Abstract
Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.
Highlights
Meloxicam (MLX) is categorized as a Class II drug in the Biopharmaceutical Classification System (BCS) [1] and is a selective inhibitor of cyclooxygenase-2
Cannulas were set into the right jugular veins of 8-week old rats under isoflurane anesthesia, and 200 μL samples of blood were collected from right jugular veins via cannulas at various times to evaluate the changes in MLX levels after the oral administration of 0.05 mg/kg or 0.2 mg/kg MLX
Solid nanoparticles are built up from drug molecules dissolved in an organic solvent in the precipitation techniques [26,27]; the organic solvent may cause toxicity when its residue remains in the final product, making the use of organic solvents undesirable
Summary
Meloxicam (MLX) is categorized as a Class II drug in the Biopharmaceutical Classification System (BCS) [1] and is a selective inhibitor of cyclooxygenase-2. MLX is a promising drug for the treatment of cancer and Alzheimer’s disease [4] Despite this attractive pharmacological profile, the peak plasma concentration of MLX is reached only 3–7 h following the administration of an oral suspension, and 5–6 h after the administration of traditional MLX tablets [5,6]. We reported that the inclusion of 2-hydroxypropyl-β-cyclodextrin (HPβCD) with nanoparticle preparations increases in solid nanoparticles prepared by the bead mill method, as well as improving permeability through the cornea [18], skin [19,20], and small intestine [21] in rats and rabbits These previous studies suggest that the method based on the bead mill with the addition of cyclodextrin is an effective and simple technique for improving the oral absorption and dissolution behavior of drugs. We demonstrate the effect of an oral administration system based on MLX solid nanoparticles on the pharmacokinetics and onset of gastrointestinal side effects, and the therapeutic effectiveness of MLX-NPs for inflammation using model RA rats
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