Optimization of Solid Lipid Nanoparticles of Ezetimibe in Combination with Simvastatin Using Quality by Design (QbD)

Abstract

Background: The objective of this study was to develop solid lipid nanoparticles (SLNs) of poorly water soluble anti-hyperlipidemic drugs-Ezetimibe in combination with Simvastatin. Methods: This study describes a 32 full factorial experimental design to optimize the formulation of drug loaded lipid nanoparticles (SLN) by the high speed homogenization technique. The independent variables amount of lipid (GMS) and amount of surfactant (Poloxamer 188) were studied at three levels and arranged in a 32 factorial design to study the influence on the response variables- particle size, % entrapment efficiency (%EE) and cumulative drug release (% CDR) at 24 h. Results: The particle size, % EE and % CDR at 24 h for the 9 batches (B1 to B9) showed a wide variation of 104.6-496.6 nm, 47.80-82.05% (Simvastatin); 48.60-84.23% (Ezetimibe) and 54.64-92.27% (Simvastatin); 43.8-97.1% (Ezetimibe), respectively. The responses of the design were analysed using Design Expert 10.0.2. (Stat-Ease, Inc, USA), and the analytical tools of software were used to draw response surface plots. From the statistical analysis of data, polynomial equations were generated. Optimized formulation showed particle size of 169.5 nm, % EE of 75.43% (Simvastatin); 79.10% (Ezetimibe) and 74.13% (Simvastatin); 77.11% (Ezetimibe) %CDR after 24 h. Thermal analysis of prepared solid lipid nanoparticles gave indication of solubilisation of drugs within lipid matrix. Conclusion: Fourier Transformation Infrared Spectroscopy (FTIR) showed the absence of new bands for loaded solid lipid nanoparticles indicating no interaction between drugs and lipid matrix and being only dissolved in it. Electron microscope of transmission techniques indicated sphere form of prepared solid lipid nanoparticles with smooth surface with size approximately around 100 nm.

Ezetimibe-Loaded Nanostructured Lipid Carrier for Oral Delivery: Response Surface Methodology; In Vitro Characterization and Assessing the Antihyperlipidemic Effect in Rats

“…This relationship could be described briefly as that the initial rise may be related to the small particle size, which gave a larger surface area existing for drug dissolution. However, accompanying the rise in the size of particles with higher liquid lipid percentages, the release rates declined. , …”

“…The FTIR spectra were measured with a resolution of 4 cm –1 over the range of 4000–400 cm –1 for 50 scans. Each data point was recorded in three replicates using absorbance mode to facilitate quantitative analysis …”

“…Each data point was recorded in three replicates using absorbance mode to facilitate quantitative analysis. 20 3.2.4.3. Differential Scanning Calorimetry (DSC).…”

“…However, accompanying the rise in the size of particles with higher liquid lipid percentages, the release rates declined. 13,20 Concerning the type of liquid lipid used, the positive sign of a [1] indicates that the addition of oleic acid contributed to higher drug release rates than IPM. However, the negative coefficient of a[2] refers to a reduced percentage of drug release as compared to IPM upon labrafac incorporation.…”

“…To our best knowledge, few comparative studies considered the utilization of SLNs and NLCs in an attempt to enhance the solubility of EZ, for example, refs ,− . However, none of them focused on optimizing the composition of different formulations to attain the maximum improvement in aqueous solubility and drug efficacy.…”