Subscribe to RSS
DOI: 10.1055/a-2560-9884
Drug Delivery Approaches for Buccal and Sublingual Administration

Abstract
Both local and systemic medication delivery benefit greatly from the sublingual and buccal modes of administration. They have shown to be a successful substitute for the conventional oral route, particularly in situations requiring a quick commencement of action. Via venous drainage to the superior vena cava, drugs can enter the systemic circulation quickly and directly. They are therefore helpful for individuals who have trouble swallowing as well as for medications that are highly cleared by the liver or degraded in the gastrointestinal system. Traditionally, medications that are delivered through the buccal and sublingual channels are made in three different dose forms: liquid (such as sprays and drops), semi-solid (such as gels), and solid (such as pills, wafers, films, and patches). Physiological variables frequently influence conventional dose forms, which might decrease the formulation’s interaction with the mucosa and result in unexpected medication absorption. Many formulation development advancements have been made to enhance medication absorption and retention in the buccal and sublingual areas. The physiological factors influencing buccal and sublingual drug delivery as well as developments in nanoparticulate drug delivery techniques for sublingual and buccal administration will be the main topics of this review. It also discusses about the clinical development pipeline, which includes formulations that have been authorized and are undergoing clinical studies.
Publication History
Received: 05 January 2025
Accepted: 15 March 2025
Article published online:
22 April 2025
© 2025. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
-
References
- 1 He S, Mu H. Microenvironmental pH Modification in Buccal/Sublingual Dosage Forms for Systemic Drug Delivery. Pharmaceutics 2023; 15: 637 [Internet]
- 2 Sattar M, Sayed OM, Lane ME. Oral transmucosal drug delivery–current status and future prospects. International journal of pharmaceutics 2014; 471: 498-506
- 3 Paderni C, Compilato D, Giannola LI. et al. Oral local drug delivery and new perspectives in oral drug formulation. Oral surgery, oral medicine, oral pathology and oral radiology 2012; 114: e25-e34
- 4 Shinkar DM, Dhake AS, Setty CM. Drug delivery from the oral cavity: A focus on mucoadhesive. PDA J Pharm Sci Technol 2012; 66: 466-500
- 5 Davis JL, Little D, Blikslager AT. et al. Mucosal permeability of water-soluble drugs in the equine jejunum: a preliminary investigation. Journal of veterinary pharmacology and therapeutics 2006; 29: 379-385
- 6 Evans EW. Treating scars on the oral mucosa. Facial Plastic Surgery Clinics 2017; 25: 89-97
- 7 Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. Journal of controlled release 2011; 153: 106-116
- 8 Canaan TJ, Meehan SC. Variations of structure and appearance of the oral mucosa. Dental Clinics of North America 2005; 49: 1-4
- 9 Sosnik A, das Neves J, Sarmento B. Mucoadhesive polymers in the design of nano-drug delivery systems for administration by non-parenteral routes: A review. Progress in Polymer Science 2014; 39: 2030-2075
- 10 Gu JM, Robinson JR, Leung SH. Binding of acrylic polymers to mucin/epithelial surfaces: structure-property relationships. Critical reviews in therapeutic drug carrier systems 1988; 5: 21-67
- 11 Kumar DR, Kumar KV, Sarma D. et al. Buccal Patches-A Review. Research Journal of Pharmaceutical Dosage Forms and Technology 2014; 6: 167-173
- 12 Squier CA. The permeability of keratinized and nonkeratinized oral epithelium to horseradish peroxidase. Journal of Ultrastructure Research 1973; 43: 160-177
- 13 Artusi M, Santi P, Colombo P. et al. Buccal delivery of thiocolchicoside: in vitro and in vivo permeation studies. International journal of pharmaceutics 2003; 250: 203-213
- 14 Hoogstraate AJ, Cullander C, Nagelkerke JF. et al. A novel in-situ model for continuous observation of transient drug concentration gradients across buccal epithelium at the microscopical level. Journal of controlled release 1996; 39: 71-78
- 15 Diaz-del Consuelo I, Jacques Y, Pizzolato GP. et al. Comparison of the lipid composition of porcine buccal and esophageal permeability barriers. Archives of oral biology 2005; 50: 981-987
- 16 Veuillez F, Kalia YN, Jacques Y. et al. Factors and strategies for improving buccal absorption of peptides. European journal of Pharmaceutics and Biopharmaceutics 2001; 51: 93-109
- 17 de Vries ME, Boddé HE, Verhoef JC. et al. Localization of the permeability barrier inside porcine buccal mucosa: a combined in vitro study of drug permeability, electrical resistance and tissue morphology. International journal of pharmaceutics 1991; 76: 25-35
- 18 Veuillez F, Rieg FF, Guy RH. et al. Permeation of a myristoylated dipeptide across the buccal mucosa: topological distribution and evaluation of tissue integrity. International journal of pharmaceutics 2002; 231: 1-9
- 19 Nicolazzo JA, Reed BL, Finnin BC. The effect of various in vitro conditions on the permeability characteristics of the buccal mucosa. Journal of pharmaceutical sciences 2003; 92: 2399-2410
- 20 Venueopnrnru P, Snpnr A, Venxnresnru N. et al. Pelleted bioadhesive polymeric nanoparticles for buccal delivery of insulin: preparation and characterization. Pharmazie 2001; 56: 217-219
- 21 Xu HB, Huang KX, Zhu YS. et al. Hypoglycaemic effect of a novel insulin buccal formulation on rabbits. Pharmacological Research 2002; 46: 459-467
- 22 Hoogstraate AJ, Senel S, Cullander C. et al. Effects of bile salts on transport rates and routes of FITC-labelled compounds across porcine buccal epithelium in vitro. Journal of controlled release 1996; 40: 211-221
- 23 Adrian CL, Olin HB, Dalhoff K. et al. In vivo human buccal permeability of nicotine. International journal of pharmaceutics 2006; 311: 196-202
- 24 de Oliveira Cardoso VM, Gremião MP, Cury BS. Mucin-polysaccharide interactions: A rheological approach to evaluate the effect of pH on the mucoadhesive properties. International Journal of Biological Macromolecules 2020; 149: 234-245
- 25 Junginger HE, Hoogstraate JA, Verhoef JC. Recent advances in buccal drug delivery and absorption—in vitro and in vivo studies. Journal of controlled release 1999; 62: 149-159
- 26 Elagamy HI, Essa EA, Nouh A. et al. Development and evaluation of rapidly dissolving buccal films of naftopidil: in vitro and in vivo evaluation. Drug development and industrial pharmacy 2019; 45: 1695-1706
- 27 Pedersen AM, Sørensen CE, Proctor GB. et al. Salivary secretion in health and disease. Journal of oral rehabilitation 2018; 45: 730-746
- 28 Zamora WJ, Campanera JM, Luque FJ. Development of a structure-based, pH-dependent lipophilicity scale of amino acids from continuum solvation calculations. The journal of physical chemistry letters 2019; 10: 883-889
- 29 Morales JO, Brayden DJ. Buccal delivery of small molecules and biologics: of mucoadhesive polymers, films, and nanoparticles. Current opinion in pharmacology 2017; 36: 22-28
- 30 30 Zamora WJ, Curutchet C, Campanera JM. et al. Prediction of pH-dependent hydrophobic profiles of small molecules from Miertus–Scrocco–Tomasi continuum solvation calculations. The. Journal of Physical Chemistry B 2017; 121: 9868-9880
- 31 Fukuda M, Peppas NA, McGinity JW. Properties of sustained release hot-melt extruded tablets containing chitosan and xanthan gum. International journal of pharmaceutics 2006; 310: 90-100
- 32 Repka MA, Gutta K, Prodduturi S. et al. Characterization of cellulosic hot-melt extruded films containing lidocaine. European Journal of Pharmaceutics and Biopharmaceutics 2005; 59: 189-196
- 33 Giunchedi P, Juliano C, Gavini E. et al. Formulation and in vivo evaluation of chlorhexidine buccal tablets prepared using drug-loaded chitosan microspheres. European Journal of Pharmaceutics and Biopharmaceutics 2002; 53: 233-239
- 34 Ameye D, Mus D, Foreman P. et al. Spray-dried Amioca® starch/Carbopol® 974P mixtures as buccal bioadhesive carriers. International journal of pharmaceutics 2005; 301: 170-180
- 35 Modi P, Mihic M, Lewin A. The evolving role of oral insulin in the treatment of diabetes using a novel RapidMist™ system. Diabetes/Metabolism Research and Reviews 2002; 18: S38-S42
- 36 Yang TZ, Wang XT, Yan XY. et al. Phospholipid deformable vesicles for buccal delivery of insulin. Chemical and pharmaceutical bulletin 2002; 50: 749-753
- 37 Li H, Zhang Z, Bao X. et al. Fatty acid and quaternary ammonium modified chitosan nanoparticles for insulin delivery. Colloids and Surfaces B: Biointerfaces 2018; 170: 136-143
- 38 Wang X, Cheng D, Liu L. et al. Development of poly (hydroxyethyl methacrylate) nanogel for effective oral insulin delivery. Pharmaceutical Development and Technology 2018; 23: 351-357
- 39 Lambrichts DP, Boersema GS, Tas B. et al. Nicotine chewing gum for the prevention of postoperative ileus after colorectal surgery: a multicenter, double-blind, randomised, controlled pilot study. International journal of colorectal disease 2017; 32: 1267-1275
- 40 Gmunder CB, Li W, Ream RL, inventors; WM Wrigley Jr Co, assignee. Sildenafil citrate chewing gum formulations and methods of using the same. United States patent US 6,592,850. 2003 Jul 15.
- 41 Attar AH, Gawade DS. Formulation and evaluation of medicated chewing gum containing caffeine salicylate. Asian J Pharm Technol Innov 2015; 3: 43-53
- 42 Lesch CA, Squier CA, Cruchley A. et al. The permeability of human oral mucosa and skin to water. Journal of dental research 1989; 68: 1345-1349
- 43 Shikanga EA, Hamman JH, Chen W. et al. In vitro permeation of mesembrine alkaloids from Sceletium tortuosum across porcine buccal, sublingual, and intestinal mucosa. Planta medica 2012; 78: 260-268
- 44 van Eyk AD, van der Bijl P. Comparative permeability of various chemical markers through human vaginal and buccal mucosa as well as porcine buccal and mouth floor mucosa. Archives of Oral Biology 2004; 49: 387-392
- 45 Thompson IO, Van der Bijl P, Van Wyk CW. et al. A comparative light-microscopic, electron-microscopic and chemical study of human vaginal and buccal epithelium. Archives of oral biology 2001; 46: 1091-1098
- 46 El-Samaligy MS, Afifi NN, Mahmoud EA. Increasing bioavailability of silymarin using a buccal liposomal delivery system: preparation and experimental design investigation. International journal of pharmaceutics 2006; 308: 140-148
- 47 Bilbault T, Taylor S, Walker R. et al. Buccal mucosal irritation studies of sublingual apomorphine film (APL-130277) in Syrian golden hamsters. Therapeutic Delivery 2016; 7: 611-618
- 48 Holm R, Meng-Lund E, Andersen MB. et al. In vitro, ex vivo and in vivo examination of buccal absorption of metoprolol with varying pH in TR146 cell culture, porcine buccal mucosa and Göttingen minipigs. European Journal of Pharmaceutical Sciences 2013; 49: 117-124
- 49 Nielsen HM, Rassing MR. TR146 cells grown on filters as a model of human buccal epithelium: V. Enzyme activity of the TR146 cell culture model, human buccal epithelium and porcine buccal epithelium, and permeability of leu-enkephalin. International Journal of Pharmaceutics 2000; 200: 261-270
- 50 Xue XY, Zhou Y, Chen YY. et al. Promoting effects of chemical permeation enhancers on insulin permeation across TR146 cell model of buccal epithelium in vitro. Drug and chemical toxicology 2012; 35: 199-207
- 51 Chen SY, Squier CA. The ultrastructure of the oral epithelium. Oxford: Pergamon Press; 1984
- 52 Guo YG, Singh AP. Emerging strategies for enhancing buccal and sublingual administration of nutraceuticals and pharamaceuticals. Journal of Drug Delivery Science and Technology 2019; 52: 440-451
- 53 Hassan DH, Ammar AA, Ramadan AA. et al. Enhanced bioavailability and pharmacokinetics parameters of Enalapril solid self nanoemulsifying oral dispersible tablet: Formulation, in vitro and in vivo evaluation. Pharmaceutical Development and Technology 2023; 28: 371-382
- 54 Kim GG, Poudel BK, Marasini N. et al. Enhancement of oral bioavailability of fenofibrate by solid self-microemulsifying drug delivery systems. Drug Development and Industrial Pharmacy 2013; 39: 1431-1438
- 55 Chen ZQ, Liu Y, Zhao JH. et al. Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system. International journal of nanomedicine. 2012: 1115-1125
- 56 Jun Y, Chunju Y, Qi A. et al. The effects of compound danshen dripping pills and human umbilical cord blood mononuclear cell transplant after acute myocardial infarction. Experimental and Clinical Transplantation: Official Journal of the Middle East Society for Organ Transplantation 2014; 12: 123-128
- 57 Wang R, Hu J, Li Y. et al. Compound Danshen Dripping Pills combined with isosorbide mononitrate for angina pectoris: A systematic review and a Meta-analysis. Chinese Herbal Medicines. 2024 16. 622-637
- 58 Fu H, Wang L, Ying S. et al. Preventive effect and mechanism of compound Danshen dripping pills on contrast-induced nephropathy after percutaneous coronary interventional. Frontiers in Cardiovascular Medicine 2023; 10: 1211982
- 59 Shi l, Liu, Gu G-J Intervention effects of compound danshen dripping Pil s and atorvastatin calcium on type 2 diabetes Mellitus patients with carotid atherosclerosis. Chin. J Integrative Medicine on Cardio/ Cerebrovascular Disease. 2016 15. 1705-1707
- 60 Bao K-Z, Wang M-H. Treatment of infantile convulsion by sublingual administration of diazepam solution. Med J West China 2006; 5: 566-567
- 61 Wang Q-N. Clinical study of methylcarboprost suppository to prevent postpartum hemorrhage. Evaluation and Analysis of Drug-Use in Hospitals of China 2016; 16: 153
- 62 Fan X-, Li L-J, Sun S. Efficacy of sublingual administration of carboprost suppositories in preventing postpartum hemorrhage and its systematic safety evaluation. China Pharmaceuticals 2016; 15: 19-23
- 63 Hua S, Marks E, Schneider JJ. et al. Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue. Nanomedicine: nanotechnology, biology and medicine 2015; 11: 1117-1132
- 64 Surendranath M, Rekha MR, Parameswaran R. Recent advances in functionally modified polymers for mucoadhesive drug delivery. Journal of Materials Chemistry B 2022; 10: 5913-5924
- 65 Baltzley S, Malkawi AA, Alsmadi M. et al. Sublingual spray drug delivery of ketorolac-loaded chitosan nanoparticles. Drug Development and Industrial Pharmacy 2018; 44: 1467-1472
- 66 Gavin A, Pham JT, Wang D. et al. Layered nanoemulsions as mucoadhesive buccal systems for controlled delivery of oral cancer therapeutics. International journal of nanomedicine 2015; 1569-1584
- 67 El-Nahas AE, Allam AN, El-Kamel AH. Mucoadhesive buccal tablets containing silymarin Eudragit-loaded nanoparticles: formulation, characterisation and ex vivo permeation. Journal of microencapsulation 2017; 34: 463-474
- 68 Mašek J, Lubasova D, Lukáč R. et al. Multi-layered nanofibrous mucoadhesive films for buccal and sublingual administration of drug-delivery and vaccination nanoparticles-important step towards effective mucosal vaccines. Journal of Controlled Release 2017; 249: 183-195
- 69 Al-Nemrawi NK, Alsharif SS, Alzoubi KH. et al. Preparation and characterization of insulin chitosan-nanoparticles loaded in buccal films. Pharmaceutical Development and Technology 2019; 24: 967-974
- 70 Mahdizadeh Barzoki Z, Emam-Djomeh Z, Mortazavian E. et al. Formulation, in vitro evaluation and kinetic analysis of chitosan–gelatin bilayer muco-adhesive buccal patches of insulin nanoparticles. Journal of Microencapsulation 2016; 33: 613-624
- 71 Morales Montecinos J, Brayden DJ. Buccal delivery of small molecules and biologics: of mucoadhesive polymers. films, and nanoparticles.
- 72 Hua S, De Matos MB, Metselaar JM. et al. Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercialization. Frontiers in pharmacology 2018; 9: 790
- 73 dos Santos Chaves P, Ourique AF, Frank LA. et al. Carvedilol-loaded nanocapsules: Mucoadhesive properties and permeability across the sublingual mucosa. European journal of pharmaceutics and biopharmaceutics 2017; 114: 88-95
- 74 Xu Y, Zhang X, Zhang Y. et al. Mechanisms of deformable nanovesicles based on insulin-phospholipid complex for enhancing buccal delivery of insulin. International journal of nanomedicine 2018; 7319-7331
- 75 Wang YY, Lai SK, Suk JS. et al. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angewandte Chemie (International ed. in English) 2008; 47: 9726
- 76 Teubl BJ, Meindl C, Eitzlmayr A. et al. In-vitro permeability of neutral polystyrene particles via buccal mucosa. Small 2013; 9: 457-466
- 77 Holpuch AS, Hummel GJ, Tong M. et al. Nanoparticles for local drug delivery to the oral mucosa: proof of principle studies. Pharmaceutical research 2010; 27: 1224-1236
- 78 Roblegg E, Fröhlich E, Meindl C. et al. Evaluation of a physiological in vitro system to study the transport of nanoparticles through the buccal mucosa. Nanotoxicology 2012; 6: 399-413
- 79 Yuan Q, Fu Y, Kao WJ. et al. Transbuccal delivery of CNS therapeutic nanoparticles: synthesis, characterization, and in vitro permeation studies. ACS chemical neuroscience 2011; 2: 676-683
- 80 Mouftah S, Abdel-Mottaleb MM, Lamprecht A. Buccal delivery of low molecular weight heparin by cationic polymethacrylate nanoparticles. International journal of pharmaceutics 2016; 515: 565-574
- 81 Mortazavian E, Dorkoosh FA, Rafiee-Tehrani M. Design, characterization and ex vivo evaluation of chitosan film integrating of insulin nanoparticles composed of thiolated chitosan derivative for buccal delivery of insulin. Drug development and industrial pharmacy 2014; 40: 691-698
- 82 Allen LV. Pharmaceutical Dosage Forms and Drug Delivery Systems.
- 83 Prasanth VV, Puratchikody A, Mathew ST. et al. Effect of permeation enhancers in the mucoadhesive buccal patches of salbutamol sulphate for unidirectional buccal drug delivery. Research in Pharmaceutical Sciences 2014; 9: 259-268
- 84 Reddy PC, Chaitanya KS, Rao YM. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods. DARU Journal of Pharmaceutical Sciences 2011; 19: 385
- 85 Yildiz Pekoz A, Sedef Erdal M, Okyar A. et al. Preparation and in-vivo evaluation of dimenhydrinate buccal mucoadhesive films with enhanced bioavailability. Drug development and industrial Pharmacy 2016; 42: 916-925
- 86 El-Nabarawi MA, Ali AA, Aboud HM. et al. Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation. Drug design, development and therapy 2016; 4031-4045
- 87 Jaipal A, Pandey MM, Charde SY. et al. Controlled release effervescent buccal discs of buspirone hydrochloride: in vitro and in vivo evaluation studies. Drug delivery 2016; 23: 452-458
- 88 Lindert S, Breitkreutz J. Oromucosal multilayer films for tailor-made, controlled drug delivery. Expert opinion on drug delivery 2017; 14: 1265-1279