For the delivery of vaccines and allergens, the buccal and sublingual routes have been extensively investigated. Consequently, good knowledge of the immune cells distributed within the oral mucosal tissue has become increasingly important. World Pharmaceutical Frontiers highlights the current status of this drug delivery method, and explores the possibilities and limitations with regard to quality, safety and efficacy issues.
A film is spread along the lining of your cheek. It rests there for a moment before beginning to melt; its constituent parts – the molecules and bonds that hold the flimsy structure together – begin to disintegrate. What gives the film its shape and texture collapses, and some of the ingredients escape, passing through the submucosal layer of the inner cheek and into the blood in the capillaries beneath. It is from here that they begin to do their work.
Oral drug delivery has been the preferred method of doctors and patients for decades. Whether it comes in pill form or secreted in a sweet-tasting syrup, we are accustomed to thinking that the easiest and most convenient way for our body to receive medication is through the mouth. These tumble down the gullet in the same fashion as the hot teas, coffees and snacks consumed: down the oesophagus and into the hydrochloric pool of the stomach.
The problem is that, in most cases, the body needs time – sometimes multiple hours – to adequately metabolise medicines swallowed, which is not ideal for patients in need of immediate relief. There are alternatives, of course, but these are mainly delivered through an injection. While syringes are a highly efficient way of making sure drugs enter the bloodstream, their use decreases in patient acceptability due to discomfort. Other methods, including the administration of drugs through the mucosal lining of the nose or eye, for example, do offer advantages in avoiding the first pass effect, but they also enjoy limited patient acceptance.
Buccal and sublingual drug deliveries – pharmaceutical products that dissolve into the cheek or the flesh beneath the tongue – sidestep these problems. By being immediately absorbed into the bloodstream through the jugular vein, they avoid being metabolised by the liver, which allows quick results. This method also avoids the necessity of swallowing, offering an alternative for those who have dysphagia or similar difficulties.
A medical renaissance
Sublingual and buccal delivery products come in a wide variety of forms, and have been around for hundreds of years; Glyceryl trinitate, a drug used to treat high blood pressure and angina, has existed in a sublingual form since at least 1847.
It is only relatively recently, however, that they have enjoyed a renaissance. As Dr Kalliopi Dodou from the University of Sunderland explained in her recent overview of modern developments in sublingual and buccal therapies, Transcept Pharmaceuticals released its ‘Intermezzo’ sublingual tablet in 2011, created to treat ‘middle-of-the-night’ insomnia. The previous year also saw the release of Suboxone Film, which is used to treat opioid addiction, and ‘Onsolis’, which used buccal transmucosal films to treat breakthrough pain for cancer patients already used to receiving opioid painkillers.
– Anya M Hillery, Saint Louis University, and Kinam Park, Akina
These types of drugs do have their limitations, however. The sublingual route can prove to be a hostile environment for efficient drug delivery, not least because the area under the tongue is constantly awash with a mix of water, mucus and epithelial cells from the salivary glands. According a treatise on drug delivery written by Anya M Hillery from Saint Louis University; and Kinam Park, founder and president of medical research company Akina, entitled ‘Drug Delivery: Fundamentals and Applications’, “dissolution can vary considerably, depending on the type, size and shape of the tablet. Thus, sublingual dosage forms generally have a high inter and intra-individual variation in absorption and bioavailability.”
Similar principles apply for buccal drug delivery. The inside of the cheek is only slightly less affected by the flow of saliva than the area under the tongue, and buccal tablets can, according to Hillery and Park, “include poor acceptability” thanks to “uncomfortable mouth feel, taste, irritation and discomfort”. There is additional risk when one considers that the separation of the initial dosage form from the oral mucosa, could, if swallowed, “adhere to the wall of the [oesophagus]”.
A ready alternative to buccal tablets comes, of course, in the form of films. As with the former category of drug, there are advantage and disadvantages to their use. Their unobtrusiveness – films are, by their very nature, thin and as such impose minimal discomfort on the patient when applied on the interior of the cheek – is counterbalanced by their susceptibility to loss of adhesion when overexposed to saliva.
Another option is sprays that, according to Hillery and Park, “offer the advantage of a rapid onset of action”. This is particularly useful when it comes to delivering insulin into the body. RapidMist, a device that delivers insulin at high velocity into the mouth, is very quickly absorbed, entering the blood stream in just five minutes. In half an hour, the amount of insulin in the bloodstream had peaked and returned to normal levels within two hours. While neither scientists were particularly enamoured with the delivery mechanism – “[a]pplication of >10U of insulin, for example, after a meal, requires more than ten puffs, which is time consuming and not very user-friendly” – they did admit that the performance matched synthetic insulin analogues that are injected subcutaneously.
Indeed, buccal and sublingual sprays are not limited to the delivery of insulin. In the US states where the sale and consumption of cannabis is legal, increased interest in sublingual, THC-laced sprays has been noticed among enthusiasts keen for a time-limited high. According to The Atlantic, activation can take place in under a minute and, since the drug is not metabolised in the liver, the body’s enzymes cannot turn delta-9-THC into the compound responsible for the more hallucinatory side-effects of cannabinoids, 11-hydroxy-THC. Overdosing is also more difficult. “The worst thing that can happen is you may feel overwhelmed,” Dr Uma Dhanabalan told the magazine, specifying nausea, vomiting, paranoia and anxiety as typical symptoms. “These are symptoms of overconsumption. You cannot die.”
Sublingual sprays have also made their mark in the treatment of more mundane, strictly medical, problems. NitroMist has been marketed as an innovative method of treating angina. A medical nitroglycerine mixture, it was intended to be sprayed into the mouth to be absorbed into the sublingual and buccal membranes contained within the jaw and cheek. The more aptly named Duromist, meanwhile, was marketed as an ameliorative treatment for erectile dysfunction.
Tackling allergies
Where sublingual and buccal treatments have elicited the most excitement, however, is in their potential for assuaging the symptoms of allergies. A treatment pioneered in Ireland in 2008 called sublingual immunotherapy (SLIT) has the patient take one tablet a day, placed under the tongue, for three years. Used to treat severe hay fever in those for whom the typical round of antihistamines or eye drops has done little to stave off symptoms, there is evidence to suggest these tablets could cure the condition outright.
“The advantage of SLIT is manifold,” Professor Stephen Lane told the Irish Independent in July 2017. “You take it for three years and it induces tolerance – in other words, it retrains your immune system not to be allergic.” All three years are mandatory. A study published in the Journal of the American Medical Association in 2017 found that just two years of treatment would not lead to consistent levels of tolerance.
– Professor Stephen Lane, Blackrock Clinic
In the US, meanwhile, the FDA’s approval of the drug Odactra has opened up sublingual therapy to the treatment of dust mite allergies. “House dust mite allergic disease can negatively impact a person’s quality of life,” explained Dr Peter Marks, the director of the center for biologics evaluation and research at the FDRA. “The approval of Odactra provides patients [with] an alternative treatment to allergy shots to help address their symptoms.”
Like the tablet for SLIT, Odactra is placed underneath the tongue to dissolve into the bloodstream. It is also taken once a day, albeit only for a year. Unlike the hay fever treatment, however, Odactra’s potential to induce “life-threatening adverse reactions” means that the first dosage requires administration by a healthcare professional “with experience in the diagnosis and treatment of allergic diseases”. These alarming side effects included itching in the ears and mouth, swelling in the lips and tongue, and nausea. Doctors were advised to prescribe auto-injectable epinephrine alongside the drug.
Perhaps the most intriguing failures in sublingual allergen therapy have been in the treatment of food allergies. The number of children suffering from extreme reactions to specific foods, ranging from nuts to soy and fish to eggs, increased by 50% between 1997 and 2011 in the US.
Attempted treatment methods have predominantly concentrated on oral immunotherapy, a treatment wherein tiny amounts of the allergen are introduced into the patient’s diet until they acquire a fragile immunity to the foodstuff. Modern medicine is no stranger to such methods. As far back as the first century BC, King Mithridates VI of Pontus guarded against assassination by poison through ingesting trace amounts during his reign, while also sleeping next to a horse, a bull and a stag in case anybody decided on a different approach by stabbing him in bed. Proof of the treatment’s success came in 63BC when the Romans invaded his kingdom. Facing imminent capture, Mithridates ingested an unidentified poison – to no apparent effect. Seeing this, the king ordered one of his servants to kill him with a sword.
There are problems with immunotherapy – the treatment requires a maintenance dose, or rather a willingness to keep ingesting the allergen lest the body’s resistance be forgotten by the immune system – yet it is proving to be more popular than sublingual therapies. While these latter treatments have been proved to build up immunity, they do so at lower levels, and at a slower pace.
Even so, advances in sublingual and buccal therapies have shown that alternative drug delivery methods are transforming the way in which we treat a range of conditions. While their effectiveness may be limited in some areas, their ability to deliver fast-acting relief that avoids the delays associated with the traditional oral route has led to promising developments in the treatment of everything from allergies to diabetes. As research in this area gathers pace, one can only hope that such methods will continue to yield similar results in the future.