Intranasal Administration of Dolutegravir-Loaded Nanoemulsion-Based In Situ Gel for Enhanced Bioavailability and Direct Brain Targeting

Abstract

Dolutegravir’s therapeutic effectiveness in the management of neuroAIDS is mainly limited by its failure to cross the blood–brain barrier. However, lipid-based nanovesicles such as nanoemulsions have demonstrated their potential for the brain targeting of various drugs by intranasal delivery. Thus, the purpose of this study was to develop a Dolutegravir-loaded nanoemulsion-based in situ gel and evaluate its prospective for brain targeting by intranasal delivery. Dolutegravir-loaded nanoemulsions were prepared using dill oil, Tween® 80, and Transcutol® P. Optimization of the nanoemulsion particle size and drug release was carried out using a simplex lattice design. Formulations (F1–F7 and B1–B6) were assessed for various pharmaceutical characteristics. Ex vivo permeation and ciliotoxicity studies of selected in situ gels (B1) were conducted using sheep nasal mucosa. Drug targeting to the brain was assessed in vivo in rats following the nasal delivery of B1. The composition of oil, surfactant, and cosurfactant significantly (p < 0.05) influenced the dependent variables (particle size and % of drug release in 8 h). Formulation B1 exhibits pharmaceutical characteristics that are ideal for intranasal delivery. The mucosal steady-state flux noticed with BI was significantly greater (p < 0.005) than for the control gel. A histopathology of nasal mucosa treated with BI showed no signs of toxicity or cellular damage. Intranasal administration of B1 resulted in greater Cmax (~six-fold, p < 0.0001) and AUC0−α (~five-fold, p < 0.0001), and decreased Tmax (1 h) values in the brain, compared to intravenous administration. Meantime, the drug level in the plasma was relatively low, suggesting less systemic exposure to Dolutegravir through intranasal delivery. In summary, the promising data observed here signifies the prospective of B1 to enhance the brain targeting of Dolutegravir by intranasal delivery and it could be used as a feasible and practicable strategy for the management of neuroAIDS.

Propranolol-Loaded Limonene-Based Microemulsion Thermo-Responsive Mucoadhesive Nasal Nanogel: Design, In Vitro Assessment, Ex Vivo Permeation, and Brain Biodistribution

“…The bags were immersed under conditions of 34 ± 0.5 °C temperature with paddle stirring at 100 rpm. Aliquots were withdrawn at regular time intervals and the sink condition was maintained by adding the same volume of the release medium [ 82 ]. The withdrawn aliquots were spectrophotometrically assayed for their propranolol content.…”

Recent Advances in Intranasal Administration for Brain-Targeting Delivery: A Comprehensive Review of Lipid-Based Nanoparticles and Stimuli-Responsive Gel Formulations

“… The ISG-NP (IN) was absorbed into the N2B route quickly and released the drug sustainedly. [ 124 ] Liposome Opiorphin (Pain) PC, CL, stearyl amine, and PEG-DSPE Poloxamer 407 and Carbopol 934P Before PS 141 nm, PDI 0.184, ZP −0.62 mV, and EE 59% After PS 143 nm, PDI 0.169, ZP −0.52 mV, and EE 58% Tem. - [ 125 ] Donepezil hydrochloride (AD) HSPC and CL DGG and xanthan gum Before PS 103 nm and EE 93% Ion The biodistribution profile showed the highest drug deposition in the brain for the ISG-NP (IN).…”

Nasal Delivery to the Brain: Harnessing Nanoparticles for Effective Drug Transport

“…Researchers can coat nanoparticles with ligands that attach to nasal epithelial receptors. Nanoparticles may enter cells and traverse the nasal epithelium into the brain via receptor-mediated endocytosis [ 35 ].…”

“…Intranasal sprays [29] Nanoparticles [30] Liposomes [31] Micelles [32] Hydrogels [33] Advantages Rapid onset of action [34,35] Bypasses blood-brain barrier [35,36] Reduced systemic side effects [37] Applications Drug delivery for neurological disorders [38] Treatment of brain tumors [39] Targeted therapy for neurodegenerative diseases [34,35] Challenges Nasal mucosa variability [35] Clearance mechanisms Dosage control and optimization Safety concerns, potential irritation Four routes involved in nose-to-brain delivery (Figure 1) are briefed below. Olfactory pathway: One of the main routes includes the olfactory pathway, where medicines may circumvent the BBB by directly entering the brain via the olfactory epithelium [40].…”