الفهرس 
Preparation, characterization and Optimization of Oxcarbazepine-Loaded EmulsomesOnly 14 pages are availabe for public view
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Abstract
Lipid-based nanovectors offer effective carriers for brain drug delivery. Emulsomes are nano-triglyceride (TG) carriers formed of lipid cores supported by at least one phospholipid (PC) sheath, forming bilayers at the aqueous interface, thereby conferring better drug solubility, bioavailability and stability. A direct nose to brain transport would be advocated by their tuned nanosize. Emulsomes of oxcarbazepine (OX) were prepared utilizing different TG cores (compritol, tripalmitin, tristearin and triolein) and soya phosphatidylcholine in different amounts and ratios.
Particles were modulated to generate nanocarriers with suitable size, zeta potential, encapsulation efficiency and prolonged release for effective and safe brain targeting.
The final selected emulsomal formulation for subsequent incorporation into gels to prolong their residence time in the nasal mucosa was TO17-Tw emulsomes. It was Tween 80-coated and composed of a triolein (TO) core in a total lipid amount of 30 mg in a 3:1 PC to TG ratio. Its size was 101.5 nm with a charge of -6.7 mV and 81% total cumulative amount of OX released after 24 hrs.
Poly ethylene glycol diacrylate (PEGDA) cryogels were prepared from different monomer and initiator/accelerator concentrations with freezing durations of 3, 6, 9 and 12 hrs. All these studied variables proved to have significant effects on the viscosities of the prepared cryogels, with the most stiff cryogels produced from higher PEGDA concentrations. On the other hand, cryogels prepared from the lowest monomer concentration had the highest swelling ability and hydrolytic degradation, in addition to, the largest mesh size and molecular weight between cross-links. It was determined from constructed rheograms and shear rate/stress charts that the flow of all cryogels was non-reversible pseudoplastic.
The cryogel of choice for subsequent sequestration of TO17-Tw emulsomes was B9 which was prepared from 2.5% PEGDA and 5 mM APS/TEMED and frozen for 9 hrs and resulted in a retardadtion in the release of OX.
Thermoreversible thermosensitive PLGA-PEG-PLGA triblock copolymer was prepared by ring-opening polymerization of D,L-lactide and glycolide initiated with PEG. The plain copolymer was characterized rheologically (temperature, time and frequency sweep tests) and by NMR, GPC, DSC and DLS. The gelation temperature was also determined for the plain and emulsome-loaded copolymer solutions by tube-inversion method, which was observed to be directly proportional to emulsomes concentrations but inversely proportional to copolymer concentration.
The chosen thermogel was G16 which consisted of 30% PLGA-PEG-PLGA copolymer and 50% TO17-Tw emulsomes. Also, sequestration of emulsomes in the thermogels resulted in a retardation of OX release but had no effect on the high mucoadhesive properties of the thermogel.
Cytotoxicity and histopathological studies were performed on the selected emulsomes and emulsomal cryo- and thermogels in order to confirm their safety for intranasal (IN) administration. The MTT assay proved a decrease in drug toxicity upon incorporation in emulsomal formulations. The histopathological study revealed intact mucosal epithelia with minimal inflammatory cell infiltration in the nasal epithelia of rats treated with OX loaded emulsomes and emulsomal cryo- and thermo-gels.
The pharmacokinetic study in the plasma and brain of rats revealed that the highest plasma Cmax was obtained after administration of the emulsomal thermogel with significant residual amounts of OX measured in the plasma after 48 hrs of administration of the emulsomal cryo- and thermo-gels. Highest similar mean residence times (MRT) in the plasma were achieved by emulsomes and emulsomal cryogel but with earlier emulsomal Tmax. However, the highest brain Cmax, earliest Tmax and largest AUC were achieved after administration of emulsomes. Moreover, emulsomes had the highest drug targeting efficiency in comparison to the cryo- and thermo-gel, as well as, the marketed product.
Finally, we proved that emulsomes had the highest direct nose-to-brain transport with significantly higher concentrations of OX in the brain at all time intervals. On the other hand, the emulsomal cryo- and thermo- gels had initial high direct transport to the brain, but overall, their systemic delivery of OX prevailed.
As for the marketed product, the plasma concentration of OX was almost always higher in the plasma than in the brain of rats and it had lowest brain Cmax, AUC and MRT than all the tested emulsomal formulations, in addition to, the longest Tmax. All which indicated its lower efficiency than the emulsomal formulations in transporting OX to the brain.
Conclusively, we can deduce that emulsomes, PEGDA emulsomal cryogels and PLGA-PEG-PLGA emulsomal thermogels are efficient promising nanosystems for the enhanced brain delivery of OX.