5 15 30

Time (minutes)

Figure 3.5 Comparison of isosorbide dinitrate absorption when drug is presented by the buccal and sublingual route

The rate of dissolution of the formulation may be position dependent, due to variations in its proximity to the major salivary gland and the water content of the saliva produced. The sublingual route is not suitable for the production of extended plasma concentration-time profiles, since absorption is completed quite quickly as the epithelium in the area is very thin (approximately 100 pm). This rapid absorption can lead to high peak plasma concentrations which may be overcome by delivering the drug to the thicker buccal mucosa which slows absorption. The metabolic activity of the oral mucosa and that of the resident population of bacteria can alter or degrade drugs17.

The barrier function of the surface layers of the buccal epithelium depends upon the intercellular lipid composition. Epithelia which contain polar lipids (Table 3.1), notably cholesterol sulphate and glucosyl ceramides, are considerably more permeable to water than keratinized epithelia18-20. Intracellular lamellae, composed of chemically unreactive lipids, have been described in human buccal mucosa, and may be relevant to drug permeability21.

During normal activities such as eating and drinking, the humidity and temperature in the oral cavity will be highly variable. The tongue is a highly sensitive organ and hence any device placed in the oral cavity will have to withstand being probed and explored by it, a process which the average patient will perform almost unconsciously. The sublingual area moves extensively during eating, drinking and speaking, so attachment of a delivery device to this region is likely to be impossible22.

Intercellular junctions do not appear to affect the permeability of these tissues and it is possible that the presence of the intercellular barrier is not due to the distribution of the keratinized and non-keratinized layers, but rather to the presence of membrane-coating granules16. Membrane coating-granules are spherical or oval organelles, about 100-300 nm in diameter which are found in many stratified epithelia. These granules usually appear in the cells of the stratified spinosum in keratinized epithelia. As differentiation proceeds, they are discharged into the intercellular spaces by exocytosis. Membrane coating granules in keratinized epithelia have a structure of parallel lamination, whilst those in non-keratinized epithelia do not, but have an enclosed trilaminar membrane with finely granular contents which aggregate centrally. These organelles are absent from junctional epithelia and at the gingival margin, the areas of highest permeability. The barrier which the granules produce exists in the outermost 200pm of the superficial layer.

Two tracers which differ in size have been used to study the effective barrier produced by membrane coating granules. These are horseradish peroxidase (m. w. 40,000 Dalton, 56 nm in size) and colloidal lanthanum (2 nm in size) which are both hydrophilic and hence would be confined to aqueous pathways23. When applied topically these tracers only penetrated the first three cell layers, but when introduced subepithelially, they extended through the intercellular spaces into the basal cell layers of the mucosal epithelium. In both keratinized and non-keratinized epithelia, the limit of penetration was related to the presence of the membrane-coating granules, implying that they cause a major barrier to penetration.

Gingival penetration

The gingival sulcus (Figure 3.6) is lined on its external surface by oral sulcular epithelium, which is continuous with the oral epithelium, but it is non-keratinized and has similar permeability to the oral epithelium. However, the "leakiest" area of the oral mucosa is the junctional epithelium in the gingival sulcus. This area has been studied extensively with respect to inflammatory periodontal disease. It is well documented that enzymes, toxins and antigens from plaque enter into the local tissue through this route and produce an immune inflammatory response in the tissue. Radioisotope and fluorescent compounds injected systemically can be detected at the surface. In healthy people, the sulcus is shallow

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