title: Potential use of phospholipids in combination with hydrophilic carriers for enhancement of the dissolution and oral bioavailability of imidazole antifungal Class II drugs.
abstract: Recently, the solid dispersion (SD) technique reattracted attention in the pharmaceutical industry due to its simplicity and effectiveness. The aim of the present study was to improve the dissolution rate and hence the oral bioavailability of a poorly water soluble imidazole antifungal model drug, ketoconazole (KET), via the preparation of SDs using phospholipid carriers either alone or in combination with other hydrophilic carriers. The results revealed that, dimyristoylphosphatidylglycerol (DMPG) exhibited the greatest enhancement effect on the dissolution rate of the drug. Interestingly, the prominent effect of SDs using DMPG alone or in combination with PEG 4000 or Poloxamer 188 on increasing drug dissolution rate was more evident at various physiological pH values. The SD combinations were superior compared to those containing only DMPG. The powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) studies demonstrated a remarkable reduction of drug crystallinity in SDs. Finally, oral bioavailability of KET SD formulations in rabbits was significantly (p < 0.05) improved compared to that of the drug, particularly, the maximum plasma concentration (C(max)) and the time to reach the peak plasma concentration (T(max)). Collectively, these results suggest that DMPG either alone or in combination with hydrophilic carriers was regarded as promising SDs for enhancement the dissolution rate and oral bioavailability of KET and potentially other imidazole antifungal Class II drugs.
authors.forename: I I
authors.initials: II
authors.lastname: Abu Hashim
authors.forename: N F
authors.initials: NF
authors.lastname: Ghazy
authors.forename: M H
authors.initials: MH
authors.lastname: El-Shabouri
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D004337:Drug Carriers / Q000737:chemistry*; D005079:Excipients; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D010316:Particle Size; D010715:Phosphatidylglycerols / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D011817:Rabbits; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D005079:Excipients; D007093:Imidazoles; D010715:Phosphatidylglycerols; D010743:Phospholipids; C002773:dimyristoylphosphatidylglycerol; D007654:Ketoconazole