Sesame Oil-Based Nanostructured Lipid Carriers of Nicergoline, Intranasal Delivery System for Brain Targeting of Synergistic Cerebrovascular Protection

Abstract

Nicergoline (NIC) is a semisynthetic ergot alkaloid derivative applied for treatment of dementia and other cerebrovascular disorders. The efficacy of sesame oil to slow and reverse the symptoms of neurodegenerative cognitive disorders has been proven. This work aimed to formulate and optimize sesame oil-based NIC-nanostructured lipid carriers (NIC–NLCs) for intranasal (IN) delivery with expected synergistic and augmented neuroprotective properties. The NIC–NLC were prepared using sesame oil as a liquid lipid. A three-level, three-factor Box–Behnken design was applied to statistically optimize the effect of sesame oil (%) of the total lipid, surfactant concentration, and sonication time on particle size, zeta potential, and entrapment efficacy as responses. Solid-state characterization, release profile, and ex vivo nasal permeation in comparison to NIC solution (NIC–SOL) was studied. In vivo bioavailability from optimized NIC–NLC and NIC–SOL following IN and IV administration was evaluated and compared. The optimized NIC–NLC formula showed an average particle size of 111.18 nm, zeta potential of −15.4 mV, 95.11% entrapment efficacy (%), and 4.6% loading capacity. The NIC–NLC formula showed a biphasic, extended-release profile (72% after 48 h). Permeation of the NIC–NLC formula showed a 2.3 enhancement ratio. Bioavailability studies showed a 1.67 and 4.57 fold increase in plasma and brain following IN administration. The results also indicated efficient direct nose-to-brain targeting properties with the brain-targeting efficiency (BTE%) and direct transport percentage (DTP%) of 187.3% and 56.6%, respectively, after IN administration. Thus, sesame oil-based NIC–NLC can be considered as a promising IN delivery system for direct and efficient brain targeting with improved bioavailability and expected augmented neuroprotective action for the treatment of dementia.

Pharmacokinetics and Pharmacodynamics of Intranasal Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Nose-to-Brain Delivery

“…First, they can improve drug solubility and permeability, and the partition of nanoparticles into the lipid bilayer of the nasal epithelial cell membrane is greater than that of free drugs due to the lipophilic natures of SLNs and NLCs [ 57 ]. The nanosized particles with sufficient lipophilicity can easily squeeze through intercellular spaces between olfactory cells [ 58 ]. In addition, the use of surfactants (e.g., Tween 80, Tween 20, and sodium lauryl sulfate) can open tight junctions between epithelial cells and enhance drug permeability [ 59 ].…”

“…It was demonstrated in one study that a coating layer of polyethylene glycol 25 stearate inhibited P-glycoprotein efflux at cerebrovascular endothelial cell membranes, and thereby increased brain drug concentration [ 65 ]. Third, SLNs and NLCs can reduce the enzymatic degradation of drugs within nasal mucus better than solution-based dosage forms (e.g., solution, suspension, and gel) [ 58 ]. Finally, the safety of SLNs and NLCs well supports their feasibilities for nose-to-brain delivery [ 57 ].…”

“…Thus, although the SLN gel exhibited effective brain targeting, absolute drug accumulations in the brain of the SLN gel (IN) were lower than those of the drug solution (IV). Abourehab et al developed NLCs loaded with nicergoline for the treatment of dementia [ 58 ]. In PK studies using rats, the DTE% value of the NLC gel (IN) (187.3) was based on the AUC of the NLC dispersion (IV), and the DTP% value of the drug solution (IN) was incorrectly reported (180.6).…”

“…SLN and NLC-based formulations have been developed and evaluated for nose-to-brain delivery in various studies, because they increase nasal retention, reduce mucociliary clearance, improve drug solubility and permeability, minimize drug enzymatic degradation, and enhance nasomucosal biocompatibility [ 57 , 58 , 59 , 60 ]. Accumulating data demonstrates that SLNs and NLCs are effective drug delivery systems that can transport drugs to the brain via direct routes.…”

“…Regarding free drugs (IN) and free drugs (IV) comparisons (Figure7b), the IN route had a higher AUC brain /AUC blood ratio in 14 of 19 cases. Five cases reported a higher AUC brain /AUC blood ratio for free drugs (IV), which were piribedil-loaded SLN gel[27], efavirenz-loaded NLCs[65], ropinirole-loaded anionic NLC gel[61], nicergoline-loaded NLCs[58], and phenytoin-loaded NLCs (of particle size < 50 nm)[36]. The AUC brain /AUC blood ratios of SLN and NLC-based formulations (IN) were always higher than those of free drug (IV) in same studies (Figure7c).The boxplots in Figure7dshow that log(AUC brain /AUC blood ) values generally followed the order: SLN and NLC-based formulations (IN) > free drugs (IN) > free drugs (IV).…”