Purpose: Fenofibrate is the isopropyl ester of 2-(4-[4-chloro-benzoyl] phenoxy)-2-methylpropanoic acid is a BCS class II drug with low solubility and high permeability. Therefore, the dissolution rate of fenofibrate may limit its absorption in the gastrointestinal tract. The aim of this study is to enhance the dissolution rate and bioavailability of fenofibrate formulations adsorbed onto pores of Neusilin UFL2 by a melt-adsorption method using supercritical CO2
Methods: Fenofibrate was loaded onto Neusilin® UFL2 at different weight ratios of fenofibrate to Neusilin UFL2 by a melt-adsorption method using supercritical CO2. 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 was also investigated. For the in vivo experiments, six groups of rats composed of five animals each were used. Each group was orally administered 1 mL of 0.2% w/v methylcellulose aqueous suspension containing the raw fenofibrate, the commercial product (Lipidil Supra), or the melt-adsorption processed formulations (equivalent to fenofibrate 50 mg/kg body weight), respectively. Blood samples were collected from the tail vein prior to the initial dose, and then at 20, 40, 60, 90, 120, 180, 240, 360, 480, and 720 minutes after dosing to examine the serum concentration of fenofibrate.
Results: Fenofibrate was distributed into the pores of Neusilin UFL2 and showed reduced crystal formation following adsorption. Supercritical CO2 facilitated the introduction of fenofibrate into the pores of Neusilin UFL2. The DSC thermograms and PXRD patterns for fenofibrate and powders prepared with various fenofibrate to Neusilin UFL2 ratios revealed that Neusilin UFL2 inhibited the crystalline formation of fenofibrate. Compared with raw fenofibrate, fenofibrate from the prepared powders showed a significantly increased dissolution rate and better bioavailability. Dissolution of the fenofibrate adsorbed onto Neusilin UFL2 was higher than that for the raw fenofibrate. Among the powders prepared using the melt-adsorption method, the dissolution rate of fenofibrate increased with decreasing crystalline fenofibrate values, and drug release from the SC3 and SC4 formulations with decreasing crystalline fenofibrate values of 0% was markedly enhanced. Within 5 minutes, approximately 80% of the drug dissolved for the prepared powders (SC3 and SC4), compared with approximately 15% for the raw fenofibrate. In particular, the SC3 formulation prepared using the supercritical method showed a faster dissolution rate than the raw fenofibrate and the commercial product, with approximately 1.89-fold and 1.25-fold increases in DE60, respectively. Based on the results of our studies, the faster dissolution rate of the drug from the SC3 formulation can be attributed to a decrease in particle size of fenofibrate after absorption of Neusilin UFL2, and a change from the crystalline to an amorphous form. The SCF3 powder showed a significantly increased AUC0→12 h and Cmax compared with raw fenofibrate. Furthermore, the AUC0→12 h and Cmax of SC3 were comparable with those of the commercial product. These results suggest that the amorphous nature and small particle size of fenofibrate allow for apparently greater solubility, thereby increasing the dissolution rate and drug concentration available for absorption. In particular, the area under the drug concentration-time curve and maximal serum concentration of the powders prepared using supercritical CO2 were 4.62-fold and 4.52-fold greater than the corresponding values for raw fenofibrate.
Conclusion: In this study, an amorphous fenofibrate formulation was successfully prepared by a melt-adsorption method using supercritical CO2. Fenofibrate adsorbed onto Neusilin UFL2 exists in an amorphous form and shows an enhanced dissolution rate and bioavailability. The enhancement in oral absorption of fenofibrate adsorbed onto Neusilin UFL2 was attributed amorphous nature and reduction of particle size. The melt adsorption method using supercritical CO2 does not require organic solvents and can be used to improve the bioavailability of other poorly water-soluble drugs with low melting points.
Sharif Md Abuzar– Yonsei University, Incheon
Sharif Md Abuzar– Yonsei University, Incheon
Gunju Kim– Yonsei University, Incheon
Sehyeon Jeong– Yonsei University, Incheon
Kyung-Jin Cho– Yonsei University, Incheon
Sung-Joo Hwang– Professor, Laboratory of Pharmaceutics, Yonsei University, Incheon
Sharif Md. Abuzar– Mr., Yonsei University, Incheon