Chiral S-flurbiprofen axetil-loaded lipid microspheres for improved analgesic effects: Preparation, characterization, and preclinical evaluation

Abstract

Flurbiprofen axetil (FPA) is a non-steroidal anti-inflammatory drug commonly used for managing post-surgical and cancer-related pain. However, FPA consists of two enantiomers, namely S-flurbiprofen axetil (S-FPA) and R-flurbiprofen axetil (R-FPA), with distinct inhibitory activities on cyclooxygenase (COX). This study focused on utilizing chiral S-FPA as the active pharmaceutical ingredient for the first time, and developed S-FPA-loaded lipid microspheres (S-FPA@LMs). The average particle size and zeta potential of S-FPA@LMs were 217.33 ± 6.66 nm and −36 ± 3.46 mV, respectively. S-FPA@LMs exhibited excellent stability for at least 6 months when stored at 5 ± 3 °C. COX activity inhibition assay revealed that S-FPA selectively inhibited COX-1, exhibiting a more potent inhibitory effect than the racemic form of FPA. In a rat model of postoperative incision pain, S-FPA@LMs demonstrated dose-dependent analgesic effects with superior efficacy compared to equimolar doses of FPA@LMs. Pharmacokinetic studies revealed comparable profiles for the metabolites, including S-flurbiprofen (S-FP) and R-flurbiprofen (R–FP), when S-FPA@LMs and FPA@LMs were administered in equimolar doses. Additionally, continuous administration for 7 days showed no significant accumulation of S-FP and R–FP. The inversion from S-FP to R–FP after S-FPA@LMs administration was also negligible. In terms of safety, S-FPA@LMs did not induce any signs of hemolysis or coagulation in rabbit erythrocytes. Moreover, no immediate allergic reactions were observed in the active systemic anaphylaxis test. The sub-acute toxicity study indicated dose-dependent adverse reactions primarily related to the gastrointestinal system, with recovery observed after a 2-week recovery period. Notably, S-FPA@LMs displayed a lower mortality rate and less severe pathological changes in the deceased rats compared to FPA@LMs. Overall, our findings highlight the potential of S-FPA@LMs as a promising candidate for acute pain management with satisfactory stability, enhanced analgesic efficacy, reduced dosage, and reduced toxicity compared to the racemic mixture. In summary, the introduction of S-FPA@LMs presents an innovative approach to managing acute pain, warranting further exploration and development in the field of pain therapeutics.