Physicochemical and Pharmacokinetic Characterization of Amorphous Solid Dispersion of Meloxicam with Enhanced Dissolution Property and Storage Stability.

The aim of the present study was to develop amorphous solid dispersion (ASD) of meloxicam (MEL) for providing rapid onset of action. ASDs of MEL with polyvinylpyrrolidone (PVP) K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and Eudragit EPO (MEL/EPO) were prepared. The physicochemical properties were characterized by focusing on morphology, crystallinity, dissolution properties, stability, and the interaction of MEL with coexisting polymers. MEL/EPO was physicochemically stable after storage at 40°C/75% RH for 30 days. In contrast, recrystallization of MEL was observed in MEL/PVP and MEL/HPC at 40°C/50% RH for 30 days. Infrared spectroscopic studies and (1)H NMR analyses of MEL/EPO revealed that Eudragit EPO interacted with MEL and reduced intermolecular binding between MEL molecules. Intermolecular interaction of drug molecules is necessary for the formation of crystalline. Thus, the interaction of MEL with Eudragit EPO and interruption of the formation of supramolecular interaction between MEL molecules might lead to the inhibition of crystal growth of MEL. Of all the MEL solid dispersions prepared, MEL/EPO showed the largest improvement in dissolution behavior. Oral administration of MEL/EPO to rats showed rapid and enhanced MEL exposure with a 2.4-fold increase in bioavailability compared with crystalline MEL. Based on these findings, MEL/EPO was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration.

Development of nanocrystal formulation of meloxicam with improved dissolution and pharmacokinetic behaviors.

The present study aimed to develop nanocrystal formulations of meloxicam (MEL) in order to enhance its biopharmaceutical properties and provide a rapid onset of action. Nanocrystal formulations were prepared by wet-milling and lyophilization with hydrophilic polymers used as aggregation inhibitors. Aggregation inhibitors were selected based on high-throughput screening of crystal growth inhibition in supersaturated MEL solution. Supersaturation of MEL was observed in PVP K-30, HPC-SSL, and POVACOAT Type F solution. Although the particle size distributions of pulverized MEL with PVP K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and POVACOAT Type F (MEL/POVA) were in the nanometer range following lyophilization, increases in micron-sized aggregates were observed after storage at 60°C for 21 days. The order of increased amount of aggregates was MEL/POVA≫MEL/HPC>MEL/PVP. These findings showed that hydrophilic polymers that inhibited crystal growth in supersaturated MEL solutions tended to prevent aggregation. The dissolution behavior of all nanocrystal formulations tested was markedly enhanced compared with that of unpulverized MEL. Oral administration of MEL/PVP showed a 2.0h shortened Tmax and a 5.0-fold increase in bioavailability compared with unpulverized MEL. These findings showed that the MEL/PVP mixture was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration.