Formulation and design optimization of nano-transferosomes using pioglitazone and eprosartan mesylate for concomitant therapy against diabetes and hypertension

Hypertension, a form of cardiovascular diseases, is considered a major risk factor associated with deaths in type 2 diabetes patients. The current medication systems for treating such chronic coexisting diseases are limited and challenging due to the difficulties in overcoming the side effects from complex therapeutic and treatment regimen. The objective of the present study is to design and optimize pioglitazone (PIO) and eprosartan mesylate (EM)-loaded nano-transferosomes (NTs) using Design-Expert software, aiming its transdermal delivery as a novel combination therapy for concomitant treatment of hypertensive diabetic patients. The developed formulations were characterized for various parameters, including in-vitro skin permeation, skin irritation, in-vivo antidiabetic, and antihypertensive activities. NTs were prepared using PIO and EM as the two model drugs and optimized using Box-Behnken design by considering phospholipid (X1), surfactant (X2), ratio of solvents (X3), and sonication time (X4), as independent variables, each at three levels. Entrapment efficiency (Y1 and Y2) and flux (Y3 and Y4) of PIO and EM, respectively, were selected as dependent variables. Among all the prepared formulations, one optimized formulation was chosen by the point prediction method and evaluated for drug-polymer compatibility, particle size, and surface charge analysis, followed by skin permeation and pharmacodynamic studies. The optimized nano-transferosomal gel (ONTF) showed all responses which confirm with the values predicted by the design. Pharmacodynamic studies showed improved and prolonged management of diabetes and hypertension in Wistar rats after the ONTF was applied, compared to oral and drug-loaded NT formulations. Results of the current study suggest that the development of such combinational delivery system can result in a rational therapeutic regimen for effective treatment of concomitant disease conditions of diabetic hypertensive patients.