The oral cavity is the point of entry for oral drug formulations but usually their contact with the oral mucosa is brief. In order to take advantage of some of the properties of the oral mucosa or to locally treat the mucosa, delivery systems have been designed to prolong residence in this area. The total surface area available for drug absorption is quite limited, being only approximately 100 cm2.
Absorption of drugs through the buccal mucosa was first described by Sobrero in 1847 who noted systemic effects produced by nitroglycerin after administration to the oral mucosa10. The lingual route of administration became established in clinical practice in 1897 when William Murrell introduced nitroglycerin drops for the treatment of angina pectoris. Subsequently, nitroglycerin was formulated in tablets for sublingual use and was renamed glyceryl trinitrate.
The blood supply from the buccal mucosa and anal sphincter, unlike the remainder of the gastrointestinal tract, does not drain into the hepatic portal vein, since these peripheral areas are not specialised for the absorption of nutrients. Drugs which are absorbed through the oral mucosa enter the systemic circulation directly via the jugular vein, thereby initially avoiding passage through the liver where they might otherwise be metabolized. Drugs which are swallowed in the saliva do not avoid first pass metabolism and will be subjected to degradation by digestive juices.
The oral cavity is rich in blood vessels and lymphatics, so a rapid onset of action and high blood levels of drug are obtained quickly. In many cases buccal dose forms can result in the same bioavailability as intravenous formulations, without need for aseptic preparations. Finally, they share with transdermal systems the advantage that treatment can be rapidly stopped by removing the dose form, although the buccal epithelium can act as a reservoir for administered drug after the delivery system has been removed. Ideally the plasma concentration versus time profile should resemble a square wave, similar to that seen after skin application of a glyceryl trinitrate patch, but this is not always achievable.
In order to be absorbed orally, the drug must first dissolve in the saliva. Extremely hydrophobic materials (those with partition coefficients greater than approximately 2000) will not dissolve well and are likely to be swallowed intact unless a specialized delivery system is used to present them to the mucosa. Saliva containing dissolved drug is constantly being swallowed, and this process competes with buccal absorption. As described in Chapter 1, a balance must be found between good dissolution (implying a large ionized fraction of drug) and a large unionised fraction of drug (implying poor solubility but good absorption). A partition coefficient range of 40-2000 has been found to be optimal for drugs to be used sublingually. The importance of partition can be seen in the absorption of p-substituted phenylacetic acids, which have approximately the same pKa. The buccal absorption at pH 6 is, (in order of increasing hydrophobicity): hydrogen—1%, nitro—1%, methoxy—3%, methyl—7%, ethyl—10%, t-butyl—25%, n-butyl—34% n-pentyl—49%, cyclohexyl—44% and n-hexyl—61%".
Not surprisingly, there are disadvantages to this route of administration. The buccal cavity, like the entire alimentary canal, behaves as a lipoidal barrier to the passage of drugs. Active transport, pinocytosis, and passage through aqueous pores play only insignificant roles in moving drugs across the oral mucosa, hence the majority of absorption is passive, and only small lipophilic molecules are well absorbed. Polar drugs, for example those which are ionized at the pH of the mouth (6.2-7.4), are poorly absorbed. Little intercellular absorption is possible across the cuboid squamous pavement epithelium of the oral cavity.
However, some amino acids such as glutamic acid and lysine12 and some vitamins such as L-ascorbic acid13, nicotinic acid14 and thiamine15 are reported to be transported via a carrier-mediated process.
Another major problem is that the dose form must be kept in place while absorption is occurring, since excessive salivary flow may wash it away. The total area for absorption is low compared to other routes, being in the region of 100-170 cm25. The taste of the drug must be bland, otherwise it will not be acceptable. The drug must also be non-irritant, and it should not discolour or erode teeth. This may be partly overcome by using a drug delivery system which has a unidirectional drug outflow which is placed against the mucosa. However, these systems do have the potential for lateral diffusion and back partitioning of the drug into the oral cavity.
Within the oral cavity, delivery of drugs can be classified into four categories: (i) sublingual delivery in which the dosage form is placed on the floor of the mouth, under the tongue, (ii) buccal delivery, in which the formulation is positioned against the mucous membranes lining the cheeks, (iii) local oropharyngeal delivery to treat mouth and throat and (iv) periodontal delivery, to treat below the gum margin. Variations in epithelia thickness and composition will undoubtedly affect drug absorption. The permeability of the oral mucosa has been reviewed by Squier and Johnson16. The usual test of buccal absorption measures the average value of penetration of the drug through all the different regions of the oral mucosa, even though it is likely that regional differences in absorption occur. It has been suggested that drug absorption through the sublingual mucosa is more effective than through the buccal mucosa, even though both these regions are non-keratinized. The sublingual epithelium is, however, thinner and immersed in saliva, both of which will aid drug absorption (Figure 3.5).
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