Courtesy: Jatin Sood, PhD
Group Leader, Formulation R&D, ARx
Buccal delivery has existed for decades but remained limited to fewer than 20 FDA-approved drugs. A recent review caught my attention because it shows how formulation scientists are addressing the three technical challenges that have kept this route niche: adequate mucoadhesion, increased permeability, and protection of peptides from enzymatic degradation.
Buccal mucosa is 4–4000 times more permeable than skin, so its absorption potential has always been there. The problem was that solving one barrier while ignoring the others still produced formulations that failed. A film that sticks well but skips permeation enhancement won’t deliver hydrophilic drugs, and enzymatic protection means nothing if the molecule never crosses the epithelial barrier.
READ MORE: The Oral Thin Film Edge: 5 Strategic Advantages Pharma Leaders of the Future Are Banking On
The Three Barriers That Kept Buccal Delivery Niche
Barrier 1: Inadequate Mucoadhesion
Upon application, even simple activities like talking and saliva flow continuously dislodge dosage forms before enough drug crosses the epithelial barrier. Traditional mucoadhesives rely on electrostatic interactions with negatively charged sialic acid in mucin. Initial adhesion is strong, but mechanical forces and saliva flow weaken the bond.
Barrier 2: Epithelial Permeation
The buccal epithelium blocks foreign substances by design. Small lipophilic drugs under 500 Daltons cross without much help. Hydrophilic compounds with molecular weights above 1000 Daltons can’t reach therapeutic concentrations in circulation.
This is why peptide delivery through buccal thin films struggled for years. The molecules that pharmaceutical development increasingly focuses on can’t cross the barrier without formulation intervention.
Barrier 3: Enzymatic Degradation
Aminopeptidases and carboxypeptidases in saliva attack peptide bonds and degrade peptides before absorption occurs, even when permeation would otherwise allow it.
Current Advances
Each of those barriers has a solution now. What changed is that formulation science developed approaches that address all three together rather than trading one problem for another.
Mucoadhesive Polymers That Actually Stay Put
The adhesion problem came down to bond strength. Thiolated polymer derivatives form covalent disulfide bonds with cysteine residues in mucin, rather than relying on the weak electrostatic forces that earlier mucoadhesives depended on. Chitosan-cysteine conjugates achieve mucoadhesion 4x stronger than unmodified chitosan, which is the difference between a dosage form that maintains contact long enough to work and one that doesn’t.
Penetration Enhancers That Work Without Tissue Damage
Beyond mucoadhesive strength, chitosan derivatives also enhance permeation by widening tight junctions, facilitating paracellular transport, and enabling the absorption of hydrophilic molecules that conventional buccal formulations cannot deliver. Bile salts and fatty acids temporarily disrupt lipid organization, with barrier function restoring within hours and no lasting impact on epithelial integrity.
In a specific example, methylpyrrolidinone-chitosan derivatives increased acyclovir permeation across porcine buccal mucosa without affecting cell viability in the TR146 human buccal epithelial cell line, confirming that enhanced flux doesn’t require sacrificing biocompatibility.
Systems That Prevent Enzymatic Degradation
Degradation occurs when proteases, esterases, or other metabolic enzymes bind and cleave drug molecules. Polymers interrupt this process by physically blocking enzyme access, limiting diffusion toward the active moiety, and forming a viscoelastic barrier that traps enzymes before they can cleave the API.
Dual-function polymers inhibit aminopeptidases while simultaneously enhancing flux, addressing enzymatic degradation and absorption barriers with a single excipient rather than requiring multiple separate formulation interventions.
Studies demonstrate that these multi-barrier approaches achieve the bioavailability gains that make previously unviable compounds feasible. Thiolated chitosan handles multiple problems at once. The polymer binds to mucin via disulfide bonds while simultaneously complexing with zinc ions required for aminopeptidase function. This keeps peptides intact while opening paracellular pathways for absorption.
When Buccal Delivery Actually Makes Sense
The advances above don’t make buccal delivery universal, as molecular weight limits, chemical constraints, and dose restrictions still apply. But, they do expand the range of viable compounds, and certain candidate profiles benefit directly when oral routes fail.
Bypassing First-Pass Metabolism
Some small molecules undergo more than 80% hepatic clearance. When oral bioavailability is below 20% due to first-pass metabolism, increasing the dose only adds side effects without improving efficacy. Buccal absorption enters the circulation via the jugular vein without encountering hepatic enzymes, thereby altering the viability of compounds with high hepatic clearance.
Protecting Peptides from GI Degradation
GI enzymes break down most peptides and proteins before they reach the circulation. Gastric pH denatures the molecule while enzymatic degradation continues throughout the GI tract. Buccal absorption avoids both, and nanocarrier systems add protection against salivary enzymes. Peptides that fail orally can reach circulation intact when formulations provide enzymatic protection and permeation enhancement.
Speed Matters for Acute Conditions
Breakthrough pain, migraine therapy, and acute seizure management need therapeutic plasma levels within minutes, not the 30–60 minutes typical for oral absorption. Direct jugular vein access delivers the drug quickly enough to be clinically meaningful.
Solving Swallowing Problems
Elderly patients, pediatric populations, and people undergoing cancer treatment often struggle with oral medications. Films eliminate the swallowing barrier while simplifying medication schedules. One application that replaces multiple daily doses matters, especially when cognitive load or physical limitations affect adherence.
Achieving Predictable Drug Levels
For molecules whose pharmacokinetic profile is sensitive to food intake or gastrointestinal variability, buccal delivery removes those confounding factors at the source, producing more consistent absorption than oral routes can reliably offer.
What Separates Success from Failure in Buccal Development
Multiple active clinical programs for palonosetron and montelukast prove the commercial path exists. What separates products that reach the market from those that fail in development is recognizing early that addressing mucoadhesion, permeation, or enzymatic degradation in isolation won’t work for complex molecules.
Formulation teams that solve one barrier at a time end up troubleshooting failures that originated from incomplete barrier assessment. Teams that design formulations to address all three simultaneously from the start of development build products that work at commercial scale for molecular candidates that struggle through conventional oral routes.
ARx is a patient-friendly, novel drug delivery partner specializing in oral thin film and transdermal patch strategies. Contact us to discuss buccal formulation strategies for your API.