Evaluation of the digestibility of solid lipid nanoparticles of glyceryl dibehenate produced by two techniques: Ultrasonication and spray-flash evaporation

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Abstract

Objective

To evaluate the digestibility of Solid Lipid Nanoparticles (SLN) of glyceryl dibehenate prepared either with surfactants by ultrasonication or without surfactant by spray-flash evaporation.

Methods

SLN of glyceryl dibehenate (Compritol® 888 ATO) were produced by two processes: (i) high-shear homogenization with a solution of water-soluble surfactants followed by ultrasonication (ii) and Spray-Flash Evaporation (SFE) of the pure lipid. The digestibility of these nanoparticles was then tested by in vitro lipolysis using a pH-stat apparatus and the assay of glycerides by gel phase chromatography.

Results

SLN of glyceryl dibehenate prepared by ultrasonication exhibited a mean particle size of 180 nm and showed a limited digestion of the lipid excipient. SLN comprising only glyceryl dibehenate produced by SFE have a mean particle size between 235 and 411 nm depending on process parameters. These nanoparticles were not digested by lipases. The presence of surfactant at the lipid/water interface of the SLN seems to be mandatory to allow the adsorption of the lipase and degradation of glyceryl behenate.

Conclusions

Glyceryl dibehenate as a solid particle – even as a SLN – is not digested by pancreatin during in vitro lipolysis test.

Introduction

Solid lipid excipients composed of long chain fatty acids are classically used for sustained-release and solid lipid nanoparticles (SLN) formulations. These lipids are considered as non-erodible and non-digestible (Rosiaux et al., 2014). Drug sustained-release or drug vectorization can only be effective if the lipid matrix/nanoparticle retains its shape during its transit through the gastrointestinal tract. However, lipid-based excipients can be digested by a large variety of lipases secreted either by the stomach or by the pancreas (N'Goma et al., 2012). The digestibility of long-chain lipids depends on the degree of unsaturation. For example, dietary lipids are often composed of unsaturated long chain fatty acids (e.g. oleic acids) that are liquid at 37 °C. Hence, these lipids can easily be emulsified by the bile components and the subsequent interfacial tension decrease at the lipid-water interface allows the adsorption of lipases. In the case of sustained-release matrix tablets or SLN, the lipid-based excipients used are mainly composed of saturated long chain fatty acids and are solid at 37 °C. For example, two such lipid excipients are glyceryl distearate (Precirol® ATO 5) (Jannin et al., 2006, Patel et al., 2015) and glyceryl dibehenate (Compritol® 888 ATO) (Keen et al., 2015, Parejiya et al., 2013, Patere et al., 2013) used to produce solid oral dosage forms by various techniques (direct compression, capsule molding, hot-melt extrusion, …). Apart from the lowering of the interfacial tension, another factor could favor the digestibility of lipids: the reduction of their particle size leading to an increased surface area. In that regard we evaluated in a previous study the digestibility of Precirol® ATO 5 when formulated as (SLN). We found that this lipid is readily digested with the degradation of glycerides in a few minutes using the in vitro pH-stat method (Jannin et al., 2015a, Jannin et al., 2015b).

In this study, we want to evaluate the digestibility of Compritol® formulated as SLN to check the impact of the fatty acid chain length - increase from 18 to 22 carbons - on the degradation of the solid lipid nanocarrier. It has been shown that the digestibility of SLN decreases with the increase of the fatty acid chain length from 14 to 18 (Christophersen et al., 2013). No comparison has been done so far between 18 (Precirol® ATO 5) and 22 (Compritol®). The digestibility of SLN is evaluated by assaying the glyceride composition of the lipid excipient and not by the volume of NaOH added during the lipolysis experiment. This technique is more accurate in order to precisely evaluate the digestibility of glycerides than the classic pH-stat technique relying on the volume of NaOH added to neutralize the released fatty acids. In fact, it was recently demonstrated that the direct titration method underestimates the real digestibility of SLN when the back-titration method tends to overestimate the digestibility of SLN (Heider et al., 2016).

We also want to check the impact of surfactants in the composition of SLN on the digestibility of Compritol® because we know that lipases are able to adsorb at the interface when the interfacial tension is sufficiently lowered. To do so we plan to produce SLN of Compritol® with surfactants by the ultrasonication technique and without surfactants by a newly developed process: Spray Flash Evaporation (Risse et al., 2013). The flash evaporation is the physical phenomenon occurring when the boiling point of a liquid is lower than its actual temperature, due to a sudden drop of pressure and/or a quick increase of temperature. The excess of heat is instantly converted into latent heat of vaporization, cooling both liquid and vapor down to the saturation temperature. In practice, the compound that needs to be nanosized is dissolved in a volatile solvent and that solution is heated just before being sprayed into vacuum, where the crystallization is triggered by the sudden temperature depression and the solvent evaporation (Pessina, 2016).

Section snippets

Materials

For the preparation of SLN, the following excipients were used: Compritol® 888 ATO (Glyceryl dibehenate, Gattefossé, Saint-Priest, France), Tween® 80 (Polysorbate 80, Sigma-Aldrich, Saint-Quentin Fallavier, France) and Pluronic® F127 (Poloxamer, Sigma-Aldrich).

For digestion experiments, CaCl₂ and Tris (hydroxymethylaminomethane) were purchased from Chimie Plus Laboratoire (Décines, France). NaCl, HCl 37%, and NaOH pellets were bought from Merck KGaA (VWR, Bourges, France). Sodium

Dimensional Characterization of SLN

Table 1 exhibits the mean particle size and polydispersity index of the SLN prepared with Compritol®. The particle size distributions were measured by DLS directly after manufacturing in the lipolysis buffer and the day after addition of the bile components (in the lipolysis medium) just prior the in vitro lipolysis assay.

SLN obtained with Compritol® have similar particle size distribution as those prepared with Precirol® in the lipolysis medium (186.9 ± 3.9 nm) (Jannin et al., 2015a, Jannin et

Conclusions

SLN containing Compritol® are less digested than the SLN containing Precirol® because of the increased length of fatty acids comprised in the lipid phase. The limited digestibility of Compritol® in SLN is mainly possible because of the presence of water-soluble surfactants at the interface. In the case of SLN of pure Compritol® (without surfactant), as obtained by SFE, the high interfacial tension impedes the adsorption of lipases at the interface of solid particles and no digestion can be

Declarations of Interest

Vincent Jannin, Stéphanie Chevrier, Cédric Miolane and Frédéric Demarne were employed by Gattefossé SAS manufacturing and selling Precirol® and Compritol® at the time this study was performed.

References (18)

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