A Strategic Formulation to Enhance the Safety and Anti-Hyperlipidaemic Activity of Simvastatin: Prototype Development

Abstract

Statins are widely regarded as the gold standard first-line treatment for hyperlipidemia, as they inhibit HMG-CoA reductase in the liver. This effectively reduces LDL cholesterol levels and reduces cardiovascular risks, such as heart attack and stroke. Simvastatin is a well-established, effective, and cost-efficient statin for lowering LDL cholesterol and reducing cardiovascular risk. However, it causes myopathy, rhabdomyolysis, myalgia, constipation, kidney failure, headache, abdominal pain, diarrhoea, nausea, and increased blood sugar levels with its use and higher doses of 80 mg/day. To address this, a liposomal simvastatin formulation with particle sizes of 150–250 nm was developed for intravenous administration. This formulation can potentially accumulate in the liver via passive targeting via the RES, thereby enhancing hepatic uptake and improving safety. The liposome was formulated using the thin-film hydration method and optimised using a central composite design. The optimized formulation's vesicle size was 204.66 ± 2.84 nm, with a PDI of 0.27 and a zeta potential of -58.11 mV, indicating uniform distribution and high stability. In-vitro drug release demonstrated controlled release of up to 92.46% over 60 h. The cellular toxicity assay showed that the optimized liposome was 10 times safer than pure simvastatin. In-vivo, the liposomal formulation significantly reduced lipid levels after administration of a 5 mg/kg dose in Triton X-100-induced hyperlipidemic rats, outperforming marketed formulations and standard drugs. Simvastatin-liposomes are safe, stable, and a more potent alternative to traditional oral simvastatin, offering improved liver targeting and a reduced toxicity profile. Simvastatin-encapsulated liposomes (particle size 150–250 nm) result in greater accumulation in the liver after intravenous administration. Optimised liposomal formulation maintained controlled drug release (released over 90% of the drug in 60 h), whereas the pure drug released only 33% in the same duration. Simvastatin-encapsulated liposomes were found to be stable and safer than the pure drug in HepG2 cells. Simvastatin liposomes result in a significant lipid-lowering ability at a 5 mg/kg dose for 24 h in hyperlipidemic rats. Simvastatin-encapsulated liposomes (particle size 150–250 nm) result in greater accumulation in the liver after intravenous administration. Optimised liposomal formulation maintained controlled drug release (released over 90% of the drug in 60 h), whereas the pure drug released only 33% in the same duration. Simvastatin-encapsulated liposomes were found to be stable and safer than the pure drug in HepG2 cells. Simvastatin liposomes result in a significant lipid-lowering ability at a 5 mg/kg dose for 24 h in hyperlipidemic rats.