Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersion on enhanced dissolution and bioavailability of ketoconazole

Abstract

Polyethylene glycol (PEG) 6000-based solid dispersions (SDs), by incorporating various pharmaceutical excipients or microemulsion systems, were prepared using a fusion method, to compare the dissolution rates and bioavailabilities in rats. The amorphous structure of the drug in SDs was also characterized by powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The ketoconazole (KT), as an antifungal agent, was selected as a model drug. The dissolution rate of KT increased when solubilizing excipients were incorporated into the PEG-based SDs. When hydrophilic and lipophilic excipients were combined and incorporated into PEG-based SDs, a remarkable enhancement of the dissolution rate was observed. The PEG-based SDs, incorporating a self microemulsifying drug delivery system (SMEDDS) or microemulsion (ME), were also useful at improving the dissolution rate by forming a microemulsion or dispersible particles within the aqueous medium. However, due to the limited solubilization capacity, these PEG-based SDs showed dissolution rates, below 50% in this study, under sink conditions. The PEG-based SD, with no pharmaceutical excipients incorporated, increased the maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC(0-6h)) two-fold compared to the drug only. The bioavailability was more pronounced in the cases of solubilizing and microemulsifying PEG-based SDs. The thermograms of the PEG-based SDs showed the characteristic peak of the carrier matrix around 60 degrees C, without a drug peak, indicating that the drug had changed into an amorphous structure. The diffraction pattern of the pure drug showed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of the numerous distinctive peaks of the drug in the PEG-based SDs demonstrated that a high concentration of the drug molecules was dissolved in the solid-state carrier matrix of the amorphous structure. The utilization of oils, fatty acid and surfactant, or their mixtures, in PEG-based SD could be a useful tool to enhance the dissolution and bioavailability of poorly water-soluble drugs by forming solubilizing and microemulsifying systems when exposed to gastrointestinal fluid.

Kneading Technique for Preparation of Binary Solid Dispersion of Meloxicam with Poloxamer 188

“…Decrease in crystallinity of the drug and polymer may contribute to enhancement of dissolution of the drug (25).…”

Thermal, spectroscopic, and dissolution studies of ketoconazole–Pluronic F127 system

“…Several approaches have been employed to improve the solubility of ketoconazole [8], such as preparation of solid dispersions with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer prepared by melt extrusion [14], solid dispersions with nicotinamide [15], and inclusion complexation of ketoconazole in bcyclodextrin obtained by solvent evaporation method [5]. Solid dispersions of ketoconazole are also prepared by melt fusion and solvent evaporation method with Pluronic F127 and PVP K-30 [16]; fusion, solvent evaporation, melt solvent, and kneading method with mannitol; and PEG 4000, PEG 6000, polyvinyl pyrrolidone K-30, and bcyclodextrin as carrier [17,18].…”

Preparation and Evaluation of Solid Dispersion of Meloxicam with Skimmed Milk

“…The persion would be mostly in amorphous state and only a with few partially crystallized drug molecules. 13) In the X-ray diŠraction spectrum of the PM, it was possible to detect crystals of MLX as the particle size was greater than the SD. However, the particle size of MLX in PM and the pure drug was similar.…”