Abstract
The purpose of this study is to develop a solid dispersion system with improved dissolution, absorption, and patient compliance of poorly water-soluble celecoxib (CXB). Instead of sodium lauryl sulfate (SLS), an anionic surfactant used in the marketed product (Celebrex®), solubilization was performed using non-ionic surfactants with low toxicity. Cremophor RH40 (Cre-RH) was selected as the optimal solubilizer. Granules and tablets containing CXB and Cre-RH were prepared via fluid-bed and tableting processes, respectively. The morphology, crystallinity, flowability, dissolution, and pharmacokinetics for CXB-solid dispersion granules (SDGs) and the hardness and friability for CXB-solid dispersion tablets (SDTs) were evaluated. The solubility of CXB was found to be increased by about 717-fold when using Cre-RH. The dissolution of granules containing Cre-RH was found to be increased greatly compared with CXB API and Celebrex® (66.9% versus 2.3% and 37.2% at 120 min). The improvement of the dissolution was confirmed to be the same as that of granules in tablets. The CXB formulation resulted in 4.6- and 4.9-fold higher AUCinf and Cmax of CXB compared with those of an oral dose of CXB powder in rats. In short, these data suggest that the solid dispersion based on Cre-RH—a non-toxic solubilizer, non-ionic surfactant— may be an effective formulation for CXB to enhance its oral bioavailability and safety.
Highlights
Among the various pharmaceutical formulations, solid dispersion is known to be one of the most effective strategies to improve the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs [1,2]
It has been reported that Cremophor RH40 (Cre-RH), Ryoto sugar ester P-1670 and L-1695 can greatly improve the solubility of poorly water-soluble drugs, and the permeability of drugs [37,38]
Cre-RH is known as an effective permeability modulator that improves drug absorption after oral administration
Summary
Among the various pharmaceutical formulations, solid dispersion is known to be one of the most effective strategies to improve the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs [1,2]. Solid dispersion shows a reduction in particle size and an increase in surface area of poorly water-soluble drugs, resulting in improved solubility, dissolution rate, and oral bioavailability [3,4]. Solid dispersion is often produced by co-precipitation, co-evaporation, or co-grinding methods [5,6]. These methods produce very poor physical properties, such as flowability, mixing properties, and compressibility, due to the semi-solid excipients used together in dosage form preparations [7], which makes them unsuitable for producing commercial products in large quantities [8]. The fluid-bed granulator can perform several unit operations within the same equipment continuously, such as pre-blending, granulation, and drying [9], and the granules produced in this process are processed by undergoing tableting and filling processes [10], which are favorable for scale-up for commercialization [11]
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