Silica Nanoparticles To Control the Lipase-Mediated Digestion of Lipid-Based Oral Delivery Systems

Abstract

We investigate the role of hydrophilic fumed silica in controlling the digestion kinetics of lipid emulsions, hence further exploring the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by silica-lipid hybrid (SLH) microcapsules. An in vitro lipolysis model was used to quantify the lipase-mediated digestion kinetics of a series of lipid vehicles formulated with caprylic/capric triglycerides: lipid solution, submicrometer lipid emulsions (in the presence and absence of silica), and SLH microcapsules. The importance of emulsification on lipid digestibility is evidenced by the significantly higher initial digestion rate constants for SLH microcapsules and lipid emulsions (>15-fold) in comparison with that of the lipid solution. Silica particles exerted an inhibitory effect on the digestion of submicrometer lipid emulsions regardless of their initial location, i.e., aqueous or lipid phases. This inhibitory effect, however, was not observed for SLH microcapsules. This highlights the importance of the matrix structure and porosity of the hybrid microcapsule system in enhancing lipid digestibility as compared to submicrometer lipid emulsions stabilized by silica. For each studied formulation, the digestion kinetics is well correlated to the corresponding in vivo plasma concentrations of a model drug, celecoxib, via multiple-point correlations (R(2) > 0.97). This supports the use of the lipid digestion model for predicting the in vivo outcome of an orally dosed lipid formulation. SLH microcapsules offer the potential to enhance the oral absorption of poorly soluble drugs via increased lipid digestibility in conjunction with improved drug dissolution/dispersion.

Bioactive Hybrid Particles from Poly(d,l-lactide-co-glycolide) Nanoparticle Stabilized Lipid Droplets

“…A similar effect was observed by Tan et al, 21 whereby the steric hindrance on lipase by silica nanoparticles increased as nanoparticle concentration increased and was greatest for nanoparticles that were oppositely charged to the lipid droplets. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 21 However, equivalent extents of digestion suggested the microstructure facilitated sustained digestion and a reduced interference effect of digestion products and PLGA nanoparticles on lipase adsorption. 47 T...…”

“…Free fatty acids (FFA) produced in the reaction vessel were immediately titrated with 0.6 M NaOH via an auto-burette to maintain a constant pH in the digestion medium at the pre-set value of 7.50 ± 0.01 throughout the experiment. 21 The hydrolysis reaction can be treated as a pseudo-first order process as the rate of reaction is dependent on the concentration of the substrate, due to the excess amount of enzyme added to the digestion media. The pseudo-first order model can be used to develop a simple rate expression but ignores the effect of interfacial composition on lipase activity.…”

Silica-Lipid Hybrid (SLH) Versus Non-lipid Formulations for Optimising the Dose-Dependent Oral Absorption of Celecoxib

“…The formation of macro-porous (50-200 nm), homogenous silica-lipid matrices has been illustrated by a previous ion beam-induced SEM analysis (15,34). The highly porous matrix structure of the SLH microparticles (BET surface area=184 m 2 /g) has been shown to contribute towards an enhanced lipid digestibility and, hence, in vivo drug bioavailability as compared to conventional lipid solutions and submicron emulsions (34).…”

“…Our previous work has illustrated the use of lipolysis kinetics to interpret, to some extent, the in vivo drug absorption profiles resulting from various lipid-based systems, including simple lipid solutions, emulsions, and SLH microparticles (34). The current phase partition results further elucidate the capability of the resultant digestion products in keeping the released drugs solubilised during and after lipolysis.…”

Biocompatibility assessment of Si-based nano- and micro-particles

“…Si and SiO-based materials are hydrophilic which increase the wettability of water-insoluble drugs in the GI tract. [176] Moreover, since Si and SiO particles are low-pH resistant there is a clear the rationale for using them as a drug delivery system for orally administered drugs to protect from low pH in stomach.…”