INTRODUCTION With the various types of oral extended-release (ER) dosage forms available, it is a challenge to accurately predict their in vivo behavior. If therapeutically appropriate, an oral ER dosage form should provide consistent drug release over the entire dosing interval, regardless of when it is given in relation to meal intake. Experience has shown, however, that this cannot be generally assumed to be the case. Substitution of one ER formulation for another or administering the same formulation under varying dosing conditions (e.g., fasted versus fed state) can have unexpected results. Unwanted effects that have been described during the last decades range from “dose-dumping” to sub-therapeutic plasma levels (1–3). As these unwanted side effects may result in severe risks for the patients, it would be highly desirable to be able to forecast the in vivo release rates under various dosing conditions using in vitro data. The aim of these experiments was to develop an in vitro test method that can discriminate dissolution performance among ER dosage forms of a given drug, with view to predicting in vivo differences. Theophylline is a particularly suitable example for this purpose. This drug represents one of the cornerstones in the management of both the acute and chronic phases of reversible airway obstruction (4). However, because the drug has a narrow therapeutic index, the efficacy and toxicity of the active drug are highly dependent on plasma theophylline concentration (5). Optimum therapeutic serum level concentrations are generally considered to range from 8 to 15 μg/mL (6–8). The incidence of serious side-effects (ranging from nausea, vomiting, abdominal cramps, and diarrhea to arrhythmias, tremor, agitation, and convulsions) increases with concentration, particularly beyond the upper end of the usual therapeutic plasma theophylline range (5, 8). Toxic symptoms commonly occur at serum concentrations greater than 25 μg/mL but are typically not noted below 15 μg/mL (8). Thus, it is very important to maintain serum drug levels in the therapeutic range. When given as a solution or an immediate-release (IR) dosage form, theophylline is rapidly and completely absorbed along the small intestine and the colon (9–12). As the elimination half-life of theophylline is short (4–9 h), 4to 6-hourly administration of IR dosage forms is required to maintain the serum concentration within the therapeutic range (12). With such a regimen, lack of patient compliance is a serious problem, and low trough levels in the morning, with a possible risk of breakthrough of symptoms, can occur (13). Accordingly, ER dosage forms are the formulations most favored for the long-term management of chronic bronchospasm. Given only once or twice daily, they should result in more constant plasma levels, increase patient compliance, and avoid therapeutic gaps while preventing serious side effects. An ideal ER product should demonstrate complete bioavailability, minimal fluctuations in drug concentration at steady state, reproducibility of release characteristics independent of food, and minimal diurnal variation. However, with the first ER formulations, it became clear that not all meet the requirements of an ideal theophylline ER product. It was shown that in many cases, drug release from various theophylline ER formulations could be influenced (either increased or decreased) by concomitant intake of food (1, 3, 14–18). Although in maintenance therapy of chronic obstructive lung disease, most drugs are given in conjunction with food, the recent literature contains very few in vivo studies (1, 5, 13, 18–20) and next to no in vitro investigations (21) of the influence of food on the bioavailability of theophylline from ER formulations. Food intake can influence the rate of drug release from the dosage form, the rate of drug absorption, the amount of drug absorbed, or all of these parameters simultaneously. The rate of drug release of various ER formulations can be affected by the composition of the intraluminal contents, which itself is at least partly determined by the size and the composition of the co-administered meal. Depending on the type of dosage form and the intraluminal conditions, a co-administered meal can result in both so-called “positive” and “negative” food effects. Positive food effects typically come along with an increase in drug release from ER formulations and in the worst case, can represent a great risk for the patient, particularly when a large amount of the dose is dumped within a short period of time (22, 23). Such positive food effects are often the result of the loss of the integrity of matrices or coatings (i.e., devices that control drug release of ER dosage forms). It has been observed that fats, high concentrations of bile components, and pH changes (18, 22) are typical triggers for increased drug-release rates.
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Dec 6, 2020
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