Enhancement of the dissolution rate and bioavailability of fenofibrate by a melt-adsorption method using supercritical carbon dioxide

Abstract

Background: The aim of this study was to enhance the bioavailability of fenofibrate, a poorly water-soluble drug, using a melt-adsorption method with supercritical CO(2).

Methods: Fenofibrate was loaded onto Neusilin(®) UFL2 at different weight ratios of fenofibrate to Neusilin UFL2 by melt-adsorption using supercritical CO(2). For comparison, fenofibrate-loaded Neusilin UFL2 was prepared by solvent evaporation and hot melt-adsorption methods. The fenofibrate formulations prepared were characterized by differential scanning calorimetry, powder x-ray diffractometry, specific surface area, pore size distribution, scanning electron microscopy, and energy-dispersive x-ray spectrometry. In vitro dissolution and in vivo bioavailability were also investigated.

Results: Fenofibrate was distributed into the pores of Neusilin UFL2 and showed reduced crystal formation following adsorption. Supercritical CO(2) facilitated the introduction of fenofibrate into the pores of Neusilin UFL2. Compared with raw fenofibrate, fenofibrate from the prepared powders showed a significantly increased dissolution rate and better bioavailability. In particular, the area under the drug concentration-time curve and maximal serum concentration of the powders prepared using supercritical CO(2) were 4.62-fold and 4.52-fold greater than the corresponding values for raw fenofibrate.

Conclusion: The results of this study highlight the usefulness of the melt-adsorption method using supercritical CO(2) for improving the bioavailability of fenofibrate.

Keywords: bioavailability; fenofibrate; melt adsorption; supercritical CO2.

Figure 1

Experimental apparatus for phase-behavior observations.

Figure 2

Schematic diagram of the experimental apparatus.

Figure 3

Solid–liquid–vapor curves for the binary system of fenofibrate + carbon dioxide.

Figure 4

Powder X-ray diffraction patterns (A) and differential scanning calorimetry thermograms (B) of raw fenofibrate and prepared powders. Abbreviations: HME, hot-melt adsorption method; SE, solvent evaporation method; SC1, supercritical method 1 (fenofibrate:Neusilin UFL2 = 67:33); SC2, supercritical method 2 (fenofibrate:Neusilin UFL2 = 50:50); SC3, supercritical method 3 (fenofibrate:Neusilin UFL2 = 40:60); SC4, supercritical method 4 (fenofibrate:Neusilin UFL2 = 33:67).

Figure 5

Three-dimensional fenofibrate molecule with corresponding interatomic distances.

Figure 6

Powder X-ray diffraction patterns of prepared powders (SC3 and SC4) after storage at 40°C and 75% relative humidity. Abbreviations: SC3, supercritical method 3 (Fenofibrate:Neusilin UFL2 = 40:60); SC4, supercritical method 4 (Fenofibrate:Neusilin UFL2 = 33:67).

Figure 7

Pore size distribution related to the weight ratio of fenofibrate/Neusilin^® UFL2 using the supercritical method (SC) (A) and the various processing methods (B). Abbreviations: HME, hot-melt adsorption method; SE, solvent evaporation method; SC1, supercritical method 1 (Fenofibrate:Neusilin UFL2 = 67:33); SC2, supercritical method 2 (Fenofibrate:Neusilin UFL2=50:50); SC3, supercritical method 3 (Fenofibrate:Neusilin UFL2 = 40:60); SC4, supercritical method 4 (Fenofibrate:Neusilin UFL2 = 33:67).

Figure 8

Scanning electron microscopy image and energy-dispersive spectrometry patterns of (A) raw fenofibrate, (B) raw Neusillin^® UFL2, and (C) prepared powder (SC3). Abbreviation: SC3, supercritical method 3 (fenofibrate:Neusilin UFL2 = 40:60).

Figure 9

Dissolution profiles of raw fenofibrate, the commercial product (Lipidi Supra^®), and prepared powders in 0.025 M sodium lauryl sulfate. Notes: (A) Dissolution profiles related to the weight ratio of fenofibrate/Neusilin UFL2 using supercritical method (SC). (B) Dissolution profiles from raw fenofibrate, the commercial product, and powders prepared using various adsorption methods. Data are expressed as the mean ± standard deviation (n = 3). Abbreviations: HME, hot-melt adsorption method; SE, solvent evaporation method; SC1, supercritical method 1 (Fenofibrate:Neusilin UFL2 = 67:33); SC2, supercritical method 2 (Fenofibrate:Neusilin UFL2 = 50:50); SC3, supercritical method 3 (Fenofibrate:Neusilin UFL2 = 40:60); SC4, supercritical method 4 (Fenofibrate:Neusilin UFL2 = 33:67).

Figure 10

Serum concentration-time profile of fenofibrate in rats after oral administration of the raw fenofibrate, the commercial product (Lipidi Supra^®), and the prepared powder (SC3) at a dose equivalent to 50 mg of fenofibrate/kg of bodyweight. Note: Data are expressed as the mean ± standard deviation (n = 5). Abbreviation: SC3, supercritical method 3 (fenofibrate:Neusilin UFL2 = 40:60).