Statistically designed novel ranolazine-loaded ethosomal transdermal gel for the treatment of angina pectoris

Abstract

Ranolazine (RZ) is a newer novel anti-anginal drug with poor solubility and high permeability features. The current research work focused on the statistical design and development of RZ-loaded ethosome as a novel carrier through entrapment and in silico binding affinity studies using molecular docking. The study investigates the prospect of ethosomes as lipid nano-carrier in the form of vesicles for the transdermal enhancement of RZ. The affinity studies of RZ with Phospholipon 90H (PL90H) and a copolymer cholesterol signified the importance of cholesterol in the entrapment of drug in polar region of lipid bilayer in ethosomal vesicle with binding affinity −10.2 kcal/mol that enhanced drug solubility and absorption. In the absence of copolymer, the drug entrapped in non-polar tail with significantly less binding affinity −1.9 kcal/mol. Based on this finding the effective RZ-loaded ethosome compositions were designed and optimized. The Box-Behnken Design (BBD) was applied to fabricate ethosomes with changing amounts of phospholipon PL90H, hydroethanol, and cholesterol. The influence of independent variables PL90H (A), hydroethanol solution (B), and cholesterol (C) on vesicle size (nm), and % entrapment efficiency (%EE) was studied. The optimized ethosome formulation (R4) containing drug in ethosomal vesicle, evaluated using FTIR and XRD techniques, revealed a change in its physical state. Results demonstrated composition R4 with PL90H (100 mg) and hydroethanol (40% w/v) was embedded into Carbopol 934P gel to screen drug permeation and skin irritation. The ethosomal suspension (R4) was demonstrated with ethosome size 165.71 ± 2.73 nm, zeta potential −36.63 ± 2.78 mV, and %EE 80.21 ± 1.27. The optimized ethosomal suspension recorded release of RZ through dialysis membrane against RZ-loaded plain gel; was superior sustained over 24 h. The drug release from ethosomal gel followed a combination of Higuchi and Peppas model. RZ ethosomal gel tested using MTT assay manifested enhanced cytotoxic potential of RZ on H9C2-mouse cardiomyoblast cell line. Incorporation of vesicles into the gel leads to significant improvement in its stability. The present study demonstrates the prospective of ethosomal vesicles in delivering RZ across transdermal layers with the least skin irritation potential proclaiming its better safety, efficacy, and patient compliance.