Yuen, Kah Hay; (1991) Gastrointestinal transit and bioavailability of a novel sustained release theophylline formulation. Doctoral thesis (Ph.D.), University College London.

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Abstract

A novel multiunit sustained release theophylline preparation has been formulated and assessed. Spherical pellets containing 80% theophylline were formed using an extrusion/spheronisation technique before being coated with an ethylcellulose-methylcellulose mixture using a fluidized bed coater. In-vitro dissolution studies established that satisfactory pH-independent release profiles were achieved, and that the rate of drug release could be varied in a predictable manner by manipulating the coat thickness. With additional thermal treatment of the coat, drug release was stable after storage of the products for one year. In- vivo evaluation of the preparation in healthy human volunteers, produced serum concentration profiles that were reflective of a controlled and sustained drug release, with complete bioavailability. A satisfactory correlation was also obtained between in-vitro and in-vivo results. Further comparison with a commercial preparation, Uniphyllin, showed that the two products were bioequivalent when dosed fasted. In the fed mode, the rate of theophylline absorption from Uniphyllin was significantly increased, whilst that of the novel preparation was essentially unaffected, although a slight delay in absorption was noted. However, for neither preparation was the amount absorbed influenced by food status. Gastrointestinal transit studies of the novel preparation using a gamma-scintigraphic technique, revealed that the presence of food delayed the gastric emptying, but was without influence on the small intestinal transit time. The delay in gastric emptying was associated with a delay in drug absorption. For both fed and fasted states, the rate of absorption whilst the pellets were in the stomach was slower than when the pellets were in the small intestine. The pellets were less well dispersed in the stomach than in the small intestine or colon. Moreover, whereas only 14% of drug was released in the stomach, 46% was released in the small intestine. It is interesting that the remaining 40% of the drug was taken up from the colon, which thus acts as a significant site of absorption.

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