Abstract
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.
Highlights
Ezetimibe is the first of a novel class of drugs used for the treatment of hyperlipidemia
Solid dispersions (SD) are one of the most widely used strategies to achieve an improvement in the dissolution of poorly soluble drugs, and solid dispersions (SD) with different hydrophilic polysaccharides such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and croscarmellose have been used in recent years
The micellar systems MS-I (1:0.75) and MS-II (1:0.75) showed poor flowability, with a slight improvement in the angle of repose, which was probably due to the presence of the croscarmellose carrier (Table 1)
Summary
Ezetimibe is the first of a novel class of drugs used for the treatment of hyperlipidemia. This active pharmaceutical ingredient is characterized as class II in the Biopharmaceutics Classification System. Solid dispersions (SD) are one of the most widely used strategies to achieve an improvement in the dissolution of poorly soluble drugs, and SD with different hydrophilic polysaccharides such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and croscarmellose have been used in recent years. The amphiphilic nature of these excipients improves the absorption of drug molecules within the polymer chains and reduces the thermodynamic instability of amorphous forms [2]. The hydrophilic nature of the carrier may improve the dispersion of drug molecules with a lower proportion of polysaccharide chains [3]
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