Advantages of targeting the oral cavity include the relatively large surface area for drug absorption [the total surface area is approximately 170 cm2 with the buccal membranes being approximately 50 cm2 of this total area (2)] and the ready accessibility of this site. The rich blood supply of the oral cavity is also advantageous for systemic absorption of drugs as well as the low metabolic activity within the mouth compared to the remainder of the GI tract. In the treatment of local infections the biggest advantage in targeting the oral cavity is retention of the dosage form, allowing prolonged exposure of the infection to the drug thereby enhancing the efficacy. This can also be coupled with zero-order release profiles that have been demonstrated with certain dosage forms. However, there are also disadvantages associated with drug delivery targeted within the oral cavity. These relate to the size of the dose that can be administered and this is of particular relevance for systemic absorption. Variability in bioavailability may also be an issue, due to variable saliva flow rates and clearance. Additionally, accidental swallowing of delivery devices designed for oral retention could be problematic. The two most important factors in formulation design for orally delivered formulations are taste masking and patient comfort, as these will dictate the compliance of such systems.
In a previous study, a comparison of release from chewing gum, sublingual tablets and lozenges was performed using 99mTc E-HIDA as a model hydrophilic agent. Gamma scintigraphy was used to visualize the distribution. No differences in distribution were observed among the three formulations in the oral cavity, esophagus, and glottis, although the duration within the oral cavity was greatest for the sublingual tablet and shortest for the lozenge (3).
Solutions, Suspensions, and Emulsions
There are many formulations readily available for the treatment of infections within the oral cavity. Reports suggest that fluconazole suspension may be better able to treat oropharyngeal candidiasis via a "swish and swallow"
technique (4) compared to the tablet formulation. The application of a suspension intended for systemic absorption has not been fully exploited yet, and this indicates that local action plays a part in therapy.
Daktarin gel is a popular therapy for mild oral infections, and this has been used successfully for many years although the high doses and relatively short retention time within the oral cavity means that it is less effective compared to more sophisticated delivery systems. Chitosan has previously demonstrated anti-fungal action, and this combined with chlorhexidine was examined as buccal gels or films for anti-fungal action by prevention of Candida binding to the mucosal surface. In vitro studies suggested that these formulations would provide prolonged levels of drug compared to oral rinses (5). Incorporation of amphotericin into Orabase prior to administration to the buccal mucosa resulted in sufficiently high salivary drug concentrations overnight to maintain therapy (6).
Buccal Tablets, Patches, and Films
Buccal tablets are small tablets designed for local administration to the buccal cavity. These can be subdivided into two categories: bioadhesive tablets that release drug in one direction into the buccal mucosa for systemic uptake and erodible tablets that erode within the oral cavity releasing drug into the saliva for both local action and systemic uptake from the oral cavity and the GI tract once swallowed. Buccal patches and films are similar to tablets in mechanism of release yet manufactured in different ways. Buccal patches refer to unidirectional release systems where an impermeable backing exists on one side of the formulation. Buccal films are flexible and have a larger surface area compared to tablets. Buccal tablets and films are generally manufactured with polymeric excipients that control the rate of drug release; these polymers may also have bioadhesive properties to retain the tablet/film within the oral cavity.
An orally erodible buccal formulation releases dissolved drug within the saliva providing an ideal means to treat local infections including mucositis. The rate at which an erodible device dissolves is dependant upon the formulation, with high molecular weight polymers providing sustained release.
A number of studies have been performed measuring bioadhesive strength and in vitro drug release from buccal tablets, patches and films for infection control. Many of the studies have been performed using miconazole as an antifungal agent (7,8); other studies have investigated clotrimazole (9); some chlorhexidine (10-12).
A comparison of a 10 mg once-daily mucoadhesive buccal tablet of miconazole with 400 mg once daily ketoconazole administered for systemic uptake was performed in HIV-positive patients with oropharyngeal candidiasis. The results demonstrated that the low dose treatment via the buccal tablet was not statistically inferior to the systemic treatment. Local therapy was associated with a lower incidence of gastrointestinal disorders and drug-related adverse events (13), demonstrating the advantages of advanced drug delivery over conventional systemic delivery.
Several studies have compared the salivary concentrations ofmiconazole from a buccal tablet to an oral gel, in all cases the dose within the tablet was much lower than the gel although both are designed for release into the oral cavity and local action (14,15). Buccal tablets, by providing sustained release, are more cost effective as lower drug loading is required. In one study, salivary miconazole pharmacokinetics of a once-daily 50 mg bioadhesive eroding tablet (Lauriad®, Bioalliance Pharma) was compared to a gel directed to be applied three times-daily with a total dose of 375 mg. The results demonstrated that salivary concentrations following the administration of the tablet were higher with prolonged duration above the MIC of some Candida species (16). Phase III studies have been carried out by Bioalliance Pharma evaluating the company's miconazole bioadhesive buccal tablet (Lauriad). The tablet has proven efficacy in cancer patients suffering from oropharyngeal candidiasis following radiotherapy, and this product is expected to launch in Europe in the very near future. In addition, this company is developing a follow-on product, acyclovir Lauriad for the treatment of oral herpes, utilizing the same delivery platform; they have completed a Phase I clinical study and a phase 2/3 study is expected in Europe in 2006 (http://www.bioalliancepharma.com/products.asp).
Orally disintegrating tablets (ODTs) are those that disintegrate upon contact with saliva within the oral cavity releasing the drug into the saliva for rapid uptake or local action. The demand for fast-dissolving/ disintegrating tablets or fast-melting tablets that can dissolve or disintegrate in the mouth has been growing particularly for those with difficulty swallowing tablets such as elderly and children. They are referred to using a range of terminologies: fast-dissolving, orodispersible, and fast-melting and the FDA has adopted the term ODTs.
ODTs disintegrate and/or dissolve rapidly in the saliva without the need for water, within seconds to minutes. Some tablets are designed to dissolve rapidly in saliva, within a few seconds, and are true fast-dissolving tablets. Others contain agents to enhance the rate of tablet disintegration in the oral cavity, and are more appropriately termed fast-disintegrating tablets, as they may take up to a minute to completely disintegrate. Increased bioavailability using such formulations is sometimes possible if there is sufficient absorption via the oral cavity prior to swallowing (17). However, if the amount of swallowed drug varies, there is the potential for inconsistent bioavailability. Patented ODTs technologies include OraSolv®, DuraSolv®, Zydis®, FlashTab®, WOWTAB®, and others.
A fluconazole orally dispersible tablet (100 mg once-daily) was prepared via microencapsulation of the drug to allow rapid dispersion of the drug. This was found to be effective for the treatment of oropharyngeal candidiasis (18). The ODT fluconazole tablet was bioequivalent to the solid dosage form of fluconazole (capsule) yet the salivary concentration of the drug was 63 times higher with the ODT compared to the capsule (18).
Chewable tablets are designed to be mechanically disintegrated in the mouth. Potential advantages of chewable tablets mainly concern patient convenience and acceptance although enhanced bioavailability is also claimed. This can be due to a rapid onset of action as disintegration is more rapid and complete compared to standard formulations that must disintegrate in the GI tract. The dosage form is an appealing alternative for pediatric and geriatric consumers. Chewable tablets are also desirable because they offer convenience for consumers, avoiding the necessity of co-administration with water, and creation of palatable formulations could increase compliance. A limitation with this system is that many pharmaceutical actives have an unpleasant bitter taste that can reduce compliance among patients.
Antacid and pediatric vitamins are often formulated as chewable tablets but other formulations include anti-histamines (Zyrtec®), antimotility agents (Imodium® Plus), antiepileptic agents (Epanutin Infatabs®), antibiotics (Augmentin Chewable), asthma treatments (Singulair®), and analgesics (Motrin®).
Augmentin chewable tablets show statistically similar pharmacokinetic profiles to the equivalent dose of Augmentin suspension (Augmentin prescribing information GSK, http://www.gsk.com/products/prescription_-medicines/us/augmentin_us.htm) in the treatment of severe dental infections, although a chewable tablet is more convenient and often associated with greater stability profile compared to liquids.
Medicated chewing gum is a drug delivery system containing gum base with a pharmacologically active ingredient that can be used for local delivery within the oral cavity or for systemic absorption. Chewing gum offers advantages in that it can be taken without water (similar to oral liquids) yet possesses stability and shelf life associated with solid dosage forms. In addition, the discrete nature and unit dose capabilities could also improve patient acceptability. Drugs that are intended for local action within the oral cavity may have low saliva solubility and chewing gum can assist in improving solubility and retention of the drug within the gum in the oral cavity. Disadvantages include the need for taste-masking of the active agent, and this has been reported to be problematic with chlorhexidine which also stains the teeth and tongue (19).
Chewing gums are formulated from water insoluble bases that incorporate elastomer to control the gummy texture and plasticizers to regulate the cohesion of the formulation. Fillers and water soluble sweeteners are also added as required. By altering the composition of the gum the release of the active ingredient can be manipulated. Factors affecting the release of medicament from chewing gum can be divided into three groups: the physicochemical properties of the drug, the gum properties, and chew-related factors, including rate and frequency. A special apparatus has been developed to measure drug release from chewing gums that accounts for these variables (Fig. 2). Drugs can be incorporated into gums as solids or liquids. For most pharmaceuticals, aqueous solubility of the drug will be a major factor affecting the release rate. In order for drugs to be released, the gum would need to become hydrated; the drugs can then dissolve and diffuse through the gum base under the action of chewing.
The promotion of sugar-free gums to counteract dental caries by stimulation of saliva secretion, which increases plaque pH aiding in the prevention of caries, has led to a more widespread use and acceptance of gums. Medicated gums for delivery of dental products to the oral cavity are marketed in a number of countries, for example, fluoride-containing gums as an alternative to mouthwashes and tablets or chlorhexidine gum for treatment of gingivitis. The potential use of medicated chewing gums in the treatment of oral infections has also been reported. Gums have been prepared containing antifungal agents such as nystatin (20) and miconazole (21) or antibiotics, such as penicillin and metronidazole for the treatment of oral gingivitis (22).
Base of chewing chamber
Figure 2 Schematic diagram of the chewing chamber of an in vitro chewing apparatus.
Clinical trials that compared miconazole oral gel with miconazole chewing gum demonstrated that the gum was at least as efficient as oral gel in the treatment of fungal infections within the mouth, although very low doses of the drug were released from the chewing gum indicating greater efficacy, likely to be due to the retention of the formulation within the oral cavity (21,23). Analgesic-antibiotic chewing troches and chewing gum have been used in post-operative care of tonsillectomized patients, however, this is now inappropriate considering sensitization and toxicology (24).
Lozenges are tablets that dissolve or disintegrate slowly in the mouth to release drug into the saliva. They are easy to administer to pediatric and geriatric patients and are useful for extending drug form retention within the oral cavity. They usually contain one or more ingredients in a sweetened flavored base. Drug delivery can be either for local administration in the mouth, such as anesthetics, antiseptics, and antimicrobials or for systemic effects if the drug is well absorbed through the buccal lining or is swallowed. More traditional drugs used in this dosage form include phenol, sodium phenolate, benzocaine, and cetylpyridinium chloride. Antifungal lozenges of AmB, and nystatin are also currently commercially available. These provide local therapy for oral infections and are used in early stage therapy prior to systemic delivery of azoles.
Lozenges containing both miconazole and chlorhexidine have been developed and initial studies demonstrated that, in comparison to a proprietary oral gel formulation, the bioadhesive lozenges produced much more uniform and effective salivary levels of miconazole over a prolonged period (25).
A novel wafer drug-delivery system intended for the treatment of microbial infections associated with periodontis is inserted into the periodontal pocket providing controlled drug release over four weeks (26). This formulation consists of poly(lactic-co-glycolic acid) (PLGA) as a primary bioerodible polymeric component, poly(ethylene glycol) as a plasticizer and encapsulation aid, and silver nitrate to provide the bioactive silver. Such sustained release is highly advantageous in terms of patient compliance. Existing products such as PerioChip®, a biodegradable, cross-linked gelatin matrix that is capable of maintaining an efficacious chlorhexidine concentration in gingival crevicular fluid for up to 7 days, are already on the market (www. periochip.com).
Adhesion of micro-organisms, such as C. albicans, is the first step in the establishment of infection; therefore, prevention of this step is a strategy in reducing infection incidence. The adhesion properties of antimicrobial agents has been examined at very low (sub-MIC) concentrations (27-30). More recent studies have examined bioadhesive polymers coating a surface as a means of modulating Candida adherence; Barembaum et al. (29) examined sodium alginate and chitosan as agents to prevent the first stage adhesion and thus combat infection and found that these agents had in vitro MIC values of 0.1% and 0.25% w/v, respectively (29). The use of non-drug loaded polymeric nanoparticles to disrupt microbial adherence was measured in vitro using buccal epithelial cells with a reduction in adherence observed, and this may be a future direction for prophylaxis of candidiasis of the oral cavity (30).
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