Drug Targeting Organ-Specific Strategies

• Colonic microflora produce a variety of enzymes that are not present in the stomach or the
small intestine and can therefore be used to deliver drugs to the colon after enzymatic
cleavage of degradable formulation components or drug carrier bonds (enzyme-controlled
drug release). It should be taken into consideration that because of the negative redox
potential in the colon, enzymatic or chemical reduction reactions are favoured.
• The relatively constant transit time in the small intestine of approximately 3–4 h is another
physiological characteristic which can be exploited to achieve colon specificity (timecontrolled
drug release). After gastric emptying, a time-controlled drug delivery system is
intended to release the drug after a predetermined lag phase.
• Another strategy relies on the strong peristaltic waves in the colon that lead to a temporarily
increased luminal pressure (pressure-controlled drug release). Pressure-sensitive
drug formulations release the drug as soon as a certain pressure limit is attained, i.e. destruction
force is exceeded.
Using mostly anti-inflammatory model drugs or drugs that are absorbable in the colon,
many colon-specific dosage forms have been developed in the past, including pro-drugs,
cross-linked hydrogels, matrices and coated dosage forms. However, whereas the synthesis of
pro-drugs is possible only if the drug has suitable functional groups that can be bound to a
carrier molecule, biodegradable hydrogels and matrices are problematic insofar as polymer
degradation rates and thus drug release are often too slow. Most colon-specific drug delivery
systems belong to the group of coated dosage forms because of the flexibility in the design of
the latter and the improved coating procedures that have been developed in the past.
With regard to peptide and protein absorption poor membrane permeability, enzymatic instability,
and large molecular size are three factors that have remained major hurdles for peptide
formulations. Absorption-enhancing agents that have been effective, at least in research
environments with smaller drug candidates, have also shown some limited efficacy in small
animal models with certain peptides. In most cases, however, effective formulations have
only achieved fairly low peptide absorption (< 10%) and have also resulted in significant alterations
in the normal cellular morphology of the gastrointestinal tract, at least on a transient
basis [13]. Current data suggest that the successful development of oral peptide formulations
remains a significant challenge.
6.4.1 pH-Controlled Drug Release
6.4 Approaches to Colon-specific Drug Delivery 161
Many of the marketed dosage forms developed for colon-specific drug delivery, such as the
enteric coated formulations Asacolitin ® , Azulfidine ® , Claversal ® , Salofalk ® , Colo-Pleon ® ,
Entocort ® and Budenofalk ® rely on the physiological pH difference between the small and
the distal large intestine. In healthy subjects this pH difference amounts to about 0.5 pH units
[4,5] (Figure 6.2). However, it has been shown that this difference in pH between the small
and the large intestine is too small to guarantee reliable drug release in the colonic region
[14–16]. Moreover, in patients with inflammatory bowel disease the luminal colonic pH drops
to values between 2.5 and 4.7 [17–19], a fact that has been attributed to a failure of bicarbonate
secretion rather than excessive bacterial fermentation [18].
Enteric coating materials not only protect a dosage form from the acidic environment in
the stomach and allow drug delivery to the small intestine, they may also pass through the