Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats
Atorvastatin calcium (ATV), a cholesterol-lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle.Objective:
The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route.Methods:
The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407-induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits.Results:
The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186–583 nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p < 0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity.Conclusion:
The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV.