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

t Drug delivery to the colon has become attrac-tive to researchers interested in the delivery ofpeptide drugs to the large intestine and the topi-cal treatment of diseases of the colon. Because ofthe unique physiological characteristics of thelarge intestine, drug delivery to the colon can beachieved in different ways. One such feature is thecolonic microflora (bacterial count 10111012 cfuml21), which consists mainly of anaerobic or fac-ultative anaerobic microorganisms1 that producea variety of enzymes2.The ability of the colon tosupport an anaerobic bacterial flora is shown by itsredox potential of between 2250 and 2480 mV(Refs 3,4). A further characteristic is the slightlyacidic environment in the proximal colon (pH 6.06.4), which results from the degrada-tion of poly- and oligosaccharides to short-chainfatty acids, and a neutral or slightly alkaline envi-ronment in the distal colon (pH 7.07.4)5.Moreover, as a result of the strong and prolongedpropulsive motility in the distal colon that occursonce or twice a day, the luminal pressure and thuspotential destructive forces increase temporarily

in this lower part of the large intestine, where thesolid faeces are formed6. It should be mentionedthat drug absorption from the colon is affectedby the small effective surface area available for ab-sorption and the tight colon epithelium; however,colonic transit time can last for up to 78 h,thereby allowing the absorption of even drugs oflow permeability.

Four strategies are currently being pursued toachieve drug release specifically in the colon.

The fact that the luminal pH of the healthydistal colon is slightly higher than that of theproximal small intestine has led to the devel-opment of oral dosage forms that are intendedto release the drug at the colonic pH (pH-controlled drug delivery).

The colonic microflora produce a variety ofenzymes that are not present in the stomachor the small intestine and could therefore beused to deliver drugs to the colon after en-zymatic cleavage of degradable formulationcomponents or drug carrier bonds (enzyme-controlled drug delivery). It should be takeninto consideration that because of the lowredox potential in the colon, enzymatic orchemical reduction reactions are favoured.

The relatively constant transit time in thesmall intestine approximately 35 h is an-other physiological characteristic that can betaken advantage of to achieve colon specificity(time-controlled drug delivery). After gastricemptying, a time-controlled drug deliverysystem is intended to release the drug after apredetermined lag phase.

Another strategy relies on the strong peri-staltic waves in the colon that lead to a tem-porarily increased luminal pressure (pressure-controlled drug delivery). Pressure-sensitivedrug formulations release the drug as soon asa certain pressure limit is exceeded.

Coated dosage forms for colon-specific drug deliveryClaudia S. Leopold

Claudia S. LeopoldDepartment of

Pharmaceutical TechnologyHeinrich Heine University

Universittsstrasse 140225 Dsseldorf

Germanytel/fax: 149 2 1181 14225

e-mail: leopold@uni-duesseldorf.de

reviews research focus

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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 pH-

dependent rate of swelling, dissolution or erosion that take advan-

tage of the constant small intestinal transit time (time-controlled re-

lease), 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

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

gives an overview of coated dosage forms that have been developed

to achieve colon specificity.

Many colon-specific dosage forms have been developed inthe past, including prodrugs, crosslinked hydrogels, matricesand coated dosage forms. However, whereas the synthesis ofprodrugs is possible only if the drug has suitable moieties thatcan be bound to a carrier molecule, with biodegradable hydro-gels and matrices slow degradation rates leading to slow drugrelease often represent a problem. Because of the widespreaduse of coated dosage forms, resulting from improved coatingtechnologies and flexibility in their design, this review willfocus on the variety of coated dosage forms that have been de-veloped for oral colon-specific drug delivery.

pH-controlled drug releaseSeveral commercial drug formulations designed for colon-spe-cific drug delivery rely on the physiological difference betweenthe luminal pH of the acidic stomach and that of the distal smallintestine. If the intended site of drug release of the coated dosageform is the colon, it must be taken into consideration that, be-tween the terminal ileum and the transverse or distal colon, thereis a slightly acidic region in the proximal colon that might affectdrug release profiles and the reproducibility of drug release.

Enteric coatings primarily protect solid oral dosage formsagainst the acidic environment in the stomach. They dissolverapidly in the lumen of the small intestine where drug releasefrom delayed release dosage forms usually depends on the dis-solution pH of the polymers and the pH of the lumen. However,if the terminal ileum or the colon is the target organ for thedrug, the start of the drug release must be further controlled byincreasing the thickness of the coating, allowing a pH- andtime-controlled polymer dissolution and drug release process.

Thus, drug release from many of the coated dosage formsdesigned for pH-controlled drug delivery to the terminal ileumor colon will also depend on the transit time through the smallintestine.These dosage forms therefore usually represent com-bined pH and time-controlled drug delivery systems for whichtime-controlled release can be achieved by selecting a suitablecoating 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, NEor ethylcellulose913 can be used as an undercoating.

Many commercial drug formulations for the oral treatmentof inflammatory bowel disease (such as Asacolitin, Claversal,Salofalk or Budenofalk) are coated with pH-sensitive entericcoating polymers such as Eudragit L or S (Table 1).These poly-mers have a dissolution pH of between 6 and 7, and are in-tended to release the drug as soon as the intestinal pH exceeds6 or 7, respectively. However, studies with Eudragit S-coatedtablets in humans have shown that drug release in the colon isnot sufficiently reproducible14,15. Disintegration sites vary fromthe ileum to the splenic flexure, indicating a lack of site speci-ficity, although results from other studies support the feasibil-ity of this targeting method1618.

One reason for these inconsistent results is the drop in pH be-yond the ileocecal junction, which results from extensive micro-bial degradation of polysaccharides and oligosaccharides toshort-chain fatty acids. It is only in the distal part of the colonthat a pH of approximately 7 is reached and this differs onlyslightly from the average pH in the small intestine, which is6.56.8 (Ref. 5).Thus, drug release may occur in the distal smallintestine, where it may be too early, or not at all. In addition, dosedumping might be a problem in cases of gastric anacidity. How-ever, methyl derivatives of Eudragit S with an appropriate de-gree of substitution are expected to delay drug release sufficientlyand not to limit polymer dissolution upon arrival in the colon19.

A further possible means of delaying drug release from en-teric-coated dosage forms is to protect the enteric coating by aninner acidic layer. Such a dosage form has been developed byKlokkersBethke and Fischer20, who used succinic acid in amixture of ethylcellulose and hydroxypropylcellulose (HPC) asthe acidic layer. pH-sensitive calcium alginate-coated gelatinmicrospheres have been developed by Rao and Ritschel11. Thecalcium alginate coat is obtained by crosslinking sodium algin-ate with calcium chloride.The formulation is a pH-controlledsystem because the alginate coat is protonated at gastric pH and

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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 SmithKline Beecham PharmaceuticalsMMunich

Mesalazine Eudragit S 7.0 Asacolitin Henning Berlin GmbH & Co., BerlinMesalazine Eudragit L 6.0 Salofalk Dr Falk Pharma GmbH, FreiburgMesalazine Ethylcellulose Pentasa FERRING Arzneimittel GmbH, WittlandSulfasalazine Cellulose acetate phthalate 6.26.5 Azulfidine Pharmacia & Upjohn GmbH, ErlangenSulfasalazine Eudragit L 10055 5.5 Colo-Pleon Henning Berlin GmbH & Co., BerlinBudesonide Eudragit L 10055, ethylcellulose (5.5) Entocort ASTRA GmbH, WedelBudesonide Eudragit S 6.0 Budenofalk Dr Falk Pharma GmbH, Freiburg

aAccording to product specification sheets.

ionized at intestinal pH. Drug release from the drug-loaded microspheres occurs predominantly in the ileocecal region.

Interestingly, in severe inflammatory bowel disease, the aver-age colonic pH of 6.47 often drops to between 1 and 5 (Refs2123), and thus the above formulations are unable to provideadequate drug release. In such cases a formulation that releasesthe drug at an acidic pH should be used. Such a drug formu-lation has been developed by Leopold and Eikeler24, consistingof a drug core, an acid-soluble basic polymer layer such asaminoalkyl methacrylate copolymer (Eudragit E) or polyvinyl-acetal diethylamino acetate (AEA Sankyo) and an enteric coat-ing as a gastroresistant outer layer.

Time-controlled drug releaseDrug release from a time-controlled colonic delivery system typi-cally occurs after a predetermined lag time, which corresponds toor exceeds the small intestinal transit time, to ensure drug deliv-ery to the large intestine.The lag time period usually starts aftergastric emptying because most of the time-controlled formu-lations are enteric-coated. However, drug release from these sys-tems is not pH-controlled.The role of the enteric coating is toprovide reliability of the dosage form and reproducibility of drugrelease by preventing drug release in the stomach where the resi-dence time of the dosage form can vary considerably.

In the case of coated dosage forms designed for time-controlled drug release, the lag time usually depends on thecoating thickness, and drug release can be triggered either by achange in pH, a change in the osmotic pressure, or by disrup-tion of the coating by swelling of the core.

pH-induced drug deliveryTime-controlled drug release with pH-induced drug deliveryis a targeting method that does not depend on changes in theluminal pH of the gastrointestinal (GI) tract but on a pHchange within the dosage form itself.

Colon-specific drug formulations relying on the time-dependent dissolution of basic polymer layers under acidic con-ditions have been developed by Ishibashi et al.25,26 and Yamada et al.27 Ishibashi et al. use enteric Eudragit E-coated gelatin cap-sules containing a solid organic acid that dissolves as soon as itcomes into contact with the penetrating intestinal fluid and in-duces the dissolution of the Eudragit E coating film and thusdrug release.The delay in drug release is the result of the slowpenetration of intestinal fluid, followed by dissolution of the or-ganic acid and subsequent dissolution of the basic polymer film.Based on the same drug-release mechanism, the dosage form ofYamada et al. consists of enteric-coated acid-soluble chitosancapsules filled with an organic acid. In both cases, the onset ofdrug release depends on the thickness of the basic polymer layerand shell. In the case of chitosan, dissolution of the capsule shell

also depends on the porosity, the molecular weight and the de-gree of acetylation of the polymer.

The organic acid-induced sigmoidal release system of Narisawaet al. consists of a drug core containing 20% of succinic acidand an Eudragit RS sustained release coating layer28,29. After alag time, the permeability of the Eudragit RS layer to the drugis drastically increased by hydration: the organic acid partitionsinto the Eudragit RS layer and facilitates the hydration of thecoating layer, thereby enabling drug release.

Swelling-induced drug deliveryThe oral Chronotopic drug delivery system30,31 consists of anhydroxypropylmethylcellulose (HPMC)-coated drug core,which is protected by the enteric coating Eudragit L. The enteric coating dissolves in the intestinal fluid and the high-viscosity HPMC layer starts to swell and slowly erodes overtime. A rapid synchronization of the eroding and swellingfronts can be observed.After dissolution of the enteric coating,drug release from this delivery system is pH-independent. Ifthe high-viscosity HPMC is replaced by a low-viscosity HPMCtype, a thicker coating layer is required. Enteric-coated gran-ules consisting of a mixture of a drug and HPMC have alsobeen shown to be suitable to deliver drugs to the colon32.

Because HPMC is difficult to apply by spray-coating, it hasbeen used in the past as a compression coat on core tablets33, inwhich case the lag time is caused by the slow erosion of thelow-viscosity HPMC. In contrast to high-viscosity HPMC, thelow-viscosity polymer type does not swell, thus preventing filmcracks that would lead to premature drug release.

An enteric capsule formulation, developed by Scherer (SchererDDS Ltd, Clydebank, UK), in which the water-insoluble capsulebody is closed by a swellable hydrogel plug, has been marketedunder the trade name of Pulsincap (Ref. 34). The soluble capdissolves in the intestinal juice, allowing the hydrogel plug toswell and expand. Ejection of the swollen plug occurs after a lagtime that depends on the hydrogel material, the length of theplug 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 appliedas a thick film to the inner surface of a conventional water-soluble hard gelatin capsule. A time-controlled ethylcellulosecapsule for colon-specific drug delivery has been developed by Niwa et al.35 The capsule body, which is equipped withmicropores on the bottom, contains an open ethylcellulosedrug container. A swellable polymer layer (low substitutedHPC) is in contact with both the bottom of the capsule bodyand the bottom of the inserted drug container. As the volumeof the HPC increases as a result of polymer swelling, the drugcontainer is slowly pushed out of the capsule body, thereby re-moving 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, thethickness of the capsule shell and the size of the micropores.

The time-controlled explosion system (TES) of Ueda et al.36 con-sists of sucrose beads covered with a drug layer and coated with aninner layer of low substituted HPC and an outer ethylcellulose film.Water that is, intestinal fluid penetrates gradually through theouter ethylcellulose membrane, and the swelling force of the HPClayer causes membrane disruption after a predetermined lag time.Drug release from the dosage form is pH-independent. A similardrug release mechanism uses calcium alginate beads as core carri-ers37. The alginate beads swell in the intestinal fluid causing dis-ruption of the outer ethylcellulose membrane.

Formaldehyde-pretreated Minicaps gelatin capsules coatedwith a 7:3 mixture of Eudragit NE 30 D and Eudragit S 100have been prepared by Ritschel and coworkers10,11. Formalde-hyde pretreatment makes gelatin resistant to water, and the Eudragit blend represents a swellable layer, which controls drugrelease together with the outer gastroresistant layer of celluloseacetate phthalate.

The lag time observed with the TIME-CLOCK system38,39 iscaused by slow hydration of the hydrophobic coating layer,which consists of wax,Tween-80 and HPMC. Drug release fromthe coated tablets is characterized by pH-independency andthere is little influence of agitation on the lag time of drug re-lease. Disaggregation of the tablets occurs in the proximal colon.

The pulsatile release tablet by Ishino et al.40 consists of a coretablet with a poorly water-permeable outer shell, made of PEG6000 and hydrogenated castor oil, which delays water pen-etration. The tablet starts to swell once the intestinal fluidreaches the core, which consists of the drug and calcium car-boxymethylcellulose as the disintegrant.The 2-mm thick outershell breaks after a lag time because of swelling of the core.Thelag time depends not only on the thickness of the outer shellbut also on the PEG:castor oil ratio.

Osmotic pressure-induced drug deliveryThe osmotic device for colon targeting developed by Theeuweset al.41 is a tablet formulation in which water penetratesthrough the pores of a semipermeable outer film, created by apore-forming agent, and slowly dissolves the delaying agentsin the drug compartment (high molecular weight PEG andlow-viscosity HPMC).As soon as the viscosity of the drug com-partment is low enough, it can be pushed out through thepores by the pressure of the osmotic compartment, which con-sists of an osmopolymer and an osmotic agent.

The lag time observed with the colon-specific osmotic tabletformulation of Quadros et al.42 is caused by dissolution and ex-trusion of a placebo layer (cellulose acetate, HPMC) throughthe orifice in an outer semipermeable membrane after waterpenetration. Drug release through the orifice occurs after dis-

solution of the drug core. The OROS-CT system of ALZA(ALZA Corporation, Palo Alto, USA) is based on a similar drug-release mechanism. This pushpull unit contains an osmoticpush compartment and a drug compartment, both surroundedby a semipermeable membrane with an orifice43.

Enzyme-controlled drug releaseEnzyme-controlled drug release relies on the existence of en-zyme-producing microorganisms in the colon.The colonic mi-croflora produce a variety of enzymes, including azoreductase,various glycosidases and, at a lower concentration, esterases andamidases, that can be exploited for colon-specific drug delivery.By taking advantage of these enzymes, prodrugs, hydrogels, ma-trices and biodegradable coating materials have been developedfor enzyme-controlled drug release. During the developmentprocess of biodegradable coating polymers for colon-specificdrug delivery several aspects must be considered. First, good film-forming properties are required.The polymers need to be water-insoluble and a sufficiently low permeability of the polymer filmto the drug is crucial to prevent premature drug release in theupper GI tract. In contrast, however, polymer swelling plays animportant role as it ensures accessibility of the degradable bondsby enzymes and thus polymer degradation in the colon. In addi-tion, the possible toxicity of the degradation products must beconsidered.The regulatory requirements are a major drawback tothe enzyme-based approach because each newly synthesizedpolymer must acquire federal agency approval.

Biodegradable coating materials mainly comprise azo poly-mers, glycosidic polymers and matrix films consisting of con-ventional coating polymers for sustained drug delivery, basedon acrylate or cellulosic polymers combined with biodegrad-able pore formers.

Azo polymeric coatingsAzo polymers were the first coating materials to be investigatedwith regard to biodegradability in the colon.They usually consistof a hydrophilic, a hydrophobic and an azo segment (Table 2).Crosslinked azo polymers consisting of hydroxyethylmethacrylate (HEMA), styrene and an azo aromatic crosslink-ing compound were tested in vitro and in vivo with insulin as themodel drug4446. The high variability observed in the insulinbioavailability was attributed to the hydrophobic nature of thecoating polymers. However, the observed variability in the insulin absorption rates might also be the result of the poorepithelial transport of peptide drugs and not necessarily unfavourable polymer properties.

Linear water-insoluble copolymers of hydrophilic HEMA,lipophilic methyl methacrylate (MMA) and azo aromatic com-pounds have also been investigated as coating materials47,48.Themicrobial degradation of these polymers depends on their

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hydrophilicity that is, the amount of HEMA. However, suffi-cient resistance to gastric and intestinal fluids is observed only ifthe polymer is more lipophilic in nature that is, if largeamounts of MMA are incorporated in the polymer. The chainlength of the azo aromatic compounds has only little influenceon the degradation rate.

Based on experiences with azo polymeric hydrogels49,50, water-insoluble, pH-sensitive terpolymers consisting of HEMA, MMA,methacrylic acid (MA) and an azo aromatic compound have beeninvestigated with poorly water-soluble model drugs5153.The en-zymatic degradation of the polymer films and thus drug releasedepends on the degree of film swelling, which increases abovepH 6 as carboxyl groups become ionized. The amount oflipophilic MMA controls the swelling rate and the swelling capac-ity of the polymers. Film permeability correlates with the concen-tration of hydrophilic HEMA and can be further increased by theaddition of hydrophilic plasticizers.

The azo polymer coatings developed by Kimura et al.54

consist of hydrophilic polyoxyethylene and hydrophobicpolyurethane 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 polymerwith no decrease in the molecular weight of the polymer was ob-served.The same observation was made with polyamides contain-ing azo bonds in their backbone55.The nature of the degradationend-products depends on the hydrophilicity of the polymer.Withhydrophobic polymers reduction stops at the hydrazine stage,whereas with the hydrophilic analogues the formation of aminesand breakdown of the polymer backbone occurred55. It should bementioned that drug release occurs even if azo polymer reductionstops at the hydrazine level because the chemical modification ren-ders the polymers much more hydrophilic and permeable54.

As a result of their poor film-forming properties, azo poly-mers based on poly(ether-esters) can only be used as biodegrad-able additives to sustained release coating materials such as Eu-dragit RS (Ref. 56). Drug release from dosage forms coated withsuch matrix films depends on the thickness and the hydrophilic-ity of the coating; hydrophilicity can be increased by addingpolyoxyethylene 400.

There are several problems that require consideration whendeveloping azo polymers for colon-specific drug delivery57. First,toxicity resulting from the microbial or chemical reduction ofazo compounds to primary aromatic amines might be critical.Moreover, reduction of polymeric azo compounds often pro-ceeds too slowly, bringing their reliability as coating polymerswith regard to drug release into question. For this reason, the useof azo compounds with a small negative redox potential appearsto be advantageous58,59. As already mentioned, reduction can, insome cases, lead to the intermediate hydrazo compounds insteadof the amines54,55. Furthermore, reduction does not necessarilydepend on the existence of the azoreductase, but can occur as aresult of the low oxidation potential in the colon, as has been ob-served with polymers containing disulphide bonds60.

Glycosidic polymer coatingsVarious polysaccharides, in both unmodified and modifiedform, have been investigated for their potential suitability ascolon-specific coating polymers.

Pectin, a polysaccharide consisting of D-galacturonic acid andits methyl ester, can be used only as a compression coat in apoorly water-soluble form such as calcium pectinate or ami-dated pectin because of its poor film-forming properties6163.Penetration of intestinal fluid into such a modified pectin coatwill be slowed down by gelation, and the enzymatic degra-dation of the polymer depends on its degree of hydration. Inorder to obtain a lower coating thickness, a biodegradable inter-polymer complex, consisting of pectin and chitosan (1:10) witha very low water solubility, has recently been introduced64.

Among the high molecular weight dextran esters, lauroyldextrans in particular have been found to be water-insoluble,swellable, biodegradable and to show satisfactory film-formingproperties65,66. Acetyl dextrans are water-insoluble but they arenot biodegradable because of the high degree of substitutionrequired to decrease their water solubility. Caproyl dextrans re-quire a lower degree of substitution and are biodegradable, buttheir film-forming properties are not satisfactory. Stearoyl dex-trans have been found to be biodegradable polymers with in-sufficient film-forming properties.

If galactomannans are used as coating materials6769 it has to betaken into consideration that microbial degradation is rapid if themannose:galactose ratio is high. Galactomannans from locustbean gum with a mannose:galactose ratio of 4:1 therefore appearto be the most suitable with regard to polymer degradability.However, the high water solubility of this polysaccharide has to bereduced by chemical modification. On the basis of purified locustbean gum, ethylated oligogalactomannans with good film-forming properties and satisfactory biodegradability have beensynthesized67. Polyurethane films consisting of diisocyanates andethylated oligogalactomannans as large biodegradable segments

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Table 2. Composition of azo polymer coatings for colon-specificdrug delivery

Hydrophilic Hydrophobic pH-sensitive Refssegment segment segment

HEMAa Styrene 4446HEMA MMAb 47, 48HEMA MMA MAc 5153Polyoxyethylene Polyurethane 54

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

are recognized by the b-mannanase in the colon and are rapidlyfermented68. Crosslinking of galactomannans leads to suitable coat-ing materials in which the degree of crosslinking is critical69,70.

Chitosan that is, deacetylated chitin is a cationic polysac-charide susceptible to degradation by microbial enzymes in thecolon. If used as a coating material for colon-specific drug de-livery, it is important to protect the acid-soluble polymer withan enteric coating71,72. Both the degree of deacetylation and themolecular weight of the polymer affect the degradation rate. Inaddition to its use as a coating material, chitosan is a suitablepolymer material for the manufacture of capsule shells73. Chito-san capsules are commercially available. Another capsule shellmaterial that has been recently developed for colon-specificdrug delivery is dextran crosslinked with glutaraldehyde74.

A combined enzyme- and pH-controlled system has beendeveloped by Watanabe et al.75. Drug release from the enterictablet formulation starts after microbial degradation of an outersaccharide layer to short-chain fatty acids and subsequent dis-solution of the underlying Eudragit E film.

Biodegradable matrix filmsBiodegradable matrix films, consisting of a sustained releasecoating material and a poorly water-soluble but degradable ad-ditive, are used if the additive by itself does not exhibit goodfilm-forming properties. As degradable additives a variety ofoligo- and polysaccharides have been investigated, such as b-cyclodextrin, galactomannans, glassy amylose, pectin andinulin (Table 3).

Eudragit RS/b-cyclodextrin (1:1) matrix films containing a lipophilic plasticizer have been developed by Bauer andcoworkers76,77. Drug release is pH-independent and beginsafter degradation of the b-cyclodextrin domains by bacterialenzymes in the colon.

Glassy amylose, which is resistant to pancreatic amylase, isanother degradable compound that can be used as a pore for-

mer in a sustained release coating material7880. If used in com-bination with an ethylcellulose dispersion in a 1:4 ratio,swelling of the amylose is sufficiently controlled. The matrixfilms are phase separated with amylose domains in the ethyl-cellulose film.When arriving in the colonic region the films arestructurally weakened, allowing the swelling and subsequentfermentation of the amylose, which ultimately leads to drug re-lease.An ethylcellulose/glassy amylose matrix film is now avail-able as COLAL (Alizyme Therapeutics Ltd, Cambridge, UK).

Galactomannans, such as guar gum, have led to satisfactorycoating films in combination with Eudragit RL, RS and NE (Refs81,82). However, high amounts of the acrylic polymers and highcoating levels are required to avoid premature drug release82.

In order to reduce its high water solubility, pectin should beeither of the high methoxyl pectin type, in amidated form, orcrosslinked with calcium ions in order to be used as a biodegrad-able additive. If used in combination with ethylcellulose83,84,Eudragit RS or NE (Ref. 85), high methoxyl pectin or calciumpectinate can act as biodegradable components in the resultingmatrix films. However, leaching of the pectin from the matrixfilms might lead to premature drug release. Best results in termsof leaching were obtained with Eudragit RS films containing upto 10% of pectin85, probably a result of ionic interactions be-tween the anionic pectin and the quaternary acrylic polymer.

Inulin, a naturally occurring glucofructan, can serve as abiodegradable compound in combination with Eudragit RS ifan inulin-type with a high degree of polymerization is used tolower its water solubility86.The films withstand gastric and in-testinal fluid, with high amounts of inulin making the filmsmore permeable.The bacterial degradation has been shown todepend on the hydrophilicity of the plasticizer.

Pressure-controlled drug releaseA pressure-controlled drug delivery system that relies on thehigh pressure in the distal colon produced by peristalsis has

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

Biodegradable component Sustained release coating material Ratio Plasticizer Refs

b-Cyclodextrin Eudragit RS 1:1 Diethyl phthalate 76, 77Galactomannans Eudragit RL 2:14:1 Diethyl phthalate 81, 82

Eudragit RS 1:4Eudragit NE 1:4

Glassy amylose Ethylcellulose 1:4 Dibutyl sebacate, Triacetin, Triethylcitrate 7880aPectin Ethylcellulose 1:191:4 Dibutyl sebacate, Triacetin 8385M(high methoxyl pectin Eudragit RS 1:10Mor calcium pectinate) Eudragit NE 1:10Inulin (high degree of Eudragit RS 1:11:2 Dibutyl phthalate 86Mpolymerization) Acetyltriethyl citrateEther-ester azo polymer Eudragit RS 1:1.5 Polyoxyethylene 400 56

aAvailable as COLAL (Alizyme Therapeutics Ltd, Cambridge, UK)

been introduced by Niwa et al.35 and Takaya et al.87 Disintegrationof the formulation, which consists of a gelatin capsule with aninner ethylcellulose coating, is induced by the pressure and thusthe destructive force produced by peristaltic waves, and de-pends on the thickness of the ethylcellulose film.The capsule isfilled with a solution of the drug; this should be advantageousin view of the small amount of fluid in the distal colon, whichcould compromise drug dissolution and absorption88.

Concluding remarks and future prospectsThe choice of a suitable colon-specific drug delivery system de-pends primarily on the application of the dosage form for ex-ample, whether a colonic disorder has to be treated where drugabsorption is desired to be low or whether a peptide drug has tobe delivered to the colon to improve its bioavailability. Moreover,it is important to know whether a drug should be released assoon as it enters the colon or whether drug delivery needs to besustained to ensure drug release in both the proximal colon andin the transverse colon. In general, coated dosage forms with asimple design are suitable systems because of their ease of manu-facture. More complex systems can cause problems with regardto manufacture and reliability of reproduction. If coated dosageforms are used for colon targeting, the different approaches pre-sented in this review need to be critically considered.

All the presented methods of drug delivery are more or less sus-ceptible to changes in the diet and to environmental variables,which questions their reliability. In addition, most of the systemshave only been tested in healthy animals or humans. Little isknown about the influence of the disease state on transit, motility,luminal pH and intraluminal pressure of the GI tract or on thecomposition of the colonic microflora. The luminal pH of thecolon depends on the composition of the diet. For instance, dietswith a high content of non-absorbable polysaccharides can lead toa drop in the luminal pH of the proximal colon. pH-controlled sys-tems often fail because of the intra- and intersubject variability inluminal pH values. Moreover, the colonic pH can drop dramaticallyin the case of inflammatory bowel disease, a fact that has not yetbeen considered if one looks at the composition of the formu-lations that are currently available on the market for this indication.

The activity of the microbial enzymes is even more susceptibleto diet, drug intake (particularly antibiotics and certain laxatives) and environmental factors.Thus, reproducibility of en-zymatic polymer degradation might be a problem. However, asthe commonly exploited enzymes such as azoreductase and vari-ous glycosidases are present only in the terminal ileum andcolon, premature drug release does not occur. Coating materialsneed to be readily degradable in order to provide reproducibledrug release in the colon.

Time-controlled delivery systems that take advantage of therelatively constant transit time through the small intestine are

the most promising so far. The small intestinal transit time isless susceptible to environmental variables, diet and diseasestate. If a reproducible lag time of drug release can be achievedand the dosage form is enteric-coated to prevent release of thedrug in the stomach, this represents a potentially suitable sys-tem for colon-specific drug delivery.

The pressure and destructive force induced by peristalticwaves is certainly high in the distal part of the large intestine.However, little is known about the reproducibility of this pres-sure and the duration of the high-pressure phase. Moreover,major peristaltic waves occur physiologically only once ortwice a day and therefore the exact time of drug release cannotbe accurately predicted. Colonic disorders such as diarrhoeacould significantly affect drug release. Drug release from coateddosage forms in the distal colon generally presents a problem asthe high viscosity of the contents could compromise drug dis-solution and drug diffusion to the epithelial cells.

In terms of future trends regarding coated dosage forms forcolon-specific drug delivery, time-controlled delivery systemsare likely to become more important and perhaps even super-sede the pH-controlled systems currently on the market. In vivostudies with several time-controlled formulations have yieldedpromising data. As these dosage forms usually consist of com-pounds that are already available on the market, no furtherdelay with dosage form approval is expected. However, the de-sign of many of the systems is rather complex and the develop-ment of formulations with a simpler design is required.

Enzymatically degradable polymers will be further opti-mized to improve their film-forming properties, their swellingbehaviour and their degradability by colonic enzymes. Thebioadhesive properties of the polymers could lead to a pro-longed residence time in the colon.The development of poly-mers with moieties that bind to specific regions of the intes-tine, such as inflamed colonic lesions or colon cancer tissue,represents another promising approach. However, because atoxicity study is required for each newly synthesized polymer,it will still be some time before a dosage form with abiodegradable coating appears on the market. A promising ap-proach with regard to biodegradable coating films is the use ofmatrix films that is, physical blends of sustained release coat-ing materials and degradable pore formers.As many of the poreformers are naturally occurring polysaccharides, no majorproblems in terms of toxicity are expected.

AcknowledgementThis review is dedicated to G. Zessin on the occasion of his65th birthday.

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