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reviews

Coated dosage forms for

colon-specific drug delivery
Claudia S. Leopold
Coating materials used in the manufacture of colon-specific solid
oral dosage forms include polymers with a pH-dependent solubility
that rely on the difference in pH between the small and the distal
large intestine (pH-controlled release), polymers with a slow or pHdependent rate of swelling, dissolution or erosion that take advantage of the constant small intestinal transit time (time-controlled release), polymers that are degradable by the microbial enzymes in the
colon (enzyme-controlled release) and polymers that form firm layers
that are destroyed by an increase of the luminal pressure in the colon

in this lower part of the large intestine, where the

solid faeces are formed6. It should be mentioned
that drug absorption from the colon is affected
by the small effective surface area available for absorption and the tight colon epithelium; however,
colonic transit time can last for up to 78 h,
thereby allowing the absorption of even drugs of
low permeability.
Four strategies are currently being pursued to
achieve drug release specifically in the colon.

caused by peristaltic waves (pressure-controlled release). This review

gives an overview of coated dosage forms that have been developed
to achieve colon specificity.

Drug delivery to the colon has become attracClaudia S. Leopold

Department of
Pharmaceutical Technology
Heinrich Heine University
Universittsstrasse 1
40225 Dsseldorf
Germany
tel/fax: 149 2 1181 14225
e-mail: leopold@uniduesseldorf.de

tive to researchers interested in the delivery of

peptide drugs to the large intestine and the topical treatment of diseases of the colon. Because of
the unique physiological characteristics of the
large intestine, drug delivery to the colon can be
achieved in different ways. One such feature is the
colonic microflora (bacterial count 10111012 cfu
ml21), which consists mainly of anaerobic or facultative anaerobic microorganisms1 that produce
a variety of enzymes2. The ability of the colon to
support an anaerobic bacterial flora is shown by its
redox potential of between 2250 and 2480 mV
(Refs 3,4). A further characteristic is the slightly
acidic environment in the proximal colon
(pH 6.06.4), which results from the degradation of poly- and oligosaccharides to short-chain
fatty acids, and a neutral or slightly alkaline environment in the distal colon (pH 7.07.4)5.
Moreover, as a result of the strong and prolonged
propulsive motility in the distal colon that occurs
once or twice a day, the luminal pressure and thus
potential destructive forces increase temporarily

The fact that the luminal pH of the healthy

distal colon is slightly higher than that of the
proximal small intestine has led to the development of oral dosage forms that are intended
to release the drug at the colonic pH (pHcontrolled drug delivery).
The colonic microflora produce a variety of
enzymes that are not present in the stomach
or the small intestine and could therefore be
used to deliver drugs to the colon after enzymatic cleavage of degradable formulation
components or drug carrier bonds (enzymecontrolled drug delivery). It should be taken
into consideration that because of the low
redox potential in the colon, enzymatic or
chemical reduction reactions are favoured.
The relatively constant transit time in the
small intestine approximately 35 h is another physiological characteristic that can be
taken advantage of to achieve colon specificity
(time-controlled drug delivery). 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 (pressurecontrolled drug delivery). Pressure-sensitive
drug formulations release the drug as soon as
a certain pressure limit is exceeded.

1461-5347/99/$ see front matter 1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00151-0

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PSTT Vol. 2, No. 5 May 1999

Many colon-specific dosage forms have been developed in

the past, including prodrugs, crosslinked hydrogels, matrices
and coated dosage forms. However, whereas the synthesis of
prodrugs is possible only if the drug has suitable moieties that
can be bound to a carrier molecule, with biodegradable hydrogels and matrices slow degradation rates leading to slow drug
release often represent a problem. Because of the widespread
use of coated dosage forms, resulting from improved coating
technologies and flexibility in their design, this review will
focus on the variety of coated dosage forms that have been developed for oral colon-specific drug delivery.
pH-controlled drug release
Several commercial drug formulations designed for colon-specific drug delivery rely on the physiological difference between
the luminal pH of the acidic stomach and that of the distal small
intestine. If the intended site of drug release of the coated dosage
form is the colon, it must be taken into consideration that, between the terminal ileum and the transverse or distal colon, there
is a slightly acidic region in the proximal colon that might affect
drug release profiles and the reproducibility of drug release.
Enteric coatings primarily protect solid oral dosage forms
against the acidic environment in the stomach. They dissolve
rapidly in the lumen of the small intestine where drug release
from delayed release dosage forms usually depends on the dissolution pH of the polymers and the pH of the lumen. However,
if the terminal ileum or the colon is the target organ for the
drug, the start of the drug release must be further controlled by
increasing the thickness of the coating, allowing a pH- and
time-controlled polymer dissolution and drug release process.
Thus, drug release from many of the coated dosage forms
designed for pH-controlled drug delivery to the terminal ileum
or colon will also depend on the transit time through the small
intestine. These dosage forms therefore usually represent combined pH and time-controlled drug delivery systems for which
time-controlled release can be achieved by selecting a suitable
coating level7,8. For further control of drug release in the colon

after dissolution of the enteric coating in the terminal ileum,

sustained release coating materials such as Eudragit RL, RS, NE
or ethylcellulose913 can be used as an undercoating.
Many commercial drug formulations for the oral treatment
of inflammatory bowel disease (such as Asacolitin, Claversal,
Salofalk or Budenofalk) are coated with pH-sensitive enteric
coating polymers such as Eudragit L or S (Table 1).These polymers have a dissolution pH of between 6 and 7, and are intended to release the drug as soon as the intestinal pH exceeds
6 or 7, respectively. However, studies with Eudragit S-coated
tablets in humans have shown that drug release in the colon is
not sufficiently reproducible14,15. Disintegration sites vary from
the ileum to the splenic flexure, indicating a lack of site specificity, although results from other studies support the feasibility of this targeting method1618.
One reason for these inconsistent results is the drop in pH beyond the ileocecal junction, which results from extensive microbial degradation of polysaccharides and oligosaccharides to
short-chain fatty acids. It is only in the distal part of the colon
that a pH of approximately 7 is reached and this differs only
slightly from the average pH in the small intestine, which is
6.56.8 (Ref. 5).Thus, drug release may occur in the distal small
intestine, where it may be too early, or not at all. In addition, dose
dumping might be a problem in cases of gastric anacidity. However, methyl derivatives of Eudragit S with an appropriate degree of substitution are expected to delay drug release sufficiently
and not to limit polymer dissolution upon arrival in the colon19.
A further possible means of delaying drug release from enteric-coated dosage forms is to protect the enteric coating by an
inner acidic layer. Such a dosage form has been developed by
KlokkersBethke and Fischer20, who used succinic acid in a
mixture of ethylcellulose and hydroxypropylcellulose (HPC) as
the acidic layer. pH-sensitive calcium alginate-coated gelatin
microspheres have been developed by Rao and Ritschel11. The
calcium alginate coat is obtained by crosslinking sodium alginate with calcium chloride. The formulation is a pH-controlled
system because the alginate coat is protonated at gastric pH and

Table 1. Coated dosage forms for the treatment of ulcerative colitis available on the German market (Eudragit is a product of Rhm GmbH,
Darmstadt, Germany)
Drug

Coating polymers

Dissolution pHa

Trade name

Manufacturer

Mesalazine

Eudragit L

6.0

Claversal

Mesalazine
Mesalazine
Mesalazine
Sulfasalazine
Sulfasalazine
Budesonide
Budesonide

Eudragit S
Eudragit L
Ethylcellulose
Cellulose acetate phthalate
Eudragit L 10055
Eudragit L 10055, ethylcellulose
Eudragit S

7.0
6.0

6.26.5
5.5
(5.5)
6.0

Asacolitin
Salofalk
Pentasa
Azulfidine
Colo-Pleon
Entocort
Budenofalk

SmithKline Beecham Pharmaceuticals

MMunich
Henning Berlin GmbH & Co., Berlin
Dr Falk Pharma GmbH, Freiburg
FERRING Arzneimittel GmbH, Wittland
Pharmacia & Upjohn GmbH, Erlangen
Henning Berlin GmbH & Co., Berlin
ASTRA GmbH, Wedel
Dr Falk Pharma GmbH, Freiburg

aAccording

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PSTT Vol. 2, No. 5 May 1999

ionized at intestinal pH. Drug release from the drug-loaded

microspheres occurs predominantly in the ileocecal region.
Interestingly, in severe inflammatory bowel disease, the average colonic pH of 6.47 often drops to between 1 and 5 (Refs
2123), and thus the above formulations are unable to provide
adequate drug release. In such cases a formulation that releases
the drug at an acidic pH should be used. Such a drug formulation has been developed by Leopold and Eikeler24, consisting
of a drug core, an acid-soluble basic polymer layer such as
aminoalkyl methacrylate copolymer (Eudragit E) or polyvinylacetal diethylamino acetate (AEA Sankyo) and an enteric coating as a gastroresistant outer layer.
Time-controlled drug release
Drug release from a time-controlled colonic delivery system typically occurs after a predetermined lag time, which corresponds to
or exceeds the small intestinal transit time, to ensure drug delivery to the large intestine. The lag time period usually starts after
gastric emptying because most of the time-controlled formulations are enteric-coated. However, drug release from these systems is not pH-controlled. The role of the enteric coating is to
provide reliability of the dosage form and reproducibility of drug
release by preventing drug release in the stomach where the residence time of the dosage form can vary considerably.
In the case of coated dosage forms designed for timecontrolled drug release, the lag time usually depends on the
coating thickness, and drug release can be triggered either by a
change in pH, a change in the osmotic pressure, or by disruption of the coating by swelling of the core.
pH-induced drug delivery
Time-controlled drug release with pH-induced drug delivery
is a targeting method that does not depend on changes in the
luminal pH of the gastrointestinal (GI) tract but on a pH
change within the dosage form itself.
Colon-specific drug formulations relying on the timedependent dissolution of basic polymer layers under acidic conditions have been developed by Ishibashi et al.25,26 and Yamada
et al.27 Ishibashi et al. use enteric Eudragit E-coated gelatin capsules containing a solid organic acid that dissolves as soon as it
comes into contact with the penetrating intestinal fluid and induces the dissolution of the Eudragit E coating film and thus
drug release. The delay in drug release is the result of the slow
penetration of intestinal fluid, followed by dissolution of the organic acid and subsequent dissolution of the basic polymer film.
Based on the same drug-release mechanism, the dosage form of
Yamada et al. consists of enteric-coated acid-soluble chitosan
capsules filled with an organic acid. In both cases, the onset of
drug release depends on the thickness of the basic polymer layer
and shell. In the case of chitosan, dissolution of the capsule shell

research focus

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also depends on the porosity, the molecular weight and the degree of acetylation of the polymer.
The organic acid-induced sigmoidal release system of Narisawa
et al. consists of a drug core containing 20% of succinic acid
and an Eudragit RS sustained release coating layer28,29. After a
lag time, the permeability of the Eudragit RS layer to the drug
is drastically increased by hydration: the organic acid partitions
into the Eudragit RS layer and facilitates the hydration of the
coating layer, thereby enabling drug release.
Swelling-induced drug delivery
The oral Chronotopic drug delivery system30,31 consists of an
hydroxypropylmethylcellulose (HPMC)-coated drug core,
which is protected by the enteric coating Eudragit L. The
enteric coating dissolves in the intestinal fluid and the highviscosity HPMC layer starts to swell and slowly erodes over
time. A rapid synchronization of the eroding and swelling
fronts can be observed. After dissolution of the enteric coating,
drug release from this delivery system is pH-independent. If
the high-viscosity HPMC is replaced by a low-viscosity HPMC
type, a thicker coating layer is required. Enteric-coated granules consisting of a mixture of a drug and HPMC have also
been shown to be suitable to deliver drugs to the colon32.
Because HPMC is difficult to apply by spray-coating, it has
been used in the past as a compression coat on core tablets33, in
which case the lag time is caused by the slow erosion of the
low-viscosity HPMC. In contrast to high-viscosity HPMC, the
low-viscosity polymer type does not swell, thus preventing film
cracks that would lead to premature drug release.
An enteric capsule formulation, developed by Scherer (Scherer
DDS Ltd, Clydebank, UK), in which the water-insoluble capsule
body is closed by a swellable hydrogel plug, has been marketed
under the trade name of Pulsincap (Ref. 34). The soluble cap
dissolves in the intestinal juice, allowing the hydrogel plug to
swell and expand. Ejection of the swollen plug occurs after a lag
time that depends on the hydrogel material, the length of the
plug and the fit ratio (diameter plug to diameter body).
In addition to acting as a sustained release coating material,
ethylcellulose may be used as a capsule shell material if applied
as a thick film to the inner surface of a conventional watersoluble hard gelatin capsule. A time-controlled ethylcellulose
capsule for colon-specific drug delivery has been developed
by Niwa et al.35 The capsule body, which is equipped with
micropores on the bottom, contains an open ethylcellulose
drug container. A swellable polymer layer (low substituted
HPC) is in contact with both the bottom of the capsule body
and the bottom of the inserted drug container. As the volume
of the HPC increases as a result of polymer swelling, the drug
container is slowly pushed out of the capsule body, thereby removing the cap and inducing drug release. The onset of drug
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release is affected by the degree of swelling of the HPC, the

thickness of the capsule shell and the size of the micropores.
The time-controlled explosion system (TES) of Ueda et al.36 consists of sucrose beads covered with a drug layer and coated with an
inner layer of low substituted HPC and an outer ethylcellulose film.
Water that is, intestinal fluid penetrates gradually through the
outer ethylcellulose membrane, and the swelling force of the HPC
layer causes membrane disruption after a predetermined lag time.
Drug release from the dosage form is pH-independent. A similar
drug release mechanism uses calcium alginate beads as core carriers37. The alginate beads swell in the intestinal fluid causing disruption of the outer ethylcellulose membrane.
Formaldehyde-pretreated Minicaps gelatin capsules coated
with a 7:3 mixture of Eudragit NE 30 D and Eudragit S 100
have been prepared by Ritschel and coworkers10,11. Formaldehyde pretreatment makes gelatin resistant to water, and the
Eudragit blend represents a swellable layer, which controls drug
release together with the outer gastroresistant layer of cellulose
acetate phthalate.
The lag time observed with the TIME-CLOCK system38,39 is
caused by slow hydration of the hydrophobic coating layer,
which consists of wax,Tween-80 and HPMC. Drug release from
the coated tablets is characterized by pH-independency and
there is little influence of agitation on the lag time of drug release. Disaggregation of the tablets occurs in the proximal colon.
The pulsatile release tablet by Ishino et al.40 consists of a core
tablet with a poorly water-permeable outer shell, made of PEG
6000 and hydrogenated castor oil, which delays water penetration. The tablet starts to swell once the intestinal fluid
reaches the core, which consists of the drug and calcium carboxymethylcellulose as the disintegrant.The 2-mm thick outer
shell breaks after a lag time because of swelling of the core.The
lag time depends not only on the thickness of the outer shell
but also on the PEG:castor oil ratio.
Osmotic pressure-induced drug delivery
The osmotic device for colon targeting developed by Theeuwes
et al.41 is a tablet formulation in which water penetrates
through the pores of a semipermeable outer film, created by a
pore-forming agent, and slowly dissolves the delaying agents
in the drug compartment (high molecular weight PEG and
low-viscosity HPMC). As soon as the viscosity of the drug compartment is low enough, it can be pushed out through the
pores by the pressure of the osmotic compartment, which consists of an osmopolymer and an osmotic agent.
The lag time observed with the colon-specific osmotic tablet
formulation of Quadros et al.42 is caused by dissolution and extrusion of a placebo layer (cellulose acetate, HPMC) through
the orifice in an outer semipermeable membrane after water
penetration. Drug release through the orifice occurs after dis200

PSTT Vol. 2, No. 5 May 1999

solution of the drug core. The OROS-CT system of ALZA

(ALZA Corporation, Palo Alto, USA) is based on a similar drugrelease mechanism. This pushpull unit contains an osmotic
push compartment and a drug compartment, both surrounded
by a semipermeable membrane with an orifice43.
Enzyme-controlled drug release
Enzyme-controlled drug release relies on the existence of enzyme-producing microorganisms in the colon. The colonic microflora produce a variety of enzymes, including azoreductase,
various glycosidases and, at a lower concentration, esterases and
amidases, that can be exploited for colon-specific drug delivery.
By taking advantage of these enzymes, prodrugs, hydrogels, matrices and biodegradable coating materials have been developed
for enzyme-controlled drug release. During the development
process of biodegradable coating polymers for colon-specific
drug delivery several aspects must be considered. First, good filmforming properties are required.The polymers need to be waterinsoluble and a sufficiently low permeability of the polymer film
to the drug is crucial to prevent premature drug release in the
upper GI tract. In contrast, however, polymer swelling plays an
important role as it ensures accessibility of the degradable bonds
by enzymes and thus polymer degradation in the colon. In addition, the possible toxicity of the degradation products must be
considered.The regulatory requirements are a major drawback to
the enzyme-based approach because each newly synthesized
polymer must acquire federal agency approval.
Biodegradable coating materials mainly comprise azo polymers, glycosidic polymers and matrix films consisting of conventional coating polymers for sustained drug delivery, based
on acrylate or cellulosic polymers combined with biodegradable pore formers.
Azo polymeric coatings
Azo polymers were the first coating materials to be investigated
with regard to biodegradability in the colon.They usually consist
of a hydrophilic, a hydrophobic and an azo segment (Table 2).
Crosslinked azo polymers consisting of hydroxyethyl
methacrylate (HEMA), styrene and an azo aromatic crosslinking compound were tested in vitro and in vivo with insulin as the
model drug4446. The high variability observed in the insulin
bioavailability was attributed to the hydrophobic nature of the
coating polymers. However, the observed variability in the
insulin absorption rates might also be the result of the poor
epithelial transport of peptide drugs and not necessarily
unfavourable polymer properties.
Linear water-insoluble copolymers of hydrophilic HEMA,
lipophilic methyl methacrylate (MMA) and azo aromatic compounds have also been investigated as coating materials47,48.The
microbial degradation of these polymers depends on their

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Table 2. Composition of azo polymer coatings for colon-specific

drug delivery
Hydrophilic
segment

Hydrophobic
segment

pH-sensitive
segment

Refs

HEMAa
HEMA
HEMA
Polyoxyethylene

Styrene
MMAb
MMA
Polyurethane

MAc

4446
47, 48
5153
54

aHEMA,

hydroxyethyl methacrylate; bMMA, methyl methacrylate; cMA, methacrylic acid.

hydrophilicity that is, the amount of HEMA. However, sufficient resistance to gastric and intestinal fluids is observed only if
the polymer is more lipophilic in nature that is, if large
amounts of MMA are incorporated in the polymer. The chain
length of the azo aromatic compounds has only little influence
on the degradation rate.
Based on experiences with azo polymeric hydrogels49,50, waterinsoluble, pH-sensitive terpolymers consisting of HEMA, MMA,
methacrylic acid (MA) and an azo aromatic compound have been
investigated with poorly water-soluble model drugs5153.The enzymatic degradation of the polymer films and thus drug release
depends on the degree of film swelling, which increases above
pH 6 as carboxyl groups become ionized. The amount of
lipophilic MMA controls the swelling rate and the swelling capacity of the polymers. Film permeability correlates with the concentration of hydrophilic HEMA and can be further increased by the
addition of hydrophilic plasticizers.
The azo polymer coatings developed by Kimura et al.54
consist of hydrophilic polyoxyethylene and hydrophobic
polyurethane segments, in addition to the azo aromatic segment.
When incubated under anaerobic conditions with intestinal flora,
reduction of the azo polymer to the intermediate hydrazo polymer
with no decrease in the molecular weight of the polymer was observed.The same observation was made with polyamides containing azo bonds in their backbone55.The nature of the degradation
end-products depends on the hydrophilicity of the polymer.With
hydrophobic polymers reduction stops at the hydrazine stage,
whereas with the hydrophilic analogues the formation of amines
and breakdown of the polymer backbone occurred55. It should be
mentioned that drug release occurs even if azo polymer reduction
stops at the hydrazine level because the chemical modification renders the polymers much more hydrophilic and permeable54.
As a result of their poor film-forming properties, azo polymers based on poly(ether-esters) can only be used as biodegradable additives to sustained release coating materials such as Eudragit RS (Ref. 56). Drug release from dosage forms coated with
such matrix films depends on the thickness and the hydrophilicity of the coating; hydrophilicity can be increased by adding
polyoxyethylene 400.

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There are several problems that require consideration when

developing azo polymers for colon-specific drug delivery57. First,
toxicity resulting from the microbial or chemical reduction of
azo compounds to primary aromatic amines might be critical.
Moreover, reduction of polymeric azo compounds often proceeds too slowly, bringing their reliability as coating polymers
with regard to drug release into question. For this reason, the use
of azo compounds with a small negative redox potential appears
to be advantageous58,59. As already mentioned, reduction can, in
some cases, lead to the intermediate hydrazo compounds instead
of the amines54,55. Furthermore, reduction does not necessarily
depend on the existence of the azoreductase, but can occur as a
result of the low oxidation potential in the colon, as has been observed with polymers containing disulphide bonds60.
Glycosidic polymer coatings
Various polysaccharides, in both unmodified and modified
form, have been investigated for their potential suitability as
colon-specific coating polymers.
Pectin, a polysaccharide consisting of D-galacturonic acid and
its methyl ester, can be used only as a compression coat in a
poorly water-soluble form such as calcium pectinate or amidated pectin because of its poor film-forming properties6163.
Penetration of intestinal fluid into such a modified pectin coat
will be slowed down by gelation, and the enzymatic degradation of the polymer depends on its degree of hydration. In
order to obtain a lower coating thickness, a biodegradable interpolymer complex, consisting of pectin and chitosan (1:10) with
a very low water solubility, has recently been introduced64.
Among the high molecular weight dextran esters, lauroyl
dextrans in particular have been found to be water-insoluble,
swellable, biodegradable and to show satisfactory film-forming
properties65,66. Acetyl dextrans are water-insoluble but they are
not biodegradable because of the high degree of substitution
required to decrease their water solubility. Caproyl dextrans require a lower degree of substitution and are biodegradable, but
their film-forming properties are not satisfactory. Stearoyl dextrans have been found to be biodegradable polymers with insufficient film-forming properties.
If galactomannans are used as coating materials6769 it has to be
taken into consideration that microbial degradation is rapid if the
mannose:galactose ratio is high. Galactomannans from locust
bean gum with a mannose:galactose ratio of 4:1 therefore appear
to be the most suitable with regard to polymer degradability.
However, the high water solubility of this polysaccharide has to be
reduced by chemical modification. On the basis of purified locust
bean gum, ethylated oligogalactomannans with good filmforming properties and satisfactory biodegradability have been
synthesized67. Polyurethane films consisting of diisocyanates and
ethylated oligogalactomannans as large biodegradable segments
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are recognized by the b-mannanase in the colon and are rapidly

fermented68. Crosslinking of galactomannans leads to suitable coating materials in which the degree of crosslinking is critical69,70.
Chitosan that is, deacetylated chitin is a cationic polysaccharide susceptible to degradation by microbial enzymes in the
colon. If used as a coating material for colon-specific drug delivery, it is important to protect the acid-soluble polymer with
an enteric coating71,72. Both the degree of deacetylation and the
molecular weight of the polymer affect the degradation rate. In
addition to its use as a coating material, chitosan is a suitable
polymer material for the manufacture of capsule shells73. Chitosan capsules are commercially available. Another capsule shell
material that has been recently developed for colon-specific
drug delivery is dextran crosslinked with glutaraldehyde74.
A combined enzyme- and pH-controlled system has been
developed by Watanabe et al.75. Drug release from the enteric
tablet formulation starts after microbial degradation of an outer
saccharide layer to short-chain fatty acids and subsequent dissolution of the underlying Eudragit E film.
Biodegradable matrix films
Biodegradable matrix films, consisting of a sustained release
coating material and a poorly water-soluble but degradable additive, are used if the additive by itself does not exhibit good
film-forming properties. As degradable additives a variety of
oligo- and polysaccharides have been investigated, such as
b-cyclodextrin, galactomannans, glassy amylose, pectin and
inulin (Table 3).
Eudragit RS/b-cyclodextrin (1:1) matrix films containing
a lipophilic plasticizer have been developed by Bauer and
coworkers76,77. Drug release is pH-independent and begins
after degradation of the b-cyclodextrin domains by bacterial
enzymes in the colon.
Glassy amylose, which is resistant to pancreatic amylase, is
another degradable compound that can be used as a pore for-

PSTT Vol. 2, No. 5 May 1999

mer in a sustained release coating material7880. If used in combination with an ethylcellulose dispersion in a 1:4 ratio,
swelling of the amylose is sufficiently controlled. The matrix
films are phase separated with amylose domains in the ethylcellulose film.When arriving in the colonic region the films are
structurally weakened, allowing the swelling and subsequent
fermentation of the amylose, which ultimately leads to drug release. An ethylcellulose/glassy amylose matrix film is now available as COLAL (Alizyme Therapeutics Ltd, Cambridge, UK).
Galactomannans, such as guar gum, have led to satisfactory
coating films in combination with Eudragit RL, RS and NE (Refs
81,82). However, high amounts of the acrylic polymers and high
coating levels are required to avoid premature drug release82.
In order to reduce its high water solubility, pectin should be
either of the high methoxyl pectin type, in amidated form, or
crosslinked with calcium ions in order to be used as a biodegradable additive. If used in combination with ethylcellulose83,84,
Eudragit RS or NE (Ref. 85), high methoxyl pectin or calcium
pectinate can act as biodegradable components in the resulting
matrix films. However, leaching of the pectin from the matrix
films might lead to premature drug release. Best results in terms
of leaching were obtained with Eudragit RS films containing up
to 10% of pectin85, probably a result of ionic interactions between the anionic pectin and the quaternary acrylic polymer.
Inulin, a naturally occurring glucofructan, can serve as a
biodegradable compound in combination with Eudragit RS if
an inulin-type with a high degree of polymerization is used to
lower its water solubility86. The films withstand gastric and intestinal fluid, with high amounts of inulin making the films
more permeable. The bacterial degradation has been shown to
depend on the hydrophilicity of the plasticizer.
Pressure-controlled drug release
A pressure-controlled drug delivery system that relies on the
high pressure in the distal colon produced by peristalsis has

Table 3. Sustained release coating materials combined with biodegradable additives as coatings for colon-specific drug delivery (Eudragit
is a product of Rhm GmbH, Darmstadt, Germany)
Biodegradable component

Sustained release coating material

Ratio

Plasticizer

Refs

b-Cyclodextrin
Galactomannans

Eudragit RS
Eudragit RL
Eudragit RS
Eudragit NE
Ethylcellulose
Ethylcellulose
Eudragit RS
Eudragit NE
Eudragit RS

1:1
2:14:1
1:4
1:4
1:4
1:191:4
1:10
1:10
1:11:2

Diethyl phthalate
Diethyl phthalate

76, 77
81, 82

Dibutyl sebacate, Triacetin, Triethylcitrate

Dibutyl sebacate, Triacetin

7880a
8385
86

Eudragit RS

1:1.5

Dibutyl phthalate
Acetyltriethyl citrate
Polyoxyethylene 400

Glassy amylose
Pectin
M(high methoxyl pectin
Mor calcium pectinate)
Inulin (high degree of
Mpolymerization)
Ether-ester azo polymer
aAvailable

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as COLAL (Alizyme Therapeutics Ltd, Cambridge, UK)

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been introduced by Niwa et al.35 and Takaya et al.87 Disintegration

of the formulation, which consists of a gelatin capsule with an
inner ethylcellulose coating, is induced by the pressure and thus
the destructive force produced by peristaltic waves, and depends on the thickness of the ethylcellulose film. The capsule is
filled with a solution of the drug; this should be advantageous
in view of the small amount of fluid in the distal colon, which
could compromise drug dissolution and absorption88.
Concluding remarks and future prospects
The choice of a suitable colon-specific drug delivery system depends primarily on the application of the dosage form for example, whether a colonic disorder has to be treated where drug
absorption is desired to be low or whether a peptide drug has to
be delivered to the colon to improve its bioavailability. Moreover,
it is important to know whether a drug should be released as
soon as it enters the colon or whether drug delivery needs to be
sustained to ensure drug release in both the proximal colon and
in the transverse colon. In general, coated dosage forms with a
simple design are suitable systems because of their ease of manufacture. More complex systems can cause problems with regard
to manufacture and reliability of reproduction. If coated dosage
forms are used for colon targeting, the different approaches presented in this review need to be critically considered.
All the presented methods of drug delivery are more or less susceptible to changes in the diet and to environmental variables,
which questions their reliability. In addition, most of the systems
have only been tested in healthy animals or humans. Little is
known about the influence of the disease state on transit, motility,
luminal pH and intraluminal pressure of the GI tract or on the
composition of the colonic microflora. The luminal pH of the
colon depends on the composition of the diet. For instance, diets
with a high content of non-absorbable polysaccharides can lead to
a drop in the luminal pH of the proximal colon. pH-controlled systems often fail because of the intra- and intersubject variability in
luminal pH values. Moreover, the colonic pH can drop dramatically
in the case of inflammatory bowel disease, a fact that has not yet
been considered if one looks at the composition of the formulations that are currently available on the market for this indication.
The activity of the microbial enzymes is even more susceptible
to diet, drug intake (particularly antibiotics and certain
laxatives) and environmental factors.Thus, reproducibility of enzymatic polymer degradation might be a problem. However, as
the commonly exploited enzymes such as azoreductase and various glycosidases are present only in the terminal ileum and
colon, premature drug release does not occur. Coating materials
need to be readily degradable in order to provide reproducible
drug release in the colon.
Time-controlled delivery systems that take advantage of the
relatively constant transit time through the small intestine are

reviews

the most promising so far. The small intestinal transit time is

less susceptible to environmental variables, diet and disease
state. If a reproducible lag time of drug release can be achieved
and the dosage form is enteric-coated to prevent release of the
drug in the stomach, this represents a potentially suitable system for colon-specific drug delivery.
The pressure and destructive force induced by peristaltic
waves is certainly high in the distal part of the large intestine.
However, little is known about the reproducibility of this pressure and the duration of the high-pressure phase. Moreover,
major peristaltic waves occur physiologically only once or
twice a day and therefore the exact time of drug release cannot
be accurately predicted. Colonic disorders such as diarrhoea
could significantly affect drug release. Drug release from coated
dosage forms in the distal colon generally presents a problem as
the high viscosity of the contents could compromise drug dissolution and drug diffusion to the epithelial cells.
In terms of future trends regarding coated dosage forms for
colon-specific drug delivery, time-controlled delivery systems
are likely to become more important and perhaps even supersede the pH-controlled systems currently on the market. In vivo
studies with several time-controlled formulations have yielded
promising data. As these dosage forms usually consist of compounds that are already available on the market, no further
delay with dosage form approval is expected. However, the design of many of the systems is rather complex and the development of formulations with a simpler design is required.
Enzymatically degradable polymers will be further optimized to improve their film-forming properties, their swelling
behaviour and their degradability by colonic enzymes. The
bioadhesive properties of the polymers could lead to a prolonged residence time in the colon. The development of polymers with moieties that bind to specific regions of the intestine, such as inflamed colonic lesions or colon cancer tissue,
represents another promising approach. However, because a
toxicity study is required for each newly synthesized polymer,
it will still be some time before a dosage form with a
biodegradable coating appears on the market. A promising approach with regard to biodegradable coating films is the use of
matrix films that is, physical blends of sustained release coating materials and degradable pore formers. As many of the pore
formers are naturally occurring polysaccharides, no major
problems in terms of toxicity are expected.
Acknowledgement
This review is dedicated to G. Zessin on the occasion of his
65th birthday.
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