Novel rivaroxaban-loaded microsphere systems with different surface microstructure for enhanced oral bioavailability.

This study compares rivaroxaban-loaded polymeric microsphere systems with three types of surface microstructure. Three types of polymeric microspheres loaded with rivaroxaban were fabricated using a spray-drying technique: solvent-evaporated, surface-attached, and solvent-wet microspheres, depending on whether the drug and additives used are soluble in the solvent. The solvent-evaporated and surface-attached microspheres had a rivaroxaban/polyvinylpyrrolidone/sodium lauryl sulfate (SLS) weight ratio of 1/0.25/2.2, and the solvent-wetted microspheres contained rivaroxaban/polyvinyl alcohol/SLS in equal weight ratio (1/0.25/2). The physicochemical properties of the microspheres were evaluated using scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and particle size distribution analysis. The aqueous solubility and dissolution rate of rivaroxaban in the three types of microspheres were compared to those of the drug powder. The solvent-evaporated, surface-attached, and solvent-wetted microspheres were approximately 208, 140, and 172 times as soluble as the drug powder, and the final dissolution rate (120 min) was approximately 5, 2, and 4 times that of the drug powder, respectively. In addition, the oral bioavailability increased by approximately 2, 1.3, and 1.6 times compared to that of the drug powder (area under drug concentration-time curve: 2101.3 ± 314.8, 1325.2 ± 333.3, and 1664.0 ± 102.6 h·ng/mL, respectively). Finally, the solvent-evaporated microspheres showed the greatest improvement (solvent evaporating microspheres > solvent wetted microspheres > surface-attached microspheres ≥ drug powder). Therefore, the solvent-evaporated microspheres may represent a novel oral dosage form that improves the oral bioavailability of rivaroxaban, a poorly soluble drug.

Enhanced Oral Bioavailability of Rivaroxaban-Loaded Microspheres by Optimizing the Polymer and Surfactant Based on Molecular Interaction Mechanisms.

This study aimed to develop microspheres using water-soluble carriers and surfactants to improve the solubility, dissolution, and oral bioavailability of rivaroxaban (RXB). RXB-loaded microspheres with optimal carrier (poly(vinylpyrrolidone) K30, PVP) and surfactant (sodium lauryl sulfate (SLS)) ratios were prepared. 1H NMR and Fourier transform infrared (FTIR) analyses showed that drug-excipient and excipient-excipient interactions affected RXB solubility, dissolution, and oral absorption. Therefore, molecular interactions between RXB, PVP, and SLS played an important role in improving RXB solubility, dissolution, and oral bioavailability. Formulations IV and VIII, containing optimized RXB/PVP/SLS ratios (1:0.25:2 and 1:1:2, w/w/w), had significantly improved solubility by approximately 160- and 86-fold, respectively, compared to RXB powder, with the final dissolution rates improved by approximately 4.5- and 3.4-fold, respectively, compared to those of RXB powder at 120 min. Moreover, the oral bioavailability of RXB was improved by 2.4- and 1.7-fold, respectively, compared to that of RXB powder. Formulation IV showed the highest improvement in oral bioavailability compared to RXB powder (AUC, 2400.8 ± 237.1 vs 1002.0 ± 82.3 h·ng/mL). Finally, the microspheres developed in this study successfully improved the solubility, dissolution rate, and bioavailability of RXB, suggesting that formulation optimization with the optimal drug-to-excipient ratio can lead to successful formulation development.

Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban.

The purpose of this study was to investigate the efficacy of hydrophilic polymers in a solid dispersion formulation in improving the solubility and dissolution rate of rivaroxaban (RXB), a poorly soluble drug. The developed solid dispersion consisted of two components, a drug and a polymer, and the drug was dispersed as amorphous particles in a polymer matrix using the spray drying method. Polymeric solid dispersions were evaluated using solubility tests, in vitro dissolution tests, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and particle size distribution analysis. To maximize physical stability against crystallization and improve the solubility and dissolution of RXB, it is important to select the appropriate polymer type and the optimal ratio of the polymer to the drug. The optimized polyvinyl alcohol (PVA)-based (1/0.5, w/w) and gelatin-based (1/5, w/w) solid dispersion formulations showed 6.3 and 3.6 times higher drug solubilities than pure RXB powder, respectively, and the final dissolution rate was improved by approximately 1.5 times. Scanning electron microscopy and particle size distribution analyses confirmed that the gelatin-based solid dispersion was smaller and more spherical than the PVA-based solid dispersion, suggesting that the gelatin-based solid dispersion had a faster initial dissolution rate. Differential scanning calorimetry and powder X-ray diffraction analyses confirmed that RXB had successfully changed from a crystalline form to an amorphous form, contributing to the improvement in its solubility and dissolution rate. This study provides a strategy for selecting suitable polymers for the development of amorphous polymer solid dispersions that can overcome precipitation during dissolution and stabilization of the amorphous state. In addition, the selected polymer solid dispersion improved the drug solubility and dissolution rate of RXB, a poorly soluble drug, and may be used as a promising drug delivery system.

Effects of different physicochemical characteristics and supersaturation principle of solidified SNEDDS and surface-modified microspheres on the bioavailability of carvedilol.

In this study, a solidified self-nanoemulsifying drug delivery system (solidified SNEDDS) and surface-modified microspheres were developed for enhancing the oral bioavailability of carvedilol. Based on the aqueous solubility test, liquid SNEDDS was composed of Peceol™ (oil), Tween® 80 (surfactant), and Labrasol® (co-surfactant) at a weight ratio of 25/50/25, generating the smallest nanoemulsion droplet size. Then, carvedilol was added to liquid SNEDDS and spray-dried with Aerosil® to fabricate the solidified SNEDDS. Surface-modified microspheres were manufactured using copovidone (polymer) and Tween® 80 (surfactant) according to aqueous solubility test results. The proper ratio of copovidone and Tween® 80 was determined based on the solubility and dissolution test. Both prepared formulations and carvedilol powder were compared using four different criteria: physicochemical characteristics, solubility, dissolution, and oral bioavailability. For solidified SNEDDS, carvedilol was encapsulated in liquid SNEDDS and absorbed to the Aerosil® surface, leading to the conversion from a crystalline to an amorphous state. However, the drug maintained its crystal form in the surface-modified microspheres. Round and even-sized particles were attached to the rough surfaces of drug, suggesting that hydrophilic carriers adhered to the hydrophobic drug. All formulations significantly improved drug solubility, dissolution, plasma concentrations, Cmax, and AUC compared to carvedilol powder. The parameters were ranked in the following order: solidified SNEDDS > surface-modified microspheres > carvedilol powder. As a result, different solubility-increasing mechanisms provided differences in performance. For carvedilol, the formation of a nano-emulsion in solidified SNEDDS resulted in an efficient supersaturated state, leading to improved solubility (~6.1 fold), dissolution (~1.8 fold), and oral bioavailability (~1.4 fold) that was superior to the hydrophilic microenvironment in surface-modified microspheres.