Improvement in the Oral Bioavailability and Efficacy of New Ezetimibe Formulations—Comparative Study of a Solid Dispersion and Different Micellar Systems

Abstract

<jats:p>Ezetimibe (EZ) is a poorly water-soluble drug with low bioavailability. Strategies such as solid dispersions (SD) and micellar systems (MS) were developed to identify the most effective drug delivery formulations with the highest oral bioavailability, and to improve their lipid-lowering effect. The EZ formulations were prepared with different proportions of Kolliphor® RH40 as a surfactant (1:0.25, 1:0.5 and 1:0.75) and croscarmellose as a hydrophilic carrier. These excipients, and the addition of microcrystalline cellulose during the production process, led to significant improvements in the dissolution profiles of MS. Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) revealed an amorphous form of ezetimibe with different semicrystalline states of microcrystalline cellulose for MS-I (1:0.75) and MS-II (1:0.75). Pharmacokinetic analysis after administration of MS-II (1:0.75) demonstrated a 173.86% increase in maximum plasma concentration (Cmax) and a 142.99% increase in oral bioavailability compared to EZ raw material (EZ-RM). Efficacy studies with the micellar system MS-II (1:0.75) in rats with hyperlipidemia showed that total cholesterol, triglycerides and high-density lipoprotein were reduced to normal levels and revealed improvements in low-density lipoprotein, aspartate and alanine aminotransferase. The improvement in the dissolution rate with micellar systems increases bioavailability and enhances the anti-hyperlipidemic effect of EZ.</jats:p>

Development of a Solid Dispersion of Nystatin with Maltodextrin as a Carrier Agent: Improvements in Antifungal Efficacy against Candida spp. Biofilm Infections

“…MD exhibited a characteristic semicrystalline halo between 11–26° 2θ ( Figure 4 ) [ 31 ]. PM-N:MD [1:6] showed a decrease in the intensity of the NYS diffraction peaks due to the dilution effect of MD [ 17 ]. However, significant changes in the intensity of the peaks were observed in the solid dispersions.…”

“…Solvent evaporation methods [ 13 , 14 ], spray drying methods [ 9 ], fusion [ 15 ], and fusion/extrusion [ 16 ] have been commonly employed for the production of solid dispersions. In many cases, the solubility increase for these systems was related to the crystallinity decrease by the inclusion of drug molecules within the carrier chains [ 14 , 17 ]. Solid dispersions with different antifungal active ingredients, such as NYS, voriconazole, or amphotericin B, have been designed to improve their solubility [ 9 , 10 , 18 ].…”

“…Semisynthetic derivatives, such as hydroxypropylcellulose or hydroxypropyl methylcellulose, were used with antifungal compounds such as itraconazole, clotrimazole, miconazole, and NYS [ 11 , 16 ]. Moreover, sodium croscarmellose [ 17 ], cyclodextrins [ 9 , 20 ], and maltodextrins (MDs) [ 21 , 22 ] increase the solid dispersion swelling and wettability of different antibiotics during dissolution essays.…”

Multiparticulate Systems of Ezetimibe Micellar System and Atorvastatin Solid Dispersion Efficacy of Low-Dose Ezetimibe/Atorvastatin on High-Fat Diet-Induced Hyperlipidemia and Hepatic Steatosis in Diabetic Rats

“…However, when Kolliphor RH40 was added to the EZ micellar system ( Figure 1B), the SEM micrograph showed a surfactant film covering the small crystals of EZ on the large croscarmellose particles identified by energy dispersive X-ray (EDX) analysis. The presence of the surfactant film decreases the crystallinity of EZ and increases its wettability in aqueous media [11,19]. Figure 1C shows the surface of ATV physical mixture.…”

“…Recent studies on other hydrophobic drugs such as voriconazole and amphotericin B showed a high liver biodistribution with similar micellar systems [ 10 ]. These active ingredients have shown an enterohepatic circulation, and the changes in the enterohepatic circulation of these drugs could be analyzed with an efficacy study in vivo in order to compare the differences between the formulations administered [ 11 ].…”