Flurbiprofen-Loaded Solid SNEDDS Preconcentrate for the Enhanced Solubility, In-Vitro Dissolution and Bioavailability in Rats

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.

Development of 20(S)-Protopanaxadiol-Loaded SNEDDS Preconcentrate Using Comprehensive Phase Diagram for the Enhanced Dissolution and Oral Bioavailability

“…PPD solubility in each vehicle system constructed with the different ratios of oil and surfactant was calculated using Equation (1) and presented as the E value. Next, each E value was plotted on the ternary phase diagram, along with the calculated composition (%) of oil (C ) and surfactant (D ) in the vehicle system [15]. In Equation (1), the combination ratios of C and D were predetermined in the range of 100:0~0:100 (C:D, %) with a 5% interval value.…”

“…Before the pharmacokinetic study, the rats were fasted overnight and allowed free access to water. For blood collection, rats were anesthetized using a intramuscular injection of Zoletil (20 mg/kg) and the femoral artery was cannulated with a polyethylene tube (PE50; Clay Adams, Parsippany, NJ, USA) filled with 20 IU/mL heparinized saline, as described previously [15,22]. After recovery from surgery, the rats were administered a single oral dose (10 mg/kg) of raw PPD or optimized PSP (#F9).…”

“…The structure of PPD comprises a tetracyclic terpene sapogenin containing hydrocarbon rings, which makes this molecule water-insoluble and fairly lipophilic (Figure 1). As a solubilization technology, the self-nanoemulsifying drug delivery system (SNEDDS) has been widely applied to enhance the aqueous solubility of highly lipophilic drugs such as PPD [15][16][17][18][19]. SNEDDS formulations are generally composed of oils, surfactants (or co-surfactants), and water, and they increase drug solubilization by forming thermodynamically stable colloidal nanoemulsions in aqueous media with a particle size range of 50-200 nm [20,21].…”

“…Drug molecules are incorporated into the interfacial film layer or oil core droplets, which have a large total surface area. Thus, SNEDDS can enhance drug solubility and gastrointestinal absorption, thereby improving oral bioavailability [15].Pharmaceutics 2020, 12, x FOR PEER REVIEW 3 of 15 by BASF (Ludwigshafen, Germany). Capmul MCM C8 (mono/diglycerides of caprylic acid) and Capryol 90 (propylene glycol monocaprylate (type II) were provided by Gattefosse (Saint-Priest, France).…”

“…Drug molecules are incorporated into the interfacial film layer or oil core droplets, which have a large total surface area. Thus, SNEDDS can enhance drug solubility and gastrointestinal absorption, thereby improving oral bioavailability [15].…”