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Figure 3.9 Inter- and intrasubject variation in the rates of release of a water soluble marker from a buccal mucoadhesive tablet in design and range from simple credible systems, through non-erodible disks to laminated systems. Sizes vary from 1 to 15 cm2, but smaller patches are much more comfortable. Patches will release drug both against the mucosa and into the oral cavity unless a backing layer is used to prevent release on the external face of the patch. Laminated systems permit local alteration of pH and inclusion of permeation enhancers which can markedly increase transport of drug. The use of the covered system removes luminal influences, such as saliva, mucus and enzymes, the presence of intercellular lipids, hence the mucosal thickness and the blood supply become rate limiting. The residence time of a bioadhesive system within the buccal cavity will depend on a variety of factors such as the strength of the mucoadhesive bond, the relative flexibility of both the system and the mucosa onto which it is adhered and the salivary flow. Hydrogels are currently being investigated extensively as bioadhesive vehicles for buccal drug delivery. They are swellable hydrophilic matrices that release a drug through the spaces in the polymer network by dissolution and disintegration.

Gamma scintigraphy was used to study the rate of release of 99mTc DTPA49 from a buccal bioadhesive tablet (Figure 3.9). The tablet was designed to deliver glyceryl trinitrate and was based on a matrix of modified hydroxypropylmethylcellulose. The surface of the tablet quickly gels which serves both to anchor the tablet in position and to control the rate of diffusion of the drug48. The tablets are friable and the gel layer breaks on removal, and the in situ dissolution can be measured by gamma scintigraphy without disturbing the tablet. When the tablet was placed in the upper buccal pouch it was noted that between subjects there were marked differences in the rates of release, whereas within an individual measured on four occasions, the variation was quite small. This did not appear to be due to differences in saliva flow rate and the rate of dissolution, but interestingly may correlate with the extent to which the subject talked during the experiment. Articulation of the cheek surfaces during speech would increase the erosion of the tablet surface and hence the rate of release of the marker or drug into the buccal cavity. Drinking hot coffee or chewing gum did not affect the rate of release of marker. In general, when the tablet was placed behind the front incisors the rate of release of the marker was faster than when it was placed in the buccal cavity. The path of saliva flow in the human mouth can be monitored by measuring the distribution of charcoal particles placed at various locations in the mouth6. When the particles were placed under the tongue, the whole mouth became covered within 1 to 3 minutes, whereas administration to the lower right or left buccal vestibule covered that side of the tongue only. Hence, it is possible that salivary flow was responsible for the different rates of dissolution observed for the tablet.

Descriptions of a "semi-topical" buccal/gingival delivery system appeared in the literature about 12 years ago50. Lidocaine was delivered in an oral mucoadhesive tablet for the relief of toothache, or prostaglandin PGF2a into a gingival plaster for orthodontic tooth removal. Gingival absorption of lidocaine was poor due to the relatively low pH caused by the presence of carbopol-934, and more lipophilic derivatives such as dibucaine may be more suitable drug candidates. Studies in monkeys showed good results with the prostaglandin and limited clinical tests showed accelerated orthodontic tooth removal in 70% of patients studied.

Cydotâ„¢ (3M) is a flexible, mucoadhesive non-eroding disk which is placed on the gum. It has been used to deliver buprenorphene to volunteers and it is reported to remain in place for up to 17 hours regardless of food and drink consumed. The OTS (oral transmucosal system, TheraTech) is another commercially available device which has been used to deliver glucagon-like insulintropic peptide.

Dental systems

The use of antimicrobial agents in the treatment of chronic periodontal disease has utilised a variety of novel vehicles including hollow fibers, polymers (especially methacrylates) and oil-based vehicles to achieve sustained delivery of chlorhexidine, metronidazole and tetracycline. These materials are placed in the socket prior to occlusion with a dental appliance or wound dressing.

A controlled release compact containing tetracycline has been developed for treatment of severe forms of the diseases such as gingivitis, acute necrotising gingivitis, periodontitis and periodontosis51. The compacts (5 mm in diameter) were bonded to an upper molar and designed to release drug over a period of 10 days. The tetracycline reduced the quantity of plaque and gingival inflammation produced by the bacterial toxins around the gum margin. It is possible that similar systems can be developed to take advantage of the "leakiest" part of the buccal mucosa, the junctional epithelium.

A range of inflammatory, atrophic and ulcerative conditions occur in the mouth which justify the local application of corticosteroids52. The effect of the steroid reduces chemo-attractants which in turn reduces the migration of white cells and prevents the increased permeability of small vessels at the site of damage. The use of mucoadhesive patches promotes transmucosal absorption and extends the duration of effective administration. Mucoadhesive tablets based on a mixture of hydroxypropylcellulose and carbopol have been used for the delivery of triamcinolone53. Following application to the mucosa, the formulation draws in water which helps promote adhesion to the lesions and more effective treatment. Restricting the distribution of the steroid may also be advantageous since it is known that the use of topical aerosol sprays in the mouth may induce fungal infection.

DRUGS ADMINISTERED VIA THE ORAL MUCOSA Nitrates

The largest number of commercially available products for buccal and sublingual delivery are for organic nitrates (nitroglycerin (GTN), isosorbide dinitrate)54-58. GTN was rapidly and more effectively absorbed (30-60 s) from 2.5-5 mg buccal doses compared to a 10 mg transdermal patch. It was shown to be effective in prolonging the time to angina pectoris during exercise after a single dose, the effect lasting about five hours. Less convincing was its beneficial effect on heart failure in elderly patients in an open study over a minimum of fourteen days. Long-term therapy with buccal or transdermal glyceryl trinitrate may be associated with tolerance to drug action caused by sustained high plasma concentrations. Buccal nitroglycerin is reported to be a better prophylactic in the treatment of angina pectoris than sublingual nitroglycerin due to its longer duration of action, whereas both routes are comparable in the treatment of acute attacks58.

Steroids

Steroids such as deoxycorticosterone are absorbed through the oral mucosa, but a threefold increase in dosage over intramuscular injections is required59. Testosterone and methyltestosterone are more efficiently absorbed when delivered buccally than by the peroral route60 61. Methyl testosterone for treating hypogonadism and delayed puberty is available commercially in devices which utilise this route for delivery. A range of inflammatory, atrophic and ulcerative conditions occur in the mouth for which topical treatment of corticosteroids is indicated62.

Figure 3.10 Plasma morphine concentration after intramuscular and buccal administration Analgesics

Opioids (morphine, pethidine) are well absorbed with systemic availability and plasma concentrations which are similar to, or even higher than, that after intramuscular administration63 (Figure 3.10). The reduction in post operative pain is comparable from both routes of administration64. Buccal morphine was reported not to be as effective as intramuscular morphine in relieving preoperative anxiety and wakefulness but this may have been produced by the lower bioavailability of the drug from the buccal dose form used65 66. A later study demonstrated that intramuscular administration of morphine produced an 8 fold increase in plasma levels compared to buccal administration. Buprenorphine is available as a sublingual commercial product for the treatment of analgesia.

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Figure 3.10 Plasma morphine concentration after intramuscular and buccal administration Analgesics

Opioids (morphine, pethidine) are well absorbed with systemic availability and plasma concentrations which are similar to, or even higher than, that after intramuscular administration63 (Figure 3.10). The reduction in post operative pain is comparable from both routes of administration64. Buccal morphine was reported not to be as effective as intramuscular morphine in relieving preoperative anxiety and wakefulness but this may have been produced by the lower bioavailability of the drug from the buccal dose form used65 66. A later study demonstrated that intramuscular administration of morphine produced an 8 fold increase in plasma levels compared to buccal administration. Buprenorphine is available as a sublingual commercial product for the treatment of analgesia.

Antibiotics

The oral cavity contains a diversity of microorganisms and over 300 different species of bacteria have been identified in the mouth. The density of microorganisms is high and saliva, which derives its flora from the oral surfaces contains 107-108 bacteria per ml. Most bacteria in the mouth are commensals and may have a protective role against pathogenic bacteria. Oral infections are categorized as primary, where bacteria cause diseases such as caries, chronic gingivitis, and inflammatory periodontal disease, and secondary, which aggravate existing damage associated with contaminated tissue. Antibacterial agents are used in the treatment of chronic gingivitis and effective agents, such as chlorhexidine, can persist for many hours. Antimicrobial plaque inhibitors are effective in preventing the formation of, rather than destroying, established plaque.

Antifungals

The predominant oral fungal pathogen belongs to the genus Candida, but in patients with HIV infection, less common species such as Crytococci, Histoplasma and Mucorales are often found67. Nystatin has been incorporated into a controlled delivery system for buccal use, but amphotericin B and clotrimazole are only available as a suspension or lozenge68. Two prolonged-release dosage forms have been devised for the treatment of oral candidiasis:

chlorhexidine and clotrimazole, for therapy against Candida albicans, and also benzocaine and hydrocortisone to combat the pain and inflammation secondary to a candidal infection69. Interestingly only chlorhexidine and clotrimazole could be delivered in a controlled manner from the mucoadhesive patches, but release of all four drugs was controlled from the mucoadhesive tablets. Optimum release of the drugs over 24 h was achieved using sodium carboxymethylcellulose and polyethylene oxide combination tablets. Recently interferon-a has also been investigated for use against fungal infections of the oral cavity70.

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