In vitro and in vivo evaluation of the therapeutic efficacy of in-situ pH-sensitive carvedilol-loaded novasomes as a therapy for diabetes-associated coronary artery disease

Coronary artery disease (CAD) is a condition in which the blood vessels that supply oxygen to the heart become narrowed. Hyperglycemia contributes to vascular dysfunction in CAD by causing damage to endothelial cells and smooth muscle in the blood vessels. Carvedilol (CRD), a nonselective β- and α1-blocker, is approved for treating diabetes-associated CAD. However, CRD's short half-life and poor solubility limit its oral bioavailability and effectiveness. This study aimed to develop a nasal formulation of in-situ pH-sensitive CRD-loaded novasomes (ISCLN) to enhance CRD's sustainability, bioavailability, and efficacy as a therapy for diabetes-associated CAD. The Box–Behnken design was employed to determine the optimized formulation of CRD-loaded novasomes. This formulation was subsequently combined with chitosan and glyceryl monooleate to create ISCLN. The ISCLN was then evaluated in vivo using a rat model of experimental diabetes and CAD. Compared to free CRD, ISCLN significantly improved sustainability, bioavailability, targeting, and permeability of CRD. Relative to the positive control group, the ISCLN group exhibited decreased levels of glucose, cholesterol, triglycerides, low-density lipoprotein, lactate dehydrogenase, and creatine kinase-MB. Additionally, this group showed increased levels of high-density lipoprotein. Histopathological and toxicity studies confirmed the efficacy and safety of the ISCLN. These findings suggest that a nasal ISCLN formulation may serve as a potential therapy for diabetes-associated CAD.