Development of a novel intramuscular liposomal injection for advanced meloxicam delivery: Preparation, characterization, in vivo pharmacokinetics, pharmacodynamics, and pain assessment in an orthopedic pain model

Abstract

Pain produces several physiological, and degenerative complications. This study aimed to formulate meloxicam (MLX) in liposomes to increase solubility and deliver MLX in a controlled manner to overcome its poor aqueous solubility and relatively short t_1/2 problems. Liposomes were prepared by thin film hydration followed by ultrasonication. Tests for characterizing formulations included particle size, span, entrapment efficiency, drug loading, stability, differential scanning calorimetry (DSC), Fourier transformation infrared (FT-IR) spectroscopy, morphology, in vitro release, release kinetics mathematical modeling, and an in vivo pain model in dogs undergoing orthopedic surgeries, followed by in vivo pharmacokinetics, pharmacodynamics, and pain assessment studies in comparison to the reference standard, Mobitil®. Liposomal MLX had a particle size of around 100 nm, 82 % entrapment efficiency, and 4.62 % drug loading. Stability studies, DSC, and FT-IR spectroscopy indicated that liposomes were highly stable. The formulation showed an improved in vitro controlled release pattern and an enhanced in vivo pharmacokinetic behavior as manifested by higher t_1/2 and AUC_{0 - 24} and lower Cl/F in comparison to Mobitil®. The pharmacodynamics study and pain scales demonstrated liposomal MLX managed postoperative pain better than Mobitil®. In conclusion, the incorporation of MLX in liposomes increased its solubility and stability, as well as its pain management properties.

Keywords: CMPS-SF pain scale; Interleukin-6; Liposomes; Meloxicam; Pain management; Pharmacokinetics.

Graphical abstract

Fig. 1

Particle size distribution curves of (a) PL 1, (b) PL 2, (c) LMLX 1, and (d) LMLX 2.

Fig. 2

Liposomes stability as indicated by (A) particle size and (B) span at 0, 30, and 60 days of preparation.

Fig. 3

(A) DSC thermograms of (a) pure meloxicam, (b) Lipoid S 40, (c) Pure CHOL, (d) physical mixture of liposomal components, (e) PL 1, and (f) LMLX 1. (B) FT-IR spectroscopy of (a) pure meloxicam, (b) PL 1, and (c) LMLX 1.

Fig. 4

Transmission electron micrograph of LMLX 1.

Fig. 5

Release patterns of the selected formula (LMLX 1) in comparison to the reference standard, Mobitil®.

Fig. 6

The drug plasma concentration-time profile after IM administration of LMLX 1 in comparison to the reference standard, Mobitil®.

Fig. 7

Effect of LMLX 1 vs. Mobitil® treatment on serum levels of (A) CRP, (B) IL-6, and (C) ALP. Data were represented as mean ± SD. Within the same group, different letters indicate a significant difference (P < 0.05). At the same time point, * indicates a significant difference (P < 0.05), and ** indicates a significant difference (P < 0.01) between the two groups.

Fig. 8

Box-and-whisker graphs show (A) CMPS-SF and (B) UMPS scores at different postoperative periods. The box represents the 25th and 75th percentile of data, with the horizontal line within indicating the median. The upper and lower whiskers indicate the range of values. The lack of a visible median line indicates the median value is toward the bottom of the box. The lack of a whisker indicates the absence of data within the relevant distance from the median, respectively. * denotes significance P < 0.05 between the two groups at the same time point.