The main objective of this study was to evaluate the influence of hydroxypropylated beta- and gamma-cyclodextrins and Me-beta-cyclodextrin (HP-beta-CD, HP-gamma-CD, and Me-beta-CD, respectively) on the dissolution rate and bioavailability of the antiepileptic agent, phenytoin (DPH). The corresponding solid complexes were prepared by a freeze-drying method and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry studies. Evidence of inclusion complex formation in the case of HP-beta-CD was obtained by (1)H- and (13)C-nuclear magnetic resonance spectroscopy. Drug solubility and dissolution rate in 0.05 M potassium phosphate buffer (pH 6) were notably improved by employing the beta-CDs. Thus a 45% w/v HP-beta-CD or Me-beta-CD solution gave rise to an increase of dissolved drug of 420- and 578-fold, respectively. The Q(10) (i.e. percentage of dissolved DPH at 10 min) was 5.2% for the pure drug and 93, 98, and 96% for DPH/HP-beta-CD, DPH/HP-gamma-CD, and DPH/Me-beta-CD complexes, respectively. Moreover, it was found that in the maximal electroshock seizure test in mice the DPH/Me-beta-CD complex exhibited anticonvulsant activity similar to DPH sodium salt (NaDPH).
Complexation of phenytoin with some hydrophilic cyclodextrins: effect on aqueous solubility, dissolution rate, and anticonvulsant activity in mice.
SERRA, MARIANGELA;
2001-01-01
Abstract
The main objective of this study was to evaluate the influence of hydroxypropylated beta- and gamma-cyclodextrins and Me-beta-cyclodextrin (HP-beta-CD, HP-gamma-CD, and Me-beta-CD, respectively) on the dissolution rate and bioavailability of the antiepileptic agent, phenytoin (DPH). The corresponding solid complexes were prepared by a freeze-drying method and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry studies. Evidence of inclusion complex formation in the case of HP-beta-CD was obtained by (1)H- and (13)C-nuclear magnetic resonance spectroscopy. Drug solubility and dissolution rate in 0.05 M potassium phosphate buffer (pH 6) were notably improved by employing the beta-CDs. Thus a 45% w/v HP-beta-CD or Me-beta-CD solution gave rise to an increase of dissolved drug of 420- and 578-fold, respectively. The Q(10) (i.e. percentage of dissolved DPH at 10 min) was 5.2% for the pure drug and 93, 98, and 96% for DPH/HP-beta-CD, DPH/HP-gamma-CD, and DPH/Me-beta-CD complexes, respectively. Moreover, it was found that in the maximal electroshock seizure test in mice the DPH/Me-beta-CD complex exhibited anticonvulsant activity similar to DPH sodium salt (NaDPH).
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