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

Abstract

Addressing disorders related to the central nervous system (CNS) remains a complex challenge because of the presence of the blood-brain barrier (BBB), which restricts the entry of external substances into the brain tissue. Consequently, finding ways to overcome the limited therapeutic effect imposed by the BBB has become a central goal in advancing delivery systems targeted to the brain. In this context, the intranasal route has emerged as a promising solution for delivering treatments directly from the nose to the brain through the olfactory and trigeminal nerve pathways and thus, bypassing the BBB. The use of lipid-based nanoparticles, including nano/microemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, has shown promise in enhancing the efficiency of nose-to-brain delivery. These nanoparticles facilitate drug absorption from the nasal membrane. Additionally, the in situ gel (ISG) system has gained attention owing to its ability to extend the retention time of administered formulations within the nasal cavity. When combined with lipid-based nanoparticles, the ISG system creates a synergistic effect, further enhancing the overall effectiveness of brain-targeted delivery strategies. This comprehensive review provides a thorough investigation of intranasal administration. It delves into the strengths and limitations of this specific delivery route by considering the anatomical complexities and influential factors that play a role during dosing. Furthermore, this study introduces strategic approaches for incorporating nanoparticles and ISG delivery within the framework of intranasal applications. Finally, the review provides recent information on approved products and the clinical trial status of products related to intranasal administration, along with the inclusion of quality-by-design-related insights.

Keywords: bypassing BBB; in situ gel; lipid based nanoparticle; nose to brain delivery system.

Figure 1

Intranasal mechanism of nose-to-brain delivery. The therapeutics can be transported from the nose to the brain through (I) neural transport through the olfactory and trigeminal nerves, (II) lymphatic system and cerebrospinal fluid (CSF), and (III) vascular transport across the blood-brain barrier (BBB). The primary routes for nose-to-brain are olfactory and trigeminal nerve pathways. In contrast, the latter two serve as secondary passages. Reprinted from J Cont Rel, Volume 327, Agrawal M, Saraf S, Saraf S, et al. Stimuli-responsive in situ gelling system for nose-to-brain drug delivery. 235–265. Copyright 2020, with permission from Elsevier.

Figure 2

Representative factors influencing intranasal drug delivery. Those factors can be classified depending on the biological environment of the nasal cavity, physicochemical properties of drugs, and characteristics of final formulation or pharmaceutical dosage forms.

Figure 3

Surface charge and PEGylation effects on nose-to-brain delivery. In-vivo liposome distribution and the surface charge effect on the distribution after intranasal administration were investigated through fluorescence and [³H]-cholesterol radioactivity analysis. The statistical analysis of the surface charge effect was assessed through one-way ANOVA analysis, followed by Tukey’s post hoc test (*P < 0.05 and **P < 0.01). Conversely, the Student’s t-test was performed for the PEGylation effect (**P < 0.01). Reprinted from J Cont Rel. Volume 344, Kurano T, Kanazawa T, Ooba A, et al. Nose-to-brain/spinal cord delivery kinetics of liposomes with different surface properties. 225–234. Copyright 2022, with permission from Elsevier.

Figure 4

Effect of NLC particle size on nose-to-brain delivery. Drug levels in the plasma, cerebrospinal fluid, and brain after administering NLCs (< 50 nm; 33 nm) by IN, NLCs (< 50 nm; 33 nm) by IN, NLCs (> 100 nm; 125 nm) by IN, a free drug control solution by IN, a commercial product of phenytoin sodium by IV, and another commercial midazolam nasal spray product. The author found that the small NLCs had the most and fastest nose-to-brain delivery transportation of the formulations tested. The statistical significance was evaluated through one-way ANOVA analysis (*p < 0.05, **p < 0.01, and ***p < 0.001). Reprinted from Nair SC, Vinayan KP, Mangalathillam S. Nose to brain delivery of phenytoin sodium loaded nano lipid carriers: formulation, drug release, permeation and in vivo pharmacokinetic studies. Pharmaceutics. 2021;13(10):1640. Creative Commons.

Figure 5

Comparison of overall drug delivered by nano systems and solutions. Box plots illustrating Log DTE %, Log DTP %, and Log ABbrain% for IN solutions and IN nanosystems showed the median, interquartile interval, and range, with the mean indicated by “+”. Group mean comparisons were analyzed using one-way ANOVA with Tukey’s post-test (^#p < 0.05, ^##p < 0.01, and ^###p < 0.001). IN nanosystems and IN solutions were compared using the Mann–Whitney U-test (++p < 0.01, ++++p < 0.0001). Differences from reference “no-change” values were assessed by a one-sample t-test assuming normal distribution and a Wilcoxon signed-rank test when not assuming normal distribution (medians) (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). Reprinted from J Cont Rel. Volume 270, Pires PC, Santos AO. Nanosystems in nose-to-brain drug delivery: a review of non-clinical brain targeting studies. J Cont Rel. 89–100. Copyright 2018, with permission from Elsevier.

Figure 6

In-vivo and in-vitro drug deposition in the nasal cavity. (A) The Cy7 deposition in the nasal cavity after intranasal administration of solution (Ctrl) or gellan gum-based ISG. Reprinted from Int J Pharm. Volume 489 (1-2), Li X, Du L, Chen X, et al. Nasal delivery of analgesic ketorolac tromethamine thermo-and ion-sensitive in situ hydrogels. 252–260, Copyright 2015, with permission from Elsevier. (B) PET images of rhesus monkey-head after intranasal administration of [¹⁸F]-labeled vaccines mixed with PBS or ISG matrix. Reprinted from Vaccine. Volume 34(9), Saito S, Ainai A, Suzuki T, et al. The effect of mucoadhesive excipient on the nasal retention time of and the antibody responses induced by an intranasal influenza vaccine. 1201–1207, Copyright 2016, with permission from Elsevier. (C) Effects of administration angle and excipient on the in-vitro 3D nasal deposition. Reprinted from Int J Pharm. Volume 563, Nižić L, Ugrina I, Špoljarić D, et al. Innovative sprayable in situ gelling fluticasone suspension: development and optimization of nasal deposition. 445–456. Copyright 2019, with permission from Elsevier.

Figure 7

Sol-gel transition behavior, in-vitro dissolution profile using dialysis membrane, ex-vivo drug permeation, and pharmacokinetics studies of amisulpride-loaded nanoemulsion (AMS-NE) with a temperature-sensitive ISG system (AMS-NE-ISG) based on Poloxamer^® 407 and supported by gellan gum. The significance level (*p < 0.05) indicates a statistically significant difference compared to the AMS-NE formulation. Reprinted from Int J Pharm. Volume 607, Gadhave D, Tupe S, Tagalpallewar A, Gorain B, Choudhury H, Kokare C. Nose-to-brain delivery of amisulpride-loaded lipid-based poloxamer-gellan gum nanoemulgel: in vitro and in vivo pharmacological studies. 121050. Copyright 2021, with permission from Elsevier.

Figure 8

Sol-gel transition behavior, in-vivo comparative MCC time, and pharmacokinetic studies of piribedil-loaded SLN (RBD-SLN) with a methylcellulose-based temperature-sensitive ISG (PBD-SLN-ISG). Reprinted from Int J Pharm. Volume 606, Uppuluri CT, Ravi PR, Dalvi AV. Design, optimization and pharmacokinetic evaluation of piribedil loaded solid lipid nanoparticles dispersed in nasal in situ gelling system for effective management of Parkinson’s disease. 120881. Copyright 2021, with permission from Elsevier.

Figure 9

Illustration of the quality by design (QbD) framework for the development of lipid-based nanoparticle and in-situ gel systems. QbD has the potential to facilitate the development of effective nose-to-brain delivery systems. The components of QbD, such as critical process parameters (CPP), critical material attributes (CMA), critical quality attributes (CQA), and the quality target product profile (QTPP), interact and influence each other, providing feedback within the design space. The representative parameters of CPP, CMA, and CQA are listed.