Biorelevant media were initially proposed in 1998 to study the dissolution of poorly soluble drugs in the gastrointestinal (GI) tract. Over time, different media have been developed to mimic various parts of the GI tract in both fasted and fed states. For the fasted state, there are specific biorelevant media for the stomach, small intestine, and colon. The stomach is represented by FaSSGF, which simulates reduced surface tension. The small intestine is simulated by FaSSIF-V1, imitating basal bile secretion in the upper SI. There are two additional versions, V2 and V3. The colon conditions in a fasted state PK study are represented by FaSSCOF.
In contrast, for the fed state, biorelevant media are designed to represent the stomach, small intestine, and colon after a standard breakfast. The fed state stomach media includes FeSSGF, a milk/buffer pH 5 combination, and FeSSGEm, which substitutes milk with Lipofundin to address analytical issues. In recent papers, FeSSGEm is referred to as FeSSGF. The small intestine media in the fed state is FeSSIF-V2, which mimics postprandial bile secretion, lipolysis products, increased buffer capacity, and osmolality in the upper SI after food intake. Finally, the colon in the fed state is simulated by FeSSCOF, representing the ascending colon conditions.
At Level 0 of biorelevant media, the focus is on simulating the luminal pH in the gastrointestinal tract without considering other dosing conditions. This level is particularly useful for certain types of APIs and drug products, especially for those classified under Development Classification System (DCS) class I or III.
The media used for Level 0 should have a pH value within the usual gastrointestinal pH range. Examples of suitable media include distilled water, purified water, or buffer systems. Compendial test solutions, such as simulated gastric and intestinal fluids without enzymes, can also be used. In these solutions, the choice of buffer capacity is made to maintain the pH of the test solution during the experiment, rather than replicating the physiological buffer capacity.
For APIs classified under DCS class I or III, Level 0 biorelevant media is particularly relevant in dissolution experiments of immediate release products. The dissolution experiments are conducted using compendial dissolution apparatus and specific pH buffers, such as pH 1.2, 4.5, and 6.8. The main goal of these experiments is to conservatively evaluate whether the dissolution of the dose is completed faster than the gastric emptying process.
By ensuring that dissolution is faster than gastric emptying under the conditions of administration, it is established that gastric emptying is the more limiting factor affecting drug absorption. This leads to the creation of a ‘safe space’ for dissolution, which means keeping dissolution within the lower 90% confidence limit boundary for gastric emptying limit. By doing so, it guarantees reproducible performance concerning this variable in-vivo.
However, in cases where dissolution rates are much slower than gastric emptying rates, Level 0 biorelevant media might still be sufficient for developing in-vitro in-vivo correlations (IVIVCs). This is especially true when the dissolving compound is not ionizable. A well-known example of this is the landmark series of studies conducted with digoxin products in the early 1970s.
Moreover, Level 0 biorelevant media can be beneficial in developing IVIVC models for certain DCS class I or III APIs housed in specific extended-release (ER) products. This applies when drug release is solely sensitive to pH or not sensitive to environmental conditions. Some illustrative examples of this include the development of IVIVC models for modified-release (MR) products of caffeine and an osmotic pump of salbutamol using Level 0 biorelevant media.
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Resource Person: Prakash Amate