Drug Targeting Organ-Specific Strategies

166 6 A Practical Approach in the Design of Colon-specific Drug Delivery Systems
6.4.3 Time-controlled Drug Release
Time-controlled drug release mechanisms rely on the fairly constant small intestinal transit
time during which no measurable drug release occurs. Only after arrival of the dosage form
in the colon may drug delivery begin. Such a delayed release mechanism can be achieved using
compounds with swelling properties or osmotically active excipients, which leads to an increase
in volume by water uptake resulting in a build-up of pressure inside the dosage form.
After a predetermined lag phase the drug is released in a more or less pulsatile fashion, often
accompanied by rupture of the outer coating layer. Such a lag phase may also be achieved
with slowly eroding or dissolving coating layers [21]. In general, drug release from time-controlled
delivery systems may be pH-induced, induced by swelling, pressure-induced or erosion-induced.
Time-controlled drug release with pH-induced drug delivery is a delivery method that does
not depend on changes in the luminal pH of the GI tract but on a pH change within the
dosage form itself.
Colon-specific drug formulations relying on the time-dependent dissolution of basic polymer
layers such as Eudragit ® E and chitosan under acidic conditions have been developed by
Ishibashi et al. (CTDC: Colon-Targeted Delivery Capsule) [86–88] and Yamada et al. [89]. A
solid organic acid incorporated in the dosage forms which dissolves as soon as it comes into
contact with the penetrating intestinal fluid generates an acidic environment and induces the
dissolution of the basic polymer layers and thus drug release. The onset of drug release depends
on the thickness of the basic polymer layer or shell.
The organic acid-induced sigmoidal release system developed by Narisawa et al. consists
of a drug core containing a solid organic acid which is coated with an ammonio methacrylate
copolymer sustained-release coating (Eudragit ® RS) [90,91]. During a lag phase,
the drug permeability of the Eudragit ® RS film increases drastically as a result of diffusion of
the organic acid into the film thereby facilitating polymer hydration and inducing drug
release.
Drug delivery induced by swelling may be achieved with swellable polymer layers based on
cellulose ethers or acrylates, where with the latter pH-dependent swelling behaviour is feasible
[92]. Examples are the oral Chronotopic ® delivery system [93], the Time-controlled Explosion
System (TES) [94,95] and the TIME-CLOCK-System [96–98] (Figure 6.4).
Swelling polymers may also be used as plugs, i.e. stoppers, to seal water-insoluble capsule
bodies, as in the case of Pulsincap ® [99,100]. The delayed drug release observed after plug
ejection at the end of the lag phase, depends on the swelling properties of the polymer plug
as well as on the geometry and chemical structure of the plug.
Swelling sustained-release coating polymers such as Eudragit ® NE 30 D, i.e. poly(ethylacrylate-methylmethacrylate)
[101,102] or Eudragit ® RS [90], lead to a delay in drug release
which is dependent on the thickness of the coating since these films have slow rates of
swelling.
One dosage form available on the market which relies on pressure-induced delivery is the
COER-24 TM delivery system (Controlled Onset Extended Release).This formulation, developed
for drugs that can be absorbed in the colon, is similar to the OROS-CT TM system (Figure
6.3). Here, a polymeric delay coat is responsible for the delayed drug release. During the
lag phase the osmotic compartment swells resulting in pressure being applied to the drug