Formulation and Pharmacokinetic Evaluation of Ethyl Cellulose/HPMC-Based Oral Expandable Sustained Release Dosage of Losartan Potassium

Prolonged retention of losartan potassium in the upper gastrointestinal tract is anticipated to increase its absorption and exposure to CYP450 enzyme subfamilies, undertaking its conversion to more potent (10-40 times) active metabolite, losartan carboxylic acid (LCA). Consistent with this, hydroxypropyl methylcellulose K4M/ethyl cellulose-based novel expandable films (EFs) containing losartan potassium (LP) suitable for prolonged retention in the stomach were developed. The films were prepared by solvent casting method. USP type II dissolution apparatus (0.1 N HCl, 37 degrees C, 100 rpm) was used to perform the dissolution testing (drug release, unfolding behavior, film integrity, erosion, and water uptake) of the films. In vivo pharmacokinetic studies were carried out in rabbits. An HPLC-UV method was used for the quantification of the drug and its active metabolite in plasma. These folded films placed inside hard gelatin capsule shells unfolded to full dimensions in dissolution medium and provided sustained drug release throughout 12 h. The plasma drug concentration-time curves obtained from the in vivo studies were used to determine pharmacokinetic parameters, such as area under the plasma drug concentration-time curve (AUC), area under first moment curve (AUMC), mean residence time (MRT), C-max, T-max, t(1/2), k(e), and F-r in comparison with that of the market formulation, Cozaar (R). The novel EFs significantly changed the pharmacokinetic parameters of the drug and its active metabolite. The apparent elimination rate constant (k(e)) significantly decreased, while MRT and elimination half-life (t(1/2)) increased in both cases. The relative bioavailabilities (F-r) of both LP and E3174 using the novel formulation were higher than that of Cozaar (R).

Automated summary

This study developed a novel expandable film based on hydroxypropyl methylcellulose K4M/ethyl cellulose for prolonged retention of losartan potassium in the stomach. The film significantly altered the pharmacokinetic parameters of the drug and its active metabolite, as demonstrated by in vivo and in vitro experiments.