The transmucosal route of delivery occurs when drugs diffuse through a mucous membrane. The oral cavity can be utilized for transmucosal delivery and the challenge of limited surface area and salivary action can be overcome with efficient agents and appropriate administration.1 Transmucosal delivery methods include dissoluble films, tinctures, oral sprays, and lozenges and target the buccal and sublingual areas. “Sublingual and buccal formulations depend on the efficient transfer of a drug from a hydrophilic vehicle to the cell membranes of the sublingual or buccal mucosa. The buccal and sublingual mucosa have venous drainage directly into the vena cava and the left side of the heart. Substances absorbed through the mucosa of these areas avoid the liver and the subsequent hepatic first-pass effect. The avoidance of the first pass effect is the rationale for the use of the transmucosal mode of delivery. Drug transport across the mucosa can be trans or paracellular. Absorption of cannabinoids likely takes place through the interstices in the membrane or by transfer into the epithelial cells.”2
When developing agents for this route of administration the formulation requires the use of mucoadhesive agents to maintain an intimate and prolonged contact of the formulation with the absorption site, penetration enhancers, to improve drug permeation across the mucosa, enzyme inhibitors to protect the drug from degradation through mucosal enzymes and solubility modifiers to enhance the solubility of poorly soluble drugs.3
The sublingual mucosa is more permeable, vascularized, and thinner than the buccal mucosa. The sublingual route of administration of cannabinoids has a rate of absorption intermediate between that achieved by smoking and the oral route. 2.This absorption delay provides patients with the ability to titrate their dose to exploit the window between wanted therapeutic effects and unwanted side effects.2 Saliva is a water-rich environment with a mucus component. Salivary flow determines the amount of time a drug spends in the oral cavity. Salvia production can cause difficulties in maintaining contact between the dosage form and the sublingual mucosa. This can result in short exposure times and unpredictable distribution of the drug on the site of action/absorption.3 Sublingual formulations may stimulate the flow of saliva making it difficult for patients not to swallow the medication. If cannabinoid medications applied to the sublingual mucosa are swallowed the cannabinoids will be subject to the first-pass effect and will be less effective and result in the production of metabolites. 2 Buccal formulations where the product is held in contact with the parietal buccal membrane may be subject to the same limitations. 2
The buccal area is the inner lining of the cheek and the lip and encompasses about one-third of the surface area of the oral cavity. 3,4The buccal mucosa consists of a surface layer of stratified epithelium linked to underlying connective tissue. There is a network of blood capillaries in the connective tissue where drugs that have permeated through the epithelium can enter the systemic circulation.1,4 The buccal membrane has lower permeability when compared to the sublingual membrane. 2,3, The absorption potential of the buccal mucosa is influenced by the lipid solubility and molecular weight of the diffusant. Solubilization of poorly water-soluble drugs by complexation with cyclodextrins is advantageous in increasing drug absorption and bioavailability via the buccal mucosa.3
When formulating a buccal medication there is a need for penetration enhancers.2,4 Penetration enhancers are substances that help open intercellular tight junctions. Permeation/penetration enhancers work by different mechanisms including changing mucus rheology, increasing the fluidity of the lipid bilayer membrane, acting on tight junctions, overcoming enzymatic activity, and increasing thermodynamic activity. These mechanisms result in better drug absorption. Examples of penetration enhancers include sodium lauryl sulfate, oleic acid, cyclodextrin, and chitosan. 2 The improper selection or use of these enhancers can cause tissue irritation The turnover of the buccal epithelium is about three to eight days and this rapid turnover can reduce the risk of tissue damage or irritation. Another concern when using these enhancers is an undesired bolus effect which may lead to an increase in the concentration of the drug in the blood to levels that may not be safe. 4Additional factors influencing the absorption of a drug through the buccal mucosa include when and what the patient eats, drinks, or smokes and the location where the patient places the dosage. 4
Mucoadhesive films are a preferred dosage form for buccal mucosa administration. Mucoadhesive films stay in contact with the mucosa longer, cover a larger surface area, and can provide more accurate drug dosing. Film composition is designed to achieve bioadhesive strength, tensile strength, pliability, flexibility, and extended disintegration. Achieving this is highly dependent on the type and concentration of the selected polymers and the dose of active ingredients being delivered.4 Film formulations include polymers, permeation enhancers, and lipids which are combined to optimize drug diffusion and permeation through the mucosa.4 There is a method of transmucosal delivery of cannabinoids via a film matrix utilizing hot-melt extrusion, hot melt molding, admixing, or solvent cast techniques. 5
Additional routes of oromucosal delivery include lozenges and tinctures. Lozenges can be
solid, soft, or chewable. Cannabinoids are usually formulated in soft or chewable forms. 6 Typically a solid lozenge dissolves and coats the oral cavity and the top one-third of the esophagus. Solid dose forms display greater inter and intraindividual variations in absorption and bioavailability. The dissolution rate of a lozenge depends on how hard the patient sucks on the lozenge and saliva production. It takes roughly 30 minutes for a lozenge to dissolve and this short time frame limits how much drug can be delivered. 1
Tinctures are a classical method of plant-based delivery and have been used for centuries to prepare cannabis medicines. Tinctures are best taken sublingually. Cannabis can be delivered in a rapid, dose measured manner as a tincture. Tinctures are extracts of cannabis in an organic solvent, such as alcohol or glycerin. When alcohol-based products like tinctures are used the alcohol acts as a delivery method and circumvents the digestive tract so it is absorbed directly into the bloodstream. as a result, tinctures are fast-acting. 7
Much of our knowledge of cannabinoid absorption via the oromucosal route comes from studies done on Sativex, a whole plant cannabis extract. Sativex (Nabximols) contains nearly equivalent THC and CBD concentrations and is delivered via spray onto the oral mucosa to improve bioavailability. Following administration of Sativex both THC and CBD are absorbed rapidly. When Sativex is administered oromucosally, plasma levels of THC and other cannabinoids are lower compared with the levels achieved following inhalation of cannabinoids at a similar dose. Researchers believe these differences are due to slower absorption and redistribution of the cannabinoids into fatty tissues. Additionally, some of the THC undergoes hepatic first-pass metabolism to 11-OH-THC and some of the CBD is metabolized to 7-OH-CBD. 8
References
1. Sapanaro DM,Winberg MA. Transmucosal Drug Delivery in the Oral Cavity. https://decisionsindentistry.com/article/transmucosal-drug-delivery-in-the-oral-cavity/. Published Dec 12, 2018. Accessed April 20, 2020.
2. Whittle BA, Guy GW, Robson P. Prospects for New Cannabis Based Prescription Medicine. http://www.cannabis-med.org/iacm/data/pdf/2001-03-04-11.pdf. Accessed April 6, 2020.
3. 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(6):385-403. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436075/ Accessed April 20, 2020.
4. Buccal Films- Better Drug Release & Patient Experience With Buccal Films. https://drug-dev.com/buccal-films-better-drug-release-patient-experiences-with-buccal-films/ Accessed April 20, 2020.
5. Eloshly M, Repka M, inventors; University of Mississippi, assignee. Transmucosal delivery of cannabinoids. United States patent application US 10/516,188. 2006 Nov. 16. https:// patioentimages.storage.googleapis.com/d5/39/4a/56cdf49477be06/US20060257463A1.pdf Accessed April 202,2020.
6. Pearson R. MCST603 Module 6 Lecture 4. Accessed April 20, 2020.
7. Nazarenus C. Medical Cannabis Handbook For Healthcare Professionals. New York, New York: Springer Publishing Company;2020
8. Sativex Oromucosal Spray 5.2 Pharmokinetic properties. http://www.medicines.org/uk/emc/medicine/23262 Accessed April 20, 2020.