Protein Delivery Using Three-Dimensional Printing of Buccal Films: Technological Advances and Clinical Potential

Abstract

Therapeutic proteins have emerged as a cornerstone of modern medicine due to their high specificity and strong biological effects. However, delivering these proteins poses significant challenges due to their instability, susceptibility to enzymatic breakdown, low permeability, and reliance on invasive parenteral routes.

Buccal drug delivery is a promising non-invasive alternative, offering quick systemic absorption while avoiding gastrointestinal degradation and hepatic first-pass metabolism. Three-dimensional (3D) printing as a fabrication method has further enhanced the potential of buccal delivery, enabling precise dosage control, multilayer structures, and patient-specific customization.

This review focuses on the current state of the traditional and 3D-printed buccal film platforms using different printing methods for protein delivery, and critically analyzes protein stability challenges, and formulation strategies. The discussion further highlights emerging proof-of-concept studies.

Introduction

Proteins are biologically abundant macromolecules composed of amino acids linked by peptide bonds and capable of adopting structures ranging from simple linear chains to highly complex three-dimensional conformations [1]. Therapeutic proteins, including hormones (like insulin and growth hormone), monoclonal antibodies, cytokines and interferons, enzymes used in replacement therapy, growth factors, fusion proteins, blood factors, and protein-based vaccines, have transformed modern pharmacotherapy because of their high specificity, strong biological activity, and relatively low off-target toxicity [2,3]. Conventionally, protein-based therapeutics are delivered through the parenteral route due to the numerous physiological and formulation challenges that hinder effective oral administration [3,4]. However, repeated doses/injections are associated with pain, infection risk, increased healthcare burden, and compromise on drug adherence at the site to elicit a therapeutic response [3,5,6]. The drug delivery to the buccal mucosa has attracted increasing attention over the past two decades as an attractive site for the delivery of macromolecules [7].

Buccal delivery offers a promising non-invasive route for systemic administration of macromolecules, bypassing gastrointestinal and hepatic first-pass metabolism, and is suitable for a range of therapeutic applications (Figure 1). It provides several advantages, such as relative physical robustness, easy accessibility, and the potential for rapid onset along with improved patient adherence [7,8]. However, the delivery remains challenging due to limited permeability, dynamic salivary environment, continuous salivary washout, restrictions on drug loading, and the inherent fragility of proteins, resulting in low bioavailability and complex formulation requirements [3,7]. To overcome these barriers, strategies like mucoadhesive polymers, permeation enhancers, enzyme inhibitors, and nanocarriers have been investigated to protect proteins and enhance mucosal transport [3,6,7].

Conventional manufacturing of buccal films by solvent casting or hot-melt extrusion offers limited flexibility for dose customization and internal structure [7,9]. In contrast, three-dimensional (3D) printing technologies allow precise control over film geometry, spatial distribution of APIs and excipients, multilayer or compartmentalized designs, and on-demand, patient-specific doses (Figure 1, Table 1) [7,10]. Importantly, semi-solid extrusion printing can be performed under mild processing conditions, making it particularly suitable for protein and peptide delivery by minimizing degradation and preserving biological activity. This review highlights technological progress and the clinical potential of 3D-printed buccal films for protein delivery, focusing on formulation approaches, 3D printing techniques, and related proof-of-concept studies.

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5.1. Materials Selection and Manufacturing Processes of Protein-Loaded Buccal Films

5.1.1. Formulation Development and Material Selection

The initial stage involves choosing film-forming and mucoadhesive polymers that enable printable formulations without compromising protein integrity. Common polymers include hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), chitosan, sodium alginate, and Carbopol. These polymers ensure adequate mechanical strength, flexibility, and adhesion to the buccal mucosa. Plasticizers such as glycerol and polyethylene glycol (PEG) are added to enhance film flexibility and reduce brittleness. Protein stabilizers, including trehalose, sucrose, mannitol, and amino acids, are often included to protect protein structure during manufacturing and storage. Additional excipients, such as permeation enhancers, buffering agents, and viscosity modifiers, may also be included depending on the desired therapeutic outcome [63,64].

Appidi, T.; Anekalla, T.R.; Chede, S.; Chakka, L.R.J.; Maniruzzaman, M. Protein Delivery Using Three-Dimensional Printing of Buccal Films: Technological Advances and Clinical Potential., Pharmaceutics 2026, 18, 789. https://doi.org/10.3390/pharmaceutics18070789

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