What is a Sublingual Tablet?

Oral drug delivery, as a flexible and versatile delivery mode, not only serves the targeted treatment of local diseases, such as direct intervention of oral infections and ulcers, but also carries the important task of promoting rapid systemic absorption of drugs. Especially in the sublingual and buccal mucosa, the vascular network is densely covered, which gives them unparalleled advantages and makes them an ideal entry point for systemic drug delivery. Sublingual delivery, a sophisticated delivery strategy, requires that the drug be placed under the tongue, utilizing the rich vascular bed beneath it to achieve rapid drug absorption and distribution throughout the body. Buccal mucosa administration is to place the drug in the hidden space between the gum and the cheek, also aiming to use the efficient absorption capacity of this area to achieve systemic treatment purposes. The sublingual and oral routes are considered to be promising alternatives to traditional oral delivery methods.

Sublingual route for drugs. (Joshi, D., 2023)

Sublingual tablets meaning

Sublingual tablets refer to tablets that can be quickly dissolved under the tongue, and drugs can be absorbed through the sublingual mucosa to play a systemic role. It is the most common sublingual mucosal drug delivery form at present. Because sublingual tablets belong to one kind of tablets, the preparation method and auxiliary materials used are similar to tablets.

Advantages of sublingual tablets

Tablets that rapidly disintegrate or dissolve in the patient's mouth are useful for patients who previously likely suffered from aphasia or hand tremors, such as infants, elderly patients, the mentally ill, and bedridden patients. Rapidly dissolving sublingual tablets disperse, or dissolve as soon as placed in the mouth and areswallowed in liquid form. A sublingual tablet placed under the tongue provides an immediate systemic effect due to rapid or direct absorption of the drug through the mucous membranes of the mouth under the tongue. Drugs absorbed from the stomach enter the mesenteric circulation, which is connected by the portal vein. Absorption through the buccal cavity thus bypasses first-pass metabolism. Because liver metabolism is avoided, a relatively low dose of the drug is required to achieve the desired efficacy, reducing the potential side effects of drug metabolites.

Sublingual tablets are usually small and flat and should be pressed gently to keep them soft. The tablet should dissolve quickly so that the drug can be absorbed. Designed to dissolve in small amounts of saliva. No need for water or other auxiliary means, or even chewing. This route of administration avoids the possible pain caused by injection, improves the compliance of patients, and is especially suitable for the management of chronic diseases requiring long-term medication, such as the treatment of depression and schizophrenia in mental health diseases. Once the tablet is placed in the mouth under the tongue, the patient should not eat, drink, smoke, and possibly talk to keep the tablet in place.

Systemic drug delivery via the sublingual route arose from the desire to provide immediate onset of pharmacological action. This property of sublingual tablets is particularly important for situations requiring urgent treatment, such as acute asthma or angina attacks, because the rich distribution of blood vessels in the sublingual area ensures that the drug is absorbed quickly, thereby increasing the blood concentration and timely relief of symptoms. Sublingual products have a wide range of indications, from migraine (where rapid onset of action is important) to mental health (where patient compliance is important to treat chronic conditions such as depression and schizophrenia). The sublingual route leads to greater drug absorption over time than the oral route, second only to subcutaneous injection. Sublingual administration is well suited for short-acting drugs.

Sublingual drugs absorption mechanism

There are three main mechanisms of sublingual drug absorption: passive diffusion, carrier mediated active transport and endocytosis.

Passive diffusion occurs spontaneously, and its rate is affected by molecular weight, solubility, concentration gradient, temperature, membrane surface area, and molecular distance from the membrane. When the drug is present in the saliva in non-ionic form, it is absorbed through passive diffusion. The speed of drug entering blood circulation through oral mucosa lipid bilayer is related to its distribution coefficient. Some compounds such as glutamic acid, L-ascorbic acid, niacin and thiamine are transported via carrier mediated transport. Absorption of the drug is affected by lipid solubility, solution permeability (i.e., osmotic pressure), ionization state, and molecular weight. Oral epithelial cells can absorb drugs through endocytosis, although this mechanism is uncommon in stratified squamous epithelium.

Acid stimulation of salivary gland dilation and vasodilation can enhance drug absorption and uptake. The oral mucosa is covered with a flat epithelium and contains mucous glands. The sublingual tissue is similar to that of the buccal mucosa. Saliva is secreted by the parotid gland, the submandibular gland, and the sublingual gland, the latter located at the base of the mouth. The more acidic the saliva, the more it stimulates saliva production. To prevent damage to acid-sensitive enamel, a neutralizing solution should be used. The sublingual artery supplies blood to the sublingual glands and branches into the adjacent muscles and mucous membranes of the mouth, tongue, and gums. This artery originates from the main artery supplying the tongue and floor of the mouth, the lingual artery, which emanates from the external carotid artery and, due to its proximity to the internal carotid artery, allows drugs to reach the cerebral hemisphere quickly.

Lipids in the oral mucosa constitute the main barrier of hydrophilic drug penetration, while fully hydrated connective tissues form resistance to hydrophobic drugs. Therefore, the path of drugs through the oral mucosa can be divided into hydrophilic and hydrophobic. Non-polar molecules travel through the upper sebum region, while polar molecules migrate through intercellular ion channels or epithelial cell water pores. The lipid solubility and hydrophilicity of a drug are the key indicators to evaluate its suitability for oral mucosal absorption. Active intracellular transport leads to rapid metabolism of substances, and molecules such as glucose, fructose, and amino acids, which are essential for cellular metabolism, have specialized mechanisms to facilitate rapid diffusion and penetration across membranes.

Factors affecting the sublingual absorption

Drug lipophilicity: For a drug to be fully absorbed under the tongue, the drug must have a lipid solubility slightly higher than that required for gastrointestinal absorption required for passive permeation.

Salivary solubility: In addition to high lipid solubility, the drug should be soluble in aqueous oral fluids. i.e., Absorption requires biphasic solubility of the drug.

Salivary pH and pKa: The average pH of saliva is 6.0, so this pH favours the absorption of non-ionized drugs. Furthermore, drug absorption through the oral mucosa occurs at pKa values greater than 2 for acids and less than 10 for bases.

Binding to oral mucosa: Drugs that bind to the oral mucosa have low systemic availability.

Thickness of oral epithelium: The thickness of the sublingual epithelium is 100-200 μm, so it is thinner than the cheek thickness. As a result, the epithelium becomes thinner and the drug is soaked in a small amount of saliva, resulting in faster absorption of the drug.

Oil-to-water partition coefficient: Compounds with good oil-water partition coefficient are easily absorbed through the oral mucosa. An oil-water partition coefficient range of 40-200 is considered optimal for drug absorption under the tongue.

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Sublingual tablets examples

Sublingual tablet for heart

Nitroglycerin sublingual tablets are one of the most common sublingual tablets used for emergency relief of Angina symptoms. Nitroglycerin can quickly relieve chest pain by dilating blood vessels and reducing the workload of the heart.

Verapamil sublingual tablets can be used to treat arrhythmias and high blood pressure.

Sublingual tablet for hypertension

Nifedipine subelingua tablets were once used in emergency hypertensive situations, but later studies have shown that they may cause a sudden drop in blood pressure, cause reflex sympathetic stimulation, and increase the risk of acute stroke, myocardial infarction, and sudden death. Therefore, it is now not recommended for sublingual administration in severe hypertension.

Nitrendipine is also available in sublingual tablet form and is used to treat high blood pressure. However, it also needs to be used with caution, especially in patients with severe hypertension.

Captopril is an angiotensin-converting enzyme (ACE) inhibitor that can be used in sublingual form to treat hypertensive emergencies.