Effect of sugar-modified beta-cyclodextrins on dissolution and absorption characteristics of phenytoin.
Inclusion complexes of phenytoin (DPH) with 6-O-alpha-D-glucosyl (G1)- and 6-O-alpha-D-maltosyl (G2)-beta-cyclodextrins (beta-CyDs) were prepared in a molecular mixing ratio of 1:1. The advantages of these preparations in terms of dissolution characteristics and the oral absorbency of DPH were evaluated in comparison with the known solid dispersions of polyvinylpyrrolidone K-30 and sodium deoxycholate (DC-Na). The results of a phase-solubility study indicated that G1- and G2-beta-CyDs provided higher solubility for DPH than 2-hydroxypropyl (HP)-beta-CyD. Irrespective of inclusion ability, the DPH/beta-CyD complexes allowed faster dissolution rates than those of the known dispersions in JP 1st and 2nd mediums. The dissolution behavior of the DPH/DC-Na dispersion was considerably different between the 1st and 2nd mediums. The complexation by the sugar-modified derivatives yielded a higher stability of dissolved DPH in the JP 2nd medium than that yielded by K-30 or DC-Na. The safe estimation of carriers themselves indicated that G1- and G2-bet-CyDs did not damage the small intestine, while 10 mM DC-Na showed some damage. Compared with the DPH/K-30 dispersion, the preparations with the sugar-modified beta-CyDs were more effective in enhancing the absorbability of DPH after oral administration. These results clearly suggest that complexation with G1- and G2-beta-CyDs are useful forms for the oral delivery of DPH. The advantage of these complexes is that they produce an increased level of DPH available for gastrointestinal absorption. Additionally, G2-beta-CyD is recommended as a safe and potent additive for DPH.
Tanino
T
T
Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Osaka, Japan.
Ogiso
T
T
Iwaki
M
M
D000818:Animals; D003505:Cyclodextrins / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D005947:Glucose / Q000737:chemistry*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D008320:Maltose / Q000737:chemistry*; D008565:Membrane Proteins / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010637:Phenolsulfonphthalein / Q000493:pharmacokinetics; D010672:Phenytoin / Q000493:pharmacokinetics*; D010743:Phospholipids / Q000378:metabolism; D011208:Powders; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D008565:Membrane Proteins; D010743:Phospholipids; D011208:Powders; D047392:beta-Cyclodextrins; D010672:Phenytoin; D008320:Maltose; D010637:Phenolsulfonphthalein; D005947:Glucose; C031215:betadex