Abstract
The aim of this work was to prepare and optimize a solid self-nanoemulsifying drug delivery system pre-concentrate (SSP) containing water-insoluble flurbiprofen (FL) using a novel pseudo-ternary phase diagram. The pseudo-ternary phase diagram, composed of FL as the drug and dispersion core, Kollisolv MCT 70 as the oil phase, and TPGS (tocopherol polyethylene glycol 1000 succinate) as the surfactant, was constructed for the determination of the SSP region. SSP was investigated in terms of particle size, physical state by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), in vitro dissolution and oral pharmacokinetics in rats. The determined SSP (FL/Kollisolv MCT 70/TPGS = 10/10/80, weight %) in the pseudo-ternary phase diagram had the melting point of 32.37 °C and uniform mean particle size of below 30 nm without any precipitation of FL in the dispersion. In the dissolution test, the SSP exhibited 95.70 ± 3.40% of release at 15 min, whereas the raw FL showed poor dissolution (i.e., 6.75 ± 1.30%) at that time point. In addition, the SSP showed the enhanced oral absorption (i.e., 1.93-fold increase in AUCinfinite) as compared to the suspension group of raw FL. Therefore, the developed SSP would be a promising drug delivery system with excellent solubilization, dissolution, and bioavailability for FL.
Highlights
Flurbiprofen (FL) (2-(2-fluoro-4-biphenyl) propionic acid) is a cyclooxygenase (COX-1 and 2) inhibitor that blocks the synthesis of prostaglandin E2 and is reported to have analgesic and anti-inflammatory effects [1]
Instead of using weight per unit volume, the measured solubility values of FL in the presence of surfactants or oils were expressed as a mass fraction, since this approach is more reasonable in terms of weighing the surfactant and oil agents in solid or highly viscous liquid states at room temperature by the scale
A novel system pre-concentrate (SSP) formulation containing FL was constructed based on the phase diagram, and physical properties were evaluated by measuring particle sizes, melting points and crystallinity; the dissolution test was performed
Summary
Flurbiprofen (FL) (2-(2-fluoro-4-biphenyl) propionic acid) is a cyclooxygenase (COX-1 and 2) inhibitor that blocks the synthesis of prostaglandin E2 and is reported to have analgesic and anti-inflammatory effects [1]. The SNEDDS are a particulate type of drug carriers with the size range of 20~200 nm dispersed in water; drug molecules are incorporated into the interfacial films or nano-sized oil droplets possessing a large interfacial surface area. With this approach, it is possible to enhance drug solubility and absorption in the gastrointestinal tract, thereby improving oral bioavailability. Some commercial drugs are available in the SNEDDS formulations, such as ritonavir (Norvir®), cyclosporine A (Sandimmune Neoral®), saquinavir (Fortovase®), and tipranavir (Aptivus®) [11,12,13] For these formulations, several reports have demonstrated some hypersensitivity reactions as side effects, presumably related to types of surfactants. These conventional SNEDDS formulations have been developed in the liquid state, which imposed several limitations on the manufacturing process, such as high production costs and physical instability issues, including drug precipitation, phase separation, and/or the incompatibility between the fill ingredients and the gelatin capsule shell at the storage temperature [15]
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