Utilization of Gelling Polymer to Formulate Nanoparticles Loaded with Epalrestat-Cyclodextrin Inclusion Complex: Formulation, Characterization, In-Silico Modelling and In-Vivo Toxicity Evaluation.

Zunaira Alvi,Amal M Sindi,Nisar U Rahman,Muhammad Akhtar,Khaled M Hosny,Imran Nazir,Barkat A Khan,Hadia Sadaquat

doi:10.3390/polym13244350

Abstract

Epalrestat (EPL) is an aldose reductase inhibitor with poor aqueous solubility that affects its therapeutic efficacy. The research study was designed to prepare epalrestat-cyclodextrins (EPL-CDs) inclusion complexes to enhance the aqueous solubility by using beta-cyclodextrin (β-CD) and sulfobutyl ether₇ β-CD (SBE7 β-CD). Furthermore, polymeric nanoparticles (PNPs) of EPL-CDs were developed using chitosan (CS) and sodium tripolyphosphate (sTPP). The EPL-CDs complexed formulations were then loaded into chitosan nanoparticles (CS NPs) and further characterized for different physico-chemical properties, thermal stability, drug-excipient compatibility and acute oral toxicity studies. In-silico molecular docking of cross-linker with SBE7 β-CD was also carried out to determine the binding site of the CDs with the cross-linker. The sizes of the prepared NPs were laid in the range of 241.5–348.4 nm, with polydispersity index (PDI) ranging from 0.302–0.578. The surface morphology of the NPs was found to be non-porous, smooth, and spherical. The cumulative percentage of drug release from EPL-CDs loaded CS NPs was found to be higher (75–88%) than that of the pure drug (25%). Acute oral toxicity on animal models showed a biochemical, histological profile with no harmful impact at the cellular level. It is concluded that epalrestat-cyclodextrin chitosan nanoparticles (EPL-CDs-CS NPs) with improved solubility are safe for oral administration since no toxicity was reported on vital organs in rabbits.

Highlights

Epalrestat (EPL) is relatively a new class of drug, prescribed in Japan as an antidiabetic drug
Physical mixture (PM) of EPL with β-CD and SBE7 β-CD was synthesized by triturating drug and CDs (1:1) separately in pestle and mortar for about 60 min [15]
The prepared mixtures were sieved through mesh no. 45 and stored in a tightly closed vial

Summary

Introduction

Epalrestat (EPL) is relatively a new class of drug, prescribed in Japan as an antidiabetic drug. Different approaches have been used in recent years for increasing the solubility and bioavailability of hydrophobic drugs. Inclusion complexation is one such approach that favorably enhances the solubility of lipophilic drugs by forming a reversible correlation between the ligand (EPL) and the substrate (CDs) [2–4]. NPs are solid colloidal particles that may be either nanocapsules or nanospheres [6] and can be prepared by different methods. NPs were prepared through the ionotropic gelation method using cationic polymers such as CS. The degree of deacetylation and weight are the significant parameters that influence the size of the particle [7]. Chitosan-cyclodextrin (CS-CD) nanocarrier systems have been fabricated. This innovative approach can successfully incorporate the lipophilic drug by creating the weak host-guest association termed as “Inclusion

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Results

Conclusion