In vitro and in vivo evaluation of isoxsuprine loaded invasomes for efficient treatment of diabetes‐accelerated atherosclerosis

Hyperglycemia in diabetes mellitus exacerbates vascular disarray in atherosclerosis by damaging endothelial cells and vascular smooth muscles. It's a major contributor to deaths from cardiovascular disease. Isoxsuprine (IXS) is an oral beta-adrenergic agonist that improves arterial blood flow due to its vasodilatation effect and boosts insulin secretion. However, oral IXS has low efficacy, low bioavailability and patient incompliance due to its high dose frequency, short biological half-life and fast clearance. The goal of this research was to develop a nasal formulation of IXS-loaded invasomes to sustain IXS's release and improve its permeation and efficacy as a potential diabetes-accelerated atherosclerosis treatment. Different IXS-loaded invasomes formulations were developed using design expert software to study the effects of ethanol, phospholipid, and cineole concentrations. Based on the desirability index, the formulation with 1 % ethanol, 0.5 % cineole, and 2.48 % phospholipid was chosen as the optimum formulation. The optimum IXS-loaded invasomes formulation showed an encapsulation efficiency of 72.03 % and a particle size of 210.26 nm. Production of nasal IXS-loaded invasomes formulation increased the permeation of IXS with a ratio of 2.25 and sustained its release. The optimum IXS-loaded invasomes formulation was non-cytotoxic and showed a good binding mode with serum proteins. When optimum IXS-loaded invasomes formulation was evaluated in vivo against a rat model of experimental diabetes and atherosclerosis, it showed anti-diabetic and anti-atherosclerotic effects. It substantially increased the levels of HDL by 45.11 % and substantially decreased the levels of glucose, LDL, triglycerides, and cholesterol by 41.35 %, 89.76 %, 51.01 %, and 60.18 %, respectively. Histopathology also showed that atherosclerotic lesions got improved in rats given optimum IXS-loaded invasomes formulation. In conclusion, nasal administration of IXS-loaded invasomes could be a potential diabetes-accelerated atherosclerosis treatment.