Compressed Medicated Chewing Gum with Lysozyme Hydrochloride and Ascorbic Acid for Xerostomia Relief and Oral Health Support: Formulation Development, Optimization, In Vitro and In Vivo Evaluation

Abstract

Background: Existing therapies for xerostomia are primarily symptomatic, providing temporary mucosal hydration without addressing underlying pathological changes in the oral cavity. In this context, medicated chewing gums containing ascorbic acid and lysozyme hydrochloride offer a promising approach, combining antimicrobial, antioxidant, and trophic effects with physiological salivary stimulation and prolonged local delivery.

Methods: For the development of compressed chewing gum formulation, the physicochemical (particle size distribution, moisture absorption capacity, and microscopic characteristics) and technological (flowability, angle of repose, bulk and tapped density, Carr’s index (CI), and Hausner ratio (HR)) properties of the active substances and their formulations with excipients were evaluated. Pharmacological activity was assessed in an atropine-induced xerostomia rat model.

Results: The physical mixture of all components showed inferior flow properties compared with the formulation containing pre-granulated lysozyme hydrochloride, as evidenced by higher Carr’s index and Hausner ratio values (CI = 17, HR = 1.20 vs. CI = 13, HR = 1.14), indicating improved processability after pre-granulation. The effect of relative humidity during formulation was also assessed, with an optimal level of 40% required to ensure process stability due to the hygroscopic nature of the components. Based on these data, technological approaches ensuring processability were established, including wet pre-granulation of lysozyme hydrochloride and premixing of ascorbic acid to reduce oxidation risk. These approaches resulted in an optimized compression mass with excellent flowability (CI = 8, HR = 1.09), suitable for the preparation of medicated chewing gum. An optimal compression force (7 kN) ensured suitable rheological and textural properties, resulting in rapid and nearly complete release of the active ingredients from the medicated chewing gum, consistent with kinetic analysis. In vivo studies using an atropine-induced xerostomia rat model demonstrated that the combination of ascorbic acid and lysozyme hydrochloride significantly increased salivary secretion (2.17-fold vs. control pathology group) and reduced salivary gland mass coefficients (by 13–18% compared with the control pathology group and groups receiving individual active ingredients), alongside improvement of oxidative stress markers, including a reduction in TBA-reactants (by 51.6%) and an increase in catalase activity (by 51.0%).

Conclusions: The developed medicated chewing gum showed favorable technological properties, efficient release of active ingredients, and anti-xerostomic activity in vivo, indicating its potential for xerostomia relief and oral health support.

Introduction

Xerostomia is a multifactorial pathological condition characterized by a subjective sensation of dryness in the mouth, usually associated with a reduction in saliva flow (hyposalivation) and/or a change in the qualitative composition of saliva [1,2]. Its prevalence in the general adult population is reported to range from approximately 5–46%, while in older adults it may reach 40–70%, and in patients receiving polypharmacy or oncological treatment it can exceed 70–80% [3,4,5]. The main causes include inflammatory dental disorders [6,7,8], medication-induced mouth dryness [9,10,11,12], systemic pathologies (endocrine, autoimmune and metabolic disorders) [13,14], as well as the effects of radiotherapy and chemotherapy [15,16], which are accompanied by damage to the secretory apparatus of the salivary glands. Other contributing factors include surgical procedures in the maxillofacial region [17], dehydration and disturbances in water and electrolyte balance [18], as well as functional and behavioural factors, including chronic stress [19], smoking [20], dietary disorders and reduced masticatory load [21]. These factors collectively disrupt the neurohumoral regulation of salivation and a reduce saliva production.

Saliva is a key component of oral homeostasis, performing protective, buffering, remineralizing and antimicrobial functions [22,23,24]. A reduction in saliva production leads to an imbalance between the processes of demineralization and remineralization of hard dental tissues, changes in the oral microbial flora, and a reduction in local immune defense. As a result, patients with xerostomia face a significantly increased risk of developing caries, inflammatory periodontal diseases, oral mucosal candidiasis, as well as erosive-ulcerative and traumatic lesions [25,26]. In addition, functional impairments are observed, including difficulties with chewing, swallowing and speech, which significantly reduce patients’ quality of life [27].

Modern approaches to the treatment of xerostomia include the use of substitutes (artificial saliva), pharmacological stimulants of salivary gland secretion (e.g., cholinergic agents), as well as topical moisturizers in the form of gels, sprays and solutions [28,29,30,31]. Despite the wide range of treatments available, their clinical efficacy is often limited. Saliva substitutes are characterized by short-acting effects and require repeated application throughout the day; systemic salivary stimulants may cause undesirable side effects and have restrictions on their use; topical formulations often have poor retention on the mucous membrane, which reduces the duration of their therapeutic effect [32]. A further drawback is poor patient compliance, due to the inconvenience of using certain dosage forms [33].

In this context, a key area of focus is the development and implementation of alternative dosage forms that both stimulate physiological salivation and provide sustained release of active ingredients in the oral cavity. One promising form is medicated chewing gum (MCG), which combines mechanical stimulation of the salivary glands with the ability to deliver active pharmaceutical ingredients (APIs) in a controlled manner. Its use helps to increase the volume and buffering capacity of saliva, improve the self-cleansing processes of the oral cavity and enhance remineralization potential [34,35,36]. Furthermore, this dosage form is characterized by its ease of use and high patient adherence to treatment, making it a promising option for the prevention and symptomatic treatment of xerostomia [35,36,37,38,39].

The mechanism of MCG action in xerostomia is based on a combination of mechanical-reflex stimulation of salivation and the controlled release of APIs from a polymeric chewing matrix. During the initial stage of chewing, thermomechanical softening of the base occurs, accompanied by an increase in the diffusion mobility of the active components and the initiation of mass transfer processes. At the same time, reflex activation of the salivary glands occurs, which is critically important for patients with xerostomia, as it helps to increase saliva volume and partially restore its physicochemical properties. Further release of the active ingredients follows a diffusion-controlled mechanism, which is determined by the characteristics of the chewing base, the solubility of the active ingredients, and the intensity of chewing. The released components are distributed in saliva and ensure prolonged contact with the mucous membrane, thereby increasing local bioavailability and the efficacy of the pharmacological action. The therapeutic effect may include moisturization of the mucous membrane, normalization of the acid–base balance, modification of microbial biocenosis, and prevention of demineralization of hard dental tissues. Therefore, MCGs act as a combined delivery system, producing a synergistic effect through the combination of stimulation of physiological salivation and the controlled release of APIs, making them a promising dosage form for the prevention and symptomatic treatment of xerostomia [21,34,40,41].

In modern dentistry, symptomatic treatment of xerostomia involves the use of saliva-stimulating MCGs, which are sugar-free, xylitol-containing polymer systems, and in some cases, further enriched with organic acids or mineral components. The most common commercial products include DENTAID® Xeros Chewing Gum (DENTAID, Barcelona, Spain), Vitis® Xeros (DENTAID, Barcelona, Spain), Miradent® Aquamed Chewing Gum (Hager & Werken GmbH & Co. KG, Duisburg, Germany), Spry® Dental Defense Gum (Xlear Inc., American Fork, UT, USA), and Biotène® Dry Mouth Gum (Haleon plc, Weybridge, Surrey, UK), which are primarily based on xylitol and are marketed as adjunctive therapies for xerostomia and caries prevention. The therapeutic effect of these products is due to a combination of masticatory stimulation and the local action of xylitol and auxiliary ingredients, which helps to increase saliva production and improve subjective oral comfort in patients with xerostomia. However, their effect on the pathogenic mechanisms of xerostomia remains limited, as the absence of antimicrobial and reparative action prevents them from fully addressing the inflammatory and trophic disorders of the oral mucosa associated with this condition [42,43,44,45].

In this context, there is an obvious need to develop a combined dosage form in the MCG form containing lysozyme hydrochloride and ascorbic acid, which would address not only reduced salivation but also the secondary effects of hyposalivation. Lysozyme hydrochloride, as a component of the innate immune defense of saliva, exerts bactericidal and immunomodulatory effects through the enzymatic destruction of the cell walls of microorganisms, which helps to reduce microbial colonization and alleviate the inflammatory changes in the mucous membrane characteristic of xerostomia [46,47,48,49,50]. Ascorbic acid, with its potent antioxidant properties and role in collagen synthesis, helps to reduce oxidative stress, improve microcirculation and restore the barrier function of the oral mucosa, as well as accelerate the regeneration processes that are impaired by chronic salivary deficiency [51,52,53,54,55].

Thus, the inclusion of these active ingredients in chewing gum will enable the therapeutic effect to be extended from a purely symptomatic level to one based on pathophysiological principles, which underscores the relevance and promise of this development.

According to the literature, MCGs can be produced using methods such as melting; freezing, grinding and tabletting; extrusion; and direct compression [35,56,57]. The most promising method in pharmaceutical technology is direct compression, which ensures high dosing accuracy, uniform distribution of active ingredients, compositional stability and the absence of thermal effects. Furthermore, this method allows for the incorporation of a significant amount of excipients and the application of protective or flavour coatings. An additional advantage is its compatibility with tableting equipment, making it cost-effective and technologically convenient for the production of MCGs [34,58].

The aim of this study is the pharmaceutical development, formulation optimization and in vitro and in vivo evaluation of compressed MCGs containing lysozyme hydrochloride and ascorbic acid as a dosage form for the relief of xerostomia symptoms and the maintenance of oral health.

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Materials

APIs: lysozyme hydrochloride (Bouwhuis Enthoven B.V., Raalte, The Netherlands), ascorbic acid (Foodchem International Corporation, Shanghai, China).

Excipients: Health in Gum® (HiG®) brand PWD-01 (Cafosa Gum SA, Barcelona, Spain), sucralose (Solo Sucralose-Non Micronised NF, VB Medicare PVT. Ltd., Hosur, India), Nat Apple Flavor Wonf (Kerry Inc., Kuala Lumpur, Malaysia), Apple FLV LQD FA-BO2980 (Kerry Inc., Kuala Lumpur, Malaysia), Syloid® 244FP (Grace GmbH & Co., KG, Worms, Germany), Aerosil brand 380 (Evonik Resource Efficiency GmbH, Essen, Germany), Neusilin® ULP2 (Fuji Chemical Industry Co., Ltd., Toyama, Japan), Magnesium stearate (S.D. Fine Chemicals Ltd., Mumbai, India), ethanol 96% (pharmaceutical grade, Fabric Vilniaus degtinė, Vilnius, Lithuania).

Analytical Reagents: Lysozyme hydrochloride JP Reference Standard was obtained from Pharmaceuticals and Medical Devices Agency (PMRJ, Tokyo, Japan). A Micrococcus luteus strain was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) and used for preparation of the bacterial suspension. Potassium iodide, soluble starch, hydrochloric acid, thiobarbituric acid, trichloroacetic acid, ammonium molybdate, hydrogen peroxide (30% solution), and thiopental sodium were purchased from Sigma-Aldrich (St. Louis, MO, USA). Phosphate-buffered saline (PBS, pH 7.4) was prepared using analytical-grade reagents and purified water. All reagents were of analytical grade and used as received.

Maslii, Y.; Herbina, N.; Ruban, O.; Bernatoniene, J. Compressed Medicated Chewing Gum with Lysozyme Hydrochloride and Ascorbic Acid for Xerostomia Relief and Oral Health Support: Formulation Development, Optimization, In Vitro and In Vivo Evaluation. Pharmaceutics 2026, 18, 700. https://doi.org/10.3390/pharmaceutics18060700