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The structure and stability of emulsions formed in the presence of nanoparticles of poly(lactic-co-glycolic acid) (PLGA) were characterised. From oil-water contact angles on PLGA films, it was deduced that particle surface hydrophobicity is linked to the oil phase polarity. Incorporation of polyvinyl alcohol molecules into the nanoparticle surfaces reduces the particle hydrophobicity sufficiently for oil-in-water emulsions to be preferentially stabilised. PLGA nanoparticles enhance the stability of emulsions formed from a wide range of oils of different polarities. The nanoparticle concentration was found to be a key parameter controlling the average size and coalescence stability of the emulsion drops. Visualisation of the interfacial structure by electron microscopy indicated that PLGA nanoparticles were located at the drop surfaces, evidence of the capacity of these particles to stabilise Pickering-type emulsions. These results provide insights into the mechanism of PLGA nanoparticle stabilisation of emulsions. Refereed/Peer-reviewed

In this review article we collect and analyse preparation, chemistry and properties of silica materials relevant for drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable, oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics of fumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials (implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role in anticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the research of silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials, anticancer and stimuli-responsive mesoporous silica materials are particularly emphasized. Refereed/Peer-reviewed

The interfacial and bulk properties of submicron oil-in-water emulsions simultaneously stabilised with a conventional surfactant (either lecithin or oleylamine) and hydrophilic silica nanoparticles (Aerosil®380) were investigated and compared with emulsions stabilised by either stabiliser. Emulsions solely stabilised with lecithin or oleylamine showed poor physical stability, i.e., sedimentation and the release of pure oil was observed within 3. months storage. The formation and long-term stability of silica nanoparticle-coated emulsions was investigated as a function of the surfactant type, charge, and concentration; the oil phase polarity (Miglyol®812 versus liquid paraffin); and loading phase of nanoparticles, either oil or water. Highly stable emulsions with long-term resistance to coalescence and creaming were formulated even at low lecithin concentrations in the presence of optimum levels of silica nanoparticles. The attachment energy of silica nanoparticles at the non-polar oil-water interface in the presence of lecithin was significantly higher compared to oleylamine in line with good long-term stability of the former compared to the sedimentation and release of oil in the latter. The attachment energy of silica nanoparticles at the polar oil-water interface especially in the presence of oleylamine was up to five-times higher compared to the non-polar liquid paraffin. The interfacial layer structure of nanoparticles (close-packed layer of particle aggregates or scattered particle flocs) directly related to the free energy of nanoparticle adsorption at both MCT oil and liquid paraffin-water interfaces Refereed/Peer-reviewed

We report on the stability, structural and dermal delivery characteristics of Pickering emulsions composed of medium chain triglycerides, hydrophilic nanoparticles ~ 50 nm and lipophilic amphiphiles in the oil phase. The emulsion stability and structural properties were analyzed as a function of the charge and concentration of the lipophilic amphiphiles, concentration and initial loading phase of nanoparticles. The determination of the chemical stability of model drug all-trans-retinol confirmed that nanoparticle layers can be engineered to enhance the shelf-life of unstable lipophilic molecules. The penetration/permeation behavior of Pickering emulsions was estimated from an ex vivo porcine skin model using all-trans-retinol and a fluorescent probe. The skin retention and depth of the penetration can be significantly increased (p 0.05), up to a skin depth of ~ 290 um by Pickering emulsions in comparison to the control emulsions. The skin permeation of nanoparticles was negligible (

The dermal delivery characteristics of hydrophilic silica nanoparticle coated medium chain triglyceride oil-inwater emulsions are reported and correlated with the physicochemical and interfacial properties of the emulsion based drug carriers. The synergistic drug/stabiliser/nanoparticle interactions are demonstrated to be a function of the charge and concentration of the initial emulsion stabiliser; charge and initial loading phase of nanoparticles and physicochemical properties of the drug molecule. The improved physical stability of the emulsions and the chemical stability of two model lipophilic agents (all-trans-retinol and acridine orange 10-nonyl bromide) confirmed that engineered nanoparticle layers can enhance the shelf-life of liable lipophilic agents. Nanoparticle coatings are shown to control the in-vitro release of active agents from emulsions and significantly promote skin retention. The lipophilic agents distributed into the deeper viable skin layers without permeation through full-thickness skin and hence systemic exposure. Nanoparticle-coated submicron oil-in-water emulsions can serve as novel dermal carriers with controlled release kinetics and targeted drug delivery. Refereed/Peer-reviewed

Clinical trials addressing the viability of lipid and nanoparticle-based solid dosage forms for the oral delivery of poorly water-soluble drugs are limited to date. This Phase I study aimed to assess the comparative tolerability and oral pharmacokinetics of a novel silica nanoparticle-lipid hybrid formulation encapsulating ibuprofen (i.e., Lipoceramic-IBU) with reference to a commercial tablet (i.e., Nurofen®). The test (Lipoceramic-IBU) and reference (Nurofen®) ibuprofen formulations were characterised for physicochemical properties and in vitro solubilisation performance prior to the clinical study. A randomised, double-blinded, one-period single oral dose (20 mg ibuprofen) study was performed in 16 healthy male subjects under fasting conditions. Encapsulation of ibuprofen in a molecularly dispersed form in the Lipoceramic nanostructured silica-lipid matrices was shown to produce superior drug solubilisation in comparison to Nurofen® and the pure drug during a two-step dissolution (or solubilisation) study in aqueous buffers of pH 1.2 followed by pH 6.5. Pharmacokinetic profiles revealed an approximately 1.95-fold increased bioavailability (p=0.02) and a 1.5-fold higher maximum plasma concentration (p=0.14) for Lipoceramic-IBU with reference to Nurofen®. Review of the safety assessments, including physical examinations, clinical laboratory tests and reports of adverse events, confirmed negligible acute side effects related to the administration of blank and ibuprofen-loaded Lipoceramic formulations. This first in man study of a dry lipid and nanoparticle-based formulation successfully demonstrated the safe use and effectiveness of the nanostructured Lipoceramic microparticles in mimicking the food effects for optimising the oral absorption of poorly water-soluble compounds. Refereed/Peer-reviewed

Submicron oil-in-water (o/w) emulsions stabilised with conventional surfactants and silica nanoparticles were prepared and freeze-dried to obtain free-flowing powders with good redispersibility and a three-dimensional porous matrix structure. Solid-state emulsions were characterised for visual appearance, particle size distribution, zeta potential and reconstitution properties after freeze-drying with various sugars and at a range of sugar to oil ratios. Comparative degradation kinetics of all-trans-retinol from freeze-dried and liquid emulsions was investigated as a function of storage temperatures. Optimum stability was observed for silica-coated oleylamine emulsions at 4 °C in their wet state. The half-life of all-trans-retinol was 25.66 and 22.08 weeks for silica incorporation from the oil and water phases respectively. This was ∼4 times higher compared to the equivalent solid-state emulsions with drug half-life of 6.18 and 6.06 weeks at 4 °C. Exceptionally, at a storage temperature of 40 °C, the chemical stability of the drug was 3 times higher in the solid-state compared to the wet emulsions which confirmed that freeze-drying is a promising approach to improve the chemical stability of water-labile compounds provided that the storage conditions are optimised. Refereed/Peer-reviewed

The influence of silica nanoparticle coating of negatively and positively charged submicron emulsion oil droplets on the dermal delivery of a lipophilic fluorescent probe, acridine orange 10-nonyl bromide (AONB) using an ex vivo porcine skin model is reported. The skin retention and depth of the penetration of AONB significantly increased (p ≤ 0.05) up to a skin depth of ∼265 µm by nanoparticle coating of negative lecithin-stabilised emulsion oil droplets especially when nanoparticles were added from the water phase. The extent and depth of penetration of AONB incorporated into positively charged silica-coated oleylamine-stabilised emulsions significantly increased up to the upper dermis (∼290 µm) with more pronounced effect by nanoparticle incorporation from the water phase of the control oleylamine emulsion. The permeation of AONB through full-thickness porcine skin was negligible (

The influence of silica nanoparticle coating on the chemical stability and phase distribution of all-trans-retinol in submicron oil-in-water emulsions is reported. The chemical stability was studied as a function of UVA+UVB irradiation, and storage temperature (4 degrees C, ambient temperature, and 40 degrees C) for emulsions stabilised with lecithin and oleylamine as the initial emulsifier with and without silica nanoparticle layers. The chemical stability of all-trans-retinol was highly dependent on the emulsifier type and charge, with negligible influence of the initial loading phase of silica nanoparticles. A significant stability improvement (approximately 2-fold increase in the half-life of the drug) was observed by nanoparticle incorporation into oleylamine-stabilised droplets (i.e. electrostatically coated), with no considerable effect for partially coated lecithin-stabilised droplets. The chemical stability of all-trans-retinol incorporated into nanoparticle-coated emulsions was well-correlated to the phase distribution of the active agent, and the interfacial structure of emulsions as determined by freeze fracture-SEM. Specifically engineered nanoparticle layers can be used to enhance the chemical stability of active ingredients in emulsion carriers.

Purpose: The aim of this research is to investigate the dermal delivery of all-trans-retinol from nanoparticle-coated submicron oil-in-water emulsions as a function of the initial emulsifier type, the loading phase of nanoparticles, and the interfacial structure of nanoparticle layers. Methods: The interfacial structure of emulsions was characterized using freeze-fracture-SEM. In-vitro release and skin penetration of all-trans-retinol were studied using Franz diffusion cells with cellulose acetate membrane, and excised porcine skin. The distribution profile was obtained by horizontal sectioning of the skin using microtome-cryostat and HPLC assay. Results: The steady-state flux of all-trans-retinol from silica-coated lecithin emulsions was decreased (up to 90%) and was highly dependent on the initial loading phase of nanoparticles; incorporation from the aqueous phase provided more pronounced sustained release. For oleylamine emulsions, sustained release effect was not affected by initial location of nanoparticles. The skin retention significantly (p ≤ 0.05) increased and was higher for positive oleylamine-stabilised droplets. All-trans-retinol was mainly localized in the epidermis with deeper distribution to viable skin layers in the presence of nanoparticles, yet negligible permeation (∼1% of topically applied dose) through full-thickness skin. Conclusions: Sustained release and targeted dermal delivery of all-trans-retinol from oil-in-water emulsions by inclusion of silica nanoparticles is demonstrated. Refereed/Peer-reviewed

The influence of hydrophilic silica nanoparticles on the emulsification of a triglyceride oil (Miglyol812) in the presence of charged surfactants (lecithin or oleylamine) and the long term stability of the resultant oil-in-water emulsions are reported. A synergistic effect of nanoparticles and surfactants in improving emulsification and stability to coalescence is evident only when the silica nanoparticles are initially added to the oil phase. When nanoparticles are included from the water phase, no synergistic stabilisation was observed due to electrostatic bridging or unfavourable attachment due to the repulsive electrostatic and hydration forces. Free energies of adsorption for silica nanoparticles at the oil-water interface calculated from experimentally determined interfacial tensions and three phase contact angles can be correlated to long-term emulsion stability only when silica is added from oil phase.

The effect of silica nanoparticle addition on the stability of O/W emulsions initially stabilized by lecithin or oleylamine has been investigated. The synergy between silica nanoparticles and the emulsifiers at stabilizing the oil-water interface has been established. The influence of variation in the number of homogenization cycles, the ratio of emulsifier to silica, oil load and the initial location of nanoparticles on the size distribution of emulsion droplets have been studied. freeze-fracture scanning electron microscopy was used to study the interfacial structure of the emulsion droplets. The results confirm improvement in the long term physical stability of emulsions in the presence of silica nanoparticles