Intraoral Drug Delivery: Bridging the Gap Between Academic Research and Industrial Innovations
Abstract
Intraoral delivery of active pharmaceutical ingredients (API) is an attractive approach to improve their local therapeutic efficacy or to enable their systemic delivery. It offers several advantages, such as high drug concentration at the intraoral target site and rapid access to the systemic circulation due to high vascularization of the oral cavity, bypassing first-pass metabolism. However, several limitations need to be addressed, such as the relatively short residence time of formulations applied in the oral cavity due to salivation, swallowing reflex, and tongue movement, as well as poor membrane permeability of, in particular, hydrophilic drugs. Within this review, a comprehensive summary of the latest strategies and formulation approaches in the field of intraoral drug delivery is provided, focusing on those pursued by academia and industry to overcome those challenges. An overview is provided of excipients that are generally recognized as safe (GRAS) and utilized to enhance the efficacy of intraoral drug delivery systems, such as mucoadhesive materials, enzyme inhibitors, and permeation enhancers. Innovative pharmaceutical dosage forms are outlined, covering solid, semi-solid, and liquid delivery systems as well as aerosols. Future trends, including self-emulsifying systems, microneedles, and in situ bioprinting, are explored, presenting new opportunities for intraoral drug delivery.
Introduction
In the dynamic landscape of pharmaceuticals, the relentless pursuit of optimizing drug delivery systems stands as a crucial endeavor, shaping therapeutic efficacy, patient adherence, and overall treatment outcomes. In this context, intraoral drug delivery, owing to its numerous advantages such as rapid onset of action, avoidance of hepatic first-pass metabolism, and improved patient compliance, has emerged as a promising frontier in the quest for more effective and patient-friendly therapeutic interventions.[1, 2] The oral cavity, with its unique anatomy and physiology, offers a promising avenue for targeted drug administration.[3, 4] This targeted approach not only enhances bioavailability but also pioneers new possibilities for personalized medicine, tailoring treatments to the specific needs of individual patients. There are two main subcategories of intraoral drug delivery: topical treatment and transorally mucosal delivery. Topical treatment is primarily linked to the therapy of gingivitis, buccal lesions, caries, and bacterial infections, highlighting its significant clinical utility [5-7] whereas transoral mucosal delivery has emerged as a prominent method for addressing conditions such as xerostomia, hypertension, diabetes, and more.[8-10]
Industrial interest in the development of intraoral delivery systems is high. A recent analysis published by Globe News wire in September 2024 highlighted the market’s impressive growth, with a compound annual growth rate of 4.88% from 2020 to 2023 just for buccal delivery systems. In 2023, the market was valued at USD 36 billion, and it is projected to rise significantly, reaching USD 55 billion by 2030.[11] Challenges in intraoral drug delivery are related to prolonged residence time on the mucosa and controlled drug release. The drug must be retained in the oral cavity and subsequently released from the formulation to achieve an enhanced local therapeutic effect.[12, 13] Intraoral residence time of dosage forms is limited due to the physiological removal mechanism of the oral cavity. Most of them are quickly washed away, leading to short retention times, uneven drug distribution, and an initial burst followed by a rapid drop below therapeutic levels. Mucosal residence time is often just minutes, with saliva flushing the drug into the stomach.[14]
Degradation of APIs by salivary enzymes or mucosal membrane-bound enzymes is for certain drugs another challenge[15-17] particularly for peptide-based drugs and biologics. Moreover, poor or variable permeability of the intraoral mucosa add complexity to achieve consistent and predictable drug absorption. To overcome these challenges, the use of mucoadhesive materials, enzyme inhibitors, and permeation enhancers is considered a promising approach. To better contextualize intraoral drug delivery, it is essential to compare its characteristics with other mucosal administration routes, including gastrointestinal (GI), ocular, nasal, and pulmonary delivery. Each route presents distinct physiological environments that influence drug absorption, permeability, enzymatic degradation, and retention. Additionally, the target modality of drug formulations—whether small molecules, peptides, biologics, or nucleic acids—plays a critical role in determining the feasibility and effectiveness of each mucosal delivery system. A comparative summary of these factors is provided in Table 1, offering a structured overview of the key differences among mucosal drug delivery routes.
Table 1. Comparison of mucosal drug delivery routes
| Characteristics | Intraoral | Oral | Ocular | Nasal | Pulmonary |
|---|---|---|---|---|---|
| Absorption Pathway | Transmucosal | Gastrointestinal | Corneal/conjunctival | Transmucosal (nasal epithelium) | Alveolar |
| Enzymatic Degradation | Low (salivary and membrane-bound enzymes) | High (acidic pH and enzymatic degradation in stomach/intestine) | Low to moderate (ocular enzymes) | Moderate (nasal enzymes) | Moderate (lung enzymes) |
| Residence Time | Short (minutes) | Long (hours) | Very short (seconds to minutes) | Short (minutes to an hour) | Moderate (hours) |
| Permeability | Moderate | Variable (depends on formulation and intestinal absorption) | Low | High | High |
| Targeted Drug Modalities | Small molecules, peptides, biologics | Small molecules, peptides (limited), biologics (rare) | Small molecules, peptides (limited), biologics (rare) | Small molecules, peptides, biologics, vaccines | Small molecules, peptides, biologics, RNA/DNA therapies |
| Advantages | Rapid onset, avoids first-pass metabolism, high patient compliance | Well-established, convenient, large absorption area | Localized delivery, avoids systemic side effects | Rapid systemic absorption, avoids first-pass metabolism, potential for CNS targeting | Large surface area, rapid absorption, direct targeting for respiratory diseases |
| Challenges | Short retention time, enzymatic degradation, variable permeability | First-pass metabolism, enzymatic degradation, variability in absorption | Poor permeability, rapid drainage, low bioavailability | Limited drug load, mucociliary clearance, potential irritation | Device-dependent delivery, mucociliary clearance, formulation challenges |
This review provides a comprehensive overview of these auxiliary agents, innovative formulation approaches, and technological solutions that have shaped the landscape of intraoral drug delivery. Bridging the gap between academic research and industrial innovations should contribute to our overall understanding for the development of even more efficient formulations.
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Soheil Haddadzadegan, Simona Summonte, Fabrizio Ricci, Matthias Sandmeier, Andreas Bernkop-Schnürch, F, Intraoral Drug Delivery: Bridging the Gap Between Academic Research and Industrial Innovations, First published: 11 April 2025, https://doi.org/10.1002/adfm.202500157