Self-Emulsifying Drug Delivery Systems: Hydrophobic Drug Polymer Complexes Provide a Sustained Release in Vitro.

Ross Kennedy,Barbara Matuszczak,Imran Nazir,Ahmad Malkawi,Aamir Jalil,Andreas Bernkop-Schnürch

doi:10.1021/acs.molpharmaceut.0c00389

Abstract

The aim of this study was to develop hydrophobic ionic drug polymer complexes in order to provide sustained drug release from self-emulsifying drug delivery systems (SEDDS). Captopril (CTL) was used as an anionic model drug to form ionic complexes with the cationic polymers Eudragit RS, RL, and E. Complexes of polymer to CTL charge ratio 1:1, 2:1, and 4:1 were incorporated in two SEDDS, namely FA which was 40% Kolliphor RH 40, 20% Kolliphor EL, and 40% castor oil and FB, which was 40% Kolliphor RH 40, 30% glycerol, 15% Kolliphor EL, and 15% castor oil. Blank and complex loaded SEDDS were characterized regarding their droplet size, polydispersity index (PDI), and zeta potential. Resazurin assay was performed on Caco-2 cells to evaluate the biocompatibility of SEDDS. Release of CTL from SEDDS was determined in release medium containing 0.2 mg/mL of 5,5′-dithiobis(2-nitrobenzoic acid) (DNTB) allowing quantification of free drug released into solution via a thiol/disulfide exchange reaction between CTL and DNTB forming a yellow dye. The droplet size of SEDDS FA and SEDDS FB were in the range of 100 ± 20 nm and 40 ± 10 nm, respectively, with a PDI < 0.5. The zeta potential of SEDDS FA and SEDDS FB increased after the incorporation of complexes. Cell viability remained above 80% after incubation with SEDDS FA and SEDDS FB in a concentration of 1% and 3% for 4 h. Without any polymer, CTL was entirely released from both SEDDS within seconds. In contrast, the higher the cationic lipophilic polymer to CTL ratio in SEDDS, the more sustained was the release of CTL. Among the polymers which were evaluated, Eudragit RL provided the most sustained release. SEDDS FA containing Eudragit RL and CTL in a ratio of 1:1 released 64.78 ± 8.28% of CTL, whereas SEDDS FB containing the same complex showed a release of 91.85 ± 1.17% within 1 h. Due to the formation of lipophilic ionic polymer complexes a sustained drug release from oily droplets formed by SEDDS can be achieved. Taking into account that drugs are otherwise instantly released from SEDDS, results of this study might open the door for numerous additional applications of SEDDS for which a sustained drug release is essential.

Highlights

Self-emulsifying drug delivery systems (SEDDS) are homogeneous isotropic mixtures of oils, surfactants, and cosurfactants that emulsify in aqueous media forming oily droplets typically in the nanosize range
The release of CTL was measured at 450 nm via a microplate reader (Tecan Spark, Tecan Trading AG, Zurich, Switzerland), with free CTL used as control. 2.2.7
SEDDS FA and SEDDS FB showed stable droplet size and nonreleasing polymers indicated by a high log SRSEDDS/release medium retaining the CTL within the SEDDS

Summary

Introduction

Self-emulsifying drug delivery systems (SEDDS) are homogeneous isotropic mixtures of oils, surfactants, and cosurfactants that emulsify in aqueous media forming oily droplets typically in the nanosize range. Drugs like therapeutic peptides and oligonucleotides that are degraded on mucosal membranes by peptidases and nucleases can be protected toward these enzymes in the oily droplets.[6,7] When peptide and protein drugs are incorporated in SEDDS unintended thiol/. Disulfide exchange reactions with endogenous thiols such as glutathione or cysteine-rich subdomains of mucins can be avoided.[8,9] as the vast majority of SEDDS contain PEG-ylated surfactants forming a muco-inert PEG-corona around the oily droplets, they are able to permeate the mucus gel barrier in a comparatively efficient manner enabling the transport of incorporated drugs to the underlying absorption membrane.[10−12]

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