Nanostructured lipid carriers

NLCs represent an enhanced generation of lipid nanoparticles and theoretically present some advantages over SLNs, namely high capacity to accommodate a greater quantity of therapeutics, while avoiding drug expulsion during storage [172]. NLCs have shown potential as ONCs to improve the bioavailability of drugs with the aim to reach therapeutic concentrations in the brain. For example, Kumar et al. [173] investigated the use of NLCs composed of Compritol 888® ATO (solid lipid) and tocopherol acetate (liquid lipid) and PC (surfactant) to encapsulate quercetin for brain delivery after oral administration [173]. As previously referred, quercetin is a natural compound which shows protective effects against neuronal cell damage and thus may play an important role in the prevention or therapy of AD and PD. However, despite possessing many advantages, its administration also presents various challenges, like poor oral bioavailability (<2%), extensive first-pass metabolism, poor brain permeability, a hydrophobic nature and physiological pH instability, which hinder its proper usage [174]. NLCs offered better loading of quercetin and controlled drug release with appreciable stability [173]. In vitro antioxidant performance of quercetin was improved after encapsulation in NLCs, and these nanoparticles were substantially uptaken by Caco-2 cells [173]. In vivo, NLCs substantially enhanced quercetin bioavailability (approx, sixfold), enhanced biological residence (2.5 times) and appreciably retarded quercetin clearance (approx, sixfold) [173]. On the other hand, NLCs were able to substantially deliver quercetin to the brain. NLCs were observed to enhance the brain drug permeability in a noticeable manner [173]. In conclusion, NLCs can significantly improve brain delivery of quercetin [173].

NLCs have also been widely exploited as ONCs in order to improve the penetration of therapeutic agents to the brain using the i.n.

administration strategy. Some studies reported that drugs loaded in NLCs provide significant differences in the pharmacokinetic profile and distribution after i.n. administration. For example, Eskandari et al. [175] developed valproic acid (VPA)-loaded NLCs with the aim of reducing the dose of the drug and maintaining therapeutic levels in the brain for a prolonged period. VPA, an anticonvulsant agent, is used in the treatment of epilepsy, bipolar disorders, migraine and cancer [176]. Generally, this therapeutic agent requires high doses to achieve effective clinical effects, since its delivery and distribution into the brain are limited. Additionally, Seism et al. [177] assessed the VPA efflux clearance at the BBB and proved that it was 2.7-fold superior than the influx clearance compared to control animals. The developed NLCs contained cetyl palmitate and octyldodecanol as solid and liquid lipids, respectively, and were stabilised with soy lecithin S 100 and Poloxamer 188 (i.e. surfactants) [175]. The mean size of NLCs was 154 ± 16 nm with drug loading of 47% ± 0.8% and drug release of 75% ± 1.9% after 21 days. In vivo pharmacodynamics studies were performed using rats which received VPA-loaded NLCs by i.p. or i.n. administration. The results revealed that VPA-NLCs provide a superior protective effect than a solution of VPA (p < 0.05) after treatment via the i.n. route. A similar protective effect to systemic administration was achieved with much lower doses when rats were treated with VPA-NLCs by the i.n. route (p > 0.05). The results proved that i.n. administration of NLCs maintains the protective effect of VPA with a much higher (about 20 times) braimplasma concentration ratio compared to i.p. administration (i.e. positive control group), requiring lower doses of VPA. Alam et al. [178] also explored the efficacy of i.n. NLC administration - using GMS as a solid lipid, oleic acid as a liquid lipid and Tween® 80 and Poloxamer 188 as surfactants - to improve the brain targeting of lamotrigine (LMT), an antiepileptic agent [178]. The brain access of LMT is limited by overexpression of P-gp in the BBB [179], requiring the administration of high doses to achieve a therapeutic concentration; however, this challenge enhances its blood concentration and, consequently, the adverse effects of LMT. Therefore, the i.n. route was evaluated in order to improve clinical utility and therapeutic efficacy of LMT. NLCs had an average size of 151.6 ± 7.6 nm, a PDI of 0.249 ± 0.035, an average zeta potential of +11.75 ± 2.96 mV and an EE of 96.64% ± 4.27%. NLCs exhibited a sustained drug concentration (24 h) after i.n. administration. Scintigraphy studies evidenced that i.n. administration of NLCs provides higher accumulation of LMT in rats' brains and a higher protective effect (even with lower doses - that is, one-fifth of the oral dose) than i.n. and oral administration of the drug solution. Likewise, duloxetine hydrochloride (DLX)-loaded NLCs for i.n. administration were developed and their efficacy against depression was investigated in a rat model [180]. DLX is a potent and balanced dual reuptake inhibitor of both serotonin and norepinephrine which is used in the treatment of major depressive disorder (MDD). This therapeutic agent has also all the properties required to be loaded into NLCs and delivered by the i.n route [181, 182]: it undergoes hepatic first-pass metabolism, presents poor oral bioavailability (~50%), has chemical instability in gastric pH and has low cerebrospinal fluid (CSF) concentration on oral administration. The lipid matrix of NLCs included Capryol™ propylene glycol monocaprylate (PGMC) and GMS, which was stabilised in a surfactant aqueous solution of Poloxamer (Pluronic F68) and bile salt (sodium taurocholate) [180]. Lyophilised DLX-NLCs had an average particle size of 137.2 ± 2.88 nm with a PDI of 0.639 ± 0.355, a zeta potential of +31.53 ± 11.21 mV and an EE of 79.15 ± 4.17%. In vivo studies conducted in rats demonstrated that i.n. DLX-NLC treatment significantly improves behaviour analysis (i.e. the total swimming, climbing time and locomotor activity), as well as revealed a higher concentration of drug in brain when compared with DLX solution.

In addition to the antioxidant effects useful in the treatment of AD, CRM is also a promising agent for cancer treatment because of its potent antiproliferative effects, although it is also associated with pharmacokinetic problems such as poor aqueous solubility, chemical instability in alkaline medium, rapid metabolism and poor absorption from the gastrointestinal tract. With the perspective to solubilise CRM in a physiologic stable medium and maybe to improve its brain targeting, Madane and Mahajan [183] also proposed its encapsulation into NLCs (solid lipid: Precirol® ATO; liquid lipid: Capmul™ MCM - mixture of monoacylglycerols; surfactant and stabiliser: Tween® 80 and soy lecithin) for i.n. delivery to the CNS. The CRM-loaded NLCs (CRM-NLCs) had a mean size of 146.8 nm, a PDI of 0.18, an EE of 90.86% and a zeta potential of-21.4 mV. CRM-NLCs presented higher cytotoxicity against astrocytoma-glioblastoma cells (U373MG) than free CRM. Biodistribution studies in rats demonstrated that CRM-NLCs after i.n. administration enhance the concentration of CRM in brain and its nasal bioavailability.

Cryptococcus neoformans-mediated meningoencephalitis is a severe infection of the human CNS. The poor penetration of therapeutic agents across the BBB limits the efficiency of available treatments. Therefore, Du et al. [184] evaluated the potential of NLCs as nose-to- brain carriers for treating meningoencephalitis [184]. The authors used Miglyol® 812 (caprylic/capric triglycerides] as a liquid lipid, glyceryl behenate as a solid lipid and Tween® 80 and Solutol HS 15 (a permeability enhancer] as surfactant agents. Firstly, fluorescent- dye-loaded NLCs were prepared to investigate their uptake into the cytoplasm of C. neoformans cells. The results suggested that NLCs present excellent penetration ability into the thick capsule structure of C. neoformans. The authors also prepared ketoconazole (keto]- loaded NLCs with the following properties: average particle size of 102.1 ± 0.44 nm; PDI of 0.195 ± 0.005, indicating a homogeneous particlesize distribution; average zetapotential of-2.1 ± 0.18 mV; EE of 70.4% ± 3.4%; and good stability over two weeks. In vitro studies revealed that keto-loaded NLCs had higher antifungal activity, with a cell inhibition rate fourfold higher than the free drug, even at low concentrations. Animal imaging analysis demonstrated that NLCs can enter brain tissues via the olfactory bulbs after i.n. administration, bypassing the BBB, as well as that the NLCs remained in tissue for longer periods. Moreover, i.n.-administrated keto-NLCs significantly inhibited cerebral C. neoformans colonisation and proliferation in mouse brain tissue when compared to free keto.

Despite i.n. administration being a useful tool for rapid transport of drugs to the brain, the low residence time in the nasal cavity because of mucocilliary clearance represents a constraint, resulting in incomplete drug absorption [185]. To prolong ONCs in the nasal cavity and improve drug absorption by the nasal mucosa, some authors proposed the development of mucoadhesive systems [186]. The mucoadhesive nanoparticles can perturb the microstructure of mucus, which increases the pore size of mucus up to 380-470 nm; thus larger-size particles can easily pass by the mucous membrane. Mucoadhesive nanoparticles can be achieved by coating the nanoparticles with mucoadhesive polymers or by using a composition which renders its surface with positive charges which will electrostatically bind to mucin negative charges. Herein we restrict our examples to lipid nanoparticles which are positively charged, as the polymeric coating of lipid nanoparticles produces hybrid polymeric lipid nanoparticles which are not a focus of this chapter. On the basis of these considerations, Gabal et al. [187] encapsulated the anti-Parkinson agent ropirinole in NLCs, with the aim to overpass the limitations in the uptake of this hydrophilic compound, and studied the influence of NLC surface charge on brain delivery through the i.n. route. The authors used Compritol 888® ATO as a solid lipid and Labrafac lipophile WL1394 (caprylic/capric triglycerides) as a liquid lipid. As mentioned before, the electrostatic attraction between cationic nanoparticles and negatively charged brain endothelial cells can increase their contact time and thus enhances the penetration of nanoparticles to the brain via AMT [188]. Previous studies also reported that in addition to cationic nanoparticles, anionic nanoparticles can also cross the BBB [189, 190]. Anionic and cationic NLCs with similar sizes (175 nm and 160 nm, respectively) and an absolute surface charge of +34 mV were successfully prepared [187]. In vivo toxicity assessment was performed on the nasal mucosa of rats and demonstrated that cationic NLCs caused severe injury and destruction of the lining epithelium, whereas mild inflammation, including inflammatory cell infiltration, was reported for anionic NLCs. However, the incorporation of aqueous dispersions of NLCs in Poloxamer 188 in situ gels resulted in no histopathological alterations in the treated animals, eliminating the adverse effects previously reported. Both anionic and cationic NLC gels increased ropirinole’s absolute bioavailability (44% and 77.3%, respectively) compared to i.n. drug solution (7.4%). In addition, a higher accumulation in the brain was observed for the cationic NLCs. Likewise, Wavikar andVavia [191] explored the potential of NLCs for nose-to-brain delivery of rivastigmine (RV), used in the treatment of AD, which was additionally enhanced by their incorporation into an in situ gelling system of gellan gum, extending the retention period in the nasal cavity. RV is a hydrophilic compound and is thus unable to overcome the BBB. NLCs were prepared using GMS (solid lipid), Capmul™ MCM (liquid lipid), lecithin and Tween® 80 (surfactants and stabilisers). NLCs had an average size of 123.2 ± 2.3 nm with an EE of 68.34% ± 3.4%. The in situ gel presented physical properties in terms of elasticity, rheology and mucoadhesion which allow its adhesion to the upper nasal mucosa, thus increasing the residence time in this region. In situ gelling RV-NLCs demonstrated a twofold enhancement in nasal permeation of the drug and superior enzyme inhibition efficacy (threefold increase) when compared to RV solution.

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