Therapeutic effects of celecoxib polymeric systems in rat models of inflammation and adjuvant-induced rheumatoid arthritis.

The incidence of rheumatoid arthritis (RA), an autoimmune inflammatory disease, is rapidly increasing in aging societies. In the current study, celecoxib (CXB) micelles were developed to improve the oral absorption and anti-inflammatory effects of CXB in cell studies and λ-carrageenan rat models, and to enhance the therapeutic effects of CXB on RA in complete Freund's adjuvant (CFA)-induced RA rat models. Moreover, CXB micelles and previously developed solid dispersion (SD6) formulations were evaluated. The physical properties of optimal CXB micelles (M3), such as crystallinity, thermal properties, and intramolecular interactions, were altered. Compared with the commercial product (Celebrex®), the M3 and SD6 formulations showed significantly improved anti-inflammatory effects in terms of nitric oxide reduction, 1.5-fold and 2.2-fold, respectively, at the cellular level. The relative bioavailability (BA) of the M3 and SD6 formulations was also significantly improved as oral bioavailability (167.2% and 219.8% respectively), compared with that of Celebrex®. In particular, M3 and SD6 significantly reduced inflammation and edema volume relative to Celebrex® in CFA-induced RA rat models. Moreover, both M3 and SD6 effectively suppressed CFA-induced pro-inflammatory cytokines (TNF-α and IL-1ß) in rat splenic tissues. In conclusion, polymeric systems improved the solubility, relative BA (%) and anti-inflammatory effects of CXB. Thus, CXB polymeric systems show potential as therapeutic agents against inflammation and RA and may need to be tested at the clinical level.

Improvement of the dissolution rate and bioavailability of fenofibrate by the supercritical anti-solvent process.

The purpose of this study was to improve solubility and oral bioavailability of fenofibrate via solid dispersion (SD) using a supercritical anti-solvent (SAS) process with amphipathic polymers P407 and TPGS. Solid dispersion techniques have been widely used to enhance the solubility and dissolution profiles of poorly soluble drugs. Fenofibrate is classified as a Biopharmaceutics Classification System class II compound because of its low solubility and high gastrointestinal permeability. Two copolymers were selected based on solubility and dissolution tests. Their physicochemical properties were compared with those prepared by conventional solvent evaporation (CSE). The SD formulations containing fenofibrate were successfully prepared using the SAS and CSE methods. The dissolution rate (%) of fenofibrate at 60 min was significantly improved compared with the solution of raw fenofibrate (19.5% ±â€¯3.7%) by 95.1% ±â€¯2.5% and 93.7% ±â€¯4.1% using the SAS and the CSE process, respectively. This approximately four-fold increase in dissolution rate indicates that oral bioavailability can be enhanced. In addition, pharmacokinetic study was analyzed using the area under the curve (AUC) and Cmax values of SAS-SD and CSE-SD in rats. The AUC was 2.1 times higher and Cmax was 1.9 times higher in SAS-SD, indicating higher concentrations of fenofibrate in the blood. In a pharmacodynamic study to evaluate the efficacy of the drug in hyperlipidemic rat models, SAS-SD showed strong lipid-lowering effects including cholesterol (1.9-fold) and triglycerides (3.3-fold), than CSE-SD. Taken together, these results suggested that SAS-SD has excellent potential as a formulation for the poorly soluble drug fenofibrate.

Design of novel proliposome formulation for antioxidant peptide, glutathione with enhanced oral bioavailability and stability.

To develop proliposome formulations to improve the oral bioavailability of l-glutathione (GSH), GSH-loaded proliposomes were prepared using the granule method. Mannitol was selected as an effective excipient to achieve the desired particle size, entrapment efficiency (EE), and solubility for oral delivery of the final formulation. To evaluate the effect of surface charge of proliposomes on the oral bioavailability of GSH, negative (F1-F4) and positive proliposomes (F5-F9) were prepared. Particle size of F1 and F5 was 167.8 ± 0.9 and 175.9 ± 2.0 nm, and zeta potential of F1 and F5 was -8.1 ± 0.7 and 21.1 ± 2.0 mV, respectively. Encapsulation efficiency of F1 and F5 was 58.6% and 54.7%, respectively. Considering their particle size, zeta potential, and EE, the proliposomes F1 and F5 were adopted as the optimal formulations for further experiments. Solid state characterization of the proliposomes confirmed lipid coating on the surface of mannitol. The release of GSH from F1 and F5 formulations was prolonged until 24 h and pH independent. The total antioxidant capacity of GSH was concentration-dependent and maintained after formulation of GSH proliposomes. Circular dichroism spectroscopy confirmed that the molecular structure of GSH was maintained in the proliposome formulations. GSH proliposomes exhibited no significant changes in particle size and zeta potential for 4 weeks. An oral bioavailability study in rats revealed that F5 exhibited 1.05-, 1.08-, and 1.11-fold higher bioavailability than F1, commercial capsule formulation, and pure GSH, respectively. In conclusion, the prepared GSH proliposomes enhanced the poor bioavailability of GSH and prolonged its duration of action.

Amorphous multi-system of celecoxib improves its anti-inflammatory activity in vitro and oral absorption in rats.

In the present study, a multi-system for solid dispersion (SD) of celecoxib (CXB) was designed to improve its solubility and anti-inflammatory effects in vitro as well as oral absorption in rats. The SD formulations were prepared by a solvent evaporation with a multi-system as the solubilizer; an alkalizer; and fumed silica (Aerosil® 200). The physicochemical properties of the SD formulations were evaluated. Polyoxyl 15 hydroxystearate (HS 15®) was chosen as the solubilizer based on the apparent solubility test. The optimal SD formulation (SD6, CXB: HS 15®: K30®: meglumine: Aerosil® 200 = 200: 50: 50: 100: 100, weight ratio) improved the dissolution (%) over 2-fold compared to that by the commercial product (Celebrex®) at pH 1.2, in distilled water (DW), and in a pH 6.8 buffer (sodium lauryl sulfate [SLS], 0.25% w/v). The SD6 formulation altered physical properties such as crystallinity, thermal stability, and intra-molecular interaction. Moreover, SD6 showed a good stability for 6 months. The anti-inflammatory effect of SD6 significantly improved 2.2-fold compared to that of Celebrex® in the cell study. The relative bioavailability (BA) of SD6 was significantly improved to 209.4% compared to that of Celebrex®. In conclusion, intra-molecular interactions between CXB and solubilizers in multi-systems increase its solubility, dissolution (%), anti-inflammatory effects in vitro, and the relative BA (%) in rats. Thus, SD6 would be effective for the treatment of inflammation in rats and should be evaluated in detail in future clinical studies.