Porous Nanostructure, Lipid Composition, and Degree of Drug Supersaturation Modulate In Vitro Fenofibrate Solubilization in Silica-Lipid Hybrids.

Ruba Almasri,Hayley B. Schultz,Kristen E. Bremmell,Nicky Thomas,Paul Joyce,Clive A. Prestidge

doi:10.3390/pharmaceutics12070687

Abstract

The unique nanostructured matrix obtained by silica-lipid hybrids (SLHs) is well known to improve the dissolution, absorption, and bioavailability of poorly water-soluble drugs (PWSDs). The aim of this study was to investigate the impact of: (i) drug load: 3–22.7% w/w, (ii) lipid type: medium-chain triglyceride (Captex 300) and mono and diester of caprylic acid (Capmul PG8), and (iii) silica nanostructure: spray dried fumed silica (FS) and mesoporous silica (MPS), on the in vitro dissolution, solubilization, and solid-state stability of the model drug fenofibrate (FEN). Greater FEN crystallinity was detected at higher drug loads and within the MPS formulations. Furthermore, an increased rate and extent of dissolution was achieved by FS formulations when compared to crystalline FEN (5–10-fold), a commercial product; APO-fenofibrate (2.4–4-fold) and corresponding MPS formulations (2–4-fold). Precipitation of FEN during in vitro lipolysis restricted data interpretation, however a synergistic effect between MPS and Captex 300 in enhancing FEN aqueous solubilization was attained. It was concluded that a balance between in vitro performance and drug loading is key, and the optimum drug load was determined to be between 7–16% w/w, which corresponds to (200–400% equilibrium solubility in lipid Seq). This study provides valuable insight into the impact of key characteristics of SLHs, in constructing optimized solid-state lipid-based formulations for the oral delivery of PWSDs.

Highlights

Due to the staggering number of new drug entities with poor physicochemical properties under development, formulation scientists are challenged to design innovative formulations that successfully overcome these molecules’ inherent slow dissolution and poor oral absorption [1]
The key findings of this study provide a valuable insight into the role of porous silica nanostructure, lipid type, and drug loading, for constructing optimized solid-state lipid-based formulations (LBFs) for the oral delivery of poorly water-soluble drugs (PWSDs)
It was evident that FEN solubility in all lipids increased considerably with temperature, achieving 4.4- to 7.7-fold greater FEN solubility at 60 ◦C compared to 25 ◦C (Figure 1)

Summary

Introduction

Due to the staggering number of new drug entities with poor physicochemical properties under development, formulation scientists are challenged to design innovative formulations that successfully overcome these molecules’ inherent slow dissolution and poor oral absorption [1]. The lipid content within these formulations triggers the release of digestive pancreatic and gallbladder enzymes and a sequence of digestive processes that result in the dynamic formation of a range of colloidal systems (e.g., micelles) [3,4]. This naturally occurring phenomenon maintains the drug in the solubilized state and creates a concentration gradient that acts as a driving force for absorption, reducing the food effect for lipophilic drugs. LBFs present promising benefits for poorly water-soluble, highly permeable, BCS (Biopharmaceutics Classification System) class II drugs [6,7]

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