**1. 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]. Amongst novel drug delivery systems, lipid-based formulations (LBFs) present opportunities for successfully delivering poorly water-soluble drugs (PWSDs), owing to their ability to mimic the postprandial effect [2]. Upon ingestion, 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, thus reducing the food effect for lipophilic drugs. Furthermore, such formulations deliver the drug to the gastrointestinal tract (GIT) in a pre-solubilized form, eliminating the requirement for dissolution as a rate limiting step for absorption [5]. As such, LBFs present promising benefits for poorly water-soluble, highly permeable, BCS (Biopharmaceutics Classification System) class II drugs [6,7].

Numerous studies have shown that, by manipulating the lipids and excipients used, enhancements in permeability, intestinal solubilization and absorption through the lymphatic system can be achieved, along with benefits in bypassing first-pass metabolism, inhibition of efflux transporters, and prevention of pre-systemic metabolism [4,8,9]. Although considerable research has been devoted to examining and refining formulation approaches to enhance the biopharmaceutical performance of LBFs, the number of successful products on the market are limited [5]. This is mainly due to their low stability, tendency to recrystallize and precipitate in vivo and costly manufacturing processes. In addition, several studies have reported poor correlation between in vitro and in vivo results [10,11].

Solidification represents an effective solution to overcome challenges associated with liquid LBFs, while optimizing the advantages related to lipids [6,12,13]. Solid-state LBFs are fabricated by adsorbing the liquid-state LBFs onto a solid carrier material. This can be achieved using various solid carriers (silica and silicate materials, polysaccharide, polymeric, and protein) and/or by adapting different techniques, including spray drying, lyophilization, rotary evaporation, melt extrusion, and melt granulation [14–16]. Silica-based adsorbents are commonly used as solid carriers for LBFs due to their biocompatibility, inert nature and highly porous structure [17,18], which provides increased surface area for adsorption of liquid lipids [19,20]. Furthermore, the high degree of versatility afforded by silica materials introduces the ability to manipulate the biopharmaceutical performance of silica lipid hybrids (SLHs) through changes in particle size, nanostructure and porosity [17,21,22]. For example, several studies have verified the ability to control both the rate and extent of lipid digestion, and the subsequent rate of drug release and absorption in SLHs through changes in nanostructure and surface chemistry [23–26]. Therefore, careful examination of the physiochemical properties of the silica carrier and composition should be considered during the fabrication of solid-state LBFs in order to seize their full therapeutic potential.

For most LBFs, typical drug loads are ≤5% *w*/*w* [24,27]. The drug loads are further reduced when LBFs are solidified by adsorption onto a solid carrier [16,19], such as for SLH, which in turn limits their potential commercial application to low dose, highly potent drugs. Thus, despite their success in stabilizing precursor liquid LBFs and significantly enhancing dissolution and solubilization of model drugs, low drug loading levels limit the commercial translation of SLHs. In addition to understanding the structure-activity relationships between porous silica properties and drug solubilization, recent attention has been afforded to improving the drug loading within SLHs through a supersaturation approach, which has led to the creation of supersaturated SLHs (super-SLH) [28–31].

Super-SLH, defined as drug dissolved in lipid above its equilibrium solubility (Seq) at room temperature, were fabricated by dissolving quantities of drug in a lipid using heat, followed by solidification employing preformed mesoporous silica microparticles, which upon cooling, generated supersaturated powders [30]. The lipid-drug solution was imbibed into the nanopores of the silica and/or stabilized on the surface of the silica particles to maintain the drug in a molecular state [31]. The method has demonstrated high drug loading, increased stability of the supersaturated drug, enhanced dissolution, and improved oral bioavailability of the PWSDs ibuprofen (IBU) [29,30] and abiraterone acetate (AbA) [28,31]. However, there is a fine balance between increasing the drug loading/supersaturation level and achieving enhanced biopharmaceutical performance, as the drug can recrystallize in the solid state, resulting in reduced dissolution. For IBU super-SLH, the ideal supersaturation level was 227% Seq, which achieved a 2.2-fold enhancement in oral bioavailability in Sprague-Dawley rats when compared to the commercial product, Nurofen [30]. In contrast, for AbA super-SLH, despite the supersaturated formulations significantly enhancing in vitro solubilization, only the unsaturated SLH (at 90% Seq) achieved an oral bioavailability that exceeded the commercial

product Zytiga (1.4-fold) in Sprague-Dawley rats [28]. Furthermore, when AbA super-SLH contained different lipids (Capmul PG8 or Capmul MCM), there were significant differences between their loading and in vitro and in vivo performances.

The published literature on super-SLH highlights that their performance is highly drug- and lipid-dependent, with only two drugs and two lipids being investigated thus far. Furthermore, only one type of silica has been applied to super-SLH. Therefore, there is significant opportunity for further investigation into the influence of these excipients to develop improved super-SLH formulations and exploit their full potential. On this basis, the focus of this study was to investigate the impact of (i) porous silica nanostructure, (ii) lipid type, and (iii) drug loading on the in vitro solubilization, dissolution, and solid-state stability of super-SLH [26]. To investigate silica nanostructure, preformed mesoporous silica microparticles were compared to a bottom-up approach to prepare porous silica microparticles that could be loaded with liquid lipid through spray drying fumed silica (FS). The lipids Capmul PG8 (monoester of caprylic acid) and Captex 300 (medium chain triglyceride) were investigated, with drug loads corresponding to 80, 200, 400, and 600% Seq. Fenofibrate (FEN), an antilipemic agent and BCS class II compound, was selected as the model drug to be applied to super-SLH for this study. It was chosen due to its poor water solubility (<3 µg/mL at 37 ◦C), its extensive use as a model drug, well documented application to LBFs, and as the first neutral compound to be applied to super-SLH [27–31]. Furthermore, this study marks the first application of FS as a solid carrier that can be loaded with supersaturated liquid lipid in super-SLH. 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 LBFs for the oral delivery of PWSDs.
