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European Biopharmaceutical Review

Mouth to Mouth

Oral diseases are common, and may be specific to the oral cavity or a manifestation of a systemic condition. Signs and symptoms are normally mild or moderate, but are occasionally severe. They are usually the consequence of complications in treatment for systemic diseases, and can result in treatment breaks – this is illustrated by cancer remedies such as radiotherapy, chemotherapy and targeted therapies, which can all induce oral complications (1,2).

A wide range of incidence and severity of different complications of cancer treatments have been reported. They include pain, caries and periodontal diseases, but also more severe problems such as mucositis, aphtous ulcers, bleeding, xerostomia, dysphagia, dysgeusia, infection (bacterial, viral and fungal), and osteoradionecrosis of the jaw. In the worst cases, these concerns can result in difficulties with eating, drinking and even speaking, and can lead to weight loss, dehydration or sometimes life-threatening complications such as systemic infections. Hospitalisation for supplemental nutrition and rehydration may be needed. In these situations, the quality of life of patients is markedly altered, and cancer treatments may be interrupted, with detrimental consequences for survival.

Treatment Issues

Despite their potential severity, oral diseases are often neglected and are hardly treated. Oral hygiene is the basis of management care. Symptomatic or curative treatments may be prescribed, but are poorly adapted to the oral signs and symptoms. Usually, treatments involve systemic agents or topical drugs, but these have not been specifically developed for this purpose, and are therefore poorly efficacious or unsafe. Systemic treatments deliver their active principle into the body without specific distribution in the oral cavity, while topical agents deliver the active principle at the site of the disease – but active concentrations are usually too low and too short to provide rapid and sustained efficacy.

This is illustrated by the treatment of oropharyngeal candidiasis, which can be cured with either topical anti-fungal gel or systemic anti-fungal tablets. The topical gel has to be applied 4-6 times per day for 7-14 days to be efficacious. In practice, patients are not compliant with their prescriptions and barely 50% of the recommended dose and duration are adhered to, resulting in only moderate efficacy (3,4). Systemic treatments, on the other hand, are given once daily for 7-14 days. Compliance is excellent, but the use of such approaches is associated with potential drug interactions and the increase in the incidence of resistant strains (5,6).

Buccal Therapies

There are many other examples illustrating poor compliance to topical treatments leading to reduced efficacy, alongside the increased occurrence of adverse drug reactions with systemic treatments. As a result, there is a medical need for buccal therapies adapted to the local treatment of oral diseases, which prevent non-compliance and minimise the risk of systemic adverse effects and drug interactions.

Several formulations using the buccal route have been developed. Many are aimed at either increasing the bioavailability of drugs with a first-pass effect, or reducing the delay of absorption through a rapid delivery of the active principle in the oral cavity for rapid systemic absorption, providing very high plasma concentrations of active principle. This approach has been used for the prevention or treatment of non-oral symptoms or diseases. Orodispersible tablets or films dissolve in a few seconds in the oral cavity, the active principle is rapidly absorbed, and the prevention or treatment of symptoms occurs more quickly than with a classic oral tablet.

In cancer supportive care, this has been used extensively – for example, with ondansetron or paracetamol orodispersible tablets. Likewise, oral transmucosal formulations are based on the swift systemic absorption of the active principle. Oral transmucosal fentanyl has been developed for a rapid and improved absorption of fentanyl for treating breakthrough pain. However, these formulations are not adapted for the prevention or treatment of oral symptoms or diseases which need prolonged exposure of the oral cavity to the active principle.

Topical Applications


Topical treatments are ideally designated for local diseases – including oral ones – and gels containing the active principle are the main forms for use. However, the intraoral exposure to the active principle is short, as a result of a rapid drug clearance. Salivary concentrations obtained after a single administration of gel are extremely high within just a few minutes, but can only be detected for a short period of time due to drug clearance from the oral cavity via saliva flow and swallowing (7).

This pharmacokinetic profile in saliva requires the active principle to be administered several times per day for a prolonged exposure. This results in major issues. Non-compliance increases with the number of daily administrations and duration of prescriptions: the higher the number of daily administrations and the longer the duration of prescription, the lower the compliance. In addition, even when a patient complies well, there will still be long periods without exposure to the drug – particularly during the night – leading to poor efficacy.

In contrast, plasma concentrations observed after gel administration are usually low, and therefore the safety profile is good (8). Local irritation and taste disturbances are the most frequently reported adverse effects. As a consequence of poor compliance and poor efficacy, topical oral gels are rarely prescribed and systemic drugs are preferred, despite the higher incidence of adverse effects and risks of drug interactions.

Mucoadhesive Formulations

Prolonging the residence time of drugs administered topically in the oral cavity is a major challenge. This has been overcome with the development of mucoadhesive buccal tablets with sustained release properties. These formulations are placed on the gum, where they slowly release the active principle they contain. The objectives of these tablets are to provide rapid, high and sustained concentrations of the active principle in saliva.

Pharmacokinetic data has been published for two anti-infectious agents – miconazole, an anti-fungal drug for the treatment of oropharyngeal candidiasis, and acyclovir, for the treatment of recurrent labial herpes (7-9). These data consistently showed that salivary concentrations are detected as soon as five minutes after mucoadhesive buccal tablet placement. They were high – greater than the MIC90 or IC50 values for candida or herpes simplex virus respectively – and sustained for 12 to 24 hours at levels still markedly larger than those required for an anti-infectious effect.

In this respect, salivary concentrations obtained with the mucoadhesive tablets compared favourably to those observed with the gel (for miconazole) or the oral tablet (for acyclovir). Interestingly, drug concentrations were measured in the labial mucosa and shown to be even higher than those observed in saliva (9).

Both salivary and mucosa concentrations of the active principle were detected several hours after disintegration of the mucoadhesive buccal tablet. These data suggest that the active principle diffuses from saliva into the oral mucosa, is stored within the mucosa (or salivary glands), and is released from the mucosa to the oral cavity after tablet disintegration, when the concentration gradient between saliva and mucosa decreases. Finally, this pharmacokinetic profile in saliva was achieved with doses markedly lower than those of traditional formulations. These properties could be used to treat oral symptoms and diseases poorly targeted by current treatments: oral acute or chronic pain, oral inflammatory diseases, and gingival or dental infections.

With these mucoadhesive formulations, it was also expected that plasma concentrations would be low. This was confirmed in a study where they were an oral tablet. Relative bioavailability was around 25%, which was expected to minimise systemic exposure and therefore the risk of adverse effects and drug-drug interactions – and the latter are further reduced by the low dose of the mucoadhesive tablets.

Recently, two drugs using these formulations have been registered by the FDA; both drugs contain a low dose of active principle. Miconazole mucoadhesive buccal tablet is administered at a daily dose of 50mg, whereas the daily dose of the gel is 500mg per day. Likewise, the dose of acyclovir mucoadhesive buccal tablet is 50mg, to be taken only once during the prodromal phase of recurrent labial herpes when acyclovir oral tablets are administered at a daily dose of 800- 1,000mg per day in 2-4 divided doses for 5-10 days. The total dose administered using this formulation is 10-50 times lower than those of the topical or systemic formulations, yet achieves a similar or even greater efficacy, as well as a better safety profile.

In terms of pharmaceutical development, the dose to be loaded within the tablet could be easily estimated without performing exploratory pharmacokinetic studies in humans or animals. Indeed, the active principle is delivered and distributed at the site of disease. The metabolism and elimination by the liver or kidney do not influence the dose to administer. Concentrations in saliva only depend on two factors: the release rate of the active principle from the tablet, and the saliva flow rate and output. The saliva elimination rate has minimal or no impact on concentrations of the active principle and is mostly related to saliva flow rate.

Saliva Flow Rates

The unstimulated flow rate is almost constant in healthy subjects over 24 hours, with few variations during the day. No significant variations in unstimulated flow rates have been reported across gender, race or age, and flow rate of 0.3mL/min (range 0.2-0.6mL/ min) can be estimated (10). Based on these two parameters, the dose to be administered and loaded in the tablet can easily be calculated and adapted to concentrations expected.

Saliva flow rates increase in physiological situations, such as before and during meals. However, these modifications are transient and do not modify the efficacy profile. Many diseases and drugs can modify saliva flow. Hyposalivation or xerostomia may have two opposite effects: the increase in salivary concentrations of the active principle could result in an increased efficacy, in case of relationship between concentrations and efficacy. On the other hand, the oral mucosa is less moistened and the active principle may be unable to reach all parts of the oral mucosa with the risk of limiting the expected efficacy.

Available clinical data do not suggest that hyposalivation or xerostomia result in a significant reduction in efficacy (11). No data are available in patients with hypersalivation. No major impact could be expected and the dose might have to be increased in order to compensate the elimination the saliva loses if the patient were to spit or swallow.

Targeted Treatments

In summary, oral diseases are better targeted by treatment delivering the active principle directly into the oral cavity. Systemic treatments deliver their active principle in the body without specific distribution in the oral cavity. Topical agents deliver the active principle at the site of the disease, but active oral concentrations are usually too low and too short to provide rapid and sustained efficacy. They require administration several times per day – raising the risk of poor compliance.

Sustained-release mucoadhesive buccal formulations provide early, high and sustained concentrations of active principle in the oral cavity and low plasma concentrations, maximising the efficacy and minimising the risk of sideeffects and drug interactions. They are therefore particularly well-adapted to the treatment of oral diseases.

References

1. Trotti A et al, Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: A systematic literature review, Radiother Oncol 66(3): pp253- 262, 2003
2. Elting LS et al, Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies, Int J Radiat Oncol Biol Phys 68(4): pp1,110-1,120, 2007
3. Krueger K, Berger B and Felkey B, Medication adherence and persistance: A comprehensive review, Advance in Therapy 22(4): pp319-362, 2005
4. Gligorov J et al, Prevalence and treatment management of oropharyngeal candidiasis in cancer patients: Results of the French candidoscope study 2010, Int J Radiat Oncol Biol Phys 80(2): pp532-539, 2011
5. Redding SW et al, A comparison between fluconazole tablets and clotrimazole troches for the treatment of thrush in HIV infection, Special Care in Dentistry 12(1): pp24-27, 1992
6. Arendrup MCK et al, Semi-national surveillance of fungaemia in Denmark 2004-2006: Increasing incidence of fungaemia and numbers of isolates with reduced azole susceptibility, Clin Microbiol Infect 14(5): pp487-494, 2008
7. Bouckaert S et al, Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel, Eur J Clin Pharmacol 43: pp137-140, 1992
8. Cardot JM et al, Comparison of the pharmacokinetics of miconazole after administration via a bioadhesive slow release tablet and an oral gel to healthy male and female subjects Br J Clin Pharmacol 58(4): pp345-351, 2004
9. Lemarchand C et al, Plasma, saliva and labial mucosa pharmacokinetics and pharmacodynamics of acyclovir Lauriad mucoadhesive buccal tablet in healthy volunteers, Journal of Clinical Pharmacology & Clinical Pharmacokinetics 1: pp1-14, 2014
10. Engelen L et al, The relation between saliva flow after different stimulations and the perception of flavor and texture attributes in custard desserts, Physiol Behav 78(1): pp165-169, 2003
11. Bensadoun RJ et al, Comparison of the efficacy and safety of miconazole 50-mg mucoadhesive buccal tablets with miconazole 500-mg gel in the treatment of oropharyngeal candidiasis: a prospective, randomized, single-blind, multicenter, comparative, phase III trial in patients treated with radiotherapy for head and neck cancer, Cancer 112(1): pp204-211, 2008


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Pierre Attali is Chief Operating Officer at BioAlliance Pharma, in charge of Strategy and Medical Affairs. He has been working in academic hospitals in Paris for several years as a specialist in liver diseases. Pierre has held the position of Head of the Clinical Research Department at Synthelabo Research, and has also managed several biotech companies – OSMO, Molecular Engines Laboratories and Urogene.
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