75 Years of Under-the-Tongue Medicine: What Sublingual Delivery Can Do

Sublingual and buccal drug delivery occupies a unique pharmacological niche: drugs placed under the tongue or against the cheek absorb directly into the rich vascular network of the oral mucosa, entering systemic circulation without passing through the gastrointestinal tract or undergoing first-pass hepatic metabolism. This review from Bahraminejad and Almoazen at the University of Tennessee Health Science Center provides a sweeping bibliometric and scientific analysis of this field from 1950 to 2025, identifying four distinct publication growth phases using PubMed as the primary data source, supplemented by Scopus, Web of Science, and regulatory documents from the FDA, EMA, and WHO.

The earliest phase (1950–1982) was characterized by exploratory and largely unsuccessful attempts. Sublingual heparin failed due to unreliable absorption across 30–40 cellular layers to reach lamina propria vasculature. Buccal alpha-amylase as an anti-inflammatory was abandoned because of the molecule's large size and negligible mucosal permeability. Propranolol absorption kinetics via the sublingual route showed first-order kinetics but significant inter-subject variability. These failures were instructive, revealing the fundamental physicochemical requirements — small molecular weight, adequate lipophilicity, and stability in the oral environment — that would guide future development.

The exploratory growth phase (1983–1993) brought the field's first major clinical successes. Sublingual and buccal nitroglycerin became cornerstones of angina management, with buccal NTG (Susadrin) offering sustained release over several hours despite its eventual commercial failure. Sublingual nifedipine demonstrated approximately 98% efficacy in reaching target blood pressure in hypertensive emergencies, while sublingual captopril provided faster time to peak concentration than oral administration. Buccal verapamil, despite oral bioavailability of only 10–20%, achieved pharmacokinetic profiles resembling intravenous administration. Opioid research intensified as clinicians sought alternatives to injections for cancer pain; buprenorphine and fentanyl emerged as promising candidates due to their high lipophilicity and favorable mucosal absorption under alkaline pH conditions.

The diversification and discovery phase (1994–2009) introduced small molecules for opioid use disorder, expanded animal model pharmacokinetic studies, and saw the first meaningful FDA approvals in this space. Penetration enhancers — including fatty acids, bile salts, and surfactants — were systematically studied to overcome the lipophilic mucosal barrier for peptides and hormones. Permeability coefficients for peptides like thyrotropin-releasing hormone and desmopressin were shown to be significantly lower than those of small lipophilic molecules, quantifying the challenge. Mucoadhesive patches and controlled-release tablets capable of delivering hormones over 6–12 hours emerged as practical solutions to salivary washout.

The innovation and integration phase (2010–2025) represents the most technologically sophisticated era. Nanoparticle-based systems, multilayered mucoadhesive films, and fast-dissolving pediatric formulations have expanded the therapeutic range dramatically. FDA-approved products now include novel fentanyl formulations for breakthrough cancer pain, diazepam nasal and buccal products for seizure rescue, sublingual buprenorphine for opioid use disorder, and buccal vitamin D3 sprays. Immunotherapy and vaccine delivery via the oral mucosa represent a frontier application. The review notes that the oral mucosa's non-keratinized sublingual tissue is more permeable than buccal tissue, making it preferable for rapid-onset drugs, while the relatively immobile buccal mucosa is better suited for sustained-release mucoadhesive systems.

Clinically, the review underscores that drug candidates best suited for this route share key properties: molecular weight below approximately 500 Da, adequate lipophilicity (log P 1–3), stability at oral pH, and low enzymatic susceptibility. Persistent challenges include the small absorptive surface area, continuous salivary dilution and clearance, patient discomfort with prolonged retention devices, and the unsuitability of the route for cognitively impaired or comatose patients. The authors conclude that sublingual and buccal delivery represents a growing, clinically meaningful alternative to oral and parenteral routes, with particular relevance for drugs requiring rapid onset, first-pass avoidance, or GI-bypass.