Investigating Drug Properties in the Colon

Sustained release of a drug from an oral dosage form can be achieved by several methods as detailed elsewhere in this book (i.e. matrix tablets, osmotic pumps, multiparticulates, etc). However, due to the gastrointestinal transit time in the fasted state (from mouth to colon) being roughly 4 h, almost all nongastroretentive, sustained release dosage forms will require substantial absorption of the drug from the colon. The colonic environment is substantially different than the upper GI tract, with a limited amount of unbound water, complex transit through the ascending colon (colonic sieving), compaction of fecal material, high microbial content, and a thicker mucus layer lining the intestinal wall. All of these factors can contribute to

poor absorption of drugs from the colonic region. Proper assessment of the challenges that can be faced in the colonic environment can be evaluated using the following techniques:

• Regional drug absorption studies

• Stability studies in simulated colonic media

Human regional drug absorption studies, utilizing nasointestinal intubation or remote drug delivery capsules, have proven extremely useful in explicitly determining a drug's extent of absorption from various regions of the gastrointestinal tract. While cell membrane transport studies have grown increasingly predictive of human intestinal permeability, they remain an indirect measure of human intestinal absorption. Human regional absorption studies remain the gold standard in assessing the extent of absorption from different regions of the gastrointestinal tract.

Human regional absorption studies first began using a nasoenteric tube to administer the drug solution. Williams et al. [7] showed that when a ranitidine solution is delivered to the cecum, its extent of absorption is approximately 15% that of the same solution administered to the stomach. Figure 17.4 provides the plasma concentration profiles as a function of time when these solutions were administered via a nasoenteric tube to the stomach, jejunum, or cecum.

Using modern technology comprising remote drug delivery capsules, one can use a less invasive technique to obtain similar information. Pithavala et al. [8] used such remote drug delivery capsules to evaluate the regional absorption of ranitidine and obtained similar results to Williams [7]. One primary advantage of using intubation tubes is that one can study the impact of various infusion rates on absorption. However, the technique has the disadvantage of being invasive and does not enable the impact of dosing a powder, which was shown to be useful by Menon and coworkers [9].

Table 17.1 Relative bioavailability of Acipimox when administered as a powder to the distal small bowel or colon as the free acid or sodium salt, using the oral dose as the reference treatment (Adapted from [8])

Dosing location

Free acid or Na salt

Stomach (immediate release capsule) Free acid

Distal small bowel Free acid

Colon Free acid

Stomach (immediate release capsule) Na salt

Distal small bowel Na salt

Colon Na salt

12.88 ± 3.03 3.94 ± 3.08 1.66 ± 1.39 14.1 ± 1.81 7.34 ± 4.98 1.80 ± 1.49

Table 17.2 Extent of absorption from the colon for GlaxoSmithKline compounds and other compounds referenced in the literature

Literature (non-GSK)

Colonic absorption (%) GSK (% of compounds) (% of compounds)

0-30 50 38

Menon et al. [9] demonstrated the value of human regional drug absorption studies to guide the appropriate formulation strategy. These investigators compared the extent of absorption of the hypolipidemic agent, Acipimox when administered as a powder to the stomach, distal small bowel (DSB) and colon. The free acid and sodium salt forms of the drug were dosed to determine the role of drug solubility. Their results are shown in Table 17.1, and demonstrate that Acipimox is poorly absorbed from the colon (<15%) as both the salt and free acid, but that the more soluble sodium salt is better absorbed than the free acid from the DSB (~50% vs. 30%). These data demonstrate that Acipimox could benefit from a GRF.

In the past, colonic absorption was used to predict the likelihood to achieve a successful modified release product with conventional techniques. It was suggested that a colonic absorption of 60% or higher was very likely to be successful, between 30 and 60% was difficult but achievable, and less than 30% was not likely to be successful with conventional techniques [10]. Therefore, the group of compounds which had a colonic absorption of less than 30% would be good candidates for a GRF. Table 17.2 provides a breakdown of GlaxoSmithKline (GSK) compounds and compounds from the literature in regard to their extent of absorption from the colon.

Based on these data it is clear that a high percentage of compounds suffer from poor colonic absorption and would be good candidates for a GRF.

Another factor that can steer product development toward a gastric retentive dosage form is the gastrointestinal stability of a drug candidate. In the fasted state, the typical transit time from mouth to the colon is 4 h. Therefore, if the duration of drug release required to obtain the target pharmacokinetic profile is more than 4 h, the drug could spend a significant amount of time in the colon. Basit et al. [11] demonstrated the susceptibility of drugs to degradation in the colon. Using a batch culture fermenter, they showed that essentially no nizatidine was intact after 12 h of incubation. Conversely, the H2-receptor antagonists cimetidine and famotidine showed no significant degradation after 24 h. These data highlight another typical challenge for successful sustained release of a drug using a conventional dosage form, while a gastric retentive dosage form enables this challenge to be avoided.

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