What makes a drug formulation ‘gastro-retentive’?
Over the past two decades, many schemes have been attempted to develop an all-purpose gastro-retentive platform for drug delivery. In retrospect, the concept seems unattainable. The stomach has the last say in what it will retain and what it will pass on to the intestine. However, many examples exist of drug formulations that have turned out to be gastro-retentive for many hours. Through the Absorption Rate Analysis, it has been possible to determine the conditions required for a drug product to be gastro-retentive. These are:
The drug substance must be a physical irritant to the stomach.
The drug formulation must mimic the effect of dosing with food.
One of the functions of the stomach is to protect the small intestine from potentially harmful substances. Its preferred response to a substance perceived as mildly harmful is to dilute it to a ‘safe’ concentration and release it slowly to the small intestine. This is the basis for gastro-retentive drug delivery. However, the stomach can also be harmed by the irritating substance and its capacity to regulate safe drug delivery is limited. Any formulation that makes it easier for the stomach to regulate delivery of an irritating drug substance can be considered to be gastro-retentive.
There is a common perception that a large, positive food effect for a drug is the result of more drug getting into solution. Examination of drug absorption rate profiles of a drug that absorbs primarily in the upper small intestine permits an alternative hypothesis. The peak absorption rate is a function of drug concentration and in this individual, is similar with and without food. However, the absorption time windows, which are a function of the gastric emptying rate, differ by several hours. For this irritating drug, food doesn’t lead to greater drug solubility but it does make the process of dilution and slow drug release easier for the stomach. How? The most likely answer is that food helps protect the stomach by dispersing the drug and reducing surface contact with the stomach lining. By reducing local irritation inside the stomach, the job of dilution and slow release becomes much easier. Any drug product that releases an irritating drug substance slowly and reduces drug contact with the gastric lining is likely to mimic the effect of dosing with food and may be properly termed a ‘gastro-retentive’ formulation.