A diverse population, ranging from 5.5 % to 46 % of adults, with a higher prevalence among women and the aging population, suffers from xerostomia, commonly referred to as dry mouth condition, resulting from hyposalivation or changes in the biochemical composition of saliva [1]. This condition arises from complete damage of the salivary glands or partial functionality and consequent reduction in the amount and quality of salivary secretions. Various physiological factors, including aging, contribute to salivary glands degeneration [2]. Additionally, pathological factors with a variety of underlying etiologies could also cause abnormal function of salivary glands including systemic diseases like diabetes mellitus, thyroid disorders, Sjögren’s syndrome, and infectious diseases such as bacterial, viral infections and HIV [1], [3]. Moreover, several medications with anticholinergic activity reducing the supply of acetyl choline by parasympathetic nerves, along with local pathological factors like head and neck radiation, and lifestyle factors such as tobacco, alcohol and caffeinated beverages consumption commonly contribute to hyposalivation [4], [5]. Clinical manifestations of xerostomia encompass difficulties in speaking, swallowing, chewing and taste alterations. The condition also predisposes individuals to oral candidiasis, halitosis, dental caries, and dry buccal mucosa [6], [7].

Drug and non-drug products used for xerostomia may be classified into systemic and topical formulations. Prescription drug products approved by the FDA as systemic sialagogues contain pilocarpine and cevimeline as active pharmaceutical ingredients [1]. Both compounds are muscarinic agonists that bind to the muscarinic acetyl choline receptor 3 (M3R) located in the acinus cells of salivary glands. However, due to their agonistic effect on all five muscarinic receptor subtypes they have several side effects such as sweating, increased urination, excessive lacrimation, and heart palpitations. Furthermore. They are used cautiously and/or contraindicated for individuals with pulmonary and cardiovascular diseases, hypertension, gastric ulcers, open angle glaucoma, and pregnant women. An additional concern is the short duration of action associated with the systemic treatments. For instance, a dose of 5–10 mg of pilocarpine must be administered three to four times daily due to rapid fall in plasma blood levels [8], [9].

Alternatively, non-prescription topical formulations in the form of gums, candies, sprays, mouthwashes, gels and lozenges are considered first-line interventions. These formulations can be subdivided into salivary substitutes and stimulants. Salivary substitutes contain carboxymethyl cellulose, xanathan gum and mucins to resemble natural saliva and are the treatment choice in case of salivary glands complete damage [1], [10]. Whereas, salivary stimulants act on partially functioning glands by stimulating salivary secretion either by gustatory stimulation or mechanically by chewing [11], [12].

Acidic salivary stimulants, also known as acidulants, are hydrophobic acids that are used in the treatment of xerostomia. These compounds stimulate salivary glands, prompting an increased flow rate and enhanced saliva secretion. The response is triggered by the need to neutralize the induced acidic local effect [6]. Moreover, acidulants are known to have minimal side effects and few contraindications as confirmed by a study assessing the efficacy of 1 % malic acid as a topical sialagogue spray [3].

APA is a GRAS listed ingredient used as a pharmaceutical excipient as an acidulant and flavoring agent [13]. APA was used as saliva stimulating ingredient in our previous work, which demonstrated the feasibility of coupling hot-melt extrusion (HME) and 3-dimensional printing (3DP) for the development of immediate release buccal films containing APA and xylitol, a noncariogenic sweetener, for treating xerostomia. Polyethyelene oxide N80 was employed as the carrier polymer at different drug loads of 20 %, 30 % and 40 % w/w. The formulations released 100 % of adipic acid in 30 min and were stable for 3 months under accelerated conditions [11]. Xylitol is commonly added to dry mouth formulations to stimulate saliva. For instance, Xersotrips® is a marketed buccal film that contains 300 mg of xylitol and lasts for up to 8 h [14].

The fundamental objective of the current study is to develop and characterize an extended-release mucoadhesive buccal film comprising APA, E RSPO, CBP 971P and PEG 1500. The films were produced using HME technology. Most commercially available formulations offer short-term relief which necessitates multiple administration of the dosage form and subsequent patient discomfort and noncompliance. Mucoadhesive buccal films are patient friendly dosage forms since they can easily fit into the mouth with minimal choking hazards and offer more accurate dosing and longer residence time than ointments and gels for use in the oral cavity [15], [16].

HME is a continuous and economical technology that has been widely employed in the development of buccal films [17], [18], [19] along with various types of films such as transdermal [20], vaginal [21], [22], [23] and ocular films [24], [25], [26]. Moreover, this versatile technology has been used to develop extended-release formulations such as tablets [27], caplets [28], pellets [29], floating systems [30], [31], polymeric micelles [32], and buccal films [33].

This study is the first to explore extending the release of APA in a buccal film formulation to increase the duration of action for alleviation of xerostomia symptoms. The HME buccal formulation is expected to augment mucosal retention and slowly release APA to stimulate salivary flow, thereby reducing the need for frequent administration. This novel approach presents a potential alternative treatment regimen to existing short-acting marketed formulations which do not adhere to the buccal mucosa. The formulations were optimized at the laboratory scale using the QbD concept. Within this framework, the critical quality attributes (CQAs) are defined, and integrated with the critical material attributes (CMAs) and critical process parameters (CPPs). This systematic approach is designed to obtain a thorough understanding of the formulation and processing variables, facilitating the development of an optimized buccal delivery system with enhanced performance characteristics.