.13±0.4(N, KT-β-CD) >3.52±0.2(N, KT-α-CD) >2.76±0.3(J, KT-DMβCD) >2.61±0.5(J, KT-β-CD) >2.42±0.4(J, KT-α-CD) at pH 4.0. The in crease in permeability of KT-DMβCD inclusion complex was 2.6 folds in the J and 4.5 folds in the N when the perfusing solution was changed from the buffer(pH 4.0) to saline. The absorption rate of KT-DMβCD inclusion complex after nasal administration was more rapid than those of ketoconazole alone and KT-DMβCD inclusion complex after oral administration to rats. In comparision with an oral administration of ketoconazole suspension in corn oil, the relative bioavailability was calculated 137.3% for the oral and 195.0% for nasal KT-DMβCD inclusion complex in rats. The present results suggest that KT-DMβCD inclusion complex may serve as a potential nasal absorption enhancer for the nasal delivery of ketoconazole.
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