Chitosan-Stabilized Lipid Vesicles with Indomethacin for Modified Release with Prolonged Analgesic Effect: Biocompatibility, Pharmacokinetics and Organ Protection Efficacy

Abstract

Background/Objectives: Indomethacin (IND) is a widely used non-steroidal anti-inflammatory drug (NSAID) effective in managing pain and inflammation. However, its therapeutic use is often limited by gastrointestinal irritation and low bioavailability. This study aimed to evaluate the biocompatibility, release kinetics, and analgesic potential of IND-loaded chitosan (CHIT)-stabilized lipid vesicles (IND-ves) in comparison to free IND, focusing on their in vivo effects and impact on somatic nociceptive reactivity in mice. Methods: IND-ves were prepared using a molecular droplet self-assembly technique, followed by CHIT coating to enhance stability and control drug release. Mice were administered either free IND or IND-ves, and various physiological parameters, including liver and kidney function, oxidative stress markers, immune cell activity, and histopathological changes in key organs, were assessed. Plasma drug release kinetics and analgesic effects were evaluated using the tail-flick test. Results: Both IND and IND-ves demonstrated good biocompatibility, with no significant changes in hematological, biochemical, or immunological profiles. IND-ves exhibited a sustained release profile, with drug release initiating at 30 min and peaking at 3 h, while free IND displayed a rapid release and potential gastric mucosal damage. IND-ves did not induce oxidative stress or inflammation and maintained organ integrity, particularly protecting against gastric injury. Additionally, the prolonged release profile of IND-ves contributed to extended analgesic effects in the tail-flick test. Conclusions: CHIT-stabilized lipid vesicles offer a promising drug delivery system for IND, enhancing drug release, prolonging analgesic efficacy, and minimizing gastrointestinal irritation. These findings suggest that IND-ves could serve as a safer and more effective alternative for NSAID therapy.

Keywords: biocompatibility; indomethacin; lipid vesicles; mice; tail flick.

Figure 1

The histological liver structure in mice belonging to the following groups: Control (a), IND (b), IND-ves (c). Masson trichrome stain ×20, scale bar = 100 µm.

Figure 2

The histological kidney structure in mice belonging to the following groups: Control (a), IND (b), IND-ves (c). Masson trichrome stain ×20, scale bar = 100 µm.

Figure 3

The histological myocardium structure in mice belonging to the following groups: Control (a), IND (b), IND-ves (c). Masson trichrome stain ×20, scale bar = 100 µm.

Figure 4

The histological stomach structure in mice belonging to the following groups: Control (a), IND (b), IND-ves (c). Masson trichrome stain ×20, scale bar = 100 µm.

Figure 5

The in vivo release kinetics of IND from IND-ves compared to free IND.

Figure 6

The effects of IND-ves in tail-flick test. Data are expressed as mean ± S.D. of mean for five mice in a group. ** p < 0.01 significant versus control group.

Figure 7

Quantification of the analgesic effect intensity of IND-ves in the tail-flick test.

Figure 8

The correlation between the plasma concentration of IND-ves in vivo and the latency time response of IND-ves in the tail-flick test.