Solidification of self-emulsifying drug delivery systems (SEDDS): Impact on storage stability of a therapeutic protein

Julian David Friedl,Arne Matteo Jörgensen,Bao Le‐Vinh,Doris Elfriede Braun,Martina Tribus,Andreas Bernkop-Schnürch

doi:10.1016/j.jcis.2020.11.051

Julian David Friedl, Arne Matteo Jörgensen + Show 4 more

Open Access

https://doi.org/10.1016/j.jcis.2020.11.051

Copy DOI

Abstract

Four solidification methods for self-emulsifying drug delivery systems (SEDDS) were compared to evaluate the impact of solidification on storage stability of an incorporated protein.Papain was loaded in SEDDS via hydrophobic ion pairing (HIP). Liquid SEDDS (l-SEDDS) were either solidified by adsorption to solid excipients such as magnesium-aluminometasilicate via wet granulation (ssilica-SEDDS) and carbohydrates via lyophilisation (scarbo-SEDDS) or by incorporation of high-melting PEG-surfactants (sPEG-SEDDS) and triglycerides (soil-SEDDS) in SEDDS preconcentrates. L- and s-SEDDS were compared regarding intrinsic emulsion properties, solid-state form of papain, enzyme stability and activity during storage.HIP with deoxycholate showed a precipitation efficiency of 82% and papain maintained 90% of its initial activity. Incorporated papain was present in an amorphous state, confirming a molecular dispersion in all preconcentrates. In comparison to l-SEDDS each solidification method investigated improved the storage stability of incorporated papain. Neither precipitation nor phase separation was observed for s-SEDDS. sPEG-SEDDS demonstrated with 87.8% the highest enzymatic activity and displayed according to the following rank order: sPEG-SEDDS > soil-SEDDS > ssilica-SEDDS > scarbo-SEDDS > l-SEDDS the highest remaining papain activity after 30 days of storage. This work clearly demonstrates that solidified SEDDS can provide a significantly improved storage stability for therapeutic proteins compared to corresponding liquid formulations.

Highlights

Therapeutic peptides and proteins are due to their high potency, specific mode of action and comparatively high safety profile on the rise [1]
In the latest studies of Zupancic et al enhanced chemical stability for bivalirudin, a 20 amino acid short peptide, was found when stored in liquid self-emulsifying drug delivery systems (SEDDS) (l-SEDDS) preconcentrates compared to a reconstituted AngiomaxÒ solution [8]
The risk of phase separation and dosage form leakage seen for l-SEDDS are further decisive criteria for the limited industrial relevance of SEDDS [9,10]

Summary

Introduction

Therapeutic peptides and proteins are due to their high potency, specific mode of action and comparatively high safety profile on the rise [1]. To incorporate hydrophilic peptides and proteins in the oil core of this colloidal carrier their lipophilic character is increased by ionic complexation with lipophilic counter-ions This so called hydrophobic ion pairing (HIP) technique is used in numerous studies to enhance the loading of drugs in nanocarriers such as polymeric nanoparticles, liposomes, and various kinds of solid lipid nanoparticles and emulsions. By combining HIP and SEDDS for oral delivery of therapeutic peptides a bioavailability in the range of 5–25% could already be achieved in recent studies [6,7] Despite these encouraging results SEDDS as liquid formulations are still facing shortcomings, especially when it comes to long-term storage stability. Peptides and especially proteins are susceptible to conformational changes and degradation under such processing conditions [13]

Methods

Results

Conclusion