Drug Targeting Organ-Specific Strategies

164 6 A Practical Approach in the Design of Colon-specific Drug Delivery Systems
Css Tissue (Pro-drug)
Css Tissue (Drug)
Css Blood DDI (Pro-drug vs. Drug) = (6.1b)
(Pro-drug)
Css Blood (Drug)
where Css is the steady-state drug concentration
The numerator of Eq. 6.1a describes to what extent drug concentrations are increased in
the target tissue (colonic mucosa or muscle tissue) after pro-drug administration as opposed
to drug administration. It may be regarded as the factor by which the pro-drug dose could be
reduced in comparison to the drug dose. The denominator of Eq. 6.1a, which corresponds to
the relative bioavailability of the drug released from the pro-drug, provides a measure of the
reduction in the systemic exposure and thus the decrease of the systemic toxicity. In Eq. 6.1b
the DDI is defined as the quotient of the tissue to blood concentration ratios after pro-drug
and drug administration. With glucoside, glucuronide and dextran pro-drugs DDI values up
to 9.7 have been reported in rats [25,38,39].
A disadvantage of the use of pro-drugs is the need for suitable functional groups such as
amino-, hydroxy- or carboxy groups in both drug and carrier molecules (see Chapter 11 for
more details on chemical synthesis routes applied in drug targeting/delivery strategies).
Sometimes spacer molecules are necessary to link the drug to the carrier molecule, which often
leads to complicated drug release kinetics. Another disadvantage of the pro-drug approach
is the fact that for the approval of any newly synthesized pro-drug a toxicity study is
required by regulatory agencies.
The group of enzymatically degradable coating materials comprises film-forming azo polymers
and polymers with glycosidic bonds as well as conventional sustained release coating
materials based on acrylates or ethylcellulose with biodegradable pore formers. The films
must not be soluble or degradable in the upper GI tract. They should only be degradable in
the colon and their degradation products need to be toxicologically harmless.
Cross-linked azo polymers were the first coating materials that were investigated with regard
to their enzymatic degradability in the colon using insulin as the model drug [40,41]. A
problem observed with these polymers was the rather slow degradation rate, probably a result
of the lipophilicity of these compounds. Sufficiently hydrophilic linear azo polymers and
pH-sensitive terpolymers based on acrylates were found to be more suitable coating materials
[42–45].
In general, several problems have to be considered if azo polymers are used as an
enzymatically degradable component of a colon-specific dosage form [46]. As a result of
the enzymatic reduction to primary aromatic amines in the colon, the toxicity of these
polymers is a critical issue. Moreover, the rate of microbial reduction of the polymeric azo
compounds is often too slow. The reduction reaction may stop at the level of the hydrazo
compounds instead of leading to the amines, which may influence the drug release
mechanism and rate. In addition, the reduction reaction does not necessarily depend on the
presence of the azoreductase, but may be induced by the negative redox potential in the
colon. The latter also applies to the degradation of pro-drugs or polymers with disulfide
bonds, which is the result of a chemical reduction step with no enzymatic reaction involved
[47].