Enhanced bioavailability and hypolipidemic activity of Simvastatin formulations by particle size engineering: Physicochemical aspects and in vivo investigations

• Particle size engineering of Simvastatin was done by media milling and SCF technology.
• Significant increase in solubility and decrease in crystallinity of drug was obtained.
• Changes in physicochemical aspects were confirmed by DSC, XRD, TEM, solubility studies.
• Nanosuspension and SCF formulations showed enhanced hypolipidemic activity in rats.
• Bioavailability enhancement for SNS was 2.6 times and SCF was 1.8 times in rats.

The objective of this study was to enhance the solubility of Simvastatin by nanosizing approaches for improving its bioavailability. Nanosuspension (Sim-NS) formulated by media milling was optimized by 32 factorial design keeping the volume of milling media (X1) and surfactant concentration (X2) as independent and the particle size (Y) as dependent variable. A minimum particle size of 250.8 ± 12.6 nm was achieved. Simvastatin was also size reduced by supercritical antisolvent (SAS) method using CO2 as antisolvent, wherein particle size was reduced from 71.3 ± 0.87 μm to 16.54 ± 0.38 μm. Sim-NS showed significant increase in saturation solubility and decrease in crystallinity of the drug as compared to Simvastatin supercritical antisolvent product (Sim-SAS) and plain drug suspension. In vitro release showed increased dissolution rate of the drug for Sim-NS followed by Sim-SAS and plain drug. Pharmacodynamic evaluation in rats showed significant decrease in the total cholesterol and triglyceride levels for Sim-NS followed by Sim-SAS and plain drug. In vivo pharmacokinetics in rats showed an increase in bioavailability of Sim-NS (2.6 times) and Sim-SAS (1.8 times) compared to plain drug. Hence, particle size engineering has tremendous potential to enhance the bioavailability and hypolipidemic activity by altering physicochemical properties of the poorly water soluble drug.

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