Oligonucleotide Delivery across the Caco-2 Monolayer: The Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS)

Oligonucleotides (OND) represent a promising therapeutic approach. However, their instability and low intestinal permeability hamper oral bioavailability. Well-established for oral delivery, self-emulsifying drug delivery systems (SEDDS) can overcome the weakness of other delivery systems such as long-term instability of nanoparticles or complicated formulation processes. Therefore, the present study aims to prepare SEDDS for delivery of a nonspecific fluorescently labeled OND across the intestinal Caco-2 monolayer. The hydrophobic ion pairing of an OND and a cationic lipid served as an effective hydrophobization method using either dimethyldioctadecylammonium bromide (DDAB) or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). This strategy allowed a successful loading of OND-cationic lipid complexes into both negatively charged and neutral SEDDS. Subjecting both complex-loaded SEDDS to a nuclease, the negatively charged SEDDS protected about 16% of the complexed OND in contrast to 58% protected by its neutral counterpart. Furthermore, both SEDDS containing permeation-enhancing excipients facilitated delivery of OND across the intestinal Caco-2 cell monolayer. The negatively charged SEDDS showed a more stable permeability profile over 120 min, with a permeability of about 2 × 10−7 cm/s, unlike neutral SEDDS, which displayed an increasing permeability reaching up to 7 × 10−7 cm/s. In conclusion, these novel SEDDS-based formulations provide a promising tool for OND protection and delivery across the Caco-2 cell monolayer

Influence of trehalose on the structure of unilamellar DMPC vesicles

The influence of trehalose on the structure and properties of unilamellar ULVs and multilamellar MLVs dimyristoylphosphatidylcholine DMPC vesicles was studied using neutron and X ray scattering, Raman spectroscopy, and differential scanning calorimetry. Trehalose solutions ranging from 0 to 30 w w have been used. It was found that trehalose increases the main phase transition temperature of the MLVs, but has no influence on the main phase transition temperature of the ULVs. In the liquid crystalline phase, the DMPC membrane thickness decreases by a value of 3.1 at 20 trehalose. The intermembrane space increases by a value of about 26 at 30 trehalose. Due to the X ray contrast variation caused by trehalose, it was possible to measure the thickness of the DMPC hydrocarbon chains directly by using X ray scatterin

New insights into the structure and hydration of a stratum corneum lipid model membrane by neutron diffraction

The structure and hydration of a stratum corneum SC lipid model membrane composed of N alpha hydroxyoctadecanoyl phytosphingosine CER6 cholesterol Ch palmitic acid PA cholesterol sulfate ChS were characterized by neutron diffraction. The neutron scattering length density across the SC lipid model membrane was calculated from measured diffraction peak intensities. The internal membrane structure and water distribution function across the bilayer were determined. The low hydration of the intermembrane space is a major feature of the SC lipid model membrane. The thickness of the water layer in the SC lipid model membrane is about 1 angstrom at full hydration. For the composition 55 CER6 25 Ch 15 PA 5 ChS, in a partly dehydrated state 60 humidity and at 32 degrees C, the lamellar repeat distance and the membrane thickness have the same value of 45.6 angstrom. The hydrophobic region of the membrane has a thickness of 31.2 angstrom. A decrease of the Ch content increases the membrane thickness. The water diffusion through the SC lipid model multilamellar membrane is a considerably slow process relative to that through phospholipid membranes. In excess water, the membrane hydration follows an exponential law with two characteristic times of 93 and 44 min. At 81 degrees C and 97 humidity, the membrane separates into two phases with repeat distances of 45.8 and 40.5 angstrom. Possible conformations of CER6 molecules in the dry and hydrated multilayers are discusse