Characterization of Liquid Formulations for Enhanced Buccal Permeation: Exploring Key Attributes

Abstract

Background: Buccal administration offers direct access to systemic circulation, improving drug bioavailability when compared with the conventional oral route. This advantage depends on the formulation’s ability to remain in contact with the buccal mucosa. Attributes such as adhesion and viscosity are suggested to be correlated and contribute to enhanced residence time at the administration site.

Methods: Buccal formulations with varying hydroxypropyl cellulose concentrations were prepared. Adhesion, viscosity, and residence time were assessed using a novel combined qualitative and quantitative approach. Drug permeation was evaluated in vitro using a biomimetic membrane and ex vivo using porcine buccal tissue, and it was further enhanced by adding the permeation enhancer benzalkonium chloride. Permeability measurements were integrated with residence time to estimate effective drug delivery.

Results: Increasing HPC concentration improved both adhesion and viscosity, with 2% HPCs (F2) showing the strongest effect (45.5 ± 13.7 g), correlating with longer residence time (43.4% drug retained at 2 min vs. ~20% for 0–1% HPC). Although the polymer slightly reduced apparent permeability, when residence time was considered, drug flux increased 1.6-fold compared to the polymer-free formulation (F0), rising from 12.9 × 10⁻⁵ cm/min (F0) to 19.4 × 10⁻⁵ cm/min (F2) after 2 min. The addition of BKC further enhanced permeation, with apparent permeability increasing 1.5-fold vs. F2 and 2.5-fold vs. F0.

Conclusions: Buccal liquid preparations’ efficacy is influenced by residence time and subsequent drug permeation. Residence time benefits from the synergistic effects of adhesion and viscosity, highlighting the importance of experimentally assessing these parameters during the development of oromucosal products.

Introduction

The pharmaceutical industry is strongly focused on overcoming the poor bioavailability of many drug products, which remains one of the main limitations to achieving effective orally administered therapies [1,2,3]. In this context, the oral mucosa has gained increasing recognition as an attractive alternative route of administration [4,5,6]. By enabling direct entry of the drug into the systemic circulation and bypassing hepatic first-pass metabolism, this pathway can enhance bioavailability and provide a faster onset of action [7,8]. In addition, buccal delivery offers advantages in terms of convenience, non-invasiveness, and improved patient compliance, particularly for populations with swallowing difficulties such as pediatric and geriatric patients [1,9,10,11].

Within the mucosal regions of the oral cavity, the buccal mucosa—lining the area between the gums and inner cheeks—exhibits robust vascularization, high permeability, and elevated local tolerance, with relatively low enzymatic activity [2,5]. The primary challenges associated with buccal delivery likely arise from the several factors that can impact buccal absorption, namely, the following: (i) the relatively small surface area of the buccal mucosa restricts the amount of drug that can be applied and absorbed [7,12]; (ii) the salivary washout contributes to dilution of the formulation, mechanical washout, and premature removal of the drug from the absorption site [13,14]; and (iii) the presence of mucus and membrane barriers can hinder drug permeation, particularly for molecules with unfavorable physicochemical properties. Moreover, the dynamic oral environment, characterized by mastication, speech, and swallowing, introduces mechanical stresses that further reduce formulation retention [11,14]. These factors often lower drug concentrations at the mucosal surface below therapeutic levels, thereby limiting clinical efficacy [11,15]. For these reasons, the successful development of buccal drug products must prioritize strategies that maintain prolonged contact between the dosage form and the mucosa, thereby increasing residence time and enhancing drug permeation across the buccal membrane [3,4,9,16].

While dosage forms such as tablets and films are often preferred for longer residence time, liquid formulations can provide a faster onset of action, flexible dosing, ease of administration, and improved patient comfort—features that are particularly relevant for pediatric and geriatric populations [1,17]. However, liquid systems face additional challenges, including rapid clearance and limited residence time compared to solid or semi-solid dosage forms, which have constrained their development and systematic evaluation [18,19]. Several strategies have been employed to optimize residence time and consequently enhance drug permeation, which are critical considerations in the development of effective liquid buccal drug products. Importantly, the incorporation of adhesive polymers has proven to be one of the more effective strategies [4,9].

Polymer-related properties, such as molecular weight, flexibility, swelling, and charge, among others [4], are expected to influence the adhesion capacity and mechanisms involved. The most widely investigated groups of adhesive polymers are predominantly hydrophilic [7] and are believed to swell and allow chain interactions—by Van der Walls, electrostatic, or hydrophobic reactions—with the mucin molecules on the buccal mucosal surface [7,8,20]. Nonetheless, the mechanisms of adhesion remain unclear due to their inherent complexity. Improving residence time in liquid formulations may ultimately be achieved through the synergistic effects of combining adhesive polymers with the increased solution viscosity [15,20]. Both strategies are expected to delay the removal of the formulation from the application site. Typical and well-studied adhesive polymers for this purpose include carbomers, chitosan, sodium alginate, and cellulose derivatives [16]. In particular, hydroxypropyl cellulose (HPC), a cellulose derivative, has been widely explored in oral and topical adhesive formulations [21,22]. Following an adequate residence time of the formulation, the drug substance (DS) must be able to cross the buccal mucosal membrane and reach the systemic circulation. Most compounds permeate by passive diffusion [6], adopting the route that offers the least resistance, which is influenced by drug lipophilicity. Drug lipophilicity is affected by the formulation’s pH, as it impacts the ionization degree of the DS and, consequently, its affinity for the buccal membrane. However, it is important to note that both low (pH < 4) and high (pH > 8) pH values can provoke mucosal irritation [10,23]. Additionally, other properties of DS, such as molecular weight, the number of rotational bonds, and the number of hydrogen bond donors, have been directly correlated with its permeability [24]. Formulation scientists have studied the incorporation of permeation enhancers to improve unfavorable properties of molecules or to act on the membrane itself, consequently enhancing the permeability of formulations [25].

Overall, residence time is a critical property for buccal formulation efficacy, particularly for liquid preparations, as it ensures that the formulation remains in place upon application despite the additional challenges these systems face. Adhesion and viscosity are key contributors to residence time, and their optimization may enhance drug retention and permeation. Most methodologies for assessing residence time for solid or semi-solid systems may not be easily applicable to low-viscosity liquids. Approaches to correlate formulation properties such as adhesion and viscosity remain, consequently, limited. In the present paper, we aim to evaluate the combined use of hydroxypropyl cellulose grades M and G (HPC-M and HPC-G) as adhesive polymers to improve adhesiveness, viscosity, and, consequently, residence time in liquid buccal formulations. Additionally, the potential of benzalkonium chloride (BKC) to enhance drug permeation is evaluated through in vitro and ex vivo models, correlating residence time with absorption. A combination of qualitative and quantitative approaches is employed to monitor residence time and its effect on drug delivery, providing a framework for the rational design of effective buccal formulations.

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Materials

Drug substance model—Naloxone Hydrochloride—was purchased from Noramco Inc., Wilmington, DE, USA. Klucel ™ Hydroxypropyl cellulose (HPC) MXF (HPC-M) Pharm (Ashland, OR, USA). Klucel ™ Hydroxypropyl cellulose GXF (HPC-G) Pharm (Ashland, OR, USA). Purified water (Bluepharma, Coimbra, Portugal); ethanol absolute anhydrous Carlo Erba (Val de Reuil, France); benzalkonium chloride (BKC) Spectrum Chemical MFG Corp. (New Brunswick, NJ, USA); Permeapad® phospholipid-based Barrier membranes (innoME GmbH, Espelkamp, Germany); collagen artificial gut SaborPlus (Leiria, Portugal); sodium chloride (NaCl) Merck (Darmstadt, Germany); potassium chloride (KCl), Merck (Darmstadt, Germany); disodium hydrogen phosphate (Na2HPO4), Panreac AppliChem ITW Reagents (Milano, Italy); potassium dihydrogen phosphate (KH2PO4), Panreac AppliChem ITW Reagents (Milano, Italy); hydrochloric acid 37% Fisher (Fontenay-sous-Bois, France) and ortho-phosphoric acid 85% Panreac (Darmstadt, Germany). Ammonium acetate (NH4CH3CO2), Merck (Darmstadt, Germany); ammonia solution 25% (NH4OH), Merck (Algés, Portugal); hydrochloric acid 37% (HCl), Fisher Chemical (Leicestershire, UK).

Sena, A.; Tabanez, A.; Bastos, F.; Costa, A.; Nunes, A.; Simões, S. Characterization of Liquid Formulations for Enhanced Buccal Permeation: Exploring Key Attributes. Biomedicines 2026, 14, 387. https://doi.org/10.3390/biomedicines14020387