In Situ Gels for Nasal Delivery: Formulation, Characterization and Applications

Abstract

The nasal route offers many advantages for drug delivery: quick onset of action, better patient compliance, avoidance of first-pass metabolism and bypassing the blood-brain barrier. Despite the potential of this route, several challenges exist, such as the short drug retention time caused by mucociliary clearance (MCC). In situ forming gels, which undergo a sol-to-gel transition with specific triggers at the site of action, present real opportunities in this field. They combine the intrinsic characteristics of hydrogels (elasticity and water-holding capacity) with responsiveness, allowing easy application of drugs (spraying or extruding through a nozzle), as well as prolonged retention in the nasal cavity. The incorporation of mucoadhesive polymers, additives and nanocarriers can further tune the properties of in situ gels as nasal delivery platforms. This review summarizes advances in in situ gels for nasal drug delivery. We first describe challenges of the nasal route, target properties of in situ nasal gels, and then present both “classic” gelling polymers (poloxamers and polysaccharides) – which form the bulk of reported studies on nasal gels – as well as novel bespoke materials; we review characterization methods, highlighting the lack of standardization and accepted target values, then discuss applications by spraying, and conclude with future prospects.

Introduction

Exploration of the intranasal route has rapidly become a focus of attention in recent years, in part due to its attractiveness for vaccination during the Covid-19 pandemic.[1, 2] As a non-invasive route, nasal delivery exhibits potential advantages such as easy application, better patient compliance and quick onset of action. Thus, the nasal route is an attractive route of administration compared to traditional administration routes.

In addition to the advantages the nasal route presents in terms of potential for rapid and patient-friendly vaccination, nasal delivery also shows some distinct advantages for drug delivery: Nasal administration has the ability to overcome first-pass effect and degradation caused by gastric acid in the oral route.[3] It has the capability of bypassing the blood-brain barrier (BBB) due to the direct connection between the olfactory region in the nasal cavity and the brain.[4-6] Furthermore, it affords quick action and compliance for systemic drug delivery because of its abundant vascular distribution.[3]

Within marketed (liquid-like) formulations, a wide range of drugs is administrated nasally, most of which are against local diseases. This variety is also reflected in the drugs that have been studied with nasal gels. Typical examples include corticosteroids and antihistamines against rhinitis;[7] as well as decongestants to reduce nasal congestion.[8] Notably, an increasing number of studies are focusing on nose-to-brain delivery. A wide range of drugs have been delivered for the treatment of Alzheimer’s disease, including quercetin,[9] donepezil,[10-12] vinpocetine[13] and resveratrol.[14] Some have also targeted the treatment of neurological disorders, delivering antiepileptic drugs through the nose to the central nervous system.[15-17] Additionally, a few studies have focused on systemic drug delivery, e.g., for painkillers[18] and insulin.[19-21] Overall, nasal delivery is a potent route that is suitable for local and systemic delivery, as well as delivery to the brain.

There are, however, challenges to nasal delivery. One is nasal mucociliary clearance (MCC), a natural mechanism in the human body, which is a major hurdle to drug retention. MCC occurs every 15–20 min to clear out foreign pathogens and particles invading the nose, but also clears drug formulations, causing short retention times of drugs at their intended site of action, which is a major factor of decreased drug efficacy.[22] In addition, due to the anatomy of the nose, upon administration liquid formulations may flow back to the throat. In addition to the problem of retention, nasal administration often requires devices such as a spray to apply the drug formulations, through which well-distributed coverage is often required. An increasing number of studies are focusing on the advancement of nasal sprays to fit diverse dosage forms; some of them are discussed in the final section of this review. However, the potential of inhalation during application still needs to be addressed. Thus, to fully develop the nasal route as a viable route of administration, the primary challenge to overcome is to prolong drug residence time. In situ gel formulations, due to their solid nature, offer an attractive strategy to overcome MCC.

In situ gelling systems are able to transform from a liquid state to a gel state at the site of action, often under the action of an external trigger; for this reason they are often referred to as “smart” materials.[23-26] For nasal delivery specifically, the formulations are designed to incorporate a drug in the liquid state and then form a gel at the site of action with specific physiological stimuli, such as temperature, pH or the presence of ions.[22] In addition, the gels should be designed to interact favourably with the nasal mucosa, either physically or chemically, in order to extend residence at the target site.

Gels that are suitable for nasal delivery should present appropriate rheological properties: they should be mechanically robust (as usually assessed through rheology shear oscillatory measurements) and gel in situ (either through the action of a trigger or because of shear-thinning behaviour, namely, recovery after the application of shear). The delivery system should facilitate drug permeation, which can be improved by the addition of permeation enhancers.[27, 28] In addition, the gel should adhere to the mucosa to prolong residence time. To meet these criteria, various traditional gelling polymers and their mixtures have been explored. In addition, a small number of novel materials have been developed, through chemical synthesis or new routes for crosslinking or modification.

In this review, we give an overview of polymers that have been proposed as in situ gelling formulations for nasal delivery, by first providing some necessary background on nasal delivery, its opportunities and challenges. We cover “traditional” systems, classified according to the stimulus for gelation, discuss classic mucoadhesive polymers, often used in combination with gelators, and describe novel, bespoke in situ gelling materials. We end by providing an overview of the methods currently used to assess the performance of in situ nasal gelling systems.

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Excipients mentioned in the study: Carbopol 934P, poloxamer 188, poloxamer 407, CMC, sodium alginate, HPMC

Li Qian, Michael T. Cook, and Cécile A. Dreiss, In Situ Gels for Nasal Delivery: Formulation, Characterization and Applications, First published: 21 January 2025 https://doi.org/10.1002/mame.202400356