Curcumin And Etoricoxib Encapsulated Liposomes: Formulation, Characterization And Anti-Inflammatory Effects In Rat Models
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Abstract
To enhance anti-inflammatory efficacy of Curcumin (CURC) and Etoricoxib (ETRX); and to reduce their notorious side effects, they were loaded into liposomal formulations (LFs). The present study aimed at formulation, characterization and evaluation of anti-inflammatory effects of LFs of CURC in combination with ETRX in experimental acute inflammation (AI) in rat model induced by carrageenan administration. The existing pharmaceuticals for treating arthritis are analgesics, steroids and non-steroidal anti-inflammatory drugs (NSAIDs), which reduce the symptoms such as severe pain and inflammation. Classical NSAIDs are cyclooxygenase (COX) inhibitors that inhibit prostaglandins (PGs) and thromboxane synthesis, thereby reducing inflammation. New NSAIDs selectively inhibit COX-2 and are usually specific to inflamed tissue, which decreases the risk of peptic ulcer. However, their long-term use cannot be sustained due to inadequate pain relief, immune disturbances and serious gastrointestinal and cardiovascular adverse events. Therefore, plant-based product like CURC with anti-inflammatory properties and minimum side effects are needed for the treatment of arthritis, including rheumatoid arthritis (RA) and osteoarthritis, especially after the withdrawal of many Food and Drug Administration (FDA)-approved anti- inflammatory drugs. However, its poor solubility, low chemical stability and short half-life following systemic absorption contribute to CURC being considered a pharmaceutical challenge. Numerous delivery systems have been proposed as means to tailor its biological properties. In this research, we are particularly interested in potential of CURC as an anti-inflammatory agent in combination with ETRX and delivery in the form of LFs. ETRX; a NSAID is proposed to treat inflammation in rat model as it is known for its anti-inflammatory, analgesic and antipyretic effects. ETRX, a widely prescribed anti- inflammatory drug belongs to class IΙ under BCS (biopharmaceutical classification system) and exhibit variable oral bioavailability due to its poor aqueous solubility. This research is aimed to study synergistic effect of a natural compound CURC and an allopathic NSAID moiety ETRX to treat inflammation in rat model, by oral ingestion in the form of LF as an efficient drug delivery system. Hence, we propose LF as a mean to overcome the CURC limitations. Liposomes (LPs) encapsulation of CURC makes this formulation amenable to circumvent the problem of poor oral availability that limits the utility of free CURC. The LFs can potentiate the effects of encapsulated drugs by sustaining the release over an extended period of time. The results of our study demonstrated that the association of CURC with ETRX in the form of LFs could potentiate the anti-inflammatory effects in reduced doses in vitro and in rat model. The LFs were spherical in shape in TEM images at various resolutions. The particle size of optimized CURC-ETRX LPs was found to be 276.1 nm with PDI value of 24.5. The maximum EE for CURC and ETRX in optimized formulation (F2) was found 98.915% and 93.877% respectively. The % EE of CURC-ETRX loaded LFs was found to be dependent on the lipid concentration, resulting almost quantitatively for a maximum 15 mg of total lipids (PC+CL) and progressively decreasing at higher 20 mg of total lipid (PC+CL) content, may be due to precipitation of drugs at higher lipid concentrations. The cumulative percentage release of CURC and ETRX from optimized formulations was found to be 59.64% and 83.11% respectively, for a period of 24 hours. We investigated the in vivo effect of CURC and ETRX loaded LF on local edema in carrageenan-induced paw edema in rat model. The percentage inhibition of edema in rat model was found to be better for CURC-ETRX LF in comparison to conventional CURC and ETRX in solution forms (p<0.05). Hence, the association of CURC and ETRX to a low dose in the form of LFs could be an appropriate combination to decrease NSAID doses used to reduce pain, inflammatory cytokines, and histological changes in AI.
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