Development, in vitro and in vivo evaluation of a self-emulsifying drug delivery system (SEDDS) for oral enoxaparin administration.
OBJECTIVE
The aim of this study was to develop SEDDS for oral enoxaparin administration and evaluate it in vitro and in vivo.


METHODS
The emulsifying properties of SEDDS composed of long chain lipids (LC-SEDDS), medium chain lipids (MC-SEDDS), short chain lipids (SC-SEDDS) and no lipids (NL-SEDDS) were evaluated. Thereafter, enoxaparin was incorporated via hydrophobic ion pairing in the chosen SEDDS, which were evaluated regarding their mucus permeating properties, stability towards pancreatic lipase, drug release profile and cytotoxicity. Finally, in vivo performance of SEDDS was evaluated.


RESULTS
The average droplet size of chosen LC-SEDDS, MC-SEDDS and NL-SEDDS ranged between 30 and 40nm. MC-SEEDS containing 30% Captex 8000, 30% Capmul MCM, 30% Cremophor EL and 10% propylene glycol and NL-SEDDS containing 31.5% Labrafil 1944, 22.5% Capmul PG-8, 9% propylene glycol, 27% Cremophor EL and 10% DMSO exhibited 2-fold higher mucus diffusion than LC-SEDDS and were therefore chosen for further studies. The enoxaparin-dodecylamine complex (ENOX/DOA) was incorporated in a payload of 2% (w/w) into MC-SEDDS and NL-SEDDS. After 90min 97% of MC-SEDDS and 5% of NL-SEDDS were degraded by pancreatic lipase. Both MC-SEDDS and NL-SEDDS showed sustained in vitro enoxaparin release. Furthermore, orally administrated MC-SEDDS and NL-SEDDS yielded an absolute enoxaparin bioavailability of 2.02% and 2.25%, respectively.


CONCLUSIONS
According to the abovementioned findings, SEDDS could be considered as a potential oral LMWH delivery system.
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Ožbej
O
Zupančič
ThioMatrix GmbH, Research Center Innsbruck, Trientlgasse 65, 6020 Innsbruck, Austria.
Julia Anita
JA
Grieβinger
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Julia
J
Rohrer
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Irene
I
Pereira de Sousa
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Lukas
L
Danninger
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Alexandra
A
Partenhauser
Division of Developmental Immunology, Center for Biomodels and Experimental Medicine (CBEM), Innsbruck Medical University, Innrain 80/82, 6020 Innsbruck, Austria.
Nadine Elli
NE
Sündermann
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Flavia
F
Laffleur
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
Andreas
A
Bernkop-Schnürch
D000284:Administration, Oral; D000588:Amines / Q000737:chemistry; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D045703:Emulsifying Agents / Q000737:chemistry*; D004655:Emulsions / Q000737:chemistry*; D017984:Enoxaparin / Q000008:administration & dosage* / Q000737:chemistry; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008055:Lipids / Q000737:chemistry; D010078:Oxazines / Q000737:chemistry; D010316:Particle Size; D012995:Solubility; D014966:Xanthenes / Q000737:chemistry
D000588:Amines; D004337:Drug Carriers; D045703:Emulsifying Agents; D004655:Emulsions; D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight; D008055:Lipids; D010078:Oxazines; D014966:Xanthenes; C005843:resazurin; C003935:dodecylamine
Hydrophobic ion pairing; Oral LMWH delivery; Self-emulsifying drug delivery systems (SEDDS)