Pain Allaying Epalrestat-Loaded Lipid Nanoformulation for the Diabetic Neuropathic Pain Interventions: Design, Development, and Animal Study

Abstract

Background: Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model. Method: Experimental diabetes in rats was induced by a single dose of streptozotocin (STZ) administration. The therapeutic efficiency of Epalrestat nanoparticles (0.25, 0.50, 1, and 5 mg/kg) in diabetic rats was studied. STZ induced diabetic rats were treated with different doses of E-SLN for 8 weeks. The nanoparticles were orally administered at a single dose in rats, and the various parameters related to peripheral neuropathy were evaluated and compared with the bare drug. The blood glucose level was estimated by standard glucometer, HbA1c, triglycerides, total cholesterol and liver function test (ALT and AST) were analysed by blood samples collected from retro-orbital plexus. Oxidative stress markers and Na+K+ATPase, TNF-α and IL-1β levels were measured in the homogenate of sciatic nerves. Behavioural tests were also performed by the hot plate method and tail-flick method. Result: E-SLN synthesized by the micro-emulsification method were 281±60 nm in size, and encapsulation efficacy was found to be 88±2%. Optimized E-SLN were characterized and found to be optimum in size, spherical shape, decent encapsulation efficiency, stable at acidic gastric pH, and suitable for oral delivery. E-SLNs did not significantly reverse the STZ-induced elevated blood glucose level (FBS and PPBS), HbA1c, triglycerides and total cholesterol but significantly improved TNF-α, IL-1β, and increased Na+K+ATPase levels, oxidative stress marker and alanine transaminase, aspartate transaminase in the treated rat group as compared to the diabetic group. Doses of E-SLN, i.e. 0.5, 1.0, 2.5, and 5 mg/kg, significantly increased the tail-flick latency time and hot plate response time in a dose-dependent manner compared to the diabetic group. Conclusion: Thus, it is suggested that E-SLN were equally effective and less hepatotoxic compared to the standard treatment of epalrestat. To the best of our knowledge, we, for the first time, propose the orally deliverable E-SLN that ameliorates STZ induced diabetes neuropathic pain effectively as compared to conventional epalrestat.

N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model

“…Besides, RA is always related to persistent pain, which severely decreases the quality of life in RA patients. It is possible that RA patients may have peripheral neuropathic pain condition 81 , 82 , in which epalrestat has been used to alleviate neuropathic pain in diabetic patients 83 . Therefore, epalrestat combined with NAC may have potentiating effect in alleviating neuropathic pain associated with RA.…”

Bioequivalence Study of Epalrestat for Healthy Chinese Subjects

“…Epalrestat is a reversible noncompetitive inhibitor of aldose reductase and has selective inhibition on aldose reductase. Clinical studies have shown that epalrestat can inhibit the accumulation of sorbitol in red blood cells in patients with DPN and significantly improve patients’ conscious symptoms and neurological dysfunction 17 . At present, fewer generic formulations have been developed in China, so the successful implementation of this bioequivalence study will bring more treatment options for Chinese patients with diabetic neuropathy.…”

Nanomaterial-Based Drug Delivery Systems for Pain Treatment and Relief: From the Delivery of a Single Drug to Co-Delivery of Multiple Therapeutics

“…The results showed that the SLNs synthesized using the micro emulsification method had good encapsulation efficiency and were stable at acidic stomach pH, which was suitable for oral administration. Compared with epalrestat standard treatment, epalrestat with SLNs had the same efficacy, was less hepatotoxic, and could effectively improve streptozotocin-induced diabetic neuropathic pain [ 36 ].…”