Structural development of self nano emulsifying drug delivery systems (SNEDDS) during in vitro lipid digestion monitored by small-angle X-ray scattering.
OBJECTIVE
To investigate the structural development of the colloid phases generated during lipolysis of a lipid-based formulation in an in vitro lipolysis model, which simulates digestion in the small intestine.


METHODS
Small-Angle X-Ray scattering (SAXS) coupled with the in vitro lipolysis model which accurately reproduces the solubilizing environment in the gastrointestinal tract and simulates gastrointestinal lipid digestion through the use of bile and pancreatic extracts. The combined method was used to follow the intermediate digestion products of a self nano emulsified drug delivery system (SNEDDS) under fasted conditions. SNEDDS is developed to facilitate the uptake of poorly soluble drugs.


RESULTS
The data revealed that a lamellar phase forms immediately after initiation of lipolysis, whereas a hexagonal phase is formed after 60 min. The change of the relative amounts of these phases clearly demonstrates that lipolysis is a dynamic process. The formation of these phases is driven by the lipase which continuously hydrolyzes triglycerides from the oil-cores of the nanoemulsion droplets into mono- and diglycerides and fatty acids. We propose that this change of the over-all composition of the intestinal fluid with increased fraction of hydrolyzed nanoemulsion induces a change in the composition and effective critical packing parameter of the amphiphilic molecules, which determines the phase behavior of the system. Control experiments (only the digestion medium) or the surfactant (Cremophor RH 40) revealed the formation of a lamellar phase demonstrating that the hexagonal phase is due to the hydrolysis of the SNEDDS formulation.


CONCLUSIONS
The current results demonstrate that SAXS measurements combined with the in vitro dynamic lipolysis model may be used to elucidate the processes encountered during the digestion of lipid-based formulations of poorly soluble drugs for oral drug delivery. Thus the combined methods may act as an efficient screening tool.
Fatouros
Dimitrios G
DG
Department of Pharmaceutics and Analytical Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100, Copenhagen, Denmark, df@dfuni.dk
Deen
G Roshan
GR
Arleth
Lise
L
Bergenstahl
Bjorn
B
Nielsen
Flemming Seier
FS
Pedersen
Jan Skov
JS
Mullertz
Anette
A
D001646:Bile / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004063:Digestion; D004337:Drug Carriers; D004655:Emulsions; D000431:Ethanol / Q000737:chemistry; D005215:Fasting; D006868:Hydrolysis; D007421:Intestine, Small / Q000737:chemistry / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008066:Lipolysis; D008954:Models, Biological; D049329:Nanostructures; D010194:Pancreatin / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D053838:Scattering, Small Angle; D012715:Sesame Oil / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods*; D013997:Time Factors; D014961:X-Ray Diffraction
D004337:Drug Carriers; D004655:Emulsions; D012997:Solvents; D013501:Surface-Active Agents; C022131:cremophor; D000431:Ethanol; D011092:Polyethylene Glycols; D012715:Sesame Oil; D010194:Pancreatin; D008049:Lipase