Improving the Therapeutic Efficacy and Bioavailability of Carvedilol for Control of Diabetes-Associated Heart Failure: In Vitro and In Vivo Characterization

Carvedilol (CRD) is an oral beta-adrenergic antagonist approved for treating heart failure (HF). However, due to its short half-life and poor solubility, CRD has limited bioavailability and effectiveness. This study aimed to develop a nasal spray of CRD-novasomes (CLN) to enhance CRD's sustainability, targeting, bioavailability, and efficacy as a therapy for diabetes mellitus-associated HF (DMHF). Several CLN formulations were created using Box-Behnken design and characterized in vitro to identify the optimized formulation, which was later evaluated in vivo using an experimental DMHF rat model. The selected optimized CLN formulation consists of 30.079 mg of oleic acid, 56.897 mg of Span 60, and 60 mg of cholesterol. The optimized CLN demonstrated significant improvements over free CRD, enhancing CRD's sustainability and permeability by 71.39% and 6.08-fold, respectively. When compared to oral free CRD, the nasal CLN increased the bioavailability and target efficiency of CRD by 5.74-fold and 4.24-fold, respectively. In relation to DMHF positive control, the nasal CLN significantly lowered glucose, LDH, and CK-MB levels by 93.68%, 94.29%, and 96.50%, respectively, showcasing its efficacy. Histopathological and toxicity studies further validated the activity and safety of the optimized CLN. These findings indicate that the nasal CLN spray shows potential as a therapy for DMHF.