Efficacy and safety of valsartan–novasomes in the mitigation of atherosclerosis-associated diabetes mellitus: <i>in vitro</i> and <i>in vivo</i> assessment

Valsartan (VAL) offers protection against atherosclerosis-associated diabetes mellitus (AADM) due to its antioxidant properties. However, VAL is hindered by poor bioavailability and effectiveness, which can be attributed to its low water solubility and significant first-pass metabolism. This research aimed to develop a nasal VAL-novasomes formulation (VNF) intended to enhance VAL's efficacy, sustainability, bioavailability and targeting for AADM treatment. The Box-Behnken design was utilised for the development and optimisation of VNF formulations. The optimum VNF was subsequently evaluated <i>in vivo</i> using an experimental rat model of AADM. Compared to free VAL, the optimum VNF improved sustainability and bioavailability by 66.02% and 3.32-fold, respectively. The VNF group demonstrated significant reductions of 70.58%, 74.15%, 77.74% and 83.87% in glucose, triglycerides, cholesterol and LDL levels, respectively, compared to the AADM group. In contrast, HDL levels increased notably by 1.67-fold. Additionally, the VNF group accumulated 4.30 times more VAL in the heart than the free VAL group. Histopathological analysis confirmed the anti-atherosclerotic effect of the optimum VNF formulation. Importantly, the VNF group did not show any toxicity when compared to the negative control group. These findings support our hypothesis that the optimum VNF, administered nasally, could serve as a potential therapy for AADM.