Improving the efficacy and targeting of carvedilol for the management of diabetes-accelerated atherosclerosis: An in vitro and in vivo assessment

Abstract

Atherosclerosis is characterized by the accumulation of lipids and inflammation in large arteries. Diabetes mellitus significantly contributes to the initiation and progression of this condition. Carvedilol, an oral beta-adrenergic antagonist, is recognized for its ability to enhance arterial blood circulation and reduce hyperglycemia. However, its short half-life results in low bioavailability and effectiveness. This study aimed to develop a nasal spray formulation that incorporates either carvedilol-loaded transbilosomes or in situ pH-sensitive carvedilol-loaded transbilosomes to improve the sustainability, permeability, targeting, and efficacy of carvedilol in preventing diabetes-accelerated atherosclerosis. Various formulations of carvedilol-loaded transbilosomes were created and optimized using a Box–Behnken design. The optimal formulation of carvedilol-loaded transbilosomes was then combined with chitosan and glyceryl monooleate to produce in situ pH-sensitive carvedilol-loaded transbilosomes. Both the optimal carvedilol-loaded transbilosomes and the in situ pH-sensitive carvedilol-loaded transbilosomes were evaluated in vivo using a rat model of experimental diabetes and atherosclerosis. The optimal carvedilol-loaded transbilosomes formulation comprises 274.3 mg of phospholipid, 26.7 mg of Span 60, and 22.5 mg of sodium deoxycholate. Both the optimal carvedilol-loaded transbilosomes and the in situ pH-sensitive carvedilol-loaded transbilosome formulations exhibited greater sustainability, permeability, and targeting capabilities compared to free carvedilol. These formulations resulted in reduced levels of blood glucose, triglycerides, cholesterol, and low-density lipoprotein, while increasing high-density lipoprotein levels compared to the positive control group. In conclusion, the nasal delivery of the optimal carvedilol-loaded transbilosomes and the in situ pH-sensitive carvedilol-loaded transbilosomes shows promise as a strategy for treating diabetes-accelerated atherosclerosis.