<p>Primary Studies on Construction and Evaluation of Ion-Sensitive in situ Gel Loaded with Paeonol-Solid Lipid Nanoparticles for Intranasal Drug Delivery</p>

Abstract

Background: Paeonol (PAE) is a potential central neuroprotective agent with poor water solubility and rapid metabolism in vivo. The key to improve the clinical application of PAE in the treatment of neurodegenerative diseases is to improve the brain delivery of it. The purpose of this study was to construct a paeonol-solid lipid nanoparticles-in situ gel (PAE-SLNs-ISG) drug delivery system based on nose-brain transport pathway. Materials and Methods: In this study, the stability of PAE in simulated biological samples was studied firstly in order to clarify the reasons for low oral bioavailability. Paeonol-solid lipid nanoparticles (PAE-SLNs) were prepared by high-temperature emulsification-low-temperature curing combined with ultrasound. The PAE-SLNs-ISG drug delivery system was constructed, and related formulation optimization, preparation characterization, cell evaluation and in vivo evaluation were performed. Results: The metabolic mechanism of PAE incubated in the liver microsomes metabolic system was in accordance with the first-order kinetics, and the half-life was 0.23 h. PAE-SLNs were polyhedral or spherical particles with good dispersion and the particle size was 166.79 nm ± 2.92 nm. PAE-SLNs-ISG solution was a Newtonian fluid with a viscosity of 44.36 mPa • S ± 2.89 mPa • S. The viscosity of PAE-SLNs-ISG gel was 1542.19 mPa • S ± 19.30 mPa • S, and the rheological evaluation showed that the gel was a non-Newtonian pseudoplastic fluid with shear thinning, thixotropy and yield value. The release mechanism of PAE from PAE-SLNs was drug diffusion; the release mechanism of PAE from PAE-SLNs-ISG was a synergistic effect of skeleton erosion and drug diffusion. The cell viabilities of PAE-SLNs and PAE-SLNs-ISG in the concentration range of 0.001 µg/mL to 10 µg/mL were higher than 90%, showing a low level of cytotoxicity. The geometric mean fluorescent intensities of RPMI 2650 cells incubated with fluorescein isothiocyanate-solid lipid nanoparticles (FITC-SLNs) for 1 h, 4 h and 6 h were 1841 ± 24, 2261 ± 27 and 2757 ± 22, respectively. Cyanine7 NHS ester-solid lipid nanoparticles-in situ gel (Cy7-SLNs-ISG) accumulated effectively in the brain area after administration through the olfactory area, and the fluorescence response was observed in olfactory bulb, cerebellum and striatum. Conclusion: SLNs-ISG nose-brain drug delivery system can effectively deliver SLNs to brain regions, and it is a potentially effective strategy to realize the brain region delivery of PAE.

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

“…The olfactory pathway has been indicated in some studies. For example, fluorescence response to IN administered Cyanine7 NHS ester-loaded SLNs (Cys7-SLNs) was clearly observed in olfactory bulb, cerebellum, and striatum [ 12 ]. Furthermore, a proportion of drugs entering the respiratory region can be transported directly to the brain through the trigeminal nerve pathway via extraneuronal or intraneuronal routes although this pathway is less important than the olfactory pathway [ 7 ].…”

“…Sun et al developed a paeonol-loaded SLN gel (0.4% deacetylated gellan gum and 0.3% HPMC) [ 12 ]. The authors found that brain accumulation was better for a cyanine7 NHS ester-loaded SLN gel (IN) than cyanine7 NHS ester-loaded SLNs (IV).…”

“…As compared to parenteral administration, IN delivery can overcome the BBB, provide faster brain delivery, and enhance drug targeting and drug bioavailability. Furthermore, IN administration avoids gastrointestinal and hepatic metabolisms, decreases drug accumulation in non-targeted organs, and reduces systemic side effects [ 12 , 13 , 14 ]. Therefore, nose-to-brain delivery is an effective approach to manage CNS diseases and psychiatric disorders.…”

In Vitro Studies on Nasal Formulations of Nanostructured Lipid Carriers (NLC) and Solid Lipid Nanoparticles (SLN)

“…Sun et al [ 80 ] evaluated the in vitro cytotoxicity in RPMI 2650 cells of an in situ gel containing paeonol-loaded SLN, paeonol-loaded SLN, blank SLN and a blank in situ gel, using the MTT method. The cell viability of all tested formulations, in the concentration range of 0.001–10 µg/mL, was higher than 90%, indicating biocompatibility.…”

Recent Developments in Ion-Sensitive Systems for Pharmaceutical Applications

“…Therefore, there were attempts to design intranasal systems aiming to increase drug concentration in the brain structures via the prolonged exposure of nasal mucosa to the drug carrier. The formulation including solid lipid nanoparticles with paeonol suspended in 0.4% deacetylated GG as an in situ gelling agent, was employed to alleviate the first-pass effect and to enable brain delivery via the olfactory nerve pathway [ 15 ]. Resveratrol loaded nanosuspension, based on 0.6% ( w/v ) deacetylated GG, was employed to exploit an analogous delivery route.…”