Intranasal Delivery: Formulation Factors and Insights Into User Experience

Abstract

Improving nasal spray use experience is typically not addressed as a key product requirement even though sensations of bitterness, sourness, astringency, or burning after intranasal application can cause significant repulsion, consumer non-compliance from recommended usage and product rejection. Extensive studies have been carried out by academia and industry alike into the formulation characteristics of sprays and consumer preferences to make nasal sprays more “acceptable” by patients. Due to lack of a collative synopsis of these works, this review article attempts to gather and summarize these studies, address the various attributes that impact post spray experience, and provide suggestions towards maximizing user compliance. We systematically categorized a range of factors which can contribute to unpleasant experiences using nasal sprays including anatomical characteristics of the nose, formulation and device properties, formulation components and dosages, etc. Furthermore, we collated relevant information from pharmaceutical and non-pharmaceutical domains to create a comprehensive knowledge base to frame the scope of the issue. Unpleasant sensorial attributes can be controlled by designing the formulation with a thorough understanding of product-device interactions and novel use of excipients. By choosing excipients such as taste masking agents, flavors, and novel polymers the behavior of the product in the nasal canal can be modulated to block the burning, astringent or bitterness sensation on spray use. This paper discusses these factors in comprehensive detail while offering solutions to ensure a superior product experience. The paper also discusses challenges to adoption and compliance strategies of some newer techniques and excipients.

Introduction

Pharmaceutical actives have long been delivered both locally and systemically as treatments for nasal and throat irritation, inflammation and congestion arising from allergenic, biological, and particulate exposure through the nose. A locally delivered active provides advantages such as reduced systemic exposure, as well as targeted effect at site of infection, inflammation or irritation. Secondary benefits to treatment can be derived from excipients including emollients and humectants. Local intervention is especially impactful for medications delivered for relief of allergy and congestion due to irritation of the nasal and proximal oral passages. Nasal dosages can also deliver actives systemically via inhalation in a rapid manner, offering advantages such as bypassing first pass metabolism and being non-invasive unlike the parenteral dosage forms.

For this article, we would like to make a distinction between nasally delivered dosages and inhalations, the former of which is targeted to the proximal structures in the airway passage namely the vestibular region, the respiratory region, and the olfactory region. Nasal sprays have a unique quality of having ‘mist-like’ plume with droplet size between 50–200 µm which restricts their availability to the anterior segments of the nasal passage. On the other hand, inhalations are targeted towards the distal portions of the airway path, the lungs [1]. This review article will specifically consider nasal delivery forms and factors influencing unpleasant perception through this route. Inhalations will not be considered.

Nasal sprays have substantial market presence due to their effectiveness, speed of action, and local/targeted intervention. However, consumer acceptance of a nasal spray is impacted by the sensation of the product itself such as bitterness, astringency, saltiness etc. and the residence time of the product in the nasal cavity. After administration, a nasally delivered product will be guided either back out of the nostrils or (predominantly) it is cleared down through the nasopharyngeal cavity which is where it encounters the taste buds of the back of the tongue [2].

If the nasal product includes components that impart bitter or undesirable taste, the natural clearance of the nasal cavity of the product leads to patient avoidance and compliance issues in the continuation of product use [3, 4]. In most cases the drugs which are delivered nasally are extremely bitter. Current nasal sprays are designed to deliver actives classified as vasoconstrictors, antihistamines, or corticosteroids. The basic nature of these actives, particularly their primary and secondary amines, often results in a bitter or fishy taste. Table I lists some active classes and literature addressing unpleasant user experiences or research aimed at improving product taste.

Tabelle1 Commercial nasal sprays and their active ingredients with associated studies highlighting the bitterness of the molecules

In addition, the taste of added excipients, in some cases used to negate bitterness (such as artificial sweeteners), can amplify sensation or perception of bitterness. Moreover, adverse effects such as nasal irritation and epistaxis (nosebleeds) can further discourage patients from adhering to their treatment plans [5]. Hence, there is a general need to optimize product characteristics to influence the residence of the spray in the nose or minimize unpleasant sensory experience.

A broad scan of review articles on nasal sprays shows an emphasis on spray characteristics and the impact on either the deposition patterns in the respiratory tract, the bioavailability, or therapeutic effects (A PubMed search as of 24th Aug 2024 with keywords ‘nasal delivery user experience’ resulted in 2 results whereas ‘nasal delivery clinical’ resulted in 2445). There is, however, limited information with emphasis on factors that influence user experiences. Unpleasant taste, with bitterness being the most predominant, is viewed as a usual side effect from nasal delivery of medication. Yet, with close to 40% of users reporting this as the side effect leading to discontinuation of therapy, it is a crucial factor to address [6]. This holds especially true for nasal products used chronically for long-term relief or in pediatrics.

Based on this impact to treatment compliance and adherence to treatment regimen for Rx and OTC medication, we believe that a review article on product design strategies to minimize bitterness and other undesirable characteristics from nasal sprays is needed.

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Table IV Excipients studied for nasal delivery and their impact on Ciliary beat frequency (CBF) and Mucin Secretion (MS)

Excipients mentioned in the paper beside others: cyclodextrin, chitosan, polysorbates, PEG, alginates, Polysorbate 80, Hydroxypropyl-beta-cyclodextrin

Lobo, S., Xi, Z., Das, D. et al. Intranasal Delivery: Formulation Factors and Insights Into User Experience. AAPS PharmSciTech 26, 179 (2025). https://doi.org/10.1208/s12249-025-03171-y