Oesophageal Adhesion Of Dosage Forms

There are normal anatomic narrowings of the oesophagus located at the cricopharyngeus, aortic arch and left main stem bronchus which increase the contact time of a bolus and hence are potential sites for adhesion in healthy subjects. It is well recognised that there is approximately a 20% incidence of adhesion of dosage forms to the oesophagus, particularly for tablets or capsules. Only 3% of patients are aware that the tablet/ capsule has stuck in the oesophagus16. The risk of adhesion of dosage forms to the oesophagus is increased to about 50% for people who take their medication whilst recumbent or semi-recumbent and/ or who take formulations with little or no water. If patients sleep whilst the dose form is lodged in the oesophagus, disintegration will be very slow since saliva production is greatly reduced compared to waking levels.

The recommended method of taking tablets and capsules to avoid oesophageal retention is upright, with a sip of water before the dose form and then at least 100 ml of water with the medication. Hospital dosing cups in particular should be marked with a minimum fill line for water to assist staff to give the correct amount when dosing patients, particularly since they are likely to be recumbent or semi-recumbent.

Although the outer surface of many dosage forms will rapidly disintegrate when placed in fluid under sink conditions, the small amount of fluid available in the oesophagus will only moisten the surface. If this quickly becomes sticky, then the dosage form has the potential to adhere, a problem that is exacerbated by the highly folded nature of the oesophageal lumen in the resting state which will press the sticky dosage form against the mucosa. The mucosa will partly dehydrate at the site of contact as the unit hydrates, resulting in formation of a gel between the formulation and the mucosa (Figure 4.5). The unit then disintegrates from its non-contact side. Disintegration of the lodged formulation is slow, firstly because the amount of dissolution fluid available is low, being dependent on the volume of swallowed saliva and secondly due to the reduced surface area available for dissolution.

In some patients, solid dosage forms will still adhere to the oesophagus even when reasonable volumes of water are taken, these patients may have reduced peristaltic pressures or have cardiac pathologies in which the left side of the heart is enlarged. In these patients liquid preparations should be used or alternative routes of drug administration should be explored to avoid oesophageal damage by delivery of high concentration of drug to a small area of mucosa.

Factors predisposing formulations to adhere

There have been many studies carried out examining the potential for various dosage forms to adhere in the oesophagus. The main discrepancies in the literature arise from whether the data is derived from in vitro preparations of animal oesophagus or human studies. In vitro studies often use isolated porcine mucosa. Here the formulations are moistened, placed in contact with the mucosa and the force required to detach them is measured. In vivo studies generally measure transit in humans using fluoroscopy or gamma scintigraphy. In the transit studies all the factors which influence the tendency of a formulation to adhere e.g. shape, size, density etc are measured, whereas the in vitro experiments only study the tendency of the surface layer to adhere.

Tablets are often coated to render them more acceptable to the patient or to protect the drug from gastric acid etc., but the coatings themselves may affect the tendency for formulations to adhere. In vitro studies using isolated oesophageal preparations have concluded that that hard gelatin capsules had the greatest tendency to adhere, followed by film coated tablets, uncoated tablets, with sugar coated tablets demonstrating the least adhesion17 18. It was estimated that hard gelatin capsules have 6 times the tendency to adhere than that of sugar coated tablets and 1.5 times that of soft gelatin capsules when calculated per unit area. The difference between hard and soft gelatin capsules in their tendency to adhere is not borne out in human studies16. Although coated tablets have significantly shorter oesophageal transit times than plain tablets, if they do lodge, they take longer to disintegrate. Coatings made from cellulose acetate phthalate, shellac, methacrylate copolymer and a copolymer composed from of vinyl acetate and crotonic acid all have a low tendency to adhere. The tendency of hydroxypropylmethylcellulose to adhere can be altered by incorporation of sucrose which reduces surface stickiness; conversely addition of lactose or titanium oxide and talc increases the tendency to adhere. In contrast, polyethylene glycol 6000 coating demonstrated the greatest tendency to adhere.

A variety of studies in humans have demonstrated that capsules lodge in the oesophagus with a much higher incidence than tablets10-12 19. If the passage through the oesophagus of a hard gelatin capsule is delayed for more than two minutes, it can absorb sufficient water to become adherent to the mucosa. Apart from gelatin, other materials which become sticky as they hydrate are cellulose derivatives and guar gum. Recently it was reported that guar gum, formulated into a slimming product, hydrated and formed a large viscous mass which was sufficient to cause oesophageal obstruction20. A further report of an anhydrous protein health food tablet, which adhered to the oesophagus so firmly that it had to be removed at endoscopy, shows that it is not only pharmaceutical dosage forms which have potential to stick, but now nutriceuticals also have to be evaluated for this possible hazard21.

Dosage forms are being developed which can be swallowed with little or no water. There has been some concern that material from these dose forms is retained in the mouth and oesophagus since they rely on saliva for clearance. The Zydis® formulation (Scherer DDS Ltd) is an examples of rapidly disintegrating solid dosage forms which can be taken without water. The general pattern of buccal clearance of the fast dissolving dosage form was either to dissolve rapidly in the mouth and hence clear with several swallows, or to pass intact through the oesophagus (Figure 4.6)12.

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