Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement

Abstract

Solid self-emulsifying drug delivery system (SSEDDS), which incorporates liquid SEDDS into a solid dosage form, has been recently introduced to improve the oral bioavail-ability of poorly water-soluble drugs. However, supersaturated drug generated by SSEDDS is thermodynamically unstable and tends to precipitate rapidly prior to absorption, resulting in compromised bioavailability. The aim of this study was to construct a novel supersaturated SSEDDS (super-SSEDDS) by combining SSEDDS with appropriate precipitation inhibitor. Fenofibrate (FNB), a sparingly soluble drug, was selected as a model drug in this study. An optimized SSEDDS was prepared by solvent evaporation by using mesoporous silica Santa Barbara Amorphous-15 as the inert carrier. Supersaturation assay was conducted to evaluate the precipitation inhibition capacity of different polymers, and the results showed that Soluplus ® could retard the FNB precipitation more effectively and sustain a higher apparent concentration for ~120 min. This effect was also clearly observed in the dissolution profiles of FNB from SSEDDS under supersaturated condition. The study of the mechanism suggested that the inhibition effect might be achieved both thermodynamically and kinetically. The area under the concentration–time curve of the super-SSEDDS was 1.4-fold greater than that of SSEDDS in the absence of Soluplus, based on an in vivo pharmacokinetic study conducted in beagle dogs. This study has demonstrated that the approach of combining SSEDDS with Soluplus as a supersaturation stabilizer constitutes a potential tool to improve the absorption of poorly water-soluble drugs.

Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems

“…As mentioned above, SEDDSs emulsify spontaneously when they come into contact with GI fluids after the formulation reaches the stomach [26]. However, the aqueous dispersion of SEDDSs containing high concentrations of water miscible excipients result in the supersaturation of the drug exceeding the equilibrium solubility of the GI fluid, as solubilizing power of SEDDS vehicle is lost through dilution.…”

“…Quan et al successfully prepared an optimized solid SEDDS containing fenofibrate using solvent evaporation with the mesoporous silica Santa Barbara Amorphous-15 as the solid carrier [26]. Powdered Soluplus ® was homogeneously mixed with the solid fenofibrate SEDDS.…”

“…The difficulty of the commercial success of conventional SEDDSs has been mainly attributed to a number of factors, including a propensity for drug precipitation in vivo and low drug loading, as state above [26]. To overcome these problems, su-SEDDS was introduced, but the limitations of liquid formulations and liquid filling capsules, such as the limited physico-chemical stability of formulation, difficult handling of liquid su-SEDDSs, poor patient compliance, and costly manufacturing, still remain.…”

“…There is a possibility of loss of volatile substances and precipitation and degradation of the highly loaded drug during storage due to relative instability in solution state of su-SEDDS [26]. In addition, the release of hydroperoxides and volatile byproducts resulted from the degradation of lipids and oils may harmfully influence on physico-chemical stability of su-SEDDSs and in vivo toxicity.…”

“…Mesoporous Silica Different grades of mesoporous silica, colloidal silicon dioxide (CSD), and magnesium aluminosilicate, which are pharmaceutically acceptable excipients with high lipid loading capacities, have been used commonly as adsorbents in the preparation of SEDDS solid dosage forms [14,200]. Several cases of solidification of su-SEDDS were reported for celecoxib using silicon dioxide (Sylysia 350 fcp) [108], fenofibrate using mesoporous silica [26], glipizide using calcium carbonate and talc, and valsartan using calcium silicate (Florite ® ) [127]. As presented in Table 2, all cases showed comparably improved performance of su-SEDDS.…”