Buccal Delivery: Simple Physical Chemical Considerations

René Holm

Efficient treatments options that are acceptable for both the patients and the physicians are the corner stones in drug development within the pharmaceutical industry.

Oral administration is the preferred route of administration as this route is normally associated with the highest patient compliance, what novel drug delivery systems must offer in particular better therapeutic outcomes compared to e.g. oral administration. One of these alternative delivery routes is oral transmucossal drug delivery – or just buccal delivery.

Buccal delivery has been explored intensively during the last decade to overcome the disadvantages of oral drug delivery. Absorption of the compound over the mucosal membrane includes bypass of first-pass metabolism and the avoidance of presystemic degradation in the gastro intestinal tract (1-3). Buccal delivery can be used for both systemic and local effects.

On the down side the relative small surface area of the oral mucosa, a limited amount of aqueous media to solubilise the dose before absorption and the significant loss of drug due to uncontrolled swallowing and salivary flow – this combined with high requirements for good organoleptic properties are the main limitations of buccal delivery.
Two important parameters for imA key issue for buccal absorption is the permeability of the drugs through the buccal mucosa. A basic assumption is that the permeability and the local environment adjacent to the mucosa can be changed to enhance drug permeation (1;4).
Most drugs delivered successfully via the buccal route are thus small dose molecules with a LogP from 1.6 to 3.3 whereas large hydrophilic molecules are generally poorly absorbed (5). LogP is by definition the partition of the unionised form of the molecule, however, as many compounds are acids or bases they may be ionised at physiological pH. A better way of evaluating the ionisation of compounds is therefore measurement of their LogD values. LogD is defined as the partitioning between octanol and an aqueous buffer at a defined pH, e.g. pH 7 as in the mouth.
The degree of ionisation of a compound is thereby influence by the concrete pH, which influences the relative lipophilicity – an important parameter for buccal absorption (6). The influence of the degree of ionisation on the permeability of a drug has been tested in several in vitro studies (7-11). Common to these studies, the buccal absorption depends on the degree of ionisation of the drug. In vivo studies with dogs and humans (12-14) have also confirmed that the buccal absorption depends on the degree of ionisation. The overall learning is therefore that the pH in the formulation should be adjusted to ensure that a sufficient fraction of the compound is un-ionised to maximise the permeability, though with reflections to local toxicity.
The other important parameter, solubility, has been systematic evaluated to a much lower extent following buccal delivery. Wang et al. described a maximal buccal permeability of propranolol at pHmax (15). Wang et al. defined pHmax as the pH value with the maximal aqueous solubility for a given drug (15).The data was obtained from in vitro models with buccal pig mucosa and from one in vivo study in pigs. Administration at pHmax can be important from a solid formulations where the solubility and solubility rate of a drug is a limiting factor, as drugs are only absorbable in its dissolved form. However, a maximal aqueous solubility is not necessarily comparable with a high permeability for an ionisable drug, why these two factors needs to be balanced in the formulations.
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