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. 2015 Jan 23:9:655-62.
doi: 10.2147/DDDT.S76194. eCollection 2015.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics

Osama A A Ahmed  1 , Khaled M Hosny  2 , Majid M Al-Sawahli  3 , Usama A Fahmy  4
Affiliations

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics

Osama A A Ahmed et al. Drug Des Devel Ther. .

Abstract

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid-liquid phase separation method, according to the Box-Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance.

Keywords: Box–Behnken design; simvastatin; sodium caseinate; zein.

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Figures

Figure 1
Figure 1
Standard Pareto charts showing the effects of independent variables and their combined effects on particle size (A), SMV EE (B), and cumulative amount permeated after 1 hour (C). Note: Factors studied were percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). +, positive effect of the factor; −, negative effect of the factor. Abbreviations: EE, encapsulation efficiency; SMV, simvastatin.
Figure 2
Figure 2
The effects of independent variables and their combined effects on Y1, Y2, and Y3, represented as three-dimensional (3D) response surface plots (left side) and contours of estimated response surface plots (right side). Notes: Factors studied were percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3).
Figure 3
Figure 3
SEM image of optimized caseinate-coated SMV-zein nanoparticles. Abbreviations: SEM, scanning electron microscopy; SMV, simvastatin.
Figure 4
Figure 4
In vitro permeation of optimized SMV-zein nanoparticles. Abbreviation: SMV, simvastatin.
Figure 5
Figure 5
Means of plasma concentrations-time profiles and in vivo pharmacokinetic parameters (Inset) of optimized SMV-zein nanoparticles and SMV suspension. Abbreviations: AUC, area under the time–concentration curve; Cmax, maximum plasma concentration; Kel, elimination rate constant; MRT, mean residence time; SMV, simvastatin; t1/2, half-life; Tmax, time to reach Cmax.
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