Mohamed Ahmed El- Nabarawi

Objective: Vortioxetine HBr is a multimodal antidepressant with a very poor aqueous solubility (50 µg base/ml at pH 7.4) and an oral bioavailability of approximately 75% due to hepatic first-pass metabolism. Nose-to-brain drug delivery can bypass hepatic first-pass metabolism and achieve targeted drug therapy by circumventing the blood-brain barrier via the olfactory and trigeminal nerve pathways using different modalities. A novel dosage form, nasal insert, containing Vortioxetine HBr lipid-based nanocarriers (VRT-NLCs) was used to improve Vortioxetine bioavailability and optimization of different additives such as D-(+)-Trehalose and D-Mannitol to enhance Vortioxetine efficacy. Methods: (VRT-NLCs) were prepared via a 24 full factorial design with four variables; surfactant (Tween 80) concentration (X1), steric stabilizer (PVA) concentration (X2), solid/liquid (Stearic/Oleic acid) ratio (X3), and co-surfactants (Span 60/Poloxamer 188) ratio (X4). Entrapment efficiency (EE%), %released after six hours (Q6h%), particle size (PS), zeta potential (ZP) and polydispersity index (PDI) were evaluated. Design Expert® software was used to select the optimum two formulae with the highest desirability values. Using D-mannitol or D-(+)-trehalose, the two optimized (VRT-NLCs) formulae were incorporated into lyophilized nasal inserts. They were characterized for physical appearance, release profile, muco-adhesion strength, residual water content by Karl Fischer, uniformity of dosage units by content uniformity, mass uniformity and friability. In addition to (DSC), (FTIR), (PXRD) and in vivo pharmacokinetics, the two optimized inserts were evaluated for (Norepinephrine (NE), Dopamine (DA), Serotonin (5-HT), Aspartate (Asp) and γ-amino butyric acid (GABA)) neurotransmitters’ level in the brain and (5-Hydroxy Indoleacetic acid (5HIAA)) metabolite using rats and compared with Vortoxicalm® 5 mg oral tablet. Results: (VRT-NLCs) exhibited (EE%) range of (67.58±1.59% to 99.42±1.91%), sustained release profile with (Q6h%) of (21.49±4.89% to 90.94±4.02%), (ZP)of (-10.4775±0.81to-27.925±2.67mV), (PS) of (81.92±0.68 to 255±5.82 nm), and (PDI)of (0.267±0.02 to 0.545±0.01). Moreover, nasal inserts had promising residual water content values of (0.0072 ±0.03% to 3.971±1.334 %), friability of (zero% to 0.9%), (Q)45 min% of (54.88 ±1.62% to 100 ±3.31%) and muco-adhesion strength of (8297.33±184.79 to 9996±122.23). Solid-state characterization (DSC and PXRD) confirmed D-(+)-trehalose superior cryoprotective effects. N4 (trehalose-based insert) demonstrated the highest brain exposure, with two-fold higher area under the curve from zero to infinity (AUC₀–∞ = 461.28±17.85ng*h/g) when compared to oral tablet (AUC₀–∞ = 230.4±11.5ng*h/g). Nasal inserts increased mood-regulating neurotransmitters’ (5-HT, DA, NE) levels and reduced (5-HIAA) metabolite compared with Vortoxicalm® 5 mg FCT. Conclusion: We recommend conducting further clinical studies to explore potential therapeutic applications of vortioxetine HBr lipid-based nanocarriers, consolidating our research findings.

Vincristine (VCR) remains a cornerstone of oncological therapy. Yet, its efficacy against central nervous system (CNS) malignancies is severely hindered by the blood-brain barrier (BBB) and dose-limiting peripheral neurotoxicity. This comprehensive review explores the promising shift from conventional systemic administration to advanced nanovesicular platforms designed for direct nose-to-brain (N2B) delivery. We evaluate the comparative performance of diverse carriers, including nanoemulsions, niosomes, liposomes, and nanostructured lipid carriers (NLCs). Central to this review is the analysis of strategic excipient chemistry, specifically the synergistic interplay between chitosan for mucoadhesion and tight-junction modulation, Tween 80 for P-glycoprotein (P-gp) efflux inhibition, and PEG 6000 for mucus penetration, as well as the impact of Soluplus® integration in nanovesicular engineering. We also provide an assessment approach using quantitative brain-targeting indices, including drug targeting efficiency (DTE%) and direct transport percentage (DTP%), which are essential for brain-targeting evaluation. We also highlight the critical role of scintigraphic validation using 99mTc-labeled formulations in providing spatial proof of the olfactory and trigeminal bypass routes. Safety considerations, particularly ciliary beat frequency (CBF) and histopathological integrity, are discussed to establish a framework for clinical translation. Ultimately, this review consolidates evidence that multifunctional nanovesicles offer a sophisticated route of entry into the CNS, optimizing therapeutic indices for VCR as a CNS drug model while mitigating systemic risks.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality, and current treatments remain restricted by limited efficacy and systemic toxicity. This study's objective was to assess the feasibility of developing a targeted platform based on cubosomal nanoparticles loaded with pitavastatin (PTV) for HCC therapy. A total of 15 formulations were created and optimized using a 33 Box-Behnken design to study the influence of glyceryl monooleate (GMO) concentration, GMO: Pluronic F127 (F127) ratio (GMO: F127), and homogenization time on formulation characteristics. The optimized cubosomes (10% GMO, 100:5 GMO: F127, 5 min homogenization) exhibited a nanoscale size (165 ± 0.6 nm), low polydispersity (0.27), high entrapment efficiency (95 ± 0.6%), and a stable zeta potential (–24.7 mV). Nanoparticle size, uniformity, and successful drug encapsulation were confirmed by morphological inspection. The optimized biphasic PTV-cubosomes showed 94.8% drug release within 24 hours, a significant increase compared to the pure drug suspension. The formulation achieved the highest cytotoxicity against HepG2 and Huh7 cells. Cyto- and drug release behavior showed in silico evidence of strong binding to EGFR with favorable pharmacokinetics. Collectively, PTV-loaded cubosomes offer a promising nanotechnological approach to enhance pitavastatin's therapeutic potential in the management of hepatocellular carcinoma.

Vildagliptin (VLD) is a powerful oral hypoglycemic agent used in the management of type II diabetes. The goal of the current research was to develop VLD-loaded zein protein-based nanoparticles (VLD-ZP NPs) for enhancing their oral hypoglycemic effect, achieving a sustained release profile, and addressing the issues associated with rapid metabolism and side effects. A 2 ³ full factorial design was utilized to assess the influence of independent formulation variables on the observed responses. The independent variables considered were VLD-to-zein weight ratio (X ₁ ), ethanol-to-water volume ratio (X ₂ ), and stirring time (X ₃ ). The dependent responses evaluated were particle size (Ps), zeta potential (Zp), entrapment efficiency (EE), and percent of drug release after 2H (Q _2H ) and 8H (Q _8H ). The optimized VLD-ZP NPs formula (F04), with a desirability value of 0.94, exhibited a small Ps (149.64 ± 1.4nm), low Q _2H (23.97 ± 2.1%), high Zp (− 37.67 ± 1.8mV), high EE (68.67 ± 2.3%), and sustained Q _8H release (62.57 ± 2.4%). Further investigations of F04 confirmed sustained drug release, spherical vesicle morphology through TEM, and effective entrapment via DSC and X-ray diffraction. In vivo pharmacokinetic studies revealed that C _max and AUC _0-12H of F04 were enhanced by 1.25-fold and 1.8-fold compared to the marketed VLD product. Also, t _1/2 and MRT were extended by 1.84-fold and 1.56-fold, respectively. These findings indicated improved oral bioavailability and prolonged residence time of VLD. Additionally, the in vivo pharmacodynamic study revealed that F04 provided markedly superior and sustained hypoglycemic effects over the marketed VLD product, with higher R _max , longer TR _½ , and a 2.8-fold increase in AUC _(0-24H) . Graphical Abstract

Background/Objectives: Glaucoma is a neurodegenerative optic disorder which occurs due to persistent elevation of the intraocular pressure. It leads to permanent blindness and currently affects over 75 million individuals worldwide. Nowadays, topical ocular medications are the leading therapy despite their poor ocular penetration and short residence time. Methods: The purpose of this research is to formulate bisoprolol hemifumarate-loaded polylactic-co-glycolic acid (PLGA) nanoparticles and improve their ocular penetration and bioavailability for the treatment of glaucoma by enhancing the delivery of the drug to the posterior part of eye. By using the solvent displacement method, formulations were prepared and optimum formula was elected using Design-Expert^® software. Results: In vitro characterization demonstrated that the optimum formula contained 25 mg BSP, 22.5 mg PLGA, and 60 mg Tween80, yielding high values of drug encapsulation (75%) and zeta potential (−18.7 ± 0.41 mV), with a low particle size (105 ± 0.35 nm) and polydispersity index (0.411 ± 0.71). Transmission electron microscopy and atomic force microscopy showed smooth and spherical nanosized particles. X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy revealed successful encapsulation of the drug inside the polymeric matrix. Ex vivo confocal laser scanning microscopy proved that there was better uptake of the drug upon using PLGA-NPs. In vitro release profiles indicated biphasic drug release from the PLGA-NPs, confirming a sustained drug release over 12 h. In vivo studies showed that BSP-PLGA-NPs significantly reduced the IOP compared to bisoprolol solution. Quantitative immunohistochemistry showed lower retinal GFAP expression with BSP-PLGA-NPs compared with induced controls and drug solution, which is indicative of attenuated glial activation. Conclusions: These data support improved ocular delivery and an improved pharmacodynamic effect; however, they demonstrate association rather than a direct mechanistic suppression of glial pathways.