Impact of lipases on the protective effect of SEDDS for incorporated peptide drugs towards intestinal peptidases

AimThe aim of this study is the development of self-emulsifying drug delivery systems (SEDDS) differing in amounts of ester substructures and to evaluate their stability in presence of pancreatic lipase and protective effect against luminal enzymatic metabolism using leuprorelin as model peptide drug.MethodsHydrophobic leuprolide oleate was incorporated into three different SEDDS formulations and their stability towards pancreatic lipases was investigated utilizing a dynamic in vitro digestion model. Protective effect of SEDDS in respect to peptide drug stability against proteolytic enzymes, trypsin and α-chymotrypsin, was determined via HPLC.ResultsResults of in vitro digestion demonstrated that 80% of SEDDS containing the highest amount of ester linkages was degraded within 60 min. In comparison to that, SEDDS without ester bonds showed no degradation. With increasing oil droplets hydrolysis the remaining amount of peptide encapsulated into formulation decreased. Furthermore, after 180 min incubation with trypsin up to 33.5% and with α-chymotrypsin up to 60.5% of leuprolide oleate was intact while leuprorelin acetate aqueous solution was completely metabolized by trypsin within 120 min and by α-chymotrypsin within 5 min. Protective effect in environment containing lipases was lower due to oil phase degradation, however, the amount of peptide in ester-free SEDDS was remarkably higher compared to SEDDS susceptible to lipases.ConclusionThe present study revealed that SEDDS stable towards hydrolysis is able to exhibit a protective effect for oral peptide delivery.

Graphical abstractSummary on properties of SEDDS to protect peptide drug towards enzymatic hydrolysis and to bring their higher concentration to the absorption site in the digestive tract. (Poly)peptide drug (♦).Figure optionsDownload full-size imageDownload high-quality image (158 K)Download as PowerPoint slide