Sublingual and Buccal Delivery: A Historical and Scientific Prescriptive
Abstract
1. Introduction
1.1. The Early Phase of Sublingual and Buccal Drug Delivery (1950–1982)
1.2. Exploratory Growth Phase (1983–1993)
1.3. Diversification and Discovery Phase (1994–2009)
1.4. Innovation and Integration Phase (2010–2025)
2. Future Directions
3. Conclusions
Funding
Conflicts of Interest
List of Abbreviations
ACE inhibitor | Angiotensin-Converting Enzyme Inhibitor |
FDA | Food and Drug Administration |
EMA | European Medicines Agency |
WHO | World Health Organization |
BN | Buccal Nitroglycerin |
SLGTN | Sublingual Glyceryl Trinitrate |
BGTN | Buccal Glyceryl Trinitrate |
NTG | Nitroglycerin |
TRH | Thyrotropin-Releasing Hormone |
GLP-1 | Glucagon-Like Peptide-1 |
FITC-dextran | Fluorescein Isothiocyanate-Dextran |
ISMO | Isosorbide Mononitrate |
APIs | Active Pharmaceutical Ingredients |
Tmax | Time to Maximum Plasma Concentration |
AUC | Area Under the Curve |
LEV-INS | Liposome-Encapsulated Insulin |
SLIT | Sublingual Immunotherapy |
BEMA® | BioErodible MucoAdhesive |
REMS | Risk Evaluation and Mitigation Strategy |
PEG | Polyethylene Glycol |
ALKS 5461 | (No abbreviation; this is a drug code for a specific investigational medication) |
VLPs | Virus-Like Particles |
CTB | Cholera Toxin B |
APC | Antigen-Presenting Cells |
CYP3A4 | Cytochrome P450 3A4 |
mRNA | Messenger Ribonucleic Acid |
RX | Prescription only |
OTC | Over the counter |
DISCN | Discontinued |
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Prodrug | Benefit | Mechanism |
---|---|---|
Nitroglycerin | Enhanced sublingual membrane permeability | Enhanced physical chemical properties such as low molecular weight and high lipophilicity improved permeability across sublingual membrane |
Isosorbide mononitrate | Metabolite activation post-absorption | Designed to remain stable during transit and become activated after mucosal uptake |
Methyl testosterone | Protection from enzymatic degradation | Enhanced stability in the oral cavity before reaching systemic circulation |
Drug Name | Brand Name | Delivery Type | Company | Indication | Therapeutic Class | Status |
---|---|---|---|---|---|---|
House dust mites allergen extract | Acarizax® | Fast-dissolving tablet (Sublingual, Lyophilized) | ALK-Abelló (Horsholm, Denmark) | Allergic rhinitis; Asthma | Allergen immunotherapy | RX |
Actair® | Tablet (Sublingual) | Stallergenes Greer (Antony, France) | ||||
Grass pollen allergen extract | Grazax® | Fast-dissolving tablet (Sublingual, Lyophilized) | ALK-Abelló (Horsholm, Denmark) | Seasonal allergy | Allergen immunotherapy | RX |
Betula verrucosa allergen extract | Itulazax® | Fast-dissolving tablet (Sublingual, Lyophilized) | ALK-Abelló (Horsholm, Denmark) | Allergic rhinitis; Conjunctivitis | Allergen immunotherapy | RX |
Short ragweed pollen allergen extract | Ragwizax® | Fast-dissolving tablet (Sublingual, Lyophilized) | ALK-Abelló (Horsholm, Denmark) | Allergic rhinitis; Conjunctivitis | Allergen immunotherapy | RX |
Fentanyl citrate | Recivit® | Tablet (Sublingual) | Grünenthal GmbH (Aachen, Germany) | Breakthrough cancer pain | Opioid analgesic | RX |
Sublivac | Sublivac® | Drop (Sublingual) | HAL Allergy Group (Leiden, The Netherlands) | Allergic rhinitis; Conjunctivitis | Allergen immunotherapy | RX |
Buprenorphine + Naloxone | Zubsolv® | Tablet (Sublingual) | Orexo AB (Uppsala, Sweden) | Opioid dependence | Opioid agonist/antagonist | RX |
Drug Name | Brand Name | Delivery Type | Company | Date of Approval | Bioavailability | Indication | Therapeutic Class | Status |
---|---|---|---|---|---|---|---|---|
Methyltestosterone | METANDREN | Tablet (Buccal/Sublingual) | Novartis Pharmaceuticals Corp. (East Hanover, NJ, USA) | Prior to 1 January 1982 | ~40% (buccal) | Male hypogonadism | Androgen | DISCN |
Ergoloid mesylates | HYDERGINE | Tablet (Sublingual) | Sanofi Aventis US LLC. (Bridgewater, NJ, USA) | Prior to 1 January 1982 | Not well quantified | Dementia, cognitive impairment | Ergot Alkaloid | DISCN |
Isoproterenol hydrochloride | ISUPREL | Tablet (Sublingual/Rectal) | Organon USA Inc. (Jersey City, NJ, USA) | Prior to 1 January 1982 | Not well quantified | Heart block, cardiac arrest, bronchospasm | Beta-Adrenergic Agonist | DISCN |
Ergotamine tartrate | WIGRETTES | Tablet (Sublingual) | Biovail Laboratories Inc. (Bridgetown, Barbados) | 29 July 1982 | ~2% | Migraine | Ergot Alkaloid | DISCN |
Isosorbide dinitrate | ISORDIL | Tablet (Sublingual) | Pohl Boskamp (Hohenlockstedt, Germany) | 29 July 1988 | ~25% | Angina | Nitrate Vasodilator | DISCN |
Nitroglycerin | NITROLINGUAL | Aerosol, Metered (Sublingual) | Pohl Boskamp (Hohenlockstedt, Germany) | 31 October 1985 | ~40% | Angina | Nitrate Vasodilator | DISCN |
NITROLINGUAL PUMPSPRAY | Spray, Metered (Sublingual) | Viatris Specialty LLC. (Morgantown, WV, USA) | 10 January 1997 | ~40% | RX | |||
NITROSTAT | Tablet (Sublingual) | Haleon US Holdings LLC. (Warren, NJ, USA) | 1 May 2000 | ~40% | RX | |||
Nicotine polacrilex | NICORETTE | Chewing Gum (Buccal) | Noven Pharmaceuticals Inc. (Miami, FL, USA) | 9 February 1996 | ~65–80% (buccal) | Smoking cessation | Nicotinic Agonist | OTC |
Lidocaine | DENTIPATCH | Film, Extended Release (Buccal) | Indivior Inc. (North Chesterfield, VA, USA) | 21 May 1996 | ~75% (localized buccal) | Local anesthesia | Local Anesthetic | DISCN |
Buprenorphine hydrochloride | SUBUTEX | Tablet (Sublingual) | BioDelivery Sciences Intl. Inc. (Raleigh, NC, USA) | 8 October 2002 | ~30–50% | Opioid dependence | Partial Opioid Agonist | DISCN |
BELBUCA | Film (Buccal) | Auxilium Pharmaceuticals LLC. (Malvern, PA, USA) | 23 October 2015 | ~15% (buccal) | RX | |||
Testosterone | STRIANT | Tablet, Extended Release (Buccal) | Cephalon LLC. (West Chester, PA, USA) | 19 June 2003 | ~30% (buccal) | Male hypogonadism | Androgen | DISCN |
Fentanyl citrate | FENTORA | Tablet (Buccal/Sublingual) | Adalvo Ltd. (San Gwann, Malta) | 25 September 2006 | ~65% (buccal) | Breakthrough cancer pain | Opioid Analgesic | DISCN |
ONSOLIS | Film (Buccal) | Allergan Sales LLC. (Irvine, CA, USA) | 16 July 2009 | ~65% (buccal) | DISCN | |||
Asenapine maleate | SAPHRIS | Tablet (Sublingual) | Viatris Specialty LLC. (Morgantown, WV, USA) | 13 August 2009 | ~35% | Schizophrenia, Bipolar Disorder | Atypical Antipsychotic | RX |
Zolpidem tartrate | EDLUAR | Tablet (Sublingual) | Indivior Inc. (North Chesterfield, VA, USA) | 13 March 2009 | ~70% | Insomnia | Sedative-Hypnotic | RX |
Buprenorphine/ naloxone | SUBOXONE | Film (Buccal/Sublingual) | Galt Pharmaceuticals LLC. (Atlanta, GA, USA) | 30 August 2010 | ~15% (buccal) | Opioid dependence | Opioid Agonist/Antagonist | RX |
Miconazole | ORAVIG | Tablet (Buccal) | Ligand Pharmaceuticals Inc. (San Diego, CA, USA) | 16 April 2010 | ~10% (buccal) | Oral candidiasis | Antifungal | RX |
Acyclovir | SITAVIG | Tablet (Buccal) | Ferring Pharmaceuticals Inc. (Parsippany, NJ, USA) | 12 April 2013 | ~30–50% (buccal) | Herpes labialis | Antiviral | RX |
Desmopressin acetate | NOCDURNA | Tablet (Sublingual) | Sumitomo Pharma America Inc. (Brisbane, CA, USA) | 21 June 2018 | ~0.25% (very low) | Nocturia | Vasopressin Analog | DISCN |
Apomorphine HCl | KYNMOBI | Film (Sublingual) | BioXcel Therapeutics Inc. (New Haven, CT, USA) | 21 May 2020 | ~17% | Parkinson’s episodes | Dopamine Agonist | DISCN |
Dexmedetomidine HCl | IGALMI | Film (Buccal/Sublingual) | Novartis Pharmaceuticals Corp. (East Hanover, NJ, USA) | 5 April 2022 | Not publicly available | Acute agitation | Alpha-2 Adrenergic Agonist | RX |
Phase | Timeframe | Milestone/Innovation | Significance/Influence |
---|---|---|---|
Pioneering Efforts (1950–1982) | 1950s | Buccal delivery of steroids | Bypassed hepatic first-pass; reduced injection dependency—foundational step for mucosal delivery. |
1970s | Propranolol sublingual absorption studies | Validated mucosal route for systemically active drugs; influenced later systemic delivery strategies. | |
1970s | Bioelectric mucosal studies (aspirin, ethanol) | Revealed drug–mucosa interactions, guiding formulation strategies and penetration enhancer exploration. | |
Exploratory Growth (1983–1993) | 1980s | Buccal/sublingual nitroglycerin (NTG) | Rapid relief for angina; inspired mucosal delivery in cardiovascular therapies. |
1980s | Nifedipine and Verapamil mucosal delivery | Enabled non-invasive emergency hypertension care; mimicked IV drug profiles. | |
Late 1980s | Sublingual captopril | Accelerated therapeutic onset for hypertensive crises; bypassed GI absorption. | |
1980s–1990s | Opioid exploration (morphine, fentanyl, buprenorphine) | Highlighted delivery challenges; spurred safer, more efficient transmucosal narcotic systems. | |
Early 1990s | Peptide drug delivery studies | Exposed enzymatic barriers and low permeability; led to interest in nanoparticles and enhancers. | |
Early 1990s | Transmucosal hormone systems (e.g., buccal testosterone) | Validated hormone delivery; emphasized role of pH, cosolvents, and formulation design. | |
Early 1990s | Adhesive patches and controlled-release tablets | Sustained hormone delivery (6–12 h); improved compliance and set standards for future platforms. | |
Diversification & Discovery (1994–2009) | Late 1990s | Buprenorphine, fentanyl, oxycodone mucosal delivery | Expanded use for pain and opioid use disorder; validated mucosal route for potent narcotics. |
Late 1990s | Buccal testosterone and estrogens | Proven hormone absorption via mucosa; led to improved hormone replacement designs. | |
Late 1990s | Mucoadhesive platforms (Cydot®, OTS® tablets) | Enabled controlled release of peptides like GLP-1; emphasized comfort and patient adherence. | |
Late 1990s–2000s | Peptide and protein drug trials (e.g., insulin, TRH) | Highlighted low permeability and enzymatic degradation; spurred interest in enhancers and nanoparticles. | |
Early 2000s | Misoprostol sublingual vs buccal pharmacokinetics | Achieved faster onset and greater bioavailability via sublingual route; refined labor protocols. | |
2000s | Liposomal buccal delivery systems | Encapsulated peptides; enhanced retention and enzymatic stability with mucoadhesive support. | |
2000s | SLIT immunotherapy validation (e.g., Grazax®) | Efficacy confirmed by meta-analysis; enabled EU approval for grass pollen allergies. | |
2000s | Human trials for buccal GLP-1, fentanyl lollipops | Demonstrated reliable absorption and clinical viability for mucosal delivery. | |
2000s | Taste improvement and patient-centric formulations | Prioritized usability, mouthfeel, and adherence in buccal systems. | |
Innovation & Integration (2010–2025) | Early 2010s | Breakyl® and Onsolis® (BEMA® buccal fentanyl films) | Enabled fast and discreet cancer pain therapy with bioerodible buccal films. |
Early 2010s | RapidMist™ buccal insulin spray (Generex Oral-lyn®) | Delivered insulin non-invasively; reduced HbA1c with high safety profile. | |
2010s | Subsys®, Abstral®, Buccolam®, Intermezzo® approvals | Validated transmucosal delivery for pain, seizures, insomnia, and pediatric emergencies. | |
2010s | Suboxone® buccal tablets and sublingual film (PharmFilm®) | Improved treatment for opioid dependence; minimized misuse risk. | |
2010s | Sativex® THC/CBD buccal spray | Approved for MS-related spasticity; expanded therapeutic cannabinoids in mucosal formats. | |
2010s | Chemical and physical enhancers (DDAIP HCl, iontophoresis, etc.) | Increased mucosal permeability for various agents; unlocked new delivery targets. | |
2010s | IntelliDrug intraoral device | Provided continuous electronic dosing; ideal for neurodegenerative conditions. | |
2010s–2020s | Nanoparticle systems (PEG-coated, lipid/polymer) | Enhanced bioavailability and lymphatic uptake; enabled mucosal nano-formulations. | |
2010s–2020s | Optimized misoprostol sublingual delivery | Superior pharmacokinetics improved labor induction protocols. | |
2013–2017 | Nanoparticle penetration studies (Teubl, Roblegg, Masek) | Size, charge, and formulation critically influenced mucosal transport. | |
2020s | Ropivacaine liposomal gel in Phase I trials | Validated nanoparticle-based anesthetic via buccal route. | |
2020s | Expanded drug indications (e.g., lorazepam, melatonin, etc.) | Demonstrated versatility across neurology, cardiology, psychiatry, and endocrinology. | |
2020s | New dosage formats (films, lozenges, gels, sprays) | Boosted ease of use, comfort, and water-free administration. | |
2020s | Mucoadhesive polymers (e.g., chitosan, hyaluronic acid) | Enhanced mucosal retention and drug absorption; improved formulation consistency. | |
2020s | Vaccine delivery via buccal/sublingual routes | Achieved systemic and mucosal immunity; safer and pain-free alternatives to nasal/injection. | |
2020s | VLPs, viral vectors, needle-free systems (e.g., MucoJet, microneedles) | Boosted antigen retention and immune activation; demonstrated clinical safety. | |
2020s | Imaging advances (confocal, fluorescence, tissue clearing) | Enabled real-time visualization of antigen delivery and lymphatic activation. |
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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Bahraminejad, S.; Almoazen, H. Sublingual and Buccal Delivery: A Historical and Scientific Prescriptive. Pharmaceutics 2025, 17, 1073. https://doi.org/10.3390/pharmaceutics17081073
Bahraminejad S, Almoazen H. Sublingual and Buccal Delivery: A Historical and Scientific Prescriptive. Pharmaceutics. 2025; 17(8):1073. https://doi.org/10.3390/pharmaceutics17081073
Chicago/Turabian StyleBahraminejad, Sina, and Hassan Almoazen. 2025. "Sublingual and Buccal Delivery: A Historical and Scientific Prescriptive" Pharmaceutics 17, no. 8: 1073. https://doi.org/10.3390/pharmaceutics17081073
APA StyleBahraminejad, S., & Almoazen, H. (2025). Sublingual and Buccal Delivery: A Historical and Scientific Prescriptive. Pharmaceutics, 17(8), 1073. https://doi.org/10.3390/pharmaceutics17081073