Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach

Abstract

This contribution describes a continuous process for the production of solid lipid nanoparticles (SLN) as drug-carrier systems via hot-melt extrusion (HME). Presently, HME technology has not been used for the manufacturing of SLN. Generally, SLN are prepared as a batch process, which is time consuming and may result in variability of end-product quality attributes. In this study, using Quality by Design (QbD) principles, we were able to achieve continuous production of SLN by combining two processes: HME technology for melt-emulsification and high-pressure homogenization (HPH) for size reduction. Fenofibrate (FBT), a poorly water-soluble model drug, was incorporated into SLN using HME-HPH methods. The developed novel platform demonstrated better process control and size reduction compared to the conventional process of hot homogenization (batch process). Varying the process parameters enabled the production of SLN below 200 nm. The dissolution profile of the FBT SLN prepared by the novel HME-HPH method was faster than that of the crude FBT and a micronized marketed FBT formulation. At the end of a 5-h in vitro dissolution study, a SLN formulation released 92-93% of drug, whereas drug release was approximately 65 and 45% for the marketed micronized formulation and crude drug, respectively. Also, pharmacokinetic study results demonstrated a statistical increase in Cmax, Tmax, and AUC0-24 h in the rate of drug absorption from SLN formulations as compared to the crude drug and marketed micronized formulation. In summary, the present study demonstrated the potential use of hot-melt extrusion technology for continuous and large-scale production of SLN.

Fig. 1

Schematic representation of continuous preparation of SLN using hot-melt extrusion connected to high-pressure homogenizer [8]

Fig. 2

Screw configuration and mixing zones used in the preparation of SLN by HME [8]

Fig. 3

Contour plot of EE vs lipid concentration, surfactant concentration, zone of liquid addition, screw speed, and barrel temperature (red color indicates the higher EE, yellow indicates less EE, and blue color indicates lowest EE)

Fig. 4

Contour plot of PS vs lipid concentration, surfactant concentration, and barrel temperature (dark blue color indicates the smaller PS and light blue color indicates larger PS)

Fig. 5

Dissolution profile of FBT SLN prepared by novel HME-HPH method marketed micronized FBT formulation (Lofibra) and crude FBT

Fig. 6

Average plasma concentration time profiles of fenofibric acid following oral administration of 50 mg/kg in the rat. Three different formulations were tested: SLN prepared by novel HME-HPH method, marketed micronized FBT formulation, and crude FBT (mean ± SD, n = 4)