Administration of small molecules via the buccal or sub-lingual routes has led to numerous FDA approvals of small molecules requiring rapid passage to the blood and fast action for immediate effect. Examples include opiates, benzodiazepines, and triptans. Formulations include drug-loaded dissolving thin films applied to the buccal mucosa and tablets placed sub-lingually. Particular advantages of these routes of administration compared to the oral route are the avoidance of the liver first-pass effect, lower enzyme activity, neutral pH environment, and the allowance of eating and drinking before and after administration. Moreover, buccal and sub-lingual mucosae have superior permeability compared to the skin. Despite this, the number of products is relatively low and there are no approved formulations of biologics.

How can successful formulations of small molecules and macromolecules be developed for buccal and sub-lingual administration? These mucosae will need to be manipulated to allow passage of macromolecules through to the blood. Strategies for macromolecules include the use of penetration enhancers, microneedles, and physical manipulations. The patches or films (buccal) or sub-lingual tablets will need to comprise safe biomaterials that facilitate the loading of macromolecules to a required level. Other challenges include patient resistance to foreign bodies in the mouth for more than a few minutes and the requirement for components of formulations ultimately to be swallowed upon dissolution. Despite clinical trials being achieved for insulin in gold nanoparticles and in an oromucosal spray, progress in the field has been slow for peptides. For small molecules, are there other molecules under consideration for oromucosal administration to treat acute pain, migraines, and angina? In terms of local delivery, can we devise patch formulations to locally treat cancers of the oral cavity and to reduce side effects from systemic administration? The dermis below the epithelium is full of antigen-presenting cells. There is potential for the buccal or sublingual site to be used as a site for vaccine administration. Can they be accessed with painless microneedle systems containing vaccines to allow for an immune response on a par with vaccine injections?

To our knowledge, this is the first attempt to put together a group of articles addressing the potential of buccal and sub-lingual administration for drug molecules. In our analysis, these routes will remain quite niche for a specific range of molecules that require rapid action from an administered formulation. We are interested in hearing about formulations for systemic and local drug delivery, how researchers can ensure high drug loading in a formulation that must work over a limited area, and issues around rapid dissolution and local toxicology. There is also some basic knowledge required where improvements are required in imaging of drugs in the mucosae, along with the development of better in vitro and ex vivo and in vivo bioassays to model permeability across these sites. How does saliva impact in vitro and in vivo dissolution rates from these dosage forms compared to standard buffers? Finally, are there better descriptors of how drugs permeate these tissues via transcellular and paracellular routes across the epithelium? Compared to the intestine, knowledge is quite sparse in this area.

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Frontiers in Drug Delivery

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