Studies on the Delivery Mechanisms of Theophylline from a Sustained Release Tablet

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Abstract
The in-vitro and in-vivo release of theophylline from an oral sustained release tablet (TheogradR) was studied. The in-vitro release profiles were determined by means of the rotating basket method, the paddle method and the modified disintegration method, described in the USP XX as apparatus 1, 2 and 3 respectively. Besides a stationary basket-rotating paddle method was used. It was demonstrated that in the stationary basket-rotating paddle apparatus and in the paddle apparatus at low rotational speeds of the paddle, mild agitation conditions were created. Under these conditions the release of theophylline from the sustained release tablet appeared to be matrix controlled. The leached matrix was found to be structurally very weak. For a matrix type of sustained release tablet this is probably beneficial as it would be less likely to cause accumulation and gastro-intestinal obstruction. In contrast the conditions of agitation in the rotating basket apparatus and in the disintegration apparatus were found to be rather severe. This was partly due to mechanical abrasion of the dosage form caused by the gauze of the basket and the basket-rack respectively, and partly the result of high solvent agitation, especially in the disintegration apparatus. Under these conditions it appeared that the empty matrix of the sustained release tablet eroded during the release process. This was confirmed by the results of studies under non-dissolving circumstances of the drug which showed that in this case only the leached matrix of the sustained release dosage form eroded and not that part of the dosage form from which the drug had not yet been dissolved. The in-vivo absorption appears to relate to the in-vitro release. When the Theograd tablet was taken on an empty stomach, it appeared that the absorption rate could succesfully be simulated by means of the stationary basket-rotating paddle method and the paddle method, both at low rotational speeds of the paddle. It was very likely that in this case the in-vivo release from the sustained release tablet was matrix controlled too. Under these conditions the bioavailability was found to be 65% compared with an oral solution of the drug. In contrast, when the Theograd tablet was taken after a meal, a relative bioavailability of 90% was observed. It was made plausible, that the greatly enhanced bioavailability, observed on postprandial administration of the tablet, was due to partial erosion of the leached matrix. This erosion was caused by the food induced increased motility of the gastro-intestinal tract. Based on the results of this study it is recommended to take TheogradR tablets after a meal.