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

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.

SUBMITTER: Torrado-Salmeron C

PROVIDER: S-EPMC7408513 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Torrado-Salmerón Carlos C Guarnizo-Herrero Víctor V Gallego-Arranz Teresa T Del Val-Sabugo Yvonne Y Torrado Guillermo G Morales Javier J Torrado-Santiago Santiago S

Pharmaceutics 20200702 7

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<sup>®</sup> RH40 as a surfactant (1:0.25, 1:0.5 and 1:0.75) and croscarmellose as a hydrophilic carrier. These excipients, and the ...[more]

PMID: 32630626

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Project description:Edaravone (EDR) is known for its free radical scavenging, antiapoptotic, antinecrotic, and anticytokine effects in neurological and non-neurological diseases. It is currently available clinically as Radicava® and Radicut®, intravenous medications, recently approved for the treatment of amyotrophic lateral sclerosis and cerebral infarction. However, the oral use of EDR is still restricted by its poor oral bioavailability (BA) due to poor aqueous solubility, stability, rapid metabolism, and low permeability. The present study reports the development of novel EDR formulation (NEF) using self-nanomicellizing solid dispersion (SNMSD) strategy with the aim to enable its oral use.The selection of a suitable carrier for the development of NEF was performed based on the miscibility study. The optimization of EDR-to-carrier ratio was conducted via kinetic solubility study after preparing SNMSDs using solvent evaporation technique. The drug-polymer carrier interaction and self-nanomicellizing properties of NEF were investigated with advanced characterization studies. In vitro permeation, metabolism, and dissolution study was carried out to examine the effect of the presence of a carrier on physico-chemical properties of EDR. Additionally, the dose-dependent pharmacokinetic study of NEF was conducted and compared with the EDR suspension.Soluplus® (SOL) as a carrier was selected based on the potential for improving aqueous solubility. The NEF containing EDR and SOL (1:5) resulted in the highest enhancement in aqueous solubility (17.53-fold) due to amorphization, hydrogen bonding interaction, and micellization. Moreover, the NEF demonstrated significant improvement in metabolism, permeability, and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2-, 16.1-, and 14.8-fold enhancement compared to EDR suspension at 46, 138, and 414 µmol/kg doses.The results demonstrated that SNMSD strategy could serve as a promising way to enhance EDR oral BA and NEF could be a potential candidate for the treatment of diseases in which oxidative stress plays a key role in their pathogenesis.

Dataset Information

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

Publications

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

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