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1.
To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated and compared with the use of the parent beta-cyclodextrin (beta-CyD). Among the three beta-CyDs, HP-beta-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of beta-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and beta-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of beta-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When beta-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-beta-CyD (approximately 26% of dose) and DM-beta-CyD (approximately 21% of dose), compared with beta-CyD (approximately 5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic beta-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
2.
Shusei Ito Yumiko Toriumi Miki Demachi Takeshi Adachi Yuji Ito Hidehumi Hayashi Fumitoshi Hirayama Kaneto Uekama 《European journal of pharmaceutical sciences》1995,3(6):323-328
The inclusion complexation of 4-t-butyl-2′-car☐ymethoxy-4′-(3-methyl-2-butenyloxy)chalcone (SU-740), a newly developed antiulcer agent, with β-cyclodextrin (β-CyD) in water and in solid state was investigated for the purpose of improving the low aqueous solubility and oral bioavailability. SU-740 formed 1:1 and 1:2 (guest:host) inclusion complexes in water and in the solid state and the 1:1 stability constant was much higher than the 1:2 stability constant. The dissolution rate of SU-740 was significantly improved by the complexation with β-CyD, suggesting the enhanced bioavailability. 相似文献
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K Uekama K Ikegami Z Wang Y Horiuchi F Hirayama 《The Journal of pharmacy and pharmacology》1992,44(2):73-78
To prevent the crystal-growth of nifedipine during storage, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) was employed as a hydrophilic drug carrier and compared with polyvinylpyrrolidone K-30 (PVP). Amorphous nifedipine powders were prepared by spray-drying with HP-beta-CyD or PVP, and their crystal-growing behaviour at accelerated storage conditions were examined by X-ray diffraction analysis and microscopy. Although PVP initially retarded the crystallization of nifedipine, it failed to control the increase of crystal size after prolonged storage at 60 degrees C, 75% r.h., resulting in a remarkable decrease in dissolution rate in water. In sharp contrast, a relatively fine and uniform size of nifedipine crystals was maintained in the HP-beta-CyD system even after accelerated storage conditions. The enhanced dissolution observed for all the HP-beta-CyD systems in a dissolution medium containing 0.1% non-ionic surfactant HCO-60 were clearly reflected in the in-vivo absorption of nifedipine following oral administration to dogs. These results suggest that HP-beta-CyD is particularly useful in solving problems encountered on storage of amorphous nifedipine in solid dosage forms. 相似文献
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Effects of penicillins on the binding of phenytoin to plasma proteins were examined in vitro and in vivo. The results from in vitro studies showed that the penicillins including oxacillin and dicloxacillin were effective in displacing phenytoin from its binding sites. In vivo, the total phenytoin concentration in serum decreased during penicillin administration, while the free phenytoin concentration increased. As a result, penicillins caused a significant increase in the apparent volume of distribution and in the total body clearance of phenytoin. These results can be explained on the basis of the displacement of phenytoin from its plasma protein binding site by penicillins. 相似文献
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The potential of starburst polyamidoamine dendrimer (dendrimer, generation 3, G3) conjugate with alpha-cyclodextrin (alpha-CyD) having an average degree of substitution of 2.4 (alpha-CDE) as a novel carrier of short hairpin RNA (shRNA) expressing plasmid DNA (shpDNA) was evaluated and the shpDNA transfer activity of alpha-CDE was compared with that of dendrimer (G3). Alpha-CDE formed a stable and condensed complex with shpDNA and induced a conformational transition of shpDNA in solution even in the low charge ratios. In addition, alpha-CDE markedly inhibited the enzymatic degradation of shpDNA by DNase I. The shpDNA complex with alpha-CDE at the charge ratio of 20/1 (alpha-CDE/shpDNA) elicited the most potent RNAi effects in cells transiently and stably expressing the GL3 and GL2 luciferase genes without cytotoxicity among the complexes with the various charge ratios. Besides, the RNAi effects were strikingly enhanced by the further addition of the adequate amounts of siRNA to the shpDNA complex with alpha-CDE. Taken together, the prominent RNAi effects of the shpDNA complex with alpha-CDE could be attributed to the stabilizing effect of alpha-CDE on enzymatic degradation of shpDNA and negligible cytotoxicity. These results suggest that alpha-CDE possesses the potential to be a novel carrier for shpDNA and siRNA. 相似文献
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Yuji Kaji Kaneto Uekama Hiroshi Yoshikawa Kanji Takada Shozo Muranishi 《International journal of pharmaceutics》1985,24(1):79-89
The β-cyclodextrin polymer (polyβCD) was used as a candidate for a macromolecular carrier of a bifunctional delivery system, and the applicability of this new biodegradable polymer was studied using 1-hexylcarbamoyl-5-fluorouracil (HCFU) by administering into the lumen of the large intestine, and into the abdominal cavity. Bifunctional delivery system (mixed micelles + HCFU-polyβCD complex) increased the selective transfer of HCFU into the lymphatics after the large intestinal administration. On the other hand, after the intraperitoneal administration, we found that the administration of HCFU-polyβCD complex without mixed micelles increased the selective transfer of HCFU into the lymphatics. The selective transfer into the lymphatics was found by administration of drug into the abdomen rather than into the large intestine. These results suggest that such a new bifunctional delivery system will be a powerful tool in the field of antitumor chemotherapy. 相似文献
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